Comparative study of anti-emetics and their association, in the prevention of postoperative nausea and vomiting in patients undergoing gynecologic surgeries

Abstracts

JUSTIFICATIVA E OBJETIVOS: A profilaxia de náuseas e vômitos pós-operatórios foi objeto de muitos estudos. O objetivo desta pesquisa foi comparar antieméticos e associações na prevenção de náuseas e vômitos pós-operatórios. MÉTODO: Setenta pacientes, ASA I e II, foram submetidas a procedimentos cirúrgicos ginecológicos, sob bloqueio peridural associado à anestesia geral. No Grupo Metoclopramida (GM), administrou-se 20 mg; no Grupo Dexametasona (GDe), injetou-se 8 mg; no Grupo Droperidol (GDr) administrou-se 1,25 mg; no Grupo Ondansetron (GO) injetou-se 8 mg; no Grupo Dexametasona-Ondansetron (GDeO) administrou-se, respectivamente, 8 mg e 4 mg; no Grupo Droperidol-Ondansetron (GDrO) injetou-se 1,25 mg e 4 mg; no Grupo Dexametasona-Droperidol-Ondansetron (GDeDrO) administrou-se 8 mg, 0,625 mg e 4 mg. A presença de náuseas e vômitos foi observada nos momentos de 6, 12, 24 e 36 horas após o término do ato operatório. RESULTADOS: A incidência total de episódios de náuseas foi de quatro no GDeDrO, seis no GO, seis no GDrO, 11 no GDe, 11 no GDeO, 18 no GM e 22 no GDr. Aplicando-se o teste do Qui-quadrado ou o teste de Fisher, ocorreu diferença estatística significativa entre o GDr e os grupos GDe, GDO, GDrO, GDeO, GDeDrO; entre o GM e os grupos GO, GDrO e GDeDrO; entre o GDeO e o grupo GDeDrO. A incidência total de episódios de vômitos foi de três no GO, três no GDeDrO, seis no GDrO, sete no GDe, sete no GDeO, desz no GDr e 13 no G. Verificou-se diferença estatística significativa entre o GDr e os grupos GO e GDeDrO; entre o GM e os grupos GO e GDeDrO. CONCLUSÕES: A associação dexametasona-droperidol-ondansetron e o ondansetron foram mais eficazes na profilaxia de náuseas e vômitos.

ANTIEMÉTICOS; ANTIEMÉTICOS; ANTIEMÉTICOS; ANTIEMÉTICOS; CIRURGIA; COMPLICAÇÕES; COMPLICAÇÕES

SCIENTIFIC ARTICLE

Comparative study of anti-emetics and their association, in the prevention of postoperative nausea and vomiting in patients undergoing gynecologic surgeries^*

Estudio comparativo de antieméticos y sus asociaciones, en la prevención de náusea y vómito postoperatorios, en pacientes sometidas a procedimientos quirúrgicos ginecológicos

Taylor Brandão Schnaider, M.D.^I; Antônio Mauro Vieira, TSA, M.D.^II; Antônio Carlos Aguiar Brandão, TSA, M.D.^III

^IProfessor Titular Doutor da UNIVAS; Responsável pelas Disciplinas de Anestesiologia e Metodologia Científica; Co-Coordenador do DINTER UNIFESP/UNIVAS

^IIProfessor Titular Doutor da UNIVAS; Responsável pela Disciplina de Farmacologia; Co-Responsável pelo CET/SBA de Pouso Alegre

^IIIProfessor Titular Doutor da UNIVAS; Responsável pela Disciplina de Biofísica; Responsável pelo CET/SBA de Pouso Alegre

Correspondence to

SUMMARY

BACKGROUND AND OBJECTIVES: Prophylaxis of postoperative nausea and vomiting has been the subject of several studies. The objective of the present study was to compare anti-emetics, and their association, in the prevention of postoperative nausea and vomiting.

METHODS: Seventy patients, ASA I and II, underwent epidural block associated with general anesthesia for gynecologic surgeries. Patients in the Metochlopramide Group (MG) received 20 mg of the drug; the Dexamethasone Group (DeG) received 8 mg; the Droperidol Group (DrG) received 1.25 mg; the Ondansetron Group (OG) received 8 mg; the Dexamethasone-Ondansetron Group (DeOG) received 8 mg and 4 mg, respectively; the Droperidol-Ondansetron Group (DrOG) received 1.25 mg and 4 mg, respectively; the Dexamethasone-Droperidol-Ondansetron Group (DeDrOG) received 8 mg, 0.625 mg, and 4 mg. The presence of nausea and vomiting was evaluated at 6, 12, 24, and 36 hours after the end of the surgery.

