a long-acting vasopressin analog for septic shock

Editorials

A long-acting vasopressin analog for septic shock: Brilliant idea ordangerous folly?*

T his issue of Pediatric CriticalCare Medicine includes twocase reports regarding thesuccessful use of terlipressin

for catecholamine-dependent and cate-cholamine-resistant septic shock in chil-dren (1, 2). As a pediatric intensivist, myfirst question is, What is terlipressin? Mynext questions are, What are the advan-tages and disadvantages of this agent, andsimilar agents, in catecholamine-depen-dent and catecholamine-resistant septicshock? Finally, do I have enough infor-mation to decide whether I should usethe medication for my patients?

Terlipressin (triglycyl lysine vasopres-sin) is a long-acting vasopressin analog (3–8). In part, it is a prodrug that is slowlycleaved in vivo to lysine vasopressin byendo- and exopeptidases in the liver andkidney over 4–6 hrs, thereby allowing pro-longed effects by intermittent intravenousinjections rather than continuous intrave-nous infusion. However, it has some othercharacteristics suggesting independentpharmacological effects. Vasopressin andterlipressin stimulate vascular V1a recep-tors and renal tubular V2 receptors result-ing in vasoconstriction and renal free waterreabsorption, respectively. Terlipressin hasrelatively higher affinity for the vascularV1a receptor and lower affinity to the V2receptor than vasopressin (7). In addition,terlipressin does not appear to increase fi-brinolytic activity, whereas vasopressindoes (8). Because of the interplay betweenthe coagulation/fibrinolytic systems andthe inflammatory system, these differentialeffects on fibrinolytic activity may be perti-nent for treatment of septic shock. Bothvasopressin and terlipressin increase leftventricular afterload and decrease splanch-nic blood flow. In an endotoxemic sheepmodel, terlipressin resulted in increased

pulmonary vascular resistance, whereas va-sopressin does not cause pulmonary vaso-constriction (6).

Terlipressin has been extensively usedand studied in adults with acute esopha-geal variceal bleeding and the hepatore-nal syndrome (9, 10). Although numer-ous pharmacological agents have beenused for acute esophageal variceal bleed-ing, terlipressin is the only one shown toreduce mortality rate compared with pla-cebo, with an impressive 34% relativerisk reduction in mortality rate (3, 4).Terlipressin is well studied and com-monly used in adults throughout theworld for this indication but is not pres-ently available in the United States.

Vasopressin and/or vasopressin ana-logs may have a role in the treatment ofvasodilatory shock states, including sep-tic shock (5, 11–14). Plasma vasopressinconcentrations initially increase substan-tially with acute hemorrhage or sepsis(11, 12). However, adults with vasodila-tory hypotensive septic shock receivingcatecholamine infusions have low plasmavasopressin concentrations (i.e., relativevasopressin deficiency), although theconcentrations are not low enough toprecipitate diabetes insipidus (11). Thelow plasma vasopressin concentrations invasodilatory septic shock are generally at-tributed to a hormonal deficiency syn-drome due to neurohypophysial vasopres-sin depletion or depressed release.Interestingly, these patients have hyper-sensitive vasopressor responses to vaso-pressin infusions. Although vasopressininfusions of 0.2–2 units/min rarely affectthe blood pressure in adults with gastro-intestinal hemorrhage (or in normal sub-jects), low-dose infusions of 0.01–0.07units/min substantially increase the meanarterial pressure and decrease catechol-amine requirements in patients with vaso-dilatory septic shock (11-13). This hyper-sensitivity to the pressor action ofvasopressin has also been observed in othervasodilatory shock states (e.g., late-phasehemorrhagic shock, severe heart failuretreated with a ventricular assist device, andpostcardiopulmonary bypass) (11–14).

These two case reports on the use ofterlipressin for pediatric septic shock inthis issue of Pediatric Critical Care Medi-cine are consistent with a small series inadult patients with septic shock: Ter-lipressin can also increase the mean arterialpressure and decrease catecholamine re-quirements; however, the vasoconstrictioncan result in lower cardiac output (1, 2, 5).An 11-year-old child was demonstrated tobe in hyperdynamic norepinephrine-depen-dent vasodilatory septic shock (1). Intrave-nous administration of 0.5 mg terlipressin(~0.14 mg/kg) promptly increased his sys-temic vascular resistance, thereby allowingrapid weaning of his norepinephrine infu-sion. However, his cardiac index promptlydecreased. The duration of the vasocon-strictor effect with each terlipressin boluswas ~6 hrs. The use of terlipressin in ananuric 8-day-old neonate was especiallybold (2). The baby improved while receiving7 �g/kg of intravenous terlipressin every 12hrs. To my knowledge, terlipressin pharma-cology had not been previously studied inneonates. It is conceivable that differencesin neonatal hepatic function could result insubstantial pharmacokinetic differences. Itis somewhat reassuring that terlipressinhad been used extensively in adults withhepatorenal syndrome and acute gastroin-testinal hemorrhage associated with portalhypertension and severe hepatic dysfunc-tion and that adverse effects seemed to berare (3, 4, 9, 10).

The use of terlipressin for hyperdynamicvasodilatory septic shock is intriguing.However, most children in septic shockhave hypodynamic cardiac function withhigh systemic vascular resistance (15, 16).In this setting, a vasoconstrictor may fur-ther impede myocardial function and de-crease tissue perfusion. Moreover, the well-known decrease in splanchnic perfusionwith both vasopressin and terlipressin isworrisome; splanchnic ischemia is associ-ated with continued systemic inflammatoryresponse syndrome and multiple-organsystem failure. In addition, children in sep-tic shock often change hemodynamic pro-files (15, 16). For example, a child withvasodilatory shock at one moment maytransform to a hypodynamic shock with

*See also pages 112 and 116.Keywords: terlipressin; vasopressin; septic shock;

vasodilatory shock; catecholamines; pediatric; child;infant

Copyright © 2004 by the Society of Critical CareMedicine and the World Federation of Pediatric Inten-sive and Critical Care Societies

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188 Pediatr Crit Care Med 2004 Vol. 5, No. 2

high systemic vascular resistance as thedisease progresses. A long-acting drug liketerlipressin cannot be easily titrated as thedisease process changes. This inflexibility ispotentially quite problematic.

Do I have enough information to decideif and when I should use terlipressin in mypatients (if it were available in the UnitedStates)? Because there are abundant adultdata indicating that terlipressin is a safeand effective agent for the treatment ofacute esophageal variceal bleeding, I be-lieve there is sufficient information to useterlipressin for adolescents with this dis-ease process. In contrast, the data are lessconvincing for septic shock. At this time,the concept of low-dose vasopressin “hor-monal replacement” therapy for cate-cholamine-resistant vasodilatory shock orfor decreasing high-dose catecholamine us-age in catecholamine-dependent vasodila-tory shock is alluring. However, there is noevidence that the hemodynamic benefitstranslate into better outcomes. Moreover,the potential decreases in splanchnic flowand myocardial function are concerning. Along-acting agent like terlipressin may beinherently more dangerous during septicshock, especially for children with their un-predictable and rapidly changing hemody-namic profiles. Finally, I would prefer morepharmacokinetic and pharmacodynamicinformation in neonates and young chil-dren before adding terlipressin to my thera-peutic armamentarium in these age groups.

These two case reports highlight thepotential benefits of terlipressin, a long-acting vasopressin analog, for cate-cholamine-dependent and/or catechol-amine-resistant vasodilatory septic

shock. They also highlight the need fordelineation of terlipressin pharmacologyin neonates, infants, and other youngchildren. Finally, the time has come forfurther studies of low-dose vasopressinand/or terlipressin hormonal replace-ment therapy for catecholamine-resistantvasodilatory septic shock and other vaso-dilatory shock states in children.

Robert A. Berg, MDThe University of ArizonaSteele Memorial Children’s

Research CenterTucson, AZ

REFERENCES

1. Peters MJ, Booth RA, Petros AJ. Terlipressinbolus induces systemic vasoconstriction inseptic shock. Pediatr Crit Care Med 2004;5:112–115

2. Matok I, Leibovitch L, Vardi A, et al: Terlip-ressin as rescue therapy for intractable hypo-tension during neonatal septic shock. Pedi-atr Crit Care Med 2004; 5:116–118

3. Ioannou GN, Doust J, Rockey DC: Systematicreview: Terlipressin in acute oesophagealvariceal haemorrhage. Aliment PharmacolTher 2003; 17:53–64

4. Ioannou G, Doust J, Rockey DC: Terlipressinfor acute esophageal variceal hemorrhage. Co-chrane Database Syst Rev 2003;1(CD002147)

5. O’Brien A, Clapp L, Singer M: Terlipressin fornorepinephrine-resistant septic shock. Lan-cet 2002; 359:1209–1210

6. Westphal M, Stubbe H, Sielenkämper AW, etal: Terlipressin dose response in healthy andendotoxemic sheep: Impact on cardiopulmo-nary performance and global oxygen trans-port. Intensive Care Med 2003; 29:301–308

7. Bernadich C, Bandi JC, Melin P, et al: Effectsof F-180, a new selective vasoconstrictor pep-

tide, compared with terlipressin and vaso-pressin on systemic and splanchnic hemody-namics in a rat model of portal hypertension.Hepatology 1998; 27:351–356

8. Douglas JG, Forrest JA, Prowse CV, et al:Effects of lysine vasopressin and glypressinon the fibrinolytic system in cirrhosis. Gut1979; 20:565–567

9. Solanki P, Chawla A, Garg R, et al: Beneficialeffects of terlipressin in hepatorenal syn-drome: A prospective, randomized placebo-controlled clinical trial. J GastroenterolHepatol 2003; 18:152–156

10. Colle I, Durand F, Pessione F, et al: Clinicalcourse, predictive factors and prognosis inpatients with cirrhosis and type 1 hepatore-nal syndrome treated with Terlipressin: Aretrospective analysis. J Gastroenterol Hepa-tol 2002; 17:882–888

11. Landry DW, Levin HR, Gallant EM, et al:Vasopressin deficiency contributes to the va-sodilation of septic shock. Circulation 1997;95:1122–1125

12. Robin JK, Oliver JA, Landry DW: Vasopressindeficiency in the syndrome of irreversibleshock. J Trauma 2003; 54:S149–S154

13. Tsuneyoshi I, Boyle WA. Vasopressin: Newuses for an old drug. Contemp Crit Care2003; 1:1–11

14. Morales DL, Garrido MJ, Madigan JD, et al: Adouble-blind randomized trial: Prophylacticvasopressin reduces hypotension after car-diopulmonary bypass. Ann Thorac Surg2003; 75:926–930

15. Carcillo JA, Fields AI: Clinical practice pa-rameters for hemodynamic support of pedi-atric and neonatal patients in septic shock.Crit Care Med 2002; 30:1365–1378

16. Ceneviva G, Paschall JA, Maffei F, et al: He-modynamic support in fluid-refractory pedi-atric septic shock. Pediatrics 1998; 102:e19

Pediatric patient safety: Identification and characterization ofadverse events, adverse drug events, and medical error*

Adverse events involving pa-tients, particularly the criti-cally ill and medically fragile,occur at an alarming frequency

(1, 2). An adverse event is defined as an

injury resulting from a medical interven-tion or the “the failure to complete aplanned action as intended or the use of awrong plan to achieve an aim” (1, 2). Thegoal of all thoughtful and conscientiouscaregivers is to provide the best care pos-sible without exposing patients to addi-tional harm and suffering by experienc-ing an adverse event. Unfortunately,adverse events are a substantial safetyconcern in health care. The increasingcomplexity in patient care, as well as thepublic’s increasing scrutiny of the healthcare system, underscores the need to

make patient safety and the reduction ofadverse events an issue of highest priority(3).

