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AMBULATORY ANESTHESIA

The Effects of Antagonizing Residual Neuromuscular Blockade by Neostigmine and Glycopyrrolate on Nausea and Vomiting After Ambulatory Surgery

Department of Anesthesiology and Pain Management, University of Texas, Southwestern Medical Center at Dallas, Dallas, Texas

Address correspondence and reprint requests to Dr. Girish P. Joshi, Department of Anesthesiology and Pain Management, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75235-9068. Address e-mail to girish.joshi @email.swmed.edu.

	Abstract

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The effects of neostigmine on the incidence of postoperative nausea and vomiting (PONV) are controversial. In this study, we evaluated the effects of neostigmine and glycopyrrolate on the incidence of PONV and the need for antiemetics in patients undergoing ambulatory surgery. One hundred healthy patients undergoing outpatient surgical procedures were included in the study. A standardized anesthetic technique was used for all patients. Patients were randomized to receive either mivacurium (n = 50) or rocuronium (n = 50) to achieve muscle paralysis. Bolus doses of mivacurium 2–4 mg or rocuronium 5–10 mg were administered to maintain one or two twitches of the train-of-four stimulation of the ulnar nerve at the wrist. After surgery, residual neuromuscular blockade was reversed with neostigmine 2.5 mg IV and glycopyrrolate 0.5 mg IV only if clinically deemed necessary (i.e., fade on train-of-four stimulation, inadequate tidal volume, reduced hand grip, or inability to maintain head lift). The incidence of PONV and the need for antiemetics were recorded in the postanesthesia care unit (PACU), in the phase II unit, and 24 h after surgery. We compared patients who received neostigmine (n = 40) for reversal of residual neuromuscular blockade with those who did not (n = 60). More patients receiving rocuronium required reversal drugs than those receiving mivacurium (68% vs 10%). There were no differences in the incidence of nausea (18% vs 15%), vomiting (8% vs 12%), and the need for antiemetics (13% in both the groups) in the PACU between patients who received neostigmine and those who did not. In addition, the duration of PACU stay and the time to home-readiness were also similar between the groups. We conclude that, compared with rocuronium, the use of mivacurium decreases the need for reversal drugs. In addition, reversal of residual neuromuscular blockade with neostigmine does not increase the incidence of PONV or the need for antiemetic medications in patients undergoing ambulatory surgery.

Implications: In this study, we showed that the incidence of postoperative nausea and vomiting and the need for antiemetics do not increase with the use of neostigmine and glycopyrrolate for reversal of residual muscle paralysis.

	Introduction

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Postoperative nausea and vomiting (PONV) is still one of the most common complications after outpatient surgery and anesthesia. Most patients consider PONV to be more distressing and debilitating than pain (1). In addition to reducing patient satisfaction, PONV may delay recovery, increase length of hospital stay, and lead to unanticipated hospitalization (2,3). One of the many factors that influence the incidence of PONV is the anesthetic technique.

Perhaps the use of neostigmine to antagonize nondepolarizing muscle relaxants increases the incidence of PONV (4–6). In contrast, a study reported that reversal of neuromuscular blockade with a combination of neostigmine and glycopyrrolate had no effect on the incidence or severity of PONV on inpatients undergoing abdominal hysterectomy (7). However, the incidence of PONV after ambulatory surgery is more frequent than that after inpatient surgery (8). The effects of a neostigmine-glycopyrrolate combination on the incidence of PONV in patients undergoing ambulatory surgery have not been determined.

We designed the present study to evaluate the effects of a neostigmine-glycopyrrolate combination on the incidence of PONV and the need for antiemetic medication in patients undergoing ambulatory surgery.

	Methods

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After obtaining institutional review board approval and written, informed consent, 100 healthy outpatients scheduled for elective surgery requiring general anesthesia were enrolled in this study. The surgeries included were superficial (e.g., biopsies), head and neck, orthopedic (e.g., arthroscopy), plastic surgery, and gynecological (e.g., cervical biopsy). Patients with known cardiovascular, pulmonary, or metabolic diseases; impaired renal or hepatic function; morbid obesity; and history of alcohol or drug abuse were excluded. In addition, patients with neuromuscular disease or those receiving medication known to influence neuromuscular transmission, as well as those with anticipated airway difficulties or at increased risk of aspiration, were excluded from the study.

