volume 82 · no. 2 · february 2016 anestesiologica...a year in review in minerva anestesiologica...

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157The quality and lifespan of guidelinesPage V. J., Casarin A.

160ORIGINAL ARTICLESIntra-abdominal pressure, Cardiac Index and vascular resistance during hyperthermic intraperitoneal chem-otherapy: a prospective observational studySchluermann C. N., Hoeppner J., Benk C., Schmidt R., Loop T., Kalbhenn J.

170Hemostasis changes during veno-venous extracorpor-eal membrane oxygenation for respiratory support in adultsPanigada M., Artoni A., Passamonti S. M., Maino A., Mietto C., L’Acqua C., Cressoni M., Boscolo M., Tripodi A., Bucciarelli P., Gattinoni L., Martinelli I.

180Desflurane and sevoflurane use during low- and mini-mal-flow anesthesia at fixed vaporizer settingsHorwitz M., Jakobsson J. G.

143EDITORIALSGuiding principles for the development of legislation regulating the doctor-patient relationship and end-of-life decisions: a joint effort by believers and non-believersAntonelli M., Gristina G. R.

147The conundrum of anticoagulation and hemostatic management in ECMO patientsRanucci M.

149Let’s reduce fresh gas flow (seriously!)De Wolf A. M., Hendrickx J. F. A.

151Percutaneous tracheostomy in animal models: it’s the year of the sheep!Cavallone L. F., Vannucci A.

154Defining the denominator to deal with the iceberg and not just its tipDe Gasperi A.

MINERVA ANESTESIOLOGICA

Vol. 82 February 2016 No. 2

CONTENTS

Vol. 82 - No. 2 MINERVA ANESTESIOLOGICA I

OFFICIAL JOURNAL OF ITALIAN SOCIETY OF ANESTHESIOLOGY, ANALGESIA,RESUSCITATION AND INTENSIVE CARE (SIAARTI)

ITALIAN JOURNAL OF ANESTHESIOLOGY AND ANALGESIAMONTHLY JOURNAL FOUNDED IN 1935 BY A. M. DOGLIOTTI

OFFICIAL JOURNAL OF ITALIAN SOCIETY OF ANESTHESIOLOGY, ANALGESIA,RESUSCITATION AND INTENSIVE CARE (S.I.A.A.R.T.I.)

CONTENTS

II MINERVA ANESTESIOLOGICA February 2016

186Treatment of intraparenchymal hypertension with hyperosmotic therapy: hypertonic saline 7.45% vs. mannitol 20%Santacruz C. A., De Backer D., Taccone F. S., Su F., Orbegozo-Cortes D., Hosokawa K., Donadello K., Vincent J. L.

196A new training approach in endoscopic percutaneous tracheostomy using a simulation model based on bio-logical tissueTerragni P., Mascia L., Faggiano C., Tenaglia T., Morello E., Succo G., Ranieri M., Brazzi L.

202Alleged malpractice in anesthesiology: analysis of a series of private insurance claimsGenovese U., Blandino A., Midolo R., Casali M. B.

210REVIEWSRecruitment maneuvers in acute respiratory distress syndrome and during general anesthesiaChiumello D., Algieri I., Grasso S., Terragni P., Pelosi P.

221Macrolides and respiratory infection in critically ill patients: what is the next step?Lisboa T., Salluh J. I. F., Friedman G.

230EXPERT OPINIONSA critical appraisal of the quality of analgosedation guidelines in critically ill patientsGirardis M., Cantaroni C., Savoia G., Melotti R., Conti G.

236Could “safe practice” be compromising safe practice? Should anesthetists have to deflate the cuff of the endotracheal tube before extubation?Priebe H.-J.

240LETTERS TO THE EDITORHydroxyzine and QTc interval: drugs without sin cast the first stone!Mistraletti G., Iapichino G.

241The association between the ultrasound-guided Serratus Plane Block and PECS I Block can represent a valid alternative to conventional anesthesia in breast surgery in a seriously ill patientFusco P., Scimia P., Marinangeli F., Pozone T., Petrucci E.

243YEAR IN REVIEWA Year in review in Minerva Anestesiologica 2015Cavaliere F., Allegri M., Calderini E., Carassiti M., Coluzzi F., Di Marco P., Piastra M., Rossi M.

255TOP 50 MINERVA ANESTESIOLOGICA REVIEWERS

About the cover: the cover shows the mean intra-parenchymal pressure (ICP, mean value mmHg, SD) and cerebral perfusion pressure during hyperosmotic therapy (hypertonic saline 7.45% vs. mannitol 20%) in pigs with intracranial hypertension (ICHT). For more information, see article by Santacruz C. A. et al. beginning on page 186.

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Vol. 82 - No. 2 MiNerVa aNestesiologica 143

of view,13 it now lies dormant in the senate, awaiting its own death by stalemate.

and yet in the italian icUs, there is a dra-matic need — perceived by physicians, nurses, patients, and their families — for well-thought-out legislation that clearly and effectively deals not only with the issue of advance directives but also with all the complexities of end-of-life care.

in the meantime, a broad ethical consensus was achieved by the intensivists around the world concerning the evidence that not all the patients can be saved, and many should be al-lowed to die.14, 15

in this regard, sound evidence is available today supporting withholding/withdrawing treatments at the end of life as licit practices from a juridical and ethical point of view, fre-quently occurring in many icUs of western countries,16 even if no uniform approach to them has been defined to date.15

in a recent review article,17 Mark et al. high-lighted the factors that influence end-of-life practices in different countries (geographical, cultural, legal factors, the attitudes of physi-cians and nurses, patients, and families) and

the current approach to end of life care in icUs is based on four fundamental prin-

ciples: 1) decision-making must be shared by physician and patient (or his/her representa-tive) in a patient and family-centered setting;1, 2 2) the dying process must not be characterized by undue suffering and disproportionate treat-ments;3, 4 3) the withholding/withdrawal of treatments and the administration of pallia-tive sedation are the physician’s main means for allaying patients’ pain and suffering at the end of life;5-7 4) the use of these clinically and ethically sound interventions cannot and must not be equated with the practice of euthana-sia.8 The ethical and scientific validity of these principles are supported by sound clinical evi-dence, and in some european countries, such as germany, France, spain, and the UK, they have been incorporated into valid end-of-life legislation.9-12 this is not the case for italy. in 2009, paralyzed by clashes of opinion in-volving lay and religious philosophers, legal experts, and politicians, the italian Parliament produced a small bill of law on advance direc-tives. rooted in strife and strongly criticized from the scientific, moral, and juridical points

E D I T O R I A L

guiding principles for the development of legislation regulating the doctor-patient

relationship and end-of-life decisions: a joint effort by believers and non-believers

Massimo aNtoNelli 1, 2, giuseppe r. gristiNa 2, 3*

1Department of anesthesiology and intensive care Medicine, catholic University of the sacred Heart, rome, italy; 2italian society of anesthesia, analgesia and intensive care (siaarti), study group on Bioethics; 3intensive care Unit and trauma center, s. camillo-Forlanini Hospital, rome, italy*corresponding author: giuseppe r. gristina, intensive care Unit and trauma center, s. camillo-Forlanini Hospital, Via Portuense 332, 00149 rome, italy. e-mail: [email protected]

anno: 2016Mese: FebruaryVolume: 82No: 2rivista: Minerva anestesiologicacod rivista: Minerva anestesiol

lavoro: titolo breve: gUiDiNg PriNciPles For tHe legislatioN oN Doctor-PatieNt relatioNsHiP aND eND-oF-liFe DecisioNsprimo autore: aNtoNellipagine: 143-6citazione: Minerva anestesiol 2016;82:143-6

Minerva anestesiologica 2016 February;82 (2):143-6© 2016 eDiZioNi MiNerVa MeDicathe online version of this article is located at http://www.minervamedica.it

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144 MiNerVa aNestesiologica February 2016

the following is a summary of the major points agreed upon.

A patient’s health/well-being is defined by objective criteria suggested by medicine along with his/her individual structure (psychologi-cal, moral, relational) and informed choices. the aim of the doctor-patient relationship is to choose appropriate treatment, i.e. a set of inter-ventions fulfilling the requisites and criteria of clinical appropriateness, in the respect of the ethical principles of proportionality between costs and benefits, and taking into full consid-eration the patient’s own feelings, principles, and preferences.

Proportionality is an essential element of care and a measure of treatment’s legitimacy. Physicians are thus obliged to avoid undertak-ing treatments that promise to violate the prin-ciple of proportionality and interrupt treatment that has been started if it subsequently proves to be incompatible with this principle. assess-ment of treatment proportionality must begin with consultation of the patients and/or of the person(s) who are supporting their requests or have been legally authorized to represent them or to safeguard their rights if they are in-capable of doing so. When urgency prevails, the assessment can be deferred, but it must be undertaken as soon as possible. the principle of shared decision-making should be respect-ed commensurately with patients’ ability and willingness to be informed about their condi-tion, to plan their own future, and to make re-sponsible decisions. support for patients’ right to self-determination must not conflict with their preference to waive that right and entrust decisions regarding their care to a person close to them or to the physician caring for them. For this reason, legal guidelines are necessary re-garding the roles of family members and legal representatives.

Patients may also be incapable of making decisions regarding a given intervention. in the absence of a clearly designated representa-tive or guardian and of previously expressed, documented preferences, the decision will be made by the physician in accordance with cri-teria of appropriateness and proportionality.

consent to treatment is ideally developed

confirmed the already large body of evidence linking end-of-life decisions to the religious beliefs and affiliation of the physicians caring for the patient.16, 18

These findings underscore the importance of the need for consensus between “believers and nonbelievers” when laws are being considered regarding the care administered at the end of life.

to address this need, a joint effort has been undertaken by the italian society of anesthe-sia, analgesia and intensive care (siaarti) together with the italian society of Pallia-tive Care (SICP) and the Vatican’s Pontifical council for culture. at the beginning of 2014, a siaarti proposal for collaboration was accepted by the council’s courtyard of the gentiles Foundation (established in 2009 to promote “dialogue between believers and non-believers” on issues that impact modern soci-ety), and a panel of religious and non-religious experts (physicians, philosophers, legal ex-perts, and politicians) was appointed to draft a shared position paper containing all the ethical and legal principles that should be considered in future efforts to provide italy with a more complete law for regulating end-of-life care.

the panel set to work in May 2014. one year later, the final draft was complete, and on september 17, 2015, the position paper was presented to the public during an official conference in the senate. the document, both in english and italian, is now available on the siaarti website.19

From the outset, the intensivists on the panel stressed that regulation of end-of-life care must occur within the framework of the doctor-patient relationship, in a way that safe-guards patients’ rights to dignity, freedom, and the pursuit of health/well-being and respects the fundamental dictates of physicians’ code of professional ethics. legislation must clarify/establish the objectives, criteria, and limits of treatment, define the prerogatives of patients and their physicians, and identify the proce-dures compatible with good clinical practice, thereby providing physicians and patients with an ethical landmark in the framework of legal certainty.

gUiDiNg PriNciPles For tHe legislatioN oN Doctor-PatieNt relatioNsHiP aND eND-oF-liFe DecisioNs aNtoNelli


entious objection by a physician is admissible when his/her intervention is required for the withdrawal of treatment. such refusal, how-ever, must never jeopardize the patient’s right to continuity of care. in the face of legitimate refusal of care that violates the criterion of proportionality, physicians have an ethical and legal duty to withhold or withdraw the treat-ment in question. they also have an inalien-able right to be assured that they will not be subject to civil or criminal sanctions for acting in accordance with this duty.

in conclusion, for policy makers, the com-plexities of the questions surrounding end-of-life care in modern medical settings can be overwhelming, and the task of providing legislative guidance in this labyrinth is further complicated by the fact that the society is in-creasingly multicultural. Dialogue, responsi-bility, and good faith are essential for success. in this sense, the present effort represents a major step forward. the siaarti’s primary goal in this important initiative was to address the issue of the end of life care from a compre-hensive and concrete “bedside” point of view, recognizing the acute, complex needs and con-cerns of patients and their families during this extremely stressful period. at the same time the intention was also to answer the legitimate demands of physicians and health-care pro-fessionals for a clear, evidence-based guide-line that helps to meet the patient’s needs. it is our sincere hope that this shared position paper will represent a useful contribution and incentive toward the approval by the italian Parliament of a valid, comprehensive law on end-of-life care, ensuring respect for cultural, religious, and individual diversity and protect-ing the autonomy of the doctor-patient rela-tionship.

References

1. carlet J, thijs lg, antonelli M, cassell J, cox P, Hill N, et al. challenges in end-of-life care in the icU. intensive care Med 2004;30:770-84.

2. Davidson Je, Powers K, Hedayat KM, tieszen M, Kon aa, shepard e, et al. clinical practice guidelines for sup-port of the family in the patient-centered intensive care unit: american college of critical care Medicine task Force 2004-2005. crit care Med 2007;35:605-22.

within the doctor-patient relationship. three instruments are important in this process.

Shared care planning: a concrete, ongo-ing, documented process in which patients, and their relatives, with their physicians’ aid, envision possible or probable states of health and express their feelings on the treatments that they would be likely to prefer under those circumstances and those they would probably refuse.

Trustee/legal guardian: designation of a trusted person who accompanies and supports the patient and if the latter is incapacitated, agrees to and is authorized to act as his/her representative when consensual decisions on treatment are necessary.

Advance directives elaborated by the pa-tient: these documents guarantee that the pa-tient will be respected as an individual and seeks to ensure equal treatment of persons who are currently capable of making decisions for themselves and those who are not. Declara-tions regarding the future require must be in-terpreted and carried out in keeping with the convictions, preferences, and wishes of the declarant. ideally, the directive represents the culmination of documented shared care plan-ning with a physician and/or significant oth-ers that has occurred after the onset of disease. Decisions reached under nebulous conditions (time, supporting parties, information levels, physical and psychological factors) are natu-rally more difficult to interpret. In the case of the incompetent patient the responsibility for interpreting directives must be undertaken by the physician, aided whenever possible by a trustee or guardian, in a shared decision mak-ing process that recapitulates as faithfully as possible the original doctor-patient relation-ship.

the patient’s right to refuse treatment must be respected, even when the decision regards ending the battle to prolong survival by with-holding/withdrawing current treatments and redirecting care toward palliative ends. infor-mation must be provided on the consequences of such a decision and on alternative forms of treatment, and therapeutic abandonment of the patient must be avoided at all costs. consci-

aNtoNelli gUiDiNg PriNciPles For tHe legislatioN oN Doctor-PatieNt relatioNsHiP aND eND-oF-liFe DecisioNs


lation.gov.uk/uksi/2007/1897/contents/made [cited 2015, oct 27].

12. garcía ortega c, cózar Murillo V, almenara Barrios J. la autonomía del paciente y los derechos en materia de infor-mación y documentación clínica en el contexto de la ley 41/2002 [internet]. available from: http://scielo.isciii.es/scielo.php?pid=s1135-57272004000400005&script=sci_arttext [cited 2015, oct 14].

13. gristina gr, Martin e, ranieri VM. regulation of ad-vance directives in italy: a bad law in the making. inten-sive care Med 2012;38:1897-900.

14. azoulay e, Metnitz B, sprung cl, timsit JF, lemaire F, Bauer P, et al. end-of-life practices in 282 intensive care units: data from the saPs 3 database. intensive care Med 2009;35:623-30.

15. sprung cl, truog rD, curtis Jr, Joynt gM, Baras M, Michalsen a, et al. seeking worldwide professional con-sensus on the principles of end-of-life care for the criti-cally ill: the Welpicus study. am J respir crit care Med 2014;190:855-66.

16. sprung cl, cohen sl, sjokvist P, Baras M, Bülow HH, Hovilehto s, et al. end-of-life practices in euro-pean intensive care units. the ethicus study. JaMa 2003;290:790-7.

17. Mark NM, rayner sg, lee, Jr, curtis Jr. global varia-bility in the withdrawal of life-sustaining treatment in the intensive care unit: a systematic review. intensive care Med 2015;41:1572-85.

18. Vincent Jl. Forgoing life support in western european in-tensive care units: the results of an ethical questionnaire. crit care Med 1999;27:1626-33.

19. linee propositive per un diritto della relazione di cura e delle decisioni di fine vita – SIAARTI [Internet]. Available from http://www.siaarti.it/ricerca/linee-propositive-per-un-diritto-alla-relazione-di-cura.aspx [cited 2015, oct 31].

3. the sUPPort Principal investigators. a controlled trial to improve care for seriously ill hospitalized pa-tients. the study to understand prognoses and prefer-ences for outcomes and risks of treatments (sUPPort). JaMa 1995;274:1591-8.

4. siaarti - italian society of anaesthesia analgesia re-suscitation and intensive care Bioethical Board end-of-life care and the intensivist: siaarti recommendations on the management of the dying patient. Minerva anes-tesiol 2006;72:927-63.

5. cherny Ni. esMo clinical Practice guidelines for the management of refractory symptoms at the end of life and the use of palliative sedation, on behalf of the esMo guidelines Working group. ann oncol 2014;25 (suppl. 3):143-52.

6. lautrette a, garrouste-orgeas M, Bertrand PM, goldgran-toledano D, Jamali s, laurent V, et al. out-comerea study group. respective impact of no escalation of treatment, withholding and withdrawal of life-sustain-ing treatment on icU patients’ prognosis: a multicenter study of the outcomerea research group. intensive care Med 2015;41:1763-72.

7. Kelley as, Morrison s. Palliative care for the seriously ill. N engl J Med 2015;373:747-55.

8. Materstvedt lJ, clark D, ellershaw J, Førde r, grav-gaard a-M, Müller-Busch Hc, et al. euthanasia and physician-assisted suicide: a view from an eaPc ethics task Force J Palliat Med 2003;17:97-101.

9. Michalsen A. Care for dying patients – German legisla-tion. intensive care Med 2007;33:1823-6.

10. Baumann a, audibert g, claudot F, Puybasset l, ethics review: end of life legislation - the French model. crit care 2009;13:204-6.

11. the Mental capacity act 2005 (commencement No. 2) order 2007 [internet]. available from http://www.legis-

Conflicts of interest.—The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript.Article first published online: December 4, 2015. - Manuscript accepted: December 3, 2015. - Manuscript revised: November 26, 2015. - Manuscript received: october 31, 2015.(Cite this article as: antonelli M, gristina gr. guiding principles for the development of legislation regulating the doctor-patient relationship and end-of-life decisions:a joint effort by believers and non-believers. Minerva anestesiol 2016;82:143-6)


ecMo patients still suffer from both sides of the hemostatic system imbalance: bleeding and thrombotic events are the most relevant complications of ecMo treatment, being of-ten the most frequent cause for intra-treatment mortality.2

The difficulties of establishing a safe and re-liable management of hemostasis and coagula-tion during ecMo rely on the multi-factorial aspect of the hemostatic system imbalance. on one side, an excessive anticoagulation may trigger bleeding events: this includes cerebral hemorrhage, gastro-enteric bleeding, retro-peritoneal hematomas, bleeding from the can-nulation sites and from chest drains in case of post-cardiotomy ecMo, and others. there are many different factors leading to bleeding dur-ing ecMo: excessive UFH dose; presence of residual effects of additional anti-thrombotic drugs (warfarin, antiplatelet agents); thrombo-cytopenia and platelet dysfunction; consump-tion of coagulation factors; hyperfibrinolysis. additionally, the possibility of an acquired von Willebrand syndrome should be considered.3

on the other side, there is the need for guaranteeing an adequate anti-coagulation. From this respect, the problem has a specific complexity. it is not just a matter of avoiding thrombosis inside the ecMo circuit and oxy-genator: this is actually related to a material--dependent blood activation, that is responsi-

in this issue of Minerva Anestesiologica, Panigada et al. present a pilot study on he-

mostasis changes during veno-venous extra-corporeal membrane oxygenation (ecMo).1 all the patients were receiving unfractionated heparin (UFH) as an antithrombotic treatment, and the hemostatic profile was addressed with different laboratory assays: activated partial thromboplastin time (aPtt); activated clotting time (act); antifactor Xa activity; thrombo-elastography (teg); and endogenous throm-bin potential (etP).

considering the anti-factor Xa activity as the gold standard monitoring for low-dose UFH, they could find that only the aPTT, among the possible monitoring assays, was significantly associated with the anti-factor Xa activity. the reaction time (R-time) at TEG was signifi-cantly associated with anti-factor Xa activity only in patients where a r-time was actually detectable. overall, 3 (25%) patients out of the 12 included in the study experienced a severe bleeding episode during the ecMo treatment.

the authors are to be congratulated for addressing a very important issue. it is my opi-nion that hemostatic changes and coagulation management are one of the less investigated albeit most relevant topics within the scena-rio of ecMo treatment. as a matter of fact,

E D I T O R I A L

the conundrum of anticoagulation and hemostatic management in ecMo patients

Marco raNUcci

Unit of clinical research, Department of anesthesia and intensive care, irccs san Donato Policlinic, san Donato Milanese, Milan, italycorresponding author: Marco ranucci, Unit of clinical research, Department of anesthesia and intensive care, irccs Policlinico s.Donato, Via Morandi 30, 20097 san Donato Milanese, Milan, italy. e-mail: [email protected]


lavoro: titolo breve: tHe coNUNDrUM oF aNticoagUlatioN iN ecMo PatieNtsprimo autore: raNUccipagine: 147-8citazione: Minerva anestesiol 2016;82:147-8

Minerva anestesiologica 2016 February;82 (2):147-8

comment on p. 170.

© 2016 eDiZioNi MiNerVa MeDicathe online version of this article is located at http://www.minervamedica.it

raNUcci tHe coNUNDrUM oF aNticoagUlatioN iN ecMo PatieNts


the present contribution from Panigada and associates confirms that the point-of-care co-agulation tests presently available (act and teg) are poor in guiding the correct dose-ad-justments of UFH, and that among the existing laboratory test, the most reliable is probably the aPtt. However, given the complexity of the above-described scenario, novel-genera-tion point-of-care tests to guide UFH or alter-native anticoagulants management would be very well received by the clinicians in charge for the ecMo treatment.

References

1. Panigada M, artoni a, Passamonti sM, Maino a, Mietto c, l’acqua c, et al. Hemostasis changes during veno-ve-nous extracorporeal membrane oxygenation for respira-tory support in adults. Minerva anestesiol 2016;2:170-9.

2. Beiras-Fernandez a, Deutsch Ma, Kainzinger s, Kac-zmarek i, sodian r, Ueberfuhr P, et al. extracorporeal membrane oxygenation in 108 patients with low cardiac output – a single-center experience. int J artif organs 2011;34:365-73.

3. Heilmann c, geisen U, Beyersdorf s, Nakamura l, Benk c, trummer g, et al. acquired von Willebrand syndrome in patients with extracorporeal life support (ecls). in-tensive care Med 2012;38:62-8.

4. Warkentin te, greinacher a, Koster a. Heparin-induced thrombocytopenia in patients with ventricular assist de-vices: are new prevention strategies required? ann tho-rac surg 2009;87:1633-40.

5. ranucci M, Baryshnikova e, isgrò g, carlucci c, cotza M, carboni g, et al. Heparin-like effect in postcardioto-my extracorporeal membrane oxygenation patients. crit care 2014;18:504.

6. Jyoti a, Maheshwari a, Daniel e, Motihar a, Bhathi-wal rs, sharma D. Bivalirudin in venovenous extracor-poreal membrane oxygenation. J extra corpor technol 2014;46:94-7.

7. Nagle el, Dager We, Duby JJ, roberts aJ, Kenny le, Murthy Ms, et al. Bivalirudin in pediatric patients main-tained on extracorporeal life support. Pediatr crit care Med 2013;14:e182-8.

8. Pieri M, agracheva N, Bonaveglio e, greco t, De Bonis M, covello rD, et al. Bivalirudin versus heparin as an anticoagulant during extracorporeal membrane oxygena-tion: a case-control study. J cardiothorac Vasc anesth 2013;27:30-4.

9. ranucci M, Ballotta a, Kandil H, isgrò g, carlucci c, Ba-ryshnikova e, et al. Bivalirudin-based versus conventio-nal heparin anticoagulation for postcardiotomy extracor-poreal membrane oxygenation. crit care 2011;15:r275.

ble for a minor degree of thrombin generation, especially when using biocompatible, coated surfaces. other more subtle and dangerous fac-tors may result in thromboembolic complica-tions: blood stagnation inside the great vessels and the cardiac chambers may trigger a mate-rial independent blood activation (mainly re-lated to tissue factor activation); antithrombin (at) consumption due to chronic UFH therapy depletes the natural anticoagulant properties of the endothelium; and, finally, heparin-induced thrombocytopenia is common during ecMo and ventricular assit device treatment.4

as a result, clinicians in charge for the ecMo treatment are presently navigating difficult seas, squeezed between the risk of thrombosis and bleeding events, and in need for point-of-care tests to guide their anti-coa-gulation strategy.

at present, UFH treatment is still the stan-dard of care for ecMo patients; however, it is well known that UFH is far from being the perfect drug. the effects of UFH in determi-ning an adequate anticoagulation greatly vary depending on the at levels, with patterns of low heparin sensitivity in presence of low at levels, and a rebound of effect when at is re-plenished; conversely, low platelet counts re-sult in an increased heparin sensitivity, with a decreased UFH effect once platelet concen-trates are administered. additionally, an hepa-rin-like effect has been recently described in ecMo patients,5 probably as a result of an en-dothelial dysfunction either directly linked to the ecMo effects or mediated by bloodstream infections.

Presently, attempts have been done to re-place UFH with other anti-thrombotic drugs, namely direct thrombin inhibitors like bivali-rudin,6-9 that theoretically could overcome the flaws of UFH. However, large-scale experien-ces with UFH alternatives are still lacking.

Conflicts of interest.—The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript.Article first published online: June 30, 2015. - Manuscript accepted: June 25, 2015. - Manuscript received: June 6, 2015.(Cite this article as: ranucci M. the conundrum of anticoagulation and hemostatic management in ecmo patients. Minerva anestesiol 2016;82:147-8)


cially when nitrous oxide is used during the last 20-30 min to allow early wash-out of the potent inhaled anesthetic.2 Finally, the time to discharge from the PacU is probably more de-termined by protocols than by the agent that was used. and we should not ignore another factor: cost. Sevoflurane seems to have a slight advantage here, but this really depends on the local pricing strategies by the pharmaceutical companies.

Reduction of FGF when using sevoflurane has become feasible by the availability of mod-ern co2 absorbers that do not produce toxins from a reaction with the potent inhaled anes-thetic. lowering FgF is desirable because it results in a reduction in agent usage (lower cost, less pollution) but requires a higher FD to compensate for rebreathing of exhaled gases (that have a lower concentration of potent in-haled anesthetic). some perceive this as a lack of control, but a sound understanding of the underlying pharmacokinetics and readily avail-able agent analyzers make this a non-issue.

Finally, technology is likely to make many of the differences moot. target controlled an-esthesia machines use low flow (thus reduc-ing agent consumption, cost and pollution to a minimum), injectors allow the concentration to rise as fast as the clinician deems appropri-ate irrespective of the FgF being used, and tools like the smartPilot® and other pharma-cokinetic/pharmacodynamic displays will help

the manuscript by Horwitz and Jakobsson 1 published in this issue of Minerva Aneste-

siologica re-enforces the concept that both our modern potent inhaled anesthetics (desflurane and sevoflurane) are suitable for low-flow an-esthesia thanks to their low solubility. Desflu-rane is the “faster” agent because its solubil-ity is lower than that of sevoflurane. We have known this for several years now, as this has been studied extensively. the low tissue solu-bility of both agents allows us to use low and minimal fresh gas flow (FGF) immediately after intubation, as long as we are willing to use the maximum vaporizer setting (FD). al-though desflurane is slightly faster than sevo-flurane, the relative higher maximum vapor-izer setting for sevoflurane (4×MAC, or 8%) compared to desflurane (3×MAC, or 18%) al-lows us to reach the desired alveolar fraction (Fa) of either agent well before the effects of the intravenous induction agents wear off. therefore, there is little clinical difference be-tween sevoflurane and desflurane in terms of rapidly reaching the desired Fa. Horwitz and Jacobsson did not use the maximum sevoflu-rane FD that was available to them; our clini-cal practice should take into consideration the equipment that we have. on the other hand, during emergence, desflurane remains the slightly faster agent. However, it is debatable how clinically significant this really is, espe-

E D I T O R I A L

Let’s reduce fresh gas flow (seriously!)Andre M. DE WOLF 1 *, Jan F. a. HeNDricKX 2

1Department of anesthesiology, Feinberg school of Medicine, Northwestern University, chicago, il, Usa; 2Department of anaesthesiology, intensive care and Pain therapy, olV Hospital aalst, Belgium*Corresponding author: Andre M. De Wolf, Department of Anesthesiology, Feinberg School of Medicine, Northwestern University, 251 east Huron street, F5-704, chicago il 60611, Usa. e-mail: [email protected]


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comment on p. 180.


DE WOLF LEt’S REDUCE FRESh GAS FLOW (SERiOUSLy!)


machine with target control capabilities (they all use reduced FgF).

References

1. Horwitz M, Jakobsson Jg. Desflurane and sevoflu-rane use during low - and minimal - flow anaesthesia at fixed vaporizer settings. Minerva anestesiol 2016; 82:180-5.

2. the european society of anaesthesiology task force on the use of nitrous oxide in clinical anaesthetic practice. the current place of nitrous oxide in clinical practice - an expert opinion-based task force consensus statement of the european society of anaesthesiology. eur J anaes-thesiol 2015; 32:1–4.

3. cirillo V, Zito Marinosci g, De robertis e, iacono c, ro-mano g, Desantis o. Navigator® and smartPilot® View are helpful in guiding anesthesia and reducing anesthetic drug dosing. Minerva anestesiol 2015;81:1163-9.

optimize the administration of combinations of agents to minimize wake up times.3 all these will likely further minimize differences be-tween agents. the old adagio still holds: it is not only the drug, but also the way you use it — and technology will greatly affect how we use these drugs. Biological variability will be the main remaining factor that results in pre-diction errors, underscoring the importance of an ever present and vigilant anesthesiologist.

it is easier than ever before to administer potent inhaled anesthetics with reduced FgF. the consequences of lowering FgF have been well explained and are easy to comprehend, and the use of low FgF is safe thanks to multi-gas analysis. if you are still reluctant to reduce FgF yourself, consider getting an anesthesia

Conflicts of interest.—the authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript.Article first published online: October 9, 2015. - Manuscript accepted: October 7, 2015. - Manuscript received: August 21, 2015.(Cite this article as: De Wolf AM, hendrickx JFA. Let’s reduce fresh gas flow (seriously!). Minerva Anestesiol 2016;82:149-50 ).



to the risk of acquiring transmittable diseases, especially if animal parts are not properly pre-pared and disposed of.10

in the study by terragni et al., published in this issue of Minerva Anestesiologica,11 the authors report their experience with a new ani-mal model and training approach. the novel biological tissue model consisted of adult sheep heads and necks with preservation of all of the tracheal rings. importantly, sheep necks models were collected as byproducts of routine sheep processing for human consumption, thus reducing costs associated with the acquisition of the tissue specimen and guaranteeing that the animals had undergone rigorous veterinary examinations. interestingly, the authors men-tioned that, due to the long trachea of sheep, one specimen may be used to simulate three procedures, making this animal model particu-larly cost-effective.

the model was utilized in a two-day simu-lation-based course held at the University of turin in italy focusing on percutaneous trache-ostomy and crichothyrotomy. During the first day of training, thirty-two physician anesthesi-ologists were taught about indications, contra-indications and complications of the different procedures. on the second day, the participants were instructed on how to perform both percu-taneous tracheostomies, under flexible video-endoscopic guidance and with three different techniques, and emergent cricothyrotomies.

Percutaneous tracheostomies and cricothy-rotomies are common procedures in the in-

tensive care unit and emergency room settings. it has recently been suggested that anesthesi-ologists who are frequently called to perform these procedures in emergent or critical condi-tions may have a high failure rate due to lack of appropriate initial training or to inadequate skill retention.1, 2

simulation has been proven effective in fa-cilitating the acquisition and maintenance of clinical procedural skills to the benefit of clini-cians’ competence and patients’ safety.3, 4 sev-eral specific tracheostomy and crichotyrotho-my models have been proposed and tested, and include homemade and commercially-avail-able training devices (manikins), and animal and human cadaveric models.5-9

commercially-available manikins are easy to acquire but can be expensive when ana-tomically accurate.5 less costly, “homemade” models, although useful to gain familiarity with the equipment and to learn and practice psychomotor skills, may have limited resem-blance to real life conditions.5

animal models are cost-effective and offer the advantage of providing a more realistic experience of the texture of biological tissues. Nevertheless, working with animal models may expose trainees and health professionals

E D I T O R I A L

Percutaneous tracheostomy in animal models: it’s the year of the sheep!laura F. caValloNe, andrea VaNNUcci *

Department of anesthesiology, Washington University in st. louis school of Medicine, st. louis, Mo, Usa*corresponding author: andrea Vannucci, Department of anesthesiology, Washington University in st. louis - school of Medicine, campus Box 8054, 660 south euclid avenue, st. louis, Mo 63110, Usa. e-mail: [email protected]


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comment on p. 196.

caValloNe PercUtaNeoUs tracHeostoMY iN aNiMal MoDels


being able to evaluate and compare the bene-fits of an open surgical procedure versus a per-cutaneous approach in each individual patient; diagnosing and treating complications, and formulating a backup plan in case of problems encountered with the technique chosen for the percutaneous approach.

Designing a simulation training that pro-motes the acquisition of these cognitive skills remains a challenge. Nevertheless, a sound simulation model such as the one proposed in the paper by terragni et al.11 to effectively train providers to execute life-like percutane-ous procedures is a very valuable first step in the right direction. the inclusion of a module to teach participants about indications, contra-indication and complications of the different procedures, as in this case, is a critical part of a successful training approach.

once the fundamental knowledge and manual skills are acquired and consolidated, it becomes easier to focus on the other relevant aspects of safe clinical practice in performing percutane-ous tracheostomies and cricothyrotomies.

(according the chinese calendar, 2015 was the year of the sheep, which made the original proposal of this novel animal model by ter-ragni et al. particularly well-timed.)

References 1. cook tM, Woodall N, Frerk c. Major complications of

airway management in the UK: results of the Fourth Na-tional audit Project of the royal college of anaesthetists and the Difficult Airway Society. Part 1: anaesthesia. Br J anaesth 2011;106:617-31.

2. Cook TM, Woodall N, Harper J, Benger J, Fourth Nation-al audit P. Major complications of airway management in the UK: results of the Fourth National audit Project of the Royal College of Anaesthetists and the Difficult airway society. Part 2: intensive care and emergency de-partments. Br J Anaesth 2011;106:632-42.

3. Murray DJ. Current trends in simulation training in anes-thesia: a review. Minerva anestesiol 2011;77:528-33.

4. Anastakis DJ, Regehr G, Reznick RK, Cusimano M, Murnaghan J, Brown M, et al. assessment of technical skills transfer from the bench training model to the hu-man model. Am J Surg 1999;177:167-70.

5. Varaday ss, Yentis sM, clarke s. a homemade model for training in cricothyrotomy. anaesthesia 2004;59:1012-5.

6. Wong DT, Prabhu AJ, Coloma M, Imasogie N, Chung FF. What is the minimum training required for successful cricothyroidotomy?: a study in mannequins. anesthesiol-ogy 2003;98:349-53.

7. gardiner Q, White Ps, carson D, shearer a, Frizelle F, Dunkley P. technique training: endoscopic percutaneous tracheostomy. Br J Anaesth 1998;81:401-3.

the course was not accompanied by a sys-tematic evaluation of the trainee’s success rate and learning curves. still, the authors observe that this approach seemed adequate and effec-tive to train anesthesiologists to perform per-cutaneous tracheostomies, and the course was well received by trainees. Particular strengths of the proposed model were the skin turgor’s more realistic feel and a facilitated recognition of landmarks compared to manikin.

the proposed novel tissue-based model and training approach for percutaneous tracheos-tomies and cricothyrotomies seem promis-ing and worth pursuing. However, the retro-spective nature of the study and the lack of a control group to evaluate potential benefits compared to other training methods in similar groups of participants limit the possibility to draw any firm conclusion on the superiority of this model. it would be interesting in the fu-ture to assess training based on this specific animal model in more detail by evaluating the trainees’ performance and their ability to reach predefined goals and expected outcomes. For example, it would be important to define how many procedures trainees must perform, on average, to become proficient with each of the percutaneous tracheostomy techniques pro-posed, and what level of experience is required to be able to perform an “emergent” crichothy-rotomy in a short, predefined time.

an ideal simulation training should address all technical aspects of performing safe percu-taneous tracheostomies: choosing a suitable level; locating landmarks and recognizing ana-tomical structures; being familiar with the ner-vous and vascular supply of the neck; choos-ing the appropriately sized cannula for size of airway; inserting the cannula while minimiz-ing tissue trauma; and recognizing the creation of a false passage, when this happens. in their future work, the authors may consider system-atically assessing these aspects and reporting their results.

aside from these important technical as-pects, clinicians need to acquire and apply judgment: this cognitive skill includes correct-ly identifying indications for tracheostomy and cricothyrotomy in complex clinical scenarios;

PercUtaNeoUs tracHeostoMY iN aNiMal MoDels caValloNe


10. Weigler BJ, Di Giacomo RF, Alexander S. A national sur-vey of laboratory animal workers concerning occupational risks for zoonotic diseases. comp Med 2005;55:183-91.

11. terragni P, Mascia l, Faggiano c, tenaglia t, Morello e, succo g, et al. a new training approach in endoscopic percutaneous tracheostomy using a simulation model based on biological tissue. Minerva anestesiol 2016;82: 196-201

8. Cho J, Kang GH, Kim EC, Oh YM, Choi HJ, Im TH, et al. comparison of manikin versus porcine models in cricothyrotomy procedure training. Emerg Med J 2008;25:732-4.

9. McCarthy MC, Ranzinger MR, Nolan DJ, Lambert CS, castillo MH. accuracy of cricothyroidotomy performed in canine and human cadaver models during surgical skills training. J Am Coll Surg 2002;195:627-9.

Conflicts of interest.—The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript.Article first published online: May 26, 2015. - Manuscript accepted: May 22, 2015. - Manuscript received: May 19, 2015.(Cite this article as: cavallone lF, Vannucci a. Percutaneous tracheostomy in animal models: it’s the year of the sheep! Minerva anestesiol 2016;82:151-3)

154 Minerva anestesiologica February 2016

tions, defined as “major” or “severe” in case of a permanent impairment of the patient are not infrequent.8, 9 Many are the problems when defining the incidence of a rare event, such as an anesthesia related death. Among them are: 1) the methodology of the observa-tion (prospective vs. retrospective; 2) the cri-teria to define the studied population (very frequently different across the studies); 3) the numerator (type of the adverse event: death, severe complications, or both; claims vs. self-reporting); 4) the follow up period (short vs. long time frame); 5) the denominator (the number of anesthetic procedures considered to define the incidence of the event, often not available or ill-defined at best.6, 8 great part of litigations and claims in which anesthesiolo-gists are implicated is closely related to sur-gery, particularly in some surgical subspecial-ties. Death in the anesthetized surgical patients is not necessarily a death due to anesthesia or related procedures. If this is the case, mortali-ty is due to or closely related to specific proce-dures performed by an anesthesiologist, such as complications associated with airway man-agement, drug administration, invasive proce-dures, blood transfusion mismatch, equipment mishaps.8 This is why it should be particularly useful or even mandatory, to start a national surveillance system based on a minimal set of data in conjunction with a (hopefully) stan-

to protect the vulnerable is, without em-phasis, the mission of every anesthesiolo-

gist.1, 2 Anesthesiologists have always been deeply involved in the safety and safeguard of all the patients exposed to any kind of surgical and non-surgical stressful condition which they are not able to fight by themselves or to react to.3 Several steps have been taken world-wide to approach, develop and strengthen the philosophy of patient safety. Launched in the 2010 Helsinki declaration on patient safety in anesthesia, this concept has been actively de-veloped in the last four years and is now sup-ported also in the developing countries.2 in recent years, improvements in anesthesia safety made anesthesia-related death a rare event, thus contributing to reduce periopera-tive mortality. The most recent reports from US, Australia, Korea, France, the Netherlands and Germany confirm the decline in “anesthe-sia mortality”, showing figures of death di-rectly related to anesthesia between 0.8/100,000 and 1/200,000 procedures.4-6 The impressive improvements made in the field of safety in anesthesia are since long acknowl-edged both by media and peers.4, 7 In the meantime, continuous efforts are needed to maintain and improve this strong commit-ment, since anesthesia associated complica-

E D I T O R I A L

Defining the denominator to deal with the iceberg and not just its tip

andrea De gasPeri*

Struttura Complessa di Anestesia e Rianimazione 2, Dipartimento Chirurgico Polispecialistico, Azienda Ospedaliera “Ospedale Niguarda Ca’ Granda”, Milan, Italy*Corresponding author: Andrea De Gasperi, Struttura Complessa di Anestesia e Rianimazione 2, Dipartimento Chirurgico Poli-specialistico, Azienda Ospedaliera “Ospedale Niguarda Ca’ Granda”, Milano, Italia. E-mail: [email protected]

Anno: 2016Mese: FebruaryVolume: 82No: 2Rivista: Minerva AnestesiologicaCod Rivista: Minerva Anestesiol

Lavoro: titolo breve: DEFINING THE DENOMINATOR IN PATIENT SAFETYprimo autore: DE GASPERIpagine: 154-6citazione: Minerva Anestesiol 2016;82:154-6

Minerva Anestesiologica 2016 February;82 (2):154-6

Comment on p. 202.

© 2016 eDiZioni Minerva MeDicaThe online version of this article is located at http://www.minervamedica.it

DEFINING THE DENOMINATOR IN PATIENT SAFETY De gasPeri

Vol. 82 - No. 2 Minerva anestesiologica 155

lyzed one of the largest Italian private insur-ance broker’s claim database. In anonymous form, the study focused on all the claims re-garding anesthesia specialists in the period 2001-2013, quite an unusual method to define the denominator of the phenomenon, not to mention the very wide timeframe. Over a pop-ulation of 3342 anesthesiologists (perhaps one-third of the Italian anesthesiologists), 271 (9%) were implicated in malpractice claim(s). Large part of the events (225, 70%,) occurred, almost equally distributed, between intraop-erative and postoperative periods. Interest-ingly enough, fatal outcomes were very fre-quently either surgery-associated (74.2%) or part of a multidisciplinary team malpractice claim (85.8%). A “pure” anesthesiological technical error was confirmed in 128 cases and only in 33 cases (17.3%) the death of the patient was attributed to the anesthetist. Worth considering are the complications associated with airways management. According to Genovese et al.,12 severe permanent central nervous system damage associated with intu-bation (one of the rarest, but perhaps the most feared anesthesiological complication) was present in 5 cases, while in the remaining six cases a direct airway lesion was responsible for the injury. More ill-defined, but relevant, were peripheral lesions associated with loco-regional techniques: over a total of 35 cases, permanent impairment was recorded in only two patients. However, as already mentioned, the absence of a clear-cut denominator (the number of performed anesthetic procedures over which the incidence of an event is calcu-lated) limits the value of these figures. Based on these data, anesthesiologists were ranked by Genovese et al. as “low-risk” specialists.12 The recent adoption of measures and devices to manage the difficult airway or the use of ultrasound guidance for a safer central vascu-lar cannulation might have played a role in reducing “true” anesthesia-related complica-tions and malpractice claims. The collection and analysis of anesthesia-related injuries data should be relevant in decreasing clinicians’ fear of litigation, improving patient care, and, possibly, containing medical costs.8 Accord-

dardized reporting system for anesthesia-re-lated adverse events (death and severe com-plications). An example is the database built by the German Society of Anesthesiology and Intensive Care Medicine.9 Using this data-base, Schiff et al. recently reviewed 1.3 mil-lion surgical procedures, and reported on an-esthesia-related major incidents and complications (severe outcome or death) in healthy subjects undergoing elective surgery in Germany over 10 years.10 In this specific context, the rate of major surgical complica-tions was about 3 per 100,000, while those identifiable as “associated with anesthesia” (as defined above) were about 10 per million cases (or 1/100,000). If for a moment we do not consider the concepts of team responsibil-ity and multidisciplinary malpractice, avail-ability of such a database should give a more realistic idea of the role played by the anesthe-siologist in the alleged malpractice, anesthesia procedures being specifically addressed. This mandates a clear separation (problematic per-haps, but indeed not impossible) between the events associated to the surgical act/manipula-tion and the complications associated to anes-thesia procedures (mainly drugs administra-tion, airway management, central vascular cannulation, locoregional procedures and, re-cently, problems related to awareness during anesthesia). Only focusing on items which are specific to our practice, it should be possible to discover the real dimension of the “anesthe-siological malpractice”. In the UK the number of claims classified under “anesthesia” from 1995 to 2007 were 2.5%. Surgery and obstet-ric surgery, on the contrary, accounted for 39 and 21% respectively of the claims.6 In Italy, according to a medical malpractice claims analysis performed by a private insurance company on claims from Italian public hospi-tals during 2014, 36% of the events occurred in the surgical setting, while 2.5% only were reported to be associated with anesthesia and intensive care.11 In this issue of Minerva Anes-tesiologica, a group of forensic specialists led by Umberto Genovese 12 addressed anesthesi-ology malpractice in Italy. In the absence of a national database, they retrospectively ana-

De gasPeri DEFINING THE DENOMINATOR IN PATIENT SAFETY


References

1. Mellin-Olsen J, Staender S, Whitaker DK, Smith AF. The Helsinki Declaration on patient safety in anaesthesiology. Eur J Anaesthesiol 2010;27:592-7.

2. Mellin Olsen J, Staender S. The Helsinki declaration on patient safety in anesthesiology: the past present and fu-ture. Curr Opin Anesthesiol 2014;27:630-34.

3. Qiu L, Chen Y. My understanding of being an Anesthesi-ologist. Anesthesiology 2014;120:236-7.

4. Clergue F. The challenges of anaesthesia for the next dec-ade. Eur J Anaethesiol 2014;32:223-29.

5. Li G, Warner M, Lang BH, Huang L, Sun LS. Epidemiol-ogy of anesthesia-related mortality in the United States, 1999-2005. Anesthesiology 2009;110:759-65.

6. Cook TM, Bland L, Mihai R, Scott S. Litigation related to anaesthesia: an analysis of claims against the NHS in England 1995–2007. Anaesthesia 2009;64:706-18.

7. Committee on Quality of Health Care in America. To err is human: building a safer health system. Washington DC: National Academy Press. U.S. Institute of Medicine; 1999.

8. Reed S, Arnal D, Frank O, Gomez-Arnau JI, Hansen J, lester o, et al. National critical incident reporting sys-tems relevant to anaesthesia: a European survey. Brit J Anaesth 2014;112:546-55.

9. Bothner U, Georgieff M, Schwilk B. Building a large-scale perioperative anaesthesia outcome-tracking data-base: methodology, implementation, and experiences from one provider within the German quality project. Br J Anaesth 2000;85:271-80.

10. Schiff JH, Welker A, Fohr B, Henn-Beilharz A, Bothner U, Van Aken H, et al. Major incidents and complications in otherwise healthy patients undergoing elective proce-dures: results based on 1.37 million anaesthetic proce-dures. Brit J Anaesth 2014;13:109.21.

11. MARSH Risk Consulting. Medical Malpractice Claims analysis. Sixth edition; Jan 2015 [Internet]. Available from: www.quotidianosanita.it/allegati/allegato5391501.pdf [cited 2016, Jan 18; document in Italian].

12. Genovese U, Blandino A, Midolo R, Casali MB. Alleged malpractice in anesthesiology: analysis of a series of pri-vate insurance claims. Minerva Anestesiol 2016;82:202-9.

13. Turillazzi E, Bello S, Bonsignore A, Neri M, Riezzo I, Fineschi V. Retrospective analysis of anaesthesia-related deaths during a 12-year period: looking at the data from a forensic point of view. Med Sci Law 2012;52:112-5.

14. Lee LA, Stephens LS, Fligner CL, Posner KL, Cheney FW, Caplan RA, et al. Autopsy utilization in medi-colegal defense of anesthesiologists. Anesthesiology 2011;115;713-17.

15. Roh WS, Kim DK, Jeon YH, Kim SH, Lee SC, Ko YK, et al. Analysis of anesthesia-related medical disputes in the 2009-2014 period using the Korean Society of Anesthesi-ologists Database. J Korean Med Sci 2015;30:207-13.

16. Metzner J, Posner KL, Lam MS, Domino KB. Closed claims’ analysis. Best Pract Res Clin Anaest 2011;263-76.

17. Cheney FW, Posner KL, Lee LA, Caplan RA, Domino KB. Trends in anesthesia-related death and brain injuries. Anesthesiology 2006;105:1081-86.

ing to the available literature, many are the options to quantify the dimensions of the an-esthesia malpractice: among them are autop-sies,13, 14 legal claims,8, 15 and “closed claims”.15-17 However, such solutions are in my opinion suboptimal, as we would be aware of part of the “indexed cases” (the numerator), but unaware of the number of cases performed among which the indexed cases occurred (the true denominator). The best option should be a dedicated national database, a true Italian Anesthesia Incidents Project, different from the already available Anesthesia Closed Claims Projects 8 set up and run by the Italian Society of Anesthesiology. Many countries do not have national systems to report anesthesia and critical care incidents, events and compli-cations yet, and there is no common European platform to share possible “teachable mo-ments” so far, despite of the manifold existing suggestions on how to start such a project.8 its goal should be to identify major safety con-cerns, patterns of injury and prevention strate-gies to improve patient safety in every single field of application of our specialty. Difficult airway management protocols and ultrasound guidance for central vascular cannulation are examples. The indexed cases (the numerator) should be extracted from an entire series of performed cases (the denominator), prospec-tively collected on a continuous basis, record-ed in registries and analyzed by appropriately trained, volunteer reviewers. “Closed claims” can only point out the tip of the iceberg: pa-tient safety and reduction of malpractice liti-gations and claims should be improved by a complete understanding of the phenomenon (epidemiology and injury profile). When nec-essary, re-adjustment of the pre-procedural evaluation and/or of the intra-procedural man-agement should make responses to the adverse events proactive instead of simply reactive.

Acknowledgments.—The author would like to thank Martin Langer and Franco Marinangeli for the useful suggestions provided dur-ing the drafting of this paper.Conflicts of interest.—The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript.Article first published online: October 9, 2015. - Manuscript accepted: October 7, 2015. - Manuscript received: September 19, 2015.(Cite this article as: De Gasperi A. Defining the denominator to deal with the iceberg and not just its tip.Minerva Anestesiol 2016;82:154-6)


the process by which it is developed needs to be decided. the best practice to create guide-lines is to use the grades of recommendation, assessment, Development and evaluation (graDe) approach, evidence is ranked, rec-ommendations are only made where evidence exists, and expert opinion is not included.5 Previously, where quality trials were not avail-able, authors made recommendations stronger than the available evidence. Four members of the italian society of anesthesia and intensive care (siaarti) council have undertaken an important critical appraisal of the development of five international guidelines for analgoseda-tion in critically ill patients, published in this issue of Minerva Anestesiologica.6 analgose-dation, i.e. sedation delivery in critical care is a complex healthcare intervention with a small evidence base. they appraised the documents for process using the appraisal of guidelines, research and evaluation (agree) instrument that has been redesigned and published in 2010 as agree ii.7 agree ii checks the method-ological quality, not the clinical content or evi-dence of guidelines.6 they concluded, reassur-ingly, that the North american Pain, agitation and Delirium guidelines (PaD), Panamerican-iberica federation and german guidelines were robust and supported for use.6

guidelines cannot have lasting value be-cause they generally lose clinical relevance as they age and newer research makes their evidence obsolete. How can guidelines be

clinical guidelines are firmly established in modern medicine, although “more hon-

oured in the breach than the observance”.1 The first article on guidelines to appear in a Medline search was published in 1947.2 the expansion of medical research after World War ii had exacerbated the problem of how to translate new knowledge into clinical prac-tice.3 An interest in quality regulation and fi-nancial considerations in medical practice escalated from the late 1960s onwards and subsequent efforts to standardize good clinical practice inevitably resulted in a proliferation of guidelines.3 Until then, standards of medi-cal care provided by clinicians had been dic-tated by their own organizations and medical schools by means of training and recognized qualifications, supplemented by expert opinion of the day. throughout the developed world clinical practice guidelines flourished in the 1980s with three main purposes: improve the cost-effectiveness of interventions, offer pro-tection to the medical population and assure regulation. Many countries have “guidelines clearinghouses” that maintain catalogs and are part of the guidelines international Network, the owner of the largest web based database of medical guidelines.4

the development of an authorative evidence based guideline is a lengthy and labor intensive task. Once the need for a guideline is identified

E D I T O R I A L

the quality and lifespan of guidelinesValerie J. Page *, annalisa casariN

intensive care Unit, Watford general Hospital, Watford, UK*corresponding author: Valerie J. Page, Department of anaesthetics, Watford general Hospital, Watford WD18 0HB, UK. e-mail: [email protected]


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comment on p. 230.


