Local anaesthetic adjuncts for peripheral regional anaesthesia: a narrative review.

Moderate-to-severe postoperative pain persists for longer than the duration of single-shot peripheral nerve blocks and hence continues to be a problem even with the routine use of regional anaesthesia techniques. The administration of local anaesthetic adjuncts, defined as the concomitant intravenous or perineural injection of one or more pharmacological agents, is an attractive and technically simple strategy to potentially extend the benefits of peripheral nerve blockade beyond the conventional maximum of 8-14 hours. Historical local anaesthetic adjuncts include perineural adrenaline that has been demonstrated to increase the mean duration of analgesia by as little as just over 1 hour. Of the novel local anaesthetic adjuncts, dexmedetomidine and dexamethasone have best demonstrated the capacity to considerably improve the duration of blocks. Perineural dexmedetomidine and dexamethasone increase the mean duration of analgesia by up to 6 hour and 8 hour, respectively, when combined with long-acting local anaesthetics. The evidence for the safety of these local anaesthetic adjuncts continues to accumulate, although the findings of a neurotoxic effect with perineural dexmedetomidine during in-vitro studies are conflicting. Neither perineural dexmedetomidine nor dexamethasone fulfils all the criteria of the ideal local anaesthetic adjunct. Dexmedetomidine is limited by side-effects such as bradycardia, hypotension and sedation, and dexamethasone slightly increases glycaemia. In view of the concerns related to localised nerve and muscle injury and the lack of consistent evidence for the superiority of the perineural vs. systemic route of administration, we recommend the off-label use of systemic dexamethasone as a local anaesthetic adjunct in a dose of 0.1-0.2 mg.kg-1 for all patients undergoing surgery associated with significant postoperative pain.

Intra-operative analgesia with remifentanil vs. dexmedetomidine: a systematic review and meta-analysis with trial sequential analysis.

Intra-operative remifentanil is associated with increased postoperative analgesic requirements and opioid consumption. Dexmedetomidine has characteristics suggesting it may substitute for intra-operative remifentanil during general anaesthesia, but existing literature has reported conflicting results. We undertook this meta-analysis to investigate whether general anaesthesia including dexmedetomidine would result in less postoperative pain than general anaesthesia including remifentanil. The MEDLINE and PubMed electronic databases were searched up to October 2018. Only randomised trials including patients receiving general anaesthesia and comparing dexmedetomidine with remifentanil administration were included. Meta-analyses were performed mostly employing a random effects model. The primary outcome was pain score at rest (visual analogue scale, 0-10) at two postoperative hours. The secondary outcomes included: pain score at rest at 24 postoperative hours; opioid consumption at 2 and 24 postoperative hours; and rates of hypotension, bradycardia, shivering and postoperative nausea and vomiting. Twenty-one randomised trials, including 1309 patients, were identified. Pain scores at rest at two postoperative hours were lower in the dexmedetomidine group, with a mean difference (95%CI) of -0.7 (-1.2 to -0.2), I2  = 85%, p = 0.004, and a moderate quality of evidence. Secondary pain outcomes were also significantly better in the dexmedetomidine group. Rates of hypotension, shivering and postoperative nausea and vomiting were at least twice as frequent in patients who received remifentanil. Time to analgesia request was longer, and use of postoperative morphine and rescue analgesia were less, with dexmedetomidine, whereas episodes of bradycardia were similar between groups. There is moderate evidence that intra-operative dexmedetomidine during general anaesthesia improves pain outcomes during the first 24 postoperative hours, when compared with remifentanil, with fewer side effects.

Analgesic impact of intra-operative opioids vs. opioid-free anaesthesia: a systematic review and meta-analysis.

