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Adding regional analgesia to general anaesthesia: increase of risk or improved outcome?

Curatolo, Michele

European Journal of Anaesthesiology: July 2010 - Volume 27 - Issue 7 - p 586–591
doi: 10.1097/EJA.0b013e32833963c8

Although it is clear that regional analgesia in association with general anaesthesia substantially reduces postoperative pain, the benefits in terms of overall perioperative outcome are less evident. The aim of this nonsystematic review was to evaluate the effect on middle and long-term postoperative outcomes of adding regional perioperative analgesia to general anaesthesia.

This study is based mostly on systematic reviews, large epidemiological studies and large or high-quality randomized controlled trials that were selected and evaluated by the author. The endpoints that are discussed are perioperative morbidity, cancer recurrence, chronic postoperative pain, postoperative rehabilitation and risk of neurologic damage.

Epidural analgesia may have a favourable but very small effect on perioperative morbidity. The influence of other regional anaesthetic techniques on perioperative morbidity is unclear. Preliminary data suggest that regional analgesia might reduce the incidence of cancer recurrence. However, adequately powered randomized controlled trials are lacking. The sparse literature available suggests that regional analgesia may prevent the development of chronic postoperative pain. Rehabilitation in the immediate postoperative period is possibly improved, but the advantages in the long term remain unclear. Permanent neurological damage is extremely rare.

In conclusion, while the risk of permanent neurologic damage remains extremely low, evidence suggests that regional analgesia may improve relevant outcomes in the long term. The effect size is mostly small or the number-needed-to-treat is high. However, considering the importance of the outcomes of interest, even minor improvement probably has substantial clinical relevance.

From the Department of Anaesthesiology and Pain Therapy, University Hospital of Bern, Inselspital, Bern, Switzerland

Received 30 December, 2009

Revised 5 February, 2010

Accepted 3 March, 2010

Correspondence to Michele Curatolo, MD, PhD, Department of Anaesthesiology and Pain Therapy, University Hospital of Bern, Inselspital, 3010 Bern, Switzerland Tel: +41 31 632 24 83; fax: +41 31 632 05 54; e-mail:

Part of this review will be presented as a refresher course at the Annual Meeting of the European Society of Anaesthesiology (ESA) in Helsinki, 12–15 June 2010. It will be published in the refresher course book.

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Adding regional to general anaesthesia for major surgery has become increasingly popular and is common practice in many institutions. The intraoperative administration of a regional block is expected to reduce the requirement for general anaesthetics and attenuate the stress response to surgery. Continuing the block postoperatively allows effective pain control and reduces opioid-related side effects.1,2 However, the advantages in terms of overall improvement in perioperative outcome are less evident, and the combination of two different anaesthetic procedures exposes patients to the risks of both techniques.

The aim of this review was to evaluate the effect of adding perioperative regional analgesia to general anaesthesia on middle and long-term postoperative outcomes. The focus was on studies conducted after major surgery, for which either epidural, intrathecal, plexus or peripheral nerve blocks were used for perioperative pain control. The endpoints that are discussed are perioperative morbidity, cancer recurrence, chronic postoperative pain, postoperative rehabilitation and risk of neurologic damage.

The objective is to educate by providing an overview on clinically relevant but nevertheless controversial outcomes and by identifying areas of uncertainty in which further research is needed. In this there is no pretence of being systematic, though the subject matter, selected and evaluated by the author, is mostly systematic reviews, large epidemiological studies and large or high-quality randomized controlled trials. If more than one systematic review or meta-analysis on the same subject was available, only the most recent one was considered.

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Effects of regional analgesic techniques on perioperative morbidity

Regional analgesia favourably benefits a number of physiological functions in the postoperative phase, such as respiration, coagulation, bowel function and hormonal stress responses. Such effects are expected to reduce the incidence of perioperative complications.

A systematic review published in 2007 evaluated meta-analyses and large randomized controlled trials that studied the effects of different anaesthetic and postoperative analgesic techniques on perioperative complications.3 With regard to the incidence of cardiovascular and pulmonary complications, the majority of the evidence favoured epidural analgesia compared with general anaesthesia alone. However, this superiority was observed only in major vascular surgery or high-risk patients. When epidural local anaesthetics were used, there was consistent support for their ability to hasten the resolution of postoperative ileus after major abdominal surgery. For other forms of regional analgesia, intravenous patient-controlled analgesia (PCA) and multimodal systemic analgesia, the review failed to find evidence for a clinically important reduction in the incidence of postoperative complications.

