Pooled analysis of three large clinical trials to determine the optimal dose of dolasetron mesylate needed to prevent postoperative nausea and vomiting. The Dolasetron Prophylaxis Study Group.

STUDY OBJECTIVE: To identify the maximally effective dolasetron dose (i.e., maximum efficacy with minimum adverse events) for prevention of postoperative nausea and vomiting (PONV) using the statistical power generated in a pooled patient sample from three large, nearly identical clinical trials. DESIGN: Three randomized, multicenter, placebo-controlled, double-blinded trials. SETTING: Trials 1, 2, and 3 enrolled patients at 10, 25, and 17 hospitals and/or surgical centers, respectively. PATIENTS: A total of 1,946 ASA physical status, I, II, and III patients. Trials 1 and 2 enrolled only female patients (n = 916) undergoing gynecologic surgery. Trial three enrolled 722 females (approximately 70% gynecologic surgeries) and 308 males (approximately 46% orthopedic surgeries) undergoing a variety of surgical procedures. INTERVENTIONS: All surgical procedures used balanced general anesthesia. Patients received 12.5, 25, 50, or 100 mg of the antiemetic, dolasetron, near the end of anesthesia. MEASUREMENTS AND MAIN RESULTS: Efficacy endpoints were identical and measured for 24 hours: complete response (no vomiting or rescue medication) and maximum nausea, reported using a 100-mm visual analog scale (VAS). Safety was assessed using adverse event reports, laboratory and electrocardiographic data, and vital signs. All four dolasetron doses produced significant increases in complete response and decreases in maximum VAS nausea compared with placebo (p < 0.01). No increased efficacy was observed with dolasetron doses higher than 12.5 mg. Safety was similar between each dolasetron dose and placebo. CONCLUSION: Dolasetron 12.5 mg, given near the end of anesthesia, is the maximally effective dose studied for preventing postoperative nausea and vomiting.

The initial clinical experience of 1819 physicians in maintaining anesthesia with propofol: characteristics associated with prolonged time to awakening.

In October 1989, propofol underwent Phase IV Food and Drug Administration testing that involved 25,981 patients, 1722 institutions, and 1819 anesthesiologists. Participants were 18-80 yr of age and ASA physical status I-III; they could not have a continuing pregnancy or prior adverse anesthetic experience. Anesthesiologists completed detailed forms to describe their use of propofol in this three-step study: propofol for induction only (Step 1), for induction and then maintenance by intermittent bolus injection (Step 2), or for continuous infusion (Step 3). In early 1992, our group of anesthesiologists and epidemiologists analyzed the resulting data base. We evaluated data from 14,882 patients (8095 given bolus injections and 6787 given continuous infusion) to determine factors predicting prolonged time (> 15 min after cessation of all anesthesia) to awakening, one measure of recovery from anesthesia. The incidence of prolonged awakening was 6.8% (1016 patients); the median and mean (+/- SD) times to awakening were, respectively, 5 min and 7.2 +/- 7.3 min. The following variables were associated (P < 0.05) with prolonged awakening from propofol maintenance anesthesia: a total dose of propofol > 8 mg/kg, male gender, endotracheal intubation, age > 65 yr, abdominal surgery, continuous infusion of propofol, and concomitant use of isoflurane or benzodiazepines. These results support the clinical impression that recovery from propofol anesthesia is remarkably rapid; although the vast majority of physicians participating in this study were using propofol for maintenance for the first time, only 6.8% of patients had awakening times exceeding 15 min.

Effects on recovery when isoflurane is used to supplement propofol-nitrous oxide anesthesia.

