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On-line version ISSN 1806-907X
Rev. Bras. Anestesiol. vol.58 no.1 Campinas Jan./Feb. 2008
Prophylactic antiemetic therapy for acute abdominal surgery. A comparative study of droperidol, metoclopramide, tropisetron, granisetron and dexamethasone*
Profilaxis antiemética en cirugía de abdomen agudo. Estudio comparativo entre droperidol, metoclopramida, tropisetrón, granisetrón y dexametasona
Víctor Contreras-DomínguezI; Paulina Carbonell-BellolioII
de Urgência e Anestesiologia, Hospital Clínico Regional de Concepción;
Professor Assistente de Anestesiologia, Universidade de Concepción, Chile
IIServiço de Anestesiologia, Hospital Traumatológico de Concepción, Chile
OBJECTIVES: It is calculated that the incidence of postoperative nausea
and vomiting (PONV) is approximately 30%. The prophylaxis of PONV has been the
subject of several studies, both to decrease this problem and to compare the
cost-benefit ration of the treatment used. The objective of this study was to
compare the efficacy of 5 antiemetic drugs with a control group in emergency
METHODS: A controlled, double-blind, prospective study with 150 patients, ASA I and II, BMI < 30, undergoing appendectomy, was undertaken. Patients were divided in six groups: Group 1 (n = 25): 5 mL of normal saline; Group 2 (n = 25): 0.625 mg of droperidol; Group 3 (n = 25): 20 mg of metoclopramide; Group 4 (n = 25): 5 mg of tropisetron; Group 5 (n = 25): 1 mg of granisetron; Group 6 (n = 25): 4 mg of dexamethasone. Monitoring included ECG, non-invasive blood pressure, O2 saturation, PETCO2, anesthetic gas analyzer and peripheral nerve stimulator. The presence of PONV, complications and the degree of satisfaction in the first 48 hours were evaluated.
RESULTS: The incidence of PONV in the droperidol group was 4% while in the granisetron, tropisetron and metoclopramide groups it was 12% (p < 0.05). The dexamethasone group had a 24% incidence and the control group 28%.
CONCLUSIONS: Low doses of droperidol were more effective in the prophylaxis of PONV in emergency appendectomy than the other drugs.
Key Words: ANTIEMETICS: dexamethasone, droperidol, granisetron, metoclopramide, tropisetron; COMPLICATIONS: nausea, vomiting; SURGERY: appendectomy, emergency.
Y OBJETIVOS: La incidencia de náuseas y vómitos peri operatorios
(NVPO) se estima en un 30%. La profilaxis de NVPO ha sido objetivo de múltiples
estudios, tanto para intentar disminuir este problema como a su vez comparar
índice costo-beneficio de la terapia utilizada. Este estudio evalúa
la utilización de 5 fármacos antieméticos en relación
a grupo control para apendicectomía de urgencia.
MÉTODO: Estudio clínico prospectivo controlado, doble ciego de 150 pacientes ASA I y II con IMC < 30, beneficiarios de apendicectomía. Los pacientes fueron divididos en seis grupos: Grupo 1 (n = 25): 5 ml solución salina; Grupo 2 (n = 25): droperidol 0,625 mg; Grupo 3 (n = 25): metoclopramida 20 mg; Grupo 4 (n = 25): tropisetrón 5 mg; Grupo 5 (n = 25): granisetrón 1 mg; Grupo 6 (n = 25): dexametasona 4 mg. El monitoreo se realizó con ECG, NIBP, SATO2, PETCO2, analizador de gases anestésicos y ENP. Se evaluó la presencia de NVPO, complicaciones y grado de satisfacción en las primeras 48 horas.
RESULTADOS: Droperidol presentó un 4,0% de NVPO en comparación con los grupos de granisetrón, tropisetrón y metoclopramida que presentaron un 12,0% de NVPO (p < 0,05). El grupo de dexametasona presento 24,0% y el control un 28,0% de NVPO.
CONCLUSIONES: En la profilaxis para NVPO en la apendicectomía de urgencia se muestra más efectivo el uso de dosis bajas de droperidol en comparación con otros fármacos.
Nausea and vomiting are the most common and unpleasant symptoms affecting patients after surgeries under general anesthesia 1 and for this reason have been the subject of several studies 2. The development of new antiemetic drugs, selective antagonists of 5-hydroxytryptamine type 3 receptors (5-HT3) in the first half of the decade of 1990 raised the question whether prophylaxis of PONV for outpatient elective surgery or emergency surgery is successful, benefits patients and is cost effective 3-7.