A more recent meta-analysis confirmed the protective effect of epidural analgesia on pneumonia following abdominal or thoracic surgery [odds ratio (OR) 0.54; 95% confidence interval (CI) 0.43–0.68].4 This review looked back at the benefits of epidural analgesia from 1971 to 1996; interestingly, the incidence of pneumonia with epidural analgesia remained about 8%, but decreased from 34 to 12% with systemic analgesia (P < 0.001). Consequently, the benefit of epidural analgesia has decreased because the baseline risk is less. The study also found that epidural analgesia reduced the need for prolonged ventilation or reintubation, improved lung function and blood oxygenation, but increased the risk of hypotension, urinary retention and pruritus.

In a population-based retrospective cohort study on intermediate-risk and high-risk noncardiac surgery, epidural analgesia was associated with a reduction in the 30-day mortality after surgery.5 The difference was 1.7 vs. 2.0% and reached statistical significance (P = 0.02). The number-needed-to-treat was 477. This suggests that about 480 intermediate-risk or high-risk patients undergoing noncardiac surgery would need to receive combined epidural analgesia and general anaesthesia to prevent one perioperative death from general anaesthesia alone.

It is worth noting that a comparison of intravenous with intrathecal opioids (without local anaesthetics) found no difference in the incidence of cardiovascular, respiratory and renal complications.6 A meta-analysis of intrathecal morphine without local anaesthetics found a pain reduction of only 2 (on a 10 cm visual analogue scale) both at rest and with movement, whereas the risk of respiratory depression increased (OR 7.86, 95% CI 1.54–40.30).7 In apparent contrast, a large randomized controlled trial in aortic surgery using epidural opioids alone found, in the epidural group, a lower incidence of death and major complications compared with systemic analgesia, but the combined technique failed to make an impact in any other type of major abdominal surgery.8

For cardiac surgery, a meta-analysis published in 2004 showed that epidural or intrathecal analgesia did not affect incidences of mortality or myocardial infarction, but epidural analgesia significantly reduced the risk of dysrhythmias (OR 0.52, 95% CI 0.29–0.93) and of pulmonary complications (OR 0.41, 95% CI 0.27–0.60).9 A more recent randomized controlled trial found that combining epidural analgesia and general anaesthesia significantly reduced the incidence of atelectasis 4 h after cardiac surgery,10 but by 3 days after surgery, there was no difference. Another trial on cardiac surgery found no difference in length of stay or recovery from surgery between combined and general anaesthesia.11

On balance reported studies show a likely favourable effect of epidural analgesia on the perioperative outcome. However, the effect size is probably very small and the influence may be restricted to major surgery performed on intermediate-risk or high-risk patients. The effect will be even smaller if local anaesthetics are omitted and there is evidence that the risk/benefit ratio of epidural or intrathecal analgesics alone is worse than that with regimens that include local anaesthetics. The influence of other forms of regional anaesthetic techniques on perioperative morbidity is unclear.

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Effects of regional analgesic techniques on cancer recurrence

The main rationale for a possible protective effect of regional blocks on cancer recurrence is that regional analgesia may attenuate the perioperative release of substances that promote tumour growth.12 Animal studies have shown that opioids at clinical doses may facilitate tumour progression,13 leading to the hypothesis that reducing opioid consumption in the perioperative phase could favourably affect the prognosis of cancer patients. General anaesthesia and surgery suppressed natural killer cell activity and promoted tumour growth in an animal experiment, with both phenomena dramatically attenuated by spinal anaesthesia.14

In a retrospective study of breast tumour surgery under general anaesthesia, either alone or combined with paravertebral analgesia, recurrence-free and metastasis-free survival at 36 months was 77% (95% CI 68–87%) and 94% (95% CI 87–100%), respectively (P = 0.012).15 More recently, the same research group has reported a retrospective study on prostate cancer resection.16 In a multivariable Cox regression model, the epidural and general anaesthesia group had an estimated 57% (95% CI 17–78%) lower risk of recurrence compared with the general anaesthesia and opioids group with a corresponding hazard ratio of 0.43 (95% CI 0.22–0.83, P = 0.012).

A retrospective study analysed follow-up data of 4329 patients on the Central Melanoma Registry of the German Dermatological Society.17 In a multifactorial Cox proportional hazard analysis, general anaesthesia for primary excision of melanoma was associated with a decrease in the survival rate (relative risk 1.46, P < 0.0001).

