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*Departments of Anesthesia, Pain, Perioperative Medicine and Intensive Care, and
Surgery, Santa Maria degli Angeli Hospital, Pordenone, Italy; and the
Department of Perioperative Medicine, Intensive Care and Emergency, Trieste University Medical School, Trieste, Italy
Address correspondence and reprint requests to Yigal Leykin, Department of Anesthesia and Intensive Care, Santa Maria degli angeli Hospital, Via Montereale 24, 33170 Pordenone, Italy. Address email to yigal.leykin{at}aopn.fvg.it
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Abstract |
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IMPLICATIONS: We investigated the effects of cisatracurium, one of the stereoisomers of atracurium, on morbidly obese patients, prompted by the conflicting evidence reported for atracurium. We concluded that the duration of action of cisatracurium is prolonged when dosed according to real body weight in morbidly obese patients.
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Introduction |
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There is conflicting evidence concerning the effects of obesity on the pharmacodynamics of nondepolarizing neuromuscular relaxants (3,4). Weinstein et al. (3) found that the duration of action of atracurium was not prolonged in the obese possibly because of its organ functioning independent elimination via Hoffman degradation (3,5). Accordingly, cisatracurium, one of the stereoisomers of atracurium that avoids histamine release, has been also suggested on a real body weight (RBW) basis and as the neuromuscular blocking drug of choice for obese patients (6,7). However, Kirkegaard-Nielsen et al. (8) showed a prolonged duration of action of atracurium-induced neuromuscular block in obese patients and concluded that the dose based on RBW should be reduced in such patients.
The purpose of our study was to compare onset and the duration time of cisatracurium-induced neuromuscular blockade in morbidly obese patients when dosed according to RBW or ideal body weight (IBW) and to compare it with non-obese patients.
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Methods |
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Ranitidine, 300 mg orally, was administered the night before and again as 150 mg IV together with metoclopramide 10 mg 1 h before surgery. No other premedication was administered. Routine monitoring was used. All airway management equipment was available including fiberoptic endoscopes, laryngeal mask airway (LMA), intubating LMA, and instrumentation for transtracheal ventilation and cricothyrotomy. A surgeon familiar with surgical airways was readily available. Neuromuscular transmission was monitored and recorded using acceleromyography of the adductor pollicis muscle (TOF-Guard; Organon Teknika, BV, NL). Cisatracurium-induced neuromuscular block was measured by the response to single twitch stimuli at 0.1 Hz during the onset time and subsequently by train-of-four (TOF) stimulation at a frequency of 4 stimuli at 2 Hz interposed by a 10-s interval with surface electrodes placed at the wrist for ulnar nerve stimulation. Using an acceleromyographic transducer placed at the volar aspect of the thumb, at the interphalangeal joint, contractions of the adductor pollicis were recorded. The position of the transducer was secured by placing the thumb in the Hand Adapter (Organon International Inc., Roseland, NJ). The Hand Adaptor incorporates the acceleromyographic transducer as well as a temperature sensor, both facing the volar aspect of the hand. Moreover, the Hand Adaptor acts as pretensioner, returning the thumb to its resting position, allowing more stability to the signal and thereby minimizing the enhancement of evoked mechanical response after repeated indirect stimulation.
Patients were positioned in the 30° reverse Trendelenburg position and breathed 100% O2 for 5 min. Cricoid pressure was applied and anesthesia was subsequently induced with remifentanil 0.25 µg · kg–1 · min–1 and propofol 2 mg/kg and maintained by 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 35–40 mm Hg.
After inducing anesthesia, autocalibration (auto II mode) of single twitch to 100% was performed on the unconscious patient by supramaximal stimulation. Once calibration was performed stimulation was paused and resumed only before the tracheal intubation dose of 0.2 mg/kg of cisatracurium was injected IV. For further precaution, before administering the muscle relaxant, laryngoscopy was performed; only subsequently cisatracurium was injected and oral endotracheal intubation performed. Difficult airway management devices were readily available. Intubating conditions were assessed by an experienced anesthesiologist who was blinded to the group allocation and not involved in the protocol and graded according to the criteria used by Pino et al. (9) as excellent, good, poor, and not possible. The time lapse from the end of cisatracurium injection until suppression of the twitch tension to 95% of its control value (onset time) and the time lapse until recovery of the first twitch to 25% of control (clinical duration of action) were measured. All obese patients were allowed to recover spontaneously. In the postoperative period patients were transferred to a postanesthesia care unit (PACU) fully equipped for institution of mechanical ventilation and monitored for a minimum of 6 h. Tracheal extubation was performed only when patients met the following criteria: awake, alert, and following commands; able to protect their airway; sustained head lift >5 s; acceptable blood gasses on FIO2 of 0.4; maximal inspiratory capacity of 25 cm H2O. Moreover, a TOF ratio >0.9 was mandatory for tracheal extubation. In the control group, neuromuscular blockade was antagonized and patients were tracheally extubated in the operating room.
