Sepsis (incomplete)

Question 1

[trial name]: 2018 large, international, prospective, multicenter RCT evaluating hydrocortisone in septic shock

Answer 1

ADRENAL

Venkatesh B, et al. “Adjunctive glucocorticoid therapy in patients with septic shock”. New England Journal of Medicine. 2018.

Question 2

ADRENAL trial: what was the primary outcome measure? Was there a differnce?

Answer 2

Death from Any Cause at 90 Days, no difference.

27.9% vs. 28.8% (OR 0.95; 95% CI 0.82–1.10; P=0.50)

Venkatesh B, et al. “Adjunctive glucocorticoid therapy in patients with septic shock”. New England Journal of Medicine. 2018.

Question 3

ADRENAL trial, 2’ outcomes: Difference in 28 day mortality?

Answer 3

No difference.

22.3% vs. 24.3% (OR 0.89; 95% CI 0.76-1.03; P=0.13)

Venkatesh B, et al. “Adjunctive glucocorticoid therapy in patients with septic shock”. New England Journal of Medicine. 2018.

Question 4

ADRENAL trial, 2’ outcomes: Difference in median time to shock reversal?

Answer 4

Yes, favoring hydrocortisone.

3 (2-5) vs. 4 (2-9) (HR 1.32; 95% CI 1.23–1.41; P<0.001)

Venkatesh B, et al. “Adjunctive glucocorticoid therapy in patients with septic shock”. New England Journal of Medicine. 2018.

Question 5

ADRENAL trial, 2’ outcomes: Difference in median time to shock reversal?

Answer 5

Yes, favoring hydrocortisone.

Median time to shock reversal, days (IQR) 3 (2-5) vs. 4 (2-9) (HR 1.32; 95% CI 1.23–1.41; P<0.001)

Venkatesh B, et al. “Adjunctive glucocorticoid therapy in patients with septic shock”. New England Journal of Medicine. 2018.

Question 6

ADRENAL trial, 2’ outcomes: Difference in ICU length of stay?

Answer 6

Yes, favoring hydrocortisone.

Median time to discharge, days (IQR) From ICU: 10 (5-30) vs. 12 (6-42) (HR 1.14; 95% CI 1.06-1.23; P<0.001)

Venkatesh B, et al. “Adjunctive glucocorticoid therapy in patients with septic shock”. New England Journal of Medicine. 2018.

Question 7

ADRENAL trial, 2’ outcomes: Difference in hospital length of stay?

Answer 7

No.

Median time to discharge, days (IQR) From the hospital: 39 (19-NA) vs 43 (19-NA) (HR 1.06; 95% CI 0.98-1.15; P=0.13)

Venkatesh B, et al. “Adjunctive glucocorticoid therapy in patients with septic shock”. New England Journal of Medicine. 2018.

Question 8

ADRENAL trial, 2’ outcomes:

Difference in duration of mechanical ventilation?

Answer 8

Yes, favoring hydrocortisone.

​Duration of initial mechanical ventilation, days (IQR) 6 (3-18) vs. 7 (3-24) (HR 1.13; 95% CI 1.05-1.22; P<0.001)

Venkatesh B, et al. “Adjunctive glucocorticoid therapy in patients with septic shock”. New England Journal of Medicine. 2018.

Question 9

ADRENAL trial, 2’ outcomes: Difference in blood transfusions?

Answer 9

Yes, favoring hydrocortisone.

Blood transfusion 37.0% vs. 41.7% (OR 0.82; 95% CI 0.72-0.94; P=0.004)

Venkatesh B, et al. “Adjunctive glucocorticoid therapy in patients with septic shock”. New England Journal of Medicine. 2018.

Question 10

ADRENAL trial:

What was the dosing and duration of hydrocortisone?

Answer 10

Continuous infusion of hydrocortisone 200 mg IV daily for 7 days or ICU discharge or death

Question 11

ADRENAL trial, 2’ outcomes:

Difference in adverse events?

Answer 11

Yes, increased in the hydrocortisone group.

21 (1.1%) vs. 6 (0.3%), p=0.009

Hyperglycemia: 6 vs. 3

Hypernatremia: 3 vs. 0

Encephalopathy: 3 vs. 0

Venkatesh B, et al. “Adjunctive glucocorticoid therapy in patients with septic shock”. New England Journal of Medicine. 2018.

Question 12

[trial name]: 2015 open label, multicenter randomized trial of 500 patients evaluating short-duration antibiotics in intra-abdominal sepsis after obtaining source control

Answer 12

STOP-IT

Sawyer RG, et al. “Trial of short-course antimicrobial therapy for intraabdominal infection”. The New England Journal of Medicine. 2015. 372(21):1996-2005.