A later analysis of cancer recurrence was made in a randomized controlled study on prostate cancer resection that had been primarily powered on other outcomes.18 Biochemical recurrence of prostate cancer (determination of prostate-specific antigen) was observed in 11 of 49 patients with combined epidural and general anaesthesia and in 17 of 50 patients with general anaesthesia alone. No difference was observed between the two groups in disease-free survival at a median follow-up time of 4.5 years. The study was clearly underpowered to detect differences in this outcome. The authors concluded that there is a need for a large randomized controlled trial to determine the ability of epidural analgesia to alter disease recurrence rates following radical prostatectomy.

A randomized controlled trial on 177 patients who underwent colon cancer resection with general anaesthesia, either alone or supplemented by epidural analgesia, found some evidence of enhanced survival in the group treated with epidural analgesia; however, this was observed only for patients without metastases before 1.46 years.19 In this subgroup, the risk of dying in the first 1.46 years after surgery was increased 4.65 times if no epidural analgesia was administered (95% CI 1.40–15.42, P = 0.012).

In summary, preliminary data suggest that regional analgesia might reduce the incidence of cancer recurrence. The retrospective nature of the former two studies and the relatively low sample size of the third do not allow clear conclusions. Based on these investigations, the quantitative effect of regional analgesia on cancer recurrence might be clinically relevant. However, the power of those studies is insufficient to provide a precise estimate of the benefit, as indicated by the large CIs.

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Effects of regional analgesic techniques on chronic postoperative pain

Chronic pain after surgery is common and is associated with substantial suffering and disability.20 One mechanism that might contribute to the development of chronic pain is the induction, by surgical trauma, of plastic changes in the central nervous system. These may be responsible for exaggerated pain after low-input nociceptive stimulation or may even cause stimulus-independent persistent pain.21 In this context, the rationale for the prevention of chronic pain by regional analgesia is its ability to block or strongly attenuate the arrival of the nociceptive impulses that are expected to trigger such plastic changes in the central nervous system.

So far, there are few reports. Two randomized controlled trials could only demonstrate a reduction in the incidence of chronic postthoracotomy pain when epidural analgesia was offered both intraoperatively and postoperatively, as compared with no epidural analgesia or merely intraoperative use.22,23 Paravertebral block compared with sham puncture reduced the incidence of postmastectomy pain at 12-month follow-up.24 On the other hand, adding epidural analgesia to general anaesthesia did not affect the incidence of phantom limb pain after amputation.25

Initial data are encouraging, but the current evidence is insufficient to clearly define the role of regional analgesia in the prevention of chronic pain.

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Effects of regional analgesic techniques on postoperative rehabilitation

Through the provision of effective pain relief, regional analgesia should facilitate early postoperative rehabilitation, which would be of considerable benefit.26 However, very few data on this topic are available.

A randomized controlled trial on knee surgery found that epidural analgesia and peripheral nerve blocks improved knee flexion and reduced the length of stay in the rehabilitation centre, compared with intravenous PCA.27 In a further investigation, epidural analgesia and continuous peripheral nerve block resulted in significantly better knee flexion at 6 weeks, faster ambulation and shorter hospital stay, when compared with intravenous morphine PCA.28 However, the outcome at 3 months was not affected.

In a randomized trial on hip surgery, postoperative epidural analgesia did not result in improved recovery of physical independence.29 Similarly, peripheral nerve blocks did not improve rehabilitation after hip surgery.30

For shoulder surgery, a randomized trial found interscalene block to be superior to intravenous PCA in terms of pain during physiotherapy, whereas function during early rehabilitation was not affected.31

Overall, the data are insufficient to draw clear conclusions on the effect of regional analgesia on rehabilitation. There might be an improvement in the immediate postoperative period, but the sparse nature of studies could not demonstrate clear advantages in the long term.

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Risk of neurologic complications

The main fear related to regional anaesthetic techniques is the risk of permanent neurologic damage. In a meta-analysis on epidural analgesia for childbirth, the estimated risk of epidural haematoma was 1: 168 000, deep epidural infection 1: 145 000 and persistent neurologic injury 1: 240 000.32 The application of these figures to surgical patients is probably invalid because of their greater morbidity and also the influence of surgery on the outcome.