After induction of anesthesia and autocalibration, the morbidly obese patients were randomly assigned to receive a dose of cisatracurium on the basis of their RBW, Group I (n = 10), or according to their IBW, Group II (n = 10). In addition, 10 NBW patients served as a control group by receiving a dose of cisatracurium on the basis of their RBW, Group III. IBW was defined as follows: IBW (female) = 100 lb + 5 lb/inches above 5 foot height (inch = 2.54 cm; foot = 30.48 cm) (3,10,11).
For purposes of statistical analysis the Kruskal-Wallis nonparametric test was performed to compare the onset time and the duration of action among the studied groups. Post hoc comparisons were performed with the Mann-Whitney U-test with univariate analysis of variance and using 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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Discussion |
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Cisatracurium is one of the 10 stereoisomers of atracurium. The main advantage of cisatracurium compared with atracurium is the clinical absence of nonimmunological histamine release (6). The pharmacokinetics of cisatracurium are similar to those of atracurium. However, the plasma clearance of cisatracurium is negatively influenced by renal failure, which is not the case with atracurium (12–13).
There are conflicting reports concerning the effects of obesity on the pharmacodynamics of nondepolarizing neuromuscular blocking drugs (3,4). Body composition and fatness may differ within individuals with the same BMI, particularly between ethnic groups. It is also difficult, in clinical settings, to assess organ function, and therefore the metabolism of neuromuscular relaxants (1). Neuromuscular blockers are polar and hydrophilic drugs; thus their distribution between fat and lean tissues may further influence their pharmacokinetics in obese individuals (1).
Weinstein et al. (3) observed that obese patients have a prolonged recovery from neuromuscular blockade when vecuronium but not atracurium is administered. The authors advance as possible explanations for this discrepancy the differing effects of a relative overdosage for the two drugs, the increased sensitivity of the neuromuscular junction to vecuronium, and the delayed elimination of vecuronium in the obese. The elimination of vecuronium is highly dependent on hepatic clearance, whereas that of atracurium depends on Hoffman degradation at body temperature and pH and on ester hydrolysis (3). Andersen et al. (14) reported abnormal liver biopsies in 88% of obese patients despite normal liver function tests. Accordingly, in the obese, fatty infiltration of the liver may be responsible for the decreased clearance of vecuronium (15).
The pharmacokinetics of rocuronium bromide are similar to those of vecuronium, although with minor volume of distribution and no active metabolites (16). Puhringer et al. (11) showed that obese patients receiving rocuronium had a slightly longer duration of action compared with normal weight patients, but this finding did not achieve statistical significance, whereas in another study by the same authors there was no difference in duration between two similar groups (17). To the contrary, in a study by our group (18) we demonstrated, with statistical significance, a considerably prolonged duration of action after administration of rocuronium in morbidly obese patients compared with NBW patients (55.5 minutes versus 24.4 minutes). The reason for the difference observed between our study and Puhringer et al.’s is probably related to the obesity class to which the patients belonged. In our study patients belonged to the morbid obesity class (BMI 43.8 ± 2.1) whereas in Puhringer et al.’s to the moderate obesity class (BMI 33.5 ± 4.4). Accordingly the total dose of rocuronium administered was significantly larger in our patients, thereby explaining the statistical difference that Puhrigner et al. were not able to meet.
Varin et al. (5) showed that plasma clearance of atracurium was not altered in obese patients and that there was no difference in atracurium elimination half-life between obese and non-obese patients. However, on a total body weight basis, the average concentration of atracurium, was larger in obese than in non-obese patients. Such larger plasma concentrations were not associated with a greater degree of neuromuscular blockade or with a delayed recovery but with a residual neuromuscular blockade effect comparable to that observed in non-obese patients. The larger concentrations of atracurium required to obtain a degree of blockade comparable to that of the non-obese was attributed to alterations in protein binding or acetylcholine receptors seen in obese patients (5). The use of cisatracurium in bariatric surgery appeared justified in the literature by its pharmacological similarities with atracurium (5,14). Alvarez et al. (7) and Gaszynski et al. (19) reported its use and concluded that total IV anesthesia with midazolam, remifentanil, propofol, and cisatracurium is effective, secure, predictable, and economical for the anesthetic management of morbidly obese patients. Yet no study has specifically addressed the pharmacodynamic effects of cisatracurium in obese patients.
