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The n e w e ng l a n d j o u r na l of m e dic i n e

Original Article

Hydrocortisone plus Fludrocortisone
for Adults with Septic Shock
D. Annane, A. Renault, C. Brun‑Buisson, B. Megarbane, J.-P. Quenot, S. Siami,
A. Cariou, X. Forceville, C. Schwebel, C. Martin, J.-F. Timsit, B. Misset,
M. Ali Benali, G. Colin, B. Souweine, K. Asehnoune, E. Mercier, L. Chimot,
C. Charpentier, B. François, T. Boulain, F. Petitpas, J.-M. Constantin,
G. Dhonneur, F. Baudin, A. Combes, J. Bohé, J.-F. Loriferne, R. Amathieu,
F. Cook, M. Slama, O. Leroy, G. Capellier, A. Dargent, T. Hissem, V. Maxime,
and E. Bellissant, for the CRICS-TRIGGERSEP Network*​​

A BS T R AC T

BACKGROUND
Septic shock is characterized by dysregulation of the host response to infection, with The authors’ full names, academic de‑
circulatory, cellular, and metabolic abnormalities. We hypothesized that therapy with hy- grees, and affiliations are listed in the
Appendix. Address reprint requests to
drocortisone plus fludrocortisone or with drotrecogin alfa (activated), which can modulate Dr. Annane at Service de Médecine Inten‑
the host response, would improve the clinical outcomes of patients with septic shock. sive et Réanimation, Hôpital Raymond
Poincaré, 104 Blvd. Raymond Poincaré,
METHODS 92380 Garches, France, or at d ­jillali​
In this multicenter, double-blind, randomized trial with a 2-by-2 factorial design, we .­annane@​­aphp​.­fr.
evaluated the effect of hydrocortisone-plus-fludrocortisone therapy, drotrecogin alfa (ac- * A complete list of investigators in the
tivated), the combination of the three drugs, or their respective placebos. The primary APROCCHSS trial is provided in the
Supplementary Appendix, available at
outcome was 90-day all-cause mortality. Secondary outcomes included mortality at inten- NEJM.org.
sive care unit (ICU) discharge and hospital discharge and at day 28 and day 180 and the
N Engl J Med 2018;378:809-18.
number of days alive and free of vasopressors, mechanical ventilation, or organ failure.
DOI: 10.1056/NEJMoa1705716
After drotrecogin alfa (activated) was withdrawn from the market, the trial continued Copyright © 2018 Massachusetts Medical Society.
with a two-group parallel design. The analysis compared patients who received hydrocor-
tisone plus fludrocortisone with those who did not (placebo group).
RESULTS
Among the 1241 patients included in the trial, the 90-day mortality was 43.0% (264 of
614 patients) in the hydrocortisone-plus-fludrocortisone group and 49.1% (308 of 627
patients) in the placebo group (P = 0.03). The relative risk of death in the hydrocortisone-
plus-fludrocortisone group was 0.88 (95% confidence interval, 0.78 to 0.99). Mortality
was significantly lower in the hydrocortisone-plus-fludrocortisone group than in the
placebo group at ICU discharge (35.4% vs. 41.0%, P = 0.04), hospital discharge (39.0% vs.
45.3%, P = 0.02), and day 180 (46.6% vs. 52.5%, P = 0.04) but not at day 28 (33.7% and
38.9%, respectively; P = 0.06). The number of vasopressor-free days to day 28 was signifi-
cantly higher in the hydrocortisone-plus-fludrocortisone group than in the placebo group
(17 vs. 15 days, P<0.001), as was the number of organ-failure–free days (14 vs. 12 days,
P = 0.003). The number of ventilator-free days was similar in the two groups (11 days in
the hydrocortisone-plus-fludrocortisone group and 10 in the placebo group, P = 0.07). The
rate of serious adverse events did not differ significantly between the two groups, but
hyperglycemia was more common in hydrocortisone-plus-fludrocortisone group.
CONCLUSIONS
In this trial involving patients with septic shock, 90-day all-cause mortality was lower among
those who received hydrocortisone plus fludrocortisone than among those who received
placebo. (Funded by Programme Hospitalier de Recherche Clinique 2007 of the French Min-
istry of Social Affairs and Health; APROCCHSS ClinicalTrials.gov number, NCT00625209.)
n engl j med 378;9 nejm.org  March 1, 2018 809
The New England Journal of Medicine
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Copyright © 2018 Massachusetts Medical Society. All rights reserved.

