insuficiencia suprarrenal del cirrÓtico
DESCRIPTION
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. Biological effects of cortisol. CORTISOL. Essential to survive critical illness. - PowerPoint PPT PresentationTRANSCRIPT
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
Biological effects of cortisol
- Catabolism of glycogen, fat and proteins- Delay in anabolic pathways
- Retention of intravascular fluid- Increases the cardiac/ vascular response to cathecolamins and angiotensin
Essential to survivecritical illness
CORTISOL
IMMUNE &INFLAMATORY
REACTIONS
METABOLICEFFECTS
CARDIOVASCULARSYSTEM
Potent immunossupresive hormone: cytokines, nitric oxide…
HYPOTHALAMUS
PITUITARY GLAND
ADRENAL CORTEX
ADHCRH
ACTH
HIGH FREE PLASMA CORTISOL LEVELS
++ +
+
Cytokines, bacterial products
STRESS
Decrease in cortisol-binding protein levels
Increased adrenalcortisol secretion
Decreased hepatic/ renal inactivation of cortisol
Upregulation of glucocorticoid receptors
INCREASED EFFECTS OF CORTISOL IN PERIPHERAL TISSUES
Hypothalamic-pituitary-adrenal axis in the acute phase of critical illness
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.
Gold standard diagnostic criteria of relative adrenal insufficiency in critical illness
Cooper et al, N Engl J Med 2003; Grinspoon et al, J Clin Endocrinol Metabol 1994 Hamrahian et al N Engl J Med 2004
hour0 1
Baseline serum total
cortisol levels
250 μgr ACTH IV Peak serumtotal cortisol
levels
Low baseline levels:< 9 or 15 µg/dL
Response to the corticotropin test:
- Increase < 9 µg/dL - Peak cortisol < 18-20 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
Serum free cortisol diagnostic criteria of relative adrenal insufficiency in critical illness
Hamrahian et al, N Engl J Med 2004
hour0 1
Baseline serum free
cortisol levels
250 μgr ACTH IV Peak serumfree cortisol
levels
Low baseline levels:< 2.0 µg/dL
Response to the corticotropin test:
Peak cortisol < 3.1 or 4.5 µg/dL
Diagnostic criteria of relative adrenal insufficiency based on salivary cortisol
Deutschbein et al. Eur J Endocrinol 2009
hour0 1
Salivarycortisol levels
250 μgr ACTH IV Salivary cortisol levels
Response to the corticotropin test: - Increase < 3 ng/ml
- Peak cortisol < 12.7 ng/ml
Low basal values < 1.8 ng/dL
* Low applicability in ICU* No blood in the mouth, refrain from eating,smoking, brushing teeth 1h before sampling
Other diagnostic criteria of relative adrenal insufficiency
The low dose short synacthen test
Abdu et al, J Clin Endocrinol Metabol 1999; Tordjman et al Clinical Endocrinology 2000
minutes0 20-30
Baseline serumtotal cortisol
levels
1 μgr ACTH IV Peak serumtotal cortisol
levels
Response to the low dose corticotropin test:
Peak cortisol < 18-20 µg/dL
Effects of low doses of steroids on shock reversal
Minnecci et al. Ann Intern Med 2004
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)
Annane et al., 2002 1.54 (1.10-2.16)
Harm No effect Benefit
■
-2 0 2-1 1
Relative shock reversalbenefit (95%CI)
■
■
■
0.14 1.0 7.390.37 2.72HR for shock
reversal (95%CI)
Effects of low doses of steroids on survival in septic shock
Minnecci et al. Ann Intern Med 2004
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)
Total 1.23 (1.01-1.50)
Relative survival benefit Harm No effect Benefit
Annane et al., 2002 1.17 (0.89-1.52)
0.37 1.0 2.70.22 0.61 1.64.5
■
Relative survivalBenefit (95%CI)
■
■
■
■
Sprung C et al. N Engl J Med 2008;358:111-124
Corticus Study Kaplan-Meier Curves for Survival at 28 days
