On the long-term footprint of pediatric critical illness and how this is affected by acute macronutrient restriction
Children are admitted to the pediatric intensive care unit (PICU) when they acutely need vital organ support to avoid imminent death. Although most of the children need intensive care for only a few days and most of them seemingly recover well from the acute insult, many of them are confronted with long-term consequences after critical illness as observed years after hospital discharge. This legacy, which remains largely unexplained, broadly affects neurocognitive development, but also growth and quality of life of the children, independently of pre-existing illnesses or conditions.
Previous research has shown that the long-term adverse outcome after critical illness is modifiable by changing certain conditions during the acute PICU management. Our group previously performed the large multicenter PEPaNIC randomized controlled trial (RCT), which included 1440 critically ill children, and demonstrated that withholding supplemental parenteral nutrition during the first week in PICU (late-PN), and thus accepting a macronutrient deficit, was clinically superior to initiating supplemental PN within the first 24 hours of admission (early-PN). Late-PN accelerated recovery and decreased the risk of acquiring a new infection during PICU admission. Interestingly, also in the longer-term 2 years after inclusion, late-PN was shown to improve and even normalize several neurocognitive outcomes, in particular the executive function of inhibitory control, as compared with early-PN. Whether impairments in physical and neurocognitive domains observed at 2-years follow-up persist or disappear, or whether other problems may emerge in relation to the randomized intervention remained unclear. The acute phase of critical illness is also hallmarked by several neuroendocrine changes, possibly influenced by the macronutrient deficit caused by late-PN, which could affect development and growth of the children in the long term. This PhD thesis first documented the changes in the hypothalamic-pituitary-thyroid (HPT) and hypothalamic-pituitary-adrenal (HPA) axis in the acute phase of pediatric critical illness, and assessed the impact of accepting a macronutrient deficit with late-PN hereon. It also investigated the long-term effects of pediatric critical illness and an early macronutrient deficit on neurocognitive development, growth and physical functioning 4 years after PICU admission. The final objective of this thesis was to assess the de-implementation of early-PN in PICUs worldwide.
In the first part of this PhD project, we confirmed the presence of non-thyroidal illness (NTI) upon PICU admission, with low serum concentrations of TSH, T4 and T3, and elevated rT3 serum concentrations. The severity of NTI upon admission was independently associated with worse intensive care outcomes. NTI is also known to occur with fasting. Consistent with the mimicking of a fasting response, the macronutrient deficit in patients from the late-PN group resulted in a worsening of NTI over the first few days in PICU as compared with early-PN patients. Interestingly, in a statistical mediation analysis, the peripheral inactivation of thyroid hormone, which was further accentuated by late-PN, contributed to the outcome benefit of late-PN and thus appeared to be a beneficial response to critical illness. In contrast, the central component of NTI attributable to suppressed TSH and evidenced by the decrease in T4, counteracted the late-PN outcome benefit and appeared to be a maladaptive response. Whether treating the central component of NTI with TRH infusion in the PICU improves outcome of critically ill children requires further investigation in adequately powered RCTs.
In the second part, the changes in the HPA axis during the acute phase of pediatric critical illness were documented. In contrast with critically ill adults, cortisol levels in critically ill children were only briefly elevated upon PICU admission and became normal thereafter, despite low binding-proteins and persistently suppressed cortisol metabolism. As ACTH was normal upon admission and decreased quickly thereafter, cortisol availability was not driven by increased ACTH. On day 3 of admission, high cortisol and low ACTH levels independently predicted poor outcome. Also, treatment with corticosteroids in the PICU further suppressed ACTH and was independently associated with poor outcomes. These findings suggest that exogenously increasing cortisol availability during the acute phase of critical illness in children might be inappropriate, and that future studies on corticosteroid treatment should plan safety analyses, as harm may be possible.
In the third part of this PhD project, we presented the results of the 4-year follow-up study of the PEPaNIC RCT, which investigated the effect of late-PN versus early-PN on anthropometrics, health status, parent- or caregiver-reported executive functions and emotional/behavioral problems, and clinical tests for intelligence, visual-motor integration, alertness, motor coordination and memory. Four years after inclusion, these children scored worse for almost every developmental domain as compared with matched healthy children. However, part of the impairment, more specifically the parent- or caregiver-reported internalizing, externalizing and total emotional/behavioral problems, could be prevented in patients from the late-PN group who did not receive supplemental PN in the first week of PICU admission. The emotional/behavioral problems thus attributable to the use of early-PN were found to be at least partially mediated by adversely altered DNA-methylation by early-PN during PICU stay. Hence, the avoidance of early-PN induced alterations in DNA-methylation status during PICU stay could be a biological mediator of the protection against emotional/behavioral problems 4 years later as observed with late-PN. Taken together, these findings provide strong further support in favor of the de-implementation of administering PN during the first week in PICU.
In the last part, the de-implementation of early PN was assessed in PICUs worldwide, by analyzing the results of a survey that was distributed one year after publication of the PEPaNIC RCT. The survey was completed by respondents of 81 different PICUs in 39 countries. At the time of the survey, two-thirds of the respondents was aware of the PEPaNIC study results, of whom 12% already did not initiate supplemental PN in the first week in their PICU. Another 12% started de-implementing early-PN after reading the PEPaNIC RCT paper, and 40% partially de-implemented early-PN by postponing the initiation of PN (though still initiated prior to day 8 in PICU) and/or providing decreased amounts of PN. Barriers for not de-implementing early-PN were concerns about the efficacy and (long-term) safety of late-PN, and waiting for updated international guidelines. In the meantime, recently published guidelines, the work presented in this PhD thesis as well as other research performed by our group, could already provide reassuring answers to the concerns practitioners had who did not de-implement early-PN. In the future, frequent careful monitoring of the nutritional practices in PICUs worldwide should be continued, in order to find strategies to accelerate de-implementation of ineffective, unproven or harmful healthcare.
In conclusion, in this PhD thesis, we showed that the peripheral inactivation of thyroid hormone during pediatric critical illness, which is further accentuated by accepting a macronutrient deficit in the first week in the PICU, might be a beneficial response, whereas the central component of NTI might be maladaptive. This implies that future research should focus on treatment of the central component to improve outcome. Next, we showed that systemic cortisol availability is elevated only transiently in critically ill children and is not driven by elevated ACTH. As low ACTH and high cortisol, as well as corticosteroid treatment, predicted poor outcome, exogenously increasing cortisol availability during the acute phase might be inappropriate. We further showed that children experience a severe legacy in multiple domains of their physical and neurocognitive development 4 years after critical illness. Whether the disturbances in the HPT or HPA axis may contribute remains to be investigated. However, part of this legacy, more specifically the emotional and behavioral problems, can be prevented by withholding of supplemental parenteral nutrition in the first week in the PICU. Prevention of altered DNA methylation was found to be a potential biological mediator hereof. These findings can provide reassuring answers to some of the concerns raised by the respondents of the survey who did not de-implement early-PN in their PICU.