Opioids are administered peri-operatively for postoperative analgesia, and intra-operatively to control the sympathetic response to surgical stimuli, frequently as a surrogate for presumed pain. However, opioid use during surgery is a matter of dispute in contemporary practice and carries the risk of side-effects such as postoperative nausea and vomiting. This meta-analysis investigated whether opioid-inclusive, compared with opioid-free anaesthesia, would reduce postoperative pain, without increasing the rate of postoperative nausea and vomiting. The electronic databases Medline and PubMed were searched until June 2018. We included trials investigating pain outcomes and comparing any type of intra-operative opioid administration with placebo injection or no intra-operative opioid. Most meta-analyses were performed using a random effects model. We rated the quality of evidence for each outcome. The primary outcome was pain score at rest (analogue scale, 0-10) at two postoperative hours. Our secondary outcomes included the rate of postoperative nausea and vomiting within the first 24 postoperative hours and length of stay in the recovery area. Twenty-three randomised controlled trials, including 1304 patients, were identified. Pain scores at rest at two postoperative hours were equivalent in the opioid-inclusive and opioid-free groups with a mean difference (95%CI) of 0.2 (-0.2 to 0.5), I2 = 83%, p = 0.38 and a high quality of evidence. Similarly, there was high-quality evidence that the rate of postoperative nausea and vomiting was reduced in the opioid-free group, with a risk ratio (95%CI) of 0.77 (0.61-0.97), I2 = 16%, p = 0.03 and high-quality evidence for a similar length of stay in the recovery area, the mean difference (95%CI) being 0.6 (-8.2 to 9.3), min, I2 = 60%, p = 0.90. As there is strong evidence that opioid-inclusive anaesthesia does not reduce postoperative pain, but is associated with more postoperative nausea and vomiting, when compared with opioid-free anaesthesia, we suggest that anaesthetists should reconsider their intra-operative opioid choices on a case-by-case basis.

Comparison of peripheral nerve blockade characteristics between non-diabetic patients and patients suffering from diabetic neuropathy: a prospective cohort study.

Animal data have demonstrated increased block duration after local anaesthetic injections in diabetic rat models. Whether the same is true in humans is currently undefined. We, therefore, undertook this prospective cohort study to test the hypothesis that type-2 diabetic patients suffering from diabetic peripheral neuropathy would have increased block duration after ultrasound-guided popliteal sciatic nerve block when compared with patients without neuropathy. Thirty-three type-2 diabetic patients with neuropathy and 23 non-diabetic control patients, scheduled for fore-foot surgery, were included prospectively. All patients received an ultrasound-guided popliteal sciatic nerve block with a 30 ml 1:1 mixture of lidocaine 1% and bupivacaine 0.5%. The primary outcome was time to first opioid request after block procedure. Secondary outcomes included the time to onset of sensory blockade, and pain score at rest on postoperative day 1 (numeric rating scale 0-10). These outcomes were analysed using an accelerated failure time regression model. Patients in the diabetic peripheral neuropathy group had significantly prolonged median (IQR [range]) time to first opioid request (diabetic peripheral neuropathy group 1440 (IQR 1140-1440 [180-1440]) min vs. control group 710 (IQR 420-1200 [150-1440] min, p = 0.0004). Diabetic peripheral neuropathy patients had a time ratio of 1.57 (95%CI 1.10-2.23, p < 0.01), experienced a 59% shorter time to onset of sensory blockade (median time ratio 0.41 (95%CI 0.28-0.59), p < 0.0001) and had lower median (IQR [range]) pain scores at rest on postoperative day 1 (diabetic peripheral neuropathy group 0 (IQR 0-1 [0-5]) vs. control group 3 (IQR 0-5 [0-9]), p = 0.001). In conclusion, after an ultrasound-guided popliteal sciatic nerve block, patients with diabetic peripheral neuropathy demonstrated reduced time to onset of sensory blockade, with increased time to first opioid request when compared with patients without neuropathy.

Intravenous dexamethasone for prophylaxis of postoperative nausea and vomiting after administration of long-acting neuraxial opioids: a systematic review and meta-analysis.

