Comparison of atracurium, cisatracurium and vecuronium during anaesthesia for laparoscopic surgery
*Marta Paśko-Majewska1, Radosław Owczuk1, Maria Wujtewicz1
1Department of Anaesthesiology and Intensive Therapy, Medical University of Gdańsk
- Fig. 1. Intubation conditions in individual groups of patients
- Fig. 2. Skin temperature in individual groups of patients (0±95% CI)
- Table 1. Intubation conditions in individual groups of patients
- Table 2. Intergroup analysis of t1, t2, and t3
- Table 3. pH according to the reference range (7.35-7.45)
- Table 4. PaCO2 according to the reference range (35-45 mm Hg)
Background. The aim of the study was to compare the intubating conditions, onset time, and duration of action of atracurium, cisatracurium, and vecuronium, when used for muscle relaxation in laparoscopic surgery with carbon dioxide inflation. In trying to find an “ideal” relaxant we compared the relative potency of these drugs, and also measured pH, PaCO2 and skin temperature.
Methods. Ninety-five ASA I and II patients were randomly allocated to three groups, to receive atracurium (I), cisatracurium (II), or vecuronium (III), during propofol/fentanyl anaesthesia. Neuromuscular transmission was monitored using accelerography (TOF GUARD). Patients were intubated after the injection of 0.5 mg kg-1 atracurium (I), 0.1 mg kg-1 cisatracurium (II), or 0.1 mg kg-1 vecuronium (III). Muscle relaxation was maintained with incremental doses of 0.1 0.2 mg kg-1 and 0.03 mg kg-1 of the relaxants respectively, given after a second response to TOF stimulation was noted. Recovery time was defined as the time from a maximal block (TOF=0) to spontaneous recovery of TOF 75%.
Results. Conditions for performing tracheal intubation were noted to be excellent in groups I and III, and good in group II. The mean recovery time was significantly shorter in groups II and III, than in group I. No significant correlations were found between the duration of neuromuscular blockade and pH, PaCO2 or palm skin temperature.
Conclusions. Vecuronium, besides providing excellent conditions for tracheal intubation, had the fastest onset time and optimal duration of action. We found the drug to be the most suitable for laparoscopic surgery.
The use of relaxant drugs resulted in dynamic development of surgical techniques . The intermediate-acting agents, both from the group of steroid derivatives (vecuronium) and benzolisoquinolines (atracurium and cisatracurium) appear to meet the expectations with respect to rapid blockade, its maintenance at a constant level and quick reversal of neuromuscular block.
Laparoscopic procedures, lasting from several minutes to several hours, require proper choices of muscle relaxants. The procedures can be performed using two techniques: with the elevation of abdominal integuments using special supporting devices and with insufflation of the peritoneal cavity with neutral and non-toxic gases (CO2, NO, Ar, He) [2, 3]. CO2 is most frequently used in clinical practice; due to its good solubility in blood, it is easily transported to the pulmonary circulation, released to the pulmonary alveoli and eliminated with the expired air [4, 5, 6, 7, 8]. An increase in abdominal CO2 during gas filling and subsequent hypercarbia in blood induce acid-base imbalance whereas the filling of the abdominal cavity with a large volume of gas induces significant changes in lung ventilation conditions [9, 10]. Moreover, homeostasis of the patient undergoing surgery is affected by the temperature of gas forced into the abdominal cavity. In most cases, the gas has room temperature (about 21º C), substantially lower than the body temperature. This is likely to cool the patient, especially during the procedures of longer duration . All the phenomena mentioned may potentially affect the pharmacokinetics of relaxants resulting in changes in the degree of relaxation, thus in surgery conditions.
The objective of the present study was: 1 – to determine whether some parameters of acid-base balance changed during laparoscopic procedures, which might affect the metabolism of relaxants, 2 – to assess if possible homeostasis changes markedly influenced the duration of relaxant action, and 3 – to decide which of the three intermediate duration relaxants came closest to an “ideal agent”.
The randomized, prospective study was approved by the Bioethics Committee for Scientific Research, Medical University of Gdańsk and involved patients of both genders fulfilling the ASA I and II criteria scheduled for laparoscopic cholecystectomy and Nissen fundoplication. The inclusion and exclusion criteria were based on the guidelines of the International Conference held in Copenhagen in 1996 and devoted to clinical research on pharmacodynamics of muscle relaxants . Depending on the striated muscle relaxant used, patients were assigned to three groups: I – those receiving atracurium; II – cisatracurium and III – vecuronium.
