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Postoperative shoulder pain after laparoscopic hysterectomy with deep neuromuscular blockade and low-pressure pneumoperitoneum: A randomised controlled trial

Madsen, Matias V.; Istre, Olav; Staehr-Rye, Anne K.; Springborg, Henrik H.; Rosenberg, Jacob; Lund, Jørgen; Gätke, Mona R.

European Journal of Anaesthesiology: May 2016 - Volume 33 - Issue 5 - p 341–347
doi: 10.1097/EJA.0000000000000360

BACKGROUND Postoperative shoulder pain remains a significant problem after laparoscopy. Pneumoperitoneum with insufflation of carbon dioxide (CO2) is thought to be the most important cause. Reduction of pneumoperitoneum pressure may, however, compromise surgical visualisation. Recent studies indicate that the use of deep neuromuscular blockade (NMB) improves surgical conditions during a low-pressure pneumoperitoneum (8 mmHg).

OBJECTIVE The aim of this study was to investigate whether low-pressure pneumoperitoneum (8 mmHg) and deep NMB (posttetanic count 0 to 1) compared with standard-pressure pneumoperitoneum (12 mmHg) and moderate NMB (single bolus of rocuronium 0.3 mg kg−1 with spontaneous recovery) would reduce the incidence of shoulder pain and improve recovery after laparoscopic hysterectomy.

DESIGN A randomised, controlled, double-blinded study.

SETTING Private hospital in Denmark.

PARTICIPANTS Ninety-nine patients.

INTERVENTIONS Randomisation to either deep NMB and 8 mmHg pneumoperitoneum (Group 8-Deep) or moderate NMB and 12 mmHg pneumoperitoneum (Group 12-Mod). Pain was assessed on a visual analogue scale (VAS) for 14 postoperative days.

MAIN OUTCOME MEASURES The primary endpoint was the incidence of shoulder pain during 14 postoperative days. Secondary endpoints included area under curve VAS scores for shoulder, abdominal, incisional and overall pain during 4 and 14 postoperative days; opioid consumption; incidence of nausea and vomiting; antiemetic consumption; time to recovery of activities of daily living; length of hospital stay; and duration of surgery.

RESULTS Shoulder pain occurred in 14 of 49 patients (28.6%) in Group 8-Deep compared with 30 of 50 (60%) patients in Group 12-Mod. Absolute risk reduction was 0.31 (95% confidence interval 0.12 to 0.48; P = 0.002). There were no differences in any secondary endpoints including area under the curve for VAS scores.

CONCLUSION Deep NMB and low-pressure pneumoperitoneum (8 mmHg) reduced the incidence of shoulder pain after laparoscopic hysterectomy in comparison to moderate NMB and standard-pressure pneumoperitoneum (12 mmHg).

TRIAL REGISTRATION identifier: NCT01722097.

From the Department of Anaesthesiology, Herlev Hospital, University of Copenhagen, Herlev, Denmark (MVM, AKS-R, MRG), Department of Anaesthesiology and Center for Minimal Invasive Gynaecology, Aleris-Hamlet Hospitals Copenhagen, Søborg, Denmark (OI, HHS, JL), and Department of Surgery, Herlev Hospital, University of Copenhagen, Herlev, Denmark (JR)

Correspondence to Matias V. Madsen, MD, Department of Anaesthesiology, Herlev Hospital, University of Copenhagen, Herlev Ringvej 75, DK 2730 Herlev, Denmark Tel: +45 38 68 90 58; fax: +45 38 68 37 24; e-mail:

Published online 3 March 2016

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Laparoscopy is used in a large variety of surgical interventions and has certain benefits compared with laparotomy such as smaller incisions with less pain, earlier mobilisation and shorter hospitalisation.1,2 Patients still experience pain after laparoscopic surgery, however, with shoulder pain as a predominant problem after certain procedures. For instance, up to 70% of patients reported shoulder pain 24 h after laparoscopic gynaecological surgery.3

