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Perioperative gabapentin and pregabalin in cardiac surgery: a systematic review and meta-analysis

Abstract

Objectives:

Sternotomy for cardiac surgeries causes significant postoperative pain and when not properly managed may cause significant morbidity. As neuropathic pain is a significant component here, gabapentin and pregabalin may be effective in these patients and may reduce postoperative opioid consumption. The purpose of this systematic review was to find out efficacy of gabapentin and pregabalin in acute postoperative pain after cardiac surgery.

Methods:

Published prospective human randomized clinical trials, which compared preoperative and/or postoperative gabapentin/pregabalin with placebo or no treatment for postoperative pain management after cardiac surgery has been included in this review.

Results:

Four RCTs each for gabapentin and pregabalin have been included in this systematic review. Three gabapentin and two pregabalin studies reported decrease in opioid consumption in cardiac surgical patients while one gabapentin and two pregabalin studies did not. Three RCTs each for gabapentin and pregabalin reported lower pain scores both during activity and rest. The drugs are not associated with any significant complications.

Conclusion:

Despite lower pain scores in the postoperative period, there is insufficient evidence to recommend routine use of gabapentin and pregabalin to reduce opioid consumption in the cardiac surgical patients.

KEYWORDS
Cardiac surgery; Gabapentin; Pregabalin; Post-operative pain

Resumo

Objetivos:

A esternotomia para cirurgias cardíacas causa dor intensa no pós-operatório e quando não tratada adequadamente pode causar morbidade grave. Como nesse caso a dor neuropática é uma componente importante, gabapentina e pregabalina podem ser eficazes nesses pacientes e podem reduzir o consumo de opioides no pós-operatório. O objetivo desta revisão sistemática foi avaliar a eficácia de gabapentina e pregabalina na dor aguda após cirurgia cardíaca.

Métodos:

Foram incluídos nesta revisão estudos clínicos prospectivos e randômicos com humanos, que compararam o uso de gabapentina/pregabalina nos períodos pré- e/ou pós-operatório com placebo ou nenhum tratamento para o controle da dor no pós-operatório de cirurgia cardíaca.

Resultados:

Quatro ECRs de gabapentina e pregabalina foram incluídos nesta revisão sistemática. Três estudos de gabapentina e dois de pregabalina relataram diminuição do consumo de opioides em pacientes cirúrgicos cardíacos; um estudo de gabapentina e dois de pregabalina não relataram. Três ECRs de gabapentina e pregabalina relataram escores menores de dor, durante a atividade e o repouso. Os medicamentos não estão associados a complicações significativas.

Conclusão:

Embora os escores de dor tenham sido menores no pós-operatório, não há evidências suficientes para recomendar o uso rotineiro de gabapentina e pregabalina para reduzir o consumo de opioides em pacientes cirúrgicos cardíacos.

PALAVRAS-CHAVE
Cirurgia cardíaca; Gabapentina; Pregabalina; Dor no pós-operatório

Introduction

Sternotomy for cardiac surgery causes significant postoperative pain,11 Meehan DA, McRae ME, Rourke DA, et al. Analgesic administration, pain intensity, and patient satisfaction in cardiac surgical patients. Am J Crit Care. 1995;4:435-42. which has both significant short term and long term consequences. Poorly managed acute postoperative pain may complicate immediate postoperative period22 Milgrom LB, Brooks JA, Qi R, et al. Pain levels experienced with activities after cardiac surgery. Am J Crit Care. 2004;13:116-25.,33 Chaney MA. How important is postoperative pain after cardiac surgery?. J Cardiothorac Vasc Anesth. 2005;19:705-7. and may also cause chronic pain.44 Eisenberg E, Pultorak Y, Pud D, et al. Prevalence and characteristics of post coronary artery bypass graft surgery pain (PCP). Pain. 2001;92:11-7. Though patients usually feel worst pain in the first postoperative day, significant pain may continue up to sixth postoperative day.55 Mazzeffi M, Khelemsky Y. Poststernotomy pain: a clinical review. J Cardiothorac Vasc Anesth. 2011;25:1163-78. Adequately managed acute pain lowers the myocardial oxygen demand and decreases the incidence of ischemic episodes.33 Chaney MA. How important is postoperative pain after cardiac surgery?. J Cardiothorac Vasc Anesth. 2005;19:705-7.,66 Mangano DT, Siliciano D, Hollenberg M, et al. Postoperative myocardial ischemia. Therapeutic trials using intensive analgesia following surgery. The Study of Perioperative Ischemia (SPI) Research Group. Anesthesiology. 1992;76:342-53. Parenteral opioids, though effective, may cause sedation, respiratory depression, nausea-vomiting and pruritus which may be troublesome.77 Baltali S, Turkoz A, Bozdogan N, et al. The efficacy of intravenous patient-controlled remifentanil versus morphine anesthesia after coronary artery surgery. J Cardiothorac Vasc Anesth. 2009;23:170-4. Moreover, opioids may have limited efficacy when pain is associated with activity such as coughing and deep breathing.88 Tverskoy M, Oren M, Dashkovsky I, et al. Alfentanil dose-response relationships for relief of postoperative pain. Anesth Analg. 1996;83:387-93. Options of central neuraxial analgesia in cardiac surgical population is also limited mostly because of perioperative anticoagulant use, and its superiority to PCA opioid is also debatable.99 Hansdottir V, Philip J, Olsen MF, et al. Thoracic epidural versus intravenous patient-controlled analgesia after cardiac surgery: a randomized controlled trial on length of hospital stay and patient-perceived quality of recovery. Anesthesiology. 2006;104:142-51.

Acute postoperative pain may also have a significant neuropathic component along with nociceptive pain due to peripheral mechanoreceptor stimulation and both central and peripheral sensitization by several mechanisms.1010 Alston RP, Pechon P. Dysaesthesia associated with sternotomy for heart surgery. Br J Anaesth. 2005;95:153-8.,1111 Dahl JB, Mathiesen O, Moiniche S. 'Protective premedication': an option with gabapentin and related drugs? A review of gabapentin and pregabalin in the treatment of post-operative pain. Acta Anaesthesiol Scand. 2004;48:1130-6. During sternotomy, intercostal nerves may be damaged by stretching of the intercostal nerves at the costo-vertebral junction due to sternal retraction and damage may also occur during dissection of internal mammary artery from the sternum; all of which ultimately contribute to neuropathic pain.

