Epidural analgesia is often considered the optimal technique for pain relief after major surgery and has been studied as a measure to improve outcome. Although conclusions from historical studies were promising, more recent studies show no relevant effect.
In the following discussion, we will assume regional analgesia does not make a difference in mortality and morbidity and will try to convince ourselves otherwise critically appraising the studies available.
Rodgers et al.1 published the first and most cited meta-analysis on this topic. They concluded that neuraxial blockade reduces postoperative mortality and other serious complications. However, many of the trials included were already outdated, had methodological flaws, and do not represent current standard of care. All studies were performed before 1997 and a substantial number before 1985.
Several studies reported an unusually high mortality rate of up to 27% in the control group.2–6 This neither represented the rest of the population in the meta-analysis nor does it represent current clinical practice with vastly improved outcomes due to less invasive surgical techniques and the widespread introduction of low molecular weight heparins.2
Ballantyne et al.7 demonstrated that the difference in mortality was related to the year in which a study was done, with newer studies finding smaller or no differences in mortality.
The study by Yeager et al.,8 included in many reviews and meta-analyses, was flawed both by a 76% incidence of adverse events in the nonepidural group (19 of 25 patients) and by premature termination of inclusion.8 When this study was excluded from the meta-analysis by Beattie et al. (both in 2001 and 2003) as well as the Cochrane review, the mortality difference between epidural and general anesthesia was no longer significantly different.9–11
In a large retrospective study, Wijeysundera et al.12 compared 88,188 patients with and without epidural anesthesia and/or analgesia and found a very small difference in patient outcome (0.2% absolute risk reduction) of borderline significance (P = 0.02). The authors concluded that “this study should not be used to justify the use of epidural analgesia for mortality reduction.”
CLINICAL OUTCOMES: CARDIOVASCULAR COMPLICATIONS
It has been suggested that epidural analgesia reduces postoperative cardiovascular complications. Three meta-analyses, mainly including studies in vascular surgery, showed a significant reduction in cardiac morbidity with epidural techniques.9–11 Beattie et al.10 included 1173 patients and found a nonsignificant risk reduction of 0.56 (confidence interval [CI], 0.30–1.03, P = 0.06) for myocardial infarction (MI). Only a post hoc subgroup analysis for thoracic epidurals achieved significance (P = 0.04) with an odds ratio of 0.43 (CI, 0.19–0.97).10 In patients undergoing open abdominal aortic surgery, Nishimori et al.9 reported a significant relative risk reduction of 0.52 (CI, 0.29–0.93) for MI in the presence of thoracic epidural analgesia.
The results of these 3 studies critically depended on inclusion of the previously discussed study by Yeager et al.8 Without this study, no significant results remained.
A meta-analysis focusing on cardiac surgery demonstrated a reduction in supraventricular arrhythmias but not in MI.13 Another meta-analysis, including 70 randomized controlled trials (RCTs) and nearly 5500 mixed surgical patients, did not find a difference in the incidence of MI.14 Two more meta-analyses and 2 RCTs, also including cardiac surgery, also did not demonstrate an effect of epidural analgesia on cardiovascular complications.14–17
In their systematic review of all available evidence, Liu and Wu18 concluded that epidural analgesia failed to significantly reduce cardiovascular complications in a general surgical population. From the evidence above, we can add that the effects on cardiac complications are minimal and limited to a subpopulation of high-risk patients and procedures.
CLINICAL OUTCOME: PULMONARY COMPLICATIONS
Based on the shortcomings mentioned before and the unknown incidence of pneumonia in the control group, the odds ratio of 0.61 demonstrated by Rodgers et al.1 should be treated with caution. When comparing thoracic epidural analgesia to IV analgesia after coronary artery bypass graft surgery, an odds ratio of 0.41 (CI, 0.27–0.60) for pulmonary complications was found.15 In a multicenter RCT, including 888 patients with at least 1 risk factor, the risk of postoperative respiratory failure was significantly reduced by epidural techniques from 30.2% to 23.3% (P = 0.02), and in a meta-analysis in cardiac surgery, a significant risk reduction of 0.53 (CI, 0.40–0.69) was shown on the compound end point “respiratory complications.”13,16
A large RCT and a meta-analysis could not reproduce these effects.14,17 Similarly, the meta-analysis by Liu and Wu18 did not find a significant difference in pulmonary outcome between systemic and epidural analgesia. Taken together, the influence of epidural analgesia on pulmonary complications, if present at all, is limited to high-risk intrathoracic procedures and high-risk patients.
