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

Used in Clinical Practice Steroids For Treatment of Infections, Sepsis and Septic Shock - Ups and Downs Weizmann(review)1974Schumer1976Sprung1984VA-CoopBone1987 Cronin Lefering (meta_ analyses) 1995 Bollaert1998 Briegel1999 Annane2002 NO YES Surviving Sepsis Campaign 2004 „high-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:

Meta-analysis of treatment with hydrocortisone on 28-day survival in patients with septic shock Marik P et al. Crit Care Med. 2008;36:

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 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:

28-Day Survival All PATIENTS Hazard Ratio: 0.71 (95% CI, ) p = 0.03 Annane JAMA 2002;288:

Hazard Ratio: 0.67 (95% CI, ) p = 0.02 NON RESPONDER 28-Day Survival Annane JAMA 2002;288:

RESPONDERS Annane JAMA 2002;288: Log-Rank-Test,  2 = 0.56 p = Day Survival

Sprung CL. 2008;358:

3. Evidence of shock Systolic BP 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 ( 1 hr) metabolic acidosis [pH 2] platelets ≤ 100,000/mm 3 GCS < 14 (or acute change from baseline) 4. Informed consent 5. ACTH stimulation test CORTICUS INCLUSION CRITERIA

RESULTS: 28-day mortality - all patients P = % mortality steroids (n=251) 86 (34.3%) placebo (n=248) 78 (31.5%) Sprung CL. NEJM 2008;358:

steroids (n=125) placebo (n=108) Non-responders % mortality steroids (n=118) placebo (n=136) Responders % mortality P =0.69P = (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:

RESULTS Reversal of shock Steroids (n=251)Placebo (n=248)p All200 (79.7%)184 (74.2%)0.18 Non-responders95 (76.0%)76 (70.4%)0.41 Responders100 (84.7%)104 (76.5%)0.13 Sprung CL. NEJM 2008;358:

RESULTS: Time to reversal of shock Median time in days (95% CI) Steroids (n=251)Placebo (n=248)P All3.3 ( )5.8 ( )< Non-responders3.9 ( )6.0 ( )0.056 Responders2.8 ( )5.8 ( )< Sprung CL. NEJM 2008;358:

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: De Jonge B. JAMA 2002;288:

COMPLICATION OF STEROID USE- WEAKNESS ICU acquired paresis 25% Risk factors OR (95% CI) – Female sex 4.66 ( ) –Number days > 2 organ dysfunction 1.28 ( ) –Mechanical ventilation 1.10 ( ) –Corticosteroids 14.9 ( ) 29% 9-month mortality with paresis De Jonghe B. JAMA 2002;288:

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:

Frequency of superinfections Steroids (n=234)Placebo (n=232) Superinfection 78 (33%) 61 (26%) No superinfection156 (67%)171 (74%) SI- Relative risk (95% CI) = 1.27 ( ) Sprung CL. NEJM 2008;358: SI+ new S + SS- Relative risk (95% CI) = 1.37 ( )

Adverse events Steroids (n=234) Placebo (n=232) RR (95% CI) Critical illness polyneuropathy 2 (1%)4 (2%) 0.50 ( ) Bleeding - any site21 (9%)16 (7%) 1.3 ( ) MSOF 34 (15%)33 (14%) 1.02 ( ) New sepsis6 (3%)2 (1%) 2.97 ( ) New septic shock14 (6%)5 (2%) 2.78 ( ) Repeat shock 72 (31%)57 (25%) 1.25 ( ) Renal7 (3%)6 (3%) 1.16 ( ) Pulmonary8 (3%)13 (6%) 0.61 ( ) Glucose >8.3 mmol/l (day 1-7) 186 (85%)161 (72%) 1.18 ( )

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:

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 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:

Peter, J. V. et al. BMJ 2008;336: Steroids and ARDS prevention

Peter, J. V. et al. BMJ 2008;336: 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: 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 2C Annane JAMA 2002;288: Sprung CL. NEJM 2008;358: Dellinger P. Crit Care Med. 2008;36:

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: Do not use corticosteroids >300 mg/day of hydrocortisone to treat septic shock Grade 1A Bone, et al. NEJM 1987; VA Sepsis Study Group. NEJM 1987; 317: 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:

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:

NO FREE LUNCH

Balancing Risks and Benefits of Steroids BENEFIT RISK