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the use of guidelines has been adopted as a measure to monitor quality of care and ser-vices.11 their legal use as evidence to pros-ecute professionals is inevitable. a healthcare professional must know relevant guidelines and be able justify a decision not to follow them.12 the legal implications differ among countries. Under UK common law acceptable standards of clinical practice do not depend on guidelines, but from responsible practice judg-ing that guidelines need to be interpreted sen-sibly by each healthcare professional.13 if the clinician implements a flawed guideline it is him/her that will be seen as being negligent, not guidelines authors. in germany, guide-lines have a strong legal status, are mandatory for specific medical fields, and will likely be used to determine minimal standard of care.14 in France a national quality assurance agency imposed regulatory practice guidelines by law in 1993 in efforts to control ambulatory care costs and to change clinical behavior. they introduced a system to fine practitioners who do not follow them but it proved difficult to implement.15 in italy guidelines are consid-ered recommendations of clinical practice, not mandatory, cam be used in court as standards of medical care.12 in Usa non-adherence to established guidelines does not necessarily in-volve an adverse outcome for the defendant.17 regardless, it is incumbent on health care pro-fessionals to adhere to authoritative evidence-based clinical practice guidelines.

the evidence based medicine era pro-vides healthcare professionals with a mas-sive amount of information whose reliability changes every day. guidelines are the means to bridge the evidence into practice gap but only if they are methodologically sound and are readily adopted.

References 1. shakespeare, William. Hamlet: act 1, scene 4, 7–16.

New York: simon & schuster, New Folger edition; 2003. 2. Micale g. Possibility of new guidelines on the subject

of kidney disease pathogenesis gravidiche. ginecologia 1947;13:197.

3. Weisz g, cambrosio a, Keating P, Knaapen l, schlich t, tournay VJ. the emergence of clinical practice guide-lines. Milbank Q 2007;85:691-727.

maintained up to date? the United Kingdom National institute for Health care excellence (Nice) not only produce clinical guidelines but also related quality standards for organi-zations to aspire to as well as implementation tools to assess local needs, to provide audit tools and aid costing reports.7 importantly they undertake regular reviews, for instance the delirium guideline from 2010 underwent a surveillance review at four years.8 at that time it was appreciated that there is ongoing research in critical care so the delirium guide-line is on an active two yearly surveillance list. Moreover the quality of guidelines may vary as pointed out in the critical appraisal by girar-dis and colleagues.6 even though graDe was used by the american college of critical care Medicine and the Panamerican and iberica Federation of the critical care Medicine so-cieties their guidelines differ in some recom-mendations, for instance the use of haloperi-dol (or not) for delirium. expert opinion will never replace robust research, but where the evidence is not there, simply because the study has not been done, is it always correct to disre-gard expert guidance? the reason propofol is not included as an alternative to midazolam for sedation-induced delirium in the PaD guide-lines is that the relevant study has not been done, it is a good alternative.

after a robust evidence-based guideline has been published the next problem is the imple-mentation of the guideline into routine practice or ‘normalised’.9 overall, utilizing multiple ap-proaches has been shown to be the best way to implement guidelines.10 a list of the most com-mon strategies includes educational materials (included the guideline in paper or electronic version, small laminated cards, posters and short versions of the guideline posted); educational meetings; input of local opinion leaders; patient-mediated interventions; audit and feedback; tar-geted, patient specific reminders (e.g. electronic pop-ups that appear on the screen when a chart is opened or a paper reminder placed in the chart); marketing techniques; newsletters and confer-ence calls to all healthcare providers. each ap-proach needs to be resources specific depending on settings and areas.

tHe QUalitY aND liFesPaN oF gUiDeliNes Page


for healthcare teams and team-based practice. int J evid Based Healthc 2010;8:79-89.

12. Mainz J. Defining and classifying clinical indica-tors for quality improvement. int J Qual Health care 2003;15:523-30.

13. carlo Brusco. linee guida, protocolli e regole deontolog-iche. Le modifiche introdotte dal c.d. decreto Balduzzi. Diritto penale contemporaneo 2013;4:51-72.

14. Brian Hurwitz. legal and political considerations of clin-ical practice guidelines. BMJ 1999;318:661.

15. the european research Network on Quality Manage-ment in health care (eNQual network). the legal status of clinical practice guidelines in eU; [internet]. available from: http://www.nivel.nl/sites/default/files/bestanden/the_legal_statusof_clinicalPracticeguidelines.pdf [cit-ed 2015, october 31].

16. Durieux P, chaix c, Durand Zaleski i, ravaud P. From clinical recommendations to mandatory practice: the in-troduction of regulatory practice guidelines in the French health care system. int J technol assess Health care 2000;16:969-75.

17. ash samanta, Michelle M. Mello, charles Foster, John tingle and Jo samanta. the role of clinical guidelines in medical negligence litigation: a shift from the Bolam standard? Med law rev 2006;14:321-66.

4. guidelines international Network; [internet]. available from: http://www.g-i-n.net [cited 2015, october 31].

5. graDe Working group. grading quality of evidence and strength of recommendations. BMJ 2004;328:1490.

6. girardis M, cantaroni, savoia g, Melotti r, conti g. a critical appraisal of the quality of analgosedation guidelines in critically ill patients. Minerva anestesiol 2016;82:230-15.

7. Brouwers Mc, Kho Me, Browman gP, Burgers Js, cluzeau F, Feder g, et al. agree ii: advancing guide-line development, reporting and evaluation in health care. cMaJ 2010;182:e839-42.

8. Nice. the guidelines manual 2012; [internet]. available from: https://www.nice.org.uk/article/PMg6/chapter/13-implementation-support-for-clinical-guidelines [cited 2015, october 31].

9. Delirium: prevention, diagnosis and management; [inter-net]. available from: https://www.nice.org.uk/guidance/cg103 [cited 2015, November 1].

10. Murray e, treweek s, Pope c, MacFarlane a, Ballini l, Dowrick c, et al. Normalisation process theory: a frame-work for developinig, evaluating and implementing com-plex interventions. BMc Medicine 2010;8:63.

11. Medves J, godfrey c, turner c, Paterson M, Harrison M, MacKenzie l, et al. systematic review of practice guideline dissemination and implementation strategies

Conflicts of interest.—The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript.Article first published online: January 5, 2016. - Manuscript accepted: January 4, 2016. - Manuscript received: November 25, 2015.(Cite this article as: Page VJ, casarin a. the quality and lifespan of guidelines. Minerva anestesiol 2016;82:157-9)


domyxomas, peritoneal mesotheliomas and also for the treatment of colorectal peritoneal metastases with limited peritoneal extension. HiPec is currently evaluated for the treatment

Hyperthermic intraperitoneal chemo-therapy (HiPec) following cytoreduc-

tive surgery (crs) is the standard of care for the oncological treatment of peritoneal pseu-

O R I G I N A L P A P E R

intra-abdominal pressure, cardiac index and vascular resistance during

hyperthermic intraperitoneal chemotherapy: a prospective observational study

christoph n. scHlUerMann 1, Jens HoePPner 2, christoph BenK 3 rene scHMiDt 4, torsten looP 1, Johannes KalBHenn 1 *

1Department of anaesthesiology and critical care Medicine, Freiburg University Medical center, Freiburg, germany; 2Department of surgery, Freiburg University Medical center, Freiburg, germany; 3Department of cardiovascular surgery, Heart center University of Freiburg, Freiburg, germany; 4Department of anaesthesiology and critical care Medicine, Marienhospital stuttgart, stuttgart, germany*corresponding author: Johannes Kalbhenn, Department of anaesthesiology and critical care Medicine, Freiburg University Medi-cal center, Hugstetter strasse 55, D-79106 Freiburg, germany. e-mail: [email protected]

anno: 2016Mese: Februaryvolume: 82no: 2rivista: Minerva anestesiologicacod rivista: Minerva anestesiol

lavoro: titolo breve: intra-aBDoMinal PressUre, ci anD vascUlar resistance in HiPecprimo autore: scHlUerMannpagine: 160-9citazione: Minerva anestesiol 2016;82:160-9

a B s t r a c tBacKgroUnD: increased intra-abdominal pressure and hemodynamic variations during hyperthermic intraperitoneal chemotherapy (HiPec) are expected to be comparable to pneumoperitoneum with decreased cardiac index (ci) and in-creased systemic vascular resistance index (svri). We hypothesized that despite comparable increased intra-abdominal pressure, hemodynamic changes during HiPec would substantially differ from those described in laparoscopic surgery.MetHoDs: in this prospective observational clinical study, after obtaining written informed consent, we assessed intra-abdominal pressure and hemodynamic and respiratory changes during HiPec in 10 consecutive patients. intra-abdominal pressure as the primary endpoint was continuously measured with a catheter placed in the abdominal cavity. secondary endpoints were hemodynamic changes measured by pulse contour analysis and respiratory alterations. Fluid management was based on stroke volume variation.resUlts: the mean intra-abdominal pressure was constantly elevated during HiPec at a level of 14.2 mmHg (P=0.002 compared to baseline). the mean svri dropped from 1716 dyn*sec/cm³/m² to 1490 dyn*sec/cm5/m² at the end of HiPec (P<0.05). Mean ci increased from 3.2 to 3.45 l/m2 (P<0.001) and Horovitz index decreased from 548 to 380 (P=0.001). Median fluid intake was 7000 mL. No patient developed acute kidney injury.conclUsions: increased intra-abdominal pressure during HiPec was comparable to pneumoperitoneum. Hemody-namic changes however were opposed with a decrease in svri and a compensative increase in ci. current guidelines for anesthetic management in patients undergoing HIPEC are mainly based on findings from laparoscopic surgery and should therefore be reconsidered critically.(Cite this article as: schluermann cn, Hoeppner J, Benk c, schmidt r, loop t, Kalbhenn g. intra-abdominal pressure, cardiac index and vascular resistance during hyperthermic intraperitoneal chemotherapy: a prospective observational study. Minerva anestesiol 2016;82:160-9)Key words: vascular resistance - Pulse wave analysis - neurovascular coupling.

Minerva anestesiologica 2016 February;82 (2):160-9© 2016 eDiZioni Minerva MeDicathe online version of this article is located at http://www.minervamedica.it

intra-aBDoMinal PressUre, ci anD vascUlar resistance in HiPec scHlUerMann

vol. 82 - no. 2 Minerva anestesiologica 161

would be comparable to laparoscopic surgery but in contrast hemodynamic changes would be different during HiPec therapy.

Materials and methods

after approval of the ethics committee of albert-ludwigs-University Freiburg, ger-many (chairperson Prof. Dr. s. Pollack) and registration to the german clinical trials reg-ister (DrKs00004292) thirteen consecutive patients gave their written informed consent to be prospectively enrolled in this study.

Anesthesia and vascular access

anesthesia was performed by one inves-tigator (c.n.s.) according to departmental standard operation procedure. thoracic epi-dural anesthesia was placed and continuously maintained with ropivacaine and sufentanil (Bolus of 6-8 ml ropivacaine 0.2% and 20-25 µg sufentanil, maintenance with continuous infusion of ropivacaine 0.18 % and sufentanil 0.5 µg/ml with 6-8 ml/h). general anesthesia was i.v. induced with sufentanil (0.4-0.6 µ/kg), propofol (1% Mct, 1-2 mg/kg), and rocuroni-um (0.9 mg/kg) and maintained with desflu-rane (<1 Mac). after decay of rocuronium, cis-atracurium was continuously administered aiming for a train of four (toF) ratio <1/4 during crs and HiPec. a left radial arterial catheter was placed in seldinger´s technique for invasive blood pressure monitoring and was additionally connected to a PulsioFlex ProaQt® Monitor (Pulsion Medical systems se, Feldkirchen, germany). all patients re-ceived a double-lumen central venous catheter through the right jugularian vein with sono-graphic guidance. continuous central venous pressure monitoring was established.

Ventilation

after endotracheal intubation lungs were ventilated with the closed anesthesia system Zeus® (Draegerwerk ag & co. Kgaa, lue-beck, germany) in a volume-controlled mode with autoFlow®. the tidal-volume was set to

of gastric and ovarian peritoneal metastases.1 Data from various studies address the com-plexity of hemodynamic changes during the procedure describing changes in heart rate and mean arterial pressure 2, 3. only three studies systemically evaluated extended hemodynam-ic parameters like cardiac output and vascular resistances derived either from esophageal Doppler 4 or transpulmonary thermodilution and pulse contour analysis.5, 6 the results in variation of systemic vascular resistance and cardiac output are not consistent and signifi-cant. a decrease in svri and increase in ci was only measured in patients during open coliseum technique of HiPec which is not re-lated to an elevated intra-abdominal pressure.4

Hemodynamic changes during HiPec are merely attributed to an increase in intra-abdomi-nal pressure and therefore assumed to be similar to pneumoperitoneum with a decrease of ci fol-lowing the decrease of venous blood return 7 and an increase in svri. although hemodynamic variations during HiPec are still not complete-ly understood current guidelines recommend a calculated and liberal (e.g. 15 mL/kg/h) fluid management to obtain hemodynamic stabil-ity.3, 4, 7 goal directed strategies however lead to decreased fluid intake and are associated with a lower rate of intensive care admissions and a shorter hospital stay in colorectal surgery.8, 9

extended hemodynamic monitoring provid-ing parameters like cardiac output or stroke volume variation is a promising device for individualized fluid therapy.10-13 salzwedel et al. even showed a decrease in postoperative in-fectious complications for patients treated with goal directed fluid therapy guided with radial artery pulse contour analysis in major abdomi-nal surgery.14

the aim of this study was to prospectively determine the intra-abdominal pressure during HiPec as a primary endpoint. as secondary endpoint we measured hemodynamic and re-spiratory changes by recording hemodynamic parameters like cardiac output, systemic vas-cular resistance, stroke volume variation, body core temperature, urinary output, fluid intake, and dose of vasopressors. We hypothesized that the value of the intra-abdominal pressure

scHlUerMann intra-aBDoMinal PressUre, ci anD vascUlar resistance in HiPec


warmed with an electrical mattress dur-ing crs as well as warmed during crs and cooled during HiPec with a BairHugger® up-per body airstream blanket (3M gmbH, ne-uss, germany). Using either warm or cold i.v. fluids in addition the protocol aimed for main-taining normal body temperature during crs and keeping it constant during HiPec.

Measurement of intra-abdominal pressure

a single lumen central venous catheter (14 charriere, 16 cm) was inserted in the intra-ab-dominal cavity by the surgeon before closing the abdomen after crs with the tip close to the mesenterial trunk. a commercially available threefold transducer system was connected with one line to the arterial cannula, one line to the central venous catheter and - once the ab-domen was closed - one to the catheter placed in the abdomen. During HiPec the intra-ab-dominal pressure was continuously measured that way.

HIPEC

after crs one hose was placed in every quadrant of the abdomen. laparotomy then was definitively closed with sutures in three layers. Depending on the localization of the main surgery one hose was connected to the HiPec-circuit (Performer lrt ™, rand-biotech, Medolla, Italy) for inflow of che-motherapeutic solution, the other three were connected for draining. tubes and abdominal cavity were filled - depending on patient´s size and weight - with approximately 3000 ml of peritoneal dialysis solution (Physioneal® 35 glucose 2,27%, Baxter gmbH, Unterschleis-sheim, germany). the system was prompted by a roller pump and controlled by technicians of the department of cardio-engineering.

First half of chemotherapeutic drug (total dose: Mitomycin c 15 mg/m² body surface (BsF) or cisplatin 50 mg/m² BsF) was added in the closed system after achieving a solution temperature of 42° celsius, the second half af-ter 45 minutes. HiPec lasted for 90 minutes. After finishing HIPEC all four drains were

a value of 6-8 ml/kg during crs and main-tained constant during the whole HiPec phase. a positive end expiratory pressure (PeeP) lev-el of 5 to 7 mbar depending on the body mass index was set and kept constant. inspiratory fraction of oxygen (Fio2) and frequency were set to control normoxemia and normocapnia depending on periodic blood gas analysis and endtidal co2 values during crs and then kept constant during HiPec.

Perioperative fluid management:

Fluid management during crs was fol-lowing departmental recommendations for intra-abdominal fast-track surgery. all pa-tients received isotonic and isoionic solutions (Jonosteril®, Fresenius Kabi ag, Bad Hom-burg, germany) with 5 ml/kg/h. the amount of serous losses during crs was estimated by the investigator and was equally substituted with additional crystalloid infusion. in HiPec phase serous losses are not detectable there-fore fluids were exclusively applicated in a goal directed approach to keep the stroke vol-ume variation (svv) below 15%. We recorded the detectable amount of blood loss in the suc-tion unit during crs but did not estimate the blood absorbed in the abdominal compresses. an isoionic Hes-preparation (volulyte®, Fre-senius Kabi ag, Bad Homburg, germany) was administered for compensating blood loss during peritonectomy. at least the blood loss measured in the suction unit was substituted. transfusion threshold for red cell concentrates was hemoglobin <7 g/dl. a continuous infu-sion of noradrenalin was routinely utilized for maintaining a mean arterial pressure not more than 20% below baseline during crs. in or-der to keep variables to a minimum the nor-adrenaline dose was kept constant during the whole HiPec phase. all patients received a transurethral urine catheter. Urine output was measured hourly. no diuretics were used.

Temperature control

temperature was continuously measured with an esophageal probe. Patients were



Statistical analysis

all data were entered and processed with excel® for Mac v14.0 (Microsoft, redmond, Wa, Usa). statistical analysis was performed with sigmastat 11 for Windows (systat soft-ware, san Jose, ca, Usa). gaussian distribu-tion of variables was tested using the shapiro-Wilk-test. one-way anova-testing was applied. a P value <0.05 was chosen as level of significance. A Student-Newman-Keuls post-hoc analysis was executed.

Results

consecutively, thirteen patients were pro-spectively enrolled in the study. three patients were excluded because of insufficient data re-cording due to network error (one patient) and withdrawal of indication for HiPec due to in-traoperative findings (two patients) resulting in data from 10 patients for analysis. Patient and surgical characteristics are demonstrated in Table I. Depending on intraoperative find-ings duration of crs ranged from 110 to 570 min. Using blood saving techniques like ca-vitron Ultrasonic surgical aspirator (cUsa) and consequent mono- and bipolar coagula-tion, median blood loss was 275 ml (0-750). Median urine output was 0.8 ml/kg/h during crs and 0.5 ml/kg/h during HiPec. overall median fluid intake was 7000 mL per patient (table ii). none of the patients received blood products.

connected to special reservoirs to empty the abdominal cavity. Patients were then referred to the critical care unit.

Measurements and recording

Medication, ventilation parameters, blood gas analysis, relaxometry and urinary output were documented in the standard anesthesia sheet. Heart rate, blood pressure, central ve-nous pressure (cvP), temperature and intra-ab-dominal pressure were continuously recorded with the patient’s monitor (Infinity®, siemens, Munich, germany) in a trend view. every 10 minutes the exact values were electroni-cally gripped via the central network with the Winview®-software application (Draegerwerk, luebeck, germany). extended hemodynamic parameters like cardiac index (ci), systemic vascular resistance index (svri), svv and others were continuously measured with the Pulsioflex® Monitor and exact values were ex-ported to PDF-files every 10 minutes.

During the HiPec additional survey points were set:

1. abdominal cavity closed;2. cavity and tubes filled with lavage solu-

tion, pump start;3. system temperature = 42°C, first dose of

chemotherapeutic drug applicated;4. 45 min after first dose = second dose ap-

plicated;5. pump stopped;6. solution drained.

Table I.—�Patient and surgical characteristics.

age (years) median (range) 54 (40-73)Female/male (n.) 3/7Weight kg median (range) 75 (61-98)Height (cm) median (range) 171 (155-188)Body Mass index (kg/m2) median (range) 24.5 (21.2-33.9)ASA-classification (N.)

iiiii

82

Primary diagnosis (n.)gastric cancerpseudomyxoma peritoneicolorectal carcinomaappendix carcinoma

3142

length of icU stay (d) median (range) 4 (2-7)length of hospital stay (d) median (range) 16.5 (8-47)



procedure (P=0.002). after draining of the cavity, intra-abdominal pressure dropped to a level of 8.4 mmHg (table iii).

Blood gas analysis and body temperaturearterial oxygen partial pressure (Pao2) de-

creased from 218 mmHg at baseline to 176

Intra-abdominal pressure

the intra-abdominal pressure was 10.7 mmHg when the abdominal cavity was com-pletely filled with Physioneal® solution. once the HiPec-machine started, intra-abdominal pressure significantly increased to 14.9 mmHg and remained unchanged during the whole

Table II.—�Details of procedure.

Duration (min) median (range)crsfilling to emptying abdominal cavityHiPec (pump running)

320 (110-570)115 (108-134)92 (87-98)

Documented blood loss (ml) median (range) 275 (0-750)Urine output (ml/kg/h) median (range)

crsHiPec

0.8 (0.3-1.8)0.5 (0.17-1.2)

Fluid intake crs (ml) median (range)cristalloidcolloidblood products

4250 (1600-12000)500 (0-1500)

0Fluid intake HiPec (ml) median (range)

cristalloidcolloidblood products

2250 (1200-4000)0 (0-500)

0lavage solution (ml) median (range) 3000 (1860-3750)chemotherapeutic drug (n.)

cisplatinmitomycin

37

crs: cytoreductive surgeryHiPec: hyperthermic intraperitoneal chemotherapy

Table III.—�Hemodynamic, respiratory and metabolic characteristics [mean (SD)].1 2 3 4 5 6 P value

Basic haemodynamic parametersHeart rate (l/min) 66 (17) 69 (20) 71 (22) 76 (20) 82 (17) 80 (16) <0.001Mean arterial pressure (mmHg) 72 (7) 71 (7) 75 (7) 75 (9) 73 (5) 74 (7) 0.611noradrenaline (µg/kg/min) 0.1 (0.08) 0.09 (0.08) 0.1 (0.09) 0.09 (0.08) 0.09 (0.08) 0.08 (0.08) 0.359central venous pressure (mmHg) 12 (3) 14 (3) 16 (3) 14 (3) 15 (3) 12 (1) <0.001

extended haemodynamic parameterscardiac index (l/min/m² BsF) 3.2 (0.8) 3.1 (0.7) 3.1 (0.7) 3.1 (0.6) 3.3 (0.7) 3.4 (0.7) <0.001stroke volume variation (%) 10.7 (5.5) 12.1 (7.1) 11.9 (7.1) 15.6 (9.7) 17.2 (9.3) 15.8 (9.3) 0.006svri (dyn*sec/cm³/m²BsF) 1716 (444) 1644 (396) 1750 (430) 1740 (458) 1516 (361) 1490 (309) <0.001intraabdominal pressure (mmHg) 10.7 (3.4) 14.9 (3.9) 14.2 (3.5) 12.7 (3.8) 8.4 (3.8) <0.001Body temperature (°c) 36.6 36.9 36.9 37.2 37.6 37.6 <0.001

Blood gas analysispH 7.36 (0.04) 7.4 (0.03) 7.38 (0.02) 0.033po2 (mmHg) 218 (25) 176 (36) 192 (100) 0.016pco2 (mmHg) 37 (1) 36 (1) 38 (1) 0.234Be (mmol) -3.0 (1.7) -1.7 (1.3) -1.7 (1.2) 0.049glucose (mg/dl) 133 (18) 243 (25) 226 (24) < 0.001lactic acid (mmol/l) 1,0 (0.3) 1.7 (1.0) 2.7 (1.1) <0.001oxygenation index po2/Fio2 548 (89) 424 (58) 380 (96) 0.001

Column 1: abdominal cavity closed; column 2: cavity and tubes filled with lavage solution, Pump start; column 3: system temperature=42° C, first dose of chemotherapeutic drug added; column 4: 45 min after first dose=second dose added; column 5: pump stopped; column 6: solution drained. svri: systemic vascular resistance index; ci: cardiac index.



chemotherapeutic solution (P<0.001). cen-tral venous pressure increased slightly during HiPec (16 mmHg) and returned to baseline at 12 mmHg after drainage of the abdominal cavity (P<0.001). Mean arterial pressure and vasopressor dose remained unchanged (table iii).

the svri decreased from 1716 dyn*sec/cm5/m² at baseline to 1516 during HiPec and to 1490 dyn*sec/cm5/m² at the end of proce-dure (P<0.05). simultaneously, the decrease of svri was accompanied by an increase of ci from 3.2 l/min/m²BsF at baseline to a maximum of 3.45 l/min/m²BsF (Figures 1, 2; P<0.001).

Discussion

The main findings of this study are that in-creased intra-abdominal pressure is compara-ble whether significant decrease of SVRI and increase of ci differ oppositional to pneumo-peritoneum. Goal-directed fluid administration was nearly 50% of recommended calculated fluid intake without causing acute kidney fail-

mmHg during and 192 mmHg at the end of HiPec (P=0.006). Horovitz index (Pao2/Fio2) significantly decreased from 548 at the beginning to 424 in the middle and 380 at the end of HiPec (table iii, P=0.001). Patients developed hyperglycemia at the end of HiPec (133 to 226 mg/dl) and lactic acid levels raised from 1.0 mmol/l to 2.7 mmol/l (P<0.001). respiratory rate, tidal volume and PeeP were kept constant during the whole HiPec phase. Paco2 values did not significantly change dur-ing the procedure. the body core temperature significantly increased despite efforts to keep it constant. all patients presented normother-mia at the end of crs with a mean of 36.5° c. By active cooling of the patient to overcome influence of 42° C lavage solution, the rise in temperature was confined by 1.2° C to a mean of 37.7° c at the end of HiPec.

Hemodynamic parameters

the heart rate during HiPec increased from 66/min to 82/min at the end of the pro-cedure end was still 80/min after drainage of

Figure 1.—changes of systemic vascular resistance index during HiPec.



relatively constant mean arterial pressure val-ues are previously published.2, 3 in our study heart rate also increased from 66/min to 80/min and mean arterial pressure did not sig-nificantly change. Data describing extended hemodynamic parameters like svri and ci however are inconsistent: esquivel reported a drop in svri in the open coliseum technique and thanigaimani also found a decrease in svr 4, 6 yet without significancy. Raue did not find significant changes in SVR, but blamed it on the small population size in his study.5 rankovic did not assess svr or co in his 71 patients.3

the system used for pulse contour analy-ses uses the area under the arterial curve to derive the stroke volume. Multiplication with the heart rate delivers values for cardiac output. svr is calculated using ohm´s law (svr=[MaP-cvP]/co).

In this study a significant decrease in SVRI compared to baseline in the second half of the HiPec procedure is - in contrast to the current opinion - not a direct result of the increased intra-abdominal pressure, which rises immedi-

ure in any of the patients. HiPec impaired pulmonary function.

recommendations for perioperative man-agement of patients during HiPec procedures are partly based on assumptions and analo-gies with laparoscopic surgery.2, 3, 7 it is as-sumed that intra-abdominal pressure during HiPec would be similar to pneumo- or car-boperitoneum.2, 7 Our study for the first time demonstrates the HIPEC-associated signifi-cant increase of intra-abdominal pressure im-mediately when HiPec-pump was started. since the level did not exceed 15 mmHg and dropped after chemotherapeutic solution was drained, it is therefore comparable to intra-ab-dominal pressure in pneumoperitoneum during and after laparoscopic surgery.15-17 the system to measure the intra-abdominal pressure used in our study was simple, cheap, feasible, and did not harm the patient because the catheter was visible placed through the laparotomy by the surgeon. We therefore recommend routine intra-abdominal pressure measurement during HiPec to detect occlusion of tubes or leakage.

an increase in heart rate during HiPec and

Figure 2.—changes of cardiac index during HiPec.



15%.6 goal-directed volume therapy by svv seems to be helpful to achieve normovolemia without harm for the kidney.

in our patients urine output dropped from 0.8 to 0.5 ml/kg/h during HiPec but none of the patients developed acute Kidney Failure according to KDIGO-definition 22 during icU-stay. the entity of kidney failure in context with HiPec is unclear. increased intra-abdom-inal pressure may lead to post-renal failure by compressing the ureters and may decrease re-nal perfusion pressure leading to renal failure due to physical compression of the parenchy-ma.23 Hypovolemia and decreased mean arte-rial pressure may induce prerenal failure. tox-ic effects of the chemotherapeutic drugs need to be taken in concern as well. some authors suggest keeping urine output up by adminis-tering diuretics such as furosemide.3, 6 in our opinion keeping mean arterial pressure stable is more organ protective than additional caus-ing prerenal failure with diuretics. Decreased urine output is a helpful warning sign which might be masked by the use of diuretics. actu-ally diuretics are detrimental in acute kidney injury 24 and should be avoided in this situa-tion. our study was designed before the recent discussion about colloid solutions containing hydroxyethylstarch (Hes) started. if acute kidney failure is apprehended, the periopera-tive use of Hes during HiPec needs to be critically reconsidered.

The influence of increased intra-abdominal pressure to functional residual capacity, air-way pressure and oxygenation ratio is summed up before 2 which has literally been adopted in the practice guidelines.7 in this study we found a slight increase in inspiratory pressure (Pinsp) while frequency and tidal volume were kept constant during HiPec. Horovitz index significantly decreased and only partly recov-ered after drainage of abdominal lavage solu-tion at the end of the procedure. atelectasis and inflammatory damage are possible etiolo-gies for the worsening of pulmonary function. Scheduled increase of PEEP before filling the abdominal cavity with lavage solution might be a helpful intervention with regard of lung recruitment and avoidance of atelectasis.

ately when HIPEC system is started. Signifi-cant increase of ci following the decrease of svri therefore may be a physiological com-pensating mechanism to obtain stable mean arterial pressure.

Our findings are in contrast to data from patients with pneumoperitoneum,15-17 where the ci decreases immediately after increase of intra-abdominal pressure. the contrary results during HiPec may be explained by a systemic inflammatory reaction and physiological as-similation to increased body temperature. some investigators singularly explain the de-crease in svr with the increased body core temperature. Despite efforts to keep the body temperature constant in our patients it raised from 36.5° to 37.7° (P=0.002) during HiPec. it is therefore not unlikely that the decrease in svr was amongst others caused by increased core temperature. this is supported by the fact that changes sustain even when abdominal cavity is drained and intra-abdominal pressure reaches the baseline. in fact level of hemody-namic parameters fulfil the criteria of SIRS.18 Whether the hot HiPec solution, the increased core temperature or the chemotherapeutic drug itself causes the inflammatory reaction needs to be found out in further research. our hy-pothesis that hemodynamic changes during pneumoperitoneum and during HiPec mark-edly differ is confirmed. Central venous pres-sure was as anticipated not a very helpful indi-cator as it did not reflect time and dimension of the hemodynamic changes during HiPec similar to Cafiero’s findings before.19

Fluid therapy is still one of the most chal-lenging issues for the anesthesia team.20 the ambivalence of liberal fluid management and abdominal surgery is an important issue in rec-ommendations for hemodynamic management during HiPec.5, 7 Extensive fluid-intake may lead to dilution coagulopathy and anastomosis insufficiency. Nevertheless in a previous study a median volume intake of up to 16 000 ml during HiPec is reported.21 in contrast, only 7000 mL of fluids where administered during crs and HiPec in our study. in analogy to Thanigaimani, we performed fluid manage-ment by changes in svv with a threshold of



— Goal directed fluid therapy decreases volume intake compared to calculated fluid therapy based on current guidelines for management during HiPec without addi-tional harm to the kidney.

References 1. elias D, goere D, Dumont F, Honore c, Dartigues P, sto-

clin a, et al. role of hyperthermic intraoperative peri-toneal chemotherapy in the management of peritoneal metastases. eur J cancer 2014;50:332-40.

2. schmidt c, creutzenberg M, Piso P, Hobbhahn J, Bucher M. Peri-operative anaesthetic management of cytoreduc-tive surgery with hyperthermic intraperitoneal chemo-therapy. anesthesia 2008;63:389-95.

3. rankovic vi, Masirevic vP, Pavlov MJ, ceranic Ms, Milenkovic Mg, simic aP, et al. Hemodynamic and cardiovascular problems during modified hyperthermic intraperitoneal perioperative chemotherapy. Hepatogas-troenterology 2007;54:364-6.

4. esquivel J, angulo F, Bland rK, stephens aD, sugar-baker PH. Hemodynamic and cardiac function param-eters during heated intraoperative intraperitoneal chemo-therapy using the open “coliseum technique”. ann surg oncol 2000;7:296-300.

5. raue W, tsilimparis n, Bloch a, Menenakos c, Hart-mann J. volume therapy and cardiocircular function dur-ing hyperthermic intraperitoneal chemotherapy. eur surg res 2009;43:365-72.

6. thanigaimani K, Mohamed F, cecil t, Moran BJ, Bell J. the use of cardiac output monitoring to guide the admin-istration of intravenous fluid during hyperthermic intra-peritoneal chemotherapy. colorectal Dis 2013;15:1537-42.

7. raspe c, Piso P, Wiesenack c, Bucher M. anesthetic management in patients undergoing hyperthermic chem-otherapy. curr opin anaesthesiol 2012;25:348-55.

8. ramirez JM, Blasco Ja, roig Jv, Maeso-Martinez s, casal Je, esteban F, et al. enhanced recovery in colorec-tal surgery: a multicentre study. BMc surg 2011;11:9.

9. conway DH, Mayall r, abdul-latif Ms, gilligan s, tackaberry c. randomised controlled trial investigating the influence of intravenous fluid titration using oesopha-geal Doppler monitoring during bowel surgery. anesthe-sia 2002;57:845-9.

10. Breukers rM, sepehrkhouy s, spiegelenberg sr, groe-neveld aB. cardiac output measured by a new arterial pressure waveform analysis method without calibration compared with thermodilution after cardiac surgery. J cardiothorac vasc anesth 2007;21:632-5.

11. Button D, Weibel l, reuthebuch o, genoni M, Zollinger a, Hofer cK. clinical evaluation of the Flotrac/vigileo system and two established continuous cardiac output monitoring devices in patients undergoing cardiac sur-gery. Br J anesth 2007;99:329-36.

12. Krejci V, Vannucci A, Abbas A, Chapman W, Kangrga iM. comparison of calibrated and uncalibrated arterial pressure-based cardiac output monitors during orthotopic liver transplantation. liver transpl 2010;16:773-82.

13. Smetkin AA, Hussain A, Kuzkov VV, Bjertnaes LJ, Ki-rov MY. validation of cardiac output monitoring based on uncalibrated pulse contour analysis vs transpulmonary thermodilution during off-pump coronary artery bypass grafting. Br J anesth 2014;112:1024-31

14. salzwedel c, Puig J, carstens a, Bein B, Molnar Z,

About this study

all procedures were performed by the same surgical team and the same anesthesiologist. the same anesthetic equipment was used in all patients. Data collection was stopped after 13 consecutive patients because of unforeseen changes in the surgical and anesthetic staff in order to keep variables to a minimum. the pro-spective design allowed a clear view to the ex-act cardiopulmonary changes and the moment they appear. a larger patient population would have been desirable.

We did not exactly measure fluid losses absorbed by abdominal compresses but con-centrated on the loss collected in the suction unit. it would have been desirable to weigh the compresses before and after surgery to more exact calculate serous and blood losses.

Conclusions

intra-abdominal pressure during HiPec is easy to monitor and is comparable to values in laparoscopic surgery. in contrast to former assumptions the hemodynamic changes dur-ing HiPec differ oppositional from those de-scribed in pneumoperitoneum: HiPec leads to a decrease in svr during the procedure followed by an increase in cardiac output like seen in SIRS. For the guidance of fluid- and vasopressor-therapy a pulse-contour based ex-tended hemodynamic monitoring seems to be helpful without additional harm to the patient. Worsening of pulmonary function lasts even after drainage of abdominal cavity.

Key messages — intra-abdominal pressure during

HiPec is comparable to pneumoperitone-um, hemodynamic changes however differ markedly.

— Our findings based on pulse con-tour analyses reveal a significant decrease of vascular resistance during HiPec fol-lowed by an increase in ci which might be a physiologic reaction to inflammation or heat stress.



20. Bell Jc, rylah Bg, chambers rW, Peet H, Mohamed F, Moran BJ. Perioperative management of patients under-going cytoreductive surgery combined with heated intra-peritoneal chemotherapy for peritoneal surface malig-nancy: a multi-institutional experience. ann surg oncol 2012;19:4244-51.

21. arakelian e, gunningberg l, larsson J, norlen K, Mahteme H. Factors influencing early postoperative recovery after cytoreductive surgery and hyperther-mic intraperitoneal chemotherapy. eur J surg oncol 2011;37:897-903.

22. levey as, de Jong Pe, coresh J, el nahas M, astor Bc, Matsushita K, et al. The definition, classification, and prognosis of chronic kidney disease: a KDigo contro-versies conference report. Kidney int 2011;80:17-28.

23. Kirkpatrick aW, roberts DJ, De Waele J, Jaeschke r, Malbrain Ml, De Keulenaer B, et al. intra-abdominal hypertension and the abdominal compartment syndrome: updated consensus definitions and clinical practice guide-lines from the World society of the abdominal compart-ment syndrome. intensive care Med 2013;39:1190-206.

24. Ejaz AA, Mohandas R. Are diuretics harmful in the man-agement of acute kidney injury? Curr Opin Nephrol Hy-pertens 2014;23:155-60.

Kiss K, et al. Perioperative goal-directed hemodynamic therapy based on radial arterial pulse pressure variation and continuous cardiac index trending reduces postop-erative complications after major abdominal surgery: a multi-center, prospective, randomized study. crit care 2013;17:r191.

15. Dexter sP, vucevic M, gibson J, McMahon MJ. He-modynamic consequences of high- and low-pressure capnoperitoneum during laparoscopic cholecystectomy. surg endosc 1999;13:376-81.

16. Bickel a, arzomanov t, ivry s, Zveibl F, eitan a. revers-al of adverse hemodynamic effects of pneumoperitoneum by pressure equilibration. arch surg 2004;139:1320-5.

17. nguyen nt, Wolfe BM. the physiologic effects of pneumoperitoneum in the morbidly obese. ann surg 2005;241:219-26.

18. Balk RA. Systemic inflammatory response syndrome (sirs): Where did it come from and is it still relevant today? Virulence 2014;5:20-6.

19. Cafiero T, Di Iorio C, Di Minno RM, Sivolella G, Con-fuorto g. non-invasive cardiac monitoring by aortic blood flow determination in patients undergoing hyper-thermic intraperitoneal intraoperative chemotherapy. Minerva anestesiol 2006;72:207-15.

Acknowledgements.—the authors greatly appreciate the valuable help of the technicians of the Heart center University of Freiburg.Funding.—The Pulsioflex® monitor was provided by Pulsion Medical systems se, Feldkirchen, germany. catheter material and disposables were supported by departmental funding.Conflicts of interest.—rene schmidt received speaker fees of Pulsion Medical systems.Article first published online: May 14, 2015. - Manuscript accepted: May 13, 2015. - Manuscript revised: May 5, 2015. - Manuscript received: March 23, 2015.


required during the whole procedure, to avoid activation of the coagulation system induced by the contact of the blood with the foreign surfaces of both the circuit and the membranes of the artificial lung. Unfractionated heparin (UH) is the anticoagulant of choice during

extracorporeal membrane oxygenation (ECMO) is increasingly being used as an

adjunct to conventional ventilatory treatment for respiratory failure.1, 2 anticoagulation is

O R I G I N A L A R T I C L E

Hemostasis changes during veno-venous extracorporeal membrane oxygenation

for respiratory support in adultsMauro PanigaDa 1 *, andrea artoni 2, Serena M. PASSAMONTI 2, alberto Maino 2 cristina Mietto 1, Camilla L’ACQUA 1, Massimo cressoni 1, Massimo Boscolo 2

armando triPoDi 2, Paolo BUCCIARELLI 2, luciano gattinoni 1, ida Martinelli 2

1Dipartimento di Anestesia, Rianimazione ed Emergenza-Urgenza, Ospedale Maggiore Policlinico, Milan, italy; 2Centro Emofilia e Trombosi A. Bianchi Bonomi, Fondazione IRCCS Ca’ Granda - Ospedale Maggiore Policlinico e Università di Milano, Milan, Italy*Corresponding author: Mauro Panigada, U.O.C. Rianimazione e Terapia Intensiva – Fondazione IRCCS Ca’ Granda – Ospedale Maggiore Policlinico. Via F. Sforza, 35 – 20122 Milano, Italy. E-mail: [email protected]


lavoro: titolo breve: HEMOSTASIS CHANGES IN VENO-VENOUS ECMO FOR RESPIRATORY SUPPORTprimo autore: PanigaDapagine: 170-9citazione: Minerva Anestesiol 2016;82:170-9

a B s t r a c tBACKGROUND: We investigated the coagulation system in patients during extracorporeal membrane oxygenation (ECMO) initiated for respiratory failure and the influence of the ECMO circuit on coagulation tests; we compared dif-ferent coagulation tests for monitoring unfractionated heparin (UH) therapy; we investigated whether or not coagulation parameters were predictive of bleeding during ECMO.METHODS: Pilot study on twelve consecutive adult patients admitted at our general ICU for acute respiratory failure and placed on ECMO from November 2011 to October 2012. Coagulation tests were performed before ECMO start and daily, including day of circuit change and day of circuit removal. UH was monitored with activated partial thromboplastin time (APTT) ratio, at a therapeutic range of 1.5-2.0.RESULTS: We observed no effect of ECMO circuit on coagulation parameters measured pre- and postlung, but platelet count decreased significantly over time (-82x103/mmc, 95%CI 40-123). APTT showed a correlation with antifactor Xa activity, whereas other global coagulation tests such as activated clotting time, thromboelastography and endogenous thrombin potential did not. Major bleeding occurred in three patients but no difference in any coagulation parameter was observed between them and those who did not bleed.CONCLUSIONS: This pilot study shows that ECMO initiated for respiratory support in adults does not change coagula-tion parameters. Over time a statistically significant reduction of platelet count was observed, possibly due to consump-tion within the circuit, consumption microangiopathy or the underlying patients’ diseases. Although APTT was appropri-ate to monitor UH, major bleedings occurred and a lower therapeutic range may be advisable.(Cite this article as: Panigada M, Artoni A, Passamonti SM, Maino A, Mietto C, L’Acqua C. Hemostasis changes during veno-venous extracorporeal membrane oxygenation for respiratory support in adults. Minerva Anestesiol 2016;82:170-9)Key words: Extracorporeal Membrane Oxygenation - Blood coagulation - Heparin - Anticoagulants therapy - Partial Thromboplastin Time.


Comment in p. 147.


HEMOSTASIS CHANGES IN VENO-VENOUS ECMO FOR RESPIRATORY SUPPORT PanigaDa


ventilatory parameters and transfusions of blood components were recorded daily. Wean-ing from ecMo, survival at discharge, death during ecMo, death after weaning, bleeding and thrombotic episodes were also recorded. Major bleeding was defined as a fatal one, or intracranial or in other critical area or organ.9 the day after ecMo removal, survived pa-tients underwent a B-mode ultrasonography to investigate thrombosis of the common femoral or iliac veins, at the site of cannulation. The study protocol and the informed-consent were approved by the ethic committee. Written in-formed consent or deferred consent was ob-tained from each patient.

Blood sampling

Blood was drawn from a radial arterial cath-eter, sampled in vacutainers with 1/10 volume of 3.2% sodium citrate as anticoagulant, cen-trifugated at 2880 g to obtain plasma that was stored at -80°C. Blood samples were taken before ECMO start (D0) and during ECMO, at four time points arbitrarily defined: D1 was the day of ECMO initiation (at least 5 hours after and within 24 hours from cannulation, following the stabilization of the APTT ratio); D7 was the 7th day after ecMo initiation; cc was the day of circuit change (blood taken im-mediately before the change); CR was the day of circuit removal (blood taken immediately before removal). As shown in Table I, some coagulation tests were performed daily and at least once. Laboratory data collection started at D0 and ended at CR. To assess the effect of ecMo on the hemostatic system, blood was

ECMO because of its quickly reversible effect and possible use despite renal function impair-ment. The laboratory test used in our depart-ment to monitor the anticoagulant effect of UH is the activated partial thromboplastin time (APTT), that is highly sensitive to the relatively low UH doses (0.1 to 1.0 IU/mL) used during ECMO.3 However, patients on ECMO often develop bleeding episodes,4 sometimes fatal.5 It is known that the circuit surface, other than the disease leading to ecMo start, causes acti-vation of the contact and complement system 6 and favors the development of an acquired von Willebrand disease.7, 8 Whether or not bleeding during ecMo is mainly related to excessive anticoagulation, to the derangements of hemo-stasis caused by the circuit itself or to the un-derlying patient disease is a matter of debate.

this study aimed to investigate the coagu-lation system in adult patients during ecMo initiated for respiratory failure, the influence of the ecMo circuit itself on coagulation tests and to compare different coagulation tests for monitoring UH therapy.


Patients

consecutive adult patients admitted at our general intensive care unit for acute respira-tory failure and placed on ecMo from no-vember 2011 to october 2012 were included in the study. Patients’ observation started at admission and ended at discharge from the intensive care unit or at death. Demographic data, causes of respiratory failure, ecMo and

Table I.—�Time of blood sampling and coagulation tests before and during ECMO.time points coagulation tests

Day 0 PT, APTT, fibrinogen, antithrombin, protein C, protein S, factor V Leiden, G20210A prothrombin, antiphospholipid antibodies

every day PT, APTT, fibrinogen, antithrombin, activated clotting time, anti-factor Xa activity, thromboelastography, D-dimer

Day 1Day 7Day of circuit changeDay of circuit removal

Prothrombin fragment 1+2, PAI-1, factor XIII, factor VIII, RiCof, VWF: Ag, ADAMTS13, endogenous thrombin potential

PT: prothrombin time; APTT: activated partial thromboplastin time; PAI: plasminogen activator inhibitor; RiCof: ristocetin co-factor; VWF:Ag: von Willebrand factor antigen.

PanigaDa HEMOSTASIS CHANGES IN VENO-VENOUS ECMO FOR RESPIRATORY SUPPORT


tested to investigate inherited or acquired thrombophilia abnormalities. Fibrinolysis was investigated by measuring fibrinogen, D-dimer, prothrombin fragment 1+2 (F1+2), plasminogen activator inhibitor-1 (PAI-1) and factor XIII. Factor VIII (FVIII)/von Wille-brand factor (VWF) system was evaluated by measuring FVIII, ristocetin cofactor (RiCof), VWF-antigen (VWF-Ag), and ADAMTS13 metalloprotease activity. All the aforemen-tioned tests were performed as previously de-scribed.11-13

Anticoagulation monitoring

Anticoagulation with UH started at the inser-tion of ECMO cannula, with a bolus of 50-70 IU/Kg followed by 10-15 IU/Kg/h in continu-ous intravenous infusion. UH was monitored with the APTT ratio (patient-to-normal clot-ting time) aimed at a desired therapeutic range of 1.5 to 2.0, as suggested.14 the aPtt ratio guided the UH dosage. Because the anticoagu-lant effect of UH is mediated by AT, plasma levels of this protein were measured daily and an at concentrate was given to the patients when needed, in order to maintain plasma lev-els above 70%.14 to calculate the percentage of time with aPtt in the therapeutic range, a linear interpolation method was used.15 in ad-dition to the aPtt, the activated clotting time (ACT, sec) and the antifactor Xa activity (UI/mL) were measured, aimed at a desired thera-peutic range from 180 to 210 sec according to our institutional protocol and from 0.3 to 0.7 IU/mL,16 respectively. Antifactor Xa activity is a direct index of inhibition of factor X by UH and is considered to be the gold standard for monitoring the UH anticoagulant effect. ACT (Hemochron® Jr. Signature, ACT-Low Range cartridges, international technidyne corpora-tion, Edison, NJ, USA), a point of care test that measures the time of fibrin clot formation in the presence of activators 17was performed on fresh whole blood according to the manufac-turer recommendations.

two additional global coagulation tests were performed: kaolin-activated thrombo-elastography (K-TEG) with and without hepa-

sampled not only from the arterial line in place on the patient, but also from a port placed be-fore and after the artificial lung.

Extracorporeal membrane oxygenation proce-dure

ECMO was provided by veno-venous by-pass through a percutaneous cannulation of both femoral veins in all patients. A 21 to 23 Fr. drainage cannula (HLS cannulae Maquet Car-diopulmonary AG, Hirrlingen, Germany) was extended under fluoroscopy into the inferior vena cava until the renal veins outflow, and a 21 Fr. reinfusion cannula (Bio-Medicus® Femo-ral Venous Cannulae, Medtronic, Inc.) up to the right atrium. The extracorporeal systems used were the QUADROX PLS Oxygenator plus the rotaFloW centrifugal Pump in nine patients and the HLS Set Advanced 5.0 - Cardiohelp® system in the remaining three (MAQUET Car-diopulmonary AG, Hirrlingen, Germany). In the cardiohelp® the centrifugal pump is incor-porated in the system and placed right in front of the artificial lung. Both systems including oxy-genator, centrifugal pump and tubing set, were Bioline® coated. An oxygen-air blender was used to ventilate the membrane lung. ECMO was performed under normothermic conditions guaranteed by the oxygenator heat exchanger. the circuit and the oxygenator membrane were inspected thrice daily in order to detect visible clots formed on the membrane surface. Deci-sion to change the circuit was taken considering the presence of visible clots, a sharp increase of D-dimer or a reduction of platelet count, the onset of hemolysis or the reduction of the membrane oxygenating performance. If platelet count decreased rapidly (≥50% from baseline), anti-PF (platelet factor) 4 antibodies for hepa-rin-induced thrombocytopenia were searched.10

Laboratory tests

At D0 antithrombin (AT), protein C, protein s, factor v leiden and g20210a prothrombin gene mutation, antiphospholipid antibodies including lupus anticoagulant, anticardiolipin and anti-ß2 glycoprotein-1 IgG and IgM were




categorical variables were expressed as number and percentage. Continuous variables were expressed as mean with standard devia-tion or median with interquartile range when not normally distributed. Differences in coagu-lation parameters during ecMo were tested with paired sample t test between D1 and D7 or CC or CR, and between the tube entering (pre-lung) and exiting (post lung) the ECMO circuit. correlations between coagulation parameters were tested calculating Spearman’s rank corre-lation coefficient (Spearman’s rho, ρ) with cor-responding P-value. P-value <0.05 was consid-ered as statistically significant. The association between each hemostatic parameter (platelets, fibrinogen and D-dimer) and a measurable K-teg was tested using unadjusted logistic re-gression, calculating odds ratios (OR) and their 95% confidence intervals (CI). Statistical anal-yses were performed using SPSS version 20.

