AMBULATORY ANESTHESIA Section Editor Patricia A. Kapur
Editorial: The Big ”Little Problem” Patricia A. Kapur,
MD
Department of Anesthesiology, University of California, Los Angeles, California
P
erioperative nausea and emesis pose problems for patients undergoing all types of procedures requiring anesthesia or sedation. Particular groups of patients have been identified as being at higher risk, i.e., those with predisposing factors to prolonged gastric emptying (e.g., obstetric, bowel obstruction, or diabetic), those with recent food or liquid intake, those with inadequate protective mechanisms (e.g., hiatal hernia, nasogastric tube in place, or anesthetized upper airway), or those undergoing nausea-producing procedures, such as laparoscopy. As the authors of the accompanying articles (1,2) have pointed out, previous pharmacologic efforts to diminish the incidence and/or reduce the risk of emesis have included administering antihistaminics, anticholinergics, and dopamine antagonists. Sometimes narcotic-based anesthetic techniques are avoided. Physical maneuvers have included imposing various ”nothing per 0s” regimens, preanesthetic suctioning of gastric contents, application of cricoid cartilage pressure, avoiding inflation of the stomach during ventilation by mask, and ingestion of antacid solutions. None of the above, alone or in combination, have been entirely successful in mitigating the distressing occurrence of emesis and its potential sequelae. The predisposing factors mentioned above are more common within the inpatient population. However, as the number of acceptable surgical procedures increases in the field of ambulatory anesthesia, the need to find more effective alternatives to the options now available becomes more urgent. The potential cost savings of performing these procedures on an ambulatory basis may be negated by an unanticipated postoperative admission for intractable nausea (3).In addition, although intractable nausea is distressing, possibly dehydrating, and not easily manageable at home, the expense of a hospital stay is disproportionate to the actual morbidity of nausea for most healthy outpatients. Thus the therapy of last resort, hospitalAccepted for publication on May 17, 1991. Address correspondence to Dr. Kapur, Department of Anesthesiology, University of California, Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90024-1778. 01991 by the International Anesthesia Research Society 0003-2999191/$3.50
ization, is ultimately unsatisfactory for the patient, the anesthesiologist, and the surgeon. Even lesser degrees of postoperative nausea are often perceived as failures of therapy, rather than as an unavoidable consequence of the perioperative experience. In most instances, the latter is in fact the case because of imperfect treatment options. When queried about previous anesthetic experiences, many patients are heard to lament about the distressing nausea after a prior procedure and beg to be spared that experience again. During preoperative evaluations for subsequent anesthetics, such patients are often assured that the latest available antiemetic medications will be administered and that a nauseasparing anesthetic technique will be used. However, anesthesia providers cannot be sure that such a goal will be realized with the antiemetic treatment alternatives now available. A potential new entry into the antiemetic pharmacopeia is ondansetron, of the class of selective 5-hydroxytryptamine subtype 3 (5-HT3) receptor antagonists, which lack effects at cholinergic, adrenergic, dopaminergic, or histaminergic receptors (4). Ondansetron (tl,2,3,9-tetrahydro-9-methyl-3[(2-methyl-lHmonohydroimidazol)-l-methyl]-4H-carbazol-4-one, chloride, dihydrate) is structurally related to serotonin. 5-HT, receptors are located both peripherally (vagal nerve terminals) and centrally (chemoreceptor trigger zone). The antiemetic properties of ondansetron may be mediated peripherally, centrally, or both. Ondansetron has been studied in relation to cancer chemotherapy-induced emesis (5,6), which is associated with serotonin release from small intestine enterochromaffin cells and urinary excretion of serotonin metabolites. Presumably, the release of serotonin stimulates vagal afferent 5-HT3 receptors and/or the central vomiting reflex. In experimental animal studies, cisplatin-induced emesis can be prevented by section of the abdominal vagus and greater splanchnic nerve, or by pretreatment with either a serotonin synthesis inhibitor or a 5-HT3 receptor antagonist. In normal volunteers, ondansetron has little effect on lower esophageal sphincter pressure, esophageal or gastric motility, or small bowel transit time. By 5-HT3 selectivity, the undesirable side effects of using anAnesth Analg 1991;73:24>5
243
244
AMBULATORY ANESTHESIA
KAPUR
