190122 timing of renal-replacement therapy with pacient ... · the new england journal of medicine...

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

n engl j med 379;15 nejm.org October 11, 2018 1431

The authors’ full names, academic de-grees, and affiliations are listed in the Ap-pendix. Address reprint requests to Dr. Quenot at the Critical Care Department, University Hospital François Mitterand, 14 rue Paul Gaffarel, 21079 Dijon, France.

*A complete list of the IDEAL-ICU Trial In-vestigators is provided in the Supplemen-tary Appendix, available at NEJM.org.

N Engl J Med 2018;379:1431-42.DOI: 10.1056/NEJMoa1803213Copyright © 2018 Massachusetts Medical Society.

BACKGROUNDAcute kidney injury is the most frequent complication in patients with septic shock and is an independent risk factor for death. Although renal-replacement therapy is the standard of care for severe acute kidney injury, the ideal time for initiation remains controversial.

METHODSIn a multicenter, randomized, controlled trial, we assigned patients with early-stage septic shock who had severe acute kidney injury at the failure stage of the risk, injury, failure, loss, and end-stage kidney disease (RIFLE) classification sys-tem but without life-threatening complications related to acute kidney injury to receive renal-replacement therapy either within 12 hours after documentation of failure-stage acute kidney injury (early strategy) or after a delay of 48 hours if renal recovery had not occurred (delayed strategy). The failure stage of the RIFLE clas-sification system is characterized by a serum creatinine level 3 times the baseline level (or ≥4 mg per deciliter with a rapid increase of ≥0.5 mg per deciliter), urine output less than 0.3 ml per kilogram of body weight per hour for 24 hours or longer, or anuria for at least 12 hours. The primary outcome was death at 90 days.

RESULTSThe trial was stopped early for futility after the second planned interim analysis. A total of 488 patients underwent randomization; there were no significant between-group differences in the characteristics at baseline. Among the 477 patients for whom follow-up data at 90 days were available, 58% of the patients in the early-strategy group (138 of 239 patients) and 54% in the delayed-strategy group (128 of 238 patients) had died (P = 0.38). In the delayed-strategy group, 38% (93 patients) did not receive renal-replacement therapy. Criteria for emergency renal-replacement therapy were met in 17% of the patients in the delayed-strategy group (41 patients).

CONCLUSIONSAmong patients with septic shock who had severe acute kidney injury, there was no significant difference in overall mortality at 90 days between patients who were assigned to an early strategy for the initiation of renal-replacement therapy and those who were assigned to a delayed strategy. (Funded by the French Ministry of Health; IDEAL-ICU ClinicalTrials.gov number, NCT01682590.)

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Timing of Renal-Replacement Therapy in Patients with Acute Kidney Injury and Sepsis

S.D. Barbar, R. Clere-Jehl, A. Bourredjem, R. Hernu, F. Montini, R. Bruyère, C. Lebert, J. Bohé, J. Badie, J.-P. Eraldi, J.-P. Rigaud, B. Levy, S. Siami,

G. Louis, L. Bouadma, J.-M. Constantin, E. Mercier, K. Klouche, D. du Cheyron, G. Piton, D. Annane, S. Jaber, T. van der Linden, G. Blasco, J.-P. Mira,

C. Schwebel, L. Chimot, P. Guiot, M.-A. Nay, F. Meziani, J. Helms, C. Roger, B. Louart, R. Trusson, A. Dargent, C. Binquet, and J.-P. Quenot,

for the IDEAL-ICU Trial Investigators and the CRICS TRIGGERSEP Network*

Original Article

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Copyright © 2018 Massachusetts Medical Society. All rights reserved.

N Engl J Med 2018; 379:1431-1442 DOI: 10.1056/NEJMoa1803213

2019/01/22 �� ICU Journal Club

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�Introduction�Septic shock AKI

�Sepsis ��AKI��42.1% ��Bagshaw SM,et al. Crit Care 2008;12:R47.

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�AKIKI studyGaudry S, et al. N Engl J Med 2016;375:122-33.

�ELAIN trialZarbock A, et al. JAMA 2016;315:2190-9.


n engl j med 375;2 nejm.org July 14, 2016122

The authors’ affiliations are listed in the Appendix. Address reprint requests to Dr. Dreyfuss at the Intensive Care Unit, Hôpital Louis Mourier, 178 rue des Re-nouillers, 92110 Colombes, France, or at didier . dreyfuss@ aphp . fr.

* A complete list of investigators in the Artificial Kidney Initiation in Kidney In-jury (AKIKI) Study Group is provided in the Supplementary Appendix, available at NEJM.org.

Drs. Hajage and Schortgen contributed equally to this article.

This article was published on May 15, 2016, at NEJM.org.


BACKGROUNDThe timing of renal-replacement therapy in critically ill patients who have acute kidney injury but no potentially life-threatening complication directly related to renal failure is a subject of debate.METHODSIn this multicenter randomized trial, we assigned patients with severe acute kidney injury (Kidney Disease: Improving Global Outcomes [KDIGO] classification, stage 3 [stages range from 1 to 3, with higher stages indicating more severe kidney injury]) who required mechanical ventilation, catecholamine infusion, or both and did not have a potentially life-threatening complication directly related to renal failure to either an early or a delayed strategy of renal-replacement therapy. With the early strategy, renal-replacement therapy was started immediately after randomization. With the delayed strategy, renal-replacement therapy was initiated if at least one of the following criteria was met: severe hyperkalemia, metabolic acidosis, pulmonary edema, blood urea nitro-gen level higher than 112 mg per deciliter, or oliguria for more than 72 hours after randomization. The primary outcome was overall survival at day 60.RESULTSA total of 620 patients underwent randomization. The Kaplan–Meier estimates of mortality at day 60 did not differ significantly between the early and delayed strategies; 150 deaths occurred among 311 patients in the early-strategy group (48.5%; 95% confi-dence interval [CI], 42.6 to 53.8), and 153 deaths occurred among 308 patients in the delayed-strategy group (49.7%, 95% CI, 43.8 to 55.0; P = 0.79). A total of 151 patients (49%) in the delayed-strategy group did not receive renal-replacement therapy. The rate of catheter-related bloodstream infections was higher in the early-strategy group than in the delayed-strategy group (10% vs. 5%, P = 0.03). Diuresis, a marker of improved kidney function, occurred earlier in the delayed-strategy group (P<0.001).CONCLUSIONSIn a trial involving critically ill patients with severe acute kidney injury, we found no significant difference with regard to mortality between an early and a delayed strategy for the initiation of renal-replacement therapy. A delayed strategy averted the need for renal-replacement therapy in an appreciable number of patients. (Funded by the French Ministry of Health; ClinicalTrials.gov number, NCT01932190.)

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Initiation Strategies for Renal-Replacement Therapy in the Intensive Care Unit

Stéphane Gaudry, M.D., David Hajage, M.D., Fréderique Schortgen, M.D., Laurent Martin-Lefevre, M.D., Bertrand Pons, M.D., Eric Boulet, M.D.,

Alexandre Boyer, M.D., Guillaume Chevrel, M.D., Nicolas Lerolle, M.D., Ph.D., Dorothée Carpentier, M.D., Nicolas de Prost, M.D., Ph.D.,

Alexandre Lautrette, M.D., Anne Bretagnol, M.D., Julien Mayaux, M.D., Saad Nseir, M.D., Ph.D., Bruno Megarbane, M.D., Ph.D., Marina Thirion, M.D.,

Jean-Marie Forel, M.D., Julien Maizel, M.D., Ph.D., Hodane Yonis, M.D., Philippe Markowicz, M.D., Guillaume Thiery, M.D., Florence Tubach, M.D., Ph.D.,

Jean-Damien Ricard, M.D., Ph.D., and Didier Dreyfuss, M.D., for the AKIKI Study Group*

Original Article

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Copyright 2016 American Medical Association. All rights reserved.