Long-acting neuraxial opioids provide excellent analgesia after surgery, but are associated with higher rates of postoperative nausea and vomiting. Dexamethasone effectively prevents postoperative nausea and vomiting after general anaesthesia, but its value in patients receiving long-acting neuraxial opioids is undetermined. Therefore, the objective of this meta-analysis was to assess the prophylactic anti-emetic efficacy of intravenous (i.v.) dexamethasone in this population. The study methodology followed the PRISMA statement guidelines. The primary outcome was the need for rescue anti-emetics during the first 24 postoperative hours, analysed according to the dose of dexamethasone (low-dose 2.5-5.0 mg; intermediate dose 6.0-10.0 mg), timing of administration (beginning or end of surgery) and route of long-acting opioid administration (intrathecal or epidural). Additionally, the rates of complications (restlessness, infection, hyperglycaemia) were sought. Thirteen trials were identified, representing a total of 1111 patients. When compared with placebo, intravenous dexamethasone reduced the need for rescue anti-emetics (risk ratio (95%CI) 0.44 (0.35-0.56); I2 = 43%; p < 0.00001; quality of GRADE evidence: moderate), without differences between dexamethasone doses (p for sub-group difference = 0.67), timing of administration (p for sub-group difference = 0.32) or route of long-acting opioid (p for sub-group difference = 0.10). No patients developed infection or restlessness among trials that sought these complications. No trial measured blood glucose levels. In conclusion, there is enough evidence to state that intravenous dexamethasone provides effective anti-emetic prophylaxis during the first 24 postoperative hours in patients who receive long-acting neuraxial opioids.

Analgesic efficacy of local infiltration analgesia vs. femoral nerve block after anterior cruciate ligament reconstruction: a systematic review and meta-analysis.

Many published reports consider blockade of the femoral nerve distribution the best available analgesic treatment after anterior cruciate ligament reconstruction. However, some argue that an alternative approach of infiltrating local anaesthetic into the surgical site has similar efficacy. The objectives of this meta-analysis were to compare the analgesic and functional outcomes of both treatments following anterior ligament reconstruction. The primary outcomes were pain scores at rest (analogue scale, 0-10) in the early (0-2 postoperative hours), intermediate (3-12 hours) and late postoperative periods (13-24 hours). Secondary outcomes included range of motion, quadriceps muscle strength and complication rates (neurological problems, cardiovascular events, falls and knee infections). Eleven trials, including 628 patients, were identified. Pain scores in the early, intermediate and late postoperative periods were significantly lower in patients who received a femoral nerve block, with mean differences (95%CI) of 1.6 (0.2-2.9), p = 0.02; 1.2 (0.4-1.5), p = 0.002; and 0.7 (0.1-1.4), p = 0.03 respectively. The quality of evidence for our primary outcomes was moderate to high. Regarding functional outcomes, only one trial reported a similar range of motion between groups at 48 postoperative hours. No trial sought to record complications. In conclusion, femoral nerve block provides superior postoperative analgesia after anterior cruciate ligament reconstruction to local infiltration analgesia. The impact of improved analgesia on function remains unclear due to the lack of reporting of functional outcomes in the existing literature.

Efficacy of perineural vs systemic dexamethasone to prolong analgesia after peripheral nerve block: a systematic review and meta-analysis.

