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Surgical Space Conditions During Low-Pressure Laparoscopic Cholecystectomy with Deep Versus Moderate Neuromuscular Blockade: A Randomized Clinical Study

Staehr-Rye, Anne K. MD*; Rasmussen, Lars S. MD, PhD, DMSc; Rosenberg, Jacob MD, DMSc; Juul, Poul MD§; Lindekaer, Astrid L. MD; Riber, Claus MD§; Gätke, Mona R. MD, PhD*

doi: 10.1213/ANE.0000000000000316
Ambulatory Anesthesiology: Research Report
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BACKGROUND: Laparoscopic cholecystectomy performed during low intraabdominal pressure (<12 mm Hg) is associated with significantly less postoperative pain than standard pressure (≥12 mm Hg). The impact on surgical space conditions and safety of operating at lower pressures has not been adequately described, but deep neuromuscular blockade may be beneficial. We investigated if deep muscle relaxation would be associated with a higher proportion of procedures with “optimal” surgical space conditions compared with moderate relaxation during low-pressure (8 mm Hg) laparoscopic cholecystectomy.

METHODS: In this assessor-blinded study, 48 patients undergoing elective laparoscopic cholecystectomy were administered rocuronium for neuromuscular blockade and randomized to either deep neuromuscular blockade (rocuronium bolus plus infusion maintaining a posttetanic count 0–1) or moderate neuromuscular blockade (rocuronium repeat bolus only for inadequate surgical conditions with spontaneous recovery of neuromuscular function). Patients received anesthesia with propofol, remifentanil, and rocuronium. The primary outcome was the proportion of procedures with optimal surgical space conditions (assessed by the surgeon as 1 on a 4-point scale). Secondary outcomes included the proportion of procedures completed at pneumoperitoneum 8 mm Hg and surgical space conditions on dissection of the gallbladder (numeric rating scale 0–100; 0 = optimal surgical space conditions; 100 = unacceptable surgical space conditions).

RESULTS: Optimal surgical space conditions during the entire procedure were observed in 7 of 25 patients allocated to deep neuromuscular blockade and in 1 of 23 patients allocated to moderate blockade (P = 0.05) with an absolute difference of 24% between the groups (95% confidence interval, 4%–43%). Laparoscopic cholecystectomy was completed at pneumoperitoneum 8 mm Hg in 15 of 25 and 8 of 23 patients in the deep and moderate group, respectively (95% confidence interval, −2% to 53%; P = 0.08). Surgical space conditions during dissection of the gallbladder assessed by use of the numeric rating scale were 20 (10–50) (median [25%–75% range]) in the deep neuromuscular blockade group and 30 (10–50) in the moderate group (P = 0.58; Wilcoxon-Mann-Whitney odds, 1.2; 95% confidence interval, 0.6–2.5). No operations were converted to laparotomy.

CONCLUSIONS: Deep neuromuscular blockade was associated with surgical space conditions that were marginally better than with moderate muscle relaxation during low-pressure laparoscopic cholecystectomy.

Published ahead of print June 23, 2014.

From the *Department of Anesthesiology, University of Copenhagen, Herlev Hospital, Herlev; Department of Anesthesia, Centre of Head and Orthopedics, University of Copenhagen, Rigshospitalet, Copenhagen; Department of Surgery, University of Copenhagen, Herlev Hospital, Herlev; and Departments of §Surgery and Anesthesia, Aleris-Hamlet Hospital, Soeborg, Denmark.

Published ahead of print June 23, 2014.

Accepted for publication April 21, 2014.

Funding: Supported by the University of Copenhagen, Denmark (to AKS-R), The Sophus Johansens Foundation of 1981, Copenhagen, Denmark (to AKS-R), Tryg Foundation, Lyngby, Denmark (to LSR), and The Lippmann Foundation, Copenhagen, Denmark (to AKS-R). This work was also supported in part by a research grant from the Investigator Initiated Studies Program of Merck Sharp & Dohme Corp (to MRG). The opinions expressed in this paper are those of the authors and do not necessarily represent those of Merck Sharp & Dohme Corp.

Conflict of Interest: See Disclosures at the end of the article.

Reprints will not be available from the authors.

Address correspondence to Anne K. Staehr-Rye, MD, Department of Anesthesiology, University of Copenhagen, Herlev Hospital, Herlev Ringvej 75, Herlev DK-2730, Denmark. Address e-mail to akstaehr1@hotmail.com.

