Transcript Steroids

Department of Anesthesiology
and Critical Care Medicine
Hadassah Medical Center
Steroids: Benefits vs. Risks
Risk/Benefit: Where are we now?
Charles L. Sprung, M.D.
Balancing Risks and Benefits of Steroids
BENEFIT
RISK
STEROIDS BENEFIT OR HARM PATIENTS
• Increased survival or mortality
• Benefits
- reversal or prevention of shock
- improve organ system dysfunction
- improve oxygenation
• Complications
- superinfection
- neuromuscular weakness
STEROID THERAPY FOR THE CRITICALLY ILL PATIENT
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Sepsis and Septic Shock
ARDS
COPD
Immunosuppression
Actual or relative adrenal insufficiency
Critical illness Related Corticosteroid Insufficiency- CIRCI
Etomidate treatment
Severe community-acquired pneumonia
Weaning from mechanical ventilation
Cardiac surgery
• Critically ill patients with liver disease
YES
Steroids For Treatment of Infections, Sepsis and Septic
Shock - Ups and Downs
NO
„high-dose“
„low-dose“
Weizmann
Schumer
Sprung
VA-Coop
Cronin
Bollaert
Briegel
Annane
(review)
1976
1984
Bone
Lefering
(meta_
analyses)
1998
1999
2002
1974
1987
1995
Surviving Sepsis
Campaign 2004
Corticus
2008
Meta-analysis of treatment with hydrocortisone on
shock reversal at day 7 in patients with septic shock
Marik P et al. Crit Care Med. 2008;36:1937-1949
Meta-analysis of treatment with hydrocortisone
on 28-day survival in patients with septic shock
Marik P et al. Crit Care Med. 2008;36:1937-1949
STEROID THERAPY OF SEPTIC SHOCK
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•
•
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18 YEARS OR OLDER
DOCUMENTED INFECTION OR SUSPICION
TEMPERATURE > 38.3OC OR < 35.6OC
HEART RATE > 90 BEATS/MIN
SBP < 90 mmHg > 1 HR DESPITE FLUID & VP
UO < 0.5 ml/kg/hr OR PaO2/FIO2 < 280
NEED FOR MECHANICAL VENTILATION
ACTH STIMULATION TEST
Annane D. JAMA 2002:288:862-871
28-Day Survival
All PATIENTS
Probability of survival
100%
90%
80%
PLACEBO
STEROIDS
70%
60%
50%
40%
Hazard Ratio: 0.71 (95%
CI, 0.53-0.97)
p = 0.03
30%
0
4
8
12
16
TIME (days)
Annane JAMA 2002;288:862-871
20
24
28
28-Day Survival
Probability of survival
100%
NON RESPONDER
90%
80%
PLACEBO
70%
STEROIDS
60%
50%
Hazard Ratio: 0.67 (95%
CI, 0.47-0.95)
40%
p = 0.02
30%
0
4
8
12
16
Time (days)
Annane JAMA 2002;288:862-871
20
24
28
28-Day Survival
Probability of survival
100%
RESPONDERS
90%
PLACEBO
STEROIDS
80%
70%
60%
50%
40%
Log-Rank-Test,
2 = 0.56
p = 0.81
30%
0
4
8
12
16
TIME (days)
Annane JAMA 2002;288:862-871
20
24
28
Sprung CL. 2008;358:111-124
CORTICUS INCLUSION CRITERIA
3. Evidence of shock
• Systolic BP < 90 mmHg or >50 mmHg fall despite adequate
fluid or need for pressors >1h (dopamine 5g/kg/min or any
dose of adr, noradr, vasopressin or phenylephrine) to maintain SBP
> 90 mmHg
• Hypoperfusion or organ dysfunction attributable to sepsis
within previous 72h including one of:
•
•
•
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sustained oliguria (<0.5 ml/kg/h for >1 hr)
metabolic acidosis [pH <7.3, base deficit ≥ 5, lactate >2]
platelets ≤ 100,000/mm3
GCS < 14 (or acute change from baseline)