According to a national poll conductedby the National Patient Safety Founda-tion, nearly half of respondents, includ-ing physicians (35%) and members of thepublic (42%), reported errors in theirown or a family member’s medical care.Almost a third (32%) of the respondentsindicated that the error had a permanentnegative effect on the patient’s health (4).Advances are being made to improve sur-

*See also pages 119 nd 124.Key Words: medical error; adverse drug event;

medication errors; patient safety; pediatrics; pediatricintensive care unit; neonatal intensive care unit


DOI: 10.1097/01.CCM.0000113928.24594.94

189Pediatr Crit Care Med 2004 Vol. 5, No. 2

veillance of medical errors and occur-rence of patient harm (5–7). Identifyingand characterizing adverse events andmedical errors comprise a necessary firststep to effectively target efforts to de-crease the risk of adverse events to ourpatients (8, 9). Current efforts to enhancepatient safety must include progress inthe capture and characterization of ad-verse events, the occurrence of harm, andthe degree of preventability of harm. No-where is this more important than in thepediatric intensive care unit (PICU).

In this month’s issue of Pediatric Crit-ical Care Medicine, two groups of re-searchers have tackled this challengingtask (10, 11). In 1984, the rate of adverseevents among newborns in New YorkState was 1.4 in 100 hospitalizations withan associated 20.8% rate of negligence(12). Nearly 20 yrs later, Dr. Kanter andcolleagues (10) have found very littleprogress. Their study determined the rateand characteristics of hospital-reportedmedical errors involving premature neo-nates (n � 824). They reported a nationalmedical error rate of 1.2 per 100 dis-charges using the Healthcare Cost andUtilization Project (HCUP) 1997 dis-charge database. This national adminis-trative database represents dischargesfrom nearly 900 hospitals, consisting ofthe International Classification of Diseas-es-9 discharge diagnosis of 996–999 formedical error (10).

HCUP is a family of health care data-bases and related software tools devel-oped through a federal-state-industrypartnership and sponsored by the Agencyfor Healthcare Research and Quality (13).In a previous study, Slonim et al. used thesame database and methods and identi-fied 1.81–2.96 medical errors per 100 dis-charges of pediatric hospitalized patients(14). Adult studies of medical errors haveranged from 3.7 to 16.6 adverse eventsper 100 admissions (12, 15, 16). There aremany strengths and limitations to admin-istrative databases. One concern is theunderrecognition and underreporting ofadverse events (1, 17, 18). Miller et al.cited significant underreporting of pa-tient safety events as a limitation in theirstudy using the 1997 HCUP database(18). Although existing administrative da-tabases can reasonably be used to define theepidemiology of adverse events and medicalerrors as done by Dr. Kanter and colleagues(10), the data provide limited clinical infor-mation, little insight into timing of events,and no ability to assess causality, and theyprobably result in underreporting (14, 18).

The HCUP database also is limited to hos-pitalized patients who survive to dischargeand does not include medication errors(18). In the Kanter study of premature ne-onates, a limitation of the HCUP database isits inability to discriminate between ad-verse events due to medical care and eventsdue to birth trauma (10). Birth trauma hasbeen reported to be at a frequency of 1.5cases per 100 births (18). Strengths in us-ing HCUP include ready availability, lowcost, and coverage of large populations(15).

The study by Dr. Kanter and col-leagues (10) contributes to the develop-ing field of patient safety by providing adescriptive epidemiology of medical er-rors in the population of premature new-borns sampled from a diverse range ofhospital settings. Despite the limitationsof administrative databases, the findingsof Dr. Kanter and colleagues are likely tobe generalizable to the national popula-tion of premature infants given the largedata set and representative sampling ofhospitals in the HCUP database.

The next step in creating a safe envi-ronment is the development of targetedpatient safety interventions. The secondpatient safety-related article in this issuefocuses on adverse drug events occurringin the PICU. Dr. Cimino and colleagues(11) successfully developed a method toassess the rate of prescribing errors innine freestanding PICUs. Dr. Cimino andcolleagues identified medication errorsprospectively for categorization and eval-uation, and they assessed the impact ofinitiatives to reduce medication error se-verity and rates. The main goal of thestudy was to assess the overall rate ofprescribing errors in nine PICUs partici-pating in Child Health Accountability Ini-tiative (CHAI) network (19) and to testthe effectiveness of a variety of hospital-specific interventions to reduce medica-tion-associated adverse events (11).

Using a pretest, posttest design,12,026 PICU medication orders at base-line and 9,187 orders postinterventionwere evaluated for prescribing errors, ex-cluding resuscitation orders. Medicationerrors were defined as errors in drug or-dering, transcribing, dispensing, admin-istering, or monitoring. Adverse drugevents are injuries that result from theuse of a drug. The authors found a 31%reduction (11.1–7.6% of orders) in pre-scribing errors. Preventable adverse drugevents were uncommon (0.13% of allmedication errors at baseline, 0.03% dur-ing the postintervention period) and of

low severity at baseline. Previous studieshave found comparably low rates of pre-ventable adverse drug events (17).

Dr. Cimino and colleagues (11) ad-dress the lack of measurement standardsor a consistent benchmark for adversedrug events by demonstrating the useful-ness of a generalizable method employedto identify, document, and analyze pre-scribing errors across a broad range ofPICUs. The technique is labor intensivebut yielded consistent results across thePICUs and correlated with other pub-lished studies (17). This method of ana-lyzing prescribing errors captures errorand harm associated with medicationuse. However, there was considerablevariation in the methods used to reduceerror rates, and the study design did notallow for testing of any specific interven-tion. In addition, there was the puzzlingfinding of two institutions reporting anincrease in identified prescribing errors.One of the most important aspects of thisstudy was the establishment of a baselinerate for medication prescribing errors,thus providing a benchmark for otherPICUs.

The published literature focusing onthe occurrence of medical errors in pedi-atrics is limited and concludes that hos-pitalized children experience significantnumbers of adverse medical events (17,18). The authors of these two articleshave taken an important step to advancethe understanding of the incidence andcharacter of medical errors and adverseevents occurring in hospitalized children.The first step in designing a health caresystem to prevent medical injury is toidentify errors and their pattern of occur-rence within delivery systems to reducethe likelihood of adverse events (3). Re-ducing the rate of medical errors andadverse events experienced by our pa-tients should be one of the main goals ofproviding optimal health care for children.

Gitte Larsen, MDMary Jo C. Grant, PNP, PhD

Pediatric Intensive Care UnitPrimary Children’s Medical CenterUniversity of UtahSalt Lake City, UT

REFERENCES

1. Institute of Medicine: To Err Is Human:Building a Safer Health System. NationalAcademy Press, Washington, DC, 2000

2. Committee on Quality of Health Care inAmerica. Crossing the Quality Chasm: A NewHealth System for the 21st Century. NationalAcademy Press, Washington, DC, 2001


3. American Academy of Pediatrics. Principlesof patient safety in pediatrics. Pediatrics2001; 107:1473–1475

4. Blendon RJ, DesRoches CM, Brodie M, et al:Views of practicing physicians and the publicon medical errors. N Engl J Med 2002; 347:1933–1940

5. Barach P, Small SD: Reporting and prevent-ing medical mishaps: Lessons from non-medical near miss reporting systems. BMJ2000; 320:759–763

6. Kivlahan C, Sangster W, Nelson K, et al:Developing a comprehensive electronic ad-verse event reporting system in an academichealth center. J Qual Improv 2002; 28:583–594

7. Weingart S: A physician-based voluntary re-porting system for adverse events and medi-cal errors. J Gen Intern Med 2001; 16:809–814

8. Layde PM, Maas LA, Teret SP, et al: Patientsafety efforts should focus on medical inju-ries. JAMA 2002; 287:1993–1997

9. McNutt RA, Abrams R, Aron DC: Patientsafety efforts should focus on medical errors.JAMA 2002; 287:1997–2001

10. Kanter DE, Turenne W, Slonim AD: Hospital-reported medical errors in premature neo-nates. Pediatr Crit Care Med 2004; 5:119–123

11. Cimino MA, Kirschbaum MS, Brodsky L, etal: Assessing medication prescribing errorsin pediatric intensive care units. Pediatr CritCare Med 2004; 5:124–132

12. Brennan TA, Leape LL, Laird NM, et al: In-cidence of adverse events and negligence inhospitalized patients: Results of the HarvardMedical Practice Study I. N Engl J Med 1991;324:370–376

13. Agency for Healthcare Research and Qual-ity: Healthcare Cost and UtilizationProject. Available at http://www.ahrq.gov/

data/hcup/hcupnet.htm. Accessed October24, 2003

14. Slonim AD, LaFleu BJ, Ahmed W, et al: Hos-pital-reported medical errors in children. Pe-diatrics 2003; 111:617–621

15. Weingart SN, Iezzoni LI: Looking for medicalinjuries where the light is bright. JAMA 2003;290:1917–199

16. Wilson RM, Runciman WB, Gibberd RW, etal: The quality in Australian health carestudy. Med J Aust 1995; 163:458–471

17. Kaushal R: Medication errors and adversedrug events in pediatric inpatients. JAMA2001; 286:915–916

18. Miller MR, Elixhauser A, Zhan C: Patientsafety events during pediatric hospitaliza-tions. Pediatrics 2003; 111:1358–1366

19. Child Health Corporation of America. ChildHealth Accountability Initiative. Available at:http://www.chca.com/servpediat.html. Ac-cessed on October 24, 2003

Mechanical ventilation of the intubated asthmatic: How much dowe really know?*

I n this issue of Pediatric CriticalCare Medicine, Dr. Sarnaik andcolleagues (1) review their 5-yr ex-perience using pressure-con-

trolled ventilation in pediatric patientswith status asthmaticus and respiratoryfailure. Although this is a retrospectivereview, the patients undergoing mechan-ical ventilation were treated by a prede-termined protocol. The 40 patients, whounderwent 51 episodes of mechanicalventilation, had a low incidence of baro-trauma and no mortality, despite the in-vestigators’ efforts at achieving and main-taining normal PaCO2 levels in thepatients.

