This article is accompanied by the following Invited Commentary:
De Hert S. Cardiac troponins and volatile anaesthetics in on-pump coronary surgery. How much longer do we need to state the obvious? Eur J Anaesthesiol 2016; 33:393–395.
Coronary artery disease is one of the leading causes of death and disability worldwide. For patients with multi-vessel coronary artery disease, the treatment of choice is coronary revascularisation by coronary artery bypass graft (CABG) surgery. Several factors, which include the ageing population, an increase in co-morbidities such as diabetes, hypertension and renal failure, and the growing need for concomitant valve surgery are responsible for increasing the risk of patients undergoing CABG surgery. The consequence of this is a higher risk of perioperative myocardial injury (PMI) and a poorer clinical outcome. The process of reperfusion can itself cause myocardial injury. Currently there is no effective therapeutic intervention to protect the heart against ischaemia–reperfusion injury (IRI). Novel cardioprotective therapies are, therefore, required to protect the heart against acute global IRI to limit the extent of PMI, preserve cardiac function and improve morbidity and mortality in this patient group. In this regard, volatile anaesthetics such as isoflurane, sevoflurane and desflurane, when used in animal studies, have been reported to protect the myocardium against acute IRI by reducing the size of the myocardial infarct. But whether volatile anaesthetics are cardioprotective in the clinical setting of CABG surgery, during which the heart is subjected to acute global IRI, has not been resolved.1 A substantial number of clinical trials have used surrogate markers of cardioprotection such as serum cardiac enzymes [creatine kinase type MB (CK-MB), troponin T (cTnT), troponin I,(CtnI)] to quantify the extent of PMI sustained during surgery. The magnitude of PMI can be quantified by measuring perioperative levels of serum cardiac enzymes such CK-MB,2 troponin-T3,4 or troponin-I,5,6 the release of which has been associated with poorer clinical outcomes following CABG surgery. Newall et al.7 found that a rise in serum CK-MB isoenzyme of three to six times the upper reference limit (URL) [hazard ratio (HR) 2.1] and a rise of six or more times the URL (HR 5.0) were independently associated with increased 1-year mortality. Croal et al.5 found that 24-h serum levels of troponin-I were independently predictive of mortality at 30 days [odds ratio (OR) 1.14 per 10 g l−1], 1 year (OR 1.14 per 10 g l−1) and at 3 years (OR 1.07 per 10 g l−1). Soraas et al.8 reported that serum levels of troponin-T measured at 7, 20 and 44 h were independently predictive of long-term mortality (HR 1.31). Finally, Wang et al.4 found that an increase in high-sensitive troponin-T at 12 to 24 h of more than 10 times the 99th percentile URL with ECG and/or echocardiographic criteria of myocardial infarction predicted 30-day (HR 4.92) and medium-term mortality (HR 3.44).
The majority of these studies have shown that volatile anaesthetics attenuate PMI compared with non-volatile anaesthesia. A number of meta-analyses have confirmed this cardioprotective effect of volatile anaesthetics, though they probably lack sufficient power, and the effect of volatile anaesthetics on clinical outcomes has been inconclusive. A large adequately powered prospective randomised control trial is required to conclude whether, compared with non-volatile anaesthesia, volatile anaesthesia can improve clinical outcomes in patients undergoing CABG surgery. We have undertaken a systematic review of peak serum cardiac troponin levels in those clinical studies that have investigated the cardioprotective effect of volatile anaesthetics in elective CABG surgery using PMI as the end point. Troponin was chosen as a surrogate marker because it is a sensitive marker of myocardial damage.9 Whether off-pump coronary artery surgery poses a different intraoperative myocardial ischaemic threat to on-pump surgery is unclear.10 This has not previously been assessed with respect to the effect of volatile anaesthetics on PMI.
Because of the substantial number of meta-analyses that have been performed there is an increased risk of a type-1 error arising from repetitive testing and analysis of the sparse data.11 We undertook a trial sequential analysis (TSA) to overcome this problem of repeated meta-analyses.12
The overall objective of our study was to demonstrate that clinical studies investigating the cardioprotective effect of volatile anaesthetics, as measuered with serum cardiac enzymes in CABG patients, are no longer warranted. Secondly, in a subpopulation of patients we investigated the cardioprotective effect of volatile anaesthetics on serum cardiac enzymes in off-pump cardiac surgery.
