Diagnosis and management of secondary adrenal crisis.

Adrenal crisis (AC) is a life threatening acute adrenal insufficiency (AI) episode which can occur in patients with primary AI but also secondary AI (SAI), tertiary AI (TAI) and iatrogenic AI (IAI). In SAI, TAI and IAI, AC may develop when the HPA axis is unable to mount an adequate glucocorticoid response to severe stress due to pituitary or hypothalamic disruption. It manifests as an acute deterioration in multi-organ homeostasis that, if untreated, leads to shock and death. Despite the availability of effective preventive strategies, its prevalence is increasing in patients with SAI, TAI and IAI due to more frequent exogenous steroid administration, pituitary immune-related effects of immune checkpoint inhibitors and opioid use in pain management. The delayed diagnosis of acute AI which remains infrequently suspected increases the risk of AC. Its main precipitating factors are infections, emotional distress, surgery, cessation or reduction in GC doses, pituitary infarction or surgical cure of endogenous Cushing's syndrome. In patients not known previously to have SAI/TAI/IAI, recognition of its symptoms, signs, and biochemical abnormalities can be challenging and cause delay in proper diagnosis and therapy. Effective therapy of AC is rapid intravenous administration of hydrocortisone (initial bolus of 100 mg followed by 200 mg/24 h as continuous infusion or bolus of 50 mg every 6 h) and 0.9% saline. In diagnosed patients, preventive education in sick-day rules adjustment of glucocorticoid replacement and hydrocortisone parenteral self-administration must be performed repeatedly by trained health care providers. Strategies to improve the adequate preventive education in patients at risk for secondary AI should be promoted in collaboration with various medical specialist societies and patients support associations.

An unusual cause of adrenal insufficiency with elevation of 17-hydroxyprogesterone: case report.

BACKGROUND: We present an intriguing case of primary adrenal lymphoma, with associated primary adrenal insufficiency (PAI), in a patient presenting a transitory partial 21-hydroxylase deficiency during the active phase of the adrenal disease. CASE PRESENTATION: An 85-years old woman was referred because of worsening asthenia, lumbar pain, generalized myalgia and arthralgia. During investigations a computed tomography (CT) scan evidenced two large bilateral adrenal masses, highly suspicious for primary adrenal tumor. The hormonal assessment revealed very low levels of morning plasma cortisol and 24-h urinary cortisol, elevated ACTH levels with low plasma concentration of aldosterone, pointing to the diagnosis of PAI. After diagnosis of PAI our patient started glucocorticoid and mineralcorticoid replacement therapy with clinical benefit. In order to further characterize the adrenal lesions, adrenal biopsy, was performed. The histology revealed a high grade non-Hodgkin lymphoma with an immunophenotype consistent with intermediate aspects between diffuse large B-cell and Burkitt lymphoma, with a high proliferation index (KI-67 > 90%). The patient received chemotherapy with epirubicin, vincristine, cyclophosphamide, and rituximab, associated with methylprednisolone that resulted in a complete clinical and radiological remission within one year. After 2 years from the diagnosis and a total of 6 cycles of rituximab, the patient was in good clinical condition and was taking only the replacement therapy for PAI. The patient initially presented also a slight increase of 17-hydroxyprogesterone (17-OHP) for age that normalize after resolution of lymphoproliferative disease. CONCLUSIONS: In the presence of bilateral adrenal disease and/or in the presence of signs and symptoms of PAI clinicians must exclude the presence of PAL. The evidence of elevated ACTH-stimulated 17-OHP levels also in patients with other adrenal masses, together with the detection of elevated basal 17-OHP levels in our patient make it more plausible, in our view, an effect of the lesion on the "healthy" adrenal tissue residue than a direct secretory activity by the adrenal tumor.

Current and future perspectives on clinical management of classic 21-hydroxylase deficiency.

