Changes in duration of action of rocuronium following decrease in hepatic blood flow during pneumoperitoneum for laparoscopic gynaecological surgery
© The Author(s). 2017
Received: 11 July 2016
Accepted: 1 March 2017
Published: 20 March 2017
A moderate insufflation pressure and deep neuromuscular blockade (NMB) have been recommended in laparoscopic surgery in consideration of the possible reduction in splanchnic perfusion due to the CO2-pneumoperitoneum. Since the liver is the major organ for rocuronium metabolism, the question of whether NMB of rocuronium would change with the variation of liver perfusion during pneumoperitoneum during laparoscopic surgery merits investigation.
In this prospective study, a total of sixty female patients scheduled for either selective laparoscopic gynaecological surgery (group laparoscopy) or laparotomy for gynaecological surgery (group control) were analyzed. Rocuronium was administered with closed-loop feedback infusion system, which was also applied to monitor NMB complied with good clinical research practice (GCRP). The onset time, clinical duration, and recovery index were measured. Hepatic blood flow was assessed by laparoscopic intraoperative ultrasonography before insufflation/after entering the abdominal cavity (T1), 5 min after insufflation in the Trendelenburg position/5 min after skin incision (T2), 15 min after insufflation in the Trendelenburg position/15 min after skin incision (T3), 30 min after insufflation in the Trendelenburg position/30 min after skin incision (T4), and 5 min after deflation/before closing the abdomen (T5) in group laparoscopy/group control respectively. The relationship between the clinical duration of rocuronium and portal venous blood flow was analyzed using linear or quadratic regression.
The clinical duration and RI of rocuronium were both prolonged significantly in group laparoscopy (36.8 ± 8.3 min; 12.8 ± 5.5 min) compared to group control (29.0 ± 5.8 min; 9.8 ± 4.0 min) (P < 0.0001; P = 0.018). A significant decrease was found in portal venous blood flow during the entire pneumoperitoneum period in group laparoscopy compared with group control (P < 0.0001). There was a significant correlation between the clinical duration of rocuronium and portal venous blood flow (Y = 51.800-0.043X + (1.86E-005) X 2; r2 = 0.491; P < 0.0001).
Rocuronium-induced NMB during laparoscopic gynaecological surgery might be prolonged due to the decrease in portal venous blood flow induced by CO2-pneumoperitoneum. Less rocuronium could be required to achieve a desirable NMB in laparoscopic gynaecological surgery.
ChiCTR. Registry number: ChiCTR-OPN-15007524. Date of registration: December 4, 2015.
KeywordsRocuronium Hepatic blood flow Pneumoperitoneum
Laparoscopic surgery has been widely used for the treatment of many gynaecological diseases on account of its minimally invasive technique . To enlarge the intra-abdominal surgical space, the induction of pneumoperitoneum created by insufflation of carbon dioxide is necessary for laparoscopic procedures. However, several animal studies have demonstrated that high intra-abdominal pressure (IAP) induced by pneumoperitoneum may cause marked reduction in splanchnic and liver perfusion, and may even induce temporary impairment of liver function [2–5]. In humans, even brief periods of CO2 insufflation (45–60 min) have been shown to significantly reduce blood flow to organs within the peritoneal space . Furthermore, patients undergoing laparoscopic surgery reacted with a transient elevation of liver enzymes, a reaction speculated to be attributable to impaired liver perfusion probably caused by IAP . Thus, a moderate insufflation pressure (no more than 15 mmHg) has been recommended in laparoscopic gynaecological surgery [6, 8].
Another strategy to prevent events associated with high IAP is maintaining deep neuromuscular blockade (NMB) during the entire laparoscopic surgery. Rocuronium, an aminosteroid neuromuscular relaxant, is commonly used for anaesthesia in laparoscopic surgery. Deep NMB produced by rocuronium can improve surgical space conditions by increasing abdominal wall compliance during pneumoperitoneum and can accelerate bowel functional recovery postoperatively [9–11]. Since rocuronium is eliminated primarily through hepatic uptake and biliary excretion, the question of whether the duration of action of rocuronium is affected by decreased hepatic blood flow in response to CO2-pneumoperitoneum merits investigation. A previous study in cats reported that when hepatic inflow was considerably decreased via a portal vein-to-inferior vena cava shunt, the clinical duration of rocuronium increased almost threefold . This result suggested that the pharmacodynamics of rocuronium should be correlated with hepatic perfusion.
The aim of the present study was to examine the duration of action of rocuronium during laparoscopic surgery and to further analyse the correlation between the rocuronium-induced NMB and decreased hepatic perfusion in response to pneumoperitoneum.
