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Anesth Analg 2002;94:50-54
© 2002 International Anesthesia Research Society

PEDIATRIC ANESTHESIA

Cisapride Does Not Prevent Postoperative Vomiting in Children

Scott D. Cook-Sather, MD, Kathleen A. Harris, RN BSN, and Mark S. Schreiner, MD

Department of Anesthesiology and Critical Care Medicine, Children’s Hospital of Philadelphia, and the University of Pennsylvania, Philadelphia, Pennsylvania

Address correspondence and reprint requests to Scott D. Cook-Sather, MD, Department of Anesthesiology and Critical Care Medicine, Children’s Hospital of Philadelphia, 34th St. and Civic Ctr. Blvd., Philadelphia, PA 19104. Address e-mail to sather@ email.chop.edu.


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
The peripherally acting prokinetic drug cisapride can overcome opioid-induced gastrointestinal paresis and may thereby eliminate a stimulus for postoperative vomiting. We conducted a prospective, randomized, double-blinded, controlled trial of 96 children undergoing inguinal surgery to determine whether cisapride would reduce the incidence of postoperative vomiting after general anesthesia supplemented with morphine. Group C1 patients (n = 38) received cisapride 0.3 mg/kg orally 1 h before surgery and placebo 6 h later, Group C2 (n = 28) received cisapride both before and after surgery, and Group P (n = 30) received placebo. Mean age (5.0 ± 2.7 yr) and weight (21.0 ± 8.6 kg), median pain scores and parent satisfaction scores, and incidence of rescue analgesic administration were similar across groups. Contrary to our hypothesis, incidences of postoperative vomiting in the hospital (32% vs 20%, P = 0.33) and at home (53% vs 46%, P = 0.33) did not vary by treatment group (with [C1 and C2] and without [P] cisapride, respectively). There was a trend toward more severe postoperative vomiting (three or more episodes) in children who received cisapride versus those who did not, both in hospital (6% vs 0%, P = 0.3) and at home (22% vs 8%) (P = 0.13). We conclude that cisapride does not prevent postoperative vomiting in this patient population and speculate that factors other than reduced gastrointestinal motility associated with general anesthesia and opioids are more important determinants of postoperative vomiting.

IMPLICATIONS: Cisapride does not prevent postoperative vomiting in children and may increase its severity.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Postoperative vomiting (POV) resulting in patient discomfort and prolonged recovery from anesthesia is a significant pediatric problem (1,2). Opioid analgesics may increase the incidence of POV in children (3,4). Mechanistic theories of POV focus on the central nervous system (CNS) and invoke stimulation of the emetic center in the parvicellular reticular formation by opioids or other agonists binding in the chemoreceptor trigger zone, sensitization of the vestibular apparatus, vagal input (5), or a combination of these. Opioids (6–8) and volatile anesthetics (9) also reduce gastrointestinal (GI) motility through both central and peripheral mechanisms (10–12). Much as Rowbotham (13) and Ogilvy and Smith (10) had speculated earlier, we wondered whether peripheral input from a GI tract slowed by anesthetics could signal the emetic center and provide an important mechanism for increased incidence of POV. Highly effective 5-hydroxytryptamine-3 receptor antagonist antiemetics, which have both central and peripheral effects (14–17), cannot be used to determine the relative importance of peripheral signaling. We hypothesized that cisapride, a prokinetic (promotility) drug which has no central effects, but which works peripherally by increasing the physiologic release of acetylcholine from myenteric plexus postganglionic nerve endings (18) and which is known to overcome the GI effects of morphine (10,19), might reduce the incidence of POV and thus lend experimental support to a peripheral triggering mechanism for POV.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
We conducted a randomized, controlled, double-blinded, parallel group study involving children undergoing inguinal surgery. We obtained IRB approval, written informed consent from parents or guardians, and documented assent from children >=7 yr of age. Patient inclusion criteria were ages 2–12 yr, inguinal hernia or hydrocele surgery, and ASA physical status I or II. Initial exclusion criteria were a history of gastroesophageal reflux (GER), gastroparesis, motion sickness from inner ear or other CNS disorders, or prior severe POV. The randomization was computer generated and administered by the hospital pharmacy. Subjects were randomized to one of three treatment groups, each given an oral medication (placebo or cisapride 0.3 mg/kg) 1 h before surgery and then 6 h later. Group P received placebo, placebo; Group C1 received cisapride, placebo; and Group C2 received cisapride, cisapride. Investigators, nursing staff, patients, and parents were blinded to treatment assignment.

