Department of Anesthesiology and Critical Care Medicine Hadassah Medical Center The use of steroids in septic shock patients Charles L. Sprung, M.D

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


• 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

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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


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


• 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)



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


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


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


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


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


• 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


• 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


• 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


• 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

Documents

Department of Anesthesiology and Critical Care Medicine Hadassah Medical Center The use of steroids in septic shock patients Charles L. Sprung, M.D