@efutier

SEPSIS : WHAT’S NEW ?

PRO / CON Hémisuccinate d’hydrocortisone

Emmanuel FUTIER, MD, PhD

Département de Médecine Périopératoire, Anesthésie Réanimation

Hôpital Estaing et Hôpital Gabriel Montpied, CHU de Clermont-Ferrand

Université Clermont Auvergne, CNRS UMR 6293, INSERM U1103, GReD

25ème ICAR – École de Santé des Armées, Bron

30 Novembre 2018

VS.

• Information / Conflits d’intérêts

— Consultant• Dräger medical

• Edwards Lifesciences

— Conférences sur invitation• Dräger medical

• GE Healthcare

• Fresenius kabi

• Fisher & Paykel Healthcare

• Edwards Lifesciences

• Getinge France

Hydrocortisone et Sepsis

JAMA. 1963

1976 - 2018

24 RCTs (ou quasi RCTs)

8859 patients inclus

18 méta-analyses

Hotchkiss RS. Nat Rev Dis Primers. 2016, 30;2:16045

Antiinflammatory Action of Glucocorticoids

N Engl J Med 2005;353:1711-23

Corticosteroid Insufficiency in Acutely Ill Patients

Mark S. Cooper

N Engl J Med 2003;348:727-34

• Quels patients ?

• Quelle indication ?

• Seule ou association ?

• Quel(s) effet(s) indésirable(s) ?

Hydrocortisone et Sepsis

N Engl J Med 1987; 317:659-65N Engl J Med 1984; 311:1137-43 N Engl J Med 1987; 317:653-8

Corticosteroid treatment for sepsis:

A criticalappraisal and meta-analysis of the literatureLisa Cronin, MD; Deborah J. Cook, MD FRCPC, MSc(Epid); Jean Carlet, MD; Daren K.

Heyland, MD MSc(Epid); Derek King, B Math; Mary Ann D. Lansang, MD; Charles J. Fisher,

Jr MD, FCCM

Crit Care Med 1995 Aug;23(8):1430-9

Figure 1. Corticosteroid

treatmentfor sepsis: Effect on mortality

Crit Care Med 1995 Aug;23(8):1430-9

Corticosteroid treatment for sepsis:

A criticalappraisal and meta-analysis of the literatureLisa Cronin, MD; Deborah J. Cook, MD FRCPC, MSc(Epid); Jean Carlet, MD; Daren K.

Heyland, MD MSc(Epid); Derek King, B Math; Mary Ann D. Lansang, MD; Charles J. Fisher,

Jr MD, FCCM

Crit Care Med 1995, Jul;23(7):1294-303

Crit Care Med 1995, Jul;23(7):1294-303

Memphis, TN, USAParis, France

JAMA 2002;288:862-871

Ger-Inf-05 trial• Randomized, double-blind multicenter

• (=19 ICUs) from October 1995 to February

1999

• N=300 patients with septic shock

• Hydrocortisone 50 mg IV every 6 hours and

Fludrocortisone 50 µg once daily (7 days)

• Primary endpoint: 28-day survival distribution

in non-responders to the short corticotropin test

JAMA 2002;288:862-871

Ger-Inf-05 trial• Randomized, double-blind multicenter

• (=19 ICUs) from October 1995 to February

1999

• N=300 patients with septic shock

• Hydrocortisone 50 mg IV every 6 hours and

Fludrocortisone 50 µg once daily (7 days)

• Primary endpoint: 28-day survival distribution

in non-responders to the short corticotropin test

N=15 trials (2022 patients)

Primary outcome measure: all cause mortality at 28 days

BMJ. 2004 Aug 28;329(7464):480

Fig 1 Effects of corticosteroids

on all cause mortality at 28

days in patients with severe

sepsis and septic shock

BMJ. 2004 Aug 28;329(7464):480

BMJ. 2004 Aug 28;329(7464):480

Surviving Sepsis Campaign guidelines for management

of severe sepsis and septic shockR. Phillip Dellinger, MD; Jean M. Carlet, MD; Henry Masur, MD; Herwig Gerlach, MD, PhD; Thierry Calandra, MD; Jonathan

Cohen, MD; Juan Gea-Banacloche, MD, PhD; Didier Keh, MD; John C. Marshall, MD; Margaret M. Parker, MD; Graham

Ramsay, MD; Janice L. Zimmerman, MD; Jean-Louis Vincent, MD, PhD; Mitchell M. Levy, MD; for the Surviving Sepsis

Campaign Management Guidelines Committee

Crit Care Med 2004; 32:858 –873

H. Steroids

Intravenous corticosteroids (hydrocortisone 200–300 mg/day, for 7 days

in three or four divided doses or by continuous infusion) are recommended

in patients with septic shock who, despite adequate fluid replacement,

require vasopressor therapy to maintain adequate blood pressure.

