Critical Illness-Related Corticosteroid Insufficiency

doi:10.1378/chest.08-1149

Chest

Volume 135, Issue 1, January 2009, Pages 181-193

https://doi.org/10.1378/chest.08-1149 Get rights and content

The diagnosis of adrenal failure and the indications for corticosteroid therapy in critically ill patients are controversial. This controversy is fueled by the complexity of the issues and the paucity of data from high quality clinical trials. Nevertheless, while the use of high-dose corticosteroids in patients with severe sepsis and ARDS failed to improve outcome and was associated with increased complications, an extended course of stress-dose corticosteroids has been reported to increase the occurrence of ventilator-free days and survival in select groups of ICU patients. These patients typically have an exaggerated proinflammatory response. Until recently the exaggerated proinflammatory response that characterizes critically ill patients with systemic inflammation has focused on suppression of the hypothalamic-pituitary-adrenal axis and adrenal failure. However, experimental and clinical data suggest that glucocorticoid tissue resistance may also play an important role. This complex syndrome is referred to as critical illness-related corticosteroid insufficiency (CIRCI) and is defined as inadequate corticosteroid activity for the severity of the illness of a patient. The paper reviews cortisol physiology, CIRCI, and the role of corticosteroid therapy in critically ill patients.

Section snippets

Cortisol Physiology

Cortisol (hydrocortisone) is the major endogenous glucocorticoid secreted by the adrenal cortex. Over 90% of circulating cortisol is bound to corticosteroid-binding globulin (CBG) with < 10% in the free, biologically active form.5, 6 CBG is the predominant binding protein with albumin binding a lesser amount. During acute illness, particularly sepsis, CBG levels fall by as much as 50%, resulting in a significant increase in the percentage of free cortisol.7, 8 The circulating half-life of

Critical Illness-Related Corticosteroid Insufficiency

There has recently been a great deal of interest regarding the assessment of adrenal function and the indications for corticosteroid therapy in critically ill patients. While the use of high-dose corticosteroid (10,000 to 40,000 mg of hydrocortisone equivalent in > 24 h) in patients with severe sepsis and ARDS failed to improve outcome and was associated with increased complications,28, 29 an extended course of stress-dose corticosteroids (200 to 350 mg hydrocortisone equivalent per day for up

Clinical Manifestations of CIRCI

Patients with chronic adrenal insufficiency (Addison Disease) usually present with a history of weakness, weight loss, anorexia, and lethargy with some patients complaining of nausea, vomiting, abdominal pain, and diarrhea. Clinical signs include orthostatic hypotension and hyperpigmentation (primary adrenal insufficiency). Laboratory testing may demonstrate hyponatremia, hyperkalemia, hypoglycemia, and a normocytic anemia. This presentation contrasts with the features of CIRCI. The clinical

Diagnosis of Adrenal Insufficiency and CIRCI

Traditionally the diagnosis of adrenal insufficiency in the critically ill has been based on the measurement of a random total serum cortisol (stress cortisol level) or the change in the serum cortisol in response to 250 ug of synthetic ACTH (cosyntropin), the so called delta cortisol.60, 61 Both of these tests have significant limitations in the critically ill.⁶² Commercially available cortisol assays measure the total hormone concentration rather than the biologically active, free cortisol

Treatment With Corticosteroids: Who and How?

