Hormonal changes and therapy for patients with TBI

In a critical-care setting, in patients with normal HPA axis function there is, usually, an early increase in plasma cortisol levels and failure to attain these high levels has been used to define corticosteroid insufficiency with a cut off at 100ng/ml for random PC according to the Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM)7.

The present study confirms that TBI, is associated to elevated PC levels in most cases, as a response to stress. Nonetheless, our study also reveals that corticosteroid insufficiency is common in the acute phase following TBI with an overall incidence of 29.5%. Similarly, the study by Hannon et al.12 showed this increase to be less pronounced after TBI.

Up until now, there have been a limited number of studies investigating HPA axis dysfunction in the first ten to fifteen days following TBI 1219. They reported an incidence of CI ranging from 4% to 78% 17,12,19,16,13,20,14,18. The variety in the published frequencies can be explained to a great extent by the use of different screening protocols, as the majority of studies reporting low incidences, relied on single readings for CI diagnosis, under-estimating by which the real incidence.

In contrast, the study by Hannon et al. documented a high incidence of CI reaching 78% using repetitive daily serum cortisol assessments 12.  This higher proportion of CI could, also, be explained by differences in the studied populations, the use of different cut offs and dynamic tests. The pathophysiological underlying mechanisms leading to these endocrine abnormalities in the acute phase after TBI are not fully understood. Damage to the hypothalamic-pituitary area could result from Skull fractures, ischemia secondary to hypoxia and hypotension, oedema leading to increased intracranial pressure or even diffuse axonal injuries 21,22.

On the other hand, the reported  modifications in hormone levels early after TBI could be related to the acute illness as major trauma is a cause of non-septic systemic inflammatory response syndrome 23 and it has been well demonstrated that there are hormonal alterations associated to acute critical illness as compared to patients baseline hormone levels 2427. In the present study we found no association between the diagnosed hormonal abnormalities and injury characteristics.

It is unclear whether the hormonal changes are related to CRH and ACTH deficiencies due to cerebral injuries or if they are actually  attributed to a decrease in adrenal cortisol secretion resulting from cytokines release 7,28,29 and the use of drugs

such as etomidate in a critically ill patients 30. In fact, reviewing literature, CI cases occurring at the early post-TBI period were due in a large proportion, to primary rather than central adrenal dysfunction and resulting from a relative adrenal insufficiency 16,20 in response to stress. Our results however cannot conclusively prove this since no ACTH test was used.

Interestingly, the association of low PC levels to the severity of the critical illness, illustrated by high SOFA and IGSII scores, lend support to this theory. Finally, we should note that alterations in albumin concentrations, directly affecting free cortisol levels, were not considered in this research since our study population consisted of young previously healthy adults, presumably with serum albumin being within normal ranges.

According to our analysis, CI was related to poor outcome and death in the ICU. Similarly, in the study by Hannon and al.12, there was a clear association between acute hypocortisolism and mortality. Besides, patients with lower PC levels had higher mortality rates. In contrast, there was no impact on 3-month-outcome in the study by Olivecrona and colleagues 19. In fact, cortisol is a major stress response hormone and it is well-Known that the rise in PC concentrations is crucial for survival 31.

Conclusively, early suppression of the pituitary-adrenal axis could expose ICU patients to life-threatening complications such as hypoglycemia and vasopressors-resistant hypotension. On the other hand, the high mortality rate in our study could be explained, by the severity of patients stated by high severity scoring on admission with a mean SAPSII at 32 ± 10, a mean SOFA score at 4.5 ± 2, and a mean ISS at 34 ± 11. The severity of critical illness is probably a major determinant of early death following TBI.

However, according to our analysis, CI was an independent risk factor of mortality using a logistic regression model including patients severity scores.Curiously, most low readings occurred during the first 3 days after admission, at the time when PC levels should be at their highest. These findings might suggest a need for replacement glucocorticoid therapy. Many studies evaluating  hormone derangements related to acute critical illness have failed to show benefits of hormone treatment on neurological outcome and short term mortality 7,19,32.

Besides, given the lack of solid data supporting the use of glucosteroids in post-trauma settings, the most recent guidelines regarding CIRCI made a conditional recommendation suggesting against the empiric use of corticosteroids in major trauma. However, we could argue that in the specific context of proven cortisol deficiency, given the critical state of patients and the known devastating consequences of CI including uncontrolled inflammation and vasopressor dependency, we suggest that patients with acute adrenal insufficiency should benefit from supplement corticosteroid therapy.