Optimizing the glucocorticoid dosage has been a major concern in classic 21OHD (21-hydroxylase deficiency) treatment, as it is essential to adjust it meticulously to the needs of the individual patient. Insufficient glucocorticoid treatment will cause adrenal insufficiency, including life-threatening adrenal crisis, while excess of androgen could cause precocious pubertal growth in children, virilization in female patients, and infertility in male and female adult patients. Meanwhile, overtreatment with glucocorticoids causes iatrogenic Cushing's syndrome which could result in growth impairment, obesity, osteoporosis, and hypertension. The dilemma of 21OHD treatment is that glucocorticoid supplementation therapy at physiological dosage does not sufficiently suppress ACTH, consequently leading to adrenal androgen excess. Accordingly, the window for the appropriate glucocorticoid treatment would have to be substantially narrower than that of other types of adrenal insufficiency without androgen excess, such as adrenal hypoplasia. For the appropriate management of classic 21OHD, the physician has to be well versed in the physiology of the adrenal cortex, growth, and reproductive function. Comprehensive understanding of patients' requirements according to their life stage and sex is essential. Furthermore, female patients with 46,XX need to be cared for as differences in sex development (DSD) with careful psychological management. In this review, we aimed to comprehensively summarize the current status of classic 21OHD treatment, including the initial treatment during the neonatal period, management of adrenal insufficiency, maintenance therapy of each life stage, and the importance of clinical management as DSD for 46,XX female patients. The recently developed agents, Chronocort, and Crinecerfont, are also discussed.

Adrenal insufficiency.

Adrenal insufficiency can arise from a primary adrenal disorder, secondary to adrenocorticotropic hormone deficiency, or by suppression of adrenocorticotropic hormone by exogenous glucocorticoid or opioid medications. Hallmark clinical features are unintentional weight loss, anorexia, postural hypotension, profound fatigue, muscle and abdominal pain, and hyponatraemia. Additionally, patients with primary adrenal insufficiency usually develop skin hyperpigmentation and crave salt. Diagnosis of adrenal insufficiency is usually delayed because the initial presentation is often non-specific; physician awareness must be improved to avoid adrenal crisis. Despite state-of-the-art steroid replacement therapy, reduced quality of life and work capacity, and increased mortality is reported in patients with primary or secondary adrenal insufficiency. Active and repeated patient education on managing adrenal insufficiency, including advice on how to increase medication during intercurrent illness, medical or dental procedures, and profound stress, is required to prevent adrenal crisis, which occurs in about 50% of patients with adrenal insufficiency after diagnosis. It is good practice for physicians to provide patients with a steroid card, parenteral hydrocortisone, and training for parenteral hydrocortisone administration, in case of vomiting or severe illness. New modes of glucocorticoid delivery could improve the quality of life in some patients with adrenal insufficiency, and further advances in oral and parenteral therapy will probably emerge in the next few years.

Diagnosis and Management of Adrenal Insufficiency and Adrenal Crisis in the Emergency Department.

BACKGROUND: Adrenal insufficiency can result in significant patient morbidity and mortality, but due to the range of symptoms and variable clinical course and etiologies, it can be a challenging condition to diagnose and manage. OBJECTIVE: This narrative review will discuss the evaluation of an adult patient at risk for a new diagnosis of adrenal insufficiency and the management of a patient with known or suspected adrenal insufficiency. DISCUSSION: A new presentation of adrenal insufficiency can range from nonspecific, minor symptoms including fatigue, to a life-threatening adrenal crisis with hemodynamic instability. Due to the variety of signs and symptoms, the diagnosis is often missed. Those with known adrenal insufficiency are at risk for adrenal crisis, which may occur due to a variety of triggers. Initial evaluation includes assessment for the underlying etiology or concomitant condition, laboratory analysis, and imaging, when clinically indicated. Although not necessary for evaluation in the emergency department setting, the diagnosis is confirmed by specific testing such as the cosyntropin stimulation test. The mainstay of treatment in adrenal crisis is hydrocortisone, intravenous fluid, glucose repletion, and treatment of the underlying acute trigger. CONCLUSIONS: Emergency clinicians must be prepared to recognize, evaluate, and manage those with known or suspected adrenal insufficiency or adrenal crisis.

