Perioperative regional anaesthesia and postoperative longer-term outcomes

Regional anaesthesia provides effective anaesthesia and analgesia in the perioperative setting. Central neuraxial blocks—that is, spinal and epidural blocks—are well established as an alternative or adjunct to general anaesthesia. Peripheral blocks may be used as part of multimodal anaesthesia/analgesia in perioperative practice, reducing the need for opioid analgesics and enhancing early recovery. Furthermore, regional anaesthesia has increased in popularity and may be done with improved ease and safety with the introduction of ultrasound-guided techniques. The effects of local anaesthetics and regional anaesthesia on long-term outcomes such as morbidity, mortality, the quality of recovery beyond the duration of analgesia, and whether it can expedite the resumption of activities of daily living are less clear. It has also been suggested that regional anaesthesia may impact the risk of metastasis after cancer surgery. This article provides an overview of current evidence around quality of recovery, risk for delirium, long-term effects, and possible impact on cancer disease progression associated with the clinical use of local and regional anaesthetic techniques. In summary, there is still a lack of robust data that regional anaesthesia has a clinical impact beyond its well-acknowledged beneficial effects of reducing pain, reduced opioid consumption, and improved quality of early recovery. Further high-quality prospective studies on long-term outcomes are warranted.

The effect of local anaesthesia on nerve conductivity has a long history. Modern amide local anaesthetics are reassuringly safe, providing dose-dependent, reversible nerve conduction blockade. The beneficial effects of regional anaesthesia on postoperative pain are well known. Local anaesthesia may be administered by local infiltration, peripheral nerve block, or central neuraxial block depending on what effects are sought. Local infiltration anaesthesia is simple and safe. Peripheral nerve blocks are increasingly popular because of ultrasound techniques, which provide enhanced visualisation of its performance. The positive effects on postoperative pain and reduced opioid consumption are well acknowledged. There are recent reviews of upper-extremity blocks 1 , lower-extremity blocks 2 , and abdominal-wall blocks 3 that demonstrate these effects. There may not be a major difference between local infiltration and peripheral nerve blocks for the management of postoperative pain in the first 24 hours following some surgical procedures (for example, total hip replacement 4 ) in contrast to total knee arthroplasty (TKA), where wide variability in postoperative pain scores is documented. In a Cochrane meta-analysis, Chan et al. supported the use of regional anaesthesia for postoperative analgesia following TKA 5 . In May 2016, Hu et al. published a meta-analysis showing that the two techniques were similarly effective for early pain management following TKA 6 .
There is also increasing interest in the systemic effects of local anaesthetics. The potential beneficial effect of local anaesthesia on inflammation and immune function has long been suggested. In 2000, Hollmann and Durieux 7 had already addressed the potential anti-inflammatory effects of local anaesthetics, reviewing the literature on local anaesthetic effects on the inflammatory response and especially on inflammatory cells (mainly polymorphonuclear granulocytes but also macrophages and monocytes) 8 . The exact mechanisms of action are not clear but seem to involve a reversible interaction with membrane proteins and lipids, thus regulating cell metabolic activity, migration, exocytosis, and phagocytosis 9,10 . The clinical anti-inflammatory effect of intravenous lidocaine is today reasonably well documented. The beneficial effects of intravenous lidocaine on recovery have been described; this technique has been shown to reduce the time to return of bowel function and shorter hospital stay after abdominal surgery 11 . The most recent metaanalysis, published in 2016 12 , supports the beneficial effects on pain but calls for further studies, as the quality of evidence was limited as a result of trial heterogeneity and small sample sizes. There are also several studies looking at the potential effect of local anaesthetics on immune function [13][14][15] . The findings of these studies have not necessarily been shown to have clinical significance and have yet to be translated into routine clinical practice.