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 andseptic 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%
Renal, hepatic and adrenal function in severe
sepsis and septic shock in cirrhosis
Tsai et al. Hepatology 2006
25
50 50
25
75
0
RENAL FAILURE (%)
100
Adrenalinsufficiency
Normalfunction
CHILD-PUGH CLASS C (%)
0
100
75
Adrenalinsufficiency
Normal function
p=0.01
p<0.001
Impact of adrenal insufficiency on clinical outcome
in critically-ill cirrhotic patients
Tsai et al. Hepatology 2006
25
50 50
25
75
0
ICU MORTALITY (%)
100
Adrenalinsufficiency
Normalfunction
HOSPITAL MORTALITY (%)
0
100
75
Adrenalinsufficiency
Normal function
p<0.001p<0.001
Resolution of septic shock, hospital and ICU mortality
75 PATIENTS WITH CIRRHOSIS AND SEPTIC SHOCK
GROUP 1 (n=25)Prospective series
Evaluation of adrenal function Hydrocortisone 50mg/6h IV
GROUP 2 (n=50) Retrospective series
No evaluation of adrenal function
Adrenal insufficiency in septic shock in cirrhosis. Effects of hydrocortisone on survival
Fernández et al. Hepatology 2006
Impact of steroid treatment on resolution of septic shock
p=0.001
Fernández et al. Hepatology 2006
%
Days
6050403020100
1,0
,8
,6
,4
,2
0,0
Pro
babi
lity
of h
ospi
tal s
urvi
val
Group 2 (n=50)
Group 1 (n=25)
p=0.003
Impact of steroid treatment on hospital survival
Fernández et al. Hepatology 2006
Prospective Retrospective
p series (n=25) series (n=50)
Refractory shock 0 20 0.001Type-1 HRS 2 3 nsLiver failure 4 4 nsVariceal bleeding 0 4 ns Fungal infection 2 0 ns
Fernández et al. Hepatology 2006
Causes of death in the ICU
Impact of steroid treatment on hospital survival . RCT
Arabi et al. CMAJ 2010
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
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?
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.
Adrenocortical reserve in stable cirrhosis
101 Patientswithout infection/instability
Adrenal Insufficiency(n=38)
Normal Adrenal Function(n=73)
p
Ascites (%) 68 37 0.01
Bilirubin (μmol/L) 51 31 <0.05
Serum albumin (g/l) 28±0.8 33±0.7 0.0001
INR 1.6 1.2 0.0001
Child-Pugh score (points) 10 7 0.0001
MELD score (points) 17 12 0.0001
Basal total cortisol (μg/dl) 7.6 14.9 0.01
Total cholesterol (mg/dl) 120 142 <0.05
• 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.
Fede et al. J Hepatol 2011
RAI: 38% (frequent event related to the severity of liver disease)
No data on clinical impact!
RAI in decompensated cirrhosis
RAI according to serum total cortisol*
RAI according to salivary cortisol**
P
RAI according to Δ, n (%) 19 (22%) 3 (3%) 0.001
Any criteria of RAI, n (%) 29/88 (33%) 8/88 (9%) 0.001
Serum total cortisol overestimates RAI compared to salivary cortisol
* 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.
Galbois A, et al. J Hepatol 2010
- 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.
Aims
• To evaluate the prevalence and clinical impact of RAI on decompensated cirrhosis.
• 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).
Study design
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.
Prevalence
168 patients with decompensated cirrhosisMain cause of admission Frequency
(n/%)RAI(%)
Ascites 25 (15%) 36
Encephalopathy 14 (8%) 29
Variceal bleeding 30 (18%) 27
SBP 29 (17%) 14
Other infections 42 (25%) 26
Hepatorenal syndrome 16 (10%) 31
Other 12 (7%) 33
TOTAL 168 (100%) 45 (27%)
* In a group of 11 compensated patients 2 (18%) presented RAI.