[Acute adrenal insufficiency: an entity that should not be missed]. / Insuffisance surrénalienne aiguë†: une entité à ne pas manquer.

Acute adrenal insufficiency is a rare pathology which can be life threatening if not diagnosed and treated adequately. Clinical presentation is aspecific. Etiologies are classified as central or adrenal origins. Diagnosis of adrenal insufficiency is based on dosage of morning cortisol combined with a Synacthen test. When acute adrenal insufficiency is suspected, 100 mg of hydrocortisone should be administered as soon as possible, even before biological confirmation. This article, illustrated by a clinical case, will review the clinical presentation, diagnostic approach, and treatment of adrenal insufficiency.

L'insuffisance surrénalienne (IS) aiguë est une pathologie qui engage le pronostic vital si elle n'est pas diagnostiquée et traitée rapidement. Sa présentation clinique est aspécifique. Les étiologies sont classées en origines surrénaliennes ou centrales. Le diagnostic d'IS repose sur le dosage du cortisol matinal ainsi que sur un test au Synacthen. Lors d'une suspicion d'IS aiguë, le traitement par hydrocortisone 100 mg IV doit être administré dans les meilleurs délais sans attendre la confirmation biologique. Cet article, illustré par un cas clinique, a pour but de rappeler la présentation clinique, la démarche diagnostique et la prise en charge médicamenteuse de l'IS.

Mechanistic insights into immune checkpoint inhibitor-related hypophysitis: a form of paraneoplastic syndrome.

BACKGROUND: Immune checkpoint inhibitors (ICIs) as a cancer immunotherapy have emerged as a treatment for multiple advanced cancer types. Because of enhanced immune responses, immune-related adverse events (irAEs), including endocrinopathies such as hypophysitis, have been associated with the use of ICIs. Most underlying mechanisms of ICI-related hypophysitis remain unclear, especially for programmed cell death-1 (PD-1)/PD-1 ligand 1 (PD-L1) inhibitors. We hypothesized that ICI-related hypophysitis is associated with paraneoplastic syndrome caused by ectopic expression of pituitary-specific antigens. METHODS: Twenty consecutive patients with ICI-related hypophysitis between 2017 and 2019 at Kobe University Hospital were retrospectively analyzed. Circulating anti-pituitary antibodies were detected using immunofluorescence staining and immunoblotting. Ectopic expression of pituitary autoantigens in tumor specimens was also examined. RESULTS: Eighteen patients were treated with PD-1/PD-L1 inhibitors, and two were treated with a combination of cytotoxic T-lymphocyte antigen-4 (CTLA-4) and PD-1 inhibitors. All patients showed adrenocorticotropic hormone (ACTH) deficiency and additionally, three showed thyroid-stimulating hormone (TSH) deficiency, and one showed gonadotropin-releasing hormone (GnRH) deficiency. Among these patients, three exhibited anti-pituitary antibodies, two with anti-corticotroph antibody and one with anti-somatotroph antibody. Interestingly, the anti-corticotroph antibody recognized proopiomelanocortin (POMC) and those two patients exhibited ectopic ACTH expression in the tumor, while the patients without anti-corticotroph antibody did not. CONCLUSIONS: We demonstrated 10% of PD-1/PD-L1 inhibitors-related hypophysitis were associated with the autoimmunity against corticotrophs and maybe caused as a form of paraneoplastic syndrome, in which ectopic expression of ACTH in the tumor was observed. It is also suggested that the pathophysiology is heterogenous in ICI-related hypophysitis.

The epidemiology of primary and secondary adrenal malignancies and associated adrenal insufficiency in hospitalised patients: an analysis of hospital admission data, NSW, Australia.