The use of some classical drugs for the prophylaxis of PONV, including droperidol, has been questioned by the Food and Drug Administration (FDA) of the United States due to the potential risk of cardiac arrhythmias by increasing the QT interval, although it has been used extensively for more than 30 years and proven to be safe 8,9. Other publications have argued whether the FDA recommendations are justified 10 or if this institution has reviewed the cases it refers to as a basis for its questioning 11. White et al. studied extensively the use of different drugs in both the prophylaxis and treatment of PONV in outpatient surgeries and concluded that low doses of droperidol, or dexamethasone alone or associated with 5 HT3 antagonists 12,13, are useful
On the other hand, the costs associated with the prophylaxis or treatment of PONV is very important on therapeutic decision-making both for patients and institutions 14-15.
It seemed interesting to study the prophylaxis of PONV in patients undergoing emergency appendectomy to compare the efficacy of the classical antiemetic drug and drugs of the last generation. The objective of this study was to evaluate the efficacy on reducing the incidence as well as the number of episodes of PONV of a single dose of five antiemetic drugs in patients undergoing emergency appendectomy with general balanced anesthesia versus placebo; risk factors associated with PONV, the incidence of side effects, postoperative use of morphine and the degree of patient satisfaction were also evaluated.
After approval by the Ethics Commission of the institution, a double-blind, randomized, prospective clinical study was undertaken with 150 adult patients, ASA I and II, stable, ages between 18 and 65 years, with body mass index (BMI) below 30, undergoing appendectomy at the Emergency Service of the Hospital Clínico Regional de Concepción, Chile, from December 2003 to February 2006. All patients signed an informed consent. They were operated under balanced general anesthesia (GA). Before induction, patients were randomly assigned to one of six groups:
- Group 1 (n = 25) 5 mL of normal saline (NS)
- Group 2 (n = 25) droperidol 0.625 mg in 5 mL of NS
- Group 3 (n = 25) metoclopramide 20 mg in 5 mL of NS
- Group 4 (n = 25) tropisetron 5 mg in 5 mL of NS
- Group 5 (n = 25) granisetron 1 mg in 5 mL of NS
- Group 6 (n = 25) dexamethasone 4 mg in 5 mL of NS
The drug studied or placebo was administered 5 minutes before induction. All patients were fasting for at least six hours before the procedure.
Upon arrival to the operating room and before induction, patients were monitored with ECG, non-invasive blood pressure, SpO2, capnography and anesthetic gas analyzer with a Cardiocap 5® monitor (Datex Ohmeda, GE Healthcare, Helsinki, Finland). A neuromuscular relaxation TOF Watch® monitor (Organon, Ltda., Dublin, Ireland) was placed and patients received 100% oxygen for 5 minutes.
Anesthesia was induced with lidocaine (1 mg.kg-1), fentanyl (2 µg.kg-1), thiopental sodium (4 mg.kg-1) and atracurium (0.4 mg.kg-1). Patients were intubated and anesthesia was maintained with 50% O2/N2O and isoflurane to maintain MAC between 1,0 a 1,2.
Fentanyl, 1-2 µg.kg-1, was administered if systolic or mean blood pressure showed a 20% increase over baseline values. A nasopharyngeal probe was used to monitor body temperature and a nasogastric tube was introduced in all patients. Before the end of the anesthesia, the stomach of all patients was emptied. Drugs were not use to reverse the neuromuscular blockade. The total duration of each procedure was also recorded.
During the intraoperative period, patients received Ringer's lactate, 12 mL.kg-1. Patients underwent the classical McBurney laparotomy and the same surgeons performed all the surgeries.
In the immediate postoperative period, monitoring consisted of ECG, non-invasive blood pressure and pulse oximetry for at least three hours, from admission to the recovery room until the discharge from the unit.
Postoperative procedures were standardized for all patients. Postoperative analgesia consisted of parenteral infusion of metamizol, intramuscular diclofenac sodium, and intravenous morphine as needed whenever pain was greater than 30 mm in the Visual Analog Scale (VAS, 0 = absence of pain and 100 = the worse pain possible). Intravenous ranitidine (50 mg) was administered for 48 hours. Ondansetron, 4 mg IV (Izofran®, GlaxoSmithKline) was administered as rescue therapy of PONV.