Question 13

STOP-IT trial:

What was the planned duration of antibiotics in the control arm, after obtaining source control?

Answer 13

2 days after resolution of infection markers, max 10 days.

Infectious markers:

1. Temperature < 38 C for one entire calendar day
2. WCC < 11,000/mm3
3. Ability to consume more than half normal diet

Sawyer RG, et al. “Trial of short-course antimicrobial therapy for intraabdominal infection”. The New England Journal of Medicine. 2015. 372(21):1996-2005.

Question 14

STOP-IT trial:

What was the duration of antibiotics in the experimental arm, after obtaining source control?

Answer 14

Antibiotics for 3-5 days

Question 15

STOP-IT trial:

What was the primary outcome measurement? Result?

Answer 15

1’ outcome: Surgical-site infection, recurrent intra-abdominal infection, or death at 30 days

No difference in primary outcome

Control vs. experimental

22.3% vs. 21.8% (P=0.92)

Sawyer RG, et al. “Trial of short-course antimicrobial therapy for intraabdominal infection”. The New England Journal of Medicine. 2015. 372(21):1996-2005.

Question 16

STOP-IT trial:

Major limitation?

Answer 16

The study was underpowered because they did not achieve their target sample size (approx 500 total patients vs goal 1000).

Question 17

STOP-IT trial:

2’ outcomes: any difference in rates of extraabdominal infection, Clostridium difficile infection, or infection with resistant pathogens?

Answer 17

None.

Sawyer RG, et al. “Trial of short-course antimicrobial therapy for intraabdominal infection”. The New England Journal of Medicine. 2015. 372(21):1996-2005.

Question 18

2014 multicenter, randomized, open-label trial evaluating Early Goal Directed Therapy in sepsis.

Centered in the US.

Answer 18

ProCESS

Angus DC, et al. “A randomized trial of protocol-based care for early septic shock”. The New England Journal of Medicine. 2014. 370(10):1683-1693.

Question 19

2014 multicenter, randomized, open-label trial evaluating Early Goal Directed Therapy in sepsis.

Centered in Australia, New Zealand, Finland, Hong Kong, and Ireland

Answer 19

ARISE

ARISE and ANZICS writers. “Goal-directed resuscitation for patients with early septic shock”. The New England Journal of Medicine. 2014. 371(16):1496-1506.

Question 20

2015 multicenter, randomized, open-label trial evaluating Early Goal Directed Therapy in sepsis.

Centered in the UK

Answer 20

ProMISe

Mouncey PR, et al. “Trial of early, goal-directed resuscitation for septic shock”. The New England Journal of Medicine. 2015. 372(14):1301-1311.

Question 21

ARISE trial:

What were the 4 target goals in the EGDT arm?

Answer 21

SpO2 > 93%

MAP > 65

CVP ≥ 8-12 (12 if on vent)

ScVO2 > 70%

ARISE and ANZICS writers. “Goal-directed resuscitation for patients with early septic shock”. The New England Journal of Medicine. 2014. 371(16):1496-1506.

Question 22

ARISE trial:

What was the primary outcome? Was there a difference?

Answer 22

All-cause mortality at 90 days. No difference.

EGDT vs usual care

18.6% vs. 18.8% (RR 0.98; 95% CI 0.80-1.21; P=0.90)

Question 23

ARISE trial:

Was there a difference in vasopressor usage?

Answer 23

More patients in EGDT arm received vasopressors.

76.3% vs. 65.8% (RR 1.16; P<0.001)

Question 24

ARISE trial:

Was there a difference in amount of fluid given?

Answer 24

Yes, patients in EGDT group received on average more fluids

Volume of fluid administered during the first 6 hours:

EGDT 1964+/-1415 vs. Usual-care group 1713+/-1401ml P<0.001

Question 25

ARISE trial:

Was there a difference in ICU or hospital LOS?

Answer 25

No difference

EGDT vs usual care:

ICU: 2.8 vs. 2.8 days (P=0.81)

Hospital: 8.2 vs. 8.5 days (P=0.89)

Question 26

ARISE trial:

Was there a difference in need for renal replacement therapy?

Answer 26

No difference

RRT: EGDT 13.4% vs. usual care 13.5% (RR 0.99; 95% CI 0.77-1.27; P=0.94)

Question 27

ARISE trial:

Was there a difference in need for invasive ventilation?

Answer 27

No difference

EGDT 30.0% vs. usual care 31.5% (RR 0.95; 95% CI 0.82-1.11; P=0.52)