The role of ondansetron and other antiemetics in ambulatory anesthesia

Ridgedale Same Day Surgery ceywor-ds:

center,

Anesthesia-ambuia~ory;

Cedar

ktoils,

antiemetics;

NJ. nausea

and

vomirmg;

ondansetron.

Postanesthetic nausea and vomiting are the most common anesiheLic complications that delay discharge from the ambulatory surgery center or lead to unanticipated overnight admission. ’ Many studies performed in outpatients have demonstrated a correlation between prolonged discharge time and emetic symptoms. An anesthetic technique that is associated with a low frequency of emesis is desirable for ambulatory anesthesia. For exa_mple, one of the main reasons for the widespread popularity of the drug propofol is its antiemetic effects. Until recently, drugs used to treat or prevent nausea and vomiting were divided into one of several categories: phenoihiazinetype anticholinergics [e.g., prochlorperazine (Compazine)]. butyrophenones (droperidol), antihistamines (hydroxyzine), or dopamine antagonists (metoclopramide). In the early I98Qs, scientists at Glaxo, Inc., developed the novel antiemetic drug ondansetron, which in studies performed to date, has had fewer side effects [especially of the central nervous system (CKS)] than the traditional antiemetics listed above. In 1991, the drug received approval from the U.S. Food and Drug Administration (FDA) for the prevention of chemotberapyinduced emesis, and it has achieved widespread success and recognition. The absence of CNS-related side effects makes such a drug very useful f~r the outpatient requiring general anesthesia or intravenous (HV) sedation, where the prophylaxis of postoperative emesis, without additional sedation, is desired. These unique properties engendered large Phase III multicenter studies designed to obtain FDA approval for its use in the prophylaxis and treatment of postoperative nausea and vomiting, and have led to several publications on its potential use in anesthesia. Ondansetron (Zofran) has a chemical structure similar to tha: of serotonin, and it is a highly selective Shydroxytryptamine (5-HT3) subtype-3 receptor antagonist. Currently, there are at least nine known subtypes of the .?hydroxytryptamine receptor. In vitro studies have found the drug to be devoid of dopamine: histamine, cholinergic, or adrenergic receptor activity.” For the time being, ondansetron appears to be in a class of its own, although similar compounds (e.g., graniesetron and dolasetron) exist and have undergone Phase II trials.3 Ondansetron has been used extensively in chemotherapy {more than I million patients to date worldwide) without reports of sedative, cardiovascular, or other major autonomic side effects, all of which commonly occur with other available antiemetics. _L

*Medical

Director

-4ddress reprint requests to Dr. Zahl at the Ridgedale Same Day Surgery Center, 14 Ridgedale Avenue, Suite 120, Cedar Knolls, NJ 07027, USA. over the past 5 years, the author has received honoraria and/or research grants from the following companies whose products are mentioned in this manuscript: Glaxo, Inc., Janssen Pharmaceutics, and Stuart Pharmaceuticals, ICI Americas. Received for publication August 12, 1993; revised manuscript accepted for publication September 22, 1993. Q 1993 Butterworth-Heinemann J. Clin. Anesth. 5 (Suppl l):52§-56S,

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Or3dan5etron

King, a previous history ofvomiting with a prior anesthetic can predispose the patient to emesis.s In addition to the typeofsurgery, the choice ofanestheua probably has a role in the development of postoperative nausea and vomiting. There has been considerable controversy about whether o oid-based or nitrous oxide (N&)-supplemented anes esia predisposes outpatients to postoperative nausea and vomiting, N20 has been ruled out as a cause by a well-controlled study by Hovorka et al.‘? Studies linking opioids to postoperative nausea and vomiting in the outpatient setting are countered by reports showing that opioids can be used without major difficulty. When alfentanil is used with pro vomiting appears to quency of postoperative nausea a rience that if opioids be lower.lO It has always been my e suiting in significant are used judiciously in procedur Dain, postoperative nausea and vomiting is less of a problem. Ether was well-known to cause prolonged emesis. Other balogenated anesthetics offer little or no protection against postoperative nausea and vomiting and may even contribute to its development. Some reports associate enilurane with a lower rate of postoperative nausea and vomsting when compared with isoflurane. However, in the outpatient undergoing laparoscopy, either drug (after induction with thiopental sodium), 1 ciated with approximately a 50% rate of post0 Je nausea and vomiting.” To date, a similarly high ency of postoperative nausea and vomiting has been encountered with desflurane in outpatient laparoscopy (see below).i2 Because of its rapid recovery profile, propofol has enjoyed widespread popularity in ambulatory anesthesia. An unexpected benefit of propofol has been the consistently lower frequency of emesis in study after study, even when just an induction dose was used. A recent study compared desflurane with propofol and NpO for outpatient l.aparoscopy. Patients ~a~do~~i~ed to receive rropofol for both induction and maintenance (with N@) tnad the lowest rate of severe emesis (15%) utmw all other groups (52% to 59%). In the group receiving a propofol induction and then desflurane in oxygen (0,) for maintenance, the frequency of severe emesis was still 52%, suggesting that the antiemetic effect of propofol may be overidden by other anesthetics.‘? In a recent study, patients who had nausea after surgery were given either !.O mg of propofol in emulsion form or the emulsion without propofol. The frequency of further emesis in chose patients receiving propofoi in emulsion was reduced.‘? The antiemetic efficacy of propofol also was srudied in children undergoing outpatient strabismus surgery. The children were randomized to one of four treatment groups after mask induction with halothane and N@. Watcha et al.14 found that th bildren whose anesthesia was maintained with a pro 1 infusion and O2 had the lowest rate of emesis.