Effect of Early vs Delayed Initiation of Renal ReplacementTherapy on Mortality in Critically Ill PatientsWith Acute Kidney InjuryThe ELAIN Randomized Clinical TrialAlexander Zarbock, MD; John A. Kellum, MD; Christoph Schmidt, MD; Hugo Van Aken, MD; Carola Wempe, PhD;Hermann Pavenstädt, MD; Andreea Boanta, MD; Joachim Gerß, PhD; Melanie Meersch, MD

IMPORTANCE Optimal timing of initiation of renal replacement therapy (RRT) for severe acutekidney injury (AKI) but without life-threatening indications is still unknown.

OBJECTIVE To determine whether early initiation of RRT in patients who are critically ill withAKI reduces 90-day all-cause mortality.

DESIGN, SETTING, AND PARTICIPANTS Single-center randomized clinical trial of 231critically ill patients with AKI Kidney Disease: Improving Global Outcomes (KDIGO) stage 2(!2 times baseline or urinary output <0.5 mL/kg/h for !12 hours) and plasma neutrophilgelatinase–associated lipocalin level higher than 150 ng/mL enrolled between August 2013and June 2015 from a university hospital in Germany.

INTERVENTIONS Early (within 8 hours of diagnosis of KDIGO stage 2; n = 112) or delayed(within 12 hours of stage 3 AKI or no initiation; n = 119) initiation of RRT.

MAIN OUTCOMES AND MEASURES The primary end point was mortality at 90 days afterrandomization. Secondary end points included 28- and 60-day mortality, clinical evidence oforgan dysfunction, recovery of renal function, requirement of RRT after day 90, duration ofrenal support, and intensive care unit (ICU) and hospital length of stay.

RESULTS Among 231 patients (mean age, 67 years; men, 146 [63.2%]), all patients in the earlygroup (n = 112) and 108 of 119 patients (90.8%) in the delayed group received RRT. Allpatients completed follow-up at 90 days. Median time (Q1, Q3) from meeting full eligibilitycriteria to RRT initiation was significantly shorter in the early group (6.0 hours [Q1, Q3: 4.0,7.0]) than in the delayed group (25.5 h [Q1, Q3: 18.8, 40.3]; difference, −21.0 [95% CI, −24.0to −18.0]; P < .001). Early initiation of RRT significantly reduced 90-day mortality (44 of 112patients [39.3%]) compared with delayed initiation of RRT (65 of 119 patients [54.7%];hazard ratio [HR], 0.66 [95% CI, 0.45 to 0.97]; difference, −15.4% [95% CI, −28.1% to −2.6%];P = .03). More patients in the early group recovered renal function by day 90 (60 of 112patients [53.6%] in the early group vs 46 of 119 patients [38.7%] in the delayed group; oddsratio [OR], 0.55 [95% CI, 0.32 to 0. 93]; difference, 14.9% [95% CI, 2.2% to 27.6%]; P = .02).Duration of RRT and length of hospital stay were significantly shorter in the early group thanin the delayed group (RRT: 9 days [Q1, Q3: 4, 44] in the early group vs 25 days [Q1, Q3: 7, >90]in the delayed group; P = .04; HR, 0.69 [95% CI, 0.48 to 1.00]; difference, −18 days [95% CI,−41 to 4]; hospital stay: 51 days [Q1, Q3: 31, 74] in the early group vs 82 days [Q1, Q3: 67, >90]in the delayed group; P < .001; HR, 0.34 [95% CI, 0.22 to 0.52]; difference, −37 days [95% CI,−" to −19.5]), but there was no significant effect on requirement of RRT after day 90, organdysfunction, and length of ICU stay.

CONCLUSIONS AND RELEVANCE Among critically ill patients with AKI, early RRT comparedwith delayed initiation of RRT reduced mortality over the first 90 days. Further multicentertrials of this intervention are warranted.

TRIAL REGISTRATION German Clinical Trial Registry Identifier: DRKS00004367

JAMA. 2016;315(20):2190-2199. doi:10.1001/jama.2016.5828Published online May 22, 2016.

Editorial page 2171

Supplemental content atjama.com

CME Quiz atjamanetworkcme.com

Author Affiliations: Department ofAnaesthesiology, Intensive CareMedicine and Pain Medicine,University Hospital Münster,Germany (Zarbock, Schmidt, VanAken, Wempe, Boanta, Meersch);Center for Critical Care Nephrology,Department of Critical Care Medicine,University of Pittsburgh,Pennsylvania (Kellum); Departmentof Internal Medicine D, UniversityHospital Münster, Germany(Pavenstädt); Institute of Biostatisticsand Clinical Research, University ofMünster, Münster, Germany (Gerß).

Corresponding Author: AlexanderZarbock, MD, Department ofAnesthesiology, Critical CareMedicine and Pain Therapy,University Hospital Münster,Albert-Schweitzer-Campus 1,Gebäude A1, 48149 Münster,Germany ([email protected]).

Research

Original Investigation | CARING FOR THE CRITICALLY ILL PATIENT

2190 (Reprinted) jama.com


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n engl j med 375;2 nejm.org July 14, 2016 127

Renal-Replacement Ther apy Initiation in the ICU

Supplementary Appendix). Sepsis was present in 494 patients (80%), and 389 patients (63%) had been exposed to nephrotoxic agents.

Renal-Replacement TherapyThe patients in the early-strategy group under-went their first renal-replacement therapy session within a median of 2 hours (interquartile range, 1 to 3) after randomization and within a median of 4.3 hours (interquartile range, 2.7 to 5.9) after documentation of stage 3 acute kidney injury and of the fulfillment of other inclusion criteria. In this group, six patients did not receive renal-replacement therapy (see the Supplementary Ap-pendix).

A total of 157 patients (51%) received renal-replacement therapy in the delayed-strategy group within a median of 57 hours (interquartile range, 25 to 83) after randomization (Fig. 1). The me-dian interval between the occurrence of at least one criterion mandating renal-replacement ther-apy and its initiation was 4.7 hours (interquartile range, 1.7 to 10.0). Five patients received renal-replacement therapy without meeting the initia-tion criteria. Persistence of oliguria or anuria for more than 72 hours after randomization and a blood urea nitrogen level higher than 112 mg per deciliter (40 mmol per liter) were the two most common reasons for renal-replacement ther-apy (Table S3 in the Supplementary Appendix).

Patient characteristics at the time of initiation of renal-replacement therapy are provided in Table S4 in the Supplementary Appendix. Meta-bolic abnormalities were more marked in the delayed-strategy group than in the early-strategy group. Details regarding the methods used for renal-replacement therapy, the changes in blood urea nitrogen and serum creatinine levels during follow-up, and the baseline predictors of renal-replacement therapy in the delayed-strategy group are provided in the Supplementary Appendix.

Primary and Secondary OutcomesFollow-up data at 60 days were available for 614 patients (99%); a total of 303 deaths had been observed by day 60 (150 in the early-strategy group and 153 in the delayed-strategy group). The mortality rates in our analysis were estimated with the use of the Kaplan–Meier method. The Kaplan–Meier estimate of the overall mortality at day 60 was 49.1% (95% confidence interval [CI], 45.0 to 52.9). Mortality did not differ sig-nificantly between the two study groups: 48.5%

(95% CI, 42.6 to 53.8) in the early-strategy group and 49.7% (95% CI, 43.8 to 55.0) in the delayed-strategy group (P = 0.79) (Fig. 1). Further stratifi-cation according to center and adjustment for important prognostic factors did not materially change the results.

A post hoc exploratory analysis was performed to compare patients who never received renal-

Figure 1. Probability of Survival and Timing of Renal-Replacement Therapy.

Panel A shows Kaplan–Meier curves of the probability of survival from ran-domization to day 60. Panel B shows the time from randomization to the initiation of renal-replacement therapy, stratified according to study group. Some patients in the early-strategy group received renal-replacement thera-py after 6 hours because of other emergencies resulting in postponement of the initiation of therapy by the medical team, a lack of availability of the renal-replacement therapy machine, or difficulties with catheter insertion. Other reasons for delay included situations such as a surgical procedure or radiologic examinations that needed to be performed before the initiation of renal-replacement therapy.

