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Anesth Analg 2000;91:1526-1530
© 2000 International Anesthesia Research Society

GENERAL ARTICLES

The Prolonged Duration of Rocuronium in Chinese Patients

Linda M. Collins, MB, BCh, BAO, FFARCSI*, Joan C. Bevan, MD, FRCA{dagger}, David R. Bevan, MB, MRCP, FRCA*, Giselle C. P. Villar, MD{dagger}, Raymond Kahwaji, MD, FRCPC{dagger}, Michael F. Smith, MD, FRCPC{dagger}, and François Donati, PhD, MD, FRCPC{ddagger}

Departments of Anesthesia, *Vancouver General Hospital and {dagger}British Columbia’s Children’s Hospital, University of British Columbia, Vancouver, British Columbia, and {ddagger}Université de Montréal, Montréal, Québec, Canada

Address correspondence and reprint requests to Linda Collins, MB, BCh, BAO, FFARCSI, Department of Anesthesia, Vancouver General Hospital, Room 3200, 910 West 10th Ave., Vancouver, British Columbia, Canada V5Z 4E3. Address e-mail to lindacollins{at}bc.sympatico.ca


   Abstract
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 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
We compared the potency and duration of action of rocuronium in Chinese and Caucasian patients during general anesthesia. Thirty-six women (18 Caucasian and 18 Chinese) and 36 children (18 Caucasian and 18 Chinese) were evaluated during the administration of propofol/fentanyl anesthesia. Patients in each age group were randomized into three subgroups to receive single doses of 0.06, 0.12, or 0.18 mg/kg rocuronium (adults) or 0.12, 0.18, or 0.24 mg/kg rocuronium (children). Neuromuscular blockade was assessed by electromyography of the adductor pollicis after train-of-four (TOF) stimulation of the ulnar nerve. Dose response curves were constructed when maximum neuromuscular depression of the first twitch of the train (T1) was obtained. A second bolus dose of rocuronium was then administered to a total dose of 0.6 mg/kg. The times of spontaneous recovery to T1 10%, 25%, and 90% of control and to TOF 0.25, 0.50, and 0.70 were recorded. For both adults and children, recovery occurred later in Chinese than in Caucasian patients (P < 0.05 for T1 of 10%, 25%, 75%, and 90% and TOF to 0.7). The 50% effective dose was smaller in Chinese adults (125 ± 63 vs 159 ± 66 µg/kg) and Chinese children (171 ± 43 vs 191 ± 46 µg/kg) than in Caucasian adults and children, but the difference was not statistically significant. In adults, time to 25% T1 recovery was 43 ± 13 min in Chinese patients and 33 ± 10 min in Caucasian patients (P < 0.05). The corresponding values were more rapid for children: 30 ± 10 and 24 ± 6 min (P < 0.05). We conclude that the recovery from rocuronium neuromuscular blockade was longer in Chinese compared with Caucasian patients and in adults compared with children.

Implications: The potency of rocuronium does not differ between adults and children of Caucasian and Chinese origins. If tracheal intubating doses of 0.6 mg/kg IV are given, similar levels of neuromuscular blockade are expected but recovery will be longer by 29%–30% in Chinese compared with Caucasian children and adults.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Geographic location and ethnic background influence the potency and duration of action of drugs. More than 30 yr ago, Katz et al. (1) observed a transatlantic difference in sensitivity to muscle relaxants. Patients in New York achieved a more intense block (75% ± 14%) than British patients in London (43% ± 21%) after the administration of d-tubocurarine, 0.1 mg/kg IV. Children also differ from adults in their sensitivity to muscle relaxants. Spontaneous recovery from rocuronium and vecuronium to train-of-four (TOF)0.7 was faster in children (28.8 ± 7.8 and 34.6 ± 9.0 min) than in adults (45.7 ± 11.5 and 52.5 ± 15.6 min) (2).