The anesthetic technique was standardized and included atropine 20 µg/kg (maximum, 1.0 mg), acetaminophen 15 mg/kg (maximum, 650 mg), and midazolam 0.5 mg/kg (maximum, 15 mg) orally as preanesthesia medications; inhaled induction and maintenance of anesthesia with oxygen, N2O, and halothane; regional nerve block (ilioinguinal or iliohypogastric, caudal, or surgical infiltration with bupivacaine); and 50–100 µg/kg morphine IV. The use of a laryngeal mask airway (LMA) or tracheal tube was at the clinicians’ discretion. When tracheal intubation was selected, rocuronium, vecuronium, or pancuronium was used to facilitate intubation, and paralysis was reversed at the end of the procedure with atropine and neostigmine. Gastric fluid was evacuated with a 14F multiorificed suction catheter after induction in all intubated patients, but not in every child managed with an LMA. Intraoperative propofol, ondansetron, metoclopramide, droperidol, and dexamethasone were not allowed.

Patient age, sex, weight, race, physical status, surgical procedure (unilateral, bilateral, laparoscopic inspection of contralateral side), and anesthetic technique were recorded. Postanesthesia care unit (PACU, Phase I) and day surgery unit (DSU, Phase II) admission and discharge times were noted. Episodes of vomiting (number, duration, and time of day) in the PACU and DSU were recorded, as was the administration of antiemetics during the admission. If a child experienced two emetic episodes in the hospital, he or she was allowed droperidol 25 µg/kg IV, and if vomiting persisted after 30 min, ondansetron 50 µg/kg IV was administered. Pain was assessed by the PACU nurse by using a 10-point visual analog scale (VAS). Pain was treated whenever VAS scores were >=5 with ketorolac 0.5–1.0 mg/kg IV. If after an additional 15 min the VAS score continued to exceed 5, morphine 50–100 µg/kg IV was administered.

Before discharge, all parents were given a diary form and were instructed to record all episodes of vomiting (number, duration, time of day, and relation to ingestion of food/drink or travel) for the subsequent day. A study nurse or investigator interviewed one of the parents by telephone approximately 24 h after surgery to discuss the subject’s course after discharge. The parents were also asked to rank on a scale of 1 (excellent) to 10 (poor) their child’s degree of pain relief and their overall satisfaction with their child’s first 24 h of recovery after surgery. Information regarding postoperative complications and adverse events was elicited and recorded.

The primary end point of this study was the total incidence of vomiting in the first 24 h after surgery. Secondary end points were incidences of vomiting in the hospital and at home, severity of emesis (severe emesis defined as three or more episodes), and recovery as reflected in time to discharge. We projected the need for 230 subjects to have 80% power at an {alpha} of 0.05 to detect a dose-related reduction in the incidence of POV from 50% to 30%. Fisher’s exact and {chi}2 tests were used for analyzing differences in POV. Kruskal-Wallis and one-way analysis of variance tests were used to analyze variations in patient age, weight, pain scores, rescue medications, and Phase I and II recovery times. For all tests, P < 0.05 was considered significant.

In August of 1996, because of reports implicating cisapride in QTc prolongation and sporadic cases of severe cardiac dysrhythmias and death, we further limited patient enrollment and began excluding those with histories of renal or cardiac disease and those who had received macrolide- or imidazole-class antibiotics in the previous week (20). Although in other settings cisapride continued to be used safely for patients with severe GER and motility disorders, our changes were made because of concern about the growing literature of rare adverse cardiac events (21,22). We believed that we could not continue to expose new subjects (with potentially undiagnosed congential prolonged QT syndrome or other conditions) to rare dysrhythmia risks associated with cisapride. Therefore, we stopped enrollment in February 1998 after enlisting 124 subjects. Janssen Pharmaceutica stopped marketing cisapride in the United States on July 14, 2000, although the drug is available under a limited-access protocol (23).