This prospective, single center and nonrandomized clinical trial was approved by the Medical Ethics Committee of Chaoyang Hospital affiliated to the Capital Medical University (NO. 2015-KE-98) and registered in the Chinese Clinical Trial Registry (NO.ChiCTR-OPN-15007524) on 04 December, 2015. Prior written informed consent was obtained from all patients.
Upon arrival in the operating room, an intravenous line containing Ringer’s lactate solution was inserted in the major left forearm of all the patients. Standard clinical monitoring included electrocardiograph, non-invasive arterial blood pressure, pulse oximetry and end-tidal carbon dioxide pressure (PETCO2) and bispectral index (BIS, Aspect Medical Systems, Dublin, Ireland). All patients were administered total intravenous anaesthesia (TIVA) with propofol and remifentanil infusion at the plasma concentration of 2–4 μg/ml and 4–8 ng/ml respectively by target-controlled infusion (TCI) (Graseby 3500®, Diprifusor module, Watford, UK). The target plasma concentration of propofol was adjusted to maintain the BIS at about 40–60 until the end of surgery. All study subjects who received the adjunctive vasoactive drugs, such as esmolol, ephidrine which could influence the pharmacodynamics of rocoronium were excluded from the analysis.
Neuromuscular block and monitoring by CLMRIS-I
The automatic infusion of rocuronium and the monitoring of NMB status were performed with the computerised Closed-Loop Muscle Relaxant Injection System (CLMRIS-I, Veryark, Nanning, Guangxi, China). The infusion rate of rocuronium was set on the basis of the anaesthesiologist’s clinical experience, and the monitoring of NMB was complied with good clinical research practice (GCRP) . Two surface electrodes were placed over the ulnar nerve at the wrist and the acceleration transducers were attached to the thumb and index finger. The ulnar nerve was stimulated supramaximally with duration of 0.2 ms in a train-of-four (TOF) mode at a frequency of 2 Hz. The degree of NMB was defined as the ratio of the measurement of T1 in the TOF sequence to the corresponding control value, and was assessed every 20 s. The EMG responses (T1 and TOF ratio) were recorded and displayed on the monitoring screen of the CLMRIS-I. The temperature probe was placed over the skin of the adductor pollicis muscle, and skin temperature was maintained above 34 °C throughout the study period.
After the patients lost consciousness, the neuromuscular transmission monitoring of CLMRIS-I was initiated to calibrate and obtain a reference control value for all subsequent measurements. A bolus dose of 0.6 mg/kg rocuronium (Esmeron, Merck Frosst, Montreal, Canada) was then automatically infused, and tracheal intubation was performed when T1 of the TOF dropped to 0% of the control value. The patients were mechanically ventilated to maintain PETCO2 32–35 mmHg. To observe the clinical duration of rocuronium, the first feedback parameter of a single additional infusion was set at 25% recovery of T1. At this point, an additional bolus of rocuronium (30 μg · kg−1 · min−1) was injected, followed by a continuous infusion of 1.8 μg · kg−1 · min−1. Subsequently, the feedback threshold was changed to recovery of T1 to 15% for maintenance of a persistent and deep NMB. The infusion of rocuronium was stopped 30 min before closing the fascia and neostigmine, a muscle-relaxant antagonist, was permit to be administrated to the patients only after finishing the study of rocuroium. When TOF recovered to 90%, all patients underwent tracheal extubation. The anaesthetists were allowed to administer rocuronium manually or switch the closed-loop infusion to manual infusion of rocuronium during the operation, if needed, but any those subjects who had received these interventions were excluded from the analysis.
Infusion rate of rocuronium infused per unit time and weight (μg · kg−1 · h−1)
Bolus injection frequency of rocuronium during the whole operation per unit time
Laparoscopic procedures and ultrasonography
Vessel diameter (VD).
Cross-sectional area (CSA) = (VD/2)2 × π.
Mean flow velocity (MV).
Blood flow volume (BFV) = CSA × MV.
Statistical analysis was performed using SPSS 19.0 (SPSS Inc., Chicago, IL, USA). A sample size calculation indicated that 25 patients in each group would be sufficient to find a statistically significant difference of 20% or more in the clinical duration between groups (0.05 two-sided significance level α = 0.05, 90% power β = 0.10). Categorical variables, expressed as numbers, were compared using the chi-squared test. Continuous variables, represented as means ± standard deviation (SD) were compared using the unpaired t-test or paired t-test of variance. The relationship between the clinical duration of rocuronium and the portal venous flow at differentiate IAP in group laparoscopy and group control at T4 was analyzed using linear or quadratic regression. A P-value < 0.05 was considered statistically significant.
