steroids: benefits vs. risks risk/benefit: where are we now? charles l. sprung, m.d
DESCRIPTION
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. - PowerPoint PPT PresentationTRANSCRIPT
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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.
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Balancing Risks and Benefits of Steroids
BENEFIT
RISK
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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
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STEROID THERAPY FOR THE CRITICALLY ILL PATIENT
• 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
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Us
ed
in C
linic
al P
rac
t ic
eU
se
d in
Clin
ica
l Pra
cti
ce
Steroids For Treatment of Infections, Sepsis and Septic Steroids For Treatment of Infections, Sepsis and Septic Shock - Shock - Ups and DownsUps and Downs
WeizmannWeizmann
(review)(review)
19741974
SchumerSchumer
19761976
SprungSprung
19841984
VA-CoopVA-Coop
Bone Bone
19871987
CroninCronin
Lefering Lefering (meta_ (meta_ analyses)analyses)
19951995
BollaertBollaert
19981998
BriegelBriegel
19991999
AnnaneAnnane
20022002
NO
NO
YE
SY
ES
Surviving Sepsis Surviving Sepsis Campaign 2004 Campaign 2004
„„high-dose“high-dose“ „„low-dose“low-dose“
Corticus
2008
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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
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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
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STEROID THERAPY OF SEPTIC SHOCK
• 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
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28-Day Survival
All PATIENTS
30%
40%
50%
60%
70%
80%
90%
100%
0 4 8 12 16 20 24 28TIME (days)
Pro
bab
ilit
y o
f su
rviv
al
PLACEBO
STEROIDS
Hazard Ratio: 0.71 (95% CI, 0.53-0.97)
p = 0.03
Annane JAMA 2002;288:862-871
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30%
40%
50%
60%
70%
80%
90%
100%
0 4 8 12 16 20 24 28
Time (days)
Pro
bab
ility
of su
rviv
al
PLACEBO
STEROIDS
Hazard Ratio: 0.67 (95% CI, 0.47-0.95)
p = 0.02
NON RESPONDER
28-Day Survival
Annane JAMA 2002;288:862-871
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30%
40%
50%
60%
70%
80%
90%
100%
0 4 8 12 16 20 24 28TIME (days)
Pro
bab
ilit
y o
f su
rviv
al
PLACEBO
STEROIDS
RESPONDERS
Annane JAMA 2002;288:862-871
Log-Rank-Test, 2 = 0.56
p = 0.81
28-Day Survival
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Sprung CL. 2008;358:111-124
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3. Evidence of shock
• Systolic BP < 90 mmHg or >50 mmHg fall despite adequate fluid or need for pressors >1h (dopamine 5g/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:
• 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
CORTICUS INCLUSION CRITERIA
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RESULTS: 28-day mortality - all patients
P = 0.510
20
40
60
80
100
% mortality
steroids(n=251)
86(34.3%)
placebo(n=248)
78(31.5%)
Sprung CL. NEJM 2008;358:111-124
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0
20
40
60
80
100
steroids(n=125)
placebo(n=108)
Non-responders
% mortality
0
20
40
60
80
100
steroids(n=118)
placebo(n=136)
Responders
% mortality
P =0.69P = 1.000
49(39.2%)
RESULTS: 28-day mortality - by response to ACTH stimulation
34(28.8%)
39(28.7%)
39(36.1%)
Sprung CL. NEJM 2008;358:111-124
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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
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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
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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
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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
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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
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STEROIDS FOR ARDS• MP was associated with significantly increased 60-
and 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
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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)
Sprung CL. NEJM 2008;358:111-124
SI+ new S + SS- Relative risk (95% CI) = 1.37 (1.05-1.79)
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Adverse events
Steroids (n=234)
Placebo (n=232)
RR(95% CI)
Critical illness polyneuropathy 2 (1%) 4 (2%) 0.50 (0.09-2.68)
Bleeding - any site 21 (9%) 16 (7%) 1.3 (0.70-2.43)
MSOF 34 (15%) 33 (14%) 1.02 (0.66-1.59)
New sepsis 6 (3%) 2 (1%) 2.97 (0.61-14.59)
New septic shock 14 (6%) 5 (2%) 2.78 (1.02-7.58)
Repeat shock 72 (31%) 57 (25%) 1.25 (0.93-1.68)
Renal 7 (3%) 6 (3%) 1.16 (0.39-3.39)
Pulmonary 8 (3%) 13 (6%) 0.61 (0.26-1.44)
Glucose >8.3 mmol/l (day 1-7) 186 (85%) 161 (72%) 1.18 (1.07-1.31)
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CMV MORE COMMON IN SEPTIC PATIENTS
• 56 ICU patients with SAPS II score > 40 and anti-HCMV 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
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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
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Peter, J. V. et al. BMJ 2008;336:1006-1009
Steroids and ARDS prevention
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Peter, J. V. et al. BMJ 2008;336:1006-1009
Steroids and ARDS mortality
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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
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Some steroid believers are religious in their beliefs
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Dellinger P et al. Crit Care Med. 2008;36:296-327
Surviving Sepsis Campaign (SSC) Updated Guidelines- Steroids
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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 2CAnnane JAMA 2002;288:862-871
Sprung CL. NEJM 2008;358:111-124
Dellinger P. Crit Care Med. 2008;36:296-327
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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
• 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
• 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
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• 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
International Task Force on Clinical Practice Guidelines for the Diagnosis and Treatment of Adrenal Insufficiency in the ICU
Marik P et al. Crit Care Med. 2008;36:1937-1949
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NO FREE LUNCH
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Balancing Risks and Benefits of Steroids
BENEFIT
RISK