Critical illness encompasses a diverse range of severe conditions that require advanced organ support in the intensive care unit (ICU) and has an estimated prevalence of 45 million cases annually. Although it is a leading cause of death, critical illness is not a single condition and should be distinguished from the underlying disease diagnosis [1,2]. A proposed definition of critical illness is "a state of ill health with the potential for reversibility characterized by vital organ dysfunction and a high risk of imminent death if care is not provided" [3]. The duration and severity of critical illness are determined by its etiology, which includes systemic inflammatory response syndrome, compensatory anti-inflammatory response syndrome, cytokine release syndrome, acute respiratory distress syndrome (ARDS), multiple organ failure, persistent inflammation, immunosuppression, and catabolism syndrome [4]. Critical illnesses are marked by heightened systemic cortisol levels, an integral component of the stress response. In instances of acute stress, the risk of an adrenal crisis is elevated. This risk is increased further with underlying hypothalamic-pituitary-adrenal (HPA) axis pathology inadequately managed with stress doses of hydrocortisone [5]. Cortisol, a glucocorticoid hormone, is a primary product of the HPA axis that serves as a vital component of the biological stress response system. Cortisol dysregulation is implicated in various mental and physical health outcomes [6]. Glucocorticoids, including endogenous cortisol, exert predominantly anti-inflammatory and immunosuppressive effects by inhibiting the production and activity of inflammatory cells and promoting their redistribution to other body compartments, resulting in decreased circulating immune cells overall [7]. These mechanisms may contribute to mediating associations between stress exposure and subsequent developmental and health outcomes, impacting the onset and progression of both mental and physical health disorders. Corticosteroids are efficiently absorbed in the gastrointestinal tract, exhibit high protein binding, undergo hepatic metabolism, and are excreted by the kidneys [8].

Critical illness-related corticosteroid insufficiency (CIRCI) is characterized by adrenal insufficiency (AI) due to impaired functioning of the HPA axis, altered cortisol metabolism, and tissue corticosteroid resistance. These result in an exaggerated prolonged proinflammatory response, especially in ICU patients [9-13] in whom the incidence of CIRCI varies widely and ranges from 0% to 30%. In specific patient populations such as those with septic shock or trauma, the incidence can be as high as 25% to 40% and 50% to 70%, respectively [10,14,15]. In addition to an elevated 28-day mortality rate compared to non-CIRCI patients, a mortality rate of 34% among post-trauma CIRCI patients was reported. Non-survivors were older (65 years and older); had more severe base deficits at admission; required prolonged ventilatory days; and had increased rates of sepsis, bacteremia, and pneumonia [15-17].

CIRCI is a common and complex phenomenon, the understanding of which is evolving [10]. A study conducted in 2021 examined medical practitioners' approaches to CIRCI management, and 72% of respondents reported having to address CIRCI at least one weekly. However, the utilization of formal protocols for CIRCI diagnosis was limited, and a notable portion of practitioners forgo laboratory testing for this purpose. Moreover, a substantial majority expressed uncertainty regarding the therapeutic role of corticosteroids in CIRCI cases [14]. Therefore, given the CIRCI prevalence in various critical conditions, medical professional education on its pathophysiology and treatment is imperative [10].

Critical illness elicits a significant physiological stress response, prompting the body to activate various mechanisms to maintain homeostasis [18,19]. One crucial mechanism involves the heightened activity of the HPA axis, which rapidly increases systemic glucocorticoid levels that are essential for survival [20]. The classic model describes that the stressors in critically ill patients consist of neuronal and inflammatory signals that act on the hypothalamic nucleus paraventricularis to release corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP). The CRH and AVP are transported to the anterior pituitary to trigger the release of adrenocorticotropic hormone (ACTH) into the systemic circulation from corticotrope cells [21]. Under the influence of ACTH, the adrenal glands synthesize glucocorticoids (cortisol), mineralocorticoids (aldosterone), and adrenal androgens (dehydroepiandrosterone) from cholesterol. Adrenal mitochondria also play a pivotal role in steroidogenesis within adrenocortical cells, facilitating the conversion of intracellular cholesterol into cortisol [22]. The cortisol then exerts its systemic effects on numerous cells and modulates inflammation, cardiovascular function, and metabolism. However, in recent years, this traditional model has faced scrutiny, and it has been shown that elevated cortisol level in critically ill patients does not necessarily coincide with high concentration of plasma ACTH [21,23-25]. Dysregulation of the HPA axis, altered cortisol metabolism, and tissue resistance to glucocorticoids are now thought to be the three main pathophysiologic events in CIRCI [12].

CIRCI in the context of prolonged critical illness poses significant challenges in diagnosis due to overlapping signs and symptoms with the expected clinical course in these patients. These signs and symptoms include fatigue, weight loss, syncope, fever, confusion, somnolence, back and leg cramps, postural dizziness, and hypotension. In severe cases, hypovolemic shock and coma may occur [5,50]. Features such as encephalopathy, poor neurological recovery after sedation cessation, and persistent need for vasopressors should raise suspicion for CIRCI [5]. Additionally, a reduction in adrenal gland volume to less than 10 cm3, found in some patients with septic shock, has been linked to increased mortality [51].

