Acute and severe illness is accompanied by increased serum levels of adrenocorticotrophic hormone (ACTH) and cortisol 123456789101112131415161718192021. Even elevated levels may be too low for the level of physiological stress and may be associated with diminished adrenal responsiveness to additional stress, so-called relative adrenal insufficiency (RAI). The most commonly used test to assess adrenal function is the short ACTH stimulation test, in which serum cortisol is measured at baseline and up to 60 min after intravenous administration of 250 μg of synthetic ACTH 234678910111214151718192021. A wide range exists in the prevalence of RAI among critically ill patients, varying from 0% to 77% 123456789101112131415171819202223. This is partly due to the heterogeneity of case-mix and of criteria for presumably insufficient cortisol response to ACTH, although a low response is most commonly empirically defined as an increase of less than 250 nmol/l (9 μg/dl) 48910111517181922.

Although there are no specific signs and symptoms of absolute adrenal insufficiency, several factors may be associated with RAI 578910121315222324. Remarkably, the literature is scarce and highly controversial on predictors and manifestations of RAI. Factors that are potentially associated with a low adrenal response are the presence of sepsis and shock 24567891112131516192224, high lactate 10, hypoalbuminaemia 1419, use of etomidate for intubation, mechanical ventilation and a low arterial oxygen tension/fractional inspired oxygen ratio 71620222425, antifungal agents 26, high percentage of eosinophils 8121324, low sodium and glucose 1213, and severe underlying disease or organ failure 7910162223. However, it is unknown whether these factors are interdependent 22. In addition, low albumin and cortisol-binding globulin (CBG) levels may lower binding capacity in blood, and this may decrease total but maintain free cortisol levels. Hence, total cortisol level may be a poor indicator of whether adrenal cortisol secretion is adequate for the degree of physiologic stress exhibited by critically ill patients 6141619272829. Indeed, although ACTH has no effect on albumin or CBG levels, the rise in total cortisol may be lower for a given rise in free cortisol when binding capacity is low 141928. Delineation of predictors and characteristics of RAI may help the clinician to select patients for ACTH testing. This may be important, because the results of the ACTH test may help to guide therapy with corticosteroids and thereby improve outcomes, particularly in vasopressor-refractory septic shock, although this is contoversial 689111317.

With the aim being to enhance understanding of RAI, the present study was undertaken to evaluate predictors of a low ACTH-induced cortisol response (exhibited by the so-called low responders), taking into account the severity of illness, baseline cortisol levels and hypoalbuminaemia. Therefore, a retrospective cohort study was conducted in 405 critically ill patients in whom an ACTH test was performed during the course of disease in our intensive care unit (ICU). The results of this analysis suggest that low pH/bicarbonate and low platelets, and greater severity of disease and organ failure are predictors of a subnormal increase in serum cortisol upon ACTH stimulation in a large series of critically ill patients; furthermore, these predictors were independent of sepsis, baseline cortisol and cortisol binding.

The main finding of the present study, comprising the largest series of ACTH tests in general ICU patients thus far reported, is the value of a set of clinical parameters for predicting RAI during critical illness. The set consisted of low arterial pH, low bicarbonate, low platelet count and high SOFA score, particularly in noncardiac (surgical) patients, and these predictors were independent of sepsis, interval until testing, intubation with etomidate, baseline cortisol and albumin levels. The results not only help in predicting a diminished response to ACTH stimulation but also provide insight into the pathophysiological mechanisms of a low response and significance of RAI. That low pH/bicarbonate is predictive of RAI can be explained by underlying circulatory insufficiency and perhaps adrenal hypoperfusion, or by metabolic acidosis directly suppressing adrenal cortisol synthesis 32. However, lactate levels did not differ among responders and low responders, thereby arguing against the former. The contribution of low platelets to a low response, independent of sepsis or infection, may be caused by circulating factors promoting platelet aggregation and impairing adrenal function; alternatively, it may be associated with adrenal microcirculatory thrombosis or bleeding, which are known to impair cortisol synthesis 33.

We used a cortisol increase of 250 nmol/l and a peak level of 500 nmol/l as the cutoff values to define RAI 24589101114151718192122, even though our data indicate a continuum of baseline cortisol and increases in cortisol values rather than a bimodal distribution. We did not exclude patients with very low baseline cortisol values or increases, which are partly attributable to low protein binding during critical illness 1419; this contributes to poor differentiation between absolute adrenocortical dysfunction and RAI in these patients. Although widely varying definitions and cutoff values have been used, and corresponding prevalences of RAI greatly differ between studies, an increase of less than 250 nmol/l appears to be associated with the greatest predictive value for steroid responsiveness in septic shock and mortality, although this is controversial 689111317. In any case, low increases can only partly be attributed to high baseline cortisol values, and the prevalence of RAI in the present study is in accordance with findings reported in the literature 6791013152223.