After premedication with midazolam 2 mg IV, general anesthesia was induced with fentanyl 1 µg/kg IV and propofol 2–2.5 mg/kg IV. Using a computer-generated random number sequence, patients were randomly assigned to receive either mivacurium or rocuronium to achieve muscle relaxation. Tracheal intubation was facilitated using either mivacurium 0.25 mg/kg IV administered in divided doses—0.15 mg/kg IV followed 30 s later by 0.1 mg/kg (n = 50)—or rocuronium 0.6 mg/kg IV (n = 50). Mivacurium 0.25 mg/kg administered in divided doses provides good to excellent intubation conditions with hemodynamic stability after a midazolam, fentanyl, and propofol induction sequence (9). Anesthesia was maintained with isoflurane (0.5%–1.5% end-tidal concentrations) in combination with nitrous oxide 60% in oxygen. The concentrations of isoflurane were adjusted according to standard clinical practice (i.e., to maintain hemodynamic variables within 20% of the baseline values). Supplemental doses of fentanyl 25–50 µg IV were administered if the volatile anesthetic failed to maintain adequate hemodynamic stability. All patients' lungs were mechanically ventilated to maintain end-tidal carbon dioxide at 32–36 mm Hg. Bolus doses of mivacurium 2–4 mg or rocuronium 5–10 mg were administered to maintain one or two twitches of the train-of-four stimulation of the ulnar nerve at the wrist. Residual neuromuscular blockade was reversed with neostigmine 2.5 mg IV and glycopyrrolate 0.5 mg IV only if deemed clinically necessary (i.e., fade on train-of-four stimulation, inadequate tidal volume, reduced hand grip, or inability to maintain head lift).

In the postoperative period, incidence of nausea, vomiting, and pain and the need for treatment were recorded by a blinded observer in the postanesthesia care unit (PACU) and the step-down (phase II) unit. Rescue medications for nausea and/or vomiting were administered if it lasted >15 min or if, at any time, a patient requested them. The choice of rescue antiemetic was left to the discretion of the attending anesthesiologist. If necessary, patients received fentanyl 25–50 µg IV or oral analgesic medications in the PACU or step-down unit, respectively. The time from end of surgery to extubation and the time to "fit for discharge" from the PACU and the hospital were noted. Patients were contacted by telephone 24 h after surgery regarding the incidence of nausea, vomiting, and pain and the need for medications after discharge. In addition, the patients rated their overall satisfaction with anesthesia using a 5-point scale ranging from completely satisfied to completely dissatisfied.

We compared patients who received neostigmine at the end of surgery with those who did not. Power analysis performed using a predicted incidence of postoperative nausea of 30%–40% (1–4) suggested that a sample size of 40 patients in each group should be adequate to achieve a power of 0.8 and an of 0.05. Continuous variables (e.g., demographic data, duration of anesthesia, anesthetic requirements) were analyzed by using Student's t-tests. Nonparametric variables were analyzed by using the Mann-Whitney U-test or 2 test with Yates' continuity correction, as appropriate. A P value of <0.05 was considered statistically significant.

	Results

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Of the 100 patients included in the study, residual neuromuscular blockade was reversed with neostigmine in 40 patients (Group 1), whereas neostigmine was not administered in 60 patients (Group 2). The data of one patient from Group 1 were excluded from the statistical analysis because of protocol violation. More patients receiving rocuronium required neostigmine than those receiving mivacurium (Table 1). The two groups were comparable with respect to demographic characteristics, intraoperative anesthetic and analgesic requirements, and the duration of anesthesia (Table 1).

	Discussion

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Interestingly, Boeke et al. (10) found that the administration of smaller doses of neostigmine 1.5 mg in combination with atropine 0.5 mg in patients undergoing outpatient peripheral surgery actually reduced the need for antiemetic medications. However, these investigators did not observe any difference in the frequency of nausea or vomiting between the patients who received the reversal drugs and those who did not. The use of atropine with neostigmine (instead of glycopyrrolate) may have been responsible for the decreased need for antiemetics. Unlike glycopyrrolate, atropine crosses the blood-brain barrier and is reported to have some antiemetic effect (11). Janhunen and Tammisto (12) reported a decreased incidence of PONV when neostigmine and atropine were administered to reverse residual neuromuscular blockade. However, current standard practice is to use combinations of neostigmine and glycopyrrolate (rather than neostigmine and atropine) because of the similarities in their onset and duration of action.

