Search strategy for meta-analyses of RCTs
Systematic [sb.] AND (surgery [tiab] OR surgical* [tiab] OR operation* [tiab]) AND [(myocardial AND infarction) OR (death* OR survival OR mortality OR prognosis)] AND (prevent* OR reduction* OR reduce*)
Search strategy for RCTs
(Surgery [tiab] OR surgical* [tiab] OR operation* [tiab]) AND [(death* OR survival OR mortality)] AND (prevent* OR reduction* OR reduce*) AND (significant* OR significance*) AND (randomized controlled trial [pt] OR controlled clinical trial [pt] OR randomized controlled trials [mh] OR random allocation [mh] OR double-blind method [mh] OR singleblind method [mh] OR clinical trial [pt] OR clinical trials [mh] OR (clinical trial [tw] OR [(single* [tw] OR double* [tw] OR treble* [tw] OR triple* [tw]) AND (mask* [tw] OR blind [tw])] OR (Latin square [tw]) OR placebos [mh] OR placebo* [tw] OR random* [tw] OR research design [mh: noexp] OR comparative study [tw] OR follow-up studies [mh] OR prospective studies [mh] OR cross-over studies [mh] OR control* [tw] OR prospective* [tw] OR volunteer* [tw]) NOT (animal [mh] NOT human [mh]) NOT [(comment [pt] OR editorial [pt] OR meta-analysis [pt] OR practice-guideline [pt] OR review [pt])]
Throughout this process, we were able to document only evidences that had been published until the moment of the consensus. It is, therefore, important to implement and repeat this process on a regular basis.
Future updates will include papers fulfilling all the following criteria: [2]
1.
published in a peer-reviewed journal,
2.
randomized controlled trial (RCT) or meta-analysis of RCTs,
3.
dealing with a nonsurgical intervention (drug/technique/strategy) in adult patients undergoing any surgery, and
4.
providing a statistically significant reduction or increase in mortality.
There are at least nine recent papers (seven topics) fulfilling these criteria. The first one describes a new intervention that might improve survival (the blood volume analysis to guide fluid resuscitation in surgical patients with severe sepsis/septic shock) [3], while the others concern interventions already discussed in the original consensus paper. Three interventions might improve survival, i.e., levosimendan [4], tranexamic acid [5, 6], and intra-aortic balloon pump (IABP) [7, 8], while three might increase mortality, i.e., aprotinin [5], perioperative supplemental oxygen [9], and intensive insulin treatment (IIT) [10].
17.1 Blood Volume Analysis-Guided Resuscitation
The direct measurement of blood volume to guide shock resuscitation is limited by cumbersome technology. Blood volume analysis is a semi-automated technique for directly measuring blood volume. A medium-sized single-center RCT enrolled 100 patients and showed mortality reduction in critically ill surgical patients using blood volume analysis in addition to pulmonary artery catheter to guide shock resuscitation, instead of pulmonary artery catheter alone (mortality 85 vs. 26 %, p = 0.02) [3]. This particular method can be included among the techniques of hemodynamic optimization, which was already addressed in the Consensus Conference as a strategy that might improve perioperative survival. Anyway, the very specific setting of this trial makes it difficult to extend blood volume analysis to the generic surgical population.
17.2 Levosimendan
The consensus identified levosimendan as a drug that seems to reduce 30-day mortality in cardiac surgery on the basis of a meta-analysis [11]. However, caution was advised because statistical significance was lost when data were evaluated separately, and furthermore, bolus administration might cause hypotension.
Recently, another meta-analysis of the same group has been published [4]. It pooled together all RCTs, comparing levosimendan with controls with no context limitations. The overall mortality rate was 17.4 % among levosimendan-treated patients and 23.3 % in the control group (p < 0.001). Reduction in mortality was confirmed in studies with placebo or dobutamine as comparators and in studies performed in cardiac surgery or cardiology settings. A great contribution to establish whether levosimendan reduces mortality in the cardiac surgery setting will be given by an ongoing multicenter RCT (NCT00994825) that planned to enroll 1,000 high-risk patients undergoing cardiac surgery and randomized to receive a continuous infusion of either levosimendan or placebo.
17.3 Aprotinin
The Consensus Conference identified aprotinin as a drug that increases 30-day mortality in adult patients undergoing cardiac surgery. The statement was largely based on the results of BART trial [12] that have been recently challenged [13] because the study was not adequately powered for the endpoint of all-cause mortality and because partial thromboplastin time was significantly longer in the aprotinin treatment group, and less heparin was used in the aprotinin arm for unclear reasons. These considerations led both Health Canada and European Medicines Agency to reintroduce the drug on the market. However, Health Canada recognized that aprotinin might increase mortality; therefore, it recommended the use only “as authorized in isolated CABG surgery, after careful consideration of the potential risks and benefits” [14].
Later, a network meta-analysis tried to assess aprotinin effects on mortality [6], compared with other antifibrinolytics or no treatment in cardiac surgery. A significant increase in mortality was seen when aprotinin was compared with tranexamic acid (OR 0.64, 95 % CI, 0.41–0.99). No effect on mortality was seen when aprotinin was compared with ε-aminocaproic acid (OR 0.79, 95 % CI, 0.47–1.55) or with no treatment (OR 0.99, 95 % CI, 0.72–1.36). Moreover, the inclusion of observational data suggested that concerns remain about the safety of aprotinin in cardiac surgery. Further studies are probably needed to assess aprotinin impact on survival.
17.4 Tranexamic Acid
The use of tranexamic acid to reduce blood loss, the need of transfusion, and mortality was classified as a major exclusion by the Consensus Conference, because available evidence on mortality mainly concerned adult trauma patients [15].
Since the Consensus Conference, two meta-analyses have been published, showing a statistically significant improvement in mortality in surgical patients due to tranexamic acid.
The first is the network meta-analysis already discussed in the above section [6]. Tranexamic acid demonstrated a survival advantage only when compared with aprotinin, and no significant difference was seen when it was compared with no treatment or ε-aminocaproic acid. The second meta-analysis focused on the effect of tranexamic acid on surgical bleeding [5] and also pooled data on mortality. Fewer deaths occurred in the tranexamic acid group (RR 0.61, 95 % CI, 0.38–0.98; p = 0.04), but statistical significance was lost when the analysis was restricted to 28 trials with adequate concealment. Tranexamic acid significantly reduced the probability of receiving a blood transfusion as shown by a cumulative meta-analysis demonstrating how reliable evidence on this has been available for over 10 years.
Related posts:
The Risks and Benefits of the Consensus Process
Can Neuraxial Anesthesia Reduce Perioperative Mortality?
Role of Inhalational Anesthetic Agents in Reducing Perioperative Mortality
Leukocyte Depletion of Transfused Blood to Reduce Perioperative Mortality
The Process of Consensus Building
Role of Perioperative Hemodynamic Optimization in Reducing Perioperative Mortality
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