Assessment of the effect of ketamine in combination with remifentanil on postoperative pain

Abstracts

JUSTIFICATIVA E OBJETIVOS: A associação de cetamina com remifentanila parece estar relacionada à analgesia de melhor qualidade e duração. O objetivo deste estudo foi avaliar se a cetamina associada à remifentanila promove melhora da analgesia pós-operatória. MÉTODO: Estudo prospectivo, aleatório, duplo encoberto em 40 pacientes submetidos à colecistectomia videolaparoscópica. A anestesia foi feita com remifentanila, propofol, atracúrio, 50% de oxigênio. Os pacientes do G1 receberam remifentanila (0,4 mcg.kg-1.min-1) e cetamina (5 mcg.kg-1.min-1); os do G2, remifentanila (0,4 mcg.kg-1.min-1) e solução salina. Foi administrado 0,1 mg.kg-1 de morfina no final da operação e a dor pós-operatória foi tratada com morfina, através de analgesia controlada pelo paciente (PCA). A intensidade da dor pós-operatória foi avaliada pela escala numérica de 0 a 10, durante 24 horas. Foram anotados o tempo para primeira complementação analgésica, a quantidade de morfina usada durante 24 horas e os efeitos adversos. RESULTADOS: Ocorreu diminuição da intensidade da dor entre a desintubação e os outros momentos avaliados no G1 e no G2. Não foi observada diferença significante na intensidade da dor entre os grupos. Não houve diferença entre G1 (22 ± 24,9 min) e G2 (21,5 ± 28,1 min) no tempo para a primeira dose de morfina e dose complementar de morfina consumida no G1 (29 ± 18,4 mg) e no G2 (25,1 ± 13,3 mg). CONCLUSÕES: A associação de cetamina (5 mcg.kg-1.min-1) a remifentanila (0,4 mcg.kg-1.min-1) para colecistectomia não alterou a intensidade da dor pós-operatória, o tempo para primeira complementação ou a dose de morfina em 24 horas.

ANALGESIA, Pós-operatório; ANALGÉSICOS, Cetamina, Opioides, remifentanil; CIRURGIA, Abdominal

JUSTIFICATIVA Y OBJETIVOS: La asociación de la cetamina con el Remifentanilo parece estar asociada con una analgesia de mejor calidad y duración. El objetivo de este estudio fue evaluar si la cetamina asociada al Remifentanilo genera una mejoría de la analgesia postoperatoria. MÉTODO: Se hizo un estudio prospectivo, aleatorio y doble ciego en 40 pacientes sometidos a la colecistectomía videolaparoscópica. La anestesia se realizó con de Remifentanilo, propofol, atracurio y 50% de oxígeno. Los pacientes del G1 recibieron Remifentanilo (0,4 mcg.kg-1.min-1) y cetamina (5 mcg.kg-1.min-1); los del G2, Remifentanilo (0,4 mcg.kg-1.min-1) y solución salina. Fue administrado 0,1 mg.kg-1 de morfina al final de la operación y el dolor postoperatorio se trató con morfina por medio de analgesia controlada por el paciente (PCA). La intensidad del dolor postoperatorio fue mensurada por la escala numérica de 0 a 10, durante 24h. Se anotó el tiempo para la primera complementación analgésica, la cantidad de morfina utilizada durante 24 h y los efectos adversos. RESULTADOS: Ocurrió una reducción de la intensidad del dolor entre el momento de la desentubación y los otros momentos calculados en el G1 y en el G2. No fue observada ninguna diferencia significativa en la intensidad del dolor entre los grupos. No hubo diferencia entre G1 (22 ± 24,9 min.) y G2 (21,5 ± 28,1 min.) en el tiempo para la primera dosis de morfina y dosis complementaria de morfina consumida en el G1 (29 ± 18,4 mg) y en el G2 (25,1 ± 13,3 mg). CONCLUSIONES: La asociación de la cetamina (5 mcg.kg-1.min-1) con el Remifentanilo (0,4 mcg.kg-1.min-1) para la colecistectomía no alteró la intensidad del dolor postoperatorio, el tiempo para la primera complementación o la dosis de morfina en 24h.

ANALGESIA; Postoperatório; ANALGÉSICOS, Cetamina, Opioides, remifentanila; CIRUGÍIA, Abdominal

SCIENTIFIC ARTICLE

^IUniversidade Federal de São Paulo, Brazil

^IITSA; Universidade Federal de São Paulo, Brazil

Corresponding author

ABSTRACT

BACKGROUND AND OBJECTIVES: The combination of ketamine and remifentanil seems to be associated with better analgesia and duration. The aim of this study was to evaluate whether a ketamineremifentanil combination promotes improved postoperative analgesia.