The gabapentinoids gabapentin and pregabalin are novel antiepileptic drugs, which also have significant efficacy in neuropathic pain1212 Moore RA, Straube S, Wiffen PJ, et al. Pregabalin for acute and chronic pain in adults. Cochrane Database Syst Rev. 2009;:CD007076.,1313 Moore RA, Wiffen PJ, Derry S, et al. Gabapentin for chronic neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev. 2011;:CD007938 [Review]. and postoperative pain.1414 Dauri M, Faria S, Gatti A, et al. Gabapentin and pregabalin for the acute post-operative pain management. A systematic-narrative review of the recent clinical evidences. Curr Drug Targets. 2009;10:716-33.

15 Eipe N, Penning J, Yazdi F, et al. Perioperative use of pregabalin for acute pain-a systematic review and meta-analysis. Pain. 2015;156:1284-300.
-1616 Straube S, Derry S, Moore RA, et al. Single dose oral gabapentin for established acute postoperative pain in adults. Cochrane Database Syst Rev. 2010;:CD008183 [Review, 35 refs]. They exert anti-nociceptive effect by binding with the α2δ subunit of voltage sensitive calcium channel.1414 Dauri M, Faria S, Gatti A, et al. Gabapentin and pregabalin for the acute post-operative pain management. A systematic-narrative review of the recent clinical evidences. Curr Drug Targets. 2009;10:716-33.,1717 Schmidt PC, Ruchelli G, Mackey SC, et al. Perioperative gabapentinoids: choice of agent, dose, timing, and effects on chronic postsurgical pain. Anesthesiology. 2013;119:1215-21. As well as having a central anti-allodynic effect they also inhibit pain transmission.1717 Schmidt PC, Ruchelli G, Mackey SC, et al. Perioperative gabapentinoids: choice of agent, dose, timing, and effects on chronic postsurgical pain. Anesthesiology. 2013;119:1215-21. The drugs are available only as oral preparations, and differ mainly in bioavailability. Gabapentin is absorbed in the duodenum by a saturable L-amino acid transport mechanism, so that bioavailability varies inversely with dose.1818 Rose MA, Kam PC. Gabapentin: pharmacology and its use in pain management. Anaesthesia. 2002;57:451-62. Bioavailability also varies widely between individuals underlining the need for dose individualization to achieve clinical goals.1919 Gidal BE, Radulovic LL, Kruger S, et al. Inter- and intra-subject variability in gabapentin absorption and absolute bioavailability. Epilepsy Res. 2000;40:123-7. In contrast, pregabalin is absorbed throughout the small intestines with linear uptake without transporter saturation.1717 Schmidt PC, Ruchelli G, Mackey SC, et al. Perioperative gabapentinoids: choice of agent, dose, timing, and effects on chronic postsurgical pain. Anesthesiology. 2013;119:1215-21. Both the drugs have very low plasma protein binding, no metabolism and is excreted unchanged in urine; dose modification is needed in renal impairment.1717 Schmidt PC, Ruchelli G, Mackey SC, et al. Perioperative gabapentinoids: choice of agent, dose, timing, and effects on chronic postsurgical pain. Anesthesiology. 2013;119:1215-21. With an elimination half-life of 4.8-8.7 h, gabapentin requires thrice daily dosing.1818 Rose MA, Kam PC. Gabapentin: pharmacology and its use in pain management. Anaesthesia. 2002;57:451-62. Altered formulations have been devised to facilitate once or twice daily regimens, e.g. Gralise (sustained release) and gabapentin enacarbil (a prodrug).2020 Moore RA, Wiffen PJ, Derry S, et al. Gabapentin for chronic neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev. 2014;4. CD380079 Pregabalin has an elimination half-life of 5.5-6.3 h, requiring twice to thrice daily dosing.1717 Schmidt PC, Ruchelli G, Mackey SC, et al. Perioperative gabapentinoids: choice of agent, dose, timing, and effects on chronic postsurgical pain. Anesthesiology. 2013;119:1215-21. Both are free from significant side effects and drug interactions in the clinically useful dosage.1717 Schmidt PC, Ruchelli G, Mackey SC, et al. Perioperative gabapentinoids: choice of agent, dose, timing, and effects on chronic postsurgical pain. Anesthesiology. 2013;119:1215-21. Gabapentin may be useful for the prevention of chronic postsurgical pain also.2121 Clarke H, Bonin RP, Orser BA, et al. The prevention of chronic postsurgical pain using gabapentin and pregabalin: a combined systematic review and meta-analysis. Anesth Analg. 2012;115:428-42. Both have also been extensively studied in various surgical population for postoperative pain management with varying degrees of success. Few RCTs2222 Joshi SS, Jagadeesh AM. Efficacy of perioperative pregabalin in acute and chronic post-operative pain after off-pump coronary artery bypass surgery: a randomized, double-blind placebo controlled trial. Ann Card Anaesth. 2013;16:180-5.

23 Menda F, Koner O, Sayin M, et al. Effects of single-dose gabapentin on postoperative pain and morphine consumption after cardiac surgery. J Cardiothorac Vasc Anesth. 2010;24:808-13.

24 Pesonen A, Suojaranta-Ylinen R, Hammaren E, et al. Pregabalin has an opioid-sparing effect in elderly patients after cardiac surgery: a randomized placebo-controlled trial. Br J Anaesth. 2011;106:873-81.

25 Rapchuk IL, O'Connell L, Liessmann CD, et al. Effect of gabapentin on pain after cardiac surgery: a randomised, double-blind, placebo-controlled trial. Anaesth Intensive Care. 2010;38:445-51.

26 Soltanzadeh M, Ebad A, Pipelzadeh M, et al. Gabapentin may relieve post-coronary artery bypass graft pain: a double blind randomized clinical trial. Iran Cardiovasc Res J. 2011;5:79-82.

27 Sundar AS, Kodali R, Sulaiman S, et al. The effects of preemptive pregabalin on attenuation of stress response to endotracheal intubation and opioid-sparing effect in patients undergoing off-pump coronary artery bypass grafting. Ann Card Anaesth. 2012;15:18-25.

