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Comparative study on the pharmacodynamics of cisatracurium: Continuous infusion or intermittent bolus injection
Contemporary Clinical Trials 33 (2012) 482–485
Contents lists available at SciVerse ScienceDirect
Contemporary Clinical Trials journal homepage: www.elsevier.com/locate/conclintrial
Comparative study on the pharmacodynamics of cisatracurium: Continuous infusion or intermittent bolus injection You-jing Dong ⁎, Xu Li Department of Anesthesiology, Shengjing Hospital of China Medical University, Shenyang 110004, China
a r t i c l e
i n f o
Article history: Received 16 August 2011 Received in revised form 24 December 2011 Accepted 10 January 2012 Available online 18 January 2012 Keyword: Neuromuscular blockade Cisatracurium Pharmacodynamics
a b s t r a c t Objective: To explore a better administration way through comparison of the pharmacodynamics of cisatracurium administered by continuous infusion or intermittent bolus injection. Methods: Thirty patients (ASAI-II) who had no neuromuscular disease and underwent selective surgery under general anesthesia were randomly divided into group I and II (each group with 15 patients). In group I, patients received cisatracurium by continuous infusion and in group II, by intermittent bolus injection. The responses of adductor pollicis to train-of-four (TOF) stimulation were monitored. The duration of neuromuscular blockade, recovery index and total dose of cisatracurium consumption were recorded in the two groups. Intravenous anesthesia was used for anesthesia induction and sevoflurane inhalation for maintenance of anesthesia. Results: The mean infusion rate was significantly lower in group I (0.78 ± 0.15 μg.kg − 1.min − 1) than in group II (1.09 ± 0.33 μg.kg− 1.min − 1) (P b 0.05). There was no significant difference in duration of neuromuscular blockade between the two groups (P > 0.05). The recovery index was 13.13 ± 3.36 min in group I and 14.38 ± 4.48 min in group II, which indicated that the recovery was faster in group I than in group II, but without statistical significance (P > 0.05). During the duration of neuromuscular blockade, 8 patients had T1 b 3%, 4 T1 of 3%–7% and 3 T1 of 7%–10% in group I; T1 was maintained between 0 and 20% in group II. Conclusions: Although cisatracurium consumption was significantly lower in continuous infusion than in intermittent bolus injection, continuous infusion can obtain more stable neuromuscular blockade than intermittent bolus injection. © 2012 Elsevier Inc. All rights reserved.
1. Introduction Muscle relaxant is one of the major drugs in general anesthesia at present. Cisatracurium, a new non-depolarizing muscle relaxant of benzyl isoquinoline, possesses many advantages such as a wide range of indications, rapid onset, moderate action time, rapid recovery and a little influence on the cardiovascular system, no histamine release and no accumulation in vivo, and the metabolites having no the effect of neuromuscular blockade. Its pharmacodynamics and influencing factors have been extensively studied [1–3], but
⁎ Corresponding author at: No 36, Sanhao Street, Herping District, Shenyang (110004), China. Tel./fax: + 86-024-23380681. E-mail address: [email protected] (Y. Dong). 1551-7144/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.cct.2012.01.002
little research has been done on the effect of different administration ways on cisatracurium consumption and neuromuscular blockade. We compared the pharmacodynamics of cisatracurium administered by continuous infusion and intermittent bolus injection under sevoflurane inhalation anesthesia to explore the best administration way. Our study provides a basis for the rational and safe applications of cisatracurium in clinical anesthesia. 2. Subjects and methods All study methods were approved by the Ethics Committee of the Shengjing Hospital of China Medical University. Before operation, we explained possible events during anesthesia, and enrollment into this study to subjects and their direct relative, and then all the subjects enrolled into
Y. Dong, X. Li / Contemporary Clinical Trials 33 (2012) 482–485
the study or their direct relative gave written formal consent to participate. 2.1. Subjects Thirty female patients (ASAI–II) aged 20–60 years who underwent selective gynecological surgery under general anesthesia were enrolled in the study. Inclusion criteria were (1) normal routine examination; (2) normal cardiopulmonary, hepatic and renal functions; (3) no histories of drug allergy and neuromuscular disorder. Exclusion criteria included (1) women in gestational and lactational period; (2) body mass index >30; (3) hyperthermia; (4) severe anaemia or malnutrition; (5) fluid and electrolyte imbalances; (6) taking drugs which interferes with neuromuscular blockade before operation. 