In laparoscopic surgery, the abdomen is insufflated with carbon dioxide (CO2) until the pneumoperitoneum pressure reaches 12 to 15 mmHg in order obtain optimal surgical visualisation.4 However, it is speculated that the pneumoperitoneum is an important cause of shoulder pain. A review suggested that the most effective intervention for reducing the incidence of shoulder pain was to lower the insufflation pressure.5 This lowering in the pressure of the pneumoperitoneum may, however, worsen the surgical view inside the abdomen and thereby increase the risk of complications and conversion to open surgery.6 As a result, laparoscopy with a low-pressure pneumoperitoneum has not been established as a routine practice.

To improve surgical conditions, neuromuscular blockade (NMB) is often used. A recent systematic review has reported the benefits of NMB on surgical conditions during laparoscopic surgery.7 NMB, however, is used variably in daily clinical practice and rarely at a deep level. In some cases, a neuromuscular blocking agent (NMBA) is administered only for facilitating tracheal intubation, while in others, a bolus dose is given as requested by the surgeon.8 In these situations, however, the NMB of the abdominal muscles and the diaphragm may be incomplete,9,10 which means that the abdominal wall may feel ‘tight’ during surgery, even though the objectively measured train-of-four (TOF) counts are less than 3 to 4. With establishment of a deep, continuous NMB, quantified on the nerve stimulator with posttetanic count (PTC) values 0 to 1, all muscles including abdominal muscles and diaphragm are paralysed.11

Results from a recent study indicate that the use of deep NMB improved surgical conditions during a low-pressure pneumoperitoneum of 8 mmHg.12 Whether low-pressure pneumoperitoneum (8 mmHg) in combination with deep NMB improves patient outcome parameters after laparoscopic hysterectomy without compromising the surgical view has yet to be investigated.

We hypothesised that deep, continuous NMB (PTC 0 to 1) and low-pressure pneumoperitoneum (8 mmHg) would reduce the incidence of shoulder pain after laparoscopic hysterectomy compared with moderate NMB (single bolus of rocuronium 0.3 mg kg−1 with spontaneous recovery) and standard-pressure pneumoperitoneum (12 mmHg).

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Materials and methods

The Danish Medicines Agency and the Regional Ethics Committee of the Capital Region of Denmark approved this randomised, double-blinded, investigator--initiated study on 22 October 2012 (Chairperson S.F. Thomsen), which was assigned with EudraCT number 2012-003787-51 and registered at (NCT01722097) prior to inclusion of the first patient. Patients included in the study also participated in another trial ‘Importance of deep neuromuscular blockade in laparoscopic surgery’ bearing the same registration number (NCT01722097). Data are presented in accordance with the CONSORT statement. The study was conducted according to Good Clinical Research Practice (GCRP) guidelines13 and monitored by an independent inspector from the Department of Good Clinical Practice, Bispebjerg Hospital, Denmark.

The study was carried out between November 2012 and June 2014 at the Center for Minimal Invasive Gynaecology, Aleris-Hamlet Hospitals, Copenhagen, Denmark. Written informed consent was obtained from all participants. Patients aged more than 18 years scheduled for total or subtotal laparoscopic hysterectomy were eligible. Exclusion criteria were BMI more than 30 kg m−2, known allergy to medications that were included in the project, severe renal disease (defined by glomerular filtration rate <30 ml min−1 or need for haemodialysis), impaired liver function, neuromuscular disease that could interfere with neuromuscular data, lactating women, indication for rapid sequence induction and daily use of opioids within the 7 days prior to surgery.

An investigator using a computer-generated code performed the randomisation; this was done immediately before arrival in the operating room to ensure adequate concealment of allocation. Group allocation was noted on a special sheet that was kept in an opaque envelope. This envelope was subsequently archived in a locked closet to which only the anaesthetic investigator had access. Patients were randomised to either deep NMB and 8 mmHg pneumoperitoneum (Group 8-Deep) or moderate NMB and 12 mmHg pneumoperitoneum (Group 12-Mod) with stratification for type of hysterectomy (total or subtotal).