The number of laparoscopic procedures is increasing with laparoscopic cholecystectomy being one of the most common procedures. Laparoscopic cholecystectomy is normally performed with an intraabdominal pressure of 12 to 15 mm Hg, but a pneumoperitoneum <12 to 15 mm Hg is associated with less postoperative pain1 and fewer adverse effects on pulmonary function2 and hemodynamics.3 However, the impact of decreasing the intraabdominal pressure on surgical space conditions and safety has not been well established.

Neuromuscular blocking drugs are used during laparoscopic surgery to improve surgical exposure. The degree of neuromuscular blockade is measured at the adductor pollicis muscle.4 However, this muscle may show no response to train-of-four (TOF) stimulation, while the diaphragm and muscles in the abdominal wall have partly recovered from the neuromuscular blockade,5–7 resulting in inadequate abdominal muscle relaxation during abdominal surgery. With the establishment of deep, continuous neuromuscular blockade, defined as a posttetanic count (PTC) of 0 to 1, all muscles will be paralyzed.8 This may optimize surgical space conditions during low-pressure laparoscopic cholecystectomy.

To the authors’ knowledge, no published studies have investigated the impact of muscle relaxation on surgical conditions during low-pressure laparoscopic surgery, and only few have investigated this aspect during standard-pressure laparoscopic surgery.9–14 One study reported a difference in the proportion of adequate pneumoperitoneum between muscle relaxation (100%) and no muscle relaxation (72%) in 40 patients undergoing gynecological laparoscopic surgery, but the degree of neuromuscular blockade was not described.14

We designed this study to assess the effect of deep, continuous neuromuscular blockade on surgical space conditions during low-pressure laparoscopic cholecystectomy. We hypothesized that deep, continuous neuromuscular blockade compared to moderate blockade was associated with a higher proportion of procedures with “optimal” surgical space conditions as assessed by the surgeon.

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METHODS

This investigator-initiated, randomized, assessor-blinded study was approved by the Danish Medicines Agency and the Regional Ethics Committee. The study (NCT01523886) was registered at ClinicalTrials.gov (January 19, 2013) before enrollment of the first patient. Written informed consent was obtained from all patients. Eligible patients were ≥18 years of age and scheduled for elective laparoscopic cholecystectomy. Women had to be postmenopausal, surgically sterilized, or use reliable birth control. Exclusion criteria were allergy to rocuronium or sugammadex, indication for rapid sequence induction, pregnancy or breastfeeding, known neuromuscular disorders that might impair neuromuscular blockade, and significant liver or renal dysfunction. Female patients, who were not postmenopausal or surgically sterilized, had to provide a negative urine pregnancy test within 24 hours before surgery.

Included patients were randomized immediately before arrival in the operating room by a computer randomization system to ensure adequate allocation concealment. The computer-generated randomization sequence allocated patients to either deep, continuous neuromuscular blockade or moderate neuromuscular blockade with stratification for body mass index (<30 vs ≥30 kg/m2).

A standardized protocol emphasized optimal perioperative care15 including ventilatory strategy, fluid therapy, antibiotics, adequate temperature control as well as administration of analgesics and antiemetics. Anesthesia was induced with propofol 2 mg/kg and remifentanil 0.5 μg/kg/min IV. Anesthesia was maintained with IV infusion of propofol and remifentanil and adjusted under guidance of entropy (Entropy Sensor, GE Healthcare, Hillerød, Denmark) and arterial blood pressure.

Neuromuscular monitoring was performed with acceleromyography (TOF-Watch SX®, MSD, Ballerup, Denmark) connected to a computer using the software TOF-Watch SX (version 2.5 INT 2007, Organon, Oss, The Netherlands) in accordance with “Good Clinical Research Practice in Pharmacodynamic Studies of Neuromuscular Blocking Agents II.”4 The study arm was immobilized and a preload was placed on the thumb for monitoring acceleration (Hand Adapter®, MSD).

After calibration and stabilization of the TOF-Watch, tracheal intubation was facilitated with rocuronium 0.3 mg/kg IV in both groups, which is the standard practice at the institution. Moreover, in patients allocated to deep muscle relaxation, an IV bolus of rocuronium (0.7 mg/kg) was given 2 minutes after the first dose, which was immediately before tracheal intubation. An IV infusion with rocuronium (3–4 mg/kg/h) was started when the PTC was >0, with titration toward PTC 0 to 1. PTC was measured every 3 to 4 minutes. In patients allocated to the moderate blockade group, no additional rocuronium was given immediately before intubation, but a similar volume of saline was given, and an infusion of saline 0.9% (0.3 mL/kg/h) was started approximately 20 to 30 minutes later. PTC was measured every 3 to 4 minutes, and TOF measurement was made every 15 seconds. In the moderate blockade group, no further rocuronium was administered unless as per protocol (see below) surgical space conditions were assessed as inadequate at 12 mm Hg. Neuromuscular function was therefore allowed to recover spontaneously.

