ORIGINAL RESEARCH

Deep Neuromuscular Blockade Improves LaparoscopicSurgical Conditions: A Randomized, Controlled Study

Jacob Rosenberg . W. Joseph Herring . Manfred Blobner .

Jan P. Mulier . Niels Rahe-Meyer . Tiffany Woo . Michael K. Li .

Peter Grobara . Christopher A. Assaid . Hein Fennema .

Armin Szegedi

Received: January 4, 2017 / Published online: March 1, 2017� The Author(s) 2017. This article is published with open access at Springerlink.com

ABSTRACT

Introduction: Sustained deep neuromuscularblockade (NMB) during laparoscopic surgerymay facilitate optimal surgical conditions. Thisexploratory study assessed whether deep NMBimproves surgical conditions and, in doing so,allows use of lower insufflation pressures duringlaparoscopic cholecystectomy. We furtherassessed whether use of low insufflation pres-sure improves patient pain scores after surgery.Methods: This randomized, controlled, blindedstudy (NCT01728584) compared use of deep

(1–2 post-tetanic-counts) or moderate (trai-n-of-four ratio 10%) NMB, and lower (8 mmHg)or higher (12 mmHg; ‘standard’) insufflationpressure in a 2 9 2 factorial design. Primaryendpoint was surgeon’s overall satisfaction withsurgical conditions, rated at end of surgeryusing an 11-point numerical scale. Post-opera-tive pain scores were also evaluated. Data wereanalyzed using analysis of covariance.Results: Of 127 randomized patients, 120 hadevaluable data for the primary endpoint. Sur-geon’s score of overall satisfaction with surgicalconditions was significantly higher with deepversus moderate NMB indicated by a least-square mean difference of 1.1 points (95%confidence interval 0.1–2.0; P = 0.026). Fur-thermore, strong evidence of an effect wasobserved for standard versus low pressure:least-square mean difference of 3.0 points (95%confidence interval 2.1–4.0; P\0.001). No sig-nificant difference was observed in average painscores within 24 h post-surgery for low versus

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Electronic supplementary material The onlineversion of this article (doi:10.1007/s12325-017-0495-x)contains supplementary material, which is available toauthorized users.

J. RosenbergGastrointestinal Unit, Surgical Section, HerlevHospital, University of Copenhagen, Herlev,Denmark

W. J. Herring � T. Woo � M. K. Li � C. A. Assaid �A. SzegediMerck, Kenilworth, NJ, USA

M. Blobner (&)Klinik fur Anaesthesiologie der TechnischenUniversitat, Munich, Germanye-mail: m.blobner@tum.de

J. P. MulierAZ Sint Jan Brugge-Oostende, Brugge, Belgium

N. Rahe-MeyerFranziskus Hospital Bielefeld, Hannover MedicalSchool, Bielefeld, Germany

P. Grobara � H. FennemaMSD, Oss, The Netherlands

Adv Ther (2017) 34:925–936

DOI 10.1007/s12325-017-0495-x

standard pressure [0.17 (95% confidence inter-val -0.67 to ?0.33); P = 0.494].Conclusions: Although associated with signifi-cantly improved surgical conditions, deep NMBalone was insufficient to promote use of lowinsufflation pressure during laparoscopiccholecystectomy. Furthermore, low insufflationpressure did not result in reduced pain, com-pared with standard pressure.Clinical Trial Registration: ClinicalTrials.govidentifier, NCT01728584.Funding: Merck Sharp and Dohme Corp., asubsidiary of Merck & Co., Inc., Kenilworth, NJ,USA.

Keywords: Deep neuromuscular blockade;Insufflation pressure; Laparoscopy; Pain;Surgical conditions

INTRODUCTION

Laparoscopic procedures are becoming increas-ingly frequent in clinical practice due to anumber of benefits versus open surgery,including faster recovery, shorter hospitaliza-tion times, less post-operative pain, and animproved cosmetic result [1]. Creating a pneu-moperitoneum with insufflation of CO2 atapproximately 12–15 mmHg is routine inlaparoscopic procedures [2] to provide anacceptable view of the surgical field. However,the raising of intra-abdominal pressure resultsin a variety of physiological changes [3], andhas been associated with pain [4]. Previousstudies have found use of lower CO2 insuffla-tion pressures to be advantageous in terms ofpain levels experienced post-operatively [4–6],although these findings have not been consis-tent across other studies [7].