RESULTS: The total incidence of episodes of nausea per group is as follows: 4 in DeDrOG, 6 in OG, 6 in DrOG, 11 in DeG, 11 in DeOG, 18 in MG, and 22 in DrG. The Chi-square and Fisher exact tests indicated statistically significant differences between DrG and DeG, DOG, DrOG, DeOG, and DeDrOG; between MG and OG, DrOG, and DeDrOG; and between DeOG and DeDrOG. And the incidence of vomiting was: 3 in OG, 3 in DeDrOG, 6 in DrOG, 7 in DeG, 7 in DeOG, and 10 in DrG, and 13 in G. There was a statistically significant difference between DrG and OG and DeDrOG; and between MG and OG and DeDrOG.

CONCLUSIONS: The association dexamethasone-droperidol-ondansetron and ondansetron alone were more effective in the prophylaxis of nausea and vomiting.

Key Words: ANTI-EMETICS: dexamethasone, droperidol, metochlopramide, ondansetron; COMPLICATIONS: nausea, vomiting; SURGERY: gynecologic.

RESUMEN

JUSTIFICATIVA Y OBJETIVOS: La profilaxis de náusea y vómito postoperatorios fue objeto de muchos estudios. El objetivo de esta investigación fue comparar antieméticos y asociaciones en la prevención de náusea y vómito postoperatorios.

MÉTODO: Setenta pacientes, ASA I y II, fueron sometidas a procedimientos quirúrgicos ginecológicos, bajo bloqueo epidural asociado a la anestesia general. En el Grupo Metoclopramida (GM), se administró 20 mg; en el Grupo Dexametasona (GDe), se inyectó 8 mg; en el Grupo Droperidol (GDr) se administró 1,25 mg; en el Grupo Ondansetron (GO) se inyectó 8mg; en el Grupo Dexametasona-Ondansetron (GDeO) se administró respectivamente 8 mg y 4mg; en el Grupo Droperidol-Ondansetron (GDrO) se inyectó 1,25 mg y 4 mg; en el Grupo Dexametasona-Droperidol-Ondansetron (GDeDrO) se administró 8mg, 0,625 mg y 4mg. La presencia de náuseas y vómitos fue observada en los momentos de 6, 12, 24 y 36 horas después del término de la operación.

RESULTADOS: La incidencia total de episodios de náuseas fue de 4 en el GDeDrO, 6 en el GO, 6 en el GDrO, 11 en el GDe, 11 en el GDeO, 18 en el GM y 22 en el GDr. Al aplicar el test del Chi-cuadrado o el test de Fisher, se comprobó la diferencia estadística significativa entre el GDr y los grupos GDe, GDO, GDrO, GDeO, GDeDrO; entre el GM y los grupos GO, GDrO y GDeDrO; entre el GDeO y el grupo GDeDrO. La incidencia total de episodios de vómitos fue de 3 en el GO, 3 en el GDeDrO, 6 en el GDrO, 7 en el GDe, 7 en el GDeO, 10 en el GDr y 13 en el G. Se comprobó así mismo, la diferencia estadística significativa entre el GDr y los grupos GO y GDeDrO; entre el GM y los grupos GO y GDeDrO.

CONCLUSIONES: La asociación dexametasona-droperidol-ondansetron y el ondansetron fueron más eficaces en la profilaxis de náuseas y vómitos.

INTRODUCTION

Specific odors, dehydration, pain, apprehension, and fear contribute for the development of postoperative nausea and vomiting ¹. Besides, nausea and vomiting do increase nosocomial costs by delaying hospital discharge, which demands unexpected hospitalizations, extended care by the medical team, and increases patient dissatisfaction ². Other complications include aspiration, aspiration pneumonia, water and electrolytes imbalance, esophageal rupture, dehiscence of sutures, and increase in intracranial pressure ².

The etiology of nausea and vomiting can be related to the patient (gender, age, weight, anxiety, history of postoperative nausea and vomiting, and smoking), anesthetic technique (nitrous oxide, halogenated, and opioids), and site and duration of the surgery ^3,4.

Female gender and gynecologic procedure are important risk factors, with an incidence around 70% of postoperative nausea and vomiting. For this reason, the search for the ideal anti-emetic for those patients continues ².

Metochlopramide and droperidol, antagonists of dopaminergic receptors, have been effective in the prevention and treatment of nausea and vomiting, but they can cause sedation, dysphoria, extrapyramidal syndrome, and spastic torticollis ^2,5.