Pneumoperitoneum was obtained with insufflation of CO2 through a Veress needle to 12 mm Hg, but reduced to 8 mm Hg after the introduction of the 4 trocars. After insufflation, patients were positioned in 20° reverse Trendelenburg verified by angle measurement.

All laparoscopies were performed by 1 of 2 experienced surgeons, and they were asked to evaluate surgical space conditions with modification of a 4-point scale previously used by others9,14,16,17: grade 1 (optimal) = optimal surgical space conditions; grade 2 (good) = nonoptimal conditions, but an intervention was not considered; grade 3 (acceptable) = an intervention was considered to improve surgical space; grade 4 (poor) = inadequate conditions and an intervention was necessary to ensure acceptable surgical space. They also rated surgical space conditions on a numeric rating scale (NRS), where NRS 0 indicated optimal surgical space conditions and NRS 100 indicated unacceptable surgical space conditions and an intervention was needed to secure acceptable surgical space. The assessments were made during dissection of the gallbladder and at the end of the surgery, based on overall space conditions as well as the time during surgery, when surgical space conditions were determined as worst.

In case of inadequate surgical space conditions, the following 3-step intervention procedure was used in both groups:

  1. Increase of preset intraabdominal pressure to 12 mm Hg.
  2. If still inadequate, patients allocated to moderate muscle relaxation were given a bolus of rocuronium (0.6 mg/kg) IV. Patients allocated to deep muscle relaxation were given an equivalent volume of 0.9% NaCl.
  3. If still not adequate, the surgeon would decide according to usual clinical practice.

If any of the above-mentioned interventions were required, surgical space conditions were automatically rated as 4 (4-point scale) and 100 (NRS) in the assessment, based on the time of surgery when surgical space conditions were determined as worst.

Sugammadex 2 to 8 mg/kg IV was given at the end of surgery, if the TOF ratio was <0.90.15 Endotracheal extubation was only performed when the patients were fully awake and had a stable T1 response between 80% and 120%, a TOF ratio ≥0.90 and a variation of the T1 response ≤5% for 2 minutes.

At the end of the surgery, the surgeon was asked if any surgical difficulties had occurred. Moreover, the patients’ charts were reviewed to assess whether macroscopic cholecystitis, adhesions, or any other surgical difficulties had been described.

The primary outcome was the proportion of procedures with optimal surgical space conditions during the entire procedure (assessed as 1 on the 4-point scale based on the time of surgery, when surgical space conditions were determined as worst). The secondary outcomes were surgical space conditions based on the time of surgery, when surgical space conditions were determined as worst (NRS), on dissection of the gallbladder (4-point scale and NRS) and overall surgical space conditions as an average of the entire procedure (4-point scale and NRS), proportion of laparoscopies performed with an intraabdominal pressure of 8 mm Hg, and duration of surgery and anesthesia. Other outcomes were pain expressed as the area under the curve from the first postoperative assessment to 1 week after surgery, pain at arrival in the postoperative care unit, 2 hours after surgery and 1 day after surgery, postoperative consumption of analgesics, antiemetics, and incidence of postoperative nausea and/or vomiting up to 24 hours after surgery, and number of days after surgery before resumption of normal activity.

Before surgery, all included patients were carefully instructed by the same investigator in use of a visual analog scale (VAS). Pain was evaluated as abdominal pain, incisional pain, shoulder pain, and overall pain using VAS (VAS 0 = no pain, 100 = worst possible pain). Each assessment was done at rest and during mobilization. Patients were discharged on the day of surgery. A questionnaire was given to the patients to be completed every morning after discharge from hospital and until they experienced no pain. The same investigator contacted the patient on the first postoperative day and again 1 week after surgery to ensure that postoperative pain assessment was made and to assess any discomfort. Any adverse event or reaction developed within the first 21 postoperative days was recorded. An adverse event or reaction was considered serious if it was fatal, life threatening, caused permanent disability, or required prolonged hospitalization.