Once ondansetroc was developed, early work by Glaxo investigators showed that, in the ferret model, in which ferrets received either cisplatin, cyclophosphamide, or radiation, it could significantly reduce retching and vomiting. Much lower doses of ondansetron compared with were effective yet did not cause unmetoclopramide wanted side effects. Experimental evidence indicates that the main site of ondansetron activity is in the area postrema, and some data suggest peripheral sites of action in the upper gastrointestinal tract. Ondansetron has been well studied in terms of its pharmacokinetics. It has a plasma elimination half-life of 3 to 3% hours in heaithy adults and a clearance of approximately 600 mlimin, which is handled principally by metabolism. Aging has linear effects on its pharmacokinetic profile, with prolongation of the half-life. Qndansetron has an oral bioavailability of approximately 60%. This should be useful in the perianesthetic setting, considering current trends COgive oral premeditation to the ambulatory patients In humans receiving cispiatin for chemotherapy, serotonin is released from the enterochromaffin cells in the small intestine. ondansetron, when given prior to cisplatin, has been shown to block the release of serotonin in these patients.4 In direct-comparison studies, where patients received either ondansetron 0.15 mg/kg IV q 4h x 3 doses or metoclopramide in a total dose of 2 mgikg IV (given every 2h x 3 doses, then q 3h x 3 more doses), complete or major control (0 to 2 emetic episodes) was achieved 65% of tbe time with ondansetron uersuS 5 1% of etoclopramide (p = 0.016).5 None of the symptoms, but tients had extrapyramidal toclopramide patients had extrapyramida1 side effects such as dystonia and akathisia.j Similar findings were reported by Marty et aL6 As in the case of ~etoclo~ramide, the addition of dexamethasone has been shown to improve the efficacy of ondansetron in highly emetogenic chemotherapy.7

esthetic

and other antiemetzcs zn ambtdaiwp anesttiesia: ZahE

Emesis

any factors are invoived in the etiology of postanesthetic emesis. Unfortunateiy, few firm scientific statements can be made about the subject. The ferret model used in chemotherapy trials cannot be used to study postanesthesia emesis in humans. With over half of all surgery now being performed on an outpatient basis, control of postanesthetic vomiting is an area of active investigation. Many commonly performed outpatient procedures-including laparoscopy, strabismus surgery, tonsillectomy, and dilatation and curettage-are associated with a high rate of vomiting. Women seem to have a higher frequency ofemesis after surgery, but this finding may be related to surgical procedure, not gender. Also, the timing of infertility surgery in relation to the menstrual cycle may correlate with the degree of postanesthetic vomiting. As is the case with chemotherapy, where patients frequently have anticipatory nausea and/or vom-

Procblorperazine is commoniy used to treat emesis in adults, but it has poor efficacy in the prophylaxis of ’ Ciin. Anesth.. voi. 3 (Suppl I), _NovernSer/

2’