Results

Patients

Twelve patients, 5 men and 7 women, were included in the study and their demographic and clinical characteristics are summarized in Table II. Median age was 69 years (range 31-84). Eight patients started ECMO for chronic obstructive pulmonary disease (including a

rinase (that neutralizes the effect of UH) and thrombin generation. K-TEG was performed on fresh whole blood (teg® 5000 Thromb-elastograph® Hemostasis Analyzer System, Haemonetics Corporation, Braintree, MA, USA) and among the various parameters re-corded the most useful is the time to initial clot formation, conventionally labeled as “R”. In case of flat R, i.e. inability to form a clot, K-TEG was arbitrarily interrupted at 80 min. thrombin generation was assessed accord-ing to Hemker et al.18 the test was based on the activation of coagulation after addition to plasma of human recombinant tissue factor (1pM) (Recombiplastin, Instrumentation Lab-oratory, Orangeburg, NY, USA) and synthetic phospholipids (1.0µM) (Avanti Polar, Alabas-ter, AL, USA) as coagulation triggers. Regis-tration of thrombin generation was obtained with a fluorogenic substrate (Z-Gly-Gly-Arg-AMC HCl, Bachem, Bubendorf, Switzerland) (617µM) by means of a fluorometer (Fluoros-kan Ascent™, ThermoLabsystem, Helsinki, Finland). Readings were recorded and calcu-lated with a dedicated software (thrombino-scopetM, thrombinoscope Bv, Maastricht, The Netherlands), which displays thrombin generation curves and calculates the area un-der the thrombin generation curve, defined as endogenous thrombin potential (ETP). ETP represents the amount of the generated throm-bin as a function of the action of pro- and anti-coagulant drivers operating in plasma.

Table II.—�Characteristics, ECMO duration, transfusion requirement, and outcome of study participants.

Patient sex age BMi Diagnosis days on ecMo

Day of circuit change

Majorbleeding

rBc transfused

(units)

Plts transfused

(units)

FFP transfused

(mL)outcome

1 M 71 33 coPD 13 Day 2 no 3 - 1500 Dead (day 13)2 F 31 15 coPD 9 - no 9 - - Dead (day 48)3 F 63 21 coPD 8 - no 3 - - Discharged4 F 74 33 coPD 7 - no 5 - - Discharged5 F 69 27 coPD 20 Day 9 no 10 2 1750 Dead (day 32)6 F 66 24 coPD 6 - no 6 - - Discharged7 F 69 20 arDs 9 - no 8 2 500 Dead (day 9)8 M 77 28 coPD 8 Day 5 no 2 - - Dead (day 8)9 M 82 24 arDs 14 - Yes1 10 1 - Dead (day 21)10 F 41 18 arDs 6 - Yes2 3 7 3750 Dead (day 6)11 M 84 31 coPD 4 - Yes3 6 1 1500 Discharged12 M 34 30 arDs 8 - no 1 - - DischargedcoPD: chronic obstructive pulmonary disease, arDs: acute respiratory distress syndrome, rBc: red blood cells, Plts: platelets, FFP: fresh frozen plasma. 1retropharyngeal; 2intracranial; 3Retroperitoneal.



Coagulation changes during ECMO

the comparison of coagulation parameters between D1 and D7 is showed in Table III. Platelet count was the only parameter that sig-nificantly changed, with a mean reduction of 82x103/mmc (95%CI 40-123) (Figure 1). This reduction was observed in all patients and none of them had heparin induced thrombocytope-nia. Six patients required infusion of AT con-centrate during ECMO. Of them, three had severe bleeding, and the other three required the change of the circuit. Fibrinogen slightly decreased, while F1+2 and D-dimer increased over time, although not significantly. RiCof and vWF:ag were high at D1 and the lat-ter increased slightly during ECMO. RiCof/vWF:ag ratio decreased from D1 to D7, indi-cating a possible loss of high-molecular-weight VWF multimers. ADAMTS-13 levels remained low and FVIII levels high during ECMO. The same comparison of coagulation parameters was done between D1 and cc or cr, obtaining similar results and an even more pronounced decrease in platelet count (117x103/mmc [95% CI 70-165]) than that observed between D1 and D7 (Table IV). FVIII decreased significantly between D1 and cc or cr, but remained al-ways within the normal range. Table V shows the comparison of coagulation parameters be-tween pre- and post-ECMO at D1. No statisti-cally significant difference was observed in any

31-year-old woman affected by cystic fibrosis who required a bridging to lung transplanta-tion) and 4 for acute respiratory distress syn-drome due to pneumonia in 3 cases and sys-temic lupus erithematosous in one. Median ECMO duration was 8 days (range 4-20) and the circuit was removed before D7 in 4 pa-tients and after D7 in 8. Three patients changed the circuit because of a sharp D-dimer increase above 3500 ng/ml, but no substantial reduction in D-dimer levels was observed after such cir-cuit change. Three patients had a major bleed-ing event (retropharyngeal, intracranial, and retroperitoneal hemorrhage) during ECMO that was fatal in one, whereas no thrombotic complications were observed nor in the ecMo circuit nor in the eight patients who survived ECMO and underwent ultrasonography. All patients were transfused, for a median number of 6 red blood units per patient (range 1-10). Five patients needed platelet and/or fresh fro-zen plasma transfusions with a large difference in units required (patient 10 received 50% of platelet units and 40% of fresh frozen plasma volume transfused in all 12 patients, Table II). Seven patients died in intensive care unit, 4 of whom during ECMO, and 5 were discharged. Mean blood flow of the circuit was 2.8±0.6 L/min, revolutions per minute (RPM) 2157±327, gas flow 4,7±2,3 L/min, artificial lung shunt 13±8% and transmembrane pressure drop 13±4 mmHg.

Table III.—�Comparison of coagulation parameters between day 1 (D1) and day 7 (D7) of ECMO.*

Parameter normal values D1Mean (SD)

D7Mean (SD) Difference (95%CI) P-value#

Antithrombin (%) 70-150 75 (30) 84 (32) 9 (-14 to 31) 0.399Platelets (103/mmc) 130-400 212 (66) 130 (68) -82 (-123 to -40) 0.002Fibrinogen (mg/dL) 140-400 379 (182) 348 (103) -31 (-181 to 119) 0.636F1+2 (pM/L) 86-128 821 (420) 847 (342) 26 (-431 to 483) 0.897D-dimer (ng/mL) 0-230 2568 (2346) 3198 (1693) 630 (-1419 to 2679) 0.491PAI-1 (ng/mL) <5 0.74 (0.44) 0.93 (0.74) 0.19 (-0.60 to 0.98) 0.592Factor XIII (%) 70-140 53 (20) 59 (23) 6 (-11 to 23) 0.344Factor VIII (%) 50-150 244 (65) 247 (46) 3 (-57 to 63) 0.902RiCof (U/dL) 41-168 331 (204) 334 (208) 3 (-62 to 68) 0.927VWF Ag (%) 40-169 386 (105) 438 (93) 52 (-33 to 137) 0.193ricof/vWF ag >0.7 0.84 (0.39) 0.72 (0.24) -0.11 (-0.25 to 0.02) 0.084ADAMTS13 (%) 42-150 48 (12) 47 (19) -1 (-9 to 6) 0.687*Calculated on 8 patients; #P-value for paired sample t-test.F 1+2: prothrombin fragments 1+2; PAI: plasminogen activator inhibitor; RiCof: ristocetin cofactor; VWF:Ag: von Willebrand factor antigen.



Figure 1.—Trend of platelet count from day 1 to day 7 (panel A) and from day 1 to day of CC/CR (panel B) for each patient.a B

Table IV.—�Comparison of coagulation parameters between day 1 (D1) and day of circuit change (CC) or circuit removal (CR).*

Parameter normal values D1Mean (SD)

cc/crMean (SD) Difference (95%CI) P value #

Antithrombin (%) 70-150 69 (34) 83 (29) 14 (-2 to 30) 0.084Platelets (103/mmc) 130-400 202 (75) 85 (50) -117 (-165 to -70) 0.0001Fibrinogen (mg/dL) 140-400 409 (143) 330 (138) -79 (-191 to 32) 0.147F1+2 (pM/l) 86-128 788 (450) 1098 (275) 310 (12 to 607) 0.043D-dimer (ng/mL) 0-230 2311 (2159) 4467 (1830) 2157 (223 to 4091) 0.032PAI-1 (ng/mL) <5 1.3 (1.6) 0.8 (0.8) -0.5 (-1.7 to 0.7) 0.386Factor XIII (%) 70-140 56(14) 59 (20) 3 (-10 to 16) 0.633Factor VIII (%) 50-150 254 (51) 211(58) -43 (-81 to -4)* 0.033RiCof (U/Dl) 41-168 272 (87) 277 (109) 5 (-68 to 78) 0.875VWF Ag (%) 40-169 393 (98) 412 (123) 19 (-77 to 115) 0.658ricof/vWF ag >0.7 0.69 (0.13) 0.68 (0.12) -0.02 (-0.13 to 0.1) 0.744ADAMTS13 (%) 42-150 44 (17) 42 (19) -2 (-10 to 7) 0.692*Calculated on 11 patients, data for Pt. 7 at CR are missing; # P-value for paired sample t-test.F 1+2: prothrombin fragments 1+2; PAI: plasminogen activator inhibitor; RiCof: ristocetin co-factor; VWF:Ag: von Willebrand factor antigen.

Table V.—�Comparison of coagulation parameters at day 1 (D1) of ECMO, pre and post-artificial lung.*

Parameter normal values Pre-lungMean (SD)

Post-lungMean (SD)

Difference(95% CI) P value#

Antithrombin (%) 70-150 65 (32) 67 (34) 2 (4 to 0.3) 0.029Platelets (103/mmc) 130-400 - - - -Fibrinogen (mg/dL) 140-400 424 (141) 412 (124) -12 (18 to -42) 0.409F1+2 (pM/L) 86-128 851 (447) 736 (439) -15 (4 to -34) 0.111D-dimer (ng/mL) 0-230 2005 (1856) 1953 (1808) -53 (39 to -145) 0.231PAI-1 (ng/mL) <5 1.3 (1.5) 1.2 (1.4) -0.1 (-0.01 to 0.1) 0.066Factor XIII (%) 70-140 53 (18) 53 (18) 0 (-2 to 2) 0.856Factor VIII (%) 50-150 255 (54) 257 (57) 3 (17 to -12) 0.629RiCof (U/dL) 41-168 293 (156) 297 (149) 5 (16 to -6) 0.38VWF Ag (%) 40-169 384 (99) 377 (104) -8 (-1 to -14) 0.027ricof/vWF ag >0.7 0.75 (0.28) 0.78 (0.25) 0.03 (0.01 to -0.05) 0.037ADAMTS13 (%) 42-150 - - - -Calculated on 12 patients; #P-value for paired sample t-testF 1+2: prothrombin fragments; PAI: plasminogen activator inhibitor; RiCof: ristocetin co-factor; VWF:Ag: von Willebrand factor antigen.



Only one patient (number 11 in Table II) al-ways formed fibrin within 80 min, whereas the other 11 had at least 40% of samples in-terrupted at 80 min. When the analysis was restricted to the non-interrupted samples, a correlation between the r parameter and antifactor Xa activity (ρ=0.59, P=0.002) or APTT (ρ 0.45, P<0.001) was observed. Plate-let count was the only hemostatic parameter predicting the probability to generate the r within 80 min (for every 10000 platelet in-crease OR 1.06, 95%CI 1.02–1.11, P=0.009). When K-TEG was performed adding hepari-nase to the test system, r values were always within 80 min (median 9.8, IQR: 7.3-11.7 min), thus confirming that UH was respon-sible for the observed results. As expected during UH therapy, thrombin generation mea-sured with etP was severely reduced in the vast majority (73/90, 81%) of tested samples the etP lag time was extremely sensitive to the concentration of the reagents. When re-combinant tissue factor was increased five times and synthetic phospholipids four times compared to normal values, the lag time de-creased from 70 minutes (IQR: 30.5-70.0) to 36.1 minutes (IQR: 20.7-70.0), and when re-combinant tissue factor was increased twen-ty times and synthetic phospholipids four times compared to normal values, lag time decreased further to 5.3 minutes (IQR: 3.2-47.0) and EPT increased from 0 nM*min to 650 nM*min (IQR: 0-1476)”

parameter, and the same was also at D7 and cc or CR (data not shown). The three patients who had a major bleeding at cc or cr had lower VWF-Ag, fibrinogen and platelet count than patients who did not bleed, but none of these parameters was reduced significantly.

Comparison of different anticoagulation moni-toring methods

at D0 the aPtt ratio was within the normal range in all patients, and no patient showed thrombophilia abnormalities. The mean APTT ratio during the study was 1.7 (IQR: 1.45-1.89) with 56% (40/71) of samples within and 20% (14/71) above the desired range, re-sulting in a mean time in therapeutic range of 76%. Median UH infusion rate was 15.2 IU/kg/h (IQR: 12.6-17.4). ACT and antifactor Xa activity were measured in 46 and 70 samples, respectively. ACT showed a mean of 176 sec (IQR 150-179) and a rate of samples within the desired range of 22% (10/46). Antifactor Xa activity showed a mean of 0.38 IU (IQR 0.23–0.52) and a rate of samples within the desired range of 57% (40/70). The correlation between APTT and ACT with antifactor Xa activity is shown in Figure 2. While APTT and antifactor Xa activity were significantly correlated (ρ 0.55, P<0.001), no correlation was observed between ACT and antifactor Xa activity (ρ -0.128, P=0.41). K-TEG showed a flat R at 80 min in 56% of samples (87/154).

Figure 2.—Correlation between APTT (panel a) or ACT (panel b) and antifactor Xa activity.a B



molecular-weight VWF multimers mimicking an acquired vW disease, as already reported in patients on ECMO.7, 8 Unfortunately, due to the low number of patients, we were unable to investigate if these coagulation changes played a role in the three major bleeding events ob-served in our study, and no conclusion can be drawn on their clinical relevance. Concerning monitoring the anticoagulant effect of UH, we observed a correlation between aPtt and antifactor Xa activity that measures the direct inhibition of UH on factor Xa and is therefore considered the gold standard to monitor UH anticoagulant effect. The suggested therapeutic range of aPtt 14 corresponded to that of anti-factor Xa activity in the majority of samples. At variance, the two point-of-care coagulation tests ACT and K-TEG, attractive alternatives to aPtt for their easy employment at patient’s bed and quick attainment of the results, as well as the most sophisticated thrombin genera-tion test, turned out unsuitable to monitor UH. ACT was successful in monitoring UH during extra-corporeal circulation for cardiopulmo-nary bypass,27 despite a limited range of ac-curacy 28 and the sensitivity to hemodilution, platelet dysfunction and temperature,29 but not in monitoring UH therapy in pediatric patients on ECMO.24, 30 Failure of K-TEG, that showed no fibrin nor clot formation for 80 min in more than half of the samples, can be explained by low platelet count but mainly by an oversensi-tivity of the test to UH concentration, because after addition of heparinase all measurements of K-TEG reverted to normal. A heparin-like effect 31 that may justify the prolonged r val-ues at K-TEG cannot be excluded and may have contributed to the high rate of flat-line TEG. Thrombin generation was totally inhib-ited, even at APTT or antifactor Xa values below the therapeutic range, indicating that thrombin generation tests when performed at low levels of tissue factor and phospholipids are too sensitive to the anticoagulant effect of UH. Nevertheless the correspondence between the high number of uncoagulable samples at global hemostatic tests (TEG and ETP) despite normal/low range of heparin infusion and an-tifactor Xa activity, and the high prevalence of

Discussion

ecMo support is increasingly used not only as a rescue therapy for acute respiratory distress syndrome, but also in other condi-tions determining acute respiratory failure. Unfortunately, patients on ECMO still have a high mortality rate due not only to the severe underlying respiratory disease and its related complications, but also to bleeding episodes. in our series of twelve patients seven died, one of them because of intracranial bleeding. The risk of bleeding may be increased by UH, that is necessarily given to patients on ecMo to prevent clot formation in the circuit. Except one study in the early 90’s 19 and a recent ret-rospective study 20 on d-dimer change in adults requiring veno-venous ECMO for ARDS, the majority of the studies investigating the co-agulation system during ecMo have been carried out in pediatric patients, who have an immature hemostatic system 21-25 and pe-culiarities on heparin pharmacodynamics.26 this pilot study investigated adult patients and aimed to answer the following questions: 1) is there a coagulation consumption in pa-tients during ECMO?; 2) does the circuit itself cause changes in coagulation tests?; 3) if any, are these coagulation changes responsible for bleeding episodes in patients on ecMo?; and 4) is the APTT an accurate test to monitor the anticoagulant effect of UH, compared to oth-er global coagulation tests? our study shows that the only parameter that changed signifi-cantly during ecMo, i.e., until the 7th day of the procedure or the day of circuit change or the day of circuit removal, was platelet count that decreased in all patients. However, only one patient (Pt. 10) had a very low platelet count (<30 *103/mmc,) refractory to platelets transfusion. This might be one of the causes of the bleeding diathesis in that patient Having excluded heparin-induced thrombocytopenia, the explanations of this finding may be the un-derlying infectious conditions, a consumption within the circuit and also a consumption mi-croangiopathy. The latter is surmised upon the observation of the decrease of ricof/vWF:ag ratio, possibly due to consumption of high-



Key messages

— the ecMo circuit is supposed to in-terfere with the coagulation system of pa-tients. In our study no difference in coagu-lation parameters was observed before and after the artificial lung during ECMO.

— Platelet count decreased significant-ly over the ECMO days.

— We compared different coagulation tests to monitor heparin therapy. The aPTT was the only test which correlated with antifactor Xa activity. Global coagulation assays such as thromboelastography and endogenous thrombin potential were too sensitive to be suitable to monitor the ef-fect of heparin during ECMO.

— Major bleeding occurred in 25% of the patients. We could not find a relation be-tween coagulation parameters and bleeding.

References

1. Peek GJ, Mugford M, Tiruvoipati R, Wilson A, Allen E, thalanany MM, et al. Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory fail-ure (CESAR): A multicentre randomised controlled trial. Lancet 2009;374:1351-63.

2. Brogan TV, Thiagarajan RR, Rycus PT, Bartlett RH, Bratton SL. Extracorporeal membrane oxygenation in adults with severe respiratory failure: A multi-center da-tabase. Intensive Care Med 2009;35:2105-14.

3. Oliver WC. Anticoagulation and coagulation manage-ment for ECMO. Semin Cardiothorac Vasc Anesth 2009;13:154-75.

4. Paden ML, Conrad SA, Rycus PT, Thiagarajan RR, ELSO Registry. Extracorporeal life support organization registry report 2012. ASAIO J 2013;59:202-10.

5. Davies A, Jones D, Bailey M, Beca J, Bellomo R, Black-well n, et al. Extracorporeal membrane oxygenation for 2009 influenza A (H1N1) acute respiratory distress syn-drome. JAMA 2009;302:1888-95.

6. Plötz FB, van Oeveren W, Bartlett RH, Wildevuur CR. Blood activation during neonatal extracorporeal life sup-port. J Thorac Cardiovasc Surg 1993;105:823-32.

7. Heilmann C, Geisen U, Beyersdorf F, Nakamura L, Benk c, trummer g, et al. Acquired von willebrand syndrome in patients with extracorporeal life support (ECLS). In-tensive Care Med 2012;38:62-8.

8. Tauber H, Ott H, Streif W, Weigel G, Loacker L, Fritz J, et al. Extracorporeal membrane oxygenation induces short-term loss of high-molecular-weight von willebrand factor multimers. Anesth Analg 2015;120:730-6.

9. Schulman S, Angerås U, Bergqvist D, Eriksson B, Lassen Mr, Fisher W, subcommittee on control of anticoagula-tion of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemosta-

severe bleeding (25%), let us hypothesize that a further reduction of the dosage of heparin guided by global hemostatic tests could be a line of research.

several limitations of this study need to be addressed. First, we performed a pooled analy-sis of a dozen patients with different clinical characteristics and disease severity. Second, the descriptive nature of our study and the small number of investigated patients makes diffi-cult to distinguish the effects of ecMo from those of the underlying disease on coagulation and does not allow definite considerations. For example, measurements pre- and post-lung were restricted to coagulation parameters and platelet count was not performed. Although no effect of ecMo on the former was observed, a selected platelet consumption by the circuit, although unlikely, cannot be ruled out. Third, whether or not the increase in D-dimer levels is a good parameter for the decision to change the circuit remains uncertain. Fourth, some pa-tients received fresh frozen plasma and plate-lets transfusions that might have influenced the concentration of coagulation factors and tests. Finally, no association between coagula-tion parameters and the risk of bleeding was observed in our series of patients but again, the small sample size is a major limitation. We can speculate that the aPtt therapeutic range, de-spite its acceptable correlation with antifactor Xa activity, should be lowered as already sug-gested by others.32 Moreover platelet function is impaired in patients with infections,33 but it has not been investigated in this study.

Conclusions

During ecMo initiated for acute respira-tory failure coagulation tests do not change but platelet count decreases. The APTT used to monitor UH anticoagulation showed a sat-isfactory correlation with the antifactor Xa ac-tivity, whereas other global coagulation tests did not. However, the clinical relevance of these observations on the risk of bleeding in patients on ecMo as well as a decrease of the aPtt therapeutical range remain to be evalu-ated in further investigations.



to heparin in adult but not in infant cardiac-surgical pa-tients. Anesth Analg 2001;92:66-71.

22. Urlesberger B, Zobel G, Zenz W, Kuttnig-Haim M, Mau-rer U, Reiterer F, et al. Activation of the clotting system during extracorporeal membrane oxygenation in term newborn infants. J Pediatr 1996;129:264-8.

23. Hundalani SG, Nguyen KT, Soundar E, Kostousov V, Bomgaars l, Moise a, et al. Age-Based difference in activation markers of coagulation and fibrinolysis in ex-tracorporeal membrane oxygenation. Pediatr Crit Care Med nguyen Kt, soundar e, Kostousov v, Bomgaars l, Moise A.

24. Bembea MM, Schwartz JM, Shah N, Colantuoni E, Leh-mann CU, Kickler T, et al. Anticoagulation monitoring during pediatric extracorporeal membrane oxygenation. ASAIO J 2013;59:63-8.

25. Arnold P, Jackson S, Wallis J, Smith J, Bolton D, Haynes S. Coagulation factor activity during neonatal extra-corporeal membrane oxygenation. Intensive Care Med 2001;27:1395-400.

26. Green TP, Isham-Schopf B, Irmiter RJ, Smith C, Uden DL, Steinhorn RH. Inactivation of heparin during ex-tracorporeal circulation in infants. Clin Pharmacol Ther 1990;48:148-54.

27. Young JA, Kisker CT, Doty DB. Adequate anticoagula-tion during cardiopulmonary bypass determined by ac-tivated clotting time and the appearance of fibrin mono-mer. Ann Thorac Surg 1978;26:231-40.

28. Despotis GJ, Summerfield AL, Joist JH, Goodnough LT, santoro sa, spitznagel e, et al. Comparison of activated coagulation time and whole blood heparin measurements with laboratory plasma anti-xa heparin concentration in patients having cardiac operations. J Thorac Cardiovasc Surg 1994;108:1076-82.

29. Martindale SJ, Shayevitz JR, D’Errico C. The activated coagulation time: suitability for monitoring heparin ef-fect and neutralization during pediatric cardiac surgery. J Cardiothorac Vasc Anesth 1996;10:458-63.

30. Liveris A, Bello RA, Friedmann P, Duffy MA, Manwani D, Killinger Js, et al. Antifactor xa assay is a superior correlate of heparin dose than activated partial thrombo-plastin time or activated clotting time in pediatric extra-corporeal membrane oxygenation. Pediatr Crit Care Med 2014;15:e72-9.

31. Ranucci M, Baryshnikova E, Isgrò G, Carlucci C, Cotza M, Carboni G, Ballotta A. Heparin-like effect in postcar-diotomy extracorporeal membrane oxygenation patients. Crit Care 2014;18:504.

32. Combes A, Bacchetta M, Brodie D, Müller T, Pellegrino V. Extracorporeal membrane oxygenation for respiratory failure in adults. Curr Opin Crit Care 2012;18:99-104.

33. Protti A, Fortunato F, Caspani ML, Pluderi M, Lucchini v, grimoldi n, et al. Mitochondrial changes in platelets are not related to those in skeletal muscle during human septic shock. PLoS One 2014;9:e96205.

sis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in surgical patients. J Thromb Haemost 2010;8:202-4.

10. Napolitano LM, Warkentin TE, Almahameed A, Nasra-way SA. Heparin-induced thrombocytopenia in the criti-cal care setting: Diagnosis and management. Crit Care Med 2006;34:2898-911.

11. Lane DA, Mannucci PM, Bauer KA, Bertina RM, Bo-chkov NP, Boulyjenkov V, et al. Inherited thrombophilia: Part 1. Thromb Haemost 1996;76:651-62.

12. Arkel YS, Paidas MJ, Ku DH. The use of coagulation acti-vation markers (soluble fibrin polymer, tpp, prothrombin fragment 1.2, thrombin-antithrombin, and d-dimer) in the assessment of hypercoagulability in patients with inher-ited and acquired prothrombotic disorders. Blood Coagul Fibrinolysis 2002;13:199-205.

13. Federici AB, Canciani MT, Forza I, Mannucci PM, Marchese P, Ware J, Ruggeri ZM. A sensitive ristocetin co-factor activity assay with recombinant glycoprotein ibalpha for the diagnosis of patients with low von wil-lebrand factor levels. Haematologica 2004;89:77-85.

14. ELSO guidelines for cardiopulmonary extracorporeal life support. Extracorporeal life support organization, version 1.3 november 2013; [Internet]. Available at: Http://Http://www.elsonet.org/index.php?Option=com_phocadownload&view=category&download=17:elso-guidelines-generalv11&id=4:guidelines&itemid=627 [cited 2014, Jun 4].

15. Rosendaal FR, Cannegieter SC, van der Meer FJ, Briët E. A method to determine the optimal intensity of oral anticoagulant therapy. Thromb Haemost 1993;69:236- 9.

16. Garcia DA, Baglin TP, Weitz JI, Samama MM, American College of Chest Physicians. Parenteral anticoagulants: antithrombotic therapy and prevention of thrombosis, 9th ed: American college of chest physicians evidence-based clinical practice guidelines. Chest 2012;141(2 Suppl):e24S-43S.

17. Bull MH, Huse WM, Bull BS. Evaluation of tests used to monitor heparin therapy during extracorporeal circula-tion. Anesthesiology 1975;43:346-53.

18. Hemker HC, Giesen P, Al Dieri R, Regnault V, de Smedt e, Wagenvoord r, et al. Calibrated automated thrombin generation measurement in clotting plasma. Pathophysiol Haemost Thromb 2003;33:4-15.

19. Uziel L, Cugno M, Fabrizi I, Pesenti A, Gattinoni L, Agostoni A. Physiopathology and management of coagu-lation during long-term extracorporeal respiratory assist-ance. Int J Artif Organs 1990;13:280-7.

20. Lubnow M, Philipp A, Dornia C, Schroll S, Bein T, creutzenberg M, et al. D-dimers as an early marker for oxygenator exchange in extracorporeal membrane oxy-genation. J Crit Care 2014;29:473.e1-5.

21. Dietrich W, Braun S, Spannagl M, Richter JA. Low pre-operative antithrombin activity causes reduced response

Conflicts of interest.—The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript.Article first published online:May 20, 2015. - Manuscript accepted: May 18, 2015. - Manuscript revised: May 4, 2015. - Manuscript received: January 29, 2015.


the atmosphere and subsequent impact on the global ecosystem.2 reducing gas consumption also reduces costs.3 FgF of 0.5 and 1 l/min are reasonably safe. the potential risk for a hypoxic gas mixture must be acknowledged. Desflurane and sevoflurane differ in blood and tissue solubility.4 The benefits of low blood and tissue solubility during fixed low-flow an-esthesia have not been well-studied yet. It is not well documented whether the theoretical benefits of the lower 0.42 blood gas solubility for desflurane translate into clinical benefits in

the low blood gas solubility of desflurane and sevoflurane makes them attractive

for general anesthesia with low fresh gas flow (FgF).1 their physiochemical properties do in theory enable a rapid wash-in/equilibra-tion while using low FgFs. reducing FgF has many benefits. The total amount of an-esthetics vaporized is reduced, and thus the risk for unnecessary work place contamina-tion is reduced, as is the amount released into


Desflurane and sevoflurane use during low- and minimal-flow anesthesia at fixed vaporizer settings

Maria HORWITZ, Jan G. JAKOBSSON *

Department of Anesthesia and Intensive Care, Institution for Clinical Sciences, Karolinska Institutet, Danderyds, University Hospital, Stockholm, Sweden*Corresponding author: Jan G. Jakobsson, Department of Anesthesia, Danderyds Hospital, 182 88 Stockholm, Sweden. E-mail: [email protected]


Lavoro: titolo breve: WASH-IN DURING LOW FLOWprimo autore: HORWITZpagine: 180-5citazione: Minerva Anestesiol 2016;82:180-5

A B S T R A C TBACKGROUND: The pharmacokinetics for sevoflurane and desflurane makes them suitable for low-flow anesthesia. The aim of the present study was to assess the use of desflurane and sevoflurane at constant vaporizer settings and fixed low fresh gas flows.METHODS: One hundred ASA 1-2 patients undergoing elective laparoscopic surgery were randomized into 4 groups (25 patients each): a fixed fresh gas flow 1.0 or 0.5 L/min with desflurane (D1.0 and D0.5) or sevoflurane (S1.0 and S0.5) throughout anesthesia. A fixed vaporizer setting, sevoflurane 6% and desflurane 18% was used during wash-in. Time to reach 1 and 1.5 minimum alveolar concentration (MAC), emergence and gas consumption from start to end of surgery was studied.RESULTS: Time to reach 1 MAC age adjusted desflurane or sevoflurane was D0.5 8.5±1.7, D1.0 3.7±0.7, S0.5 15.2±2.4 and S1.0 6.2±1.3 minutes, respectively (P<0.001), and times to increase from 1 to 1.5 MAC differed also significantly. Desflurane anesthesia was associated to significantly shorter time to extubation 6.7±2.3 vs. 10±2.3 minutes for sevoflu-rane (P<0.001). The amount of agent consumed g/min. was significantly reduced for both 0.5 L/min groups: 30% less for desflurane and 19% for sevoflurane.CONCLUSIONS: We found an almost twice as rapid wash-in with desflurane and expectedly faster emergence. Gas con-sumption was lower at 0.5 L/min than it was at 1 L/min for both gases studied however most pronounced for desflurane. Desflurane has clear advantages for minimal fresh gas flow anesthesia.(Cite this article as: Horwitz M, Jakobsson JG. Desflurane and sevoflurane use during low- and minimal-flow anesthesia at fixed vaporizer settings. Minerva Anestesiol 2016;82:180-5)Key words: General anesthesia - Inhalation anesthesia - Desflurane - Sevoflurane.


Comment in p. 149.


WASH-IN DURING LOW FLOW HorWitZ


the operating theatre. Randomization was done by envelope technique created from 4 random lists. Patients were randomized to receive ei-ther desflurane or sevoflurane to maintain an-esthesia with one of the two fixed FGF; 0.5 l/min or 1 l/min FgF both with an inspired fraction (Fio2) 0.5 oxygen in air throughout anesthesia.

Apart from the randomized gas and FGF, all patients followed departmental routines. all patients received an intravenous access, 1000 ml ringer acetate and were induced with pro-pofol (2.5 mg/kg) and remifentanil (0.5 µg/kg/min). intubation of the trachea was performed following 3 minutes preoxygenation with an Fio2 0.8. Rocuronium 0.4-0.5 mg/kg was used for muscle relaxation. all patients were anesthetized using an Aisys Care Station (GE Healthcare, Madison, WI, USA). After start of surgery, remifentanil was titrated according to clinical needs.

no inhaled aesthetic agent was administered during induction and intubation. the FgF was adjusted in accordance to randomization fol-lowing intubation of the trachea. The vapor-izer was set at 18% or 6% for desflurane or sevoflurane, respectively, after the patient was properly intubated and airway secured. addi-tional 20 mg boluses of propofol were admin-istered if any signs of insufficient anesthesia were noticed.

Mechanical ventilation was used to main-tain EtCO2 with 6-7 mL/kg tidal volume and kept constant during wash-in. Ventilation was further adjusted to maintain an EtCO2 of 4.5-5.3 kPa with a respiratory rate of 14-16 breaths per minute.

Within each of the four groups, we recorded the time from opening the vaporizer until the end-tidal aesthetic gas concentration reached 1 and 1.5 MAC. The Et MAC values were age adjusted according to the algorithm within the Aisys monitoring equipment. Once the end-expired concentration of the inhaled agent was 1.5 MAC, based upon the age corrected MAC display of the Aisys, the vaporizer was adjust to maintain 0.8 Mac during surgery.

Maintenance of anesthesia was adjusted in accordance to clinical needs by the attend-

clinical practice during low-flow anesthesia. In 2008 Hendrickx and De Wolf published an ex-tensive review of the pharmacokinetics of in-haled anesthetics and their use with low FgF.5 they state that the kinetics can be assessed using routine monitoring, dialed, inhaled and end-tidal (Et) gas concentration, and that the focus should be shifted to “what combination of delivered concentration and fresh gas flow (FGF) can be used to attain the desired al-veolar concentration.” However, it should be acknowledged that, when a desired end-tidal concentration is maintained with a FgF that is lower than minute ventilation, re-breathing will dilute the circle gas concentration and cre-ate a discrepancy between the dialed and the concentration delivered by the anesthesia ma-chine.3 the discrepancy between dialed and inspired gas concentration is not uncommonly assessed as “lack of control” and is one reason why some anesthesiologists increases the FgF to ensure that the delivered gas matches the inspired concentration. The wash-in time, the time to reach an et gas concentration is impor-tant to assure adequacy of anesthesia. Differ-ences in pharmacology and FgF are the main determinants for the wash-in time to reach a defined Et.

the focus of the present study is to study the wash-in times to, the time to reach 1 and 1.5 minimum alveolar concentration (MAC) con-centrations at 1 and 0.5 l/min constant FgF at fixed vaporizer settings and comparing desflu-rane and sevoflurane.


This study (No. 2013/2:7) was approved by the Ethical Review Board on August 15th, 2013 (chairperson: Ulla Eriksson; EudraCT No. 2012-004852-13).

One-hundred ASA 1-2 patients aged 20-65 years scheduled for elective laparoscopic sur-gery under general anesthesia were recruited. Patients with chronic obstructive pulmonary disease (COPD) or other lung or cardiovascu-lar pathology that could possibly compromise wash-in were excluded.

Patients were randomized before entering

HorWitZ WASH-IN DURING LOW FLOW


subjects was based on a power analysis for gas consumption found in a previous study.6 the sample size, 25 patients in each group, was calculated in order to detect a difference in sevoflurane consumption of 50% with a stan-dard deviation (SD) of ±4 mL, using an alpha level of 0.05 and a power of 0.80. Compari-sons of normally distributed variables were by student’s t-test and ANOVA. Variables not fol-lowing a normal distribution were compared by Wilcoxon test.

Results

One hundred patients were randomized, one patient was lost for technical reasons. Thus, 99 patients (67 female and 32 male, 68 ASA 1 and 31 ASA 2, mean age 46±12 years) were included in the analysis of the primary and sec-ondary endpoints. there were no differences in patient characteristics, surgery or duration of anesthesia between the four groups studied (Table I). Induction, wash-in and maintenance of anesthesia were all uneventful, and no com-plications of serious adverse events were no-ticed.

The average time from opening the vapor-izer until an age adjusted 1 MAC end-tidal gas concentration was reached for all 4 groups was 8.4±4.6 minutes. The mean time for in-creasing the end tidal concentration from 1 to 1.5 MAC was 9.0±6.2 minutes for all 4 groups studied. the times to reach 1 Mac was signif-icantly faster for desflurane (P<0.01) as com-pared to sevoflurane both at 1 and 0.5 L/min. the time to increase 0.5 Mac from 1 Mac to 1.5 Mac was marginally shorter than the time needed to go from 0 to 1 MAC for desflurane and slightly longer than time needed to go from 0 to 1 EtMAC for sevoflurane. The time

ing anesthesiologist, a 0.8 MAC Et anesthetic agent (etaa) was kept throughout surgery and remifentanil was added to maintain appropri-ate heart rate, blood pressure and other clinical signs. Muscle relaxation was monitored with train-of-four.

agent administration was discontinued at end of surgery. the FgF was increased to 4 l/min oxygen and 2 l/min air when the last stitch was made. Time events; time to extuba-tion, ability to state name and date of birth and to discharge from the PACU were recorded.

the aladin cassette was weighed before and after each patient on a precise scale and gram inhaled anesthesia per minute (g/min) anesthe-sia was calculated.

All patients received PONV prophylaxis in accordance to departmental routines: 8 mg be-tamethasone, 0.625 mg droperidol and 4 mg odansetron iv.

The primary study end-point was aver-age time from opening the vaporizer until an Et of 1 MAC sevoflurane and desflurane was reached and subsequently the time between 1 and 1.5 MAC Etaa for sevoflurane and desflu-rane, respectively.

Secondary end-points were average set con-centration needed to maintain a etaa of 0.8 MAC for sevoflurane and desflurane, respec-tively, during maintenance and gas consump-tion g/min from opening the vaporizer until closing. the FgF was kept constant in ac-cordance to randomization from opening the vaporizer until end of surgery and closing the vaporizer.


Data is presented as mean and standard de-viation unless otherwise stated. The number of

Table I.—�Patients’ demographics.age

(years) BMI asa 1/2(n.)

gender F/M(n.)

Duration of anesthesia(min)

Desflurane 0.5 L/min (N.=25) 46±12 26±2 11/14 17/8 78±21Desflurane 1.0 L/min (N.=25) 42±11 25±3 21/4 12/13 78±19Sevoflurane 0.5 L/min (N.=25) 40±14 25±3 19/5 17/7 73±27Sevoflurane 1.0 L/min (N.=25) 43±11 25±3 21/4 17/8 78±28Not significant for P>0.5.



Discussion

The hypothesis that desflurane is associated to a more rapid wash-in compared to sevoflu-rane under fixed FGF and fixed 6% sevoflurane or 18% desflurane vaporizer settings was veri-fied. The time to increase from 1 to 1.5 MAC was also almost twice as fast for desflurane. The time needed to increase 0.5 MAC, from 1 to 1.5 MAC was however almost as long as for the initial 0 to 1 Mac. the time needed for sevoflurane to increase from 1 to 1.5 was actually even longer than the 1 MAC from 0 to 1 MAC. The time for wash-in with the setting of our protocol makes sevoflurane use a none appropriate option. The positive effect of low flow on gas consumption was also verified and interesting the reduction in gas consumed was more pronounced for desflurane as compared to sevoflurane. We did also find a faster emer-gence for desflurane than for sevoflurane.

Desflurane has lower blood gas solubility as compared to sevoflurane and thus our results are expected, in line with theory.7 We still be-lieve that confirming theory with clinical stud-ies is of value.1-5 our protocol may be consid-ered “not fully clinical”, although we aimed at keeping as many factors as possible constant in order to evaluate the independent impact of the inhaled agent’s physiochemical properties and the FGF. Desflurane was associated to a

needed to increase etaa from 1 to 1.5 Mac was however significantly faster for desflu-rane as compared to sevoflurane at both FGFs studied (P<0.01). The wash-in times were sig-nificantly increased for both desflurane and sevoflurane reducing the fixed flow rate from 1 to 0.5 l/min (table ii).

Duration of anesthesia was 77±24 min-utes with no difference between the 4 groups (table i). time from cessation of gas admin-istration until extubation and open eye was 8.4±2.8 and 8.6±2.8 minutes, respectively. Desflurane anesthesia was associated to sig-nificantly shorter time to extubation and eye opening compared to sevoflurane at both FGF studied (P<0.001). Awakening characteristics are shown in table iii.

gas consumption (g/min) was lower using 0.5 L/min gas flow. The consumption was in average 29% less for desflurane 0.44±0.06 and 0.62±0.06 and g/min for the 0.5 and 1.0 L/min respectively (P<0.001). The sevoflurane con-sumption was reduced 0.5 vs. 1 L/min 19%; 0.22±0.05 and 0.27±0.04 g/min (P<0.002). The vaporizer set concentrations to maintain an end-expired concentration corresponding to 0.8 age adjusted MAC during maintenance in-creased with the 0.5 L/min flow from mean 5.6 to 6.2 for desflurane and 2.2 to 2.4 for sevo-flurane.

Table II.—�Time to 1 MAC desflurane or sevoflurane and further between 1 and 1.5 MAC desflurane or sevoflurane gas concentrations during wash-in at fixed fresh gas and vaporizer settings.

Time 0-1 MAC(min)

Time 1-1.5 MAC(min)

Desflurane 0.5 L/min (N.=25) 8.5±1.7* 8.3±2.1*Sevoflurane 0.5 L/min (N.=24) 15.2±2.4 19±4.4Desflurane 1.0 L/min (N.=25) 3.7±0.7* 3.2±1.2*Sevoflurane 1.0 L/min (N.=25) 6.2±1.3 7.5±2.5* P<0.01 desflurane vs. sevoflurane, and fresh gas flow 0.5 vs. 1.0 L/min for respective gas.

Table III.—�Perioperative observations; duration of anesthesia, time to extubation, eye opening and time to dis-charge from recovery room.

Duration of anesthesia(min)

extubation(min)

eye opening(min)

time to discharge from PACU

(min)

Desflurane (N.=50) 78±20 6.7±2.3* 6.9±1.9* 213±86Sevoflurane (N.=49) 73±27 10±2.3 10.3±2.6 238±71* P<0.01 desflurane vs. sevoflurane.

HorWitZ WASH-IN DURING LOW FLOW


FgF throughout anesthesia. We did not use any step-wise decrease but started at the set one or half a liter per minute FgF rates from wash-in until end of surgery and closing the vaporizer. There are several other physiologi-cal aspects that need to be considered for the assessment of target organ effect, e.g. cardiac output, and shunt, especially in elderly patients with potentially compromised cardiovascular reserves.13 lokoff and lokoff 14 showed a re-duced inhaled anesthetic consumption follow-ing the introduction of a new device including Et control and start of low-flow anesthesia in a clinical observational study. We did not in-clude any Et target control but adjusted fresh gas and vaporizer setting manually. We used a fixed 6% and 18% vaporizer setting during induction. It is on most vaporizers possible to increase the sevoflurane dialed concentra-tion to eight to facilitate wash-in. However, our aim was to study equal Mac multiples using as standardized anesthetic procedures as possible. MAC is age-dependent and we used the age algorithm in the aisys care sta-tion for the primary end point 1 and 1.5 MAC, respectively. The set vaporizer concentration was however not compensated for age, but set at 6% and 18% for sevoflurane and desflu-rane, respectively. There is a potential risk for sympathetic stimulation with a steep increase in inhaled desflurane concentration. The high 18% dialled desflurane should be used only with a low fresh gas flow and proper opioid co-induction.15 Sevoflurane was in this study used at a FGF of 0.5 or 1 L/min, lower than what is recommended in the Us. there are dif-ferent recommendations for minimal FgF to be used during sevoflurane anesthesia due to the risk for Compound-A formation/accumu-lation. The use of newer soda products have been shown to eliminate the Compound-A production also at lower, e.g. half a litre per minute FgF.16, 17 There is currently no fresh-gas flow rate limitation in the EU. The risk for a hypoxic gas mixture must be acknowledged when low fresh gas flows are used and moni-toring of the Fio2 is essential.

In conclusion, the presents study confirms basic inhaled anesthetic theory. Desflurane’s

rapid wash-in. We are however unable to pro-mote the technique used for induction of an-esthesia. Desflurane may cause air way irrita-tion during induction with face mask or other supraglottic airway devices.8 We did introduce gases first when airway was secured. The time to reach MAC was found to be significantly faster with desflurane and time different of seemingly clear clinical importance. the time needed to increase et concentration differed for different phases of wash-in. We noticed that the time required for increasing from 1 to 1.5 Mac was more or less equal to the time needed to go from 0 to 1 Mac. We are not aware of any clinical studies that have previ-ously documented these differences in expo-nential uptake.

Low flow is indeed associated with numer-ous beneficial effects.3 Low flow is associated with better preservation of airway moisture, less heat loss and reduced gas consumption, waste and cost. the decrease in gas consump-tion is also what would be expected.9 gas con-sumption was calculated as grams of anesthet-ic liquid consumed from opening the vaporizer until end of surgery and anesthesia. thus the wash-in period is also included in the gram per minute gas consumption calculation. We found a more pronounced gas sparing effect for des-flurane. This may to some extent be associated with the more rapid wash-in.

there was a degree of “lack of control” for both agents with a more pronounced discrep-ancy at the half-a-liter flow rate. The vaporizer setting must be adjusted based on the gas mon-itoring as the vaporizer set number is not re-flected in the circle.10 the gas was set at an et concentration of 0.8 Mac throughout surgery and anesthetic depth was titrated only by ad-justing the remifentanil. Adjusting depth of an-esthesia by the use of an EEG-parameter such as the auditory evoked response index increas-ing the Et when need has been shown improv-ing recovery.11 We found still desflurane to be associated to a more rapid emergence well in line with modelling done by Dexter et al.12

There are several limitations that must be acknowledged. the study protocol had strict inclusion and exclusion criteria, and a fixed



bsson J. Brief review: theory and practice of minimal fresh gas flow anesthesia. Can J Anaesth 2012;59:785-97.

4. Soares JH, Brosnan RJ, Fukushima FB, Hodges J, Liu H. solubility of haloether anesthetics in human and animal blood. Anesthesiology 2012;117:48-55.

5. Hendrickx JF, De Wolf A. Special aspects of pharmaco-kinetics of inhalation anesthesia. Handb Exp Pharmacol 2008;(182):159-86.

6. Jakobsson I, Heidvall M, Davidson S. The sevoflurane-sparing effect of nitrous oxide: a clinical study. Acta An-aesthesiol Scand 1999;43:411-4.

7. Jakobsson J. Desflurane: a clinical update of a third-generation inhaled anaesthetic. acta anaesthesiol scand 2012;56:420-32.

8. Oofuvong M, Geater AF, Chongsuvivatwong V, Pattara-vit N, Nuanjun K. Risk over time and risk factors of in-traoperative respiratory events: a historical cohort study of 14,153 children. BMC Anesthesiol 2014;14:13.

9. Ekbom K, Assareh H, Anderson RE, Jakobsson JG. The effects of fresh gas flow on the amount of sevoflurane va-porized during 1 minimum alveolar concentration anaes-thesia for day surgery: a clinical study. Acta Anaesthesiol Scand 2007;51:290-3.

10. Leelanukrom R, Tuchinda L, Jiamvorakul P, Koomwong A. Desflurane concentrations and consumptions during low flow anesthesia. J Med Assoc Thai 2014;97:64-70.

11. Jildenstål PK, Hallén JL, Rawal N, Gupta A, Berggren L. Effect of auditory evoked potential-guided anaesthesia on consumption of anaesthetics and early postoperative cognitive dysfunction: a randomised controlled trial. Eur J Anaesthesiol 2011;28:213-9.

12. Dexter F, Bayman EO, Epstein RH. Statistical modeling of average and variability of time to extubation for meta-analysis comparing desflurane to sevoflurane. Anesth Analg 2010;110:570-80.

13. Van Zundert T, Hendrickx J, Brebels A, De Cooman S, Gatt S, De Wolf A. Effect of the mode of administration of inhaled anaesthetics on the interpretation of the F(a)/F(I) curve--a GasMan simulation. Anaesth Intensive Care 2010;38:76-81.

14. Lokoff A, Lokoff P. Volatile gas consumption after intro-duction of the Dräger Zeus® anesthesia machine. Can J Anaesth 2014;61:680-1.

15. Weiskopf RB, Eger EI 2nd, Noorani M, Daniel M. Fen-tanyl, esmolol, and clonidine blunt the transient cardio-vascular stimulation induced by desflurane in humans. Anesthesiology 1994;81:1350-5.

16. Di Filippo A, Marini F, Pacenti M, Dugheri S, Focardi L, Novelli GP. Sevoflurane low-flow anaesthesia: best strategy to reduce compound a concentration. acta an-aesthesiol Scand 2002;46:1017-20.

17. Marini F, Bellugi I, Gambi D, Pacenti M, Dugheri S, Fo-cardi L, et al. formaldehyde and methanol concentrations during low-flow sevoflurane anaesthesia: comparison of three carbon dioxide absorbers. acta anaesthesiol scand 2007;51:625-32.

lower blood and tissue solubility was found to be associated with a significantly faster wash-in during fixed low FGF general anesthesia as compared to sevoflurane. The time needed to increase from zero to 1 MAC is lower as com-pared to that for a further increase of et gas concentration from 1 to 1.5 Mac. emergence was also as expected more rapid following desflurane anesthesia. The gas sparing effect reducing flow from 1 to 0.5 L/min was higher for desflurane than for sevoflurane.

Key messages

— Desflurane’s wash-in is almost twice as fast as sevoflurane at fixed vaporizer 18% and 6% settings during fixed minimal (0.5 or 1 L/min) fresh gas flow.

— A fixed 1 L/min fresh gas flow and a vaporizer setting of 18% provide a one Mac within 4 minutes.

— Reducing flow from 1 to a 0.5 L/min provides a 30% reduction in desflurane gas consumption.

— Desflurane’s low blood gas solubil-ity is associated not only with favorable wash-in but also with faster emergence as compared to sevoflurane during routine low-flow anesthesia.

References

1. Hendrickx JF, Lemmens H, De Cooman S, Van Zundert AA, Grouls RE, Mortier E, et al. Mathematical method to build an empirical model for inhaled anesthetic agent wash-in. BMC Anesthesiol 2011;11:13.

2. Ishizawa Y. Special article: general anesthetic gases and the global environment. Anesth Analg 2011;112:213-7.

3. Brattwall M, Warrén-Stomberg M, Hesselvik F, Jako-

Funding.—This stady has been supported by a grant from Baxter Healthcare Corporation.Conflicts of interest.—Jan Jakobsson has received grants from Baxter, Abbott, MundiPharma and PhaseIn. He is a lecturer for and is on the advisory board of Baxter, Linde, Pfizer and Nycomed, and is a consultant for Linde. Maria Horwitz has no conflicts of interest to disclose regarding the material discussed in this paper.Article first published online: July 22, 2015. - Manuscript accepted: July 20, 2015. - Manuscript revised: July 16, 2015. - Manuscript received: March 31, 2015.


space.4, 5 Hypertonic saline (Hs) reduces icP, but unlike mannitol, has been associated with increases mean arterial pressure (MaP) and central venous pressure (cvP), as well as benefits on vasoregulation, immune response and neurotransmission.4 the Brain trauma Foundation lists mannitol as a level 2 recom-mendation of for treating ICHT in patients with traumatic brain injury (tBi).5 Mannitol may also increase cerebral perfusion (cPP)

intracranial hypertension (icHt) associ-ated with various disease states,1 can lead

to cerebral ischemia and brain herniation with major neurologic disability, or death.2 Osmotic agents remain an important thera-peutic option for increased intra-cranial pres-sure (icP).3 by creating an osmotic gradient between the intravascular and the intersti-tial/cellular fluids at the blood brain barrier that shifts fluids towards the intravascular


treatment of intraparenchymal hypertension with hyperosmotic therapy: hypertonic

saline 7.45% vs. mannitol 20%Carlos A. SANTACRUZ, Daniel DE BACKER, Fabio S. TACCONE, Fuhong SU

Diego ORBEGOZO-CORTES, Koji HOSOKAWA, Katia DONADELLO, Jean-Louis VINCENT *

Department of Intensive Care, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium*Corresponding author: Jean-Louis Vincent, Department of Intensive Care, Hôpital Erasme, Université Libre de Bruxelles (ULB), Route de Lennik 808, 1070 Brussels, Belgium. E-mail: [email protected]

anno: 2016Mese: Februaryvolume: 82no: 2Rivista: Minerva Anestesiologicacod rivista: Minerva anestesiol

lavoro: titolo breve: osMotic tHeraPY eFFects on cereBral oXYgenation anD MetaBolisMprimo autore: santacrUZpagine: 186-95citazione: Minerva Anestesiol 2016;82:186-95

a B s t r a c tBacKgroUnD: there is controversy about the superiority of hypertonic saline (Hs) over mannitol (M) to treat in-tracranial hypertension (ICHT). We aim to compare the effects of HS 7.45% vs. M 20% on systemic hemodynamics, intracranial pressure (ICP) and brain regional metabolism or oxygenation during experimental ICHT.METHODS: In 16 sedated and mechanically-ventilated pigs, ICHT was obtained by inflation of a balloon catheter insert-ed in the right frontal lobe. Ventilation was set to maintain normoxia and normocapnia. Mean arterial pressure was main-tained above 80 mmHg by IV isotonic fluids. Animals were randomized to receive a 30-minute IV load of 255 mOsm/dose of either HS 7.45% (N.=7) or M 20% (N.=7). Brain oxygen tension (PbO2) was measured hourly by a parenchymal Clark electrode and cerebral lactate/pyruvate ratio (LPR) was assessed using brain microdialysis. A linear mixed model was used to analyze the time course of considered variables from baseline to 180 minutes after infusion.RESULTS: There was no significant difference in systemic hemodynamics between the two groups over the study period. HS 7.45% administration maintained a lower ICP and a higher cerebral perfusion pressure at 180 minutes, but with no significant difference in PbO2 or lPr.CONCLUSIONS: In this model of ICHT, only small differences were found in maintaining a better cerebral perfusion using HS 7.45% compared to M 20% in the early phase of therapy. These differences were not dependent on changes in systemic hemodynamics and did not result in significant differences in brain regional oxygenation or metabolism.(Cite this article as: Santacruz CA, De Backer D, Taccone FS, Su F, Orbegozo-Cortes D, Hosokawa K, Donadello K, Vincent J-L. Treatment of intraparenchymal hypertension with hyperosmotic therapy: hypertonic saline 7.45% vs. mannitol 20%. Minerva Anestesiol 2016;82:186-95)Key words: Osmotic therapy - Intracranial hypertension - Oxygenation - Metabolism.