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Table 2. Primary and Secondary Outcomes and Adverse Events.*

OutcomeEarly Strategy

(N = 311)Delayed Strategy

(N = 308) P ValueHazard Ratio

(95% CI)

Death — no. (% [95% CI])†

Day 28 129 (41.6 [35.9–46.9]) 134 (43.5 [37.7–48.8])

Day 60 150 (48.5 [42.6–53.8]) 153 (49.7 [43.8–55.0]) 0.79 1.03 (0.82–1.29)

Adjusted analysis‡ 0.84 1.02 (0.81–1.29)

Patients with treatment limitation in ICU — no. (%)§ 71 (23) 73 (24) 0.78

Median study day on which a treatment limitation first occurred (IQR)§ 6 (2–12.5) 8 (3–14) 0.23

Patients who received renal-replacement therapy — no. (%) 305 (98) 157 (51) <0.001

Median renal-replacement therapy–free days (IQR) 17 (2–26) 19 (5–29) <0.001

Median mechanical ventilation–free days (IQR) 7 (0–22) 6 (0–21) 0.76

Median vasopressor-free days (IQR) 20 (1–26) 20 (0–26) 0.67

SOFA score

Day 3 10±4 10±4 0.14

Day 7 8±4 8±4 0.63

SOFA score without renal component

Day 3 8±4 8±4 0.62

Day 7 6±4 6±3 0.94

Median length of ICU stay (IQR)

Survivors 13 (8–23) 13 (7–23) 0.87

Nonsurvivors 6 (2–14) 6 (2–13) 0.92

Median length of hospital stay (IQR)

Survivors 29 (17–51) 32 (20–51) 0.58

Nonsurvivors 6 (2–14) 6 (2–13) 0.85

Nosocomial infection

Catheter-related bloodstream infection

Patients with infection — no. (%)¶ 31 (10) 16 (5) 0.03

Median incidence per 1000 catheter-days (IQR) 3.4 (2.3–4.6) 2.1 (1.1–3.1) 0.09

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(95% CI)

Death — no. (% [95% CI])†

Day 28 129 (41.6 [35.9–46.9]) 134 (43.5 [37.7–48.8])

Day 60 150 (48.5 [42.6–53.8]) 153 (49.7 [43.8–55.0]) 0.79 1.03 (0.82–1.29)








SOFA score

Day 3 10±4 10±4 0.14

Day 7 8±4 8±4 0.63


Day 3 8±4 8±4 0.62

Day 7 6±4 6±3 0.94


Survivors 13 (8–23) 13 (7–23) 0.87

Nonsurvivors 6 (2–14) 6 (2–13) 0.92


Survivors 29 (17–51) 32 (20–51) 0.58

Nonsurvivors 6 (2–14) 6 (2–13) 0.85




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(95% CI)

Death — no. (% [95% CI])†

Day 28 129 (41.6 [35.9–46.9]) 134 (43.5 [37.7–48.8])

Day 60 150 (48.5 [42.6–53.8]) 153 (49.7 [43.8–55.0]) 0.79 1.03 (0.82–1.29)








SOFA score

Day 3 10±4 10±4 0.14

Day 7 8±4 8±4 0.63


Day 3 8±4 8±4 0.62

Day 7 6±4 6±3 0.94


Survivors 13 (8–23) 13 (7–23) 0.87

Nonsurvivors 6 (2–14) 6 (2–13) 0.92


Survivors 29 (17–51) 32 (20–51) 0.58

Nonsurvivors 6 (2–14) 6 (2–13) 0.85




Median incidence per 1000 catheter-days (IQR) 3.4 (2.3–4.6) 2.1 (1.1–3.1) 0.09

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Editorial page 2171





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⇨Early��


system were used in this trial because it has been demon-strated that plasma NGAL is a good predictor for the need ofRRT in critically ill patients with AKI.31,32 Moreover, NGAL con-centration can be measured at the bedside within 20 min-utes, making this biomarker suitable for a trial testing a time-sensitive intervention. Our data demonstrate that thecombination of the KDIGO classification system in combina-tion with plasma NGAL can reliably detect patients with pro-gressively deteriorating AKI. Only 5% (6 of 119 patients) of thepatients in the delayed group did not receive RRT, because theyspontaneously recovered or died.

Fluid accumulation in patients with AKI is associatedwith adverse outcomes.33 However, in our study we couldexclude that fluid accumulation was responsible for aworse outcome in the delayed group because there were nodifferences in daily fluid balance before and within 3 daysafter randomization. As some data suggest that initiation ofRRT before the onset of severe AKI may attenuate kidney-specific and non–kidney organ injury from systemicinflammation.28,29 It is possible that the reduced plasma lev-els of inflammatory mediators in the early group are respon-sible for the reduced mortality. Our data extend the findings

Table 3. Clinical Outcomes for Early vs Delayed Renal Replacement Therapy (RRT) Among Critically Ill Patients

Early(n = 112)

Delayed(n = 119)

PValue

AbsoluteDifference, %(95% CI)

OR or HR(95% CI)

Primary Outcome, No. (%)

90-d All-cause mortality 44 (39.3) 65 (54.7) .03 −15.4(−28.1 to −2.6)

HR: 0.66(0.45 to 0.97)

Secondary Outcomes, No. (%)

28-d All-cause mortality 34 (30.4) 48 (40.3) .11 −10.0(−22.2 to 2.3)

OR: 0.64(0.37 to 1.11)

Requirement of RRT on day 28,No./total No. patients aliveat day 28 (%)

18/78 (23.1) 26/71 (36.6) .07 −13.5(−28.1 to 1.1)

OR: 0.52(0.25 to 1.06)


OR: 0.61(0.36 to 1.03)


11/69 (15.9) 14/59 (23.7) .27 −7.8(−21.7 to 6.1)

OR: 0.61(0.25 to 1.47)

Duration of RRT,median (Q1, Q3), da

9 (4, 44)(n = 112)

25 (7, >90)(n = 108)b

.04 −18(−41 to 4)

HR: 0.69(0.48 to 1.00)c

Organ dysfunction, No. (%)d 107 (95.5) 118 (99.2) .11 −3.6(−7.8 to 0.5)

OR: 0.18(0.02 to 1.58)

Respiratory 103 (92.0) 116 (97.5) .06 −5.5(−11.3 to 0.3)

OR: 0.30(0.08 to 1.12)

Coagulation 68 (60.7) 87 (73.1) .05 −12.4(−24.5 to −0.3)

OR: 0.57(0.33 to 0.99)

Liver 52 (46.4) 65 (54.6) .21 −8.2(−21.1 to 4.7)

OR: 0.72(0.43 to 1.21)

Cardiovascular 103 (92.0) 115 (96.6) .12 −4.7(−10.7 to 1.3)

OR: 0.40(0.12 to 1.33)

Central nervous system 102 (91.1) 114 (95.8) .15 −4.7(−11.1 to 1.7)

OR: 0.45(0.15 to 1.35)

Recovery of renal functionat day 90e

Yes 60 (53.6) 46 (38.7) .02 14.9(2.2 to 27.6)

OR: 0.55(0.32 to 0.93)f

Nog 52 (46.4) 73 (61.3)


Yes 60 (88.2) 46 (85.2) .62 3.1(−9.1 to 15.2)

OR: 0.77(0.27 to 2.17)h

Noi 8 (11.8) 8 (14.8)


9/67 (13.4)j 8/53 (15.1)k .80 −1.7(−14.3 to 11.0)

OR: 0.87(0.31 to 2.44)

ICU stay, median (Q1, Q3), d 15.5(8.0, 28.0)

16.0(6.8, 30.0)

.95 0.0(−3.0 to 3.0)

ICU stay, median (Q1, Q3), dl 19(9, 29)

22(12, 36)

.33 −3.0(−12.0 to 4.5)

HR: 0.85(0.61 to 1.19)m

Hospital stay, median (Q1, Q3), d 33.0(18.0, 58.0)

43.0(19.5, 81.3)

.05 −9.0(−19.0 to 0.0)

Hospital stay, median (Q1, Q3), dn 51(31, 74)

82(67, >90)

<.001 −37(−! to −19.5)

HR: 0.34(0.22 to 0.52)o

Duration of mechanical ventilation,median (Q1, Q3), h

125.5(41, 203)

181.0(65, 413)

.002 −60.0(−110.0 to −22.0)

Abbreviations: HR, hazard ratio;ICU, intensive care unit; Q, quartile;OR, odds ratio.a Duration of RRT was censored at

patients’ date of death or at day 90where applicable, whicheveroccurred first.

