1、ADRENAL INSUFFICIENCY IN CRITICALLY ILL PATIENTSDalal Abdelgadir R2 pediaticsObjectives 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 glucocorticoi
2、ds Case presentation Recommendation for diagnosis and management in adult patientsPhysiology of the adrenal glandCRH produced by hypothalamusCRH stimulates pituitary gland to produce ACTHACTH stimulates adrenals to produce cortisolCortisol exerts a negative feedback on production of CRH and Cortisol
3、Zona fasiculata 75%Zona Glomerulosa 15%Zona reticularis 10%mineralocorticoidsStress cortisol, androgensBasal cortisol, androgensProduction of steroid hormonesPhysiology of glucocorticoids 90% bound to corticosteroid binding globulin and albumin to a lesser extent 10% free cortisol is physiologically
4、 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 genesPhysiology of glucocorticoidsMetabolic: Stimulates gluconeogenesis, decrease glucose utilization Decreases pr
5、otein synthesis and increases catabolism Increases lypolysis and oxidation of fatty acidsCardiovascular: Increases blood pressure Increases sensitivity of vasculature to catecholamines & angiotensin IIPhysiology of glucocorticoids Anti-inflammatory effects: Reduces circulating T, B lymphocytes, esin
6、ophils, monocytes and neutrophils at sites of inflammation Decreases production of cytokines & chemokines Increased production of microphage migration inhibitory factorIncreases red cell productionAdrenal insufficiencyAdrenal insufficiency Primary adrenal insufficiency Secondary adrenal insufficienc
7、y Critical illness related corticosteroid insufficiencyPrimary adrenal insufficiencyCongenital: CAH Adrenal hypoplasia congenita Familial glucocorticoid deficiency Adrenoleukodystrophy Aldosterone deficiencyAcquired: Autoimmune Infectious diseases Infiltrative processes Drugs Secondary adrenal insuf
8、ficiencyCongenital ACTH, CRH deficiency: Isolated Panhypopituitarism Associated with structural defects e.g. supra optic dyplasiaAcquired: Lymphocytic hypophysitis Neoplasms Exogenous steroidsCritical illness related GC insufficiencyIs inadequate cellular corticosteroid activity for the severity of
9、the patients illnessNormal 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 cortisolNormal HPA response to
10、 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 functionAdrenal insufficiency - pathophysiology Is inadequate cell
11、ular 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 AIAI pathophysiology Most critically ill develop rev
12、ersible 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
13、inflammatory mediators (systemic inflammation-associated GC resistance)Translocation inhibited by endotoxins and cytokinesDecreased or abnormal receptorsFailure of GR to down regulate proinflammatory factorsCRHACTHcortisolAI pathophysiology Some studies showed non survivors of severe sepsis have ran
14、dom cortisol level 20 mcg/dl (552 nmol/l) but incremental increase 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
15、11 deoxycortisolDiagnosis of AI Currently based on random cortisol levels and delta cortisol after high dose ACTH stimulation testIssues: Free cortisol is of more physiological importance but normal levels in acute illness not established, test not widely available Low dose ACTH stimulation test tho
16、ught 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 s
17、hock? 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 Cortis
18、ol is thought to modulate biochemical pathways associated with those processesRational 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 o
19、f proinflammatory factorsShould we treat with glucocorticoids Menon survey based study revealed: 50% of Canadian intensivists would sometimes or often empirically treat hypotensive patients with glucocorticoids81% of endocrinologist would never or occasionally recommend glucocorticoids Should we tre
20、at with glucocorticoids Min et al. RCT of cortisol Vs placebo in Dengue shock syndrome (1975)48/98 received cortisolFatality 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