The patients received paracetamol 1000 mg, etodoloc 300 mg, gabapentin 600 mg and dexamethasone 8 mg as oral (p.o.) premedication. Anaesthesia was induced with propofol 2 mg kg−1 and remifentanil 0.5 μg kg−1 min−1 and maintained with propofol 3 mg kg−1 h−1 and remifentanil 0.25 to 0.5 μg kg−1 min−1 adjusted under the guidance of arterial blood pressure and an entropy target of 30 to 50 (Entropy Sensor; GE Healthcare, Hillerød, Denmark). During induction, patients received 100% oxygen. After tracheal intubation, patients received 40% oxygen and the lungs were ventilated using pressure control ventilation [tidal volume 7 ml kg−1, positive end-expiratory pressure (PEEP) 5 cmH2O, respiratory frequency of 10 to 12 min−1], aiming for an end-tidal CO2 between 4.5 and 5.5 kPa.

Neuromuscular monitoring followed GCRP guidelines for pharmacodynamic neuromuscular studies.14 The skin was cleaned with alcohol and rubbed with a piece of gauze and small surface electrodes were placed over the right ulnar nerve near the wrist with a distance of 3 to 6 cm. Forearm and ulnar fingers were immobilised and the acceleration transducer was placed on the thumb using a Hand Adapter (MSD, Ballerup, Denmark). Response to ulnar nerve stimulation was recorded with a TOF-Watch SX (MSD) and data were collected on a computer using the TOF-Watch SX monitor programme (version 2.5 INT 2007; Organon, Oss, The Netherlands). Intravenous (i.v.) cannulae were placed in the opposite arm. Once the patient was anaesthetised, a 50 Hz tetanic stimulus was applied for 5 s, and after baseline stabilisation (<5% variation for at least 2 min), supramaximal stimulation and calibration was ensured using the calibration function (CAL 2). Tracheal intubation was performed 2 min after administration of 0.3 mg kg−1 rocuronium in both groups. In Group 8-Deep, a bolus of 0.7 mg kg−1 rocuronium was administered just after tracheal intubation and then an infusion of rocuronium (0.3 to 0.4 mg kg−1 h−1) was started when PTC was more than 0 and titrated towards PTC 0 to 1. In Group 12-Mod, no additional rocuronium was administered after tracheal intubation, but instead a similar volume of saline 0.9% was given and an infusion of 0.9% saline (0.3 ml kg−1 h−1) was started after 20 to 30 min and the neuromuscular function was allowed to recover spontaneously. PTC was measured every 3 to 4 min and TOF measurements every 15 s. The investigator managed the insufflator and set the insufflation pressure. The infusions were stopped when suturing of the fascia began.

After introduction of the Veress needle, the abdomen was insufflated to either 8 or 12 mmHg pneumoperitoneum according to allocation. Subsequently, trocars were introduced and the patients were placed in the lithotomy position in 30° Trendelenburg position verified by angle measurement. In patients scheduled for total hysterectomy, the uterus was removed vaginally and the vagina was sutured with laparoscopic instruments. In patients scheduled for subtotal hysterectomy, uterine morcellation was performed and the pieces were removed through the umbilicus. The uterus was removed with the use of bipolar and ultrasound energy sources. The same two gynaecologists performed all the operations.

In cases of poor surgical view, the protocol allowed for increasing the pneumoperitoneum to 12 mmHg in combination with a bolus of 0.9% saline in patients allocated to Group 8-Deep. In Group 12-Mod, the protocol allowed a placebo increase in the pressure of the pneumoperitoneum (the investigator pretended to increase the insufflator pressure) in combination with 0.6 mg kg−1 bolus of rocuronium. If none of these interventions improved the surgical view, the gynaecologists could decide any intervention according to their clinical practice.