The surgeons, surgical staff, patients, personnel in the postoperative care unit as well as the investigator collecting postoperative data were blinded to group allocation. In a separate room, syringes containing rocuronium, sugammadex, and NaCl were prepared. The patient’s hand with the neuromuscular monitoring equipment and the connecting neuromuscular monitor were covered to keep the surgical team blinded to group allocation. However, the investigator who gave rocuronium was able to follow the level of neuromuscular blockade via a connected computer using the software TOF-Watch SX (version 2.5 INT 2007, Organon). Information about group allocation, administered doses of rocuronium and sugammadex, and neuromuscular data were recorded on a separate form and placed in a sealed opaque envelope when the patient left the operating room. After the end of surgery, the surgeon was asked which group he/she believed the patient was allocated to and to indicate why. The patient was asked the same questions on postoperative day 7.

The study was monitored by an independent inspector from the department of Good Clinical Practice, Bispebjerg, Denmark and conducted according to the International Conference on Harmonization/Good Clinical Practice guidelines.

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Statistical Analysis

All outcomes were reported with median (interquartile range) or number (%) and compared with the Mann-Whitney U test, the χ2 test, or the Fisher exact test. The Wilcoxon-Mann-Whitney odds and 95% confidence intervals were calculated for the continuous outcomes.18,19 A P value of <0.05 was considered statistically significant. Analyses were performed using SAS statistical software version 9.2 (SAS Institute Inc., Cary, NC).

A difference in the proportion of adequate pneumoperitoneum of 28% was previously found between no muscle relaxation (72%) and muscle relaxation (100%) in laparoscopic surgery.14 We calculated that a sample size of 48 patients would allow us to detect a clinically relevant difference of 28% in the proportion of optimal surgical space conditions during the entire procedure with a power of 80% and a type 1 error risk of 5%.

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RESULTS

Forty-eight patients were included and received the intervention (Fig. 1). Demographic and perioperative characteristics were similar in the 2 groups (Table 1, Fig. 2).

Figure 1

Figure 1

Table 1

Table 1

Figure 2

Figure 2

The intended depth of neuromuscular blockade was achieved during 91% (median; range, 70%–100%) of the procedure from surgical incision to administration of sugammadex in the deep group (PTC, 0–1). In the moderate group, a TOF count ≥2 was present during 87% (median; range, 67%–100%) of the procedure. Neuromuscular data are shown in Table 2.

Table 2

Table 2

Optimal surgical space conditions during the entire procedure were found in 7 of 25 (28%) patients allocated to deep blockade and in 1 of 23 (4%) patients allocated to moderate blockade (P = 0.05) with an absolute difference of 24% between the groups (95% confidence interval, 0.04–0.43; Table 3).

Table 3

Table 3

Laparoscopic cholecystectomy was completed at pneumoperitoneum 8 mm Hg in 15 (60%) patients in the deep group compared with 8 (35%) patients in the moderate group, respectively (95% confidence interval, −0.02 to 0.53; P = 0.08). Twenty-five patients had pneumoperitoneum increased to 12 mm Hg due to inadequate surgical space conditions. PTC was 0 to 1 in 7 of 8 (88%) of the patients in the deep group when the pneumoperitoneum was increased and TOF count was ≥2 in 12 of 13 (92%) of the patients in the moderate group when the pressure was increased. Data were missing in 4 patients. In the moderate group, 3 patients coughed during the recruitment maneuvers at the end of surgery, but no other signs of poor relaxation were seen. The median duration of anesthesia and postoperative hospitalization was 60 and 230 minutes in patients in the deep group and 58 and 236 minutes in the moderate group (P = 0.77 and P = 0.60).

We conducted correlation analyses to assess concurrent validity of the 4-point scale and the NRS (Table 4). A logistic regression analysis showed that none of the following factors was predictive of inferior surgical space conditions based on the time during surgery, when surgical space conditions were determined as worst: male, age >60 years, previous intraabdominal surgery and cholecystitis (Table 5).

Table 4

Table 4

Table 5

Table 5

Forty-three of 48 patients had returned the questionnaire by postoperative day 21. There were no significant differences in postoperative pain between the 2 groups. The median consumption of oxycodone within 24 hours postoperatively was 20 mg in both groups. The median number of days after surgery before resumption of normal activity was 6 and 5 days in the deep and moderate group, respectively (P = 0.29). There were no significant differences in postoperative nausea, vomiting, or administered ondansetron within 24 hours postoperatively.