The authors indicate that pressure-controlled ventilation may represent asafe alternative to the “traditional” modeused in these patients, which the authorsbelieve to be volume-controlled ventila-tion. Although volume-controlled venti-lation may be the most commonly usedmode in reported series in children (2, 3)and adults (4–6), some series do not

mention the specific modes of ventilationused in the patients reported (7). Casereports of the use of pressure support (8),noninvasive ventilation (9, 10), and high-frequency oscillatory ventilation (11)suggest that physicians are using many ofthe numerous modes available on today’ssophisticated ventilators. This phenome-non probably indicates a lack of content-ment with the traditional approach tomechanically ventilating these criticallyill patients and the continual search for abetter way. There have been previoussuggestions in the literature that pres-sure control may be a rational alternativeto volume control (12, 13), but Dr. Sar-naik and colleagues (1) are the first todemonstrate its safety and effectivenessin a relatively large group of patients.

How likely is it that the data presentedin Dr. Sarnaik and colleagues’ article willbe applicable to the practice of the read-ers of this journal? To answer that ques-tion, one would need to know the preva-lent approach to status asthmaticus inpediatric intensive care units across thenation or throughout the world. At thispoint, it is impossible to state what thestandard is for initiating mechanical ven-tilation in critically ill pediatric patientswith status asthmaticus, let alone toknow what the standard approach is oncethe patients are intubated. We know that

the frequency of intubation in these pa-tients is very different in different cen-ters. Roberts et al. (14) previously showedthat the approach of the pediatric criticalcare community varies widely with re-spect to frequency of the use of invasivemonitoring, blood gas determination,and use of mechanical ventilation. Somecenters were classified as “high-use”(�20% of admitted patients with statusasthmaticus went on to intubation) andpatients at these centers had a more thantwo-fold higher risk of intubation, afteradjustment for severity of illness, thanpatients at “low-use” institutions (where�20% of their patients with status asth-maticus were intubated). Patients athigh-use centers had a longer pediatricintensive care unit and hospital length ofstay than patients at the low-use centers,but mortality rates were not different be-tween the two types of centers. In Robertset al.’s (14) database interrogation study,the overall rate of intubation and me-chanical ventilation for status asthmati-cus was 17%, but the incidence rangedfrom a low of 3% to a high of 46%.

Twenty percent of the patients caredfor by Dr. Sarnaik and colleagues (1) re-ceived mechanical ventilation, puttingtheir center at the breakpoint betweenthe high- and low-use centers describedby Roberts et al. (14). What does this tell

*See also p. 133.Key Words: pressure-controlled ventilation; status

asthmaticus; respiratory failureCopyright © 2004 by the Society of Critical Care

Medicine and the World Federation of Pediatric Inten-sive and Critical Care Societies

DOI: 10.1097/01.CCM.0000113929.14813.51


us about the practice of this group ofinvestigators? Most of their patients wereintubated for respiratory arrest or respi-ratory acidosis, but 22% were intubatedfor the “clinical impression of fatigue.”This latter group of patients proves prob-lematic in its evaluation and emphasizesthe subjective nature of our approach tothis disease. It therefore makes it evenmore difficult to compare the reportedpopulation to that in other intensive careunits or to compare the results in thisarticle to other reported series of patientsventilated for status asthmaticus.

Despite these problems, the strength ofthe current research lies in the nature ofthe initial approach to these patients’ respi-ratory failure. Once intubated, the peak in-spiratory pressure was adjusted in a tightlycontrolled manner, to achieve normal PCO2

values as quickly as possible. When readyfor weaning, patients were handled in avariety of ways, clearly at the discretion ofthe treating physician. The median lengthof mechanical ventilation was 29 hrs, com-paring favorably with previous reports inchildren (2) and adults (5, 15). There wasno mortality, and the incidence of baro-trauma was low, in most cases predatingthe initiation of mechanical ventilation.

There are no randomized controlledtrials comparing different modes of me-chanical ventilation in asthma. Nor arethere likely to ever be any. There is nosingle gold standard of how, when, andwhy to initiate mechanical ventilation inthis disease. Newer therapeutic optionshave been embraced by many, includingthe use of noninvasive ventilation toavoid some of the perils of intubation (9,10). Despite the availability of NationalInstitutes of Health guidelines on thetreatment of asthma, many patients re-ceive nonstandard care. In the populationpresented by Dr. Sarnaik and colleagues(1), a varying percentage of patients weretreated with heliox, isoproterenol, the-ophylline, magnesium, ketamine, and

terbutaline. These are all agents that havebeen reported but not proven to be ofbenefit in the intensive care unit. Any ofthese adjunctive measures may have af-fected the course of the patients pre-sented.

The use of inhaled ipatropium, al-though recommended by both NationalInstitutes of Health panels (16, 17), wasonly used in 47% of the patients. Thereasons for this variation are not clear,nor are they addressed in the article.

Does this article prove the safety of pres-sure-controlled ventilation in caring forchildren with status asthmaticus? No. Itsuggests that in the hands of this particulargroup of physicians, with this particularpopulation, pressure-controlled ventilationhas been successful. It does not precludethe safe use of other modes of ventilation inother people’s hands. It does not addressthe issues of how long one can safely waitfor medical therapies to work, without re-sorting to mechanical ventilation. As pedi-atric critical care practitioners read this ar-ticle, they should compare the results totheir own practice and consider letting therest of the world know how they care forsuch patients in their own institutions. Addi-tional reports of well-described approaches tothis care would be most helpful.

Alice D. Ackerman, MD, FCCMUniversity of Maryland Medical

SystemBaltimore, MD

REFERENCES

1. Sarnaik AP, Daphtary KM, Meert KL, et al:Pressure-controlled ventilation in childrenwith severe status asthmaticus. Pediatr CritCare Med 2004; 5:133–138

2. Cox RG, Barker GA, Bohn DJ: Efficacy, re-sults and complications of mechanical venti-lation in children with status asthmaticus.Pediatr Pulmonol 1991; 11:120–126

3. Abd-Allah SA, Rogers MS, Terry M, et al:Helium-oxygen therapy for pediatric acutesevere asthma requiring mechanical ventila-tion. Pediatr Crit Care Med 2003; 4:353–357

4. Mutlu GM, Factor P, Schwartz DE, et al:Severe status asthmaticus: Management withpermissive hypercapnia and inhalation anes-thesia. Crit Care Med 2002; 30:477–480

5. Afessa B, Morales I, Cury JD: Clinical courseand outcome of patients admitted to an ICUfor status asthmaticus. Chest 2001; 120:1616–1621

6. Georgopoulos D, Kondili E, Prinianakis G:How to set the ventilator in asthma. MonaldiArch Chest Dis 2000; 55:74–83

7. Malmstrom K, Kaila M, Korhonen K, et al:Mechanical ventilation in children with se-vere asthma. Pediatr Pulmonol 2001; 31:405–411

8. Wetzel RC: Pressure-support ventilation inchildren with severe asthma. Crit Care Med1996; 24:1603–1605

9. Fernandez MM, Villagra A, Blanch L, et al:Non-invasive mechanical ventilation in sta-tus asthmaticus. Intensive Care Med 2001;27:486–492

10. Meduri GU, Cook TR, Turner RE, et al:Noninvasive positive pressure ventilationin status asthmaticus. Chest 1996; 110:767–774

11. Duval EL, van Vught AJ: Status asthmati-cus treated by high-frequency oscillatoryventilation. Pediatr Pulmonol 2000; 30:350 –353

12. Werner HA: Status asthmaticus in children.A review. Chest 2001; 119:1913–1929

13. Lopez-Herce J, Gari M, Bustinza A, et al: Tothe editor: On pressure-controlled ventila-tion in severe asthma. Pediatr Pulmonol1996; 21:401–403

14. Roberts JS, Bratton SL, Brogan TV: Acutesevere asthma: Differences in therapies andoutcomes among pediatric intensive careunits. Crit Care Med 2002; 30:581–585

15. Braman SS, Kaemmerlen JT: Intensive careof status asthmaticus: A 10-year experience.JAMA 1990; 264:366–368

16. National Heart Lung and Blood Institute:The Expert Panel Report: Guidelines for theDiagnosis and Treatment of Asthma. Be-thesda, MD, National Institutes of Health,1991

17. National Heart Lung and Blood Institute:The Expert Panel Report 2: Guidelines forthe Diagnosis and Management of Asthma.Bethesda, MD, National Institutes of Health,1997


Don’t forget the “single chromosome polymorphism”: A need forgender-stratification in pediatric patients?*

Appropriately, a recent flurry ofclinical study has been directedtoward genetic associations anddisease (1). With �1 million

genetic polymorphisms (2), this becomes ofclear significance given that many futuretherapies are likely to be genotype-directedand many studies genotype-stratified. Thesimplest polymorphism is referred to as asingle nucleotide polymorphism. Thesegenetic polymorphisms can significantlyinfluence susceptibility and/or outcome inmanydiseasestates,forinstance,theapolipo-protein E allele, which is important inAlzheimer’s disease (3) and traumatic braininjury (TBI) (4). In this issue of PediatricCritical Care Medicine, Dr. Morrison andcolleagues (5) attempt to determinewhether there is an association betweena much more common “polymorphism”after TBI, namely the Y-chromosome.