3 Apart France XI.25 μg per kilogram of body weight per cogin alfa (activated) would improve the clinical minute or ≥1 mg per hour) for at least 6 hours outcomes of patients with septic shock. Assessment (SOFA)16 score of 3 or 4 (on a scale of namic status and organ function. No other uses without permission.for at least 24 hours. have been reported previously14.11. Participants or their citation and appropriate antiinfective treatments. conducted with four of its commercial form (Xigris) from the market. tistical analysis plan.2 and 50% of survivors of sepsis may have (Comité de Protection des Personnes d’Ile de subsequent long-term cognitive decline. initially showed a survival consent was obtained from patients. Trial Patients roids improve survival in septic shock. 810 n engl j med 378. However. was published previously13 cellular. proved the trial protocol. or any other vasopressor at a dose cortisone-plus-fludrocortisone therapy or drotre- of ≥0.org  March 1.org on February 28. drotre. and risks of corticosteroids and drotrecogin alfa sponse of the hypothalamic–pituitary–adrenal (activated) given alone or in combination. signed a trial to test the hypothesis that hydro- epinephrine.5. with higher showed survival benefits. we report on the effects of hydrocortisone- ratio. their benefit-to-risk article.1 The and is available with the full text of this article short-term mortality is approximately 45 to at NEJM. resulting in the withdrawal Our placebo-controlled trial. aimed to evaluate the benefits that sepsis is associated with a dysregulated re.10 putable or probable septic shock15 for less than This uncertainty about the use of corticoste- 24 hours. Saint-Germain-en-Laye.12 Although both trials mented infection.13 (See also the trial protocol. An independent ethics committee 50%. benefit in sepsis.13 To resolve this discrepancy. 2018. The effects of drotrecogin alfa (activated) patients with severe infections since the mid. with approximately one third of physicians believing that corticoste.4 informed consent before inclusion whenever A human recombinant activated protein C. and metabolic abnormalities. and one third being gible for inclusion in the trial if they had indis- unsure.9 nejm. After axis that may involve any of the steps from cor. remains plus-fludrocortisone therapy. possible. in subsequent trials. . a Sequential Organ Failure showed treatment benefits in terms of hemody. this benefit was not confirmed This investigator-led trial was publicly funded. only one trial11 0 to 4 for each of six organ systems.7 Corti. France) ap- from early hemodynamic and respiratory resus.org. in the current twentieth century. the trial protocol and amendments and the sta- resulting in life-threatening circulatory. physicians’ clinical practice. ness of the data and analysis and for the adher- This has resulted in substantial heterogeneity in ence of the trial to the protocol. For personal use only.6 parallel groups that were organized in a 2-by-2 Experimental and clinical evidence suggests factorial design. and of the trials. Quantitative analysis of these trials full and independent access to all data and has variably confirmed8 or refuted9 the survival vouch for the integrity. the trial continued with two parallel costeroids have been used in the treatment of groups. All the authors had controversial. Septic shock was defined as the pres- roids may relate to the differences in the results ence of a clinically or microbiologically docu- of the two largest trials. to maintain a systolic blood pressure of at least 90 mm Hg or a mean blood pressure of at least 65 mm Hg. 2018 The New England Journal of Medicine Downloaded from nejm. The n e w e ng l a n d j o u r na l of m e dic i n e S eptic shock is characterized by a man Septic Shock (APROCCHSS) trial. and complete- benefit of corticosteroids in patients with sepsis. legally authorized next of kin provided written there is no approved adjunct therapy for sepsis. deferred written informed cogin alpha (activated). one third Patients in intensive care units (ICUs) were eli- believing that they do not. we de- receipt of vasopressor therapy (norepinephrine. All rights reserved. Me thods The exclusion criteria have been detailed else- Trial Design and Oversight where. Otherwise. Copyright © 2018 Massachusetts Medical Society. tober 2011.) Major ex- Information on the design and conduct of the clusion criteria were the presence of septic shock Activated Protein C and Corticosteroids for Hu. accuracy. including dysregulated host response to infection. The divergent findingsscores indicating more severe organ dysfunction) may have resulted from differences in the designfor at least two organs and at least 6 hours. the withdrawal of Xigris from the market in Oc- tisol production to cortisol use by cells. albeit evaluated in numerous trials. a high risk of bleeding.

were alive and free of vasopressors (vasopressor- sone was administered as a 50-mg intravenous free days) up to day 28 and day 90 (patients who bolus every 6 hours. discharge. . (For more details on vasopressors. see the protocol.05 and power at 95%) between n engl j med 378. All adverse events were recorded according to Medical Dic- Trial Measurements and Procedures tionary for Regulatory Activities classification Before randomization. Hydrocortisone plus Fludrocortisone for Septic Shock pregnancy or lactation. Active agents score below 6 (organ-failure–free) at day 28 and and placebos had similar appearances (checked day 90. after. and certified by qualified persons for each batch) organ-failure–free days up to day 28 and day 90. Copyright © 2018 Massachusetts Medical Society. and day 90.org. 2018 811 The New England Journal of Medicine Downloaded from nejm. and sodium phos. centage of patients weaned from vasopressors at vated). drotrecogin alfa (acti.13 Non. patients with septic shock. After first 24 hours in the presence of refractory hy- the withdrawal of Xigris