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 ).

Keywords: Adrenal axis; Critical illness; Long-term; Physical function; Somatotropic axis; Thyroid axis.

Conflict of interest statement

The authors declare that they have no competing interests.

© 2021. The Author(s).

Figures

Fig. 1

Flowchart of study participants and study design. The major focus of this study is on the patients who participated in the 5-year morbidity follow-up of the EPaNIC study and for whom a serum sample had been collected at this time point. A small subgroup of these patients had also participated at one or more earlier time points, 1-, 2-, 3- or 4-years post-ICU. aFor feasibility reasons only a random subset of short-stay patients in ICU for fewer than 8 days were eligible for the 5-year EPaNIC follow-up study [24]. The subgroup of short-stay patients was a random, computer-generated “3 out of 10” sample, weighed within admission diagnostic categories to a distribution similar to that among long-stay patients in ICU for at least 8 days (who all were eligible). Of the short-stay patients, 1721 were not in that random selection. The total 5-year follow-up cohort consisted of 398 short-stay and 276 long-stay patients. bOf the eligible patients, 275 were subsequently excluded for meeting one or more exclusion criteria. These were patients with pre-ICU neuromuscular disorders, unable to walk without assistance prior to ICU or other disabilities present before follow-up potentially confounding morbidity endpoints (i.e. cardiac assist device, pulmonary resection, psychiatric disease, dementia, vegetative state, in hospital/rehabilitation center/nursing home); patients who could not be not contacted; patients who died after five years post-ICU before the planned testing; patients for whom the time window had passed (predefined time window for the 5-year follow-up had been set at 5 ± 0.5 years after ICU admission); or patients for whom there was a language barrier [24]. ICU: intensive care unit

Fig. 2

Thyroid axis 5 years after ICU admission: comparison with controls and within-patient evolution from ICU discharge. Data are shown as mean and standard error of the mean. The gray rectangles at the right side of the panels reflect mean plus or minus the standard error of the mean of the controls matched to the patients at 5-year follow-up. TSH concentrations were square root-square root transformed and rT3 and T3/rT3 were square root transformed to obtain a near normal distribution, allowing repeated-measures ANOVA and t test. Y-axes were transformed back to original values. Patients who received thyroid hormone treatment in ICU or were on chronic thyroid hormone treatment at follow-up were excluded. TBG concentrations were measured in all available LD and 5y samples, but only in a subset of the samples available for the other time points (Adm: n = 34, d4: n = 44, d7: n = 33, 1y: n = 12, 2y: n = 11, 3y: n = 18, 4y: n = 18). Adm: ICU admission, d4: day 4 in ICU, d7: day 7 in ICU, LD: last day in ICU, 1y: one year after ICU admission, 2y: two years after ICU admission, 3y: three years after ICU admission, 4y: four years after ICU admission, 5y: five years after ICU admission, ICU: intensive care unit

Fig. 3

Somatotropic axis 5 years after ICU admission: comparison with controls and within-patient evolution from ICU discharge. Data are shown as mean and standard error of the mean. The gray rectangles at the right side of the panels reflect mean plus or minus the standard error of the mean of the controls matched to the patients at 5-year follow-up. Growth hormone and IGFBP1 concentrations were square root-square root transformed to obtain a near normal distribution, allowing repeated-measures ANOVA and t test. Y-axes were transformed back to original values. Patients on chronic GHRH or somatostatin analogue treatment at follow-up were excluded. Adm: ICU admission, d4: day 4 in ICU, d7: day 7 in ICU, LD: last day in ICU, 1y: one year after ICU admission, 2y: two years after ICU admission, 3y: three years after ICU admission, 4y: four years after ICU admission, 5y: five years after ICU admission, ICU: intensive care unit

Fig. 4

Adrenal axis 5 years after ICU admission: comparison with controls and within-patient evolution from ICU discharge. Data are shown as mean and standard error of the mean. The gray rectangles at the right side of the panels reflect mean plus or minus the standard error of the mean of the controls matched to the patients at 5-year follow-up. Total and free cortisol concentrations were square root-square root transformed to obtain a near normal distribution, allowing repeated-measures ANOVA and t test. Y-axes were transformed back to original values. Patients on corticosteroid treatment in ICU or on chronic corticosteroid treatment at follow-up were excluded. Adm: ICU admission, d4: day 4 in ICU, d7: day 7 in ICU, LD: last day in ICU, 1y: one year after ICU admission, 2y: two years after ICU admission, 3y: three years after ICU admission, 4y: four years after ICU admission, 5y: five years after ICU admission, ICU: intensive care unit