METHODS: Prospective, randomized, double blind study of 40 patients undergoing video laparoscopic cholecystectomy. Anesthesia was performed with remifentanil, propofol, atracurium, and 50% oxygen. Group 1 (GI) patients received remifentanil (0.4 mcg.kg-1.min-1) and ketamine (5 mcg.kg-1.min-1) and Group 2 (G2) received remifentanil (0.4 mcg.kg-1.min-1) and saline solution. Morphine 0.1 mg.kg-1 was administered at the end of the procedure, and postoperative pain was treated with morphine via PCA. We evaluated the severity of postoperative pain by a numerical scale from zero to 10 during 24 hours. We registered the time to the first analgesic supplementation, amount of morphine used in the first 24 hours, and adverse effects.

RESULTS: There was a decrease in pain severity between extubation and other times evaluated in G1 and G2. There was no signifi cant difference in pain intensity between the groups. There was no difference between G1 (22 ± 24.9 min) and G2 (21.5 ± 28.1 min) regarding time to first dose of morphine and dose supplement of morphine consumed in G1 (29 ± 18.4 mg) and G2 (25.1 ± 13.3 mg).

CONCLUSION: The combination of ketamine (5 mcg.kg-1.min-1) and remifentanil (0.4 mcg.kg-1.min-1) for cholecystectomy did not alter the severity of postoperative pain, time to first analgesic supplementation or dose of morphine in 24 hours.

Keywords: Analgesia; Postoperative Period; Ketamine; Cholecystectomy; Piperidines/remifentanil.

Introduction

Although there have been many advances in the pathophysiology of postoperative pain and emergence of new drugs and analgesic techniques, postoperative pain control remains inadequate^1,2. About half of patients undergoing surgeries presents with severe pain during hospitalization³.

Remifentanil is an opioid with very short action⁴. It is used for analgesia when fast recovery is important⁵. Due to the nonspecific metabolism by plasma and tissue esterases, its clearance is independent from the liver function⁴. In subjects with renal impairment, there was no increased sensitivity to remifentanil⁵. Despite these advantages, there is also a rapid termination of the analgesic effect. Moreover, some authors have reported that a factor involved in the hyperalgesia is the short duration of action of opioids, such as remifentanil^7-10. The main mechanism of hyperalgesia induced by opioids is the activation of N-methyl-D-aspartate (NMDA) receptors ^11-14.

Ketamine is a NMDA receptor antagonist, which acts by non-competitive blockage, binding itself to the intra-channel phencyclidinic site and changing the channel opening time. S(+) Ketamine affinity for this binding site is three to four times higher compared to isomer R(-). Analgesic potency of S(+) ketamine is two times that of racemic mixture ¹⁵.

We observed preemptive analgesic effect of S(+)ketamine and reduction of the hyperalgesia phenomenon induced by remifentanil, using low-dose infusion intravenously^7,16,17. When administered both prior to anesthesia induction and throughout the perioperative period, ketamine is able to promote significant reduction in the consumption of anesthetic agents during surgical anesthetic procedure, exerting an "opioid sparing" effect, aside from promoting adequate postoperative analgesia ¹⁸.

Thus, the combination of ketamine and remifentanil seems to relate to better analgesia and duration. The aim of this study was to evaluate whether the combination of ketamine and remifentanil promotes improved postoperative analgesia.

Method

After approval by the Ethics Committee and signing of informed consent, we conducted a prospective, randomized, double-blind study of 40 patients over 18 years of age, both sexes, ASA I or II, undergoing video laparoscopic cholecystectomy. Patients were allocated into two equal groups. Group allocation was determined by drawing envelopes containing numbers. On the morning of the operation and before starting anesthesia, a nurse or anesthesiologist blind to the patient's group opened this patient's envelope and prepared the syringes with remifentanil and ketamine or remifentanil and saline. None of the other researchers involved in the study or collecting data knew which group the patient belonged. In case of an emergency, the anesthesiologist attending the patient could see the group to which he belongs, breaking the protocol. Patients with chronic pain, myocardial ischemia, psychiatric illness, drug user, and those receiving opioids in the previous week were excluded.