from the market.098 mg]. sodium phosphate [8. The variables that were in. the percentage of patients with a total SOFA for the requirements of the trial. an intravenous bolus of 250 μg of cortico- tropin (Synacthen). Patients were randomly assigned in permuted and day 180. freeze-dried powder for the percentage of patients discharged from the parenteral use of hydrocortisone hemisuccinate ICU and hospital up to day 28 and day 90. di. the percentage of patients weaned tube once daily in the morning. blocking agents were discouraged except in the or previous treatment with corticosteroids. a total of 1280 patients) to detect an abso- infective treatments.3 mg]) in blister episodes of hyperglycemia up to day 7. plasma total cortisol levels (Tables S13 and S14 in the Supplementary Ap- were measured before. and neu- packs of 10.9 nejm. Trial agents from mechanical ventilation at day 28 and day were administered for 7 days without tapering. gastrointestinal bleeding up to day 28. or day 28 and day 90.19 According to the experimental interventions were harmonized 2-by-2 factorial design with a two-sided formula- across centers according to the 2008 Surviving tion. lation. All rights reserved. the per- fludrocortisone therapy. tisone or placebo (microcrystalline cellulose Safety outcomes included superinfection up to [59. the time to weaning from their respective placebos.73 mg].org  March 1. the percentage of patients from blocks of eight to receive hydrocortisone-plus.92 mg]) and tablets of oral fludrocor. mortality (α = 0. — that is. vials of white. available at NEJM. colloidal anhydrous silica [0. drotrecogin alfa (activated) were removed. time to discharge from the ICU and hospital. the combination of the three drugs. 90.6 mg]. the number of days that patients randomization. and fludrocortisone was died before day 28 or day 90 were assigned zero given as a 50-μg tablet through a nasogastric free days).) The primary outcome was 90-day all-cause mor- tality. day 28. lute difference of 10 percentage points in 90-day tory management. and 30 and 60 minutes pendix). ventilator-free days up to day 28 and day cortisone and fludrocortisone were manufactured 90.6 mg]. No other uses without permission. For personal use only.e.13 (Pro- tocol amendments are detailed in the Supple. the (100 mg) or placebo (mannitol [133. Secondary outcomes were all-cause mortal- Randomization and Trial Agents ity at ICU discharge. the poxemia. Statistical Analysis vestigated at baseline and during the 180-day We anticipated a 90-day mortality of 45% among follow-up have been detailed elsewhere.) Hydrocorti. Outcomes mentary Appendix. known prevention of superinfection.org on February 28. and day 180. magnesium stearate [0. 2018. the time to weaning from mechanical venti- Placebos of French commercial forms of hydro. Investigators’ adherence to guidelines exclusion criteria that were relevant only to was checked at each investigators’ meeting. hospital discharge. and blood glucose control.17 including anti­ (i.. 320 patients were needed in each group Sepsis Campaign guidelines. The details of administration of rologic sequelae (cognitive impairment and mus- drotrecogin alfa (activated) are available in the cle weakness) at the time of ICU and hospital protocol. whom care was withheld or withdrawn. the time to reaching a SOFA score below 6. day 90. underlying conditions Investigators followed national guidelines for the that could affect short-term survival.18 Neuromuscular- hypersensitivity to drotrecogin alfa (activated). and day 180. hemodynamic and respira. and ICU-free and hospital-free days up to day 28 phate [0.

was planned to be performed after all the par. Owing to the withdrawal of Xigris from the 2014. ness). The Fine and Gray subdistribu. The effects a medical ward and had severe septic shock. The n e w e ng l a n d j o u r na l of m e dic i n e either drotrecogin alfa (activated) or corticoste. Table 1 shows the signed to receive hydrocortisone plus fludrocor. to check ticipants had completed the 180-day follow-up the quality of the trial agents and the distribu- and according to the 2-by-2 factorial design. costeroids (Tables S2.1) in the placebo group (P = 0. the trial continued with two firmed the conformity of the trial to the market- parallel groups (see the protocol) and was under. were used to compare the effects of trial agents (time to weaning from Outcomes vasopressors. (See also Tables S1 through S7 in the Supple- ing placebos. The sponsor terminated the trial when cebos. The trial sample size) had been enrolled.0) in the hydrocortisone-plus-fludro- software. 2012. with the ICU or hospital. after the withdrawal of cortisone-plus-fludrocortisone group than in the 812 n engl j med 378. Xigris from the market.4 (SAS Institute). to the site of infection and the sensitivity of the pital discharge). the board also confirmed that the distri- the expiration dates of the trial agents were bution of serious adverse events between the reached and 1241 patients (97% of the expected groups did not justify halting the trial. Con. version 9. No other uses without permission. and last patients were recruited on September 2. 2018 The New England Journal of Medicine Downloaded from nejm. to October 7. lative incidence function.13 tion of serious adverse events.1 to 53. and at day 180) and safety higher scores indicating greater severity of ill- outcomes were compared with the use of logistic. Categorical severity-of-illness scores. Most patients were admitted from ages. No At day 90. and Cox mod. the data and safety monitoring board con- market in 2011. primary baseline characteristics of the patients. For personal use only. and treatments at baseline were similar in in each category and the corresponding percent. at day 90. as of trial agents on the frequency of fatal events evidenced by high Simplified Acute Physiology (mortality at day 28.org on February 28. 0. The first therapy. 