Corticosteroids in septic shock: Do we finally have an answer? Slides Final.pdf · Study Annane, et al. CORTICUS Results Decreased 28-day mortality No 28-day mortality difference

©2018 MFMER | slide-1

Corticosteroids in septic shock: Do we finally have an answer?Victoria Milano, PharmDPGY-1 Pharmacy Resident


Objectives• Review the pathophysiology of septic shock and

the mechanism of action of corticosteroids in septic shock

• Describe the recent clinical trials investigating the use of corticosteroids in septic shock

• Discuss the role of corticosteroids in septic shock based on current evidence


Sepsis and Septic Shock Definitions• Sepsis: life-threatening organ dysfunction

caused by a dysregulated host response to infection

• Septic shock: subset of sepsis with circulatory, cellular, and metabolic dysfunction associated with a higher risk of mortality

Singer M, et al. JAMA 2016; 315:801-810


Epidemiology• The mortality for patients with septic shock is

around 50%• Septic shock accounts for up to 10% of

admissions to intensive care units

Angus, D., et al. NEJM 2013; 369:840-851.Mayr, F., et al. Virulence. 2014;5:4-11.Rhodes A, et al. Crit Care Med 2017;45:486-552Walkey, A. et al. Crit Care Med. 41(6):1450-1457

020406080

100

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

Septic shockmortality (age-adjusted)Septic shockincidence


Anti-inflammatory

Septic Shock Pathophysiology

Gandhi N., The Hospitalist. 2012.

Proinflammatory

Hemodynamic alterations

Organ dysfunction

Coagulation disorders


Septic Shock PathophysiologyInfection

Plasma Plasma Plasma

Finfer, S. Crit Care Med. NEJM. 2013; 369:840-851

NO

Cytokines NOCytokines

Red blood cellOxygenTissueWhite blood cell


Septic Shock PathophysiologyInfection

Plasma Plasma Plasma

Finfer, S. Crit Care Med. NEJM. 2013; 369:840-851

Cortisol

Cortisol

Red blood cellOxygenTissueWhite blood cell


Critical Illness-Related Corticosteroid Insufficiency (CIRCI) in Septic Shock

Annane D, et al. Intensive Care Med 2017; 43:1781-1792

• Incidence of adrenal dysfunction may be as high as 50%

Dysregulation of HPA axis

Altered cortisol metabolism

Tissue resistance to

glucocorticoids


Identifying CIRCI

Give 250 mcg IV cosyntropin

Nonresponders:Change in cortisol level

≤9 mcg/dl

Responders: Change in cortisol level

>9 mcg/dl

Measure response at 30 and 60 minutes

Measure baseline cortisol


Corticosteroids in Septic Shock• Proinflammatory response

• Decreased production of cytokines• Decreased production of nitric oxide• Maintain endothelial integrity• Maintain vascular tone

• Subpopulation of patients with CIRCI


Poll-Everywhere Question• Which of the following is NOT a proposed

mechanism of corticosteroids in septic shock?• A) Counteract inflammatory cascade• B) Maintain vascular tone• C) Increase production of nitric oxide• D) Maintain endothelial integrity


History of Corticosteroids in Septic Shock

1950s-1980s

1950s-1980s

Dellinger et al. Crit Care Med. 2004; 32:858-873.Dellinger et al. Intensive Care Med. 2008; 34:17-60.Dellinger et al. Crit Care Med. 2013;41:580-637.Gandhi N., The Hospitalist. 2012.Rhodes et al. Intensive Care Med. 2017;43: 304-377.

19951950s-1980s 1995 2002 2004 2008 2018

2008/2012/2016

High-dose steroids

found to be beneficial

Two meta-analyses: high-dose steroids ineffective and

potentially harmful

Annane et al. trial

published

SSG: hydrocortisone

if requiring vasopressors

CORTICUS trial

published

SSG: hydrocortisone

if blood pressure

unresponsive to fluids and

vasopressors

ADRENAL and

APROCCHSS trials

published

SSG: surviving sepsis guidelines


Hydrocortisone and FludrocortisoneSteroid Hydrocortisone Fludrocortisone

Anti-Inflammatory Activity

1 10

Mineralocorticoid Activity

1 125

Duration (T1/2 hr) 8-12 8-12How supplied Injection and tablet Tablet

Adverse effects Hyperglycemia, neuropathy, myopathy,

delirium, immunosuppression

Edema, hypokalemia


Annane TrialAdult ICU patients requiring mechanical ventilation

within 8°of onset of septic shock19 ICUs in France

Hydrocortisone + Fludrocortisone50 mg IV every 6 hours

50 µg PO daily for 7 days

Hydrocortisone Placebo + Fludrocortisone Placebo

7 days

n=150 n=149

Annane, et al. JAMA 2002;288:862-871.