The patients included had an ideal body weight ±20%, calculated according to the formula: males= (height in cm−100) − 2; females = (height in cm–100) − 6.
The exclusion criteria were: taking drugs interacting with muscle relaxants, e.g. antibiotics, loop diuretics, magnesium and lithium salts, ganglionic blockers, chronic diseases impairing the function of organs involved in the metabolism of relaxants or impairing neuromuscular conduction, renal failure, enzymatic defects, diseases of the peripheral and central nervous system, and muscular diseases. Moreover, patients with anticipated difficult intubation were excluded.
Patients were premedicated with oral midazolam 0.1-0.25 mg kg-1 ninety minutes before the beginning of anaesthesia. On arrival in the operating room, patients were placed in the supine position with both upper limbs abducted to 90º. The neuromuscular activity was monitored using the TOF-GUARD (Organon Teknika, Holland) peripheral nerve stimulator and electrodes placed on the forearm below the ulnar nerve. Before the relaxant administration, stimulation with a single stimulus of 1 Hz frequency was used to achieve the optimal supramaximum stimulus. After initial preoxygeneation and administration of fentanyl 2-3 μg kg-1 and propofol 2 mg kg-1, the intubating dose of a randomly chosen muscle relaxant was injected and the TOF-GUARD started.
Muscle relaxants were administered at the following doses: atracurium (Tracrium, Smith Glaxo, USA) in the intubating dose of 0.5 mg kg-1 and the maintenance dose of 0.1-0.2 mg kg-1, cisatracurium (Nimbex, Smith Glaxo, USA) 0.1 mg kg-1 and 0.03 mg kg-1 whereas vecuronium (Norcuron, MSD, USA) 0.1 mg kg-1 and 0.03 mg kg-1, respectively.
After the relaxant administration, stimulation with a single stimulus of 0.1 Hz frequency was carried out until the muscle response vanished. During intubation, its conditions were assessed according to the Krieg scale; after assessment, the mode of stimulation was changed into train-of-four (TOF) until the 75% muscle power was restored.
Anaesthesia was administered with a continuous infusion of propofol (Diprivan, Zeneca, USA) – 10 mg kg-1 h-1 over the first 10 min, followed by 8 mg kg-1 h-1over the next 10 min and 6 mg kg-1 h-1 until the completion of surgery. During anaesthesia, fractionated doses of fentanyl 2-3 μg kg-1 and maintenance doses of muscle relaxants were used. The lungs were ventilated with the mixture of 65% air and 35% oxygen. The flow rate of fresh gases was 3 L min-1. The concentrations of CO2 in the expired air were systematically corrected by suitable adjustment of ventilation parameters. Once the peritoneal cavity was filled with CO2 patients were placed in the anti-Trendelenburg position with the body rotated to the left; when gas was released from the peritoneal cavity, patients were placed in the initial supine position. Patients were extubated after recovery and return of muscular power at TOF ≥0.75 (examinations were performed in the years 2001-2003). At present, fully reversed block is accepted at TOF ≥0.9.
The heart rate, CO2 concentration in the expired air, saturation of arterial blood with haemoglobin, arterial pressure measured indirectly and skin body temperature (palm) were monitored. Acid-base balance was determined twice: before CO2 filling (pH-1, PaCO2-1) and after its deflation (pH-2, PaCO2-2).
Measurements were performed at individual stages of relaxation: t1 – (the onset of action of muscle relaxants) measured from the administration of a muscle relaxant until complete loss of motor response to a single stimulus 0% (TW); t2 – (time of muscular power return to the level of surgical relaxation) calculated from 0% (TW) or lack of TOF response to 2 responses in TOF stimulation; t3 – (time of muscular power return enabling extubation) from 0% (TW) or lack of TOF response to TOF=0.75. Moreover, superficial body temperature was measured at the same points (T1, T2, T3).
Normality of distribution was checked using the Shapiro-Wilk W test. Data were presented as means (95% CI) or standard deviation. For intergroup comparisons, the post-hoc Neuman-Keuls test was applied for parametric data and the ANOVA signed rank Kruskal-Wallis test with post-hoc Dunn’s test for non-parametric data. To compare the results in individual groups of muscle relaxants, ANOVA with the post-hoc Scheffe test was used. Correlations of parameters were analysed using Pearson r correlation with linear regression analysis. P <0.05 was considered significant.
The study involved 95 patients, 63 females (66.3%) and 32 males (33.7%). Group I consisted of 32, group II of 32 and group III of 31 individuals. The mean age in all groups was comparable – 48.0±12.41 years. There were no significant intergroup differences in body weight and height.