2015 (Fig. with the Kaplan–Meier procedure.9% of those who received corti- Cox model to competing risk data by consider. as means and standard deviations. and a high degree of regression models and the chi-square test. according the effects of trial agents (time to ICU and hos.13 On October 1.2% of the patients who received tion hazard regression models. The relative R e sult s risk of death was 0. at discharge from Score II (SAPS II) values (range. and S7 in the Supple- ing the hazard function associated with the cumu.78 to 0. S1 in The analysis compared all the patients as. to May 12. characteristics of infec- variables are presented as the number of patients tion. from July 22. vasopressor dependency (mean dose of norepi- tinuous variables were compared with the use of nephrine. S5. All patients (43. high lactate levels. and second.) Patient demographic data. The initial antimicrobial treatment was judged els and the log-rank test were used to compare adequate (by the steering committee. 2014. at the re- roids and placebo. to weaning from mechanical ven. 1). analyses were conducted with SAS statistical 39. and to reaching a SOFA score <6).03) (Table 2 and Fig. from October 25. ing-authorization application for fludrocortisone powered to assess the effect of drotrecogin alfa and hydrocortisone and the quality of their pla- (activated).1%. 2008. Most analyses of variance and t-tests. . Continuous variables are presented mentary Appendix. was completed on December 23. Cumulative event patients had community-acquired infection. 2015.org  March 1. 0 to 163. 2014. which extend the placebo and 96. All rights reserved. the Supplementary Appendix).99) Baseline Patient Characteristics in favor of hydrocortisone-plus-fludrocortisone There were 34 participating centers. the two groups. An intention-to-treat analysis quest of the data and safety monitoring board.0 to 47.9 nejm.0%. tisone with those assigned to receive correspond. 1 μg per kilogram per minute). 95% confidence interval [CI]. 2018. cortisone group and in 308 of 627 patients (49. and curves (censored end points) were estimated the lung was the most common site of infection. 90-Day All-Cause Mortality tilation. The trial Secondary Outcomes was suspended twice: first. pathogens) in 96. Missing data were not replaced. and June 23. mentary Appendix). 95% CI. Copyright © 2018 Massachusetts Medical Society. 45. death had occurred in 264 of 614 adjustment for multiple testing was made.88 (95% CI. Mortality was significantly lower in the hydro- 2011. respectively.

6) Site of infection — no. Copyright © 2018 Massachusetts Medical Society. No other uses without permission. (%) 602/626 (96.31±6. with higher scores indicating greater severity of illness.6) Age — yr† 66±15 66±14 66±14 Admission from a medical ward — no. (%) 459/608 (75.63 Mechanical ventilation — no.62 2. P = 0. SAPS II values were missing for one patient in the placebo group and two patients in the hydrocortisone- plus-fludrocortisone group.7) 927/1210 (76./total no. Baseline Characteristics of the Patients.9) 11/614 (1.9) 1197/1240 (96. those in the placebo group to weaning from P = 0.0) 373/614 (60. and 52. (%) 228/626 (36.9) 74/614 (12.6) 454/1240 (36. S2 in the Supplementary Appendix). to weaning patients] vs.001).4% [217 of sone group had a significantly shorter time than 613 patients] vs.66 1.3) 891/1240 (71.4) 450/614 (73.1) 142/1240 (11.org on February 28. (%) 229/626 (36. patients in the hydrocortisone- Patients in the hydrocortisone-plus-fludrocorti. Hydrocortisone plus Fludrocortisone for Septic Shock Table 1.6) Documented pathogen — no.7) Positive blood culture — no. of patients 58 53 111 Dose — μg/kg/min 1.001) (Fig.0% [239 of 613 mechanical ventilation (P = 0./total no.9) Gram-positive bacteria — no.3) Adequate antimicrobial therapy — no.4) Abdomen 68/626 (10. (%) 569/623 (91.5) Urinary tract 118/626 (18.41 2./total no.6) 225/614 (36.7) 736/1240 (59.8) 102/614 (16.5) 468/602 (77.1) 161/596 (27./total no. 41. There were no significant differences between the two groups.0) 329/1194 (27. The SOFA score was calculated from admission data and was missing for one patient in the placebo group. † One patient in the placebo group had a missing value for age.88 Norepinephrine No. (%) 499/616 (81.8) 29/1240 (2. (%) 168/598 (28.01±4. 2018 813 The New England Journal of Medicine Downloaded from nejm.3% [284 of 627 patients]. (%) 441/626 (70./total no. S3 through S5 in the Supplementary Appen- and Fig.5) 525/1240 (42. from vasopressor therapy (P<0.4) 235/614 (38./total no.14±1. P = 0.04) (Table 2. .3) 463/1240 (37.61 1. placebo group at ICU discharge (35./total no. (%)¶ Unknown 18/626 (2. 2018.0) 495/601 (82.3) Gram-negative bacteria — no. Figs.02).5% [328 of 625 patients]./total no.2) 261/614 (42.6) * Plus–minus values are means ±SD.04).006). and patients could have had more than one site of infection. All rights reserved. ¶ Not all sites of infection are listed here.* Hydrocortisone plus Placebo Fludrocortisone All Patients Characteristic (N = 627) (N = 614) (N = 1241) Male sex — no.5) Vasopressor administration Epinephrine No. dix)./total no. of patients 552 534 1086 Dose — μg/kg/min 1./total no.6% [285 of 611 patients] vs. (%) 424/626 (67. and to reach- and day 180 (46.7) SAPS II‡ 56±19 56±19 56±19 SOFA score§ 11±3 12±3 12±3 Community-acquired infection — no. plus-fludrocortisone group had significantly more n engl j med 378.0% [257 of 627 patients].4) 994/1217 (81.8) Renal-replacement therapy — no.9 nejm. 2. For personal use only.5) 826/1240 (66.3) Lung 363/626 (58.3) 567/614 (92.08±1./total no. (%) 264/626 (42.7) 402/614 (65. § Scores on the Sequential Organ Failure Assessment (SOFA) range from 0 to 24. ing a SOFA score below 6 (P<0. with higher scores indicating greater severity of illness. ‡ The Simplified Acute Physiology Score II (SAPS II) ranges from 0 to 163.3) 1136/1237 (91.74±2. Similarly. hospital discharge (39.org  March 1.02±1. 45.6) 220/1240 (17.2) 595/614 (96.