Neuromuscular blocking agents (NMBAs) areused adjunctively to anesthesia to facilitate tra-cheal intubation, relax the abdominal musclesand reduce patient movements during surgery.Use of deeper levels of neuromuscular blockade(NMB) can improve surgical conditions inlaparoscopic procedures [8], with potential ben-efits of sustained NMB throughout the wholeprocedure including an enhanced visual field, aswell as increased ease of surgical access and

manipulation and facilitation of closure. A limi-tation of the use of deep NMB in the past was thelack of reversal agent that would allow the anes-thesiologist to reliably, predictably and rapidlyreverse a deep NMB at any given time duringsurgery. However, sugammadex has now beenapproved in more than 80 countries as a novelcompound proven to reverse deep levels of NMBrapidly and safely.

The relationship between insufflation pres-sure and depth of NMB has not been systemat-ically studied. Therefore, the present study wasintended as a first step to investigate thepotential of a combination of deep NMB with alower level of insufflation pressure to provide apotential two-fold benefit in the setting ofendoscopic abdominal surgery: optimal surgicalconditions for the surgeon and reducedpost-operative pain for the patient. The primaryobjective of the study was to assess the benefitof deep NMB on surgical conditions whencompared with moderate NMB, assessed in thecontext of low and standard insufflation pres-sure during laparoscopic cholecystectomy. Asecondary objective was to assess whether theuse of low insufflation pressure improves thepatient’s overall pain score within 24 h aftersurgery.

METHODS

Study Design and Patients

This was a randomized, controlled, paral-lel-group, blinded study (Clinicaltrials.govidentifier NCT01728584; Sponsor ProtocolNumber P076), conducted at eleven centers(two in Austria, two in Finland, five in Ger-many, one in Italy and one in the UnitedKingdom) from January 2013 to April 2014. Thestudy was conducted in accordance with prin-ciples of Good Clinical Practice and with theHelsinki Declaration of 1964, as revised in 2013,and was approved by the appropriate institu-tional review board/ethics committees.Informed consent was obtained from allpatients for being included in the study. Thestudy is reported according to the CONSORTstatement.

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Included patients were adults of AmericanSociety of Anesthesiologists Class 1–3, withbody mass index (BMI)\35 kg/m2, scheduled toundergo laparoscopic cholecystectomy undergeneral anesthesia and rocuronium-inducedNMB. All patients were required to providewritten, informed consent. Patients wereexcluded if they had suspected difficult intuba-tion, a history of previous abdominal surgery, ahistory of substance abuse or dependence, evi-dence of acute cholecystitis, renal or liver dys-function, a history of a chronic pain condition,known intolerance to any drug used or plannedto use for anesthesia, or if they had participatedin any other clinical trial within 30 days. Femalepatients were also excluded if they were preg-nant or were planning to become pregnant

within the study period or had given birth toone or more children within the last year.

The study examined two depths of blockadeand two insufflation pressures in a 2 9 2 facto-rial design: moderate blockade [train-of-four(TOF) ratio of 10%; range TOF count 2–3 to TOFratio of 20%], deep blockade [1–2 post-tetaniccounts (PTC); range 1–5 PTC], standard pressure(set as 12 mmHg), and low pressure (8 mmHg).This design allows for inferential statisticalanalysis of the effect of depth of blockade aswell as insufflation pressure.

Using an interactive voice response system,patients were randomized centrally in a 1:1:1:1ratio to one of each of the four combinations(Fig. 1) stratified by the surgeon/surgical team(i.e., surgeon with anesthesiologist) at the site

Fig. 1 Patient flow-through study; NMB neuromuscular blockade. aSurgeons were allowed to change surgical conditions asneeded; therefore, a patient’s final treatment may be different from their randomized assignment

Adv Ther (2017) 34:925–936 927

level. Any patients that prematurely discontin-ued from the study and had missing outcomefor the primary/key secondary endpoint(s) werereplaced by a patient assigned to the same sur-geon with the same treatment assignment.