Over the last three decades, approximately 20 randomized controlled trials (RCTs) have been conducted evaluating the role of glucocorticoids in patients with sepsis, severe sepsis, septic shock, and ARDS. Varying doses (37.5 to 40,000 mg of hydrocortisone eq/day), dosing strategies (eg, single bolus, repeat boluses, continuous infusion, and dose taper) and duration of therapy (1 to 32 days) were used in these studies.28, 29 The results of these studies together with our current understanding of

Conclusion

Critical illness-related corticosteroid insufficiency (CIRCI) is a complex disease, and our understanding of this disease continues to evolve. In critically ill patients with catecholamine refractory septic shock and patients with persistent severe ARDS for > 48 h after supportive therapy, a course of stress-dose corticosteroids (200 to 350 mg/d of hydrocortisone or 40 to 70 mg/d of methylprednisolone) should be considered. Treatment for at least 7 days (and up to 14 days) is suggested,

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Disorganized adrenocortical zonational structure in COVID-19 patients: Implications of critical illness duration
2024, Pathology Research and Practice
Aberrant adrenal function has been frequently reported in COVID-19 patients, but histopathological evidence remains limited. This retrospective autopsy study aims to scrutinize the impact of COVID-19 duration on adrenocortical zonational architecture and peripheral corticosteroid reactivity. The adrenal glands procured from 15 long intensive care unit (ICU)-stay COVID-19 patients, 9 short ICU-stay COVID-19 patients, and 20 matched controls. Subjects who had received glucocorticoid treatment prior to sampling were excluded. Applying hematoxylin and eosin (H&E) and immunohistochemical (IHC) staining, we disclosed that the adrenocortical zonational structure was substantially disorganized in COVID-19 patients, which long ICU-stay patients manifested a higher prevalence of severe disorganization (67%) than short ICU-stay patients (11%; P = 0.0058). The adrenal cortex of COVID-19 patients exhibited a 40% decrease in the zona glomerulosa (ZG) area and a 74% increase in the zona fasciculata (ZF) area (both P < 0.0001) relative to controls. Furthermore, among long ICU-stay COVID-19 patients, the ZG area diminished by 31% (P = 0.0004), and the ZF area expanded by 27% (P = 0.0004) in comparison to short ICU-stay patients. The zona reticularis (ZR) area remained unaltered. Nuclear translocation of corticosteroid receptors in the liver and kidney of long ICU-stay COVID-19 patients was at least 43% lower than in short ICU-stay patients (both P < 0.05). These findings underscore the necessity for clinicians to monitor adrenal function in long-stay COVID-19 patients.
Longitudinal assessment of adrenocortical steroid and steroid precursor response to illness in hospitalized foals
2023, Domestic Animal Endocrinology
Sepsis is a major cause of morbidity and mortality in neonatal foals. Relative adrenal insufficiency (RAI), defined as an inadequate cortisol response to stress, has been associated with sepsis, prematurity, and poor outcome in newborn foals. In addition to cortisol, the adrenal gland synthesizes several biologically important steroids and steroid precursors, including aldosterone, androgens, and progestogens. However, concentration of these hormones during hospitalization and their association with the severity of disease and mortality in critically ill foals have not been completely evaluated. We hypothesized, that in addition to cortisol and aldosterone, concentration of steroid precursors (progestogens and androgens) will be altered in critically ill foals. We also proposed that septic foals will have higher concentrations of steroid precursors than healthy foals, and steroid concentrations will be persistently increased during hospitalization in non-surviving septic and premature foals. Foals <4 days of age were categorized as healthy, septic, sick non-septic, and premature based on physical exam, medical history, and laboratory data. Blood samples were collected on admission (0 h), 24 h, and 72 h after admission. Concentrations of steroids and ACTH were measured by immunoassays. The area under the curve over 72 h (AUC0-72h) of hospitalization was calculated for each hormone. Serum