Introduction
Critical illness is associated with various endocrinological dysfunctions, which has also been linked to increased mortality, but this association has been reported primarily in acute rather than protracted (>7 days) critical illness [
1‐
4]. As endocrine status changes with the course of critical illness [
5], the prognostic value of a given hormone may differ between the acute and prolonged phases. There is an extensive literature on the prognostic value of endocrinological markers in the acute phase of critical illness, in contrast to the prolonged phase. Most hormonal studies on protracted critical illness have either included a small or particular cohort [
6] or assessed one endocrine axis [
7]. Therefore, we assessed the relationships between various endocrine markers and in-hospital mortality in a large population of patients with protracted critical illness [
8]. The endocrine functions that we have assessed included the adrenal, thyrotropic, somatotropic and gonadotropic axes, as they have been shown to be impaired during and after critical illness [
1‐
4] and play a major role not only in the response to stress [
9,
10] but also with regard to patient outcomes [
2,
3]. These endocrine markers were assessed in a study on ICU-acquired paresis [
11] because they affect muscle metabolism. However, although the present study is based on the same population [
8,
12] and the same hormonal measurements [
11] as previously published ones, its objective (that is, in-hospital mortality) is entirely original.
Discussion
Protracted critical illness is associated with dysfunction of the neuroendocrine axes and the adrenal gland [
5,
6,
17,
19‐
21], which is characterized by low circulating levels of hypophyseal and adrenal hormones, notably DHEA and DHEAS. In accord with our previous study [
11], the present results are consistent with this endocrine pattern, indicating that hormonal status has been assessed at the postacute phase of critical illness.
We found that nonsurvivors had increased plasma cortisol levels, suggesting persisting stress. Increased plasma cortisol level was associated with decreased plasma DHEA and DHEAS levels in men who subsequently died, suggesting adrenal exhaustion [
22]. Although the association of mortality with adrenal exhaustion has also been reported previously in septic shock [
1,
2], we do not have any explanation for the fact that it was observed only in men in the present study. Interestingly, neither high circulating cortisol levels nor adrenal exhaustion were related to the administration of corticosteroids, suggesting that corticosteroid therapy has no deleterious effect on adrenal function. This is an important finding, considering the controversy regarding the usefulness of corticosteroids in patients in septic shock [
23]. Arlt
et al. [
1] previously showed a lack of association between DHEA (increased) and DHEAS (decreased) and that mortality was associated with an increased cortisol-to-DHEA ratio. However, these results were obtained when patients were in an early stage of septic shock. Conversely, Marx
et al. [
2] measured the plasma levels of adrenocortical hormones in 30 patients at the onset, the halfway point and the last day of sepsis, with a total duration of about 9 days. On the last day of sepsis, they found that plasma levels of cortisol and DHEA tended to be higher and those of DHEAS were lower in nonsurvivors. The discrepancy between the DHEA findings between the study by Marx
et al. and our study might result from differences in the populations studied, especially with regard to admission diagnosis (sepsis vs. critical illness) and male-to-female sex ratio. The immune system-activating properties of DHEA may account for the association of DHEA levels with mortality [
1,
2]. These findings would support an assessment of the benefit of DHEA treatment in the postacute phase of critical illness, notably in men [
24].
We found that in-hospital mortality was associated with low plasma IGF-1 levels. To our knowledge, this postacute phase relationship has been assessed in only one small cohort study [
6]. A low IGF-1 level is considered a valuable marker of growth hormone (GH) deficiency, which is considered deleterious [
25] and has inspired clinical trials [
26,
27]. Unfortunately, one randomized clinical trial has shown that the administration of GH increased mortality in critically ill patients [
26]. Because GH was administered during the acute phase of critical illness in the Takala
et al. trial [
26], one may argue that GH administration should be tested during the prolonged phase of critical illness. Moreover, it has recently been shown that critical illness-associated mortality was not associated with IGF-1 level but with increased GH level (measured in the acute phase) [
28]. It has to be noted that decreases in circulating IGF-1 levels can result from various causes frequently encountered in critically ill patients, such as malnutrition, chronic liver disease or diabetes [
17]. In contrast to previous reports [
29,
30], we did not find that plasma IGF-1 levels differed between women and men.
Female sex and increased blood glucose levels have been shown to be independently associated with increased mortality [
31‐
33]. Therefore, these relationships can support our finding that blood glucose levels were higher in women who did not survive. It is also known that menopause is associated with type 2 diabetes mellitus. Preexisting diabetes was not more frequent in female patients who did not survive. It is conceivable that the conjunction of menopause and critical illness induce insulin resistance. Although such a benefit has not been reported in a large trial [
34,
35], it would be worth assessing the effect of strict glucose control in postmenopausal female patients in the ICU.
Limitations of the study
The biological effects of hormones depend not only on their circulating levels but also on specific and nonspecific hormone-binding proteins and on the expression and regulation of hormone receptors. Since we did not assess binding protein levels or hormone receptor activity, we cannot exclude that a given hormone is associated with mortality on the basis of serum levels alone. Similarly, tissue hormone levels might also have a prognostic value, but obviously they are not assessable in a living patient. Thus, Arem
et al. [
36] found that tissue thyroid hormone levels were lower in most organs of more patients who died as a result of critical illness than in those of patients who died as a result of trauma. Finally, single circulating levels of hormones must be interpreted with caution because these levels may fluctuate with time, and dynamic assessments were not performed in the present study [
17]. Similarly, assessment of pulsatile secretion of hypothalamohypophyseal hormones would also have been interesting. Because such assessments require repeated measurements, comprehensive hormonal studies have included a relatively small number of patients [
37].
We acknowledge that a statistical association does not signify a causal relationship. Endocrinological dysfunction and mortality might be two independent consequences of critical illness. Because of the relatively low number of events, we did not perform multivariate analyses to determine whether endocrinological dysfunction was independently associated with in-hospital mortality. It is also possible that a larger patient cohort would have allowed us to identify other endocrinological factors. Despite these limitations, our study remains original, as we have assessed the relationships between various hormones and mortality at the postacute phase of critical illness in a patient cohort that is relatively large in comparison with other similar studies. It has to be noted that hormones were not chosen at random, but rather because they might affect outcomes, including even gonadotropic hormones [
3,
38].
We have used the term "protracted" because assessment of plasma hormone levels was done after the seventh day of critical illness. Indeed, this time point is often used to discriminate the acute phase from the postacute phase of critical illness. We acknowledge that this definition is too simple, because "time" is not the same for all patients and all types of critical illness. From a clinical point of view, awakening is a major milestone in the course of critical illness. It often indicates recovery, and it is a time when important therapeutic decisions are made, such ventilator weaning or physiotherapy.
Competing interests
The authors declare that they have no competing interests
Authors' contributions
TS conceived of the study, helped recruit the patients and wrote the manuscript. SBG participated in the design of the study, performed the statistical analysis and helped to draft the manuscript. AP helped to draft the manuscript. BDJ participated in the design of the study and helped to recruit the patients and draft the manuscript. RDS helped to draft the manuscript. VM helped to recruit the patients and draft the manuscript. PR helped to recruit the patients. CC helped to recruit the patients. HO helped to recruit the patients. PT participated in the design of the study and helped to draft the manuscript. KL participated in the design of the study, performed the measurement of plasma hormones levels and helped to draft the manuscript.