TBI is unarguably a major publichealth problem in the United States, il-lustrated by the fact that TBI is the lead-ing cause of death and disability in in-fants and children. Among children aged0–14 yrs in the United States, there are3,000 deaths, 29,000 hospitalizations, and400,000 emergency department visits an-nually associated with TBI (6). Studieshave shown that the highest pediatric ageincidence of TBI is among persons aged15–24 yrs followed by ages 5 andyounger, and males are more than twiceas likely as females to become victims ofTBI. Current understanding suggeststhat being of female gender (XX) impartsa degree of protection from the sequelaeof TBI compared with male gender (XY).This experimental evidence is based en-tirely on carefully controlled studies inreproductive-aged animals using hor-mone replacement therapy, and as such

many of the beneficial effects seen in fe-males are attributed to the influence ofsex hormones. Estrogen has been shownto preserve cerebral blood flow after TBIin rats, and endogenous and injected pro-gesterone reduced cerebral edema in fe-male rats after TBI (7, 8). Indeed, a clin-ical trial in adult patients usingprogesterone as a neuroprotective agentafter TBI is underway.

Not discounting an important role forsex hormones in the pathophysiology andoutcome after TBI, it remains possible, oreven likely, that innate, sex hormone-independent gender effects also contrib-ute. This may be of particular importancein terms of TBI patients outside of thereproductive years (i.e., children and theelderly), when the influence of circulat-ing sex hormones is less dominant. In-deed, these age-group subpopulations areknown to have unfavorable outcomes af-ter TBI (9, 10). Furthermore, boys arebelieved to have poorer memory function(11) and a higher incidence of neuropsy-chiatric sequelae (12) than girls after TBI.

This issue’s report by Dr. Morrisonand colleagues (5) is important because itattempts to correlate gender and age withintensive care unit length of stay, hospi-tal length of stay, survival, and neuro-logic outcome after TBI in a pediatricpopulation. Importantly, it begins to di-rect our attention to the possible need for“gender-stratification” in terms of treat-ment and study design in pediatric pa-tients with acute brain injury cared for inour pediatric intensive care units. In con-trast to the previously mentioned studies(11, 12), there was no gender differencein neurologic outcome in the currentstudy by Dr. Morrison and colleagues (5).There was, however, a shorter intensivecare unit length of stay for boys vs. girls.The impact of gender in pediatric inten-sive care unit patient populations extendsbeyond TBI, as gender differences areseen in either outcomes or responses totherapy in children with stroke (13), pre-maturity (14), and cancer (15,16).

As with previous studies, Dr. Morrisonand colleagues (5) found that youngerage was a significant risk factor for deathafter TBI (9). This may be related to thepredominance of inflicted trauma (childabuse) in infants and toddlers. These pa-tients often present for medical care aftera significant time delay after injury andperhaps after repeated insults, and theyhave notoriously poor outcomes com-pared with TBI due to noninflicted (acci-dental) trauma (17). Thus, the presenceof inflicted TBI in the younger age groupmay have contributed to the higher mor-tality rate. Biochemical differences alsoexist in these two patient populations(18–20).

Although the study by Dr. Morrisonand colleagues (5) disproved their origi-nal hypothesis that boys would fare worsethan girls after TBI, this and other pedi-atric studies support the notion that theinfluence of gender should be consideredin the study design, clinical management,and outcome assessment in pediatric in-tensive care unit patients. Just as futur-istic approaches to intensive care unitmedicine will likely include genotype-and phenotype-specific management andtherapy, perhaps present-day approachesto intensive care unit medicine shouldbegin to identify pathologic processes re-quiring gender-, age-, and mechanism-specific treatment.

Ericka L. Fink, MDRobert S. B. Clark, MD

University of Pittsburgh School ofMedicine and Children’sHospital of Pittsburgh

Pittsburgh, PA

REFERENCES

1. Ioannidis JP, Trikalinos TA, Ntzani EE, et al:Genetic associations in large versus smallstudies: An empirical assessment. Lancet2003; 361:567–571

2. Sachidanandam R, Weissman D, SchmidtSC, et al: A map of human genome sequencevariation containing 1.42 million single nu-cleotide polymorphisms. Nature 2001; 409:928–933

3. Fallin D, Cohen A, Essioux L, et al: Genetic

*See also p. 145.Key Words: child abuse; gender; head injury; pe-

diatric; sex hormones; traumatic brain injuryCopyright © 2004 by the Society of Critical Care


DOI: 10.1097/01.PCC.0000115621.73210.B9


analysis of case/control data using estimatedhaplotype frequencies: Application to APOElocus variation and Alzheimer’s disease. Ge-nome Res 2001; 11:143–151

4. Crawford FC, Vanderploeg RD, Freeman MJ,et al: APOE genotype influences acquisitionand recall following traumatic brain injury.Neurology 2002; 58:1115–1118

5. Morrison WE, Arbelaez JJ, Fackler JC, et al:Gender and age effects on outcome after pe-diatric traumatic brain injury. Pediatr CritCare Med 2004; 5:145–151

6. Traumatic Brain Injury in the United States:Assessing Outcomes in Children. Atlanta,Centers for Disease Control and Prevention,2000

7. Roof RL, Hall ED: Estrogen-related genderdifference in survival rate and cortical bloodflow after impact-acceleration head injury inrats. J Neurotrauma 2000; 17:1155–1169

8. Roof RL, Hoffman SW, Stein DG: Progester-one protects against lipid peroxidation fol-lowing traumatic brain injury in rats. MolChem Neuropathol 1997; 31:1–11

9. Levin HS, Aldrich EF, Saydjari C, et al: Se-vere head injury in children: Experience of

the traumatic coma data bank. Neurosurgery1992; 31:435–444

10. Susman M, DiRusso SM, Sullivan T, et al:Traumatic brain injury in the elderly: In-creased mortality and worse functional out-come at discharge despite lower injury sever-ity. J Trauma 2002; 53:219–223

11. Donders J, Hoffman NM: Gender differencesin learning and memory after pediatric trau-matic brain injury. Neuropsychology 2002;16:491–499

12. Poggi G, Liscio M, Adduci A, et al: Neuropsy-chiatric sequelae in TBI: A comparisonacross different age groups. Brain Injury2003; 17:835–846

13. Hurvitz EA, Beale L, Ried S, et al: Functionaloutcome of paediatric stroke survivors. Pedi-atr Rehabil 1999; 3:43–51

14. Hindmarsh GJ, O’Callaghan MJ, Mohay HA,et al: Gender differences in cognitive abilitiesat 2 years in ELBW infants. Extremely lowbirth weight. Early Hum Dev 2000; 60:115–122

15. Weil MD, Lamborn K, Edwards MS, et al:Influence of a child’s sex on medulloblas-toma outcome. JAMA 1998; 279:1474–1476

16. Ishii E, Eguchi H, Matsuzaki A, et al: Out-

come of acute lymphoblastic leukemia inchildren with AL90 regimen: Impact of re-sponse to treatment and sex difference onprognostic factors. Med Pediatr Oncol 2001;37:10–19

17. Duhaime AC, Christian CW, Rorke LB, et al:Nonaccidental head injury in infants—the“shaken-baby syndrome.” N Engl J Med 1998;338:1822–1829

18. Kochanek PM, Clark RS, Ruppel RA, et al:Biochemical, cellular, and molecular mech-anisms in the evolution of secondary damageafter severe traumatic brain injury in infantsand children: Lessons learned from the bed-side. Pediatr Crit Care Med 2000; 1:4–19

19. Clark RS, Kochanek PM, Adelson PD, et al:Increases in bcl-2 protein in cerebrospinalfluid and evidence for programmed celldeath in infants and children after severetraumatic brain injury. J Pediatr 2000; 137:197–204

20. Ruppel RA, Kochanek PM, Adelson PD, et al:Excitatory amino acid concentrations in ven-tricular cerebrospinal fluid after severe trau-matic brain injury in infants and children:The role of child abuse. J Pediatr 2001; 138:18–25

Incidence and risk factors for oropharyngeal aspiration inmechanically ventilated infants and children*

Mechanically ventilated in-fants and children are atrisk for aspiration of oro-pharyngeal and gastric

contents into their tracheobronchial tree.Although aspiration can be clinically si-lent, aspiration of large volumes or recur-rent aspiration of small volumes can leadto lower respiratory tract disease. Aspira-tion pneumonitis is a chemical injurycaused by the inhalation of sterile gastricacid, whereas aspiration pneumonia is aninfectious process caused by the inhala-tion of oropharyngeal secretions or gas-tric contents colonized with pathogenicbacteria (1). The incidence of aspirationin critically ill patients is difficult to as-certain from the literature, with reportedvalues ranging from 0.8 to 95% (2–6).

The wide range in reported incidence islikely due to differences in the methodsused to detect aspiration and in the pop-ulations studied. In this issue of PediatricCritical Care Medicine, Dr. Amantea andcolleagues (7) take on the challenge ofestimating the incidence and describingthe risk factors for oropharyngeal aspira-tion in a group of 50 mechanically venti-lated infants and children. The overallincidence of oropharyngeal aspirationwas 28%. Among the risk factors identi-fied were frequent swallowing move-ments detected by surface electromyogra-phy, the presence of an oral endotrachealtube, and lack of adequate sedation (in-creased wakefulness).

Research on the epidemiology of aspi-ration has been complicated by the lackof sensitive and specific bedside markersto detect aspiration. In the study by Dr.Amantea and colleagues (7), aspiration oforopharyngeal secretions is assessed bythe application of blue dye to the base ofthe tongue and subsequent testing of tra-cheal secretions for the dye’s presence.No data are available to show that results

from the dye method correlate with thosefrom established diagnostic methods todetect aspiration. To the contrary, how-ever, there are data to show that the dyemethod lacks sensitivity. For example,Thompson-Henry et al. (8) demonstratedthat dye added to small volumes of oralliquid and semisolid feedings failed to de-tect aspiration in tracheotomized adultsin whom aspiration was confirmed bymodified barium swallow or fiberopticendoscopic evaluation. Other studies inwhich blue dye was used to color enteralformulas delivered through nasogastricfeeding tubes also have shown that bluedye lacks sensitivity in detecting aspira-tion (9, 10). Considering the methodsused by Dr. Amantea and colleagues (7),their findings suggest that the incidenceof aspiration in their population is�28%.