Fifteen minutes before termination of anaesthesia, patients received sufentanil 0.2 μg kg−1 and ondansetron 4 mg i.v. At the end of surgery, pulmonary recruitment was performed by five manual pulmonary inflations and together with gentle manual abdominal pressure helped to remove the insufflated CO2 through the trocars. After suturing, the incisions were infiltrated with 20 ml bupivacaine 0.5% with adrenaline. The NMB was then reversed using either 0.9% saline (placebo) or sugammadex in recommended doses if the TOF ratio was less than 0.90. When the patients had a stable TOF ratio of more than 0.9 for 2 min and were fully awake, tracheal extubation was performed.

Blinding of the gynaecologists to the level of NMB and pneumoperitoneum pressure was ensured by turning the insufflator away from the operating field and covering the display with a blanket. Moreover, the hand with the neuromuscular monitoring equipment was covered under the sterile drapes and the nerve stimulator and computer were placed behind the sterile drapes away from the gynaecologists. All study medicines were prepared by the investigator in the operating room before the gynaecologists entered and labelled ‘study medicine’. Postanaesthetic care nurses and the investigator assessing pain postoperatively were blinded to group allocation. The attending anaesthetic staff, the investigator in the operating room and the operating nurses were not blinded.

Postoperatively patients received oxycodone 2.5 to 5.0 mg i.v. or p.o. according to verbal rating scale (VRS) pain scores (0 to 10) if VRS was more than 3 during rest or more than 5 during mobilisation. Patients were carefully instructed to take paracetamol 1000 mg four times daily and etodolac 300 mg two times daily for 4 days. Patients were also allowed to take oxycodone 5 mg (maximum 30 mg per day) when needed. After 4 days, patients were allowed to take paracetamol, etodolac and oxycodone when needed. Before surgery, patients were carefully instructed by the investigators to record , each night before bedtime, any pain from shoulder, incisions, lower abdomen and overall pain (including other types of pain, e.g. headache) that occurred both during rest and mobilisation for 14 days using a 100 mm visual analogue scale (VAS) (0 indicating no pain and 100 worst imaginable pain). During the hospital stay, an investigator assessed levels of pain by the use of a 100 mm VAS on arrival to the postanaesthetic care unit, at 2, 4 and 8 h, and at discharge from hospital. VAS scores, number of days before resumption of daily activities and consumption of analgesics were noted on a separate sheet and returned to the investigator by mail 14 days after surgery.

On the first and seventh postoperative day, patients were interviewed by telephone regarding potential side effects. In addition, instructions in the use of VAS ratings and consumption of medicine were repeated to the patients. In addition, patients’ case files were reviewed after the 21st postoperative day to identify any adverse events or reactions. Adverse events or reactions were considered serious if it was fatal, life-threatening, caused permanent disability or required prolonged hospitalisation.

The primary outcome measure was the incidence of shoulder pain or discomfort in the shoulder region (defined as VAS >20) within 14 days after surgery. Secondary outcomes were pain (shoulder, incisional, abdominal and overall pain) estimated as the VAS area under the curve (AUC) from baseline until 4 and 14 days after operation, number of days before resumption of daily activities, duration of surgery, length of hospital stay, use of oxycodone within 24 h postoperatively, incidence of nausea and vomiting and use of antiemetics within 24 h postoperatively.

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Statistical analyses and sample size calculation

Normally distributed data are described as mean ± standard deviation (SD). Nonnormally distributed data are described with median and range. Chi-squared test were used to compare the groups with respect to the primary outcome. Differences between the groups with respect to continuous variables were tested with Mann–Whitney U tests. P value less than 0.05 was considered statistically significant and analyses were performed using SPSS Statistics version 19 (IBM, Armonk, New York, USA).