Study Procedures

Anesthesia and NMB RegimenAll patients received a standard regimen forgeneral anesthesia using total intravenousanesthesia. Propofol (2.5 mg/kg) and remifen-tanil (1 lg/kg) were given for anesthesia induc-tion. Anesthesia was maintained with apropofol infusion, titrated to maintain a bis-pectral index of 40–50 throughout surgery witha starting infusion rate of 6–12 mg/kg/h(100–200 lg/kg/min). Remifentanil infusionwas adapted (0.25 lg/kg/min) as required by theanesthesiologist based on the hemodynamicreactions. An intravenous bolus dose of0.45 mg/kg rocuronium was given for intuba-tion, with additional bolus doses or rocuroniuminfusion used to maintain NMB at the requireddepth. NMB was monitored using the TOF-Watch� SX (Organon Ireland, a subsidiary ofMerck, Swords, Co. Dublin, Ireland). ModerateNMB was maintained at a targeted TOF ratio of10% (range TOF count of 2–3 to a TOF ratio of20%). Deep NMB was maintained at a targeteddepth of 1–2 PTC (range 1–5 PTC).

Once the target depth of NMB was reached,CO2 insufflation was initiated. The pneu-moperitoneum was continuously controlled bythe anesthesiologist, with the surgical teamblinded to the applied insufflation pressure. Ifsurgical conditions were deemed unaccept-able with the assigned treatment, rescue inter-ventions could be performed. For patientsrandomized to moderate NMB, the depth ofNMB could be increased to 1–2 PTCs. Further,the pneumoperitoneum pressure could beincreased by 4 mmHg. For patients alreadyunder deep NMB, pneumoperitoneum pressurecould be increased by 4 mmHg.

The surgical conditions assessment score wasobtained from the surgeon shortly after surgery.Patients who underwent rescue intervention

were assigned the worst possible surgical con-ditions assessment score of 0.

After the last dose of rocuronium, a singleintravenous bolus dose of sugammadex 2 or4 mg/kg was administered within 10 s into afast-running intravenous infusion for reversal ofmoderate and deep NMB, respectively.

Pain Management RegimenAt the end of the remifentanil infusion andprior to extubation, a bolus dose of 8 mg mor-phine was administered. Patients receivedmorphine via patient-controlled analgesia for2 h while in the post-anesthesia care unit(PACU). After discharge from the PACU,patients were provided with oral pain medica-tion of 4 9 400 mg ibuprofen and 4 9 1000 mgparacetamol until day 5. Additional pain medi-cation could be taken as needed by the patient,with use of all pain medications systematicallyrecorded until day 8.

BlindingThe patient, surgeon, and safety assessors wereall blinded to treatment. The anesthesiologistswere not blinded as they needed to control thedepth of NMB and record the dose and time ofadministration of all medications, insufflationpressures, and changes to the insufflation pres-sure or NMB as requested by the surgeon. Thesurgeon was also blinded to the type of rescueintervention.

Assessments

Surgeons rated several parameters of surgicalconditions at end of surgery (primary endpoint)using an 11-point (discrete) numerical scalefrom 0 (poor, needs intervention) to 10 (excel-lent). The pre-specified primary endpoint in thisstudy was the surgeon-rated overall satisfactionat end of surgery. Additional secondary end-points included specific aspects of the surgicalconditions, surgeon’s satisfaction with surgicalfield visibility, surgeon’s overall rating of ade-quacy of muscle relaxation and insufflationpressure, the number of patient movementsinterfering with surgical conditions, and the

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number of rescue actions performed duringsurgery to improve surgical conditions.

After completion of surgery, patients recor-ded their pain intensity at rest and when pro-voked by transition from lying to sittingposition, and post-operative shoulder pain atthe time of the assessment, using a numericalscale from 0 (no pain) to 10 (severe pain).Patients rated their pain score at 1, 2, 4, 24 and48 h, post-operatively as well as daily in themorning on days 3–8. The key secondary end-point was the pain score within 24 h (average ofthe pain assessments at 1, 2, 4 and 24 h). Theamount of pain medication received post-oper-atively was assessed as an exploratory endpoint.