Since 1980, there has been a 20% increase in the population of Canada. In British Columbia, there has been considerable immigration of Chinese people from Hong Kong, and 15.4% of inhabitants of Metropolitan Vancouver are Chinese (3). We have noted, in retrospective analysis of previous studies performed by our group, that Chinese patients appeared to be more sensitive to neuromuscular blocking drugs than Caucasian patients (4). The population diversity of Vancouver (the majority of Chinese adults and children are first and second generation, respectively) provided an opportunity to study the potency and duration of action of rocuronium in Chinese and Caucasian adult and pediatric ethnic groups.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
After IRB approval and written, informed consent, we studied 36 ASA physical status I and II, 18–60-yr-old women undergoing elective gynecological surgery, and 36 ASA physical status I and II, 2–9-yr-old pediatric dental patients, undergoing surgery of at least 1 h duration. There were 18 Caucasian and 18 Chinese patients in each group. Adult patients who deviated >30% from ideal body weight and pediatric patients who were outside the 5th–95th percentile range on normal growth charts were excluded. Patients were also excluded if they had hepatic, renal, or neuromuscular disease, malnutrition, electrolyte abnormalities, a history of drug abuse, or if they were taking medication that may interfere with neuromuscular function. Patients in each age group were randomized to receive one of three initial bolus doses of rocuronium: (adults) 0.06, 0.12, or 0.18 mg/kg and (children) 0.12, 0.18, or 0.24 mg/kg by a computer-generated assignment to six groups of 6 patients. A further dose of rocuronium (to a total of 0.6 mg/kg per patient) was given before tracheal intubation.

Preoperative care and premedication were at the discretion of the anesthesiologist. Routine monitoring was used. In adults, anesthesia was induced with 1–2 µg/kg fentanyl and 1.5–3 mg/kg propofol followed by intermittent positive pressure ventilation with O2/N2O (1:2) to achieve normocapnia. Propofol infusion commenced at 140 µg · kg-1 · min-1 and was titrated to maintain heart rate and systolic blood pressure within 10% of baseline values. Intermittent IV boluses of fentanyl (1–2 µg/kg) or morphine (0.05 mg/kg) were administered as indicated.

In children, anesthesia was induced with 5 mg/kg propofol, 0.02 mg/kg atropine, 0.3 mg/kg lidocaine, and 2 µg/kg fentanyl. Maintenance of anesthesia was similar to that in adults, but the propofol infusion was started at a higher rate (200 µg · kg-1 · min-1). In the pediatric group, sevoflurane was inhaled until consciousness was lost if IV cannulation was difficult. In all other respects, the study protocol was similar in adults and children.

Neuromuscular transmission was monitored by electromyography (EMG) with the Relaxograph® (Datex, Helsinki, Finland) and following Good Clinical Research Practice guidelines (5). Surface electrodes were applied over the ulnar nerve on the forearm. Recording electrodes were placed on the hand to record the EMG response of the adductor pollices, and the arm was secured. A skin thermistor was taped to the hand close to the monitoring site, and the arm was wrapped in a blanket to reduce cooling. Skin temperature was maintained at >32°C, and central temperature, measured at the axilla (children) or esophagus (adults), was maintained at >35°C. The ulnar nerve was stimulated supramaximally at a frequency of 2.0 Hz for 2 s and repeated every 10 s. The evoked EMG response of the adductor pollices was recorded. Stimulation commenced before the administration of rocuronium and was allowed to stabilize for a period of 3 min before the injection of rocuronium. Then rocuronium (0.06, 0.12, or 0.18 mg/kg in adults and 0.12, 0.18, and 0.24 mg/kg in children) was injected into a free-flowing IV infusion. Maximum depression of T1 was defined as occurring when the response to the first stimulus in the train, T1, was stable for three consecutive trains. At this time, a second dose of rocuronium IV (0.54, 0.48, and 0.42 mg/kg in adults and 0.48, 0.42, and 0.36 mg/kg in children) was administered, so that each patient received a total dose of 0.6 mg/kg. Tracheal intubation was then performed. Monitoring was continued until the end of the administration of anesthesia. Dose-response curves were constructed from the logit transformation of maximum T1 depression versus the log of the dose of rocuronium, expressed in mg/kg. Recovery of block (times to T1 10%, 25%, and 90% of control and to TOF 0.25, 0.50, and 0.70) was assessed by using the final EMG baseline (T1 height at TOF >= 0.70 recovery) as a reference to calculate neuromuscular recovery. For each recovery variable, the time from the administration of the first bolus of rocuronium was calculated. Recovery index was calculated as the time from T1 25% to T1 75% recovery.

Demographic data including age, height, and weight in adults and children were compared between ethnic groups by using Student’s t-test. The slopes of the dose response curves were compared for parallelism, and the groups of data were compared by using analysis of covariance. In each age group, the 50% effective dose (ED50) for rocuronium of the Chinese and Caucasian patients were compared by using Student’s t-test. Comparison of duration of block between adults and children and Caucasian and Chinese patients were made by using Student’s t-test (GraphPad PRISM Version 2.0; GraphPad Software, San Diego, CA). A statistical significance level of P < 0.05 was chosen. All data were expressed as mean values ± SD (range) unless otherwise stated. An initial sample estimate was performed to allow detection of a 30% difference in time to TOF0.25, the primary outcome variable ({alpha} = 0.05, ß = 0.8). At the end of the study, power analysis was performed to determine the possibility of a type II error in the potency estimation (GraphPad PRISM, Version 2.0).