Central blocks, epidural and spinal anaesthesia, and morbidity and mortality in general surgery
Neuraxial blocks are widely used in addition or as an alternative to general anaesthesia for general surgery as well as for postoperative pain management. The beneficial effects during the early phase of recovery are well documented. A recent meta-analysis comparing general anaesthetic with epidural and general anaesthetic with opioid analgesia showed improved pain control and bowel function in the epidural and general anaesthesia group 16 . The impact of regional anaesthesia on longer-term outcomes has become of increasing interest 17 . An overview of Cochrane systematic reviews of neuraxial blockade for the prevention of postoperative mortality and major morbidity found weak evidence for reduced mortality and pneumonia in high-risk patients who received neuraxial anaesthesia 18 . There is still a lack of evidence to show a difference in morbidity and mortality between regional anaesthesia and general anaesthesia for urological and vascular surgery 19,20 . In 2014, Popping et al. published a meta-analysis supporting the use of combined general and epidural anaesthesia, since epidural analgesia reduced mortality and improved a multitude of cardiovascular, respiratory, and gastrointestinal morbidity endpoints compared with patients receiving systemic analgesia 21 . However, this article had numerous limitations, including certain methodological flaws and the inclusion of unpublished data.

Regional anaesthesia and orthopaedic surgery
In a meta-analysis published in 2013, Barbosa et al. found no significant long-term benefit associated with regional anaesthesia as compared with general anaesthesia for orthopaedic surgery 22 . Memtsoudis et al. found that regional anaesthesia reduced the risk of major complications in a subset of patients with obstructive sleep apnoea undergoing joint arthroplasty in comparison with patients who received combined neuraxial and general or general anaesthesia alone (16.0%, 17.2%, and 18.1%, respectively; P = 0.0177) 23 .
However, the benefits associated with epidural anaesthesia have been questioned. The quality of studies included in meta-analyses is low and some of the positive effects are merely dependent on single studies in high-risk patients 24 . The potential benefit on morbidity and mortality from regional anaesthesia for acute femoral fracture repair surgery has also recently been challenged. Neuman et al. showed shorter hospital stay but no difference in mortality 25 . Seitz et al. showed regional anaesthesia to be associated with similar mortality but a lower need for intensive care unit admission compared with general anaesthesia in older adults with dementia who underwent surgery for hip fracture repair 26 . Brox et al. found one-year mortality to be only marginally lower in patients with neuraxial anaesthesia compared with general anaesthesia (odds ratio (OR) = 0.84, confidence interval (CI) 0.70-1.0) but to be similar in patients with combined regional and general anaesthesia (OR = 1.3, CI 0.70-2.3) 27 . White et al. likewise found no difference in mortality associated with neuraxial block or general anaesthesia but emphasised the importance of maintaining adequate blood pressure 28 . In February 2016, Johnson et al. published a meta-analysis of neuraxial anaesthesia compared with general anaesthesia for hip or knee arthroplasty (or both) showing no significant differences in any outcomes studied: mortality, surgical duration, surgical site or chest infections, nerve palsies, postoperative nausea and vomiting, or thromboembolic disease when anti-thrombotic prophylaxis was used 29 . Thus, regional anaesthesia provides effective early postoperative analgesia and is a valid alternative to general anaesthesia. The effects on early postoperative pain are well documented, but its impact beyond the early period and effects on major morbidity and mortality are not obvious.

Regional anaesthesia and delirium
Postoperative delirium (PD) is commonly seen in the elderly. The risk in the elderly having orthopaedic surgery has been reported to be around 17% with huge variability 30 . The impact of anaesthetic technique on early PD and more long-lasting cognitive deficits such as postoperative cognitive dysfunction (POCD) has been under scrutiny for decades. In 1995, Williams-Russo et al. 31 compared epidural and general anaesthesia in 262 patients undergoing elective primary total knee replacement with a median age of 69 years. The type of anaesthesia-general or neuraxial-did not affect the magnitude or pattern of POCD. The International Study of Postoperative Cognitive Dysfunction (ISPOCD) group 32 published the results of a multi-centre study assessing POCD and the impact of anaesthetic technique, general anaesthesia versus regional anaesthesia. Early testing (one week postoperatively) showed a higher incidence among patients having general anaesthesia, but no difference was noted at 3 months. In 2010, Mason et al. conducted a meta-analysis and found no impact of anaesthetic technique on the risk for PD, but general anaesthesia was found to have a small, non-significant association with an increased rate of POCD (OR = 1.34, CI 0.93-1.95) 33 . There was no evidence of publication bias. Davis et al. came to a similar conclusion in a meta-analysis published in 2014; of 16 included studies, 13 showed no difference and three showed some minor effect 34 . There is a need for further high-quality studies, and there are ongoing studies on this topic.