28 Ucak A, Onan B, Sen H, et al. The effects of gabapentin on acute and chronic postoperative pain after coronary artery bypass graft surgery. J Cardiothorac Vasc Anesth. 2011;25:824-9.
-2929 Ziyaeifard M, Mehrabanian MJ, Faritus SZ, et al. Premedication with oral pregabalin for the prevention of acute postsurgical pain in coronary artery bypass surgery. Anesth Pain Med. 2015;5:e24837. have addressed the efficacy of perioperative administration of gabapentinoids on acute postoperative pain after cardiac surgery and they reported variable results. Hence, we conducted this systematic review to find out efficacy of gabapentin and pregabalin in acute postoperative pain after cardiac surgery.

Methods

Published prospective human clinical trials, which compared preoperative and/or postoperative gabapentin/pregabalin with placebo or no treatment for postoperative pain management after cardiac surgery has been included in this review.

Date source and search method

We did an electronic search in the following database: PubMed, PubMed Central, EMBASE and CENTRAL with the Keywords: "gabapentin"; "pregabalin"; "cardiac" and "sternotomy" to find out the eligible clinical trials on 20th September 2013. Another literature search was also done on 9th August; 2015 to update the result of the previous search. The search strategy in PubMed has been mentioned in Appendix 1 Appendix 1 ("gabapentin" [Supplementary Concept] OR "gabapentin" [All Fields]) AND ("heart"[MeSH Terms] OR "heart" [All Fields] OR "cardiac" [All Fields]) ("gabapentin" [Supplementary Concept] OR "gabapentin" [All Fields]) AND ("sternotomy" [MeSH Terms] OR "sternotomy" [All Fields]) ("pregabalin" [Supplementary Concept] OR "pregabalin" [All Fields]) AND ("heart" [MeSH Terms] OR "heart" [All Fields] OR "cardiac" [All Fields]) ("pregabalin" [Supplementary Concept] OR "pregabalin" [All Fields]) AND ("sternotomy" [MeSH Terms] OR "sternotomy" [All Fields]) . References from the primary search results were also manually searched for potentially eligible trials.

Study selection

Published prospective randomized human clinical trials, which compared preoperative and/or postoperative gabapentin/pregabalin with placebo or no treatment for postoperative pain management after cardiac surgery have been included in this study. We did not impose any language restriction in the search strategy. Studies that have been done on either adult or pediatric population have been included in this review. We did not search for unpublished trials. Authors were not asked for unpublished data in the included trials. A PRISMA flow diagram3030 Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6:e1000097. of study selection is depicted in Fig. 1.

Figure 1
PRISMA flow diagram for study selection.

Exclusion criteria

Clinical trials where oral gabapentin or pregabalin has been compared with placebo or any other drug in surgical populations other than cardiac surgery were not included in this review. Studies which did not report the effects of the study drug on acute postoperative pain were also excluded. We also excluded studies where a postoperative regional analgesia technique was used as a part of multimodal regimen.

Data collection

Potentially eligible trials were manually searched from the abstracts to determine their eligibility in this review. We collected the required data from the full-text of the trials. Two authors independently (DKB, SB) extracted all data from the eligible trials. Initially all data were tabulated in Microsoft ExcelTM spread sheet.

Data items

The following data were extracted from the eligible trials: Name of the first author, year of publication, methods of randomization and blinding, study population, protocol of study drug administration, postoperative opioid consumption and pain scores, incidence of chronic pain following sternotomy and chronic pain scores, duration of mechanical ventilation and ICU stay, and adverse reactions. All the extracted data were tabulated in a Microsoft Excel spreadsheet.

Primary outcome measure of this review was postoperative pain scores (both at rest and dynamic). Secondary outcome measures were postoperative opioid consumption, effects of the study drugs on opioid related adverse effects, duration of mechanical ventilation and ICU stay.

Where a quantitative meta-analysis was not possible a qualitative systemic review of the reported data was performed.

Risk of bias in individual studies

The quality of eligible trials was assessed using the 'risk of bias' tool within Review Manager, version 5.2.3 software (Review Manager [RevMan]. Version 5.2. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2012) by two authors working independently (SM and AS). Random sequence generation, allocation concealment, blinding, incomplete data, and selective reporting were assessed; based on the method of the trials, each was graded "yes", 'no', or 'unclear', which reflected a high risk of bias, low risk of bias, and uncertain bias, respectively. Risks of bias summary in the individual studies have been provided in Fig. 2.

Figure 2
Summary of "risk of bias" at individual study level.

Results

Database searching revealed 174 articles. In six clinical studies gabapentin was used as an analgesic in cardiac surgeries. However, in one3131 Biyik I, Gulculer M, Karabiga M, et al. Efficacy of gabapentin versus diclofenac in the treatment of chest pain and paresthesia in patients with sternotomy. Anadolu Kardiyol Derg. 2009;9:390-6. of them it was compared with diclofenac; hence it was excluded from analysis. Another RCT3232 Rafiq S, Steinbruchel DA, Wanscher MJ, et al. Multimodal analgesia versus traditional opiate based analgesia after cardiac surgery, a randomized controlled trial. J Cardiothorac Surg. 2014;9:52. compared a gabapentin containing multimodal regimen with opioid-based analgesic regimen. Finally, four RCTs2323 Menda F, Koner O, Sayin M, et al. Effects of single-dose gabapentin on postoperative pain and morphine consumption after cardiac surgery. J Cardiothorac Vasc Anesth. 2010;24:808-13.,2525 Rapchuk IL, O'Connell L, Liessmann CD, et al. Effect of gabapentin on pain after cardiac surgery: a randomised, double-blind, placebo-controlled trial. Anaesth Intensive Care. 2010;38:445-51.,2626 Soltanzadeh M, Ebad A, Pipelzadeh M, et al. Gabapentin may relieve post-coronary artery bypass graft pain: a double blind randomized clinical trial. Iran Cardiovasc Res J. 2011;5:79-82.,2828 Ucak A, Onan B, Sen H, et al. The effects of gabapentin on acute and chronic postoperative pain after coronary artery bypass graft surgery. J Cardiothorac Vasc Anesth. 2011;25:824-9. evaluating gabapentin and another four studying pregabalin2222 Joshi SS, Jagadeesh AM. Efficacy of perioperative pregabalin in acute and chronic post-operative pain after off-pump coronary artery bypass surgery: a randomized, double-blind placebo controlled trial. Ann Card Anaesth. 2013;16:180-5.,2424 Pesonen A, Suojaranta-Ylinen R, Hammaren E, et al. Pregabalin has an opioid-sparing effect in elderly patients after cardiac surgery: a randomized placebo-controlled trial. Br J Anaesth. 2011;106:873-81.,2727 Sundar AS, Kodali R, Sulaiman S, et al. The effects of preemptive pregabalin on attenuation of stress response to endotracheal intubation and opioid-sparing effect in patients undergoing off-pump coronary artery bypass grafting. Ann Card Anaesth. 2012;15:18-25.,2929 Ziyaeifard M, Mehrabanian MJ, Faritus SZ, et al. Premedication with oral pregabalin for the prevention of acute postsurgical pain in coronary artery bypass surgery. Anesth Pain Med. 2015;5:e24837. met our inclusion criteria for this systematic review. Risk of bias in the individual studies has been furnished in Fig. 2. Study protocol of the individual studies and patient population have been described in Table 1. The pooled results have been summarized in the following section.