Dexamethasone, a corticosteroid with anti-emetic action by an unknown mechanism, has also been effective in the prevention of postoperative nausea and vomiting, but it has higher efficiency in association with other anti-emetics ^2,5.

Ondansetron, a serotoninergic receptor antagonist (5-HT3 receptor), has had greater acceptation for the prevention of postoperative nausea and vomiting in patients with higher risk factors ^2,5.

Anti-emetic drugs with different mechanisms of action are synergistic when combined, resulting in greater efficacy in the prevention and treatment of postoperative nausea and vomiting ^2,5-9.

Due to the frequent episodes of postoperative nausea and vomiting and evolution of anesthetic and anti-emetic drugs, the objective of the present study was to compare several anti-emetics, administered as a single medication or in associations, in the prevention of those adverse effects in gynecologic surgeries.

METHODS

After approval by the Ethics Committee on Human Research of the Universidade do Vale do Sapucaí, patients were asked to sign an informed consent. Seventy female patients, ages 20 to 50 years, physical status ASA I and II, undergoing total abdominal hysterectomy with adnexectomy under general anesthesia associated with epidural block participated in this prospective an analytical clinic study.

Patients received oral diazepam (10 mg) the day before surgery and oral midazolam (15 mg) 40 minutes before surgery. Patients were monitored with electrocardioscope, non-invasive blood pressure, pulse oximeter, and inspiratory and expiratory gas analyzer. After venipuncture with an 18G catheter, a solution containing midazolam (5 mg) and fentanyl (50 µg) was administered.

Afterwards, the anti-emetic or its association, diluted in 500 mL of NS, was administered before the epidural puncture. The Metochlopramide Group (MG) received 20 mg of metochlopramide; the Dexamethasone Group (DeG) received 8 mg; the Droperidol Group (DrG) received 1.25 mg; the Ondansetron Group (OG) received 8 mg; the Dexamethasone-Ondansetron Group (DeOG) received 8 mg and 4 mg, respectively; the Droperidol-Ondansetron Group (DrOG) received 1.25 mg and 4 mg, respectively; the Dexamethsone-Droperidol-Ondansetron Group (DeDrOG) received 8 mg, 0.625 mg, and 4 mg, respectively.

Epidural block was carried out with the patient in the sitting position, in the L₂-L₃ space, with a 15G Tuohy needle, and 20 mL of 0.75% ropivacaine were administered at 1 mL.s^-1.

Etomidate (0.2 mg.kg^-1), alfentanil (30 µg.kg^-1), and rocuronium (0.6 mg.kg^-1) were used for anesthetic induction, and isoflurane (0.5% vol. to 3.0% vol.) was used for maintenance. When clinical signs or hemodynamic responses suggesting inadequate levels of anesthesia (diaphoresis, tearing, hypertension, and tachycardia) were observed, intravenous alfentanil (500 µg) was administered in intermittent doses.

Controlled ventilation was carried out with a low flow anesthesia system, allowing for the humidification and warming of inspired gases. Tidal volume varied from 8 to 10 mL.kg^-1 and the respiratory rate was adjusted to maintain the expired pressure of carbon dioxide (P_ETCO₂) between 30 and 35 mmHg.

Blood pressure, heart rate, peripheral hemoglobin saturation (SpO₂), expired carbon dioxide (P_ETCO₂), and inspired concentration of isoflurane were recorded after installation of monitoring, epidural block, tracheal intubation, and every 15 minutes until the end of the surgery.

After the surgery, patients were transferred to the post-anesthetic care unit (PACU). Neuromuscular blockade antagonists were not used at the end of the procedure.

The incidence of nausea and vomiting was observed at 6 h, 12 h, 24 h, and 36 h after the surgery.

Analgesia consisted on the administration of dypirone, a pyrazolonic derivative, at 15 mg.kg^-1 every 4 hours after the surgery.

Analysis of Variance with Scheffé's test was used to analyze the anthropometric data; the Student t test was used to analyze the length of the surgery; postoperative nausea and vomiting were analyzed by the Chi-square test and Fisher Exact test. A p < 0.05 was considered significant.

RESULTS

Analysis of Variance with Scheffé's test did not show statistically significant differences in the weight and age of the patients (Table I).

The Student t test did not detect statistically significant differences in the length of surgery (Table II).

Patients did not require supplemental doses of opioids.

The Chi-square test showed statistically significant differences in the incidence of nausea among the groups, as follows: between the Droperidol Group and the Dexamethasone, Ondansetron, Droperidol-Ondansetron, Dexamethasone-Ondansetron, and Dexamethasone-Droperidol-Ondan- setron Groups; between the Metochlopramide and the Ondansentron, Droperidol-Ondansetron, and Dexamethasone-Droperidol-Ondansetron Groups; and between the Dexamethasone-Ondansetron and the Dexamethasone-Droperidol-Ondansetron Groups (Table III).

