the use of steroids in septic shock patients charles l. sprung, m.d
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Department of Anesthesiology and Critical Care Medicine Hadassah Medical Center. The use of steroids in septic shock patients Charles L. Sprung, M.D. Treating the Septic Shock Patient- An interactive case. - PowerPoint PPT PresentationTRANSCRIPT
Department of Anesthesiology and Critical Care
MedicineHadassah Medical Center
The use of steroids in septic shock patients
Charles L. Sprung, M.D.
Treating the Septic Shock Patient- An interactive case
• A 65 year old man is admitted with septic shock. After two fluid challenges of a liter of normal saline each and noradrenaline 0.02 mcg/kg/min, the BP was 95/45 mmHg after 30 minutes.
• This patient SHOULD receive adjunct therapy with intravenous hydrocortisone 50 mg every 6 hours for 5-7 days.
1. Strongly agree 2. Agree 3. No opinion or Unsure 4. Disagree 5. Strongly disagree
Treating the Septic Shock Patient
• The difference between the mortalities of patients and the steroid affect in the Annane (JAMA 2002) and the Corticus (NEJM 2008) studies were primarily due to:
1. The entry window of 8 hours vs. 72 hours
2. SBP < 90 mmHg greater than 1 hour or not
3. Fludrocortisone treatment or not 4. Treatment duration of 7 or 11 days 5. Weaning or not
Treating the Septic Shock Patient
• The following statements concerning the use of steroids for patients with septic shock are true according to the latest Surviving Sepsis Campaign guidelines (Crit Care Med 2008;36:296-327).
1. Treat patients who still require vasopressors despite fluid replacement with hydrocortisone.
2. ACTH stimulation tests should be used to identify the subset of adults with septic shock who should receive hydrocortisone.
3. Fludrocortisone must be added to hydrocortisone
4. Wean the patient from steroid therapy once the septic shock has resolved
5. Hydrocortisone should be administered for severe sepsis
without shock
Balancing Risks and Benefits of Steroids
BENEFIT
RISK
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
Surviving Sepsis Campaign (SSC) Guidelines- Steroids
• Treat patients who still require vasopressors despite fluid replacement with hydrocortisone 200-300 mg/day, for 7 days in three or four divided doses or by continuous infusion
Grade C• Optional:
- Adrenocorticotropic hormone (ACTH) stimulation test (250-µg)- Continue treatment only in nonresponders (delta cortisol 9 µg/dl) Grade E Dellinger P. Crit Care Med 2004;32:858-873
STUDY DESIGN
H0
H8
ONSET OF SHOCK
RANDOMIZATION
ELIGIBILITY AND
ACTH TEST
HC (IV 50 mg q 6h) + FC (PO 50 µg/d) FOR 7 D
PLACEBO
FOR 7 DAYSDAY 28
Annane D. JAMA 2002:288:862-871
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
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
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
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
Sprung CL. 2008;358:111-124
• Investigator-initiated, European double-blind PRCT
• Patients enrolled from March ‘02 - Nov ‘05
• 52 enrolling centers
• Intended sample size: 800
(80% power to detect 10% absolute fall in mortality)
• Final enrollment: 500 patients
• 499 patients analyzable
CORTICUS STUDY
Sprung CL. NEJM 2008;358:111-124
1. Clinical evidence of infection within previous 72h
Any of…
• presence of neutrophils in normally sterile body fluid
(excluding blood)
• positive culture or Gram stain of blood, sputum, urine or
normally sterile body fluid
• identified focus of infection
• other clinical evidence of infection - pneumonia, purpura
fulminans, necrotising fascitis, etc.
CORTICUS INCLUSION CRITERIA
2. Systemic response to infection … as defined by ≥2 of
following signs within previous 72h:
• fever (>38.30C) or hypothermia (<35.60C)
• tachycardia (>90 bpm)
• tachypnea (> 20 breaths/min, PaCO2<32mmHg) .or patient
requires mechanical ventilation
• WBC count >12,000 or < 4000 cells/mm3 or >10% immature
neutrophils
CORTICUS INCLUSION CRITERIA
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
• Chronic corticosteroid therapy in last 6 months or acute steroid therapy (any dose) within 4 months (including inhaled steroids)
• Drug-induced immunosuppression, including chemotherapy or radiation therapy within 4 weeks
• Presence of advanced directive to withhold or withdraw life sustaining treatment
• Moribund patients likely to die within 24 hours
• In ICU >2 months at time of onset of septic shock
• HIV positivity
CORTICUS EXCLUSION CRITERIA
IV bolus
• 50mg hydrocortisone q 6h x 5 days (days 1-5)
• 50mg hydrocortisone q 12h x 3 days (days 6-8)
• 50mg hydrocortisone q 24h x 3 days (days 9-11)
no repeat dose or “real” steroids
no fludrocortisone
CORTICUS STUDY MEDICATION
Sprung CL. NEJM 2008;358:111-124
RESULTS Demographics
Steroids (n=251) Placebo (n=248)
Age (y) 63 ± 14 63 ± 15
Male 166 (66%) 166 (67%)
Medical 80 (32%) 93 (38%)
Emergency surgical 138 (55%) 132 (54%)
Elective surgical 31 (12%) 21 (9%)
SAPS II Score 49.5 ± 17.8 48.6 ± 16.7
Sprung CL. NEJM 2008;358:111-124
RESULTSSource of infection
Steroids (n=251) Placebo (n=248)
Lung 76 (30%) 95 (38%)
GI tract 123 (49%) 116 (47%)
Urinary tract 20 (8%) 17 (7%)
Soft tissue 17 (7%) 17 (7%)
Other 50 (20%) 48 (19%)
Sprung CL. NEJM 2008;358:111-124
RESULTS: ACTH stimulation test
Steroids (n=251)
