There is no doubt that both cortisol excess and cortisol deficiency are associated with increased morbidity and mortality.1,2 Having an intact hypothalamo-pituitary-adrenal (HPA) axis that can mount an appropriate cortisol response at times of stress and, indeed, critical illness is fundamentally important to survival.
As endocrinologists, we are often faced with an acutely unwell patient. We are asked whether inadequate cortisol production could be contributing to their clinical course and, if so, whether replacement with parenteral hydrocortisone would be beneficial. Whilst the questions are very reasonable and, on the surface, seem straightforward, when one begins to probe both the questions and the published literature a little more deeply, the waters become a little murky to say the least.
WHAT IS A CRITICALLY ILL PATIENT?
The first issue is in defining ‘a critically ill patient’. Much of the literature relates to the HPA axis (its assessment and subsequent replacement) in the context of sepsis. However, we cannot necessarily generalise across all conditions. There are many other acute medical and surgical presentations where patients may be critically ill.
Assessment of the HPA axis is complex and, over the last decade, several publications have reported evidence suggesting inadequate cortisol secretion in the setting of critical illness, most commonly septic shock, associated with an adverse outcome.3 Differing cut-offs for random cortisol measurements, as well as incremental increases in cortisol across the short synacthen test (SST), have been proposed. Furthermore, estimates have suggested that inadequate cortisol responses may be present in up to 60% of patients with sepsis.4
INCREASED UNDERSTANDING OF THE HPA AXIS
However, more recently, our understanding of the physiological response of the HPA axis to critical illness and sepsis has changed. There is adrenocorticotrophin (ACTH) resistance at the adrenal gland with elevated circulating levels, which is paralleled by changes in glucocorticoid metabolism. Cortisol clearance is decreased at a tissue-specific level, increasing cortisol half-life and decreasing production rate. In addition, cortisol-binding globulin concentrations are decreased, increasing the bioactive available cortisol.5
In this context, interpretation of a one-off, random, circulating cortisol measurement becomes very hard, as does a meaningful assessment of the response to a pharmacological dose of synthetic ACTH.
ASSESSING PATIENTS’ INDIVIDUAL NEEDS
Faced with these challenges, one has to adopt a pragmatic safety first approach. In certain situations the ‘pre-test probability’ of cortisol deficiency is high. These might include patients who are known to have underlying adrenal or pituitary disease, or situations where the pathophysiology of the acute critical illness may cause acute cortisol deficiency (e.g. adrenal haemorrhage, use of etomidate, use of antifungals or CYP3A4 inducers). In these cases, treatment is either mandatory or the threshold for treatment should be very low. Importantly, there is little, if any, evidence that treating with parenteral hydrocortisone is detrimental.
‘Assessing the HPA axis in critically ill patients is as challenging as ever ... The interpretation of isolated cortisol measurements from the circulation must be set in the clinical context in which they are taken’
In some patients, there is a high index of clinical suspicion, for example, where there is unexplained hypovolaemia, vasopressor-resistant hypotension, hyponatraemia or hyperkalaemia. In these situations, we are often presented with a random cortisol measurement. Each patient must be assessed individually, but it is reasonable to treat patients with clinical features such as those described above, and a random cortisol lower than 500nmol/l, with parenteral hydrocortisone. Levels higher than this are likely to suggest an adequate adrenal reserve, although the evidence base to confirm this is limited.
The most recent guidelines, published as part of the surviving sepsis campaign, would endorse this approach. They suggest that hydrocortisone should only be considered in individuals who have shock that is resistant to standard therapeutic approaches (and not used at all in the absence of shock). ACTH stimulation tests should not be used and the level of 500nmol/l should be considered as the threshold suggestive of an inappropriately low cortisol level in critical illness.6
Finally, this leads to the question of replacement therapy in individuals who have inappropriately low cortisol levels that may be contributing to their clinical presentation. Whilst initial reports had suggested that giving hydrocortisone (and fludrocortisone) replacement improved survival in patients with inadequate cortisol reserve (as measured by SST),7 a subsequent larger study failed to show any difference in response when stratified by SST cortisol measurement, although in this study only hydrocortisone was administered.8
IN SUMMARY
Certainly there is no rationale for the widespread use of hydrocortisone replacement. Bearing in mind the changes in the HPA axis associated with critical illness, there is the potential for replacing with too much glucocorticoid. Administering 200mg hydrocortisone over a 24-h period (as an infusion or as 50mg boluses every 6h) probably achieves a level of cortisol that one might expect in the context of critical illness. Although infusions are recommended as part of the sepsis guidance,6 there are currently no data to suggest any differences in outcome between the two approaches to replacement.
In conclusion, assessing the HPA axis in critically ill patients is as challenging as ever. Our increased understanding of cortisol secretion, metabolism and action means that the interpretation of isolated cortisol measurements from the circulation must be set in the clinical context in which they are taken. They really only serve as one part of the patient’s assessment (alongside clinical judgement), to guide, but not dictate, the necessity of treatment.
Jeremy W Tomlinson
Professor of Metabolic Endocrinology & Consultant Endocrinologist, Oxford Centre for Diabetes, Endocrinology & Metabolism
REFERENCES
1. Graversen D et al. 2012 European Journal of Internal Medicine 23 278–282.
2. Souverein PC et al. 2004 Heart 90 859–865.
3. Annane D et al. 2000 JAMA 283 1038–1045.
4. Annane D et al. 2006 American Journal of Respiratory & Critical Care Medicine 174 1319–1326.
5. Peeters B et al. 2015 Molecular & Cellular Endocrinology 408 235–240.
6. Dellinger RP et al. 2012 Intensive Care Medicine 39 165–228.
7. Annane D et al. 2002 JAMA 288 862–871.
8. Sprung CL et al. 2008 New England Journal of Medicine 358 111–124.
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