BACKGROUND: Adrenal insufficiency (AI) causes considerable morbidity but may remain undiagnosed in patients with adrenal malignancy (AM). The epidemiology of AI and adrenal crises (AC) in AM is uncertain. METHODS: This was a retrospective study examining hospital admission data from 2006 to 2017. All admissions to all hospitals in NSW, Australia over this period with a principal or comorbid diagnosis of an adrenal malignancy were selected. Data were examined for trends in admissions for AM and associated AI/AC using population data from the corresponding years. RESULTS: There were 15,376 hospital admissions with a diagnosis of AM in NSW over the study period, corresponding to 1281 admissions/year. The AM admission rate increased significantly over the study period from 129.9/million to 215.7/million (p < 0.01). An AI diagnosis was recorded in 182 (1.2%) admissions, corresponding to an average of 2.1/million/year. This rate increased significantly over the years of the study from 1.2/million in 2006 to 3.4/million in 2017 (p < 0.01). An AC was identified in 24 (13.2%) admissions with an AI diagnosis. Four patients (16.7%) with an AC died during the hospitalisation. CONCLUSION: Admission with a diagnosis of AM has increased over recent years and has been accompanied by an increase in AI diagnoses. While AI is diagnosed in a small proportion of patients with AM, ACs do occur in affected patients.

Metabolic and Endocrine Challenges.

This review aims to provide an overview of metabolic and endocrine challenges in the setting of intensive care medicine. These are a group of heterogeneous clinical conditions with a high degree of overlap, as well as nonspecific signs and symptoms. Several diseases involve multiple organ systems, potentially causing catastrophic dysfunction and death. In the majority of cases, endocrine challenges accompany other organ failures or manifest as a complication of prolonged intensive care unit stay and malnutrition. However, when endocrine disorders present as an isolated syndrome, they are a rare and extreme manifestation. As they are uncommon, these can typically challenge both with diagnosis and management. Acute exacerbations may be elicited by triggers such as infections, trauma, surgery, and hemorrhage. In this complex scenario, early diagnosis and prompt treatment require knowledge of the specific endocrine syndrome. Here, we review diabetic coma, hyponatremia, hypercalcemia, thyroid emergencies, pituitary insufficiency, adrenal crisis, and vitamin D deficiency, highlighting diagnostic tools and tricks, and management pathways through defining common clinical presentations.

Pediatric Post-Cardiac Arrest Care: A Scientific Statement From the American Heart Association.

Successful resuscitation from cardiac arrest results in a post-cardiac arrest syndrome, which can evolve in the days to weeks after return of sustained circulation. The components of post-cardiac arrest syndrome are brain injury, myocardial dysfunction, systemic ischemia/reperfusion response, and persistent precipitating pathophysiology. Pediatric post-cardiac arrest care focuses on anticipating, identifying, and treating this complex physiology to improve survival and neurological outcomes. This scientific statement on post-cardiac arrest care is the result of a consensus process that included pediatric and adult emergency medicine, critical care, cardiac critical care, cardiology, neurology, and nursing specialists who analyzed the past 20 years of pediatric cardiac arrest, adult cardiac arrest, and pediatric critical illness peer-reviewed published literature. The statement summarizes the epidemiology, pathophysiology, management, and prognostication after return of sustained circulation after cardiac arrest, and it provides consensus on the current evidence supporting elements of pediatric post-cardiac arrest care.

GLUCOCORTICOID-INDUCED ADRENAL INSUFFICIENCY: A STUDY OF THE INCIDENCE IN HOSPITAL PATIENTS AND A REVIEW OF PERI-OPERATIVE MANAGEMENT.