Placebo (n=248)All
(n=499)
Non-responders 125 (49.8%) 108 (43.5%) 233 (46.7%)
Responders 118 (47%) 136 (54.8%) 254 (50.9%)
Unknown 8 (3.2%) 4 (1.6%) 12 (2.4%)
Sprung CL. NEJM 2008;358:111-124
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
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
P value for log rank test: 0.753
RESULTS: 28 day survival curves - all patients
placebo
steroid
survival
0
0.25
0.50
0.75
1.00
0 5 10 15 20 25 30
day
Sprung CL. NEJM 2008;358:111-124
P value for log rank test: 0.786
placebo
steroid
survival
0
0.25
0.50
0.75
1.00
0 5 10 15 20 25 30
day
RESULTS: 28 day survival curves - ACTH non-responders
Sprung CL. NEJM 2008;358:111-124
P value for log rank test: 0.937
placebo
steroid
survival
0
0.25
0.50
0.75
1.00
0 5 10 15 20 25 30
day
RESULTS: 28 day survival curves - ACTH responders
Sprung CL. NEJM 2008;358:111-124
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
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)
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)
ResponderCentral
Nonresponder Central
Total
Responder Local 154 (36%) 23 (5%) 177 (42%)
NonresponderLocal
76 (18%) 172 (40%) 248 (58%)
230 (54%) 195 (46%) 425
Corticus Harmonization StudyCentral Method: Roche
Briegel J. Am J Resp CCM 2007, 175: A436
Hydrocortisone Rx
• did not decrease mortality in non-
responders, responders or all patients
• did not reverse shock in non-responders,
responders or all patients
• did decrease the time to shock reversal in
non-responders, responders and all patients
Conclusions
Hydrocortisone Rx
• was not associated with an increased
incidence of polyneuropathy
• was associated with an increased
incidence of superinfection and new
sepsis and septic shock
Conclusions
• The short corticotropin test does not appear
useful for guiding steroid therapy
• The gain achieved by earlier shock reversal in
patients receiving hydrocortisone was
counterbalanced by later superinfections and
new sepsis and septic shock
Conclusions
• Hydrocortisone therapy cannot be
recommended as routine adjuvant therapy
for septic shock nor can corticotropin testing
• Hydrocortisone may have a role among
patients who are treated early after the
onset of septic shock who remain
hypotensive despite the administration of
high-dose vasopressors
Recommendations
28-day Mortality
Annane Corticus
Steroids 82/150 (55%) 86/251 (34.3%)
Placebo 91/149 (61%) 78/248 (31.5%)
Total 173/299 (58%) 164/499 (32.9%)
Entry window 8 hours 72 hours
SBP < 90 mmHg > 1 hour < 1 hour
Treatment Fludrocortisone None
Treatment duration 7 days 11 days
Weaning No Yes
Practice/Guidelines None Steroids used
SAPS II 59 + 21 49 + 17
Non-responders 229 (77%) 233 (47%)
STUDY DIFFERENCES Annane Corticus
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
Peter, J. V. et al. BMJ 2008;336:1006-1009
Steroids and ARDS prevention
Peter, J. V. et al. BMJ 2008;336:1006-1009
Steroids and ARDS mortality
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
Surviving Sepsis Campaign (SSC) Guidelines for Management of
Severe Sepsis and Septic Shock Updated Guidelines
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 2CAnnane 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
• We suggest the ACTH stimulation test not be used to identify the subset of adults with septic shock who should receive hydrocortisone Grade 2B
Sprung CL. NEJM 2008;358:111-124 Briegel AJRCCM (abst). 2007: 175:A436
• Oral fludrocortisone (50 µg) is considered optional if hydrocortisone is used Grade 2CAnnane 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
• 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
Corticosteroids in Septic Shock
Déjà vu
Sprung CL. N Engl J Med 1984; 11:1137-43;358:111-124
MORTALITY
SPRUNG CL. N ENGL J MED 1984; 311:1137-1143
REVERSAL OF SHOCK
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
Treating the Septic Shock Patient- An interactive case
• A 65 year old man is admitted with septic shock. After two fluid challenges of a liter of normal saline each and noradrenaline 0.02 mcg/kg/min, the BP was 95/45 mmHg after 30 minutes.
• This patient SHOULD receive adjunct therapy with intravenous hydrocortisone 50 mg every 6 hours for 5-7 days.
1. Strongly agree 2. Agree 3. No opinion or Unsure 4. Disagree 5. Strongly disagree
Treating the Septic Shock Patient
• The difference between the mortalities of patients and the steroid affect in the Annane (JAMA 2002) and the Corticus (NEJM 2008) studies were primarily due to:
1. The entry window of 8 hours vs. 72 hours
2. SBP < 90 mmHg greater than 1 hour or not
3. Fludrocortisone treatment or not 4. Treatment duration of 7 or 11 days 5. Weaning or not
Treating the Septic Shock Patient
• The following statements concerning the use of steroids for patients with septic shock are true according to the latest Surviving Sepsis Campaign guidelines (Crit Care Med 2008;36:296-327).
1. Treat patients who still require vasopressors despite fluid replacement with hydrocortisone.
2. ACTH stimulation tests should be used to identify the subset of adults with septic shock who should receive hydrocortisone.
3. Fludrocortisone must be added to hydrocortisone
4. Wean the patient from steroid therapy once the septic shock has resolved
5. Hydrocortisone should be administered for severe sepsis
without shock