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GENERAL ARTICLES

The Onset Time of Rocuronium Is Slowed by Esmolol and Accelerated by Ephedrine

Department of Anesthesiology, University of Texas Medical School at Houston, Houston, Texas

Address correspondence and reprint requests to Peter Szmuk, MD, The University of Texas, Houston Medical School, Department of Anesthesiology, 6431, Fannin, MSB 5.020, Houston, TX 77030. Address e-mail to pszmuk{at}anes1.med.uth.tmc.edu

	Abstract

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Administration of ephedrine prior to rocuronium decreases the onset time of neuromuscular blockade from rocuronium by 26%. This effect was attributed to a increased cardiac output. If so, ß adrenergic-blocking drugs, which decrease cardiac output, should prolong the onset time of rocuronium. In a double-blind study, 60 patients were randomly assigned to three groups (n = 20) to receive either 70 µg · kg^-1 of ephedrine, 0.5 mg · kg^-1 esmolol or placebo, 30 s before induction of anesthesia. Onset time of rocuronium was defined as the time from the end of its injection to disappearance of all four twitches of the train-of-four. The onset time of rocuronium was significantly shorter after ephedrine (22%) and longer after esmolol (26%), as compared to placebo. No differences were observed among the three groups with regard to heart rate, systolic, diastolic or mean blood pressure. We concluded that a dose of 0.5 mg · kg^-1 of esmolol significantly prolongs the onset time of rocuronium with minimal hemodynamic changes.

Implications: We concluded that a dose of 0.5 mg · kg^-1 of esmolol significantly prolongs the onset time of rocuronium with minimal hemodynamic changes.

	Introduction

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Munoz et al. (1) found that coadministration of ephedrine (70 µg/kg) reduced the onset time of neuromuscular block of rocuronium by 26%. This beneficial effect was attributed to increased cardiac output and muscle blood flow, and therefore, a more rapid delivery of rocuronium to the neuromuscular junction was achieved. If so, ß-adrenergic blocker drugs show decreased cardiac output and consequently prolong the onset time of rocuronium.

Esmolol is a cardio-selective ß-adrenergic blocking drug that has a rapid onset and short duration of action. For the same reason that ephedrine increases the onset time of rocuronium, esmolol is likely to decrease it. We therefore tested the hypothesis that esmolol decreases the onset time of rocuronium; as a positive control, we simultaneously confirmed that ephedrine speeds the onset of neuromuscular block.

	Methods

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With approval of our Human Research Committee and written consent, we studied 60 ASA physical status I and II patients, aged 18–60 yr. They were scheduled for elective general surgery (hernioplasty, cholecystectomy), gynecological procedures (laparascopy, total abdominal hysterectomy), and ear, nose, and throat procedures (septoplasty, endoscopic sinus surgery) under general anesthesia. Patients at risk for aspiration of gastric content (e.g., pregnant, full stomach, or history of regurgitation), those in whom difficult endotracheal intubation (Malampati class III–IV) was anticipated, and those on chronic preoperative ß-adrenergic blocker treatment were excluded.

Patients were randomly assigned to receive either 70 µg/kg of ephedrine (Group E; n = 20), 0.5 mg/kg of esmolol (Group ES; n = 20), or a saline placebo (Group P; n = 20).

The anesthesiologist performing the induction of anesthesia was blinded to the study drug (esmolol, ephedrine, or placebo). The induction of anesthesia consisted of fentanyl 3 µg/kg IV and the study drug, followed 30 s later by thiopental 4 mg/kg. After assessment of mask ventilation, rocuronium 0.6 mg/kg IV was administered and isoflurane 1.5% was added to oxygen, while the patient was mask ventilated. After intubation, anesthesia was maintained with a mixture of nitrous oxide-oxygen (70%/30%), isoflurane and fentanyl.

Neuromuscular function was assessed by stimulating the ulnar nerve at the wrist by using surface electrodes with train-of-four monitoring with supramaximal square wave impulses of 0.2-s duration administered at 2 Hz every 10 s by using a battery-operated stimulator. The resulting contraction force of the adductor pollicis brevis muscle was measured and recorded continuously by using a force transducer.

Onset time of rocuronium was defined as the time from the end of its injection to disappearance of all four twitches of the train-of-four.

Noninvasive arterial blood pressure and heart rate were recorded at 1-min intervals, starting with the administration of fentanyl at the start of the induction of anesthesia and up to 15 min. The baseline blood pressure and heart rate were considered as the third consecutive reading after the patient entered the operating room.

Data were analyzed by using a repeated-measure analysis of variance followed by Dunnett’s t-test. When significant, an unpaired t-test was performed among groups. Results were reported as mean ± SD; P < 0.01 was considered statistically significant.

	Results

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Morphometric and demographic characteristics of the patients were similar in each group. The onset time of rocuronium was significantly shorter after ephedrine and longer after esmolol, as compared with the onset of rocuronium in patients who received saline (Table 1).