Regional anaesthesia and quality of recovery
The impact of regional anaesthesia on the quality of recovery, as assessed by objective multi-dimensional tools (for example, Quality of Recovery 15 or Postoperative Quality of Recovery score), beyond the early postoperative phase is sparsely studied. Catro-Alves et al. compared spinal anaesthesia and general anaesthesia for elective hysterectomy and assessed recovery by using the global quality of recovery-40 questionnaire (QoR-40) up to 48 hours after surgery but not beyond 35 . The beneficial effects on pain and quality of early recovery were confirmed. Liu et al. conducted a study amongst elderly patients undergoing knee arthroplasty in general anaesthesia or peripheral block and followed intraoperative and postoperative course up to day 7 with the Postoperative Quality of Recovery Scale (PostopQRS) tool 36 . The intraoperative and early postoperative course favoured the block technique, but at day 7 no difference was found. Resumption of activities of daily living and patient satisfaction were similar between the two groups.

Regional anaesthesia and cancer
There is considerable interest in whether local anaesthetics and regional anaesthesia may impact cancer progression and recurrence. The potential mechanisms by which cancer progression may be influenced include attenuation of the surgical stress response, reduced pain and opioid requirements, and also the direct action that some local anaesthetics may have on cancer cells. It is also suggested that local anaesthetics and regional anaesthesia may have an effect on immune function and inflammation. There are studies assessing immune function in the experimental setting 37 . Despite mounting in vitro data suggesting positive effects 38,39 , in vivo studies and well-designed human trials are lacking 40 . The clinical relevance of these results must be interpreted with great caution and cannot necessarily be directly translated into human clinical practice. Several recent articles have raised the question of whether anaesthetic technique and drug choice could influence long-term tumour progression 41,42 . However, these articles are retrospective analyses of studies designed to address a different clinical question. In 2006, Exadaktylos et al. published a retrospective study suggesting that paravertebral block in combination with general anaesthesia for primary breast cancer surgery could reduce the risk for tumour progression as compared with standard anaesthesia and postoperative opioids for pain management 43 . In 2014, however, a Cochrane systematic review concluded that the evidence is insufficient to make any firm recommendations 44 .
Although regional anaesthesia provides effective early postoperative analgesia and promotes enhanced recovery, there is insufficient data to promote a change in clinical practice in order to affect cancer progression 45-48 . We await results from ongoing studies to better define the role of anaesthesia for patients with cancer 49 .

Conclusions
Regional anaesthesia is effective at reducing pain and opioid consumption during the early postoperative phase. The impact of regional anaesthesia on the risk for cognitive side effects of surgery, PD, and POCD seems minor. Data on the effects of local anaesthesia, local infiltration, and regional anaesthesia on quality of recovery assessed by multi-domain tools are sparse. The documentation around long-term outcomes and the potential beneficial effects on morbidity and mortality is also weak, and further highquality studies are warranted. The potential effect on cancer progression is not proven. There are several ongoing prospective randomised studies that may help define whether regional anaesthesia techniques could not only provide effective postoperative pain but also impact cancer progression. However, it should be acknowledged that the number of patients needed to have sufficient power to show any potential significant effect is large, such studies are expensive, and long follow-up times are required.
Competing interests JJ declares that he has no competing interests in relation to this article. MZJ declares that he has no competing interests.
Grant information JJ has received research grants from and taken part in advisory boards for Abbott, Baxter, AstraZeneca, Pfizer, MSD, and Marquette and acts as safety physician for Linde Healthcare.
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.