Table 1
Summary of study protocol and results of individual studies.

Postoperative pain

All the included studies reported pain scores at different points of time; hence a pooled analysis has not been possible.

Gabapentin

Ucak et al.2828 Ucak A, Onan B, Sen H, et al. The effects of gabapentin on acute and chronic postoperative pain after coronary artery bypass graft surgery. J Cardiothorac Vasc Anesth. 2011;25:824-9. reported a lower pain score with the use of gabapentin both during rest and cough at 6 h, 12 h, 18 h, 24 h, 48 h and 72 h. Soltanzadeh et al.2626 Soltanzadeh M, Ebad A, Pipelzadeh M, et al. Gabapentin may relieve post-coronary artery bypass graft pain: a double blind randomized clinical trial. Iran Cardiovasc Res J. 2011;5:79-82. reported that pain scores, both at rest and during coughing at 2 h, 6 h, and 12 h after extubation were significantly lower in patients who received gabapentin. Menda et al.2323 Menda F, Koner O, Sayin M, et al. Effects of single-dose gabapentin on postoperative pain and morphine consumption after cardiac surgery. J Cardiothorac Vasc Anesth. 2010;24:808-13. reported lower pain scores during rest up to 48 h after extubation but only up to 12 h for pain during coughing. However, Rapchuk et al.2525 Rapchuk IL, O'Connell L, Liessmann CD, et al. Effect of gabapentin on pain after cardiac surgery: a randomised, double-blind, placebo-controlled trial. Anaesth Intensive Care. 2010;38:445-51. reported a similar VAS score both during rest and coughing up to 72 h postoperative period. Rafiq et al.3232 Rafiq S, Steinbruchel DA, Wanscher MJ, et al. Multimodal analgesia versus traditional opiate based analgesia after cardiac surgery, a randomized controlled trial. J Cardiothorac Surg. 2014;9:52. evaluated pain scores by 11 point NRS and found that patients in the gabapentin containing multimodal group, in all categories, except "worst pain" on day 4, had lower mean pain scores. Patients had significantly lower average pain sensation from day 0 (day of surgery) throughout to day 3. The least pain experienced during the day was also lower in the multimodal group from day 1 to day 3.

Pregabalin

In the study of Joshi et al.2222 Joshi SS, Jagadeesh AM. Efficacy of perioperative pregabalin in acute and chronic post-operative pain after off-pump coronary artery bypass surgery: a randomized, double-blind placebo controlled trial. Ann Card Anaesth. 2013;16:180-5. pain-scores at rest at 6 h, 12 h, 24 h and 36 h from extubation and pain scores at deep breath at 4 h, 6 h, 12 h, 24 h and 36 h from extubation were less in pregabalin treated patients (p < 0.05). They also found that peak inspiratory flow rates as assessed by incentive spirometry were higher in pregabalin group as compared to control group at 12 h, 24 h and 36 h from extubation (p < 0.05). Pesonen et al.2424 Pesonen A, Suojaranta-Ylinen R, Hammaren E, et al. Pregabalin has an opioid-sparing effect in elderly patients after cardiac surgery: a randomized placebo-controlled trial. Br J Anaesth. 2011;106:873-81. reported significantly lower percentage of patients requiring analgesia at 2 h, 10 h and 12 h after extubation in the pregabalin group (p < 0.05). Sundar et al.2727 Sundar AS, Kodali R, Sulaiman S, et al. The effects of preemptive pregabalin on attenuation of stress response to endotracheal intubation and opioid-sparing effect in patients undergoing off-pump coronary artery bypass grafting. Ann Card Anaesth. 2012;15:18-25. could not detect any difference in VAS scores measured at 6 h, 12 h, and 24 h after surgery; while Ziyaeifard et al.2929 Ziyaeifard M, Mehrabanian MJ, Faritus SZ, et al. Premedication with oral pregabalin for the prevention of acute postsurgical pain in coronary artery bypass surgery. Anesth Pain Med. 2015;5:e24837. found pain scores to be significantly lower in the pregabalin group at 4 h, 12 h, and 24 h of surgery (p < 0.05).