View larger version (22K): [in this window] [in a new window]   Figure 1. Effect of esmolol, ephedrine, and placebo on systolic blood pressure. Significant differences versus baseline (*P < 0.05) were observed only in the esmolol group. No differences were found among the three groups.

View larger version (24K): [in this window] [in a new window]   Figure 2. Effect of esmolol, ephedrine, and placebo on heart rate. Significant differences versus baseline (*P < 0.05) were observed in the esmolol and ephedrine groups. No differences were found among the three groups.

	Discussion

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Interestingly, the effects of cardiac output and circulation time may be considerably greater for fast-acting muscle relaxants, such as succinylcholine and rocuronium, than intermediate-onset relaxants including mivacurium and vecuronium. Audibert and Donati (7), for example, showed that reducing the muscle blood flow by inflation of a tourniquet produced a delay in onset time of rocuronium (fast-onset drug) but not of vecuronium and mivacurium. Similarly, atropine administration failed to shorten the onset time of atracurium in pediatric patients (8).

Although to confirm the role of cardiac output in the modulation of rocuronium onset time, direct measurement of cardiac output is required, our finding that esmolol delays the onset of neuromuscular block is of special interest because esmolol is indicated (9) and commonly used to improve hemodynamic stability, both during rapid-sequence induction (9) and in patients with hypertension (10). The 30-second prolongation in onset time produced by esmolol could increase the time during which the patient is at risk of aspiration of gastric content, eliminating one of the advantages of using rocuronium.

Esmolol, a short-acting, selective ß-1 blocker possesses negative inotropic and chronotropic effects, thereby decreasing cardiac output in both anesthetized healthy patients (11) and those with left ventricular dysfunction (12). The reduction in cardiac output is dose-dependent and was observed both with boluses of 100 and 200 mg and continuous infusion of esmolol (11,13). As might be expected, hemodynamic changes were less impressive at the dose we used (0.5 mg/kg). Nonetheless, the effect was sufficient to significantly prolong the onset of rocuronium.

Our results are consistent with those published by Cheng et al. (14), who showed that esmolol delays the onset of mivacurium in rabbits. This finding was subsequently confirmed by another group (15) that demonstrated that the neuromuscular blocking effect of mivacurium was prolonged 30% after the administration of esmolol (100–500 µg · kg^-1 · min^-1). In this latter case, the mechanism by which esmolol interferes with mivacurium neuromuscular blocking properties was considered to be an esmolol-mediated decrease in the activity of the plasma cholinesterase (15).

Our findings, although consistent with Munoz et al.’s (1) data, cannot confirm the proposed mechanism through esmolol’s effects on cardiac output. First, we did not measure cardiac output in this healthy group of patients. Second, the lack of significant heart rate and blood pressure response after the administration of esmolol and ephedrine make this mechanism questionable. The hemodynamic response to esmolol administration might have been counteracted by the combined effect of the drugs used to induce anesthesia and laryngoscopy.

Although the activity of esmolol itself on neuromuscular blockade has not been demonstrated, a direct effect of esmolol on the neuromuscular junction cannot be excluded. We conclude that a dose of 0.5 mg/kg of esmolol significantly prolongs the onset time of rocuronium without significant hemodynamic changes.

	Acknowledgments

 
The authors thank Daniel I. Sessler, MD, for critical reading of the manuscript and Y. Liang, MD, for technical assistance.

	Footnotes

 
Presented at the 1998 Annual Meeting of the American Society of Anesthesiologists, Orlando, FL, October 17–21.

	References

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4. Musich J, Walts LF. Pulmonary aspiration after a priming dose of rocuronium. Anesthesiology 1986;64:517–9.[ISI][Medline]
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7. Audibert G, Donati F. Onset of neuromuscular block after tourniquet inflation: comparison of suxamethonium and vecuronium. Br J Anaesth 1996;75:436–40.[Abstract/Free Full Text]
8. Simhi E, Brandom BW, Lloyd ME, Woelfel SK. Administration of atropine and onset of neuromuscular block produced by atracurium in infants. Paediatr Anaesth 1997;7:375–8.[ISI][Medline]
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10. Sharma S, Mitra S, Grover VK, Kalra R. Esmolol blunts the hemodynamic responses to tracheal intubation in treated hypertensive patients. Can J Anaesth 1996;43:778–82.[Abstract/Free Full Text]
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14. Cheng RY, Hau HR, Sun YC, et al. The interaction of the neuromuscular effects between mivacurium and esmolol in rats. Acta Anaesthesiol Sin 1995;33:97–100.[Medline]
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This Article Abstract Full Text (PDF) An erratum has been published Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (13) Citing Articles via Google Scholar Google Scholar Articles by Szmuk, P. Articles by Katz, J. Search for Related Content PubMed PubMed Citation Articles by Szmuk, P. Articles by Katz, J.

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