Persisting neuroendocrine abnormalities and their association with physical impairment 5\xa0years after critical illness

Ilse Vanhorebeek,Inge Derese,Jan Gunst,Greet Hermans,Pieter J Wouters,Greet Van Den Berghe

doi:10.1186/s13054-021-03858-1

Abstract

BackgroundCritical illness is hallmarked by neuroendocrine alterations throughout ICU stay. We investigated whether the neuroendocrine axes recover after ICU discharge and whether any residual abnormalities associate with physical functional impairments assessed 5 years after critical illness.MethodsIn this preplanned secondary analysis of the EPaNIC randomized controlled trial, we compared serum concentrations of hormones and binding proteins of the thyroid axis, the somatotropic axis and the adrenal axis in 436 adult patients who participated in the prospective 5-year clinical follow-up and who provided a blood sample with those in 50 demographically matched controls. We investigated independent associations between any long-term hormonal abnormalities and physical functional impairments (handgrip strength, 6-min walk distance, and physical health-related quality-of-life) with use of multivariable linear regression analyses.ResultsAt 5-year follow-up, patients and controls had comparable serum concentrations of thyroid-stimulating hormone, thyroxine (T4), triiodothyronine (T3) and thyroxine-binding globulin, whereas patients had higher reverse T3 (rT3, p = 0.0002) and lower T3/rT3 (p = 0.0012) than controls. Patients had comparable concentrations of growth hormone, insulin-like growth factor-I (IGF-I) and IGF-binding protein 1 (IGFBP1), but higher IGFBP3 (p = 0.030) than controls. Total and free cortisol, cortisol-binding globulin and albumin concentrations were comparable for patients and controls. A lower T3/rT3 was independently associated with lower handgrip strength and shorter 6-min walk distance (p ≤ 0.036), and a higher IGFBP3 was independently associated with higher handgrip strength (p = 0.031).ConclusionsFive years after ICU admission, most hormones and binding proteins of the thyroid, somatotropic and adrenal axes had recovered. The residual long-term abnormality within the thyroid axis was identified as risk factor for long-term physical impairment, whereas that within the somatotropic axis may be a compensatory protective response. Whether targeting of the residual abnormality in the thyroid axis may improve long-term physical outcome of the patients remains to be investigated.Trial registration ClinicalTrials.gov: NCT00512122, registered on July 31, 2007 (https://www.clinicaltrials.gov/ct2/show/NCT00512122).Graphical

Highlights

Critical illness is hallmarked by neuroendocrine alterations throughout Intensive care unit (ICU) stay
This study obviously focused on a subgroup of survivors, who were overall younger, had fewer comorbidities, were less severely ill upon ICU admission, and showed fewer complications during ICU stay as compared with non-surviving patients (Additional file 1: Table S1)
Inherent to the study design, the studied patient cohort was relatively enriched in long-stay patients when compared with the original EPaNIC cohort [23], presenting with more severe illness upon ICU admission and suffering from more complications during ICU stay as compared with the cohort of other surviving patients (Additional file 2: Table S2)

Summary

Introduction

Critical illness is hallmarked by neuroendocrine alterations throughout ICU stay. We investigated whether the neuroendocrine axes recover after ICU discharge and whether any residual abnormalities associate with physical functional impairments assessed 5 years after critical illness. When illness is prolonged beyond the first few days, the neuroendocrine axes are uniformly suppressed, with low target organ hormone levels or, in case of cortisol, insufficiently elevated or normal levels [1, 2, 5, 7, 10, 14]. This suppression during the prolonged phase of illness is of central/hypothalamic origin [1, 2, 15]

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