Adrenal insufficiency in critically ill patients Dalal Abdelgadir R2 pediatics

Objectives To review normal physiology of adrenal gland and glucocorticoids Normal adrenal response to stress Adrenal insufficiency in critical illness: pathophysiology and incidence Evidence of treatment with glucocorticoids Case presentation Recommendation for diagnosis and management in adult patients

Physiology of the adrenal gland CRH produced by hypothalamus Cortisol exerts a negative feedback on production of CRH and Cortisol CRH stimulates pituitary gland to produce ACTH ACTH stimulates adrenals to produce cortisol

mineralocorticoids Zona Glomerulosa 15% Zona fasiculata 75% Stress cortisol, androgens Basal cortisol, androgens Zona reticularis 10%

Production of steroid hormones

Physiology of glucocorticoids 90% bound to corticosteroid binding globulin and albumin to a lesser extent 10% free cortisol is physiologically active, half life is 70 -120 mins Cortisol is not stored in adrenal gland Glucocorticoids bind to intracelullar receptors then moves into the nucleus affecting transcription of various genes

Physiology of glucocorticoids Metabolic: Stimulates gluconeogenesis, decrease glucose utilization Decreases protein synthesis and increases catabolism Increases lypolysis and oxidation of fatty acids Cardiovascular: Increases blood pressure Increases sensitivity of vasculature to catecholamines & angiotensin II

Physiology of glucocorticoids Anti-inflammatory effects: Reduces circulating T, B lymphocytes, esinophils, monocytes and neutrophils at sites of inflammation Decreases production of cytokines & chemokines Increased production of microphage migration inhibitory factor Increases red cell production

Adrenal insufficiency

Adrenal insufficiency Primary adrenal insufficiency Secondary adrenal insufficiency Critical illness related corticosteroid insufficiency

Primary adrenal insufficiency Congenital: CAH Adrenal hypoplasia congenita Familial glucocorticoid deficiency Adrenoleukodystrophy Aldosterone deficiency Acquired: Autoimmune Infectious diseases Infiltrative processes Drugs

Secondary adrenal insufficiency Congenital ACTH, CRH deficiency: Isolated Panhypopituitarism Associated with structural defects e.g. supra optic dyplasia Acquired: Lymphocytic hypophysitis Neoplasms Exogenous steroids

Critical illness related GC insufficiency Is inadequate cellular corticosteroid activity for the severity of the patients illness

Normal HPA response to stress Multiple changes occur to maintain homeostasis during stress Activation of sympathoadrenal system leading to secretion of epinephrine and norepinephrine Activation of HPA axis lead to release of CRH, ACTH and eventually cortisol

Normal HPA response to stress Corticosteroid binding protein levels fall as low as 50% leading to increase in free cortisol Increased translocation of GR complexes into the nucleus Results in alteration of systemic inflammatory response and cardiovascular function

Adrenal insufficiency - pathophysiology Is inadequate cellular corticosteroid activity for the severity of patients illness Dynamic process, patient may not have it on admission but develop it later Poorly understood Structural damage to adrenal gland due to hemorrhage or infarction may lead to long term AI

AI – pathophysiology Most critically ill develop reversible HPA axis dysfunction Decreased production of CRH, ACTH or cortisol Decrease and alterations of glucocorticoid receptors Decrease nuclear translocation of glucocorticoid- receptor complexes due to endotoxins and proinflammatory cytokines Failure of activated GRs to down regulate production of inflammatory mediators (systemic inflammation- associated GC resistance)

CRH Decreased or abnormal receptors ACTH Translocation inhibited by endotoxins and cytokines Failure of GR to down regulate proinflammatory factors cortisol

AI – pathophysiology Some studies showed non survivors of severe sepsis have random cortisol level > 20 mcg/dl (552 nmol/l) but incremental increase < 9 (248) after ACTH stim test Others found that non survivors had lower random cortisol level compared to survivors Lower levels of cortisol and high ACTH associated with severe disease and poor outcome

When to suspect AI in critically ill pts Shock poorly responding to fluids and vasopressors especially septic shock Catecholamine-dependant shock Prolonged mechanical ventilation Sudden deterioration of seriously ill patients with DIC, traumatic shock, severe burns or sepsis may be due to adrenal hemorrhage or infarction

Incidence of AI Incidence variable within studies ranging 15 – 60% Probably due to different definitions used, different study populations Sarthi et al. assessed children with fluid refractory shock 30% of patients with septic shock identified with AI ( increase < 9 (248) after low dose ACTH stim test) Patients with AI had higher incidence of catecholamine refractory shock, but no difference in mortality

