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Extended Duration of Action of Rocuronium in Postpartum Patients

Puhringer, F. K. MD; Sparr, H. J. MD; Mitterschiffthaler, G. MD; Agoston, S. MD, PhD; Benzer, A. MD, PhD

Obstetric Anesthesia

We studied the time course of action of a single bolus of 600 micro g/kg rocuronium given during anesthesia with propofol, fentanyl, and nitrous oxide was studied in 12 nonpregnant and 12 postpartum patients.Neuromuscular effects were quantified by recording the indirectly evoked twitch response of the adductor pollicis muscle after ulnar nerve stimulation. In all patients, the trachea was intubated 60 s after administration of rocuronium. Onset time was similar in both groups (nonpregnant: 91 +/- 28 s vs. postpartum: 95 +/- 30 s), with the time to 25% twitch recovery being significantly longer (P < 0.001) in the postpartum patients (31.1 +/- 3.6 min) compared with the nonpregnant group (24.9 +/- 4.0 min). The time required for recovery from 25% to 75% of the control twitch response after reversal with neostigmine and atropine was significantly longer (P = 0.003) in postpartum (4.8 +/- 0.9 min) than in nonpregnant patients (3.2 +/- 0.6 min). These data suggest that pregnancy-induced changes result in prolonged effects of rocuronium in postpartum patients.

(Anesth Analg 1997;84:352-4)

Department of Anaesthesia and General Intensive Care Medicine, University of Innsbruck, Innsbruck, Austria.

(Agoston) Deceased.

This study was supported in part by a grant from Organon GesmbH, Division Organon Teknika, Vienna, Austria.

Accepted for publication October 21, 1996.

Address correspondence and reprint requests to Friedrich K. Puhringer, Department of Anaesthesia and General Intensive Care Medicine, University of Innsbruck, Anichstrasse 35, A-6020 Innsbruck, Austria.

Pregnancy is associated with major changes of physiological status and body composition. These changes may modify the pharmacologic and/or pharmacokinetic profile of some drugs [1], including neuromuscular blocking drugs. In a study of the pharmacokinetics of pancuronium and vecuronium [2] in patients undergoing cesarean section, a shorter elimination half-life and a higher total body clearance of both drugs was observed when compared with nonpregnant patients. Indeed, in the postpartum period, the reestablishment of normal blood pressure and body weight as well as the ongoing changes in hormone levels and lactation have been reported to appreciably prolong the duration of action of vecuronium in patients within four days after delivery [3,4]. In contrast, the duration of action of atracurium, whose elimination kinetics are less dependent on organ function, was not prolonged in postpartum patients [4].

Rocuronium is a steroidal, nondepolarizing neuromuscular blocking drug chemically related to vecuronium. Compared with vecuronium, rocuronium is six times less potent but has a much faster onset of action with comparable intermediate duration of action [5]. Its plasma clearance is primarily via liver uptake and biliary excretion, with renal elimination being less than 9% [5]. Rocuronium is the first nondepolarizing neuromuscular blocking drug to challenge the superiority of succinylcholine for early endotracheal intubation [6]. Abouleish et al. [7] demonstrated that rocuronium provides good to excellent intubating conditions in 90% of cesarean section patients. Unfortunately, no detailed data regarding the pharmacodynamics of rocuronium are available for pregnant or postpartum patients.

The aim of this study was to investigate the duration 25% and the induced recovery time after administration of 600 micro g/kg rocuronium in postpartum and nonpregnant patients.

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After approval by our university's ethics committee, 24 consenting ASA physical status class I or II women of normal weight, between 18 and 45 years of age, were enrolled in the study. Twelve were within 4 days of delivery (range 2-4 days) and scheduled to undergo sterilization via laparoscopic tubal cauterization. The remaining patients underwent laparoscopic tubal cauterization (n = 9) or minor otorhinolaryngeal (n = 3) procedures of comparable duration (approximately 30-50 min). Patients known or suspected to have neuromuscular disorders, metabolic diseases, or impaired kidney or liver function, or patients taking medication known to alter neuromuscular transmission were excluded. None of the patients received any prophylaxis against aspiration pneumonitis, and no premedication was given.

Anesthesia was induced with 3 micro g/kg fentanyl and up to 2.5 mg/kg propofol intravenously and maintained by controlled ventilation with 2:1 nitrous oxide/oxygen and continuous infusion of propofol (4-5 mg [center dot] kg-1 [center dot] h-1). Then assessment of neuromuscular transmission was commenced. Recordings of the single twitch contractions of the adductor pollicis muscle were obtained by stimulating the ulnar nerve at the wrist using surface electrodes with supramaximal square-wave stimuli of 0.2-ms duration at a frequency of 0.1 Hz. The resultant force of thumb adduction was quantified via a force displacement transducer after applying a resting tension of 200-400 g and recorded via a Relaxometer 2 (University of Groningen, Netherlands). Ventilation was controlled during determination of the maximal twitch response and the supramaximal stimulation current. After a stable twitch response was obtained for approximately 5 min, rocuronium (600 micro g/kg) was administered.

