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Effect of Antagonism of Mivacurium-Induced Neuromuscular Block on Postoperative Emesis in Children

Watcha, Mehernoor F. MD; Safavi, Faye Z. FFARCS; McCulloch, D. A. MD; Tan, T. S. H. FANZCA; White, Paul F. PhD, MD, FFARACS

Pediatric Anesthesia
Free
SDC

The routine use of cholinesterase inhibitors to antagonize residual neuromuscular block may be associated with increased postoperative emesis.Rapid spontaneous recovery from mivacurium may obviate the need for these drugs. In this randomized, double-blind, placebo-controlled study of 113 healthy children who had received mivacurium as part of a standardized anesthetic regimen, we compared the incidence of postoperative complications after spontaneous recovery and after the use of neostigmine-glycopyrrolate or edrophonium-atropine. The anesthetic regimen consisted of halothane, nitrous oxide, fentanyl, 2 micro gram/kg intravenous (IV), mivacurium in an initial dose of 0.2 mg/kg, followed by an infusion, adjusted to maintain >or=to1 evoked contraction response to a supramaximum train-of-four stimulus. At the end of the procedure, patients received by random assignment one of three drug combinations: 1) neostigmine 70 micro gram/kg + glycopyrrolate 10 micro gram/kg, IV, 2) edrophonium 1 mg/kg + atropine 10 micro gram/kg, IV, and 3) saline. The trachea was extubated when evoked responses to peripheral nerve stimulation and clinical signs of adequate neuromuscular recovery were present. Postoperative pain was treated with morphine and emesis with metoclopramide. There were no significant differences between the three groups with respect to age, surgery, intraoperative fentanyl, and mivacurium use, time from the end of surgery to tracheal extubation, postanesthesia care unit (PACU) arrival and discharge, or in postoperative oxygen saturation values and analgesic requirements. Compared to the placebo group, emesis occurred more often in the PACU in patients receiving the neostigmine-glycopyrrolate combination, but not after edrophonium-atropine. However, after discharge from the PACU, emesis rates were similar in the three study groups. We conclude that spontaneous recovery or reversal with edrophonium from a moderate degree of mivacurium-induced block may offer advantages over the use of neostigmine, without increasing time to PACU arrival.

(Anesth Analg 1995;80:713-17)

Department of Anesthesiology and Pain Management, Texas Scottish Rite Hospital for Children, and the University of Texas Southwestern Medical Center, Dallas, Texas.

Section Editor: Paul R. Hickey.

This work was supported in part by a grant from the Texas Scottish Rite Hospital for Children, Dallas, TX.

Accepted for publication November 18, 1994.

Address correspondence and reprint requests to Mehernoor F. Watcha, MD, Department of Anesthesiology and Pain Management, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75235-9068.

The potential for airway-related complications from weakness induced by neuromuscular blocking drugs has led to the routine administration of anticholinesterase drugs such as neostigmine and edrophonium, to ensure adequacy of recovery of neuromuscular function prior to tracheal extubation [1]. However, the muscarinic actions of these drugs on the gastrointestinal tract may lead to increased postoperative emesis [2-6].

Mivacurium, a relatively new, shorter acting nondepolarizing neuromuscular blocking drug, has a brief clinical duration, which may obviate the need for routine antagonism of block [2]. This double-blind, randomized study was designed to determine whether antagonism of residual mivacurium-induced neuromuscular block with neostigmine-glycopyrrolate or edrophonium-atropine was associated with increased postoperative emesis in children.

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Methods

The study was approved by our institutional review board and written, informed consent was obtained from the parent or legal guardian of each child, along with assent by the child when appropriate. We studied 113 ASA physical status I or II children scheduled for brief, elective peripheral procedures (not involving body cavities) under general endotracheal anesthesia. We excluded children with a known history of allergies or other contraindications to the use of the study medications, those with acute neurologic, hepatic, renal, or cardiovascular disease, and those judged to be at risk for regurgitation and aspiration of stomach contents.

After an appropriate fast (minimum 3 h for clear liquids, 8 h for solid food), all patients received oral midazolam 0.5 mg/kg, 20-45 min prior to induction of anesthesia with halothane and nitrous oxide in oxygen via a face mask. After vascular access was obtained, we administered fentanyl 2 micro gram/kg intravenously (IV) and maintained anesthesia with halothane and nitrous oxide. A loading dose of mivacurium (0.2 mg/kg IV) was administered to facilitate tracheal intubation, and was followed by an infusion adjusted to maintain a single twitch response to a supramaximum train-of-four stimulus. At the end of the surgical procedure, patients received one of three drug combinations by random assignment: Group A, neostigmine 70 micro gram/kg with glycopyrrolate 10 micro gram/kg; Group B, edrophonium 1 mg/kg with atropine 10 micro gram/kg; and Group C, saline (placebo). All drugs were diluted to a fixed volume of 10 mL by the pharmacist to maintain the blinded nature of the study. Anesthetics were discontinued when a 5-s sustained response to a 50-Hz tetanic stimulus was present and the trachea was extubated when the patient was awake and had demonstrated a head or leg lift.

