Transcript Kein Folientitel
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 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
Steroids For Treatment of Infections, Sepsis and Septic Shock - Ups and Downs „high-dose“ „low-dose“ Weizmann (review) 1974 Schumer 1976 Sprung 1984 VA-Coop Bone 1987 Cronin Lefering (meta_ analyses) 1995 Bollaert 1998 Briegel 1999 Annane 2002 Surviving Sepsis Campaign 2004 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 ONSET OF SHOCK RANDOMIZATION H8 ELIGIBILITY AND ACTH TEST HC ( IV 50 mg q 6h) + FC ( PO 50 µ g/d ) FOR 7 D PLACEBO FOR 7 DAYS DAY 28 Annane D. JAMA 2002:288:862-871
STEROID THERAPY OF SEPTIC SHOCK
• • • • • • • •
18 YEARS OR OLDER DOCUMENTED INFECTION OR SUSPICION TEMPERATURE > 38.3
O C OR < 35.6
O C 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
100% 90% 80% 70% 60% 50% 40% 30% 0 Hazard Ratio: 0.71 (95% CI, 0.53-0.97) p = 0.03
4 8 All PATIENTS 12 16 TIME (days) 20 PLACEBO STEROIDS 24 28 Annane JAMA 2002;288:862-871
28-Day Survival
100% 90% 80% 70% 60% 50% 40% 30% 0 NON RESPONDER Hazard Ratio: 0.67 (95% CI, 0.47-0.95) p = 0.02
4 8 12 16
Time (days)
20 PLACEBO STEROIDS 24 28 Annane JAMA 2002;288:862-871
28-Day Survival
100% 90% 80% 70% 60% 50% 40% 30% RESPONDERS Log-Rank-Test,
2 = 0.56
p = 0.81
PLACEBO STEROIDS 0 4 8 12 16 TIME (days) 20 24 Annane JAMA 2002;288:862-871 28
Sprung CL. 2008;358:111-124
CORTICUS STUDY
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Investigator-initiated, European double-blind PRCT
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Patients enrolled from March ‘02 - Nov ‘05
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52 enrolling centers
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Intended sample size: 800 (80% power to detect 10% absolute fall in mortality)
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Final enrollment: 500 patients
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499 patients analyzable Sprung CL. NEJM 2008;358:111-124
CORTICUS INCLUSION CRITERIA 1. Clinical evidence of infection within previous 72h Any of…
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presence of neutrophils in normally sterile body fluid (excluding blood)
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positive culture or Gram stain of blood, sputum, urine or normally sterile body fluid
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identified focus of infection
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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 (>38.3
0 C) or hypothermia (<35.6
0 C)
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tachycardia (>90 bpm)
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tachypnea (> 20 breaths/min, PaCO 2 <32mmHg) .
or patient requires mechanical ventilation
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WBC count >12,000 or < 4000 cells/mm 3 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
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:
• • • •
sustained oliguria (<0.5 ml/kg/h for >1 hr) metabolic acidosis [pH <7.3, base deficit ≥ 5, lactate >2] platelets ≤ 100,000/mm 3 GCS < 14 (or acute change from baseline) 4. Informed consent 5. ACTH stimulation test
CORTICUS EXCLUSION 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 STUDY MEDICATION IV bolus
•
50mg hydrocortisone q 6h x 5 days (days 1-5)
•
50mg hydrocortisone q 12h x 3 days (days 6-8)
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50mg hydrocortisone q 24h x 3 days (days 9-11) no repeat dose or “real” steroids no fludrocortisone Sprung CL. NEJM 2008;358:111-124
RESULTS Demographics Age (y) Male Medical Emergency surgical Steroids (n=251) Placebo (n=248) 63 ± 14 166 (66%) 80 (32%) 63 ± 15 166 (67%) 93 (38%) 138 (55%) 132 (54%) Elective surgical SAPS II Score 31 (12%) 49.5 ± 17.8
Sprung CL. NEJM 2008;358:111-124 21 (9%) 48.6 ± 16.7
RESULTS Source of infection Steroids (n=251) Placebo (n=248) Lung GI tract Urinary tract Soft tissue 76 (30%) 123 (49%) 20 (8%) 17 (7%) 95 (38%) 116 (47%) 17 (7%) 17 (7%) Other 50 (20%) Sprung CL. NEJM 2008;358:111-124 48 (19%)