Skin temperature at the site of the surface electrodes was monitored, recorded continuously with the Relaxometer 2, and kept at 33.0 +/- 0.5 degrees C.

All patients were tracheally intubated 1 min after the administration of rocuronium. Neuromuscular monitoring was continued throughout the operation, and all patients were given 30 micro g/kg neostigmine and 15 micro g/kg atropine for reversal of the neuromuscular block when the twitch height returned to 25% of its control. In assessing the neuromuscular effects, we measured onset time (time from end of injection of the total intubating dose of rocuronium until maximum twitch depression), maximum block, the duration 25% (time from end of injection until recovery of twitch height to 25% of its control value) and induced recovery time (time required from 25% to 75% recovery of twitch tension after administration of 30 micro g/kg neostigmine and 15 micro g/kg atropine).

Neuromuscular data and demographic characteristics between the two groups were compared using the Student's t-test. Differences were considered significant at P < 0.05. All values are given as mean +/- SD.

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Demographic data did not differ significantly between postpartum and nonpregnant patients (Table 1). Onset times were comparable between the two groups (Table 2). All patients developed 100% block. Tracheal intubation was accomplished in all patients at 1 min after administration of rocuronium. All patients in both groups presented clinically acceptable (good or excellent) intubating conditions.

Table 1

Table 1

Table 2

Table 2

Both the duration 25% and the induced recovery time (Table 2) were significantly longer in the postpartum group when compared with the nonpregnant group.

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The main finding of this study is the extended duration of action by six minutes and the slower induced recovery time by about 1.5 minutes in postpartum patients after administration of 600 micro g/kg rocuronium. This observation favorably correlates with previous observations of prolonged duration of action of vecuronium, a chemically related aminosteroidal muscle relaxant in postpartum patients [3,4]. In contrast, no prolongation of action was observed after atracurium [4]. Furthermore, in an additional in vitro investigation, Khuenl-Brady et al. [4] reported that no differences had been proven in the response of postpartum and nonpregnant rat diaphragms to vecuronium.

Rocuronium, like vecuronium, is rapidly taken up by the liver, as are steroidal sexual hormones metabolized in the liver [9]. Rocuronium may compete with these hormones at various binding sites on their way through the liver. Transport mechanisms and metabolism in the liver may become saturated by the elevated hormone levels in the pregnant and postpartum states. In this study, the duration of action after rocuronium in postpartum patients was increased by approximately 25%, whereas Khuenl Brady et al. [4] reported that the duration of vecuronium is increased by 45% in postpartum patients. Magorian et al. [10] demonstrated a slightly prolonged duration of action of rocuronium in patients with liver disease. This finding was attributed to an increased volume of distribution and increased elimination half-life, since rocuronium clearance was not altered in these patients. During pregnancy, total plasma volume increases by 30-40%, but liver blood flow is maintained at nonpregnant levels. Thus, a relative decrease (when expressed as a percentage of cardiac output) in liver blood flow (approximately 20%) exists during pregnancy [9]. Because rocuronium is highly dependent on hepatic clearance, its elimination might be profoundly affected by liver blood flow [5]. The relative decrease in hepatic flow might be partly responsible for its decreased rate of elimination in postpartum patients. Nevertheless, the difference in the extent of prolongation between rocuronium (+25%) and vecuronium (+45%) needs further explanation. It is conceivable that the difference in the elimination of rocuronium (which is excreted through the liver without undergoing metabolism) compared with vecuronium (which is metabolized in the liver) might be responsible for the less dramatic prolongation of action after rocuronium. This, however, needs further pharmacokinetic clarification.

Body weight, as well as total body fat, may increase during pregnancy. Postpartum patients usually weigh more than nonpregnant patients. A previous study [8] demonstrated that the time course of action after rocuronium in overweight patients is not prolonged when compared with patients of normal weight.

Adequate depth of anesthesia is important in achieving good intubating conditions with rocuronium. In the Abouleish et al. study [7], the unpremedicated cesarean section patients, who had inadequate (2.5%) or poor (7.5%) intubating conditions, received only 4 mg/kg thiopental for induction of anesthesia. When the dose was increased to 6 mg/kg, the intubating conditions were good to excellent. In our report, all patients were adequately anesthetized using fentanyl, propofol, and nitrous oxide prior to rocuronium administration, and they were all easily intubated.

In conclusion, this study shows that the duration of action and the induced recovery time of rocuronium is prolonged by 25% in postpartum patients.

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