b Eleven patients did not receive RRT.c An HR less than 1 indicates a shorter

duration of RRT in the early groupthan in the delayed group.

d Organ dysfunction is defined as anindividual nonrenal SequentialOrgan Failure Assessment score of 2or higher during ICU stay (partialpressure of oxygen/fraction ofinspired oxygen [PaO2/FIO2] <300mm Hg, Glasgow coma scale "12,requirement of vasopressoradministration, bilirubin #2 mg/dL,platelets <100 ×103/µL).

e Renal recovery is defined as dialysisindependency at day 90.

f An OR less than 1 indicates a higherrecovery rate in the early group thanin the delayed group.

g Including patients who died within90 days.

h An OR less than 1 indicates a higherrecovery rate in the early group thanin the delayed group.

i Excluding patients who died within90 days.

j Patients alive at day 90 (n = 68),1 patient with missing value.

k Patients alive at day 90 (n = 54),1 patient with missing value.

l ICU stay was censored at day 90 orat patients’ deaths whereapplicable.

mAn HR less than 1 indicates a shorterduration of ICU stay in the earlygroup than in the delayed group.

n Hospital stay was censored at day90 or at patients’ deaths whereapplicable.

o An HR less than 1 indicates a shorterduration of hospital stay in the earlygroup than in the delayed group.

Early vs Delayed RRT in Critically Ill Patients With AKI Original Investigation Research

jama.com (Reprinted) JAMA May 24/31, 2016 Volume 315, Number 20 2197




uremic symptoms developed. No differences in kidney recov-ery or mortality were observed. In line with these results, a re-cently published multicenter trial investigating accelerated vsstandard initiation of RRT in 101 critically ill patients with AKIalso demonstrated no mortality difference between bothgroups.10 However, this was a feasibility trial, and the trial wasnot powered to investigate mortality. Finally, 1 small random-ized clinical trial demonstrated that early initiation of RRT wasassociated with a reduced mortality compared with late ini-tiation of RRT.18 In this study, the authors evaluated the roleof early RRT in 28 patients with AKI following cardiac sur-gery. Fourteen patients were started on continuous hemodi-alysis when their urine volume decreased to less than 30 mL/hfor 3 hours. In patients in the “late” group (n = 14), RRT wasdelayed until urine output had fallen to less than 20 mL/h for2 hours. Survival was significantly better in the group of pa-tients who started RRT earlier. There were no differences be-tween the 2 groups with respect to age, sex, Acute Physiologyand Chronic Health Evaluation (APACHE) II score, and serumcreatinine level at the time of initiation of RRT.

The results of a recently published meta-analysis suggestthat earlier initiation of RRT in critically ill patients with AKImay have beneficial association with survival (OR, 0.45 [95%CI, 0.28-0.72]).7 However, this conclusion is based on hetero-geneous studies of variable quality. Therefore, more random-ized trials are required to answer this question. This researchpriority has been articulated by the KDIGO clinical practiceguidelines,5 and the Acute Kidney Injury Network26 has pri-oritized this research topic.

Potential benefits of earlier initiation are attributable tomore rapid metabolic or uremic control and more effective pre-vention and management of fluid overload.27 Some data alsosuggest that RRT before the onset of severe AKI may attenu-ate kidney-specific and non–kidney organ injury from acide-mia, uremia, fluid overload, and systemic inflammation andcould potentially translate into improved survival and earlier

recovery of kidney function.28,29 The counterargument is thata strategy of early initiation of RRT might subject patients whowould recover renal function with conservative treatmentalone to the potential risks associated with RRT. However, AKIconfers a substantial increased risk of death even in patientsnever treated with RRT.30 As such, although there may be arisk of “unnecessary” RRT, there could be an even greater riskassociated with not providing it. To avoid treating patients withRRT who may have otherwise spontaneously recovered kidneyfunction, biomarkers in addition to the KDIGO classification

Figure 2. Mortality Probability Within 90 Days After Study Enrollmentfor Patients Receiving Early and Delayed Initiation of RenalReplacement Therapy (RRT)

100

80

60

40

20

00

112119

10

9290

20

8279

30

7870

40

7563

50

7362

60

6959

70

6958

80

6654

90

5548

Over

all M

orta

lity

Prob

abili

ty, %

Days Since Randomization

No. at riskEarly RRTDelayed RRT

Early RRT

Delayed RRT

Inverse normal log-rank test, P = .03; HR = 0.66 (95% CI, 0.45-0.97)

KDIGO indicates Kidney Disease: Improving Global Outcomes. In the delayedgroup, 18 patients received RRT without reaching KDIGO stage 3 (these patientshad an absolute indication). The median (quartile 1 [Q1], quartile 3 [Q3])duration of follow-up was 90 days (Q1, Q3: 90, 90) in the early groupand 90 days (Q1, Q3: 90, 90) in the delayed group. The vertical ticks indicatecensored cases.

Table 2. Patient Characteristics at the Time of Renal Replacement Therapy (RRT) Initiation

Early(n = 112)

Delayed(n = 119)

Absolute DifferenceEarly vs Delayed(95% CI) P Value

Received RRT, No. 112 108

Time from meeting eligibility criteria torandomization, median (Q1, Q3), h

2.0(1.0, 3.0)

2.0 (1.0, 3.0) 0.0 (0.0 to 0.0) .36

Time from KDIGO 2 to RRT, mean (SD), h 5.4 (2.2) 40.0 (54.5) −34.5(−45.0 to −24.0)

<.001

Time from KDIGO 2 to RRT,median (Q1, Q3), h

6.0(4.0, 7.0)

25.5(18.8, 40.3)

−21.0(−24.0 to −18.0)

<.001

Urinary output, median (Q1, Q3), mL 445.0(175.0, 807.5)

270.0(112.5, 670.0)

115.0(25.0 to 220.0)

.01

Serum creatinine, mean (SD), mg/dL 1.9 (0.6) 2.4 (1.0) −0.5(−0.7 to −0.3)

<.001

Blood urea nitrogen, mean (SD), mg/dL 38.5 (15.5) 47.5 (21.6) −9.0(−14.1 to −3.9)

.001

Potassium, mean (SD), mEq/L 5.1 (0.9) 5.1 (0.9) 0.0(−0.2 to 0.3)

.69

Bicarbonate, mean (SD), mEq/L 20.9 (3.6) 20.7 (3.7) 0.1(−0.9 to 1.1)

.79

Hemoglobin, mean (SD), g/dL 8.6 (1.3) 8.6 (1.4) −0.1(−0.4 to 0.3)

.74

White blood cells, mean (SD), ×109/L 16.2 (9.8) 16.5 (9.5) −0.3(−2.9 to 2.3)

.83

Abbreviations: KDIGO, KidneyDisease: Improving Global Outcomes,Q, quartile.SI conversion factor: To convertcreatinine to μmol/L, multiply by88.4; urea nitrogen to mmol/L,multiply by 0.357.

Research Original Investigation Early vs Delayed RRT in Critically Ill Patients With AKI

2196 JAMA May 24/31, 2016 Volume 315, Number 20 (Reprinted) jama.com







Early(n = 112)

Delayed(n = 119)

PValue


OR or HR(95% CI)



HR: 0.66(0.45 to 0.97)



OR: 0.64(0.37 to 1.11)


18/78 (23.1) 26/71 (36.6) .07 −13.5(−28.1 to 1.1)

OR: 0.52(0.25 to 1.06)


OR: 0.61(0.36 to 1.03)


11/69 (15.9) 14/59 (23.7) .27 −7.8(−21.7 to 6.1)

OR: 0.61(0.25 to 1.47)


9 (4, 44)(n = 112)

25 (7, >90)(n = 108)b

.04 −18(−41 to 4)

HR: 0.69(0.48 to 1.00)c


OR: 0.18(0.02 to 1.58)

Respiratory 103 (92.0) 116 (97.5) .06 −5.5(−11.3 to 0.3)

OR: 0.30(0.08 to 1.12)

Coagulation 68 (60.7) 87 (73.1) .05 −12.4(−24.5 to −0.3)

OR: 0.57(0.33 to 0.99)