The Endocrine Society advises stimulatory testing for cortisol deficiency in suspected primary adrenal insufficiency (PAI) cases. Confirmation of PAI typically involves morning cortisol level <140 nmol/l with elevated plasma ACTH, followed by the 250 μg Synacthen stimulation test [26,52,53]. ACTH measurement aids in distinguishing primary from secondary or tertiary AI. An ACTH value > 66 pmol/l is suggestive of PAI in patients with confirmed hypocortisolemia [52]. Stimulatory testing, using both low and high Synacthen doses, aids in diagnosis. Simultaneous renin and aldosterone measurement is recommended for mineralocorticoid deficiency confirmation [52,54]. Secondary AI diagnosis involves dynamic stimulatory testing; the insulin tolerance test is the gold standard for this [55]. The American College of Critical Care Medicine suggests considering AI in patients with random cortisol <10 μg/dl (275.9 nmol/L) [11-12,54].

However, diagnosing CIRCI is more complex. While a low random plasma cortisol concentration may raise suspicion, there is no clearly established guidelines for definitive CIRCI diagnosis [5,52]. Critically ill patients requiring mechanical and pharmacological support in the ICU for four weeks or longer, especially those with hemodynamic instability despite adequate resuscitation and vasopressor support, should be considered at risk for CIRCI. Furthermore, exposure to medications that affect the HPA axis or cortisol synthesis should heighten suspicion for CIRCI [5,54]. Laboratory findings in CIRCI may include hyponatremia, elevated creatinine levels, normochromic anemia, lymphocytosis, eosinophilia, hypoglycemia, and mild hypercalcemia [50]. Patients with CIRCI may also exhibit normal or low cortisol levels, low albumin and cortisol-binding globulin levels, normal or low ACTH levels, and high bile acid and bilirubin levels [5,21,25,56]. Elevated inflammatory cytokine levels, such as those for tumor necrosis factor, interleukin (IL)-1β, and IL-6, at ICU admission and throughout the ICU stay correlate with disease severity and increased mortality risk [57].

A total serum cortisol of <9 μg/dl post-ACTH stimulation or a random total cortisol level <10 μg/dl was considered reliable for diagnosing AI in critically ill patients according to the 2008 task force guidelines by the American College of Critical Care Medicine [11]. However, these criteria were not widely adopted in clinical practice, and recent guideline updates in 2017 do not include the use of these specific tests. Instead, the Endocrine Society confirms that the high-dose (250 μg) ACTH stimulation test is superior to other tests such as plasma or serum free cortisol, salivary free cortisol, low-dose ACTH stimulation, hydrocortisone levels (50–300 mg), and corticotropin levels in diagnosing CIRCI. Peak plasma total cortisol level <18 μg/dL at 30 or 60 minutes on high-dose ACTH stimulation is considered confirmatory in diagnosing CIRCI. Despite these suggestions, new pathophysiological evidence of CIRCI has had diagnostic implications. For example, the increase in distribution cortisol volume and the suppression of cortisol-binding globulin have invalidated the use of the classic 250 µg ACTH stimulation test [26,53,58]. Due to these pathophysiological changes, the stimulation test result is confounded as the incremental response of total plasma cortisol to the ACTH injection is suppressed. Although the ACTH stimulation test cannot be used as a marker of AI, a low cortisol response does reflect increased severity of the illness [25-26,59]. Random total cortisol concentrations are also unlikely to provide useful information to clinicians for diagnosis as they vary widely between patients and even within a single patient [26,53]. Additionally, specific imaging techniques like bedside ultrasound, computed tomography, or magnetic resonance imaging can assist in diagnosing CIRCI by distinguishing it from rare complications of critical illnesses, such as adrenal hemorrhage [38].

Although there are many findings that suggest the diagnosis, there is no single diagnostic test or imaging technique to reliably diagnose CIRCI [5]. When diagnosing CIRCI in critically ill patients, a comprehensive approach that considers clinical presentation, laboratory findings, and dynamic stimulatory testing is required. Acknowledging the challenges posed by altered cortisol dynamics and the evolving understanding of CIRCI pathophysiology also are required [26,53,58,59]. A better understanding of the presentation and diagnosis of AI in critically ill patients can help clinicians manage patients effectively and improve outcomes.

Once CIRCI is accurately diagnosed, treatment with intensive medical care and hydrocortisone is recommended. However, the exact hydrocortisone dose that is needed to manage CIRCI and prevent mortality is uncertain [5,21,60]. Traditionally, the recommendation was to administer doses ranging from 200 to 400 mg per day to critically ill patients in the ICU. This is equivalent to approximately 10 to 20 times the standard substitution or replacement dose [5,61,62]. The assumption behind this was that the dose would meet the daily cortisol requirement necessary to generate the elevated plasma concentration associated with severe stress in healthy HPA axis individuals [5,63,64].