Characteristics of the patients
Group control (n = 30)
Group laparoscopy (n = 29)
46.2 ± 8.9
45.1 ± 7.3
163.9 ± 2.1
162.8 ± 2.5
Body weight (kg)
62.6 ± 5.1
63.7 ± 7.6
22.8 ± 1.7
23.2 ± 1.8
Operation duration (min)
163.7 ± 16.4
157.6 ± 12.0
Infusion rate of propofol (μg · kg−1 · min−1)
88.6 ± 13.6
92.5 ± 16.1
Infusion rate of remifentanil (ng · kg−1 · min−1)
134.1 ± 47.5
128.9 ± 53.3
Comparison of the effect of rocuronium in the two groups
Group control (n = 30)
Group laparoscopy (n = 29)
Onset time (min)
95.5 ± 12.3
94.3 ± 12.7
Duration time (min)
29.0 ± 5.8
36.8 ± 8.3 **
Recovery index (min)
9.8 ± 4.0
12.8 ± 5.5 *
2.8 ± 0.7
2.4 ± 0.6 *
Infusion rate (μg · kg−1 · min−1)
6.3 ± 1.8
5.4 ± 1.4 *
Parameters of hepatic blood flow in two groups assessed by laparoscopic intraoperative ultrasonography
Group control (n = 30)
Group laparoscopy (n = 29)
0.99 ± 0.22
0.99 ± 0.21
24.02 ± 9.24
23.71 ± 7.25
990.77 ± 133.65
1007.59 ± 145.36
0.99 ± 0.23
0.68 ± 0.18 ** ##
24.12 ± 9.82
21.81 ± 8.98
991.50 ± 136.77
432.90 ± 113.37 ** ##
1.00 ± 0.24
0.65 ± 0.18 **##
23.91 ± 10.04
21.13 ± 6.55
989.87 ± 135.42
379.07 ± 101.42 ** ##
0.99 ± 0.23
0.62 ± 0.18 **##
23.79 ± 9.39
23. 08 ± 6.31
987.03 ± 107.15
389.38 ± 106.68 ** ##
1.00 ± 0.23
0.98 ± 0.22
23.63 ± 9.61
23.81 ± 7.59
995.13 ± 128.33
997.97 ± 144.60
0.42 ± 0.12
0.42 ± 0.13
37.79 ± 12.93
37.18 ± 13.07
275.43 ± 77.73
273.62 ± 79.32
0.42 ± 0.12
0.35 ± 0.10 * ##
37.69 ± 13.55
60.88 ± 18.11 * *##
273.80 ± 76.33
320.31 ± 93.93 * ##
0.42 ± 0.12
0.38 ± 0.12
37.43 ± 13.30
46.89 ± 15.72 *
273.33 ± 77.88
287.83 ± 87.37
0.41 ± 0.12
0.41 ± 0.13
37.39 ± 12.05
38.05 ± 12.56
274.50 ± 81.28
274.72 ± 83.69
0.42 ± 0.12
0.42 ± 0.13
37.14 ± 12.01
36.77 ± 12.93
276.23 ± 80.66
273.62 ± 81.20
Total Hepatic blood flow
1266.20 ± 207.16
1281.21 ± 218.34
1265.30 ± 207.88
753.21 ± 194.84 ** ##
1263.20 ± 208.19
666.90 ± 179.72 **##
1261.53 ± 184.02
664.10 ± 185.95 **##
1271.37 ± 203.12
1271.59 ± 219.67
There are three major findings in the present study. First, CO2-pneumoperitoneum at 14 mmHg in the Trendelenburg position induced a significantly long clinical duration of rocuronium. Second, hepatic portal venous blood flow decreased significantly in patients undergoing laparoscopic surgery compared to those undergoing conventional open surgery. Third, the prolongation of the clinical duration of rocuronium correlated with the decrease in hepatic portal venous blood flow in response to CO2-pneumoperitoneum.