. 1. (%) Vasopressor-free days to day 28‡ Mean 15±11 17±11 16±11 — <0.6) 0. (%) 257/627 (41.56). 2018. 1. the risk of hyperglycemia was signifi- rate was significantly higher in the hydrocortisone-plus-fludrocortisone cantly higher with hydrocortisone plus fludro- group than in the placebo group. P = 0.0) 572 (46.2 P=0.03 — no. 814 n engl j med 378.003 Median (IQR) 12 (0–24) 19 (0–25) 15 (0–24) * Plus–minus values are means ±SD. Shown are survival curves from randomization up to 90 days. 90-Day Survival Distributions.99) 0.07 Median (IQR) 4 (0–21) 10 (0–22) 8 (0–21) Organ-failure–free days to day 28‡ Mean 12±11 14±11 13±11 — 0.5) 285/611 (46.7) 451 (36.01) 0.7) 64/614 (10. (%) 328/625 (52. 95% CI.76–0. (%) 284/627 (45.02 by log-rank test hydrocortisone-plus-fludrocortisone group and 0.02 At day 180 — no. Copyright © 2018 Massachusetts Medical Society. No other uses without permission.34.1%) in the 0.04 Decision to withhold or withdraw active treat‑ 61/626 (9. ‡ Patients who died before day 28 were assigned zero free days. 0.58 to 1. For personal use only.001 Median (IQR) 19 (1–26) 23 (5–26) 21 (2–26) Ventilator-free days to day 28‡ Mean 10±11 11±11 11±11 — 0.98) 0. P = 0.06 At ICU discharge — no.04 At hospital discharge — no. Placebo 627 381 333 319 P = 0.08) (Table 3).86 (0.99) 0.0) 217/613 (35.0 had at least one serious adverse event by day 180 0 30 60 90 (P = 0./total no. and Tables S8 and S9 in the Supplemen- Probability of Survival 0. All rights reserved. 1. † Shown is the relative risk for hydrocortisone plus fludrocortisone versus placebo.07.1) 0.86 (0. 2018 The New England Journal of Medicine Downloaded from nejm.6) 613/1236 (49.1) 264 (43.org on February 28.3) 239/613 (39.99) 0.4 Serious Adverse Events 0.org  March 1.4) 125/1240 (10.87 (0. at Risk drocortisone plus fludrocortisone than with Hydrocortisone+ 614 405 372 353 fludrocortisone placebo (relative risk.* Hydrocortisone plus Placebo Fludrocortisone All Patients Relative Risk Outcome (N = 627) (N = 614) (N = 1241) (95% CI)† P Value Primary outcome: death from any cause at day 90 308 (49. The survival However.3 A total of 326 of 614 patients (53.75–0.07 (0.9 nejm.03 to 1.0) 523/1240 (42. (%) Secondary outcomes Death from any cause At day 28 — no. 0.7 Hydrocortisone+fludrocortisone 0.09.8 (Table 2. cortisone (relative risk.88 (0.003) 0.9) 207 (33.77–1.4) 474/1240 (38. vasopressor-free days to day 28 than those in the 1. The risk of gastroduodenal Days bleeding was not significantly higher with hy- No.9 organ-failure–free days to day 28 (P = 0./total no.5 Placebo 0.1 363 of 626 patients (58.001) and significantly more 0./total no.6 tary Appendix).12.75–1.30.88. 95% CI.1) 1.89 (0. (%) 244 (38.2) 0.78–0.69 ment by day 90 — no.3) 0./total no.2) 0.0 placebo group (P<0. nor was the risk of superinfection Figure 1.79–0. Trial Outcomes. 95% CI.49) 0.0%) in the placebo group 0.002). 0. The n e w e ng l a n d j o u r na l of m e dic i n e Table 2. IQR denotes interquartile range. (relative risk.92 to 1. 0.30).