OBJECTIVE: Glucocorticoid (GC) pharmacotherapy is an effective treatment for a range of diseases, but exposure can suppress the hypothalamic-pituitary-adrenal axis, leading to glucocorticoid-induced adrenal insufficiency (GC-AI) in some patients. However, the incidence of diagnosed GC-AI and the associated health burden, including the incidence of adrenal crises (ACs), are unknown. Although GC-AI treatment is based on well-established principles, there are no agreed protocols regarding the peri-operative management of exposed patients. The aims of this study were to assess the incidence of diagnosed GC-AI in hospital patients and review current approaches to peri-operative management of surgical patients with GC exposure. METHODS: An analysis of hospital admission data concerning adult patients diagnosed with GC-AI and a review of published recommendations for peri-operative GC cover. RESULTS: Between 2001 and 2013, admission with a diagnosis of GC-AI in New South Wales, Australia was rare (annual average of 22.5 admissions/year) and ACs were even more rare (n = 3). Almost two-thirds (64.4%, n = 188) of the patients with diagnosed GC-AI were aged between 50 and 79 years and 45.2% (n = 132) had a comorbid infection. The current approach to peri-operative management of patients with GC exposure appears to be influenced by both the absence of clear guidelines and historic practices. This results in the exposure of some patients to supraphysiologic doses of GCs during the peri-operative period. CONCLUSION: Hospital admission with a diagnosis of GC-AI (with or without an AC) is very rare. Clear guidelines on peri-operative GC cover are necessary to avoid overreplacement with supraphysiologic doses in susceptible patients. ABBREVIATIONS: AC = adrenal crisis; ACTH = adrenocorticotropic hormone; AI = adrenal insufficiency; CI = confidence interval; GC = glucocorticoid; GC-AI = glucocorticoid-induced adrenal insufficiency; HPA = hypothalamic-pituitary-adrenal; OR = odds ratio.

Primary Adrenal Failure in the Emergency Department.

BACKGROUND: Primary adrenal failure is considered to be an extremely rare disease presenting in the ED, with an incidence reported to be as low as 50 cases per 1,000,000 persons (Klauer, 2017). I would like to present a case of a young man who presented to the ED, with what I suspected to be this rare entity. CASE REPORT: A 26year old otherwise healthy male presented to our ED with complaints of weakness, nausea, vomiting, and hiccups of 1.5-day duration. He also complained of lightheadedness, describing it as if he was going to pass out. Other than slight tachycardia (100) and darkened skin, his physical exam, ROS, PMH, Family and Social History, were all unremarkable. His sodium returned at 111, and he was later noted to become more confused in the ED prompting the emergent use of Hypertonic Saline. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Albeit a rare disease entity, EPs need to keep this life threatening disease process in the back of their minds when presented with a patient with vague symptoms such as weakness or fatigue, electrolyte abnormalities and darkening of their skin.

Prolonged adrenal insufficiency after high-dose glucocorticoid in infants with leukemia.

Although outcomes for infant leukemia have improved recently, transient adrenal insufficiency is commonly observed during treatment, especially after glucocorticoid administration. We identified three infants with acute leukemia who suffered from prolonged adrenal insufficiency requiring long-term (from 15 to 66 months) hydrocortisone replacement. All infants showed life-threatening symptoms associated with adrenal crisis after viral infections or other stress. Severe and prolonged damage of hypothalamo-pituitary-adrenal (HPA) axis is likely to occur in early infants with leukemia, therefore routine tolerance testing to evaluate HPA axis and hydrocortisone replacement therapy are recommended for infants with leukemia to avoid life-threatening complications caused by adrenal crisis.

Russell's Viper Envenomation-Associated Addisonian Crisis.

Snakebite envenomation is an important public health problem in tropical countries. We report a case of bilateral adrenal hemorrhage in a 28-y-old man with Russell's viper bite that occurred in the Sathyamangalam forest range in the Indian state of Tamil Nadu. In this case, a combination of early bite recognition, hospital-based supportive care, corticosteroid therapy, and timely administration of polyvalent antivenom resulted in a favorable clinical outcome.

Revised consensus statement on the preventive and symptomatic care of patients with leukodystrophies.

Leukodystrophies are a broad class of genetic disorders that result in disruption or destruction of central myelination. Although the mechanisms underlying these disorders are heterogeneous, there are many common symptoms that affect patients irrespective of the genetic diagnosis. The comfort and quality of life of these children is a primary goal that can complement efforts directed at curative therapies. Contained within this report is a systems-based approach to management of complications that result from leukodystrophies. We discuss the initial evaluation, identification of common medical issues, and management options to establish a comprehensive, standardized care approach. We will also address clinical topics relevant to select leukodystrophies, such as gallbladder pathology and adrenal insufficiency. The recommendations within this review rely on existing studies and consensus opinions and underscore the need for future research on evidence-based outcomes to better treat the manifestations of this unique set of genetic disorders.