Monitoring was performed with cardioscope, capnography, pulse oximetry, noninvasive blood pressure, and thermometer. Infusion was administered with midazolam (3 mg, 30 min), remifentanil (1 mcg.kg^-1), propofol (2-4 mg.kg^-1), and atracurium (0.5 mg.kg^-1). G1 received remifentanil (0.4 mcg.kg^-1.min^-1) and ketamine (5 mcg.kg^-1.min^-1) and G2 received remifentanil (0.4 mcg.kg^-1.min^-1) and saline (0.9%). Remifentanil was increased or decreased as needed, based on hemodynamic data (hypotension, defined as systolic blood pressure below 80 mm Hg or mean arterial blood pressure below 60 mm Hg). Infusion of solutions was maintained until wound closure. Atracurium doses were titrated to maintain muscle relaxation. Anesthesia was maintained with sevoflurane and 50% oxygen without nitrous oxide. Before extubation, atropine (0.02 mg.kg^-1), neostigmine (0.04 mg.kg^-1), metoclopramide (20 mg), and ondansetron (4 mg) were administered. Morphine (0.1 mg.kg^-1) was administered at the end of surgery.

Postoperative pain was treated with morphine via patient controlled analgesia (PCA) by intravenous route, with bolus of 2 mg in 3 mL, 10 minutes safety interval (administration blockade), dose limit of 20 mg in four hours, and without infusion.

We registered the total dose of remifentanil used during operation. To evaluate the severity of postoperative pain, a numerical scale from zero to 10 was used (where zero: no pain and 10: the most severe pain possible; scores between one and four: mild pain; five and six: moderate pain; and seven to 10: severe pain). Evaluations were made every 30 minutes during four hours and six, 12, 18 and 24 hours after awakening. Time to first postoperative analgesic supplementation, amount of analgesic used during 24 hours, and adverse effects were registered.

The statistical program used to calculate the number of patients and analyze the results was the Instat Graph^®. A difference of 3 cm in pain intensity was considered clinically significant. Based on preliminary assessment, we estimated a standard deviation (SD) score of pain intensity within group of 2.2⁷. For a power of 80% and a confidence interval of 95%, the sample size for each group was calculated at 15 patients. Data were expressed as mean ± standard deviation. We used the Mann Whitney test for remifentanil dosage, duration of anesthesia and surgical procedure, time to supplementation need, total dose of morphine used, and pain intensity between groups; the Student's t-test for weight, age, height, and body mass index; ANOVA for pain intensity during evolution; and Fisher's exact test for gender, ASA, and adverse effects. We used central tendency, mean, and dispersion (standard deviation) measurements. We set the statistical significance level at 5%.

Results

Patient's demographic data were similar (Table 1). Duration of operation was 131.2 ± 39.5 min in G1 and 128 ± 57.5 min in G2, with no statistically significant difference between groups (p = 0.279, Mann-Whitney). Duration of anesthesia was 173.2 ± 39.9 min in G1 and 175.1 ± 63.8 min in G2, with no statistically significant difference between groups (p = 0.250, Mann-Whitney). Remifentanil dose used was 0.35 ± 0.10 mcg.kg^-1.min^-1 in G1 and 0.38 ± 0.10 mcg.kg^-1. min^-1 in G2, with no statistically significant difference between groups (p = 0.310, Mann-Whitney).

There was a significant decrease in pain intensity by the verbal numerical scale between the time after awakening and other times evaluated in G1. There was no statistically significant difference in pain intensity between groups at each time evaluated (Table 2).

There was no difference between G1 (22 ± 24.9 min) and G2 (21.5 ± 28.1 min) in time to first dose of postoperative morphine supplementation (p = 0.516, Mann-Whitney test). There was no significant difference between groups regarding additional dose of morphine consumed in G1 (29 ± 18.4 mg) and G2 (25.1 ± 13.3 mg) (p = 0.598, Mann-Whitney test).

Adverse effects were agitation (G1: 3 and G2: 1, p = 0.605), hallucinations (G1: 3, p = 0.231), vertigo (G1: 6 and G2: 12; p = 0.111), discomfort (G1: 10 and G2: 5; p = 0.191), diplopia (G1: 1, p = 1.00), nystagmus (G1: 2, p = 0.487), loss of reality perception (G1: 1, p = 1.00), change in hearing (G1: 1, p = 1.00), reduced visual acuity (G1: 1, p = 1.00), malaise (G1: 11 and G2: 7, p = 0.341), nausea (G1 18 and G2: 15, p = 0.407), vomiting (G1: 12 and G2: 4; p = 0.022), and pruritus (G1: 2 and G2: 1; p = 1.00).