There were no major anesthetic or surgical intraoperative complications, and no procedure was converted to open surgery. Overall, 48% of the patients experienced an adverse event in the follow-up period. Serious adverse events were seen in 4 patients: prolonged hospitalization due to postoperative observation (2 patients) and readmission to hospital because of pain from undiagnosed gallstones in the common bile duct (2 patients). There were no reported adverse reactions or serious adverse reactions considered related to rocuronium or sugammadex by the investigators.

The surgeons correctly identified 20 of 48 patients’ allocation and 12 of the 48 patients correctly identified their allocation. There were no indications of unblinding in their answers.

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DISCUSSION

Deep, continuous neuromuscular blockade was associated with surgical space conditions that were marginally better than with moderate muscle relaxation during low-pressure laparoscopic cholecystectomy. There tended to be more procedures completed at 8 mm Hg in the deep muscle relaxation group than in the moderate group.

Forty-eight percent of laparoscopies were successfully completed at 8 mm Hg, which is less than the success rates of approximately 70% to 100% previously reported in studies comparing pain after low- and standard-pressure laparoscopic cholecystectomy.20–23 However, in the present study, the proportion of patients having acute or chronic inflammation of the gallbladder was relatively high (50%) compared with previous studies (18%),20 which may explain the need for better exposure. The lower completion rate at 8 mm Hg in our study may also have been caused by a less restrictive inclusion of patients. Some of the previous studies only included patients with uncomplicated symptomatic gallstones and excluded patients with previous upper abdominal surgery.20,21 Also, the level of neuromuscular blockade was not described uniformly in the previous studies. Other influential factors could have been administration of total IV anesthesia instead of inhaled anesthesia, blinding of the surgeons, and other surgical difficulties experienced intraoperatively including adhesions and increased amount of intraabdominal fat. Moreover, the surgeons in our study were not familiar with low-pressure laparoscopic surgery before beginning the study. However, we found no significant difference between the first 24 and the last 24 procedures or between the 2 surgeons with respect to successfully completed procedures at low-pressure pneumoperitoneum.

Many factors contribute to pain after laparoscopic cholecystectomy with pain coming from the incision sites, the dissected viscera, and from the pneumoperitoneum. The exact mechanism of pain related to pneumoperitoneum has not been clarified. Low-pressure pneumoperitoneum has been associated with significantly less postoperative pain,1,20,21,24 including shoulder tip pain.20,22,24,25 We found no difference in postoperative pain characteristics or incidence of postoperative nausea or vomiting between patients, who had received a deep or a moderate neuromuscular blockade during laparoscopic cholecystectomy, but the results may have been impacted by the need to increase the intraabdominal pressure when exposure was inadequate.

Neuromuscular blockade is often used during laparoscopic surgery to improve surgical space conditions, but only few studies have focused on defining optimal or necessary muscle relaxation in the context of abdominal surgical space conditions. To our knowledge, only 7 studies have described the association between neuromuscular blockade and surgical conditions during laparoscopic surgery,9–14,26 and only 3 reported the actual degree of muscle relaxation.9,13,26 Traditionally, a TOF count of the adductor pollicis muscle between 1 and 2 has been associated with adequate surgical relaxation.27 However, the clinical situation in which abdominal muscle and diaphragmatic relaxation seems inadequate despite minimal response of the adductor pollicis to ulnar nerve stimulation is frequently encountered. This may primarily be explained by the effects of neuromuscular blocking drugs being muscle dependent6; the diaphragm shows a lower peak effect5,7,28 and a more rapid recovery5,7,28–31 of a given dose of a neuromuscular blocking drug than the adductor pollicis muscle. The lateral abdominal muscles have a time course somewhere between the diaphragm and the adductor pollicis regarding sensitivity and time to recovery.7 Therefore, there may be no response of the adductor pollicis muscle to TOF stimulation, while the diaphragm and the muscles in the abdominal wall have recovered partly from the neuromuscular blockade. To ensure total paralysis of the diaphragm, the neuromuscular blockade measured at the adductor pollicis muscle should be intense, that is, PTC = 0. The results of our study indicate that deep, continuous muscle relaxation optimizes the surgical space conditions compared with moderate muscle relaxation during low-pressure laparoscopic cholecystectomy, although it is not effective in all patients. Thus, 60% of patients in the deep group had optimal to acceptable conditions compared with 35% in the moderate group.