Orzginal Contributiom

postoperative nausea and vomiting. Young cl aE.IS reported results with a sustained-release Prochlorperazine 15 mg oral formulation. One hundred twenty females Iundergoing outpatient laser laparoscopy received Prochlorperazine or a placebo 1 hour prior to N@--fentanyl anesthesia. Fifty-four percent of the treated patients vomited in the postanesthesia care unit (PAW) (us. 7 I % of the placebo controls). Prochlorperazine was associated with fewer emetic symptoms in the PACIJ. However, when both groups were followed for 24 hours, the rates ofnausea and vomiting were equivalent in both groups.15 Hydroxyzine also has limited efficacy as an antiemetic in anesthetic practice.I‘j Droperidol is possibly the most commonly used antiemetic. Valanne and Kortilla17 showed that a 14 kg/kg dose was superior to a placebo in outpatient surgery. In the case of strabismus surgery in children, doses as high as 75 Fg/kg has been traditionally used.r8 The main problem associated with this high dose is seen in the PAW, where children who do not have postoperative nausea and vomiting are kept for long periods of time until they meet home discharge criteria, just because they were sedated. This excessive sedation often negates the antiemetic effect of droperidol. Other studies with droperido1 in outpatient strabismus surgery have found a lower dose not to be equally effective. Another common problem seen in adults, in addition to sedation, is postoperative dysphoria or anxiety. In 100 females undergoing outpatient gynecologic and breast surgery with general anesthesia, Melnick et al.lg found that those patients who randomly received 1.25 mg of droperidol experienced anxiety or restlessness when carefully questioned the day after surgery. When droperidol has been given as a premedication with fentanyl (Innovar) prior to plastic surgery, there have been anecdotal reports of patients w refused surgery or developed acute anxiety. As mentioned earlier, metoclopramide is a commonly used antiemetic prior to chemotherapy. It is a dopaminereceptor blocker, and although probably not as sedating as droperidol and prochlorperazine, it is st associated cent work with extrapyramidal and CNS side effects. indicates that it weakly antagonizes 5-hydroxytryptamine receptors, which may be responsible for its antiemetic oroperties. Some studies support the use of metoclo&-amide versuS placebo in the prophylaxis of postopera;ive nausea and vomiting. Given immediately after outpatient strabismus surgery in children, IV metoclopramide 0.15 mg/kg was superior to a placebo.* Ilowever, studies of inpatientsSo and outpatients*’ have found greater efficacy with droperidol when the two drugs were randomly compared. In females undergoing major gutpatient laparoscopic surgery, the addition of 20 mg of IV metoclopramide to droperidol I5 yg/kg modestly re-

duced the rate of PACU vomiting and, when compared with droperidol alone, greatly improved postdischarge emesis8 In the ambulatory patient, the occurrence ofpostoperative nausea and vomiting is inexorably linked to prolonged recovery and discharge time, since discharge criteria almost universally call for the absence of nausea and vomiting. In a study performed at the rdniversity of Pennsylvania on unpremeditated female outpatients undergoing laparoscopic surgery with general endotracheal anesthesia, 11% developed nausea and an additional 18% had vomiting. Xausea increased PACU time by 19 minutes, and vomiting prolonged PAW time by approximately 47 minutes, with a concomitant increase in cost.? Scopolamine is commonly to prev motion sickness in a sustained release placed ind the ear. In a study performed on inpatients, a scopolamine patch was found to be superior to a placebo to prevent postoperative nausea and vomiting.+ Mowever, when its use was attempted in children to prevent postoperative nausea and vomiting, the study had to be terminated due to a high frequency of side effects.$ Anecdotal experience in adult outpatients bas confirmed the problem of CNS and visual side effects Another ~nco~~~ntio~.a~ approach to antiemesis in anesthesia is the use of acupuncture. Dundee et al. 22 have shown that P6 point acupuncture (Neiguan point, which is located between the flexor carpi radialis and palmaris longus tendons proximal to the wrist crease) can be effective as prophylaxis for postoperative nausea and vomiting. ~ti~~~lati~~ of this area may use acupressure bands or transcutaneous electric current. Acupuncture has the advantage of being noninvasive and nonsedating, but it has the disadvantage of limited efficacy and duration. In addition, patients are sent home with apparatus that must be returned. Ephedrine 25 mg administered intramuscularly has been used in outpatients undergoing laparoscopy, and it is sometimes useful in patients who develop orthostatic hypotension and vomiting.

Leeser and Lipz3 published their experience with ondansetron 16 mg given orally preoperatively and then 8

tMetter SE, Sitz DS, Young ML, Baldeck AM, Apfeeibaum JL: Nausea and vomiting after outpatient laparoscopy: incidence, impact on recovery room stay and cost [Abstract]. An&h &r&g 1987; 66:S116. jjackson SE, Schmitt L, McGuire J, Hall M: Transdermal scopolamine as a preanesthetic drug and postoperative antinauseant and antiemetic [Abstract]. Anesthesiology 1982;57:A336

*Broadman LM, Cerruzi W, Patane PS, Hannallah RS, Ruttiman U, Friendly D: Metoclopramide reduces the incidence of vomiting following strabismus surgery in children [Abstract]. Anesthesiolo,g i 988;69:A747.

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OGibbons, PA, Nicolson SC, Betts EM, Rosenberry RR, Jobes DR: Scopolamine does not prevent postoperative emesis after pediatric eye surgery [Abstract]. Anesthesiology 1984;6 1 :A435.