An observer who was unaware of the medications administered recorded the times from the end of surgery to tracheal extubation, eye opening, response to commands, arrival and discharge from the postanesthesia care unit (PACU), along with any complications, such as airway obstruction, emesis, and the need for supplemental oxygen to maintain oxyhemoglobin saturation greater than 95%. In the PACU, pain was assessed by an objective pain scale [7]. Patients judged to be in severe pain (objective pain score >6) received morphine, 50-100 micro gram/kg IV, at 10-min intervals until they were comfortable. Persistent postoperative emesis (>1 episode) was managed with metoclopramide, 0.2 mg/kg IV.

Power analysis suggested that 34 patients would need to be enrolled in each group to have an 80% chance at the 0.05 level of significance of detecting a 30% change in the incidence of patients free from emesis. Statistical analysis included analysis of variance, chi squared with Yates' correction, and Fisher's exact test. Intergroup comparisons were made by Scheffe's F test. The comparisons of emesis were repeated for a subset of patients who did not receive analgesic therapy in the PACU. P values of <0.05 were considered significant.

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Results

There were no significant differences between the three groups in age, gender, weight, previous history of postoperative emesis or motion sickness, type and duration of surgery and duration of anesthesia, and intraoperative fentanyl or mivacurium usage Table 1. There were also no differences in the end-tidal nitrous oxide and halothane concentrations at the end of surgery and at tracheal extubation, or in the time from the end of surgery to tracheal extubation, arrival in the PACU, response to commands, and time to discharge. In addition, no significant differences between the groups were noted in the incidence of postextubation airway obstruction, lowest oxygen saturation recorded in the PACU, the duration of postoperative supplemental oxygen therapy or postoperative analgesic requirements Table 2.

Table 1

Table 1

Table 2

Table 2

Compared to the placebo group, patients who received the neostigmine-glycopyrrolate mixture had a significantly higher incidence of emesis and mean number of emetic episodes and required more rescue antiemetic therapy while in the PACU Table 2. There were no significant differences between the edrophonium-atropine and placebo groups in the incidence of emesis, mean number of emetic episodes, or need for antiemetic therapy while in the PACU. The mean number of emetic episodes and the need for rescue antiemetic therapy were significantly greater in the neostigmine-glycopyrrolate group compared to the edrophonium-atropine group Table 2. However, the differences between these two groups in the incidence of emesis in the PACU did not achieve statistical significance (34% vs 18%, P = 0.18). After discharge from the PACU, there were no significant differences in the incidence of emesis among the three groups Table 2.

When the comparisons of the incidence of emesis were repeated for a subset of patients who did not receive analgesic therapy with morphine in the PACU, similar results were noted. In this subpopulation, the incidence of emesis in the PACU remained significantly higher in the group that had received neostigmine-glycopyrrolate than in the group where spontaneous recovery from block had occurred (36% vs 10%, P = 0.04). Finally, the incidence of emesis after discharge from the PACU did not differ among the three subgroups.

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Discussion

It is unclear whether anticholinesterases should be used routinely to antagonize residual neuromuscular block from the shorter acting nondepolarizing drugs such as mivacurium or whether spontaneous recovery should be permitted [1,8]. As anticholinesterase drugs inhibit both acetylcholinesterase and plasma cholinesterase, they have multiple potential interactions with mivacurium, especially if the block is less intense [1]. This study has demonstrated that avoidance of neostigmine may be of some benefit after moderate mivacurium-induced block, as its use may be associated with increased emesis in the PACU.

Neostigmine increases intestinal motility, and some surgeons have concerns regarding the integrity of their intestinal anastomoses if these drugs are used [9]. However, the effects of neostigmine on postoperative nausea and vomiting are conflicting. Janhunen and Tammisto [10] reported that the use of neostigmine-atropine was associated with a decreased incidence, but not severity of emetic symptoms, in patients undergoing venous stripping or uncomplicated open cholecystectomy procedures. Boeke et al. [4], using a smaller dose of neostigmine (1.5 mg vs 2.5 mg) in a similar patient population, found no differences in the incidence of nausea or vomiting. However, this group reported a decreased requirement for antiemetic therapy in patients receiving neostigmine-atropine compared to those undergoing spontaneous recovery from block.