2.2. Anesthesia The 30 patients were randomly divided into continuous infusion group (group I, n = 15) and intermittent bolus injection group (group II, n = 15). ECG, noninvasive blood pressure, heart rate, pulse, oxygen saturation and body temperature were continuously monitored. Propofol (2 mg/ kg) and fentanyl (2 μg/kg) were used in anesthesia induction. Assisted respiration was carried out when patients lost consciousness. At the same time, the muscle relaxation monitor (TOF-Watch) was calibrated (T1 = 100%) followed by giving a single bolus of 2ED95 cisatracurium (0.1 mg/kg) in both groups. After T1 reached the maximum blocking (response completely disappeared), tracheal intubation, mechanical ventilation, adjustment of respiratory parameters (PETCO2 in 30–40 mmHg) were performed. Anesthesia was maintained by sevoflurane inhalation, and exhaled sevoflurane concentration was monitored to keep it at 1.3MAC until operative end. Body and thumb skin temperature were maintained at not lower than 36 °C and 32 °C respectively, and the fluctuation of blood pressure was less than 20% of baseline value. 2.3. Monitoring of neuromuscular blockade Neuromuscular transmission monitor of type TOF-Watch SX (purchased from Organon Limited, Holland) was applied to measure the changes in adductor pollicis twitch. Surface electrodes were placed on the surface skin covering the ulnar nerve near the wrist of the left forearm, the sensor probe of acceleration transducer was fixed on the palm side of thumb, and the temperature probe was fixed on the surface skin of thenar eminence. Continuous train-of-four (TOF) (with a stimulus intensity of 50 mA, frequency of 2 Hz; 15 s-interval between strings) to the ulnar nerve was monitored, the value of T1 twitch inhibition was served as an indicator to evaluate neuromuscular blocking effects. When TOF-Watch indicated that T1 recovered to 20%, the
483
continuous infusion of cisatracurium started in group I. The infusion liquid was prepared based on formula: body weight (kg) × 0.12(mg)/20 ml saline, that is the concentration of 10 ml/h = 1 μg.kg − 1.min − 1. The infusion rate was first at 3 μg.kg − 1.min − 1, and then was regulated to maintain T1 b 10%. In group II, When TOF-Watch indicated that T1 recovered to 20%, cisatracurium was injected intravenously in a dose of 0.03 mg/kg. In group I, cisatracurium was given until abdominal closure, while in group II, cisatracurium was administrated for the last time according to the operative process and neuromuscular blocking effects. All patients recovered spontaneously without the rivalry of neuromuscular blockade. Neuromuscular blockade was monitored until TOF ratio (T1/Tc) ≥75%.The patients were extubated when ventilation was satisfactory. In group I, the continuous infusion time and total dose of cisatracurium consumption were recorded to calculated the mean infuse rate. The duration of neuromuscular blockade was from the beginning of continuous infusion to T1 recovering to 10% after stopping continuous infusion. The recovery time of T1 from 10% to 25% and 75%, and the recovery index (the recovery time of T1 from 25% to 75%) were recorded. In group II, the duration of neuromuscular blockade was from the time of the first administration to T1 recovering to 10% after the last administration. The frequency of administration and the total dose of cisatracurium consumption were recorded to calculated the mean infuse rate. The recovery time of T1 from 10% to 25% and 75%, and the recovery index (the recovery time of T1 from 25% to 75%) were recorded. All patients were observed the adverse reactions such as dizziness, difficulty in opening eyes, diplopia and dyspnea in each group after administration of cisatracurium.
2.4. Statistical analysis Measurement data were expressed as mean ± standard deviation (x s), t-test or ANOVA was applied in comparison between groups. P values below 0.05 were considered statistically significant.
3. Results 3.1. General status in both groups There were no significant differences in age, body height and weight, total protein, albumin and operation duration between the two groups (P > 0.05) (Table 1). Hemodynamics was stable, and body and thumb skin temperature were maintained at not lower than 36 °C and 32 °C, respectively, during anesthesia induction and maintenance. In the 30 patients, no clinical manifestations of histamine release such as tachycardia, flushing and bronchospasm occurred.
Table 1 General data in both groups (x s). Groups
Case (n)
Age (year)
Body weight (kg)
Body height (cm)
Total protein (g/L)
Albumin (g/L)
Operation duration (min)
Group I Group II
15 15
47.20 ± 8.56 47.20 ± 8.56
56.2 ± 5.75 57.6 ± 5.69
161.70 ± 3.13 160.38 ± 3.67
71.4 ± 6.55 70.3 ± 4.71
42.7 ± 3.09 41.5 ± 3.97
165.60 ± 45.52 142.88 ± 44.90
484
Y. Dong, X. Li / Contemporary Clinical Trials 33 (2012) 482–485
3.2. Duration of neuromuscular blockade and the mean infuse rate in both groups During the duration of neuromuscular blockade, 8 patients had T1 b 3%, 4 T1 of 3%–7% and 3 T1 of 7%–10% in group I; T1 was maintained between 0 and 20% by intermittent bolus injection of cisatracurium when it recovered to 20% in group II. The mean infuse rates were (0.78 ± 0.15) μg.kg − 1.min − 1 in group I and (1.09 ± 0.33) μg.kg − 1.min − 1 in group II, with P b 0.01. There was no significant difference in the duration of neuromuscular blockade between the two groups (P > 0.05) (Table 2). 3.3. Recovery of neuromuscular blockade in both groups Recovery index was (13.13 ± 3.36) min in group I and (14.38 ± 4.48) min in group II, with P > 0.05. There were no significant differences in the recovery time of T1 from 10% to 25% and 75% between the two groups (P > 0.05) (Table 3). 3.4. Follow-up and adverse events We followed up for 3 days, and no adverse as well as serious adverse events occurred. 