cortisol, aldosterone, progesterone, pregnenolone, dehydroepiandrosterone sulfate (DHEAS), and 17 α-hydroxyprogesterone concentrations were higher in septic and premature foals compared to healthy foals at 0 h and throughout 72 h of hospitalization (P < 0.05). Plasma ACTH concentrations were higher in septic and premature foals on admission compared to healthy controls (P < 0.05). The progesterone (AUC0-72h) cut-off value above which non-survival could be reliably predicted in hospitalized foals was 1,085 ng/mL/h, with 82% sensitivity and 77% specificity. Critically ill neonatal foals had an appropriate response to stress characterized by increased concentrations of cortisol and steroid precursors on admission. A rapid decline in steroid concentration was observed in healthy foals. However, persistently elevated progestogen and androgen concentrations were associated with a lack of improvement in the course of disease and poor outcome.
Impact of duration of critical illness and level of systemic glucocorticoid availability on tissue-specific glucocorticoid receptor expression and actions: A prospective, observational, cross-sectional human and two translational mouse studies
2022, eBioMedicine
Reduced glucocorticoid-receptor (GR) expression in blood suggested that critically ill patients become glucocorticoid-resistant necessitating stress-doses of glucocorticoids. We hypothesised that critical illness evokes a tissue-specific, time-dependent expression of regulators of GR-action which adaptively guides glucocorticoid action to sites of need.
We performed a prospective, observational, cross-sectional human study and two translational mouse studies. In freshly-isolated neutrophils and monocytes and in skeletal muscle and subcutaneous adipose tissue of 137 critically ill patients and 20 healthy controls and in skeletal muscle and adipose tissue as well as in vital tissues (heart, lung, diaphragm, liver, kidney) of 88 septic and 26 healthy mice, we quantified gene expression of cortisone-reductase 11β-HSD1, glucocorticoid-receptor-isoforms GRα and GRβ, GRα-sensitivity-regulating-co-chaperone FKBP51, and GR-action-marker GILZ. Expression profiles were compared in relation to illness-duration and systemic-glucocorticoid-availability.
In patients’ neutrophils, GRα and GILZ were substantially suppressed (p≤0·05) throughout intensive care unit (ICU)-stay, while in monocytes low/normal GRα coincided with increased GILZ (p≤0·05). FKBP51 was increased transiently (neutrophils) or always (monocytes,p≤0·05). In patients’ muscle, 11β-HSD1 and GRα were low-normal (p≤0·05) and substantially suppressed in adipose tissue (p≤0·05); FKBP51 and GILZ were increased in skeletal muscle (p≤0·05) but normal in adipose tissue. GRβ was undetectable. Increasing systemic glucocorticoid availability in patients independently associated with further suppressed muscle 11β-HSD1 and GRα, further increased FKBP51 and unaltered GILZ (p≤0·05). In septic mouse heart and lung, 11β-HSD1, FKBP51 and GILZ were always high (p≤0·01). In heart, GRα was suppressed (p≤0·05), while normal or high in lung (all p≤0·05). In diaphragm, 11β-HSD1 was high/normal, GRα low/normal and FKBP51 and GILZ high (p≤0·01). In kidney, 11β-HSD1 transiently increased but decreased thereafter, GRα was normal and FKBP51 and GILZ high (p≤0·01). In liver, 11β-HSD1 was suppressed (p≤0·01), GRα normal and FKBP51 high (p≤0·01) whereas GILZ was transiently decreased but elevated thereafter (p≤0·05). Only in lung and diaphragm, treatment with hydrocortisone further increased GILZ.
Tissue-specific, time-independent adaptations to critical illness guided GR-action predominantly to vital tissues such as lung, while (partially) protecting against collateral harm in other cells and tissues, such as neutrophils. These findings argue against maladaptive generalised glucocorticoid-resistance necessitating glucocorticoid-treatment.
Research-Foundation-Flanders, Methusalem-Program-Flemish-Government, European-Research-Council, European-Respiratory-Society.
Sepsis
2022, Greene's Infectious Diseases of the Dog and Cat, Fifth Edition
- •
  Sepsis is the systemic inflammatory response to an infectious agent. The presence of organ function is now included in the human definitions.
- •
  The pathophysiology of sepsis is complex and includes both a proinflammatory and anti-inflammatory response that, when exuberant, can lead to organ dysfunction and death of the host.