Minerva Anestesiologica 2016 February;82 (2):186-95© 2016 eDiZioni Minerva MeDicathe online version of this article is located at http://www.minervamedica.it

osMotic tHeraPY eFFects on cereBral oXYgenation anD MetaBolisM santacrUZ



Animal use

the university ethical committee approved the protocol (no. 447n), which was developed in adherence to local guidelines on the use of laboratory animals. We used the ARRIVE guidelines for Animal Research: Reporting In-Vivo experiments.10 Assuming a type I error of 5% and confidence level of 95%, a sample of 14 pigs (7 pigs per group) was needed to detect a 2-mmHg difference in ICP between the two osmotic agents. This threshold was selected according to recent studies and meta-analysis comparing HS and mannitol in the treatment of elevated icP.11-14 two additional animals were included as sham. Sham surgery was defined as all surgical procedures, except balloon inflation (Figure 1). All experiments were performed during daytime at specialized surgery theaters for animals at a constant room temperature of 20-22 °C. We used domestic crossbreed pigs (Petrai and Topix, 35-45 kg) obtained from a local farm and brought in the

by reducing blood viscosity and red blood cell rheology.6 However, it is associated with an increased risk of hypovolemia and osmot-ic tubular renal injury.

in previous animal models the effectiveness of mannitol and Hs to reduce icHt was com-pared.7-9 Hs was associated with a more sus-tained reduction in ICP, and greater increase cPP, cvP and MaP. However, these trials are limited by the few data available on the effects of such therapies on brain flow and metabo-lism. thus, we hypothesized that if an osmotic agent was to be superior it had to reduce not only ICP but also improve tissue oxygenation, increased tissue perfusion and reduce anaero-bic metabolism. our main objective was then to evaluate, in an experimental porcine model of icHt secondary to focal intra-parenchymal neurologic injury, the effects of different hy-perosmotic solutions on icP, brain metabo-lism, oxygenation and regional flow. Second-ary outcomes were the effects on systemic perfusion (MaP; cardiac output and serum lactate).

Figure 1.—Flow diagram for inclusion and randomization of animals included in the experiment.

santacrUZ osMotic tHeraPY eFFects on cereBral oXYgenation anD MetaBolisM


renchymal balloon (Foley bladder catheter, 14 F, Beiersdorf ag), respectively. icP catheter was inserted just below the dura mater. the active tip of the catheter lied in the frontal white matter. Since brain oxygenation (PbO2) catheters senses partial pressure of oxygen in a 13-mm tissue cylinder around the active tip, distance between multimodal neurological monitoring catheters and the limit at maxi-mal balloon inflation was measured to keep a maximal distance of 1.3 cm. the dura mater was then punctured to insert a microdialysis (MD) catheter (cMa 20, cut-off membrane 20 kDa, membrane length 10 mm, CMA Mi-crodialysis aB, solna, sweden), a clark elec-trode (Licox catheter, Integra Lifesciences, Zaventem, Belgium) for PbO2 measurement, an ICP monitoring (Camino® icP catheter and monitor, Integra Life Sciences) and a laser Doppler flowmetry (LDF - OXYFLO 2000 Microvascular Perfusion Monitor, oxford Optronix, England, UK) to assess tissue per-fusion. Microdialysis, Pbo2 and lDF devices were placed at a depth of 0.8-1 cm into the brain parenchyma; icP was placed just below the level of the dura mater. the cMa 20 cath-eter was perfused with CNS perfusion fluid (148 mM nacl, 2.7 mM Kcl, 1.2 mM cacl2 and 0.85 mM MgCl2; osmolality 305 mosm/kg; pH 6) at a flow rate of 0.6 μL/min by a miniaturized infusion pump (cMa 402, cMa Microdialysis aB, solna, sweden). samples were analyzed for lactate, pyruvate, glyc-erol, glutamate and glucose by an automatic analyzer (ISCUSflex, microdialysis analyser, cMa Microdialysis aB, stockholm, swe-den). the lactate/pyruvate ratio (lPr) was calculated automatically. In the sham group, neurosurgery was performed and multimodal monitoring initiated, but no ICHT was in-duced.

Hemodynamic, respiratory and regional brain monitoring parameters

Monitored hemodynamic variables includ-ed heart rate (Hr), MaP, mean pulmonary artery pressure (MPaP), cvP, pulmonary ar-tery occlusion pressure (PaoP), and cardiac

day before of the experiment. they were fast-ing the night before the experiment with only access to water.

Anesthesia

all animals received an intra-muscular in-jection of 2-3 mg/kg ketamine plus 0.1 mg/kg midazolam as sedation induction. For in-tubation and mechanical ventilation we used a continuous intravenous infusion of midazolam (1-2 mg/kg/h), fentanyl (1-2 mcg/kg/h) and rocuronium bromide (0.6-1 mg/kg/h). Normo-volemia was maintained by an infusion of iso-tonic fluid (Plasmalyte, Baxter SA®) at a rate of 200 cc/h via a central venous line (1.3 ml/kg/h). Mechanical ventilation (Servo 300 ven-tilator; siemens-elema, solna, sweden) was set to maintain normocapnia (Paco2 38 to 42 mmHg) and normoxia (PaO2>60 mmHg) using an initial tidal volume of 10 mL/kg, 5 cmH2o positive end-expiration pressure (PeeP) and 30% Fio2. a Foley catheter (14 F, Beiersdorf AG, Hamburg, Germany) was placed in the bladder for continuous urine output monitoring.

Surgical procedures

The right femoral artery and vein were sur-gically exposed to place the arterial catheter (6 F Vygon, Cirencester, UK) and the venous introducer. a 7-F pulmonary artery catheter (edwards life sciences, irvine, ca, Usa) was advanced into a pulmonary artery via the introducer under monitoring of pressure wave-forms. the catheters were connected to pres-sure transducers (edwards life sciences) with the zero pressure reference at mid-thorax level. the animal was placed prone and allowed to stabilize.

a cruciate incision was made to open the scalp and two independent craniotomy and durotomy holes (0.5 × 0.5 cm) were per-formed in the right frontal lobe. Brain local-ization of catheters was 1.0 cm right from frontal midline in the horizontal plane and 1.5 cm and 2.8 cm from anterior right frontal lobe in the anterior posterior plane for the multi-modal neurological monitoring and intra-pa-



ables among different groups were compared using Student’s t-test or Wilcoxon test accord-ingly.

For all final comparisons, a P value of less or equal to 0.05 was considered statistically significant.

Results

Baseline data of the included animals are reported in table i. there were no differences at baseline between the Hs, mannitol or the sham groups in terms of ICP, PbO2, lPr, co, MaP, serum lactate, sodium (na+), chloride (cl–) or blood glucose. PaO2 remained above 90 mmHg and PaCO2 between 38-42 mmHg during the entire experiment. After reaching 30 mmHg of ICP and osmotic agents admin-istered, no significant difference between the groups was found in MAP, CO, laser Doppler flowmetry or serum lactate over the study pe-riod (table i).

Differences in intracranial and cerebral perfu-sion pressure

All animals had ICP below 10 mmHg and a CPP above 70 mmHg at baseline (Figure 2). Before hyper osmotic therapy (icP 30 mmHg) ICP and CPP were similar in the HS and in the mannitol groups (P=0.4). At T180, ICP was higher in the mannitol than in HS group (P<0.05). At T60 CPP was also higher in the HS group than in the mannitol group (P<0.05).

Differences in brain regional oxygen pressure (PbO2)

all animals had Pbo2 levels above 60 mmHg at baseline (Figure 3), but PbO2 levels before intervention were slightly higher in the HS group than in the mannitol group (P=0.07). At t120 and t180, Pbo2 was significantly higher in the HS than in the mannitol group (Figure 3) (34±14 vs. 27±11 at t120 and 36±12 vs. 27±12 at t180, respectively) (table i).

output (co). Hr, MaP, MPaP (sirecust 404, siemens, germany), co, core temperature (Vigilance Baxter, Edwards Critical Care) and ventilator parameters were continuously moni-tored; cvP and PaoP were measured at ev-ery observation point. We aimed to achieve at baseline a MAP>80 mmHg, PaO2>60 mmHg, Paco2 38-42 mmHg, arterial lactate <1.5 mEq/L, ICP<10 mmHg, CPP 70-100 mmHg, LPR<25 and PbO2>60 mmHg. Measurement initiation was withheld until all the variables were achieved.

Experimental protocol

icP was raised to two different pre-speci-fied values (ICP 15 and ICP 30) by balloon inflation. Balloon inflation was achieved by sterile instillation of distilled water. volume instilled varied between 3-10 cm of sterile wa-ter depending of the desired ICP. At ICP 30 mmHg, all animals were randomized to re-ceive a dose of either M 20% or Hs 7.45% (255 mosm/dose) as a 30 minutes bolus by a central vein. the two solutions were manu-factured in hospital’s pharmacy and carefully prepared to obtain the same osmotic load. He-modynamic and cerebral measurements were taken at baseline, at ICP 15 and 30 mmHg and repeated at 30, 60, 120 and 180 minutes (t30, t60, t120 and t180, respectively) after the end of the osmotic agent bolus. After 5 hours, all animals were euthanized by intra-venous potassium chloride under deep sedation. icP above 20 mmHg was considered pathologic. anaerobic brain parenchyma metabolism was considered if lPr was >25.

Statistical analyses

Statistical analysis was performed using SPSS 13.0 for Windows (SPSS Inc., Chica-go, IL, USA). Results are reported as means with standard deviation (±sD). a linear mixed model was used to analyze the time courses of considered variables. Distribution of data was evaluated using Q-Q and P-P plots. The pri-mary variables of interest were MaP, co, Pw, Pvc, icP, cPP, lDF, lPr, and Pbo2. vari-



Table I.—�Characteristics of included animals at baseline and during the experiment.

variable/time group Baseline icP 15 mmHg

icP 30 mmHg t30 t60 t120 t180

core temperature, °c M 20%Hs 7.45%sham

38.8±1.039.2±0.5

39±0.9

38.9±1.139.7±0.739.2 ±0.9

38.7±1.139.8±0.839.3 ±1.1

38.8±1.140.1±0.839.3±1

38.8±1.040±1.1

39.4±1.0

38.3±1.140.1±0.439.6±0.8

38.8±1.140.2±139.6±0.6

Brain temperature, °c M 20%Hs 7.45%sham

37.3±1.438.2±1.238.2±0.1

36.5±3.137.5±2.738.1±0.1

36.2±3.937.7±2.938.4±0.1

36.1±5.437.7±2.938.4±0.1

37.1±1.538±3.9

38.7±0.1

37.1±1.637.7±4.038.7±0.1

35.6±6.937.3±3.938.8±0.3

cardiac output, l/min M 20%Hs 7.45%sham

4.3±1.04.0±1.04.4±1.0

3.9±1.04.2±1.04.9±2.0

4.2±1.04.1±1.04.9±1.0

4.4±1.14.1±1.05.2±1.0

4.1±1.04.4±1.15.1±1.0

3.8±1.04.4±1.1

5±1.0

3.8±1.04.4±1.0

5±1.1serum lactate, meq/l M 20%

Hs 7.45%sham

1.1±0.51.1±0.11.2±0.3

1.1±0.31±0.1

1.2±0.3

1±0.30.9±0.11.2±0.2

0.8±0.20.9±0.21.1±0.2

0.7±0.20.9±0.21.1±0.1

0.7±0.20.9±0.3

1±0

0.8±0.21±0.31±0.0

spo2, % M20%Hs7.45%sham

98±2.499±1.099±0.2

99±1.299±1.099±0.2

99±1.299±1.099±1.0

99±1.499±1.0

100±0.1

99±1.899±1.3

100±0.1

99±1.399±1.0

100±0.1

99±1.599±1.0

100±0.1serum pH M 20%

Hs 7.45%sham

7.44±0.037.45±0.027.44±0.01

7.42±0.037.46±0.037.45±0.01

7.45±0.047.46±0.037.43±0

7.45±0.027.44±0.037.44±0

7.44±0.037.44±0.047.45±0.03

7.45±0.027.44±0.037.46±0.01

7.45±0.037.45±0.037.46±0.01

Pao2, mmHg M 20%Hs 7.45%sham

145±26134±26162±42

135±26136±19152±28

136±25136±21157±35

138±22133±21155±31

136±23135±23156±31

138±24134±25153±26

135±26135±21157±37

Paco2, mmHg M 20%Hs 7.45%sham

40±240±240±1

40±240±242±0

41±240±142±0

40±240±241±2

40±141±241±2

40±140±240±0

40±239±140±1

na+, meq/l M 20%Hs 7.45%sham

134±2135±1137±2

134±2133±1136±1

135±2137±3135±0

132±3137±2 a

135±2

133±2135±3 a

135±0

131±3136±2 a

135±1

132±2135±3 a

135±1cl–, meq/l M 20%

Hs 7.45%sham

102±2103±2104±1

103±4102±2104±0

101±2104±4104±0

98±3107±3 b

104±0

99±2107±2 b

104±0

101±5106±2 b

104±0

100±2106±3 b

104±1Serum glucose, mg/dL M 20%

Hs 7.45%sham

140±47106±27136±72

139±36115±26132±74

139±36103±21130±75

124±10104±17129±72

117±10100±11126±70

113±7.2100±11111±46

109±7100±11108±31

ICP, mmHg M 20%Hs 7.45%sham

4±25±37±1

15±116±16±2

31±233±35±1 c

22±622±66±2

29±1424±86±2

34±1427±115±2

36±1227±12 d

6±3CVP, mmHg M 20%

Hs 7.45%sham

10±18±2

10±0

8±14±1

11±1

8±28±1

10±1

8±19±1

10±1

8±29±1

10±1

8±19±1

11±1

8±19±1

10±1MAP, mmHg M 20%

Hs 7.45%sham

104±14104±3103±8

95±794±899±17

94±1091±5

102±23

92±895±397±25

94±1099±996±26

93±1290±1293±23

91±882±687±17

CPP, mmHg M 20%Hs 7.45%sham

101±17101±1290±13

81±1081±1892±19

64±1170±1796±21 e

71±1282±1391±22

64±1183±10 f

89±23

58±1072±1386±24

55±1062±1981±20

Urine output, ml/h M 20%Hs 7.45%sham

129±182 c

100±80150±0

97±10589±5250±9

124±75 c

101±6550±9

290±184 b, c

95±3950±9

209±176 b, c

104±5349±1

246±188 b, c

101±5549±1.4

90±3196±50

135±35lPr M 20%

Hs 7.45%sham

14±415±611±1

56±7728±514±0

88±8782±2915±1

102±11899±4017±5

100±12966±5019±6

73±11465±3913±4

65±11567±3213±4

Pbo2, mmHg M 20%Hs 7.45%sham

66±1766±761±0

38±1553±861±1

29±1242±1760±2

33±1641±1661±3

27±1539±1459±2

26±1641±14 f

58±3

22±1341±15 f

64±2lDF, BPU M 20%

Hs 7.45%sham

237±76304±231141±28

168±97222±275205±47

116±74138±74198±26

140±147138±96184±9

153±186143±61180±11

116±94142±96191±1

112±103117±97191±8

Data are presented as mean ± sD. BPU: blood perfusion units; cPP: cerebral perfusion pressure; icP: intracranial hypertension; cl–: serum chloride; Hs 7.45%: hypertonic saline 7.45%; lPr: lactate/pyruvate ratio; Pbo2: brain local oxygen pressure; LDF: laser Doppler flowmetry; M 20%: mannitol 20%; na+: serum sodium; cvP: central venous pressure.a P<0.001 vs. M 20%; b P<0.05 vs. M 20%; c P<0.001 vs. sham; d P<0.05 vs. Hs 7.45%; e P<0.05 vs. sham.



Differences in tissue perfusion

Before intervention, lDF values where sim-ilar between the HS and the mannitol group (P=0.7). no differences could be shown at any time between the HS and the mannitol group (P=0.9).

Differences in regional brain metabolism

Before the osmotic therapy infusion (icP 30 mmHg), LPR were similar in the HS and the mannitol groups (P=0.8) (Figure 4). No differ-ence in local brain metabolism was observed after administration of Hs 7.45% or M 20%.

Figure 2.—Mean intraparenchymal pressure (ICP, mean value mmHg, SD) and cerebral perfusion pressure during the entire experiment. 1Black squares: mannitol 20%; white squares: hypertonic saline 7.5%.

Figure 3.—Mean PbO2 (mean value, SD) during the entire experiment. 1Black squares: mannitol 20%; white squares: hyper-tonic saline 7.5%.



lined as, in the human setting, HS solutions were associated with a significant better con-trol of ICP and a higher ICP reduction than mannitol.11-14 However, the small number of patients included in these studies and the presence of significant heterogeneity in pa-tients’ cohorts limits any conclusion on the first-line osmotic therapy that should be used to treat ICHT. Although we found that HS 7.45% resulted in a lower icP values only at t180 when compared to M 20%, we may still speculate that long-term effects (i.e. after 5-6 hours) would have been more relevant and could not be assessed because of the limited observational time in our study. also, whether a higher osmotic load of both drugs may have resulted in different effects on brain perfusion and metabolism, it remains undefined from our findings. Future studies should also com-pare different concentrations of Hs and man-nitol in order to identify the optimal osmotic load to control icHt and improve cerebral perfusion.

Different hypothesis could explain why the effects of osmotic therapy on brain metabo-lism were different than those on brain perfu-sion. First, the decrease in icP was associ-

Differences in serum sodium and chloride con-centration

as expected, serum sodium and serum chloride concentration were higher in the HS 7.45% group than in the M 20% group after infusion (Figure 5).

Discussion

in this model of icHt secondary to an in-tracranial mass lesion, no differences on brain parenchyma metabolism or microcirculatory flow could be found between HS 7.45% and M 20%. small decrease in icP and increase in cPP was found with the use of Hs 7.45% when compared to M 20%. Regional brain me-tabolism and Pbo2 were not significantly dif-ferent between the Hs 7.45 % and the M 20% groups. A decrease in ICP with increase in CPP was not associated with a normalization of the LPR or a significant increase in PbO2 levels. However, differences in Pbo2 could be influ-enced by a higher value before administration of osmotic therapy in the Hs 7.45% compared to the M 20% group.

Different randomized trials have under-

Figure 4.—Mean lactate/pyruvate ratio (mean LPR [SD]), during the entire experiment.



hemorrhagic shock to compare HS with nor-mal saline (NS), using cerebral blood flow (cBF) as the primary outcome measure.23 Both fluids restored CBF to near normal but animals given HS had significantly lower ICP values. schmoker et al. used a swine model of hemorrhagic shock to evaluate cerebral blood flow and cerebral oxygen delivery (CDO2) after resuscitation with HS or lactated Ring-er’s solution.24 Significantly higher MAP, cBF, and cDo2 and lower icP values were observed with use of Hs. in human popula-tions, hypertonic saline has demonstrated to be more effective in reducing ICP than mannitol in models of TBI, non-traumatic neurological injury and pediatric patients.12-14 also, while mannitol has been shown to significantly re-duce icP and improve lPr in patients under-going brain multimodal monitoring because of severe hemorrhagic stroke,25 rockswold et al. showed that Hs decreased icP while im-proving CPP and PbO2 in patients with severe tBi.26 in one study, Hs improved cerebral per-fusion and oxygenation in patients with poor-grade subarachnoid hemorrhage and favorable outcome was associated with a sustained Pbo2 increase for more than 210 minutes.27 in an-other study, oddo et al. showed that Hs 7.5% administered as second tier therapy (i.e. when mannitol therapy failed) was associated with a significant increase in PbO2 and improved cPP in patients with severe tBi and refractory icHt.28 Thus, considering the few data avail-able comparing mannitol and HS on cerebral oxygenation and metabolism in the human set-ting and the potential risk of renal injury as-sociated with high chloride load,29 we urgently need additional studies to better characterize the cerebral effects of these different osmotic agents.

this study has several limitations. First, the inflated balloon during the entire experiment could have altered the regional microcircula-tion and Do2/vo2 ratios in surrounding peri-lesional area where the multimodal neurologi-cal probes were located. second, we did not monitor the electroencephalographic activ-ity to exclude probable non-convulsive status epilecticus. the most important limitation is

ated with a CPP below 70 mmHg at several different time-points in both groups. In the clinical setting, physicians would have tried to increase MaP to avoid secondary brain hypoperfusion. Although we did not use va-sopressors in this study to eliminate any ad-ditional confounders on cerebral perfusion, one can argue that additional benefits of os-motic solutions on cerebral oxygenation and metabolism may have observed in case of CPP>70 mmHg over the study period. Sec-ond, despite an ongoing increase of ICP and decrease of CPP in the mannitol group, LPR decreased at t120 and t180. Mannitol is an osmotic diuretic that is metabolically inert in humans and does not influence glucose or lactate metabolism. However, it may exerts some beneficial effects on microvascular per-fusion and red blood cells rheology,5, 6 which may explain how, despite a higher ICP, tis-sue microperfusion (estimated by lDF) re-mained similar to the HS 7.45% group and progressively resulted in similar metabolic activity.15 Third, a pro-inflammatory reaction may occur within minutes from the initial brain insult 16, 17 where the expression of pro-inflammatory mediators increases the risk of thrombosis and induces the inhibition of key enzymes in the respiratory chain reaction al-tering vascular regulation and ATP produc-tion.18-21 all these pathways may enhance microcirculatory dysfunction and promote an insufficient and heterogeneous oxygen sup-ply, independently from systemic and cere-bral global hemodynamics. Finally, regional electro-chemical disturbances may also ac-count from uncoupling of regional metabo-lism with cerebral perfusion. We did not as-sess the presence of seizures using continuous electroencephalogram (EEG); although with a LPR<25 at baseline the presence of seizures was unlikely, non-convulsing epileptic dis-charge may have occurred during the period of elevated ICP and have resulted in high lPr in our model.

Other groups have reported controversial results on the use of HS in cerebral blood flow and oxygen delivery.22 gunnar et al. used a dog model of epidural balloon inflation and



M 20%. these differences were not associ-ated with significant difference in the systemic variables. Results suggest that the control of icP and cPP does not improve cellular me-tabolism in this acute model.

Key messages

— There was no significant difference in systemic hemodynamics between Hs 7.45% and M 20% in anesthetized animals suffering from ICHT.

— Hs 7.45% administration resulted in a lower ICP and a higher cerebral perfusion pressure only for a short period of time when compared to mannitol.

— No significant difference in cerebral oxygenation and metabolism were ob-served between the two osmotic agents.

References

1. Fink Me. osmotherapy for intracranial Hypertension: Mannitol Versus Hypertonic Saline. Continuum Lifelong Learning Neurol 2012;18:640-54.

2. Mariano GSL, Fink ME, Hoffman C, Rosengart AJ. In-tracranial pressure: monitoring and management. In: Hall J, Schmidt G, Wood L, editors. Principles of critical care. Fourth edition. new York, nY: Mcgraw-Hill; 2012.

3. Bhardwaj a. osmotherapy in neurocritical care. curr neurol neurosci rep 2007;7:513-21.

4. tawfeeq na, Halawani MM, al-Faridi K, aal-shaya WA, Taha WS. Traumatic brain injury: neuroprotective anaesthetic techniques, an update. Injury 2009;40(Suppl 4):s75-s81.

5. Brain trauma Foundation, american association of neu-rological Surgeons, Congress of Neurological Surgeons, AANS/CNS Joint Section on Neurotrauma and Critical Care. Guidelines for the management of severe traumatic brain injury. Third edition. J Neurotrauma 2007;24(Suppl 1) [Internet]. Available from: https://www.braintrauma.org/uploads/06/06/Guidelines_Management_2007w_bookmarks_2.pdf [cited 2016, Jan 15].

6. Burke AM, Quest DO, Chien S, Cerri C. The effects of mannitol on blood viscosity. J Neurosurg 1981;55:550-3.

7. Prough DS, Whitley JM, Taylor CL, Deal DD, DeWitt DS. Regional cerebral blood flow following resuscitation from hemorrhagic shock with hypertonic saline. Influ-ence of a subdural mass. Anesthesiology 1991;75:319-27.

8. Berger S, Schurer L, Härtl R, Deisböck T, Dautermann c, Murr r, et al. 7.2% nacl/10% dextran 60 versus 20% mannitol for treatment of intracranial hypertension. acta Neurochir Suppl (Wien) 1994;60:494-8.

9. Ziai WC, Toung TJK, Bhardwaj A. Hypertonic saline: First-line therapy for cerebral edema? Journal of the Neu-rological Sciences 2007;261:157-66.

10. Kilkenny C, Browne WJ, Cuthill IC, Emerson M, Alt-

related to the model used to evaluate icHt. In small rodents, several groups have studied TBI and elevated ICP using the “impact ac-celeration” model, i.e. 450-g weight drop from 1.8 m on animal’s head.30 this method has also been used also in large animals;31 how-ever, other groups have developed alternative methods to mimic brain injury and/or elevated ICP, using a balloon catheter inflated in the su-perior vena cava, epidural balloon inflation or intracerebral balloon inflation.32-34 in particu-lar, this last method — which is the same we used in our study — has been shown to be use-ful to understand some of the pathophysiologi-cal characteristics of acute intracranial hemor-rhage and related-ICHT, whatever would be the origin (i.e. traumatic or spontaneous). of course, whether this model is actually compa-rable to the clinical situation of tBi and icHt, this remains to be further evaluated. indeed, elevated ICP in the setting of TBI may be re-lated to large and severe intra-cranial hemor-rhages or contusions, or it may evolve more progressively as a consequence of increasing brain edema following brain trauma. Thus, this therapeutic strategy has already been test-ed in the some injury model we used 35 and our findings remain reliable when applied to the setting of ICHT associated with intra-cranial expanding lesions. Forth, although a 2-mmHg reduction in ICP could be considered as “clini-cally irrelevant”, osmotic agents were unlikely to induce further reduction in icP because the intracerebral balloon remained inflated over the study period. Finally, we did not assess changes in clinical status in our study; how-ever, because of the invasive surgical proce-dures, it would have been unethical to awaken animals to provide some additional clinical data.

Conclusions

in this model of focal intraparenchymal neurologic injury, HS 7.45% was not differ-ent from M 20% in decreasing brain regional cellular anaerobic metabolism. small differ-ences were found in maintaining a lower ICP and higher CPP using HS 7.45% compared to



resuscitation improves cerebral oxygen delivery and re-duces intracranial pressure after hemorrhagic shock. J Trauma 1991;31:1607-13.

25. Yunos NM, Bellomo R, Hegarty C, Story D, Ho L, M, Bailey M. association between a chloride-liberal vs. chloride-restrictive intravenous fluid administration strategy and kidney injury in critically ill adults. JAMA 2012;308:1566-72.

26. rockswold gl, solid ca, Paredes-andrade e, rocks-wold SB, Jancik JT, Quickel RR. Hypertonic saline and its effect on intracranial pressure, cerebral per-fusion pressure, and brain tissue oxygen. Neurosurgery 2009;65:1035-41.

27. Al-Rawi PG, Tseng MY, Richards HK, Nortje J, Timo-feev i, Matta BF, et al. Hypertonic saline in patients with poor-grade subarachnoid hemorrhage improves cerebral blood flow, brain tissue oxygen, and pH. Stroke 2010;41:122-8.

28. Oddo M, Levine JM, Frangos S, Carrera E, Maloney-Wilensky E, Pascual JL, et al. effect of mannitol and hypertonic saline on cerebral oxygenation in patients with severe traumatic brain injury and refractory in-tracranial hypertension. J Neurol Neurosurg Psychiatry 2009;80:916-20.

29. Helbok R, Kurtz P, Schmidt JM, Stuart RM, Fernandez L, Malhotra r, et al. effect of mannitol on brain metabolism and tissue oxygenation in severe haemorrhagic stroke. J Neurol Neurosurg Psychiatry 2011;82:378-83.

30. Blanié A, Vigué B, Benhamou D, Duranteau J, Geeraerts t. the frontal lobe and thalamus have different sensitivi-ties to hypoxia-hypotension after traumatic brain injury: a microdialysis study in rats. J Neurotrauma 2012;29:2782-90.

31. Imam AM, Jin G, Sillesen M, Duggan M, Jepsen CH, Hwabejire JO, et al. early treatment with lyophilized plasma protects the brain in a large animal model of com-bined traumatic brain injury and hemorrhagic shock. J Trauma Acute Care Surg 2013;75:976-83.

32. Purins K, Enblad P, Wiklund L, Lewén A. Brain tissue oxygenation and cerebral perfusion pressure thresholds of ischemia in a standardized pig brain death model. Neu-rocrit Care 2012;16:462-9.

33. Nusbaum DM, Clark JB, Brady KM, Kibler KK, Sut-ton JP, Easley RB. Intracranial pressure and optic nerve sheath diameter as cephalic venous pressure increases in swine. Aviat Space Environ Med 2013;84:946-51.

34. andrade aF, soares Ms, Patriota gc, Belon ar, Paiva WS, Bor-Seng-Shu E, et al. experimental model of in-tracranial hypertension with continuous multiparametric monitoring in swine. Arq Neuropsiquiatr 2013;71:802-6.

35. da Silva JC, de Lima Fde M, Valença MM, de Azevedo Filho HR. Hypertonic saline more efficacious than man-nitol in lethal intracranial hypertension model. neurol Res 2010;32:139-43.

man DG. Improving bioscience research reporting: the ARRIVE Guidelines for reporting animal research. PLoS Biol 2010;8:e1000412.

11. Qureshi A, Wilson D, Traystman R. Treatment of elevat-ed intracranial pressure in experimental intracerebral he-morrhage: comparison between mannitol and hypertonic saline. Neurosurgery 1999;44:1055-63.

12. Kamel H,Navi BB, Nakagawa K, Hemphill III JC, Ko nU. Hypertonic saline versus mannitol for the treatment of elevated intracranial pressure: a meta-analysis of ran-domized clinical Trials. Crit Care Med 2011;39:554-9.

13. Mortazavi MM, Romeo AK,Deep A, Griessenauer CJ, Shoja MM, Tubbs RS, Fisher W. Hypertonic saline for treating raised intracranial pressure: literature review with meta-analysis. J Neurosurg 2012;116:210-21.

14. Rickard AC, Smith JE, Newell P, Bailey A, Kehoe A, Mann C. Salt or sugar for your injured brain? A meta-analysis of randomised controlled trials of mannitol ver-sus hypertonic sodium solutions to manage raised intrac-ranial pressure in traumatic brain injury. Emerg Med J 2014;31:679-83.

15. Marcoux J, McArthur DA, Miller C, Glenn TC, Villablanca P, Martin NA, Hovda DA, Alger JR, Vespa PM. Persistent metabolic crisis as measured by elevated cerebral microdialysis lactate-pyruvate ratio predicts chronic frontal lobe brain atrophy after traumatic brain injury. crit care Med 2008;36:2871-7.

16. chesnut rM, Marshall lF, Klauber Mr, Blunt Ba, Bald-win N, Eisenberg HM, et al. the role of secondary brain injury in determining outcome from severe head injury. J Trauma 1993;34:216-22.

17. Miller JD, Sweet RC, Narayan R, Becker DP. Early in-sults to the injured brain. JAMA 1978;240:439-42.

18. Wee Yong V. Inflammation in neurological disorders: a help or a hindrance? neuroscientist 2010;16:408.

19. Yoshimoto Y, Tanaka Y and Hoya K. Acute systemic in-flammatory response syndrome in subarachnoid hemor-rhage. Stroke 2001;32:1989-93.

20. Morganti-Kossmann MC, Rancan M, Stahel PF, Ko-ssmann T. Inflammatory response in acute traumatic brain injury: a double-edged sword. Curr Opin Crit Care 2002;8:101-5.

21. Morganti-Kossmann MC, Rancan M, Otto VI, Stahel PF, Kossmann T. Role of cerebral inflammation af-ter traumatic brain injury: a revisited concept. shock 2001;16:165-77.

22. Doyle JA, Davis DP, Hoyt DB. The use of hypertonic sa-line in the treatment of traumatic brain injury. J Trauma 2001;50:367-83.

23. Gunnar W, Kane J, Barrett J. Cerebral blood flow fol-lowing hypertonic saline resuscitation in an experimental model of hemorrhagic shock and head injury. Braz J Med Biol Res 1989;22:287-9.

24. Schmoker J, Zhuang J, Shackford S. Hypertonic fluid

Conflicts of interest.—The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript.Article first published online: May 21, 2015. - Manuscript accepted: May 19, 2015. - Manuscript revised: April 23, 2015. - Manu-script received: February 18, 2015.


neither able to replicate the complex anatomy nor able to provide a realist model for learning Pt especially in terms of manipulation of hu-man tissue, threat of an emergency situation, bleeding and edema.5

recently, gardiner et al.1 proposed a simu-lation model based on animal tissue to allow monitoring of skill acquisition in the setting

traditionally, training for percutaneous tra-cheostomy (Pt) has been performed using

manikins or animal models.1-3 the usefulness of manikins is well recognized and a strong potential for transfer of skills to the operating theatre has been shown.4 However, they are


a new training approach in endoscopic percutaneous tracheostomy using a simulation

model based on biological tissuePierpaolo terragni 1*, luciana Mascia 1, chiara Faggiano 1, tommaso tenaglia 1

emanuela Morello 2, giovanni sUcco 3, Marco ranieri 1, luca BraZZi 1

1Dipartimento di scienze chirurgiche, a.o.U. città della salute e della scienza di torino, Università di torino, torino, italia; 2Dipartimento di scienze veterinarie, Università di torino, torino, italia; 3Dipartimento di scienze cliniche e Biologiche osp. s. luigi gonzaga orbassano (torino), Università di torino, torino, italia*corresponding author: Pierpaolo terragni, Dipartimento di scienze chirurgiche, a.o.U. città della salute e della scienza di torino, Università di torino, corso Dogliotti 14, 10126 torino. e-mail: [email protected]


lavoro: titolo breve: a neW training aPProacH in enDoscoPic Ptprimo autore: terragnipagine: 196-201citazione: Minerva anestesiol 2016;82:196-201

a B s t r a c tBacKgroUnD: ciaglia et al. originally proposed the percutaneous tracheostomy in 1985 as an alternative to the surgi-cal approach. several variants have been developed in the years with a convincing evidence that, compared to surgical tracheostomy, the percutaneous approach is more cost effective without compromising safety. However the procedure is not immune from complications and requires procedural skills and adequate level of expertise with a steep learning curve. In this contest, to optimize safety and efficacy of percutaneous tracheostomy in different clinical scenarios, physicians should be familiar with the different available percutaneous techniques. traditionally, the training has been performed using manikins or animal models. However, by definition the manikin is not able to replicate the complex anatomy and does not provide a realist model for learning.MetHoDs: a sheep model was implemented and was tested in a simulation based course for percutaneous dilational tracheostomy and cricothyrotomy organized by the Department of surgical sciences of University of turin at the special educational section of the veterinary sciences Department (University of turin).resUlts: From september 2012 to December 2014, 2 sessions of the training course were performed. thirty-two anesthesiologists (16 men and 16 women, mean (sD) age 40.4 (sD 8.6) attended the course. a quality assessment of the course was then collected by participants.conclUsions: the biological model we implemented proved to be adequate and effective. Future studies are required to compare its efficacy with previously proposed training methods.(Cite this article as: terragni P, Mascia l, Faggiano c, tenaglia t, Morello e, succo g, et al. a new training approach in en-doscopic percutaneous tracheostomy using a simulation model based on biological tissue. Minerva anestesiol 2016;82:196-201)Key words: tracheostomy - Models, biological - Manikins.


comment in p. 151.

© 2016 eDiZioni Minerva MeDicathe online version of this article is located at http://www.minervamedica.it

a neW training aPProacH in enDoscoPic Pt terragni


Course design

a 2-days course with the title: “Training course in Percutaneous Endoscopic Trache-ostomy using a Simulation Model based on Biological Tissue” was organized by the De-partment of surgical sciences of University of turin at the special educational section of the veterinary sciences Department (University of turin). Participants were trained on three per-cutaneous tracheostomy techniques (Portex griggs Percutaneous Dilatation tracheostomy Kit, smiths Medical, Dublin, oH, Usa; ciaglia Blue rhino advanced Percutaneous tracheos-tomy, cook Medical, Bloomington, in, Usa; Dolphin Bt ciaglia Ballon-assisted tracheos-tomy introducer, cook Medical) and emergen-cy cricothyrotomy (Melker emergency crico-thyrotomy catheter sets, cook Medical).

During the first day, participants were taught about indications, contraindication and com-plications of the different procedures. a video session showing the technical aspects of the different procedures was also included. Dur-ing the second day, small group of participants were asked to actively perform the four tech-niques on biological simulation models. all participants adopted the safeguards of protec-tion against potential infections even if the risk was minimized by the selection and safety cer-tification of all biological materials directly in the slaughter by a dedicated veterinarian.

of percutaneous endoscopic tracheostomy. cho et al.6 tested a porcine model of larynx freed of prelaryngeal tissue and covered with thinned pig skin to train cricothyrotomy. Fio-relli et al. proposed an elaborate model of lar-ynx and trachea free from perilaryngeal and peritracheal tissues covered with sponge and plastic wrapping (simulating the skin) and inserted into a neck of the manikin allowing residents to develop the skill required for suc-cessful Pt.7

although these models showed to be su-perior to manikins in terms of reality of skin turgor, and recognition of landmarks, they still present major limitations. First, number of tracheotomy attempts is reduced (only 2 each package in the cho model). second secretions are absent and the surgical field lacks blood and the endotracheal tube. third, a trachea free from perilaryngeal tissues and the absence of all external landmarks does not represent a real condition to introduce the needle with the oesophagus beneath and the restraining effect of para-tracheal tissues.

to overcome these limitations we imple-mented a sheep model that was tested in a simulation-based course for Pt and cricothy-rotomy training.


Biological model

adult sheep heads and necks bought from the slaughterhouse were used. the necks were cut as to preserve the head and all the trache-al rings (Figure 1). sheep necks model were collected as “by products” of routine sheep processing for human consumption and no sheep were killed for the purpose of this train-ing. at the end of the course the biological models were eliminated according to the vet-erinary rules. the tracheostomy training trial was approved by Bioethics committee of the University of turin and informed consent was obtained from each participant regarding the use of personal data, baseline experience and overall course evaluation.

Figure 1.—the biological model (adult sheep head and neck) implemented to train on Pt. the whole head and neck reproduce the real skin turgor and the difficulties in skin pen-etration during tracheostomy procedure.

terragni a neW training aPProacH in enDoscoPic Pt


most inferior portion of the trachea. cricothy-rotomy was always performed through the cri-cothyroid membrane.

the three tracheostomy training stations were prepared with an orotracheal tube cor-rectly positioned through the larynx of the sheep necks (Figure 2). A single-use flexible video-endoscope (ambu ascope® – ambu, Ballerup, Denmark) was available in each training station to allow participant perform-ing the procedure to see the results of their manipulations and the teacher to monitor and advise as they proceeded (Figure 3) Due to the fact that the sheep trachea is about twice as long as the human, two to four procedures were performed on each neck starting from the

Figure 2.—Description of needle introduction, choosing the best point of penetration among tracheal rings with the aid of transillumination. the anterior wall of the trachea is then visualized with bronchoscopy view confirming the middle approach of the needle insertion.

Figure 3.—all PDts, performed under endoscopic view, al-low participants to observe in real-time results of their ma-nipulations. teachers are able to monitor and advise how to proceed, detect and correct procedural errors.

Figure 4.—a detail of the Blue rhino ciaglia introducer during intersection into the trachea of the sleep model.

Table I.—�Demographic and characteristics of participants

trainees n.=32resident in anesthesia n. (%) 7 (22.7)Physician specialized in anesthesia n. (%) 25 (77.3)Male/female 16/16Years in tracheostomy practice (*) (mean/sD) 4.5 (4.2)

ProFessional FielD oF Practice n. (%)icU 26 (81.8)or 22 (68.1)er 9 (27.3)other 3 (9.1)

PrevioUs eXPerience n. (%)Percutaneous tracheostomy models (**)

Biological 1 (4.5)Mannequins 4 (13.6)clinical settings 23 (72.3)Use of flexible-video-endoscope 30 (95.4)

icU: intensive care unit; or: operative room; er: emergency room.*related to Physician specialized in anesthesia**some participants stated more than one experience



that complications appear to decrease as the operator gains experience.8, 9

Donalds et al. found that complications (13% vs. 33%, P=0.030), operative time (12 vs. 24 min, P<0.0001) and total procedure time (37 vs. 80 min, P<0.001) were signifi-cantly reduced in the percutaneous trache-ostomy group when compared with standard tracheotomy after a training program, while the initial outcome data were equal in both groups.8 similarly, Massick et al., in a case series of 100 consecutive percutaneous tra-cheotomy performed in a community hospital, found that the first cohort of 20 patients ac-counted for the majority of the perioperative, postoperative and late complications, while a significant reduction in the overall complica-tion incidence rate was seen after the first 20 procedures, confirming the importance of the learning curve.9 lecture and verbal instruc-tion are both effective in providing steps for procedure performance, but procedure accu-racy, especially in mature learners, can only be taught through the performance of those

Results

From september 2012 to December 2014, 2 sessions of the course were performed. thirty-two anesthesiologists (16 men and 16 wom-en, mean [sD] age 40.4 [sD 8.6]) attended the course (table i). at the end of the 2-days course, participants evaluated the course as re-ported in table ii.

All participants passed the final test and the practical examination and obtained physician’s continuous Medical education credits. a qual-ity assessment of the course was then collected by participants (table iii) the video that illus-trates the concepts that underlie different Pt techniques, as described during the course, can be find as supplementary online content.

Discussion

acquisition of new skills, such as percuta-neous endoscopic tracheostomy, requires both supervised training and the opportunity for sufficient practice. Several authors reported

Table II.—�Course evaluation.Positive elements of the training n. (%)

skills in different techniques 17 (54.5)greater safety in the procedure 29 (90.9)Deepening on the risks related to the individual techniques 20 (63.6)More skills in the bronchoscopy use during the procedure 6 (18.2)Biological model results more realistic than manikins 21 (65.1)Technique that has been perceived more difficult to learn (*)

ssDt 4 (12.5)gWDF 6 (18.7)BFDt 9 (28.1)ec 2 (6.2)none 12 (37.5)

elements considered less favorablylittle time dedicated to practical sections 4 (13.6)the theory part of the course is too long 1 (4.5)none 26 (81.9)

ssDt: single-step dilation technique; gWDF: guidewire dilating forcep; BFDt: Balloon-Facilitated Dilational tracheostomy; ec: emergency cricothyrotomy.*some participants stated more than one technique.

Table III.—�Quality assessment of the course.trainees (n.=32) Sufficient good excellent

relevance for clinical practice (%) 0 31.8 68.2Quality (%) 0 45.5 54.5Efficacy (%) 4.5 36.4 59.1



the elasticity of sheep trachea with its tracheal rings, despite being dead tissues, is more simi-lar to that of humans and allows one to rep-licate realistic situations such as the collapse of the anterior tracheal wall when pressure is applied during the procedure (see the video on supplementary online content). in addition, because all percutaneous tracheostomies were performed under endoscopic view, participants observed in real-time the results of their ma-nipulations. this allowed the teachers to super-vise and advise as they proceeded, identifying and correcting the ‘mistakes’ made during the procedure.

similar results were previously obtained with a pig model but the sponge and plastic fillings used to cover the larynx-trachea cannot closely resemble the true anatomy of skin.7 We solve the problem using the whole head and necks as to reproduce the real skin turgor and the difficulties in skin penetration.

Conclusions

the biological model we implemented to train on Pt proved to be adequate and particu-larly effective. Future studies are required to compare its efficacy with previously proposed training methods.

Key messages

— tracheostomy procedure is being used increasingly in critical care. as to avoid consequences to patients during the clinical training period, simulation training is necessary.

— Pt training using manikin models proved effective in teaching different tech-niques.

— a simulation model based on animal tissue seems to be more realistic than mani-kin in terms of reality of skin turgor, recog-nition of landmarks. Moreover it provide a particular “tactile feeling” in trainees and allows better monitoring of skill acquisi-tion in endoscopic Pt settings.

procedures, either in a real or simulated set-tings. Different models have been proposed. Moran et al. compared the perceived realism of the live sheep model to that of the manikin and concluded that live sheep model appear to be a better training tool than a manikin model for all forms of cricothyrotomy training.10 Mc-carthy et al. compared the use of dogs and human cadavers for cricothyrotomy training and found that participants misplaced 30.2% of cricothyrotomy when performing the pro-cedure on live animals, compared with only 3.6% when using human cadavers.11 Block et al. compared the use of the simulab’s trauma Man simulator (simulab, seattle, Wa, Usa) with the use of live animals, and defined the simulator to be superior to the animal model in teaching surgical airways.12 But it has even been acknowledged that performance of crico-thyrotomy on mannequins is artificial and dif-ferent from real-life situations.5

to overcome these limitations we imple-mented a new biological model based on iso-lated sheep head and trachea as a unique block since the anatomy is similar to the human one except for the trachea length that is twice lon-ger than the human. We used video-endoscopic guidance during the whole procedure because it has been reported to decrease percutaneous tracheostomy complications.13, 14 Moreover, it helped instill confidence in the participants who learned the procedure and allowed them to see the results of their own manipulations and the teacher to monitor and advise as they proceed-ed.

We do believe that the animal model we pro-pose is more realistic than the manikin model especially in creating in participants the “tac-tile feeling” when passing through the anterior wall of the trachea. this is crucial considering that posterior tracheal injury is the main dis-advantage of any percutaneous tracheostomy with the anterior dilatation approach and may be incidentally caused by introduction of the needle, by kinking of the guidewire or during dilatation of the stoma.15-17 all these maneu-vers can be realistically reproduced and repli-cated using a sheep model rather than a mani-kin model. Compared with an artificial trachea,



g, Forrest la, et al. Quantification of the learning curve for percutaneous dilatational tracheotomy. laryngoscope 2000;110:222-8.

10. Moran aPM DJ, lacquiere Da, Heard aMB. compari-son of manikin models vs live sheep in ‘can’t intubate can’t ventilate’ training. anaesthesia 2010;65:431- 2.

11. Mccarthy Mc, ranzinger Mr, nolan DJ, lambert cs, castillo MH. accuracy of cricothyroidotomy performed in canine and human cadaver models during surgical skills training. J am coll surg 2002;195:627-9.

12. Block eF, lottenberg l, Flint l, Jakobsen J, liebnitzky D. Use of a human patient simulator for the advanced trauma life support course. am surg 2002;68:648-51.

13. oberwalder M, Weis H, nehoda H, Kafka-ritsch r, Bon-atti H, Prommegger r, et al. videobronchoscopic guid-ance makes percutaneous dilational tracheostomy safer. surg endosc 2004;18:839-42.

14. Ferraro F, Di lorenzo a, lettieri B, chiefari M. ana-tomical particularities and difficulties in tracheostomy: seeking the best way. Minerva anestesiol 2011;77:378-9; author reply 80-1.

15. Fiorelli a, accardo M, D’elia a, santini M, Ferraro F. acute life-threatening airway obstruction with pseu-domembrane formation after percutaneous dilational tra-cheostomy. anaesth intensive care 2012;40:904-5.

16. tordiglione P, Magni g, imperiale c, Baisi F, De Bla-siis n, Manganozzi v, et al. Dedicated endotracheal tube for percutaneous tracheostomy. eur J anaesthesiol 2009;26:936-9.

17. Fiorelli a, vicidomini g, Messina g, santini M. sponta-neous expectoration of an obstructive fibrinous tracheal pseudomembrane after tracheal intubation. eur J cardi-othorac surg 2011;40:261-3.

References

1. gardiner Q, White Ps, carson D, shearer a, Frizelle F, Dunkley P. technique training: endoscopic percutaneous tracheostomy. Br J anaesth 1998;81:401-3.

2. Fikkers Bg, van vugt s, van der Hoeven Jg, van den Hoogen FJ, Marres Ha. emergency cricothyrotomy: a randomised crossover trial comparing the wire-guid-ed and catheter-over-needle techniques. anaesthesia 2004;59:1008-11.

3. stringer Kr, Bajenov s, Yentis sM. training in airway management. anaesthesia 2002;57:967-83.

4. anastakis DJ, regehr g, reznick rK, cusimano M, Murnaghan J, Brown M, et al. assessment of technical skills transfer from the bench training model to the hu-man model. am J surg 1999;177:167-70.

5. Wong Dt, Prabhu aJ, coloma M, imasogie n, chung FF. What is the minimum training required for successful cricothyroidotomy?: a study in mannequins. anesthesiol-ogy 2003;98:349-53.

6. cho J, Kang gH, Kim ec, oh YM, choi HJ, im tH, et al. comparison of manikin versus porcine models in cricothyrotomy procedure training. emerg Med J 2008;25:732-4.

7. Fiorelli a, carelli e, angioletti D, orsini a, D’elia a, torino a, et al. a home-made animal model in compari-son with a standard manikin for teaching percutaneous dilatational tracheostomy. interact cardiovasc thorac surg 2015;20:248-53.

8. Donaldson Dr, emami aJ, Wax MK. endoscopically monitored percutaneous dilational tracheotomy in a resi-dency program. laryngoscope 2000;110:1142-6.

9. Massick DD, Powell DM, Price PD, chang sl, squires

Acknowledgments.—the authors wish to thank: lucia valli, veterinary surgeon, (asl to4) for performing selection of all biological models in the slaughter. Mattia Mancardi MD, sara tardivo MD, Yaroslava longhitano MD and ilaria De Domenici MD for setting up the training workstations with sheep model equipped by an oral endotracheal tube and the devices for performing different trache-ostomy procedures. smiths Medical, ambu, cook and coviden for providing technical equipment.Conflicts of interest.—The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript.Article first published online: April 24, 2015. - Manuscript accepted: April 23, 2015. Manuscript revised: April 2, 2015. - Manuscript received: February 13, 2015.For supplementary materials, please see the online version of this article.