The screening and management of pituitary dysfunction following traumatic brain injury in adults: British Neurotrauma Group guidance.

Pituitary dysfunction is a recognised, but potentially underdiagnosed complication of traumatic brain injury (TBI). Post-traumatic hypopituitarism (PTHP) can have major consequences for patients physically, psychologically, emotionally and socially, leading to reduced quality of life, depression and poor rehabilitation outcome. However, studies on the incidence of PTHP have yielded highly variable findings. The risk factors and pathophysiology of this condition are also not yet fully understood. There is currently no national consensus for the screening and detection of PTHP in patients with TBI, with practice likely varying significantly between centres. In view of this, a guidance development group consisting of expert clinicians involved in the care of patients with TBI, including neurosurgeons, neurologists, neurointensivists and endocrinologists, was convened to formulate national guidance with the aim of facilitating consistency and uniformity in the care of patients with TBI, and ensuring timely detection or exclusion of PTHP where appropriate. This article summarises the current literature on PTHP, and sets out guidance for the screening and management of pituitary dysfunction in adult patients with TBI. It is hoped that future research will lead to more definitive recommendations in the form of guidelines.

Adrenal disorders: Is there Any role for vitamin D?

An emerging branch of research is examining the linkage between Vitamin D and nonskeletal disorders, including endocrine diseases. In this regard, a still little studied aspect concerns the involvement of vitamin D in adrenal gland disorders. Adrenal gland disorders, which might be theoretically affected by vitamin D unbalance, include adrenal insufficiency, Cushing's syndrome, adrenocortical tumors and hyperaldosteronism. In this review, we provide an updated document, which tries to collect and discuss the limited evidence to be found in the literature about the relationship between vitamin D and adrenal disorders. We conclude that there is insufficient evidence proving a causal relationship between vitamin D levels and adrenal disorders. Evidence coming from cross-sectional clinical studies can hardly clarify what comes first between vitamin D unbalance and adrenal disease. On the other hand, longitudinal studies monitoring the levels of vitamin D in patients with adrenal disorders or, conversely, the possible development of adrenal pathologies in subjects affected by impaired vitamin D levels would be able to elucidate this still unclear issue.

Achalasia: Outcome in children.

BACKGROUND: Oesophageal achalasia is well-recognized but relatively rare in children, occasionally appearing as the "triple A" syndrome (with adrenal insufficiency and alacrima). Treatment modalities, as in adult practice, are not curative, often needing further interventions and spurring the search for better management. The outcome for syndromic variants is unknown. We sought to define the efficacy of treatments for children with achalasia with and without triple A syndrome. METHODS: We conducted a retrospective analysis of presentation and outcomes for 42 children with achalasia presenting over three decades to a major pediatric referral center. Long term impact of the diagnosis was assessed by questionnaire. RESULTS: We identified 42 children including six with triple A syndrome. The median overall age at diagnosis was 10.8 years and median follow-up 1593 days. Initial Heller myotomy in 17 required further interventions in 11 (65%), while initial treatment with botulinum toxin (n = 20) was ultimately followed by myotomy in 17 (85%). Ten out of 35 patients who underwent myotomy required a repeat myotomy (29%). Patients with triple A syndrome developed symptoms earlier, but had delayed diagnosis, were more underweight at diagnosis and at last follow up. Questionnaire results suggested a significant long term deleterious impact on the quality of life of children and their families. CONCLUSION: Many children with achalasia relapse after initial treatment, undergoing multiple, different procedures, despite which symptoms persist and impact on quality of life. Symptoms develop earlier in patients with triple A syndrome, but the diagnosis is delayed and this has substantial nutritional impact.