- •
  Potential septic foci should be determined as soon as possible, and cultures of infected fluid or tissue obtained to help guide long-term therapy.
- •
  Pending culture results, treatment should be aimed at the most likely etiologic agent(s) and tissue infected.
- •
  Intensive monitoring and aggressive supportive care are of utmost importance to increase the chance for survival. The presence of multiple organ dysfunction syndrome increases the mortality rate.
- •
  The prognosis for patients with sepsis relies on the severity and pathogenicity of the underlying infection, as well as the ability to provide appropriate and early treatment.
Critical illness-related corticosteroid insufficiency in dogs with systemic inflammatory response syndrome: A pilot study in 21 dogs
2021, Veterinary Journal
Critical illness-related corticosteroid insufficiency (CIRCI) refers to a lack of adequate corticosteroid activity, which occurs in up to 48% of dogs with sepsis. However, data regarding the occurrence of CIRCI in critically-ill dogs are still scarce. This study aimed to assess: (1) the relationship between CIRCI and clinicopathological inflammatory markers, hypotension and mortality; and (2) the impact of low-dose hydrocortisone treatment on survival. Twenty-one dogs diagnosed with systemic inflammatory response syndrome (SIRS) were enrolled in a prospective case-control study. All dogs were initially evaluated for adrenal function with an ACTH stimulation test and dogs with Δcortisol ≤ 3 μg/dL were diagnosed with CIRCI. Mean arterial pressure (MAP), white blood cell (WBC), band neutrophils (bNs), c-reactive protein (CRP), and 28-day mortality rate were assessed. Fourteen dogs were treated with low-dose hydrocortisone. The relationships between CIRCI and MAP, WBC, bN, CRP, basal cortisol and mortality were investigated, as was the association between mortality and hydrocortisone treatment.
Ten of 21 (48%) dogs were diagnosed with CIRCI. Increased bNs were associated with the presence of CIRCI (P = 0.0075). CRP was higher in dogs with CIRCI (P = 0.02). Fourteen of 21 (66%) dogs died during the study (6/14 had CIRCI). Basal hypercortisolemia (>5 μg/dL) was associated with increased risk of mortality (P = 0.025). Based on our diagnostic criteria, CIRCI occurs frequently in dogs with SIRS and was associated with increased bNs and increased CRP. In this study, CIRCI and low-dose hydrocortisone treatment were not significantly associated with mortality, but basal hypercortisolemia was associated with increased mortality.
Combined Treatment With Hydrocortisone, Vitamin C, and Thiamine for Sepsis and Septic Shock: A Randomized Controlled Trial
2020, Chest
Whether hydrocortisone, vitamin C, and thiamine treatment can reduce the mortality of patients with sepsis is controversial.
To evaluate the efficacy and safety of hydrocortisone, vitamin C, and thiamine combination treatment for patients with sepsis or septic shock (HYVCTTSSS).
This single-blind, randomized controlled trial evaluated treatment with hydrocortisone (50 mg every 6 h for 7 days), vitamin C (1.5 g every 6 h for 4 days), and thiamine (200 mg every 12 h for 4 days) vs placebo (normal saline) in patients with sepsis. The intention-to-treat analysis was used. Primary outcome was 28-day all-cause mortality, and secondary outcomes were organ protection, procalcitonin reduction, and adverse events related to hydrocortisone, vitamin C, and thiamine.
Eighty patients were randomized to receive combination treatment (n = 40) or normal saline (n = 40). No difference in 28-day all-cause mortality was observed (27.5% vs 35%, respectively; P = .47); however, treatment was associated with a significant improvement of 72-h change in Sequential Organ Failure Assessment score (P = .02). In adverse events analysis, the treatment group exhibited more incidents of hypernatremia (P = .005). In prespecified subgroup analysis, patients of the treatment subgroup diagnosed with sepsis within 48 h showed lower mortality than those in the control subgroup (P = .02). The study was terminated after the midterm analysis.
Among patients with sepsis or septic shock, the combination of hydrocortisone, vitamin C, and thiamine did not reduce mortality compared with placebo.
ClinicalTrials.gov; No.: NCT03258684; URL: www.clinicaltrials.gov