   Results
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Discussion
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The study was completed in 36 children and 36 adults. In the adult group, the Caucasian population was older than the Chinese (P < 0.05), and the height (P < 0.01) and weight (P < 0.05) of the Chinese patients were less than that of the Caucasian patients (Table 1). All adult patients were female, and in the pediatric group, 16 patients were female and 20 were male. There was no difference between the two pediatric ethnic groups with respect to weight, age, sex, or height. In adults, two Chinese patients were born in Canada. All other patients had immigrated to Canada from China at a mean of 10 yr previously (range 3–24 yr).


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  		Table 1. Demographic Data
 
Dose-response curves for adults and children are shown in Figures 1 and 2. The slopes of the regression lines did not differ from parallelism. The ED50 values of the adult and pediatric Caucasian population were numerically greater than that of the Chinese, but these were not statistically significant (Table 2). There was also no difference in ED50 between the adults and children. The power of the study to detect a statistically significant interethnic difference was 30% in children and 40% in adults.



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  		Figure 1. Adults: Maximum first twitch depression (logit scale) versus dose of rocuronium in mg/kg (log scale) for Chinese({square}- - -{square}) and Caucasian ({blacksquare}- - -{blacksquare}) patients. Lines represent regression lines. Individual points represent mean and the bars standard deviation.

 

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  		Table 2. ED50 Values of Rocuronium
 


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  		Figure 2. Children: Maximum first twitch depression (logit scale) versus dose of rocuronium in mg/kg (log scale) for Chinese({square}- - -{square}) and Caucasian ({blacksquare}- - -{blacksquare}) patients. Lines represent regression lines. Individual points represent mean and the bars standard deviation.

 
Recovery of neuromuscular function to T1 of 10%, 25%, 75%, and 90% and TOF to 0.70 was prolonged in the Chinese compared with the Caucasian populations at both ages (P < 0.05). The duration of recovery from rocuronium for all indices in the pediatric population was greater than in the corresponding adult population (Table 3) (P < 0.05).


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  		Table 3. Recovery Times After Rocuronium Administration
 

   Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
In this study, we demonstrated that spontaneous recovery from neuromuscular blockade after 0.6 mg/kg rocuronium was slower in Chinese than in Caucasian patients in both adults and children. Also, recovery of most indices was more rapid in children than in adults of both ethnic groups. Although the potency of rocuronium in the Caucasian patients was numerically higher than that of Chinese in either age group, the study had insufficient power to detect a statistically significant difference.

Previous studies have shown that the response to muscle relaxants differs between geographical areas. Katz et al. (1) reported that the neuromuscular blocking effect of succinylcholine (1 mg/kg) in adults was shorter in London (9.1 ± 2.9 min) than in New York (14.6 ± 3.6 min). This transatlantic difference was confirmed by Fiset et al. (6) who showed that the ED50 and 90% effective dose of vecuronium were larger in Paris (33 ± 3.3, 71.9 ± 7.2 µg/kg) than in Montreal (26.0 ± 1.4, 44.2 ± 2.5 µg/kg). Also, Salib at al. (7) found that the duration of action of vecuronium (0.1 mg/kg) from injection to 25% first twitch recovery was shorter (28.5 ± 6.8 min) in Paris than in Montreal (39.1 ± 7.3 min) (P < 0.0001) but, neostigmine given at 25% first twitch recovery was as effective in Montreal as in Paris.

Few studies have compared the sensitivity of muscle relaxants in different ethnic groups. Houghton et al. (8) reported that the recovery of spontaneous ventilation after succinylcholine was 35% slower in Asian patients than in European patients, but no difference in the incidence of myalgia was seen between the two ethnic groups. Hosseini at al (9) showed that Irish subjects (7.82 ± 0.14 U/mL) had more serum cholinesterase activity than Iranian subjects (4.22 ± 0.90 U/mL). Furthermore, the percentage of inhibition of enzyme activity by dibucaine and fluoride was more in the Irish subjects (9).

