Corticosteroid Use in Septic Shock V5 · ICU for sepsis and ARF secondary to PNA requiring...

CORTICOSTEROID USE IN SEPTIC SHOCK – THE ONGOING DEBATE

DIEM HO, PHARMD | PGY1 PHARMACY RESIDENT

VALLEY BAPTIST MEDICAL CENTER – BROWNSVILLE

1

ABBREVIATIONS

• ACCP = American College of Chest Physicians• ARF = acute respiratory failure • ICU = intensive care unit • IV = intravenous• ITT = intention to treat • NE = norepinephrine • RCT = randomized control trial • DAA = drotrecogin alfa, activated • SOFA = Sequential Organ Failure Assessment • SCCM = Society of Critical Care Medicine • RRT = renal replacement therapy • PNA = pneumonia • SIRS = systemic inflammatory response syndrome• CNS = central nervous system • GCS = Glasglow Coma Scale

• HPA = hypothalamic-pituitary-adrenal • CRH = corticotropin releasing hormone• ACTH = adrenocorticotropic hormone• IVP = intravenous push • CIF = continuous infusion • MICU = medical ICU• SICU = surgical ICU• LOS = length of stay

2

OBJECTIVES

1. Differentiate sepsis versus septic shock and describe current recommendation for

management.

2. Describe the clinical evidence behind current guideline recommendation for

adjunctive corticosteroid use in septic shock.

3. Evaluate APROCCHSS and ADRENAL trials .

4. Select appropriate patient population for the use of adjunctive corticosteroid.

3

PATIENT CASE

• MA is a 65 year-old female admitted to the

ICU for sepsis and ARF secondary to PNA

requiring mechanical ventilation

• On admission:

• Lactate = 7.2 mmol/L

• Received Hour-1 Bundle

• After 2 hours:

• NE drip started


• After 4 hours:

• NE drip at 50 mcg/min

• Vasopressin drip started


4

WHICH CORTICOSTEROID REGIMEN WOULD YOU RECOMMEND FOR PATIENT MA?

A. Hydrocortisone 50 mg IVP q6h x7 days

B. Hydrocortisone 200 mg CIF x7 days

C. Hydrocortisone 50 mg IVP q6h + fludrocortisone 50 mcg via PEG tube daily x7 days.

D. None

5

SEPSIS AND SEPTIC SHOCK –THE 1991 AND 2001DEFINITIONS

Definition ACCP & SCCM 1991 International Sepsis Definition Conference 2001

Sepsis SIRS + infection Expanded on signs of system inflammation in response to infection

Severe sepsis Sepsis + organ dysfunction or hypoperfusion or hypotension

Unchanged

Septic shock Sepsis + hypotension despiteadequate fluid resuscitation

Persistent hypotension unexplained by other causes

Bone RC et al. Crit Care Med. 1992;20(6):864-874Levy MM et al. Intensive Care Med. 2003;29(4):530-538 6

SEPSIS AND SEPTIC SHOCK – SEPSIS-3 2016

7Singer M et al. JAMA. 2016;315(8):801–810.

• Sepsis:

• Life threatening organ dysfunction

caused by a dysregulated host response

to infection

• Acute increase of SOFA ≥ 2 points

• Severe sepsis:

• Removed

• Septic shock:

• Underlying circulatory and cellular or

metabolic abnormalities

• Vasopressors to maintain MAP ≥ 65

mmHg

• Lactate > 2 mmol/L

SEPSIS-3 – ORGAN DYSFUNCTION MEASURED BY SOFA SCORE

8

System 0 1 2 3 4

RespirationPaO2/FiO2 , mmHg, (kPa)

≥400 (53.3) <400 (53/3) <300 (53.3) <200 (26.7) w/ respiratory support

<100 (13.3) w/ respiratory support

CoagulationPlatelets, x103/µL

≥ 150 < 150 < 100 < 50 < 20

Liver Bilirubin, mg/dL

< 1.2 1-.2-1.9 2.0-5.9 6.0-11.9 >12.0

Cardiovascular, mmHg MAP ≥ 70 MAP < 70 Dopamine <5 or dobutamine

Dopamine 5.1-15 or epinephrine ≤ 0.1 or NE

≤ 0.1

Dopamine >15 or epinephrine >0.1 or

NE>0.1

CNS, GCS score 15 13-14 10-12 6-9 <6

Renal, SCr (mg/dL) < 1.2 1.2-1.9 2.0-3.4 3.5-4.9 >5.0

Urine output, mL/d - - - < 500 <200

Singer M et al. JAMA. 2016;315(8):801–810.