4. Discussion The clinical application of muscle relaxants has created a new era of anesthesiology. How to use muscle relaxants to obtain satisfactory muscle relaxation and a relatively quiet operative field without postoperative delayed recovery of neuromuscular excitatory transmission is yet to be resolved in the clinical anesthesia. It is very important to select appropriate dose of non-depolarizing muscle relaxants to meet the operation requirements with avoidance of overdosage. In order to reduce the possibility of postoperative residual neuromuscular blockade, the usage of muscle relaxants should be as few as possible under the condition to meet the operation requirements. Administration way is one of the key factors for rational application of muscle relaxants. Cisatracurium, a new benzyl isoquinoline nondepolarizing muscle relaxants, is one of the ten isomers of atracurium. It possesses many advantages including stronger action, quicker recovery, no accumulation, no histamine release, metabolism being independent of liver and kidney and little effects on cardiovascular system [1,2]. When its ED95 is 0.05 mg.kg− 1, it possesses a similar metabolic pathway to atracurium, the elimination of non-organ dependent manner, and its titer is 3 times as much as atracurium. Hofmann elimination accounts for 77% of the total clearance rate, mainly occurs in plasma and tissue. Hofmann elimination is associated only with PH value and temperature of body. An-
Table 2 The duration of neuromuscular blockade and the mean infusion rates in both group (x s). Groups
Case (n)
Duration of neuromuscular blockade (min)
Mean infusion rate (μg.kg− 1.min− 1)
Group I Group II
15 15
113.10 ± 33.13 108.86 ± 18.49
0.78 ± 0.15a 1.09 ± 0.33
a
Indicates P b 0.01, compared with group II.
Table 3 Recovery time of neuromuscular blockade in both groups (x s). Groups
Case (n)
T1 from 10% to 25% (min)
T1 from 10% to 75% (min)
Recovery index (min)
Group I Group II
15 15
7.67 ± 1.76 7.98 ± 4.06
20.80 ± 4.72 21.79 ± 7.01
13.13 ± 3.36 14.38 ± 4.48
other 23% is eliminated through organ-dependent manner, and esterolysis accounts for about 5% and prototype for about 16%. Cisatracurium is not directly hydrolyzed by plasmic non-specific esterase, and its metabolites do not have the effect of neuromuscular blockade. The pharmacological characteristics of cisatracurium determine that it can be administrated either by intermittent bolus injection or continuous infusion. Currently, most of non-depolarizing muscle relaxants are administrated by single intravenous injection in clinical anesthesia. Due to the lack of neuromuscular blockade monitoring, administration is often based on clinical experience, namely that when increased airway pressure, spontaneously breathing, bucking, or body movement occur, muscle relaxants would be added. This leads to a drastic fluctuation in the degree of neuromuscular blockade, so it is difficult to keep the degree of neuromuscular blockade at a stable level. Especially during the period before operative end, the timing and dose of administration are more difficult to control. Because of estimated bias, inappropriate administration leads to overdosage of muscle relaxants, which causes delayed recovery of neuromuscular blockade. Residual neuromuscular blockade can suppress the respiratory center, decrease hypoxic ventilatory response and forced inspiratory flow, and increase the incidences of upper respiratory tract obstruction, dysphagia, regurgitation, and pulmonary complications [3]. Moreover, intermittent bolus injection readily leads to a sudden increase in blood drug concentration which makes not only acetylcholine in saturation but also drug excretion increase, resulting in a waste of muscle relaxants. Our study showed that during the duration of neuromuscular blockade, 8 patients had T1 b 3%, 4 T1 of 3%–7% and 3 T1 of 7%–10% in group I; T1 was maintained between 0 and 20% by intermittent bolus injection of cisatracurium when it recovered to 20% in group II. However the mean infusion rate was significantly lower in group 1 (0.78 ± 0.15 μg.kg − 1.min − 1) than in group II (1.09 ± 0.33 μg.kg − 1.min − 1) (P b 0.05). Above results suggest that continuous infusion can obtain effective and stable neuromuscular blockade although cisatracurium consumption is less. Therefore, under the condition that neuromuscular blockade monitoring has not become popular in clinical anesthesia, continuous infusion is better than intermittent bolus injection. In this study, anesthesia was maintained only by sevoflurane to avoid the effects of combined medication on test results. All patients were female, which excluded gender effects on test results [4]. Low temperature can prolong action time of muscle relaxants and delay spontaneous recovery time [5,6]. The body temperature and the thumb skin temperature were maintained constant during the operation, which avoided the interference of temperature with test results. Since there was no difference in general status of the
Y. Dong, X. Li / Contemporary Clinical Trials 33 (2012) 482–485
