Objective

Experimental studies have demonstrated that endogenous nitric oxide bioavailability (NOb) is reno-protective against a range of injuries. In a swine model of extracorporeal circulation, the administration of Sildenafil prevented acute kidney injury (AKI) with an increase in NOb. REVAKI evaluates the pharmacokinetic profile of Sildenafil in cardiac surgery patients at risk of acute kidney injury and to determine the safety and tolerability of Sildenafil in cardiac surgery patients at risk of AKI.

Methods

36 patients, undergoing cardiac surgery with CPB, were allocated to 6x6 groups for different regime treatment in a single centre, dose escalation, phase I study. Sildenafil was given intravenously in a single bolus dose before cardiopulmonary bypass and a subsequent continuous dose for 2 hrs, depending on the treatment schedule (from 2.5mg to 10mg). Vital sign measurements and clinical laboratory assessments from screening until 96hr after drug administration were performed.

Results

Plasma levels of Sildenafil following administration at a bolus of 10mg followed by an infusion of 2.5mg over 2 hours were achieved in the first 10 mins, with CMAX and AUC 189.4 and 528.6 ng ml−1. The dose also produced a transient (5 min) drop in blood pressure, which was reversible by acutely acting vasoconstrictors (phenylephrine, ephedrine) that are routinely used to maintain mean arterial blood pressure within the desired range.

Conclusion

This trial demonstrated that Sildenafil can be administered to patients undergoing cardiopulmonary bypass; there were no severe adverse events attributable to Sildenafil identified during the study. Therefore Sildenafil may be safely used to protect cardiac surgery patients against AKI, at doses with known therapeutic efficacy.