We conducted a systematic literature search for all relevant randomised clinical trials in all languages. Relevant trials between January 1985 and March 2015 were obtained from the following sources: electronic databases [Medline and Excerpta Medica (EMBASE) EMBASE], the Cochrane Controlled Trial Register, abstracts in major journals related to anaesthesia and cardiac surgery and reference lists of relevant randomised trials and review articles. The following Medical Subject Headings electronic search was conducted in Medline using a search string, modified from Bignami et al.13
Inclusion and exclusion criteria
We included all trials of adult patients undergoing: CABG surgery including both on-pump and off-pump, CABG in combination with valve replacement/repair and one congenital heart surgery trial. All three authors independently screened all of the abstracts produced by the searches to identify eligible studies. Trials not using cardiopulmonary bypass, off-pump (OPCAB) or minimally invasive direct angioplasty coronary procedures (MIDCAB), were selected for a separate meta-analysis and were not included in the meta-analysis of peak postoperative troponin release after CABG with volatile anaesthetics.
Studies were included irrespective of the timing or interval of the volatile anaesthetic used for cardioprotection. No subgroup analyses of volatile administration were conducted. Previous studies show that there were no significant differences between the pre, per or postoperative administration of volatile anaesthetics and end points such as myocardial ischaemia, troponin-I level and length of ICU stay.1 Halothane and enflurane studies were excluded because they were considered not to reflect current clinical practice, thus restricting inclusion to isoflurane, desflurane and sevoflurane studies. Those studies that did not include both a volatile anaesthetic group and a non-volatile control group were excluded. Valve surgery alone was omitted since this group is heterogeneous with regard to myocardial ischaemia. Remote ischaemic pre-conditioning as a comparator was also excluded. We excluded trials not reporting data in the English language only after we obtained no response to our questions from the authors. In studies in which there was more than one volatile or non-volatile group, the volatile groups were combined and the non-volatile groups were combined for the pooled analyses.
The Jadad scale14 was used to quantify individual study quality (validity) using five criteria (one point each): proper randomisation, double blind, withdrawals documented, randomisation adequately described and blinding adequately described. The Jadad score is an instrument to assess the quality of reports of randomised controlled trials (RCTs) and it was used to assess the risk of high or low probability of bias, which in turn was used to meet the requirements for the TSA.
This study focused entirely on examining the peak postoperative release of cardiac troponins (both cTnI and cTnT), as this reflects the extent of PMI and because the clinical presentation of ischaemia shows considerable heterogeneity in the surrogate markers (clinical signs, ST-segment change, etc.). For studies where the median and range were reported, mean and SD were estimated by using the O’Rourke method15 whereby the median was used as the estimate of the mean and the SD was a quarter of the range (SD equals the interquartile range multiplied by 1.35). To standardise cTnT and cTnI measurements to allow pooling of data, cardiac troponin-T concentration was converted to troponin-I concentration using a conversion factor of 3.076 (2/0.65), based on the ratio of the upper limit of their respective reference ranges, as has previously been used.1 A forest plot was performed using the pooled troponin means and SD to form an estimate of standardised mean difference.
Under the fixed effects model, it is assumed that the studies share a common true effect, and the summary effect is an estimate of the common effect size. Under the random effects model, the true effects in the studies are assumed to vary between studies and the summary effect is the weighted average of the effects reported in the different studies.16 The random effects model will tend to give a more conservative estimate (with wider confidence interval), but the results from the two models usually agree when there is no heterogeneity. When heterogeneity is present, the random effects model is the preferred model.
I2 is the percentage of observed total variation across studies, that is, because of real heterogeneity rather than chance. It was calculated as I2 = 100% × (Q − df) Q−1, where Q is Cochran's heterogeneity statistic, and df the degrees of freedom. Negative values of I2 are put equal to zero so that I2 lies between 0 and 100%. A value of 0% indicates no observed heterogeneity, and larger values show increasing heterogeneity.17 We used MedCalc Statistical Software version 15.2.2 (MedCalc Software bvba, Ostend, Belgium; http://www.medcalc.org; 2014) in the collation, analysis, interpretation and presentation of data.
Trial sequential analysis
Repeated updates (sequential multiplicity) and sparse data increase the risk of random error.18 TSA is a method of meta-analysis that aims to correct for this increased risk.12, 19–21 Similar to monitoring boundaries for interim analyses in single trials, TSA provides an estimate of the required information size (RIS) for meta-analysis combined with monitoring boundaries used as thresholds for statistical significance. TSA also provides an early prediction when an intervention is unlikely to have an important effect (‘futility boundaries’).
