The leading indication for lower extremity amputation (LEA) in the United States is peripheral vascular disease, primarily in the older person with diabetes mellitus complicated by peripheral neuropathy, ulcers, gangrene or osteomyelitis. Generally, these patients are at a high-risk for poor postoperative outcomes because of their old age, sepsis and multiple medical comorbidities (such as ischaemic heart disease, renal impairment and stroke). Consequently, LEA has been associated with 30-day postoperative mortality rates that are as high as 7-32%.
In theory, regional anaesthesia (RA) may confer some advantages over general anaesthesia (GA). For example, RA may result in less hypotension, bleeding, venous thromboembolism, surgical stress and pulmonary complications. For this reason, in the recent years, a number of studies have examined whether RA is associated with lower 30-day postoperative mortality when compared to GA for patients undergoing LEA.
This pooled analysis was performed to determine if RA reduces the 30-day mortality of patients undergoing LEA surgery, when compared to GA.
This review followed the recommendations outlined in the Cochrane handbook for systematic reviews and was reported according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. The protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) (registration number CRD42021231265).
An electronic search was conducted using the following databases from January 2010 to August 2021: PubMed, Embase, Scopus and Cochrane Central Register of Controlled Trials. No language restrictions were applied. All publications including conference abstracts were included in the initial search. The search used key terms such as “anesthesia”, “lower extremity” and “amputation”. The details of the search strategy are available in the Appendix 1. The reference lists of all included studies were manually searched to identify other studies which were eligible for inclusion.
Two reviewers (NP and SQ) independently reviewed the titles and abstracts of all search entries to exclude irrelevant studies. The full text of the remaining studies was further examined for inclusion based on the inclusion and exclusion criteria. Disagreements about the study eligibility were arbitrated by another author (CL).
The inclusion criteria were studies involving:
- Population: adult patients (>18 years old) undergoing non-traumatic LEA
- Intervention: RA (central neuraxial and/or peripheral nerve block)
- Comparator: GA
- Outcome (primary): 30-day mortality
- Studies that involved any ongoing trials, children, animals, combined GA/RA technique and LEA for trauma/malignancy were excluded.
Two reviewers (NP, SQ) independently assessed the quality of each included study. The Newcastle-Ottawa Scale (NOS), an instrument for assessing the quality of non-randomised studies, was used to assess for bias. This scale contains eight items within three domains (selection, comparability and outcomes). NOS scores of 7-9, 4-6 and 0-3 indicate that the studies are of high quality, high risk of bias and very high risk of bias, respectively. The level of evidence was assessed in accordance to the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) system. As all of the included studies were retrospective in nature, the evidence for each outcome was initially graded as low. The grade was then upgraded or downgraded based on the risk of bias, imprecision, inconsistency, indirectness and publication bias. Any disagreement was resolved through consultation with another author (CL). The NOS and GRADE tables may be found in the Appendix 2 and 3.
Two reviewers (NP, SQ) independently extracted data into a standardised template created using Microsoft Excel version 2016 (Redmond: Microsoft Corporation, 2015). The following data was collected from each study: author names, publication year, study design, sample size, characteristics of study participants, type of intervention, 30-day mortality, 90-day mortality, intensive care unit (ICU) admission, length of stay, cardiovascular outcomes, respiratory outcomes, stroke, renal failure, vasopressor use, wound complications, bleeding and blood transfusion. Any disagreements were resolved through consultation with another reviewer (CL).
Statistical analyses were performed using the Review Manager (RevMan) software version 5.3. (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014) and R Studio software Version 1.2.1335 (Boston: R Studio Inc, 2018). Only studies that utilised propensity-score matched outcomes were pooled. Continuous data were compared using mean differences and 95% confidence intervals (CIs). If studies reported the variables in median and interquartile range, the Box-Cox method was used to estimate the sample mean and standard variance. Dichotomous data were pooled and analysed using the Mantel-Haenszel odds ratio with 95% CIs. Random effects model was applied to all pooled data. The Higgin’s I2 test was used to estimate the degree of statistical heterogeneity. I2 of <40%, 30-50%, 50-75% and 75-100% were considered to represent non-important, moderate, substantial and considerable heterogeneity, respectively. Funnel plots for the primary outcome were constructed and visually inspected to evaluate for the risk of publication bias.