Risk factors for aspiration in criticallyill patients are numerous; most com-monly cited are decreased level of con-sciousness, supine positioning, presenceof a nasogastric or endotracheal tube, in-termittent feeding delivery methods, and

*See also p. 152.Key Words: aspiration; intubation; mechanical ven-

tilation; infant; childCopyright © 2004 by the Society of Critical Care


DOI: 10.1097/01.PCC.0000113267.04557.7D


high-risk conditions such as neurologicdisorders (11). A randomized trial of su-pine vs. semirecumbent body positioningconducted by Drakulovic et al. (12) dem-onstrated that the frequency of clinicallysuspected and microbiologically con-firmed nosocomial pneumonia was sig-nificantly greater in supine positioned pa-tients. The incidence of nosocomialpneumonia was highest for patients re-ceiving enteral nutrition in the supineposition. Mechanical ventilation for �7days and decreased level of consciousness(Glasgow Coma Scale �9) were addi-tional risk factors. In a prospective obser-vational study, Adnet and Baud (13) dem-onstrated an increased frequency ofsuspected aspiration pneumonia on in-tensive care unit admission in adults withimpaired consciousness at the time ofinitial contact with prehospital person-nel. Most investigators agree that supinepositioning and impaired consciousnessare major risk factors for aspiration.

Dr. Amantea and colleagues (7) evalu-ated the contribution of various risk fac-tors for aspiration using both univariateand multivariate analyses. On univariatetesting, inadequate sedation (i.e., in-creased wakefulness), increased fre-quency of swallowing movements, andoral intubation were associated with in-creased aspiration risk. On multivariatetesting, inadequate sedation was not anindependent risk factor, presumably dueto the high correlation between level ofsedation and frequency of swallowingmovements. These findings are in con-trast with previous studies of both intu-bated and nonintubated patients in whichdecreased levels of consciousness werefound to contribute to aspiration risk (12,13). The contrasting findings may be ex-plained by the nature of the impairedconsciousness, whether pharmacologi-cally induced in the critical care settingor due to preexisting neurologic compro-mise before endotracheal intubation. It isalso possible that the questionable effi-cacy of the detection method used in thestudy partially explains why risk factorsidentified by the investigators are incon-gruent with what is typically reported inthe literature.

Dr. Amantea and colleagues (7) spec-ulate that the presence of an oral endo-tracheal tube impairs tongue movementand laryngeal closure, and that childrenwho swallow frequently expose their air-ways to oropharyngeal secretions moreoften than sedated children who swallowless. The latter speculation is not sup-

ported by a comprehensive review of thephysiology and pathophysiology of upperairway reflexes by Nishino (14). Accord-ing to Nishino, the main function of theswallowing reflex is to propel food andsecretions from the oral cavity to thestomach, thereby keeping the oropharynxclear of foreign materials. Lack of swal-lowing thus could be expected to result inaccumulation of colonized secretions inthe oropharynx, predisposing the patientto aspiration pneumonia, the presence ofan endotracheal tube not withstanding.The integrity of the barrier preventingoropharyngeal secretions from gainingaccess to the tracheobronchial tree ismarkedly influenced by the interactionbetween the swallowing reflex and therespiratory cycle. Awake swallowing oc-curs during the expiratory phase of res-piration, thus serving as a protectivemechanism that prevents low-grade aspi-ration from occurring. Swallowing in theunconscious state, on the other hand,occurs equally during inspiration and ex-piration, rendering the patient suscepti-ble to aspiration.

All of the patients studied by Dr.Amantea and colleagues (7) were me-chanically ventilated with uncuffed endo-tracheal tubes and were evaluated for as-piration in the supine body position.These features make their findings diffi-cult to apply to those intensive care unitswhere patients are routinely cared for inthe semirecumbent position and cuffedendotracheal tubes are frequently used.Several studies have found the use ofcuffed endotracheal tubes to be protectiveagainst aspiration (4, 15–16). Due to theanatomy of the infant’s airway, practitio-ners are cautious about using cuffed en-dotracheal tubes in these patients (17).The infant’s airway is narrowest at thelaryngeal subglottis, which is surroundedby a rigid cartilaginous complete cricoidring. Compression of the respiratory mu-cosa by a tight-fitting endotracheal tubecan cause subglottic edema. Short-termcomplications include postextubationstridor, whereas in the long term trachealstenosis can develop. Recent studies inboth the pediatric intensive care unit andoperating room settings have demon-strated the safety and efficacy of cuffedendotracheal tubes in infants and youngchildren. Deakers et al. (15) studied 282consecutive tracheal intubations in a pe-diatric intensive care unit to compare theoutcomes of patients with cuffed and un-cuffed endotracheal tubes. The overall in-cidence of postextubation stridor was

15% with no significant difference be-tween the two endotracheal tube groupseven after controlling for age, duration ofintubation, trauma, leak around the en-dotracheal tube before extubation, andPediatric Risk of Mortality Score. No pa-tient experienced any long-term airwaycomplications. Khine et al. (16) com-pared the use of cuffed vs. uncuffed en-dotracheal tubes in 488 children mechan-ically ventilated during anesthesia.Cuffed tubes prevented the need for re-peat intubations due to airleak, allowedthe use of lower rates of fresh gas flow,and reduced the concentration of anes-thetics in the operating room atmo-sphere. The incidence of postextubationstridor was low and similar betweengroups. These studies suggest that cuffedendotracheal tubes can be safely used inyoung children as long as cuff pressuresare carefully followed.

It is clear that pulmonary aspiration ininfants and children is a multifactorialprocess. Less clear, however, are the find-ings from this study concerning the in-fluence of sedation and swallowing abilityon aspiration in critically ill children. As-sessing the adequacy of sedation requiresclinical judgment; furthermore, decisionsmust be based on the underlying diseaseprocess, planned interventions, antici-pated outcomes, and patient preferences.Practitioners would be amiss to concludethat sedation is inadequate in mechani-cally ventilated children unless swallow-ing reflexes are inhibited. The degree ofsedation required to suppress swallowingmay be associated with other unwantedoutcomes such as prolonged mechanicalventilation, suppression of cough andpredilection for atelectasis, and hemody-namic instability. An important finding ofthis study is the benefit of nasal intuba-tion compared with oral intubation inreducing aspiration risk. The relationshipbetween route of intubation and clinicallysignificant pulmonary aspiration needs tobe further addressed in a randomizedcontrolled trial.

Kathleen L. Meert, MDNorma A. Metheny, PhD

Department of PediatricsChildren’s Hospital of MichiganWayne State University School of

MedicineDetroit, MISt. Louis University School of

NursingSt. Louis, MO


REFERENCES

1. Marik PE: Aspiration pneumonitis and aspi-ration pneumonia. N Engl J Med 2001; 344:665–671

2. Winterbauer RH, Durning RB, Barron E, etal: Aspirated nasogastric feeding solution de-tected by glucose strips. Ann Intern Med1981; 95:67–68

3. Cataldi-Betcher E, Seltzer MH, Slocum BA,et al: Complications occurring during en-teral nutrition support: A prospective study. JParenter Enteral Nutr 1983; 7:546–552

4. Browning DH, Graves SA: Incidence of aspi-ration with endotracheal tubes in children.J Pediatr 1983; 102:582–584

5. Kingston GW, Phang PT, Leathley MJ: In-creased incidence of nosocomial pneumoniain mechanically ventilated patients with sub-clinical aspiration. Am J Surg 1991; 161:589–592

6. Strong RM, Condon SC, Solinger MR, et al:Equal aspiration rates from postpyloric and

intragastric-placed small bore nasoentericfeeding tubes: A randomized, prospectivestudy. J Parenter Enteral Nutr 1992; 16:59–63

7. Amantéa SL, Piva JP, Sanches P, et al: Oro-pharyngeal aspiration in pediatric patientswith endotracheal intubation. Pediatr CritCare Med 2004; 5:152–156

8. Thompson-Henry S, Braddock B: The modi-fied Evan’s blue dye procedure fails to detectaspiration in the tracheotomized patient:Five case reports. Dysphagia 1995; 10:172–174

9. Potts RG, Zaroukian MH, Guerrero PA, et al:Comparison of blue dye visualization andglucose oxidase test strip methods for detect-ing pulmonary aspiration of enteral feedingsin intubated adults. Chest 1993; 103:117–121

10. Metheny NA, Dahms TE, Stewart BJ, et al:Efficacy of dye-stained enteral formula in de-tecting pulmonary aspiration. Chest 2002;122:276–281

11. Metheny NA: Risk factors for aspiration. JParenter Enteral Nutr 2002; 26:S26–S33

12. Drakulovic MB, Torres A, Bauer TT, et al:Supine body position as a risk factor fornosocomial pneumonia in mechanically ven-tilated patients: A randomized trial. Lancet1999; 354:1851–1858

13. Adnet F, Baud F: Relation between GlasgowComa Scale and aspiration pneumonia. Lan-cet 1996; 348:123–124

14. Nishino T: Physiological and pathophysiolog-ical implications of upper airway reflexes inhumans. Jpn J Physiol 2000; 50:3–14

15. Deakers TW, Reynolds G, Stretton M, et al:Cuffed endotracheal tubes in pediatric inten-sive care. J Pediatr 1994; 125:57–62

16. Khine HH, Corddry DH, Kettrick RG, et al:Comparison of cuffed and uncuffed endotra-cheal tubes in young children during generalanesthesia. Anesthesiology 1997; 86:627–631

17. Erb T, Frei FJ: The use of cuffed endotrachealtubes in infants and small children. Anaes-thesist 2001; 50:395–400

Nitric oxide: To inhale or not to inhale*

Cardiopulmonary bypass (CPB)is an iatrogenic hierarchicalkill of vital organ perfusion. Itis associated with a defined

period of altered perfusion of lung andmyocardium. After CPB, increases in pul-monary artery pressure and pulmonaryvascular resistance may lead to deteriora-tion in the postoperative period. Inhalednitric oxide (INO) has been proposed as alikely candidate to ameliorate these un-toward effects. However, the effect of INOin decreasing the deranged physiology ofischemic reperfusion injury has met withcontrasting results. Most of the studiesexamining INO effects on pulmonarypathophysiology were performed in iso-lated lung models (1–5) and in situ lungmodels, which do not mimic the clinicalscenario after CPB (6–7).

