Effect of withholding early parenteral nutrition in PICU on ketogenesis as potential mediator of its outcome benefit

Abstract

Background: In critically ill children, omitting early use of parenteral nutrition (late-PN versus early-PN) reduced infections, accelerated weaning from mechanical ventilation, and shortened PICU stay. We hypothesized that fasting-induced ketogenesis mediates these benefits.

Methods: In a secondary analysis of the PEPaNIC RCT (N = 1440), the impact of late-PN versus early-PN on plasma 3-hydroxybutyrate (3HB), and on blood glucose, plasma insulin, and glucagon as key ketogenesis regulators, was determined for 96 matched patients staying ≥ 5 days in PICU, and the day of maximal 3HB-effect, if any, was identified. Subsequently, in the total study population, plasma 3HB and late-PN-affected ketogenesis regulators were measured on that average day of maximal 3HB effect. Multivariable Cox proportional hazard and logistic regression analyses were performed adjusting for randomization and baseline risk factors. Whether any potential mediator role for 3HB was direct or indirect was assessed by further adjusting for ketogenesis regulators.

Results: In the matched cohort (n = 96), late-PN versus early-PN increased plasma 3HB throughout PICU days 1-5 (P < 0.0001), maximally on PICU day 2. Also, blood glucose (P < 0.001) and plasma insulin (P < 0.0001), but not glucagon, were affected. In the total cohort (n = 1142 with available plasma), late-PN increased plasma 3HB on PICU day 2 (day 1 for shorter stayers) from (median [IQR]) 0.04 [0.04-0.04] mmol/L to 0.75 [0.04-2.03] mmol/L (P < 0.0001). The 3HB effect of late-PN statistically explained its impact on weaning from mechanical ventilation (P = 0.0002) and on time to live PICU discharge (P = 0.004). Further adjustment for regulators of ketogenesis did not alter these findings.

Conclusion: Withholding early-PN in critically ill children significantly increased plasma 3HB, a direct effect that statistically mediated an important part of its outcome benefit.

Keywords: Intensive care; Ketogenesis; Ketone body; Parenteral nutrition; Recovery.

Fig. 1

Rationale and stepwise design of the study. In step 1, a time course analysis to investigate any impact of late-PN versus early-PN on daily plasma concentrations of 3HB. Therefore, all patients with a PICU stay of at least 5 days and plasma samples available from admission until day 5 in the PICU were selected and matched for center, demographics, and type and severity of illness. In the resulting matched cohort of 96 children, daily plasma 3HB, insulin, glucagon, and glucose concentrations were determined and the time point of “maximal 3HB effect” was identified. In step 2, in the total study population, the concentration of plasma 3HB and in step 1 affected ketogenic regulators were determined on the average time point of “maximal 3HB effect” identified in step 1. For patients with a shorter PICU stay, the sample on the last day in PICU was used as surrogate (1142 patients with available plasma, of which 580 randomized to late-PN and 562 randomized to early-PN). In step 3, a multivariable statistical analysis was performed to assess whether any impact of late-PN as compared with early-PN on 3HB could explain its beneficial effects on outcome. “a” represents the effect of the intervention (late-PN versus early-PN) on the outcome of interest (time to live weaning from mechanical ventilatory support, time to live PICU discharge, and acquisition of new infection), “b” represents the effect of the intervention (late-PN versus early-PN) on the hypothesized mediator—plasma 3HB concentration, and “c” represents the association of the potential mediator with the outcome of interest (time to live weaning from mechanical ventilatory support, time to live PICU discharge, and acquisition of new infection)

Fig. 2

Total caloric intake, plasma insulin, plasma glucagon, blood glucose, and plasma 3HB concentrations during the first 5 days in PICU in a matched cohort of early-PN and late-PN patients. Data are shown as median and IQR

Fig. 3

Total caloric intake, plasma insulin, blood glucose, and plasma 3HB concentrations on day 1/2 in the total cohort of early-PN and late-PN patients. Plasma concentrations of 3-HB and insulin were determined on day 2 in PICU or on day 1 for patients with a shorter PICU stay. Boxes show median and IQR, whiskers 10th and 90th percentile