Liver 52 (46.4) 65 (54.6) .21 −8.2(−21.1 to 4.7)

OR: 0.72(0.43 to 1.21)


OR: 0.40(0.12 to 1.33)


OR: 0.45(0.15 to 1.35)


Yes 60 (53.6) 46 (38.7) .02 14.9(2.2 to 27.6)

OR: 0.55(0.32 to 0.93)f

Nog 52 (46.4) 73 (61.3)


Yes 60 (88.2) 46 (85.2) .62 3.1(−9.1 to 15.2)

OR: 0.77(0.27 to 2.17)h

Noi 8 (11.8) 8 (14.8)


9/67 (13.4)j 8/53 (15.1)k .80 −1.7(−14.3 to 11.0)

OR: 0.87(0.31 to 2.44)


16.0(6.8, 30.0)

.95 0.0(−3.0 to 3.0)


22(12, 36)

.33 −3.0(−12.0 to 4.5)

HR: 0.85(0.61 to 1.19)m


43.0(19.5, 81.3)

.05 −9.0(−19.0 to 0.0)


82(67, >90)

<.001 −37(−! to −19.5)

HR: 0.34(0.22 to 0.52)o


125.5(41, 203)

181.0(65, 413)

.002 −60.0(−110.0 to −22.0)

























Early(n = 112)

Delayed(n = 119)

PValue


OR or HR(95% CI)



HR: 0.66(0.45 to 0.97)



OR: 0.64(0.37 to 1.11)


18/78 (23.1) 26/71 (36.6) .07 −13.5(−28.1 to 1.1)

OR: 0.52(0.25 to 1.06)


OR: 0.61(0.36 to 1.03)


11/69 (15.9) 14/59 (23.7) .27 −7.8(−21.7 to 6.1)

OR: 0.61(0.25 to 1.47)


9 (4, 44)(n = 112)

25 (7, >90)(n = 108)b

.04 −18(−41 to 4)

HR: 0.69(0.48 to 1.00)c


OR: 0.18(0.02 to 1.58)

Respiratory 103 (92.0) 116 (97.5) .06 −5.5(−11.3 to 0.3)

OR: 0.30(0.08 to 1.12)

Coagulation 68 (60.7) 87 (73.1) .05 −12.4(−24.5 to −0.3)

OR: 0.57(0.33 to 0.99)

Liver 52 (46.4) 65 (54.6) .21 −8.2(−21.1 to 4.7)

OR: 0.72(0.43 to 1.21)


OR: 0.40(0.12 to 1.33)


OR: 0.45(0.15 to 1.35)


Yes 60 (53.6) 46 (38.7) .02 14.9(2.2 to 27.6)

OR: 0.55(0.32 to 0.93)f

Nog 52 (46.4) 73 (61.3)


Yes 60 (88.2) 46 (85.2) .62 3.1(−9.1 to 15.2)

OR: 0.77(0.27 to 2.17)h

Noi 8 (11.8) 8 (14.8)


9/67 (13.4)j 8/53 (15.1)k .80 −1.7(−14.3 to 11.0)

OR: 0.87(0.31 to 2.44)


16.0(6.8, 30.0)

.95 0.0(−3.0 to 3.0)


22(12, 36)

.33 −3.0(−12.0 to 4.5)

HR: 0.85(0.61 to 1.19)m


43.0(19.5, 81.3)

.05 −9.0(−19.0 to 0.0)


82(67, >90)

<.001 −37(−! to −19.5)

HR: 0.34(0.22 to 0.52)o


125.5(41, 203)

181.0(65, 413)

.002 −60.0(−110.0 to −22.0)

























Early(n = 112)

Delayed(n = 119)

PValue


OR or HR(95% CI)



HR: 0.66(0.45 to 0.97)



OR: 0.64(0.37 to 1.11)


18/78 (23.1) 26/71 (36.6) .07 −13.5(−28.1 to 1.1)

OR: 0.52(0.25 to 1.06)


OR: 0.61(0.36 to 1.03)


11/69 (15.9) 14/59 (23.7) .27 −7.8(−21.7 to 6.1)

OR: 0.61(0.25 to 1.47)


9 (4, 44)(n = 112)

25 (7, >90)(n = 108)b

.04 −18(−41 to 4)

HR: 0.69(0.48 to 1.00)c


OR: 0.18(0.02 to 1.58)

Respiratory 103 (92.0) 116 (97.5) .06 −5.5(−11.3 to 0.3)

OR: 0.30(0.08 to 1.12)

Coagulation 68 (60.7) 87 (73.1) .05 −12.4(−24.5 to −0.3)

OR: 0.57(0.33 to 0.99)

Liver 52 (46.4) 65 (54.6) .21 −8.2(−21.1 to 4.7)

OR: 0.72(0.43 to 1.21)


OR: 0.40(0.12 to 1.33)


OR: 0.45(0.15 to 1.35)


Yes 60 (53.6) 46 (38.7) .02 14.9(2.2 to 27.6)

OR: 0.55(0.32 to 0.93)f

Nog 52 (46.4) 73 (61.3)


Yes 60 (88.2) 46 (85.2) .62 3.1(−9.1 to 15.2)

OR: 0.77(0.27 to 2.17)h

Noi 8 (11.8) 8 (14.8)


9/67 (13.4)j 8/53 (15.1)k .80 −1.7(−14.3 to 11.0)

OR: 0.87(0.31 to 2.44)


16.0(6.8, 30.0)

.95 0.0(−3.0 to 3.0)


22(12, 36)

.33 −3.0(−12.0 to 4.5)

HR: 0.85(0.61 to 1.19)m


43.0(19.5, 81.3)

.05 −9.0(−19.0 to 0.0)


82(67, >90)

<.001 −37(−! to −19.5)

HR: 0.34(0.22 to 0.52)o


125.5(41, 203)

181.0(65, 413)

.002 −60.0(−110.0 to −22.0)

























Early(n = 112)

Delayed(n = 119)

PValue


OR or HR(95% CI)



HR: 0.66(0.45 to 0.97)



OR: 0.64(0.37 to 1.11)


18/78 (23.1) 26/71 (36.6) .07 −13.5(−28.1 to 1.1)

OR: 0.52(0.25 to 1.06)


OR: 0.61(0.36 to 1.03)


11/69 (15.9) 14/59 (23.7) .27 −7.8(−21.7 to 6.1)

OR: 0.61(0.25 to 1.47)


9 (4, 44)(n = 112)

25 (7, >90)(n = 108)b

.04 −18(−41 to 4)

HR: 0.69(0.48 to 1.00)c


OR: 0.18(0.02 to 1.58)

Respiratory 103 (92.0) 116 (97.5) .06 −5.5(−11.3 to 0.3)

OR: 0.30(0.08 to 1.12)

Coagulation 68 (60.7) 87 (73.1) .05 −12.4(−24.5 to −0.3)

OR: 0.57(0.33 to 0.99)

Liver 52 (46.4) 65 (54.6) .21 −8.2(−21.1 to 4.7)

OR: 0.72(0.43 to 1.21)


OR: 0.40(0.12 to 1.33)


OR: 0.45(0.15 to 1.35)


Yes 60 (53.6) 46 (38.7) .02 14.9(2.2 to 27.6)

OR: 0.55(0.32 to 0.93)f

Nog 52 (46.4) 73 (61.3)


Yes 60 (88.2) 46 (85.2) .62 3.1(−9.1 to 15.2)

OR: 0.77(0.27 to 2.17)h

Noi 8 (11.8) 8 (14.8)


9/67 (13.4)j 8/53 (15.1)k .80 −1.7(−14.3 to 11.0)

OR: 0.87(0.31 to 2.44)


16.0(6.8, 30.0)

.95 0.0(−3.0 to 3.0)


22(12, 36)

.33 −3.0(−12.0 to 4.5)

HR: 0.85(0.61 to 1.19)m


43.0(19.5, 81.3)

.05 −9.0(−19.0 to 0.0)


82(67, >90)

<.001 −37(−! to −19.5)

HR: 0.34(0.22 to 0.52)o


125.5(41, 203)

181.0(65, 413)

.002 −60.0(−110.0 to −22.0)





















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Renal-Replacement Ther apy in Acute Kidney Injury

Primary Outcome

Follow-up data at 90 days were available for 477 patients (98%). The early initiation of renal- replacement therapy did not result in lower mor-tality at 90 days than the delayed strategy; 138 of 239 patients (58%) in the early-strategy group died and 128 of 238 patients (54%) in the de-layed-strategy group died (P = 0.38) (Table 2).