Postoperative follow-up was done by another anesthesiologist, who did not know which drug was given to the patient. The presence or absence (incidence) of PONV was recorded. When the patient experienced PONV, the number of episodes (frequency) and their severity in the first 48 hours, rescue therapy indicated, postoperative consumption of morphine, side effects (headache, nausea, extrapyramidal signs and perianal burning or pruritus) were recorded. Risk factors for PONV were also evaluated: smoking, history of PONV, female gender, and postoperative administration of morphine. The degree of patient satisfaction was evaluated by asking patients, 48 hours after the procedure, how they would classify the treatment: excellent, very good, good, regular, or bad.
Analysis of study power determined that each group should be composed of 20 patients for a 90% probability (b = 0.1) of detecting a 50% relative reduction in the incidence of postoperative nausea and/or vomiting, considering that the incidence of PONV in our institution is 70%, with a confidence interval of 95% (a = 0.05). To aggregate more statistic validity to the results of the study, it was decided to include 25 patients in each study group.
Results were analyzed using the Fisher exact test (c2), for qualitative demographic parameters and the Wilcoxon test for quantitative parameters. The Kruskal-Wallis test was used for the non-parametric analysis among the different groups, considering a p < 0.05 as statistically significant. The Epi-Info 6.0 (Centers for Disease Control, World Health Organization, Switzerland) software was used for the statistical analysis.
There were no statistically significant differences regarding gender, BMI, duration of anesthesia and postoperative morphine consumption among the study groups (Table I).
The incidence of PONV was not significant and Table II shows the incidence for each study group.
The droperidol group had an incidence of 4% of PONV, while in the granisetron, tropisetron and metoclopramide groups it was 12% (p < 0.05). The dexamethasone group had an incidence of 24% of PONV and the control group 28% (p < 0.005 when compared to the droperidol group) (Table III). The frequency of nausea was significantly greater in the control group when compared with the droperidol group (p < 0.0001) and metoclopramide, tropisetron and granisetron groups (p < 0.001). The frequency of vomiting was significantly higher in the control group when compared with the droperidol group (p < 0.01) and metoclopramide, tropisetron, and granisetron groups (p < 0.02). One patient in the control group developed severe vomiting 12 hours after the surgery, which was associated with the introduction of feeding.
Side effects of the drugs were not observed in this study. Intra and postoperative cardiac arrhythmias were not detected. Table IV shows the degree of patient satisfaction, which was similar for the droperidol, tropisetron, and granisetron groups.
The results of this double-blind, randomized, clinical study with 150 patients, demonstrated that one small dose of droperidol is more effective in the prophylaxis of nausea and vomiting after appendectomy, with a high degree of patient satisfaction when compared with newer drugs or placebo.
Postoperative nausea and vomiting are one of the most frequent post-anesthetic complications. They are a frequent cause of delayed discharge from the recovery room and are also responsible for re-hospitalizations after early discharge of patients undergoing outpatient surgeries 17,18.
Gan et al. 19, demonstrated that the costs associated with an effective antiemetic therapy surpass US$ 100.00. However, in more than one fourth of all patients with PONV symptoms persist during the first 24 hours 20.
An interesting study by Gan et al. 21, consensus forms were generated for the management of PONV. Among the basic recommendations to reduce the incidence of this problem is the use of propofol for induction and maintenance of GA, avoiding the use of nitrous oxide and volatile anesthetic agents and minimizing the intra and postoperative use of opioids. In this study, propofol was not used for induction and/or maintenance of general anesthesia; this was done to avoid the influence of this parameter in the results. Besides, since it is much more expensive than other drugs that induce general anesthesia, one has to think carefully whenever choosing this type of medication, such as alkylphenol, due to a considerable increase in hospital pharmacy costs and, in private practice, for patients.
Among the medications used for the prophylaxis of PONV, droperidol has been widely used, especially in lower doses (below 1 mg IV), with good results 8,22,23. Recently, the FDA issued a warning on droperidol, including this drug in a "black box". This warning was based on events that might increase the risk of death associated with an increase in the QT interval and torsades des points. This warning was based on 10 reported cases associated with the use of this drug (approximately 1.25 mg) during more than 30 years that this medication has been used 11. It is important to note that a review of the literature did not find any reported cases of arrhythmias, prolonged QT interval, or cardiac arrest associated with the use of low doses of droperidol in the management of PONV24. Recently, Zhang et al. 25 demonstrated, in an electrophysiological study with healthy volunteers, that low doses of droperidol did not influence the incidence of arrhythmias and prolongation of the QT interval. Those results are corroborated by the studies of Charbit 26 and White 27. Considering those two reports, there are no doubts that low doses of droperidol should be the drug of choice for the management of PONV. In this current series of patients with acute appendicitis, a pathology prevalent in all surgical emergency services, droperidol was the most effective drug in the prophylaxis of PONV, demonstrating a significant advantage on reducing PONV when compared to granisetron, tropisetron and metoclopramide (p < 0.05) as well as dexamethasone and placebo (p < 0.005). The frequency of nausea and vomiting was much lower in the droperidol group (p < 0.0001), and in the metoclopramide, tropisetron and granisetron groups (p < 0.001) than in the placebo group. Abreu et al. 23 validated our results in a series of 100 patients undergoing gynecologic videolaparoscopy, in which the incidence of nausea was similar for droperidol and ondasentron.
