Adrenal Insufficiency in the Critically Ill

Transcription

1 Adrenal Insufficiency in the Critically Ill Stephen M. Pastores, MD, FACP, FCCP, FCCM Director, Critical Care Medicine Fellowship Program Memorial Sloan Kettering Cancer Center Professor of Medicine and Anesthesiology Weill Medical College of Cornell University New York, NY

2 Disclosures Grant Support (MSKCC P.I. for Sepsis Trials) Eisai Medical Research Artisan Pharma

3 Corticosteroids in Critical Care Objectives: 1. Review the stress response and role of HPA axis 2. Discuss clinical and laboratory diagnosis of adrenal insufficiency during critical illness 3. Examine controversies in adrenal function testing 4. Review evidence-based recommendations for the diagnosis and treatment of AI during critical illness

4 Stress Response and the HPA Axis Marik PE. Curr Opin Crit Care 2007

5 Cortisol Physiology Major endogenous glucocorticoid secreted by adrenal cortex > 90% bound to corticosteroid-binding globulin, 5-10% free, biologically active form Synthesis Under ACTH control; adrenal gland does not store cortisol Adrenal cortex norm. produces 5-24 μg/dl of cortisol daily Cholesterol principal precursor, converted to pregnenolone and to cortisol, aldosterone and dehydroepiandrostenedione Oelkers W, NEJM 1996

6 Cortisol and Glucocorticoid Receptors Rhen T, Cidlowski J. NEJM 2005

7 Critical Illness Related Corticosteroid Insufficiency - CIRCI Severe Sepsis, Septic Shock and ARDS are characterized by relative corticosteroid insufficiency with an exaggerated pro-inflammatory response Anti-inflammatory mediators Cortisol Immune dysregulation Pro-inflammatory mediators NF-kB Homeostasis

8 Adrenal Insufficiency in the Critically Ill Mechanisms Hypothalamic-Pituitary Impaired release/synthesis of CRH, ACTH Head injury CNS depressants Pituitary infarction Cytokines Suppression of HPA axis Exogenous corticosteroids Medroxyprogesterone Megestrol acetate Cooper MS, NEJM 2003

9 Causes of Adrenal Insufficiency Reversible HPA axis dysfunction Sepsis/SIRS Drugs (ketoconazole, etomidate, rifampin, phenytoin, megesterol, corticosteroids) Primary AI Autoimmune HIV, TB, Fungi Acute hemorrhage, DIC Metastatic cancer CMV Secondary AI Pituitary or metastatic tumor, HIV, head trauma, sarcoidosis, craniopharyngioma, empty-sella syndrome

10 Incidence of Adrenal Insufficiency in Critical Illness Varies from 0-77% depending on population studied and diagnostic criteria used 20%-60% in patients with septic shock in MICU 21%-75% in critically ill HIV-infected patients 15% in patients with traumatic brain injury

11 61% Paul Marik & GaryZaloga

12 Adrenal Insufficiency in Critical Illness Clinical Features Hemodynamic instability despite adequate fluid resuscitation Fever and inflammation w/o obvious source that does not respond to empiric therapy Altered mental status Nausea, vomiting, diarrhea Hypoglycemia Eosinophilia Hyponatremia, hyperkalemia (uncommon)

13 Adrenal Function Testing in the Critically Ill

14 Adrenal Insufficiency Laboratory Diagnosis Insulin tolerance test: gold standard; impractical and unsafe to perform in unstable or critically ill patients Traditional approach: Cosyntropin stimulation test 250 μg IV cosyntropin Baseline, 30-min and 60-min cortisol level Serum cortisol < 18 μg/dl at 30- or 60-min or increase of < 9 μg/dl Dorin RI, Ann Intern Med 2003

15 HD-ACTH Stimulation Test: Limitations Lacks sensitivity: test based on responses in normal non-stressed, healthy control subjects Cortisol level of 18 μg/dl as threshold is inappropriately low in critically ill patients 250 μg dose is supraphysiologic (> 100-fold higher than normal maximal-stress ACTH levels) Potentially misses AI secondary to hypothalamic or pituitary failure Marik PE, Zaloga GP, Chest 1992 Minneci PC, Ann Intern Med 2004 Morel J, Intensive Care Med 2006

16 LD-ACTH Stim Test In Critically Ill Mediocre sensitivities in patients with septic shock (69%) and in pts with HIV infection (62%) - Marik PE, Zaloga GP. Crit Care Med Marik PE, et al. Crit Care Med 2002 HIV patients may have underlying AI independent of their critical illness More of a test for adrenal responsiveness or reserve