Exploration of knowledge and understanding in patients with primary adrenal insufficiency: a mixed methods study.

BACKGROUND: Primary adrenal insufficiency (PAI) is a rare and severe condition requiring lifelong steroid replacement. During acute illness or stressful events, it is important to appropriately adjust glucocorticoid dose; failure to do so may lead to an adrenal crisis. The aim of the study was to explore patients PAI knowledge and understanding of the condition, steroid replacement adjustment during acute illness or stress and provided education. METHODS: Ten adult patients with PAI were purposefully recruited from two hospitals in a tertiary NHS Trust in England, UK. Data was collected using a mixed method approach utilising semi-structured audio-recorded interviews and hospital case note review. Interviews were transcribed verbatim and analysed using Burnard's content analysis framework. Information from the hospital case note review was captured using a matrix table based on pre-defined criteria. RESULTS: Four key themes emerged: 'Addison's disease and hydrocortisone replacement'; 'stress and corticosteroids'; 'patient compliance/adherence' and 'transition'. Patients reported feelings of 'going through a transition from uncertainty to adaption' following diagnosis. All participants had a good level of knowledge and understanding of required medication however application in times of need was poor. Medication adherence and prevention of a crisis relied not only on patient knowledge and application but also the support of family and health professionals. Health care professional knowledge required improvement to aid diagnosis and management of PAI. CONCLUSION: Patients with PAI did not apply existing knowledge to adjust steroid dose during acute illness or stress. Although a sample of limited size, our study identified there is a need to further explore why patients with Addison's disease do not apply existing knowledge during times of increased need. Future research should consider appropriate behaviour change interventions to promote medication adherence to reduce risk of an adrenal crisis.

EVALUATION AND MANAGEMENT OF ADRENAL INSUFFICIENCY IN CRITICALLY ILL PATIENTS: DISEASE STATE REVIEW.

OBJECTIVE: The definition of normal adrenal function in critically ill patients remains controversial, despite a large body of literature. We review the clinical presentation, diagnosis, and treatment of adrenal insufficiency in critically ill patients and discuss the authors' personal approach to patient management. METHODS: Extensive literature review, guidelines from professional societies, and personal experience. RESULTS: A decrease in cortisol breakdown rather than an increase in cortisol production has been suggested as the main contributor to elevated cortisol levels in critically ill patients. The concept of relative adrenal insufficiency has multiple pathophysiologic flaws and is not supported by current evidence. Patients with septic shock who are pressor dependent or refractory to fluid resuscitation may receive a short course of hydrocortisone regardless of their serum cortisol levels or their response to a cosyntropin stimulation test (CST). Patients without septic shock who are suspected to have adrenal insufficiency should have their random cortisol levels measured. In patients with low and near-normal cortisol-binding proteins, a serum cortisol of <10 or 15 µg/dL, respectively, may trigger need for glucocorticoid treatment. Assays of free cortisol levels offer an advantage over total cortisol levels in patients with low binding proteins. Most critically ill patients have a normal random free cortisol level of >1.8 µg/dL, although further studies are needed to define a normal range in critically ill patients based on both severity and duration of illness. A CST may be used to further evaluate adrenal function in patients without septic shock who have borderline random serum or free cortisol levels. CONCLUSION: Evaluation of adrenal function in critically ill patients is complex. Recent findings of decreased cortisol breakdown in critically ill patients as the main contributor to elevated cortisol levels calls for better-designed studies to explore the optimal evaluation and treatment of adrenal insufficiency in critically ill patients. ABBREVIATIONS: ACTH = adrenocorticotropic hormone; AI = adrenal insufficiency; CBG = corticosteroid-binding globulin; CORTICUS = Corticosteroid Therapy of Septic Shock; CRH = corticotropin-releasing hormone; CST = cosyntropin stimulation test; GC = glucocorticoid; GR = glucocorticoid receptor; HPA = hypothalamic-pituitary-adrenal; IL = interleukin; RAI = relative adrenal insufficiency.