In conclusion, adding epidural analgesia to general anesthesia does not reduce postoperative morbidity and mortality in a general surgical population. It is unlikely that such evidence will appear in the next years because of the decreased incidence of complications. For example, the incidence of pneumonia has decreased from 20% to 28% in the 1980s to 8% to 10% in more recent trials.17,19–22 Moreover, the beneficial effects of epidural analgesia on deep venous thrombosis and pulmonary embolism have been diminished by routine antithrombotic prophylaxis. Finally, surgical techniques advancing toward less invasive procedures, such as endovascular aortic aneurysm repair or thoracoscopic and laparoscopic surgery, are associated with less short-term postoperative morbidity and mortality, thereby further diminishing any potential for a benefit caused by epidural analgesia.23
QUALITY OF ANALGESIA AND FAILURE RATE
Most studies comparing epidural analgesia with systemic analgesia reported a difference, which was often statistically significant and in favor of epidural analgesia.24–27 However, the absolute difference ranged from 6 to 17 mm on a 100-mm visual analog scale. Since a commonly accepted minimum difference to detect clinical superiority is 20 to 30 mm difference on a 100-mm visual analog scale, the small statistical difference is not clinically relevant.28,29
Second, treatment of control groups in most studies consisted of parenteral opioids alone or combined with acetaminophen, which cannot be considered state of the art.30,31 An optimal regimen should contain a cyclooxygenase inhibitor (nonsteroidal anti-inflammatory drugs, cyclooxygenase-2 inhibitor, or dipyrone), an N-methyl-D-aspartate receptor antagonist ((S) ketamine), a descending inhibitory pain pathway inhibitor (e.g., clonidine) and possibly an anticonvulsive drug (e.g., pregabalin) in addition to opioids. IV lidocaine has also been proven beneficial.32–41
Clinically most important, the statistical superiority of epidural analgesia was offset by a failure rate of 13% to 47% in experienced hands.42 In the MASTER trial, 42.5% of the inserted epidural catheters were removed before the scheduled 72 hours.16 This was in accordance with other reports.43–47
In conclusion, epidural analgesia provides statistically, but not clinically, superior analgesia to 53% to 87% of patients. The other 13% to 47% will likely experience a period of inadequate analgesia, often requiring rescue systemic analgesia. Therefore, the effect on a group level is not superior to systemic analgesia.
ALTERNATIVES TO EPIDURAL ANALGESIA
For extremity surgery, continuous peripheral nerve blocks are widely used. As for epidural analgesia, there was no evidence for any effect on long-term outcome.18 Nevertheless, 2 meta-analyses suggested that peripheral nerve blocks facilitated a quicker rehabilitation with less opioid use and less sleep disturbance.48,49
Epidural analgesia and femoral nerve block resulted in comparable analgesia, opioid consumption, postoperative nausea and vomiting incidence and speed of rehabilitation for major knee surgery although femoral blocks caused fewer side effects (hypotension, pruritus, and urinary retention), and increased patient satisfaction.50
For truncal surgery, paravertebral, intercostal, and transversus abdominal plane blocks and wound infusion catheters are alternatives for epidural or systemic analgesia.51 Currently, there is insufficient evidence to judge their value.
Local anesthetics work beyond the direct inhibition of local signal transmission in the nerve and modulate the inflammatory response by acting on G protein-coupled receptors.52 Clinical studies demonstrated that a perioperative IV infusion of lidocaine yielded a reduction in duration of postoperative ileus and length of hospital stay accompanied by a reduced stress/inflammation response.33–38,41,53,54
ENHANCED RECOVERY PROGRAMS
Thoracic epidural analgesia is sometimes promoted as part of fast-track or enhanced recovery after surgery (ERAS) programs.55 There was substantial heterogeneity in the studies regarding type of surgery, care in the control group as well as the type, and number of interventions that were implemented. Although ERAS reduced length of stay and sometimes postoperative complications, it remains unclear which elements are essential for success and actually contribute to an improved outcome.56 A meta-analysis concluded that implementation of at least 4 interventions, not necessarily including epidural analgesia, resulted in reduction of hospital stay of 2 days and a nearly 50% reduction in complications.47 Success of ERAS is primarily based on a structured and protocol-based approach and a modified attitude toward rehabilitation goals.