Safety was assessed via monitoring of adverseevents (AEs) and vital signs. Incidences of nau-sea and vomiting were recorded, as were anal-gesic and anti-emetic medication consumption,until day 8. Clinical evidence of residual NMBor recurrence of NMB (e.g., significant changein respiratory rate or oxygen saturation level)was assessed from time of reversal of NMB withsugammadex until the patient was ready fordischarge from the PACU.

Statistical Analysis

The primary hypothesis was that use of sus-tained deep NMB improves the surgeon’s over-all satisfaction with surgical conditions,compared with moderate NMB. The key sec-ondary hypothesis was that use of low insuffla-tion pressure improves the patient overall painscore within 24 h.

A sample size of 30 patients per each of thefour treatment groups was determined to have apower of more than 80% to analyze the primaryhypothesis at an overall two-sided 5% alpha-level, if the underlying treatment difference inthe mean surgical conditions score was at least52% of the standard deviation [9]. The samplesize was also determined to provide 80% powerto analyze the key secondary hypothesis.

The efficacy analyses were performed on thefull analysis set (FAS), defined as all randomizedpatients who received rocuronium-inducedNMB and pneumoperitoneum, according torandomization, and who did not convert to

open surgery before the start of application ofNMB and/or insufflation pressure. Analysis ofcovariance (ANCOVA) was performed, usingfactors for depth of NMB, level of insufflationpressure, surgeon; with BMI added for the pri-mary efficacy analysis and gender added for thekey secondary analysis. ANCOVA was per-formed using SAS 9.1 (SAS Institute, Cary, NC,USA). A hierarchical approach was taken tocontrol for multiple testing: the primary con-trast for the primary endpoint was tested at alevel of 5%. Only if the associated nullhypothesis could be rejected at that level, thecontrast of interest for the key secondary end-point was tested at a level of 5%. A rescuechange in the level of insufflation pressure and/or depth of NMB due to unacceptable surgicalconditions was permitted per the protocol.According to the pre-defined analysis plan, thescore for any patients for whom rescue wasrequired was to be imputed as the worst possibleassessment score of 0.

The interaction between the two treatmentfactors (depth of NMB and insufflation pressure)was investigated in a sensitivity analysis, byadding an interaction term to the ANCOVAmodel. In the case of deviation from normality,a stratified Wilcoxon (non-parametric) test wasalso performed as a supportive analysis. Thisanalysis compared the two levels of one treat-ment factor [providing Hodges–Lehmann esti-mates for the median difference and associated95% confidence interval (CI)] while using thetwo levels of the other treatment factor as strata.For the primary parameter, the main compar-ison was deep NMB versus standard NMB, andfor the key secondary parameter (average painscore), low pressure versus standard pressure.The sensitivity analyses were interpreted in anexploratory sense, with unadjusted P val-ues\0.05 considered nominally significant.

All safety analyses were performed on theall-patients-as-treated (APaT) set, defined as allrandomized patients who received rocuro-nium-induced NMB or pneumoperitoneum,according to actual treatment conditions (depthof NMB and level of insufflation pressure).

Amount of pain medication receivedpost-operatively was analyzed via ANCOVA.

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RESULTS

Of 127 randomized patients, 122 receivedtreatment with rocuronium and pneumoperi-toneum according to randomization, and wereincluded in the FAS population for efficacyanalyses. Two patients discontinued prema-turely and were not evaluable; therefore 120had evaluable data for the primary endpoint(Fig. 1). There was a greater proportion of male(62.2%) versus female (37.8%) patients. Patientcharacteristics are shown in Table 1.

In total, 122 patients were included in theAPaT population for safety analyses; 12 patients(moderate blockade/low pressure, n = 7; deepblockade/low pressure, n = 5) had a permittedrescue change in level of insufflation pressureand/or depth of NMB after start of surgery dueto unacceptable surgical conditions. No patientin the standard pressure groups required rescueintervention.

Efficacy

The surgeon’s score of overall satisfaction withsurgical conditions was significantly better withdeep versus moderate NMB by 1.1 points on the10-point scale (95% CI 0.1–2.0; P = 0.026)(Table 3; Fig. 2). Improvement in surgical con-ditions was also observed with standard versuslow pressure by 3.0 points (95% CI 2.1–4.0;unadjusted P\0.001; Fig. 2). This analysis wasnot associated with a pre-specified hypothesis,but was performed for completeness of theassessment of the effect of both factors in thefactorial design. The breakdown of surgicalscores and ANCOVA results for the combinedNMB and pressure groups are shown in Table 2.