In an attempt to settle the score, Dr.Hubble and colleagues (8) conducted ex-periments in an in vivo ischemic reper-fusion lung injury model, reported in this

issue of Critical Care Medicine. Their el-egant experiments in a piglet model ofCPB compared the effects of INO on car-diopulmonary status when INO was ad-ministered during ischemia only, duringreperfusion only, and during both isch-emia and reperfusion (8). They found thatadministering INO during the ischemicperiod of CPB worsens post-CPB hemo-dynamic status, whereas administrationof INO after CPB only may be beneficial;INO during both ischemia and reperfu-sion yielded intermediate benefits.

These findings are puzzling in thatintuitively we would expect that if INOadministered after CPB is beneficial,there should be, at a minimum, no ad-verse effects on hemodynamic status ifgiven during CPB. The finding of NO be-ing good and bad in differing amounts orcircumstances has posed a dilemma forinvestigators. The seemingly good andbad effects on a single organ are amplydemonstrated in the lung, in which basalconcentrations of NO are important fornormal lung physiology (bronchodilationand maintenance of normal arterial tone)but the large amounts produced duringasthma exacerbations may increase lungedema and mucus secretion (9). In fact,the beneficial effects of steroids used inasthma may be partly due to decreasedNO production. Similarly, basal NO pro-

duction is needed to maintain normalvascular tone whereas large amounts, asseen in septic shock, are detrimental.

An explanation of the detrimental ef-fect of INO during CPB is elusive. It ispossible that the study (90 mins) may notbe of sufficient duration to determine thefull extent of the effect of INO on thecardiopulmonary variables in piglets. It isalso possible that the authors found nodifference in lung damage using drylung-weight ratio, myeloperoxidase, andhistologic evaluation because of the shorttime frame or because the histologic eval-uation is crude and subjective (hemor-rhage, neutrophil number, and alveolardestruction on a score of 0 for best to 3for worst for each of category). However,what are likely explanations if these find-ings of worsening hemodynamics arereal?

The authors offered several plausibleexplanations; however, none can fullyexplain the phenomenon seen. It is pos-sible that accumulation of NO in thelung tissue of the piglets that receivedINO during the ischemic phase of CPBmay set up the milieu for the genera-tion of potentially toxic substances un-der hyperoxic study conditions. An-other explanation was the up-regulation of endothelin with aconcomitant down-regulation of intrin-

*See also p. 157.Key Words: nitric oxide; inhaled nitric oxide; car-

diopulmonary bypass; ischemic reperfusion injury; pul-monary hypertension


DOI: 10.1097/01.CCM.0000113927.64484.C0


sic NO synthesis resulting in the eleva-tion of pulmonary vascular resistanceand pulmonary hypertension. However,both theories go adrift because worsehemodynamics than the control group(no INO) would be expected but did notoccur in the group that received INOonly during CPB. It is also possible thatdosing of INO during CPB altered theresponse to post-CPB INO without up-regulation of endothelin. This is likelyto explain the hemodynamic valuesseen in the INO during CPB only groupand also may explain the blunted re-sponse to INO in the group receivingINO both during and after CPB.

An examination of endogenous NOgeneration in lung ischemic reperfusioninjuries may provide the physiologic un-derpinning of the seemingly contradic-tory findings. Nitric oxide is produced bymany cells within the lung (albeit insmall amounts—parts per billion) andappears to play a critical role in thepathophysiology of the pulmonary vascu-lar bed and airways (10–12). Endothelialcells constitutively express a relativelylow output of NO via NO synthase I en-zymatic pathway, and airway epithelialcells normally produce NO via the NOsynthase III pathway. Output of NO viaNO synthase II, which could be furtherinduced by inflammatory mediators, pro-duces larger quantities of NO (13, 14).

Endogenous NO production and bio-activity are subject to great alterationsdue to hypoxia, ischemia, and reperfu-sion. Experiments in both cell culture inanimal and human lungs have shownthat enzymatic NO production exhibits acharacteristic oxygen dependence andthus hypoxia reduces enzyme activity tosynthesize NO (15–18). Hypoxia, how-ever, might increase NO generation fromnonenzymatic sources involved in the re-duction of inorganic nitrate to NO, a re-action that takes place predominantlyduring acidic/reducing conditions as maybe seen during ischemic reperfusion in-jury (19, 20). Although the potential rel-evance of this phenomenon to lung pa-thology has been demonstrated byshowing alteration of acid-base balanceand increase in NO production from ni-trate and acidic pH in asthma (21), it alsohas been suggested that pH changes as-sociated with ischemia can trigger thischemistry in the heart and aorta (22, 23).Therefore, hypoxia and ischemia mightalter NO concentrations and bioactivityby multiple and sometimes opposingmechanisms.

Mechanical forces imposed on cellsby dynamically changing blood (pulsa-tile vs. nonpulsatile flow) and air flow(including positive end-expiratory pres-sure) are also important contributors toboth microvascular and airway NO pro-duction. During ischemia, these me-chanical stimuli are reduced with thepotential effect of decoupling NO syn-thesis from shear stresses. During isch-emia and reperfusion, NO can serveboth as an antioxidant (by inhibitinglipid free radicals) and as an oxidant (bycontributing to peroxynitrite forma-tion), which both lead to its consump-tion. These complex interactions arelikely to alter NO production. In fact,NO production measured by exhaled NOis reduced postoperatively and is thought tobe due to lung epithelial or pulmonary vas-cular endothelial injury (24).

Based on these iterations, one can pre-dict that ischemic reperfusion injurywould be associated with a complicatedpicture of NOS expression, generation,and consumption. An appreciation of thecomplexity of NO physiology in lung in-jury, however, although important, doesnot enable us to fully explain the studyfindings. The relative contribution ofeach of these complex interactions willneed to be unraveled to fully explain theobserved phenomenon.

Regardless of the explanation, howrelevant are these findings to the clini-cian? Does the piglet’s physiology ap-proximate the human neonate in whomCPB may be used? It is possible that thebasal NO production and response toINO during CPB seen in healthy pigletswould be different from that seen inneonates with congenital heart diseasein whom hypoxia, acidosis, increased ordecreased pulmonary blood flow, andaltered pulmonary mechanics may bepresent before CPB. Several authorshave reported that preoperative pulmo-nary hypertension and left to rightshunts seem to be related to postoper-ative pulmonary vascular reactivity(25–27). The findings of the study,therefore, need to be verified underconditions more likely to be seen in theneonate undergoing CPB. Moreover, inview of the complex relationships in NOproduction during ischemic reperfu-sion injury, control for the multitude offactors involved will be needed to un-ravel their relative contribution—adaunting task indeed. In the meantime,INO should be used with caution if atall during CPB. The tantalizing data

remind us that too much of a goodthing may be good for nothing.

Niranjan Kissoon, MD, CPEDivision of Pediatric Critical Care

MedicineUniversity of Florida

HSC/JacksonvilleJacksonville, FL

REFERENCES

1. Barbotin-Larrieu F, Mazmanian M, Baudet B,et al: Prevention of ischemic-reperfusionlung injury by inhaled nitric oxide in neona-tal piglets. J Appl Physiol 1996; 80:782–788

2. Murakami S, Bacha EA, Mazmanian GM, etal: Effects of various timings and concentra-tions of inhaled nitric oxide in lung isch-emia-reperfusion. Am J Respir Crit Care Med1997; 156:454–458

3. Guidot DM, Repine MJ, Hybertson BM, et al:Inhaled nitric oxide prevents neutrophil-mediated, oxygen radical-dependent leak inisolated rat lungs. Am J Physiol 1995; 269:L2–L5

4. Eppinger MJ, Ward PA, Jones ML, et al: Dis-parate effects of nitric oxide on lung isch-emia-reperfusion injury. Ann Thorac Surg1995; 60:1169–1176

5. Kavanagh BP, Mouchawar A, Goldsmith J, etal: Effects of inhaled NO and inhibition ofendogenous NO synthesis in oxidant-inducedacute lung injury. J Appl Physiol 1994; 76:1324–1329

6. Wehberg KE, Foster AG, Wise RM, et al:Nitric oxide mediates fluid accumulationduring cardiopulmonary bypass. J ThoracCardiovasc Surg 1996; 112:168–174

7. Serraf A, Robotin M, Bonnet N, et al: Alter-ation of the neonatal pulmonary physiologyafter total cardiopulmonary bypass. J ThoracCardiovasc Surg 1997; 114:1061–1069

8. Hubble CL, Cheifetz IM, Craig DM, et al:Inhaled nitric oxide results in deterioratinghemodynamics when administered duringcardiopulmonary bypass in neonatal swine.Pediatr Crit Care Med 2004; 5:157–162

9. Barnes PJ: NO or no NO in asthma? Thorasc1996; 51:218–220

10. Barnes PJ: Nitric oxide and airway disease.Ann Med 1995; 27:389–393

11. Pinsky DJ: The vascular biology of heart andlung preservation for transplantation.Thromb Haemost 1995; 74:58–65

12. Pinsky DJ, Naka Y, Chowdhury NC, et al: Thenitric oxide/cyclic GMP pathway in organtransplantation: Critical role in successfullung preservation. Proc Natl Acad Sci U S A1994; 91:12086–12090

13. Guo FH, De Raeve HR, Rice TW, et al: Con-tinuous nitric oxide synthesis by induciblenitric oxide synthase in normal human air-way epithelium in vivo. Proc Natl Acad Sci US A 1995; 92:7809–7813

14. Asano K, Chee CB, Gaston B, et al: Constitu-tive and inducible nitric oxide synthase geneexpression, regulation, and activity in human


lung epithelial cells. Proc Natl Acad SciU S A 1994; 91:10089–10093

15. Dweik RA, Laskowski D, Abu-Soud HM, et al:Nitric oxide synthesis in the lung. Regulationby oxygen through a kinetic mechanism.J Clin Invest 1998; 101:660–666

16. Phelan MW, Faller DV: Hypoxia decreasesconstitutive nitric oxide synthase transcriptand protein in cultured endothelial cells.J Cell Physiol 1996; 167:469–476