tagonists of dopaminergic, cholinergic, or histaminergic receptors as antiemetic agents, such as dysphoria, sedation, or extrapyramidal symptoms, will presumably be avoided. Ondansetron is hepatically metabolized, with a half-life of 3-5 h in healthy volunteers. Clearance decreases and half-life increases with increasing age. There was no difference, however, in the prevention of nausea and emesis in pediatric chemotherapy patients over 4 yr of age or in elderly patients in trials to date (7). Based on the success of ondansetron in the treatment of cytotoxic chemotherapy-induced emesis, several groups describe the clinical application of ondansetron to the treatment of postoperative nausea and vomiting. In a study published in the June 1991 issue of Anesthesia and Analgesia, Leeser and Lip (8) found that the preoperative administration of ondansetron, 16 mg orally, reduced the incidence of postoperative nausea and vomiting from 52% and 40% (i.e., placebo) to 17% and 12%, respectively, in patients undergoing abdominal gynecologic operations. The accompanying two articles (1,2) also report clinical applications of ondansetron to the treatment of postoperative nausea and vomiting. Larijani et al. (l), compared a single intravenous dose of 8 mg of ondansetron with placebo in a randomized, doubleblind scheme, for the treatment of nausea or vomiting within 2 h of a thiopental-N,O-narcotic-muscle relaxant anesthetic in a unselected group of 36 inpatients (18 received each treatment). The 36 patients represented a 16% incidence of nausea and vomiting out of a total of 229 patients who consented to participate in the study. Success was defined as no requirement for a prochlorperazine rescue treatment because of abatement of nausea by 10 min after study drug administration as well as no vomiting. Twenty-eight percent of ondansetron-treated patients and 78% of placebotreated patients failed these criteria. Arterial blood pressure, heart rate, and respiratory rate were stable during the study; side effects were minor and questionably related to the treatments, according to the authors. Bodner and White (2) looked at a more homogeneous group of young female patients undergoing outpatient laparoscopic gynecologic procedures, again using a narcotic-based anesthetic technique (thiopental-alfentanil-succinylcholine-N,O),in a randomized, double-blind, placebo-controlled design. Forty-six percent of 155 patients met the criteria for study drug administration, i.e., nausea lasting greater than 10 min or at least two episodes of emesis or retching in the recovery room. Of these, 35 received ondansetron (8 mg IV), and 36 received placebo. Those who were still nauseated 30 min after receiving the study drug, or who vomited, were given a rescue treatment consisting of metoclopra-
ANESTH ANALG 1991;73:24%5
mide-hydroxyzine. A second rescue treatment with droperidol was also available. Noninvasive vital signs were stable, and side effects were minor and similar in number between the two groups. Forty-three percent of the ondansetron group received a first rescue treatment vs 86% of the placebo group. Forty-two percent of the placebo group who received metoclopramide-hydroxyzine met the treatment failure criteria and received a subsequent droperidol rescue treatment. These three studies (1,2,8) clearly represent initial investigations in determining the suitability of ondansetron for the treatment of perioperative nausea and emesis. The difference in occurrence of nausea and emesis resulting in entry into the treatment wing of each study (16%Larijani et al. [l]vs 46% Bodner and White [2])presumably reflects the high incidence of these sequelae in laparoscopic patients. In contrast to the Leeser and Lip (8) study, these two studies used ondansetron only for the treatment of established nausea and emesis, rather than prophylactically for the prevention of its occurrence. All three studies gave only one dose based on information in cancer patients (for whom it is recommended to receive ondansetron in three divided doses over the course of the day in which the chemotherapeutic agents are administered [6]). None of the studies were designed to compare ondansetron with other currently available perioperative antiemetic therapies. Although an inference can be drawn from the Bodner and White study (2) in which 43% of the ondansetron- and 42% of the placebo/metoclopramide-hydroxyzine-treated patients required other subsequent antiemetic treatment, the optimum dose of ondansetron is not known for this application, and the circumstances of the administration of ondansetron vs metoclopramide-hydroxyzine were not equivalent in the study. Finally, the role of a 5-HT3 receptor antagonist in combination with other antiemetic agents with different mechanisms of action will need to be evaluated to determine (a) if additional efficacy can be obtained by drug combinations, (b) if drug doses can be lowered should combinations prove efficacious, and (c) that no untoward side effects occur with antiemetic combinations that include ondansetron. Thus, although there is reason to be hopeful, it is too early to tell whether ondansetron will prove to be a significant improvement over extant therapies for the vexing problem of perioperative nausea and emesis. As compared with specific cytotoxic chemotherapeutic agents that trigger 5-HT release, perioperative nausea and emesis may be a multifactorial issue, related to a variety of physical, anatomic, physiologic, and pharmacologic interactions. On the other hand, despite a variety of etiologic factors in the
ANESTH ANALC
AMBULATORY ANESTHESIA
KAPUR
245
1991:73:243-5
perioperative period, it is possible that ondansetron, alone or in combination with other agents with different mechanisms of action, may increase the probability of preventing or aborting nausea and emesis in perioperative patients. Future studies with ondansetron, as well as with other potentially novel antiemetic agents, will be eagerly awaited. The impact and applicability of a significant improvement in antiemetic therapy for surgical patients would be enormous.