MANAGEMENT OF SEPSIS AND SEPTIC SHOCK

• Initial resuscitation and infection management:

• IV crystalloids

• IV broad spectrum antibiotic within 1 hour

• Source control

• Hemodynamic support:

• IV vasopressors

• Inotropic therapy

9Rhodes A et al. Intensive Care Med. 2017;43(3):304-77

NORMAL HPA AXIS ACTIVATION IN ACUTE ILLNESS

10Annane. Front Endocrinol. 2016;7:70. Cooper et al. N Engl J Med. 2003; 348:727-734.

Hypothalamus

Pituitary

Adrenal glands

TissueCortisol

CRH

ACTH

NORMAL HOST RESPONSE IN ACUTE ILLNESS

11

Sepsis

HPA axis activated,

releasing cortisol

Improve cardiac function

Attenuate inflammation

Sympathetic nervous system

Endogenous catecholamines

Annane. Front Endocrinol. 2016;7:70.

DISRUPTION OF HPA FUNCTION IN ACUTE ILLNESS

12Annane. Front Endocrinol. 2016;7:70. Cooper et al. N Engl J Med. 2003; 348:727-734.

• Hemorrhage or necrosis of neuroendocrine cells• Infection • Hypoxia • Coagulopathy

• Decreased cortisol synthesis • Enzymes inhibition • Depleted lipid droplets storage • Decreased cholesterol production

• Inactivation by high level of cytokines • Decreased cortisol delivery to local

tissues • Increased cortisol clearance

FRENCH TRIAL 2002 – STUDY DESIGN

13

Objective Assess 28-day survival benefits of low-dose corticosteroids in patients with septic shock and relative adrenal insufficiency

Design Single center, double-blind, parallel, RCT in 19 ICU from 10/9/95 to 02/23/99

Population N = 300; Septic shock patients with documented infection requiring mechanical ventilation within 8 hours of shock onset

Intervention • Hydrocortisone 50 mg IVP q6h + fludrocortisone 50 mcg daily for 7 days • Placebo • Short corticotropin test prior to randomization

• Nonresponders ≤ 9 mcg/dL

Outcomes • Primary: 28-day survival in nonresponders to corticotropin test• Secondary: 28-day survival in responders and all patients, 28-day, ICU, hospital and 1-

year mortality rates; time to vasopressor withdrawal

Annane D et al. JAMA. 2002;288:862–871.

FRENCH TRIAL 2002 - RESULT

14Annane D et al. JAMA. 2002;288:862–871.

Primary Outcome: 28-day mortality

Placebo (%) Corticosteroids (%)

Adjusted OR NNT

Nonresponders 73/115 (63) 60/114 (53) 0.54 (0.31-0.97) 10

Responders 18/34 (53) 22/3 (61) 0.97 (0.32-2.99) -

All patients 91/149 (61) 82/150 (55) 0.65 (0.39-1.07) -

Adverse events 33/149 (22) 32/150 (21) - -

Nonresponder Placebo Corticosteroids HR P-value

Time to vasopressor withdrawal (median) 10 day 7 day 1.91 (1.29-2.84) 0.001

28-day vasopressor withdrawal (%) 46/115 (40) 65/114 (57) - -

CORTICUS – STUDY DESIGN

15

Objective Evaluate the efficacy and safety of low-dose hydrocortisone therapy in patients with septic shock

Design Multicenter, double-blind, placebo, RCT from 03/2002 to 11/2005

Population N = 499 (needed 800) Septic shock patients randomized within 72 hours of onset.

Intervention • Hydrocortisone 50 mg IVP q6h for 5 days then 6 day taper • Placebo • Short corticotropin test prior to randomization


Outcomes • Primary: 28-day mortality in nonresponders to corticotropin test• Secondary: 28-day mortality in responders and all patients, 28-day, ICU, hospital and 1-

year mortality; time to shock reversal, ICU and hospital LOS

Sprung CL et al. N Engl J Med. 2008;358:111-124.

CORTICUS – RESULT

16Sprung CL et al. N Engl J Med. 2008;358:111-124.

