RAI has been well described in the literature, yet it remains a life-threatening and potentially fatal entity. Chronic AI is a rare entity [10], with an incidence of less than 0.01% in the general population [5]. RAI, however, is more common, with an incidence of up to 28% (range = 0.1–28%), yet it is frequently unrecognized or occult in critically ill patients [5]. The incidence of RAI, when recognized in critically ill patients, is variable and depends on the underlying disease. Reported incidence varies widely from 0 to 77% depending on the population of patients studied and the diagnostic criteria used to diagnose RAI [10–12]. Despite this variable incidence recorded in the literature, RAI remains underrecognized and has emerged as a contributing factor to morbidity and mortality during critical illness. If left untreated, it can lead to a dismal prognosis. Therefore, a very high index of clinical suspicion is required and delayed treatment and management cannot be justified by pending diagnostic confirmatory testing.
RAI results from an inadequate basal or stress level of plasma cortisol, in addition to a malfunctioning hypothalamic–pituitary–adrenal (HPA) axis that fails to respond to a combination of underlying disease, trauma, or postoperative homeostatic adaptation after surgery among other causes. The most common cause of acute RAI is sepsis and systemic inflammatory response syndrome (SIRS) [10].
Activation of the HPA axis in response to internal or external stress leads to an increased secretion of corticotropin-releasing hormone (CRH) and arginine vasopressin from the paraventricular nucleus of the hypothalamus. CRH then stimulates the anterior pituitary to release ACTH. This induces an increased secretion of cortisol from the zona fasciculata of the adrenal cortex [11–16]. Cholesterol is the principal precursor for steroid biosynthesis. In a series of sequential enzymatic steps, cholesterol is converted to pregnenolone and then to the end products of adrenal biosynthesis, which includes cortisol [11]. Prolonged elevation of serum cortisol, however, triggers a negative feedback inhibition loop that subsequently results in decreased secretion of both ACTH and cortisol [5]. Cortisol, a glucocorticoid, is an essential multifunctional stress response hormone that has anti-inflammatory, immunosuppressive, catabolic, metabolic, and vasoactive properties on peripheral vessels and cardiac muscles. From an anti-inflammatory and immunosuppressive perspective, cortisol decreases the accumulation and function of immune and inflammatory cells like macrophages, natural killer cells, mast cells, and eosinophils at inflammatory sites as a consequence of the activity of cytokines and other inflammatory mediators [10]. A metabolic property of cortisol entails elevation of blood glucose levels by increasing the rate of hepatic gluconeogenesis and inhibition of adipose tissue glucose uptake, thereby facilitating glucose delivery to cells during stress, both acute and chronic. Corticol also stimulates adipose tissue to release free fatty acids and proteins to release amino acids, hence supplying needed energy and substrate for cells to adequately respond to injury or stress [10].
RAI is primarily attributable to mineralocorticoid deficiency; thus, the clinical presentation is dominated by vasopressor-dependent refractory hypotension or refractory fluid-resuscitated hypotensive shock [1–3]. The shock, which is caused mainly by sodium and plasma volume depletion [13], is characterized by decreased systemic vascular resistance and increased cardiac output.
The classic signs or clinical presentations of AI are hypotension, hyperthermia, hyponatremia, hyperkalemia, hypercalcemia, hypoglycemia, metabolic acidosis, and eosinophilia. These conditions exist in other clinical settings and are features that can mimic sepsis and septic shock or underlying diseases, therefore making it difficult to identify AI in a population prone to these conditions, as was seen in the population studied. Hypotension refractory to fluids and requiring vasopressors is the most common feature of acute RAI. Without these presenting symptoms, it becomes difficult to determine which patients arriving in the critical care unit in shock and sepsis should be tested and treated for RAI by using the classic signs alone. A simple quick screening test would provide a way to select a set of patients at high risk of RAI.
We have seen in multiple studies that during stress, patients consistently increase their serum cortisol level to above 25 μg/dl, and often above the 30th threshold [1, 10]. This is well supported in the literature as an adequate cortisol response to critical illness [1, 2, 5, 9, 10, 16–20]. Schein et al. [18] reported a mean cortisol level of 50.7 μg/dl (range = 5.6–400 μg/dl) in 37 patients with septic shock and only 8% of those patients had a cortisol level <25 μg/dl. Chernow et al. [19] reported a mean cortisol level of 32 μg/dl an hour after the moderate stress of cholecystectomy and a level of 52 μg/dl an hour after the severe stress of subtotal colectomy. In the study by Rothwell et al. [20], the mean cortisol level was 27 μg/dl in patients admitted to the critical care unit who had cortisol levels drawn on admission and who had survived. In stressed patients in the critical care setting, a random cortisol level of >25 μg/dl [10] should be considered an adequate response to stress. This is why we defined RAI as a random serum cortisol concentration <25 μg/dl rather than using the cosyntropin stimulation test with its cutoff cortisol value of 18–20 μg/dl, which does not adequately test stressed patients in the critical care setting. The choice of 18–20 μg/dl is based primarily on the response to exogenous high-dose ACTH stimulation and the response to insulin-induced hypoglycemia in nonstressed non-critically ill patients [10]. It therefore should not be used in the diagnosis of RAI.