A review of neuropathy after regional anaesthesia found the rate after central nerve blockade and peripheral nerve block to be less than 4: 10 000 and less than 3: 100, respectively.33 However, permanent neurological injury was rare, ranging from 0 to 4.2: 10 000 after spinal and from 0 to 7.6: 10 000 after epidural anaesthesia. Only one case of permanent neuropathy was reported among 16 studies of neurological complications after peripheral nerve block.

An audit of a teaching hospital acute pain service with more than 8000 epidural catheters found the incidence of epidural haematoma to be less than 5: 10 000 and less than 1: 1000 for epidural abscess.34

A 2-week national census identified 707 455 central neural blockades performed over 1 year in the UK National Health Service and reported all major complications that occurred during this period.35 The incidence of permanent injury due to central neural blockade (expressed per 100 000 cases) was ‘pessimistically’ 4.2 (95% CI 2.9–6.1) and ‘optimistically’ 2.0 (95% CI 1.1–3.3). The incidence of paraplegia or death was ‘pessimistically’ 1.8 (95% CI 1.0–3.1) and ‘optimistically’ 0.7 (95% CI 0–1.6) per 100 000. Two-thirds of initially disabling injuries resolved fully.

In a prospective analysis of postoperative patients in a university hospital,36 epidural haematoma occurred in 3: 14 233 cases, without permanent neurological sequelae. Epidural abscess was observed in 2: 14 233 cases, one with a permanent neurological deficit and another with meningitis with complete resolution. In the same study, transient severe neurological deficit occurred in 2: 3111 peripheral nerve blocks, with no cases of permanent damage.

In a prospective multicentre study on continuous peripheral nerve blocks, nerve lesions were observed in three of the 1416 patients analysed; all lesions resolved within 10 weeks and no patient developed permanent neurological damage.37

Permanent neurological damage is extremely rare after regional analgesia.

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Tables 1 and 2 summarize the data presented in this review. The answer to the question of whether combined anaesthetic techniques lead to improved outcome or increased risk is obvious: they lead to both. To date, the information in the public domain allows only a partial quantification of the benefit/risk ratio. The quantitative impact of regional analgesia on postoperative morbidity and mortality is probably very small. Regional analgesia may decrease the risk of developing chronic pain. Although the effect size is probably small, even a high number-needed-to-treat probably has substantial clinical significance for such outcomes.

Table 1

Table 1

Table 2

Table 2

At present, the main reason for performing combined techniques is the clearly superior quality of postoperative pain treatment, compared with systemic opioids.1 The possible effects on perioperative morbidity, cancer recurrence and occurrence of chronic pain are additional arguments in favour of regional anaesthetic techniques. However, qualifications apply to the evaluation of these outcomes, mostly related to equivocal evidence, and a small or unclear effect size. Regional analgesia can cause permanent neurological damage, but the risk is extremely small.

It is the author's opinion that the advantages of regional analgesia overcome the risks. However, the last decision belongs to the patient. Informed consent with a full discussion of the risks and benefits is an essential precondition for the performance of combined anaesthesia techniques.

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Research agenda

Research on the influence of regional analgesia on perioperative outcome is difficult to conduct, but it could have a high impact on healthcare in terms of optimization of patient treatment and reduction of social costs.

Although there is now reasonable material with which to evaluate the effect of epidural analgesia on perioperative morbidity, there is very little research on the similar role of peripheral nerve blocks. Because of the increasing use of the latter techniques, particularly in orthopaedic surgery, large randomized controlled trials are needed to evaluate their effect on perioperative morbidity, rehabilitation and long-term restoration of function. So far, these outcomes have been mainly reported by studies that primarily have outcomes from the acute postoperative period, such as pain reduction or opioid consumption. Future studies need to be powered with long-term outcomes as main endpoints.

Chronic pain after surgery remains a largely unresolved issue. Future randomized controlled studies should differentially analyse the types of surgery that typically induce chronic pain and identify the optimal perioperative analgesic regimens that reduce its development. An effective preventive regimen for chronic postoperative pain could have an enormous impact on patients' quality of life, healthcare and social costs.

The influence of regional analgesic techniques on cancer recurrence is a priority of future research that needs to be addressed by large randomized controlled trials. If the available preliminary data are confirmed by such trials, the perioperative management of cancer surgery would undergo a revolution.

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anaesthesia; analgesia; cancer; complications; epidural; morbidity; mortality; pain; postoperative; regional

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