Nonrespondersn=114

Respondersn=36

Nonrespondersn=115

Respondersn=34


Annane OutcomesOutcome Steroids Placebo OR/HR P-value

All Patients28-Day mortality 82 (55%) 91 (61%) 0.65 (0.39-1.07) 0.091-Year mortality 102 (68%) 112 (75%) 0.62 (0.36-1.05) 0.08Vasopressor withdrawal 7 days 9 days 1.54 (1.10-2.16) 0.01

Nonresponders28-Day mortality 60 (53%) 73 (63%) 0.54 (0.31-0.97) 0.04

1-Year mortality 77 (68%) 88 (77%) 0.57 (0.31-1.04) 0.07

Vasopressor withdrawal 7 days 10 days 1.91 (1.29-2.84) 0.001Responders

28-Day mortality 22 (61%) 18 (53%) 0.97 (0.32-2.99) 0.961-Year mortality 25 (69%) 24 (71%) 0.70 (0.20-2.40) 0.57Vasopressor withdrawal 9 days 7 days 0.49

Annane, et al. JAMA 2002;288:862-871.


CORTICUSAdult ICU patients within 72° of onset of septic shock

52 ICUs

Hydrocortisone50 mg IV Q6H for 5d, then Q12H for

days 6-8, then Q24H for days 9-11, then stopped

Placebo

n=251 n=248

Sprung, et al. NEJM 2008;358:111-24.

Nonrespondersn=125

Respondersn=118

Nonrespondersn=108

Respondersn=136


CORTICUS Trial Outcomes

Nonresponders28-Day mortality 49 (39%) 39 (36%) 1.09 (0.77-1.52) 0.69

1-Year mortality 73 (59%) 60 (57%) 1.03 (0.83-1.29) 0.89

Time to shock reversal 3.9 days 6.0 days 0.06

Outcome Steroid Placebo RR P-valueAll Patients

28-Day mortality 86 (34%) 78 (32%) 1.09 (0.84-1.41) 0.511-Year mortality 137 (57%) 127 (54%) 1.05 (0.89-1.23) 0.58Time to shock reversal 3.3 days 5.8 days <0.001

Responders28-Day mortality 34 (29%) 39 (29%) 1.00 (0.68-1.49) 1.001-Year mortality 61 (55%) 67 (53%) 1.03 (0.82-1.31) 0.80Time to shock reversal 2.8 days 5.8 days <0.001

Sprung, et al. NEJM 2008;358:111-24.


Baseline CharacteristicsBaseline Characteristics Annane, et al. CORTICUS

Steroids Placebo Steroid PlaceboMedicalEmergencyElective

89 (59%)50 (37%)

6 (4%)

90 (60%)55 (37%)

4 (3%)

80 (32%)138 (55%)31 (12%)

93 (38%)132 (54%)

21 (9%)Mean arterial pressure 54±10 55±9

Systolic blood pressure 94±23 95±27

SAPS II score 60±19 57±19 50±18 49±17DopamineDobutamineEpinephrineNorepinephrine

136 (91%)53 (35%)41 (27%)46 (31%)

137 (92%)51 (34%)31 (21%)48 (32%)

27 (11%)

35 (14%)224 (89%)

29 (12%)

22 (9%)231 (93%)

Annane, et al. JAMA 2002;288:862-871. Sprung, et al. NEJM 2008;358:111-24.


ComparisonStudy Annane, et al. CORTICUS

Results Decreased 28-day mortality No 28-day mortality differenceSimilarities Quicker time to shock reversal Quicker time to shock reversal

Differences • SBP <90 mmHg despite fluid replacement and vasopressors

• Addition of fludrocortisone• Abrupt stop of steroids after 7d• Enrolled earlier• Met power• Higher SAPS II scores

• Hypotensive OR receiving vasopressors at time of enrollment

• Tapered over 11d• Enrolled later• Did not meet power• Lower SAPS II scores

Annane, et al. JAMA 2002;288:862-871. Sprung, et al. NEJM 2008;358:111-24.


Poll-Everywhere Question• What finding was consistent between the

Annane and CORTICUS trials?