During propofol-nitrous oxide (N2O) anesthesia, volatile anesthetics are frequently administered to treat signs of inadequate anesthesia and to decrease the possibility of intraoperative awareness. Because the clinical effects of this combination have not been examined rigorously, we used data from the 1989-90 Phase IV clinical trial with propofol to evaluate recovery from propofol-N2O anesthesia with and without supplementation with isoflurane. In this study involving 15,806 patients at 1722 institutions, propofol was administered for induction and maintenance of anesthesia with N2O for procedures lasting less than 60 min. At the discretion of the anesthesiologist, volatile anesthetics were administered as needed during maintenance of anesthesia (the incidence of use of inhaled anesthetics was 14.7% for isoflurane, 2.2% for enflurane, and 0.2% for halothane). Other intraoperative medications included opioid analgesics, muscle relaxants, and anticholinergic drugs. The present study concerns the subset of 7796 patients given propofol-N2O maintenance anesthesia (intermittent bolus or continuous infusion) with or without isoflurane supplementation for procedures lasting less than 60 min. Isoflurane was used more frequently for procedures lasting 30-60 min than for those less than 30 min. Nevertheless, the maintenance dose of propofol was significantly (P < 0.05) less with isoflurane (178 vs 235 mg). Adjunctive use of isoflurane prolonged the time to awakening and to becoming oriented, but discharge times were similar for the two groups. The incidence of postoperative nausea, vomiting, recall, and excitement did not differ between the two groups. We conclude that the addition of isoflurane to a propofol-N2O anesthetic does not alter recovery from anesthesia.

Hemodynamic effects of propofol: data from over 25,000 patients.

To investigate clinically important hypotension and bradycardia after induction of anesthesia with propofol, we analyzed data from a Phase IV stepwise study involving 25,981 patients, 1722 institutions, and 1819 anesthesiologists. In Step 1, propofol was used for induction only. In Step 2, propofol was used for induction and then maintenance by intermittent injection. In Step 3, an induction dose was followed by a maintenance infusion. Participants were to be 18-80 yr of age and ASA physical status I-III; they could not have a continuing pregnancy or prior adverse anesthetic experience. Detailed data on demographic, perioperative, and outcome variables were recorded on data collection forms. The overall incidence of hypotension (systolic blood pressure < 90 mm Hg) was 15.7%; 77% of the episodes were recorded within 10 min of induction of anesthesia with propofol. Bradycardia (heart rate < 50 beats/min) occurred in 4.8% of patients, with 42% of the episodes in the first 10 min. Only 1.3% of patients had both hypotension and bradycardia. The incidence of hypotension was significantly higher for the elderly, females, Caucasians, those undergoing abdominal and integumentary procedures, and those given propofol with opioids, benzodiazepines, or propranolol. Bradycardia was significantly more common when propofol was combined with opioids or chronically taken beta-adrenergic receptor-blocking drugs. Bradycardia and hypotension were not commonly associated. Giving this new drug by protocol, even inexperienced anesthesiologists incurred few adverse hemodynamic changes. Hemodynamic changes were transient and rarely (< 0.2%) required drug therapy. Cardiovascular changes and drug interactions were predictable and manageable based on knowledge of the pharmacology of propofol.

Adverse events in a multicenter phase IV study of propofol: evaluation by anesthesiologists and postanesthesia care unit nurses.

Phase II and III studies are tightly controlled trials investigating adverse effects before government approval of a new drug. However, because postapproval Phase IV studies involve a much larger and more complex population, the true nature of adverse effects can be seen. We analyzed Phase IV data for the new drug propofol with regard to the incidence of adverse events, and evaluations of such events by anesthesiologists versus postanesthesia care unit (PACU) nurses. Data pertained to 25,981 patients, 1722 institutions, and 1819 anesthesiologists giving propofol in three anesthetic regimens. Inclusion criteria were liberal: age, 18-80 yr; ASA physical status I-III; no continuing pregnancy; and no prior adverse anesthetic experience. Anesthesiologists and PACU nurses used data collection forms to record demographic, perioperative, and outcome variables; to evaluate recovery (excellent, good, or poor); and to describe adverse events. Adverse events were reported for 2813 patients (10.8%); the most common events were pain on injection (5.2%), hypotension (1.1%), nausea/vomiting (1.9%), and excitement (1.3%). The incidences of pain on injection and nausea/vomiting were approximately one-half and one-fifth, respectively, the values reported in earlier studies. Six hundred thirty-three patients (2.4%) had a "poor" recovery according to one or both of the evaluators (the anesthesiologist or PACU nurse). The PACU nurse was more influenced by nausea, vomiting, or postoperative pain; and the anesthesiologist was more influenced by postoperative confusion or delayed emergence from anesthesia. For only 0.6% of patients did both evaluators rate recovery as poor. Anesthesiologists gave more weight to intraoperative adverse events, and nurses to postoperative events.(ABSTRACT TRUNCATED AT 250 WORDS)