Postoperative opioid consumption

Gabapentin

Three studies2323 Menda F, Koner O, Sayin M, et al. Effects of single-dose gabapentin on postoperative pain and morphine consumption after cardiac surgery. J Cardiothorac Vasc Anesth. 2010;24:808-13.,2626 Soltanzadeh M, Ebad A, Pipelzadeh M, et al. Gabapentin may relieve post-coronary artery bypass graft pain: a double blind randomized clinical trial. Iran Cardiovasc Res J. 2011;5:79-82.,2828 Ucak A, Onan B, Sen H, et al. The effects of gabapentin on acute and chronic postoperative pain after coronary artery bypass graft surgery. J Cardiothorac Vasc Anesth. 2011;25:824-9. reported postoperative opioid consumption up to 24 h after extubation and one2525 Rapchuk IL, O'Connell L, Liessmann CD, et al. Effect of gabapentin on pain after cardiac surgery: a randomised, double-blind, placebo-controlled trial. Anaesth Intensive Care. 2010;38:445-51. reported fentanyl consumption up to 48 h. Two2323 Menda F, Koner O, Sayin M, et al. Effects of single-dose gabapentin on postoperative pain and morphine consumption after cardiac surgery. J Cardiothorac Vasc Anesth. 2010;24:808-13.,2626 Soltanzadeh M, Ebad A, Pipelzadeh M, et al. Gabapentin may relieve post-coronary artery bypass graft pain: a double blind randomized clinical trial. Iran Cardiovasc Res J. 2011;5:79-82. of them used morphine and one2828 Ucak A, Onan B, Sen H, et al. The effects of gabapentin on acute and chronic postoperative pain after coronary artery bypass graft surgery. J Cardiothorac Vasc Anesth. 2011;25:824-9. used tramadol. Menda et al.2323 Menda F, Koner O, Sayin M, et al. Effects of single-dose gabapentin on postoperative pain and morphine consumption after cardiac surgery. J Cardiothorac Vasc Anesth. 2010;24:808-13. found that preoperative gabapentin reduces morphine consumption than placebo (6.7 ± 2.5 mg vs. 15.5 ± 4.6 mg, p < 0.01). Soltanzadeh et al.2626 Soltanzadeh M, Ebad A, Pipelzadeh M, et al. Gabapentin may relieve post-coronary artery bypass graft pain: a double blind randomized clinical trial. Iran Cardiovasc Res J. 2011;5:79-82. reported pre and postoperative gabapentin reduces opioid consumption than placebo (0.9 ± 1.5 mg vs. 1.5 ± 4 mg, p = 0.01). Ucak et al.2828 Ucak A, Onan B, Sen H, et al. The effects of gabapentin on acute and chronic postoperative pain after coronary artery bypass graft surgery. J Cardiothorac Vasc Anesth. 2011;25:824-9. reported intravenous tramadol consumption and found that gabapentin reduces tramadol consumption than placebo (99 ± 53.8 mg vs. 149.4 ± 72.5 mg, p < 0.05). Rapchuk et al.2525 Rapchuk IL, O'Connell L, Liessmann CD, et al. Effect of gabapentin on pain after cardiac surgery: a randomised, double-blind, placebo-controlled trial. Anaesth Intensive Care. 2010;38:445-51. reported similar fentanyl consumption at 48 h after extubation (1355 ± 995 mcg vs. 1562 ± 1056 mcg; p = 0.46; n = 54).

Pregabalin

Joshi et al.2222 Joshi SS, Jagadeesh AM. Efficacy of perioperative pregabalin in acute and chronic post-operative pain after off-pump coronary artery bypass surgery: a randomized, double-blind placebo controlled trial. Ann Card Anaesth. 2013;16:180-5. found that tramadol consumption was reduced by 60% in the pregabalin group compared to placebo (67.8 ± 60.25 mg vs. 167.1 ± 52.1 mg, p < 0.001). Pesonen et al.2424 Pesonen A, Suojaranta-Ylinen R, Hammaren E, et al. Pregabalin has an opioid-sparing effect in elderly patients after cardiac surgery: a randomized placebo-controlled trial. Br J Anaesth. 2011;106:873-81. reported that pregabalin reduced consumption of parenteral oxycodone during 16 h after extubation by 43% (8 ± 5 mg vs. 14 ± 6 mg, p < 0.001) and total oxycodone consumption from extubation to the end of the fifth postoperative day by 48% (48 ± 28 mg vs. 93 ± 44 mg, p < 0.001). However, Sundar et al.2727 Sundar AS, Kodali R, Sulaiman S, et al. The effects of preemptive pregabalin on attenuation of stress response to endotracheal intubation and opioid-sparing effect in patients undergoing off-pump coronary artery bypass grafting. Ann Card Anaesth. 2012;15:18-25. and Ziyaeifard et al.2929 Ziyaeifard M, Mehrabanian MJ, Faritus SZ, et al. Premedication with oral pregabalin for the prevention of acute postsurgical pain in coronary artery bypass surgery. Anesth Pain Med. 2015;5:e24837. found no difference in fentanyl (241.67 ± 178.87 mcg vs. 251.67 ± 181.47 mcg, p > 0.05) and morphine (3 ± 0.17 mg vs. 3.1 ± 0.15 mg, p > 0.05) consumption up to 24 h after surgery respectively. Of note, pregabalin was continued in the postoperative period in the first two RCTs (till days 2 and 5 respectively),2222 Joshi SS, Jagadeesh AM. Efficacy of perioperative pregabalin in acute and chronic post-operative pain after off-pump coronary artery bypass surgery: a randomized, double-blind placebo controlled trial. Ann Card Anaesth. 2013;16:180-5.,2424 Pesonen A, Suojaranta-Ylinen R, Hammaren E, et al. Pregabalin has an opioid-sparing effect in elderly patients after cardiac surgery: a randomized placebo-controlled trial. Br J Anaesth. 2011;106:873-81. and was used as a single preoperative dose in the last two.2727 Sundar AS, Kodali R, Sulaiman S, et al. The effects of preemptive pregabalin on attenuation of stress response to endotracheal intubation and opioid-sparing effect in patients undergoing off-pump coronary artery bypass grafting. Ann Card Anaesth. 2012;15:18-25.,2929 Ziyaeifard M, Mehrabanian MJ, Faritus SZ, et al. Premedication with oral pregabalin for the prevention of acute postsurgical pain in coronary artery bypass surgery. Anesth Pain Med. 2015;5:e24837.

Chronic pain

Gabapentin

Ucak et al.2828 Ucak A, Onan B, Sen H, et al. The effects of gabapentin on acute and chronic postoperative pain after coronary artery bypass graft surgery. J Cardiothorac Vasc Anesth. 2011;25:824-9. found that pain scores at 1 and 3 months postoperatively were lower in the gabapentin group but the difference was not statistically significant (p > 0.05).

Pregabalin

In the study by Joshi et al.2222 Joshi SS, Jagadeesh AM. Efficacy of perioperative pregabalin in acute and chronic post-operative pain after off-pump coronary artery bypass surgery: a randomized, double-blind placebo controlled trial. Ann Card Anaesth. 2013;16:180-5. pain at rest and deep breathing at 1 month and 3 months after surgery were comparable among the groups. Pesonen et al.2424 Pesonen A, Suojaranta-Ylinen R, Hammaren E, et al. Pregabalin has an opioid-sparing effect in elderly patients after cardiac surgery: a randomized placebo-controlled trial. Br J Anaesth. 2011;106:873-81. reported that the incidence of pain during movement was significantly lower in the pregabalin group at 3 months postoperatively, but pain after 1 month was similar.

Duration of mechanical ventilation

A pooled analysis found that duration of mechanical ventilation is significantly increased with the use gabapentin (MD = 0.81 h; 95% CI 0.43-1.19; p < 0.0001; n = 214) (Fig. 3) but not with pregabalin (MD = 0.60 h; 95% CI -0.94-2.13; p = 0.45; n = 160) (Fig. 4).

