One of the most frequent life-threatening nosocomial infection in patients undergoing cardiac surgery is VAP (ventilator-associated pneumonia), which is associated with 15–45 % [10, 11] (or even higher) [12] rate of mortality. Since oropharyngeal secretions contaminated with nosocomial organisms are the major route for lower respiratory tract invasion [13–15], the use of an antiseptic drug for oral decontamination seemed to be a promising intervention to reduce the incidence of VAP. Chlorhexidine’s antimicrobial activity, together with its capability of binding to mucosal proteins, makes its use as oral rinses interesting.

The only randomized evidence reporting a mortality reduction from oral rinse with chlorhexidine was that by DeRiso et al. in cardiac surgical patients admitted to ICU [13]. In this RCT comparing patients receiving chlorhexidine gluconate 0.12 % oral rinse with placebo, the group randomized to receive treatment showed a mortality rate significantly lower than the ones receiving placebo (mortality rate of 1.16 % in the chlorhexidine group, 5.56 % in the placebo group, p < 0.05). Although this RCT suggested that 0.12 % chlorhexidine gluconate might reduce perioperative mortality in patients undergoing cardiac surgery, other studies investigating the role of chlorhexidine oral rinse failed to demonstrate a significant mortality reduction.

Klompas et al. conducted a systematic review and meta-analysis which concluded that even if chlorhexidine oral care reduces the incidence of hospital-acquired pneumonia in cardiac surgery patients, in noncardiac surgery settings, it does not decrease the incidence of VAP [16]. Authors concluded that the role of chlorhexidine oral care should be reevaluated.

Furthermore a recent network meta-analysis by Price et al. demonstrated that both oropharyngeal and digestive selective decontamination were superior to chlorhexidine for mortality prevention in intensive care units [17]. This study also highlighted a possible detrimental effect on survival related to topical oropharyngeal chlorhexidine, since its use was associated with an increase in mortality (odds ratio 1.25, 1.05–1.50). An important limitation about this evidence, contrasting with previous findings, is that in the studies considering the effect of chlorhexidine on mortality, mortality was not the primary outcome.

During the Consensus Conference update held in 2015, only 64.1 % of participants agreed about the survival benefit of chlorhexidine oral rinse, and this topic was therefore excluded.

Oxygen is a drug routinely administered during the perioperative period. Supplemental oxygen is a possible strategy to maintain an adequate DO₂, together with respiratory support, hemodynamic optimization, blood administration, temperature management, and adequate analgesia [18]. Moreover, oxygen tension exerts a key role in reducing surgical site infections [19]: hyperoxia increases the oxidative killing of bacteria by neutrophils [20–22], it helps wound healing enhancing tissues’ reparative processes, and it also activates the immune response due to the interaction with tumor necrosis factor α [22–24]. On the other hand, the prolonged exposure to high oxygen can cause some undesired effects, such as lung atelectasis, increased alveolar-capillary gradient, inflammation of the upper airways (especially in patients with chronic obstructive pulmonary disease), and an increase in systemic and coronary vascular resistances, probably attributable to ROS production, oxidative stress, and DNA damage [23–26].

The first Consensus Conference included perioperative supplemental oxygen among the drugs presenting a survival benefit. This conclusion was based on the meta-analysis performed by Brar et al., which didn’t attribute the result of mortality reduction to a statistically significant reduction in surgical site infection [27].

However, the recent RCT by Hayes et al., identified during the Consensus Conference Update, found a higher mortality in the group treated with a DO₂, maintained above the target level. The authors suggested that the DO₂ increase seemed anyway associated with a reduction in the oxygen-extraction ratio. Moreover, a more recent, large mRCT conducted in patients undergoing elective or emergency laparotomic surgery, and randomized to receive either 0.8 or 0.3 inspiratory oxygen fraction during the perioperative period, demonstrated an increased long-term mortality in the group randomized to receive 0.8 oxygen fraction [28]. Thus, since evidences on perioperative supplemental oxygen administration are contrasting, a clear mechanism of action is lacking, and the web vote by the Consensus Conference participants met low agreement (30.5 %), this topic was no more included in the Consensus Conference Update.

Clonidine is a commonly used α2-adrenergic agonist antihypertensive drug that may prevent myocardial infarction in patients at risk for cardiovascular complications, thanks to its analgesic, anxiolytic, anti-inflammatory, and anti-shivering effects [29–32]. Clonidine can also blunt surgical stress response, by the reduction of the central sympathetic outflow and the inhibition of the pre-junctional nerve catecholamine release [33, 34]. This pathophysiological basis was supported in the clinical practice by the results of small RCTs [29, 35, 36], meta-analysis of RCTs [37, 38], and a large quantitative systematic review [39], suggesting that in noncardiac surgery, the perioperative administration of low-dose clonidine may reduce mortality due to the prevention of myocardial ischemia. In the first Consensus Conference by Landoni et al., the authors suggested caution in the application of this strategy to general population, in view of reported episodes of hemodynamic instability attributable to clonidine administration. Furthermore, the only RCT finding a reduction in perioperative mortality with the use of clonidine was the work by Wallace et al. [40], which was considered too small and underpowered to make firm conclusions [41].

The POISE-2 investigators conducted a more recent mRCT [42], involving 10,010 patients in 135 centers in 23 countries, randomly comparing the administration of low-dose clonidine with placebo in patients undergoing noncardiac surgery. This study confirmed the safety concerns about hemodynamic instability, since significantly more patients in the clonidine group had clinically important hypotension. Furthermore, in the clonidine group, an increased rate of nonfatal cardiac arrest was noted. The POISE-2 trial also did not confirm the findings of improved outcome in terms of lower mortality and less myocardial infarction [34].