Hydrocortisone plus Fludrocortisone for Septic Shock Figure 2.2 ing greater severity of illness) (Panel C) was significant‑ ly shorter in the hydrocortisone-plus-fludrocortisone 0. with higher scores indicat‑ 0. to weaning from mechanical ventila. In addition. and to Reaching a SOFA 1. 0.9 Probability of a SOFA Score <6 was some imbalance between the two groups 0.org on February 28.8 Hydrocortisone+fludrocortisone in the distribution of pathogens.3 septic shock have been detailed recently. or neurologic sequelae Days was not significantly higher with hydrocortisone plus fludrocortisone than with placebo.006 by Gray test). hydrocortisone- Corticosteroids attenuate inflammation in various plus-fludrocortisone therapy accelerated the reso- organs in both animals and humans with sepsis.0 0 7 14 21 28 Days Discussion B Time to Weaning from Mechanical Ventilation 1.6 Placebo fludrocortisone group than in the placebo group. Copyright © 2018 Massachusetts Medical Society. 2018.3 below 6 (on a scale of 0 to 24. No other uses without permission.001 by Gray test). with slightly 0.0 with hydrocortisone plus fludrocortisone.0 Probability of Freedom from Vasopressors Score below 6.2 brief. 0 7 14 21 28 gastroduodenal bleeding. 0 7 14 21 28 creasing systemic vascular resistance. 2018 815 The New England Journal of Medicine Downloaded from nejm. corticosteroids improve cardiovascular func- 0.7 Hydrocortisone+fludrocortisone and at day 180. an effect Days that is partly related to endothelial glucocorticoid receptors.2 free of vasopressors and organ failure was higher 0.8 Placebo vasopressor therapy (Panel A) was significantly shorter 0.5 time to weaning from mechanical ventilation (Panel B) (P = 0. 0.4 ing a Sequential Organ Failure Assessment (SOFA) score 0. n engl j med 378.0 with placebo. an effect partly related to inhibition of nuclear cortisone plus fludrocortisone than with placebo. . The time to weaning from 0.6 pressors.org  March 1.9 Hydrocortisone+fludrocortisone Shown are cumulative incidence functions from ran‑ domization up to 28 days. to Weaning A Time to Weaning from Vasopressors from Mechanical Ventilation. the time to reach‑ 0.1 tion by restoring effective blood volume through 0. lution of organ failure in adults with septic shock.0 In this trial involving adults with septic shock. All rights reserved. For personal use only.5 The mechanisms by which corticosteroids may 0. The number of days alive and 0.7 In 0.20 This might explain why in our trial there was less need for vasopressors with hydro. at discharge from the ICU and hospital.4 shorter with hydrocortisone plus fludrocortisone 0.9 nejm.6 in the placebo group (P<0.0 increased mineralocorticoid activity and by in. The time to weaning from vaso. There 0. 0.1 with hydrocortisone plus fludrocortisone than 0. 0.7 in the hydrocortisone-plus-fludrocortisone group than 0. The risk of secondary infections.8 day 90.9 all-cause mortality was lower with hydrocorti- Probability of Freedom from sone plus fludrocortisone than with placebo at Mechanical Ventilation 0. Time to Weaning from Vasopressors. but the C Time to Reaching a SOFA Score <6 risk of hyperglycemia was significantly higher 1.5 Placebo tion. factor κB (NF-κB). as was the 0. 0.001 by Gray test). 0.7 more viral infections in the hydrocortisone-plus.4 favorably affect the outcome of patients with 0. 0.21 In our trial. and to reaching a SOFA score below 6 was 0. 0.1 group than in the placebo group (P<0.3 than with placebo.

fludro- The second trial (Corticosteroid Therapy of Sep.3) 40/614 (6./total no. 2018.46 Gastroduodenal bleeding — no.11 the APROCCHSS and Ger-Inf-05 trials.12 (0. ‡ Neurologic sequelae were assessed according to the score on the Muscular Disability Rating Scale (MDRS). .17 Last MDRS score = 5 65/626 (10.org  March 1./total no.9) 1.9) 1. cortisone was added to hydrocortisone to pro- 816 n engl j med 378. cortisone alone.71–1./total no.5 — <0.90–1.70) 0.08 ≥1 Serious bleeding event by day 28 — no. 3 distal motor deficit.89–1.1) 547/614 (89.0) 326/614 (53.18 New sepsis — no.36) 0.84–1.7) 49/614 (8. The n e w e ng l a n d j o u r na l of m e dic i n e Table 3.98–1.83–1.56 ≥1 Episode of superinfection by day 180 — no.88 (0.5) 134/614 (21. these findings are in keeping with for Prevention of Septic Shock [HYPRESS]). † Shown is the relative risk for hydrocortisone plus fludrocortisone versus placebo.4) 1.1) 0.7) 1. For personal use only.3±2.30) 0./total no./total no.09 (0.57) 0. 4 mild-to-moderate proximal motor deficit.84–1. showed an absolute differ./total no.8 In this sys. (%) 178/626 (28.20 (0.34 Blood 48/626 (7. (%) Lung 116/626 (18.71–1.8) 1. First.03–1.53) 0.9 nejm. with a score of 1 indicating no deficit.35 Other 57/626 (9.74) 0.4) 191/614 (31.002 — no.5) 1.30 Site of superinfection — no.22 those of a recent Cochrane review. (%) No.40) 0. only 2 of 33 trials were powered shock. Copyright © 2018 Massachusetts Medical Society.87–1.1) 1.79–1.15 (0.66 Urinary tract 33/626 (5.7) 108/614 (17.4) 0. 