Primary Outcome28-day mortality

Placebo (%) Hydrocortisone (%) P-value

Nonresponders 39/108 (36.1) 49/125 (39.2) 0.69

Responders 39/136 (28.7) 34/118 (28.8) 1.00

All patients 78/248 (31.5) 86/251 (34.3) 0.51

Hyperglycemia (BG ≥150 mg/dL) 67/232 (29) 42/234 (18) 1.18 (1.07-1.31)

Outcome Placebo (%) Hydrocortisone (%) P-value

Time to shock reversal (median)Nonresponders

RespondersAll patients

6.0 days 5.8 days 5.8 days

3.9 days 3.3 days 2.8 days

0.06<0.001<0.001

ADJUNCTIVE MANAGEMENT OF SEPTIC SHOCK

17

“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. Intensive Care Med. 2017;43(3):304-77

APROCCHSS – STUDY DESIGN & METHODS

18

Objective Evaluate the mortality benefit of hydrocortisone plus fludrocortisone in patients with septic shock

Design • Multicenter, double-blinded, RCT • Initially 2x2 factorial designed to evaluate corticosteroids and DAA

Inclusion • ICU with septic shock < 24 hours • Infection • SOFA 3 or 4 for at least 2 organs and at least 6 hours in duration • Vasopressor for at least 6 hours targeting SBP>90 mmHg or MAP>65 mmHg

Exclusion Septic shock > 24 hours, high bleeding risk, pregnancy, lactation, limited short-term survival, previous treatment with corticosteroid

Annane D et al. N Engl J Med. 2018; 378:809.


19

Settings • 34 ICUs • September 2008 – June 2015.

• Suspended Oct 2011 – May 2012 -> DAA withdrawal• July 2014 – October 2014 -> interim analysis

Intervention • Placebo + DAA placebo or DAA • Corticosteroid + DAA placebo or DAA• Corticosteroid = hydrocortisone 50 mg IV q6h & fludrocortisone 50 mcg

NGT daily for 7 days • Short 250 mcg corticotropin test prior to randomization:




20

Outcomes • Primary: 90 days all-cause mortality • Secondary:

• All-cause mortality at ICU discharge, hospital discharge, day 28, day 180.• % of patients weaned from vasopressor, mechanical ventilation, reach total

SOFA score < 6, organ-failure –free-day, ICU discharge, hospital discharge at day 28 and 90

• Safety: • Superinfection day 180, GI bleeding day 28, hyperglycemia day 7

Statisticalanalysis

• ITT analysis • 45% 90-day mortality; 320 pts in each group to detect 10% difference. Alpha = 0.05


APROCCHSS – BASELINE CHARACTERISTICS

21

Characteristics Placebo(n=627)

Corticosteroids (n=614)

Age, year 66 ± 15 66 ± 14

Medical ward admission 499/616 (81%) 495/601 (82.4)

SAPS II 56 ± 19 56 ± 19

SOFA score 11 ± 3 12 ± 3

Site of infection – lung 363/626 (58%) 373/614 (60.7)

Adequate antimicrobial therapy 602/626 (96.2%) 595/614 (96.9%)

Receipt of NE NE dose, mcg/kg/min

552/627 1.14 ± 1.66

534/6141.02 ± 1.61

Mechanical ventilation 569/623 (91.3%) 567/614 (92.3)


APROCCHSS – MORTALITY

22Annane D et al. N Engl J Med. 2018; 378:809.



Outcome Placebo (n=627)


Relative risk (95% CI)

P values NNT

90-day all cause mortality (%)Nonresponders

Responders

308 (49.1)115/228 (50.4)67/170 (39.4)

264 (43)101/198 (51.0)61/184 (33.2)

0.88 (0.78-0.99)1.01 (0.84 – 1.22)0.84 (0.64-1.11)

0.03 0.910.22

17--

28-day all cause mortality (%) 244 (38.9) 207 (33.7) 0.87 (0.75-1.01) 0.06 -

180-day all cause mortality (%) 328/625 (52.5) 285/611(46.6) 0.89 (0.79-0.99) 0.04 -

All-cause mortality at ICU discharge (%)

257/627 (41) 217/613 (35.4) 0.86 (0.75-0.99) 0.04 -

All-cause mortality at hospital discharge (%)

284/627 (45.3) 239/613 (39.0) 0.86 (0.76-0.98) 0.02 -



PrimaryOutcome

Placebo-placebo

DAA-placebo

Corticosteroid-placebo

Corticosteroid-

DAA

P value

DAA Effects

Corticosteroid Effects

Interaction

90-day all cause

mortality

257/524 (49.0)

51/103 (49.5)

215/509 (42.2) 49/105 (46.7) 0.93 0.003 0.60

APROCCHSS – SECONDARY OUTCOMES


Outcomes Placebo (n=627)


P values

% Weaned off vasopressor at day 28 Mean vasopressor-free day to day 28

Median (IQR)

505/626 (80.7)15 ± 11

19 (1-26)

520/611 (85.1)17.1± 10.823 (5-26)

0.04< 0.001

% Organ-failure-free at day 28Mean organ failure free day to day 28

Median (IQR)