A 2008 study by Marik et al. [11] recommended a hydrocortisone management regimen for CIRCI in septic shock cases. This recommendation was to administer 200 mg/day hydrocortisone in four divided doses or a continuous infusion at a rate of 240 mg/day (10 mg/hr), for at least 7 days in cases of septic shock. The study also recommended methylprednisolone at a daily dose of 1 mg per kg of body weight for at least 14 days, specifically for patients with severe early ARDS. Gradual glucocorticoid tapering, rather than abrupt discontinuation, is necessary. If symptoms of sepsis, hypotension, or worsening oxygenation recur, treatment should be reinstated. Dexamethasone is not recommended for treatment of CIRCI [11].

In a 2017 study, these guidelines were updated by a multi-specialty task force of 16 international experts in critical care medicine and endocrinology. Their recommendations were based on the evidence cited in the 2008 study and more recent findings from an updated systematic review. The recommendations were formulated using the Grading of Recommendations Assessment, Development, and Evaluation methodology and required approval by 80% of the task force members. This study further emphasized the need for an individualized approach that considers the patient's presentation, etiology, vital signs, and responsiveness to vasopressors and fluids in various critical illness conditions. For patients suffering from septic shock and not responding to standard treatments such as fluid resuscitation and vasopressor therapy, intravenous (IV) hydrocortisone at a dosage below 400 mg/day for a minimum of 3 days is recommended [12]. A 2018 study found that a hydrocortisone plus fludrocortisone regimen resulted in lower 90-day all-cause mortality compared to placebo in patients with septic shock [65]. Similarly, for patients with early moderate to severe ARDS, IV methylprednisolone at a dose of 1 mg/kg/day is suggested. For patients hospitalized with community-acquired pneumonia, corticosteroids for 5–7 days at a daily dose less than 400 mg IV hydrocortisone or its equivalent is recommended. Corticosteroids are also recommended for patients with bacterial meningitis and those undergoing cardiopulmonary bypass surgery. In the context of cardiac arrest, the use of corticosteroids is suggested. However, caution is needed when using corticosteroids in cases of major trauma and in adult patients with sepsis without shock. Several trials have shown no clear benefit in these cases, and the risks may outweigh benefits in such patients. Corticosteroids should not be administered in adults with influenza [12,66]. A 2022 study by Téblick et al. [5] proposed a more generalized approach for managing CIRCI, advising a daily hydrocortisone regimen of 60 mg split into two IV boluses, 40 mg in the morning and 20 mg in the evening. This replicates the normal diurnal rhythm that is disrupted in critically ill patients. Once corticosteroid treatment for CIRCI is initiated, administration should be tapered to the lowest effective maintenance dose. Discontinuation of the medication should be achieved as soon as possible [5,31,67].

The administration of corticosteroids in critically ill patients is associated with significant adverse effects that necessitate careful consideration. These include hyperglycemia due to disrupted glucose homeostasis, hypernatremia and fluid retention from altered renal function, and increased susceptibility to nosocomial infections due to immunosuppression. Corticosteroid use has also been linked to neuropsychiatric complications such as delirium and the development of ICU-acquired weakness [68]. However, emerging evidence suggests that the risk of ICU-acquired weakness may be mitigated by lower steroid dosages, better glycemic control, and reduced sedation. Thus, the appropriate steroid dosage balancing the therapeutic benefits with these potential adverse effects is crucial (Table 1) [69-71].

The increasing rate of ICU admissions highlights the importance of recognizing complications such as CIRCI. CIRCI presents a difficult diagnostic and therapeutic challenge in ICUs, necessitating a comprehensive understanding of its latest pathophysiology and evolving treatment strategies. CIRCI is characterized by AI and is triggered by use of certain medications and by various pathophysiological changes that occur in critically ill patients. These pathophysiological changes include dysfunction of the HPA axis, altered cortisol metabolism, and increased tissue resistance to cortisol. Diagnosing CIRCI requires evaluation of the patient's clinical signs and symptoms, laboratory results, and dynamic testing results. Although there is controversy regarding the exact recommended doses, glucocorticoid treatment approaches have evolved from traditional and generalized to individualized regimens that are specifically tailored to the patient's condition. Updates in treatment guidelines for CIRCI demonstrate ongoing research by incorporating the latest pathophysiological evidence and insights from various clinical trials. The aim is to improve management of critically ill patients. However, further research is needed, particularly randomized clinical trials investigating the short- and long-term outcomes of suggested treatments. Optimization of dosing and tapering strategies is also required. By enhancing understanding of CIRCI, clinicians can optimize patient care and mitigate the detrimental effects of this complex condition in the ICU setting.