RESULTS: ACTH stimulation test Non-responders Responders Unknown Steroids (n=251) Placebo (n=248) 125 (49.8%) 118 (47%) 8 (3.2%) 108 (43.5%) 136 (54.8%) 4 (1.6%) All (n=499) 233 (46.7%) 254 (50.9%) 12 (2.4%) Sprung CL. NEJM 2008;358:111-124
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%) P = 0.51
steroids (n=251) placebo (n=248)
RESULTS: 28-day mortality by response to ACTH stimulation Sprung CL. NEJM 2008;358:111-124 % mortality % mortality 100 Responders 100 Non-responders 80 80 60 60 40 20 0 34 (28.8%) 39 (28.7%) steroids (n=118) placebo (n=136) P = 1.000
40 20 0 49 (39.2%) 39 (36.1%) steroids (n=125) placebo (n=108) P =0.69
RESULTS: 28 day survival curves - all patients survival 1.00
0.75
0.50
0.25
0 0 5 10 Sprung CL. NEJM 2008;358:111-124 steroid placebo 15 day 20 25 30 P value for log rank test: 0.753
RESULTS: 28 day survival curves - ACTH non-responders survival 1.00
0.75
0.50
0.25
0 0 5 10 Sprung CL. NEJM 2008;358:111-124 steroid placebo 15 day 20 25 30 P value for log rank test: 0.786
RESULTS: 28 day survival curves - ACTH responders survival 1.00
0.75
0.50
0.25
0 0 5 10 Sprung CL. NEJM 2008;358:111-124 steroid placebo 15 day 20 25 30 P value for log rank test: 0.937
RESULTS Reversal of shock All Non-responders Responders Steroids (n=251) Placebo (n=248) 200 (79.7%) 95 (76.0%) 100 (84.7%) 184 (74.2%) 76 (70.4%) 104 (76.5%) p 0.18
0.41
0.13
Sprung CL. NEJM 2008;358:111-124
RESULTS: Time to reversal of shock Median time in days (95% CI) All Non-responders Responders Steroids (n=251) Placebo (n=248) 3.3 (2.9-3.9) 3.9 (3.0-5.2) 2.8 (2.1-3.3) 5.8 (5.2-6.9) 6.0 (4.9-9.0) 5.8 (5.2-6.9) P < 0.001
0.056
< 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) SI+ new S + SS- Relative risk (95% CI) = 1.37 (1.05-1.79) Sprung CL. NEJM 2008;358:111-124
Adverse events Critical illness polyneuropathy Steroids (n=234) 2 (1%) Bleeding - any site MSOF New sepsis New septic shock 21 (9%) 34 (15%) 6 (3%) 14 (6%) Repeat shock Renal Pulmonary Glucose >8.3 mmol/l (day 1-7) 72 (31%) 7 (3%) 8 (3%) 186 (85%) Placebo (n=232) 4 (2%) 16 (7%) 33 (14%) 2 (1%) 5 (2%) 57 (25%) 6 (3%) 13 (6%) 161 (72%) RR (95% CI) 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)
Corticus Harmonization Study Central Method: Roche
Responder Central Nonresponder Central Responder Local 154 (36%) 23 (5%) Total 177 (42%) Nonresponder Local 76 (18%) 230 (54%) 172 (40%) 195 (46%) 248 (58%) 425 Briegel J. Am J Resp CCM 2007, 175: A436
Conclusions
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
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The gain achieved by earlier shock reversal in patients receiving hydrocortisone was counterbalanced by later superinfections and new sepsis and septic shock
Recommendations
•
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
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%)
STUDY DIFFERENCES
Annane Corticus Entry window 8 hours 72 hours SBP < 90 mmHg > 1 hour < 1 hour Treatment Fludrocortisone None Treatment duration 7 days 11 days Weaning No Practice/Guidelines None Yes Steroids used SAPS II 59 + 21 49 + 17 Non-responders 229 (77%) 233 (47%)
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
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
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 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
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 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 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 REVERSAL OF SHOCK SPRUNG CL. N ENGL J MED 1984; 311:1137-1143
Steroids For Treatment of Infections, Sepsis and Septic Shock - Ups and Downs „high-dose“ „low-dose“ Weizmann (review) 1974 Schumer 1976 Sprung 1984 VA-Coop Bone 1987 Cronin Lefering (meta_ analyses) 1995 Bollaert 1998 Briegel 1999 Annane 2002 Surviving Sepsis Campaign 2004 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