Although excellent analgesia and dampening of the surgical stress response are needed, epidural analgesia is not the only way to achieve this. The 2 ERAS trials comparing thoracic epidural analgesia with IV analgesia did not find any difference in length of stay, morbidity, or mortality.57,58 The reduction in length of stay achieved within an ERAS program using systemic lidocaine was comparable with that of studies using epidural analgesia.38,41,54
We conclude that there is no evidence that thoracic epidural analgesia should be a compulsory part of an ERAS program.
A small retrospective study suggested that regional analgesia could improve cancer-free survival, but more recent trials could not reliably reproduce these results.59–62 This leaves the effect itself as well as dependent variables, such as tumor type, anesthesia technique, and molecular mechanisms as a matter of debate.60–63
COMPLICATIONS OF EPIDURAL ANALGESIA
Epidural analgesia was considered a safe technique with an incidence of serious complications (neuraxial hematoma and abscess) of <1 in 100,000 patients. However, several studies demonstrated that the setting in which a neuraxial block was performed, as well as the technique used, made a difference in the risk of complications.64–69 The incidence of permanent harm (including paraplegia and death) ranged from <1 in 200,000 spinal punctures performed in an obstetric setting to 1 in 5700 to 12,000 cases for thoracic epidurals in surgical patients.66 These numbers were confirmed by several large studies, some of which report an incidence of up to 1 in every 1000 cases.64–68 Considering the evidence from the last decade, it should now be accepted that a thoracic epidural catheter in surgical patients carries a 10- to 100-fold higher risk, that is, 1 in 1000 to 10,000 for serious complications.64–68 It is unclear whether better reporting of complications is responsible for the higher figures or whether the incidence of neuraxial hematoma has actually increased over the years. Thromboprophylaxis with low molecular weight heparins and other agents might have caused both the decrease in thrombotic surgical complications as well as an increased risk of epidural hemorrhage.70 Anesthesia societies have proposed guidelines for management of anticoagulated patients undergoing neuraxial block.71 Most recommendations in these guidelines are based on case series, pharmacology, and expert opinion, but it is clear that anticoagulant therapy should prevail over the indication for neuraxial anesthesia/analgesia since the evidence for thromboprophylaxis (or other anticoagulants) is much stronger than the evidence for an epidural catheter.
In conclusion, there is strong evidence that epidural analgesia or peripheral regional analgesic techniques improve neither perioperative mortality nor postoperative pulmonary and cardiovascular complications to a clinically significant extent for the general surgical population. If any, the advantages of epidural analgesia are limited to high-risk morbid patients undergoing high-risk procedures.51,70 Analgesia is statistically, but not clinically, superior using epidural techniques. The marginal superiority is further offset by failure rates and analgesic alternatives such as (S)-ketamine, clonidine, and IV lidocaine. Epidural analgesia is associated with a small but relevant number of serious complications, especially in the presence of anticoagulant therapy. The risk/benefit balance should be discussed with the patient in the preoperative consultation.
In our opinion, epidural analgesia remains a valid option for postoperative analgesia, and all authors regularly use it for patients undergoing major surgery after careful individual risk assessment. However, given the arguments discussed above, epidural analgesia can no longer be considered the standard of care for a general surgical population.
Name: Fabian O. Kooij, MD.
Contribution: This author helped analyze the data and write the manuscript.
Attestation: Fabian O. Kooij approved the final manuscript.
Name: Wolfgang S. Schlack, MD, PhD, DEAA.
Contribution: This author helped write the manuscript.
Attestation: Wolfgang S. Schlack approved the final manuscript.
Name: Benedikt Preckel, MD, PhD, DEAA.
Contribution: This author helped write the manuscript.
Attestation: Benedikt Preckel approved the final manuscript.
Name: Markus W. Hollmann, MD, PhD, DEAA.