Baseline clinical characteristics
Adrenal Insufficiency
(n=45)
Normal Adrenal Function
(n=123)
p
Ascites (%) 76 70 0.57
Infection (%) 38 49 0.23
SBP 9 20 0.11
Other infections 29 29 1.00
Variceal bleeding (%) 20 20 1.00
Encephalopathy (%) 38 33 0.59
Hepatorenal syndrome (%) 11 9 0.77
MAP (mmHg) 77 ± 11.3 82 ± 13.2 0.02
Heart rate (bpm) 83.5 ± 10.8 82.3 ± 15.5 0.59
SIRS (%) 54 27 0.004
ICU admission* (%) 29 21 0.31* Variceal bleeding (24), severe hepatic encephalopathy (5), HRS (3),acute-on-chronic liver failure (3), severe sepsis (2), secondary peritonitis (1), respiratory failure (1)
Baseline analytical data
Adrenal Insufficiency
(n=45)
Normal Adrenal Function
(n=123)
p
Bilirubin (mg/dL) 6.7 ± 9.2 4.9 ± 5.9 0.24
Albumin (mg/dL) 27.4 ± 4.5 29.0 ± 5.5 0.08
Prothrombin time (%) 48.5 ± 14.8 49.7 ± 14.0 0.64
Creatinine (mg/dL) 1.4 ± 1.1 1.3 ± 1.0 0.35
Serum sodium (mEq/L) 131 ± 7.6 134 ± 5.4 0.049
Total cholesterol (mg/dL) 87.0 ± 30.2 99.8 ± 36.3 0.046
HDL (mg/dL) 18.3 ± 12.5 22.6 ± 12.1 0.052
LDL (mg/dL) 52.5 ± 22.4 61.8 ± 27.8 0.055
Child-Pugh (points) 9.8 ± 2.2 9.3 ± 2.1 0.19
MELD (points) 20.1 ± 8.4 18.5 ± 6.8 0.20
Baseline hormonal, proinflammatory and cortisol/CBG profile
Adrenal Insufficiency
(n=45)
Normal Adrenal Function
(n=123)
p
Vasoactive hormones
PRA (mg/mL.h-1) 1.7 (0.4-12.8) 1.3 (0.2-4.3) 0.07
Noradrenaline (pg/mL) 492 (284-742) 367 (216-536) 0.03
Cytokines and nitric oxide
TNF (pg/mL) 20 (16-40) 20 (13-33) 0.21
IL-6 (pg/mL) 103 (74-409) 112 (53-206) 0.30
Nitric oxide (nMol/mL) 34.6 (17.7-64.0) 26.1 (18.7-45.1) 0.33
Cortisol/transcortin levels
Basal total cortisol (mg/dL) 17.7 ± 7.3 15.7 ± 6.9 0.12
Post ACTH cortisol (mg/dL) 23.1 ± 7.4 30.6 ± 8.3 <0.001
Transcortin (µg/dL) 29.3 ± 10.2 27.4 ± 9.1 0.25
Clinical evolution during hospitalization
Clinical eventAdrenal
Insufficiency(n=45)
Normal Adrenal Function(n=123)
P(probability)
Variceal bleeding 1 (2%) 0 0.27
Type 1 or 2 HRS 4 (9%) 4 (3%) 0.23
New bacterial infections 11 (24%) 15 (12%) 0.07
SBP 4 (9%) 3 (2%) 0.24
Non SBP infections 7 (16%) 12 (10%) 0.10
Septic shock 6 (24%) 1 (1%) 0. 006
Death 10 (22%) 9 (7%) 0.004
Probability of remaining free of septic shock during hospitalization in infected patients
p< 0.001
Normal adrenal function=69
Adrenal insufficiency=26
Probability of survival during hospitalization
p=0.004
Adrenal insufficiency=45
Normal adrenal function=123
Probability of septic shock after nosocomial infection
p=0.04
RAI (n=11)
No RAI (n=16)
Causes of death during hospitalization
Clinical eventAdrenal
Insufficiency(n=45)
Normal Adrenal Function(n=123)
P
Variceal bleeding 1 1 ns
Respiratory failure 1 2 ns
Other 1 1 ns
Refractory shock 1 0 ns
Acute on chronic liver failure
6 6 ns
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.
0
20
40
60
80
100
120
140
0 8 16 24 32 40 48
MAP (mmHg)
Heart rate(b.p.m)Noradrenaline(microgr/Kg/h)
hours
ICUadmission
Hydrocortisone