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: The author has no conflicts of interest to disclose.

: Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml).

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Chest

Recent Advances in Chest MedicineCritical Illness-Related Corticosteroid Insufficiency

Section snippets

Cortisol Physiology

Critical Illness-Related Corticosteroid Insufficiency

Clinical Manifestations of CIRCI

Diagnosis of Adrenal Insufficiency and CIRCI

Treatment With Corticosteroids: Who and How?

Conclusion

Eur J Pharmacol

Metab Clin Exp

Biochemical Pharmacology

Endocrinol Metab Clin North Am

Life Sci

J Lipid Res

Mol Cell Endocrinol

Lancet

J Steroid Bioch Mol Biol

J Biol Chem

J Steroid Biochem Mol Biol

Lancet

Chest

Gen Comparat Endocrinol

J Steroid Biochem Mol Biol

J Steroid Biochem Mol Biol

J Biol Chem

Surgery

Am J Med

Mol Cell Endocrinol

Chest

Lancet

Chest

Chest

Chest

A syndrome produced by diverse nocuous agents

Nature

The hypothalamic-pituitary-adrenal axis and immune-mediated inflammation

N Engl J Med

Transport of steroid hormones: binding of 21 endogenous steroids to both testosterone-binding globulin and corticosteroid-binding globulin in human plasma

J Clin Endocrinol Metab

Septic shock and sepsis: a comparison of total and free plasma cortisol levles

J Clin Endocrinol Metab

Pituitary-adreanl response to human corticotropin-releasing hormone in critically ill patients

Intensive Care Med

Blood cholesterol and hydrocortisone production in man: quantitative aspects of the utilization of circulating cholesterol by the adrenals at rest and under adrenocorticotropin stimulation

J Clin Invest

Identification of scavenger receptor SR-BI as a high density lipoprotein receptor

Science

CLA-I is an 85-kD plasma membrane glycoprotein that acts as a high affinity receptor for both native (HDL, LDL, and VLDL) and modified (OxLDL and AcLDL) lipoproteins

Arterioscler Thromb Vasc Biol

Expression of low and high density lipoprotein receptor genes in human adrenals

Eur J Endocrinol

SR-B1 protects against endotoxemia in mice through its roles in glucocorticoid production and hepatic clearance

J Clin Invest

Mineralocorticoid action: target tissue specificity is enzyme, not receptor, mediated

Science

Regulation of expression of 11β-hydroxysteroid dehydrogenase type 1 in adipose tissue: tissue-specific induction by cytokines

Endocrinology

Human glucocorticoid receptor β binds RU-486 and is transcriptionally active

Mol Cell Biol

Selective regulation of bone cell apoptosis by translational isoforms of the glucocorticoid receptor

Mol Cell Biol

Molecular chaperones function as steroid receptor nuclear mobility factors

Proc Natl Acad Sci U S A

New insights into the molecular mechanisms of corticosteroids actions

Curr Drug Targets

Corticosteroids for severe sepsis and septic shock: a systematic review and meta-analysis

BMJ

Meta-analysis: the effect of steroids on survival and shock during sepsis depends on the dose

Ann Intern Med

Hydrocortisone infusion for severe community-acquired pneumonia: a preliminary randomized study

Am J Respir Crit Care Med

Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock

JAMA

Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: consensus statements from an international task force by the American College of Crit Care Med

Crit Care Med

Decreased histone deacetylase activity in chronic obstructive pulmonary disease

N Engl J Med

Relative corticosteroid insensitivity of peripheral blood mononuclear cells in severe asthma

Am J Respir Crit Care Med

Recent Advances in Chest Medicine
Critical Illness-Related Corticosteroid Insufficiency