Feasibility Study to Determine Ability to Recruit and Assess Patients for a Neurodevelopment Follow-up Study in Pediatric Intensive Care

The majority of human cohort investigations of neurotoxicity have studied general anesthesia for surgery. However, many animal studies have involved exposure to agents for significantly longer than the average duration of a general anesthetic in infants, some even for 24 hours (8).This is closer in exposure characteristics to prolonged sedation in PICU: days as compared to a few hours. However, although sedation in the Pediatric Intensive Care Unit (PICU) may continue for several days, there are no studies of its effects on subsequent neurodevelopment in previously healthy young infants. The only intensive care studies thus far have examined high risk subgroups, including the EPIPAGE study (20) in premature newborns and studies of infants after congenital heart surgery. The latter studies have shown a small but significant association between cumulative benzodiazepine dose and Visual-Motor integration at 4 years of age (21), and an association between higher exposure to volatile anesthetic agents and lower cognitive scores on the Bailey Scales of Infant Development III at 12 months (22), respectively.

It is essential that Pediatric Intensivists start investigating the effect of our commonly used sedation protocols, which frequently include benzodiazepines, on our patients' neurodevelopment. The standard sedative regimen in use for many years at Montreal Children's PICU is midazolam infusion (benzodiazepine) plus opioid (commonly fentanyl or morphine) infusion. Other agents including ketamine may be added. This is not an easy field of study since we cannot randomize patients to receive sedation or not.

Therefore this programme of research aims to:

a) Identify a suitable group of PICU patients who were exposed to PICU sedation, along with a comparable group who were not exposed to sedation during their PICU admission who will act as controls; b) Assess the feasibility of recruiting these retrospectively identified patients and performing the requisite neurodevelopmental assessments around 6 years after PICU admission; c) Expand to a multicentre study, if feasibility is confirmed, to allow the recruitment of sufficient numbers of cases to determine if PICU sedation has a significant effect on long-term neurodevelopment; d) Investigate alternative sedation protocols and/or interventions to minimize the adverse effects on development.

1. The initial aim of this study programme has been achieved by means of a Chart Review completed in March 2017. We hypothesized that previously healthy infants requiring ventilation for an acute respiratory illness would divide into two groups depending on their respiratory management: intubation with sedation versus non-invasive ventilation without sedation, and that these infants, with a unifying pathological diagnosis, could act as cases and controls for an investigation of PICU sedation. In order to optimize the validity of our comparison, patients must be as similar as possible, therefore many exclusion criteria and also matching are required. The chart review has determined that the two described groups are similar in terms of severity of illness scores (Pediatric Risk of Mortality [PRISM] and Pediatric Logistic Organ Dysfunction [PELOD]) therefore making them suitable subjects for a follow-up study (23). This phase of the programme has been presented and discussed at Canadian Critical Care Trials Group (CCCTG) meetings and endorsed by CCCTG.
2. Having identified an appropriate group of patients, the next phase of the research programme is to perform a feasibility study to determine if our methodology will lead to adequate recruitment to move forward to a large multicentre study. This is the subject of this protocol.