INSUFICIENCIA SUPRARRENAL DEL CIRRÓTICO

1. INSUFICIENCIA SUPRARRENAL DEL CIRRÓTICO J. Fernández, Liver Unit, Hospital Clinic of Barcelona, Spain III Curso Residentes. Diagnóstico y tratamiento de las enfermedades hepáticas. AEEH Barcelona 2011

2. Biological effects of cortisol CORTISOL Essential to survive critical illness IMMUNE & INFLAMATORY REACTIONS CARDIOVASCULAR SYSTEM METABOLIC EFFECTS - Retention of intravascular fluid - Increases the cardiac/ vascular response to cathecolamins and angiotensin Potent immunossupresive hormone: cytokines, nitric oxide… • Catabolism of glycogen, • fat and proteins • - Delay in anabolic pathways

3. Hypothalamic-pituitary-adrenal axis in the acute phase of critical illness STRESS HYPOTHALAMUS + + ADH + CRH Cytokines, bacterial products PITUITARY GLAND ACTH + ADRENAL CORTEX Increased adrenal cortisol secretion Decrease in cortisol-binding protein levels HIGH FREE PLASMA CORTISOL LEVELS Upregulation of glucocorticoid receptors Decreased hepatic/ renal inactivation of cortisol INCREASED EFFECTS OF CORTISOL IN PERIPHERAL TISSUES

4. Definition and clinical impact of relative adrenal insufficiency on critical illness • Definition: inadequate production of cortisol, although high • in terms of absolute value, with respect to the peripheral demands • (functional adrenal insufficiency). • Incidence in septic shock: 20-65%. • Importance: it is associated with a poor outcome in critically ill patients: • - Resistance to vasoconstrictor drugs- refractory shock. • - Higher mortality. • Diagnosis: It is not possible on clinical grounds and nowadays • relies on the determination of total/free cortisol levels.

5. Gold standard diagnostic criteria of relative adrenal insufficiency in critical illness Peak serum total cortisol levels 250 μgr ACTH IV Baseline serum total cortisol levels 1 0 hour • Response • to the corticotropin test: • Increase < 9 µg/dL • - Peak cortisol < 18-20 µg/dL Low baseline levels: < 9 or 15 µg/dL Major problem: Free cortisol (active fraction): 10% of serum total cortisol (70-80% linked to CBG and 10-20% to albumin) 40% of critically-ill patients with subnormal total cortisol have normal adrenal function Cooper et al, N Engl J Med 2003; Grinspoon et al, J Clin Endocrinol Metabol 1994 Hamrahian et al N Engl J Med 2004

6. Serum free cortisol diagnostic criteria of relative adrenal insufficiency in critical illness Peak serum free cortisol levels 250 μgr ACTH IV Baseline serum free cortisol levels 1 0 hour • Response • to the corticotropin test: • Peak cortisol < 3.1 or 4.5 µg/dL Low baseline levels: < 2.0 µg/dL Hamrahian et al, N Engl J Med 2004

7. Diagnostic criteria of relative adrenal insufficiency based on salivary cortisol Salivary cortisol levels 250 μgr ACTH IV Salivary cortisol levels 0 hour 1 Low basal values < 1.8 ng/dL Response to the corticotropin test: - Increase < 3 ng/ml - Peak cortisol < 12.7 ng/ml • * Low applicability in ICU • * No blood in the mouth, refrain from eating, • smoking, brushing teeth 1h before sampling Deutschbein et al. Eur J Endocrinol 2009

8. Other diagnostic criteria of relative adrenal insufficiencyThe low dose short synacthen test Peak serum total cortisol levels 1 μgr ACTH IV Baseline serum total cortisol levels 0 minutes 20-30 Response to the low dose corticotropin test: Peak cortisol < 18-20 µg/dL Abdu et al, J Clin Endocrinol Metabol 1999; Tordjman et al Clinical Endocrinology 2000

