Aim: Midazolam like other benzodiazepines is supposed to be neurotoxic in small children and to represent a risk factor for the development of delirium. The aim of this study was to evaluate whether a modified analgesia and sedation protocol is feasible and effective to reduce the requirement of midazolam in neonates and young infants after cardiac surgery. Methods: Patients aged 6 months or younger who underwent surgery for congenital heart disease with cardiopulmonary bypass were enrolled and divided into a pre-modification group (January-December 2016) and after adjusting our sedation protocol into a post-modification group (January-December 2018). We assessed the doses of midazolam, morphine and clonidine as well as sedation scores according to our nurse-driven sedation protocol every 8 h until 120 h after cardiac surgery. During weaning from analgesia and sedation, children were monitored regarding withdrawal symptoms and pediatric delirium. Results: Sixty-five patients were included (33 patients in the pre-modification group, 32 patients in the post-modification group). The number of patients receiving midazolam and the cumulative dose of midazolam could be successfully reduced. The sedation scores were still within the desired target range for adequate sedation without any negative side effects. Conclusions: It is feasible and safe to reduce the use of midazolam in infants after cardiac surgery maintaining sedation goals based on a modified nurse-driven analgesia and sedation protocol.