The pre-specified sensitivity analysis of theprimary endpoint, using the actual assessmentscore for surgical conditions before any rescueintervention, supported the results of the pri-mary approach (Table 3). Additionally, a

Table 1 Patient baseline characteristics (all-patients-as-randomized set)

n (%) ModerateNMB 1 moderatepressure (n5 36)

ModerateNMB 1 lowpressure (n5 30)

DeepNMB 1 moderatepressure (n5 31)

DeepNMB 1 lowpressure (n5 30)

Total(n5 127)

Gender

Male 21 (58.3) 19 (63.3) 18 (58.1) 21 (70.0) 79 (62.2)

Female 15 (41.7) 11 (36.7) 13 (41.9) 9 (30.0) 48 (37.8)

Age, years

\65 28 (77.8) 29 (96.7) 29 (93.5) 26 (86.7) 112 (88.2)

C65 8 (22.2) 1 (3.3) 2 (6.5) 4 (13.3) 15 (11.8)

Mean (SD) 46.1 (17.7) 39.1 (13.6) 43.5 (15.6) 46.7 (13.8) 43.9 (15.5)

ASA Class

1 15 (41.7) 16 (53.3) 17 (54.8) 17 (56.7) 65 (51.2)

2 13 (36.1) 13 (43.3) 10 (32.3) 11 (36.7) 47 (37.0)

3 2 (5.6) 1 (3.3) 3 (9.7) 2 (6.7) 8 (6.3)

Unknown 6 (16.7) 0 (0.0) 1 (3.2) 0 (0.0) 7 (5.5)

BMI, kg/m

Subjects with data, n 34 30 31 30 125

Mean (SD) 25.9 (2.9) 27.5 (4.0) 27.1 (3.7) 28.7 (2.7) 27.2 (3.4)

ASA American Society of Anesthesiologists, BMI body mass index, NMB neuromuscular blockade

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pre-specified non-parametric analysis was per-formed due to evidence that the residuals of theANCOVA model of the primary endpoint werenon-normally distributed with non-homoge-neous variance. This supportive analysis resul-ted in a P value of 0.321 for deep versusmoderate NMB and P\0.001 for low versusstandard pressure. Surgical conditions assess-ments are shown in Table 3.

Another sensitivity analysis, adjusting forthe estimated interaction between depth ofNMB and insufflation pressure, showed nearlyidentical results as the primary approach fordeep versus moderate NMB by 1.07 points(0.12–2.02); P = 0.028. Results of this analysisthus supported the primary result demonstrat-ing the effect of deep versus moderate NMB.

The difference in overall average pain scorein the first 24 h after surgery was not statisticallysignificant for either low versus standard pres-sure or for deep versus moderate NMB (Fig. 3).No significant differences in shoulder pain wereobserved between the groups. Results for thekey secondary analysis were supported byresults of the sensitivity analyses by 0.3 points(95% CI -0.2 to ?0.8; P = 0.223) for deep versus

moderate NMB and 0.2 points (95% CI -0.4 to?0.7; P = 0.565) for standard versus low pres-sure. There was no significant departure fromnormality or homogeneity of variance for theresiduals of the ANCOVA model for the painscores.

Safety

There were similar incidences of AEs betweenthe four treatment groups. The majority of theAEs were of mild severity, and none were con-sidered drug-related. The most frequentlyrecorded AE was pain (88%), followed by nausea(21%), vomiting (13%), pyrexia (13%), andwound hemorrhage (9%) (SupplementaryTable 1). Six serious AEs were reported for fourpatients: procedural pain and procedural hem-orrhage in one subject each, wound hemor-rhage and hematoma in one subject, andnecrotizing fasciitis and sepsis in one subject.None were considered related to studymedication.

DISCUSSION

This study confirmed the primary hypothesisthat use of deep NMB has an advantage overmoderate NMB in improving surgeon satisfac-tion with surgical conditions in laparoscopiccholecystectomy. A greater degree of musclerelaxation afforded by deep levels of NMB pro-vides improved visibility for the surgeon andfewer involuntary patient movements [9].