To evaluate surgical space conditions, we used the 4-point scale as well as a NRS. It is, however, a limitation that these scales have not been validated for assessment of surgical space conditions. The correlation analyses indicated concurrent validity of the 4-point scale and the NRS, even though the evaluation of surgical space conditions could be influenced by other factors. There were more patients with cholecystitis and of male gender in the deep relaxation group, which together with previous upper abdominal surgery, advanced age (>60 years), and higher body weight (>65 kg) has been associated with increased risk of converting laparoscopic cholecystectomy to open surgery.32,33 However, a logistic regression analysis showed no significant impact of sex, cholecystitis, previous abdominal surgery, or age on the primary outcome. All patients received a small dose of rocuronium (0.3 mg/kg) to facilitate tracheal intubation. This was the only dose given to the moderate group, because it is the standard regime for laparoscopic cholecystectomy at the institution. Completely omitting giving rocuronium to patients in the control group could have allowed a better separation regarding surgical space conditions but could also have impaired tracheal intubation conditions. Most importantly, there was a clear separation in the degree of neuromuscular blockade between the 2 groups during dissection of the gallbladder as well as in the situations where the pneumoperitoneum was increased.

We assessed the effect of deep, continuous muscle relaxation compared with moderate neuromuscular blockade on abdominal surgical space conditions during low-pressure laparoscopic cholecystectomy, for which surgical conditions and safety have not been adequately described. All laparoscopies were performed by only 2 surgeons, each with >10 years of surgical experience and >1000 performed laparoscopic cholecystectomies, which reduces the variability in assessment of surgical space conditions. Two experts conducted neuromuscular monitoring in accordance with “Good Clinical Research Practice in Pharmacodynamic Studies of Neuromuscular Blocking Agents II.”4 All patients scheduled for laparoscopic cholecystectomy during the study period were consecutively evaluated for fulfillment of inclusion and exclusion criteria regardless of age, gender, or body mass index. All randomized, evaluable patients had a thorough follow-up with assessment of adverse intra- and postoperative events. We therefore believe that the results of this study are applicable to a general surgical population undergoing low-pressure laparoscopic cholecystectomy performed by experienced surgeons; however, the results may not be generalizable to standard-pressure laparoscopic cholecystectomy, other laparoscopic procedures, or other types of anesthesia.

In conclusion, we found that the proportion of optimal surgical space conditions with deep neuromuscular blockade was marginally greater than with moderate muscle relaxation during low-pressure laparoscopic cholecystectomy. However, intraabdominal pressure was increased from 8 to 12 mm Hg in approximately half of the procedures to secure acceptable surgical space conditions.

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DISCLOSURES

Name: Anne K. Staehr-Rye, MD.

Contribution: This author helped in study design, patient recruitment, data collection, data analysis, and writing of the first draft of the manuscript.

Attestation: Anne K. Staehr-Rye approved the final manuscript and is the archival author.

Conflicts of Interest: The author has no conflicts of interest to declare.

Name: Lars S. Rasmussen, MD, PhD, DMSc.

Contribution: This author helped in study design, data analysis, and critical revision.

Attestation: Lars S. Rasmussen approved the final manuscript.

Conflicts of Interest: Spouse has received payments and travel funding for lectures from MSD. Total funding was approximately €8700. Spouse has received investigator-initiated research funding of €93,800 from MSD.

Name: Jacob Rosenberg, MD, DMSc.

Contribution: This author helped in study design, data analysis, and critical revision.

Attestation: Jacob Rosenberg approved the final manuscript.

Conflicts of Interest: Jacob Rosenberg has been a member of the advisory board in MSD.

Name: Poul Juul, MD.

Contribution: This author helped in study design, patient recruitment, data collection, and critical revision.

Attestation: Poul Juul approved the final manuscript.

Conflicts of Interest: The author has no conflicts of interest to declare.

Name: Astrid L. Lindekaer, MD.

Contribution: This author helped in study design, data collection, and critical revision.

Attestation: Astrid L. Lindekaer approved the final manuscript.

Conflicts of Interest: The author has no conflicts of interest to declare.

Name: Claus Riber, MD.

Contribution: This author helped in patient recruitment, data collection, and critical revision.

Attestation: Claus Riber approved the final manuscript.

Conflicts of Interest: The author has no conflicts of interest to declare.

Name: Mona R. Gätke, MD, PhD.

Contribution: This author helped in study design, data collection, data analysis, and critical revision.

Attestation: Mona R. Gätke approved the final manuscript.

Conflicts of Interest: Mona R. Gätke has received payments and travel funding for lectures from MSD. Total funding was approximately €8700. Mona R. Gätke has received investigator-initiated research funding of €93,800 from MSD.

This manuscript was handled by: Peter S. A. Glass, MB, ChB.

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