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

Abstract

Background 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. Methods In 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. Results At 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). Conclusions Five 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 Abstract

Poor physical recovery after critical illness: incidence, features, risk factors, pathophysiology, and evidence-based therapies

“…Additionally, neuroendocrine alterations in patients with sustained muscle weakness are associated with decreased physical recovery. A higher reverse T3, and lower T3-reverse T3 ratio was found to be associated with lower HGS and shorter 6MWD five years after critical illness [ 32 ▪ ]. Persisting abnormalities within the thyroid axis may increase the risk of long-term physical impairment.…”

The hypothalamus-pituitary-adrenal axis in sepsis- and hyperinflammation-induced critical illness: Gaps in current knowledge and future translational research directions

“…In this regard, a recent study found normalized ACTH and cortisol concentrations 5 years after critical illness. 41 However, this study included both short- and long-stay critically ill patients and may be confounded by survivor bias.…”

A schedule for tapering glucocorticoid treatment in patients with severe SARS-CoV 2 infection can prevent acute adrenal insufficiency in the geriatric population

“…In the case of suspicion of CIRCI and GC treatment, mainly with hydrocortisone, endocrinological follow-up is suggested for the patient. On the other hand, two studies have demonstrated that CIRCI is likely a reversible condition [28,29]. In our experience, adequate follow-up of patients who developed central adrenal insufficiency, even in a mild form, after GC treatment is essential in order to better evaluate HPA axis integrity without interfering conditions related to concomitant drugs or even hospitalization-induced stress.…”