Study selection and characteristics
A total of 1082 studies were identified during the initial search. After the removal of 435 duplicate studies, 649 titles and abstracts were screened. Thirty-two studies were identified for full-text review, of which 19 studies were excluded as they did not fulfil the inclusion criteria. Another three studies were excluded because their study population were derived from the same National Surgical Quality Improvement Program database. To avoid double-counting, the study with the larger sample size was used. Ten studies were included in the review [Figure 1].
All of the studies that were included in this review were retrospective observational studies that examined the impact of anaesthetic technique on 30-day mortality and perioperative outcomes in adult patients undergoing LEA. These studies were conducted between 2013 and 2018. Eight studies were restricted to patients undergoing major LEA, while two studies involved patients undergoing major and minor LEA. Six studies compared GA with either peripheral nerve blocks or central neuraxial anaesthesia. Three studies compared GA with central neuraxial anaesthesia alone, and one study compared GA with peripheral nerve blocks alone. Eight out of 10 studies were assessed to be of high quality on the NOS [Table 1].
1.30-day Mortality after LEA
The overall incidence (GA and RA groups) of 30-day mortality following LEA ranged from 3.7% to 15%. Out of the 10 studies, two did not control for confounders. The rest of the studies utilised either multivariate logistic regression or propensity score matching to adjust for confounders. With the exception of one study which was reported by SA Khan et al., all of the eight studies that controlled for confounders reported no significant benefit of RA over GA in reducing the incidence of 30-day mortality after LEA [Table 2].
A meta-analysis was performed using the results of the four studies which utilised propensity score matching. A funnel plot constructed to investigate publication bias showed a symmetrical distribution [Figure 2] and no important heterogeneity was observed among the studies. Based on these four studies which involved 6647 patients (of whom, 1933 received RA), the use of RA did not result in a significant reduction in incidence of 30-day mortality following LEA (odds ratio (OR) 0.83, 95% CI: 0.65, 1.05, I2 20%, P = 0.12) [Figure 3]. This evidence was graded as low.
It was postulated that the impact of RA may be greater in patients undergoing major LEA (defined as amputation above the ankle joint) as major LEA is associated with higher mortality rates when compared to minor LEA. As such, a subgroup analysis was performed with studies that looked only at patients undergoing major LEA. Two studies involving 2570 patients (of whom, 1015 received RA) were included in this subgroup meta-analysis which found that RA significantly reduced 30-day mortality compared to GA (OR 0.73; 95% CI (0.57, 0.94), I2 0%, P = 0.01). See Figure 3 (forest plot).
2.90-day Mortality after LEA
90-day mortality was reported in two propensity-matched studies. Individually, neither study found a significant difference in the 90-day mortality with the use of either RA or GA. A meta-analysis including the two studies also showed no difference in the 90-day mortality with the use of RA (OR 0.78; 95% CI (0.57,1.07), I2 0%, P = 0.13) [Figure 4]. This evidence was graded as low. A summary of all relevant secondary outcomes, including 90-day mortality, may be found in Table 3.
3.Hospital length of stay
Six studies reported the length of hospital stay (H-LOS). There is some evidence that H-LOS is shorter in patients who received RA compared to GA. Three studies reported a statistically significant shorter H-LOS with the use of RA with mean differences ranging between 3.7 to 5 days.
4.Intensive care unit admission
There is limited evidence that RA is associated with reduced ICU admission. The admission rate to ICU following LEA was about 8%. Two studies reported ICU admission as an outcome measure. Both these studies reported a significantly lower ICU admission (by 52.1% and 84%) in the RA group compared to the GA group. Among the patients who were admitted to the ICU, RA and GA were associated with similar durations of ICU stay.
Cardiac outcomes appear to be similar between the RA and GA groups. Six out of seven studies reported no differences in the incidences of myocardial infarction between the RA and GA groups. A study by Dittman et al. found a small but statistical increase in the incidence of myocardial infarction in patients who received RA for above-knee amputation. The reason for this is unclear and may represent a chance error. Two further studies examined composite cardiac outcomes and were unable to detect a statistically significant benefit of RA over GA.