patients between the two groups, and the experimental conditions were the same except administration ways, two groups are comparable. In this study, the 30 patients had no clinical manifestations of histamine release such as tachycardia, flushing and bronchospasm occurred, which is consistent with the reports from home and abroad [7,8]. Our results showed that the duration of neuromuscular blockade was similar in both groups; spontaneous recovery was slightly faster in continuous infusion than in intermittent bolus injection, but without significant difference. It has been reported that once spontaneous recovery of neuromuscular blockade begin, recovery speed is not associated with dosage, which may be related to Hofmann elimination or may be that metabolites have no the effects of neuromuscular blockade [5]. Theoretically, drug consumption per unit time is less; the recovery speed should be more rapid. No statistical significance in recovery speed between the two groups in this study may be due to small sample size, and further studies with larger sample size will be needed to confirm it. Moreover, in continuous infusion group, less cisatracurium consumption per unit time reduced post-operative residual neuromuscular blockade to some extent, which was conducive to postanesthesia recovery. In this study, 1.3MAC sevoflurane was used to maintain anesthesia. Inhalation anesthetics may enhance the effect of non-depolarizing muscle relaxant action, manifesting in prolonging the duration of neuromuscular blockade and reducing the maintenance dose of muscle relaxants [9,10]. Therefore, in this study, total dose of cisatracurium consumption and the recovery process were influenced by sevoflurane. It is reported that muscle relaxant consumption was decreased by 41% in the anesthesia performed with sevoflurane than with propofol [11], which may be related to higher sevoflurane concentration in inhalation group, and no usage of remifentanil in propofol group. In order to make this study more comparable, the subjects were strictly screened and the patients with liver and kidney dysfunction, cardiovascular disorder, neuromuscular disorders, anemia, malnutrition, or hypoalbuminemia were excluded from this study. Therefore, further studies will be needed to compare the pharmacodynamics of cisatracurium between the two administration ways in the patients mentioned above. In addition, we found that the infusion rate varied according to different patients in continuous infusion group, which suggests an individual difference in cisatracurium consumption. Therefore, muscle relaxant consumption should be based on the principle of individualization. Intermittent bolus
485
injection is difficult to meet individualization, while continuous infusion is more suitable for individualization. In this study, the use of 2ED 95 (0.1 mg/kg) of cisatracurium in anesthesia induction can make T1 recover to 20% quickly for starting continuous infusion or intermittent bolus injection, and can prolong the time windows of the two administration ways to get more precise data. In clinical anesthesia, the dose of cisatracurium as inducer may be increased to 3ED 95-5ED 95 to shorten the risk period from administration to tracheal intubation. In summary, neuromuscular blockade monitoring indicates that both administration ways of cisatracurium all can provide good neuromuscular blockade, but continuous infusion can maintain more stable neuromuscular blockade, save drug consumption and better meet individualization. The spontaneous recovery was slightly faster in continuous infusion group than in intermittent bolus injection group, but without statistical significance. The exact cause is yet to be further confirmed. References [1] Mo Li-qiu, Huang Qi-wen, Tan Jie-fang. New muscle relaxantcisatracurium. Foreign Med: Anesthesiol Resusc 2000;21:170–2. [2] Adamusa M, Belohlavekb R, Koutnaa J, Vujcikova M, Janaskova E. Cisatracurium vs. rocuronium: a prospective, comparative, randomized study in adult patients under total intravenous anaesthesia. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2006;150:333–8. [3] Kahl M, Ledowski T. Augmentation of the neuromuscular blocking effects of cisatracurium during desflurane, sevoflurane, isoflurane or total i.v. anaesthesia. Br J Anaesth 1998;80:308–12. [4] Fu-shan Xue Xu, Liao Nong He, An Gang. Influences of age and gender on dose-response and recovery time-course of atracurium. Acta Acad Med Sin 2001;23:54–7. [5] Heier T, Caldwell JE. Impact of hypothermia on the response to neuromuscular blocking drugs. Anesthesiology 2006;104:1070–80. [6] Yang Gui-ying, Min Su. Pharmacokinetics of cisatracurium with different dose in rabbits undergoing three kinds of body temperature. J Chongqing Med Univ 2008;33:446–9. [7] Selcuk M, Celebioglu B, Celbiker V, Basqul E, Aypar U. Infusion and bolus administration of cisatracurium–effects on histamine release. Middle East J Anesthesiol 2005;18:407–19. [8] Wen Da-xiang, Chen Xi-ming, Hang Yan-nan, Sun Da-jin. Histamine release and hemodynamic changes caused by cisatracurium. Chin J Anesthesiol 2001;21:69–72. [9] Nagahama S, Nishimura M, Mochizuki M, Sasaki N. The effects of propofol, isoflurane and sevoflurane on vecuronium infusion rates for surgical muscle relaxation in dogs. Vet Anaesth Analg 2006;33:169–74. [10] Maidatsi PG, Zaralidou AT, Gorgias NK, Amaniti EN, Karakoulas KA, Giala MM. Rocuronium duration of action under sevoflurane, desflurane orpropfol anaesthesia. Eur J Anaesthesiol 2004;21:781–6. [11] Hemmerling TM, Schuettler J, Schwilden H. Desflurance reduces the effective therapeutic infusion rate (ETI) of cisatracurium more than isoflurane, sevoflurane, or propofol. Can J Anaesth 2001;48:532–7.