Further stratification according to center and adjustment for preexisting chronic renal failure and exposure to nephrotoxic agents did not change the results.

Secondary OutcomesThe delayed strategy resulted in a significantly larger number of days free of renal-replacement

Figure 1. Screening, Randomization, and Follow-up.

ICU denotes intensive care unit.

488 Underwent randomization

1728 Met inclusion criteria

3573 Patients with septic shock and acutekidney injury were assessed for eligibility

1240 Were excluded85 Had end-stage kidney disease45 Had acute kidney injury caused by

obstruction340 Received emergency renal-replacement

therapy40 Received renal-replacement therapy

in the ICU107 Were moribund112 Had do-not-resuscitate order in place336 Were enrolled in another mortality trial31 Did not give consent

144 Had other reason

246 Were assigned to receive early renal-replacement therapy

242 Were assigned to receive delayedrenal-replacement therapy

93 Did not receiverenal-replacement therapy

149 Receivedrenal-replacement therapy



21 Died before renal-replace-ment therapy was initiated

70 Had spontaneous recoveryof renal function

2 Did not receive renal-replacement therapy for other reasons

41 Underwent renal-replace-ment therapy before 48 hrbecause condition thatmet criteria for emergencyrenal-replacement therapyhad developed

28 Died108 Underwent renal-replace-

ment therapy after 48 hr59 Died


1 Had catheter-insertion failure4 Had spontaneous recovery

of renal function1 Died

134 Died



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Interim Analyses

Two interim analyses (for a total of three analyses) were planned in this study.

The first and second interim analyses of the primary outcome, with data cutoff dates set at

January 1st, 2015 (after 200 inclusions followed until day 90) and June 13th, 2016 (after 393

inclusions followed until day 90) respectively, were conducted by the statistician (AB). After the

first analysis, the DSMB recommended continuing the study, but at the second analysis, a sample

size reassessment based on the observed difference was performed and indicated that 9669

patients per arm would be required to draw conclusions. The DSMB therefore recommended that

the study be terminated for futility. The steering committee followed this recommendation. The

last patient was randomized on July 18th 2016.

The frequency of death within 90 days after randomization was recorded in both groups and

compared using a chi-squared test with an alpha risk set at 0.0001 for both interim analyses,

according to the method proposed by Peto (1) so as not to change the level of significance of the

final primary analysis. The conditional power calculated at the time of the second interim

analysis, when the recommendation to terminate the study due to futility was made, was 51.44%.

The following table summarizes the number of deaths and the p-value of testing at each interim

analysis:

Early RRT Delayed RRT p-value First interim analysis Death at Day 90 61 (61%) 57 (57%) 0.75 Second interim analysis Death at Day 90 114 (57%) 107 (55%) 0.51 Final analysis Death at Day 90 138 (58%) 128 (54%) 0.38

1. Peto R, Pike MC, Armitage P, et al. Design and analysis of randomized clinical trials requiring prolonged observation of each patient. I. Introduction and design. Br J Cancer 1976, 34:585–612

�Results��"&



Primary Outcome

Follow-up data at 90 days were available for 477 patients (98%). The early initiation of renal- replacement therapy did not result in lower mor-tality at 90 days than the delayed strategy; 138 of 239 patients (58%) in the early-strategy group died and 128 of 238 patients (54%) in the de-layed-strategy group died (P = 0.38) (Table 2).

Further stratification according to center and adjustment for preexisting chronic renal failure and exposure to nephrotoxic agents did not change the results.

Secondary OutcomesThe delayed strategy resulted in a significantly larger number of days free of renal-replacement

Figure 1. Screening, Randomization, and Follow-up.

ICU denotes intensive care unit.

488 Underwent randomization

1728 Met inclusion criteria

3573 Patients with septic shock and acutekidney injury were assessed for eligibility

1240 Were excluded85 Had end-stage kidney disease45 Had acute kidney injury caused by

obstruction340 Received emergency renal-replacement

therapy40 Received renal-replacement therapy

in the ICU107 Were moribund112 Had do-not-resuscitate order in place336 Were enrolled in another mortality trial31 Did not give consent

144 Had other reason

246 Were assigned to receive early renal-replacement therapy

242 Were assigned to receive delayedrenal-replacement therapy






70 Had spontaneous recoveryof renal function

2 Did not receive renal-replacement therapy for other reasons

41 Underwent renal-replace-ment therapy before 48 hrbecause condition thatmet criteria for emergencyrenal-replacement therapyhad developed

28 Died108 Underwent renal-replace-

ment therapy after 48 hr59 Died


1 Had catheter-insertion failure4 Had spontaneous recovery

of renal function1 Died

134 Died



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12

Table S4. Baseline Characteristics of the Study Population – Full Version Characteristic Early RRT

(N=246) Delayed RRT (N=242)

Age - years 69.3 (±11.6) 68.7 (±12.8)

Sex, no. (%)

Men 142 (58%) 154 (64%)

Women 104 (42%) 88 (36%)

BMI — Kg/m2 28.8 (±7.7) 29.0 (±8.3)

Sepsis - site of infection — no. (%)

Lung 88 (36%) 76 (31%)

Digestive 42 (17%) 57 (24%)

Urinary tract infection 54 (22%) 45 (19%)

Bloodstream infection 93 (38%) 84 (35%)

Sepsis due to Hospital acquired infection 75 (30%) 82 (34%)

Coexisting conditions — no. (%)

Chronic renal failure 32 (13%) 44 (18%)

Hypertension 145 (59%) 137 (57%)

Diabetes 80 (33%) 69 (29%)

Congestive heart failure (NYHA III/IV) 20 (8%) 20 (8%)

Chronic respiratory failure 19 (8%) 10 (4%)

Chronic liver disease 31 (13%) 31 (13%)

Immunosuppression 69 (28%) 74 (31%)

Median number of days of pre-ICU hospital stay 1 (1-2) 1 (1-3)

SAPS II at ICU admission ‡ 65.1 (±16.5) 64.1 (±15.6)

SOFA score at enrollment ∫ 12.2 (±2.9) 12.4 (±2.9)

Exposure to at least one nephrotoxic agent in past 4 days — no. (%)¶ 128 (52%) 106 (44%)

Intravenous contrast 43 (34%) 32 (30%)

Aminoglycoside 103 (80%) 83 (78%)

12

Table S4. Baseline Characteristics of the Study Population – Full Version Characteristic Early RRT

(N=246) Delayed RRT (N=242)

Age - years 69.3 (±11.6) 68.7 (±12.8)

Sex, no. (%)

Men 142 (58%) 154 (64%)

Women 104 (42%) 88 (36%)

BMI — Kg/m2 28.8 (±7.7) 29.0 (±8.3)

Sepsis - site of infection — no. (%)

Lung 88 (36%) 76 (31%)

Digestive 42 (17%) 57 (24%)

Urinary tract infection 54 (22%) 45 (19%)

Bloodstream infection 93 (38%) 84 (35%)

Sepsis due to Hospital acquired infection 75 (30%) 82 (34%)

Coexisting conditions — no. (%)

Chronic renal failure 32 (13%) 44 (18%)

Hypertension 145 (59%) 137 (57%)

Diabetes 80 (33%) 69 (29%)

Congestive heart failure (NYHA III/IV) 20 (8%) 20 (8%)

Chronic respiratory failure 19 (8%) 10 (4%)

Chronic liver disease 31 (13%) 31 (13%)

Immunosuppression 69 (28%) 74 (31%)

Median number of days of pre-ICU hospital stay 1 (1-2) 1 (1-3)

SAPS II at ICU admission ‡ 65.1 (±16.5) 64.1 (±15.6)

SOFA score at enrollment ∫ 12.2 (±2.9) 12.4 (±2.9)

Exposure to at least one nephrotoxic agent in past 4 days — no. (%)¶ 128 (52%) 106 (44%)