References 1. Larijani GE, Gratz I, Afshar M, Minassian S. Treatment of postoperative nausea and vomiting with ondansetron: a randomized, double-blind comparison with placebo. Anesth Analg 1991;73:24&9.
2. Bodner M, White PF. Antiemetic efficacy of ondansetron after outpatient laparoscopy. Anesth Analg 1991;73:250-4. 3. Gold BS, Kitz DS, Lecky JH, Neuhaus JM. Unanticipated admission to the hospital following ambulatory surgery. JAMA 1989;262:3008-10. 4. Tyers MB, Bunce KT, Humphrey PPA. Pharmacological and anti-emetic properties of ondansetron. Eur J Cancer Clin Oncol 1989;25(Suppl 1):S15-9. 5. Cubeddu LX, Hoffman IS, Fuenmayor NT, Finn AL. Antagonism of serotonin S3 receptors with ondansetron prevents nausea and emesis induced by cyclophosphamide-containing chemotherapy regimens. J Clin Oncol 1990;8:1721-7. 6. Cubeddu LX, Hoffman IS, Fuenmayor NT, Finn AL. Efficacy of ondansetron (GR 38032F) and the role of serotonin in cisplatininduced nausea and vomiting. N Engl J Med 1990;322:810-6. 7. Complete Prescribing Information, ZOFRANR (ondansetron HC1) Injection. January 1991. Glaxo Pharmaceuticals, Research Triangle Park, N.C. 8. Leeser J, Lip H. Prevention of postoperative nausea and vomiting using ondansetron, a new, selective, 5-HT3 receptor antagonist. Anesth Analg 1991;72:751-5.
Editorial: The Big ”Little Problem” Patricia A. Kapur,
MD
Department of Anesthesiology, University of California, Los Angeles, California
P
erioperative nausea and emesis pose problems for patients undergoing all types of procedures requiring anesthesia or sedation. Particular groups of patients have been identified as being at higher risk, i.e., those with predisposing factors to prolonged gastric emptying (e.g., obstetric, bowel obstruction, or diabetic), those with recent food or liquid intake, those with inadequate protective mechanisms (e.g., hiatal hernia, nasogastric tube in place, or anesthetized upper airway), or those undergoing nausea-producing procedures, such as laparoscopy. As the authors of the accompanying articles (1,2) have pointed out, previous pharmacologic efforts to diminish the incidence and/or reduce the risk of emesis have included administering antihistaminics, anticholinergics, and dopamine antagonists. Sometimes narcotic-based anesthetic techniques are avoided. Physical maneuvers have included imposing various ”nothing per 0s” regimens, preanesthetic suctioning of gastric contents, application of cricoid cartilage pressure, avoiding inflation of the stomach during ventilation by mask, and ingestion of antacid solutions. None of the above, alone or in combination, have been entirely successful in mitigating the distressing occurrence of emesis and its potential sequelae. The predisposing factors mentioned above are more common within the inpatient population. However, as the number of acceptable surgical procedures increases in the field of ambulatory anesthesia, the need to find more effective alternatives to the options now available becomes more urgent. The potential cost savings of performing these procedures on an ambulatory basis may be negated by an unanticipated postoperative admission for intractable nausea (3).In addition, although intractable nausea is distressing, possibly dehydrating, and not easily manageable at home, the expense of a hospital stay is disproportionate to the actual morbidity of nausea for most healthy outpatients. Thus the therapy of last resort, hospitalAccepted for publication on May 17, 1991. Address correspondence to Dr. Kapur, Department of Anesthesiology, University of California, Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90024-1778. 01991 by the International Anesthesia Research Society 0003-2999191/$3.50
ization, is ultimately unsatisfactory for the patient, the anesthesiologist, and the surgeon. Even lesser degrees of postoperative nausea are often perceived as failures of therapy, rather than as an unavoidable consequence of the perioperative experience. In most instances, the latter is in fact the case because of imperfect treatment options. When queried about previous anesthetic experiences, many patients are heard to lament about the distressing nausea after a prior procedure and beg to be spared that experience again. During preoperative evaluations for subsequent anesthetics, such patients are often assured that the latest available antiemetic medications will be administered and that a nauseasparing anesthetic technique will be used. However, anesthesia providers cannot be sure that such a goal will be realized with the antiemetic treatment alternatives now available. A potential new entry into the antiemetic pharmacopeia is ondansetron, of the class of selective 5-hydroxytryptamine subtype 3 (5-HT3) receptor antagonists, which lack effects at cholinergic, adrenergic, dopaminergic, or histaminergic receptors (4). Ondansetron (tl,2,3,9-tetrahydro-9-methyl-3[(2-methyl-lHmonohydroimidazol)-l-methyl]-4H-carbazol-4-one, chloride, dihydrate) is structurally related to serotonin. 