17 Why not use just a random cortisol? ACTH testing not required to diagnose AI in severely stressed pts because the CNS-HPA axis should already be maximally activated Random cortisol level provides information on the integrity of entire HPA axis Severely stressed pts should have a random cortisol > 25 µg/dl Random cortisol < 25 µg/dl = AI Marik PE, Chest 2002;722:1784

18 Drawbacks of Cortisol Assays Wide variability between commonly used methods of measuring total serum cortisol May be explained by differing degrees of cross-reactivity to steroids other than cortisol Heterophile antibodies can falsely serum cortisol in immunoassays Depending on type of assay being used, ~ 50% of pts may receive steroids unnecessarily Cohen J, et al. Intensive Care Med 2006

19 Why not use serum free cortisol? 66 critically ill patients and 33 healthy volunteers Similar demographics Base-line serum total cortisol, ACTH-stimulated serum total cortisol, aldosterone, and free cortisol concentrations were measured Of the 66 patients 36 had hypoproteinemia (albumin < 2.5 g/dl) 30 had near-normal serum albumin (> 2.5 g/dl) Hamrahian AH, NEJM 2004

20 Base-Line and ACTH-Stimulated Serum Total Cortisol Base-line and ACTHstimulated total cortisol concentrations were lower in the patients with hypoproteinemia than in those with near-normal serum albumin (P<0.001) Hamrahian AH et al. NEJM 2004

21 Base-Line and ACTH-Stimulated Serum Free Cortisol Base-line and ACTHstimulated free cortisol concentrations did not differ significantly between ICU pts with or w/o hypoproteinemia but several times higher than in healthy volunteers. Hamrahian AH et al. NEJM 2004

22 Serum free cortisol in critically ill patients: Conclusions Severe hypoproteinemia results in lower-thanexpected serum total cortisol levels in ~40% of ICU patients, even though their adrenal function was normal Serum free cortisol levels were consistently elevated with or w/o hypoproteinemia Measuring serum free cortisol in ICU patients with hypoproteinemia may help prevent unnecessary use of glucocorticoid therapy Hamrahian AH et al. NEJM 2004

23 2 consecutive cohorts n=61 and 40 Severe sepsis or septic shock Control groups 44 ICU patients without sepsis 32 healthy volunteers Standard cosyntropin test, overnight metyrapone test ACTH, 11β-deoxycortisol, cortisol (total and free), CBG 62% pts met criteria for adrenal insufficiency AJRCCM 2006; 174:1319

24 Diagnosis of AI in Sepsis 62% pts with sepsis met criteria for adrenal insufficiency Best predictive criteria Baseline < 10 ug/dl Delta < 9 ug/dl Patients with AI more likely to Vasopresor dependent Positive blood cultures Gram ve sepsis AJRCCM 2006; 174:1319

25 Effects of steroids on survival in previous and recent sepsis trials Trials published before 1989 revealed a non-beneficial treatment effect of steroids (relative survival benefit, 0.97 [CI, 0.89 to 1.04]; P > 0.2) Trials published after 1997 revealed a consistent and overall improvement in survival associated with glucocorticoid use (relative survival benefit, 1.23 [CI, 1.01 to 1.50]; P = 0.036) Minneci PC, et al. Ann Intern Med 2004;141:47-56

26 n=41 catecholamines > 48 hrs p=0.007 Bollaert et al. Crit Care Med 1998;26:645

27 Rapid ACTH Test Can Identify Septic Patients at High Risk of Death Relative adrenal insufficiency Failure to increase cortisol by > 9 µg/dl at 30- or 60-min following 250 µg ACTH stimulation test Annane D, et al. JAMA 2000;283:

28

29 Low Dose Steroids in Septic Shock Study Design Onset of shock Randomization Time 0 At 8 Hours Eligibility and ACTH test Hydrocortisone IV 50-mg every 6 hours x 7 days + Fludrocortisone 50 mcg NG daily x 7 days Placebo X 7 days Main Outcome: 28-day survival Annane, D. JAMA 2002; 288 (7): 863

30 Probability of surviva 100% 90% 80% 70% 60% 50% 40% 30% 28-Day Survival Hazard Ratio: 0.71 (95% CI, ) p = 0.03 All PATIENTS PLACEBO STEROIDS TIME (days) Annane et al. JAMA 2002;288:862

31 28-Day Survival Probability of survival 100% 90% 80% 70% 60% 50% 40% 30% Hazard Ratio: 0.67 (95% CI, ) p = 0.02 NON RESPONDER Time (days) PLACEBO STEROIDS Annane et al. JAMA 2002;288:862