Figure 3
Forest plot showing pooled analysis of mean difference of duration of mechanical ventilation for gabapentin.
Figure 4
Forest plot showing pooled analysis of mean difference of duration of mechanical ventilation for pregabalin.

Length of ICU stay

Use of perioperative gabapentin (MD = 1.06 h; 95% CI -0.67-2.79; p = 0.23; n = 120) or pregabalin (MD = 0.63 h; 95% CI -3.59-4.85; p = 0.77; n = 220) does not affect the duration of ICU stay significantly.

Postoperative complications

Gabapentin

Commonly reported adverse effects of gabapentin are sedation, dizziness and somnolence.1717 Schmidt PC, Ruchelli G, Mackey SC, et al. Perioperative gabapentinoids: choice of agent, dose, timing, and effects on chronic postsurgical pain. Anesthesiology. 2013;119:1215-21. Ucak et al.2828 Ucak A, Onan B, Sen H, et al. The effects of gabapentin on acute and chronic postoperative pain after coronary artery bypass graft surgery. J Cardiothorac Vasc Anesth. 2011;25:824-9. reported no increased incidence of any of the adverse effects of gabapentin. Menda et al.2323 Menda F, Koner O, Sayin M, et al. Effects of single-dose gabapentin on postoperative pain and morphine consumption after cardiac surgery. J Cardiothorac Vasc Anesth. 2010;24:808-13. reported an increased incidence of sedation (Ramsay sedation score > 2) with the use of gabapentin at 2 h, 6 h and 12 h after extubation. They also reported a significantly less incidence of nausea in gabapentin treated patients. Rapchuk et al.2525 Rapchuk IL, O'Connell L, Liessmann CD, et al. Effect of gabapentin on pain after cardiac surgery: a randomised, double-blind, placebo-controlled trial. Anaesth Intensive Care. 2010;38:445-51. and Soltanzadeh et al.2626 Soltanzadeh M, Ebad A, Pipelzadeh M, et al. Gabapentin may relieve post-coronary artery bypass graft pain: a double blind randomized clinical trial. Iran Cardiovasc Res J. 2011;5:79-82. also reported no increased adverse effect with the use of gabapentin.

Pregabalin

Pregabalin has a side effect profile similar to that of gabapentin.1717 Schmidt PC, Ruchelli G, Mackey SC, et al. Perioperative gabapentinoids: choice of agent, dose, timing, and effects on chronic postsurgical pain. Anesthesiology. 2013;119:1215-21. Sedation scores and incidence of nausea/vomiting as reported by three RCTs2222 Joshi SS, Jagadeesh AM. Efficacy of perioperative pregabalin in acute and chronic post-operative pain after off-pump coronary artery bypass surgery: a randomized, double-blind placebo controlled trial. Ann Card Anaesth. 2013;16:180-5.,2424 Pesonen A, Suojaranta-Ylinen R, Hammaren E, et al. Pregabalin has an opioid-sparing effect in elderly patients after cardiac surgery: a randomized placebo-controlled trial. Br J Anaesth. 2011;106:873-81.,2727 Sundar AS, Kodali R, Sulaiman S, et al. The effects of preemptive pregabalin on attenuation of stress response to endotracheal intubation and opioid-sparing effect in patients undergoing off-pump coronary artery bypass grafting. Ann Card Anaesth. 2012;15:18-25. were comparable between groups. Joshi et al.2222 Joshi SS, Jagadeesh AM. Efficacy of perioperative pregabalin in acute and chronic post-operative pain after off-pump coronary artery bypass surgery: a randomized, double-blind placebo controlled trial. Ann Card Anaesth. 2013;16:180-5. also reported similar incidence of respiratory depression and Sundar et al.2727 Sundar AS, Kodali R, Sulaiman S, et al. The effects of preemptive pregabalin on attenuation of stress response to endotracheal intubation and opioid-sparing effect in patients undergoing off-pump coronary artery bypass grafting. Ann Card Anaesth. 2012;15:18-25. found similar occurrence of dizziness between the groups. On the other hand, CAM-ICU scores were significantly lower in the placebo group on the 1st postoperative day in the study of Pesonen et al.2424 Pesonen A, Suojaranta-Ylinen R, Hammaren E, et al. Pregabalin has an opioid-sparing effect in elderly patients after cardiac surgery: a randomized placebo-controlled trial. Br J Anaesth. 2011;106:873-81.

Discussion

The principal findings of this review are that gabapentin did not reduce postoperative opioid consumption after cardiac surgery; but may reduce pain scores at the expense of increased duration of mechanical ventilation. However, gabapentin was safe and free of serious adverse effects and a single study2323 Menda F, Koner O, Sayin M, et al. Effects of single-dose gabapentin on postoperative pain and morphine consumption after cardiac surgery. J Cardiothorac Vasc Anesth. 2010;24:808-13. reported decreased incidence of nausea also. Pregabalin, on the other hand, decreased postoperative pain scores; reduced opioid consumption when it was continued in the postoperative period; and did not increase duration of mechanical ventilation, sedation or other side effects.

Efficacy of perioperative gabapentin in reducing pain is well established in other surgeries like spine surgeries,3333 Yu L, Ran B, Li M, et al. Gabapentin and pregabalin in the management of postoperative pain after lumbar spinal surgery: a systematic review and meta-analysis. Spine (Phila Pa 1976). 2013;38:1947-52. breast surgeries,3434 Bharti N, Bala I, Narayan V, et al. Effect of gabapentin pretreatment on propofol consumption, hemodynamic variables, and postoperative pain relief in breast cancer surgery. Acta Anaesthesiol Taiwan. 2013;51:10-3. gynecologic surgeries3535 Frouzanfard F, Fazel MR, Abolhasani A, et al. Effects of gabapentin on pain and opioid consumption after abdominal hysterectomy. Pain Res Manag. 2013;18:94-6. etc. However, it may not have efficacy in management of post craniotomy pain.3636 Misra S, Parthasarathi G, Vilanilam GC. The effect of gabapentin premedication on postoperative nausea, vomiting, and pain in patients on preoperative dexamethasone undergoing craniotomy for intracranial tumors. J Neurosurg Anesthesiol. 2013;25:386-91. It is likely that gabapentin will be more effective where neuropathic component is significant. Futility of single preoperative dose of gabapentin has been found in various settings.3737 Paul JE, Nantha-Aree M, Buckley N, et al. Gabapentin does not improve multimodal analgesia outcomes for total knee arthroplasty: a randomized controlled trial. Can J Anaesth. 2013;60:423-31.