Minerva anestesiologica February 2016

SuppLEMENTARy MATERIALS

Use of the Blue rhino ciaglia introducer on the trachea of a sleep model (video download).


safety.3, 4 the prompt detection of any error-producing situation is now considered funda-mental in the medical field and the anesthetists were actually among the first physicians to in-tegrate crisis resource management techniques into their everyday practice.5 anesthesiology has thus become a pioneering field in recom-mending the routine use of checklists, thereby encouraging other specialties to adopt similar risk-reduction strategies.6, 7

in spite of this, deaths and permanent im-

Medical malpractice is currently a crucial topic both for clinical risk management

and forensic pathology, the former dealing with the correction and the prevention of er-rors and the latter with the administration of justice.1, 2 Dealing with the complex phenom-enon of medical malpractice, anesthesiology represents a unique and very interesting field as a key specialty in improving global patient


alleged malpractice in anesthesiology: analysis of a series of private insurance claims

Umberto genovese *, alberto BlanDino, riccardo MiDolo, Michelangelo B. casali

laboratorio di responsabilità sanitaria, Dipartimento di scienze Biomediche per la salute, istituto di Medicina legale e delle assicurazioni, Università degli studi di Milano, Milan, italy*corresponding author: Umberto genovese, istituto di Medicina legale e delle assicurazioni, Università degli studi di Milano, via luigi Mangiagalli 37, Milan, italy. e-mail: [email protected]


lavoro: titolo breve: allegeD MalPractice in anestHesiologYprimo autore: genovesepagine: 202-9citazione: Minerva anestesiol 2016;82:202-9

a B s t r a c tBacKgroUnD: Medical malpractice is currently a crucial topic and anesthesia is a key specialty for the improvement of patient safety. However, death and permanent impairment due to anesthesia still occur and studies of insurance analysis data are increasing. We investigated the main features of a major italian insurance broker’s archive in order to identify possible recurrent pitfalls in this critical field of medicine.METHODS: Three hundred seventeen Italian claims were analyzed, filling out a standardized form that recorded infor-mation on patient and physician’s characteristics, procedures, sequence and location of events and outcomes. the opera-tive setting, the type of anesthesia performed the origin of the multidisciplinary team malpractice hypothesis, the final clinical outcome and the malpractice investigation results were also analyzed.resUlts: in 225 malpractice claims, the adverse event was surgery-linked, either intraoperatively (114 cases) or postoperatively (111 cases): abdominal surgery (26%), orthopedics (22%), gynecology (20%), heart surgery (11%) and neurosurgery (9.5%) were the most frequently involved surgical specialties. in 92 cases, the claim was unlinked to a surgeon’s activity, with dental damage in oral intubation procedures as the greatest contributor (42.3%). anesthetists’ malpractice was technically ascertained in 39% of cases, 74.8% resulting in permanent impairment.conclUsions: Malpractice was mainly suspected in surgery-linked procedures. Most of the claims were settled for procedural error in performing locoregional anesthesia and oral intubation procedures. 60% of all closed claims resulted in no malpractice ascertained. Confirmed malpractice typically deals with non surgery-linked and non multidisciplinary team cases, causing permanent impairment.(Cite this article as: genovese U, Blandino a, Midolo r, casali MB. alleged malpractice in anesthesiology: analysis of a series of private insurance claims. Minerva anestesiol 2016;82:202-9)Key words: Malpractice - anesthesia - Forensic medicine.


comment in p.154.

© 2016 eDiZioni Minerva MeDicathe online version of this article is located at http://www.minervamedica.it

allegeD MalPractice in anestHesiologY genovese


were 17.46 claims per 100 physicians and that 2.65% of all claims were anesthesia-related.18 However, there is still no national register of claims and thus data on the total number of claims is lacking. likewise no information on the number of anesthesia performed annually is available; this data should be considered fundamental to evaluate the incidence of ad-verse events, also in the perspective of future studies.

the aim of the present study was to assess the possibility of analyzing the medical mal-practice phenomenon through the study, in anonymous form, of one of the largest italian private insurance broker’s claims database. the key features of all claims regarding an-esthesia specialists were investigated in order to map professional risk and identify possible recurrent pitfalls in this pivotal clinical field.


a retrospective study was carried out, on the basis of an archival data analysis of one of the largest insurance brokers in italy, with focus on all claim files regarding anesthesia specialists. Each file typically consisted of hospital and medical records, included personnel reports, depositions from plaintiffs and medico-legal reports. Investigators filled out a standardized form that recorded information on patient and physician characteristics, all procedures car-ried out, sequence and location of events, clin-ical manifestations of injuries and final clinical outcomes.

the available archive covered cases from January 2001 to December 2013 and com-prised files on 3342 different anesthetists na-tionwide. All 516 files containing malpractice claims were originally selected: 189 files were not considered in the subsequent analysis be-cause of insufficient data on causal events; the remaining 317 files (62% of all registered anesthesia malpractice claims) were carefully studied with a special focus on operative set-ting (icU versus operating room), type of an-esthesia procedure carried out (locoregional versus general anesthesia), original hypothesis of multidisciplinary team malpractice ver-

pairment resulting from anesthesiology pro-cedures still occur. according to olsen et al. (2010), the frequency of anesthesia-related death is less than 1 per 100.000 patients and severe perioperative complications resulting in “permanent damage” occur in 1 per 170-500 patients.8 in a study performed by Bothner et al. serious complications due to periopera-tive anesthesia were reported in 0.2% of pro-cedures undergone: however no distinction between permanent damage and death of the patient was considered.9 today, medical lit-erature reports a wide range of complication frequencies, since differences in definition of investigated outcomes and resulted impair-ments exist. Furthemore, difficulties due to the differences in reporting sources have been considered by previous authors.7, 10

although a large body of data is currently available from private insurance databases, there is a lack of national and international studies which specifically address the synop-tic analysis of claims concerning suspected medical malpractice. in addition to this lack of national databases, several studies have pri-marily focused their attention on anesthesia-related mortality, without considering perma-nent impairment related to anesthesiology.11 although not every adverse event results in an overt claim, insurance companies’ data sup-plies a wider range of data than the archives of necroscopy departments, allowing an analysis of the most frequent bases for claims involv-ing anesthesiologists and allowing researchers to investigate the important subgroup of medi-cal malpractice not resulting in fatal outcomes. indeed this type of studies is fast growing: one example is the american society of anesthesia closed claims Project (asaccP), which was created to provide a structured evaluation of adverse anesthetic outcomes through the anal-ysis of closed claims files from professional liability insurance companies in the United states.12 Many countries have insisted on a systematic approach to anesthesia malpractice and adverse events would be a useful tool for learning, promoting and implementing patient safety.13-17

in 2013, in italy it was estimated that there

genovese allegeD MalPractice in anestHesiologY


allegations of malpractice were made dur-ing the weekend in 17% of all claims, while a night-time occurrence was filed in 25%.

gender distribution in the group of alleged malpractice victims was equal and the mean age of victims was 49.9±22.3 years. about 10% of the patients involved were younger than 30 years. endocrine system (24%), heart (23.5%), lung (20%), kidney (16%) and gut (12%) pathologies were the most frequently observed morbidities. less than 5% of patients cited traumatic lesions as the original com-plaint for which they had been admitted.

a historical graphic of malpractice claim trends for the years 2001 to 2013 is shown in Figure 1.

in 225 malpractice claims (71% of cases), the adverse event was surgery-linked, either intraoperatively (114 cases) or postoperatively (111 cases) and the most frequently involved surgical fields were abdominal surgery (26%), orthopedics (22%), gynecology (20%), heart surgery (11%) and neurosurgery (9.5%). the 114 alleged cases of intraoperative medical malpractice events were mainly represented by

sus single anesthetist malpractice claim, final clinical outcome (death versus permanent im-pairment) and malpractice investigation out-come (confirmed malpractice versus rejected malpractice claim). a descriptive statistic ap-proach was used to analyze and display the data thus obtained.

Results

the population of the 3342 selected anes-thetists was composed by 60% of men, and the mean age of physicians was 37±25.4 years. among these, 226 anesthetists (6.7%) had at least one malpractice claim filed against them, while 45 anesthetists (1.3%) were the object of one malpractice claim more than once. approximately 60% of all malpractice claim files had been opened as the result of crimi-nal charges leading to civil litigation. in just two cases the malpractice claim dealt with a medical act carried out by the anesthetist in a non-institutional setting (two alleged cases of delayed advanced life support procedures, both resulting in a non-malpractice verdict).

Figure 1.—alleged malpractice claims (historical trend).



anesthetists’ malpractice was technically confirmed in 128 cases (39%). The patient’s dying was attributed to malpractice on the part of the anesthetist in 33 cases, that is, on aver-age, 2.5 lethal cases every year. considering the studied population, 33 cases represent the 17.3% of the claims having the patient’s death as the final clinical outcome, therefore mean-ing that in 82.7% of cases the anesthetists re-sulted not causally involved.

anesthetists with at least one claim against them where 70% men, and the mean age of the practitioners involved was 45.5±10.8 years. about 30% of malpractice claims were made against anesthetists less than 40 years of age. epidemiological data (such as male-to-female ratio, mean age of physicians and patients in-volved) about confirmed malpractice cases do not differ from the population sampled in this analysis.

table ii summarizes the main analytical variables observed, while table iii lists the in-criminated anesthesia procedures for all con-firmed case of medical malpractice claims.

Discussion

anesthesia specialists frequently have to make decisions quickly, with incomplete data and in a setting which is intolerant of errors.19 lienhart et al. have found that anaesthesia-related death actually is a rare event and, therefore, particularly hard to analyze.10 the present study retrospectively reviews claims made between 2001 and 2013 in italy. Dur-

acute iatrogenic injuries incurred during anes-thesia procedures (66 cases) and adverse reac-tions to the administration of local or system-ic drugs (45 cases). in three cases, the claim against the anesthetist concerned the sciatic nerve dysfunction subsequent to incorrect po-sitioning of the patient on the surgical bed. the 111 postoperative adverse events were mainly represented by icU infections (54 cases) and surgical site haemorrhage (47 cases), or both (14 cases). the postoperative adverse events showed a bimodal distribution of their post-surgical timing: most hemorrhaging occurred mainly during the first 24 hours and anesthe-tists were involved in the claim being part of the surgical team or because of alleged delay of diagnosis, while infections were mostly ob-served and diagnosed during the second week of hospital stay: in these cases nosocomial in-fection due to icU negligence was suspected. the authors have no information on the number of infections due to drug resistant organisms.

in 92 cases the claim regarded an adverse event unrelated to surgery (no surgery was performed on the patient), with nerve or vessel needlestick injuries and oral intubation injuries attributed to anesthetists’ procedures being the main contributors.

in 210 claims there was an original allega-tion of a multidisciplinary team malpractice. the greatest part of such claims (68.5%) con-cerned surgery-linked adverse events, with a distribution among surgical subspecialties very similar to the one presented above. For the others 107 cases the claim was initially fo-cused only on anesthetists.

in 190 actions (60% of cases) the claim concerned a clinical case resulting in a fatal-ity, while in the remaining 127 (40% of cases) the adverse outcome was represented by vari-ous forms of permanent impairment (mostly traumatic dental damage [29.9%], peripheral neurological impairment [11.8%], superficial scars [7.1%] and permanent central nervous system damage associated with intubation pro-cedures [6.3%]). in 85% of fatalities, a judicial autopsy was performed and table i reports all encountered causes of death among autoptic cases.

Table I.—�Causes of death as determined by autopsy.cause of death n. cases (%)

Myocardial infarction/ventricular arrhythmia 53 (33.3)Multiorgan failure 48 (29.6)cerebral hemorrhage/ischemia 14 (8.6)arDs 12 (7.4)gastrointestinal perforation 8 (4.9)Hemorrhagic shock 8 (4.9)Pulmonary embolism 6 (3.7)Pulmonary edema 4 (2.4)anaphylactic shock 2 (1.2)eclampsia 2 (1.2)neoplasia 2 (1.2)Pneumonia 2 (1.2)



give more statistical relevant data. the lack of such a denominator value has already been stressed and discussed in other non-italian studies.20, 21

in the present study, only 6.7% of anes-thesia specialists incurred at least one claim, while 1.3% received two or more malpractice claims, over a 13-year period. offset against a recent rough estimate of an 18% prevalence of italian physicians accused of malpractice, our data appear to identify anesthesia special-ists as a low risk subgroup.21 Male anesthetists seem to be more frequently involved in litiga-tion (60% of cases), however there is no data on anesthetists’ gender distribution in italy. in 2012 tessler et al. reported that anesthe-tists aged 65 and over are approximately 1.5 times more likely of being found responsible for malpractice, compared with colleagues less than 51 years of age, although no underlying mechanism was determined.22 in 2014 Fergu-son et al. analyzed 38 closed claims from the

ing this period, we find that the number of malpractice claims underwent a non-constant increase, with a temporary decrease in 2012-13; however, a claim usually requires two to three years to be processed, so we are likely to experience a higher number of claims for the years 2012 and 2013. Permanent impairment was the most frequent final outcome cited as the basis for most malpractice claims (74.8%). a fatal outcome mostly concerned surgery-linked (74.2%) and multidisciplinary team malpractice claims (85.8%). in the population studied, we recognized 33 cases of death due to anesthesia malpractice, i.e. about one fatal malpractice case for every 100 anesthetists present in the archive. it is important to stress that the percentages shown only refer to the ar-chive of one italian insurance broker. We still do not know the overall annual number of an-esthesia interventions performed in italy, nor even the number of procedures performed by the insured physicians, which would certainly

Table II.—�Main study variables.sus-

pected multi-disciplinary malpractice

suspectedindividual

malpracticesurgery-

linked aenon surgery-

linked ae Death Permanent invalidity

Confirmed anesthetist malpractice

absence of anesthetist malpractice

suspected multidisciplinary malpractice (100%)

144(68.6%)

66(31.4%)

163(77.6%)

47(22.4%)

56(26.7%)

154(73.3%)

suspected individualmalpractice (100%)

81(75.7%)

26(24.3%)

27(25.2%)

80(74.8%)

72(67.3%)

35(32.7%)

surgery-linked ae (100%) 144(64%)

81(36%)

141 (62.6%)

84(37.4%)

57(25.3%)

168(74.7%)

non surgery-linked ae (100%) 66(71.8%)

26(28.2%)

49 (53.3%)

43(46.7%)

71(77.2%)

21(22.8%)

Death (100%) 163(85.8%)

27(14.2%)

141(74.2%)

49(25.8%)

33(17.3%)

157(82.7%)

Permanent invalidity (100%) 47(37%)

80(63%)

84(66.1%)

43(33.9%)

95(74.8%)

32(25.2%)

ae: adverse event.

Table III.—�Alleged medical error confirmed in malpractice cases.n. (%) Fatalities (%)

Procedural error during general anesthesia 18 (14.0) 14 (42.5)Procedural error during locoregional anesthesia 36 (28.1) 0 (0)incorrect patient positioning 3 (23.4) 0 (0)Management error in icU 20 (15.6) 9 (27.3)incorrectly performed oral intubation 35 (27.3) 0 (0)incorrectly performed intravascular procedure (cvc) 16 (12.5) 8 (24.2)total 128 (100) 33 (100)cvc: central venous catheter. icU: intensive care unit.



of all claims) being dental damage (in 68.5% of these cases the responsibility of the anes-thesiologist was ascertained). the individual patient cost of the so-called “dental claims” is usually low, but the high frequency of such events makes iatrogenic dental injury a rel-evant topic in anesthesia malpractice.28 in the remaining 53% of cases (41 cases) in which airways management error was suspected, responsibility of anesthesiologists was ascer-tained in 26.8% of cases (11 cases): in 45% (5 cases) of them, the impairment was due to permanent brain damage, in 65% (6 cases) the impairment was due to direct airways’ iatro-genic lesions.

locoregional anesthesia is now extreme-ly common and there are reports of serious complications developing more often than expected by several researchers.29-31 the inci-dence of injuries related to spinal anesthesia has been estimated to range between 0.08 and 0.12%.24, 32 Our data seem to confirm the risk arising from procedures not carried out under general anesthesia, as 28.1% of confirmed malpractice claims did concern an incorrect lo-coregional anesthesia procedure. in particular, 8 claims regarded spinal anesthesia, 21 epi-dural anesthesia and 7 events were linked to peripheral nerve blocks. none of these claims, however, resulted in the patient dying and per-manent impairment was assessed in only two cases (both caused by epidural injections re-sulting in lumbosacral paralysis). the lack of data regarding the overall italian prevalence of locoregional anesthesia procedures is again a limitation for the purpose of further discussion of the issue.

Major postoperative adverse events usually concern respiratory and circulation problems.26 in this study, there was a strong prevalence of nosocomial infections (above all surgical site infections or postoperative pulmonary compli-cations) and postoperative hemorrhage. Both types of adverse events may usually be consid-ered as extraneous to the anesthetist’s actions, even if they can prominently feature in claims filed against anesthetists.

an issue of note to emerge from our study is that the anesthetist’s liability in the adminis-

Detroit Medical center: the majority of claims were about female anesthetists and the most involved age group was specialists between 51 and 55 years.23 in contrast with trends reported by other authors in our study most of the phy-sicians accused of malpractice were younger than 45, suggesting that younger anesthetists, probably because less experienced, may be more exposed to claims. However there is a wide discrepancy in the number of cases analyzed in the different studies, and epide-miological statistics may also show place and time variations. We speculate this suggests that physicians’ and patients’ demographics have but a poor relevance to an actual risk manage-ment perspective.

it has been estimated that around 230 mil-lion patients worldwide undergo anesthesia for major surgery every year and that seven mil-lion patients develop severe complications as-sociated with the surgical procedures, resulting in one million deaths (200000 in europe).4 in the population studied, 66% of the claims re-garded multidisciplinary malpractice, involv-ing at least an anesthetist and a surgeon team and confirming that surgery-linked events are a major source of litigation also implicating anesthetists: in those cases, abdominal surgery, orthopedics and gynecology were the most in-volved surgical subspecialties.

airways management has always been con-sidered one of the most accident-prone fields in anesthesia and several countries proposed in-depth studies on this topic.24, 25 in the asaccP database, respiratory system man-agement complications or failures accounted for 17% of all claims.26 cook et al. analyzed 841 claims against the nHs in england be-tween 1995 and 2011 and found that 8.6% of complaints derived from airway management issues and that 11% involved dental damage.27 in 2005, aitkenhead et al. reported that dental damage was the cause of 63% of claims filed against anesthetists with the Medical Defence Union.28 in the present study, claims regard-ing airways management errors accounted for 24.3% of cases (most events directly con-nected to the surgical operation which the pa-tient underwent), 47% of which (and 11.4%



methods among published studies of anes-thesia malpractice does not allow immediate comparisons between settings. With such a perspective in view, even experimental contri-butions to medical malpractice would be bet-ter organized by multicenter and trans-national designs for studies with standardized database. anesthesiology could be once again a leader in this field.

Key messages — Medical malpractice is currently a

crucial topic and anesthesia is known to be a key specialty for the improvement of pa-tient safety.

— in the present study, malpractice was mainly suspected in surgery-linked pro-cedures, with locoregional anesthesia and intubation procedures as the main contribu-tors for the settlement of claims.

— in cases where malpractice was con-firmed, most of the cases concerned non surgery-linked procedures and non multi-disciplinary team cases, causing permanent impairment.

— Heterogeneity of experimental meth-ods among published studies of anesthe-sia malpractice does not allow immediate comparisons between settings: it would be desirable to support multicenter and trans-national studies in order to share homo-geneous methods of evaluations between countries.

References 1. Madea B. Medico-legal autopsies as a source of infor-

mation to improve patient safety. leg Med (tokyo) 2009;11(2 suppl):s76-s79

2. casali MB, Mobilia F, Del sordo s, Blandino a, gen-ovese U. the medical malpractice in Milan-italy. a retro-spective survey on 14 years of judicial autopsies. Foren-sic sci int 2014;242:38-43.

3. gaba DM. anaesthesiology as a model for patient safety in health care. BMJ 2000;320:785-8.

4. Whitaker DK, Brattebø g, smith aF, staender s. the Helsinki Declaration on Patient safety in anaesthesiol-ogy: Putting words into practice. Best Pract res clin an-aesthesiol 2011;25:277-90.

5. Kontogiannis t. a systems perspective of managing error recovery and tactical re-planning of operating teams in safety critical domains. J safety res 2011;42:73-85.

6. staender s, smith a, Brattebø g, Whitaker D. three

tration and monitoring of anesthetic drugs re-mains an important claim element to establish. in literature it is estimated that an anesthetist’s error occurs once out of 1300 drug administra-tion act.33, 34 owing to the complexity and im-portance of such an analysis, a judicial autopsy is mandatory in case of intraoperative fatality to establish the cause of death and the liabil-ity of the involved practitioners.11 this may be also of assistance to physicians, as in the vast majority of deaths where medical malpractice is suspected, the autopsy investigation fails to establish a causal relationship between death and the alleged malpractice, as our own data indirectly confirm.2, 35

there were several limitations to this study. We were unable to determine the total number of procedures undergone, and thus we cannot estimate what percentage of procedures lead to claims. as stated above, this problem has also been highlighted by several reports in the literature and certainly remains an important concern to address. there was no possibility of providing details on the experience of phy-sicians, and thus it was impossible to provide data on the level of knowledge among the in-volved physicians. Finally, the analyzed da-tabase covers only parts of our country. the creation of a national register to carry out an in-depth analysis of a larger share of the popu-lation is desirable. this type of registry could be the first step towards sharing trans-national data on the topic.

Conclusions

From the analysis of our data, anesthesia ap-pears to be a medical specialty at a low risk for medical malpractice claims. about 60% of all the analyzed claims were not finally con-firmed as ascertained malpractice cases. Con-firmed malpractice cases typically concerned non-surgery-linked errors committed by a sin-gle anesthetist with a final patient outcome of permanent impairment. Death from anesthesia malpractice can and does occur but it repre-sents only the tip of a much wider iceberg. national registers are necessary for in-depth analysis. the heterogeneity of experimental



to anaesthesia: an analysis of claims against the nHs in england 1995-2007. anaesthesia 2009;64:706-18.

22. tessler MJ, shrier i, steele rJ. association between anesthesiologist age and litigation. anesthesiology 2012;116:574-9.

23. Ferguson K, Young J, Panagopoulos P, Khoury P, McK-elvey gM, Fuleihan sF, et al. anesthesia related closed claims and litigations at the Detroit Medical center: anal-ysis, lessons learned, and conclusions. open Journal of anesthesiology 2014;4:88-98.

24. Hove lD, nielsen HB, christoffersen JK. Danish pa-tient insurance association. Patient injuries in response to anaesthetic procedures: cases evaluated by the danish patient insurance association. acta anaesthesiol scand 2006;50:530-5.

25. Peterson gn, Domino KB, caplan ra, Posner Kl, lee LA, Cheney FW. Management of the difficult airway: a closed claims analysis. anesthesiology 2005;103:33-9.

26. gisvold se, Fasting s. How do we know that we are doing a good job – can we measure the quality of our work?. Best Pract res clin anaesthesiol 2011;25:109-22.

27. cook tM, scott s, Mihai r. litigation related to airway and respiratory complications of anaesthesia: an analysis of claims against the nHs in england 1995-2007. anaes-thesia 2010;65:556-63.

28. aitkenhead ar. injuries associated with anaesthesia. a global perspective. Br J anaesth 2005;95:95-109.

29. auroy Y, Benhamou D, Bargues l, ecoffey c, Falissard B, Mercier FJ, et al. Major complications of regional an-esthesia in France: the sos regional anesthesia hotline service. anesthesiology 2002;97:1274-80.

30. compère v, rey n, Baert o, ouennich a, Fourdrinier v, roussignol X, et al. Major complications after 400 con-tinuous popliteal sciatic nerve blocks for postoperative analgesia. acta anaesthesiol scand 2009;53:339-45.

31. Moen v, Dahlgren n, irestedt l. severe neurological complications after central neuraxial blockades in swe-den1990–99. anesthesiology 2004;101:950-9.

32. currie M, Webb rK, Williamson Ja, russell WJ, Mackay P. the australian incident Monitoring study. clinical an-aphylaxis: an analysis of 2000 incident reports. anaesth intensive care 1993;21:621-5.

33. Webster cs, Merry aF, larsson l, Mcgrath Ka, Weller J. the frequency and nature of drug administration error during anaesthesia. anaesth intensive care 2001;29:494-500.

34. Webster cs, larsson l, Frampton cM, Weller J, Mc-Kenzie a, cumin D, et al. clinical assessment of a new anaesthetic drug administration system: a prospective, controlled, longitudinal incident monitoring study. an-aesthesia 2010;65:490-9.

35. lee la, stephens ls, Fligner cl, Posner Kl, cheney FW, caplan ra, et al. autopsy utilization in medi-colegal defense of anesthesiologists. anesthesiology 2011;115:713-7.

years after the launch of the Helsinki Declaration on pa-tient safety in anesthesiology: the history, the progress and quite a few challenges for the future. eur J anaesthe-siol 2013;30:651-4.

7. lagasse rs. anesthesia safety: model or myth? a review of the published literature and analysis of current original data. anesthesiology 2002;97:1609-17.

8. Mellin-olsen J, staender s, Whitaker DK, smith aF. the Helsinki Declaration on patient safety in anaesthesiology. eur J anaesthesiol 2010;27:592-7.

9. Bothner U, georgieff M, schwilk B. Building a large-scale perioperative anaesthesia outcome-tracking data-base: methodology, implementation, and experiences from one provider within the german quality project. Br J anaesth 2000;85:271-80.

10. lienhart a, auroy Y, Péquignot F, Benhamou D, Warsza-wski J, Bovet M, et al. survey of anesthesia-related mor-tality in France. anesthesiology 2006;105:1087-97.

11. turillazzi e, Bello s, Bonsignore a, neri M, riezzo i, Fineschi v. retropsective analysis of anaesthesia-related deaths during a 12-year period: looking at the data from a forensic point of view. Med sci law 2012;52:112-5.

12. closed claims Project and its registries [internet]. avail-able from http://depts.washington.edu/asaccp/projects/anesthesia-closed-claims-project [cited 2015, June 8].

13. Fasting s, gisvold se. Data recording of problems dur-ing anaesthesia: presentation of a well functioning and simple system. acta anaesthesiol scand 1996;40:1173-83.

14. Fasting s, gisvold se. serious intraoperative problems. A five-year review of 83,844 anaesthetics. Can J Anaesth 2002;49:545-53.

15. Mellin-olsen J, Fasting s, gisvold se. routine preop-erative gastric emptying is seldom indicated. a study of 85,594 anaesthetics with special focus on aspiration pneumonia. acta anaesthesiol scand 1996;40:1184-8.

16. Fasting s, gisvold se. equipment problems during an-aesthesia–are they a quality problem?. Br J anaesth 2002;89:825-31.

17. Fasting s, gisvold se. adverse drug errors in anaesthesia and the impact of coloured syringe labels. can J anaesth 2000;47:1060-7.

18. Marsh risk consulting, Medical malpractice claims analysis 2013 [internet]. available from http://www.sanita.ilsole24ore.com/pdf2010/sanita2/_ogget-ti_correlati/Documenti/imprese/stUDio_MarsH.pdf?uuid=66674138-9e21-11e3-9f80-88df8305bae5 [cited 2015, June 8].

19. stiegler MP, ruskin KJ. Decision-making and safety in anesthesiology. curr opin anaesthesiol 2012;25:724-9.

20. Merry aF, shipp DH, lowinger Js. the contribution of labelling to safe medication administration in anaesthetic practice. Best Pract res clin anaesthesiol 2011;25:145-59.

21. cook tM, Bland l, Mihai r, scott s. litigation related

Conflicts of interest.—The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript.Article first published online: June 30, 2015. - Manuscript accepted: June 25, 2015. - Manuscript revised: June 22, 2015. - Manuscript received: February 18, 2015.


the current mechanical ventilation strategy for minimizing vili is to apply relatively low tidal volume (vt) and positive end-expiratory pressure (PeeP) in order to maintain plateau pressure below the 30 cmH2o threshold. How-ever, low vt and/or inadequate PeeP levels promote alveolar derecruitment.3 recruitment maneuvers (rMs), aimed to reopen not aerated lung regions through a transient elevation in transpulmonary pressure has been proposed.4

invasive mechanical ventilation is routinely used to support patients during general anes-

thesia and with acute respiratory distress syn-drome (arDs). However mechanical ventila-tion has the potential to induce a iatrogenic form of acute lung injury named ventilator-induced lung injury (vili).1 thus it now clearly stated that the main target of mechanical ventilation in arDs is not only to improve gas exchange but to minimize vili as much as possible.2

R E V I E W

recruitment maneuvers in acute respiratory distress syndrome and during general anesthesia

Davide cHiUMello 1, 2 *, ilaria algieri 2 salvatore grasso 3, Pierpaolo terragni 4, Paolo Pelosi 5

1Dipartimento di anestesia, rianimazione (intensiva e subintensiva) e terapia del Dolore, Fondazione irccs ca’ granda, ospedale Maggiore Policlinico, Milan, italy; 2Dipartimento di Fisiopatologia Medico-chirurgica e dei trapianti, Università degli studi di Milano, Milan, italy; 3Dipartimento dell’emergenza e trapianti d’organo (Deto), Università degli studi di Bari “aldo Moro”, Bari, italy; 4Dipartimento di scienze chirurgiche, Università degli studi di torino, azienda ospedaliero-Universitaria città della salute e della scienza di torino, turin, italy; 5Dipartimento di scienze chirurgiche e Diagnostiche applicate, irccs san Martino ist, genoa, italy*corresponding author: Davide chiumello, Dipartimento di anestesia, rianimazione (intensiva e subintensiva) e terapia del dolore, Fondazione irccs ca’ granda, ospedale Maggiore Policlinico, via F. sforza 35, 20122, Milano, italy. e-mail: [email protected]


lavoro: titolo breve: recrUitMent ManeUvers in arDsprimo autore: cHiUMellopagine: 210-20citazione: Minerva anestesiol 2016;82:210-20

a B s t r a c tthe use of low tidal volume ventilation and low to moderate positive end-expiratory pressure (PeeP) levels is a wide-spread strategy to ventilate patients with non-injured lungs during general anesthesia and in intensive care as well with mild to moderate acute respiratory distress syndrome (arDs). Higher PeeP levels have been recommended in severe arDs. Due to the presence of alveolar collapse, recruitment maneuvers (rMs) by causing a transient elevation in airway pressure (i.e. transpulmonary pressure) have been suggested to improve lung inflation in non-inflated and poorly-inflated lung regions. Various types of RMs such as sustained inflation at high pressure, intermittent sighs and stepwise increases of PeeP and/or airway plateau inspiratory pressure have been proposed. the use of rMs has been associated with mixed results in terms of physiological and clinical outcomes. The optimal method for RMs has not yet been identified. The use of rMs is not standardized and left to the individual physician based on his/her experience. Based on the same grounds, rMs have been proposed to improve lung aeration during general anesthesia. the aim of this review was to present the clinical evidence supporting the use of rMs in patients with arDs and during general anesthesia and as well their poten-tial biological effects in experimental models of acute lung injury.(Cite this article as: chiumello D, algieri i, grasso s, terragni P, Pelosi P. recruitment maneuvers in acute respiratory distress syndrome and during general anesthesia. Minerva anestesiol 2016;82:210-20)Key words: Mechanical ventilation - general anesthesia - acute respiratory distress syndrome.

Minerva anestesiologica 2016 February;82 (2):210-20© 2016 eDiZioni Minerva MeDicathe online version of this article is located at http://www.minervamedica.it

recrUitMent ManeUvers in arDs cHiUMello


(usually in cPaP mode) is transiently applied (20-40 s); 3) the extend sigh rM, where a step-wise PeeP increases is applied in order to in-crease airway pressure in volume or pressure controlled mode.

In Figure 1 is a suggested flow chart for lung recruitment.

Sigh RM

in a small group of arDs patients, a sigh rM based on three consecutive higher vts per minute, able to reach 45 cmH2o of plateau airway pressure, lead to a significant improve-ment in arterial oxygenation, lung aeration and elastic properties of the respiratory system.9 of note after only 30 minutes from sigh interrup-tion, all these physiological beneficial effects were lost. Pelosi et al. showed that a sigh rM applied in the prone position could provide greater lung recruitment in the early stage of arDs, as compared to supine position.10 in a larger population of arDs patients, villagrà et al. investigated the effect of sigh rMs in patients with early and late arDs.11 Despite arterial oxygenation was not affected, the rMs

although several experimental data showed that rMs could reduce or prevent the vili, clinical studies did not report homogenous data. in addition three recent systematic re-views and meta-analysis were discordant: one concluded that rMs could improve the sur-vival 5 while the two others stated that there is no evidence that rMs could reduce mortality 6 and concluded that, at the moment, rM cannot be recommended or discouraged.7

lung derecruitment may also occur during general anesthesia though with different mech-anisms than in arDs. since several years rMs have been suggested to improve lung aeration during general anesthesia.8

aim of this clinical review is to revise the role of rMs (if any) during general anesthesia and in arDs patients.

Acute respiratory distress syndrome

the most frequently reported rMs are (ta-ble i): 1) the sigh rM in which higher vts and inspiratory airway pressures are intermit-tently delivered; 2) the sustained inflation RM in which a static increase in airway pressure

Figure 1.—Suggested flow chart for lung recruitment.

cHiUMello recrUitMent ManeUvers in arDs


Table I.—�Clinical studies evaluating recruitment maneuvers.author, year n. Diagnosis study type ventilation strategy rM type gas exchange Mortality complications

Pelosi (1999) 9

10 arDs observational vt 6-8 ml/kgPeeP 14±2.2 cmH2o

sigh Pao2 significantly increased; reduction of Paco2

overall mortality n.=5 (50%)

no data

Pelosi (2003) 10

10 arDs (early) observational vt 7 ml/kg aBWPeeP 14±3 cmH2o

sigh Pao2 significantly increased in both supine and prone

overall mortality n.=4 (40%)

no major complication

villagrà (2002) 11

17 arDs (early: 8 patient were also studied in late phase)

observational vt <8 ml/kgPeeP 14±1 cmH2o

sigh Pao2 not increased during rM. Paco2 increased and pH decreased significantly. Values returned to baseline 15 min after rM in early but remained altered in late arDs group

no data no major complication

lapinski (1999) 12

14 arDs (early) observational vt 12 ml/kgPeeP mean 10.4 cmH2o

sustained inflation

spo2 significantly increased by 10 min after rM


oczenski (2004) 13

30 arDs (early) randomized vt 6 ml/kg iBWPeeP, rM group 15.1±1.2 cmH2o, no-rM group: 14.5±1.3 cmH2o

sustained inflation

Pao2 significantly increased at 3 min after rM, baseline values were reached again within 30 min


Xi (2010) 14 110 arDs randomized vt, rM group 6.6±0.9 ml/kg, no-rM group 6.8±1.1 ml/kgPeeP, rM-group 10.5±3.2 cmH2o, no-rM group 9.7±2.4 cmH2o

sustained inflation

no differences in Pao2 between two groups

no differences in hospital and 28-day mortality. icU mortality significantly lower in rM group

Hypotension: in one instance rM was terminated early

Brower (2003) 15

96 ali/arDs (only in patients with high PeeP)

crossover study

vt 6.0±0.8 ml/kg PBWPeeP 13.8±3.0 cmH2o

sustained inflation

spo2 were greater within 10 and 60 mins after rMs than after sham rMs; no significant differences at the other time points

no data Hypotension and low spo2: in three instances rMs were terminated early.Barotrauma after one rM and after one sham rM

grasso (2002) 16

22 arDs observational vt, rM-responding group 6.1±0.1 ml/kg, rM-non-responding group 6.0±0.2 ml/kgPeeP, rM-responding group 9.4±2.2 cmH2o, rM-non-responding group 9.1±2.7 cmH2o

sustained inflation

Pao2 significantly increased in rM-responding group than in non-responding; 20 min after values of Pao2 tended to return toward baseline values in both groups

no data Hypotension (transitory) in PeeP non-responding group

Meade (2008) 17

27 ali/arDs observational vt 8.4±3.0 ml/kgPeeP 10±4 cmH2o

sustained inflation

Pao2 not significantly increased following the first or subsequent rMs. augmenting the inflation pressure or duration had no significant effect

no data Barotrauma: 4 (3.2%), ventilator asynchrony: 5 (4%), appeared uncomfortable: 3 (2.4%), experienced transient hypotension: 2 (1.6%)

Foti (2000) 18

15 arDs (only PeeP responders)

observational vt 7.9 ml/kgPeeP 13.3±27.7 cmH2o

extended sigh

Pao2 and sao2 significantly increased after rMs, no difference in Paco2





Johannigman (2003) 19

12 arDs (early) observational vt (study) 6.3 ml/kg iBWPeeP 12.3±3.2 cmH2o

extended sigh

Pao2 significantly increased 3 mins after rM. two hours after the rM, oxygenation fell below 30-min values but remained greater than pre-rM values


Borges (2006) 20

26 ali/arDs (early)

observational vt 6 ml/kg PBWPeeP 5-10 cmH2o

extended sigh

Pao2 significantly increased

overall icU mortality: 11 (42.3%), hospital death 14 (57.7%)


Moràn (2011) 21

13 ali/arDs (early)

observational vt 7.8 ml/kg iBWPeeP 15±4 cmH2o

extended sigh

Pao2 significantly increased and remained greater than pre-rM values

no data transitory hypotension

Katsiari (2012) 22

25 arDs (early) observational vt 8.5±1.4 ml/kg iBWPeeP 10±3 cmH2o

sighsustained inflationthree consecutive sighs

Pao2 significantly improved after all rMs. in patients with BMi>27 kg/m2 only sustained inflation induced a longer improvement

overall icU mortality: 8 (32%)


lim (2003) 23

47 arDs (early) randomized vt 8 ml/kgPeeP of 10 cmH2o

extended sigh

Pao2 significantly increased in rM+PeeP group. Pao2 in rM-only and in PeeP-only group did not differ. Patients with extrapulmonary arDs showed greater increase in Pao2 after rM

rM+PeeP 10 (50%); rM 10 (52.6%); PeeP-only group 7 (87.5%)


constantin (2008) 24

19 arDs (early) randomized vt 6 ml/kgPeeP 14±2 cmH2o

sustained inflationextended inflation

Both rMs increased oxygenation; increase in Pao2 was significantly higher with extended sigh than sustained inflation RM at 5 and 60 min

overall mortality: 6 (31%); cPaP 2 (22%), extended sigh 4 (40%)

Hypotension: in two instances rM was terminated early

iannuzzi (2010) 25

40 arDs randomized vt 6 ml/kgPeeP 14 cmH2o

sustained inflationextended inflation

Pao2 significantly increased after extended inflation; Paco2 levels were lower compared to sustained inflation group

no data Hypotension: more during sustained inflation RM

amato (1998) 26

53 arDs (early) randomized vt, protective ventilation 6 ml/kg, control group 12 ml/kgPeeP, protective ventilation 16.4±0.4 cmH2o, control group 6.2±0.5 cmH2o

sustained inflation

Pao2 significantly increased in protective ventilation group; Paco2 higher in protective group

28 days-mortality: 11 (38%) in protective ventilation group vs. 17 (71%) in control group (P=0.001)

Barotrauma: 2 (7%) in protective-ventilation vs. 10 (42%) in control group (significantly lower)

Meade (2008) 27

983 ali/arDs randomized vt, lov group 6.8±1.4 ml/kg, control group 6.8±1.3 ml/kgPeeP, lov group 14.6±3.4 cmH2o, control group 9.8±2.7 cmH2o

sustained inflation

lov group had lower rates of refractory hypoxemia and lower mortality rates with refractory hypoxemia; no difference in Paco2

Hospital mortality: 36.4% in lov group and 40.4% in the control group

Hypotension: 4.5%, desaturation: 4.2%, bradycardia or tachycardia: 1.8%, cardiac arrhythmia: 0.3%, new air leak through an existing thoracostomy tube: 0.3%; barotrauma: lov 53 (11.2%) control 47 (9.1%)

Table I.—�Continues from previous page.




Huh (2009) 28

57 arDs randomized vt, experimental group 7.9±1.9 ml/kg, control group 8.0±1.4 ml/kgPeeP, experimental group 8.4±3.1 cmH2o, control group 7.0±3.7 cmH2o

extended sigh

Pao2 significantly increased in decremental PeeP titration group than in control group. Paco2 was higher in decremental PeeP titration group than in control group on day 1. improvement of Pao2 and Paco2 level were not different between two groups during follow-up

overall mortality 37%. 28 and 60-day mortality did not differ between two groups

Barotrauma: 3 (11%) in experimental vs. 3 (11%) in control group

Hogdson (2011) 29

20 arDs randomized vt 6 ml/kg in both groupsPeeP, experimental group 15±1 cmH2o, control group 10±0.5 cmH2o

extended sigh

Pao2 significantly increased in experimental group than control group over the first 24 hours and over 7 days

any difference in hospital mortality between two group

Desaturation in three instances at maximum PeeP of 40 cmH2o (no lasting adverse effects)

Park (2009) 30

53 total laparoscopic hysterectomy

randomized vt 10 ml/kg and ZeeP

sigh Pao2 increased during pneumoperitoneum in rM group than in no-rM group

no data no data

cinnella (2013) 31

29 elective gynecologic laparoscopic surgery

observational vt 8 ml/kg iBWPeeP 5 cmH2o

extended sigh

Pao2 increased during and after rM


ProvHilo (2014) 32

900 elective open abdominal surgery, with intermediate or high risk for postoperative pulmonary complications

randomized vt 8 ml/kg PBW in both groupsPeeP, experimental group 12 cmH2o with rMs, control group ≤2 cmH2o without rMs

extended sigh

spo2 significantly higher in the higher PeeP group

no difference at day 5 (<1%) or in-hospital (2%)

intraoperative hypotension in higher PeeP group

Futier (2013) 33

400 elective laparoscopic or open major abdominal surgery and intermediate to high preoperative risk for pulmonary complications

randomized vt, control group 6 to 8 ml/kg PBW, control group 10 to 12 ml/kg PBWPeeP, experimental group 6-8 cmH2o and rMs repeated every 30 mins, control group ZeeP and no rM

sustained inflation

no differences between groups

no difference in mortality at 30 days between the two groups

no difference between the two groups

severgnini (2013) 34

56 elective open abdominal surgery

randomized vt, experimental group 7 ml/kg iBW, control group 9 ml/kg iBWPeeP, experimental group 10 cmH2o, control group ZeeP

extended sigh

Pao2 higher in patient ventilated protectively at days 1, 3, and 5

none of the patients died

Hypotension: 9 (33.3%); bradycardia: 2 (7.4%)

rM: recruitment maneuver; aBW: actual body weight; iBW: ideal body weight; PBW: predicted body weight; ali: acute lung injury; arDs: acute respiratory distress syndrome; vt: tidal volume; PeeP: positive end-expiratory pressure; ZeeP: zero end-expiratory pressure.

induced a significant increase in the lung gas volume only in the early arDs group.

Sustained inflation RM

lapinsky et al. evaluated sustained infla-tion RMs (CPAP; inflation pressure between 30 and 45 cmH2o sustained for 20 seconds)

in patients with hypoxemic respiratory failure. The arterial saturation significantly increased significantly after 10 minutes.12 The benefi-cial effect of the rM in terms of oxygenation lasted at least 4 hours in the majority of the patients. Patients with pulmonary and extra-pulmonary arDs presented a similar change in oxygenation. oczenski et al. studied a group

Table I.—�Continues from previous page.



ing from trauma ventilated with a low tidal volume strategy, the arterial oxygenation was not affected after thirty minutes and two hours of rMs.19 rMs were performed by increasing PeeP to 30 cmH2o for 40 seconds and setting the ventilator in pressure control mode with a delta pressure of 10 cmH2o. to maximize the lung recruitment Borges et al. proposed a new maximum recruitment strategy.20 this strategy consisted of a progressively increase of PeeP from 25 to 45 by maintaining constant the driving pressure at 15 cmH2o during pressure control ventilation. At the final step (i.e. higher airway pressure) the arterial oxygenation and the amount of collapsed lung tissue were sig-nificantly higher and lower, respectively, com-pared to baseline ventilation. By applying a similar aggressive recruitment strategy in the early phase of ali/arDs Morán et al. found in the average a better oxygenation compared to baseline but with a greater variability with a transitory hypotension; however in forty per-cent of the patients it was discontinued.21

considering the possible effect of the body mass in altering the chest wall elastance, three different rMs were tested in obese patients.22 The first RM consisted of a pressure controlled ventilation with an inspiratory pressure of 40 and PeeP of 5 cmH2o for 1 minute, the second consisted of a cPaP of 45 cmH2o for 20 seconds and the least 3 consecutive sighs with a tidal volume to reach a plateau pres-sure of 45 cmH2O. All the RMs significantly improved the oxygenation however in patients with a body mass index higher than 27 kg/m2 only the sustained inflation caused a longer improvement in oxygenation compared to the other two up to thirty minutes. lim et al. ran-domized early arDs, after applying a PeeP of 15 cmH2o, to receive a rM or to continue mechanical ventilation.23 the rMs were per-formed by an extended sigh with a progres-sive increase in pressure and time twice with 1 minute interval. after 60 minutes the arterial oxygenation was not higher in the rMs group. the arterial oxygenation was higher in the ex-trapulmonary arDs compared to pulmonary arDs with a mean increase of 130% vs. 27% respectively. constantin et al. compared the

of patients with early arDs ventilated with low a tidal volume.13 The RMs significantly increased the arterial oxygenation within 3 minutes, however after 30 minutes the oxy-genation returned to baseline values. Xi et al. in a randomized multicenter study evaluated the effect of a rM delivered every eight hours for five successive days.14 except for day one and two, arterial oxygenation was not differ-ent between the two groups as well as hospital mortality (42% vs. 56%). in patients enrolled in the higher PeeP arm of the alveoli study, the application of rMs (cPaP up to 35 cmH2o for 30 seconds) significantly increased the ar-terial saturation with a highly variability after 60 minutes.15

grasso et al. evaluated the physiological ef-fects of sustained inflation RMs. The results were related to partitioned lung and chest wall mechanics.16 in only the half of twenty two pa-tients enrolled, arterial oxygenation increased after the rM (responders). chest wall elas-tance was significantly higher in non-respond-ers and consequently the transpulmonary pres-sure applied to the lung during the rMs was significantly lower in non-responders than in responders. Meade et al. investigated the ef-fects of different inflation pressures and du-ration of the rMs on arterial oxygenation.17 they started from standard rMs (cPaP, 35 cmH2o, for 20 seconds) twice a day. if the re-sponse to the standard rMs was sub-optimal, different rMs were tested by either increasing inflation pressure (40-45 cmH2o) or duration (30-40 seconds). the standard rMs slightly increased the oxygenation only in 14% of the patients; both the increase in rMs duration and inflation pressure did not further improve the oxygenation.

Extended sigh RM

Foti et al. investigated the effect of an ex-tend sigh delivered by an intermittent in-crease in PeeP for two consecutive ventilator cycles.18 arterial oxygenation and lung gas volume significantly increased compared to baseline ventilation within 30 minutes. on the contrary in a group of arDs patients result-



genation and PeeP the hospital mortality was not different (36% vs. 40%, P=0.19). similarly Huh et al. randomized a group of arDs pa-tients to a ventilation strategy with rMs with PeeP selected at the end of the rM versus a control strategy in which PeeP was selected based on a Fio2/PeeP table.28 rMs were ap-plied as an extended sigh with incremental PeeP from baseline to 25 cmH2o and reduc-ing the vt to not overcome an airway pressure of 55 cmH2o. the oxygenation and the 28 day mortality at were not different (40% vs. 33%). Hodgson et al. evaluated an open lung venti-lation using rMs, high PeeP and permissive hypercapnia compared to a control strategy in arDs patients.29 the rMs were delivered in pressure control ventilation with a fixed delta pressure of 15 cmH2o above different levels of PeeP from 20 to 40 cmH2o every two min-utes. the PeeP and arterial oxygenation were significantly higher in the treatment group compared to control strategy, the hospital sur-vival was not different.

in synthesis, for arDs patients, since the era of large tidal volume ventilation should be over, the application of protective ventilation settings with small tidal volume and high lev-els of PeeP and rMs have the most impact on outcome leading to an increase on oxygenation but not in a mortality reduction.

General anesthesia

the role of rMs, although tested in some trials,15, 27 in clinical practice remains uncer-tain because of questions about its effect on outcomes and concerns regarding compli-cations (e.g., hemodynamic compromise or pneumothorax).17 two trials explored the ef-ficacy of RMs and PEEP in “non-obese pa-tients” during gynecologic laparoscopic sur-gery: the randomized controlled trial by Park et al. demonstrated the effectiveness of “pre-emptive use” of rMs coupled to 15 cmH2o of PEEP (applied before insufflation of the peri-toneal cavity) by improving oxygenation with the alveolar recruitment.30 in the same surgi-cal contest, cinnella et al. evaluating an open-lung approach with the combination of rMs

respiratory effects of two RM a sustained infla-tion with a cPaP at 40 cmH2o for 40 seconds and an extended sighs consisting of increasing PeeP 10 cmH2O above the lower inflection point maintaining a volume controlled venti-lation.24 At 5 minutes both RM significantly increased the arterial oxygenation compared to baseline, however the extended sighs in a greater extension. By comparing the extend-ed sighs and the sustained inflation RM for a similar peak airway pressure (45 cmH2o) and time (40 seconds), iannuzzi et al. showed that the extended sighs caused a major increase in arterial oxygenation.25

in summary, for arDs patients the effects of rMs in addition to adequate PeeP levels as a component of ventilation strategy may be greater in whom there is a higher potential for lung recruitment. the use of rMs and its posi-tive effects on lung collapse and gas exchange will continue to be guided by individual clini-cian experience and patient factors as sever-ity of lung disease, amount of edema and the reached airway pressure

Lung open ventilation

Four randomized studies tested in arDs pa-tients the efficacy of a global lung ventilation strategy (i.e., lung open ventilation) consisting of low tidal volume with high levels of PeeP and rMs compared to conventional strate-gy.26–29 The first study compared a tidal vol-ume lower than 6 ml/kg with a PeeP set high-er than the inflection point and RMs performed with cPaP mode at 40 cmH2o for 40 seconds versus a tidal volume of 12 ml/kg with the lowest acceptable PeeP.26 the lung open ven-tilation significantly reduced the 28 days mor-tality but not the hospital mortality (38% vs. 71%, P<0.01; and 45% vs. 71%, P=0.09). the second study evaluated a lung ventilation with similar tidal volume (i.e. 6 ml/kg) with high levels of PeeP and rMs a versus low levels of PeeP.27 rMs were performed by a 40 sec-onds breath-hold at 40 cmH2o airway pressure followed each disconnection from the venti-lator, up to 4 times daily. although the lung open ventilation showed a higher arterial oxy-



of the ProvHilo study that instead tests the protective effects (absent) of high PeeP with rM vs. non-use of PeeP coupled to the low vt. a more recent meta-analysis including 3365 individual patients showed that postop-erative lung injury is associated with increases in in-hospital mortality and durations of stay in intensive care and hospital. attributable mor-tality due to postoperative lung injury is higher after thoracic surgery than after abdominal sur-gery. lung protective mechanical ventilation strategies reduces incidence of postoperative lung injury but does not improve mortality.36

in summary, patients with normal lungs dur-ing general anesthesia can improve respiratory function if ventilated with protective ventila-tion strategy with low vt but associated to rMs and adequate level of PeeP. the only use of high levels of PeeP even if associated to low vt, or high vt without PeeP and rMs do not improve patient outcomes. We point out the effectiveness of high PeeP levels and rMs in obese patients undergoing to laparoscopy, to preserve recruitment of the lungs from the detrimental effects of pneumoperitoneum and trendelenburg position.

Biological response to RMs in experimental models of acute lung injury

recruitment maneuvers may induce differ-ent biological and morpho-functional response on the pulmonary structure, mainly the epithe-lium, the endothelium, as well as the extracel-lular matrix. Specifically, the effects of recruit-ment maneuvers may depend on the following factors: type of acute lung injury (primary or secondary insult to the lung); the extent of lung injury (predominance of alveolar collapse or alveolar edema); the volemic status (hypervol-emia, normovolemia or hypovolemia) and the type of the recruitment maneuvers (sustained inflation, sigh, extended sigh, slow vs. fast re-cruitment maneuvers).