Contents lists available at SciVerse ScienceDirect
Contemporary Clinical Trials journal homepage: www.elsevier.com/locate/conclintrial
Comparative study on the pharmacodynamics of cisatracurium: Continuous infusion or intermittent bolus injection You-jing Dong ⁎, Xu Li Department of Anesthesiology, Shengjing Hospital of China Medical University, Shenyang 110004, China
a r t i c l e
i n f o
Article history: Received 16 August 2011 Received in revised form 24 December 2011 Accepted 10 January 2012 Available online 18 January 2012 Keyword: Neuromuscular blockade Cisatracurium Pharmacodynamics
a b s t r a c t Objective: To explore a better administration way through comparison of the pharmacodynamics of cisatracurium administered by continuous infusion or intermittent bolus injection. Methods: Thirty patients (ASAI-II) who had no neuromuscular disease and underwent selective surgery under general anesthesia were randomly divided into group I and II (each group with 15 patients). In group I, patients received cisatracurium by continuous infusion and in group II, by intermittent bolus injection. The responses of adductor pollicis to train-of-four (TOF) stimulation were monitored. The duration of neuromuscular blockade, recovery index and total dose of cisatracurium consumption were recorded in the two groups. Intravenous anesthesia was used for anesthesia induction and sevoflurane inhalation for maintenance of anesthesia. Results: The mean infusion rate was significantly lower in group I (0.78 ± 0.15 μg.kg − 1.min − 1) than in group II (1.09 ± 0.33 μg.kg− 1.min − 1) (P b 0.05). There was no significant difference in duration of neuromuscular blockade between the two groups (P > 0.05). The recovery index was 13.13 ± 3.36 min in group I and 14.38 ± 4.48 min in group II, which indicated that the recovery was faster in group I than in group II, but without statistical significance (P > 0.05). During the duration of neuromuscular blockade, 8 patients had T1 b 3%, 4 T1 of 3%–7% and 3 T1 of 7%–10% in group I; T1 was maintained between 0 and 20% in group II. Conclusions: Although cisatracurium consumption was significantly lower in continuous infusion than in intermittent bolus injection, continuous infusion can obtain more stable neuromuscular blockade than intermittent bolus injection. © 2012 Elsevier Inc. All rights reserved.
1. Introduction Muscle relaxant is one of the major drugs in general anesthesia at present. Cisatracurium, a new non-depolarizing muscle relaxant of benzyl isoquinoline, possesses many advantages such as a wide range of indications, rapid onset, moderate action time, rapid recovery and a little influence on the cardiovascular system, no histamine release and no accumulation in vivo, and the metabolites having no the effect of neuromuscular blockade. Its pharmacodynamics and influencing factors have been extensively studied [1–3], but
⁎ Corresponding author at: No 36, Sanhao Street, Herping District, Shenyang (110004), China. Tel./fax: + 86-024-23380681. E-mail address: [email protected] (Y. Dong). 1551-7144/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.cct.2012.01.002
little research has been done on the effect of different administration ways on cisatracurium consumption and neuromuscular blockade. We compared the pharmacodynamics of cisatracurium administered by continuous infusion and intermittent bolus injection under sevoflurane inhalation anesthesia to explore the best administration way. Our study provides a basis for the rational and safe applications of cisatracurium in clinical anesthesia. 2. Subjects and methods All study methods were approved by the Ethics Committee of the Shengjing Hospital of China Medical University. Before operation, we explained possible events during anesthesia, and enrollment into this study to subjects and their direct relative, and then all the subjects enrolled into
Y. Dong, X. Li / Contemporary Clinical Trials 33 (2012) 482–485
the study or their direct relative gave written formal consent to participate. 2.1. Subjects Thirty female patients (ASAI–II) aged 20–60 years who underwent selective gynecological surgery under general anesthesia were enrolled in the study. Inclusion criteria were (1) normal routine examination; (2) normal cardiopulmonary, hepatic and renal functions; (3) no histories of drug allergy and neuromuscular disorder. Exclusion criteria included (1) women in gestational and lactational period; (2) body mass index >30; (3) hyperthermia; (4) severe anaemia or malnutrition; (5) fluid and electrolyte imbalances; (6) taking drugs which interferes with neuromuscular blockade before operation. 2.2. Anesthesia The 30 patients were randomly divided into continuous infusion group (group I, n = 15) and intermittent bolus injection group (group II, n = 15). ECG, noninvasive blood pressure, heart rate, pulse, oxygen saturation and body temperature were continuously monitored. Propofol (2 mg/ kg) and fentanyl (2 μg/kg) were used in anesthesia induction. Assisted respiration was carried out when patients lost consciousness. At the same time, the muscle relaxation monitor (TOF-Watch) was calibrated (T1 = 100%) followed by giving a single bolus of 2ED95 cisatracurium (0.1 mg/kg) in both groups. After T1 reached the maximum blocking (response completely disappeared), tracheal intubation, mechanical ventilation, adjustment of respiratory parameters (PETCO2 in 30–40 mmHg) were performed. Anesthesia was maintained by sevoflurane inhalation, and exhaled sevoflurane concentration was monitored to keep it at 1.3MAC until operative end. Body and thumb skin temperature were maintained at not lower than 36 °C and 32 °C respectively, and the fluctuation of blood pressure was less than 20% of baseline value. 