Grade C

CORTICUS study

• Multicenter, randomized, double-blind,

placebo-controlled trial

• N=499 patients with septic shock

• Primary endpoint: Rate of death at 28 days in

patients who did not have a response to

corticotropin

N Engl J Med 2008;358:111-24

RR 1.09 (0.84 to 1.41)

Absolute difference 2.8% (−5.5 to 11.2)

RR 1.09 (0.77 to 1.52)

Absolute difference 3.1% (−9.5 to 15.7)

• N=20 trials (2384 patients)

• Primary Outcome: 28-Day All-Cause

• Mortality

• 35.3% vs 38.5%, RR, 0.84; 95% CI,

0.71-1.00; P=.05

Cochrane Database Syst Rev.2011 Mar 16;(3):CD007720

Primary Outcome: 30-Day All-Cause Mortality

Intention-to-Treat Regression analysis: OR 0.75 (0.46 to 1.21), P = .24Clin Infect Dis. 2018; 66(3):346-354

Intensive Care Med (2018) 44:1470–1482

Intensive Care Med (2018) 44:1470–1482

COIITSS study

• Multicenter, randomized, 2×2 factorial, open-label trial

• IV insulin therapy vs conventional glucose control in

patients treated with 50-mg hydrocortisone/6 hours

for 7 days

• N=509 patients with septic shock

• Primary endpoint: In-hospital mortality

• Time spent with glucose levels in the range of 80 to

110 mg/dL significantly greater in the intensive insulin

therapy group than in the control group (P<10−5)

COIITSS study

HYPRESS trial

• Multicenter, placebo-controlled, double-blind RCT

• N=380 patients with severe sepsis (without septic

shock)

• Continuous infusion of 200-mg hydrocortisone for 5

days (followed by dose tapering until day 11)

• Primary endpoint: Septic shock within 14 days

JAMA. 2016 Nov 1;316(17):1775-1785

JAMA. 2016 Nov 1;316(17):1775-1785

ADRENAL trial• International, pragmatic, double-blind,

parallel-group RCT

• N=3800 patients with septic shock

• Hydrocortisone IV 200-mg per day for a

maximum of 7 days (or until ICU discharge

• or death)

• Primary outcome: Death from any cause at

90 days after randomization

• 27.9% vs 28.8%, OR 0.95 (95%CI 0.82 to

1.10)

N Engl J Med. 2018 Mar 1;378(9):797-808

N Engl J Med. 2018 Mar 1;378(9):797-808

N Engl J Med. 2018 Mar 1;378(9):797-808

N Engl J Med. 2014;371(16):1496-506

ARISE PROCESS

N Engl J Med. 2014; 370:1683-93

ProMISE

N Engl J Med. 2015;372(14):1301-11

Goal-directed (ScvO2) protocol during septic shock

APROCCHS trial• Multicenter, double-blind, 2×2 factorial,

randomized trial

• N=1241 patients with septic shock

• Hydrocortisone 50-mg IV bolus every 6 hours

+ Fludrocortisone 50-μg tablet once daily for 7

days without tapering

• Primary outcome: 90-day all-cause mortality

43% vs 49.1%, RR 0.88 (95% CI, 0.78 to 0.99)

N Engl J Med 2018;378:809-18

Intensive Care Med. 2018;44(7):1003-1016

APROCCHS ●

ADRENAL ●

CORTICUS ●

Ger-Inf-05 ●

• N=22 studies

• 7297 participants

• Primary outcome: Short-term (≤ 90 days)

mortality

• RR 0.96 (95%CI 0.91-1.02)

Intensive Care Med. 2018;44(7):1003-1016

Hydrocortisone

Hydrocortisone

+ Fludrocortisone

11β-Hydroxystéroïde déshydrogénase 2 (11β-HSD)

• 11β-HSD métabolise les glucocorticoïdes en un dérivé inactif (cortisone)

• Pas d’activité de la 11β-HSD sur les minéralocorticoïdes

• 11β-HSD up-régulée dans le sepsis

Glucocorticoids and neuromuscular weakness?

• HYPRESS study (JAMA 2016)

• N= 380 patients with severe sepsis

• APROCCHS study (NEJM 2018)

• N= 1241 patients with septic shock

Intensive Care Med. 2018;44(7):1003-1016

Conclusion

Hydrocortisone et Sepsis

50 ans d’études successives

>10000 patients inclus

Hydrocortisone et Sepsis

• Toujours pas de bénéfice évident en terme de mortalité

• Doses faibles moins délétères que doses élevées

• Peu d’effets indésirables

− Prudence glycémie, natrémie, atteinte musculaire

• Quels patients éligibles ?

• Hydrocortisone ± Fludrocortisone ± Vit B1, Vit B6 … ?

H. CORTICOSTEROIDS

1. We suggest against using IV hydrocortisone to treat septic shock

patients if adequate fluid resuscitation and vasopressor therapy are

able to restore hemodynamic stability.

2. If this is not achievable, we suggest IV hydrocortisone at a dose of

200 mg per day

3. (weak recommendation, low quality of evidence).

Intensive Care Med. 2017 Mar;43(3):299-303

JAMA. 2016 Nov 1;316(17):1775-1785

J Crit Care. 2018 Oct;47:70-79

Hydrocortisone et Sepsis

• Toujours pas de bénéfice évident en terme de mortalité

• Doses faibles moins délétères que doses élevées

• Peu d’effets indésirables

− Prudence glycémie, natrémie, atteinte musculaire

• Quels patients éligibles ?

• Hydrocortisone ± Fludrocortisone ± Vit B1, Vit B6 … ?

• Quels types de sepsis ?

Patient phenotypes and genetic polymorphisms

Inflammopathic, Adaptative and Coagulopathic Sepsis endotypes

Timothy E. Sweeney et al. Crit Care Med. 2018;46:915-925

II with HydrocortisoneII without Hydrocortisone

ID/DD with HydrocortisoneID/DD without Hydrocortisone

PLOS One 2014; 9: e104953

FINMerci de votre attention