Leykin, Yigal MD, MSc*; Pellis, Tommaso MD†; Lucca, Mariella MD*; Lomangino, Giacomina MD†; Marzano, Bernardo MD‡; Gullo, Antonino MD†
Obesity is considered to be a worldwide concern, and in 1997 the World Health Organization published a report on preventing and managing the epidemic (1). Morbid obesity (body mass index [BMI] >40 kg/m2) occurs in 2%–5% of the population of the Western world and causes or exacerbates major physical morbidities (2,3). The International Association for the Study of Obesity estimates that the cost for comorbidities of 2%–8% of the costs of public health is just as expensive as complete cancer therapy (4). Nonsurgical treatment has been of little long-term use, but the introduction of laparoscopic gastric banding has been a considerable breakthrough (5).
However, the adaptation of drug dosages to obese patients is a subject of major concern. The main factors that affect the tissue distribution of drugs are body composition, regional blood flow, and the affinity of the drug to plasma proteins and/or tissue components. Obese people have larger absolute lean body masses as well as fat masses and a decreased proportion of muscle mass and body water than nonobese individuals of the same age, sex, and height (6). Obesity may also alter both liver function and protein binding (6,7).
Pharmacokinetic studies in obesity show that the behavior of molecules with weak or moderate lipophilicity, such as vecuronium, is generally rather predictable, because these drugs are distributed mainly in lean tissues (8). Accordingly, the dosage of these drugs should be based on ideal body weight (IBW) rather than on real body weight (RBW).
The pharmacokinetics of rocuronium bromide are similar to those of vecuronium, although with a minor volume of distribution and no active metabolites (9). In a study by Puhringer et al. (10), obese patients receiving rocuronium had shorter onset time and slightly longer duration of action compared with normal weight patients (NBW), but this finding did not achieve statistical significance, whereas in another study by the same authors (8) there was no difference in duration between the two groups.
The purpose of this study was to investigate the onset time, the duration of action, and the recovery time from neuromuscular blockade in morbidly obese patients admitted for laparoscopic gastric banding when the total dose of rocuronium was based on the RBW or IBW.
After obtaining approval from the institutional ethics committee and obtaining written, informed consent, we studied 12 patients admitted for laparoscopic gastric banding to treat their obesity. Inclusion criteria were female sex, age 20–50 yr, ASA status III (morbid obesity) and BMI >40 kg/m2, calculated as follows:
An additional control group of 6 female patients admitted for gynecological laparoscopic surgery (aged 20–50 yr, ASA status I–II, and BMI 20–24 kg/m2) served as control. Patients who were receiving medications known to influence neuromuscular function were excluded. All patients were free from neuromuscular diseases.
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No premedication was given. Routine monitoring was used. Neuromuscular transmission was monitored and recorded by using acceleromyography of the adductor pollicis muscle (TOF-Guard; Organon Teknika, BV, The Netherlands). Neuromuscular blockade was measured by the response to single twitch stimuli at 0.1 Hz during the onset time and then by train-of-four stimulation. Surface electrodes were placed at the wrist for ulnar nerve stimulation. Contractions of the adductor pollicis muscle were recorded with an acceleromyographic transducer placed at the volar aspect of the thumb at the interphalangeal joint. The position of the transducer was secured by placing the thumb in the Hand Adapter (Organon International Inc., Roseland, NJ). Both the acceleromyographic transducer and a temperature sensor, facing the volar aspect of the hand, are incorporated in the Hand Adaptor. The Hand Adaptor acts as pretensioner, taking the thumb back to its resting position, allowing more stability to the signal, and minimizing the enhancement of the evoked mechanical response after repeated indirect stimulation.
The patients were positioned in the 30° reverse Trendelenburg position and were breathing oxygen for 5 min with 100% oxygen. Anesthesia was then induced with remifentanil 0.25 μg · kg−1 · min−1 and propofol 2 mg/kg and was maintained by a continuous infusion of remifentanil 0.25–0.50 μg · kg−1 · min−1 and propofol 4–6 mg · kg−1 · h−1. Ventilation was controlled with 50% air in oxygen, and end-tidal CO2 was maintained between 35 and 40 mm Hg.
Once the patient was unconscious, autocalibration (auto II mode) of single twitch to 100% was performed by using supramaximal stimulation. After calibration was performed, stimulation was paused and resumed only before the intubation dose of rocuronium 0.6 mg/kg was injected IV. Intubating conditions were assessed and graded as excellent, good, poor, and not possible according to the criteria of Pino et al. (11) by an experienced anesthesiologist who was blinded to the group allocation and not involved in the protocol. The time lapse from the end of rocuronium injection until suppression of the twitch tension to 95% of its control value (onset time) and the time lapse until recovery of twitch tension to 25% of control (clinical duration of action) were measured. All patients were allowed to recover spontaneously. The time lapse from 25% to 75% recovery of T1 (recovery index) was also recorded.