2.3. Monitoring of neuromuscular blockade Neuromuscular transmission monitor of type TOF-Watch SX (purchased from Organon Limited, Holland) was applied to measure the changes in adductor pollicis twitch. Surface electrodes were placed on the surface skin covering the ulnar nerve near the wrist of the left forearm, the sensor probe of acceleration transducer was fixed on the palm side of thumb, and the temperature probe was fixed on the surface skin of thenar eminence. Continuous train-of-four (TOF) (with a stimulus intensity of 50 mA, frequency of 2 Hz; 15 s-interval between strings) to the ulnar nerve was monitored, the value of T1 twitch inhibition was served as an indicator to evaluate neuromuscular blocking effects. When TOF-Watch indicated that T1 recovered to 20%, the
483
continuous infusion of cisatracurium started in group I. The infusion liquid was prepared based on formula: body weight (kg) × 0.12(mg)/20 ml saline, that is the concentration of 10 ml/h = 1 μg.kg − 1.min − 1. The infusion rate was first at 3 μg.kg − 1.min − 1, and then was regulated to maintain T1 b 10%. In group II, When TOF-Watch indicated that T1 recovered to 20%, cisatracurium was injected intravenously in a dose of 0.03 mg/kg. In group I, cisatracurium was given until abdominal closure, while in group II, cisatracurium was administrated for the last time according to the operative process and neuromuscular blocking effects. All patients recovered spontaneously without the rivalry of neuromuscular blockade. Neuromuscular blockade was monitored until TOF ratio (T1/Tc) ≥75%.The patients were extubated when ventilation was satisfactory. In group I, the continuous infusion time and total dose of cisatracurium consumption were recorded to calculated the mean infuse rate. The duration of neuromuscular blockade was from the beginning of continuous infusion to T1 recovering to 10% after stopping continuous infusion. The recovery time of T1 from 10% to 25% and 75%, and the recovery index (the recovery time of T1 from 25% to 75%) were recorded. In group II, the duration of neuromuscular blockade was from the time of the first administration to T1 recovering to 10% after the last administration. The frequency of administration and the total dose of cisatracurium consumption were recorded to calculated the mean infuse rate. The recovery time of T1 from 10% to 25% and 75%, and the recovery index (the recovery time of T1 from 25% to 75%) were recorded. All patients were observed the adverse reactions such as dizziness, difficulty in opening eyes, diplopia and dyspnea in each group after administration of cisatracurium.
2.4. Statistical analysis Measurement data were expressed as mean ± standard deviation (x s), t-test or ANOVA was applied in comparison between groups. P values below 0.05 were considered statistically significant.
3. Results 3.1. General status in both groups There were no significant differences in age, body height and weight, total protein, albumin and operation duration between the two groups (P > 0.05) (Table 1). Hemodynamics was stable, and body and thumb skin temperature were maintained at not lower than 36 °C and 32 °C, respectively, during anesthesia induction and maintenance. In the 30 patients, no clinical manifestations of histamine release such as tachycardia, flushing and bronchospasm occurred.
Table 1 General data in both groups (x s). Groups
Case (n)
Age (year)
Body weight (kg)
Body height (cm)
Total protein (g/L)
Albumin (g/L)
Operation duration (min)
Group I Group II
15 15
47.20 ± 8.56 47.20 ± 8.56
56.2 ± 5.75 57.6 ± 5.69
161.70 ± 3.13 160.38 ± 3.67
71.4 ± 6.55 70.3 ± 4.71
42.7 ± 3.09 41.5 ± 3.97
165.60 ± 45.52 142.88 ± 44.90
484
Y. Dong, X. Li / Contemporary Clinical Trials 33 (2012) 482–485
3.2. Duration of neuromuscular blockade and the mean infuse rate in both groups During the duration of neuromuscular blockade, 8 patients had T1 b 3%, 4 T1 of 3%–7% and 3 T1 of 7%–10% in group I; T1 was maintained between 0 and 20% by intermittent bolus injection of cisatracurium when it recovered to 20% in group II. The mean infuse rates were (0.78 ± 0.15) μg.kg − 1.min − 1 in group I and (1.09 ± 0.33) μg.kg − 1.min − 1 in group II, with P b 0.01. There was no significant difference in the duration of neuromuscular blockade between the two groups (P > 0.05) (Table 2). 3.3. Recovery of neuromuscular blockade in both groups Recovery index was (13.13 ± 3.36) min in group I and (14.38 ± 4.48) min in group II, with P > 0.05. There were no significant differences in the recovery time of T1 from 10% to 25% and 75% between the two groups (P > 0.05) (Table 3). 3.4. Follow-up and adverse events We followed up for 3 days, and no adverse as well as serious adverse events occurred. 