Contribution: This author helped write the manuscript.
Attestation: Markus W. Hollmann approved the final manuscript.
This manuscript was handled by: Terese T. Horlocker, MD.
1. Rodgers A, Walker N, Schug S, McKee A, Kehlet H, van Zundert A, Sage D, Futter M, Saville G, Clark T, MacMahon S. Reduction of postoperative mortality and morbidity with epidural or spinal anesthesia: results from overview of randomised trials. BMJ. 2000;321:1493
2. Borovskikh NA, Lebedev LV, Strashkov VI, Vinogradov AT. [Comparative evaluation of the effectiveness of epidural anesthesia with spontaneous respiration and general anesthesia in aorto-femoral bifurcation shunt]. Vestn Khir Im I I Grek. 1990;145:95–8
3. McLaren AD, Stockwell MC, Reid VT. Anesthetic techniques for surgical correction of fractured neck of femur. A comparative study of spinal and general anesthesia in the elderly. Anaesthesia. 1978;33:10–4
4. Valentin N, Lomholt B, Jensen JS, Hejgaard N, Kreiner S. Spinal or general anesthesia for surgery of the fractured hip? A prospective study of mortality in 578 patients. Br J Anesth. 1986;58:284–91
5. McKenzie PJ, Wishart HY, Smith G. Long-term outcome after repair of fractured neck of femur. Comparison of subarachnoid and general anesthesia. Br J Anesth. 1984;56:581–5
6. Davis FM, Laurenson VG. Spinal anesthesia or general anesthesia for emergency hip surgery in elderly patients. Anesth Intensive Care. 1981;9:352–8
7. Ballantyne JC, Kupelnick B, McPeek B, Lau J. Does the evidence support the use of spinal and epidural anesthesia for surgery? J Clin Anesth. 2005;17:382–91
8. Yeager MP, Glass DD, Neff RK, Brinck-Johnsen T. Epidural anesthesia and analgesia in high-risk surgical patients. Anesthesiology. 1987;66:729–36
9. Nishimori M, Ballantyne JC, Low JH. Epidural pain relief versus systemic opioid-based pain relief for abdominal aortic surgery. Cochrane Database Syst Rev. 2006;3:CD005059
10. Beattie WS, Badner NH, Choi P. Epidural analgesia reduces postoperative myocardial infarction: a meta-analysis. Anesth Analg. 2001;93:853–8
11. Beattie WS, Badner NH, Choi PT. Meta-analysis demonstrates statistically significant reduction in postoperative myocardial infarction with the use of thoracic epidural analgesia. Anesth Analg. 2003;97:919–20
12. Wijeysundera DN, Beattie WS, Austin PC, Hux JE, Laupacis A. Epidural anesthesia and survival after intermediate-to-high risk non-cardiac surgery: a population-based cohort study. Lancet. 2008;372:562–9
13. Svircevic V, van Dijk D, Nierich AP, Passier MP, Kalkman CJ, van der Heijden GJ, Bax L. Meta-analysis of thoracic epidural anesthesia versus general anesthesia for cardiac surgery. Anesthesiology. 2011;114:271–82
14. Guay J. The benefits of adding epidural analgesia to general anesthesia: a metaanalysis. J Anesth. 2006;20:335–40
15. Liu SS, Block BM, Wu CL. Effects of perioperative central neuraxial analgesia on outcome after coronary artery bypass surgery: a meta-analysis. Anesthesiology. 2004;101:153–61
16. Rigg JR, Jamrozik K, Myles PS, Silbert BS, Peyton PJ, Parsons RW, Collins KSMASTER Anethesia Trial Study Group. . Epidural anesthesia and analgesia and outcome of major surgery: a randomised trial. Lancet. 2002;359:1276–82
17. Park WY, Thompson JS, Lee KK. Effect of epidural anesthesia and analgesia on perioperative outcome: a randomized, controlled Veterans Affairs cooperative study. Ann Surg. 2001;234:560–9
18. Liu SS, Wu CL. Effect of postoperative analgesia on major postoperative complications: a systematic update of the evidence. Anesth Analg. 2007;104:689–702
