Although evidence for the superiority of continuous feeding over intermittent feeding is lacking, in most paediatric intensive care units (PICU) artificial feeding is administered continuously for 24 h per day. Until now, studies in PICU on intermittent feeding have primarily focused on surrogate endpoints such as nutritional intake and gastro-intestinal complaints and none have studied the effects of an extended fasting period. Intermittent fasting has been proven to have many health benefits in both animal and human studies. The observed beneficial effects are based on multiple metabolic and endocrine changes that are presumed crucial in critical illness as well. One key element is the transition to ketone body metabolism, which, among others, contributes to the stimulation of several cellular pathways involved in stress resistance (neuro)plasticity and mitochondrial biogenesis, and might help preserve brain function. Secondly, the fasting state stimulates the activation of autophagy, a process that is crucial for cellular function and integrity. Of the different intermittent fasting strategies investigated, time-restricted feeding with a daily extended fasting period appears most feasible in the PICU. Moreover, planning the fasting period overnight could help maintain the circadian rhythm. Although not investigated, such an overnight intermittent fasting strategy might improve the metabolic profile, feeding tolerance and perhaps even have beneficial effects on tissue repair, reperfusion injury, muscle weakness, and the immune response. Future studies should investigate practical implications in critically ill children and the optimal duration of the fasting periods, which might be affected by the severity of illness and by age.

Background Intermittent fasting is a time-restricted feeding strategy with proven health benefits, which is based on multiple metabolic and endocrine changes, in several patient populations and healthy participants. In the pediatric intensive care unit (PICU), artificial feeding is usually administered 24 hours a day, although solid evidence supporting this practice is lacking. This discards the potential benefits of fasting in this population. We hypothesize that intermittent nutrition with a focus on an overnight feeding interruption (intermittent fasting), as compared with 24-hour continuous nutrition, is a feasible and safe strategy, with potential benefits, for critically ill children. Objective The aim of the Continuous versus Intermittent Nutrition in Pediatric Intensive Care randomized controlled trial (RCT) is to investigate a strategy of intermittent nutrition with a focus on an overnight feeding interruption period versus 24-hour nutrition during the first 14 days in the PICU. Methods The Continuous versus Intermittent Nutrition in Pediatric Intensive Care study is an investigator-initiated RCT in a tertiary referral PICU. Critically ill children (term newborn to 18 years), expected to stay in the PICU for ≥48 hours, and dependent on artificial nutrition, are eligible for inclusion. This study will randomize critically ill children (n=140) to a continuous versus intermittent nutrition strategy. In both groups, similar daily caloric targets will be prescribed. In the continuous group (control), nutrition will be administered 24 hours a day, with a maximum interruption period of 2 hours. In the intermittent group (intervention), nutrition will be interrupted during an age-dependent overnight fasting period. The study intervention will last until admission day 14, initiation of oral intake, or discharge from the PICU, whichever comes first. The primary outcome is the difference in ketosis between the groups under the condition of noninferiority regarding caloric intake. Secondary outcomes are feeding intolerance; the proportion of severe and resistant hypoglycemic events and severe gastrointestinal complications; and additional observed effects on nutritional intake, circadian rhythm, and clinically relevant outcome measures of the intermittent feeding strategy compared with continuous nutrition. Results The study was approved by the Dutch national ethical review board in February 2020. The first patient was enrolled on May 19, 2020. By May 2022, a total of 132 patients had been included in the study. Recruitment of the last patient is expected in Q3 2022. Conclusions Although intermittent fasting has been proven to have many health benefits in both animal and human studies, the feasibility and safety of this strategy in a PICU setting must be investigated. This RCT will help physicians gain more insight into the feasibility, safety, and potential clinical effects of intermittent feeding with overnight fasting in critically ill children. Trial Registration Netherlands Trial Register NL7877; https://trialsearch.who.int/Trial2.aspx?TrialID=NL7877 International Registered Report Identifier (IRRID) DERR1-10.2196/36229

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UNSTRUCTURED Background: ‘Intermittent fasting’ is a time-restricted feeding strategy with proven health benefits in several patient populations and healthy subjects, which are based on multiple metabolic and endocrine changes. In the pediatric intensive care unit (PICU) artificial feeding is usually administered 24 hours a day, although solid evidence supporting this practice is lacking. This discards the potential benefit of fasting in this population. We hypothesize that intermittent nutrition with the focus on an overnight feeding interruption (‘intermittent fasting’), as compared with 24 hours continuous nutrition, is a feasible and safe strategy for children during critical illness with potential benefits. Methods: The Continuous versus Intermittent Nutrition in Pediatric Intensive Care (ContInNuPIC) study is an investigator-initiated, randomized controlled trial (RCT) in a tertiary referral PICU. Critically ill children (term newborn - 18 years), expected to stay in the PICU ≥ 48 hours and dependent on artificial nutrition, are eligible for inclusion. This study randomizes critically ill children (n=140) to a ’Continuous’ versus ‘Intermittent’ nutrition strategy. In both study groups similar daily caloric targets are prescribed. In the Continuous group (control), nutrition is administered 24 hours a day with a maximum interruption of two hours. In the Intermittent group (intervention), nutrition is interrupted during an age-dependent overnight fasting period. The study intervention lasts until admission day 14, initiation of oral intake, or discharge from the PICU, whichever comes first. The primary outcome is the difference in ketosis between the groups, under the condition of non-inferiority regarding the caloric intake. Secondary outcomes are the feeding intolerance, the proportion of severe and/or resistant hypoglycemic events and severe gastro-intestinal complications, and additional observed effects on nutritional intake, circadian rhythm and clinically relevant outcome measures of the intermittent feeding strategy as compared with continuous nutrition. Results: The study was approved by the Dutch national ethical review board in February 2020. The first patient was enrolled on May 19th, 2020. By January 2022, 111 patients have been included in the study. The study is still in progress and recruitment of the last patient is expected in Q2 2022. Discussion: Although ‘intermittent fasting’ has been proven to have many health benefits in both animal and human studies, the feasibility and safety of such strategy in PICU setting must be investigated. This RCT will help physicians to gain more insight in the feasibility, safety and potential clinical effects of intermittent feeding with an overnight fast in critically ill children. Trial registration: Netherlands Trial Register: NL7877 on July 16th, 2019.

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