4. Discussion The clinical application of muscle relaxants has created a new era of anesthesiology. How to use muscle relaxants to obtain satisfactory muscle relaxation and a relatively quiet operative field without postoperative delayed recovery of neuromuscular excitatory transmission is yet to be resolved in the clinical anesthesia. It is very important to select appropriate dose of non-depolarizing muscle relaxants to meet the operation requirements with avoidance of overdosage. In order to reduce the possibility of postoperative residual neuromuscular blockade, the usage of muscle relaxants should be as few as possible under the condition to meet the operation requirements. Administration way is one of the key factors for rational application of muscle relaxants. Cisatracurium, a new benzyl isoquinoline nondepolarizing muscle relaxants, is one of the ten isomers of atracurium. It possesses many advantages including stronger action, quicker recovery, no accumulation, no histamine release, metabolism being independent of liver and kidney and little effects on cardiovascular system [1,2]. When its ED95 is 0.05 mg.kg− 1, it possesses a similar metabolic pathway to atracurium, the elimination of non-organ dependent manner, and its titer is 3 times as much as atracurium. Hofmann elimination accounts for 77% of the total clearance rate, mainly occurs in plasma and tissue. Hofmann elimination is associated only with PH value and temperature of body. An-
Table 2 The duration of neuromuscular blockade and the mean infusion rates in both group (x s). Groups
Case (n)
Duration of neuromuscular blockade (min)
Mean infusion rate (μg.kg− 1.min− 1)
Group I Group II
15 15
113.10 ± 33.13 108.86 ± 18.49
0.78 ± 0.15a 1.09 ± 0.33
a
Indicates P b 0.01, compared with group II.
Table 3 Recovery time of neuromuscular blockade in both groups (x s). Groups
Case (n)
T1 from 10% to 25% (min)
T1 from 10% to 75% (min)
Recovery index (min)
Group I Group II
15 15
7.67 ± 1.76 7.98 ± 4.06
20.80 ± 4.72 21.79 ± 7.01
13.13 ± 3.36 14.38 ± 4.48
other 23% is eliminated through organ-dependent manner, and esterolysis accounts for about 5% and prototype for about 16%. Cisatracurium is not directly hydrolyzed by plasmic non-specific esterase, and its metabolites do not have the effect of neuromuscular blockade. The pharmacological characteristics of cisatracurium determine that it can be administrated either by intermittent bolus injection or continuous infusion. Currently, most of non-depolarizing muscle relaxants are administrated by single intravenous injection in clinical anesthesia. Due to the lack of neuromuscular blockade monitoring, administration is often based on clinical experience, namely that when increased airway pressure, spontaneously breathing, bucking, or body movement occur, muscle relaxants would be added. This leads to a drastic fluctuation in the degree of neuromuscular blockade, so it is difficult to keep the degree of neuromuscular blockade at a stable level. Especially during the period before operative end, the timing and dose of administration are more difficult to control. Because of estimated bias, inappropriate administration leads to overdosage of muscle relaxants, which causes delayed recovery of neuromuscular blockade. Residual neuromuscular blockade can suppress the respiratory center, decrease hypoxic ventilatory response and forced inspiratory flow, and increase the incidences of upper respiratory tract obstruction, dysphagia, regurgitation, and pulmonary complications [3]. Moreover, intermittent bolus injection readily leads to a sudden increase in blood drug concentration which makes not only acetylcholine in saturation but also drug excretion increase, resulting in a waste of muscle relaxants. Our study showed that during the duration of neuromuscular blockade, 8 patients had T1 b 3%, 4 T1 of 3%–7% and 3 T1 of 7%–10% in group I; T1 was maintained between 0 and 20% by intermittent bolus injection of cisatracurium when it recovered to 20% in group II. However the mean infusion rate was significantly lower in group 1 (0.78 ± 0.15 μg.kg − 1.min − 1) than in group II (1.09 ± 0.33 μg.kg − 1.min − 1) (P b 0.05). Above results suggest that continuous infusion can obtain effective and stable neuromuscular blockade although cisatracurium consumption is less. Therefore, under the condition that neuromuscular blockade monitoring has not become popular in clinical anesthesia, continuous infusion is better than intermittent bolus injection. In this study, anesthesia was maintained only by sevoflurane to avoid the effects of combined medication on test results. All patients were female, which excluded gender effects on test results [4]. Low temperature can prolong action time of muscle relaxants and delay spontaneous recovery time [5,6]. The body temperature and the thumb skin temperature were maintained constant during the operation, which avoided the interference of temperature with test results. Since there was no difference in general status of the