Intravenous contrast 43 (34%) 32 (30%)

Aminoglycoside 103 (80%) 83 (78%)

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21

Table S8. Characteristics of RRT Sessions during the First 7 Days after Enrollment

Characteristic Early RRT

(N=239) Delayed RRT

(N=149) P Value First RRT modality 0.62

Continuous RRT 137 (57%) 81 (55%) Intermittent Hemodialysis 102 (43%) 67 (45%)

RRT modalities during ICU stay

Continuous RRT only 111 (46%) 68 (46%) 0.88 Intermittent Hemodialysis only 82 (34%) 50 (34%) 0.88 Continuous RRT and Intermittent Hemodialysis 46 (19%) 31 (21%) 0.71

Intermittent Hemodialysis Median number of sessions per patient/week 2 (1-3) 2 (1-3) 0.53 Median duration of a session – hours (IQR) 4 (3.9-4.9) 4.3 (4-5.5) 0.02 Median interval between sessions – hours (IQR)* 41 (26-63) 36 (24-58) 0.28 Median prescribed blood flow - ml/minute (IQR) 225 (200-250) 250 (200-250) 0.98 Median prescribed dialysate flow - ml/hour (IQR) 500 (400-500) 500 (350-500) 0.98 Anticoagulation 0.46

Systemic heparin 53 (52%) 35 (52%) Low-molecular-weight heparin 36 (35%) 25 (37%) Regional citrate 1 (1%) 0 (0%) No anticoagulation 12 (11%) 7 (11%)

Continuous RRT Continuous first RRT modality 0.95

Continuous HemoDialysis 26 (19%) 17 (20%) Continuous HemoFiltration 55 (40%) 32 (39%) Continuous HemoDiaFiltration 57 (41%) 34 (41%)

Median prescribed blood flow - ml/minute (IQR) 200 (135-250) 180 (120-250) 0.09 Median prescribed dose – ml/kg/hr (IQR) 36.2 (30.9-50.2) 29.9 (27-37.9) 0.019 Median delivered dose – ml/kg/hr (IQR) 27.6 (19.6-38.9) 25.5 (18.8-28.6) 0.20 Anticoagulation 0.66

Systemic heparin 71 (51%) 49 (59%) Regional citrate 37 (27%) 22 (27%) No anticoagulation 15 (11%) 8 (10%)

*74 patients had only one session of intermittent hemodialysis RRT denotes Renal Replacement Therapy, ICU Intensive Care Unit, IQR Interquartile range

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n engl j med 379;15 nejm.org October 11, 20181438


VariableEarly Strategy


(N = 242) P Value

Primary outcome

Death at 90 days — no./total no. (%) 138/239 (58) 128/238 (54) 0.38

Secondary outcomes

Death at 28 days — no. (%) 111 (45) 102 (42) 0.48


Median time from diagnosis of failure-stage acute kidney injury to initiation of renal-replacement therapy (IQR) — hr†

7.6 (4.4–11.5) 51.5 (34.6–59.5) <0.001


Patients in the delayed-strategy group who received emergency renal-replace-ment therapy before 48 hr, according to criterion — no. (%)‡

41 (17)

Metabolic acidosis

No. of patients (%) 20 (8)

Median pH (IQR) 7.10 (7.06–7.13)

Hyperkalemia


Median potassium level (IQR) — mmol/liter 7.0 (6.7–7.3)

Fluid overload — no. (%) 6 (2)

Other criterion — no. (%)§ 6 (2)

Median days of renal-replacement therapy (IQR) 4 (2–8) 2 (0–6) <0.001

Median days free of renal-replacement therapy (IQR)¶ 12 (1–25) 16 (2–28) 0.006

Median days free of mechanical ventilation (IQR)¶ 2 (0–19) 3 (0–21) 0.19

Median days free of vasopressors (IQR)¶ 16 (0–25) 17 (0–25) 0.87

Median length of ICU stay (IQR) — days 11 (4–19) 10 (5–19) 0.91

Survivors 12 (8–21) 12 (8–21) 0.88

Nonsurvivors 5 (2–15) 6 (3–14) 0.64

Median length of hospital stay (IQR) — days 23 (10–40) 23 (10–44) 0.34

Survivors 22.0 (9.0–38.0) 21.0 (10.0–42.5) 0.53

Nonsurvivors 25 (15–53) 42 (33–56) 0.08

SOFA score without renal component∥

Day 1 9.3±3.5 9.3±3.2 0.84

Day 2 8.6±3.8 8.4±3.9 0.57

Day 3 8.0±4.0 7.8±4.1 0.64

Day 7 5.9±3.8 6.3±3.9 0.30

Fluid balance — ml

Cumulative fluid balance after day 2 3737±3925 3437±3371 0.40

Cumulative fluid balance at day 7 5570±8761 5878±7472 0.75

Receipt of diuretics from day 0 to 7

No. of patients (%) 121 (49) 124 (51) 0.65

Median cumulative dose of furosemide from day 0 to 7 (IQR) — mg 215 (65–760) 295 (80–1160) 0.18

Dependence on renal-replacement therapy among survivors — no./total no. (%)

Day 28 17/134 (13) 17/140 (12) 0.89

Day 90 2/101 (2) 3/110 (3) 1.00

Table 2. Primary and Secondary Outcomes.*



n engl j med 379;15 nejm.org October 11, 20181438




(N = 242) P Value

Primary outcome


Secondary outcomes

Death at 28 days — no. (%) 111 (45) 102 (42) 0.48


Median time from diagnosis of failure-stage acute kidney injury to initiation of renal-replacement therapy (IQR) — hr†

7.6 (4.4–11.5) 51.5 (34.6–59.5) <0.001


Patients in the delayed-strategy group who received emergency renal-replace-ment therapy before 48 hr, according to criterion — no. (%)‡

41 (17)

Metabolic acidosis


Median pH (IQR) 7.10 (7.06–7.13)

Hyperkalemia


Median potassium level (IQR) — mmol/liter 7.0 (6.7–7.3)

Fluid overload — no. (%) 6 (2)

Other criterion — no. (%)§ 6 (2)

Median days of renal-replacement therapy (IQR) 4 (2–8) 2 (0–6) <0.001

Median days free of renal-replacement therapy (IQR)¶ 12 (1–25) 16 (2–28) 0.006

Median days free of mechanical ventilation (IQR)¶ 2 (0–19) 3 (0–21) 0.19

Median days free of vasopressors (IQR)¶ 16 (0–25) 17 (0–25) 0.87

Median length of ICU stay (IQR) — days 11 (4–19) 10 (5–19) 0.91

Survivors 12 (8–21) 12 (8–21) 0.88

Nonsurvivors 5 (2–15) 6 (3–14) 0.64

Median length of hospital stay (IQR) — days 23 (10–40) 23 (10–44) 0.34

Survivors 22.0 (9.0–38.0) 21.0 (10.0–42.5) 0.53

Nonsurvivors 25 (15–53) 42 (33–56) 0.08

SOFA score without renal component∥

Day 1 9.3±3.5 9.3±3.2 0.84

Day 2 8.6±3.8 8.4±3.9 0.57

Day 3 8.0±4.0 7.8±4.1 0.64

Day 7 5.9±3.8 6.3±3.9 0.30

Fluid balance — ml

Cumulative fluid balance after day 2 3737±3925 3437±3371 0.40

Cumulative fluid balance at day 7 5570±8761 5878±7472 0.75

Receipt of diuretics from day 0 to 7

No. of patients (%) 121 (49) 124 (51) 0.65

Median cumulative dose of furosemide from day 0 to 7 (IQR) — mg 215 (65–760) 295 (80–1160) 0.18

Dependence on renal-replacement therapy among survivors — no./total no. (%)

Day 28 17/134 (13) 17/140 (12) 0.89

Day 90 2/101 (2) 3/110 (3) 1.00

Table 2. Primary and Secondary Outcomes.*



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performed easily or safely in patients with hemo-dynamic instability in the early phases of septic shock, so starting such therapy earlier would not improve fluid balance.