How do anesthesiologists select patients when introducing a new drug into practice?

As part of the marketing strategy for the anesthetic drug propofol (Diprivan), Stuart Pharmaceuticals began a Phase IV postmarketing study soon after the drug received Food and Drug Administration approval in 1989. We used data from this study to test the hypothesis that anesthesiologists would initially use propofol for young, relatively healthy patients and then, with experience, for older, sicker patients. The Phase IV study involved 1722 institutions, 1819 anesthesiologists, and 25,981 patients. The study incorporated three sequential steps, each to be tested in five patients. In Step 1, propofol was used for induction only; in Step 2, for induction and maintenance of anesthesia by intermittent injection; and, in Step 3, for induction and maintenance by continuous infusion. Inclusion criteria were age 18-80 yr and ASA physical status I-III. Exclusion criteria were continuing pregnancy and a previous adverse anesthetic experience. Physicians used standardized data collection forms to voluntarily compile detailed demographic, perioperative, and outcome variables for patients. Data were then evaluated by an independent, multicenter team of seven anesthesiologists and three epidemiologists to determine whether the first two patients selected to participate in each step (Patients 1 and 2, 6 and 7, and 11 and 12) were less sick, younger, or undergoing less invasive or shorter procedures than patients enrolled later in the same steps (Patients 4 and 5, 9 and 10, and 14 and 15). Physicians gave propofol first to patients with fewer concurrent diseases than are found in the general population (10% were hypertensive versus 16%; 3% were diabetic versus 10%).(ABSTRACT TRUNCATED AT 250 WORDS)

Phase IV study of propofol: validation of the data set.

In 1989-1990, Stuart Pharmaceuticals conducted a Phase IV study of propofol on over 26,000 patients, later making the large data base available to a team of epidemiologists and anesthesiologists for analysis. We now describe the process of verifying the data to provide a sound basis for further analyses. Original data were collected by 1819 physicians at 1761 hospitals. In that study, anesthesia was induced by bolus injection of propofol and was maintained by inhaled drug and N2O-O2 (Step 1), or by propofol (either intermittent bolus injection [Step 2] or continuous infusion [Step 3]) and N2O-O2. Forty-six recorded variables described history, physical examination, course and quality of anesthesia and recovery, and adverse events. Data were scrutinized for inaccuracy or bias regarding adverse events, completeness of data, data entry, and violations of the study protocol. The initial data set pertained to 26,841 patients (10,698, Step 1; 8886, Step 2; and 7257, Step 3). Because we excluded data if 25% of the items were missing from the data set, 3.2% of the case reports were eliminated: the final data set used for subsequent analyses contained 25,981 patients (10,184, Step 1; 8672, Step 2; and 7125, Step 3). Inaccuracy of data entry was not excessive, and violations of study protocol were less frequent than in similar studies. The nature and frequency of adverse events were similar to those reported in Phase II and III clinical trials of propofol. Analysis showed that missing data occurred randomly and did not introduce obvious bias. We conclude that the data set was valid and most likely represents perioperative events occurring in similar patients; that Phase IV studies can be valuable because of the range of patients studied and the ability to detect even rare events; and that future Phase IV studies could be improved by more efficient design of data collection forms for both hypotheses to be tested and the entry of data onto forms.