In the current study, maintenance of deepNMB throughout surgery was not shown toallow use of lower insufflation pressures with-out compromising acceptable surgical condi-tions. Higher levels of intra-abdominal pressureprovide increased elevation of the anteriorabdominal wall and thus more space for surgicaldissection and an enhanced visual field [4].While not a pre-specified comparison, theresults also suggest the possibility of a larger rolefor insufflation pressure on surgical conditionscompared with that of depth of blockade. Forinstance, no patient in the standard pressuregroups required rescue intervention in the pre-sent study, whereas a total of 12 patients in the

Fig. 2 Surgeon’s assessment of overall satisfaction withsurgical conditions during surgery (estimates fromANCOVA; full analysis set)a. D difference, LSM least-squares means, NMB neuromuscular blockade. aStatisti-cally significant (P\0.05). bNominally significant (ex-ploratory objective, unadjusted P\0.05)

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low pressure groups (7 in the moderate NMBgroup and 5 in the deep NMB group) underwentrescue intervention via increase in insufflationpressure and/or level of NMB due to surgicalconditions which were deemed unacceptable bythe surgeon.

Use of deep NMB and low pressure resultedin an improvement in surgical conditionscompared with use of moderate NMB with low

pressure (the group with the worst surgicalconditions), with 1.7 points (95% CI 3.0–0.4)(Table 2). In contrast, use of deep NMB andstandard pressure resulted in an improvementin surgical conditions compared with use ofmoderate NMB with low pressure of 4.1 points(95% CI 5.4–2.8) (Table 2). Use of deep NMBwith low pressure was found to provide lessbenefit on conditions than moderate NMB with

Table 2 Surgeon’s assessment of overall satisfaction with surgical conditions (full analysis set)

n (%) ModerateNMB 1 moderatepressure(n5 31)

ModerateNMB 1 lowpressure(n5 30)

DeepNMB 1 moderatepressure (n5 31)

DeepNMB 1 lowpressure (n5 30)

Scorea

0 0 (0.0) 8 (26.7) 0 (0.0) 5 (16.7)

2 0 (0.0) 2 (6.7) 0 (0.0) 0 (0.0)

3 1 (3.3) 1 (3.3) 0 (0.0) 0 (0.0)

4 0 (0.0) 2 (6.7) 0 (0.0) 1 (3.3)

5 0 (0.0) 0 (0.0) 0 (0.0) 3 (10.0)

6 1 (3.3) 2 (6.7) 2 (6.7) 1 (3.3)

7 1 (3.3) 4 (13.3) 1 (3.3) 2 (6.7)

8 5 (16.7) 3 (10.0) 5 (16.7) 6 (20.0)

9 5 (16.7) 2 (6.7) 6 (20.0) 4 (13.3)

10 17 (56.7) 6 (20.0) 16 (53.3) 8 (26.7)

Missingb 1 0 1 0

Mean (SD) 9.03 (1.56) 5.23 (3.94) 9.10 (1.21) 6.77 (3.52)

LSM (95% CI) 8.65 (7.58, 9.72) 4.99 (3.88, 6.11) 9.09 (8.02, 10.17) 6.69 (5.57, 7.80)

Estimated difference Difference in LSM (95% CI)

Moderate NMB ? moderate pressure vs moderate NMB ? low pressure 3.66 (2.30–5.02)

Moderate NMB ? moderate pressure vs deep NMB ? moderate pressure –0.44 (–1.80 to ?0.91)

Moderate NMB ? moderate pressure vs deep NMB ? low pressure 1.96 (0.57–3.36)

Moderate NMB ? low pressure vs deep NMB ? moderate pressure –4.10 (–5.42 to –2.78)

Moderate NMB ? low pressure vs deep NMB ? low pressure –1.70 (–3.01 to –0.38)

Deep NMB ? moderate pressure vs deep NMB ? low pressure 2.41 (1.08–3.74)

LSM least-squares mean, NMB neuromuscular blockadea A score of 0 was used for patients with a rescue change in level of NMB or pressureb Not included in summary statistics for score

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standard pressure with 2.0 points (95% CI0.5–3.4) (Table 2). Therefore, the results fromthe present study indicate that deep NMB doesnot replace the need for use of appropriateinsufflation pressure with respect to surgicalconditions.