32 28-Day Survival Probability of survival 100% 90% 80% 70% 60% 50% 40% 30% Log-Rank-Test, χ 2 = 0.56 p = 0.81 RESPONDERS PLACEBO STEROIDS TIME (days) Annane et al. JAMA 2002;288:862

33 CORTICUS Study Multicenter, double-blind, RCT 52 ICUs, March 2002 Nov 2005 (3 ½ yrs) Pts > 18 yrs with sepsis and onset of shock within the previous 72h (SBP < 90 despite fluids or need for vasopressors for > 1 hour) Hydrocortisone or Placebo: 50 mg IV q 6h x 5 days 50 mg IV q 12h on days 6 to 8 50 mg IV q 24h on days 9 to 11 then stopped Sprung C, et al. NEJM 2008;358:111-24

34 ACTH Stimulation Test* Steroids n=252 Placebo n-248 Non responders 125 (49.8%) 108 (43.5%) Responders 118 (47%) 136 (54%) Unknown 8 (3.2%) 4 (1.6%) *Etomidate was used in 51 of 251 pts in HC group (20.3%) and in 45 of 248 pts in placebo group (18.1%) before study entry Sprung C, et al. NEJM 2008;358:111-24

35 28 day mortality: all patients survival steroid placebo day p value for log rank test: 0.813

36 28 day mortality: non-responders survival steroid placebo day p value for log rank test: 0.850

37 28 day mortality: responders survival steroid placebo day p value for log rank test: 0.938

38 Time to shock reversal: non-responders septic shock steroid placebo day p value for log rank test: 0.152

39 Time to shock reversal: responders septic shock steroid placebo day p value for log rank test: <0.001

40 CORTICUS: Conclusions Hydrocortisone RX Did not decrease mortality Deceased time to shock reversal Was associated with an increased incidence of new infections Sprung C, et al. NEJM 2008

41 Devil is in the Details

42 Differences in Study Populations Treatment start Fludrocortisone Steroid taper More medical pts More surg pts More intra-abd l source of infxn Placebo mortality # Nonresponders Annane < 8h of shock Yes No Yes No No 61% 77% CORTICUS < 72 h of shock No Yes No Yes Yes 31% 44%

43 Moderate-Dose Hydrocortisone and 28-day Mortality in Septic Shock Marik PE, Pastores SM, Annane D, Meduri GU, Sprung C, et al. Crit Care Med 2008;36:

44 ARDS and Corticosteroids Insufficient glucocorticoid receptor-mediated inhibition of NF-κB is a central pathogenetic mechanism of dysregulated systemic and pulmonary inflammation in ARDS Potentially reversed by quantitatively and temporally adequate prolonged glucocorticoid administration Meduri GU, AJRCCM 2002;165:983-91

45 Objectives: To compare the design and results of randomized trials investigating prolonged glucocorticoid treatment ( 7 days) in patients with ALI-ARDS and review factors affecting response to therapy, including the role of secondary prevention. Intensive Care Med 2008;34:61-69

46

47 Prolonged GC Rx in ALI-ARDS Significant improvement AJRCCM 2005 Confalonieri CCM 2006 Annane Chest 2007 Meduri JAMA 1998 Meduri NEJM 2006 Steinberg Inflammation Yes Yes Yes Yes Yes PaO 2 :FiO 2 Yes Yes Yes Yes Yes MV Duration Yes Yes Yes Yes Yes ICU LOS Yes N/A Yes Yes Yes Mortality Yes Yes Yes Yes <14 No>14 Slide courtesy of Umberto Meduri, MD

48 Mortality- GC Rx before day 14 Meduri GU, Marik PE, Chrousos G, Pastores SM, Annane D, et al. Intensive Care Med 2008;34:61-9 Mortality Treated Control P value MP-treatment Trials (N = 245) 24% 40% 0.01 Number needed to treat 6 Chest 2007;131:954 JAMA 1998;280:159 NEJM 2006;354:1671

49 Conclusions: Prolonged glucocorticoid treatment substantially and significantly improves meaningful patient-centered outcome variables, and has a distinct survival benefit when initiated before day 14 of ARDS. Intensive Care Med 2008;34:61-69

50 Downside of Steroids Muscular weakness (myopathy, neuropathy) Superinfections Hyperglycemia Upper GI bleeding Psychosis Hypernatremia Arrhythmias

51 Lessons from the Corticosteroid Trials in ARDS (My take!) Don t use steroids after 14 days or for persistent ARDS Corticosteroids could be useful for their morbidity benefits (ie, ventilator-free days) Timing of corticosteroid therapy and duration of treatment are important factors Use of low tidal volume ventilation, conservative fluid strategy, infection surveillance, glycemic control, avoidance of neuromuscular blockers also key factors