The intubation conditions assessed according to the Krieg scale were excellent in group I and III and good in group II (cisatracurium) (Table 1). Significant differences in intubation conditions were found between group I and III (p=0.01) as well as II and III (p=0.002). No significant differences were observed between group I and II (Fig.1).
Significant differences in t 1 were found between group I and II (p=0.016), I and III (p=0.00011) as well as II and III (p=0.0001). Similar differences were demonstrated in t2 in group I vs II (p=0.028), I vs III (p= 0.0001) and II vs III (p=0.002). Moreover, t3 varied between the groups: I vs II (p=0.0009) and I vs III (p=0.002) (Table 2).
There were no intergroup differences in body temperature measured at the same time points (p=0.85) (Fig. 2). Likewise, pH (Table 3) and PaCO2 (Table 4) were not found to be statistically different.
Furthermore, there were no correlations between times of successive relaxation phases, pH, PaCO2 and skin temperature.
Laparoscopic procedures with pneumoperitoneum require good relaxation of striated muscles and its maintenance at constant level throughout the surgery. CO2 insufflated to the abdominal cavity at the pressure of 15 mm Hg (2 kPa) diffuses into blood and causes respiratory acidosis [2, 3, 4, 5, 6, 7] due to which, as demonstrated by animal  and human  studies, the minute lung ventilation has to be increased; and such a rule was accepted in our study. An increase in CO2 concentration in the expiratory air was observed, particularly several minutes after filling the abdominal cavity with gas and after placing the body in the anti-Trendelenburg position. The increased minute volume was maintained for several minutes after CO2 relase to prevent postoperative hypercarbia.
The onset of action of a relaxant and the strength of its binding with acetylcholinergic receptors are inversely correlated [13, 14]. Numerous authors suggest that to provide good intubation conditions, increased doses of relaxants, even 3-4×ED95, should be administered [13, 15]. In our study, standardized intubating doses were used – 2×ED95. In many patients administered cisatracurium, the diaphragm movements were observed despite the lack of response to a single stimulus, which worsened Krieg scores of intubation conditions and spoke in favour of the intubating doses used. The mean onset of action of an initial dose (t1) was 4.8 min for atracurium, 5.4 min for cisatracurium and 3.6 min for vecuronium. Comparing the action of atracurium and cisatracurium, Lepage and colleagues  demonstrated comparably longer t1 for cisatracurium. According to Mellinghoff and co-workers , however, there were no significant differences between the drugs in question. At t1 the best agent was vecuronium with the shortest onset of action.
The shortest onset of action of the maintenance dose (t2) was found for vecuronium – 19.2 min; t2 for atracurium and cisatracurium were longer than those reported by Mellinghoff and colleagues , yet shorter compared to those given by Lepage and co-workers . However, the findings in vecuronium patients were comparable with those reported by Suzuki and colleagues . In our study, the shortest t3 was demonstrated for cisatracurium (39.3 min), which was shorter by 0.9 min compared to vecuronium yet the difference was not significant.
In vitro studies showed prolonged action of atracurium at lower body temperature: t½ at 23º C prolonged from 18 min to 49 min, at 5º C – to 15.5min . In the present study, there was no correlation between the duration of action of muscle relaxants and body temperature, which was likely to be associated with continuous correction of temperature.
The analysis of pH and PaCO2 before gas insufflation into the peritoneal cavity and its deflation demonstrated normalization of both parameters, which might have been caused by the ETCO2 correction in the expired air. Other reports show that to maintain normocarbia in blood, lung ventilation should be increased by 25% [4, 6, 10]. In our study, almost 74% of patients still had decreased CO2 partial pressure after its deflation although the number of patients with post-procedure PaCO2 values approaching the reference values (35-45 mm Hg/4.6-6.0 kPa) tended to increase slightly. The number of patients with PaCo2 values higher than reference ones after CO2 release was relatively low, which differs from the findings reported by many authors, i.e. maintained marked hypercarbia after laparoscopic procedures [2, 3, 4, 5]. These differences are likely to be associated with the fact that in our study the recommendations regarding increased minute volume during anaesthesia for laparoscopic procedures were applied [4, 5,
1. Among the striated muscle relaxants used for laparoscopic procedures, vecuronium comes closest to an ideal agent.
2. There is no correlation between the duration of action of muscle relaxants, parameters reflecting homeostasis, pH, PaCO2 and skin temperature.
3. The altered values of pH and PaCO2 during laparoscopic procedures tend to normalise by the end of surgery, which is likely to result from systematic correction of ETCO2.
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