Does Regional Analgesia for Major Surgery Improve Outcome? Focus on Epidural Analgesia

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. HISTORICAL OVERVIEW 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 However, many of the trials included were already outdated, had methodological flaws, and do not represent current standard of care.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. CANCER RECURRENCE 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. DISCLOSURES 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.