Incidence of AI Hatherill et al. reported incidence of 52% in children with septic shock Menon and Clarson reported 31% of critically ill Menon conducted a study to determine beliefs and practices regarding AI revealed that 41% of endocrinologist thought it rarely or never happen in PICU setting, 81% of intensivists thought it sometimes or often happens

Diagnosis of AI Different criteria in literature include: Delta cortisol after high dose ACTH stim test < 9 (248) Baseline cortisol < 5 (138) Baseline cortisol < 7 (193) Basal cortisol< 20 (552), Delta cortisol < 9 (248) Delta cortisol < 9 (193) Peak < (baseline x 2)

Diagnosis of AI Annane et al used metyrapone stim test to assess high dose ACTH stim test: Baseline < 10 (276) or delta cortisol < 9 (248) were best predictors of adrenal insufficiency Best predictor of normal adrenal response is baseline > 44 (1214) or increase > 17 (464) Metyrapone stimulation test: inhibits conversion of 11 deoxycortisol to cortisol, leading to increase in 11 deoxycortisol and drop of cortisol Low cortisol increases ACTH leading to further increase in 11 deoxycortisol

Diagnosis of AI Currently based on random cortisol levels and delta cortisol after high dose ACTH stimulation test Issues: Free cortisol is of more physiological importance but normal levels in acute illness not established, test not widely available Low dose ACTH stimulation test thought to be more physiologic and sensitive but limited data Delta cortisol assess ability of adrenal cortex to produce cortisol but does not confirm integrity of HPA axis Above tests do not evaluate resistance at end organ level

Should stress dose glucocorticoids be included in management of septic shock?

Rational behind treatment with GC Studies showing association between AI and refractory shock Some studies showing favorable outcome with administration of glucocorticoids In severe sepsis there is compromised endothelial integrity, systemic vasoplegia and impaired cardiac contractility Cortisol is thought to modulate biochemical pathways associated with those processes

Rational behind treatment with GC Adults with sepsis have different dose response to norepinephrine compared to adults without sepsis Marked improvement of dose response is seen after administration of GC Down regulation of proinflammatory factors

Should we treat with glucocorticoids Menon survey based study revealed: 50% of Canadian intensivists would sometimes or often empirically treat hypotensive patients with glucocorticoids 81% of endocrinologist would never or occasionally recommend glucocorticoids

Should we treat with glucocorticoids Min et al. RCT of cortisol Vs placebo in Dengue shock syndrome (1975) 48/98 received cortisol Fatality was 19% in cortisol group, 44% in placebo group Sumarmo et al. studied treating with cortisol (50 mg/kg single dose) in Dengue shock syndrome (1982) Mortality, length of shock, volume of fluid resuscitation similar in both groups

Should we treat with GC Tassinyom et al. RCT studied single dose methlprednisone Vs placebo in Dengue shock syndrome (1993) Similar rates of mortality and organ dysfunction in both treatment and placebo groups Slusher et al. studies administering dexamethasone 0.05 mg/kg/dose q 8hrs for 2 days (1996) No improved survival or time to hemodynamic stability observed

Should we treat with GC Markovitz et al. Retrospective cohort study using Pediatric Health information system database 2005 6693 children with severe sepsis Mortality 30% in those treated with steroids Mortality 18% in those not treated with steroids Longer duration of inotropic support and mechanical ventilation in steroid treated group Limitation: no data on severity of illness

PALS algorithm for septic shock

Can we make conclusions? Comparison of those studies difficult Small sample size Different definitions of adrenal insufficiency Different indications for treatment Different steroid regimens

Downside of treating with GC Attenuating immunity and delaying wound healing Hyperglycemia Adult data raised concerns of increase risk of nosocomial infections, multiple organ dysfunctions Possibly alteration of brain development e.g. neurodevelopmental outcome in neonates treated with dexamethasone for BPD

Downside of treating with GC Increased mortality and morbidity associated with methylprednisone administration in traumatic brain injury Increased mortality in ARDS patients started on steroids after 14 days of illness Higher rates of neuromuscular weakness

Case presentation

Case presentation 14 yr old boy with Trisomy 21 Admitted to the PICU after cervical fusion for atlantoaxial instability Presented with gradual decline of motor function over 1.5 yrs No past hx of hypothyroidism, other endocrinological disorders or exposure to exogenous steroids

Case presentation Initial plan was to keep him intubated for 48 hrs post op On POD 3 developed fever and increased ventilatory requirements Later developed hypotension requiring fluid resuscitation and eventually vasopressors Subsequently diagnosed with pneumonia and sepsis Continued to be vasopressor dependant for 6 days Adrenal insufficiency suspected