None of the classic signs and symptoms associated with adrenal insufficiency (for instance, fever, hyponatraemia and hyperkalaemia) was predictive of RAI in our patients, even though the blood glucose level was somewhat lower in low responders. Other investigators demonstrated an association of relative eosinophilia with low response to ACTH 8121324. A lower percentage of eosinophils among low responders in our study could be attributed to somewhat higher baseline cortisol levels. In any case, advanced age was not a predictor, which is in accordance with many other reports 8131522. Although prior cardiovascular disease or cardiac surgery was not associated with RAI, sepsis at admission, which was already present at admission in about 20% of low responders, was an independent predictor for a low response. This is in accordance with the literature, which indicates that there is a high incidence of RAI in patients with sepsis and shock 4578911121316192224. Plasma from patients with septic shock impairs synthesis of corticosteroids by adrenocortical cells 34. We evaluated predictors of low response in patients who had sepsis at admission and who met criteria for sepsis at the time of the ACTH test separately; these predictors appeared to be similar, in multivariate analyses. Because sepsis on the test day occurred in about 57% of low responders and was not an independent predictor, we cannot exclude the possibility that RAI also occurred in nonseptic hypotensive patients.

Low responders (cortisol increase < 250 nmol/l) were more often treated by vasopressors, which is in agreement with findings reported in the literature 57810152224. Etomidate is commonly used to facilitate endotracheal intubation; it is an inhibitor of 11β-hydroxylase, which is involved in cortisol synthesis. A single bolus of etomidate has been shown to diminish transiently the response to ACTH in critically ill patients 16202225. Indeed, depression of adrenal function by etomidate may be transient, but lasts for at least 24 hours 202225. However, in our study, intubation with the help of etomidate and the interval between intubation and the test were associated with low response in univariate analysis but not in multivariate analysis. Mechanical ventilation did not predict a low ACTH response either, which is in contrast to the literature 1724. Similarly, prior treatment of fungal infection with fluconazole, which utilizes the cytochrome P450 system for metabolism and which inhibits 11β-hydroxylase, did not predict RAI in our study; this is in accordance with the literature 26.

This study has some limitations. By virtue of the study design and rationale, the patients studied represent a selected group. We did not separately score for head trauma in our patients, which may carry risk for endocrine dysfunction. Nevertheless, a GCS score below 8 in the presence of trauma did not contribute to prediction of a low cortisol response (peak or increase). The CBG and free cortisol levels were not directly measured, and we might have underestimated baseline free cortisol levels and rises upon ACTH stimulation, as pointed out previously 6141619272829. However, we used albumin levels to estimate free cortisol, because albumin may also bind cortisol, albeit to a lesser extent than CBG, and both albumin and CBG levels may decrease to the same extent in critical illness 1619272829. Hamrahian and coworkers 14 also used blood albumin level as a surrogate marker of plasma cortisol binding capacity. Low albumin levels were associated with low baseline cortisol values and increases. However, hypoalbuminaemia independently increased the risk for a low response, suggesting that the latter was only partly caused by diminished cortisol-binding proteins; Ho and colleagues 19 concurred with this view, but Hamrahian and coworkers 14 attributed a low total cortisol response mainly to low serum cortisol-binding capacity. In groups divided on the basis of the Hamrahian criterion of an albumin level of less than (n = 309) or greater than 25 g/l (n = 23), there were no differences in baseline cortisol values and increases. Moreover, our findings with high baseline levels and low increases in cortisol associated with increasing severity of disease (Figure 1) and organ failure were not affected by cortisol binding, and the multivariate predictors of low responses were independent of baseline cortisol and albumin levels. Some studies 123, but not all, indeed suggest that (total) cortisol values increase and ACTH-induced increases diminish with increasing Acute Physiology and Chronic Health Evaluation II score or other disease severity and organ failure scores, unless limited by progressive and severe hypoalbuminaemia and decreased cortisol binding 12371019212223. Hence, the diminished (total and free) cortisol response to ACTH was a marker of severity of disease in our critically ill patients. Nevertheless, we cannot determine whether the free cortisol response to ACTH was sufficient in terms of ability to cope with additional stress. Conversely, the existence of RAI is doubtful when baseline (free) cortisol levels are high or when 250 μg ACTH is regarded as a supraphysiologic stimulus 51824.

We conclude that low pH/bicarbonate and low platelets, and increased severity of disease and organ failure were predictors of a subnormal increase in serum cortisol upon ACTH stimulation in a large series of critically ill patients, and these predictors were independent of sepsis, baseline cortisol and cortisol binding. This suggests that adrenocortical suppression occurs as a result of metabolic acidosis and coagulation disturbances. Even though increases in cortisol form a continuum and the cutoff values chosen are relatively arbitrary, our findings may help to better define RAI, which may be associated with increased mortality.

• In a large series of critically ill patients, low pH/bicarbonate and low platelets, and increased severity of disease and organ failure were predictors of a subnormal increase in serum cortisol upon ACTH stimulation.

• These predictors are independent of sepsis, baseline cortisol and cortisol binding.

• Adrenocortical suppression may be caused, in part, by metabolic acidosis and coagulation disturbances.

ACTH = adrenocorticotrophic hormone; CBG = cortisol-binding globulin; GCS = Glasgow Coma Scale score; ICU = intensive care unit; RAI = relative adrenal insufficiency; SAPS = Simplified Acute Physiology Score; SOFA = Sequential Organ Failure Assessment.

The authors declare that they have no competing interests.

AB participated in the design of the study and helped to draft the manuscript. AG helped to draft the manuscript. JG participated in the design and coordination of the study, and helped to draft the manuscript. JS helped to draft the manuscript. JT participated in the statistical analysis. MJ participated in the design of the study, carried out the data collection, performed the statistical analysis, and drafted the manuscript. RS helped to draft the manuscript.

All authors read and approved the final manuscript.