The Fisher Exact test demonstrated significant differences between the following groups: Droperidol Group and Ondansetron and Dexamethasone-Droperidol-Ondansetron Groups; and between the Metochlopramide Group and the Ondansetron and Dexamethasone-Droperidol-Ondansetron Groups (Table IV).

DISCUSSION

Postoperative nausea and vomiting continue to be one of the most common post-anesthetic complications.

Neostigmine and nitrous oxide were not used in the present study, and the intraoperative use of opioids was reduced to a minimum. Propofol was not the hypnotic of choice due to its potential anti-emetic activity and interaction with negative chronotropic drugs.

In this study, 36 hours, the time of hospital discharge, was the maximal observation time for nausea and vomiting. A study conducted by telephone interviews from 24 to 48 after the discharge, and questionnaires up to the fifth day after hospital discharge demonstrated that 35.7% of patients developed nausea and vomiting ¹⁰. A study with prophylactic drugs for nausea and vomiting evaluated the presence of those adverse effects, complications, and degree of patient satisfaction in the first 48 hours ¹¹.

In the present study, the use of low doses of droperidol did not cause cardiac arrhythmias or an increase in the QT interval. An electrophysiological study in healthy volunteers suggested that it would be unlikely that low doses of droperidol, used as an anti-emetic, had intraoperative proarrhythmogenic activity ¹², which was corroborated by studies that evaluated the effects of droperidol on the QT interval ^13-15.

Studies using dexamethasone alone or associated with ondansetron in laparoscopic surgeries in humans demonstrated a reduction in the incidence of nausea and vomiting, and recommended the routine use of those drugs ^16,17. In the present study, the association of dexamethasone and ondansetron did not reduce the incidence of nausea and vomiting when compared to dexamethasone alone; however, the addition of droperidol decreased their incidence.

A study comparing the efficacy of droperidol, metochlopramide, and ondansetron ^18,19 demonstrated that ondansetron and droperidol were more effective in the prophylaxis of postoperative nausea and vomiting. In the present study, the effects of ondansetron corroborated those studies; however, the effects of droperidol were similar to that of metochlopramide.

In the present study, Ondansetron and the association droperidol-ondansetron and dexamethasone-droperidol-ondansetron were more effective in the prophylaxis of nausea, while ondansetron and the association dexamethasone-droperidol-ondansetron were more effective in the prevention of vomiting. Nausea and vomiting have a multifactorial etiology ^2,20, being associated with four types of neurotransmitters that modulate the chemoreceptor trigger zone located in the area postrema: dopamine, serotonin, histamine, and acetylcholine¹⁹. Anti-emetics are classified according to their action on pharmacologic receptors and, usually, the administration of a single agent might not be adequate for prophylaxis of postoperative nausea and vomiting. Some authors suggest the association of two or more anti-emetics for better results ^21-23, which was observed in the present study with the association dexamethasone-droperidol-ondansetron.

In the present study, ondansetron alone was the most effective agent in the prophylaxis of postoperative nausea and vomiting, and the association dexamethasone-droperidol-ondansetron is a good option for pelvic gynecological surgeries since, despite the cost of the three drugs, it is more effective in the prophylaxis of nausea and vomiting, has a greater degree of patient satisfaction, and does not delay discharge from the hospital, decreasing hospital costs.

The association dexamethasone-droperidol-ondansetron and ondansetron alone were more effective in the prevention of postoperative nausea and vomiting, and adverse reactions related to their use were not observed.