2018 The New England Journal of Medicine Downloaded from nejm. and 5 severe proximal motor deficit.31 New septic shock — no. No other uses without permission./total no. (%) 103/626 (16. With respect to 90-day all-cause mortality.39) 0.84 Catheter-related 37/626 (5./total no. of days with ≥1 episode of blood glucose levels ≥150 mg/dl by day 7 Mean 3. first trial (Ger-Inf-05).24 (0. (%)‡ Last MDRS score >1 130/626 (20.8) 1. (%) 119/626 (19.8 The cluded patients with shock.4) 73/614 (11.92 (0.7) 1. (%) 363/626 (58. All rights reserved.0) 1.38) 0.58–1.10 (0.12) 0. tic Shock [CORTICUS]) showed no significant there was an absolute difference of 6 percentage survival benefit from an 11-day course of hydro- points and a relative difference of 12% that fa.5) 1.5) 127/614 (20.1) 1. hydrocortisone alone failed to prevent septic tematic review.12 (0.92–1.20 (0.54 Hyperglycemia ≥1 Episode of blood glucose levels ≥150 mg/dl by day 7 520/626 (83. Adverse Events.6) 1.54) 0.93–1.5) 109/614 (17.12 In a more recent trial involving vored hydrocortisone plus fludrocortisone over 380 adults with severe sepsis (Hydrocortisone placebo. (%) 45/626 (7. That trial was not powered to address the to address the effects of a long (≥5 days) course effects of hydrocortisone on mortality and ex- of low-dose corticosteroids on mortality.40 * Plus–minus values are means ±SD. 2 minor deficit with no functional disability.90–1.34) 0.9) 40/614 (6.08 (0.org on February 28.5 4.04 (0.1) 70/614 (11. (%) 122/626 (19.2) 39/614 (6. in in favor of hydrocortisone plus fludrocortisone./total no.4±2.8) 153/614 (24.25 (0.07 (1.01) 0. in which patients received There are two main differences between trials hydrocortisone plus fludrocortisone or matching that showed a survival benefit from corticosteroid placebos for 7 days. therapy (APROCCHSS and Ger-Inf-05) and those ence of 6 percentage points in 28-day mortality that did not (CORTICUS and HYPRESS).001 Median (IQR) 3 (1–6) 5 (2–6) Neurologic sequelae by day 28 — no.09 (0.93) 0.08 Last MDRS score >3 92/626 (14.47) 0.* Hydrocortisone plus Placebo Fludrocortisone Relative Risk Event (N = 627) (N = 614) (95% CI)† P Value ≥1 Serious event by day 180 — no.0) 127/614 (20.

2018 817 The New England Journal of Medicine Downloaded from nejm. AP-HP. M.T. In conclusion.. Bruno François. CHU de Rouen–Hôpital Charles Nicolle. Infection et Immunité.24 ed) and corticosteroids. For personal use only. Service de Réanimation Médicale...17 For these patients.. Service de Pharmacologie Clinique–Centre d’Investigation Clinique (CIC) INSERM 1414.B..D. All rights reserved.D. Megarbane).. M. Gilles Capellier. M. of oral fludrocortisone resulted in lower mortal- lines.D.D. M. Olivier Leroy. Claude Martin. ment with a 50-mg intravenous bolus of hydro- tion according to the 6-hour bundle of care out.R. A.D.D.).. Infection. Hence.... the Ger-Inf-05 and APROCCHSS contractile response to phenylephrine.. E. F.D. CIC 1409. 7-day treat- condition did not improve after initial resuscita. Université Paris Diderot. and Université Paris Sorbonne INSERM. enteral administration of 50 μg of dependency and organ failures. helpful contribution at the time of designing this trial.org  March 1.D. M.D. M. Roland Amathieu. Christian Brun‑Buisson. Hôpital Pontchaillou. Université de Burgundy. Franck Petitpas. Marseille (C.). Alain Cariou. Meaux (X.. and Eric Bellissant. M. Combes).D. a mineralocorticoid-receptor agonist. Montigny- le-Bretonneux (D. and Service de Réanimation Médicale.B. The rationale reported by the Sepsis-3 task force.Sc. fludrocortisone resulted in plasma concentrations Although this trial could not assess the poten- of the drug that exerted significant mineralocorti.A. M.. Etampes (S.. Centre Hospitalier de Valenciennes. Garches (D.D. M. Modélisation.H. trials independently showed a survival benefit proved survival in mice with endotoxic shock. M. Antimicrobiens.). M.9 nejm. Jean‑François Loriferne. Auguste Dargent. M.D.A. Dijon (J.) and Service d’Anesthésie et des Réanimations Chirurgicales (G. M...D. Nutrition. M.). No other uses without permission. Disclosure forms provided by the authors are available with the full text of this article at NEJM. Karim Asehnoune. Grenoble (C. Hôpitaux Universitaires Paris Centre–Site Cochin (AP-HP) (F. Virginie Maxime. This group of patients was selected P070128)... M. University of Versailles Saint-Quentin-en-Yvelines.. INSERM Unité Mixte de Recherche Scientifique (UMRS) 1144 (B.15 The crude in-hospital mortal. Pôle 2i..D.D. M. minute for more than 6 hours was required in Supported by Programme Hospitalier de Recherche Clinique order for hemodynamic stabilization to be 2007 of the French Ministry of Social Affairs and Health (contract achieved. and CIC 1432.D.. Centre Hospitalier Universitaire (CHU) de