17. Nelin LD, Thomas CJ, Dawson CA: Effect ofhypoxia on nitric oxide production in neona-tal pig lung. Am J Physiol 1996; 271:H8–H146

18. Ziesche R, Petkov V, Mosgoller W, et al:Regulation of human endothelial nitricoxide synthase by hypoxia and inflamma-tion in human pulmonary arteries—implications for the therapy of pulmonaryhypertension in COPD patients. Acta

Anaesthesiol Scand Suppl 1996; 109:97–98

19. Zweier JL, Samouilov A, Kuppusamy P: Non-enzymatic nitric oxide synthesis in biologicalsystems. Biochim Biophys Acta 1999; 1411:250–262

20. Modin A, Bjorne J, Herulf M, et al: Nitrite-derived nitric oxide: A possible mediator of“acidic-metabolic” vasodilation. Acta PhysiolScand 2001; 171:9–16

21. Hunt JF, Fang K, Malik R, et al: Endogenousairway acidification. Implications for asthmapathophysiology. Am J Respir Crit Care Med2000; 161:694–699

22. Zweier JL, Samouilov A, Kuppusamy P: Non-enzymatic nitric oxide synthesis in biologicalsystems. Biochim Biophys Acta 1999; 1411:250–262

23. Modin A, Bjorne J, Herulf M, et al: Nitrite-derived nitric oxide: A possible mediator of

“acidic-metabolic” vasodilation. Acta PhysiolScand 2001; 171:9–16

24. Beghetti M, Silkoff PE, Caramori M, et al:Decreased exhaled nitric oxide may be amarker of cardiopulmonary bypass-in-duced injury. Ann Thorac Surg 1998; 66:532–534

25. Hoffman JIE, Rudolph AM, Heymann MA:Pulmonary vascular disease with congenitalheart lesions: Pathologic features and causes.Circulation 1958; 28:533–547

26. Del Nido PJ, Williams WG, Villamater J, et al:Changes in pericardial surface pressure dur-ing pulmonary hypertensive crises after car-diac surgery. Circulation 1987; 76(Suppl III):III-93–III-96

27. Meyrick B, Reid L: Ultrastructural findings inlung biopsy material from children with con-genital heart defects. Am J Pathol 1980; 101:527–542

Is it time to revisit a role for antithrombotic therapy in asphyxianeonatorum?*

I t has been estimated that approx-imately 130 million births occurworldwide each year with fourmillion newborns suffering birth

asphyxia, of whom one million die andone million have serious neurologic im-pairment (1). A great deal of excitementhas been generated by recent studies thatsuggest that hypoxic-ischemic brain in-jury can be reversed or ameliorated bythe use of therapeutic postresuscitativehypothermia. Independent groups inAustria and Australia demonstrated, in arandomized, controlled trial format, thatpostresuscitative cooling led to a signifi-cant improvement in neurologic out-come in adults who, for the most part,had ventricular fibrillation-induced car-diac arrest (2, 3). Compagnoni and col-leagues (4) simultaneously reported, in asequential series trial format from 1997to 1999, that newborns with asphyxiawho were subjected to whole-body cool-ing within 6 hrs of birth to a temperaturebetween 32°C and 34°C for 72 hrs had asignificant reduction in major neurologicabnormalities and abnormal magnetic

resonance imaging findings. At the timeof the writing of this editorial, the resultsof a multicenter, randomized, controlledtrial of postresuscitative hypothermia forperinatal asphyxia are expected to be dis-cussed at a “Hot Topics” conference inneonatology. If therapeutic hypothermiabecomes a mainstay, then the next clini-cal question is which approach can actsynergistically with this therapy to fur-ther improve both survival and neuro-logic outcome from asphyxia neonato-rum?

In this issue of Pediatric Critical CareMedicine, El Beshlawy et al. (5) demon-strate that neonatal asphyxia is associatedwith systemic thrombosis and depletionof two important anticoagulant proteins:antithrombin III and protein C. The au-thors speculate that the use of antithrom-bin III concentrate and protein C concen-trate should be investigated in asphyxianeonatorum. The link between perinatalasphyxia, thrombosis, and “defibrinationsyndrome” was first described in the1960s. Leissring and Vorlecky (6) re-ported autopsy findings of a term new-born with asphyxia after breech deliveryfor severe preeclampsia. The child hadvasoocclusive fibrin thrombi (consistentwith disseminated intravascular coagula-tion pathophysiology) and hyalinethrombi (platelet thrombi consistentwith thrombotic thrombocytopenic pur-

pura pathophysiology) occluding vessels.Skyberg and Jacobsen (7) reported thefirst successful treatment of this syn-drome in an asphyxic term newborn in-fant who presented with severe spasticityand opisthotonus 5.5 hrs after birth. Histemperature was 35.8°C, he was in shockwith deep blue skin, and his cerebrospi-nal fluid contained visible blood. He wastreated as defibrination syndrome withone exchange transfusion of 500 mL ofheparinized whole blood (containing2500 international units of heparin) plusan 8-day course of corticosteroid therapy.The child had a remarkable recovery andwas considered neurologically normal at1 yr of life. The neonatal community wasfavorably impressed by this report, andseveral subsequent reports refer to treat-ment with heparinized whole blood ex-change transfusion as the establishedtherapy for asphyxia neonatorum. In1973, Hambleton and Appleyard (8) per-formed a controlled trial of fresh frozenplasma infusion alone in asphyxiated lowbirthweight infants (�2.5 kg) and foundno reduction in intraventricular hemor-rhages with this treatment. They and oth-ers concluded that although fresh frozenplasma infusion was not effective, hepa-rinized whole blood exchange transfusionwas “well established” as an effectivetherapy for asphyxia with defibrinationsyndrome in the term newborn (9). In

*See also p. 163.Copyright © 2004 by the Society of Critical Care


DOI: 10.1097/01.PCC.0000121302.62216.D6


agreement with the findings of Hamble-ton and colleagues, a 1996 randomized,controlled trial similarly showed thatprophylactic treatment of preterm babieswith fresh frozen plasma had no effect onoutcomes (10).

Much has changed since the 1970s.The collective memory for the use of hep-arinized whole blood exchange has beenlost. Indeed, whole blood is no longeravailable in much of the Western worldwhere blood is presently banked as com-ponents. However, there has been a greatimprovement in knowledge about antico-agulant and procoagulant proteins andtheir role in thrombotic microangio-pathic syndromes. Three clinically im-portant circulating anticoagulant pro-teins have been identified, namely,antithrombin III, protein C, and von Wil-lebrand factor-cleaving protease, orADAM TS 13 (11). Antithrombin III is anactive anticoagulant only when it is com-plexed with heparin. It is common prac-tice in veterinary medicine today to treatdefibrination syndrome by infusing hep-arin-treated fresh frozen plasma. The ra-tionale given is that heparin “activates”antithrombin III, preventing ongoing co-agulation while the procoagulant factorsprevent bleeding from consumptive co-agulopathy. Protein C is an active antico-agulant when it is complexed with endo-thelial thrombomodulin. Activatedprotein C resistance (also known as factorV Leiden deficiency) has been reported asa cause of ischemic stroke in neonatesand infants (12, 13). Patients with acti-vated protein C resistance can be success-fully anticoagulated with warfarin or hep-arin therapy. The von Willebrand factor-cleaving protease ADAM TS 13 is alwaysactive. Unlike antithrombin III and pro-tein C, it is not thought to have any effecton fibrin. Instead, this enzyme cleavesthrombogenic large and ultralarge vonWillebrand factor multimers, preventinguncontrolled platelet thrombosis (hyalinethrombi). Absence or inhibition of ADAMTS 13 is considered to be the cause ofthrombotic thrombocytopenic purpura-mediated thrombotic microangiopathy(11). Newborns have markedly reducedlevels of antithrombin III, protein C, andADAM TS 13 compared with adults (14,15). Pathophysiologic processes thatcause endotheliopathy, including sepsis(15) and perinatal asphyxia (5), consumeantithrombin III and protein C, leavingthe newborn with severe anticoagulantprotein deficiency and a proclivity to sys-temic thrombosis (5, 15). Replacement of

these anticoagulant factors can beachieved with plasma infusion or withconcentrates. Each 10 mL/kg of plasmagiven replaces approximately 10% of nor-mal activity. Antithrombin III and pro-tein C can be more efficiently given ascommercially purified concentrates.

In the past, when neurologic outcomewas considered immutable after perinatalasphyxia, little thought was given totreating or reversing the associatedthrombotic microangiopathy. However,now that brain injury appears to be atleast partly reversible with therapeutichypothermia, it is time to think about thepotential role of anticoagulant therapiesto further improve outcome and neuro-logic function after perinatal asphyxia.Preparatory studies will likely be needed.First, because temperature itself has ef-fects on coagulation, the effects of hypo-thermia on thrombosis and fibrinolysiswill need to be considered. Coagulation isdecreased at 32°C; coagulation is not de-creased at 35°C. Second, because somepatients with perinatal asphyxia have de-fibrination syndrome whereas others donot, patient selection will be important toany study design. For example, patientswith consumptive coagulopathy may re-quire anticoagulant therapy as well asprocoagulant replacement, whereas pa-tients without “defibrination” may onlyrequire anticoagulant therapies.

In summary, in this issue of PediatricCritical Care Medicine, El Beshlawy et al.(5) provide a modern day evaluation ofthe coagulopathy associated with As-phyxia Neonatorum. Their findings sup-port severe depletion of the anticoagulantproteins antithrombin III and protein Cin the setting of systemic thrombosis.Antithrombin III concentrate and proteinC concentrate are recommended thera-pies for newborns with congenital anti-thrombin III and protein C deficiency.These therapies have little to no risk forcausing bleeding when administered inthe absence of heparin. Based on thefindings of El Beshlawy et al. (5), weagree that it is time to investigatewhether antithrombin III concentrateand protein C concentrate have a ther-apeutic role in newborns with asphyxiaand acquired antithrombin III and pro-tein C deficiency.