The intravenous administration of 20 mg of metoclopramide IV for the prophylaxis of PONV at the end of laparoscopyc cholecystectomy was comparable to the administration of 8 mg of ondansetron 20. The incidence of PONV, in this study, was 12% with 20 mg of metoclopramide as well as with granisetron and tropisetron.
The efficacy of 5-HT3 antagonists was studied fundamentally in the prophylaxis of PONV of elective surgeries 30-32. The costs associated with the use of those drugs represent a minor problem. The use of latest generation drugs should not be the first choice in detriment of drugs classically used pathologies highly prevalent in emergency surgical services, as well as in elective surgeries, since scientific evidence is still controversial whether they have a better cost/benefit ratio. The new 5-HT3 antagonists should be a second choice in the treatment of PONV, whenever traditional drugs with a much lower cost have failed. In patients with important risk factors for PONV, with well-document susceptibility to PONV and failure of the usual antiemetic therapy, 5-HT3 antagonists could be administered 33.
Dexamethasone were more effective when administered before induction 33. The effectiveness of small doses of dexamethasone (2.5 5 mg) in the prevention of PONV has already been validated 34,35. The inherent risks of this drug include infection and adrenal suppression among others. There are no reports so far of complications associated with a single bolus of dexamethasone 36. In this current series the incidence of PONV was increased in the dexamethasone group comparable only to the placebo group. Therefore, we do not recommend its use in the prophylaxis of PONV in this type of surgery, especially if associated with an infection.
The multifactorial etiology of PONV is well-known; it is related with four types of neurotransmitters that modulate the action in the posterior area of the chemoreceptor trigger zone: dopamine, serotonin, histamine, and acetylcholine. Droperidol and metoclopramide are dopaminergic receptor antagonists and exert their action in the central nervous system They stimulate the excitability of the bulbar chemoreceptor zone (trigger zone) responsible for vomiting. Tropisetron and granisetron are antagonists of 5-HT3 receptors; they inhibit the action of serotonin released from the enterochromaffin cells of the gastrointestinal tract on 5-HT3 receptors on abdominal vagal afferent endings, those that end directly under the posterior area of the tractus solitarius, responsible for vomiting. As for dexamethasone, although its mechanism of action is not known, it is supposed that it is through the antagonism of prostaglandins or the reduction in the secretion of intestinal serotonin 37. Pharmacokinetically, it is hard to discuss the superiority of droperidol over anti-5-HT3 drugs; however, several authors have confirmed it as well as the results of our study. Recently, Muñoz et al. 38 demonstrated the greater efficacy of droperidol on the treatment of postoperative vomiting when compared with dexamethasone and ondasentron.
Preoperative hydration is one of the factors that influence the incidence of PONV 39. Maharaj et al. 40 demonstrated the usefulness of an adequate and generous preoperative hydration with a balanced saline solution (2 mL.-1kg.-1h-1 of Ringer's lactate) in reducing the incidence, frequency and severity of PONV. In this study, to avoid the influence of this parameter on the results, intraoperative hydration was standardized with the administration of 10-12 mL.kg-1 of Ringer's lactate to all patients. On the other hand, postoperatively, fluid intake was standardized at 25-30 mL.kg-1/day in the first 48 hours.
In the prophylaxis of PONV for McBurney laparotomy for emergency appendectomy, low doses of droperidol, along with last generation drugs, are more effective than dexamethasone and placebo. In this series of 150 patients, adverse reactions to the drugs or the presence of perioperative arrhythmias were not observed.
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Submitted em 13
de dezembro de 2006
Accepted para publicação em 22 de outubro de 2007
* Received from Serviço de Urgências, Hospital Clínico Regional de Concepción, Universidade de Concepción, Concepción, Chile