Cause of acute lung injury

Using experimental models of pulmonary and extrapulmonary acute lung injury induced

and PeeP (5 cmH2o) after pneumoperitoneum induction showed similar data.31

the ProvHilo trial (Protective ventila-tion using High versus low PeeP) tested the hypothesis that high PeeP levels (12 cmH2o) associated with rMs could decrease postop-erative pulmonary complications during pro-tective ventilation.32 The trial confirmed the ineffectiveness of high level of PeeP and rMs in reducing the incidence of postoperative pulmonary complications while there was an increased risk of hemodynamic instability, if compared with use of low PeeP without rMs. Futier et al. investigated the effectiveness of rMs and high PeeP levels, in a group of obese patients undergoing to laparoscopy, demon-strating the role of rMs associated to PeeP 10 cmH2o to preserve recruitment of the lungs from the detrimental effects of pneumoperito-neum and trendelenburg position.33 Focusing on the protective role of low vt and PeeP with rMs in patients during general anesthesia for more than 2 hours with open abdominal sur-gery, severgnini et al. found a significant en-hancement of postoperative pulmonary func-tion and confirmed the detrimental effects of large vt during general anesthesia.34 a similar study design was performed by the iMProve study group.35 authors assigned patients dur-ing general anesthesia to receive ventilation according to one of two strategies: a) non protective ventilation with high vt (10-12 ml/kg PBW), without PeeP and no rMs, b) protective ventilation with low vt (6-8 ml/kg PBW) with PeeP (6-8 cmH2o) and rMs repeated every 30 minutes after tracheal intu-bation; airway plateau pressure was limited to 30 cmH2o in each group. the study based on a large number of patients recruited (at risk of pulmonary complications), demonstrated that an intraoperative lung-protective mechanical ventilation improved clinical outcomes and re-duced health care utilization after abdominal surgery in patients at high risk of complica-tions. this study addresses the issue of lung protection in patients without pulmonary func-tion abnormalities and match the beneficial ef-fects of low tidal volume with PeeP, but does not support, at least in appearance, the results



interferon-gamma, and type iii procollagen mrna expressions in lung tissue and lung epi-thelial cell apoptosis decreased more in PrM. in conclusion, PrM improved lung function, with less damage to alveolar epithelium, re-sulting in reduced pulmonary injury.

silva et al.41 in experimental model of acute lung injury induced by cecal ligation and punc-ture in rats found that longer-duration rMs with slower airway pressure increase efficient-ly improved lung function, while minimizing the biological impact on lungs as compared to sustained inflation or stepwise with reduced duration.

in another study, silva et al.42 in experimen-tal models of pulmonary and extrapulmonary acute lung injury induced by Escherichia coli lipopolysaccharide in rats, found that sus-tained inflation worsened markers of poten-tial epithelial cell damage in pulmonary acute lung injury, whereas both sustained inflation and stepwise recruitment maneuver yielded endothelial injury in extrapulmonary acute lung injury. in both acute lung injury groups, recruitment maneuvers improved respiratory mechanics, but stepwise recruitment maneu-ver without sustained airway pressure ap-peared to associate with less biological impact on lungs.

Conclusions

rMs in arDs are able to increase in the majority of the patients the oxygenation for a limited period of time, however they seem to not affect the outcome. in healthy subjects dur-ing general anesthesia, rMs as a component of an open lung strategy, could improve pulmo-nary function especially in selected categories of patients with high potential of lung recruit-ment and without primary pulmonary disease (i.e. in presence of impairment of chest wall elastance due to obesity or during laparoscopy surgery).

Future studies will be helpful to determine whether protective lung ventilation strategy with rMs could improve major clinical out-comes thus achieving consensus regarding its appropriate function in clinical practice.

by escherichia coli lipopolysaccharide admis-tration intratracheally or intraperitoneally in rats, with similar transpulmonary pressures, riva et al.37 reported that sustained infla-tion recruitment maneuver is more effective at opening collapsed alveoli, thus improving lung mechanics and oxygenation with limited damage to alveolar epithelium in extrapulmo-nary than in pulmonary acute lung injury.

Extent of lung injury (alveolar collapse versus edema)

santiago et al.38 in an experimental model of acute lung injury induced by different increas-ing dosage of Escherichia coli lipopolysac-charide intraperitoneally in rats reported that recruitment maneuvers promoted a decrease in inflammatory and fibrogenic response, and greater improvement in lung function in the presence of alveolar collapse alone as com-pared to alveolar collapse associated with al-veolar edema.

Effect of volemia

Fluid management plays a relevant role in the management of arDs. silva et al.39 inve-stigated the effects of recruitment maneuvers on lung and distal organs in the presence of hypovolemia, normovolemia, and hypervole-mia in mice. in hypervolemic animals, recruit-ment maneuver improved oxygenation but increased lung injury and led to higher inflam-matory and fibrogenic responses, suggesting that volemic status should be taken into ac-count during recruitment maneuvers.

Type of RMs: sustained inflation vs. stepwise or slow recruitment

rzezinski et al. investigated the effects of prolonged recruitment maneuver (PrM) com-pared with sustained inflation (SI) in paraquat-induced mild acute lung injury in rats.40 lung static elastance and the amount of alveolar col-lapse were more reduced with PrM than si, yielding improved oxygenation. additionally, tumor necrosis factor-alpha, interleukin-6,



recruitment in adults with respiratory failure. intensive care Med 1999;25:1297-301.

13. oczenski W, Hörmann c, Keller c, lorenzl n, Kepka a, schwarz s, et al. recruitment maneuvers after a posi-tive end-expiratory pressure trial do not induce sustained effects in early adult respiratory distress syndrome. an-esthesiology 2004;101:620-5.

14. Xi X-M, Jiang L, Zhu B, RM group. Clinical efficacy and safety of recruitment maneuver in patients with acute res-piratory distress syndrome using low tidal volume venti-lation: a multicenter randomized controlled clinical trial. chin Med J (engl) 2010;123:3100-5.

15. Brower rg, Morris a, Macintyre n, Matthay Ma, Hay-den D, thompson t, et al. effects of recruitment maneu-vers in patients with acute lung injury and acute respi-ratory distress syndrome ventilated with high positive end-expiratory pressure. crit care Med 2003;31:2592-7.

16. grasso s, Mascia l, Del turco M, Malacarne P, giunta F, Brochard l, et al. effects of recruiting maneuvers in patients with acute respiratory distress syndrome venti-lated with protective ventilatory strategy. anesthesiology 2002;96:795-802.

17. Meade MO, Cook DJ, Griffith LE, Hand LE, Lapinsky se, stewart te, et al. a study of the physiologic re-sponses to a lung recruitment maneuver in acute lung in-jury and acute respiratory distress syndrome. respir care 2008;53:1441-9.

18. Foti g, cereda M, sparacino Me, De Marchi l, villa F, Pesenti a. effects of periodic lung recruitment maneu-vers on gas exchange and respiratory mechanics in me-chanically ventilated acute respiratory distress syndrome (arDs) patients. intensive care Med 2000;26:501-7.

19. Johannigman Ja, Miller sl, Davis Br, Davis K, Campbell RS, Branson RD. Influence of low tidal vol-umes on gas exchange in acute respiratory distress syn-drome and the role of recruitment maneuvers. J trauma 2003;54:320-5.

20. Borges JB, okamoto vn, Matos gFJ, caramez MPr, arantes Pr, Barros F, et al. reversibility of lung col-lapse and hypoxemia in early acute respiratory distress syndrome. am J respir crit care Med 2006;174:268-78.

21. Morán i, Blanch l, Fernández r, Fernández-Mondéjar e, Zavala e, Mancebo J. acute physiologic effects of a step-wise recruitment maneuver in acute respiratory distress syndrome. Minerva anestesiol 2011;77:1167-75.

22. Katsiari M, Koulouris ng, orfanos se, Maguina n, sotiropoulou c, Koutsoukou a. intercomparison of three recruitment maneuvers in acute respiratory distress syn-drome: the role of Body Mass index. Minerva anestesiol 2012;78:675-83.

23. lim c-M, Jung H, Koh Y, lee Js, shim t-s, lee s-D, et al. effect of alveolar recruitment maneuver in early acute respiratory distress syndrome according to antidere-cruitment strategy, etiological category of diffuse lung injury, and body position of the patient. crit care Med 2003;31:411-8.

24. constantin J-M, Jaber s, Futier e, cayot-constantin s, verny-Pic M, Jung B, et al. respiratory effects of differ-ent recruitment maneuvers in acute respiratory distress syndrome. crit care lond engl 2008;12:r50.

25. iannuzzi M, De sio a, De robertis e, Piazza o, ser-villo g, tufano r. Different patterns of lung recruitment maneuvers in primary acute respiratory distress syn-drome: effects on oxygenation and central hemodynam-ics. Minerva anestesiol 2010;76:692-8.

26. amato MB, Barbas cs, Medeiros DM, Magaldi rB, schettino gP, lorenzi-Filho g, et al. effect of a protec-tive-ventilation strategy on mortality in the acute respira-tory distress syndrome. n engl J Med 1998;338:347-54.

27. Meade Mo, cook DJ, guyatt gH, slutsky as, arabi YM, cooper DJ, et al. ventilation strategy using low

Key messages

— recruitment maneuvers in acute re-spiratory distress syndrome improve oxy-genation in the majority of the patients.

— the effects of the recruitment ma-neuvers depend on the transpulmonary pressure generated in the patients.

— recruitment maneuvers do not im-prove the outcome in patients with arDs.

— During general anesthesia, recruit-ment manures could be used in selected categories of patients.

References 1. Dreyfuss D, saumon g. ventilator-induced lung injury:

lessons from experimental studies. am J respir crit care Med. 1998;157:294-323.

2. Kacmarek rM, villar J. lung recruitment maneuvers during acute respiratory distress syndrome: is it useful? Minerva anestesiol 2011;77:85-9.

3. Halter JM, steinberg JM, schiller HJ, Dasilva M, gat-to la, landas s, et al. Positive end-expiratory pressure after a recruitment maneuver prevents both alveolar col-lapse and recruitment/derecruitment. am J respir crit care Med 2003;167:1620-6.

4. lapinsky se, Mehta s. Bench-to-bedside review: recruit-ment and recruiting maneuvers. crit care lond engl 2005;9:60-5.

5. suzumura ea, Figueiró M, normilio-silva K, laranjei-ra l, oliveira c, Buehler aM, et al. effects of alveolar recruitment maneuvers on clinical outcomes in pa-tients+ with acute respiratory distress syndrome: a sys-tematic review and meta-analysis. intensive care Med 2014;40:1227-40.

6. Hodgson c, Keating Jl, Holland ae, Davies ar, smir-neos l, Bradley sJ, et al. recruitment manoeuvres for adults with acute lung injury receiving mechanical venti-lation. cochrane Database syst rev 2009;(2):cD006667.

7. Fan e, Wilcox Me, Brower rg, stewart te, Mehta s, lapinsky se, et al. recruitment maneuvers for acute lung injury: a systematic review. am J respir crit care Med 2008;178:1156-63.

8. rothen HU, neumann P, Berglund Je, valtysson J, Mag-nusson a, Hedenstierna g. Dynamics of re-expansion of atelectasis during general anaesthesia. Br J anaesth 1999;82:551-6.

9. Pelosi P, cadringher P, Bottino n, Panigada M, carrieri F, riva e, et al. sigh in acute respiratory distress syndrome. am J respir crit care Med 1999;159:872-80.

10. Pelosi P, Bottino n, chiumello D, caironi P, Panigada M, gamberoni c, et al. sigh in supine and prone position during acute respiratory distress syndrome. am J respir crit care Med 2003;167:521-7.

11. villagrá a, ochagavía a, vatua s, Murias g, Del Mar Fernández M, lopez aguilar J, et al. recruitment maneu-vers during lung protective ventilation in acute respira-tory distress syndrome. am J respir crit care Med 2002;165:165-70.

12. lapinsky se, aubin M, Mehta s, Boiteau P, slutsky as. Safety and efficacy of a sustained inflation for alveolar



ing general anesthesia for open abdominal surgery im-proves postoperative pulmonary function. anesthesiol-ogy 2013;118:1307-21.

35. Futier e, constantin J-M, Paugam-Burtz c, Pascal J, eurin M, neuschwander a, et al. a trial of intraopera-tive low-tidal-volume ventilation in abdominal surgery. n engl J Med 2013;369:428-37.

36. neto as, Hemmes sn, Barbas cs, Beiderlinden M, Fernandez-Bustamante a, Futier e, et al. incidence of mortality and morbidity related to postoperative lung injury in patients who have undergone abdominal or thoracic surgery: a systematic review and meta-analysis. lancet respir Med 2014;2:1007-15.

37. riva Dr, oliveira MBg, rzezinski aF, rangel g, capelozzi vl, Zin Wa, et al. recruitment maneuver in pulmonary and extrapulmonary experimental acute lung injury. crit care Med 2008;36:1900-8.

38. santiago vr, rzezinski aF, nardelli lM, silva JD, gar-cia csnB, Maron-gutierrez t, et al. recruitment maneu-ver in experimental acute lung injury: the role of alveolar collapse and edema. crit care Med 2010;38:2207-14.

39. silva Pl, cruz FF, Fujisaki lc, oliveira gP, samary cs, ornellas Ds, et al. Hypervolemia induces and potenti-ates lung damage after recruitment maneuver in a model of sepsis-induced acute lung injury. crit care lond engl 2010;14:r114.

40. rzezinski aF, oliveira gP, santiago vr, santos rs, ornellas Ds, Morales MM, et al. Prolonged recruitment manoeuvre improves lung function with less ultrastruc-tural damage in experimental mild acute lung injury. respir Physiol neurobiol 2009;169:271-81.

41. silva Pl, Moraes l, santos rs, samary c, ornellas Ds, Maron-gutierrez t, et al. Impact of pressure profile and duration of recruitment maneuvers on morphofunctional and biochemical variables in experimental lung injury. crit care Med 2011;39:1074-81.

42. silva Pl, Moraes l, santos rs, samary c, ramos MBa, santos cl, et al. recruitment maneuvers modulate epi-thelial and endothelial cell response according to acute lung injury etiology. crit care Med 2013;41:e256-65.

tidal volumes, recruitment maneuvers, and high positive end-expiratory pressure for acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JaMa 2008;299:637-45.

28. Huh JW, Jung H, choi Hs, Hong s-B, lim c-M, Koh Y. Efficacy of positive end-expiratory pressure titration after the alveolar recruitment manoeuvre in patients with acute respiratory distress syndrome. crit care lond engl 2009;13:r22.

29. Hodgson cl, tuxen Dv, Davies ar, Bailey MJ, Higgins aM, Holland ae, et al. a randomised controlled trial of an open lung strategy with staircase recruitment, titrated PeeP and targeted low airway pressures in patients with acute respiratory distress syndrome. crit care lond engl 2011;15:r133.

30. Park HP, Hwang J-W, Kim YB, Jeon Y-t, Park s-H, Yun MJ, et al. effect of pre-emptive alveolar recruitment strategy before pneumoperitoneum on arterial oxygena-tion during laparoscopic hysterectomy. anaesth intensive care 2009;37:593-7.

31. cinnella g, grasso s, spadaro s, rauseo M, Mirabella l, salatto P, et al. effects of recruitment maneuver and positive end-expiratory pressure on respiratory mechan-ics and transpulmonary pressure during laparoscopic sur-gery. anesthesiology 2013;118:114-22.

32. Prove network investigators for the clinical trial network of the european society of anaesthesiology, Hemmes snt, gama de abreu M, Pelosi P, schultz MJ. High versus low positive end-expiratory pressure during general anaesthesia for open abdominal surgery (ProvHilo trial): a multicentre randomised controlled trial. lancet 2014;384:495-503.

33. Futier e, constantin J-M, Pelosi P, chanques g, Kwiatko-skwi F, Jaber s, et al. intraoperative recruitment maneu-ver reverses detrimental pneumoperitoneum-induced respiratory effects in healthy weight and obese patients undergoing laparoscopy. anesthesiology 2010;113:1310-9.

34. severgnini P, selmo g, lanza c, chiesa a, Frigerio a, Bacuzzi a, et al. Protective mechanical ventilation dur-

Conflicts of interest.—The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript.Article first published online: April 17, 2015. - Manuscript accepted: April 15, 2015. - Manuscript revised: March 30, 2015. - Manu-script received: December 23, 2014.


including include M. pneumoniae, C. pneu-moniae, Legionella species. the impact of macrolides on clinical outcomes in caP is a matter for debate. they are currently recom-mended as a drug of choice for severe commu-nity acquired pneumonia, in combination with beta-lactams.1

some concerns regarding acquired macro-lide resistance have emerged in the last de-cades, particularly for S. pneumoniae, and re-sistance induction is common. However, some authors and data suggest that benefit is beyond antibiotic effects and some immunomodulato-

Macrolides are an antibiotic class with greatest use in upper respiratory infec-

tions. they bind to the 50s subunit of bacte-rial ribosomes, leading to inhibition of trans-peptidation, translocation, chain elongation, and, ultimately, bacterial protein synthesis. this class includes the erythromycin-type agents (including dirithromycin), clarithromy-cin, and the azalide azithromycin. Macrolides have been commonly prescribed for treatment of community acquired pneumonia (caP) and respiratory infections due to their activity against S. pneumoniae and atypical pathogens,

R E V I E W

Macrolides and respiratory infection in critically ill patients: what is the next step?

thiago lisBoa 1-3 *, Jorge i. F. sallUH 4, gilberto FrieDMaN 1, 3

1critical care Department, Postgraduation Program (PPg) Pneumology, rio grande do sul Federal University, de clinicas de Porto alegre Hospital, Porto alegre, Brazil; 2infection control committee, de clinicas de Porto alegre Hospital, Porto alegre, Brazil; 3rede institucional de Pesquisa e inovação em Medicina intensiva (riPiMi), santa casa Hospital, Porto alegre, Brazil; 4D’or institute for research and education, Postgraduate Program, cancer National institute, rio de Janeiro, Brazil*corresponding author: thiago lisboa, critical care Department, Hospital de clinicas de Porto alegre, rua ramiro Barcelos, 2350; ceP 90035-003 – Porto alegre – Brasil. e-mail: [email protected]


lavoro: titolo breve: MacroliDes aND resPiratorY iNFectioNprimo autore: lisBoapagine: 221-9citazione: Minerva anestesiol 2016;82:221-9

a B s t r a c tseveral observational studies as well as experimental data suggest that the use of macrolides is associated with better outcomes in patients with severe pneumonia. in severe community acquired pneumonia (scaP), data demonstrate a benefit of combination therapy, including a beta-lactam plus a macrolide or floroquinolone, at least in the subgroup of patients with critical disease. Such combination seems to have a more significant impact in those with increased disease severity, particularly in those presenting with shock. in addition, data suggest that not all combinations are the same, and scaP patients receiving combination therapy with macrolides have lower mortality than patients receiving combination with fluoroquinolones. Better results could be associated with a potential immunomodulatory effect of macrolides as well as inhibition to bacterial growth and virulence factors expression (e.g. Streptococcus pneumoniae pneumolysin). addi-tionally, recent studies try to incorporate these drugs to our therapeutic options in patients with other sepsis causes (e.g. nosocomial pneumonia) and pathogens (e.g. Pseudomonas aeruginosa). in this review, we will assess these issues, dis-cussing the available evidence on macrolides use and highlighting potential research questions to be assessed on this field.(Cite this article as: lisboa t, salluh JiF, Friedman g. Macrolides and respiratory infection in critically ill patients: what is the next step? Minerva anestesiol 2016;82:221-9)Key words: Macrolides - Pneumonia - streptococcus pneumoniae.


lisBoa MacroliDes aND resPiratorY iNFectioN


peutic success through a synergistic effect of associated antimicrobial agents and assuring an adequate coverage of more likely causative pathogens by an extended spectrum of activ-ity.5-7 However, in critically ill patients, some data suggests that an additional benefit is pres-ent in the subset of patients with more severe forms of disease.6, 7

The potential benefits of combination ther-apy approach besides its intuitive appeal are unclear. available evidence is not conclusive and clinical benefit appears to be more associ-ated with enhancement of appropriateness of empirical therapy than with potential synergic effects. Moreover, potential disadvantages to using combination therapy include a greater risk of drug toxicity, increased costs and po-tential emergence of resistant pathogens.8, 9 a clinical setting, however, in which combina-tion therapy seems the best option is in scaP patients.

SCAP is defined as a respiratory infection acquired outside a healthcare environment that requires admission to the icU. it can be caused by a wide variety of pathogens, but Streptococcus pneumoniae, Hemophilus in-fluenzae and Legionella species are the main pathogens to cover.1 Until more accurate and rapid diagnostic methods are available, initial treatment for most patients remains empirical, and physicians should consider specific risk factors for specific pathogens coverage in each patient.1, 2, 10

scaP is a leading cause of morbidity and mortality. the impact of the combination ther-apy on mortality in critically ill patients with scaP is well demonstrated in literature. the benefit of combination therapy with macro-lides might be due to: 1) the coverage of un-detected co-pathogens, as atypical bacteria; 2) antibiotic synergy; or 3) immunomodulatory effects of macrolides.

in the last years, many different studies have evaluated the impact of the dual antibi-otic treatment for scaP on mortality. Muf-son et al. 11 reported that when mortality was compared between regimes containing a mac-rolided and a ß-lactam with those containing ß-lactam alone, there was a significant dif-

ry properties of macrolides might affect clini-cal evolution in severely ill patients with caP regardless of the susceptibility to the classic antimicrobial effect.2-4

in this review we will discuss some issues regarding macrolides prescription in respira-tory infection in the critically ill patient, par-ticularly in scaP patients.

Clinical recommendations in respiratory infections

commonly, primary indication for mac-rolides in the severe caP (scaP) treatment was to assure coverage for atypical pathogens. However, data demonstrated lower mortality rates for patients with bacteremic pneumo-coccal pneumonia and scaP associated with macrolides use.1-4 recent iDsa/ats guide-lines recommended for patients with scaP admitted to icU, using combination therapy with two different antibiotics that include a potent antipneumococcal β-lactam (cefotaxi-me, ceftriaxone or ampicillin-sulbactam) plus a macrolide (level ii evidence) or a respiratory fluoroquinolone (level I evidence). This rec-ommendation of combination treatment with a β-lactam plus a macrolide or fluoroquinolone is based mostly on observational studies dem-onstrating a significant reduction in mortality compared with administration of a cephalo-sporin alone.1 so, the evidence that supports these recommendations is not obtained from clinical trials and for critically ill patients it is frequently extrapolated from non-severe cases, in conjunction with observational data from cohorts with scaP.1 in fact, many of clinical trials in pneumonia deliberately excluded icU patients. thus, the implications of these results for empirical antibiotic therapy in icU patients with scaP remain unknown and further high quality prospective randomized studies are necessary to clarify this clinical issue.

Macrolides and combination therapy in severe community-acquired pneumonia

combination therapy in critically ill patients is believed to increase the likelihood of thera-

MacroliDes aND resPiratorY iNFectioN lisBoa


mortality between regimens with coverage of atypical pathogens and regimens without such coverage, persisting in all subgroup analysis. Waterer et al. 21 observed that the coverage of these microorganisms did not contribute to the apparent benefit of combination therapy after the multivariate analysis. thus, the impact of the atypical pathogens in critically ill patients with scaP is still on discussion. recently a randomized clinical trial showed that among patients with clinically suspected caP admit-ted to non-icU wards, a strategy of preferred empirical treatment with beta-lactam mono-therapy was not inferior to strategies with a beta-lactam-macrolide combination or fluoro-quinolone monotherapy with regard to 90-day mortality,22 in accordance with observational studies suggesting potential benefit might be more important in the subgroup of patients with more severe disease.

indeed, observational studies have shown beneficial effects of macrolides treatment in patients with bacteremic pneumococcal pneu-monia, hospitalized caP and scaP, even when the infection was due to a macrolide resistant pathogen proposing an effect based mostly on immunomodulation as opposed to a direct anti-bacterial activity.23, 24 another study 25 observed that the empiric use of a β-lactam plus a fluoroquinolone was associ-ated with higher 30-day mortality when com-pared to other guideline-concordant regimes for patients hospitalized with scaP. it is in accordance with Metersky et al. 26 who stud-ied the relationship between the initial antibi-otic regimen and mortality in a large cohort of Medicare patients with bacteremic pneumonia and observed that patients treated with a mac-rolide had a lower risk of adjusted in-hospi-tal mortality (or=0.59, 95% ic, 0.40-0.88; P=0.01) and 30-day mortality (or=0.61, 95% ic: 0.43-0.87; P=0.007). interestingly, there were no significant associations between fluo-roquinolones and patients outcome (or=0.94, 95% ic: 0.69-1.28). also, Martin-loeches et al. showed in mechanically ventilated criti-cally ill patients a potential benefit on survival of patients treated with therapeutic options in accordance to ats/iDsa guidelines based

ference in mortality. other analysis 12, 13 have suggested higher rates of survival in patients who are treated with combination antibiotic therapy. indeed, Waterer et al. 14 observed an 11.3% absolute mortality difference (18.2% vs. 6.9%, P=0.02) favoring the dual therapy. However, as most deaths occurred in patients with a Psi score over 90, there was no mor-tality difference between antibiotic strategies in milder disease. Nevertheless, Baddour et al. 15 reported benefit on 14-day survival using combination therapy when the analysis was re-stricted to patients with severe disease (23.4% vs. 55.3%, P=0.001). also, Martinez Ja et al. 16 examined 409 patients with bacteremic pneumococcal pneumonia and compared out-comes in patients receiving monotherapy with a β-lactam or combination therapy. After mul-tivariate analysis, shock, age >65 years, infec-tion with resistant pathogens, and no inclusion of a macrolide to a β-lactam were associated with higher mortality.

Although the consistent findings of these studies are very suggestive, they arise from observational studies. However, these findings are still confirmed in further observational studies recently, suggesting benefit in some specific populations. In patients with shock, combination antibiotic therapy was associ-ated with significantly higher 28-day adjusted in-icU survival (hazard ratio, 1.69; 95% ci, 1.09-2.6; P=0.01).17 these data suggest that icU patients at higher risk of death (i.e. those with shock) will benefit more from combina-tion therapy than patients in mild-to-moderate risk.17

controversy still exists in the literature re-garding the need to use antimicrobials cover-ing atypical pathogens when initially treat-ing non-icU hospitalized caP patients. an international multicenter study 18 observed a significant global presence (about 20%) of atypical pathogens in caP. authors reported that patients treated with atypical coverage had lower time to clinical stability (3.2 vs. 3.7 days, P<0.001), lower length of stay (6.1 vs. 7.1 days, P<0.01) and lower caP-related mortality (3.8% vs. 6.4%, P=0.05). in contrast, two meta-analysis 19, 20 found no difference in



use and mortality among patients hospitalized with caP. overall, macrolide use was associ-ated with a statistically significant mortality reduction compared with absence of macro-lides (3.7% [1738 of 47 071] vs. 6.5% [5861 of 90 503]; RR, 0.78; 95% confidence interval [ci], 0.64-0.95; P=0.01; i2=85%). But when analyses were restricted to rcts or to patients treated with guideline-concordant antibiotics, there was no survival advantage.

However, this same group in sligl et al. 30 performed a systematic review of studies with mortality endpoints that compared macrolide therapy with other regimens only in critically ill patients with community-acquired pneumo-nia. twenty-eight observational studies (no rct) were included. Primary analysis showed that in 9850 patients, macrolide use was asso-ciated with statistically significant lower mor-tality compared with absence of macrolides (21% [846 of 4036 patients] vs. 24% [1369 of 5814]; risk ratio, 0.82; 95% ci, 0.70-0.97; P=0.02; i2=63%). When macrolide mono-therapy was excluded, the macrolide mortality benefit was maintained (21% [737 of 3447 pa-tients] vs. 23% [1245 of 5425]; risk ratio, 0.84; 95% ci, 0.71-1.00; P=0.05; i2=60%). overall, macrolide use was associated with a signifi-cant 18% relative (3% absolute) reduction in mortality compared with non-macrolide-based therapies, suggesting that macrolides might be considered first-line combination treatment in critically ill patients with community-acquired pneumonia and supporting current guidelines.

still, since most studies showing the im-portance of adding a macrolide to a β-lactam regimen for scaP are observational, we con-sider high-quality evidence from prospective multicenter randomized double-blind trial is absolutely necessary to clarify whether combi-nation therapy with a macrolide is truly more effective than other therapeutic strategies for scaP.

on macrolide, when compared to those based on fluoroquinolones. Cox regression analysis showed that macrolide use was associated with survival benefit at 60 days (hazard ratio =0.48, P=0.004); similar findings were present when analysis included only patients with severe sepsis/shock (hazard ratio =0.44, P=0.03).27

However, due to a lack of prospective ran-domized clinical trials answering the question whether macrolides are better to treat scaP patients, we should go further on the evidence level, trying to get the best available answer for this clinical question.

Putting the pieces together: what the meta-analyses tell us

several meta-analyses have approached this clinical question (table i).27-29 Nie et al. 28 performed a systematic review to com-pare the clinical effect of beta-lactam/macro-lide combination therapy versus beta-lactam monotherapy in caP patients. Four prospec-tive cohort studies and 12 retrospective cohort studies were included (N=42,942). compared with monotherapy, macrolide combination therapy was significantly associated with reduced mortality (adjusted or 0.67, 95% ci 0.61–0.73, P<0.001, i2.3%). subsequent subgroup analyses confirmed that combina-tion therapy was superior to monotherapy in reduction of mortality. authors purpose some potential explanations for benefit of adding a macrolide to a beta-lactam. it includes: better coverage of atypical pathogens than mono-therapy; combined therapy acts in two differ-ent ways in bacteria; beta-lactams act on the cell wall and macrolides inhibit protein syn-thesis; and immunomodulatory properties of macrolides probably playing a major role in the effects of combined therapy independent-ly of its antibacterial activity. asadi et al. 29 systematically reviewed studies of macrolide

Table I.—�Summary of meta-analysis assessing macrolide combination therapy.author Population studies N. effects on mortality

Nie et al. 28 caP patients 16 studies 42,942 patients or 0.67, 95% ci 0.61–0.73asadi et al. 29 Hospitalized caP patients 23 studies 137,574 patients rr 0.78; 95% ci 0.64–0.95sligl et al. 30 icU caP patients 28 studies (no rct) 9850 patients rr 0.82; 95% ci, 0.70–0.97



Macrolides have shown to reduce the tu-mor necrosis factor (tNF) and il-6 produc-tion after stimuli with heat-killed pneumo-cocci.36 More specifically, macrolides have been shown to affect NF-kB and erK MaPK activation, decrease il-8 secretion, and de-crease MUc5ac expression 37 and reduce the igg mediated lung damage in rats, probably by the reduction in both TNF and IL-1β release from the alveolar macrophages.38 Macrolides decreased production of proinflammatory cy-tokines by circulating monocytes and by al-veolar macrophages and decreased apoptosis of circulating lymphocytes in animal models of acute infections.39 Macrolide-mediated in-hibition of neutrophil mobilization is achieved predominantly via inhibition of production of the neutrophil-mobilizing cytokines/chemo-kines il-8, il-17, and tNF, not only by cells of the innate immune system, but also by vari-ous types of structural cells.31, 36, 40-42 these in-hibitory effects of macrolides on the synthesis of proinflammatory cytokines/chemokines ap-pear to be achieved at the level of gene tran-scription.32, 43 in addition, a study examining patterns of cytokine gene expression showed 44 greater proinflammatory (IL-10 and TNF-α)

Immunomodulation: a target for macrolide therapy?

the immunomodulatory effect of the mac-rolides is not dependent of their antibacterial activity (table ii).31-45, 52-54 Pathogen-targeted anti-inflammatory activity of macrolides is obtained via inhibitory effects of these agents on bacterial protein synthesis, thereby attenu-ating the production of pro-inflammatory tox-ins, such as pneumolysin in S. pneumoniae. in addition, abrupt bacteriolysis and accompany-ing excessive inflammation due to release of cell-wall components and endotoxins, as may occur with bactericidal antibiotics, are reduced by the predominantly bacteriostatic activity of macrolides.32 regarding virulence factor pneumolysin transcription and production, some studies suggest that macrolides have an effect reducing pneumolysin expression more effectively than other antibiotics drugs in some experimental models.33-35 it might impact on inflammatory response (reducing cell invasion and destruction by the pathogen), severity of disease, arising of complications (such as de-velopment of acute respiratory distress syn-drome) or even outcomes.

Table II.—�Main immunomodulatory findings associated with macrolides.effect references

Attenuating the production of pro-inflammatory toxins, such as pneumolysin in S. pneumoniae Witzenrath et al. 33

anderson et al. 34

Fukuda et al. 35

inhibition neuthrophil mobilisation schultz et al. 36

Yamada et al. 38

affect NF-kB and erK MaPK activation Kanoh et al. 37

reduce the igg mediated lung damage Yamada et al. 38

Decreased apoptosis of circulating lymphocytes Koch et al. 39

reduce the production of:tumor necrosis factor (tNF), il-6, il-8, il-1, il-17, il-10

schultz et al. 36

Yamada et al. 38

Verleden et al. 40

lin et al. 41

Zarogoulidis et al. 42

Kikuchi et al. 43

o’Dwyer et al. 44

Inhibition of proinflammatory level of gene transcription and messenger RNA levels Kikuchi et al. 43

o’Dwyer et al. 44

enhance polimorphonuclear activity against pneumococcus labro et al. 45

inhibit P. aeruginosa virulence factors giamarellos-Bourboulis et al. 52

laserna et al. 54

Reduce cystic fibrosis and COPD exacerbations giamarellos-Bourboulis et al. 52

saiman et al. 53



pathogen. in addition, it inhibits gene expres-sion of proteins participating in quorum sens-ing of P. aeruginosa. in addition, clinical data suggest a positive effect using macrolides in cystic fibrosis patients colonized by P. aerugi-nosa, as it reduces exacerbations.53 although P. aeruginosa is not covered by macrolides antimicrobial spectrum of coverage, some data show that macrolides are potential inhibitors of its growth and may potentially affect its vir-ulence factors. Macrolides inhibition of quo-rum sensing of P. aeruginosa affects creation of biofilms and firm adherence to the airways. in several studies of sepsis caused by MDr P. aeruginosa in animal models, macrolides achieve a considerable benefit of survival.52, 54 However, a recently published study evaluat-ing 402 patients with P. aeruginosa caP fail to find association between macrolide therapy and decreased 30-day mortality, icU admis-sion, need for mechanical ventilation and los in P. aeruginosa caP hospitalized patients.54 it could provide some insights on adjuvant therapy for difficult to treat infection due to re-sistant pathogens in caP or health-care associ-ated pneumonia (HcaP) patients. We suggest that immunological effects of drugs should be considered in study designs to assess potential benefit from different antibiotic strategies to treat difficult to treat respiratory infections in critically ill patients.

Safety concerns

Recent literature findings have raised some questions regarding macrolides safety, particu-larly in older patients, and considering wide-spread use in respiratory infections, even in non-severe episodes. Beyond a high frequency of minor adverse events like gastrointestinal ones, macrolides might prolong Qt interval and have been reported associated with in-creased frequency of sudden cardiac death and cardiovascular events. recently ray et al. reported in a large database analysis, an in-creased risk of cardiovascular death and death for any cause associated with 5-days azithro-mycin therapy (Hr 2.88 and Hr 1.85, respec-tively), with special attention for high baseline

messenger rNa levels were observed in icU patients with severe sepsis and septic shock when compared with not critically ill bactere-mic patients or healthy controls.

Macrolides appear to enhance polimorpho-nuclear activity against pneumococci even when the isolates are macrolide resistant.45 this activity is further suggested also in clini-cal studies, with benefit in resistant pneumo-coccal strains and in bacteria out of its anti-microbial spectrum, such as Pseudomonas aeruginosa (P. aeruginosa).23 it is worth not-ing that macrolides have become widely used in panbronchiolitis and cystic fibrosis with their efficacy attributed to immunomodulation rather than antibacterial effects.46 in addition, macrolides have been shown to inhibit biofilm formation and decrease mucus hypersecretion, leading to improved mucociliary clearance.47 Even influenza infections might be affected by macrolide use, as suggested by some experi-mental data.48, 49

New developments of macrolides agents without antibacterial effects are promising to explore its effects on inflammatory response minimizing impact on bacterial resistance emergence.50

these potential effects have led to investiga-tion on macrolide role in different clinical set-tings. one randomized clinical trial has been published assessing the impact of macrolides on nosocomial sepsis. two hundred patients with VaP were randomly assigned to placebo (N.=100) or clarithromycin (N.=100) for three days. although the rate of resolution of VaP did not differ between the two arms, the time for VAP resolution was significantly shortened in the clarithromycin arm as well as median time to weaning from mechanical ventilation. these are promising results for future studies on macrolide use in critically ill patients in-cluding nosocomial infection as a target sub-population.51

interestingly, some authors have demon-strated that macrolides may affect adher-ence, inhibit mobility and decrease biofilm formation,52 which are all virulence factors expressed by P. aeruginosa strains, although primary bacterial resistance found in this



Key messages

— combination therapy including a beta-lactam plus a macrolide is currently the best therapeutic option for severe caP patients in icU.

— Benefit associated with macrolides includes potential immunomodulatory ef-fect as well as inhibition to bacterial growth and virulence factors expression, beyond straight antibacterial role.

— New study designs should consider non-antibiotic properties of macrolides in severely ill patients.

References

1. Mandell la, Wunderink rg, anzueto a, Bartlett Jg, campbell gD, Dean Nc, et al. infectious Disease soci-ety of america /american thoracic society consensus guidelines on the management of community-acquired pneumonia in adults. clin infect Dis 2007;44:s27-72.

2. lisboa t, rodriguez a, rello J. antibiotic combination vs. monotherapy in critically ill patients with pneumo-nia. in: Kuhlen r, Moreno r, ranieri M, rhodes a, editors. controversies in intensive care Medicine. Ber-lin: Medizinisch Wissenschaftliche Verlagsgesellschaft; 2008. p. 175-82.

3. remington lt and siligl W. community acquired pneu-monia. curr opin Pulm Med 2014;20:215-24.

4. shorr aF, Zilberberg MD, Kan J, Hoffman J, Micek st, Kollef MH. azithromycin and survival in Streptococ-cus pneumoniae pneumonia: a retrospective study. BMJ Open 2013;3:e002898.

5. leibovici l, Paul M. aminoglycoside/beta-lactam com-binations in clinical practice. J antimicrob chemother 2007;60:911-2.

6. Kumar a, Zarychanski r, light B, Zarychanski r, light B, Parrillo J, Maki D, simon D, et al. early combination antibiotic therapy yields improved survival compared with monotherapy in septic shock:a propensity-matched analysis. crit care Med 2010;38:1773-85.

7. Kumar a, safdar N, Kethireddy s, chateau D. a survival benefit of combination antibiotic therapy for serious in-fections associated with sepsis and septic shock is con-tingent only on the risk of death:a meta-analytic/meta-regression study. crit care Med 2010;38:1651-64.

8. Brunkhorst FM, oppert M, Marx g, Bloos F, ludewig K, Putensen c, et al. effect of empirical treatment with moxifloxacin and meropenem vs. meropenem on sepsis-related organ dysfunction in patients with severe sepsis: a randomized trial. JaMa 2012;307:2390-9.

9. Paul M, Benuri-silbiger i, soares-Weiser K, leibovici l. Beta-lactam monotherapy versus beta-lactam aminogly-coside combination therapy for sepsis in immunocom-petent patients: systematic review and meta-analysis of randomized trials. BMJ 2004;328:668-82

10. File tM Jr, Marrie tJ. Does empiric therapy for atypi-cal pathogens improve outcomes for patients with caP? infect Dis clin North am 2013;27:99-114.

11. Mufson Ma, stanek rJ. Bacteremic pneumococcal

risk patients.55 Nevertheless, svanström et al. later evaluated in a general population of young and middle-aged adults and found no increase in risk of death from cardiovascular causes.56 another relevant study published recently evaluating association of azithromy-cin with mortality and cardiovascular events among older patients hospitalized with pneu-monia treatment that included azithromycin compared with other antibiotics was associ-ated with a lower risk of 90-day mortality and a smaller increased risk of myocardial infarc-tion, consistent with a net benefit associated with azithromycin use.57

Conclusions

although several studies suggest a clini-cal benefit from macrolides in SCAP patients, with a potential use in other clinical settings, we still lack high-quality studies to support any unequivocal recommendation. Better re-sults could be associated with a potential im-munomodulatory effect of macrolides as well as inhibition to bacterial growth and virulence factors expression (e.g. Streptococcus pneu-moniae pneumolysin). Nevertheless, recent studies try to incorporate these drugs to our therapeutic strategies in patients with other sepsis causes (e.g. nosocomial pneumonia) and pathogens (e.g. P. aeruginosa). Specifi-cally for scaP, it seems that a combination therapy including a beta-lactam plus a mac-rolide is currently the best therapeutic option considering a few recent meta-analysis avail-able. our approach is to recommend for every icU patient with scaP a combination therapy including a macrolide agent. assessing even-tual new subpopulations (e.g. nosocomial in-fections or specific pathogens) with potential to benefit more as well as identify other targets (e.g. immunomodulation or virulence factors) for more individualized therapy might be ap-propriate to assess relevant outcomes in icU patients receiving macrolides. New study de-signs considering theranostics concept with macrolides seems to be the next step on mac-rolide research for critically ill patients with severe respiratory infections.



28. Nie W, Li B, Xiu Q. β-Lactam/macrolide dual thera-py versus β-lactam monotherapy for the treatment of community-acquired pneumonia in adults:a system-atic review and meta-analysis. J antimicrob chemother 2014;69:1441-6.

29. asadi l, sligl Wi, eurich Dt, colmers iN, tjosvold l, Marrie tJ, Majumdar sr. Macrolide-based regimens and mortality in hospitalized patients with community-acquired pneumonia:a systematic review and meta-anal-ysis. clin infect Dis 2012;55:371-80.

30. sligl Wi, asadi l, eurich Dt, tjosvold l, Marrie tJ, Ma-jumdar sr. Macrolides and mortality in critically ill pa-tients with community-acquired pneumonia:a systematic review and meta-analysis. crit care Med 2014;42:420-32.

31. Morton B, Pennington sH, gordon sB. immunomodu-latory adjuvant therapy in severe community-acquired pneumonia. expert rev respir Med 2014;8:587-96.

32. steel Hc, cockeran r, anderson r, Feldman c. over-view of community-acquired pneumonia and the role of inflammatory mechanisms in the immunopathogenesis of severe pneumococcal disease. Mediators Inflamm 2013;2013:490346.

33. Witzenrath M, gutbier B, Hocke ac, schmeck B, Hip-penstiel s, Berger K, et al. role of pneumolysin for the development of acute lung injury in pneumococcal pneu-monia. crit care Med 2006;34:1947-54.

34. anderson r, steel Hc, cockeran r, von gottberg a, de gouveia l, Klugman KP, et al. comparison of the effects of macrolides, amoxicillin, ceftriaxone, doxycycline, tobramycin and fluoroquinolones, on the production of pneumolysin by streptococcus pneumoniae in vitro. J antimicrob chemother 2007;60:1155-8.

35. Fukuda Y, Yanagihara K, Higashiyama Y, Miyazaki Y, Hirakata Y, Mukae H, et al. effects of macrolides on pneumolysin of macrolide-resistant streptococcus pneu-moniae. eur respir J 2006;27:1020e5.

36. schultz MJ, speelman P, Zaat s, van Deventer sJ, van der Poll t, et al. erythromycin inhibits tumor necrosis factor alpha and interleukin 6 production induced by heat-killed Streptocuccus pneumoniae in whole blood. antimicrob agents chemother 1998;42:1605-9.

37. Kanoh s, rubin BK. Mechanisms of action and clinical application of macrolides as immunomodulatory medica-tions. clin Microbiol rev 2010;23:590-615,

38. Yamada K, Yanagihara K, Kaku N, Harada Y, Migiyama Y, Nagaoka K, et al. Azitromycin attenuates lung inflam-mation in a mouse model of ventilator associated pneu-monia by multidrug resistant acinetobacter baumannii. antimicrob agents chemother 2013;57:3883-8.

39. Koch cc, esteban DJ, chin ac, olson Me, read rr, ceri H, et al. apoptosis, oxidative metabolism and in-terleukin-8 production in human neutrophils exposed to azithromycin: effects of streptococcus pneumoniae. J antimicrob chemother 2000;46:19-26.

40. Verleden gM, Vanaudenaerde BM, Dupont lJ, Van rae-mdonck De. azithromyci reduces airway neutrophilia and interleukin-8 in patients with bronchiolitis obliterans syndrome. am J respir crit care Med 2006;174:566-70.

41. lin sJ, Yan Dc, lee Wi, Kuo Ml, Hsiao Hs, lee PY. effect of azithromycin on natural killer cell function. int immunopharmacol 2012;13:8-14.

42. Zarogoulidis P, Papanas N, Kioumis i, chatzaki e, Malt-ezos e, Zarogoulidis K. Macrolides: from in vitro anti-inflammatory and immunomodulatory properties to clini-cal practice in respiratory diseases. eur J clin Pharmacol 2012;68:479e503.

43. Kikuchi t, Hagiwara K, Honda Y, gomi K, Kobayashi t, takahashi H, et al. clarithromycin suppresses lipopol-ysaccharide-induced interleukin-8 production by human monocytes through AP-1 and NF-ΚB transcription fac-tors. J antimicrob chemother 2002;49:745-55.

pneumonia in one american city:a 20-year longitudinal study, 1978-1997. am J Med 1999;107:34s-43s.

12. Weiss K, tillotson gs. the controversy of combination vs. monotherapy in the treatment of hospitalized commu-nity-acquired pneumonia. chest 2005;128:940-6.

13. Bodí M, rodríguez a, solé-Violán J, gilavert Mc, gar-nacho J, Blanquer J, et al. antibiotic prescription for community-acquired pneumonia in the intensive care unit:impact of adherence to infectious Diseases soci-ety of america guidelines on survival. clin infect Dis 2005,41:1709-16.

14. Waterer gW, somes gW, Wunderink rg. Monotherapy may be suboptimal for severe bacteriemic pneumococcal pneumonia. arch intern Med 2001;161:1837-42.

15. Baddour lM, Yu Vl, Klugman KP, Feldman c, ortqvist a, rello J, et al. combinations antibiotic therapy lowers mortality among severely ill patients with pneumoccocal bacteriemia. am J respir crit care Med 2004;170:440-4.

16. Martínez Ja, Horcajada JP, almela M, Marco F, soriano a, garcía e, et al. Addition of macrolide to a β-lactam-based empirical antibiotic regimen is associated with lower in-hospital mortality for patients with bacteremic pneumococcal pneumonia. clin infect Dis 2003;36:389-95.

17. rodríguez a, Mendia a, sirvent JM, Barcenilla F, de la torre-Prados MV, solé-Violán J, et al. combination an-tibiotic therapy improves survival in patients with com-munity-acquired pneumonia and shock. crit care Med 2007,35:1493-9.

18. arnold FW, summersgill Jt, lajoie as, Peyrani P, Mar-rie tJ, rossi P, et al. a worldwide perspective of atypi-cal pathogens in community-acquired pneumonia. am J respir crit care Med 2007;175:1086-93.

19. shefet D, robenshtok e, Mical P, leibovici l. empiri-cal atypical coverage for inpatients with community-acquired pneumonia. systematic review of randomized controlled trials. arch intern Med 2005;165:1992-2000.

20. robenshtok e, shefet D, gafter-gvili a, Paul M, Vidal l, leibovici l. empiric antibiotic coverage of atypical path-ogens for community acquired pneumonia in hospitalized adults. cochrane Database syst rev 2008;23:cD004418.

21. Waterer gW, Kessler la, Wunderink rg. Delayed ad-ministration of antibiotics and atypical presentation in community-acquired pneumonia. chest 2006;130:11-5.

22. Postma DF, van Werkhoven cH, van elden lJ, thijsen sF, Hoepelman ai, Kluytmans Ja, et al. antibiotic treat-ment strategies for community acquired pneumonia in adults. N engl J Med 2015;372:1312-23.

23. restrepo Mi, Mortensen eM, Waterer gW, Wunderink rg, coalson JJ, anzueto a. impact of macrolide therapy on mortality for patients with severe sepsis due to pneu-monia. eur respir J 2009;33:153-9.

24. Kohno s, tateda K, Kadota J, Fujita J, Niki Y, Watan-abe a, et al. contradiction between in vitro and clini-cal outcome:intravenous followed by oral azithromycin therapy demonstrated clinical efficacy in macrolide-resistant pneumococcal pneumonia. J infect chemother 2014;20:199-207.

25. Mortensen eM, restrepo i, anzueto a, Pugh J. the im-pact of empiric antimicrobial therapy with a β-lactam and fluoroquinolone on mortality for patients hospitalized with severe pneumonia. crit care 2006;10:r8

26. Metersky Ml, Ma a, Houck PM, Bratzler DW. antibi-otic for bacteremic pneumonia:improved outcome with macrolide but not fluoroquinolones. Chest 2007;131:466-73.

27. Martin-loeches i, lisboa t, rodriguez a, Putensen c, annane D, garnacho-Montero J, et al. combination antibiotic therapy with macrolides improves survival in intubated patients with community-acquired pneumonia. intensive care Med 2010;36:612-20.



ciated pneumonia and sepsis caused by gram-negative bacteria:results from a randomized clinical study. anti-microb agents chemother 2012;56:3819-25.

52. giamarellos-Bourboulis eJ, adamis t, laoutaris g, sa-bracos l, Koussoulas V, Mouktaroudi M, et al. immu-nomodulatory clarithromycin treatment of experimental sepsis and acute pyelonephritis caused by multidrug-resistant Pseudomonas aeruginosa. antimicrob agents chemother 2004;48:93-9.

53. saiman l, Marshall Bc, Mayer-Hamblett N, Burns Jl, Quittner al, cibene Da, et al. azithromycin in patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa:a randomized controlled trial. JaMa 2003;290:1749-56.

54. laserna e, sibila o, Fernandez JF, Maselli DJ, Mortens-en eM, anzueto a, et al. impact of Macrolide therapy in Patients Hospitalized with Pseudomonas aeruginosa community-acquired Pneumonia. chest 2014;145:1114-20.

55. ray Wa, Murray Kt, Hall K, arbogast Pg, stein cM. azithromycin and the risk of cardiovascular death. N engl J Med 2012;366:1881-90.

56. svanström H, Pasternak B, Hviid a. Use of azithromy-cin and death from cardiovascular causes. N engl J Med 2013;368:1704-12.

57. Mortensen eM, Halm ea, Pugh MJ, copeland la, Me-tersky M, Fine MJ, et al. association of azithromycin with mortality and cardiovascular events among older patients hospitalized with pneumonia. JaMa 2014;311:2199-208.

44. o’Dwyer MJ, Mankan aK, stordeur P, o’connell B, Duggan e, White M, et al. the occurrence of severe sep-sis and septic shock are related to distinct patterns of cy-tokine gene expression. shock 2006;26:544-550.

45. labro Mt, el Benna J, abdelghaffar H. Modulation human polymorhonuclear neutrophil function by mac-rolides: preliminary data concerning dirithromycin. J an-timicrob chemother 1993;31 suppl. c:51-64.

46. schultz MU. Macrolide activities beyond their antimicro-bial effects: macrolides in diffuse panbronchiolitis and cystic fibrosis. J Antimicrob Chemother 2004;54:21-2.

47. Healy DP. Macrolide immunomodulation of chronic res-piratory diseases. curr infect Dis rep 2007;9:7-13.

48. Karlstro¨Ma, Boyd Kl, english BK, Mccullers Ja. treatment with protein synthesis inhibitors improves out-comes of secondary bacterial pneumonia after influenza. J infect Dis 2009;199:311-9.

49. Kakeya H, seki M, izumikawa K, Kosai K, Morinaga Y, Kurihara s, et al. Efficacy of Combination Therapy with Oseltamivir Phosphate and Azithromycin for Influenza: A Multicenter, open-label, randomized study. Plos oNe 2014;9:e91293.