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patients between the two groups, and the experimental conditions were the same except administration ways, two groups are comparable. In this study, the 30 patients had no clinical manifestations of histamine release such as tachycardia, flushing and bronchospasm occurred, which is consistent with the reports from home and abroad [7,8]. Our results showed that the duration of neuromuscular blockade was similar in both groups; spontaneous recovery was slightly faster in continuous infusion than in intermittent bolus injection, but without significant difference. It has been reported that once spontaneous recovery of neuromuscular blockade begin, recovery speed is not associated with dosage, which may be related to Hofmann elimination or may be that metabolites have no the effects of neuromuscular blockade [5]. Theoretically, drug consumption per unit time is less; the recovery speed should be more rapid. No statistical significance in recovery speed between the two groups in this study may be due to small sample size, and further studies with larger sample size will be needed to confirm it. Moreover, in continuous infusion group, less cisatracurium consumption per unit time reduced post-operative residual neuromuscular blockade to some extent, which was conducive to postanesthesia recovery. In this study, 1.3MAC sevoflurane was used to maintain anesthesia. Inhalation anesthetics may enhance the effect of non-depolarizing muscle relaxant action, manifesting in prolonging the duration of neuromuscular blockade and reducing the maintenance dose of muscle relaxants [9,10]. Therefore, in this study, total dose of cisatracurium consumption and the recovery process were influenced by sevoflurane. It is reported that muscle relaxant consumption was decreased by 41% in the anesthesia performed with sevoflurane than with propofol [11], which may be related to higher sevoflurane concentration in inhalation group, and no usage of remifentanil in propofol group. In order to make this study more comparable, the subjects were strictly screened and the patients with liver and kidney dysfunction, cardiovascular disorder, neuromuscular disorders, anemia, malnutrition, or hypoalbuminemia were excluded from this study. Therefore, further studies will be needed to compare the pharmacodynamics of cisatracurium between the two administration ways in the patients mentioned above. In addition, we found that the infusion rate varied according to different patients in continuous infusion group, which suggests an individual difference in cisatracurium consumption. Therefore, muscle relaxant consumption should be based on the principle of individualization. Intermittent bolus
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injection is difficult to meet individualization, while continuous infusion is more suitable for individualization. In this study, the use of 2ED 95 (0.1 mg/kg) of cisatracurium in anesthesia induction can make T1 recover to 20% quickly for starting continuous infusion or intermittent bolus injection, and can prolong the time windows of the two administration ways to get more precise data. In clinical anesthesia, the dose of cisatracurium as inducer may be increased to 3ED 95-5ED 95 to shorten the risk period from administration to tracheal intubation. In summary, neuromuscular blockade monitoring indicates that both administration ways of cisatracurium all can provide good neuromuscular blockade, but continuous infusion can maintain more stable neuromuscular blockade, save drug consumption and better meet individualization. The spontaneous recovery was slightly faster in continuous infusion group than in intermittent bolus injection group, but without statistical significance. The exact cause is yet to be further confirmed. References [1] Mo Li-qiu, Huang Qi-wen, Tan Jie-fang. New muscle relaxantcisatracurium. Foreign Med: Anesthesiol Resusc 2000;21:170–2. [2] Adamusa M, Belohlavekb R, Koutnaa J, Vujcikova M, Janaskova E. Cisatracurium vs. rocuronium: a prospective, comparative, randomized study in adult patients under total intravenous anaesthesia. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2006;150:333–8. [3] Kahl M, Ledowski T. Augmentation of the neuromuscular blocking effects of cisatracurium during desflurane, sevoflurane, isoflurane or total i.v. anaesthesia. Br J Anaesth 1998;80:308–12. [4] Fu-shan Xue Xu, Liao Nong He, An Gang. Influences of age and gender on dose-response and recovery time-course of atracurium. Acta Acad Med Sin 2001;23:54–7. [5] Heier T, Caldwell JE. Impact of hypothermia on the response to neuromuscular blocking drugs. Anesthesiology 2006;104:1070–80. [6] Yang Gui-ying, Min Su. Pharmacokinetics of cisatracurium with different dose in rabbits undergoing three kinds of body temperature. J Chongqing Med Univ 2008;33:446–9. [7] Selcuk M, Celebioglu B, Celbiker V, Basqul E, Aypar U. Infusion and bolus administration of cisatracurium–effects on histamine release. Middle East J Anesthesiol 2005;18:407–19. [8] Wen Da-xiang, Chen Xi-ming, Hang Yan-nan, Sun Da-jin. Histamine release and hemodynamic changes caused by cisatracurium. Chin J Anesthesiol 2001;21:69–72. [9] Nagahama S, Nishimura M, Mochizuki M, Sasaki N. The effects of propofol, isoflurane and sevoflurane on vecuronium infusion rates for surgical muscle relaxation in dogs. Vet Anaesth Analg 2006;33:169–74. [10] Maidatsi PG, Zaralidou AT, Gorgias NK, Amaniti EN, Karakoulas KA, Giala MM. Rocuronium duration of action under sevoflurane, desflurane orpropfol anaesthesia. Eur J Anaesthesiol 2004;21:781–6. [11] Hemmerling TM, Schuettler J, Schwilden H. Desflurance reduces the effective therapeutic infusion rate (ETI) of cisatracurium more than isoflurane, sevoflurane, or propofol. Can J Anaesth 2001;48:532–7.