The three search strings described in Box 18.1 identified 362, 355, and 1,092 results, respectively. After a careful screening, nine studies [5–13], dealing with seven different interventions, were included in the present update. The summary of new evidences at the end of this chapter reports the main characteristics of the selected papers.

Three interventions not already selected by the Consensus Conference have been found to possibly improve survival: miniaturized extracorporeal circulation (MECC) [5], non-adrenergic vasopressors [6], and perioperative goal-directed hemodynamic therapy (GDHT) [7]. The other six papers dealt with four interventions already present in the Consensus Conference Update: volatile agents [8], perioperative intra-aortic balloon pump (IABP) [9, 10], levosimendan [11, 12], and remote ischemic preconditioning (RIPC) [13].

Eight out of nine studies were set in cardiac surgery [5, 6, 8–13]. Two papers focused on a mixed population (i.e., surgical and medical) [6, 13]. All the selected papers were meta-analyses of RCTs; one of them included also observational studies which were analyzed separately [10], and two were network meta-analyses [5, 8]. All selected papers dealt with intervention that showed a positive effect on survival.

Coronary artery bypass grafting is associated with a reduction of mortality in extensive coronary artery disease. The gold standard technique is the CABG with the use of cardiopulmonary bypass (CPB). Nevertheless conventional extracorporeal circulation (CECC) is believed to be a major determinant for postoperative morbidity. Consequently novel solutions have been developed to reduce its impact, such as off-pump CABG (OPCAB) and MECC. Miniaturized extracorporeal circulation reduces the air-blood contact using a shorter circuit and no venous reservoir: therefore, it lowers blood loss and need for transfusions and minimizes inflammatory response.

Kowalewski et al. [5] conducted a network meta-analysis comparing the effect of these three strategies on mortality and postoperative complications. They selected 134 RCTs, enrolling 22,778 patients. Data on mortality were extracted from 50 RCTs (17,638 patients). MECC and OPCAB were associated with a significant reduction of all-cause mortality (OR (95 % CI), 0.46 (0.22–0.91), and 0.75 (0.51–0.99)) when compared with CECC. These techniques offered a significantly higher protection against cerebral stroke, postoperative atrial fibrillation, and renal dysfunction, while no significant differences among three strategies were seen in regard to myocardial infarction. No significant difference between OPCAB and MECC was observed from direct comparison, but the hierarchy of numerical treatments emerging from the probability inference analyses was MECC >OPCAB >CECC.

Previous observational studies and meta-analyses reported increased long-term mortality with OPCAB. Selection bias seems to be the obvious explanation for the discrepancies between observational and randomized strata. Patients included in the OPCAB group were more likely to be at higher baseline risk.

The main limitations of this work are that the authors did not have access to individual patients’ data and that the number of event observed was small.

Non-adrenergic vasopressors are a group of drugs that are used in hemodynamic shock in association with or instead of catecholamines. Their use reduces catecholamines side effects, such as increased myocardial oxygen consumption and arrhythmias. Moreover, they are essential in the treatment of late-phase shock, when standard treatment became ineffective.

Belletti et al. conducted an extensive meta-analysis, including twenty RCTS (1,608 patients), to investigate the effect on mortality of non-adrenergic vasopressor in vasodilatory shock [6]. The intervention agents were vasopressin, terlipressin, and methylene blue. The comparators were placebo, standard treatment, norepinephrine, and dopamine. Most of the selected studies were performed in the setting of sepsis (10/20) and in the setting of cardiac surgery (7/20). Overall pooled analysis showed that the use of non-adrenergic vasopressors was associated with a significant mortality reduction (RR (95 % CI): 0.88 (0.79–0.98), p = 0.02). Considering the study drugs independently, all agents were associated with a nonsignificant trend toward improved survival of the same direction and magnitude. When analyzing different settings, non-adrenergic vasopressors were found to reduce mortality both in sepsis (RR (95 % CI): 0.87 (0.77–0.98), p = 0.02) and cardiac surgery (RR (95 % CI): 0.16 (0.04–0.69), p = 0.01). The authors speculate that the survival benefit observed might be a consequence of their catecholamine-sparing effect, rather than a beneficial effect per se.

Goal-directed hemodynamic therapy (GDHT) is the use of a hemodynamic optimization algorithm that aims to achieve normal or supranormal hemodynamic values, through fluids, vasopressors, and inotropes. This implies the use of more or less invasive hemodynamic monitoring. The objective is to prevent hypoperfusion and imbalance between oxygen delivery and consumption.

Ripollés-Melchor and colleagues [7] conducted a meta-analysis of RCTs to assess whether this approach reduces complications and mortality compared to conventional fluid therapy in noncardiac surgery patients. Studies where GDHT was limited to the intraoperative period were excluded. Twelve RCTs and 1,527 patients were included. Mortality was analyzed in all RCTs included and was significantly reduced by perioperative GDHT (RR (95 % CI): 0.63 (0.42–0.94), p = 0.02). In subgroup analyses, mortality was reduced only when a supranormal target was set (RR (95 % CI): 0.42 (0.23–0.76), p = 0.004) and when perioperative GDHT was performed (RR (95 % CI): 0.61 (0.39–0.96), p = 0.03). No significant difference in the complication rate was detected. In sensitivity analysis, authors found that if studies with lower methodological quality were excluded, there were no differences between GDHT and standard fluid therapy.

Volatile agents are among the few interventions that might reduce perioperative mortality [3, 4], probably through their ability to mimic the early phase of ischemic preconditioning.

Here we sum the results of the only meta-analysis published since the Consensus Conference Update, while details on this intervention are discussed in a dedicated chapter (Chap. 4).

Zangrillo et al. [8] performed a Bayesian network meta-analysis to assess whether the cardioprotective properties of volatile agents and of RIPC have survival effects in patients undergoing cardiac surgery. To be included, the studies had to compare TIVA to a combined plan including the administration of a volatile agent and/or to include the comparison between the use of RIPC and not. A total of 55 RCTs were selected, randomizing 6,921 patients, of whom 39 % (in 50 studies) received volatile agents, 37 % (in 41 studies) received TIVA, 13 % (in 7 studies) received RIPC+TIVA, and 11 % (in 15 studies) received RIPC+volatile agents. The most common pairwise comparison was volatile agents versus TIVA, present in 34 (62 %) of the selected studies. Through simple direct comparison, volatile agents significantly reduced mortality when compared to TIVA (OR (95 % CI): 0.56 (0.36–0.88), p = 0.01). This advantage was maintained when the Bayesian hierarchical model was used (OR (95 % CI): 0.50 (0.28–0.91)). As discussed later on this chapter, the Bayesian network meta-analysis assessed an additive positive effect of volatile agents and RIPC when compared to TIVA with or without RIPC.