However, consistent with our findings on cisatracurium, Kirkegaard-Nielsen et al. (8) demonstrated that the duration of action of atracurium block is prolonged in obese patients and that atracurium dose in milligrams per kilogram of total body weight should be reduced in these patients. Considering the contrasting evidence on atracurium and the scarce substantiation on cisatracurium we were prompted to specifically investigate the pharmacodynamic effects of cisatracurium in morbidly obese patients. Differences with previous studies may be explained by the limited number and large interindividual variations of the patients studied by Weinstein et al. (3) and Varin et al. (5). Although our groups were also somewhat limited, we were able to minimize interindividual variations and to maximize differences in BMI between the study groups and the control group.
The reason for the longer duration of action observed in the RBW group compared with the NBW group is not entirely clear, but whereas in the study by Weinstein et al. (3) the weight of the obese patients was, in the atracurium group, 146% of IBW, our patients belonged to the morbid obesity class (BMI >40), which corresponds on average to 204% of their IBW. Therefore, the dose of cisatracurium received by the obese patients in the RBW group was larger than the total dose of atracurium administered to the obese patients in the Weinstein et al. study and twice the dose administered to our IBW group. This may in part explain the highly significant differences in duration of action observed between RBW and IBW, and RBW and NBW groups in the present study.
The shorter duration of action observed in the IBW group (45 min) versus the NBW group (59 min) may be explained by considering that 20%–40% of the global weight increment in the obese patient is attributable to an increase in lean body mass, and therefore as suggested by Savarese et al. (4) adding 20% to the estimated IBW dose of hydrophilic medications is sufficient to include the lean body mass (1). Moreover, in a similar study by our group the duration of action of rocuronium was shorter in the IBW group (33 min) than in the NBW group (38 min) even without reaching statistical significance (18).
It is commonly believed that tracheal intubation is more difficult in obese than in NBW patients. The airway of the obese may be narrowed by fleshy cheeks, a large tongue, and copious flaps of palatal, pharyngeal, and supralaryngeal soft tissue. These patients can also present a poor extension of the head; therefore the use of awake intubation or rapid sequence induction with cricoid pressure is suggested (20). However, data concerning the impact of obesity on difficult laryngoscopy are still controversial. Brodsky et al. (21) conclude that obesity alone is not predictive of tracheal intubation difficulties; large neck circumference and high Mallampati score (>3) were the only predictors of potential problematic intubation. The experience and ability of the laryngoscopist was the most important determinant to establishing an airway in morbidly obese patients (21). In the study of Ezri et al. (22) the magnitude of BMI had no influence on the difficulty with which laryngoscopy was performed. Increased age, male gender, temporomandibular joint pathology, Mallampati 3 or 4, a history of obstructive apnea, and abnormal teeth were associated with more frequent difficult laryngoscopy. Gaszynski et al. (19) successfully used 0.2 mg/kg of cisatracurium based on IBW to facilitate oral endotracheal intubation in a super-obese patient (BMI, 70.7), and Boyce et al. (23) successfully intubated on the first or second attempt of laryngoscopy 26 super-obese patients (BMI, 56 ± 3) after 0.15 mg/kg of cisatracurium. There is no disagreement that when difficult airway management is encountered dangerously low O2 saturation levels occur more rapidly in obese patients (24). Mask-bag ventilation can be improved by reverse Trendelenburg position because this position offers a longer and safe apnea period reducing the potential for hypoxemia and facilitating bag mask ventilation because lower peak inspiratory pressures are required (23). Moreover, the common problem of gastric reflux may be reduced by simple gravitational effects. Furthermore, difficult mask ventilation can be overcome with the aid of LMA even in morbidly obese patients, as reported by Boyce et al. (23). Based on the literature and our clinical experience we identified 20 patients with anticipated reasonably easy laryngoscopy and expected successful mask ventilation. Moreover, we investigated female patients because of a different fat distribution compared with the male patients. Whereas obesity of the male, android type, shows a dominant visceral and upper thoracic distribution of adipose tissue, in the feminine, gynoid type, adipose tissue is found predominantly in the lower part of the body, particularly hips and thighs (25).
Obese patients are at higher risk for postoperative pulmonary complications (26,27). Accordingly tracheal extubation must be carefully considered, and a conservative approach is strongly recommended to achieve a condition of maximum stability before proceeding to tracheal extubation. For this reason our patients were followed for a minimum of 6 hours in PACU and tracheally extubated only when they were able to fulfill all tracheal extubation criteria described in the Methods section. Objective monitoring permits reserving the use of anticholinesterase only for those patients who actually need a reversal drug (28).
In conclusion, the duration of action of cisatracurium was prolonged when dosed according to RBW in morbidly obese patients compared with a control group of NBW patients and between NBW patients and morbidly obese patients to whom the drug was administered on the basis of their IBW.
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This article has been cited by other articles:
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  T. Suzuki, G. Masaki, and S. Ogawa Neostigmine-induced reversal of vecuronium in normal weight, overweight and obese female patients Br. J. Anaesth., August 1, 2006; 97(2): 160 - 163. [Abstract] [Full Text] [PDF]
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