pro / con hémisuccinate d’hydrocortisone€¦ · 1976 - 2018 24 rcts (ou quasi rcts) 8859...
TRANSCRIPT
@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