In contrast to these findings, King et al. (4) reported a more frequent incidence of PONV with the administration of neostigmine 2.5 mg and atropine 1.2 mg in 38 patients (19 in each group) undergoing joint replacement surgery. Ding et al. (5) reported that the administration of neostigmine 2.5 mg and glycopyrrolate 0.5 mg after neuromuscular blockade with mivacurium increased the incidence of PONV in the PACU in women undergoing laparoscopic sterilization. However, they did not observe any difference in the incidence of PONV or the need for antiemetics after discharge from the PACU. Watcha et al. (6) reported that emesis occurred more often in the PACU in children receiving a neostigmine-glycopyrrolate combination, but not after receiving edrophonium-atropine. These investigators also found that the increased incidence of PONV due to reversal drugs was limited to the early recovery period. The conflicting results may be related to a number of factors, including the type of surgery (laparoscopic versus peripheral), the differences in the IV anesthetic drug (propofol versus thiopental), the dose of opioids, and the dose of neostigmine.

The incidence of PONV we observed is less frequent than that reported previously (4–6,13). This may be related to our use of propofol, compared with thiopental used by other investigators. A number of studies have reported a less frequent incidence of PONV with the use of propofol (14). In addition, differences in surgical procedures (i.e., peripheral surgical procedures versus abdominal procedure) may also have affected the incidence of PONV.

It is recommended that the dose of neostigmine should be matched with the degree of neuromuscular blockade (15). Furthermore, the routine administration of reversal drugs is controversial. In standard clinical practice, reversal drugs need not be administered in the presence of clinical recovery from neuromuscular blockade. Therefore, we evaluated the effects of neostigmine on the incidence of PONV in patients who would have received reversal drugs as a part of standard clinical practice compared with those who may not have received reversal drugs. This is in contrast to previous studies, in which reversal drugs were administered without considering the degree of neuromuscular blockade at the end of surgery.

Many practitioners avoid the use of reversal drugs because of their potential effects on the incidence of PONV. However, Kopman et al. (16) reported that even a minor degree of residual paralysis (train-of-four ratio of 0.9) can cause various visual disturbances, decreased grip strength, inability to maintain incisor teeth apposition, inability to sit up without assistance, severe facial weakness (including inability to maintain an airtight seal around drinking straw with the lips), and overall weakness and tiredness. These symptoms may be present despite the signs of clinical recovery from neuromuscular blockade. In addition to being distressing to the patients, these symptoms can prolong the time to home-readiness and delay discharge. Because of these potential complications, particularly in an outpatient setting, it is necessary that reversal drugs be used (in appropriate doses) frequently.

The choice of muscle relaxant is an important factor in the avoidance of residual neuromuscular blockade (13,15). Because short-acting nondepolarizing neuromuscular blocking drugs such as mivacurium facilitate rapid spontaneous recovery, it is not surprising that the need for reversal drugs after the use of mivacurium was significantly decreased compared with that after the use of rocuronium. Pino et al. (9) reported a more predictable recovery profile with the use of mivacurium compared with the use of rocuronium. Therefore, using shorter acting muscle relaxants may be more advantageous in patients undergoing ambulatory surgery.

In conclusion, in this study we demonstrated that, compared with rocuronium, the use of mivacurium decreased the need for reversal drugs. However, reversal of residual neuromuscular blockade with neostigmine 2.5 mg and glycopyrrolate 0.5 mg does not increase the incidence of PONV or the need for rescue antiemetic medications in patients undergoing ambulatory surgery.

	Acknowledgments

 
This study was funded in part by GlaxoWellcome Inc.

	Footnotes

 
Presented in part at the annual meeting of the American Society of Anesthesiologists, Orlando, FL, October 1998.

	References

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11. Dundee JW, Kirwan MK, Clarke RSJ. Anaesthesia and premedication as factors in postoperative vomiting. Acta Anaesthesiol Scand 1965;9:223–31.[Web of Science][Medline]
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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