The less data accumulated, the more conservative the TSA boundaries, making it less probable that statistical significance is declared before the RIS has been reached. Similar to a sample size calculation for a single trial, estimating RIS involves a calculation that includes type-1 error, type-2 error, the control event proportion and the effect size. The calculation for RIS also requires an estimate of heterogeneity; if more heterogeneity is present RIS increases.22 In the current TSA, we estimated the RIS using 0.05 for type-1 error, 0.20 for type-2 error and the control event proportions calculated from the non-volatile anaesthetic groups in all included trials. The effect size was estimated from the included trials with a low risk of bias, derived from the Jadad scale evaluation.
We used the D2 (diversity)23 present in the included trials as the estimate for heterogeneity. The TSA is interpreted by examining the boundaries and whether the cumulative meta-analysis (Z-score line) has crossed them. Web-based free TSA analysis software used in the current study was obtained from the Copenhagen Trials Unit (http://www.ctu.dk/tools-and-links/trial-sequential-analysis.aspx).
Retrieved and analysed trials
Our literature search from January 1985 to March 2015 combined with the studies included in Symons’ and Myles’ original meta-analysis,1 identified 75 studies eligible for inclusion and detailed assessment. Of these, seven were excluded, as they were non-human studies, leaving 68. Of these, a further six were not randomised controlled trials, leaving 62 RCTs for analysis. Off-Pump Coronary Artery Bypass (OPCAB) or Minimally Invasive Direct Coronary Artery Bypass (/MIDCAB) was used in 11 trials,24–34 which were then isolated for a separate meta-analysis. One other MIDCAB study was excluded because of missing mean/median.35 Other studies excluded dealt with congenital heart disease36 (1), heart valve replacement (2 atrial, 2 mitral),37–40 non-cardiac procedures41–46 (6), stenting47,48 (2), and 1 trial was a direct comparison (isoflurane vs. sevoflurane) with no non-volatile comparator.49 Of the remaining 37 studies, for three there was no English language data even after direct communication with the authors (Russian,50,51 Turkish52), and four had remote ischaemic pre-conditioning, or no non-volatile comparator, or no relevant cardiac troponin outcomes were reported.53–56 This left 30 studies57–86 with 2578 patients to be included in the meta-analysis. Figure 1 is a flow chart illustrating this process.
The Jadad scores evaluating the validity of the included trials are given in Tables 1 and 2. Trials with a Jadad score of 3 or above were included in the TSA of on-pump CABG surgery, whereas scores less than 3 were excluded from the TSA.
Volatile anaesthetics during on-pump coronary artery bypass graft: meta-analysis
The meta-analysis (Fig. 2 and Table 3) resulted in a significant outcome favouring volatile anaesthetic use (at all times; iso, sevo and desflurane) over non-volatile anaesthetic during on-pump CABG surgery with respect to peak postoperative cardiac troponin-I serum levels [fixed effects −0.551 mg l−1 standardised mean difference (95% confidence interval (CI), −0.633 to −0.469; P < 0.001); random effects −0.995 mg l−1 standardised mean difference (95% CI, −1.316 to −0.673; P < 0.001)]. Back conversion to troponin-T1 corresponds to −306.15 ng l−1 (95% CI, −404.92 to −207.07). The test for heterogeneity (I2) showed significant inconsistency in the 30 analysed randomised clinical trials (92.41%) (95% CI, 90.24 to 94.10), indicating that the random effects result above should be chosen over the fixed effects model when interpreting the results.
Volatile anaesthetics during off-pump coronary artery bypass graft: meta-analysis
Eleven RCTs were analysed separately from the main meta-analysis, because they consisted of an intervention-control comparison of peak postoperative troponin levels after OPCAB or MIDCAB procedures (Fig. 3 and Table 4). The test for heterogeneity (I2) showed significant inconsistency in the 11 analysed trials (85.64%) (95% CI, 76.06 to 91.39) indicating that the random effects result should be chosen over the fixed effects model. The meta-analysis did not reach a statistically significant level favouring either non-volatile (control), or volatile anaesthetic (intervention) with respect to peak postoperative cardiac troponin-I serum levels. Random effects −0.385 mg l−1 standardised mean difference (95% CI, −0.857 to 0.087).