Our results show that initiating renal-replace-ment therapy too early could unnecessarily ex-pose patients in whom renal dysfunction would have recovered spontaneously to the risks associ-ated with renal-replacement therapy. Indeed, 29% of the patients in the delayed-strategy group did not require renal-replacement therapy because they had spontaneous recovery of renal function, although 26% of these patients (18 of 70 pa-tients) subsequently died, which is similar to rates reported in other studies.22 It is possible that more patients might have recovered without renal-replacement therapy if the delay had been longer than 48 hours, as was observed in a re-cent study.12 Mortality was higher among pa-tients assigned to the delayed-strategy group who met criteria for emergency renal-replacement ther-apy (68% [28 of 41 patients]) than among those who did not meet the criteria. However, the de-velopment of these complications may be identi-fying a subgroup of patients with more severe underlying disease, and we cannot conclude that death was related to the delay in renal-replace-ment therapy or that earlier initiation of renal-replacement therapy would have saved a given patient.

Although our trial did not show any benefit to expediting the initiation of renal-replacement therapy in the absence of emergency criteria, our



(N = 242) P Value

Creatinine — mg/dl**

At ICU discharge 2.00±1.26 2.19±1.47 0.15

At hospital discharge 1.46±0.98 1.61±1.30 0.31

* Plus–minus values are means ±SD.† Acute kidney injury in failure stage was defined according to the RIFLE classification.‡ This category includes patients in the delayed-strategy group who met criteria for emergency renal-replacement therapy. Metabolic acido-

sis was defined as a pH less than 7.15 and a base deficit of more than 5 mmol per liter or a bicarbonate level of 18 mmol or less per liter. Hyperkalemia was defined as a potassium level of more than 6.5 mmol per liter with characteristic electrocardiographic changes. The me-dian pH and median potassium values were calculated only in patients who underwent renal-replacement therapy because they met these specific criteria. Fluid overload was defined as extravascular fluid overload that was refractory to diuretics, with pulmonary edema. Other reasons included worsening of the patient’s clinical status, with acidosis and hyperkalemia below the prespecified threshold, associated with hyperlactatemia, with the need for emergency renal-replacement therapy as determined by the clinician treating the patient.

§ Other criterion was worsening of multiple organ failure that mandated the initiation of renal-replacement therapy in the opinion of the cli-nician caring for the patient, confirmed by an increase of at least 2 points in the SOFA score (not a prespecified criterion for emergency renal-replacement therapy).

¶ The number of days free of renal-replacement therapy, mechanical ventilation, or vasopressor therapy was calculated according to the number of days the patient was alive without the intervention at day 28; patients who died were assigned zero free days.

∥ In patients who received renal-replacement therapy, the renal component of the SOFA score was calculated on the basis of urine output only.** Creatinine values are for all living patients who were no longer receiving renal-replacement therapy.

Table 2. (Continued.)

Figure 2. Overall Survival among Patients Assigned to Early Renal-Replacement Therapy and Delayed Renal-Replacement Therapy.

In the early-strategy group, renal-replacement therapy was initiated within 12 hours after documentation of acute kidney injury. In the delayed-strategy group, renal-replacement therapy was initiated 48 hours after the documen-tation of acute kidney injury, if renal recovery had not occurred. If criteria for emergency renal-replacement therapy were met by a patient in this group, renal-replacement therapy was initiated as soon as possible. The tick marks indicate censored data. The P value is for the comparison of overall survival between the two groups.

Pro

port

ion

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ivin

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0.75

0.50

1.00

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0.000 30 60 90 120 150 180

Days since Randomization

P=0.52

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11299

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Delayed strategy



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22

Table S9. Fluid Balance in the First 7 Days after Randomization

EARLY RRT N= 246 DELAYED RRT n=242 p Value*

Fluid intake Urinary output

RRT ultrafiltration

Net fluid balance Fluid intake Urinary

output RRT

ultrafiltration Net fluid balance

Day 1 (ml) 3024 (2261; 3977)

400 (100; 1088)

0 (0; 500)

1812 (850; 3450)

2941 (2135; 3827)

700 (157; 1480)

0 (0; 0)

1754 (750; 2948) 0.3513

Day 2 (ml) 2791 (1963; 3470)

570 (121; 1450)

0 (0; 1300)

1179 (180; 2263)

2802 (2121; 3599)

1043 (200; 2052)

0 (0; 420)

1214 (28; 2190) 0.9888

Day 3 (ml) 2490 (1680; 3240)

646 (98; 1720)

0 (0; 1200)

720 (-575; 1823)

2509 (2010; 3180)

930 (200; 1800)

0 (0; 1153)

949 (-727; 1768) 0.9738

Day 4 (ml) 2420 (1835; 3344)

1253 (200; 2335)

0 (0; 1013)

529 (-1095; 1481)

2550 (1900; 3168)

1250 (210; 2300)

0 (0; 1770)

295 (-944; 1290) 0.487

Day 5 (ml) 2450 (1918; 3200)

1532 (345; 2544)

0 (0; 1000)

37 (-940; 1200)

2546 (1830; 3182)

1600 (125; 2500)

0 (0; 1500)

0 (-1320; 1361) 0.7507

Day 6 (ml) 2454 (1720; 3194)

1400 (400; 2753)

0 (0; 1365)

-192 (-1371; 1337)

2499 (1845; 3036)

1585 (413; 2832)

0 (0; 1938)

100 (-1051; 1033) 0.7631

Day 7 (ml) 2382 (1579; 3180)

1700 (505; 3001)

0 (0; 0)

-220 (-1324; 1050)

2414 (1850; 3041)

1500 (415; 2300)

0 (0; 1000)

268 (-1031; 1360) 0.2189

Day 1-Day 7 Sum (ml)

19035 (15615; 22392)

10090 (4121; 15500)

4094 (0; 9665)

2275 (-2770; 8820)

18479 (16137; 21831)

11050 (4540; 15585)

1188 (0; 9285)

3678 (-585; 8311) 0.4784

All values are expressed as median (inter-quartile range); RRT denotes Renal Replacement Therapy. *p values are calculated only for net fluid balance.

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29,8�D3 3737�3925 3437�3371 0.4079,8�D3 5570�8761 5878�7472 0.75

0-79�A:)�*@�-2 121 (49) 124 (51) 0.65furosemideD3*@C-6�5�+=�;�� 215 (65-760) 295 (80-1160) 0.18

0'%!��92-6�5<289,8> 2(0-19) 3(0-21) 0.19

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Table S10. Protocol Violations in Terms of Renal Replacement Therapy Timing

Early RRT (N=51/246) Delayed RRT (N=11/242) 1) Time between acute kidney injury at

stage Failure and renal replacement therapy initiation >12 hours but < 48 hours. N= 43*

2) Time between acute kidney injury at stage Failure and renal replacement therapy initiation > 48hours. N= 3

3) Renal replacement therapy was not initiated because of a spontaneous rapid improvement of renal function immediately after enrollment; the physicians in care of the patients considered unethical initiate renal replacement therapy in this setting. N=4

4) Renal replacement therapy was not

initiated because the placement of the dialysis catheter was impossible. N=1

1) Time between acute kidney injury at stage Failure and renal replacement therapy initiation <48 hours (but >12 hours), without predefined emergency criteria, but with worsening of multiple organ failure that mandated the initiation of RRT in the opinion of the clinician caring for the patient, confirmed by augmentation of SOFA score of at least 2 points. N=4#

2) Time between acute kidney injury at stage

Failure and renal replacement therapy initiation < 12 hours without predefined emergency criteria, but with worsening of multiple organ failure that mandated the initiation of RRT in the opinion of the clinician caring for the patient, confirmed by augmentation of SOFA score of at least 2 points. N=2##

3) Time between acute kidney injury at stage

Failure and renal replacement therapy initiation <48 hours (but >12 hours) without predefined emergency criteria, due to a misunderstanding of the protocol. N=5

*in 20 of them the delay was <4 hours # 4 patients with SOFA degradation (from 9 to 12, from 12 to 14, from 17 to 18 and from 17 to 19) ## SOFA degradation (from 17 to 19 and from 18 to 20).

Early% (N=51/246)

43=12-48) � RRT

3=48) �'RRT

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5=$#RRT�!+8612-48) � RRT-9��3/��

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190122 timing of renal-replacement therapy with pacient ... · the new england journal of medicine...

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