Non-Thyroidal Illness Syndrome in Critically Ill Children: Prognostic Value and Impact of Nutritional Management

Abstract

Introduction: Non-thyroidal illness (NTI), which occurs with fasting and in response to illness, is characterized by thyroid hormone inactivation with low triiodothyronine (T3) and high reverse T3 (rT3), followed by suppressed thyrotropin (TSH). Withholding supplemental parenteral nutrition early in pediatric critical illness (late-PN), thus accepting low/no macronutrient intake up to day 8 in the pediatric intensive care unit (PICU), accelerated recovery compared to initiating supplemental parenteral nutrition early (early-PN). Whether NTI is harmful or beneficial in pediatric critical illness and how it is affected by a macronutrient deficit remains unclear. This study investigated the prognostic value of NTI, the impact of late-PN on NTI, and whether such impact explains or counteracts the outcome benefit of late-PN in critically ill children.

Methods: This preplanned secondary analysis of the Early versus Late Parenteral Nutrition in the Pediatric Intensive Care Unit randomized controlled trial quantified serum TSH, total thyroxine (T4), T3, and rT3 concentrations in 982 patients upon PICU admission versus 64 matched healthy children and in 772 propensity score-matched early-PN and late-PN patients upon admission and at day 3 or last PICU day for shorter PICU stay. Associations between thyroid hormone concentrations upon admission and outcome, as well as impact of late-PN on NTI in relation with outcome, were assessed with univariable analyses and multivariable logistic regression, linear regression, or Cox proportional hazard analysis, adjusted for baseline risk factors.

Results: Upon PICU admission, critically ill children revealed lower TSH, T4, T3, and T3/rT3 and higher rT3 than healthy children (p < 0.0001). A more pronounced NTI upon admission, with low T4, T3, and T3/rT3 and high rT3 was associated with higher mortality and morbidity. Late-PN further reduced T4, T3, and T3/rT3 and increased rT3 (p ≤ 0.001). Statistically, the further lowering of T4 by late-PN reduced the outcome benefit (p < 0.0001), whereas the further lowering of T3/rT3 explained part of the outcome benefit of late-PN (p ≤ 0.004). This effect was greater for infants than for older children.

Conclusion: In critically ill children, the peripheral inactivation of thyroid hormone, characterized by a decrease in T3/rT3, which is further accentuated by low/no macronutrient intake, appears beneficial. In contrast, the central component of NTI attributable to suppressed TSH, evidenced by the decrease in T4, seems to be a harmful response to critical illness. Whether treating the central component with TSH releasing hormone infusion in the PICU is beneficial requires further investigation.

Keywords: critical illness; non-thyroidal illness syndrome; nutrition; pediatrics; prognostic value.

FIG. 1.

Diagram of the study design. A PICU admission serum sample was available for 982/1440 patients included in the PEPaNIC trial. Those 982 admission samples were used to compare thyroid hormones in critically ill children to those in healthy control children, and to study the association of baseline thyroid hormone concentrations with clinical outcome. A subgroup of early-PN and late-PN patients was selected with propensity score matching to investigate the effect of the randomized intervention on the thyroid axis, as well as the impact of these changes on the outcome benefit of late-PN. *Data were incomplete for one early-PN patient as not enough serum was available to perform the complete analysis. Results of another early-PN patient were retrospectively excluded because of severely aberrant thyroid hormone concentrations after radioactive iodine metaiodobenzoguanidine therapy. PN, parenteral nutrition.

FIG. 2.

Impact of critical illness on thyroid hormone concentrations upon PICU admission in infants and children. Infants are younger than one year old. Bars represent means, and whiskers represent the standard error (SE). The black boxplots represent healthy children, and the light-gray boxes represent critically ill patients.

FIG. 3.

Univariable analyses for the association between upon admission thyroid hormones and outcome. Bars represent means, and whiskers represent the SE.

FIG. 4.

Total daily caloric intake of the patients in the propensity score matched subgroup. Bars show the mean daily amount of energy (kilocalories/kg/day) provided by the combination of the enteral and parenteral route, with whiskers representing the SE. The open and filled bars represent the patients randomized to the early-PN and late-PN groups, respectively.

FIG. 5.

Effect of early-PN versus late-PN on the thyroid axis. Bars (mean ± SE) represent the changes (referred to as Δ) from the admission values to day 3 in the PICU (or to the last day for patients with shorter PICU stay) in serum thyrotropin (TSH), thyroxine (T4), triiodothyronine (T3), reverse T3 (rT3), and the T3/rT3 ratio. The open and filled bars represent the patients randomized to the early-PN and late-PN groups, respectively. Infants are younger than one year old. *p-Values obtained with univariable analysis; **p-values obtained with multivariable analysis after adjustment for baseline risk factors (treatment center, risk of malnutrition [STRONGkids score], age, diagnosis upon admission, and severity of illness [PeLOD and PIM2 score]). PeLOD, Pediatric Logistic Organ Dysfunction score; PIM2, Pediatric Risk of Mortality 2 score; STRONGkids, Screening Tool for Risk On Nutritional Status and Growth (score of 0 indicating a low risk of malnutrition, a score of 1–3 indicating medium risk, and a score of 4–5 indicating high risk).