Trial sequential analysis
In the futility analysis 6 trials were ignored by the software application in the interim analyses because of low quality according to their Jadad score (<0.1%) Belhomme et al. (1999),57 De Hert et al. (2002),60 Nader et al. (2004),63 Kawamura et al. (2006),70 Amr et al. (2010)79 and Sirvinskas et al. (2015).84 The cumulative Z-score shows, that the RIS is 1072 patients, the point at which the Z-line crosses the 0.05% significance boundary for accumulated test results under due α-spending limitations. The futility boundary for the current study was achieved at 3018 patients (Fig. 4).
Trial sequential analysis, OPCAB/MIDCAB
No trials were ignored in interim looks by the software application because of low information use (<0.1%) in the futility analysis. The required information size was estimated to be 1442 patients (Fig. 5).
The major findings of our study are that our meta-analysis shows that volatile anaesthetics, when used in elective coronary artery bypass graft surgery, reduce postoperative peak serum cardiac troponin enzyme levels by approximately 8% compared with non-volatile anaesthesia. The effect is seen in on-pump but not in off-pump bypass surgery. The novel aspect of this report is the analysis of the results of 11 OPCAB/MIDCAB studies (n = 593 study participants). However, data in this meta-analysis were not sufficiently powered to assess the influence of volatile anaesthetics on peak postoperative cTnI and cTnT.
The pooled TSA of on-pump CABG shows conclusively that no further trials evaluating surrogate markers of ischaemia are necessary, because the RIS is approximately 1000 patients and this was reached in late 2006. Thus, further investigation of this question appears unnecessary, as the current level of clinical evidence has almost attained futility. However, further investigations appear warranted for volatile anaesthetics in off-pump CABG surgery where RIS is estimated to be 1442 patients, a higher number than for on-pump CABG because of inconsistency in the findings of the available studies.
Volatile anaesthetic conditioning (VAC) has been repeatedly put forward as a means of mitigating the irreversible myocardial injury sustained by acute ischaemia and reperfusion. The anti-ischaemic effects of volatile anaesthetics were first proposed in 1976 by Bland and Lowenstein,87 who found evidence that experimental myocardial ischaemia in canine hearts was reduced by halothane. In 1997, two groups working independently of each other, first proposed the pharmacologic concept of preconditioning with the volatile anaesthetic, isoflurane.88,89 Volatile anaesthetics consistently appear to be superior to intravenous anaesthetics with regard to experimental myocardial protection but, several decades after it was first proposed, clinical VAC remains divisive. A large adequately powered prospective RCT is still required to determine whether volatile anaesthesia compared with non-volatile anaesthesia can improve clinical outcomes in patients undergoing CABG surgery. The relative reduction in peak postoperative enzyme release carries with it no immediate clinical significance; however, it remains a surrogate marker for morbidity and mortality in patients undergoing open heart surgery.90–93
The use of volatile anaesthetics in coronary stenting procedures has not been sufficiently investigated. A recent study found that sevoflurane administration during primary percutaneous coronary intervention did not reduce infarct size but there was a trend towards its reduction among patients with anterior myocardial ischaemia. Sevoflurane was associated with improvement in ST-segment resolution.48
Postoperative troponin levels increase after virtually all open heart surgery. They not only reflect myocardial infarction but also myocardial cell injury caused by reperfusion, surgical trauma, defibrillation and operation time. Lehrke et al.90 found that a cTnT concentration more than 0.46 μg l−1 48 h postoperatively was associated with a 6.7-fold higher long-term risk for subsequent cardiac death and an 11-fold higher risk for severe postoperative heart failure requiring mechanical support. In addition, Fellahi et al.92 found that a high postoperative peak cTnI (23.8 mg ml−1; range, 13.4 to 174.6) was associated with increased long-term mortality and mortality from cardiac causes.
Lowering the peak troponin-T level by 300 ng l−1 should, therefore, be expected to achieve clinically relevant reductions in morbidity and mortality. Nevertheless, factors such as cardiac function, clinical signs and length of ICU stay should continue to be used in the overall evaluation of VAC.