408/622 (65.5)12 ± 11

12 (0-24)

448/612 (73.2)14 ± 11

19 (0-25)

0.0040.003

Ventilator free day at day 28 Mean ventilator free day to day 28

Median (IQR)

348/622 (55.9)10 ± 114 (0-21)

383/611 (62.7)11 ± 111 (0-22)

0.020.07

APROCCHSS – ADVERSE EVENTS


Adverse events Placebo (n=627)


Relative risk (95% CI)

P values

GI bleeding 45/626 (7.2) 39/614 (6.4) 0.88 (0.58-1.34) 0.56

Superinfection 178/626 (28.4) 191/614 (31.1) 1.09 (0.92-1.30) 0.30

Hyperglycemia• ≥ 1 episode of BG ≥ 150

mg/dL by day 7 • Mean # of days with ≥ 1

episode of BG ≥ 150 mg/dL by day 7

Median (IQR)

520/626 (83.1)

3.4 ± 2.5

3 (1-6)

547//614 (89.1)

4.3 ± 2.5

5 (2-6)

1.07 (1.03-1.12)

-

-

0.002

< 0.001

APROCCHSS – AUTHORS’ CONCLUSION

• Hydrocortisone plus fludrocortisone lowered 90-day-all-cause-mortality in patients with septic shock compared to placebo.


Strengths Limitations• Multi-centered• RCT• ITT• Appropriate antibiotic used • Appropriate fluid resuscitation

• Sample size originally calculated for a 2x2 factorial design

• 461 pts did not receive short corticotropin test due to shortage

• Treatment based on Surviving Sepsis 2008 Guideline

APROCCHSS – PRESENTER’S CONCLUSION


• Hydrocortisone 50 mg IVP q6h and fludrocortisone 50 mcg daily for 7 day can be used as adjunctive therapy in patients with refractory shock requiring mechanical ventilation and IV vasopressor to improve mortality benefit

• The addition of low-dose corticosteroid use may facilitate IV vasopressor and ventilator weaning, as well as decreasing the time to reverse organ failure.

ADRENAL – STUDY DESIGN & METHODS

29

Objective Evaluate the mortality benefit of hydrocortisone plus fludrocortisone in patients with septic shock

Design • Double-blinded, multicenter, placebo, parallel-group RCT• Stratified based on medical vs. surgical admission

Inclusion • ICU adults patients with septic shock requiring mechanical ventilation • Infection – documented or strong suspicion • 2 out of 4 SIRS criteria • Vasopressor or inotropes for at least 4 hours targeting SBP > 90 mmHg or MAP > 60

mmHg or physician’s target.

Exclusion • Met all exclusion criteria >24 hours prior to study, corticosteroids for another indication, prior treatment with etomidate or amphotericin B, cerebral malaria or strongloides infection, inevitable death or expected death in 90 days

Settings • 69 MICU/SICUs in Australia, UK, NZ, Saudi Arabia and Denmark • March 2013 – April 2017

Venkatesh et al. N Engl J Med. 2018; 378:797

ADRENAL – STUDY DESIGN & METHODS

30Venkatesh et al. N Engl J Med. 2018; 378:797

Intervention • Hydrocortisone 200 mg daily CIf for 7 days or until ICU discharge • Placebo

Outcomes • Primary: 90-day all-cause mortality • Secondary:

• 28-day all-cause mortality • Time to resolution of shock; recurrence of shock; ICU LOS; hospital LOS;

frequency and duration of mechanical ventilation, RRT • New onset of bacteremia or fungemia between day 2-14 • Receipt of blood transfusion

Statistical analysis

• ITT• 33% mortality; 3800 pts to detect 5% ARR with 90% power, allowing 1% rate of

withdrawal and loss. Alpha = 0.05

ADRENAL – BASELINE CHARACTERISTICS


Characteristics Placebo(n=1853)

Hydrocortisone (n=1860)

Age, year 62.3 ± 14.9 62.7 ± 15.2

Medical ward admission 1273/1849 (68.8) 1266/1857 (68.2)

APACHE II 24.0 23.0

Site of infection – lung Abdominal

623/1844 (33.8)477/1844 (25.9)

677/1854 (36.5)467/1854 (25.2)

Receipt of antimicrobial therapy 602/626 (96.2) 595/614 (96.9)

Receipt of NE 1823/1853 (98.4) 1821/1860 (97.9)

Mechanical ventilation 1845/1849 (99.8) 1855/1857 (99.9)