9. Effects of low doses of steroids on shock reversal Relative shock reversal benefit (95%CI) Bollaert et al., 1998 3.24 (1.50-7.01) ■ Briegel et al., 1999 1.13 (0.86-1.46) ■ Chawla et al., 1999 2.09 (1.14-3.83) ■ 0.14 0.37 1.0 2.72 7.39 HR for shock reversal (95%CI) ■ Annane et al., 2002 1.54 (1.10-2.16) -2 -1 0 1 2 Harm No effect Benefit Minnecci et al. Ann Intern Med 2004

10. Effects of low doses of steroids on survival in septic shock Relative survival Benefit (95%CI) Bollaert et al., 1998 1.85 (1.01-3.40) ■ Briegel et al., 1999 1.06 (0.80-1.42) ■ Yildiz et al., 2002 1.50 (0.79-2.83) ■ Annane et al., 2002 1.17 (0.89-1.52) ■ Total 1.23 (1.01-1.50) ■ 0.22 0.37 0.61 1.0 1.6 2.7 4.5 Relative survival benefit Harm No effect Benefit Minnecci et al. Ann Intern Med 2004

11. Corticus Study Kaplan-Meier Curves for Survival at 28 days Sprung C et al. N Engl J Med 2008;358:111-124

12. Relative adrenal insufficiency in critically-ill patients with chronic liver failure Number of patients Critical illness Incidence Harry et al (2003) 20 Acute or chronic 69% liver failure and septic shock Marik et al (2005) 147 Chronic liver 66% disease Tsai et al (2006) 101 Cirrhosis and 51% severe sepsis or shock Fernandez et al (2006) 25 Cirrhosis and 68% septic shock Thierry et al (2007) 14 Cirrhosis and shock 77% Cheyron et al (2008) 50 Cirrhosis 62%

13. Renal, hepatic and adrenal function in severe sepsis and septic shock in cirrhosis RENAL FAILURE (%) CHILD-PUGH CLASS C (%) 100 100 75 75 p=0.01 p<0.001 50 50 25 25 0 0 Adrenal insufficiency Normal function Adrenal insufficiency Normal function Tsai et al. Hepatology 2006

14. Impact of adrenal insufficiency on clinical outcome in critically-ill cirrhotic patients ICU MORTALITY (%) HOSPITAL MORTALITY (%) 100 100 75 75 p<0.001 p<0.001 50 50 25 25 0 0 Adrenal insufficiency Normal function Adrenal insufficiency Normal function Tsai et al. Hepatology 2006

15. Adrenal insufficiency in septic shock in cirrhosis. Effects of hydrocortisone on survival 75 PATIENTS WITH CIRRHOSIS AND SEPTIC SHOCK GROUP 2 (n=50) Retrospective series No evaluation of adrenal function GROUP 1 (n=25) Prospective series Evaluation of adrenal function Hydrocortisone 50mg/6h IV Resolution of septic shock, hospital and ICU mortality Fernández et al. Hepatology 2006

16. Impact of steroid treatment on resolution of septic shock % p=0.001 Fernández et al. Hepatology 2006

17. Impact of steroid treatment on hospital survival 1,0 ,8 Group 1 (n=25) ,6 Probability of hospital survival ,4 p=0.003 Group 2 (n=50) ,2 0,0 0 10 20 30 40 50 60 Days Fernández et al. Hepatology 2006

18. Causes of death in the ICU Prospective Retrospective p series (n=25) series (n=50) Refractory shock 0 20 0.001 Type-1 HRS 2 3 ns Liver failure 4 4 ns Variceal bleeding 0 4 ns Fungal infection 2 0 ns Fernández et al. Hepatology 2006

19. Impact of steroid treatment on hospital survival . RCT Arabi et al. CMAJ 2010

20. Conclusions • Relative adrenal insufficiency (RAI) has a negative impact on prognosis in critically-ill cirrhotic patients (refractory shock, mortality). • The effects of low dose steroids on survival are unclear. Final answer: RCT under design

21. Non-critically ill cirrrhotic patientsQuestions • Is RAI an underlying condition or a triggered event (i.e sepsis, variceal bleeding) in cirrhosis? • Which is its clinical impact on decompensated cirrhosis? REAL CLINICAL PROBLEM?