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Ninety-six of the 124 randomized subjects were evaluable. Figure 1 shows subject flow through the study. Insufficient time for premedication resulted from either late patient hospital arrival or changes in surgical schedules. Protocol violations included discovery that a child had a history of severe nausea and vomiting after a previous radiographic study (an exclusion criterion), patient refusal of premedication, and intraoperative ondansetron administration.



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  		Figure 1. Subject flow.

 
Subject sex, age, weight, and rescue medications were similar among study groups (Table 1). Mean (median) Phase I/II recovery times were not different between groups: Group P was 2.37 h (2.2) versus Groups C1 and C2 combined of 2.31 h (2.25). Median (range) VAS pain scores were 1 (1–10) in the PACU; they peaked at 3 (1–8) at 6 h postsurgery and decreased to 1 (1–8) 24 h postsurgery without variation among groups. Parental satisfaction scores (median [range]) did not vary by group: Group P was 1 (1–5), Group C1 was 1 (1–4), and Group C2 was 1 (1–8).


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  		Table 1. Demographics and Rescue Medications
 
In-hospital, at-home, and total incidences of emesis did not vary by treatment group (Table 2). Because there were no significant differences in any of the outcomes between the C1 and C2 groups, the two groups were combined for further analysis and report. There seemed to be a trend toward increased severity of POV in those subjects given cisapride (Fig. 2). Vomiting at home was associated with antecedent travel (60%), or with food or drink (36%), and medication administration (11%) and did not vary across groups. No patient was readmitted for intractable POV.


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  		Table 2. Incidence of Emetic Episodes
 


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  		Figure 2. Severe emesis was defined as three or more episodes of vomiting. In the Placebo group, there were no subjects who experienced severe emesis in the hospital.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Despite cisapride’s known effect of reducing opioid-induced GI paresis (19), it did not seem to decrease emesis in healthy children after inguinal surgery. Incidences of POV in our study, both with and without cisapride, were consistent with previous findings in children given intraoperative morphine (50%–60%) (3). Although the intended sample size was not achieved, the results do not support our hypothesis that cisapride might reduce the incidence of POV in this patient population. For our original hypothesis to have been fully supported, approximately 77 (or 88%) of the next 88 patients in the cisapride groups would need to complete the trial without vomiting—a very unlikely course of events. Only one other published study has suggested that cisapride might reduce vomiting (24). It was conducted in an adult breast cancer population with prolonged nausea and vomiting after chemotherapy. The treatment arm included not only cisapride, but also large-dose corticosteroids, the latter known to reduce POV.

A primary question surrounding a negative study is whether or not the study drug dose and timing were adequate. In related studies, 20 mg of cisapride (~0.3 mg/kg scaled to a 70-kg adult) was administered to adult patients, but without reduction in gastric fluid volume (25,26). In children, cisapride is prescribed for GER at a dose of 0.8 mg/d administered 0.2 mg/kg orally every six hours (27). It is rapidly absorbed and reaches peak plasma concentrations in 1–1.5 hours (28,29). In the only published pharmacokinetic study of cisapride in a pediatric population (young preterm and term infants), plasma concentrations and weight-adjusted clearance (l · h-1 · kg-1) were similar in adults and infants, whereas the volume of distribution (l/kg) was slightly smaller in infants than in adults (30). The dosage chosen for our study (0.3 mg/kg per dose) and the administration interval (every six hours) were intended to cover the time period associated with both immediate (one to two hours) and delayed (four to six hours) POV. The C2 group was designed to address the latter peak in the bimodal POV distribution. It is possible that neither the single nor the double dosing was sufficient to promote a sustained prokinetic effect and that an alternate dosing strategy might have been successful. However, despite these theoretical points on dose and dosing interval, it would seem that the chosen cisapride treatment regimen did elicit an effect. If anything, the results show a tendency for cisapride to increase POV severity. Cisapride seemed to stimulate the GI system and, in a manner paradoxical to our original hypothesis, worsen POV.

