1. Adrenal insufficiency in critically ill patients
Dalal Abdelgadir 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
Zona Glomerulosa 15%
Zona fasiculata 75%
Stress cortisol, androgens
Basal cortisol, androgens
Zona reticularis 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 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 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

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 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

51. 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

52. 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 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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