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Adrenal insufficiency in critically ill patients

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

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Adrenal insufficiency in critically ill patients

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  1. Adrenal insufficiency in critically ill patients DalalAbdelgadir R2 pediatics

  2. 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

  3. 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

  4. mineralocorticoids ZonaGlomerulosa 15% Zonafasiculata 75% Stress cortisol, androgens Basal cortisol, androgens Zonareticularis 10%

  5. Production of steroid hormones

  6. 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

  7. 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

  8. 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

  9. Adrenal insufficiency

  10. Adrenal insufficiency • Primary adrenal insufficiency • Secondary adrenal insufficiency • Critical illness related corticosteroid insufficiency

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

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

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

  14. 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

  15. 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

  16. 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

  17. 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)

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

  19. 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

  20. 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

  21. 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

  22. 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

  23. 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)

  24. Diagnosis of AI • Annane et al used metyraponestim 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

  25. 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

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

  27. 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

  28. 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

  29. 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

  30. 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

  31. 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

  32. 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

  33. PALS algorithm for septic shock

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

  35. 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

  36. 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

  37. Case presentation

  38. 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

  39. 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

  40. 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)

  41. 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

  42. 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

  43. 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

  44. 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

  45. 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)

  46. 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)

  47. 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)

  48. 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

  49. 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

  50. 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

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