Discussion

Cholecystectomy was chosen because it is a procedure that provokes nociceptive stimulus sufficient to cause algogenic substance release, which allows evaluation of the analgesic effect of drugs. The study was conducted only with patients undergoing laparoscopic procedure because the stimulus intensity was similar. Patients' age group was 40-50 years, and females were most affected, as in most studies of patients undergoing cholecystectomy^19,20. The frequency of gallstones increases with age, more significantly after the age of 40²¹. Females are more predisposed to stone formation due to hormonal factors^21,22. Patients of this study were overweight, which is a risk factor for gallstone^21,23.

Dosage of remifentanil used was based on the ideal weight of patients, as recommended by a study in the literature²⁴. This is due to the fact that remifentanil volume of distribution is small, limited primarily to central compartment. In one study, the authors recommend using remifentanil bolus of 1 mcg.kg^-1, followed by an infusion of 0.5 mcg.kg^-1.min^-1, titrated according to surgical stimulation²⁵.

The factors that seem to be more associated with severe postoperative pain after the use of remifentanil are age (over 16 years), duration of surgery (> 2 hours), and high dosage use ^26,27. In this study, the duration of surgery was greater than two hours in both groups and remifentanil dosage was high and similar between groups (> 0.3 mcg.kg^-1.min^-1), which may be associated with more intense postoperative pain.

There is a study that assesses the analgesic effect of ketamine-remifentanil combination ¹⁸. Several studies of other surgical procedures were conducted using ketamine and remifentanil^7,28-30. Due to the effects on NMDA receptors, ketamine can reduce central sensitization and intensity of postoperative pain. The combination of ketamine and remifentanil may promote prolonged analgesia, since this opioid's great disadvantage of producing no analgesic effect after infusion discontinuation. A study has shown that ketamine administration both before induction of anesthesia and during surgery markedly reduced the need for opioids, in addition to adequate postoperative analgesia¹⁸.

In some studies that did not assess the combination with remifentanil administered intravenously during the intraoperative period, ketamine decreased pain intensity and opioid consumption postoperatively^31-34. From such evidence, protocols were developed to evaluate the combination of ketamine and remifentanil.

This study used 5 mcg.kg^-1.min^-1, without initial bolus dose. This dose, which is considered low, was also used in another study¹⁰. A dose is considered low when < 1 mg.kg^-1 (intravenous bolus) or < 20 mcg.kg^-1.min^-1 (infusion)³⁴. The doses used for induction were 0.15 mg.kg^{-1 30}, 0.3 mg.kg¹⁷, and 0.5 mg.kg^{-1 7,29}. For infusion, the authors used 0.3 mcg.kg^-1.min^{-1 17}, 2 mcg.kg^-1.min^{-1 30}, 4 mcg.kg^-1.min^{-1 29}, and 5 mcg.kg^-1.min^{-1 7}. Moreover, in one study, infusion was maintained with 2 mcg.kg^-1.min^-1 for the first 48 hours postoperatively⁷. Differences in infusion dosage and use of bolus for induction and postoperative maintenance may modify the results of the studies.

Adverse effects caused by remifentanil increased as the dose increased. In a multicenter study, during the period of induction or maintenance with remifentanil, adverse events occurred in about 2% of patients. The most common were hypotension, hypertension, and bradycardia³⁸. These effects were not observed in this study. In this study, the most prevalent adverse effects in both groups were nausea and vomiting, despite the use of metoclopramide and ondansetron administered before extubation. Several factors may have contributed to this, such as the use of inhalational anesthetic, laparoscopic procedure, being overweight, female prevalence, and postoperative analgesia with morphine via PCA^39-41. Other effects (hallucinations, diplopia, nystagmus, loss of reality perception) are related to ketamine. Besides the lack of analgesic effect, there was an increase of adverse effects related to ketamine in G1.

One can conclude that the combination of ketamine (5 mcg.kg^-1.min^-1) and remifentanil (0.4 mcg.kg^-1.min^-1) for video laparoscopic cholecystectomy did not alter the intensity of postoperative pain, time to first analgesic supplementation or morphine dose during 24 hours.

The difference in results may be related to surgical stimulation intensity, amount of remifentanil used during operation, as well as the dose of ketamine used, in addition to the study method, which may modify the response of ketamine-remifentanil combination.