The effect of ethnicity on other drugs has been studied (10–11). Zhou et al. (12) showed that morphine clearance after 0.15 mg/kg IV was 50% more rapid in Chinese than Caucasian patients. Metabolism to the major conjugative metabolites, morphine-3-glucuronide and morphine-6-glucuronide, was higher in Chinese by 51% and 60%, respectively, than in Caucasian subjects, while formation of the oxidative metabolite, normorphine, was not different between groups. Chinese patients were less sensitive to the respiratory and vasodepressant effects of morphine but not to the nausea-producing effects (12). Codeine may exert its analgesic action through the O-demethylated metabolite morphine (13). Metabolism is diminished in Chinese patients because a single codon difference (T188) results in a decrease in metabolicactivity of CYP2D6. Thus, Chinese patients require larger doses of codeine for analgesia (14). Houghton et al. (15) compared meperidine requirements for patient-controlled analgesia in European and Asian patients undergoing upper abdominal surgery and found that the Chinese patients were more sedated than the Caucasian patients in the first four hours after upper abdominal surgery, even though they used 24% less meperidine.

We defined Chinese subjects as people of first or second generation originating from China. Caucasian people were defined as members of the white race, Indo European (from supposed origin in the Caucasus). In adults, two Chinese patients were born in Canada. All other patients immigrated to Canada from China at a mean of 10 years previously (range 3–24 years). All subjects lived in Vancouver at the time of the study.

We found that the potency and duration of action of rocuronium were similar to that previously described in Asian and Caucasian women (16–18). In adults, to reduce sex-related differences in response, we studied only women (16,19). The more rapid recovery from rocuronium blockade in children and the ED50 of rocuronium in the Caucasian children were similar to other studies (2,20). There are no reports of the pharmacological response to neuromuscular blocking drugs in Asian children.

In this study, which was performed according to Good Clinical Research Practice (5), the doses of rocuronium used to produce dose-response curves were less than in previous studies in the anticipation that requirements would be reduced in the Chinese groups. The potency of rocuronium is less in children than in adults; therefore, we increased the initial dose of rocuronium in children to 0.12, 0.18, or 0.24 mg/kg (20). Although this allowed direct comparisons of the effect at each dose, it impaired our ability to produce data throughout the dose-response curve. In Chinese and Caucasian patients, 0.18 mg/kg of rocuronium produced maximum block of 72% ± 22% and 64% ± 21% in adults and 49% ± 23% and 42% ± 22% in children (Table 4). Although the intensity of block produced by the same dose of rocuronium was numerically greater in Chinese than in Caucasian patients (maximum block and dose responses), the study had insufficient power (ß = 40%–70%) to rule out type II error.


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  		Table 4. Maximum Block (%) Attained with Different Doses of Rocuronium
 
Assuming that the ED50 is actually 21% less in Chinese adults than in Caucasian adults, as found in the present study, and assuming that the standard deviations reported here are a good index of the variability in the whole population, 60 patients per group would have been required to have an 80% chance of finding a difference. The same calculation in children, where the measured ED50 difference was 11% but the standard deviation somewhat less than in adults, indicates that 80 patients per group would have been necessary. Because of the large interindividual variability in the response to neuromuscular blocking drugs, it is difficult to demonstrate small differences in ED50 between two populations. However, the number of patients in the present study, although too small to demonstrate small differences in ED50, was large enough to show a prolongation of the clinical duration of action of a clinically relevant dose (0.6 mg/kg) by as much as one-third.

The reason for the difference in response between Chinese and Caucasian patients is not known but is likely multifactorial. Previously reported differences in response to vecuronium in men and women were shown to be related to pharmacokinetic differences (21) and pharmacodynamic (22) entities. Pharmacodynamic differences also lead to increased sensitivity of women to rocuronium (16). We have assumed that the reasons for the differences have a similar pharmacokinetic background. A decrease in volume of distribution in women leads to increased circulating concentration and more intense and longer-lasting blockade. Thus, in the present study, all adults were female. There are no pharmacokinetic studies comparing the response in Asian and Caucasian patients to nondepolarizing neuromuscular blocking drugs. Nondepolarizing blocking drugs are basic drugs that bind to plasma proteins, although the degree of binding shows considerable variation among studies (23,24). Recently, {alpha}-1-acid glycoprotein has been shown to accelerate recovery from rocuronium and pancuronium by increasing protein binding (25,26). Chinese patients have decreased {alpha}-1-acid glycoprotein concentrations compared with Caucasian patients, and this might be responsible for changes seen in this study (27).

This study demonstrated interethnic differences in the duration of action of rocuronium between pediatric and adult populations. Despite a numerical difference of 21% in the ED50 values of rocuronium between the adult Chinese and Caucasian populations, this failed to reach statistical significance. The longer duration of action in Chinese patients may be kinetic or dynamic in origin or both. The difference in duration of action may be the result of differences in potency that were undetected in this study, but they may also be related to pharmacokinetic differences. Awareness of interethnic differences in responses to anesthetic drugs should lead to dosage recommendations that differ among different populations.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication August 8, 2000.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press