4. Informed consent
5. ACTH stimulation test
RESULTS: 28-day mortality - all patients
Sprung CL. NEJM 2008;358:111-124
% mortality
100
80
60
40
20
0
86
(34.3%)
78
(31.5%)
steroids
placebo
(n=251)
(n=248)
P = 0.51
RESULTS: 28-day mortality by response to ACTH stimulation
Sprung CL. NEJM 2008;358:111-124
% mortality
% mortality
100
Responders
100
80
80
60
60
40
40
20
0
34
(28.8%)
steroids
(n=118)
39
(28.7%)
placebo
(n=136)
P = 1.000
20
0
Non-responders
49
(39.2%)
39
(36.1%)
steroids
(n=125)
placebo
(n=108)
P =0.69
RESULTS
Reversal of shock
Steroids (n=251)
Placebo (n=248)
p
All
200 (79.7%)
184 (74.2%)
0.18
Non-responders
95 (76.0%)
76 (70.4%)
0.41
Responders
100 (84.7%)
104 (76.5%)
0.13
Sprung CL. NEJM 2008;358:111-124
RESULTS: Time to reversal of shock
Median time in days (95% CI)
Steroids (n=251)
Placebo (n=248)
P
All
3.3 (2.9-3.9)
5.8 (5.2-6.9)
< 0.001
Non-responders
3.9 (3.0-5.2)
6.0 (4.9-9.0)
0.056
Responders
2.8 (2.1-3.3)
5.8 (5.2-6.9)
< 0.001
Sprung CL. NEJM 2008;358:111-124
COMPLICATIONS OF STEROID USE
• We must not forget about the
complications of steroid use in septic
shock patients
• The complications outweigh the
advantages of steroid use in most
septic shock patients
COMPLICATION OF STEROID USE- WEAKNESS
ICU acquired paresis and muscle
weakness has been associated
with corticosteroid use in the ICU
Herridge MS. NEJM 2003;348:683-693
De Jonge B. JAMA 2002;288:2859-2867
COMPLICATION OF STEROID USE- WEAKNESS
• ICU acquired paresis 25%
• Risk factors
OR (95% CI)
– Female sex
4.66 (1.2-18.3)
–Number days > 2 organ
dysfunction
1.28 (1.1-1.5)
–Mechanical ventilation 1.10 (1.0- 1.2)
–Corticosteroids
14.9 (3.2-70.8)
• 29% 9-month mortality with paresis
De Jonghe B. JAMA 2002;288:2859-2867
STEROIDS FOR ARDS
• MP was associated with significantly increased 60and 180-day mortality rates among patients
enrolled at least 14 days after the onset of ARDS
• MP increased the number of ventilator-free and
shock-free days during the first 28 days in
association with an improvement in oxygenation,
respiratory-system compliance, and blood pressure
with fewer days of vasopressor therapy
• As compared with placebo, MP did not increase the
rate of infectious complications but was associated
with a higher rate of neuromuscular weakness
• 9 had neuromuscular weakness; all occurred in
patients receiving MP, p < 0.05
ARDSnet NEJM 2006; 354:1671-1684
Frequency of superinfections
Steroids (n=234)
Placebo (n=232)
Superinfection
78 (33%)
61 (26%)
No superinfection
156 (67%)
171 (74%)
SI- Relative risk (95% CI) = 1.27 (0.96-1.68)
SI+ new S + SS- Relative risk (95% CI) = 1.37 (1.05-1.79)
Sprung CL. NEJM 2008;358:111-124
Adverse events
Steroids
(n=234)
Placebo
(n=232)
RR
(95% CI)
2 (1%)
4 (2%)
Bleeding - any site
21 (9%)
16 (7%)
MSOF
34 (15%)
33 (14%)
New sepsis
6 (3%)
2 (1%)
New septic shock
14 (6%)
5 (2%)
Repeat shock
72 (31%)
57 (25%)
Renal
7 (3%)
6 (3%)
Pulmonary
8 (3%)
13 (6%)
186 (85%)
161 (72%)
0.50
(0.09-2.68)
1.3
(0.70-2.43)
1.02
(0.66-1.59)
2.97
(0.61-14.59)
2.78
(1.02-7.58)
1.25
(0.93-1.68)
1.16
(0.39-3.39)
0.61
(0.26-1.44)
1.18
(1.07-1.31)