Time from shock onset to randomization 20.9 ± 91.9 21.2 ± 83.4

ADRENAL – RESULTS


ADRENAL – RESULTS


Outcome Hydrocortisone(n=1860)

Placebo (n=1853)

OR (95% CI)

P values

90-day all cause mortality (%) 511/1832 (27.9) 526/1826 (28.8) 0.95 (0.82-1.10) 0.50

28-day all cause mortality (%) 410/1841 (22.3) 338/1840 (24.3) 0.89 (0.76-1.03) 0.13

Median time to resolution of shock (IQR, day)

3 (2-5) 4 (2-9) 1.32 (1.23 – 1.41)* < 0.001

Median time to discharge from ICU (IQR, day)

10 (5-30) 12(6-42) 1.14 (1.06 – 1.23)* < 0.001

Median time to cessation of ventilation (IQR, day)

6 (3-18) 7 (3-24) 1.13 (1.05 - 1.22)* < 0.001

New-onset bacteremia or fungemia 262 (14.1) 262 (14.1) 1.00 (0.86 -1.16) 0.96

* Hazard ratio

ADRENAL – ADVERSE EVENTS


Adverse events Hydrocortisone (n=1835) Placebo (n=1829)

Number of patients with adverse events 21 6

Hyperglycemia 6 3

Bleeding 2 1

Hypernatremia 3 0

ADRENAL – AUTHORS’ CONCLUSION


• Continuous hydrocortisone infusion did not result in lower 90-day mortality in septic shock patients requiring mechanical ventilation.

Strengths Limitations• Multi-centered• ITT• Largest RCT to date

• Appropriate use of antibiotic not assessed

• Greater rate of loss to follow up and withdrawal

• Used 2001 septic shock definition

ADRENAL – PRESENTER’S CONCLUSION


• Did not improve 90-day mortality in patients with septic shock requiring mechanical ventilation,

• However, time to resolution of shock, ICU discharge, and ventilator cessation, which are important patient-centered outcomes, was significantly less in hydrocortisone group

APROCCHSSVS. ADRENAL – COMPARSION

37Venkatesh et al. N Engl J Med. 2018; 378:797Annane D et al. N Engl J Med. 2018; 378:809

Characteristics APROCCHSS ADRENAL

Time to onset of shockfor inclusion

24 h 24 h

Mean age 66 63

Mechanical ventilation 91.8% 99.9%

NE dose at enrollment 2.1 mcg/kg/min 0.2 mcg/kg/min (assuming 70kg)

Severity of illness SAPS II score: 56 APACHE II score: 24

Site of infection – lung 60% 33 -36%

APROCCHSSVS. ADRENAL – ADDITION OF FLUDROCORTISONE

38Venkatesh et al. N Engl J Med. 2018; 378:797Annane D et al. N Engl J Med. 2018; 378:809Annane. JAMA 2010; 303(4): 341-348.


Intervention Hydrocortisone 50 mg IVP q6h and fludrocortisone 50 mcg daily x7 days

Hydrocortisone 200 mg CIF daily for 7 days or until ICU discharge

• COIITSS 2010: • Multicenter, 2x2 factorial design, RCT in 11 ICUs • Objective: evaluate in-hospital mortality benefits of tight glycemic control and of fludrocortisone in septic shock patients

receiving corticosteroid • Intervention: hydrocortisone IVP 50 mg IVP q6h

• Arm 1: BG target 80-110 mg/dL vs. < 150 mg/dL• Arm 2: fludrocortisone 50 mcg daily vs. no fludrocortisone

• Outcomes: • There is no significant difference between the fludrocortisone group vs placebo in addition to hydrocortisone

APROCCHSSVS. ADRENAL – COMPARSION

39Venkatesh et al. N Engl J Med. 2018; 378:797Annane D et al. N Engl J Med. 2018; 378:809


Mechanical ventilator Use Reduce Reduce

Shock resolution/Free of organ failure

Faster to achieve Faster to achieve

IV vasopressor use Reduce Not assessed

Hyperglycemia Increase Increase

Superinfection No significant difference No significant difference





D. None

40





D. None

41

TAKE HOME POINTS

42

• Sepsis: • Infection + acute SOFA score change ≥ 2

• Septic shock: • Sepsis + circulatory and metabolic

abnormalities • Septic shock management: • Prompt fluid resuscitation, IV

antibiotic, source control • IV vasopressor

• Hydrocortisone 50mg IVP q6h for 7 days • Refractory septic shock • Mechanical ventilator • Within 24 hours of septic shock onset• High dose NE • Risks: hyperglycemia • Benefit: • Reduce vasopressor use • Facilitate ventilator weaning

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