5-HT, receptors are located both peripherally (vagal nerve terminals) and centrally (chemoreceptor trigger zone). The antiemetic properties of ondansetron may be mediated peripherally, centrally, or both. Ondansetron has been studied in relation to cancer chemotherapy-induced emesis (5,6), which is associated with serotonin release from small intestine enterochromaffin cells and urinary excretion of serotonin metabolites. Presumably, the release of serotonin stimulates vagal afferent 5-HT3 receptors and/or the central vomiting reflex. In experimental animal studies, cisplatin-induced emesis can be prevented by section of the abdominal vagus and greater splanchnic nerve, or by pretreatment with either a serotonin synthesis inhibitor or a 5-HT3 receptor antagonist. In normal volunteers, ondansetron has little effect on lower esophageal sphincter pressure, esophageal or gastric motility, or small bowel transit time. By 5-HT3 selectivity, the undesirable side effects of using anAnesth Analg 1991;73:24>5
243
244
AMBULATORY ANESTHESIA
KAPUR
tagonists of dopaminergic, cholinergic, or histaminergic receptors as antiemetic agents, such as dysphoria, sedation, or extrapyramidal symptoms, will presumably be avoided. Ondansetron is hepatically metabolized, with a half-life of 3-5 h in healthy volunteers. Clearance decreases and half-life increases with increasing age. There was no difference, however, in the prevention of nausea and emesis in pediatric chemotherapy patients over 4 yr of age or in elderly patients in trials to date (7). Based on the success of ondansetron in the treatment of cytotoxic chemotherapy-induced emesis, several groups describe the clinical application of ondansetron to the treatment of postoperative nausea and vomiting. In a study published in the June 1991 issue of Anesthesia and Analgesia, Leeser and Lip (8) found that the preoperative administration of ondansetron, 16 mg orally, reduced the incidence of postoperative nausea and vomiting from 52% and 40% (i.e., placebo) to 17% and 12%, respectively, in patients undergoing abdominal gynecologic operations. The accompanying two articles (1,2) also report clinical applications of ondansetron to the treatment of postoperative nausea and vomiting. Larijani et al. (l), compared a single intravenous dose of 8 mg of ondansetron with placebo in a randomized, doubleblind scheme, for the treatment of nausea or vomiting within 2 h of a thiopental-N,O-narcotic-muscle relaxant anesthetic in a unselected group of 36 inpatients (18 received each treatment). The 36 patients represented a 16% incidence of nausea and vomiting out of a total of 229 patients who consented to participate in the study. Success was defined as no requirement for a prochlorperazine rescue treatment because of abatement of nausea by 10 min after study drug administration as well as no vomiting. Twenty-eight percent of ondansetron-treated patients and 78% of placebotreated patients failed these criteria. Arterial blood pressure, heart rate, and respiratory rate were stable during the study; side effects were minor and questionably related to the treatments, according to the authors. Bodner and White (2) looked at a more homogeneous group of young female patients undergoing outpatient laparoscopic gynecologic procedures, again using a narcotic-based anesthetic technique (thiopental-alfentanil-succinylcholine-N,O),in a randomized, double-blind, placebo-controlled design. Forty-six percent of 155 patients met the criteria for study drug administration, i.e., nausea lasting greater than 10 min or at least two episodes of emesis or retching in the recovery room. Of these, 35 received ondansetron (8 mg IV), and 36 received placebo. Those who were still nauseated 30 min after receiving the study drug, or who vomited, were given a rescue treatment consisting of metoclopra-
ANESTH ANALG 1991;73:24%5