REFERENCES

• 01. Watcha MF, White PF - Postoperative nausea and vomiting. Its etiology, treatment, and prevention. Anesthesiology, 1992;77: 164-184.
• 02. Lages N, Fonseca C, Neves A et al. - Náuseas e vômitos no pós-operatório: uma revisão do "pequeno-grande" problema. Rev Bras Anestesiol, 2005;55:575-585.
• 03. Kenny GN - Risck factors for postoperative nausea and vomiting. Anaesthesia, 1994; 49:(Suppl)6-10.
• 04. Lerman J - Surgical and patient factor envolved in postoperative nausea and vomiting. Br J Anaesth, 1992; 69:(Suppl)24S-32S.
• 05. Gan TJ - Postoperative nausea and vomiting Can it be eliminated? JAMA, 2002; 287:1233-1236.
• 06. Yuen HK, Chiu JW - Multimodal antiemetic therapy and emetic risck profiling. Ann Acad Med Singapore, 2005; 34:196-205.
• 07. Abreu MP - Náuseas e vômitos Antieméticos, em: Cangiani LM Anestesia ambulatorial. São Paulo, Atheneu, 2001; 339-357.
• 08. Ganem EM, Fabris P, Moro MZ et al. - Eficácia do ondansetron e da alizaprida na prevenção de náuseas e vômitos em laparoscopia ginecológica. Rev Bras Anestesiol, 2001;51:401-406.
• 09. Koivuranta M, Ala-Kokko TI, Jokela R et al. - Comparison of ondansetron and tropisetron combined with droperidol for the prevention of emesis in women with a history of postoperative nausea and vomiting. Eur J Anaesthesiol, 1999;16:390-395.
• 10. Carroll NV, Miederhoff P, Cox FM et al. - Postoperative nausea and vomiting after discharge from outpatient surgery centers. Anesth Analg, 1995;80:903-909.
• 11. Contreras-Domínguez V, Carbonell-Bellolio P - Estudio clínico comparativo, randomizado y doble ciego entre droperidol, metoclopramida, tropisetrón, granisetrón e dexametasona para profilaxis antiemética en apendicectomia. Rev Argent Anestesiol, 2007;65:107-116.
• 12. Zhang Y, Luo Z, White PF - A model for evaluating droperidol´s effect on the median QTc interval. Anesth Analg, 2004;98:1330-1335.
• 13. Nuttall GA, Eckerman KM, Jacob KA et al. - Does low-dose droperidol administration increase the risk of drug-induced QT prolongation and torsade de pointes in the general surgical population? Anesthesiology, 2007; 107:531-536.
• 14. Contreras-Domínguez V, Carbonell-Bellolio P - Profilaxia antiemética em cirurgia de abdome agudo. Estudo comparativo entre droperidol, metoclopramida, tropisetron, granisetron e dexametasona. Rev Bras Anestesiol, 2008;58:35-44.
• 15. White PF, Song D, Abrão J et al. - Effect of low-dose droperidol on the QT interval during and after general anesthesia: a placebo-controlled study. Anesthesiology, 2005;102:1101-1105.
• 16. Leksowski K, Peryga P, Szyca R - Ondansetron, metoclopramide, dexamethasone, and their combinations compared for the prevention of postoperative nausea and vomiting in patients undergoing laparoscopic cholecystectomy: a prospective randomized study. Surg Endosc, 2006; 20:878-882.
• 17. Elhakim M, Nafie M, Mahmoud K et al. - Dexamethasone 8 mg in combination with ondansetron 4 mg appears to be the optimaldose for the prevention of nausea and vomiting after laparoscopic cholecystectomy. Can J Anaesth, 2002;49: 922-926.
• 18. Abreu MP, Vieira JL, Silva IF et al. - Eficácia do ondansetron, metoclopramida, droperidol e dexametasona na prevenção de náuseas e vômitos após laparoscopia ginecológica em regime ambulatorial. Estudo comparativo. Rev Bras Anestesiol, 2006; 56:8-15.
• 19. Domino KB, Anderson EA, Polissar NL et al. - Comparative efficacy and safety of ondansetron, droperidol, and metoclopramide for preventing postoperative nausea and vomiting: a meta-analysis. Anesth Analg, 1999;88:1370-1379.
• 20. Schmidt A, Bagatini A - Náuseas e vômitos pós-operatório: fisiopatologia, profilaxia e tratamento. Rev Bras Anestesiol, 1997; 47:326-334.
• 21. Fugii Y, Saitoh Y, Tanaka H et al. - Granisetron/dexametasone combination for reducing nausea and vomiting during and after spinal anesthesia for cesarean section. Anesth Analg, 1999; 88:1346-1350.
• 22. Fugii Y, Saitoh Y, Tanaka H et al. - Prophylatic therapy with combined granisetron and dexametasone for the prevention of post-operative vomiting in children. Eur J Anaesthesiol, 1999; 16:376-379.
• 23. Mckenzie R, Uy NT, Riley TJ et al. - Droperidol/ondansetron combinations controls nausea and vomiting after tubal banding. Anesth Analg, 1996;83:1218-1222.

*

Recebido do Centro de Ensino e Treinamento do Serviço de Anestesiologia do Hospital das Clínicas da Faculdade de Ciências Médicas de Pouso Alegre (HC-FCM-UNIVAS), Pouso Alegre, MG

Publication Dates

• Publication in this collection
  14 Nov 2008
• Date of issue
  Dec 2008

History

• Received
  12 Feb 2008
• Accepted
  18 Aug 2008