The role of pharmacoepidemiology research in postmarketing surveillance and anesthesia practice/critical care medicine.

Despite tremendous efforts to ensure the safety and effectiveness of newly marketed medications, a number of these have had significant problems after introduction of the drug to the market. Such problems highlight the practical limitations of clinical trials performed to obtain FDA approval for marketing. Pharmacoepidemiology research methodologies provide a powerful mechanism for exploring the determinants of drug safety and effectiveness in broad-based populations and can serve as a scientific foundation for outcome research. Using these methodologies, largescale postmarketing surveillance studies similar to the type described in the accompanying articles would constitute an important way of confirming and identifying the determinants of drug safety and effectiveness in large, diverse patient populations.

Comparison of ondansetron versus placebo to prevent postoperative nausea and vomiting in women undergoing ambulatory gynecologic surgery.

BACKGROUND: Postoperative nausea and emesis, especially in ambulatory surgical patients, remains a troublesome problem. This study was performed to compare the incidence of nausea and emesis during the 24-h postoperative period in ondansetron-treated patients versus placebo-treated patients. METHODS: Using a randomized prospective double-blind study design, women between the ages of 18 and 70 yr undergoing gynecologic surgical procedures with general opioid anesthesia on an outpatient basis were enrolled. Ondansetron or placebo was administered prior to induction of anesthesia. Patients were stratified according to history of nausea and emesis during previous exposure to general anesthesia and randomized to dose received. RESULTS: Data from the 544 women showed that all doses of intravenous ondansetron tested (1, 4, and 8 mg) were significantly more effective (62%, 76%, and 77%, respectively) than placebo (46%) in reducing the incidence of emesis following surgery until 24 h after recovery room entry. All these doses were more effective than placebo in patients with no prior history of emesis following surgery and the 4- and 8-mg doses were more effective than placebo in patients with a prior history of emesis following surgery. All doses of ondansetron tested were generally well tolerated with adverse events, clinical laboratory tests, and recovery room vital signs similar to those of placebo. Serum aspartate transaminase (AST) was increased in five patients (1 mg, 2 patients; 4 mg, 1 patient; 8 mg, 2 patients). In the three patients in whom subsequent analysis were performed, the serum AST had decreased to preoperative levels. CONCLUSIONS: Ondansetron given intravenously to prevent postoperative nausea and emesis was highly effective in the 4- and 8-mg doses in women having ambulatory gynecologic surgery.

Prophylactic intravenous ondansetron in female outpatients undergoing gynaecological surgery: a multicentre dose-comparison study.

The efficacy and safety of prophylactic intravenous ondansetron in preventing postoperative nausea and vomiting was investigated in a randomized, stratified, double-blind, placebo-controlled, dose-comparison study of 580 ASA physical class I and II female outpatients undergoing gynaecological surgery and receiving general anaesthesia. Patients received either ondansetron 1, 4 or 8 mg, or placebo i.v. immediately prior to a standardized technique for induction and maintenance of anaesthesia. All patients were intubated and received nitrous oxide and a narcotic. All doses of ondansetron were significantly more effective than placebo in preventing emesis over the 24 h postoperative period. Ondansetron significantly decreased nausea and emesis scores over 24 h postoperatively without causing sedation. No changes in laboratory parameters (haematology, blood chemistry, and liver enzymes) or vital signs (heart rate, blood pressure, and respiratory rate) were observed. Headache and dizziness were the most common side-effects; however, their incidence was the same as with placebo. Ondansetron was generally well tolerated, as evidenced by an adverse event, laboratory safety, and vital sign profile similar to placebo. Ondansetron 4 mg was found to be the optimal prophylactic i.v. dose for female outpatients over the entire 24 h postoperative period. Higher doses may offer an added benefit in some patients, such as those with a history of nausea and vomiting following general anaesthesia.