19. Addison NV, Brear FA, Budd K, Whittaker M. Epidural analgesia following cholecystectomy. Br J Surg. 1974;61:850–2
20. Cuschieri RJ, Morran CG, Howie JC, McArdle CS. Postoperative pain and pulmonary complications: comparison of three analgesic regimens. Br J Surg. 1985;72:495–8
21. Hjortsø NC, Neumann P, Frøsig F, Andersen T, Lindhard A, Rogon E, Kehlet H. A controlled study on the effect of epidural analgesia with local anesthetics and morphine on morbidity after abdominal surgery. Acta Anesthesiol Scand. 1985;29:790–6
22. Peyton PJ, Myles PS, Silbert BS, Rigg JA, Jamrozik K, Parsons R. Perioperative epidural analgesia and outcome after major abdominal surgery in high-risk patients. Anesth Analg. 2003;96:548
23. Schanzer A, Messina L. Two decades of endovascular abdominal aortic aneurysm repair: enormous progress with serious lessons learned. J Am Heart Assoc. 2012;1:e000075
24. Werawatganon T, Charuluxanun S. Patient controlled intravenous opioid analgesia versus continuous epidural analgesia for pain after intra-abdominal surgery. Cochrane Database Syst Rev. 2005;1:CD004088
25. Marret E, Remy C, Bonnet FPostoperative Pain Forum Group. . Meta-analysis of epidural analgesia versus parenteral opioid analgesia after colorectal surgery. Br J Surg. 2007;94:665–73
26. Liu SS, Wu CL. The effect of analgesic technique on postoperative patient-reported outcomes including analgesia: a systematic review. Anesth Analg. 2007;105:789–808
27. Block BM, Liu SS, Rowlingson AJ, Cowan AR, Cowan JA Jr, Wu CL. Efficacy of postoperative epidural analgesia: a meta-analysis. JAMA. 2003;290:2455–63
28. Jensen MP, Chen C, Brugger AM. Interpretation of visual analog scale ratings and change scores: a reanalysis of two clinical trials of postoperative pain. J Pain. 2003;4:407–14
29. Farrar JT, Portenoy RK, Berlin JA, Kinman JL, Strom BL. Defining the clinically important difference in pain outcome measures. Pain. 2000;88:287–94
30. Elia N, Lysakowski C, Tramèr MR. Does multimodal analgesia with acetaminophen, nonsteroidal antiinflammatory drugs, or selective cyclooxygenase-2 inhibitors and patient-controlled analgesia morphine offer advantages over morphine alone? Meta-analyses of randomized trials. Anesthesiology. 2005;103:1296–304
31. Chandrakantan A, Glass PS. Multimodal therapies for postoperative nausea and vomiting, and pain. Br J Anesth. 2011;107(Suppl 1):i27–40
32. Bell RF, Dahl JB, Moore RA, Kalso E. Perioperative ketamine for acute postoperative pain. Cochrane Database Syst Rev. 2006;1:CD004603
33. De Oliveira GS Jr, Fitzgerald P, Streicher LF, Marcus RJ, McCarthy RJ. Systemic lidocaine to improve postoperative quality of recovery after ambulatory laparoscopic surgery. Anesth Analg. 2012;115:262–7
34. McCarthy GC, Megalla SA, Habib AS. Impact of intravenous lidocaine infusion on postoperative analgesia and recovery from surgery: a systematic review of randomized controlled trials. Drugs. 2010;70:1149–63
35. Vigneault L, Turgeon AF, Côté D, Lauzier F, Zarychanski R, Moore L, McIntyre LA, Nicole PC, Fergusson DA. Perioperative intravenous lidocaine infusion for postoperative pain control: a meta-analysis of randomized controlled trials. Can J Anesth. 2011;58:22–37
36. Grigoras A, Lee P, Sattar F, Shorten G. Perioperative intravenous lidocaine decreases the incidence of persistent pain after breast surgery. Clin J Pain. 2012;28:567–72
37. Sun Y, Li T, Wang N, Yun Y, Gan TJ. Perioperative systemic lidocaine for postoperative analgesia and recovery after abdominal surgery: a meta-analysis of randomized controlled trials. Dis Colon Rectum. 2012;55:1183–94