50. tarran r, sabater Jr, clarke tc, tan cD, Davies cM, liu J, et al. Nonantibiotic macrolides prevent human neu-trophil elastase-induced mucus stasis and airway surface liquid volume depletion. am J Physiol lung cell Mol Physiol 2013;304:l746-l756.

51. spyridaki a, raftogiannis M, antonopoulou a, tsaganos t, routsi c, Baziaka F, et al. effect of clarithromycin in inflammatory markers of patients with ventilator-asso-

Conflicts of interest.—The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript.Article first published online: September 16, 2015. - Manuscript accepted: September 15, 2015. - Manuscript revised: September 14, 2015. - Manuscript received: May 13, 2016.

230 MINERVA ANESTESIOLOGICA February 2016

tion and intensive care unit (ICU) organization processes often make this approach difficult to adopt. In recent years, many tools for bedside assessment of pain, sedation and delirium have been proposed, and their systematic application in clinical practice seems to offer a relevant benefit.2-4 By contrast, few high level clinical trials have evaluated the efficacy of pharmaco-logical and non-pharmacological strategies for PAD treatment. For instance, although current-

The management of pain, agitation and de-lirium (PAD) is still a challenge in criti-

cally ill patients. Clinical studies have demon-strated that a protocolized and evidence based approach to PAD is cost-effective and can sig-nificantly improve patient outcomes.1 Never-theless, factors related to pre-existing patients’ conditions, type and degree of organ dysfunc-

E X P E R T O P I N I O N

A critical appraisal of the quality of analgosedation guidelines in critically ill patients

Massimo GIRARDIS 1*, Cosetta CANTARONI 1, Gennaro SAVOIA 2

Rita MELOTTI 3, Giorgio CONTI 4

1Anesthesia and Intensive Care Department, University of Modena and Reggio Emilia, Modena, Italy; 2Anesthesia Intensive Care Department, Hospital Cardarelli, Naples, Italy; 3Anesthesia and Intensive Care Department, University of Bologna, Bologna, Italy; 4Anesthesia and Intensive Care Department, Catholic University of Rome, Rome, Italy

Anno: 2016Mese: FebruaryVolume: 82No: 2Rivista: MINERVA ANESTESIOLOGICACod Rivista: Minerva Anestesiologica

Lavoro: titolo breve: ANALGOSEDATION GUIDELINES IN CRITICALLY ILL PATIENTSprimo autore: GIRARDISpagine: 230-5

A B S T R A C TBACKGROUND: The management of analgesia and sedation in critically ill patients is still a challenge due to the short-age of evidence-based treatments. The main objectives of the present study were to critically evaluate the quality of cur-rent clinical practice guidelines (CPGL) published on this matter and to identify the contrasting positions and unsolved questions.METhODS: Four members of the Italian Society of Anesthesia and Intensive Care (SIAARTI) council, with an extensive background in the management of critically ill patients and practice guidelines, evaluated CPGL on sedation and anal-gesia in critically ill patients published from January 2006 to December 2013. Evaluation was performed in accordance with the appraisal of guidelines for research and evaluation tool (AGREE II).RESULTS: Five documents proposed by European and American scientific societies of critical care medicine were identi-fied and evaluated. The CPGL published in 2013 by the American Society of Critical Care Medicine showed the highest scores in all domains of the AGREE II tool, whereas scores for CPGL published in 2006 by SIAARTI showed the lowest scores. In all documents, most recommendations on the use of drugs or non-pharmacological strategies for analgesia, sedation and delirium treatment had low evidence.CONCLUSIONS: This quality evaluation indicated that CPGLs published by the German Association of Scientific Medi-cal Societies, the American College of Critical Care Medicine and the PanAmerican and Iberica Federation of the Critical Care Medicine Societies should be recommended for use. Even in guidelines with a high quality rating, numerous recom-mendations have moderate or low levels of evidence. (Cite this article as: Girardis M, Cantaroni C, Savoia G, Melotti R, Conti G. A critical appraisal of the quality of analgoseda-tion guidelines in critically ill patients. Minerva Anestesiol 2015;82:230-5)Key words: Analgesia - Delirium - Intensive Care Units - Guidelines as Topic.

*Corresponding author: Massimo Girardis, Azienda Ospedaliera Universitaria di Modena, L. go del Pozzo, 71, 41100 Modena, Italy. E-mail: [email protected]

© 2016 EDIZIONI MINERVA MEDICAThe online version of this article is located at http://www.minervamedica.it Minerva Anestesiologica 2016 February;82 (2):230-5

Comment in p. 157.

ANALGOSEDATION GUIDELINES IN CRITICALLY ILL PATIENTS GIRARDIS

Vol. 82 - No. 2 MINERVA ANESTESIOLOGICA 231

of development, clarity and presentation, ap-plicability and editorial independence. Each of the AGREE II items are rated on a 7-point scale (1–strongly disagree; 7–strongly agree). Domain scores are calculated by adding to-gheter all the scores of the individual items in a domain, and by scaling the total as a percent-age of the maximum possible score for that domain.10 In addition, the AGREE II tool also includes an overall assessment of the guide-line and whether it should be strongly recom-mended, recommended with provisos, or not recommended.

Assessments were performed independently by the four members using a specific electronic database with accompanying explanatory notes. To determine whether errors may have occurred during item scoring, one investigator (GM) ex-amined all final item scores across the 4 apprais-als. Discrepancies were defined as inter-rate score differences of three points on any domain item. All appraisers were then asked to perform another AGREE II assessment on the discord-ant item in question. For each selected CPGL, the median scores for the various domains were calculated and compared among the CPGLs using the Kruskal-Wallis Test. Analysis was performed using SPSS version 20 (SPSS Inc., Chicago, IL, USA) and P<0.05 was considered statistically significant.

Results

Clinical practice guideline selection and char-acteristics

The databases analysis provided 5 CPGL on PAD management in critically ill adult patients published from January 2006 to December 2013. Throughout the years, the methodolo-gies for developing CPGL have changed from the Delphi method to the Grading of Recom-mendations, Assessment, Development and Evaluation (GRADE) method.12, 13 The topics included were quite similar, except for deliri-um identification and management that were discussed extensively only in the more recent CPGLs. Specific indications for particular pop-ulations (e.g. elderly, trauma and burns) were

ly recommended by recent guidelines,1, 5 the use of quetiapine and of re-orientation strate-gies for the prevention and management of de-lirium is based on low-quality studies.6

Due to these aforementioned considerations, the use of clinical practice guidelines (CPGL) based on the best available evidence is essen-tial for supporting the decision-making pro-cess in PAD management. In the last decade, numerous CPGL documents on this issue have been published worldwide by several scientific societies of critical care medicine. As for other publications, a CPGL ought to be critically ap-praised prior to endorsing its use, because poor quality guidelines may contribute to inappro-priate recommendations and low adherence.7-9 The appraisal of guidelines, research and eval-uation (AGREE) tool has been developed and validated as an useful instrument to assess the methodological rigour and transparency with which a guideline has been developed.10, 11 The aim of our study, supported by the Italian So-ciety of Anaesthesia and Intensive Care Medi-cine (SIAARTI), was to assess the quality of the published guidelines on PAD management using the AGREE II tool.


Four members of the SIAARTI council, with an extensive background in the management of critically ill patients and CPGL methodol-ogy, were involved in the quality assessment. CPGL documents were selected by searching the Medline (PubMed), Scopus and Intercol-legiate Studies Institute Web of Knowledge databases from 2006 to 2013. Relevant da-tabases of guidelines including the National Guideline Clearing House, National Institute for Healthcare Excellence, Scottish Intercol-legiate Guidelines Network and the National Guideline System were also searched. We re-stricted our search to the adult population.

For the quality assessment of CPGL, the appraisal of guidelines, research and evalu-ation (AGREE) tool has been developed and validated.10 AGREE II evaluation includes 23 items subdivided within 6 domains: scope and purpose, stakeholder involvement, rigor

GIRARDIS ANALGOSEDATION GUIDELINES IN CRITICALLY ILL PATIENTS


90.5%) (Figure 1). In all the CPGLs evalu-ated, the applicability domain achieved the lowest quality scores, whereas the scope and purpose domain achieved the highest quality scores.

The CPGLs by SIAARTI and by the French Society of Anesthesia and Intensive Care and the French Society of Intensive Care Medi-cine (SFAR-SRLF) 15, 16 had the lowest scores (P<0.05) compared to other CPGLs for 3 do-mains (scope and purpose, stakeholder in-volvement and applicability) and in the overall assessment. The evaluators recommended the use of the CPGLs by AWMF, the Pan-Ameri-can and Iberica Federation of the Critical Care Medicine Societies and the American College of Critical Care Medicine (ACCM).1, 5, 14 The last CPGL showed the highest overall quality score (Figure 1).

Discussion

In our quality evaluation, the three CPGLs on PAD management in critically ill patients provided by the German Association of Scien-tific Medical Societies, the American College

included for all documents. The CPGL by the German Association of Scientific Medical So-cieties (AWMF) 14 also included indications for pregnant, lactating and moribund patients, while those by Pan-American and Iberica Fed-eration of the Critical Care Medicine Societies 5 provided indications for patients with renal and liver failure. The number of statements and rec-ommendations ranged from 6 in the CPGL by the Italian Society of Anesthesia and Intensive Care (SIAARTI) 15 to 137 in those by the Pan-American and Iberica Federation of the Critical Care Medicine Societies.5 An executive sum-mary was provided in only 2 documents 1, 14 and the strength of the majority of the recom-mendations was strong (or very strong) with moderate or low evidence (Table I).1, 5, 14-16

Appraisal of guidelines by the AGREE II in-strument

Agreement among reviewers for the 5 doc-uments was high (>80%). The median qual-ity scores for the six domains and the overall assessment were 78.6, 58.7, 72.6, 69.8, 41.7, 57.1 and 66.7% respectively (range 33.3-

Table I.—�Year of publication, target population, main areas, layout, and summary of the recommendations of the evaluated documents.

Reference Year Targetpopulation Main areas Layout Summary of

recommendations

Italian Society of Anesthesia and Intensive Care 15

2006 Adults with specific populations

Monitoring (pain, sedation); drugs (analgesia, sedation, withdrawal); specific population

30 pages with 6 tables

1 high level + 4 low level + 1 very low level; total 6

French Society of Anesthesia and Intensive Care and the French Society of Intensive Care Medicine 16

2008 Adults with specific populations and children

Definition and goals (pain, sedation); drugs and other methods; monitoring (pain, sedation, delirium); sedation withdrawn; practical issues

11 pages with 4 tables

8 without strength and evidence

German Association of Scientific Medical Societies 14

2010 Adults with specific populations, children and neonates

Monitoring (pain, sedation, delirium); treatment (pain, sedation, delirium); economy, quality, implementation; specific populations

39 pages with 24 figures and tables

56 very strong; 30 strong; 27 weak; total 123

American College of Critical Care Medicine 1


Pshycometric scales; analgesics; pain (incidence, monitoring, treatment); agitation and sedation (depth, monitoring, drugs); delirium (outcomes, monitoring, risk factors, prevention, treatment); practical issues

43 pages with 8 tables and 3 figures

14 strong; 11 weak; 7 no recommendation; total 32

Pan-American and Iberica Federation of the Critical Care Medicine Societies 5


Indications patient oriented; monitoring (sedation, analgesia, delirium); treatment (delirium, withdrawal)

55 pages with 14 tables and 7 figures

114 strong, 23 weak; total 137



ACCM Pan-American

ACCM Pan-American

ACCM Pan-American

ACCM

ACCM

ACCM

Pan-American

Pan-American

Pan-American

AWMF

AWMF

AWMF

SIAARTI

1.00

0.80

0.60

0.40

0.20

0.00SFAR-SRLF AWMF AWMF

AWMF

AWMF

ACCM Pan-American SIAARTI

SIAARTI

1.00

1.00

0.80

0.80

0.60

0.60

0.40

0.40

0.20

0.20

0.00

0.00

SFAR-SRLF

SFAR-SRLF AWMF ACCM Pan-American SIAARTI

1.00

0.80

0.60

0.40

0.20

0.00SFAR-SRLF

SIAARTI SIAARTI

1.00 1.00

0.80 0.80

0.60 0.60

0.40 0.40

0.20 0.20

0.00 0.00SFAR-SRLF SFAR-SRLFAWMF ACCM Pan-American

SIAARTI

1.00

0.80

0.60

0.40

0.20

0.00

SFAR-SRLF AWMF ACCM Pan-American

Figure 1.—Fraction of the maximal score of the six domains and the overall assessment for the clinical practice guidelines (CPGL) evaluation by the AGREE II tool. X-axis: CPGL; y-axis: fraction of maximal score. SIAARTI: Italian Society of Anesthesia and Intensive Care; SFAR-SRLF: French Soci-ety of Anesthesia and Intensive Care and the French Society of Intensive Care Medicine; AWMF: German Association of Scientific Medical Societies; ACCM: American College of Critical Care Medicine; Pan-American: Pan-American and Iberica Federation of the Critical Care Medicine Societies.

ACCM Pan-American

ACCM Pan-American

ACCM Pan-American

GIRARDIS ANALGOSEDATION GUIDELINES IN CRITICALLY ILL PATIENTS


contrast with the others, the CPGL by the Pan-American and the Iberica Federation of the Critical Care Medicine Societies strongly rec-ommend the use of low dose remifentanil con-tinuous infusion for analgesia and sedation in patients undergoing weaning from mechanical ventilation despite the low level of evidence.5 Moreover, although the evidence from litera-ture was the same, the recommendations for the use of antipsychotic drugs in the manage-ment of delirium are clearly different between the CPGLs by the ACCM and the Pan-Ameri-can and Iberica Federation of the Critical Care Medicine Societies.1, 5 The shortage of high level studies for many of the items included in the CPGLs poses questions on the reliabil-ity of these recommendations, and their effects remain uncertain and may vary in different pa-tients, contexts and organizations.

Conclusions

Our quality evaluation provides useful in-dications for the appropriate use of available CPGLs on PAD management. Considering the possible legal implications of guidelines produced by national professional bodies and accepted as “the standard to be achieved”, old and low-quality level documents should be discarded in favor of the more recent and high-quality level ones. Unfortunately, the adop-tion of CPGLs developed in different regions may be difficult due to possible differences in availability of resources and in clinical behav-ior. Therefore, an urgent revision and updat-ing of the SIAARTI and SFAR-SRLF docu-ments 15, 16 is highly recommended. Moreover, our study advises different CPGL developers to integrate the GRADE approach, used for grading the quality of evidence and strength of recommendations, with the suggestions by the AGREE II Collaboration when preparing future guidelines on PAD, with particular fo-cus on stakeholder involvement and methods for its implementation in clinical practice. Last but not least, as for many other issues in criti-cally ill patients, there is an urgent need for large and appropriate clinical studies on anal-gosedation and delirium treatment.

of Critical Care Medicine and the Pan-Ameri-can and Iberica Federation of the Critical Care Medicine Societies revealed high overall as-sessment scores and, thereby, are recommended for use.1, 5,14 To our knowledge, this is the first systematic evaluation of the quality of CPGLs for the management of PAD.

The highly scored CPGLs adequately coped with the majority of domains included in the AGREE II tool. Indeed, applicability and stakeholder involvement were the domains that performed most poorly. Compliance in clinical practice to the recommendations of a CPGL is still difficult and the reasons are wide-ranging. Among these, difficulty in CPGL dis-semination and implementation play a pivotal role. Therefore, a CPGL should include a clear description of facilitators and barriers to its application, tools on how recommendations can be put into practice, and the potential re-source implications. Unfortunately, as report-ed in other CPGL quality evaluations,7, 17 these items were not or only partially included in the CPGLs on PAD management.

The scarce involvement of stakeholders in the development of a CPGL may further hin-der its implementation in clinical practice. In the AGREE II tool, the domain on the stake-holders’ involvement explores whether the CPGL represents the views of its intended us-ers. Involving stakeholders is recognized as an important part of producing credible, rigor-ous, and transparent CPGLs.18 A review of the NICE guideline program by the World Health Organization stated that “collaboration with stakeholders in the development of the guide-lines through the consultation and feedback mechanisms available was in general very ef-fective”.19

It is important to note that the AGREE II tool has been developed to assess the method-ological quality of a guideline, but it does not evaluate the clinical content and the quality of the evidence supporting the recommenda-tions.11 In fact, our CPGLs appraisal outlined common criticisms related to the low level of evidence for the majority of the strong rec-ommendations, particularly on analgesia and delirium management.1, 5, 14 For instance, in



algesia in critically ill adult patients. Med Intensiva 2013; 37:519-74.

6. Reade MC, Finfer S. Sedation and delirium in the inten-sive care unit. N Engl J Med 2014;370:444-54.

7. Sinuff T, Patel RV, Adhikari NK, Meade MO, Schüne-mann HJ, Cook DJ. Quality of professional society guidelines and consensus conference statements in criti-cal care. Crit Care Med 2008;36:1049-58.

8. Eldh AC, Vogel G, Söderberg A, Blomqvist H, Weng-ström Y. Use of evidence in clinical guidelines and everyday practice for mechanical ventilation in Swed-ish intensive care units. Worldviews Evid Based Nurs 2013;10:198-207.

9. Pun BT, Balas MC, Davidson J. Implementing the 2013 PAD guidelines: top ten points to consider. Semin Respir Crit Care Med 2013;34:223-35.

10. Brouwers MC, Kho ME, Browman GP, Burgers JS, Cluzeau F, Feder G, et al. AGREE II: advancing guide-line development, reporting, and evaluation in health care. Prev Med 2010;51:421-4.

11. AGREE Collaboration. Development and validation of an international appraisal instrument for assessing the quality of clinical practice guidelines: the AGREE pro-ject. Qual Saf Health Care 2003;12:18-23.

12. Schünemann HJ, Jaeschke R, Cook DJ, Bria WF, El-Solh AA, Ernst A, et al. An official ATS statement: grading the quality of evidence and strength of recommendations in ATS guidelines and recommendations. Am J Respir Crit Care Med 2006;174:605-14.

13. Guyatt G, Gutterman D, Baumann Mh, Addrizzo-harris D, Hylek EM, Phillips B, et al. Grading strength of rec-ommendations and quality of evidence in clinical guide-lines: report from an american college of chest physicians task force. Chest 2006;129:174-81.

14. Martin J, Heymann A, Bäsell K, Baron R, Biniek R, Bür-kle H, et al. Evidence and consensus-based German guide-lines for the management of analgesia, sedation and delir-ium in intensive care--short version. Ger Med Sci 2010;8: Doc02.

15. Mattia C, Savoia G, Paoletti F, Piazza O, Albanese D, Amantea B, et al. SIAARTI recommendations for anal-go-sedation in intensive care unit. Minerva Anestesiol 2006;72:769-805.

16. Sauder P, Andreoletti M, Cambonie G, Capellier G, Feis-sel M, Gall O,Goldran-Toledano D, et al. Sedation and analgesia in intensive care (with the exception of new-born babies). French Society of Anesthesia and Resus-citation. French speaking Resuscitation Society. Ann Fr Anesth Reanim 2008;27:541-51.

17. Gorman SK, Chung MH, Slavik RS, Zed PJ, Wilbur K, Dhingra VK. A critical appraisal of the quality of criti-cal care pharmacotherapy clinical practice guidelines and their strength of recommendations. Intensive Care Med 2010;36:1636-43.

18. Kastner M, Bhattacharyya O, Hayden L, Makarski J, Es-tey E, Durocher L, et al. Guideline uptake is influenced by six implementability domains for creating and com-municating guidelines: a realist review. J Clin Epidemiol 2015;10: S0895-4356.

19. National Institute for Health and Clinical Excellence The guideline development process: an overview for stake-holders, the public and the NHS. Third edition; 2007.

Key messages

— A protocolized and evidence based approach to pain, analgesia and delirium management is cost-effective and can sig-nificantly improve the patient outcomes.

— The use of clinical practice guide-lines is essential for supporting the deci-sion-making process, and numerous docu-ments on pain, analgesia and delirium management have been published in the last decade.

— The recent guidelines by the Ger-man Association of Scientific Medical Societies, the American College of Criti-cal Care Medicine and the Pan-American and Iberica Federation of the Critical Care Medicine Societies are recommended for use.

— The shortage of high level studies poses some questions on the true effects of guideline recommendations on pain, analgesia and delirium management. High quality clinical trials on this issue are ur-gently needed.

References 1. Barr J, Fraser GL, Puntillo K, Ely EW, Gélinas C, Dasta

JF, et al. American College of Critical Care Medicine: Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med 2013; 41:263-306.

2. Chanques G, Jaber S, Barbotte E, Violet S, Sebbane M, Perrigault PF, et al. Impact of systematic evaluation of pain and agitation in an intensive care unit. Crit Care Med 2006; 34:1691-9.

3. Payen JF, Bosson JL, Chanques G, Mantz J, Labarere J, DOLOREA Investigators. Pain assessment is associated with decreased duration of mechanical ventilation in the intensive care unit: a post Hoc analysis of the DOLOREA study. Anesthesiology 2009; 111:1308-16.

4. Devlin JW, Fong JJ, Fraser GL, Riker RR. Delirium as-sessment in the critically ill. Intensive Care Med 2007; 33:929-40.

5. Celis-Rodríguez E, Birchenall C, de la Cal MÁ, Castorena Arellano G, Hernández A, Ceraso D, et al. Clinical prac-tice guidelines for evidence-based management of sedoan-

Conflicts of interest.—G. Conti received honoraria for consulting and lecturing from GSK and Orion Pharma. The Catholic Univer-sity received research grants from Orion Pharma.Article first publication online: October 16, 2015. - Manuscript accepted: October 14, 2015. - Manuscript revised: September 9, 2015. - Manuscript received on May 5, 2015.


Very likely, the standard practice of deflating the cuff of the endotracheal tube (ett) before extubation is considered an even “safer” prac-tice than demonstrating effective face mask ventilation before muscle relaxation. From the very first day of training it is entrenched in the mind of every anesthetist that there is no safe alternative to deflating the cuff of the ETT be-fore removing it because of the risk of laryn-geal injury associated with “pulling the tube” without prior cuff deflation. This concern ob-viously prevents any critical assessment of the rationale of this “safe practice”. as everyone else, i had used the traditional extubation tech-

in 2008, calder and Yentis questioned the “safe practice” of having to demonstrate

effective face mask ventilation before ad-ministering neuromuscular blocking drugs.1 Despite the lack of convincing evidence sup-porting such practice, the idea of ‘blind’ mus-cle relaxation before establishing ventilation seemed unacceptable to most anesthetists. only three years later, the authors of the 4th National Audit Project of the Royal College of Anaesthetists and The Difficult Airway Soci-ety on Major Complications of Airway Man-agement in the UK encouraged early muscle relaxation.2

E X P E R T O P I N I O N

Could “safe practice” be compromising safe practice? Should anesthetists have to deflate the cuff of the endotracheal tube before extubation?

Hans-Joachim PrieBe

Department of Anesthesia, Albert-Ludwigs-University of Freiburg, Freiburg, GermanyCorresponding author: Hans-Joachim Priebe, Department of Anaesthesia University Medical Center Freiburg, Hugstetter Str. 55, 79106 Freiburg, Germany. E-mail: [email protected]


Lavoro: titolo breve: NEW EXTUBATION TECHNIQUEprimo autore: PRIEBEpagine: 236-9citazione: Minerva Anestesiol 2016;82:236-9

a B s t r a c tDeflation of the cuff of the endotracheal tube (ETT) before tracheal extubation is considered mandatory and safe practice. However, there are potential shortcomings associated with this practice (e.g., aspiration around the uncuffed ett, loss of positive airway pressure, difficulty in generating an effective cough at the time of extubation). By contrast, keeping the cuff inflated during extubation will minimize the risk of tracheal aspiration around the ETT, and it will reliably allow maintenance of positive airway pressure until extubation, effective lung recruitment before extubation, and generation of an effective cough during extubation. All of these factors might reduce the overall risk of immediate postextubation and postoperative respiratory and pulmonary complications. Mandatory monitoring of cuff pressure ensures a remaining rather small, highly compressible cuff volume around the ETT which is unlikely to carry per se the risk of producing laryngeal trauma. In my view, as the overall advantages of not deflating the cuff before extubation outweigh the disad-vantages, anesthetists should not have to deflate the cuff of the ETT before extubation. Ultimately, only a randomized controlled trial will be able to assess the effect of such practice on patient outcome.(Cite this article as: Priebe HJ. Could “safe practice” be compromising safe practice? Should anesthetists have to deflate the cuff of the endotracheal tube before extubation? Minerva Anestesiol 2016;82:236-9)Key words: Airway extubation - Airway management - Anesthesia, endotracheal.

Minerva Anestesiologica 2016 February;82 (2):236-9© 2016 eDiZioni Minerva MeDicaThe online version of this article is located at http://www.minervamedica.it

NEW EXTUBATION TECHNIQUE PrieBe


support. if a “de-blocked” ett cannot imme-diately be removed, positive airway pressure will abruptly be discontinued with possible adverse effects on oxygenation. When the cuff is deflated, positive airway pressure cannot be maintained until the moment of extubation, and effective lung inflation and recruitment prior to extubation not be performed. this hin-ders the generation of an “artificial cough”, thereby impairing effective removal of secre-tions from glottic and subglottic areas during extubation. all of these factors increase the po-tential for postextubation hypoxemia, airway obstruction, laryngospasm, and atelectasis.

With these shortcomings of the traditional practice of extubation in mind, there are, in-deed, several real and potential advantages of not deflating the cuff before tracheal extuba-tion. the risk of tracheal aspiration “around the tube” will be minimized in those situations in which the ETT cannot be removed because the patient bites down on it. Absence of posi-tive airway pressure is reliably avoided if the cuff of the ETT remains inflated during extu-bation. Even if following extubation no addi-tional positive airway pressure is applied by some respiratory device, the extubated patient will be able to generate some degree of posi-tive airway pressure by intermittent vocal cord closure.

The sealed airway allows effective lung inflation and recruitment immediately before extubation. Experimental lung inflation de-creased laryngeal adductor excitability.7, 8 this may possibly reduce the risk of postextuba-tion laryngospasm. On this basis, the recom-mendation to remove the ETT while the lungs are inflated by positive pressure9 makes sense. Effective lung recruitment before extubation may decrease the incidence of postoperative hypoxemia, atelectasis and, in turn, pulmonary complications.10-12 it may counteract the de-velopment of pulmonary atelectasis associated with the routine use of high inspired oxygen concentrations at the time of extubation.13

Increasing airway pressure up to 30-40 cm H2o immediately before extubation ensures that removal of the ETT reliably occurs during the expiratory phase. In addition, it generates

nique without exception from the start of my training in the year 1974 until the year 2006.

then back in 2006, i came across a letter to the editor of Anesthesia & Analgesia in which Shamsai reported his “new” technique of removing the ETT without deflating the cuff.3 He stated to no longer experiencing the typical sequelae of extubation (e.g., laryngo-spasm, bronchospasm, coughing, breath-hold-ing, cyanosis) since he had begun using this practice seven years earlier. not unexpectedly, this communication triggered a highly critical comment by Wax who questioned the safety of this technique and emphasized its entirely anti-conventional nature.4 in his reply shamsai explained his rationale for using this technique and provided subjective evidence for its safety and superiority based on more than 4000 such extubations.5 the debate over the possible pros and cons of this “new” technique was basically closed in 2007 with an interesting, thought-provoking comment by Saidman, the Section editor of the correspondence section of An-esthesia & Analgesia.6 He noted that there is lack of type I evidence supporting the routine practice of deflating the cuff of the ETT before tracheal extubation. since that time i have not come across further reference to this extuba-tion technique.

When first reading Shamsai’s correspon-dence,3 I was as sceptical as Wax had been 4 because the proposed “new” technique was en-tirely opposite to traditional teaching and prac-tice. However, Saidman’s comment 6 on the lack of type i evidence for the standard practice of deflating the cuff of the ETT before tracheal extubation made me reflect on the traditional extubation technique and on my personal more than 30 years of experience with this practice. No doubt, there are several shortcomings asso-ciated with routine cuff deflation before extu-bation. Occasionally, even when routinely us-ing a bite block the ETT cannot immediately be removed upon deflation of the cuff because the patient bites down on it. This increases the risk of tracheal aspiration around the deflated cuff.

it is standard practice today to adminis-ter some amount of positive airway pressure during controlled ventilation or ventilatory

PrieBe NEW EXTUBATION TECHNIQUE


inflate and recruit the lungs. When the airway pressure shortly afterwards reaches 30-40 cm H2O, I remove the ETT without deflating the cuff. this is usually accompanied by a “pop”-like sound and a forceful cough. This tech-nique does not require “synchronization” be-tween manual squeeze of the bag and deflation of the cuff as during the traditional technique. Important, monitoring of cuff pressure is an absolute prerequisite of this technique.

Just as shamsai 3 I had been “guilty” of re-moving ETTs “the old way” for well over 30 years. For reasons detailed above i started to routinely use the “new” technique by the end of 2007 and continued this practice without exception until my recent retirement. My per-sonal experience with this technique is based on more than 2500 tracheal extubations with routine follow-up on postoperative days 1 or 2 in all patients in whom I had practiced it. I share Shamsai’s experience 3 of lack of pa-tient complaints which could be attributed to this technique per se. it is my impression that this ‘new’ technique not only reduces the in-cidence of postextubation upper airway prob-lems, but also the incidence of postextubation hypoxemia unrelated to airway problems. I attribute this to the maintained positive air-way pressure, lung recruitment and genera-tion of an artificial cough associated with this technique.

Surely, subjective impression is not a sub-stitute for findings of a randomized controlled trial which prospectively assesses the validity of this practice. nevertheless, i like to report my experience with this technique because it has its real merits. In my opinion, definite shortcomings associated with the traditional technique of deflating the cuff before extuba-tion, lack of type I evidence supporting such practice, and definite advantages associated with the ‘new’ technique, merit a prospective trial on this issue. After all, just as insisting to demonstrate effective mask ventilation before administering the muscle relaxant may com-promise safe practice, the ‘safe practice’ of insisting to deflate the cuff of the ETT before extubation may possibly also be compromis-ing safe practice.

an effective “artificial cough” which expels secretions and blood from the glottic and sub-glottic areas during tracheal extubation which can be expected to decrease the risk of laryn-gospasm and, in turn, the incidence of post-ex-tubation airway obstruction. All of these fac-tors might reduce the overall risk of immediate postextubation and postoperative respiratory and pulmonary complications.

The obvious concern with not deflating the cuff before extubation is the potential for la-ryngeal trauma. This is why I was particularly concerned with Shamsai’s practice of (merely) manually checking the “pilot” balloon of the ETT as a means of making sure “it is not too tight”.3 Manual check of the “tightness” of the pilot balloon of the ett is a notoriously unreli-able means of assessing the extent of cuff pres-sure and distention.14-17 i had been routinely monitoring cuff pressure throughout the entire period of endotracheal intubation for the past 25 years, keeping it between 20 and maximally 30 cm H2O which is in accordance with pres-ent recommendations.18 Under such condition, visual inspection of a non-deflated low-pres-sure, high-volume cuff following extubation shows a remaining rather small, highly com-pressible cuff volume around the ETT which is unlikely to carry per se the risk of producing laryngeal trauma. Accidental extubation in in-tensive care units is not all that rare. However, to my knowledge there is no documentation of a causal relationship between accidental extu-bation (in the presence of an inflated cuff with usually unmonitored cuff pressure) and subse-quent laryngeal injury.

After having overcome the initial “shock” over this “new” technique, I reflected on the respective correspondences and their reason-ing,3-5 Saidman’s comment (which made this technique appear less “outrageous”),6 and on my long experience with definite shortcom-ings of the traditional techniques. As a result, I changed to the following modified ‘new’ technique. At the end of surgery, I thoroughly suction the oropharynx. i maintain positive airway pressure until tracheal extubation. Im-mediately before planned extubation, i set the expiratory pressure valve to 30-40 cm H2o to

NEW EXTUBATION TECHNIQUE PrieBe


tube. (Letter to the Editor). Anesth Analg 2006;103:1040. 4. Wax D. Where is the evidence (Letter to the Editor)? An-

esth Analg 2007;105:284-5. 5. Shamsai J. Where is the evidence (Reply)? Anesth Analg

2007;105:285. 6. Saidman LJ. Editor’s note. Anesth Analg 2007;104:285. 7. Ikari T and Sasaki CT. Glottic closure reflex: control

mechanisms. Ann Otol Rhinol Laryngol 1980;89:220-4. 8. aviv Je, Biller HF. abductor vocal cord spasm. otolaryn-

gol Head Neck Surg 1990;102:233-8. 9. Landsman IS. Mechanism and treatment of laryngos-

pasm. Int Anesthesiol Clin 1997;3:67-73.10. Hemmes snt, serpa neto a, schultz MJ. intraoperative

ventilator strategies to prevent postoperative pulmonary complications: a meta-analysis. Curr Opin Anesthesiol 2013;26:126-33.

11. tusman g, Bohm sH, suarez-sipmann F. alveolar re-cruitment during mechanical ventilation – Where are we in 2013? Trends Anaesth Crit Care 2013;3:238-45.

12. Tusman G and Bohm SH. Prevention and reversal of lung collapse during the intra-operative period. Best Pract Res Clin Anaesthesiol 2010;24:183-97.

13. Benoit Z, Wicky S, Fischer JF, Frascarolo P, Chapuis c, spahn Dr, et al. the effect of increased Fio2 before tracheal extubation on postoperative atelectasis. anesth Analg 2002;95:1777-81.

14. Fernandez R, Blanch L, Mancebo J, Bonsoms N, Artigas A. Endotracheal tube cuff pressure assessment: pitfalls of finger estimation and need for objective measurement. Crit Care Med 1990;18:1423-6.

15. Granja C, Faraldo S, Laguna P, Gois L. Control of the endotracheal cuff balloon pressure as a method of pre-venting laryngotracheal lesions in critically ill intubated patients. Rev Esp Anestesiol Reanim 2002;49:137-40.

16. Sole ML, Su X, Talbert S, Penoyer DA, Kalita S, Jime-nez e, et al. evaluation of an intervention to maintain endotracheal tube cuff pressure within therapeutic range. Am J Crit Care 2011;20:109-18.

17. Sultan P, Carvalho B, Rose BO, Cregg R. Endotracheal tube cuff pressure monitoring: a review of the evidence. J Periop Pract 2011;21:379-86.

18. Sole ML, Penoyer DA, Su X, Jimenez E, Kalita SJ, Po-alillo e, et al. assessment of endotracheal cuff pressure by continuous monitoring: a pilot study. Am J Crit Care 2009;18:133-43.

Key messages — The traditional practice of deflation

of the cuff of the ett before tracheal ex-tubation is considered mandatory and safe practice.

— this traditional practice has real and potential shortcomings, e.g., aspiration around the uncuffed ett, loss of positive airway pressure, and difficulty in generat-ing an effective cough at the time of extu-bation.

— The supposed new practice of keep-ing the cuff inflated during extubation ef-fectively counteracts the shortcomings of the traditional practice, thereby possibly reducing the overall risk of immediate postextubation and postoperative respira-tory and pulmonary complications.

— The new extubation technique re-quires mandatory monitoring of cuff pres-sure to avoid laryngeal injury.

References 1. Calder I and Yentis SM. Could ‘safe practice’ be compro-

mising safe practice? Should anaesthetists have to demon-strate that face mask ventilation is possible before giving a neuromuscular blocker? Anaesthesia 2008;63:113-5.

2. The Royal College of Anaesthesists. 4th National Audit Project (NAP4). Major complications of airway manage-ment in the UK [Internet]. Available from http://www.rcoa.ac.uk/nap4 [cited 2016, Jan 13].

3. Shamsai J. A new technique for removal of endotracheal

Conflicts of interest.—The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript.Article first published online: July 1, 2015. - Manuscript accepted: June 29, 2015. - Manuscript revised: June 23, 2015. - Manuscript received: May 14, 2015.


© 2016 eDiZioni Minerva MeDicathe online version of this article is located at http://www.minervamedica.itMinerva anestesiologica 2016 February;82 (2):240-1

Hydroxyzine and Qtc interval: drugs without sin cast the first stone!

Dear editor,

recently, the Pharmacovigilance risk assessment committee (Prac) of the european Medicines agency (eMa) released a recommendation 1 highlighting the arrhythmic risks of a very old, first-generation antihis-taminic drug, Hydroxyzine. this lead to substantially lowering the maximal daily dose, from 300 mg to 100 mg in adults, and to 50 mg in older people.

For 50 years, more than 80 Hydroxyzine-containing medicines have been authorized in 24 european states to treat anxiety disorders, itching, sleep disorders, and for premedication before surgery. this eMa’s Prac recommendation confirms the previously known risk of Qtc interval prolongation, an electrical heart alteration which could potentially elicit arrhythmias and cardiac arrest (torsades de Pointes, tdP), and is based on 41 reported cases with narrow and 184 with broad criteria for tdP, 61 of them with fatal outcome. such events are

most likely to occur in patients who have other risk fac-tors, like congestive heart failure or cardiac hypertro-phy, baseline ecg showing prolonged Qtc or t-wave lability, significant electrolytes imbalance (hypokale-mia, hypomagnesaemia), family history of sudden car-diac death, significant bradycardia, or concomitant use of drugs known to prolong the Qtc interval and induce tdP.

as authoritatively stated,2 rare and poorly under-stood side effects occur with many highly effective drugs, and the withdrawal of these medications from the market would probably harm more patients than it would help. the eMa’s Prac indeed recommended this risk should be managed by restricting Hydroxyzine use in those most at risk of heart rhythm problems and generally reducing the exposure to the medicine.

First, it is necessary to observe that a very high number of drugs commonly used in icU prolong the Qtc interval, even if used at approved doses: they could have a clear, a possible, or a conditional associa-tion, evident only along with other risk factors. Hy-droxyzine belongs to the third group (table i).3 sec-ond, these drugs are frequently used in quo ad vitam conditions, and are always managed with continuous monitoring that permits a timely titration of drug dos-ing. For example, something could be learned from the Metoclopramide history: after the eMa recommended its use only up to 5 subsequent days, international au-thors suggest every case should be individually evalu-

L E T T E R T O T H E E D I T O R


lavoro: titolo breve: primo autore: letter to tHe eDitorpagine: 000-000citazione: Minerva anestesiol 2016;82:000-000

Table I.—�Some drugs associated with QTc prolongation and development of TdP.

Known risk Possible risk conditional risk

amiodarone aripiprazole chloral hydrateCiprofloxacin clozapine Fluoxetine

clarithromycin Dexmedetomidine FurosemideFluconazole lithium HydrochlorothiazideHaloperidol Mirtazapine Hydroxyzine

Levofloxacin Norfloxacin KetoconazoleMethadone olanzapine Metoclopramide

ondansetron Promethazine MetronidazolePropofol Quetiapine Pantoprazole

Sevoflurane Vardenafil Paroxetinesotalol venlafaxine sertraline

the complete list is available at www.torsades.net.3 Known risk: substantial evidence supports the conclusion that these drugs prolong the Qt interval AND are clearly associated with a risk of TdP, even when taken as directed in official labeling. Possible risk: Substantial evidence supports the conclusion that these drugs can cause QT prolongation, but there is insufficient evidence at this time that these drugs, when used as directed in official labeling, are associated with a risk of causing TdP. Conditional risk: substantial evidence supports the conclusion that these drugs are associated with a risk of tdP, but only under certain conditions (e.g. excessive dose, hypokalemia, congenital long Qt or by causing a drug-drug interaction that results in excessive Qt interval prolongation).

letter to tHe eDitor


© 2016 eDiZioni Minerva MeDicathe online version of this article is located at http://www.minervamedica.it Minerva anestesiologica 2016 February;82 (2):241-2

the association between the ultrasound-guided serratus Plane Block and Pecs i Block can represent a valid alternative to conventional anesthesia in breast surgery in a seriously ill patient

Dear editor,

the recent introduction of pectoral nerves block (Pecs block) 1 and serratus Plane Block (sPB) 2 in breast surgery, represents an alternative to general anes-thesia and locoregional conventional techniques,3 like epidural anesthesia or paravertebral block 4-9 in onco-logical breast surgery, especially in high anesthetic risk patients, like in elderly women. 10

the combination of sPB with Pecs i block can pro-vide a high-quality analgesia after modified radical ma-stectomy, as suggested by Bouzinac et al.11

in our University Hospital of l’aquila (italy), the as-sociation between sPB and Pecs i block was performed in a 78-year-old woman underwent to radical mastectomy and axillary dissection. she was 162 cm tall, weighed 80 kg (BMi 30.48, asa iii) and affected by a severe respira-tory insufficiency for pulmonary fibrosis (in therapy with cPaP ventilation) heart failure (ejection Fraction 32%), arterial hypertension, diabetes ii type and renal chronic in-sufficiency. The patient needed of dual antiplatelet therapy. Written informed consent was obtained from the patient.

regional anesthesia was performed under ultra-sound-guidance; to realize serratus Plane Block a 12.5 Mhz linear probe was positioned at fifth rib, along the middle axillary line. the in-plane approach was used and after that the interfascial plane between latissimus dorsi and serratus anterior muscles was identified, 3-4 ml of saline solution were injected to open this fascia, and then a total of 25 ml of 0.5% levobupivacaine so-lution were injected (Figure 1).

Pecs i Block was performed by injecting in the fas-cia between minor and major pectoral muscles, 10 ml of 0.375% levobupivacaine (Figure 2). an ipsilateral parasternal injection under ultrasound guide, was per-formed at 2nd and 4th intercostal space, in the external intercostal membrane between major pectoral and in-tercostal muscles. two injections of 5 ml of 0.375% levobupivacaine were performed.

a sedation with easy arousability was ensured with 3-4 mg/kg/h of intravenously propofol. supplemental ox-ygen (8 l/min, 40% of inspired fraction of oxygen) is ad-ministered by venturi mask under end tidal co2 control (etco2) to ensure an oxygen saturation (o2sa%) major than 90%; heart rate, ecg, arterial blood pressure and o2sa% were monitored during the surgery. a good qual-ity anesthesia of the mammary and axillary regions was obtained, with a good hemodynamic stability and without

ated in icU,4 explicitly accepting an off label use of this drug.

Definitely, we agree that EMA’s PRAC indications have to be respected, but also wisely interpreted and applied with careful attention: for the home therapy or in the general hospital ward, it is correct to avoid daily doses higher than 100 mg. in critically ill, monitored pa-tients without risk factors, an initial Hydroxyzine daily dose up to 600 mg 5 appears adequate to reduce their “total proarrhythmic” risk, provided that the exposure is reduced with the earliest reduction/interruption of the administrations. this attention is anyway manda-tory for all sedatives! For other patients, reducing the initial daily doses to 300 or 100 mg seems to be the most adequate strategy.6 since in icU there are not free-from-risk drugs or procedures, intensivist physicians (and hospital pharmacists) should avoid a priori stated, fundamentalist positions based on recommendations addressed to general practitioners.

giovanni Mistraletti *, gaetano iaPicHino

Dipartimento di Fisiopatologia medico-chirurgica e dei trapianti, Università degli studi di Milano, Milano, italia

*corresponding author: giovanni Mistraletti, Dipartimento di Fisiopatologia medico-chirurgica e dei trapianti, Univer-sità degli studi di Milano, a.o. san Paolo, Polo Universita-rio, via a. Di rudinì, 8 - 20142 Milano, italia.e-mail: [email protected]

References

1. european Medicine agencies. Hydroxyzine; [in-ternet]. available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/refer-rals/Hydroxyzine/human_referral_prac_000043.jsp&mid=Wc0b01ac05805c516f [cited 2016, Jan 14].

2. roden DM. Drug-induced prolongation of the Qt inter-val. n engl J Med 2004;350:1013-22.

3. long Qt. syndrome torsades des pointes; [internet]. available from: www.torsades.net [cited 2016, Jan 14].

4. van der Meer Yg, venhuizen Wa, Heyland DK, van Zanten ar. should we stop prescribing metoclopramide as a prokinetic drug in critically ill patients? crit care 2014;18:502.

5. Mistraletti g, Umbrello M, sabbatini g, Miori s, taverna M, cerri B, et al. Melatonin reduces the need for sedation in icU patients. a randomized controlled trial. Minerva anestesiol 2015;81:1298-310.

6. Mistraletti g, Mantovani es, cadringher P, cerri B, cor-bella D, Umbrello M, et al. enteral vs. intravenous icU sedation management: study protocol for a randomized controlled trial. trials 2013;14:92.

Conflicts of interest.—The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript.Article first published online: September 16, 2015. - Manuscript accepted: september 15, 2015. - Manuscript received: July 31, 2015.(Cite this article as: Mistraletti g, iapichino g. Hydroxyzine and QTc interval: drugs without sin cast the first stone! Minerva anestesiol 2016;82:240-1)

letter to tHe eDitor


Pierfrancesco FUsco 1, Paolo sciMia 2, Franco Marinangeli 2, tullio PoZone 1, emiliano PetrUcci 1 *

1Department of anesthesia and intensive care Unit, san salvatore academic Hospital of l’aquila, l’aquila,

italy; 2Department of life, Health and environmental sciences, University of l’aquila, l’aquila, italy

*corresponding author: emiliano Petrucci, Department of anesthesia and intensive care Unit, san salvatore aca-demic Hospital of l’aquila, Piazza Paride stefanini, 67100, l’aquila, italy. e-mail: [email protected].

References

1. Blanco r. the “pecs block”: a novel technique for providing analgesia after breast surgery anaesthesia 2011;66:847-8.

2. Blanco r, Parras t, McDonnell Jg, Prats-galino a serra-tus plane block: a novel ultrasound-guided thoracic wall nerve block. anaesthesia 2013;68:1107-13.

3. Blanco r, Fajardo M, Parras t. Maldonado Ultrasound description of Pecs II (modified Pecs I): A novel ap-proach to breast surgery. rev esp anestesiol reanim 2012;59:470-5.

4. lynch eP, Welch KJ, carabuena JM, eberlein tJ. tho-racic epidural anesthesia improves outcome after breast surgery. ann surg 1995;222:663-9.

5. naja MZ, Ziade MF, lonnqvist Pa. nerve-stimulator guided paravertebral blockade vs. general anaesthesia for breast surgery: a prospective randomized trial. eur J anaesth 2003;20:897-903.

6. Klein sM, Bergh a, steele sM, georgiade gs, green-grass ra. thoracic paravertebral block for breast sur-gery. anesth analg 2000;90:1402-5.

7. terheggen Ma, Wille F, rinkes iHB, ionescu ti, Knape Jt. Paravertebral blockade for minor breast surgery. an-esth analg 2002;94:335-9M.

8. Buggy DJ, Kerin MJ. Paravertebral analgesia with lev-obupivacaine increases postoperative flap tissue oxygen tension after immediate latissimus dorsi breast recon-struction compared with intravenous opioid analgesia. anesthesiology 2004;100:375-80.

9. Burlacu cl, Frizelle HP, Moriarty Dc, Buggy DJ. Fenta-nyl and clonidine as adjunctive analgesics with levobupi-vacaine in paravertebral analgesia for breast surgery. an-aesthesia 2006;61:932-7.

10. Murata H, ichinomiya t, Hara t. Pecs block for anesthe-sia in breast surgery of the elderly J anesth 2015;29:644.

11. Bouzinac a, Brenier g, Dao M, Delbos a Bilateral asso-ciation of pecs i block and serratus plane block for posto-perative analgesia after double modified radical mastec-tomy. Minerva anestesiol 2015;81:589-90.

12. chung F. recovery pattern and home-readiness after am-bulatory surgery. anesth analg 1995;80:896-902.

Conflicts of interest.—The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript.Article first published online: November 27, 2015. - Manuscript accepted: november 24, 2015. - Manuscript revised: november 11, 2015. - Manuscript received: october 1, 2015.(Cite this article as: Fusco P, scimia P, Marinangeli F, Pozone t, Petrucci e. the association between the ultrasound-guided serratus Plane Block and Pecs i Block can represent a valid alternative to conventional anesthesia in breast surgery in a se-riously ill patient. Minerva anestesiol 2016;82:241-2)

discomfort for the patient and surgeon; so at the end of surgical procedure, the infusion of propofol was stopped and the patient was admitted in PacU phase 1 and then in PacU phase 2, according to the PacU policy.12

the association between sPB, Pecs i block and parasternal la injections, ensured a good quality and a long lasting analgesia. In the first 24 hours after surgery, the patient did not request opiates, and only 2000 mg of acetaminophen were administered.

this experience shows that, although the epidural and paravertebral thoracic block represent the gold standard in breast surgery 4-9 the hypothesis of Bouzinac et al. 11 about the analgesic efficacy of the association between sPB and Pcs i block, could be true.

this case report could suggest the idea that the com-bination between these two anesthetic procedures could have a good anesthetic potency and be a valid alterna-tive to conventional techniques, especially in high an-esthetic risk patients undergoing breast cancer surgery.

Further studies should be needed to demonstrate the validity of sPB and Pecs i block as an anesthetic stan-dardized method for breast cancer surgery.

Figure 1.—Ultrasound-guided serratus Plane Block.lD: latissimus dorsi muscle; al: local aesthetic; serratus: serratus anterior muscle; 5thrib: fifth rib.