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Ondansetron

hours after surgery ~rsus a placebo control. Eighty-four r hysterectomy (abdominal or vaginal) arotomy with thiopental-N@-isoflurNausea and vomiting QCa~e-a~~~~~a~~~ anesthesia. curred with a 40% and 52% frequency, res placebo-treated controls patients versw 17% those receiving ondansetron (p < 0.005). These dramatic differences were maintained throughout the 24-hour postoperative period; 60% of the placebo patients vomited uersFus26% of the ondansetron patients (p < 0.001). There were also differences in the number of patients requiring antiemetic treatment. Eight ondansetron patients required I2 doses of prochlorperazine versus 33 doses given to 22 patients in the placebo group. Similar data from other stu.dies are on file at Glaxo but not yet published. Two treatment studies were published in 1991. Lari8 mg IV given to jani et al. 24 found that ondansetron inpatients experiencing postoperative nausea and vomiting after N,O-opioid anesthesia was superior to a plaassociated with cardiovascular changes in cebo and n odner and Whitez5 studied 71 outpatients the PACK. undergoing laparoscopy. Patients had to experience at least IO minute5 of postoperative nausea and/or vomiting to receive treatment with 8 mg of ondansetron or a placebo. Nausea scores and the frequency of vomiting were significantly reduced by ondansetron without changes in vital signs, sedation, or anxiety scores. Minor side effects were similar in both groups and not felt to be study drug

related. sst

omitin

As required by the FDA, ondansetron has been evaluated at many institutions in randomized, blind, placebo-controlled studies for both the prophylaxis and treatment of postoperative nausea and vomiting. In one large trial, 589 females undergoing outpatient surgery received a placebo or 1 mg, 4 mg, or 8 mg of ondansetron IV just prior to induction. Sixty one percent of patients receiving the placebo were asymptomatic for the first 2 hours after sargery, compared with 74% to 78% of those who were given ondansetron. The ideal dose seemed to be 4 mg, as no increased benefit was obtained with the higher 8 mg dose. There were no significant differences in placebo or ondansetron patients in vital signs, complete blood count, serial multiple analysis of electrolytes and enzymes (SMA 20), urinalysis, or awakening time. Minor adverse events were equivalent in all groupsz6 As part of this study, two investigators found no differences in psychomotor recovery using digit symbol substitution and tapping board testsz7 The results of a large multicenter study using oral tablets for the prophylaxis of postoperative nalusea and vomiting are not available at this time. Once postoperative nausea and vomiting has developed, treatment is difficult with currently available drugs. Because of the sedative and other side effects and limited efficacy of conventional drugs, many anesthesiologists prefer to withhold treatment for the first emetic

and other antiemetics

m x&6ator~

anestka: Zahl

for fear of compounding postanest tion. However, in some patients, once the cycle of emesis develops, it is difficult to break. A large multicenter postoperative nauesa and vomiting treatment trial was recently completed using the same doses described above and a Imgo sesimilar protocol design.z8 In this stu Won was found to be superior to 2 pl bo, aga ng otency of this drug; 4 mg seemed to be the ideal with no added advantage of 8 me. Although no formal psychomotor testing was peforme and placebo patients had similar sedation patients receiving ondansetron required a cue antiemetic therapy.‘*

episode

‘Until recently, anesthesiologists had limited ability to control postoperative nausea an vomiting. Before the advent of propofol and now ondansetron, available drugs were of limited benefit (whether used for prophylaxis or treatment) and often were associa ceptably high frequency of CKS-relate dansetron holds great promise as a better antiemetic for use in ambulatory anesthesia. owever, studies with other conventional tkrPa&CS performed. Furthermore, in all trials: been has been used with an anesthetic regimen sisting of a tbiopental induction follow Eiberal amounts of opioids for maintenance to attempt COprovoke emesis. It has not been eva’!uated -with propo?ol, for example, which would presumably lower the frequency of postoperative nausea and vo No review would be complete without mentioning the or-ice of ondansetron. For them erapy, where 0.15 mglkg is recommended for three tient cost is $150. If 4 to 8 mg pro used dose, that would translate to $ I5 to $30 per patient at current prices. However, preventing emesis may lead ry and ultimately lower nursing costs or more procedures er day. These issues have already been raised with propofol to justify the higher price.“’ It could be argued that the approval of ondansetron for postoperative nausea and vomiting would expand its market and, hopefully, lower its price. Nevertheless, as with any new drug, the reality is that the cost of obtaining FDA approval will be reflected in the price.

On August 13, 1993, the FDA approved a supplemental new drug application for the addition of “‘the prevention of postoperative nausea and vomiting as an indication for Zofran@.” This approval applies to the IV formulation.

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surgery. JAMA

3riginul

Contribubons

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