• A) Quicker time to shock reversal

• B) Decreased 28-day mortality

• C) Decreased 1-year mortality

• D) Increased time to vasopressor withdrawal


Surviving Sepsis Guidelines• “We suggest against using IV hydrocortisone to

treat septic shock patients if adequate fluid resuscitation and vasopressor therapy are able to restore hemodynamic stability. If this is not achievable, we suggest IV hydrocortisone at a dose of 200 mg per day.” (weak recommendation, low quality of evidence)

Rhodes A, et al. Crit Care Med 2017; 45:486-552


APROCCHSS (Hydrocortisone plus Fludrocortisone for Adults with Septic Shock)

Annane D, et al. NEJM 2018; 378:809-818

Adult ICU patients within 24° of onset of septic shock

34 ICUs

Hydrocortisone + Fludrocortisone

Drotrecogin alfa (activated)

Hydrocortisone + Fludrocortisone + Drotrecogin alfa

(activated)Placebos

n=614 n=627

Primary outcome = 90-day all-cause mortality

Hydrocortisone + Fludrocortisone

50 mg IV every 6 hours50 µg PO daily for 7 days

Hydrocortisone Placebo + Fludrocortisone Placebo

7 days


Population• Indisputable or probable septic shock for less

than 24 hours• SOFA score of ≥3 for at least two organs for at

least 6 hours• Receipt of vasopressor therapy for at least 6

hours to maintain a SBP ≥90 mmHg or MAP ≥65 mmHg

• Dose of ≥0.25 mcg/kg/min or ≥1 mg/hr



Baseline Characteristics Hydrocortisone +Fludrocortisone

Placebo

Male 65.5% 67.7%Age 66±14 66±15Admission from medical ward 82.4% 81%

SAPS II 56±19 56±19SOFA score 12±3 11±3Infection source

PulmonaryUrinary TractAbdomen

60.7% 16.6%12.1%

58%18.8%10.9%

EpinephrineDose (mcg/kg/min)

NorepinephrineDose (mcg/kg/min)

8.6%2.31±6.62

87%1.02±1.61

9.3%1.74±2.41

88%1.14±1.16



Mortality

4334 35

474939 41

53

0

10

20

30

40

50

60

90 days 28 days ICUdischarge

180 days

Hydrocortisone +Fludrocortisone

Placebo

P=0.04

P=0.04


% o

f Pat

ient

s

P=0.03

P=0.06


Secondary OutcomesOutcome to 90-days Hydrocortisone +

Fludrocortisone(n=614)

Placebo

(n=627)

Pvalue

Vasopressor-free days 54±39 47±40 0.007

Ventilator-free days 45±39 40±39 0.04Organ-failure free days 51±39 45±40 0.006Discharge from ICU 382 (62.3%) 359 (57.4%) 0.08Discharge from hospital 334 (54.5%) 310 (49.6%) 0.09Mortality from any cause

NonrespondersResponders

101/198 (51%)61/184 (33%)

115/228 (50%)67/170 (39%)

0.910.22



Adverse EventsAdverse Events

(≥1 event)Hydrocortisone + Fludrocortisone

Placebo Pvalue

By day 180Serious event 53.1% 58.0% 0.08

Serious bleeding event 20.7% 19.0% 0.46Episode of superinfection 31.1% 28.4% 0.30

By day 7Episode of blood glucose ≥150 89.1% 83.1% 0.002No. of days with ≥1 episode of blood glucose ≥150 mg/dl

4.3±2.5 3.4±2.5 <0.001



ADRENAL(Adjunctive Glucocorticoid Therapy in Patients with Septic Shock)

Adult ICU patients requiring mechanical ventilation within 24° of

onset of septic shock69 ICUs (Australia, UK, New Zealand,

Saudi Arabia, Denmark)

HydrocortisoneContinuous IV infusion of 200 mg over 24 hours for 7 days or until

ICU discharge/death

PlaceboContinuous IV infusion over 24

hours for 7 days or until ICU discharge/death

Primary outcome = 90-day all-cause mortality

Venkatesh B, et al. NEJM 2018; 378:797-808

n=1853 n=1860


Population• Documented or strong clinical suspicion of

infection• Fulfilled two or more SIRS criteria• Treated with vasopressors or inotropic agents

for ≥4 hours up to and at the time of randomization


SIRS=systemic inflammatory response syndrome


Baseline CharacteristicsHydrocortisone Placebo

Male 60.4% 61.3%Age 62.3±14.9 62.7±15.2Admission type

MedicalSurgical

68.8%31.2%

68.2%31.8%

APACHE II Score 24 (19-29) 23 (18-29)Mean arterial pressure-mmHg 72.5±8.2 72.2±8.3Infection source

PulmonaryAbdomen

33.8% 25.9%

36.5%25.2%

NorepinephrineVasopressinEpinephrine

98.4%15.1%7.2%

97.9%17.3%6.1%



Mortality

2822

2924

0

5

10

15

20

25

30

35

90 days 28 days

HydrocortisonePlacebo

P=0.50

P=0.13

% o

f Pat

ient

s



Subgroup AnalysisSubgroup Hydrocortisone Placebo OR P value

Catecholamine Dose ≤15 mcg/min>15 mcg/min

224/968 (23%)281/849 (33%)

