Silverstein and Hopper Chapter 81: Critical Illness-Related Corticosteroid Insufficiency

Critical Illness Related Corticosteroid Insufficiency (CIRCI)

• Inadequate cellular corticosteroid activity for the severity of the patient's disease

  • Pressor-resistant hypotension is the most commonly reported clinical manifestation

Cortisol

Hormone released by the adrenal glands in small amounts in a circadian rhythm and in larger amounts during times of physiologic stress

Important Homeostatic Functions of Cortisol

• Regulation of carbohydrate, lipid, and protein metabolism

• Immune system modulation

• Ensuring proper production of catecholamines and function of adrenergic receptors

• Stabilizing cell membranes

Pathway of Cortisol Release

• Hypothalamus produces corticotropin-releasing hormone (CRH) -> stimulates the anterior pituitary to release ACTH

• Hypothalamus-derived arginine vasopressin works synergistically with CRH to enhance ACTH secretion

• ACTH in circulation stimulates the zona fasciculata and zona reticularis of the adrenal gland to release cortisol

Negative Feedback of Cortisol

• Cortisol has negative feedback action on the hypothalamic and pituitary release of these stimulatory hormones

  • When circulating cortisol concentration is low, CRH and ACTH increase, which stimulates cortisol production -> increased serum cortisol concentration inhibits the release of more CRH, arginine vasopressin, and ACTH

Cortisol in Circulation

• Once in circulation, most cortisol is bound to corticosteroid binding globulin (CBG) and a small fraction is bound to albumin

  • Cortisol not protein-bound is free cortisol, the biologically active fraction

Action of Free Cortisol

• Free cortisol enters target cells and binds the glucocorticoid receptor (GR) in the cytoplasm

  • GR-cortisol complex translocates to the nucleus where it affects the transcription of hundreds to thousands of genes which alters cell function

  • Cortisol exerts is nongenomic effects by intercalating into cell or mitochondrial membranes

What can decrease circulating cortisol?

Direct trauma, infarction or hemorrhage, or cytokine influence may impair the HPA axis function, decreasing circulating cortisol
Multiple medications are known to decrease cortisol production

• Ketoconazole

• Etomidate

• Propofol

• Opiates

Increased Cortisol in Critically Ill People

• Critically ill people often have increased free and total cortisol concentrations in the face of low ACTH concentrations

  • Evidence that molecules other than ACTH, such as cytokines, lipopolysaccharide-bound toll-like receptors, and endothelin drive adrenal cortisol production and release independent of ACTH

  • The fraction of total cortisol that circulates as free (active) cortisol is increased in critical illness which may inhibit the hypothalamus and pituitary, leading to lower ACTH concentration

    • Free cortisol is increased because systemic inflammation decreases hepatic synthesis of cortisol's carrier proteins CBG and albumin

    • Acidemia, hyperthermia, and increased neutrophil activation lead to structural changes in CBG that lower its affinity for cortisol

    • There is also impaired cortisol metabolism by the kidney and liver

• While circulating free cortisol concentration is often increased in critical illness, target tissues may be cortisol resistant

  • Glucocorticoid receptor structure and number are altered in sepsis

What is CIRCI likely due to?

The combination of altered production, plasma protein binding, metabolism, and target tissue effects of cortisol

Clinical Manifestations of CIRCI

• Most common clinical abnormality is pressor-resistant hypotension

  • Logical since glucocorticoids influence adrenergic receptor function

• Studies in people with septic shock have shown that low-dose corticosteroid administration leads to more rapid improvement in blood pressure than placebo

• Critically ill dogs with poor response to exogenous ACTH may be more likely to be hypotensive than those with more robust response

• People with altered cortisol response to ACTH may be more likely to die than those with similar illness severity and a normal HPA axis function

• Complete adrenal failure is an uncommon manifestation of CIRCI

Diagnosing CIRCI in People

• Unknown how to diagnose CIRCI

  • Current clinical guidelines recommend using either a resting cortisol or the 250 ug standard ACTH stimulation test to diagnose CIRCI in people in favor of using the patient's hemodynamic response to hydrocortisone

  • Two large clinical trials found no relationship between plasma cortisol testing and benefit from hydrocortisone therapy in pressor-resistant septic shock

  • Suggested that ACTH stimulating testing and resting cortisol measurements are unlikely to accurately diagnose the condition

• The best way to identify critically ill patients that would benefit from corticosteroid therapy is unclear

Diagnosing CIRCI in Dogs and Cats

• No recommendation can be made regarding how to make a diagnosis of CIRCI in dogs or cats

Treating CIRCI in Septic Shock in People

• Current guidelines for CIRCI recommend the use of low-dose hydrocortisone (<400 mg/day/adult) for 3 or more days in people with septic shock that is not responsive to fluid and moderate to high-dose vasopressor therapy

• The current Surviving Sepsis Campaign guidelines make the recommendation as a negative, suggesting against using hydrocortisone if fluid and vasopressor therapy are able to restore hemodynamic stability

  • If hydrocortisone is used, it should be 200 mg/day/adult

• Both sets of guidelines recognize these recommendations as "conditional" or "weak", supported by low quality of evidence

• In general hydrocortisone is given either as four divided doses daily (e.g. 50 mg every 6 hours, to total 200 mg/adult/day) or as a loading dose of 100 mg hydrocortisone followed by 10 mg/hr as a CRI (240 mg/adult/day) in people

  • Unclear whether tapering of hydrocortisone is required

• Fludrocortisone is not recommended in any guidelines, likely because it was found not to improve survival when used in conjunction with hydrocortisone and because at relevant doses of hydrocortisone, all aldosterone receptors would be occupied

• Corticosteroids are not recommended for people with sepsis that are not in septic shock

Treating CIRCI in Cardiopulmonary Arrest in People

• Limited evidence for improved survival with good neurological function after administration of methylprednisolone during cardiopulmonary resuscitation in people

• Limited evidence for improved survival with good neurological outcome after administration of hydrocortisone for people who are in shock after return of spontaneous circulation

Treating CIRCI in Dogs and Cats

• Dogs and cats with fluid-loaded, pressor-refractory septic shock can be treated with 2.5-3 mg/kg/day of hydrocortisone as a CRI

  • Reasonable to continue steroid therapy only in patients that show significant improvement in cardiovascular status within 24 hours of starting the drug

Prognosis for CIRCI

• Within a week of ICU discharge, ACTH and cortisol increase to supra-normal levels in people

• If the patient survives the primary underlying illness, prognosis for return of normal HPA axis function is good