The incidence of shoulder tip pain followinglaparoscopic cholecystectomy is approximately30–50% in the literature [10, 11]. Prior to thedesign of this study, a Cochrane review [5]concluded that low insufflation pressures wereassociated with lower post-operative painscores. This in part formed the hypothesis of thecurrent study that low insufflation pressurecombined with deep NMB would result in alower incidence of patient post-operative pain.However, no significant differences in shoulderpain were observed between the groups in thepresent study.

The etiology of post-operative pain is com-plex, although diaphragmatic irritation is gen-erally considered the likely causative factor ofpost-operative shoulder tip pain, whether byconversion of CO2 to carbonic acid [12] oroverstretching of the diaphragmatic musclefibers [13]. However, stretched pain receptors inthe peritoneum can occur both due to highrates of insufflation and as a result of the sur-gical procedure itself. In addition, the stan-dardized post-operative pain regimenestablished for this protocol may have maskedpossible differences in post-operative pain levelsbetween the two groups, contributing to thelack of observed effect.

Of note, during the conduct of the presentstudy, the Cochrane report was revised,

Table 3 Surgeon’s surgical conditions assessments (full analysis set)

Assessment score after surgery Pairwise comparison

Moderate NMB Deep NMB Deep versus moderate NMB

n LSM n LSM (95% CI)a Difference in LSM (95% CI) P value

Surgical conditions 60 6.8 60 7.9 1.1 (0.1–2.0) 0.026

Visual field 60 6.9 60 7.8 0.9 (–0.1 to –1.9) 0.063

Muscle relaxation adequacy 60 8.1 60 8.9 0.8 (0.3–1.4) 0.004

Insufflation pressure adequacy 60 6.7 60 7.9 1.1 (0.3–1.9) 0.006

Number of movements interfering 60 0.9 59 0.3 –0.6 (–1.3 to ?0.1) 0.073

Disruption of surgical performance 60 9.2 60 9.9 0.7 (0.2–1.3) 0.009

LSM least-squares mean, NMB neuromuscular blockadea Based on an analysis of covariance model with factors for depth of NMB (two levels: deep, moderate), level of pressure(two levels: low, standard), body mass index and surgeon

Fig. 3 Average pain score in the first 24 h after sugam-madex administration (estimates from ANCOVA; all-pa-tients-as-treated set). LSM least-squares means, NMBneuromuscular blockade

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suggesting insufficient evidence for lower painlevels using low pressure pneumoperitoneum,which is in line with our findings in this study[6]. Therefore, it remains a challenge to inves-tigate pain protection while still maintainingadequate surgical conditions.

This was a pilot study which aimed toinvestigate the potential for a two-fold benefitfor surgeons and patients via use of a combi-nation of deep NMB and low insufflation pres-sure for endoscopic surgery. Laparoscopiccholecystectomy was chosen for this explora-tory study as it is a frequently performed pro-cedure; however, it cannot be ruled out that thegreater effects observed with insufflation pres-sure compared with NMB are at least in part dueto the insufflation pressures chosen for investi-gation. Retrospectively, 8 mmHg may havebeen too low a pressure to use in a standardsurgical population and assessment of a greaterrange of insufflation pressures may be needed toconfirm the benefit of deep neuromuscularblock for surgical conditions.

CONCLUSION

This study demonstrated that the use of sus-tained deep NMB improves surgical conditionswhen a low insufflation pressure was applied.However, deep NMB alone cannot adequatelyreplace standard insufflation pressure withrespect to surgical conditions. Further studiesutilizing a greater range of insufflation pressuresmay be warranted to ascertain any potentialbenefits of a lower pressure with respect to sur-gical conditions. The level of insufflation pres-sure did not influence the average pain scoresmeasured during 24 h post-surgery.

ACKNOWLEDGEMENTS

Sponsorship, article processing charges and theopen access fee for this study was funded by wasprovided by Merck Sharp and Dohme Corp., asubsidiary of Merck & Co., Inc., Kenilworth, NJ,USA.