Robert ClarkJoseph A. Carcillo

Children’s Hospital of PittsburghPittsburgh, PA

REFERENCES

1. Buonocore G, Perrone S, Longini M, et al:Non protein bound iron as early predictivemarker of neonatal brain damage. Brain2003; 126(Pt 5):1224–1230

2. Bernard SA, Gray TW, Buist MD, et al: Treat-ment of comatose survivors of cardiac arrestwith induced hypothermia N Engl J Med2002; 346:557–563

3. The Hypothermia After Cardiac Arrest StudyGroup. Mild hypothermia to improve neuro-logic outcome after cardiac arrest. N EnglJ Med 2002; 346:549–556

4. Compagnoni G, Pogliani L, Lista G, et al:Hypothermia reduces neurologic damage inasphyxiated newborn infants. Biol Neonate2002; 82:222–227

5. El Beshlawy A, Hussein HA, Abou-Elew HH,et al: Study of protein C, protein S, andantithrombin III in hypoxic newborns. Pedi-atr Crit Care Med 2004; 5:163–166

6. Leissring JC, Vorlicky LN: Disseminated in-travascular coagulation in a neonate. Am JDis Child 1968; 115:105–111

7. Skyberg D, Jacobsen CD: Defibrination syn-drome in a newborn and its treatment withexchange transfusion. Acta Paediatr Scand1969; 58:83–86

8. Hambleton G, Appleyard WJ: Controlled trialof fresh frozen plasma in asphyxiated lowbirthweight infants. Arch Dis Child 1973; 48:31–38

9. Kirsch W, Buttner M, Wenzel E: Diagnostictherapeutic problems of defibrination syn-drome in shock, sepsis, and neonatal hypoxia.Monatsschr Kinderheilkd 1977; 125:621–627

10. A randomized trial comparing the effect ofprophylactic intravenous fresh frozenplasma, gelatin or glucose on early mortal-ity and morbidity in preterm babies. TheNorthern Neonatal Nursing Initiative(NNNI) Trial Group Eur J Pediatr 1996;155:580 –588

11. Nguyen T, Hall M, Han Y, et al: Microvascu-lar thrombosis in pediatric multiple organfailure: Is it a therapeutic target? Pediatr CritCare Med 2001; 2:187–186

12. Thorarensen O, Ryan S, Hunter J, et al: Fac-tor V Leidien mutation: An unrecognizedcause of hemiplegic cerebral palsy, neonatalstroke, and placental thrombosis Ann Neurol1997; 42:372–375

13. Nowak-Gottl U, Strater R, Dubbers A, et al:Ischaemic stroke in infancy and childhood:Role of the Arg506 to Gln mutation in thefactor V gene. Blood Coagul Fibrinolysis1996; 7:684–688

14. Kavakli K, Canciani MT, Mannucci PM:Plasma levels of the von Willebrand FactorCleaving Protease in physiological andpathophysiological conditions in children.Pediatr Hematol Oncol 2002; 19:467–473

15. Roman J, Velasco F, Fernandez F, et al:Coagulation, fibrinolytic and kallikreinsystems in neonates with uncomplicatedsepsis and septic shock. Haemostasis 1993;23:142–148


Surface properties and the meconium aspiration syndrome*

I n this issue of Pediatric CriticalCare Medicine, Dr. Fuloria andcolleagues (1) explore the physicalproperties and interactions of sa-

line-suspended meconium, calf lung sur-factant, and perflubron. The picture thatemerges may help to elucidate the patho-physiology of the meconium aspirationsyndrome. It also illustrates the weaknessof the link between the behavior of meco-nium and the disease it produces.

The authors show that, althoughmeconium reduces the surface tension ofsaline, it interferes with the surface ten-sion lowering effect of surfactant in pro-portion to the concentration of the sus-pension. This interaction has beenstudied in vitro (2) and in intact animals(3–5) and has generated interest in sur-factant therapy as a treatment of meco-nium aspiration (6, 7).

Dr. Fuloria and colleagues (1) furthershow that meconium suspension spreadspoorly over Teflon but readily over per-flubron. This ability to wet a perflubronfilm is not directly correlated to the dis-ease process, but the implication is thatperflubron, which itself spreads readilyover saline or Teflon, may enhance theclearance of sticky meconium from air-ways by making it more slippery.

Using a third technique, distraction(de Nouy ring), the authors show that theinterfacial tension between a perflubronlayer and a meconium/saline suspensionis variable and is inversely related to thelogarithm of the meconium concentra-tion. The greater the concentration ofmeconium, the lower is the interfacialsurface tension. Of great interest here isthe finding that at very low meconiumconcentration, a saline-perflubron inter-face has surface tension near 40 dyne/cm,roughly halfway between the surface ten-sions of perflubron (at air) and water (atair). But let’s come back to that.

So which of these properties of meco-nium are relevant to clinical meconiumaspiration syndrome? Clearly meconiumaspiration makes the lungs stiff. Thiswould appear to correlate with loss ofsurfactant function. We are comfortablyfamiliar with this. The rationale for high-dose surfactant instillation in meconiumaspiration syndrome is that giving moresurfactant may reverse or overwhelm thisinterference. Polymers such as dextranand polyethylene glycol can be added tosurfactant to make it more resistant tothis inhibition (8, 9), and surfactants hav-ing higher concentrations of surfactantproteins (A, B, and C) are more resistantto inactivation (10), suggesting the po-tential for “designer surfactants” ofgreater resistance. Surfactant dysfunc-tion is a widely recognized component ofother lung diseases, including acute re-spiratory distress syndrome. Designersurfactants might, therefore, have wide-spread use.

Could perfluorocarbons like per-flubron be used to reduce surface tensionin meconium aspiration syndrome? Dr.Fuloria and colleagues (1) have shownthat the surface properties of perflubronare not altered by exposure to meconium.Laboratory and clinical experience arguesthat perflubron might prove useful.

But at what interface does perflubronreduce surface tension? Gas/perflubroninterfaces have modest surface tension(18 dyne/cm). But what of the interfacebetween perflubron and immiscible alve-olar tissue surface material? If that inter-face had a surface tension of 40 dyne/cm,like that of saline to perflubron, perfluo-rocarbons could not be helpful. However,even in the lung exposed to meconium,the alveolar tissue is covered by a surfaceof complex composition. Dr. Fuloria andcolleagues (1) have shown that at highmeconium concentration, a saline/meco-nium-perflubron interface has a surfacetension near that of perflubron and gas.The interface truly at issue during partialor tidal liquid ventilation for meconiumaspiration is that of perflubron to a mix-ture (in one phase) of surfactant andmeconium.

What of the other properties of meco-nium? Meconium suspension does notspread over Teflon. Perhaps this impairsmucociliary clearance of meconium.Might mucociliary clearance of meco-nium be enhanced by perflubron lavage,wetting surfaces to spread, lift, slip, andmobilize droplets of meconium?

Meconium is “sticky” and relatively“dry.” Perhaps meconium particles ob-struct airways and are hard to dislodge by“cough (air flow) transport.” Can suchparticles be washed away? There is recentinterest in lavage using dilute surfactantas a means to mobilize and remove meco-nium (11, 12). Does the “wetting” prop-erty of perflubron offer an opportunityhere?

Rubin et al. (13) discussed variousproperties of meconium, describing it ascharacterized by cohesiveness (“spinabil-ity”), dryness, cough transportability, cil-iary transportability, “wetability,” andnon-Newtonian interfacial adhesion ten-sion. We know little of the relation ofthese properties to the lung dysfunctionof meconium aspiration.

It is probably simplistic to think ofmeconium aspiration syndrome as justanother surfactant dysfunction state, butat least that aspect of it is tangible.

Bradley P. Fuhrman, MDState University of New York at

BuffaloWomen’s and Children’s Hospital

of Buffalo

REFERENCES

1. Fuloria M, Wu Y, Brandt ML, et al: Effect ofmeconium on the surface properties of per-flubron. Pediatr Crit Care Med 2004;5:167–171

2. Moses D, Holm BA, Spitale P, et al: Inhibitionof pulmonary surfactant function by meco-nium. Am J Obstet Gynecol 1991; 164:477–481

3. Sun B, Herting E, Curstedt T, et al: Exogenoussurfactant improves lung compliance and oxy-genation in adult rats with meconium aspira-tion. J Appl Physiol 1994; 77:1961–1971

4. Al-Mateen KB, Dailey K, Grimes MM, et al:Improved oxygenation with exogenous sur-factant administration in experimentalmeconium aspiration syndrome. Pediatr Pul-monol 1994; 17:75–80

5. Sun B, Curstedt T, Robertson B: Exogenous

*See also p. 167.Key Words: saline-suspended meconium; calf lung

surfactant; perflubron; meconium aspirationCopyright © 2004 by the Society of Critical Care


DOI: 10.1097/01.PCC.0000115958.23002.D5


surfactant improves ventilation efficiencyand alveolar expansion in rats with meco-nium aspiration. Am J Respir Crit Care Med1996; 154:764–770

6. Lotze A, Knight GR, Martin GR, et al: Improvedpulmonary outcome after exogenous surfactanttherapy for respiratory failure in term infantsrequiring extracorporeal membrane oxygen-ation. J Pediatr 1993; 122:261–268

7. Lotze A, Mitchell B, Bulas DI, et al: Multicenterstudy of surfactant (beractant) use in the treat-ment of term infants with severe respiratoryfailure. J Pediatr 1998; 132:40–47

8. Taeusch W, Lu KW, Goerke J, et al: Non-ionic polymers reverse inactivation of sur-factant by meconium and other substances.Am J Respir Crit Care Med 1999; 159:1391–1395

9. Tashiro K, Kobayashi T, Robertson B: Dex-tran reduces surfactant inhibition bymeconium. Acta Paediatrica 2000; 89:1439 –1445

10. Taeusch HW, Keough KM: Inactivation ofpulmonary surfactant and the treatment ofacute lung injuries. Pediatr Pathol Molecu-lar Med 2001; 20:519–536

11. Lam BC, Yeung CY, Fu KH, et al: Surfac-tant tracheobronchial lavage for the man-agement of a rabbit model of meconiumaspiration syndrome. Biol Neonate 2000;78:129 –138

12. Lam BC, Yeung CY: Surfactant lavage formeconium aspiration syndrome: A pilotstudy. Pediatrics 1999; 103:1014–1018

13. Rubin BK, Tomkiewicz RP, Patrinos ME,et al: The surface and transport proper-ties of meconium and reconstituted meco-nium solutions. Pediatr Res 1996; 40:834 – 838


a long-acting vasopressin analog for septic shock

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