A more likely explanation for cisapride’s apparent failure to reduce POV is that mechanisms other than simply overcoming GI paresis were more important determinants of POV. It is possible that through residual effects of opioids/inhaled anesthetics, the CNS remains "sensitized" to changes in bowel motility for many hours beyond surgery. In this context, vagal signaling from peripheral stimuli, such as ingestion of food or the administration of a prokinetic medication like cisapride, might worsen POV. It is also possible that the manner in which perioperative GI dysmotility is overcome is important. Perhaps GI opioid receptors are key elements to POV control. Novel medications that act specifically on peripheral opioid receptors may be effective in reducing postoperative ileus and, unlike cisapride, also reduce POV incidence (12,31).

There were minor differences in the distribution of surgical procedures (unilateral, bilateral, and/or laparoscopic inspection of the contralateral side) and anesthesia technique (tracheal tube versus LMA) among the treatment groups. Of note, during laparoscopic inspections, no insufflation gas was used to distend the abdominal cavity—a condition that may otherwise have contributed to an increased incidence of POV. When a tracheal tube was placed, most children received atropine and neostigmine for reversal of neuromuscular blockade, and these medications may have effects on POV.

In addition, those children with LMA tended not to have their stomach contents evacuated by suction catheters in the operating room and may have had increased gastric fluid volume and propensity for POV. Despite these theoretical considerations, the incidences of POV were almost identical: POV occurred in 53% of patients with tracheal tubes and in 51% of those with LMAs.

Several features of the PACU/DSU protocol deserve comment. To ensure that the cause for reduced GI function was limited to the primary anesthetic and opioid administration, we treated pain in the immediate postoperative period with ketorolac so as not to further interfere with GI motility (32). During the conduct of our study, PACU observation times were mandatory by procedure and might not have reflected real differences in readiness for discharge. Current practice, following "Medically Fit for Discharge Criteria," may have facilitated finding differences in the secondary outcome of length of stay. However, even though the minimum PACU time was set by protocol, making it impossible to determine whether cisapride expedited recovery, times could still be prolonged by poorly controlled pain, or, most significantly, by POV. In fact, when all subjects were examined, mean total Phase I/II recovery time tended to be longer in patients who vomited in the hospital (2.6 ± 0.6 hours) than in those who did not (2.2 ± 0.5 hours).

This study was stopped early because of our safety concerns over cisapride after we reviewed experiences of other investigators (20–22). There was no adverse event in this trial that influenced our decision to terminate the study. We believe that investigators must actively monitor the evolving clinical experience with new drugs for changes in risks and benefits that may affect subjects and warrant altering research strategies.

In summary, cisapride administered in the standardized regimen described does not prevent postoperative emesis in children and may even increase POV severity. This counters the hypothesis that simple increases in bowel motility may decrease POV. With increasing literature on the adverse effects of cisapride, this study was subject to an interim analysis short of original recruitment goals, and it was not possible to state absolutely that there was no reduction in POV in the cisapride groups. Because related studies fail to demonstrate a cisapride effect on fasting gastric fluid volumes (25,26), because rare cardiac disturbances are associated with cisapride (20–22), and because our findings suggest the possibility of cisapride’s worsening emesis, further clinical investigation into cisapride’s effect on POV does not seem warranted.


   Acknowledgments
 
We would like to thank the following for their help with this project: Rosetta Chiavacci, RN, BSN; Catherine Cho; Hilary Kleine, BA; Susan C. Nicolson, MD; Mateen Raazi, MD; Mehernoor F. Watcha, MD; Paul R. Gallagher, MA; and the periooperative staff at the Children’s Hospital of Philadelphia.


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


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication August 31, 2001.





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Lippincott, Williams & Wilkins 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 HighWire Press