38. Herroeder S, Pecher S, Schönherr ME, Kaulitz G, Hahnenkamp K, Friess H, Böttiger BW, Bauer H, Dijkgraaf MG, Dijkgraaf OG, Durieux ME, Hollmann MW. Systemic lidocaine shortens length of hospital stay after colorectal surgery: a double-blinded, randomized, placebo-controlled trial. Ann Surg. 2007;246:192–200
39. Hollmann MW, Strümper D, Durieux ME. The poor man’s epidural: systemic local anesthetics for improving postoperative outcomes. Med Hypotheses. 2004;63:386–9
40. McDaid C, Maund E, Rice S, Wright K, Jenkins B, Woolacott N. Paracetamol and selective and non-selective non-steroidal anti-inflammatory drugs (NSAIDs) for the reduction of morphine-related side effects after major surgery: a systematic review. Health Technol Assess. 2010;14:1–153, iii–iv
41. Swenson BR, Gottschalk A, Wells LT, Rowlingson JC, Thompson PW, Barclay M, Sawyer RG, Friel CM, Foley E, Durieux ME. Intravenous lidocaine is as effective as epidural bupivacaine in reducing ileus duration, hospital stay, and pain after open colon resection: a randomized clinical trial. Reg Anesth Pain Med. 2010;35:370–6
42. Hermanides J, Hollmann MW, Stevens MF, Lirk P. Failed epidural: causes and management. Br J Anesth. 2012;109:144–54
43. Van Aken H, Gogarten W, Brüssel T, Brodner G. Epidural anesthesia and analgesia in mayor surgery. Lancet. 2002;360:568
44. Rigg JR, Jamrozik K, Myles PS, Silbert BS, Peyton PJ. Epidural anesthesia and analgesia in mayor surgery (author reply). Lancet. 2002;360:569
45. Ready LB. Acute pain: lessons learned from 25,000 patients. Reg Anesth Pain Med. 1999;24:499–505
46. Low J, Johnston N, Morris C. Epidural analgesia: first do no harm. Anaesthesia. 2008;63:1–3
47. Varadhan KK, Neal KR, Dejong CH, Fearon KC, Ljungqvist O, Lobo DN. The enhanced recovery after surgery (ERAS) pathway for patients undergoing major elective open colorectal surgery: a meta-analysis of randomized controlled trials. Clin Nutr. 2010;29:434–40
48. Ilfeld BM. Continuous peripheral nerve blocks: a review of the published evidence. Anesth Analg. 2011;113:904–25
49. Richman JM, Liu SS, Courpas G, Wong R, Rowlingson AJ, McGready J, Cohen SR, Wu CL. Does continuous peripheral nerve block provide superior pain control to opioids? A meta-analysis. Anesth Analg. 2006;102:248–57
50. Fowler SJ, Symons J, Sabato S, Myles PS. Epidural analgesia compared with peripheral nerve blockade after major knee surgery: a systematic review and meta-analysis of randomized trials. Br J Anesth. 2008;100:154–64
51. Rawal N. Epidural technique for postoperative pain: gold standard no more? Reg Anesth Pain Med. 2012;37:310–7
52. Hollmann MW, Gross A, Jelacin N, Durieux ME. Local anesthetic effects on priming and activation of human neutrophils. Anesthesiology. 2001;95:113–22
53. Marret E, Rolin M, Beaussier M, Bonnet F. Meta-analysis of intravenous lidocaine and postoperative recovery after abdominal surgery. Br J Surg. 2008;95:1331–8
54. Wongyingsinn M, Baldini G, Charlebois P, Liberman S, Stein B, Carli F. Intravenous lidocaine versus thoracic epidural analgesia: a randomized controlled trial in patients undergoing laparoscopic colorectal surgery using an enhanced recovery program. Reg Anesth Pain Med. 2011;36:241–8
55. Kehlet H, Wilmore DW. Multimodal strategies to improve surgical outcome. Am J Surg. 2002;183:630–41
56. Vlug MS, Bartels SA, Wind J, Ubbink DT, Hollmann MW, Bemelman WACollaborative LAFA Study Group. . Which fast track elements predict early recovery after colon cancer surgery? Colorectal Dis. 2012;14:1001–8
