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

• 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

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

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

• 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

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

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

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 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

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)

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

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

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

Some steroid believers are religious in their beliefs

Dellinger P et al. Crit Care Med. 2008;36:296-327

Surviving Sepsis Campaign (SSC) Updated Guidelines- Steroids

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

• 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

• 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

NO FREE LUNCH

Balancing Risks and Benefits of Steroids

BENEFIT

RISK