In contrast, King et al. [3] found that the combination of neostigmine (2.5 mg) with atropine (1.2 mg) was associated with increased emesis compared to spontaneous recovery in an older population undergoing knee or hip prosthesis operations. Recently, Ding and White [2] compared the influence of mivacurium (with or without reversal) and succinylcholine on the recovery profile in women undergoing laparoscopic surgery. In this study, patients who developed nausea and vomiting within 30 min of opioid administration in the PACU were excluded from the statistical analysis. The use of mivacurium without reversal was associated with decreased nausea (but not emesis) in the PACU compared to the use of succinylcholine. Furthermore, both nausea and vomiting were decreased after spontaneous recovery from mivacurium-induced block compared to antagonism with neostigmine-glycopyrrolate.

Our study confirmed that antagonism of mivacurium-induced block with a neostigmine-glycopyrrolate combination is associated with an increased incidence and severity of postoperative emesis in the PACU. Although significantly more patients in the neostigmine group required rescue antiemetic therapy compared to the group where block was permitted to resolve spontaneously, the times to discharge from the PACU did not differ between the three groups in our study (or in previous studies).

This study also demonstrated that the incidence and severity of emesis was not significantly increased by the use of edrophonium. Thus, if antagonism of mivacurium-induced block is indicated this drug should be considered, even though it is more expensive than neostigmine [11]. However, the lack of differences in the times from end of surgery to tracheal extubation, arrival and discharge from the PACU, as well as the similar incidence of postdischarge emesis, suggest that the benefits of the use of edrophonium are small compared to the avoidance of anticholinesterase drugs.

In our study, the surgical procedures did not require the maintenance of an intense degree of neuromuscular block. The rapidity of spontaneous recovery from a moderate degree of mivacurium-induced block may explain the lack of significant differences in the times from the end of surgery to tracheal extubation and arrival in the PACU in patients who did or did not receive reversal drugs. With a more profound neuromuscular block, there may be differences in the time from end of surgery to tracheal extubation, as the time for achievement of a train-of-four ratio of 0.75 from a block in excess of 90% is greater with spontaneous recovery compared to recovery after the administration of neostigmine or edrophonium [12].

Our study was designed such that tracheal extubation was delayed until the patient demonstrated stimulus-evoked responses and clinical signs in keeping with satisfactory recovery from neuromuscular block. This may explain the lack of differences in the incidence of postoperative airway obstruction, hypoxemia, or duration of supplemental oxygen therapy in the PACU. The relatively small number of patients studied (n = 38) preclude us from concluding that it is safe to avoid the antagonism of residual neuromuscular blocking effects of mivacurium in all patients. The risks of emesis in the PACU may be judged to be of less concern than the risks of postoperative respiratory complications from residual neuromuscular block in the presence of factors such as preoperative airway obstruction, diminished respiratory reserve, atypical pseudocholinesterase, or after intense block [1,13]. These data would suggest that edrophonium may be used to advantage in these patients, as it provides for a more rapid recovery than neostigmine without increasing the incidence of postoperative emesis in the PACU [11,12].

This study can be criticized for not limiting the patient population to one operative procedure, and that the differences in the rate of recovery after the administration of the study drug may have unmasked the blinded nature of the study. However, the lack of significant differences in the type of operations performed suggests that this confounding factor did not affect the conclusions of our study. More importantly, the observer in the PACU was not present at the time of injection of the study drugs. Finally, the study can be criticized because of the use of different anticholinergic drugs (atropine and glycopyrrolate) to counter the muscarinic actions of the anticholinesterase drugs. Atropine, unlike the quaternary anticholinergic glycopyrrolate, can diffuse into the central nervous system, and is known to reduce emesis associated with morphine premedication [14]. Thus, it is possible that the differing antiemetic effects are related to the anticholinergic drug rather than the anticholinesterase. Given the similarity in onset and duration of action of atropine and edrophonium, and of neostigmine and glycopyrrolate, these combinations have become the standard in clinical practice [1,15].

In conclusion, this pediatric study has demonstrated that the use of a neostigmine-glycopyrrolate combination to antagonize residual block from mivacurium is associated with an increase in vomiting in the PACU compared to spontaneous recovery or reversal with edrophonium. However, use of an edrophonium-atropine combination for reversal of residual mivacurium-induced block does not increase postoperative vomiting.

The authors are grateful to the Texas Scottish Rite Hospital for the support provided for this study. We thank Richard Browne, PhD, for his assistance in the randomization schedule and the nurses and pharmacists at the Texas Scottish Rite Hospital for Children for their patience during the study. We also gratefully acknowledge the help of C. T. Payne, BA, and A. E. Teufel, BA, for their assistance in data collection during the study, and Medfusion, Inc. for the loan of a pump for the study.

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