References

• 1. Coluzzi F, Savoia G, Paoletti F et al. - Postoperative pain survey in Italy (POPSI): a snapshot of current national practices. Min Anesthesiol, 2009;75(11):622-631.
• 2. Vickers A, Bali S, Baxter A et al. - Consensus statement on the anticipation and prevention of acute postoperative pain: multidisciplinary RADAR approach. Curr Med Res Opin, 2009;25(10):2557-2569.
• 3. Apfelbaum JL, Chen C, Mehta SS et al. - Postoperative pain experience: results from a national survey suggest postoperative pain continues to be undermanaged. Anesth Analg, 2003;97(2):534-540.
• 4. Davis PJ, Stiller RL, Wilson AS et al. - In vitro remifentanil metabolism: the effects of whole blood constituents and plasma butyrilcholinesterase. Anesth Analg, 2002;95(5):1305-1307.
• 5. Battershill AJ, Keating GM - Spotlight on remifentanil: its analgesic and sedative use in the intensive care unit. CNS Drugs, 2006;20(6):519-522.
• 6. Beers R, Camporesi E - Remifentanil update: clinical science and utility. CNS Drugs, 2004;18(15):1085-1104.
• 7. Joly V, Richebe P, Guignard B et al. - Remifentanil-induced postoperative hyperalgesia and its prevention with small-dose ketamine. Anesthesiology. 2005;103(1):147-155.
• 8. Koppert W, Schmelz M - The impact of opioid-induced hyperalgesia for postoperative pain. Best Pract Res Clin Anaesthesiol, 2007;21:65-83.
• 9. Crawford MW, Hickey C, Zaarour C et al. - Development of acute opioid tolerance during infusion of remifentanil for pediatric scoliosis surgery. Anesth Analg, 2006;102:1662-1667.
• 10. Koppert W, Sittl R, Scheuber K, Alsheimer M, Schmelz M, Schüttler J - Differential modulation of remifentanil-induced analgesia and postinfusion hyperalgesia by S-ketamine and clonidine in humans. Anesthesiology, 2003;99(1):152-159.
• 11. Angst MS, Clark JD - Opioid-induced hyperalgesia: a quantitative systematic review. Anesthesiol, 2006;104(3):570-587.
• 12. Dupen A, Sben D, Ersek M - Mechanisms of opioid-induced tolerance and hyperalgesia. Pain Mange Nurs, 2007;8(3):113-121
• 13. Mao J - Opioid-induced abnormal pain sensitivity: implications in clinical opioid therapy. Pain, 2002;100:213-217.
• 14. Leal PC, Clivatti J, Garcia JBS et al. - Hiperalgesia induzida por opioides. Rev Bras Anestesiol, 2010;60;6:639-747.
• 15. Jaksch W, Lang S, Reichhalter R et al. - Perioperative smalldose S(+)-ketamine has no incremental beneficial effects on postoperative pain when standard-practice opioid infusions are used. Anesth Analg, 2002;94(4):981-986.
• 16. Guignard B, Menigaux C, Dupont X et al. - The effect of remifentanil on the bispectral index change and hemodynamic responses after orotracheal intubation. Anesth Analg, 2000;90(1):161-167.
• 17. Hong BH, Lee WY, Kim YH, Yoon SH, Lee WH - Effects of intraoperative low dose ketamine on remifentanil-induced hyperalgesia in gynecologic surgery with sevoflurane anesthesia. Korean J Anesthesiol, 2011;61(3):238-243.
• 18. Himmelseher S, Durieux ME - Ketamine for perioperative pain management. Anesthesiology, 2005;102(1):211-220.
• 19. Estivalet FF, Bagatini A, Gomes CR - Remifentanil associado ao propofol ou sevoflurano para colecistectomia videolaparoscópica. Estudo comparativo. Rev Bras Anestesiol, 2002;52(4):385-393.
• 20. Imbelloni LE, Fornsani M, Fialho JC et al. - Anestesia geral versus raquianestesia para colecistectomia videolaparoscópica. Rev Bras Anestesiol, 2010;60(3):217-227.
• 21. Shaffer EA - Gallstone disease: epidemiology of gallbladder stone disease. Best Pract Res Clin Gastroenterol, 2006;20(6):981-996
• 22. Cirillo DJ, Wallace RB, Rodabough RJ et al. - Effect of estrogen therapy on gallbladder disease. JAMA, 2005;293(3):330-339.
• 23. Tsai CJ, Leitzmann MF, Willet WC et al. - Prospective study of abdominal adiposity and gallstone disease in us men. Am J Clin Nutr, 2004;80(1):38-44.
