On how to feed critically ill children in intensive care: A slowly shifting paradigm

Abstract

Critically ill children requiring treatment in a pediatric intensive care unit (PICU) suffer from anorexia and/or feeding intolerance. The resulting macronutrient deficit associates with poor outcome. Until recently, this association formed the basis for initiating enteral or parenteral feeding early to improve outcome. The multicenter "Early-versus-Late-Parenteral-Nutrition-in-the-Pediatric-Intensive-Care-Unit" randomized controlled trial (PEPaNIC-RCT) addressed whether this association is causal. It showed that early supplementation of insufficient/contraindicated enteral nutrition with parenteral nutrition, as compared with accepting a macronutrient deficit throughout the first week in the PICU, did not improve outcome. On the contrary, it caused more infections and prolonged organ support and PICU stay, and adversely affected neurodevelopmental outcomes 2 and 4 years later. Harm was present in all subgroups and appeared explained by the macronutrient dose, more specifically the amino-acid dose, not lipid or glucose doses. These findings corroborated results from large-scale adult RCTs. Mechanisms of harm from early enhanced nutrition comprised suppressed cellular repair pathways like autophagy and ketogenesis, suppressed illness-induced alterations in thyroid hormone metabolism, more iatrogenic hyperglycemia, increased urea cycle activity through anabolic resistance, and induction of epigenetic modifications that mediate longer-term developmental impairments. These results came unexpected to many pediatric intensivists. Hence, the paradigm has only slowly begun to shift toward more restrictive macronutrient administration in the acute phase of critical illness. Benefits of early fasting responses have become clear, provided micronutrients are given to prevent deficiencies and refeeding syndrome. These insights open perspectives for studies investigating novel nutritional strategies to activate fasting-induced cellular repair while avoiding prolonged starvation.

Keywords: Amino-acids; Children; Critical illness; Long-term development; Morbidity; Parenteral nutrition.

Fig. 1

Harm by early supplemental parenteral nutrition on short-term outcomes of critically ill children. Bars represent the incidence of acquiring a new infection in the PICU (percentage), the duration of PICU stay (days), the duration of mechanical ventilation (days), or the duration of total hospital stay (days). Whiskers indicate standard errors of the mean. Asterisks represent p values < 0.05, obtained from multivariable analyses adjusting for baseline risk factors (treatment center, age, risk of malnutrition (STRONGkids score), diagnosis upon admission and severity of illness (Pediatric Logistic Organ Dysfunction (PeLOD) score, and Pediatric Risk of Mortality 2 (PIM2) score) for all patients, undernourished patients and severely undernourished patients; treatment center, risk of malnutrition, diagnosis upon admission and severity of illness for children and infants; and treatment center, type of illness upon admission (medical, surgical cardiac, surgical other), severity of illness and weight for age z score for neonates). Figures were compiled from information in [15,27,28].

Fig. 2

Macronutrient dose response for harm by early-PN in the PICU. The left panels show, for each of the first 7 days in the PICU, associations of average daily total doses of the individual macronutrients up to that day with likelihood of acquiring a new infection in the PICU and live PICU discharge as hazard ratios and 95 % confidence intervals per 10 % added, with macronutrients entered as continuous variables. The right panels show the dose relationship between average total macronutrient administration up to day 4 and likelihood of acquiring a new infection in the PICU and live PICU discharge. The average daily total doses up to day 4 of each macronutrient were split up in deciles, with doses above 90 % combined in a single class. The associations of the classes of average daily total doses of the individual macronutrients up to day 4 with the respective outcomes are shown as hazard ratios and corresponding 95 % confidence intervals, compared with the reference class of 0–10 %. The y-axis has been cut to better visualize the dose response. All these data were obtained after adjustment for type of illness, age group, severity of risk of malnutrition, severity of illness, and treatment center. A hazard ratio above 1 indicates a detrimental effect for likelihood of acquiring a new infection, but a beneficial effect for likelihood of live PICU discharge, and vice versa for a hazard ratio below 1. n indicates the number of patients still in the PICU on the day of analysis for the left panels and number of participants within a certain decile of macronutrient intake for the right panels. Figures were compiled from information in [43]. PICU: pediatric intensive care unit.

Fig. 3

Mechanisms underlying absence of benefit from early full nutritional support of critically ill children. Mechanistic studies have attributed absence of benefit from early full nutritional support (including early parenteral nutrition) to suppression of beneficial fasting responses, to feeding-resistant catabolism, and to increased metabolic damage including de novo epigenetic alterations. See text for further explanation. T3: triiodothyronine, rT3: reverse T3, PN: parenteral nutrition. Created in https://BioRender.com.

Fig. 4

Early supplemental parenteral nutrition alters DNA methylation of critically ill children which explains its harmful impact on long-term neurocognitive development. During pediatric critical illness, de novo alterations in DNA methylation arise (big dark red and purple circles). For a substantial part, these DNA methylation changes are evoked by early initiation of supplemental parenteral nutrition (big stars). Those de novo changes in DNA-methylation caused by the early use of PN statistically explained part of the adverse impact of early-PN on long-term development of the patients, more specifically the worse visual-motor integration and executive functioning and the more pronounced behavioral problems as compared with healthy children. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article).