Several reports have suggested that deep NMB was essential for improving surgical conditions without decreasing perfusion of the internal organs during pneumoperitoneum [9, 10]. Conversely, Paek CM et al. demonstrated that a single intubating dose of rocuronium could satisfy the requirements of laparoscopic pelvic surgery . To the authors’ knowledge, the present study is the first to investigate the pharmacodynamics of rocuronium throughout laparoscopic gynaecological surgery. During the entire surgery, rocuronium was administered with CLMRIS-I, a closed-loop infusion system. It had the dual functions of both monitoring NMB as well as delivering automatic feedback infusion of rocuronium. TOF ratio could be used to help regulating the infusion of rocuronium automatically, which could provide stable and uniform muscle relaxation. The findings of pharmacodynamics of muscle relaxants have shown that the duration of action of rocuronium was prolonged significantly during the laparoscopic surgery compared to laparotomy surgery. In addition, a slower recovery of neuromuscular function was observed in laparoscopic surgery than in laparotomy surgery. These variabilities in NMB may be due to the decrease in hepatic perfusion in response to pneumoperitoneum. Portal venous blood flow accounts for about two-thirds of the total blood flow to the liver, and the clear correlation between the duration of action of rocuronium and portal venous blood flow was found in the present study, which confirmed our previous hypothesis that the prolongation of NMB of rocuronium might be attributable to the depression of hepatic perfusion during the lapaoscopic surgery and portal venous blood flow might have a predominant influence on the time course of action of rocuronium.
There has been controversy regarding the effect of CO2-pneumoperitoneum on decrease in hepatic perfusion [19, 20], which may be explained as follows: First, different extents of IAP by pneumoperitoneum and operative positions of the patients should be considered. In the previous studies, the opinions that the changes in hepatic blood flow were IAP-related have been remained consistent, while the conclusions regarding the thresholds at which IAP reduced the hepatic blood flow were not in agreement. The operative position, especially Trendelenburg in contrast to the supine and supine-lithotomy, might be associated with the decreases in hepatic perfusion resulting from the physiological response to increased IAP [21, 22]. Second, TEE has limitations for the assessment of hepatic venous blood flow as the angle of insonation is more than 60°. By contrast, LIOU-based measurements of the portal venous and hepatic artery blood flow are reliable and accurate owing to direct placement of probes closer to the target vessels. Third, blood flows in the hepatic artery and portal vein have different responses to elevated IAP caused by CO2-pneumoperitoneum. The portal venous blood flow was decreased significantly with the decrease of venous diameter at 14 mmHg of abdominal pressure. However, hepatic artery blood flow was selectively preserved to maintain the liver blood supply during laparoscopy-associated portal venous blood flow reduction, which might provide protection for liver function during CO2-pneumoperitoneum [22, 23]. However, this increase in hepatic artery blood flow in virtue of the increased flow rate has not remained long in the present study during sustained elevations in IAP.
We acknowledge the limitations of this study. First, the study was not randomised or blinded. The close matching of the two groups could reduce potential bias in the analysis of the primary outcome. Second, we did not directly measure the plasma concentrations of rocuronium to clarify the elimination of rocuronium. CLMRIS-I used in our study was an automated delivery system based on pharmacodynamic, but not pharmacokinetic parameters of NMBAs.
In conclusion, this study indicated that the duration of action of rocuronium might be prolonged due to the decrease in portal venous blood flow induced by CO2-pneumoperitoneum. Therefore, less rocuronium could meet the requirement of achieving a desirable NMB in laparoscopic gynaecological surgery. Meanwhile, neuromuscular monitoring is worth considering so that residual action of rocuronium could be avoided in laparoscopic gynaecological surgery.
American Society of Anesthesiologists
Blood flow volume
Body mass index
Closed-loop muscle relaxant injection system
Good clinical research practice
Laparoscopic intraoperative ultrasonography
Mean flow velocity
Neuromuscular blocking agents
- PETCO2 :
End- tidal carbon dioxide pressure
Total intravenous anaesthesia
Our gratitude goes to all of the staff of the Department of Anaesthesiology, Chaoyang Hospital, Capital Medical University. We wish to thank Dr Shuzhen Wang of the Department of Gynaecology and Obstetrics at Chaoyang Hospital who has put trust in our work and allowed us to recruit their patients for this study. We would also like to thank the members of the statistical department, particularlyProf, Xiaoxia Wang at Beijing Children’s Hospital, who have been of great help to us in the statistical work.
Availability of data and materials
YL1 designed and conducted the study, analyzed the data, and prepared the manuscript. WC and RL helped conduct the study. YL2 recruited the patients, performed many of measurements, and collected and analyzed data. YW helped design the study and supervised data collection. YY and AW designed the study, and reviewed and revised the manuscript. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
Consent for publication
Ethics approval and consent to participate
This study was approved by the Medical Ethics Committee of Chaoyang Hospital affiliated to the Capital Medical University (NO. 2015-KE-98). All participants provide written informed consent in accordance with the Medical Ethics Committee approvals granted by the Capital Medical University. Trial registration: ChiCTR. Registry number: ChiCTR-OPN-15007524. Registered 04-12-2015.
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