57. Zutshi M, Delaney CP, Senagore AJ, Mekhail N, Lewis B, Connor JT, Fazio VW. Randomized controlled trial comparing the controlled rehabilitation with early ambulation and diet pathway versus the controlled rehabilitation with early ambulation and diet with preemptive epidural anesthesia/analgesia after laparotomy and intestinal resection. Am J Surg. 2005;189:268–72
58. Hemmerling TM, Prieto I, Choinière JL, Basile F, Fortier JD. Ultra-fast-track anesthesia in off-pump coronary artery bypass grafting: a prospective audit comparing opioid-based anesthesia vs thoracic epidural-based anesthesia. Can J Anesth. 2004;51:163–8
59. Exadaktylos AK, Buggy DJ, Moriarty DC, Mascha E, Sessler DI. Can anesthetic technique for primary breast cancer surgery affect recurrence or metastasis? Anesthesiology. 2006;105:660–4
60. Forget P, Tombal B, Scholtès JL, Nzimbala J, Meulders C, Legrand C, Van Cangh P, Cosyns JP, De Kock M. Do intraoperative analgesics influence oncological outcomes after radical prostatectomy for prostate cancer? Eur J Anesthesiol. 2011;28:830–5
61. Cummings KC 3rd, Xu F, Cummings LC, Cooper GS. A comparison of epidural analgesia and traditional pain management effects on survival and cancer recurrence after colectomy: a population-based study. Anesthesiology. 2012;116:797–806
62. Capmas P, Billard V, Gouy S, Lhommé C, Pautier P, Morice P, Uzan C. Impact of epidural analgesia on survival in patients undergoing complete cytoreductive surgery for ovarian cancer. Anticancer Res. 2012;32:1537–42
63. Doornebal CW, Klarenbeek S, Braumuller TM, Klijn CN, Ciampricotti M, Hau CS, Hollmann MW, Jonkers J, de Visser KE. A preclinical mouse model of invasive lobular breast cancer metastasis. Cancer Res. 2013;73:353–63
64. Cameron CM, Scott DA, McDonald WM, Davies MJ. A review of neuraxial epidural morbidity: experience of more than 8000 cases at a single teaching hospital. Anesthesiology. 2007;106:997–1002
65. Christie IW, McCabe S. Major complications of epidural analgesia after surgery: results of a six-year survey. Anaesthesia. 2007;62:335–41
66. Moen V, Dahlgren N, Irestedt L. Severe neurological complications after central neuraxial blockades in Sweden 1990-1999. Anesthesiology. 2004;101:950–9
67. Pöpping DM, Zahn PK, Van Aken HK, Dasch B, Boche R, Pogatzki-Zahn EM. Effectiveness and safety of postoperative pain management: a survey of 18 925 consecutive patients between 1998 and 2006 (2nd revision): a database analysis of prospectively raised data. Br J Anesth. 2008;101:832–40
68. Cook TM, Counsell D, Wildsmith JARoyal College of Anesthetists Third National Audit Project. . Major complications of central neuraxial block: report on the Third National Audit Project of the Royal College of Anesthetists. Br J Anesth. 2009;102:179–90
69. Bateman BT, Mhyre JM, Ehrenfeld J, Kheterpal S, Abbey KR, Argalious M, Berman MF, Jacques PS, Levy W, Loeb RG, Paganelli W, Smith KW, Wethington KL, Wax D, Pace NL, Tremper K, Sandberg WS. The risk and outcomes of epidural hematomas after perioperative and obstetric epidural catheterization: a report from the Multicenter Perioperative Outcomes Group Research Consortium. Anesth Analg. 2013;116:1380–5
70. Horlocker T, Kopp S. Epidural hematoma after epidural blockade in the United States: it’s not just low molecular heparin following orthopedic surgery anymore. Anesth Analg. 2013;116:1195–7
71. Horlocker TT, Wedel DJ, Rowlingson JC, Enneking FK, Kopp SL, Benzon HT, Brown DL, Heit JA, Mulroy MF, Rosenquist RW, Tryba M, Yuan CS. Regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy: American Society of Regional Anesthesia and Pain Medicine Evidence-Based Guidelines (Third Edition). Reg Anesth Pain Med. 2010;35:64–101