Figure 2.—Ultrasound-guided Pecs i Block.PMm: pectoral major muscle; Pmm: pectoral minor muscle.


underlines that not only the biophase kinetics, but also the receptor kinetics of remifentanil should be incorporated into a tci model to im-prove the calculation of the right dose of the drug. consequently, to date the computerized drug administration systems cannot replace the competence and the skills of an experienced anesthetist.2

in clinical practice, the achievement of ad-equate levels of anesthesia and analgesia is mainly based on clinical parameters. two re-cently introduced devices, Navigator® by ge Healthcare and smartPilot® View by Dräger Medical, may help anesthetists by providing estimates of the concentrations of anesthetics and analgesics and by predicting the effect of the interaction between the drugs.3, 4 cirillo et al. performed a prospective, non-randomized study to evaluate if Navigator® or smartPilot® View guided anesthesia was associated with an adequate depth of hypnosis, good quality of analgesia, and reduced anesthetic dosing.5 two groups of patients in whom anesthesia was carried out with standard monitoring were compared with two groups in whom Naviga-tor® or smartPilot® View were utilized. in all

General anesthesia

in last years, target controlled infusion (tci) has been increasingly utilized in anesthe-

sia and sedation to achieve the desired drug concentration in the plasma and at the effect site. Piacevoli et al. presented an interesting pharmacokinetic paper that verifies the corre-lation between estimated and real remifentanil concentrations in the blood and in the cerebral extracellular fluid during TCI.1 the study was performed during intracranial surgery for ce-rebral supratentorial neoplasms. cerebral ex-tracellular concentration was assessed with a push-pull perfusion brain microdialysis probe. results showed that: a) interindividual vari-ability of measured blood and of intracranial concentrations of remifentanil was very high and b) measured remifentanil concentrations in the blood and the brain were significantly low-er than those calculated with the Minto’s phar-macokinetic model loaded in the tci pump. the authors concluded the effect-site concen-tration obtained during remifentanil tci can significantly differ from that estimated by the device. the accompanying editorial by Freye

Y E A R I N R E V I E W

a year in review in Minerva anestesiologica 2015Franco caValiere 1 *, Massimo allegri 2, edoardo calDeriNi 3

Massimiliano carassiti 4, Flaminia colUZZi 5 Pierangelo Di Marco 6, Marco Piastra 7, Marco rossi 1

1istituto di anestesia e rianimazione, Università cattolica del sacro cuore, Policlinico “a. gemelli”, rome, italy; 2Dipartimento di scienze chirurgiche, Università degli studi di Parma, Parma, italy; 3Unità di terapia intensiva Pediatrica, Dipartimento di anestesia e terapia intensiva, Fondazione irccs ca’ granda, ospedale Maggiore Policlinico, Milan, italy; 4campus Bio-Medico Università di roma, rome, italy; 5Dipartimento di scienze e Biotecnologie Medico-chirurgiche, Università di roma “sapienza”, rome, italy; 6Dipartimento di anestesia e terapia intensiva, Università di roma “sapienza”, rome, italy; 7terapia intensiva Pediatrica e trauma center Pediatrico, Università cattolica del sacro cuore, Policlinico “a. gemelli”, rome, italy*corresponding author: Franco cavaliere, istituto di anestesia e rianimazione, Università cattolica del sacro cuore, Policlinico “a. gemelli”, largo Francesco Vito 1, roma, italia. e-mail: [email protected]


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caValiere a Year iN reVieW iN MiNerVa aNestesiologica 2015


of using DeX intraoperatively outweighs the high cost of the drug.7

since 1990, the autonomic nervous sys-tem (aNs) function has been studied dur-ing anesthesia for various purposes and with discordant results.12, 13 Ma published some interesting papers on this topic. raimondi et al. used heart rate variability (HrV) to pre-dict the occurrence of arterial hypotension after spinal anesthesia for caesarean delivery and showed that preoperative analysis of aNs activity can help to identify patients at risk.14 guzzetti et al. used the variability of heart rate (eKg-rr intervals) and systolic arterial pres-sure (saP) to compare the impact of different anesthetic strategies (sevoflurane+fentanyl, sevoflurane+remifentanil, and propofol+ remi-fentanil) on cardiovascular autonomic modula-tion.15 they found that modulation was blunt-ed, but not abolished during general anesthesia; that propofol+remifentanil anesthesia better preserved active autonomic sympathetic mod-ulation; and that the three anesthetic strategies did not differ about the effects on baroreflex gain. as noxious stimuli generate a stress re-sponse with an increased sympathetic activity, ANS could reflect pain intensity. Surgical Pleth index (sPi) was proposed to measure pain in-tensity by evaluating aNs activity.16 colombo et al. randomized 64 patients who underwent elective laparoscopic cholecystectomy to sPi-guided or standard anesthesia.17 they found that sPi-guided anesthesia could prevent sym-pathetic activation triggered by pneumoperito-neum insufflation, but apparently provided no further, clinically-relevant advantages. simi-larly, Boselli et al. used analgesia/anesthesia index (aNi; range 0-100), based on HrV, to evaluate analgesia/nociception balance during general anesthesia and, particularly, to predict hemodynamic reactivity during suspension laryngoscopy.18 Ninety-six patients were ini-tially enrolled, but 46 were excluded because they were given drugs like atropine, ephedrine, or beta-blockers, that affect HrV. aNi values over 55 predicted hemodynamic reactivity to laryngoscopy with 88% sensitivity and 83% specificity. Overall, the above summarized studies show how intriguing and useful could

groups, the clinical endpoints of adequate hyp-nosis and analgesia were achieved, but lower dosages of anesthetic drugs were necessary when Navigator® or smartPilot® View were utilized. the authors concluded that both de-vices proved to be suitable for preventing drug overdosage and, potentially, to reduce intra and postoperative side effects.

recollection of dreams after anesthesia is a frequently reported, but poorly understood side-effect. aceto et al. performed a random-ized controlled study, in which two groups of patients who underwent general anesthesia with sevoflurane for elective thyroidectomy were compared. anesthetic concentration was adjusted on the basis of Bispectral index (Bis) in the first group, and of hemodynamic param-eters (HP) in the second.6 overall frequency of reported dreams was high, since recollec-tion occurred in 29 out of 127 patients (23%). Dreams were pleasant, similar to those occur-ring during sleep, and were not related with the auditory recordings administered to the patients during anesthesia. No difference was detected between the two groups of patients concerning both sevoflurane concentration utilized and the incidence of dreams. in both groups, the absence of postoperative dream recall was associated with sevoflurane concen-trations higher than 0.9%.

Dexmedetomidine (DeX) is an alpha-2 adrenergic receptor agonist developed in the 1990s and utilized for short-term sedation in intensive care units.7 Further studies have demonstrated its potential as an adjuvant for pain treatment and suggested that intraopera-tive administration of DeX could be utilized for postoperative pain control,8 and to de-crease hypnotic consumption.9, 10 le Bot et al. carried out a meta-analysis on the effects of DeX on postoperative pain.11 their analy-sis demonstrated that DeX decreases both in-tra- and post-operative opioid consumption, whereas the recovery time from anesthesia is not affected, probably because of the sedative action of the drug. the opioid sparing effect may explain why DeX lowers the incidence of PoNV. as pointed out by spieth in his edi-torial, the question is whether the advantages

a Year iN reVieW iN MiNerVa aNestesiologica 2015 caValiere


exhaustive analysis of oxygenation patho-physiology and of the techniques proposed to achieve an optimal preoxygenation in order to increase the length of tolerable apnea.27 the authors pointed out that factors predictive of inadequate pre-oxygenation overlap with those predictive of difficult mask ventilation; consequently, anesthetists should be familiar with preoxygenation techniques and able to handle life-threatening emergency situations by alternative methods, i.e. trans-tracheal ven-tilation.28

Finally, genovese et al. commented on a re-cent judgment of the Milan court of assizes that punished three surgeons for having per-formed operations without therapeutic indica-tion.29 Four anesthetists were also involved. two of them were charged for negligence in evaluating operative risk and two for not with-drawing because of the lack of therapeutic in-dication. What really matters in that kind of situations is whether the anaesthetist should discuss and even refuse surgical indications made by the surgeon: of course he does, being the anesthetist’s role far beyond just putting the patient asleep.30

Pediatric anesthesia

Preoperative anxiety is associated with in-creased postoperative analgesic requirements, higher incidence of emergence delirium, sleep disturbance, and other maladaptive behavioral changes. in an attempt to reduce preoperative anxiety, various behavioral, contextual, and pharmacological approaches have been tried.31 Berghmans et al. analyzed the risk factors for children anxiety at induction and for emer-gence delirium.32 consistently with previous findings, the Authors were able to demonstrate that the levels of anxiety at the induction of an-esthesia correlated well with the levels of anx-iety at the admission to the operating theatre and with pre-existing emotional/behavioral problems occurred in the last six months prior to surgery.33 Other significant predictors were children age lower than 6 yr and poor parental educational status. in line with previous re-search, also emergence delirium was predicted

be a precise evaluation of aNs activity dur-ing anesthesia because aNs modulation on cardiovascular system reflects not only noci-ception, but a multitude of inputs, like those from thermoregulatory and endocrine systems, intravascular volume, respiratory pattern, and drug effects.19

Kawano et al. evaluated the efficacy of aprepitant, a high selective NK-1 receptor an-tagonist, on PoNV in patients who undergo epidural opioid therapy.20 they found a lower incidence (3% vs. 27%; p<0,001) in patients treated with aprepitant plus dexamethasone in comparison with those treated with dexameth-asone alone. These data confirm the impor-tance of multiple drugs treatment in PoNV.21 However, clinical experiences with aprepitant are still limited and its routine use will depend on cost-analysis, because the drug price is rather expensive and uneven among countries.

corneal abrasion (ca) and ischemic opti-cal neuropathy (ioN) are the two main ocular complications reported during robotic-assisted laparoscopic prostatectomy (ralP) for can-cer.22 ca is a traumatic injury of corneal epi-thelium, causes pain and photophobia, and is often characterized by a favorable evolution. ioN is a serious complication; it is rare, often bilateral, of multifactorial origin, and can lead to severe visual dysfunction and even to blind-ness.23 Kan et al. reviewed the pathophysiolo-gy and incidence of ocular complications after ralP, highlighting the lack of proven thera-pies for ioN, and stressing the importance of preventive measures, such as decreasing the amount of IV fluid administration and shorten-ing the time spent by the patient in steep tren-delemburg position.

in a large prospective multicenter study, Polderman et al. investigated perioperative glycaemia in patients who underwent ambula-tory surgery.24 Mean blood glucose increased slightly, probably due to PoNV prophylaxis with dexamethasone. However, the incidence of hyperglycemia was lower than expected and not associated with postoperative complica-tions.25

Preoxygenation in anesthesia is still a mat-ter of debate.26 Bouroche et al. provided an



transplanted liver function in comparison with standard donors, even for organs from donors on ecMo. of course, a small series of patients was reported, and results should be confirmed by larger studies.41 on this purpose the authors suggested implementing a transplant registry that includes organs from patients in advanced circulatory support.

in their deep insight on solid organ trans-plantation, reske et al. reminded the concept of immune-suppressants as drugs that can interact with the organ function, pathogens surrounding the transplanted patients, and co-medications taken chronically. Some specific pathologic entities were depicted, like new on-set diabetes mellitus after transplant, and the post- transplant lymphoproliferative disorder (PtlD), which can resemble multi-organ dys-function syndrome.42

Airway

in emergency situations, securing airways for adequate oxygenation and ventilation is a life-saving procedure. the current gold stan-dard is endotracheal intubation (eti). Video-laryngoscopes are becoming an indispensable tool for airway management because they of-fer some advantages over direct laryngoscopy and their use is likely to become the rule, rath-er than the exception in next years.43 Pieters et al. showed that the forces exerted on maxillary incisors using video-assisted laryngoscopy are lower than those exerted during direct laryn-goscopy.44 The Difficult Airway Society has included videolaryngoscopes into the algo-rithm for unanticipated difficult intubation,21 which accounts for most of difficult bag mask ventilation and difficult intubation cases (93 and 94%, respectively).45 of course, the awake intubation remains the gold-standard in the management of anticipated difficult airways and should not be abandoned.46,47 alvis et al. compared the rigid flexible laryngoscope (RIFL) vs. fiberoptic broncoscope (FOB) for intubation in potentially difficult airway in 40 patients, and found that the new riFl required less time to successful intubation and fewer airway assist maneuvres.48

by the younger age of the child as well as his/her first experience with anesthesia.34 surpris-ingly and unlike previous studies, emergence delirium was not associated to preoperative emotional/behavioral problems.35, 36 this dis-crepancy may be attributed to the use of non-validated scores for emergence delirium in the earlier studies. in conclusion, appropriate scoring systems can help anesthesiologists to fit the anesthesia procedure to the individual needs of anxious and vulnerable children.

experimental data collected in animal mod-els suggest that many general anesthetics may affect brain development. the relevance of those findings in young children who undergo general anesthesia is still unknown. green et al. conducted a retrospective autopsy-based study comparing infants exposed and non-exposed to general anesthetics.37 Postmortem neuropathological findings were analyzed and showed that gliosis was significantly more rep-resented in children exposed to general anes-thetics compared to those non exposed. gliosis is known to be a non specific reactive process activated by various brain injuries, such as infarction, infection, or malignancy. Further-more, gliosis can also be a non-specific cellular response to various toxic insults, which may include general anesthetics. the authors ar-gued that no clinical correlation can be drawn from this finding alone and further studies are necessary to better understand the effect of an-esthesia on the developing brain. of note, a re-cently published multicenter randomized trial has demonstrated that in young infants sevo-flurane anesthesia does not increases the risk of neurocognitive sequelae at a 2 year follow up compared with awake-spinal anaesthesia.38

Transplantation

organ shortage prompts clinical research-es towards the definition of extended donors criteria.39 the study by Valenza et al. offers a retrospective insight into the control of qual-ity of livers from 26 brain death donors who suffered different degrees of cardio-circulato-ry collapse before organ procurement.40 the acute event did not impact negatively on the



sive status associated with spinal anesthesia (SA). An intravenous fluid load, as well as mechanical counteracting of aortocaval com-pression and vasopressors, is commonly used to prevent maternal hypotension.57 ripollés Melchor et al. performed a meta-analysis to compare colloids and crystalloids to prevent arterial hypotension induced by sa in elective caesarean delivery. eleven randomized con-trolled trials (rcts) were included. colloids resulted superior to crystalloids to prevent ar-terial hypotension. Phenylephrine associated with fluid therapy reduced the relative risk of hypotension, whereas the use of colloid vol-umes greater than 500 ml did not add any sig-nificant benefit.58 5-Ht3 receptor antagonists may be an alternative strategy for preventing sa-induced hypotension since serotonin is in-volved in Bezold-Jarisch reflex, which causes bradycardia and hypotension. a study by gao et al. showed that prophylactic administration of ondansetron can reduce the incidence of sa-induced hypotension in both obstetric and non-obstetric patients.59 analogously, owc-zuk et al. found that preventive use of ondan-setron, 8 mg, in elderly patients, significantly attenuated the decrease in diastolic and mean arterial pressure, without significant effect on systolic pressure.60 These findings are particu-larly attractive in geriatric patients, in whom excessive fluid load and vasopressors may be contraindicated because of cardiovascular co-morbidities.

in the last decades, the focus of regional analgesia has changed from central to periph-eral blocks, because of contraindications and potential complications of the formers. the transversus abdominis plane (taP) block may provide adequate postoperative analgesia and decrease opioid consumption in women undergoing caesarean section.61 Fusco et al. systematically reviewed the literature and evaluated the results of 11 trials in which taP block was performed at the end of caesarean delivery.62 taP block alone was less effec-tive than intratecal morphine (itM) in terms of postoperative opioid consumption, time to first analgesic requirement, and postoperative pain score; however, itM can cause opioid

training has an important role in anesthesia practice. anaesthesiologists should master the most common devices to best use them in the unanticipated difficulties, but it’s difficult to achieve these skills if not adequately trained. Despite technical limits regarding materials and the obvious difference from a reacting living body, manikins play an important role in training, particularly in simulated difficult scenarios. they are effective to teach endotra-cheal intubation,49 but less similar to humans regarding chest movements to verify lMa correct placement and effective face-mask ventilation.50 thierbach et al. compared air-way management in a simMan with laryngeal Mask airway (lMa), laryngeal tube, and easytube in standard conditions and in case of tongue edema, trismus, and limited mobility of the cervical spine.51 they found that lMa was rated the best under standard conditions, but was overcome by EasyTube in difficult set-tings.

tracheostomy is performed in critically-ill patients with prolonged need of an endotra-cheal tube. in the past two decades, the inci-dence of tracheostomy in icUs increased by 106%.52 of note, early tracheostomy is not associated with evidence of reduced mortal-ity, duration of mechanical ventilation, inten-sive care stay, or incidence of VaP. 53,54 Prior to closing a tracheostomy and to resume oral feeding, it is necessary to rule out the pres-ence of swallowing disorders by fiberoptic endoscopic evaluation or videofluoroscopy.55 ceriana et al. performed videofluoroscopy in a group of patients discharged from an icU with a tracheostomy.56 incomplete backward epiglottis folding, pharyngeal retention, pen-etration, and aspiration were the main swal-lowing dysfunctions observed. Patients with chronic respiratory disease exhibited a worse swallowing function compared to neurologic patients, but most abnormalities were at least partially reversible.

Regional anesthesia

Pregnant women are particularly susceptible to complications arising from severe hypoten-



tional status was not among the independent predictive factors of one-year mortality. other authors have shown that preadmission func-tional status did not influence the perceived quality of life in survivors and the willingness to be acutely supported again if an acute dis-ease recurred.66 the editorial by Maclaren re-inforced the need of a holistic approach to the aged patients, matching the health care poli-cies with the beliefs and wishes of patients and relatives.67

a review by Bassetti et al. tried to put a bit of order in the stereotypes of surgical site in-fection prevention,68 where over-consumption of antimicrobial drugs, inadequate use of an-tibiotics, and inappropriate timing of admin-istration remain still unresolved issues.69 the authors pointed out that antibiotic prophylaxis should be made with a single dose within 30 minutes before surgery and should not exceed 24 hours if further doses of antibiotics are needed.

Literature on perioperative fluid manage-ment is extensive, but heterogeneous and somewhat inconsistent.70 Berger et al. per-formed a systematic review and a meta-analy-sis on the targets of perioperative fluid therapy and their effects on postoperative outcome.71 they found an association between three tar-gets (systolic/pulse pressure variation <10-12%, increase in SV <10% in response to fluid loading, and a corrected flow time of 0.35-0.4 sec with an increase in stroke volume <10%) with less postoperative complications and a shorter icU/hospital length of stay, but not with mortality. Besides, goal directed fluid therapy resulted effective in high-risk patients. Finally, a correct timing of fluid loading was important and other co-interventions were of-ten needed.

Patient Blood Management strategy is an evidence-based, multidisciplinary, multimod-al, and patient-tailored approach for reducing blood transfusions, adverse effects, and hospi-tal costs.72 Liumbruno and Biancofiore wrote an expert opinion on this topic.73 the three pillars of this strategy are optimizing patient erythropoiesis, minimizing bleeding, and har-nessing and optimizing patient-specific physi-

side effects. the value of a multimodal analge-sic strategy that includes both taP block and itM, was still unclear, because of controver-sial results, trial heterogeneity, and low numer-osity. the authors concluded that larger stud-ies on the association of taP block and itM were warranted.

Zhang et al. performed a meta-analysis, comparing sciatic–femoral nerve block (sFB) with unilateral spinal anesthesia (Usa) for knee arthroscopy in outpatients.63 sFB was as-sociated with shorter time to discharge, faster bladder function recovery, longer anesthesia length, and better postoperative analgesia. conversely, time to perform sFB resulted sig-nificantly longer and the quality of achieved blockade lower, probably due to the two dis-tinct positions required for sFB. Both anes-thetic techniques provided high levels of pa-tients’ satisfaction.

regional anesthesia has been associated with reduced perioperative inflammation. Gro-su et al. analyzed the mechanisms involved in modulation of inflammation by local anes-thetics (la) and adjuvants, such as alpha-2 adrenergic agonists.64 experimental studies show that LA may reduce neurogenic inflam-mation and have a direct action on immune cells. Moreover, the opioid-sparing effect of la may reduce opioid-related immunosup-pression. on the other hand, available clinical data do not point out any benefit of regional analgesia on patient outcome. Further clinical trials are needed which focus on the impact of regional anesthesia on delayed outcomes, such as persistent post-operative pain, progression of inflammatory diseases, and cancer-free sur-vival time.

Perioperative medicine

the decision to admit patients to icUs is often influenced by the evaluation of their functional status as a determinant of the prob-ability of success. even if quite reasonable, this assumption was challenged by Magnette et al. who studied 96 elderly patients (>80 years old) admitted to an icU for more than 24 hours.65 they showed that preadmission func-



raphy (Fate) in 282 surgical patients.80 they found that at least two Fate views could be obtained in 91% of patients. interestingly, ab-normal findings were found in 30% of stable patients. the editorial by sangalli and rubino underlined the utility of intraoperative tee to prevent cardiocirculatory complications in el-derly patients who undergo complex surgical procedures.81

guarracino et al.82 reviewed preoperative cardiovascular assessment in non-cardiac-sur-gery patients, highlighting the novel aspects of esc-esa 2014 guidelines.83 the authors underlined the importance of risk stratification and advised against the indiscriminate use of routine preoperative cardiac testing.

coagulation and anticoagulation are crucial points in cardiovascular surgery. ranucci et al. investigated the effects of moderate acidosis on postoperative bleeding in cardiac surgery.84 their results showed that both low blood pH (<7.35) and high serum lactate (>4.0 mmol/l) were associated with excessive postoperative bleeding and the need of surgical revision; however, the authors recommended to rely mostly on substrates replacement (fibrinogen and/or platelets), rather on pH correction by bicarbonates. De robertis et al. reviewed the factors involved in postoperative coagulopa-thy.85 the association of acidosis and hypo-thermia is particularly dangerous since both can act synergistically to produce coagulation derangement; a further factor is hypocalcaemia caused by massive transfusion requirement. of note, mild hypothermia slightly reduces plate-let adhesion and fibrinogen synthesis, but sel-dom causes severe bleeding.86, 87 the use of procoagulant agents was also examined, being an issue still on debate.88

Perioperative cerebral damage is a potential complication of cardiac surgery, which mostly affects elderly patients.89 it ranges from minor neurocognitive deficits to catastrophic neuro-logical morbidity with permanent impairment and death. overall, some degree of brain inju-ry occurs in 30-70% of patients and is mainly of ischemic origin.90 Hypoperfusion leading to brain ischemia may arise during cardiopulmo-nary bypass (cPB). in order to monitor the ad-

ological reserve of anemia. a further contribu-tion on this topic was given by iapichino in an interesting editorial on the age-old question about safe levels of hemoglobin and albumin related to circulating volume in critically ill patients.74 applying a mathematical model to clinical scenarios, he showed that hemoglobin effective levels are dependent on the mainte-nance of intravascular oncotic forces. there-fore, a safe degree of anemia and the transfu-sion threshold should be targeted according to albumin serum levels.75 a value of about 25 g/l may be a satisfactory compromise to man-age anemia and to minimize blood volume reduction and the associated microcirculatory impairment.

obstructive sleep apnea (osas) can cause severe hypoxemic episodes in the postopera-tive period. Deflandre et al. investigated how to identify low preoperative adherence to cPaP treatment in 90 patients scheduled for surgery.76 Non-adherent patients were charac-terized by a feeling of breathlessness when us-ing cPaP or of fatigue not improved by cPaP and no awareness of the risk of complications caused by OSAS nor of the efficacy of CPAP to reduce this risk. in these patients, preopera-tive evaluation by anesthetists may have an important educational role if performed well before surgery.77

cancer is associated with thrombotic as well as hemorrhagic coagulation derangements.78 cuomo et al. revised the literature about perioperative management of antithrombotic therapy in cancer patients.79 they pointed out that prothrombotic and hemorrhagic risks of the suspension and resumption of each drug should be contextualized to the oncologic set-ting. Also of great importance is the identifi-cation of patients at higher risk, particularly those who are thrombocytopenic, frail, mal-nourished, and with vitamin K deficiency.

Focused transthoracic echocardiography (tee) is largely utilized in critical and periop-erative medicine, less frequently in the intra-operative setting due to the difficult access to the patient. Kratz et al. studied the feasibility of intraoperative tee performed according to Focused assessed transthoracic echocardiog-



eleven recommendations and a useful algo-rithm were issued.

Postoperative pain can affect short and long term patients’ outcome.99, 100 Hughes et al. reviewed the literature on the best anal-gesic treatment following open liver resec-tion.101 they found that epidural thoracic an-algesia provides superior pain relief, but is associate with prolonged length of stay when compared with continuous wound infiltration and intrathecal morphine. No difference was observed in systemic complication rates.

Magnesium has been widely studied as pos-sible adjuvant in acute and chronic pain ther-apy, but results are controversial.102 Frassanito et al. failed to confirm the effectiveness of magnesium on postoperative pain after ortho-pedic surgery. in fact, the authors demonstrated that intravenous perioperative administration of the cation did not influence postoperative pain and opioid consumption after total knee arthroplasty.103

several devices are available to assess the depth of general anesthesia, but none are rou-tinely utilized to measure intraoperative anal-gesia. on this purpose, gruenewald et al. 104 compared the analgesia Nociception index105, derived from heart rate variability, and the surgicalPleth index,106 derived from photo-plethysmographic signal, in 24 patients who underwent elective surgical procedures under general anesthesia with sevoflurane and remi-fentanil. the authors observed that both the devices were able to register the painful stimu-li that occurred during the anesthesia induction and the surgical procedure. Yet, further stud-ies are needed to understand if these measures could effectively monitor the nociception-anti-nociception balance.

genetics seems to be promising in fore-seeing the amount of patient postoperative pain.107, 108 De gregori et al. reviewed the pos-sible role that single nucleotide polymorphisms (sNP) in the human oPrM1 gene could play both in short-term and in long-term follow-up after breast surgery.109 their results suggested that OPRM1 variability, by influencing phar-macodynamics, can potentially help predicting short- and long-term postoperative outcomes,

equacy of cerebral perfusion intraoperatively, near-infrared spectroscopy, trans-cranial Dop-pler and, rarely, jugular bulb oxygen saturation are utilized. in addition, cerebral function can be monitored by eeg analysis and by evoked potentials.90 these techniques can be also uti-lized to monitor cerebral perfusion during ca-rotid surgery performed in general anesthesia. Malcharek et al. compared the effectiveness of evoked potentials with awake neurological evaluation in patients undergoing carotid end-arterectomy.91

Finally, Westerdahl wrote an expert opin-ion on the optimal technique for prevention of respiratory complication after cardiac surgery by deep breathing exercises.92 she underlined that deep breathing exercises with or without mechanical devices have been shown to have positive effects on atelectasis, lung volumes, oxygenation and dyspnea, thereby reversing restrictive postoperative respiratory pattern.93

Pain

as pain is one of the most common causes of access to medical care, research continues to face this clinical problem.94 Despite this extensive global effort, chronic pain remains a challenging issue for clinicians and a huge socio-economic problem in europe.95

Within the chronic pain population, low back pain is one of the most prevalent and dis-abling disorders.96 Kozlov et al. reviewed evi-dences on epidural injection in the treatment of this disease.97 they found that transforaminal route appears to be more effective than the in-terlaminar one, but is characterized by a higher risk of vascular injection or neurologic injury. regarding the type of drugs, evidences favor lower non-particulate steroid doses.

Pain is often present at the admission to the emergency Department. However, pain man-agement in this setting is often inadequate for several reasons, which include the fear of opioid side effects. the Italian Intersociety Recommendations on pain management in the emergency setting stated how to perform pain diagnosis and treatment and how to approach sedation in different emergency contexts.98



meta-analysis of published studies. Minerva anestesiol 2015;81:1105-17.

12. latson tW. Heart rate variability and anesthesiology: reasons for cautious optimism. J cardiothoracVasc an-esth 1992;6:647-50.

13. luginbühl M, Yppärilä-Wolters H, rüfenacht M, Pe-tersen-Felix s, Korhonen i. Heart rate variability does not discriminate between different levels of haemody-namic responsiveness during surgical anaesthesia. Br J anaesth 2007;98:728-36.

14. raimondi F, colombo r, spazzolini a, corona a, cas-telli a, rech r, et al. Preoperative autonomic nervous system analysis may stratify the risk of hypotension after spinal anesthesia. Minerva anestesiol 2015;81:713-22.

15. guzzetti s, Bassani t, latini r, Masson s, Barlera s, citerio g, et al. autonomic cardiovascular modulation with three different anesthetic strategies during neuro-surgical procedures. Minerva anestesiol 2015;81:3-11.

16. Park JH, lim Bg, Kim H, lee io, Kong MH, Kim Ns. comparison of surgical Plethindex-guided anal-gesia with conventional analgesia Practices in chil-dren: a randomized controlled trial. anesthesiology 2015;122:1280-7.

17. colombo r, raimondi F, rech r, castelli a, Fossali t, Marchi a, et al. surgical Plethindex guided anal-gesia blunts the intraoperative sympathetic response to laparoscopic cholecystectomy. Minerva anestesiol 2015;81:837-45.

18. saddawi-Konefka D, alston ta. an electrocardio-graphic monitor for reducing hemodynamic suspense during suspension laryngoscopy. Minerva anestesiol 2015;81:255-7.

19. Boselli e, Bouvet l, Bégou g, torkmani s, allaouchiche B. Prediction of hemodynamic reactivity during total in-travenous anesthesia for suspension laryngoscopy using analgesia/Nociception index (aNi): a prospective ob-servational study. Minerva anestesiol 2015;81:288-97.

20. Kawano H, Matsumoto t, Hamaguchi e, Manabe s, Nakagawa M, Yamada a, et al. Antiemetic efficacy of combined aprepitant and dexamethasone in patients at high-risk of postoperativenausea and vomiting from epiduralfentanyl analgesia. Minerva anestesiol 2015;81:362-8.

21. Frerk c, Mitchell Vs, McNarry aF, Mendonca c, Bha-grath r, Patel a, et al. Difficult Airway Society 2015 guidelines for management of unanticipated difficult in-tubation in adults. Br J anaesth 2015;115:827-48.

22. Kan KM, Brown se, gainsburg DM. ocular compli-cations in robotic-assisted prostatectomy: a review of pathophysiology and prevention. Minerva anestesiol 2015;81:557-66.

23. roth s. Perioperative visual loss: what do we know, what can we do? Br J anaesth 2009;103suppl 1:i31-40.

24. Polderman Ja, Van Velzen l, Wasmoeth lg, eshuis JH, Houweling Pl, Hollmann MW, et al. Hyperglycemia and ambulatory surgery. Minerva anestesiol 2015;81:951-9.

25. evans cH, lee J, ruhlman MK. optimal glucose man-agement in the perioperative period. surg clin North am 2015;95:337-54.

26. tanoubi i, Drolet P, Donati F. optimizing preoxygena-tion in adults. can J anaesth 2009;56:449-66.

27. Bouroche g, Bourgain Jl. Preoxygenation and general anesthesia: a review. Minerva anestesiol 2015;81:910-20.

28. simon M, Metschke M, Braune sa, Püschel K, Kluge s. Death after percutaneous dilatational tracheostomy: a systematic review and analysis of risk factors. crit care 2013;17:r258.

29. genovese U, Del sordo s. should the anaesthetist’s role as “warrantor” of patients’ health undergo courts’ judge-ments? Minerva anestesiol 2015;81:1283-5.

such as opioid requirement, analgesic response to opioids, and breast cancer recurrence.

Finally, it is evident that cancer pain con-tinues to be an urgent unmet need for the so-ciety. the european association for Palliative care initiated a comprehensive program to achieve an over-all review of multiple cancer pain management strategies in order to extend the current guideline for treatment of cancer pain.110 Klepstad et al. reviewed the role of peripheral blocks.111 they pointed out that pe-ripheral blocks could provide adequate relief of cancer pain for at least several weeks, par-ticularly if administered continuously. None-theless, current knowledge is based upon case stories or case series, while randomized trials are still lacking.

References

1. Piacevoli Q, Del gaudio a, Mincolelli g, tonti MP, Wouters g, Mastronardi P. No correlation between remifentanil blood, cerebrospinal fluid and cerebral extracellular fluid levels and TCI prediction: a pharma-cokinetic study. Minerva anestesiol 2015;81:305-11.

2. Freye e. effect-site concentration and plasma concentra-tion of remifentanil during tci are not the same. Min-erva anestesiol 2015;81:261-3.

3. gin t. clinical Pharmacology on Display. anesth analg 2010;111:256-8.

4. Velik-salchner c. computed advisory systems in daily practice for predicting concentrations and effects of combined anesthetics: a new field in anesthesia? Min-erva anestesiol 2015;81:1151-2.

5. cirillo V, Zito Marinosci g, De robertis e, iacono c, romano g, Desantis o, et al. Navigator® and smart-Pilot® View are helpful in guiding anesthesia and re-ducing anesthetic drug dosing. Minerva anestesiol 2015;81:1163-9.

6. aceto P, Perilli V, lai c, sacco t, Modesti c, luca e, et al. Minimum alveolar concentration threshold of sevoflurane for postoperative dream recall. Minerva An-estesiol 2015;81:1201-9.

7. spieth PM, geier c, reske aW. alpha-2 agonists: back to the future of human anesthesia? Minerva anestesiol 2015;81:1158-60.

8. Movafegh a, shoeibi g, ansari M, sadeghi M, azi-maraghi o, aghajani Y. Naloxone infusion and post-hysterectomy morphine consumption: a double-blind, placebo controlled study. acta anaesthesiol scand 2012;56:1241-9.

9. Fragen rJ, Fitzgerald Pc. effect of dexmedetomidine on the minimum alveolar concentration (Mac) of sevoflurane in adults age 55 to 70 years. J Clin Anesth 1999;11:466-70.

10. Dutta s, Karol MD, cohen t, Jones rM, Mant t. ef-fect of dexmedetomidine on propofol requirements in healthy subjects. J Pharm sci 2001;90:172-81.

11. le Bot a, Michelet D, Hilly J, Maesani M, Dilly MP, Brasher c, et al. Efficacy of intraoperative dexmedeto-midine compared with placebo for surgery in adults: a



adults: an overview. Minerva anestesiol 2015;81:342-51.

47. Kleine-Brueggeney M, theiler l. Videolaryngos-copy: may the force be with you! Minerva anestesiol 2015;81:825-6.

48. alvis BD, King aB, Hester D, Hughes cg, Higgins Ms. Randomized controlled pilot trial of the rigid and flex-ing laryngoscope versus the fiberoptic bronchoscope for intubation of potentially difficult airway. Minerva Anes-tesiol 2015;81:946-50.

49. Campos JH. High fidelity manikins for airway training: can it be successfully translated into clinical practice? Minerva anestesiol 2015;81:1-2.

50. Schebesta K, Spreitzgrabner G, Hörner E, Hüpfl M, Kimberger O, Rössler B. Validity and fidelity of the up-per airway in two high-fidelity patient simulators. Min-erva anestesiol 2015;81:12-8.

51. thierbach a, Piepho t, göbler s, rützler K, Frass M, Kaye aD, et al. comparative study of three different su-praglottic airway devices in simulated difficult airway situations. Minerva anestesiol 2015;81:1311-7.

52. Mehta aB, syeda sN, Bajpayee l, cooke cr, Walkey aJ, Wiener rs. trends in tracheostomy for Mechani-cally Ventilated Patients in the United states, 1993-2012. am J respir crit care Med 2015;192:446- 54.

53. siempos ii, Ntaidou tK, Filippidis Ft, choi aM. effect of early versus late or no tracheostomy on mortality and pneumonia of critically ill patients receiving mechani-cal ventilation: a systematic review and meta-analysis. lancet respir Med 2015;3150-8.

54. szakmany t, russell P, Wilkes ar, Hall Je. effect of early tracheostomy on resource utilization and clinical outcomes in critically ill patients: meta-analysis of ran-domized controlled trials. Br J anaesth 2015;114:396-405.

55. gregoretti c, Pisani l. tracheostomy, swallowing dis-orders and rehabilitation: it is never too late. Minerva anestesiol 2015;81:357-9.

56. ceriana P, carlucci a, schreiber a, Fracchia c, cazzani c, Dichiarante M, et al. changes of swallowing function after tracheostomy: a videofluoroscopy study. Minerva anestesiol 2015;81:389-97.

57. Mitra J K, roy J, Bhattacharyya P, Yunus M, lyngdoh NM. changing trends in the management of hypoten-sion following spinal anesthesia in cesarean section. J Postgrad Med 2013;59:121-6.

58. ripollès Melchor J, espinosa Á, Martìnez Hurtado e, casans Francés, Navarro Pérez r, abad gurumeta, et al. colloids versus crystalloids in the prevention of hypo-tension induced by spinal anesthesia in elective cesarean section. a systematic review and meta-analysis. Minerva anestesiol 2015;81:1019-30.

59. gao l, Zheng g, Han J, Wang Y, Zheng J. effects of prophylactic ondansetron on spinal anesthesia-induced hypotension: a meta-analysis. int J ostet anaesth 2015;24:335-43.

60. owczuk r, Wenski W, twardowski P, Dylczyk-sommer a, sawicka W, Wujtewicz Ma, et al. ondansetron at-tenuates the decrease in blood pressure due to spinal anesthesia in the elderly: a double blind, placebo-con-trolled study. Minerva anestesiol 2015;81:598-607.

61. sharkey a, Finnerty o, McDonnell Jg. role of transver-sus abdominis plane block after caesarean delivery. curr opin anaesthesiol 2013;26:268-72.

62. Fusco P, scimia P, Paladini g, Fiorenzi M, Petrucci e, Pozone t, et al. transversus abdominis plane block for analgesia after cesarean delivery. a systematic review. Minerva anestesiol 2015;81:195-204.

63. Zhang l, tong Y, li M, Niu X, Zhao X, lin F, et al. sciatic–femoral nerve block versus unilateral spinal an-

30. Brazzi l, Di Vella g. is there a need for a support in the surgical decision-making process? Minerva anestesiol 2015;81: 86-7.

31. gomez-rios Ma. evaluation and treatment of preopera-tive anxiety in children: are we doing what we should do? Minerva anestesiol 2015;81:1113-5.

32. Berghmans JM, Poley M, Weber F, Van De Velde M, adriaenssens P, Klein J, et al. Does the child Behav-ior checklist predict levels of preoperative anxiety at anesthetic induction and postoperative emergence de-lirium? a prospective cohort study. Minerva anestesiol 2015;81:145-56.

33. Manyande a, cyna aM, Yip P, chooi c, Middleton P. Non-pharmacological interventions for assisting the in-duction of anaesthesia in children. cochrane Database syst rev 2015;14:7 cD006447.

34. Kain ZN, caldwell-andrews aa, Maranets i, Mcclain B, gaal D, Mayes lc, et al. Preoperative anxiety and emer¬gence delirium and postoperative maladaptive be-haviors. anesth analg 2004;99:1648-54.

35. Voepel-lewis t, Malviya s, tait ar. a prospective co-hort study of emergence agitation in the pediatric pos-tanesthesia care unit. anesth analg 2003;96:1625-30.

36. Kain ZN, Mayes lc, caldwell-andrews aa, Karas De, Mcclain Bc. Preoperative anxiety, postoperative pain, and behavioral recovery in young children undergoing surgery. Pediatrics 2006;118:651-8.

37. green Ms, aman MM, stevens l, Voralu K, saththasi-vam P, Mychaskiw g, et al. Histopathological observa-tions in the brains of children exposed to inhalational anesthetic agents: a retrospective autopsy-based study. Minerva anestesiol 2015;81:1329-37.

38. Davidson aJ, Disma N, de graaff Jc, Withington De, Dorris l, Bell g, et al. gas consortium. Neurodevel-opmental outcome at 2 years of age after general anaes-thesia and awake-regional anaesthesia in infancy (gas): an international multicentre, randomised controlled tri-al. lancet 2015 oct 23. pii: s0140-6736(15)00608-X. [epub ahead of print].

39. Pezzati D, Ghinolfi D, De Simone P, Balzano E, Filip-poni F. strategies to optimize the use of marginal donors in liver transplantation. World J Hepatol 2015;7:2636-47.

40. Valenza F, Villa a, Froio s, coppola s, Barretta F, Mela-da e, et al. early outcome of liver transplantation per-formed with organs procured from brain death donors with transient or sustained cardio-circulatory collapse. Minerva anestesiol 2015;81:507-15.

41. costa Mg, Della rocca g. Brain death in patients sup-ported with ecMo: a potential new source of liver grafts? Minerva anestesiol 2015;81:472-4.

42. reske a, reske a, Metze M. complications of immuno-suppressive agents therapy in transplant patients. Min-erva anestesiol 2015;81:1244-61.

43. Van Zundert a, Pieters BM. Videolaryngoscopy - the New standard for intubation. ten Years experience. Minerva anestesiol 2015;81:1159-62.

44. Pieters B, Maassen r, Van eig e, Maathuis B, Van Den Dobbelsteen J, Van Zundert a. indirect videolaryngos-copy using Macintosh blades in patients with non-an-ticipated difficult airways results in significantly lower forces exerted on teeth relative to classic direct laryngos-copy: a randomized crossover trial. Minerva anestesiol 2015;81:846-54.

45. Nørskov aK, rosenstock cV, Wetterslev J, astrup g, afshari a, lundstrøm lH. Diagnostic accuracy of an-aesthesiologists’ prediction of difficult airway manage-ment in daily clinical practice: a cohort study of 188 064 patients registered in the Danish anaesthesia Database. anaesthesia 2015;70:272-81.

46. agrò Fe, Doyle DJ, Vennari M. Use of glidescope® in



operative medicine. Minerva anestesiol 2015;81:469- 71.

82. guarracino F, Baldassarri r, Priebe HJ. revised esc/esa guidelines on non-cardiac surgery: cardiovas-cular assessment and management. implications for preoperative clinical evaluation. Minerva anestesiol 2015;81:226-33.

83. Kristensen sD, Knuuti J, saraste a, anker s, Bøtker He, De Hert s, et al. 2014 esc/ esa guidelines on non-cardiac surgery: cardiovascular assessment and man-agement: the Joint task Force on non- cardiac surgery: cardiovascular assessment and management of the eu-ropean society of cardiology (esc) and the european society of anaesthesiology (esa). eur J anaesthesiol 2014;31:517-73.

84. ranucci M, Baryshnikova e, simeone F, ranucci M, scolletta s. Moderate-degree acidosis is an independent determinant of postoperative bleeding in cardiac sur-gery. Minerva anestesiol 2015;81:885-93.

85. De robertis e, Kozek-langenecker sa, tufano r, ro-mano gM, Piazza o, Zito g, et al. coagulopathy in-duced by acidosis, hypothermia and hypocalcaemia in severe bleeding. Minerva anestesiol 2015;81:65-75.

86. Wolberg as, Meng ZH, Monroe DM, 3rd, Hoffman M. a systematic evaluation of the effect of temperature on coagulation enzyme activity and platelet function. J trauma 2004;56:1221-8.

87. Martini WZ. The effects of hypothermia on fibrinogen metabolism and coagulation function in swine. Metabo-lism 2007;56:214-21.

88. cappabianca g, Mariscalco g, Biancari F, Maselli D, Papesso F, cottini M, et al. Safety and efficacy of pro-thrombin complex concentrate as first-line treatment in bleeding after cardiac surgery. critical care 2016;20_5.

89. salazar JD, Wityk rJ, grega Ma, Borowicz lM, Doty Jr, Petrofski Ja, et al. stroke after cardiac sur-gery: short- and long-term outcomes. ann thorac surg 2001;72:1195-201.

90. scolletta s, taccone Fs, Donadello K. Brain injury after cardiac surgery. Minerva anestesiol 2015;81:662-77.

91. Malcharek MJ, Herbst V, Bartz gJ, Manceur aM, gille J, Hennig g, et al. Multimodal evoked potential moni-toring in asleep patients versus neurological evalua-tion in awake patients during carotid endarterectomy: a single-centre retrospective trial of 651 patients. Minerva anestesiol 2015;81:1070-8.

92. Westerdahl e. optimal technique for deep breath-ing exercises after cardiac surgery. Minerva anestesiol 2015;81:678-83.

93. Westerdahl e, lindmark B, eriksson t, Friberg o, Hedenstierna g, tenling a. Deep-breathing exercises reduce atelectasis and improve pulmonary function after coronary artery bypass surgery. chest 2005;128:3482-8.

94. allegri M, clark Mr, De andrés J, Jensen ts. acute and chronic pain: where we are and where we have to go. Minerva anestesiol 2012;78:222-35.

95. Breivik H, eisenberg e, o’Brien t;oPeNMinds. the in-dividual and societal burden of chronic pain in europe: the case for strategic prioritisation and action to improve knowledge and availability of appropriate care. BMc Public Health 2013;13:1229.

96. ghanei i, rosengren Be, Hasserius r, Nilsson JÅ, Mell-ström D, ohlsson c, et al. the prevalence and severity of low back pain and associated symptoms in 3,009 old men. eur spine J 2014;23:814-20.

97. Kozlov N, Benzon Ht, Malik K. epidural steroid injec-tions: update on efficacy, safety, and newer medications for injection. Minerva anestesiol 2015;81:901-9.

98. savoia g, coluzzi F, Di Maria c, ambrosio F, Della corte F, oggioni r, et al. italian intersociety recom-mendations on pain management in the emergency set-

esthesia for outpatient knee arthroscopy: a meta-analy-sis. Minerva anestesiol 2015;81:1359-68.

64. grosu i, lavand’Homme P. continuous regional an-esthesia and inflammation: a new target. Minerva Anes-tesiol 2015;81:1001-9.

65. Magnette c, De saint Hubert M, swine c, Bouhon s, Jamart J, Dive a, et al. Functional status and medium-term prognosis of very elderly patients after an icU stay: a prospective observational study. Minerva anestesiol 2015;81:743-51.

66. Ferrão c, Quintaneiro c, camila c, aragão i, cardoso t. evaluation of long-term outcomes of very old patients admitted to intensive care: survival, functional status, quality of life, and quality-adjusted life-years. J crit care 2015 May 19, epub ahead of print.

67. Maclaren g. rage, rage against the dying of the light? intensive care for the very elderly. Minerva anestesiol 2015;81:709-10.

68. Bassetti M, righi e, astilean a, corcione s, Petrolo a, Farina ec, et al. antimicrobial prophylaxis in minor and major surgery. Minerva anestesiol 2015;81:76-91.

69. Najjar Pa, smink Ds. Prophylactic antibiotics and pre-vention of surgical site infections. surg clin North am 2015;95:269-83.

70. raiman M, Mitchell cg, Biccard BM, rodseth rN. comparison of hydroxyethyl starch colloids with crys-talloids for surgical patients: a systematic review and meta-analysis. eur J anaesthesiol 2015 sep 8. [epub ahead of print].

71. Berger MM, gradwohl-Matis i, Brunauer a, Ulmer H, Dünser MW. Targets of perioperative fluid therapy and their effects on postoperative outcome: a system-atic review and meta-analysis. Minerva anestesiol 2015;81:794-808.

72. Muñoz M, gómez-ramírez s, Kozek-langeneker s. Pre-operative haematological assessment in patients scheduled for major surgery. anaesthesia 2016;71 suppl 1:19-28.

73. liumbruno gM, Vaglio s, grazzini g, spahn Dr, Bian-cofiore G. Patient blood management: a fresh look at a fresh approach to blood transfusion. Minerva anestesiol 2015;81:1127-37.

74. iapichino g. low hemoglobin level with low oncotic pressure in critically ill patients. is it a safe strategy? Minerva anestesiol 2015;81:1047-9.

75. Holst lB, Haase N, Wetterslev J, Wernerman J, gut-tormsen aB, Karlsson s, et al. lower versus higher hemoglobin threshold for transfusion in septic shock. N engl J Med 2014;371:1381-91.

76. Deflandre E, Degey S, Bonhomme V, Donneau AF, Poirrier r, Brichant JF, et al. Preoperative adherence to continuous positive airway pressure among obstructive sleep apnea patients. Minerva anestesiol 2015;81:960-7.

77. Vasu ts, grewal r, Doghramji K. obstructive sleep apnea syndrome and perioperative complications: a systematic review of the literature. J clin sleep Med 2012;8:199-207.

78. Zwicker Ji. Unconventional approaches to the pre-vention of cancer associated thrombosis. thromb res 2014;133 suppl 2:s44-8.

79. cuomo a, cascella M, Bifulco F, Marracino M, Di Min-no g, cerbone a. Periprocedural management of anti-thrombotic therapy and open issues in cancer patients. Minerva anestesiol 2015;81:1229-43.

80. Kratz t, campo Dell’orto M, exner M, timmesfeld N, Zoremba M, Wulf H, et al. Focused intraoperative transthoracic echocardiography by anesthesiologists: a feasibility study. Minerva anestesiol 2015;81:490-6.

81. sangalli F, rubino a. intraoperative transthoracic echocardiography: another arrow to the bow of peri-



106. colombo r, raimondi F, corona a, rivetti i, Pagani F, Porta VD, et al. comparison of the surgical Pleth index with autonomic nervous system modulation on cardiac activity during general anaesthesia: a randomised cross-over study. eur J anaesthesiol 2014;31:76-84.

107. ren ZY, Xu XQ, Bao YP, He J, shi l, Deng JH, et al. the impact of genetic variation on sensitivity to opioid anal-gesics in patients with postoperative pain: a systematic review and meta-analysis. Pain Physician 2015;18:131-52.

108. De gregori M, garbin g, De gregori s, Minella ce, Bu-gada D, lisa a, et al. genetic variability at coMt but not at oPrM1 and Ugt2B7 loci modulates morphine analgesic response in acute postoperative pain. eur J clin Pharmacol 2013;69:1651-8.

109. De gregori M, Diatchenko l, Belfer i, allegri M. oPrM1 receptor as new biomarker to help the predic-tion of post mastectomy pain and recurrence in breast cancer. Minerva anestesiol 2015;81:894-900.

110. Kurita gP, Benthien Ks, Nordly M, Mercadante s, Klep-stad P, sjøgren P, et al. the evidence of neuraxial admin-istration of analgesics for cancer-related pain: a system-atic review. acta anaesthesiol scand 2015;59:1103-15.

111. Klepstad P, Kurita gP, Mercadante s, sjøgren P. evi-dence of peripheral nerve blocks for cancer-related pain: a systematic review. Minerva anestesiol 2015;81:789-93.

ting (siaarti, siMeU, sis 118, aisD, siareD, si-cUt, irc). Minerva anestesiol 2015;81:205-25.

99. lirk P, Hollmann MW. outcome after regional anesthe-sia: weighing risks and benefits. Minerva Anestesiol 2014;80:610-8.

100. Hanna MN, Murphy JD, Kumar K, Wu cl. regional techniques and outcome: what is the evidence? curr opin anaesthesiol 2009;22:672-7.

101. Hughes M, McNally s, McKeown DW, Wigmore s. ef-fect of analgesic modality on outcome following open liver surgery: a systematic review of postoperative anal-gesia. Minerva anestesiol 2015;81:541-56.

102. turnbull D. Magnesium: looking for a role in anesthe-sia. Minerva anestesiol 2015;81:1156-58.

103. Frassanito l, Messina a, Vergari a, colombo D, chie-richini a, Della corte F, et al. intravenous infusion of magnesium sulfate and postoperative analgesia in total knee arthroplasty. Minerva anestesiol 2015;81:1184-91.

104. gruenewald M, Herz J, schoenherr t, thee c, steinfath M, Bein B. Measurement of the nociceptive balance by analgesia Nociception index and surgical Pleth index during sevoflurane-remifentanil anesthesia. Minerva anestesiol 2015;81:480-9.

105. gruenewald M, ilies c, Herz J, schoenherr t, Fudickar a, Höcker J, et al. Influence of nociceptive stimulation on analgesia nociception index (aNi) during propofol-remifentanil anaesthesia. Br J anaesth 2013;110:1024-30.

Conflicts of interest.—Marco Rossi received fees for symposiums, scientific courses and lectures from Baxter, Fresenius.Article first published online: January 28, 2016. - Manuscript accepted: January 22, 2016. - Manuscript received: January 19, 2016.

(Cite this article as: cavaliere F, allegri M, calderini e, carassiti M, coluzzi Flaminia, Di Marco P, et al. a year in review in Minerva anestesiologica 2015. Minerva anestesiol 2016;82:243-54)

errata corrige

in volume 82, issue no. 1 – January, pages 125-38, in the article entitled “a Year in review in Minerva anestesiologica 2015. critical care. experimental and clinical studies”, the correct authors’ names are: Franco caValiere, gi-anni BiaNcoFiore, elena BigNaMi, edoardo De roBertis, alberto giaNNiNi, salvatore grasso, sabino scolletta, Fabio s. taccoNe, Pierpaolo terragNi.


T O P 5 0 M I N E R V A A N E S T E S I O L O G I C A R E V I E W E R S

Anno: 2016Mese: FebruaryVolume: 82No: 2Rivista: MINERVA ANESTESIOLOGICACod Rivista: Minerva Anestesiol

Lavoro: titolo breve: primo autore: ACKNOWLEDGEMENTSpagine: 255

Most active reviewers between July 2015-December 2015

Surname Name Numberof revisions

Savoia Gennaro 10Biasucci Daniele Guerino 9Cata Juan P. 6Brazzi Luca 6Cattano Davide 6Della Rocca Giorgio 5Montini Luca 5Agrò Eugenio Felice 5Guarracino Fabio 5Bertini Pietro 5Calzavacca Paolo 5Peris Adriano 5Camporesi Enrico Mario 5Chelazzi Cosimo 5Sorbello Massimiliano 4El Tahan Mohamed 4De Pascale Gennaro 4Tritapepe Luigi 4Oropello John Mark 4Zanella Alberto 4Cunha Francisco 4Gómez-Ríos Manuel Ángel 4Dalfino Lidia 4Caruselli Marco 4Szakmany Tamas 4Deflandre Eric P. 4Aceto Paola 4Benes Jan 4Somaini Marta 4Donadello Katia 4Borghi Battista 4Alston Theodore 3Weiner Menachem 3Bruder Nicolas 3Faraoni David 3Sakai Tetsuro 3Riem Nicole 3Mallat Jihad 3Vannucci Andrea 3Cavallone Laura Francesca 3Kopp Rüdger 3De Cosmo Germano Amilcare 3Turnbull David 3Algarra Nelson Nicolás 3Cinnella Gilda 3Ezzeldin Ibrahim Saleh 3Camporota Luigi 3Beilin Yaakov 3Boer Christa 3Ting Chien-Kun 3

volume 82 · no. 2 · february 2016 anestesiologica...a year in review in minerva anestesiologica...

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