mide-hydroxyzine. A second rescue treatment with droperidol was also available. Noninvasive vital signs were stable, and side effects were minor and similar in number between the two groups. Forty-three percent of the ondansetron group received a first rescue treatment vs 86% of the placebo group. Forty-two percent of the placebo group who received metoclopramide-hydroxyzine met the treatment failure criteria and received a subsequent droperidol rescue treatment. These three studies (1,2,8) clearly represent initial investigations in determining the suitability of ondansetron for the treatment of perioperative nausea and emesis. The difference in occurrence of nausea and emesis resulting in entry into the treatment wing of each study (16%Larijani et al. [l]vs 46% Bodner and White [2])presumably reflects the high incidence of these sequelae in laparoscopic patients. In contrast to the Leeser and Lip (8) study, these two studies used ondansetron only for the treatment of established nausea and emesis, rather than prophylactically for the prevention of its occurrence. All three studies gave only one dose based on information in cancer patients (for whom it is recommended to receive ondansetron in three divided doses over the course of the day in which the chemotherapeutic agents are administered [6]). None of the studies were designed to compare ondansetron with other currently available perioperative antiemetic therapies. Although an inference can be drawn from the Bodner and White study (2) in which 43% of the ondansetron- and 42% of the placebo/metoclopramide-hydroxyzine-treated patients required other subsequent antiemetic treatment, the optimum dose of ondansetron is not known for this application, and the circumstances of the administration of ondansetron vs metoclopramide-hydroxyzine were not equivalent in the study. Finally, the role of a 5-HT3 receptor antagonist in combination with other antiemetic agents with different mechanisms of action will need to be evaluated to determine (a) if additional efficacy can be obtained by drug combinations, (b) if drug doses can be lowered should combinations prove efficacious, and (c) that no untoward side effects occur with antiemetic combinations that include ondansetron. Thus, although there is reason to be hopeful, it is too early to tell whether ondansetron will prove to be a significant improvement over extant therapies for the vexing problem of perioperative nausea and emesis. As compared with specific cytotoxic chemotherapeutic agents that trigger 5-HT release, perioperative nausea and emesis may be a multifactorial issue, related to a variety of physical, anatomic, physiologic, and pharmacologic interactions. On the other hand, despite a variety of etiologic factors in the
ANESTH ANALC
AMBULATORY ANESTHESIA
KAPUR
245
1991:73:243-5
perioperative period, it is possible that ondansetron, alone or in combination with other agents with different mechanisms of action, may increase the probability of preventing or aborting nausea and emesis in perioperative patients. Future studies with ondansetron, as well as with other potentially novel antiemetic agents, will be eagerly awaited. The impact and applicability of a significant improvement in antiemetic therapy for surgical patients would be enormous.
References 1. Larijani GE, Gratz I, Afshar M, Minassian S. Treatment of postoperative nausea and vomiting with ondansetron: a randomized, double-blind comparison with placebo. Anesth Analg 1991;73:24&9.
2. Bodner M, White PF. Antiemetic efficacy of ondansetron after outpatient laparoscopy. Anesth Analg 1991;73:250-4. 3. Gold BS, Kitz DS, Lecky JH, Neuhaus JM. Unanticipated admission to the hospital following ambulatory surgery. JAMA 1989;262:3008-10. 4. Tyers MB, Bunce KT, Humphrey PPA. Pharmacological and anti-emetic properties of ondansetron. Eur J Cancer Clin Oncol 1989;25(Suppl 1):S15-9. 5. Cubeddu LX, Hoffman IS, Fuenmayor NT, Finn AL. Antagonism of serotonin S3 receptors with ondansetron prevents nausea and emesis induced by cyclophosphamide-containing chemotherapy regimens. J Clin Oncol 1990;8:1721-7. 6. Cubeddu LX, Hoffman IS, Fuenmayor NT, Finn AL. Efficacy of ondansetron (GR 38032F) and the role of serotonin in cisplatininduced nausea and vomiting. N Engl J Med 1990;322:810-6. 7. Complete Prescribing Information, ZOFRANR (ondansetron HC1) Injection. January 1991. Glaxo Pharmaceuticals, Research Triangle Park, N.C. 8. Leeser J, Lip H. Prevention of postoperative nausea and vomiting using ondansetron, a new, selective, 5-HT3 receptor antagonist. Anesth Analg 1991;72:751-5.