After the induction of anesthesia, the obese patients were randomly assigned to receive the dose of rocuronium on the basis of their RBW (Group 1; n = 6) or according to their IBW (Group 2; n = 6). The six NBW patients of the control group received the dose of rocuronium on the basis of their RBW (Group 3). IBW was defined as follows (1 inch = 2.54 cm; 1 foot = 30.48 cm) (8,12,13):
For statistical analysis, the Kruskal-Wallis nonparametric test was performed to compare the onset time, the duration, and recovery index among the studied groups. Post hoc comparisons were performed with the Mann-Whitney U-test with univariate analysis of variance and with the Bonferroni correction for multiple comparisons. Values are presented as median and range. A P value of <0.05 was considered significant.
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There were no demographic differences among groups (Table 1). The BMI, RBW, and IBW of the three groups are shown in Table 1. The onset time, the duration, and the recovery index are illustrated in Table 2. The onset time was longer in the IBW group compared with the RBW and the NBW groups, but this did not achieve statistical significance. The duration time was more than double in the RBW group (55 min) compared with the IBW and NBW groups (22 and 25 min, respectively; P < 0.001) and was comparable between the IBW and the NBW groups. The spontaneous recovery time was slightly longer in the RBW group, approximately 3–5 min, but this was not statistically significant.
Tracheal intubating conditions were good or excellent in all patients. The average surgical time was 97 min (range, 55–270 min), and the average hospital stay was 3.2 days (range, 2–7 days). No serious adverse clinical or laboratory effects were noted during postoperative hospitalization.
We demonstrated that in morbidly obese patients, the duration of action of rocuronium was significantly prolonged when the dose was calculated according to RBW. In contrast, in NBW patients or when rocuronium was dosed according to the IBW, the clinical duration of action was less than half.
There are conflicting reports concerning the effects of obesity on the pharmacodynamics of nondepolarizing neuromuscular blocking drugs (14,15). Individuals with the same BMI may differ in their body composition and fat distribution, particularly among ethnic groups. It is also difficult to assess the hepatic metabolism of drugs in clinical settings (6).
Puhringer et al. (8) demonstrated that the pharmacokinetics of rocuronium were not altered in obese patients when compared with NBW patients. Volumes of distribution, distribution and elimination half-lives, plasma clearance, and mean residence times were similar in both groups. The pharmacodynamic data such as onset time, duration 25%, and recovery time were also comparable. However, in a previous study by the same authors (10), the onset time tended to be faster and the duration of action longer in obese patients than in NBW patients (31.5 vs 25.0 minutes), although these differences were not significant. No differences were observed in spontaneous and induced recovery time. On the contrary, in this study, we demonstrated, with statistical significance, a considerably longer duration of action in obese patients than in NBW patients (55.5 vs 24.4 minutes, respectively).
The internationally recommended classification of obesity published by the World Health Organization (1) is based on the BMI. Overweight is defined as BMI >25–29.9 kg/m2 and obesity as BMI >30 kg/m2. Obesity is divided into three classes: moderate (BMI 30–34.9 kg/m2), severe (BMI 35–39.9 kg/m2), and morbid (BMI > 40 kg/m2). The difference between the results of our study and the studies by Puhringer et al. (8) is probably because our patients belonged to the morbid obesity class (BMI 43.8 ± 2.1 kg/m2), whereas the patients in the Puhringer et al. studies were in the moderate obesity class (BMI 33.5 ± 4.7 kg/m2 and 34.3 ± 4.6 kg/m2). Accordingly, the total dose of rocuronium administered was significantly larger in our patients, thereby explaining the statistical difference that Puhringer et al. were not able to produce.
The onset time tended to be faster in the RBW group (77 seconds) than in the IBW group (87 seconds) but not in comparison to the NBW group (67 seconds). The reason for the slightly longer onset time in the IBW group may have been that in this group, the total dose of rocuronium was calculated by using the formula of IBW, whereas in the NBW group, it was based on RBW. Likewise, the duration of action in the IBW group was slightly shorter (22.3 minutes) than in the NBW group (25.4 minutes). However, these differences did not reach the level of statistical significance.
Fisher and Rosen's (15) pharmacokinetic and pharmacodynamic modeling explains the slowing of the recovery of neuromuscular function with increasing initial doses of vecuronium. With smaller total doses of vecuronium, the recovery from blockade will occur during the distribution phase as the drug plasma concentration decreases relatively rapidly, whereas with larger doses, recovery will occur when plasma concentration is decreasing more slowly (i.e., the elimination phase). Even if our dosing of rocuronium by patient weight resulted in a larger total dose and a larger plasma concentration for the obese patients, we failed to achieve a difference in recovery consistent with the Fisher and Rosen model (15).
Although the differences observed in the study of Puhringer et al. (10) were not statistically significant, the authors insisted on the clinical relevance of the prolonged duration of action and concluded that rocuronium should be administered to obese patients on the basis of IBW and not RBW. The results of our study offer statistical support to this statement.
We recognize the limitations of a low-powered study due to the small number of patients enrolled in each group. Variables such as onset time and recovery index might have achieved statistical significance with more patients.
Within these limitations, we conclude that, although the present knowledge of the influence of obesity on pharmacokinetics is still limited, in clinical practice, rocuronium bromide should be administered to morbidly obese patients on the basis of IBW and not RBW.
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