Perineural dexamethasone has gained popularity in regional anaesthesia to prolong the duration of analgesia, but its advantage over systemic administration is disputed. The objective of this meta-analysis was to compare the analgesic efficacy of both routes of administration during peripheral nerve block. The methodology followed the PRISMA statement guidelines. The primary outcome was the duration of analgesia analysed according to the type of local anaesthetic administered (bupivacaine or ropivacaine). Secondary outcomes included cumulative opioid consumption in morphine i.v. equivalents, pain scores, and complication rates (neurological complications, infection, or hyperglycaemia). Eleven controlled trials, including 914 patients, were identified. The duration of analgesia was significantly increased with perineural dexamethasone vs systemic dexamethasone by a mean difference of 3 h [95% confidence interval (CI): 1.4, 4.5 h; P=0.0001]. Subgroup analysis revealed that the duration of analgesia was increased by 21% with bupivacaine (mean difference: 4.0 h; 95% CI: 2.8, 5.2 h; P<0.00001) and 12% with ropivacaine (mean difference: 2.0 h; 95% CI: -0.5, 4.5 h; P=0.11). The quality of evidence for our primary outcome was moderate according to the GRADE system. There were no significant differences in other secondary outcomes. No neurological complications or infections were reported. Glucose concentrations were not increased when dexamethasone was injected systemically, but this outcome was reported by only two trials. There is, therefore, moderate evidence that perineural dexamethasone combined with bupivacaine, but not ropivacaine, slightly prolongs the duration of analgesia, without an impact on other pain-related outcomes, when compared with systemic dexamethasone. Injection of perineural dexamethasone should be cautiously balanced in light of the off-label indication for this route of administration.

The analgesic efficacy of sciatic nerve block in addition to femoral nerve block in patients undergoing total knee arthroplasty: a systematic review and meta-analysis.

The aim of this meta-analysis was to assess the postoperative analgesic efficacy of sciatic nerve block when combined with femoral nerve block after total knee arthroplasty. Outcomes included resting pain scores (analogue scale, 0-100), intravenous morphine consumption at 12 h, 24 h and 48 h postoperatively, and functional outcomes comprising knee flexion, distance walked, and length of stay. Twelve randomised controlled trials were included, with a total of 600 patients. When combined with femoral nerve block, sciatic nerve block significantly reduced resting pain scores at 12 h postoperatively with a mean difference of 10 (95% CI: -15 to -5; p < 0.00001). Resting pain scores at 24 h, and intravenous morphine consumption at 12 h, 24 h and 48 h postoperatively were also significantly reduced, but without clinical significance beyond 12 h and without affecting functional outcomes. In conclusion, sciatic nerve block confers additional postoperative analgesia within the first 12 postoperative hours compared with femoral nerve block alone for patients undergoing total knee arthroplasty.

The analgesic efficacy of local infiltration analgesia vs femoral nerve block after total knee arthroplasty: a systematic review and meta-analysis.

Many consider femoral nerve block the gold standard in pain management following knee arthroplasty. Local infiltration analgesia is an alternate approach that applies the concept of surgical wound infiltration with local anaesthetics. This meta-analysis aims to compare both analgesic treatments for analgesia and functional outcomes after total knee arthroplasty. This meta-analysis was performed according to the PRISMA statement guidelines. The primary outcomes were cumulative i.v. morphine consumption, pain scores at rest and on movement on postoperative day one (analogue scale,0-10). Secondary outcomes included range of motion, quadriceps muscle strength, length of stay and rates of complications (neurologic events, cardiovascular events, falls and knee infections). Fourteen trials, including 1122 adult patients were identified. There was no difference in i.v. morphine consumption (mean difference: -2.0 mg; 95% CI: -4.9, 0.9 mg; I(2)=69%; P=0.19), pain scores at rest (mean difference: -0.1; 95% CI: -0.4, 0.3; I(2)=72%; P=0.80) and pain scores on movement (mean difference: 0.2; 95% CI: -0.5, 0.8; I(2)=80%; P=0.64) on postoperative day one (a negative mean difference favours local infiltration analgesia). The qualities of evidence for our primary outcomes were moderate according to the GRADE system. There were no clinical differences in functional outcomes or rates of complications. Complication rates were captured by three trials or fewer with exception of knee infection, which was sought by eight trials. Local infiltration analgesia provides similar postoperative analgesia after total knee arthroplasty to femoral nerve block. Although this meta-analysis did not capture any difference in rates of complications, the low number of trials that specifically sought these outcomes dictates caution.