A previous Cochrane review has reported a 47% relative risk reduction in the incidence of postoperative shoulder pain at low (<12 mmHg) compared with high intra-abdominal pressures (12 to 16 mmHg) during laparoscopic cholecystectomy.15 The incidence of shoulder pain 24 h after gynaecological laparoscopic surgery (including pulmonary recruitment manoeuvers at the end of surgery) has been reported to be 66%.3 We sought to detect a decrease in the incidence of shoulder pain from 66 to 38%. With a power of 0.80 and a P value less than 0.05 considered significant, 49 patients were required in each group (total 98 patients). Up to 120 patients were planned to be included in order to allow evaluation of the primary outcome in 98 patients.

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During the study period, a total of 181 patients were eligible of whom 71 were excluded (Fig. 1). Eleven patient sheets were not returned (six in Group 8-Deep and five in Group 12-Mod) and these patients were excluded, leaving 99 patients for analysis (Table 1).

Fig. 1

Fig. 1

Table 1

Table 1

Fourteen of 49 patients (28.6%) allocated to Group 8-Deep reported shoulder pain (VAS >20) during the 14 days following surgery compared with 30 of 50 patients (60%) allocated to Group 12-Mod (P = 0.002). Absolute risk reduction of shoulder pain was 0.31 [95% confidence interval (CI) 0.12 to 0.48].

We found no significant differences between the pain (shoulder, lower abdominal, incisional or overall pain) in the two groups as measured by the VAS AUC for 4 and 14 postoperative days (Table 2, Figs. 2 and 3). Moreover, we found no significant difference in the number of days before resumption of daily activities, duration of surgery, length of hospital stay or use of oxycodone within the first 24 h after surgery (Table 3). In a posthoc analysis, we compared total use of oxycodone during the 14 days after surgery and found no significant difference (Table 3). Finally, the incidence of nausea and vomiting (P = 0.685) and use of antiemetics (P = 0.111) were not different between the two groups. All operations were completed according to group of allocation. Accordingly, no patients needed an increased pneumoperitoneum pressure or additional doses of rocuronium.

Table 2

Table 2

Fig. 2

Fig. 2

Fig. 3

Fig. 3

Table 3

Table 3

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In this study, deep NMB and 8 mmHg pneumoperitoneum compared with moderate NMB and 12 mmHg pneumoperitoneum significantly reduced the incidence of shoulder pain during the 14 days following laparoscopic hysterectomy. To our knowledge, this is the first study describing patient outcomes combining deep NMB and low-pressure pneumoperitoneum as requested in a recent editorial.16 Our results are important, as the use of deep NMB in combination with low-pressure pneumoperitoneum reduced the incidence of shoulder pain without prolonging operating time or influencing the completion of the operation.

Apart from the occurrence of shoulder pain, we did not see any differences in other pain outcomes, neither in AUC values nor in consumption of opioids. In this matter, one obvious explanation could be that patients were already sufficiently treated with the standardised multimodal pain regimen. This included gabapentin, etodolac, paracetamol, sufentanil, pulmonary recruitment manoeuvers at the end of surgery and infiltration of local anaesthetics into the incisions. Furthermore, as standard care at our institution, patients’ surgery was undertaken with a relatively low pneumoperitoneum pressure of 12 mmHg. The combination of the multimodal pain regimen and low-pressure pneumoperitoneum may, therefore, have blurred a possible analgesic effect of the intervention on the pain outcomes other than shoulder pain.

We found an absolute risk reduction in the occurrence of shoulder pain of 31% with the combination of deep NMB and low-pressure pneumoperitoneum. One previous study on laparoscopic hysterectomy comparing low-pressure (8 mmHg) with standard-pressure pneumoperitoneum (12 mmHg) reported an absolute risk reduction of 31% in the occurrence of shoulder pain. This reduction, however, was only seen within the first 3 postoperative hours.17 Moreover, all operations were completed according to allocation. In contrast to our study, however, the gynaecologists were not blinded to the level of pneumoperitoneum pressure and shoulder pain was only measured within the first 24 h following surgery. The results from this study raise the question of whether deep NMB contributed to our findings, or whether it was the low-pressure pneumoperitoneum employed that was responsible for the reduction in shoulder pain. Due to the combination of the two interventions in our study, we cannot exclude the possibility that deep NMB or sugammadex may have contributed to the reduction in the occurrence of postoperative shoulder pain. We speculate, however, that our results are mainly due to the lower insufflation pressure, as there seems no rational explanation for an analgesic effect of deep NMB or sugammadex.