38 Short J, Downey K, Bernstein P, et al. A single preoperative dose of gabapentin does not improve postcesarean delivery pain management: a randomized, double-blind, placebo-controlled dose-finding trial. Anesth Analg. 2012;115:1336-42.
-3939 Siddiqui NT, Fischer H, Guerina L, et al. Effect of a preoperative gabapentin on postoperative analgesia in patients with inflammatory bowel disease following major bowel surgery: a randomized, placebo-controlled trial. Pain Pract. 2014;14:132-9. Gabapentin may be more effective in postoperative pain management at higher doses and when administered both pre and postoperatively.1717 Schmidt PC, Ruchelli G, Mackey SC, et al. Perioperative gabapentinoids: choice of agent, dose, timing, and effects on chronic postsurgical pain. Anesthesiology. 2013;119:1215-21. Amongst the included studies in our review, Ucak et al.2828 Ucak A, Onan B, Sen H, et al. The effects of gabapentin on acute and chronic postoperative pain after coronary artery bypass graft surgery. J Cardiothorac Vasc Anesth. 2011;25:824-9. and Rapchuk et al.2525 Rapchuk IL, O'Connell L, Liessmann CD, et al. Effect of gabapentin on pain after cardiac surgery: a randomised, double-blind, placebo-controlled trial. Anaesth Intensive Care. 2010;38:445-51. used gabapentin at a dose of 1200 mg·day-1 2 h before surgery and continued in the postoperative period also. However, Menda et al.2323 Menda F, Koner O, Sayin M, et al. Effects of single-dose gabapentin on postoperative pain and morphine consumption after cardiac surgery. J Cardiothorac Vasc Anesth. 2010;24:808-13. used only in the preoperative period and Soltanzadeh et al.2626 Soltanzadeh M, Ebad A, Pipelzadeh M, et al. Gabapentin may relieve post-coronary artery bypass graft pain: a double blind randomized clinical trial. Iran Cardiovasc Res J. 2011;5:79-82. used a lower dose of gabapentin (800 mg·day-1). It is notable that despite using gabapentin at a dose of 1200 mcg·day-1 both pre and postoperatively, Rapchuk et al.2525 Rapchuk IL, O'Connell L, Liessmann CD, et al. Effect of gabapentin on pain after cardiac surgery: a randomised, double-blind, placebo-controlled trial. Anaesth Intensive Care. 2010;38:445-51. did not find any reduction of pain scores and fentanyl consumption. Parlow et al.4040 Parlow J, Gilron I, Milne B, et al. Cardiopulmonary bypass does not affect plasma concentration of preoperatively administered gabapentin. Can J Anaesth. 2010;57:337-42. in 2010 found that plasma concentration of gabapentin is unaffected by cardio-pulmonary bypass and patients who received gabapentin consume similar amount of morphine in the postoperative period as those who did not. In previous studies,4141 Kinney MA, Mantilla CB, Carns PE, et al. Preoperative gabapentin for acute post-thoracotomy analgesia: a randomized, double-blinded, active placebo-controlled study. Pain Pract. 2012;12:175-83. where gabapentin was found to be ineffective, use of regional anesthesia in those studies was blamed and a speculation was made that regional anesthesia could have prevented central sensitization. However, none of the studies included here used any regional anesthesia technique. From a clinical point of view, a reduced opioid requirement may be more important than only pain scores. Again pain scores recorded at specific time points only does not imply patients' analgesia over a time period. None of the studies reported patients' satisfaction level here.

Data reporting chronic pain was inadequate for any conclusion.