A systematic review of ultrasound-guided methods for brachial plexus blockade.

We systematically reviewed 25 randomised controlled trials of ultrasound-guided brachial plexus blockade that recruited 1948 participants: either one approach vs another (axillary, infraclavicular or supraclavicular); or one injection vs multiple injections. There were no differences in the rates of successful blockade with approach, relative risk (95% CI): axillary vs infraclavicular, 1.0 (1.0-1.1), p = 0.97; axillary vs supraclavicular, 1.0 (1.0-1.1), p = 0.68; and infraclavicular vs supraclavicular, 1.0 (1.0-1.1), p = 0.32. There was no difference in the rate of successful blockade with the number of injections, relative risk (95% CI) 1.0 (1.0-1.0), p = 0.69, for one vs multiple injections. The rate of procedural paraesthesia was less with one injection than multiple injections, relative risk (95% CI) 0.6 (0.4-0.9), p = 0.004.

A systematic review and meta-analysis of perineural dexamethasone for peripheral nerve blocks.

We systematically reviewed the safety and efficacy of perineural dexamethasone as an adjunct for peripheral nerve blockade in 29 controlled trials of 1695 participants. We grouped trials by the duration of local anaesthetic action (short- or medium- vs long-term). Dexamethasone increased the mean (95% CI) duration of analgesia by 233 (172-295) min when injected with short- or medium-term action local anaesthetics and by 488 (419-557) min when injected with long-term action local anaesthetics, p < 0.00001 for both. However, these results should be interpreted with caution due to the extreme heterogeneity of results, with I2 exceeding 90% for both analyses. Meta-regression did not show an interaction between dose of perineural dexamethasone (4-10 mg) and duration of analgesia (r2 = 0.02, p = 0.54). There were no differences between 4 and 8 mg dexamethasone on subgroup analysis.

Peri-operative intravenous administration of magnesium sulphate and postoperative pain: a meta-analysis.

Intravenous magnesium has been reported to improve postoperative pain; however, the evidence is inconsistent. The objective of this quantitative systematic review is to evaluate whether or not the peri-operative administration of intravenous magnesium can reduce postoperative pain. Twenty-five trials comparing magnesium with placebo were identified. Independent of the mode of administration (bolus or continuous infusion), peri-operative magnesium reduced cumulative intravenous morphine consumption by 24.4% (mean difference: 7.6 mg, 95% CI -9.5 to -5.8 mg; p < 0.00001) at 24 h postoperatively. Numeric pain scores at rest and on movement at 24 h postoperatively were reduced by 4.2 (95% CI -6.3 to -2.1; p < 0.0001) and 9.2 (95% CI -16.1 to -2.3; p = 0.009) out of 100, respectively. We conclude that peri-operative intravenous magnesium reduces opioid consumption, and to a lesser extent, pain scores, in the first 24 h postoperatively, without any reported serious adverse effects.

The analgesic efficacy and safety of neuraxial magnesium sulphate: a quantitative review.

Eighteen published trials have examined the use of neuraxial magnesium as a peri-operative adjunctive analgesic since 2002, with encouraging results. However, concurrent animal studies have reported clinical and histological evidence of neurological complications with similar weight-adjusted doses. The objectives of this quantitative systematic review were to assess both the analgesic efficacy and the safety of neuraxial magnesium. Eighteen trials comparing magnesium with placebo were identified. The time to first analgesic request increased by 11.1% after intrathecal magnesium administration (mean difference: 39.6 min; 95% CI 16.3-63.0 min; p = 0.0009), and by 72.2% after epidural administration (mean difference: 109.5 min; 95% CI 19.6-199.3 min; p = 0.02) with doses of between 50 and 100 mg. Four trials monitored for neurological complications: of the 140 patients included, only a 4-day persistent headache was recorded. Despite promising peri-operative analgesic effect, the risk of neurological complications resulting from neuraxial magnesium has not yet been adequately defined.