Some researchers argue that the true VAC effect results in 30 to 40% reductions if enzyme release is plotted over time (area-under-the-curve) and that this is a better estimate of PMI because it better quantifies the extent over that particular period.94
No attempt was made to compare within-group volatile anaesthetics because the pooled data were too sparse. There could be differences between the anaesthetics used to prevent irreversible myocardial injury as some experimental results have suggested that isoflurane might be more effective than sevoflurane in this respect, This is despite differences in relative potency. More comparative trials would be needed to resolve this and other relevant issues such as the questions of dose response, timing and duration of volatile anaesthetic exposure. The result of the meta-analysis did not take into account the considerable heterogeneity associated with these factors. Conversely, experimental VAC indicates that even low doses of volatile agents can have an effect.95,96
A recent Bayesian network meta-analysis supports the hypothesis that volatile anaesthetics are superior to TIVA-based anaesthesia in improving survival after cardiac surgery, but the data could not support the theory that one volatile agent was more beneficial than another.97 The overall results of that meta-analysis are statistically fragile as there were only 68 deaths, and statistical significance was reached only by combining all volatile agents and comparing them with total intravenous anaesthesia.
The current analysis contains the potential weaknesses inherent in meta-analysis. Being able to pool many smaller studies increases the power of the analyses, but varied clinical practices and lack of uniformity of definition and reporting of end points limit the certainty of our findings. The TSA analysis is an attempt to adjust for this using a more conservative estimate.
Interpretation of our findings should take into account the different practices with regard to anaesthesia, surgery and ICU management of CABG patients between the various institutions and the way that techniques have developed. Much has changed since 1985 in regard to surgical technique and intraoperative and postoperative care. It is probable that clinical and technical advances have reduced postoperative myocardial injury and with it the amount of total troponin released, minimising the difference between groups. This uncertainty is best resolved by a large prospective randomised trial to establish the true role of volatile anaesthetic agents in myocardial protection. We believe such a trial is warranted, and recommend that common end point definitions should be established. An important multi-centre RCT that promises to be adequately powered is currently underway.98 As for the estimate of the benefit in terms of outcome, we expect about a 10% troponin reduction, so a 2 to 3% mortality reduction does not seem improbable in the current trial. This statement is based on a reduction of 2 to 300 ng l−1 (cTnT) relative to the control group, so in conclusion, a reduction in both morbidity and mortality could surely be expected in a trial of over 1000 patients.
The result of the current analyses cannot be extrapolated from elective CABG to valve surgery or to emergency bypass surgery, since Jakobsen et al.99 found in a retrospective study of 10,535 patients, that overall mortality was reduced by volatile anaesthetics in elective surgery, but not in emergency surgery, probably because of haemodynamic instability.
The relative reduction in myocardial infarct size is less than the 50 to 60% reduction often reported in laboratory studies.100–102 This could be because of factors such as the age, comorbidity and the use of extracorporeal circulation. Guidelines have been drawn up to address the lack of animal disease models used to assess these factors.102 Although the mechanisms of action remain unclear, volatile anaesthetics act in similar ways to ischaemic pre-conditioning by activating a number of known mechanisms, including intracellular salvage kinase pathways, endothelial nitric oxide production, modulation of calcium homeostasis and prevention of mitochondrial permeability transition pore opening.100 Overall, the effects of volatile anaesthetics in pre-conditioning are triggered by multiple pathways, and this has been reviewed elsewhere.95,96,103
There is an overlap between our meta-analysis and that of Symons and Myles and their 10 included studies. Of our included studies, 15 were published in or after 2006. Also, we made a separate analysis of OPCAB/MIDCAB procedures and excluded studies with combined CABG and valve surgery, and those using halothane and enflurane. The present study is larger and more adequately powered with regard to troponin than Symons, and Myles’ 2006 analysis.
In conclusion, we have shown that a systematic review, meta-analysis and TSA of all existing clinical CABG trials point unquestionably towards a reduction in the level of serum markers of myocardial injury by volatile anaesthetics. Moreover, the total amount of existing evidence supporting our conclusion goes beyond adequacy, and further studies will be futile. This achieves the overall objective of our study-to demonstrate that clinical studies investigating the cardioprotective effect of volatile anaesthetics on serum cardiac enzymes in CABG patients are no longer warranted. This provides support for the notion that a large prospective randomised trial, investigating the effect of volatile anaesthetics on clinical outcomes, should be a priority. Meanwhile, the potential effect of volatile anaesthetics in OPCAB/MIDCAB procedures still needs to be clarified.
Acknowledgements related to the article
Assistance with the analyses: none.
Financial support and sponsorship: none.
Conflicts of interest: none.
Presentation: preliminary data was presented as a poster and an oral presentation at the annual meeting of DASAIM (Danish Association of Anaesthesiology and Intensive Care Medicine) in 2014.
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