52 Crit Care Med 2008;36:

53 Modified GRADE System Grading of Evidence 1A: Strong recommendation, high quality evidence 1B: Strong recommendation, moderate quality of evidence 1C: Strong recommendation, low quality or very low quality 2A: Weak recommendation, high quality evidence 2B: Weak recommendation, moderate quality 2C: Weak recommendation, low quality or very low quality Guyatt G, et al. Chest 2006;129:174-81

54 Task Force Recommendations Critical Illness Related Corticosteroid Insufficiency (CIRCI) best describes HPA axis dysfxn in critical illness Inadequate corticosteroid activity for the severity of the pt s illness May result from adrenal steroid production (AI) or tissue resistance to steroids with or without AI Dynamic process Usually reversible, caused by pro-inflammatory cytokines but may also arise from structural damage of adrenals Marik PE, Pastores SM, Annane D, Meduri GU, Sprung C, et al. Crit Care Med 2008;36:

55 Diagnosis of Adrenal Insufficiency in Critical Illness (CIRCI) Task Force Recommendations Delta cortisol following 250 µg cosyntropin of < 9 µg/dl or a random total cortisol of < 10 µg/dl (2B) Free cortisol has advantages over total cortisol but not widely available (2B) The ACTH stim test should not be used to identify the subset of pts with septic shock or ARDS who should receive corticosteroids (2B) Marik PE, Pastores SM, Annane D, Meduri GU, Sprung C, et al. Crit Care Med 2008;36:

56 Who and How To Treat with Corticosteroids? Task Force Recommendations for Septic Shock Hydrocortisone should be considered in the management strategy of pts with septic shock, particularly those pts who have responded poorly to fluid resuscitation and vasopressor agents (2B) Similar to Surviving Sepsis Guidelines recommendation (2C) IV hydrocortisone should be given in a dose of 200 mg/day in four divided doses or as a bolus of 100 mg followed by a continuous infusion at 10 mg/hr (240 mg/day) (1B) Marik PE, Pastores SM, Annane D, Meduri GU, Sprung C, et al. Crit Care Med 2008;36: Dellinger RP, Levy MM, Carlet JM, et al. Crit Care Med 2008;36:

57 How To Treat with Corticosteroids? Task Force Recommendations for Septic Shock Hydrocortisone should be tapered slowly and not stopped abruptly (1B) Fludrocortisone is considered optional if hydrocortisone is used (2B) Patients with septic shock should not be treated with dexamethasone (1B) Marik PE, Pastores SM, Annane D, Meduri GU, Sprung C, et al. Crit Care Med 2008;36:

58 How Long To Treat with Corticosteroids? Task Force Recommendations for Septic Shock Optimal duration of glucocorticoid treatment in pts with septic shock is unclear Based on published studies and pathophysiological data, pts should be treated for > 7 days before tapering, assuming there are no recurrence of signs of sepsis or shock (2B) Marik PE, Pastores SM, Annane D, Meduri GU, Sprung C, et al. Crit Care Med 2008;36:

59 Hydrocortisone withdrawal induces hemodynamic and immunologic rebound effects AJRCCM 2003;167:512-20

60 Who To Treat with Corticosteroids? Task Force Recommendations for ALI/RDS Moderate-dose glucocorticoids should be considered in the management strategy of patients with early severe ARDS (PaO2/FiO2 < 200) and before day 14 in patients with unresolving ARDS. (2B) The role of glucocorticoid treatment in acute lung injury (PaO2/FiO2 > 200) is less clear. Marik PE, Pastores SM, Annane D, Meduri GU, Sprung C, et al. Crit Care Med 2008;36:

61 How To Treat with Corticosteroids? Task Force Recommendations for Early ARDS Optimal initial dosing regimen in pts with early severe ARDS is 1 mg/kg/day methylprednisolone as a continuous infusion. (1B) Patients with early ARDS should be treated for > 14 days before tapering. (2B) Marik PE, Pastores SM, Annane D, Meduri GU, Sprung C, et al. Crit Care Med 2008;36:

62 Summary CIRCI is common in the critically ill, especially in severe sepsis/septic shock and ARDS Key clinical features: Hemodynamic instability despite adequate fluid resuscitation Unexplained fever or inflammation that does not respond to empiric therapy ACTH stim test can identify septic patients at high risk of death but should not be used to guide decision on use of corticosteroids

63 Summary Hydrocortisone should be considered in pts with septic shock who have responded poorly to fluids and vasopressors Moderate dose corticosteroids should be considered in pts with early severe ARDS and before day 14 in pts with unresolving ARDS Corticosteroids can have serious side effects

64 THANK YOU

65 QUESTIONS?