There is evidence that RA does not result in reduced incidences of pneumonia, pulmonary embolism, prolonged ventilation, hypoxia and unplanned intubation. A study utilising a composite pulmonary outcome yielded similar results.
There is evidence that RA does not result in increase in cerebrovascular accidents. Five studies reported no association between the choice of anaesthesia and cerebrovascular accidents. A meta-analysis performed on two propensity-matched studies involving a total of 1,962 patients showed that RA and GA were associated with similar incidences of cerebrovascular accidents. (OR 1.45; 95% CI (0.57, 3.70), I2 0%, P = 0.44) [Figure 4]. This evidence was graded as very low.
There is very low evidence that RA does not reduce renal failure. Five studies examined the association between RA and renal failure. None of them found an association between RA and decrease in incidence of renal failure. A meta-analysis of two propensity-matched studies showed that RA and GA were associated with similar incidences of renal failure (OR 1.27; 95%CI (0.73, 2.23), I2 0%, P = 0.4) [Figure 4]. This evidence was graded as low.
9.Blood loss and blood transfusion
Five studies reported blood transfusion and one reported blood loss. None of these studies show a difference between the RA and GA groups.
Consistent with the published literature, this study found that LEA is associated with a high mortality. The main finding of this study is that RA, when compared to GA, does not appear to reduce the incidence of 30-day and 90-day mortality following LEA. However, one study pointed out that in the high risk patients, there might be a benefit of RA over GA in terms of reducing the 30-day mortality.
There is also evidence that RA is not associated with reduced cardiac, neurological, renal and bleeding complications after LEA. However, some studies have found that RA is associated with a lower H-LOS and ICU admission rate. But since these studies were not designed to assess H-LOS and ICU admission rates, these findings should be considered exploratory rather than definitive. Further studies are required to understand the impact of RA on H-LOS and ICU admission.
The strength of this study is that, it is the first review that has examined this clinical question. The studies included in this review had large sample sizes and looked at an objective outcome measure. Most of the studies scored well on the NOS, an instrument to assess the risk of bias in non-randomised trials. Across most of the outcome measures, the results were fairly homogenous. Although this review included only observational studies, the role of observational studies should not be downplayed when studying a harmful outcome. Randomised controlled trials, while useful for the examination of efficacy, may not be as useful for determining the rates of adverse events. This is due to the low frequency of events, small number of participants, restrictive inclusion/exclusion criteria and short follow-up periods. Furthermore, it is considered unethical to randomise patients to a study that is evaluating a harmful outcome. In this context, this review presents the best level of evidence till date on this topic.
The major limitation of this review is that while many studies adjusted for confounders, not all utilised a propensity score-matching technique. Hence, some of the studies were not pooled in the meta-analysis. Moreover, the results of secondary outcomes such as 90-day mortality, H-LOS and ICU admission should be interpreted with caution. Nevertheless, the results from these papers appear to have fairly uniform results in the primary and secondary outcome measures. This strengthens our confidence that the assessment is accurate. Another limitation is that most studies reported both peripheral and central neuraxial anaesthesia as RA. Since, peripheral nerve blocks result in less physiological derangement than central neuraxial anaesthesia, future studies that compare peripheral nerve blocks to GA may possibly give rise to opposing results from this review.
Taken together, during the informed consent process, patients should not be routinely counselled that RA reduces the risk of mortality. The choice of the anaesthesia technique should be individualised based on factors such as patient comorbidities, presence of a bleeding diathesis, haemodynamic stability, patient preference etc. It is nevertheless, still reasonable to offer RA to reduce the risk of ICU admission, reduce opioid consumption, reduce pain scores and prevent chronic pain.
LEA is a commonly performed surgery that carries significant mortality and morbidity. In this study, RA was not found to reduce the 30-day mortality after LEA when compared to GA. There is very low level of evidence that RA may decrease hospital length of stay and ICU admission rates
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Conflicts of interest
There are no conflicts of interest.
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