Critical illness polyneuropathy
Glucose >8.3 mmol/l (day 1-7)
CMV MORE COMMON IN SEPTIC PATIENTS
• 56 ICU patients with SAPS II score > 40 and antiHCMV IgG seropositivity were studied
• 20 (36%) developed an active HCMV infection
• HCMV infected patients
- had higher mortality (55% vs. 36%)
- ICU duration (30 vs. 23 days)
• Multivariate analysis: only sepsis independently
associated with active HCMV infection
Heininger A. Crit Care Med 2001;29:541-547
COMPLICATIONS OF STEROID USE- CMV
• 237 ICU nonimmunosuppressed patients with fever >
72 hours, without positive cultures and with CMV
antigenemia assays
• 40 (17%) had positive CMV assays
• CMV diagnosis in 20 + 12 days
• CMV mortality higher (50% vs. 28%)
(p < 0.02), longer ICU LOS (41 vs. 31 days)
(p < 0.04), longer MV (35 vs. 24 days) (p < 0.03)
• CMV infection was linked to steroid use
(p < 0.04) and renal failure (p < 0.02)
Jaber S. Chest 2005;127: 233-241
Steroids and ARDS prevention
Peter, J. V. et al. BMJ 2008;336:1006-1009
Steroids and ARDS mortality
Peter, J. V. et al. BMJ 2008;336:1006-1009
STEROID USE
• Doctors see the reversal of shock very quickly
and associate the improvement to steroid use
• Doctors do not associate the late complications
with steroids as they are not temporally related
• These include superinfections, new sepsis, new
septic shock, CMV and ARDS mortality
Some steroid believers are religious
in their beliefs
Surviving Sepsis Campaign (SSC)
Updated Guidelines- Steroids
Dellinger P et al. Crit Care Med. 2008;36:296-327
Surviving Sepsis Campaign (SSC)
Updated Guidelines- Steroids
•
We suggest intravenous hydrocortisone be
given only to adult septic shock patients after
blood pressure is identified to be poorly
responsive to fluid resuscitation and
vasopressor therapy
Grade 2C
Annane JAMA 2002;288:862-871
Sprung CL. NEJM 2008;358:111-124
Dellinger P. Crit Care Med. 2008;36:296-327
Surviving Sepsis Campaign (SSC)
Updated Guidelines- Steroids
•
Wean the patient from steroid therapy once the septic
shock has resolved
Grade 2D
Keh AJRCCM 2003; 167:512-520
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Do not use corticosteroids >300 mg/day of
hydrocortisone to treat septic shock
Grade 1A
Bone, et al. NEJM 1987; 317-658
VA Sepsis Study Group. NEJM 1987; 317:659-665
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In the absence of shock, corticosteroids should not be
administered for the treatment of sepsis
Grade 1D
There is no contraindication to continuing maintenance
steroid therapy or to using stress does steroids if the
patient’s endocrine or corticosteroid administration
history warrants
Grade 1D
Dellinger P. Crit Care Med 2008;36:296-327
International Task Force on Clinical Practice Guidelines for the
Diagnosis and Treatment of Adrenal Insufficiency in the ICU
• The committee voiced concern about as
yet undiscovered harmful effects of
hydrocortisone exposure occurring
subsequent to its current widespread use
in patients with septic shock
Marik P et al. Crit Care Med. 2008;36:1937-1949
NO FREE LUNCH
Balancing Risks and Benefits of Steroids
BENEFIT
RISK