Rennes–Université de Rennes 1.23 Treatment with SAPS II values (by approximately 7 points).D.F. Mohamed Ali Benali.. Service d’Anesthésie et de Réanimation.. CHU de Grenoble.. as evidenced by higher SOFA NF-κB–mediated down-regulation of vascular scores (by approximately 1. Hôpital Pitié-Salpêtrière (AP-HP). Claire Charpentier. M.. M. and aldosterone. n engl j med 378. In a with hydrocortisone plus fludrocortisone in adults recent pharmacokinetic study involving adults with with septic shock and persistent vasopressor septic shock. Hôpital Saint Faron.D. Misset). Hydrocortisone plus Fludrocortisone for Septic Shock vide additional mineralocorticoid potency.D. Réanimation Médicale–Hôpitaux Universitaires Paris Centre–Site Cochin (AP-HP) and Université Paris Descartes (A. Service de Réanimation Médicale (C. Alain Renault.D. norepinephrine at a ity at day 90 and at ICU and hospital discharge dose of more than 0. UMRS 1166–Institute of Cardiometabolism and Nutrition (A. and CIC 9502. because they may be at high risk for death. Ph. Emmanuelle Mercier. Thierry Boulain. Créteil.. Loïc Chimot. M. M. Ph.-B.. M.B. Hôpital Universitaire François Mitterrand.D.D.)... M. Evolution (IAME) Unité 1137.D.D.D. M. Fabrice Cook. Service d’Anesthésie–Réanimation. group of the APROCCHSS trial is close to that venous formulation of this drug. Paris. François Baudin..org. Jean‑Michel Constantin. CIC INSERM 1414.D.. M. Alain Combes. were more likely to be admitted from medical restored α1-adrenoceptor expression. Copyright © 2018 Massachusetts Medical Society.. It was ity of 45. M..S. 2018. and im. cortisone every 6 hours and a daily dose of 50 μg lined in the Surviving Sepsis Campaign guide.D.D. Service de Réanimation Médicale. this question is no lon- Second.D. Médecine Intensive et Réanimation.25 μg per kilogram per than placebo among adults with septic shock.D.D. Benoît Misset.). Grand Hôpital de l’Est Francilien Site de Meaux..). V. M. INSERM (J. M.. Bertrand Souweine. Tarik Hissem.Q. Michel Slama.M. Laboratory of Infection and Inflammation Unité 1173. which makes them the best target group for We thank Jean Carlet and Jean-François Dhainaut for their adjunct therapy. Hôpital Raymond Poincaré. The authors’ affiliations are as follows: Service de Médecine Intensive et Réanimation. Cariou).D. Xavier Forceville.C.D.1.)..2 Patients in for adding mineralocorticoid treatment is that the APROCCHSS trial were sicker than those in an experimental sepsis study showed marked the CORTICUS trial. Rouen (B.. M..D.. and Service de Réanimation Médi- cale. Carole Schwebel..D.M. Bruno Megarbane. Ph.D.D. Hôpital Nord.. INSERM Research Center Lipids. Appendix The authors’ full names and academic degrees are as follows: Djillali Annane. Aix Marseille Université. Hôpital Lariboisière (AP-HP). with some interindividual variability. Cancer–Unité Mixte de Recherche (UMR) 1231 and Laboratoire d’Excellence Lip- STIC. M.5 points) and higher mineralocorticoid receptors. M.S.. Gilles Dhonneur. Lipness Team.D. Jean‑Pierre Quenot.).). the APROCCHSS and Ger-Inf-05 trials ger relevant since the withdrawal of Xigris from focused on patients with septic shock whose the market in 2011. Réanimation Médico-Chirurgicale.D. M. M.. Réanimation Médicale et Toxicologique.3% that was observed in the placebo administered enterally in the absence of an intra.. M. Rennes (A. Centre Hospitalier d’Etampes. Shidasp Siami. Université Paris-Diderot. M. M. Epidémiologie Clinique. Jean‑François Timsit. M. tial interaction between drotrecogin alfa (activat- coid effects. T. Hôpital Bichat–Claude Bernard.-F. Assistance Publique–Hôpitaux de Marseille. M. Gwenhael Colin.D. Service d’Anesthésie et Réanimations Chirurgicales. Service de Réanimation Polyvalente. INSERM. Julien Bohé.org on February 28. Service de Réanimation Polyvalente.-P.D. Groupe Hospitalier Paris Saint Joseph. . Hôpital Henri-Mondor (Assistance Publique–Hôpi- taux de Paris [AP-HP]). improved wards.).

Goodwin JE. 1220-34. Hôpital Jean Verdier (AP-HP). Proc Natl Acad Sci U S A 2013. The role of ACTH and cor. et al.A. the incidence of organ dysfunction/failure 2016. 14. Feng Y. Annane D. Lancet Respir Med 2015. 306-11. US practitio. Vignon P. Tours (E. References 1. INSERM CIC 1435–CHU Dupuytren.​ 6. and Service de Réanimation Médicale–SAMU 25. Singer M.com/​releasedetail2​. Annane D. et al. induced target tissue resistance to gluco- ReleaseID=617602). surveillance et la préventions des infections Copyright © 2018 Massachusetts Medical Society. Am J Respir Crit corticoids.​187:​1091-7. Service de Réanimation Chirurgicale. Annane D. Deutschman CS. corticosteroids for sepsis: systematic review sis and septic shock: 2008. October 25. tress syndrome: evidence for inflammation- investor​. Hamitouche N. Keh D. guidelines for management of sepsis and Design and conduct of the Activated Pro. et al. 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