• 24. Egan TD, Huizinga B, Gupta SK et al. - Remifentanil pharmacokinetics in obese versus lean patients. Anesthesiology, 1998;89(3):562-573.
• 25. Camu F, Royston D - Inpatient experience with remifentanil. Anesth Analg, 1999;89:(4S):15-21.
• 26. Ma JF, Huang ZL, Li J et al. - Cohort study of remifentanilinduced hyperalgesia in postoperative patients. Zhonghua Yi Xue Za Zhi, 2011;91(14):977-979.
• 27. Jo HR, Chae YK, Kim YH et al. - Remifentanil-induced pronociceptive effect and its prevention with pregabalin. Korean J Anesthesiol, 2011;60(3):198-204.
• 28. Guignard B, Coste C, Costes H et al. - Supplementing desflurane- remifentanil anesthesia with small dose ketamine reduce perioperative opioid analgesia requeriments. Anesth Analg, 2002;95(1):103-108.
• 29. Engelhardt T, Zaarour C, Naser B et al. - Intraoperative low-dose ketamine does not prevent a remifentanil-induced increase in morphine requirement after pediatric scoliosis surgery. Anesth Analg 2008;107(4):1170-1175.
• 30. Ganne O, Abisseror M, Menault P et al. - Low-dose ketamine failed to spare morphine after a remifentanil-based anesthesia for ear, nose and throat surgery. Eur J Anesthesiol, 2005;22:426-430
• 31. De Kock MF, Lavand'homme PM - The clinical role of NMDA receptor antagonist for the treatment of postoperative pain. Best Pract Res Clin Anaesthesiol, 2007;21(1):85-98.
• 32. Subramaniam K, Subramaniam B, Steinbrook RA - Ketamine as adjuvant analgesic to opioids: a quantitative and qualitative systematic review. Anesth Analg, 2004;99(2):482-495.
• 33. Aveline C, Gautier JF, Vautier P et al. - Postoperative analgesia and early rehabilitation after total knee replacement: a comparison of continuous low-dose intravenous ketamine versus nefopam. Eur J Pain, 2009;13(6):613-619.
• 34. Parikh B, Maliwad J, Shah VR - Preventive analgesia: effect of small dose of ketamine on morphine requirement after renal surgery. J Anaesthesiol Clin Pharmacol, 2011;27(4):485-488.
• 35. Albrecht S, Fechner J, Geisslinger G et al. - Postoperative pain control following remifentanil-based anaesthesia for major abdominal surgery. Anaesthesia, 2000;55(4):315-322.
• 36. Kochs E, Cote D, Deruyck L et al. - Postoperative pain management and recovery after remifentanil-based anaesthesia with isoflurane or propofol for major abdominal surgery. Br J Anaesth, 2000;84(2):169-173.
• 37. Munoz HR, Guerrero ME, Brandes V et al. - Effect of timing of morphine administration during remifentanil-based anaesthesia on early recovery from anaesthesia and postoperative pain. Br J Anaesth, 2002;88(6):814-818.
• 38. Joshi GP, Warner DS, Twersky RS et al. - A comparison of the remifentanil and fentanyl adverse effect profile in a multicenter phase IV study. J Clin Anesth, 2002;14(7):494-499.
• 39. Fujii Y - Management of postoperative nausea and vomiting in patients undergoing laparoscopic cholecystectomy. Surg Endosc, 2011;25(3):691-695.
• 40. Rüsch D, Eberhart LH, Wallenborn J et al. - Nausea and vomiting after surgery under general anesthesia: an evidence-based review concerning risk assessment, prevention, and treatment. Dtsch Arztebl Int, 2010;107(42):733-741.
• 41. Rüsch D, Becke K, Eberhart LH et al. - Postoperative nausea and vomiting (PONV) - Recommendations for risk assessment, prophylaxis and therapy - Results of an expert panel meeting. Anasthesiol Intensivmed Notfallmed Schmerzther, 2011;46(3):158-170.

Assessment of the effect of ketamine in combination with remifentanil on postoperative pain

Plínio Cunha Leal^I; Rioko Kimiko Sakata^II; Reinaldo Salomão^I; Eduardo Jun Sadatsune^I; Adriana Machado Issy^I

Publication Dates

• Publication in this collection
  23 Apr 2013
• Date of issue
  Apr 2013

History

• Received
  19 Dec 2011
• Accepted
  27 Feb 2012