Case presentation Random cortisol was 83 nmol/L (3) ACTH stimulation test: Baseline cortisol: 95 nmol/L (3.4) At 30 min: 483 (17.5) Delta: 388 (14) At 60 min: 472 (17.1) Delta: 374 (13.5)

Case presentation Received hydrocortisone: 80 mg/m2/day x 1 day then weaned gradually over 1week Dramatic improvement, weaned off vasopressors within 24 hrs Hydrocortisone gradually weaned

Case presentation Course complicated by chylothorax and recurrent pneumonia leading to prolonged ventilation Subsequently was difficult to wean off ventilator, failed extubation due to deconditioning of respiratory muscles Tracheostomy preformed 4 months later still ventilator dependant & G-tube fed Transferred to Bloorview hospital for rehabilitation

More in the adult world Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: Consensus statements from and international task force by the American College of Critical Care Medicine

Recommendations for diagnosis and management in adults Dysfunction if the HPA axis in critical illness is best described by the term critical illness related corticosteroid insufficiency The terms absolute or relative adrenal insufficiency are best avoided in context of critical care Diagnosed by delta cortisol < 9 mcg/dl after 250 mcg cosyntropin or random total cortisol of < 10 mcg/dl Use of free cortisol can not be recommended at this time

Recommendations for diagnosis and management in adults The ACTH stimulation test should not be used to identify those patients with septic shock or ARDS who should receive GC Hydrocortisone should be considered in the management strategy of patients with septic shock, particularly those who have responded poorly to fluids and vasopressor agents (2B)

Recommendations for diagnosis and management in adults Moderate dose GC should be considered in the management strategy of patients with early severe ARDS and before day 14 in patients with unresolved ARDS. The role of GC treatment in less severe ARDS and ALI is less clear (2B) In patients with septic shock IV hydrocortisone should be given in a dose of 200 mg/day in 4 different doses or as bolus of 100 mg followed by a continuous infusion of 10 mg/hr (1B)

Recommendations for diagnosis and management in adults The optimal duration of GC treatment in patients with septic shock and early ARDS is unclear. Patients with septic shock should be treated > 7days before tapering and those with ARDS > 14 days before tapering (2B) GC treatment should be tapered slowly and not stopped abruptly (2B) Treatment with fludrocortisone ( 50mcg PO OD) is considered optional Dexamethasone is not recommended for treatment of septic shock or ARDS (1B)

Landmark studies in adults: CORTICUS Double blinded, randomized, placebo controlled multicentre study 500 patients with shock and evidence of organ dysfunction attributable to shock were enrolled Randomized to hydrocortisone or placebo 50 mg q6hrs IV x 5days 50 mg q12hrs x 3days 50mg q24hrsx 1day

CORTICUS - results Results: More rapid resolution of shock in treatment group No difference in 28 d mortality Higher incidence of new infections and septic shock

Landmark studies in adults Annane et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock 300 patients with refractory shock randomized to treatment with hydrocortisone 50mg IV q6hrs x 7days + oral fludracortisone 50 mg PO OD or placebo 30% decrease in mortality confined to the non- responder group

In summary HPA activation necessary to help with adaptation to stress There is evidence to support existence of adrenal insufficiency in critically ill patients The clinical relevance of adrenal insufficiency in critically ill pediatric patients not clear Safety and efficacy of steroid use in critically ill children is not proven Wide practice variability exists Risks of adverse effects such as hyperglycemia, nosocomial infections and myopathy/neuropathy are unknown

References 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 Critical Care Medicine, Crit Care Med 2008 Vol. 36, No. 6 Adrenal function in sepsis: The retrospective Corticus cohort study, Crit Care Med 2007 Vol. 35, No. Endocrine Problems in Critically Ill Children, AACN Clinical Issues Volume 17, Number 1, pp. 66–78 A history of adjunctive glucocorticoid treatment for pediatric sepsis: Moving beyond steroid pulp fiction toward evidence-based medicine, Jerry J. Zimmerman, MD, PhD, FCCM, Pediatr Crit Care Med 2007 Vol. 8, No. 6 Adrenal status in children with septic shock using low-dose stimulation test, Manjunatha Sarthi, MD, Pediatr Crit Care Med 2007 Vol. 8, No. 1 Identification of adrenal insufficiency in pediatric critical illness, Kusum Menon, MD, MSc, FRCPC; Margaret Lawson, MD, MSc, FRCPC, Pediatr Crit Care Med 2007 Vol. 8, No. 3

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