Adrenal Crisis

Intermediary 2012

Adrenal failure
Incidence rising in critical care patients. Failure of the HPA during severe stress/ resistance to the effects of cortisol. Occurs during sepsis, trauma, septic shock, severe community acquired pneumonia, head injury, burns, liver failure, HIV- infection, pancreatites and post cardiac surgery. Caused either by structural damage of the adrenal cortex or resistance to cortisol.

Physiology.
Hypothalamo pituitary axis regulates stress responses coordinated to improve survival. Hans Seyele general adaptation syndrome. Mediated via the HPA system and sympatho adrenal system. (refers to release of catecholamines from the medulla). Hypothalamus release corticotropin releasing hormone acting on the pituitary. Anterior pituitary release ACTH.

 ACTH (adreno corticotrophic hormone) then stimulates the middle layer of the cortex zona fasciculata to release glucocorticosteroids. Cortisol. Cortisol acts as a stress hormone having metabolic (glucogenolysis, gluconeogenesis), cardiovascular and immune responses. Half life of 6-8 hours.

Hypothalamus pituitary adrenal axis

Physiology
Cholesterol is used for cortisol synthesis. Cholesterol converts to pregnolone then to cortisol or aldosterone or DHEA. Each formed separately in the zona fascicularis, zona glomerulosa and zona reticularis of the adrenal cortex. Normal cortisol unstressed cortisol production is 15 -25 mg/d. Stressed up ton200 -350 mg/d.

Physiology.
Cortisol binds to intracellular receptors GRs and MRs Glucocorticoid receptor complex moves from the cytoplasm to nucleus. This mediates transcription of certain genes and modulate transcription factors. Nuclear factor Kappa B plays a role in inducing cytokine gene transcription. Leads to production of IL 1 IL 6 and TNF and other mediators of inflammation. Cortisol inhibits activity of NF kB by producing IkB proteins that bind to NFkB and decreasing activity and by directly binding to NFkB.

Pathophysiology:
In ARDS and sepsis there is an exaggerated pro inflammatory response. This leads to decreased cortisol levels and tissue resistance to cortisol effects. Causes hypotension resistant to resuscitative measures and vasopressors. Leads to adrenal crisis in the critical ill patient.

HPA function in acute illness.

HPA axis activation and sympathoadrenal activation. Rise in cortisol, rise in free cortisol, formation of the GR complex and translocate into the nucleus. In critical ill patients this pathway may be impaired. Adrenal insufficiency present in up to 60% in Septic Shock.

Pathophysiology
Mechanism of HPA axis dysfunction are poorly understood but include a CRH reduction. Low levels of ACTH and cortisol follows together with a dysfunction of their receptors. Structural damage to adrenals are also present in some. Adrenal haemorrhage following blunt trauma, DIC, burns, heparin induced thrombocytopenia and antiphospholipid syndrome.

Pathophysiology
Failure to down regulate transcription of cytokines despite elevated levels of cortisol is common in sepsis. Systemic inflammation associated GC resistance. Pro inflammatory cytokines released during sepsis impair effect of cortisol.

Critical illness related corticosteroid insufficiency. (CIRCI)

Inadequate cellular corticosteroid activity in relation to the illness severity. Insufficient down regulation of pro- inflammatory cytokines. Occurs due to a deficient production of cortisol or a increased tissue resistance to cortisol. CIRCI is usually a reversible condition caused by pro inflammatory cytokines. May be because of structural damage to the adrenal gland.

Manifestations.
Symptoms are none specific but should be strongly suspected in a patient with refractory hypotension unresponsive to fluid therapy and inotropes or vasopressor therapy.

Diagnosis.
ACTH stimulation test using 250 ug synthetic ACTH and testing the delta cortisol level. Level of less than 9 ug/dl is a poor response. Random total cortisol less than 10 ug/dl. Limitations of random cortisol testing is the decrease in cortisol binding globulin in sepsis. ACTH stimulation tests the ability to produce cortisol and doesnt test the HPA axis.

Management.
CORTICUS and French studies did not demonstrate benefits in survival. Other RCTs demonstrated earlier weaning from ventilators and earlier discharge from ICU. Rationale- Use moderate to stress doses of steroids in septic patients that are poorly responsive to fluid and vasopressor support.

References:
Critical illness related corticosteroid insufficiency. Paul E. Marik: Chest 2009; 135; 181-193 Recommendations for the diagnosis and management of corticosteroid insufficiency in critical ill adult patients. Consensus statements from the international task force by the American College of Critical Care Medicine. Paul E. Marik, Stephen M. Pastores; Critical Care Med 2008; 36; 1937-46. Adrenal insuficiency. Wiebke Arlt; Clinical Medicine 2008; 2; 211-215 Therapeutic management of adrenal insufficiency; S Hahner, B allolio; Best Practice and Research Clinical Endocrinology and Medabolism: 2009; 23; 167-179.