Another recent laparoscopic study demonstrated that the use of deep NMB compared with no NMB prevented sudden movements and accidental perforations.18 We chose to compare a low-pressure pneumoperitoneum with deep NMB, as preliminary observations have reported that the use of deep NMB during gynaecological laparoscopy enlarges the size of the abdomen.19 As all operations in patients allocated to low-pressure pneumoperitoneum and deep NMB were completed without the need for any increase in the pneumoperitoneum pressure, we believe that our results indicate that the use of deep NMB with a paralysed abdominal wall and diaphragm compensated for the lower pressure and potentially poorer surgical view.

The strengths of this study include the use of a standardised multimodal analgesia regimen that commenced preoperatively as prophylaxis and continued for 4 consecutive days after surgery. The intention was to ensure that the patients received the same amount of medicine during the first 4 days, thereby increasing the chance that any difference in shoulder pain was due to the intervention not due to differences in pain medication. Furthermore, patients were blinded to allocation and measurement of pain scores were performed by blinded assessors using the VAS. The occurrence of shoulder pain was defined as a score more than 20 on a 100 mm VAS. A VAS less than 20 was considered as pain without clinical relevance based on the findings of a previous study that demonstrated that VAS pain scores less than 18 mm may have little clinical importance.20

This study has some limitations. First, the assessment of pain after discharge from hospital was performed once a day before bedtime both during rest and after mobilisation. However, this single assessment did not capture other moments during the day at which patients may have felt pain. We were aware of this limitation in our design but chose assessment of pain at that certain time point to improve measurement compliance. Second, both gynaecologists operating on the patients were very experienced having performed more than 1000 hysterectomies each. This may have influenced the completion rate and potentially have reduced levels of postoperative pain. Finally, the patients enrolled in this study were nonobese women undergoing laparoscopic hysterectomy for benign conditions and the results may not be generalisable to major surgery or to obese patients.

Our study contributes to recently published results from a study reporting a marginal improvement in surgical conditions by the use of deep NMB and low-pressure pneumoperitoneum during laparoscopic cholecystectomy.12 However, in order to establish sufficient surgical conditions, the pressure had to be increased in half of the patients regardless of the level of NMB.12 This may indicate that the use of a low-pressure pneumoperitoneum and deep NMB is not necessarily applicable to all surgical procedures. Future studies need to address possible benefits of the use of deep NMB in combination with low-pressure pneumoperitoneum in other types of laparoscopic surgery, for example bariatric surgery, herniotomy or minor gynaecologic surgery. Finally, when performing anaesthesia with deep NMB, it is important to underline the need for objective neuromuscular monitoring and proper reversal to prevent residual NMB.21,22

In conclusion, the combination of deep NMB and low-pressure pneumoperitoneum (8 mmHg) reduced the incidence of shoulder pain after laparoscopic hysterectomy in comparison to moderate NMB and standard-pressure pneumoperitoneum (12 mmHg) without prolonging operating time or effecting completion rate.

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Acknowledgements relating to this article

Assistance with the study: none.

Financial support and sponsorship: this work was supported in part by a research grant from the Investigator Initiated Studies Program of Merck Sharp & Dohme Corp, USA. The opinions expressed in this article are those of the authors and do not necessarily represent those of Merck Sharp & Dohme Corp.

Conflicts of interest: MRG, OI and MVM have received research grants from Merck. MVM, MRG, JR and OI have received speakers’ fees and honoraria from Merck. None of the authors have shares or options in any pharmaceutical company.

Presentation: none.

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