22. Adrenal insufficiency as an underlying condition in cirrhosis. First evidences • McDonald et al, J Gastroenterol Hepatol 2003: • - N= 51 patients with end-stage non-alcoholic cirrhosis. • - 64% reduction in peak plasma cortisol to indirect adrenal stimulation • (insulin-induced hypoglycemia) compared to healthy controls. • - 39% reduction to direct adrenal stimulation by ACTH. • - Significant negative correlation between Child-Pugh score and peak • plasma cortisol levels. • Marik et al, Crit Care Med 2005 : • 92% of patients submitted to recent liver transplantation with a • steroid-free regimen had RAI.

23. Adrenocortical reserve in stable cirrhosis RAI: 38% (frequent event related to the severity of liver disease) • Definition of AI: serum total cortisol <18 μg/dl at 20 or 30 min after 1μg of ACTH. • Weak point: no direct free cortisol assessment. • Good correlation between total cortisol and calculated free cortisol. No data on clinical impact! Fede et al. J Hepatol 2011

24. RAI in decompensated cirrhosis - Eighty-eight patients with decompensated cirrhosis (68% Child-Pugh C) without hemodynamic instability. - Assessment of salivary and serum total cortisol before and 1h after 250µg of ACTH. * RAI using serum total cortisol: basal value (T0) < 9 µg/dL or peak value (T60) < 18 µg/dL or Δ < 9µg/dL; ** RAI using salivary cortisol was defined as T0 < 1.8 ng/mL or T60 < 12.7 ng/mL or Δ < 3 ng/mL. Serum total cortisol overestimates RAI compared to salivary cortisol Galbois A, et al. J Hepatol 2010

25. Aims • To evaluate the prevalence and clinical impact of RAI on decompensated cirrhosis.

26. Study design • Prospective observacional study (2008-2010). • Inclusion criteria: hospitalization for complications related to cirrhosis • Exclusion criteria: • HIV infection, use of steroids, history of pituitary/adrenal disease, advanced CHC, other advanced diseases that could affect short-term prognosis. • Septic shock (hemodynamic inestability).

27. Study protocol • Within the 1st 24h of hospitalization: • Standard laboratory tests. • Short synacthen test (8:00-9:00 AM): serum total cortisol before and 1h after the administration of 250 µg of ACTH. • Vasoactive hormones, cytokines, NO, CBG and choleterol levels (total, HDL and LDL). • Definition of RAI: delta of cortisol < 9 µg/dL. • Follow-up during hospitalization.

28. Prevalence 168 patients with decompensated cirrhosis * In a group of 11 compensated patients 2 (18%) presented RAI.

29. Baseline clinical characteristics * Variceal bleeding (24), severe hepatic encephalopathy (5), HRS (3),acute-on-chronic liver failure (3), severe sepsis (2), secondary peritonitis (1), respiratory failure (1)

30. Baseline analytical data

31. Baseline hormonal, proinflammatory and cortisol/CBG profile

32. Clinical evolution during hospitalization

33. Probability of remaining free of septic shock during hospitalization in infected patients Normal adrenal function=69 Adrenal insufficiency=26 p< 0.001

34. Probability of survival during hospitalization Normal adrenal function=123 Adrenal insufficiency=45 p=0.004

35. Probability of septic shock after nosocomial infection RAI (n=11) No RAI (n=16) p=0.04

36. Causes of death during hospitalization

37. Conclusions • RAI is relatively common in decompensated cirrhosis and it is associated with circulatory dysfunction and SIRS. • RAI (delta of cortisol < 9 µg/dL) seems to be independent from the degree of liver failure (marker of another failing organ). • RAI seems to predispose patients who develop bacterial infections to septic shock and has a negative impact on hospital survival.

38. ICU admission Hydrocortisone hours