Medical writing assistance was provided byMelanie More, of Prime (Knutsford, UK); this

assistance was funded by Merck Sharp andDohme Corp., a subsidiary of Merck & Co., Inc.,Merck, Kenilworth, NJ, USA.

The overall design and conduct of the study,data and opinions, conclusions and interpreta-tion of the data, are the responsibility of theauthors. All named authors meet the Interna-tional Committee of Medical Journal Editors(ICMJE) criteria for authorship for this manu-script, take responsibility for the integrity of thework as a whole, and have given final approvalfor the version to be published.

List of investigators: Walter Klimscha, MD(Donauspital, Viienna, Austria); Harald J Sparr,MD (Krankenhaus Dornbirn, Dornbirn, Aus-tria); Aki Lumme, MD (Valkeakosken alue-sairaala, Valkeakoski, Finland); Hannu Kokki,MD (Kuopion Yliopistollinen Sairaala, Kuopio,Finland); Friedrich Puehringer, MD, PhD (Aca-demic Hospital of the University of Tuebingen,Reutlingen, Germany); Urs Bergner, MD(Kreiskliniken Reutlingen GmbH, Bad Urach,Germany); Michael Moellmann, MD, PhD (St.Franziskus-Hospital, Muenster, Germany); Hin-nerk Wulf, MD, PhD (University Hospital Mar-burg, Marburg, Germany); Alexander Reich(Josephs Hospital, Warendorf, Germany); CarloOri, MD (Institute of Anesthesiology andIntensive Care, University Hospital of Padova,Padova, Italy); Martin Shields, MBBCh, BAO(Royal Victoria Hospital, Belfast, UK).

Jacob Rosenberg, Manfred Blobner, HeinFennema, Peter Grobara, Jan Mulier, NielsRahe-Meyer, Michael Li, W Joseph Herring,Armin Szegedi and Tiffany Woo were involvedin the design of the study and in interpretationof the data. Christopher Assaid was involved inthe interpretation of the data. All authors madecritical revisions to the manuscript andapproved the final version for submission.

Data from this study were presented as aposter at the Annual meeting of the AmericanSociety of Anesthesiologists, October 24–28,2015, San Diego, California.

Disclosures. Jan Mulier has been involved inconsultant activity for MSD and has receivedspeaker’s honoraria from MSD. Jacob Rosenberghas received speaker’s honoraria from Merck.Neils Rahe-Meyer has received speaker’s

934 Adv Ther (2017) 34:925–936

honoraria and board membership from Merck.Manfred Blobner has been involved in consul-tant activity and received speaker’s honorariafrom Merck. W Joseph Herring is an employeeof Merck, Kenilworth, NJ, USA, whom may ownstock options in the company. Tiffany Woo isan employee of Merck, Kenilworth, NJ, USA,whom may own stock options in the company.Christopher Assaid is an employee of Merck,Kenilworth, NJ, USA, whom may own stockoptions in the company. Armin Szegedi is astock holder and former employee of Merck,Kenilworth, NJ, USA (current affiliation: Aller-gan, Jersey City, NJ, USA). Michael Li is a formeremployee of Merck, Kenilworth, NJ, USA (cur-rent affiliation: Janssen Pharmaceuticals). PeterGrobara is a former employee of MSD, Oss, TheNetherlands. Hein Fennema is a formeremployee of MSD, Oss, The Netherlands.

Compliance with Ethics Guidelines. Thestudy was conducted in accordance with prin-ciples of Good Clinical Practice and with theHelsinki Declaration of 1964, as revised in 2013,and was approved by the appropriate institu-tional review board/ethics committees.Informed consent was obtained from allpatients for being included in the study. Thestudy is reported according to the CONSORTstatement.

Data Availability. Merck & Co., Inc.’s datasharing policy, including restrictions, is avail-able at http://engagezone.merck.com/ds_documentation.php. Requests for access to thestudy data can be submitted through theEngageZone site or via email todataaccess@merck.com.

Open Access. This article is distributedunder the terms of the Creative CommonsAttribution-NonCommercial 4.0 InternationalLicense (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommer-cial use, distribution, and reproduction in anymedium, provided you give appropriate creditto the original author(s) and the source, providea link to the Creative Commons license, andindicate if changes were made.

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