228/995 (23%)291/805 (36%)

1.02 (0.82-1.26)0.86 (0.70-1.05)

0.25

APACHE II Score≥25<25

326/840 (39%)184/990 (19%)

297/785 (38%)229/1039 (22%)

1.01 (0.83-1.24)0.82 (0.66-1.02)

0.17

Time from shockonset to randomization<6 hr6 to <12 hr12 to <18 hr≥18 hr

110/352 (31%)127/511 (25%)119/437 (27%)154/525 (29%)

96/344 (28%)153/486 (32%)106/423 (25%)167/566 (30%)

1.16 (0.83-1.61)0.71 (0.54-0.94)1.13 (0.83-1.54)0.99 (0.76-1.29)

0.08



Secondary OutcomesOutcome Hydrocortisone

(n=1853)Placebo(n=1860)

P value

Blood transfusion 683 (37%) 773 (41.7%) 0.004Recurrence of mechanical ventilation

180 (9.8%) 154 (8.3%) 0.11

Median time in daysResolution of shock 3 (2-5) 4 (2-9) <0.001Discharge from the ICU 10 (5-30) 12 (6-42) <0.001Cessation from initial mechanical ventilation

6 (3-18) 7 (3-24) <0.001

Mean number of daysAlive and out of the ICU 58.2±34.8 56.0±35.4 0.047Alive and free from RRT 42.6±39.1 40.4±38.5 0.29



Adverse EventsAdverse Events Hydrocortisone

(N=1835)Placebo(N=1829)

Hyperglycemia 6 3Hypernatremia 3 0Myopathy 3 0Total adverse events 27 6



ComparisonAPROCCHSS ADRENAL

Results Decreased 90-day mortality No 90-day mortality differenceSimilarities Quicker time to shock reversal Quicker time to shock reversalDifferences • Receiving vasopressors ≥6h

• Hydrocortisone boluses + fludrocortisone

• Majority of medical admissions• 28% renal-replacement therapy• Pulmonary, UTI, abdominal

source most common• Patients sicker

• Receiving vasopressors ≥4h• Continuous IV hydrocortisone• Majority of medical admissions,

many surgical admissions• 13% renal-replacement therapy• Pulmonary, abdominal, UTI

source most common• Patients not as sick

Suffredini, A. NEJM 2018; 378:860-861.Annane D, et al. NEJM 2018; 378:809-818Venkatesh B, et al. NEJM 2018; 378:797-808


Comparison of all Four Trials

Study # of Pts

Mortality Treatment Start

(hours)

Mortality Benefit

Shock Reversal

(days)Annane, et al. 299 58% ≤8 6% 2CORTICUS 499 33% ≤72 None 3

APROCCHSS 1241 46% ≤24 6.1% 2ADRENAL 3800 28% ≤24 None 1

Annane, et al. JAMA 2002;288:862-871. Sprung, et al. NEJM 2008;358:111-24.Annane D, et al. NEJM 2018; 378:809-818Venkatesh B, et al. NEJM 2018; 378:797-808


Summary• The data still shows conflicting evidence if

corticosteroids have a mortality benefit• Corticosteroids improve time to shock reversal• Hyperglycemia is the most significant adverse

event consistently shown in trials


Case• LM is a 68-year-old male with new onset septic

shock from a community acquired pneumonia. He is requiring high doses of vasopressors despite adequate fluid resuscitation and is still not maintaining goal MAP. He has respiratory, liver, and renal failure. Would you use hydrocortisone in this patient?


Poll-Everywhere Question• Would you use hydrocortisone in this patient?

• A) Yes• B) No


Recommendations• Patients with adequate fluid resuscitation

requiring high dose vasopressors with higher SOFA/SAPS II scores (SOFA >10, SAPS II >55) regardless of MAP within 24h of septic shock

• Would recommend hydrocortisone 200 mg IV for 7 days

• Septic shock patients beyond 24 hours, not requiring vasopressors, with lower scores

• Would not recommend hydrocortisone


Remaining Questions• Taper vs. abruptly stop corticosteroids• Duration of corticosteroids • Bolus vs. continuous infusion• When to start corticosteroids• Should fludrocortisone be added to

hydrocortisone


• Questions?

Documents

Corticosteroids in septic shock: Do we finally have an answer? Slides Final.pdf · Study Annane, et al. CORTICUS Results Decreased 28-day mortality No 28-day mortality difference