Efficacy of pregabalin in reducing post-operative acute pain has been reviewed in several meta-analyses.1515 Eipe N, Penning J, Yazdi F, et al. Perioperative use of pregabalin for acute pain-a systematic review and meta-analysis. Pain. 2015;156:1284-300.,4242 Mishriky BM, Waldron NH, Habib AS. Impact of pregabalin on acute and persistent postoperative pain: a systematic review and meta-analysis. Br J Anaesth. 2015;114:10-31.,4343 Zhang J, Ho KY, Wang Y. Efficacy of pregabalin in acute postoperative pain: a meta-analysis. Br J Anaesth. 2011;106:454-62. Eipe et al.1515 Eipe N, Penning J, Yazdi F, et al. Perioperative use of pregabalin for acute pain-a systematic review and meta-analysis. Pain. 2015;156:1284-300. came to the conclusion that pregabalin decreases analgesic consumption following various types of surgeries, but had a small effect in improving pain control and this effect is primarily observed in surgeries associated with pronociceptive mechanisms, e.g. spine, joint arthroplasty, and amputations. As sternotomy and sternal retraction involves intercostal nerve damage and associated central and peripheral sensitization, acute allodynia and hyperalgesia often occur.1010 Alston RP, Pechon P. Dysaesthesia associated with sternotomy for heart surgery. Br J Anaesth. 2005;95:153-8. This may explain the finding of reduced pain scores with pregabalin in three of the included RCTs.2222 Joshi SS, Jagadeesh AM. Efficacy of perioperative pregabalin in acute and chronic post-operative pain after off-pump coronary artery bypass surgery: a randomized, double-blind placebo controlled trial. Ann Card Anaesth. 2013;16:180-5.,2424 Pesonen A, Suojaranta-Ylinen R, Hammaren E, et al. Pregabalin has an opioid-sparing effect in elderly patients after cardiac surgery: a randomized placebo-controlled trial. Br J Anaesth. 2011;106:873-81.,2929 Ziyaeifard M, Mehrabanian MJ, Faritus SZ, et al. Premedication with oral pregabalin for the prevention of acute postsurgical pain in coronary artery bypass surgery. Anesth Pain Med. 2015;5:e24837. Two RCTs2222 Joshi SS, Jagadeesh AM. Efficacy of perioperative pregabalin in acute and chronic post-operative pain after off-pump coronary artery bypass surgery: a randomized, double-blind placebo controlled trial. Ann Card Anaesth. 2013;16:180-5.,2424 Pesonen A, Suojaranta-Ylinen R, Hammaren E, et al. Pregabalin has an opioid-sparing effect in elderly patients after cardiac surgery: a randomized placebo-controlled trial. Br J Anaesth. 2011;106:873-81. which had continued pregabalin 150 mg·day-1 in the postoperative period, demonstrated reduced opioid consumption, whereas the other two RCTs2727 Sundar AS, Kodali R, Sulaiman S, et al. The effects of preemptive pregabalin on attenuation of stress response to endotracheal intubation and opioid-sparing effect in patients undergoing off-pump coronary artery bypass grafting. Ann Card Anaesth. 2012;15:18-25.,2929 Ziyaeifard M, Mehrabanian MJ, Faritus SZ, et al. Premedication with oral pregabalin for the prevention of acute postsurgical pain in coronary artery bypass surgery. Anesth Pain Med. 2015;5:e24837. using single preoperative 150 mg dose of pregabalin did not find any reduction. In the case of Sundar et al.,2727 Sundar AS, Kodali R, Sulaiman S, et al. The effects of preemptive pregabalin on attenuation of stress response to endotracheal intubation and opioid-sparing effect in patients undergoing off-pump coronary artery bypass grafting. Ann Card Anaesth. 2012;15:18-25. their study was not adequately powered to detect differences in pain scores or opioid consumption. The absence of effect in the other one2929 Ziyaeifard M, Mehrabanian MJ, Faritus SZ, et al. Premedication with oral pregabalin for the prevention of acute postsurgical pain in coronary artery bypass surgery. Anesth Pain Med. 2015;5:e24837. corroborates the conclusion of Schmidt et al.1717 Schmidt PC, Ruchelli G, Mackey SC, et al. Perioperative gabapentinoids: choice of agent, dose, timing, and effects on chronic postsurgical pain. Anesthesiology. 2013;119:1215-21. that continuing the drug postoperatively is likely to be more effective than a single preoperative dose, though it is in contrast to the finding by Mishriky et al. in their meta-analysis.4242 Mishriky BM, Waldron NH, Habib AS. Impact of pregabalin on acute and persistent postoperative pain: a systematic review and meta-analysis. Br J Anaesth. 2015;114:10-31. Mishriky et al.4242 Mishriky BM, Waldron NH, Habib AS. Impact of pregabalin on acute and persistent postoperative pain: a systematic review and meta-analysis. Br J Anaesth. 2015;114:10-31. had found no significant difference between single and multiple dosing regimens, but their analysis had a significant component of heterogeneity because of pooling of different surgeries and anesthesia techniques. This contradiction calls for further research in this area. However, it should be noted that the effect of cardio-pulmonary bypass on pregabalin has not been studied. In at least one study,2222 Joshi SS, Jagadeesh AM. Efficacy of perioperative pregabalin in acute and chronic post-operative pain after off-pump coronary artery bypass surgery: a randomized, double-blind placebo controlled trial. Ann Card Anaesth. 2013;16:180-5. improved analgesia translated into improved peak inspiratory flow rates as assessed by incentive spirometry.

Increased duration of mechanical ventilation after gabapentin use may be due to a well-known side effect of gabapentin i.e. increased sedation. However, the increment is clinically insignificant: mean difference is only 0.81 h (48 min). It is to be kept in mind that the studies used different extubation and weaning protocol and this result is to be interpreted cautiously. Pregabalin did not increase duration of mechanical ventilation. Both drugs did not have any effect on the duration of ICU stay.

Despite popular belief, gabapentin was shown to increase sedation in one RCT only. None of the studies reported any serious adverse effects of gabapentin. Moreover, one study2323 Menda F, Koner O, Sayin M, et al. Effects of single-dose gabapentin on postoperative pain and morphine consumption after cardiac surgery. J Cardiothorac Vasc Anesth. 2010;24:808-13. found that gabapentin may reduce postoperative nausea also. It is not surprising, because it may have similar efficacy after craniotomy also.3636 Misra S, Parthasarathi G, Vilanilam GC. The effect of gabapentin premedication on postoperative nausea, vomiting, and pain in patients on preoperative dexamethasone undergoing craniotomy for intracranial tumors. J Neurosurg Anesthesiol. 2013;25:386-91. A lower morphine requirement in gabapentin treated patients may be responsible for this. Incidences of sedation, respiratory depression and nausea/vomiting were not altered with pregabalin as well. This lack of significant side effects may be explained by the use of a lower dose (150 mg) of the drug.

The clinical relevance of our review is that in spite of small individual studies reporting benefit of using perioperative gabapentinoids in cardiac surgery, our analysis failed to corroborate any unambiguous clinical efficacy, though no significant adverse effect is associated. So, there is no strong evidence to support using perioperative gabapentin and pregabalin in cardiac surgical patients at this time.

Limitations

The most important limitation of our review is the inclusion of limited number of studies. Despite extensive database searching, only eight studies could be included. Individual studies, though well designed, comprise small number of patients. A large RCT in the future may alter our finding. The dosage protocols of gabapentin and pregabalin are also varied in the studies. Data on chronic pain is also very limited.

Conclusion

At this time there is insufficient evidence to recommend routine use of gabapentin and pregabalin to reduce opioid consumption in the cardiac surgical patients primarily for the management of acute postoperative pain.

Appendix 1

("gabapentin" [Supplementary Concept] OR "gabapentin" [All Fields]) AND ("heart"[MeSH Terms] OR "heart" [All Fields] OR "cardiac" [All Fields])

("gabapentin" [Supplementary Concept] OR "gabapentin" [All Fields]) AND ("sternotomy" [MeSH Terms] OR "sternotomy" [All Fields])

("pregabalin" [Supplementary Concept] OR "pregabalin" [All Fields]) AND ("heart" [MeSH Terms] OR "heart" [All Fields] OR "cardiac" [All Fields])

("pregabalin" [Supplementary Concept] OR "pregabalin" [All Fields]) AND ("sternotomy" [MeSH Terms] OR "sternotomy" [All Fields])

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Publication Dates

  • Publication in this collection
    May-Jun 2017

History

  • Received
    26 Oct 2015
  • Accepted
    20 July 2016
Sociedade Brasileira de Anestesiologia R. Professor Alfredo Gomes, 36, 22251-080 Botafogo RJ Brasil, Tel: +55 21 2537-8100, Fax: +55 21 2537-8188 - Campinas - SP - Brazil
E-mail: bjan@sbahq.org