Vous êtes sur la page 1sur 12

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

Initiation Strategies for Renal-Replacement


Therapy in the Intensive Care Unit
Stphane Gaudry, M.D., David Hajage, M.D., Frderique Schortgen, M.D.,
Laurent MartinLefevre, M.D., Bertrand Pons, M.D., Eric Boulet, M.D.,
Alexandre Boyer, M.D., Guillaume Chevrel, M.D., Nicolas Lerolle, M.D., Ph.D.,
Dorothe Carpentier, M.D., Nicolas deProst, 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., JeanMarie 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., JeanDamien Ricard, M.D., Ph.D.,
and Didier Dreyfuss, M.D., for the AKIKI Study Group*

A BS T R AC T

BACKGROUND
The timing of renal-replacement therapy in critically ill patients who have acute The authors affiliations are listed in the
kidney injury but no potentially life-threatening complication directly related to Appendix. Address reprint requests to
Dr. Dreyfuss at the Intensive Care Unit,
renal failure is a subject of debate. Hpital Louis Mourier, 178 rue des Re
METHODS nouillers, 92110 Colombes, France, or at
didier.dreyfuss@aphp.fr.
In this multicenter randomized trial, we assigned patients with severe acute kidney
injury (Kidney Disease: Improving Global Outcomes [KDIGO] classification, stage 3 *A complete list of investigators in the
Artificial Kidney Initiation in Kidney In
[stages range from 1 to 3, with higher stages indicating more severe kidney injury]) jury (AKIKI) Study Group is provided in
who required mechanical ventilation, catecholamine infusion, or both and did not the Supplementary Appendix, available
have a potentially life-threatening complication directly related to renal failure to either at NEJM.org.
an early or a delayed strategy of renal-replacement therapy. With the early strategy, Drs. Hajage and Schortgen contributed
renal-replacement therapy was started immediately after randomization. With the equally to this article.
delayed strategy, renal-replacement therapy was initiated if at least one of the fol- This article was published on May 15,
lowing criteria was met: severe hyperkalemia, metabolic acidosis, pulmonary edema, 2016 at NEJM.org.
blood urea nitrogen level higher than 112 mg per deciliter, or oliguria for more than DOI: 10.1056/NEJMoa1603017
72 hours after randomization. The primary outcome was overall survival at day 60. Copyright 2016 Massachusetts Medical Society.

RESULTS
A total of 620 patients underwent randomization. The KaplanMeier 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% con-
fidence 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).
CONCLUSIONS
In 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 strat-
egy 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.)

n engl j mednejm.org 1
The New England Journal of Medicine
Downloaded from nejm.org by ALVARO MONTANEZ on June 26, 2016. For personal use only. No other uses without permission.
Copyright 2016 Massachusetts Medical Society. All rights reserved.
The n e w e ng l a n d j o u r na l of m e dic i n e

A
cute kidney injury is a common unblinded, prospective, multicenter, open-label,
condition among patients in the intensive two-group randomized trial conducted in 31 in-
care unit1-4 and is associated with high tensive care units in France from September 2013
morbidity and mortality.2,5-8 Renal-replacement through January 2016. The protocol (which has
therapy is the cornerstone of the management of been published previously23) was approved by the
severe acute kidney injury. Many studies have fo- ethics committee of the French Society of Inten-
cused on methods of renal-replacement thera- sive Care Medicine and by the appropriate French
py,5,6,8,9 but the issue of when to initiate the ther- legal authority (Comit de Protection des Per-
apy in the absence of a potentially life-threatening sonnes dIle de France VI) for all participating
complication directly related to renal failure re- centers and is available with the full text of this
mains a subject of debate. Indirect evidence has article at NEJM.org. The Direction de la Recher-
suggested that early renal-replacement therapy che Clinique de lAssistance Publique-Hpitaux de
could confer a survival benefit.10-12 However, two Paris, French Ministry of Health, supervised the
observational studies reported high survival rates use of the study funding.
among patients who did not receive renal-replace- The investigators informed patients or their
ment therapy,13,14 and one study reported adverse surrogates about the trial both orally and with a
outcomes in association with very early renal- written document. In accordance with French
replacement therapy in patients with sepsis.15 law, written informed consent was not required,
Early initiation of renal-replacement therapy may because the standard of care encompasses both
allow for better control of fluid and electrolyte study interventions. Patients or their surrogates
status, removal of uremic toxins, and prevention of were informed that they could decline to partici-
complications such as gastric hemorrhage and pate at any time, and their decision was recorded
metabolic encephalopathy.16 Delaying renal-replace- in patient files (see the Supplementary Appendix,
ment therapy initiation is intuitively unlikely to available at NEJM.org).
have any immediate benefit per se. However, a The trial was overseen by a steering commit-
delay may allow time for the stabilization of a tee that presented information regarding the rate
patients condition before renal-replacement ther- of inclusion of new patients to the investigators
apy is initiated and may avoid the need for such by e-mail every 3 months and during meetings
support, which is not devoid of risk.17 in January 2014 and January 2015. Two planned
Given such uncertainties, there is heterogene- interim analyses were performed by an indepen-
ity among criteria for the initiation of renal- dent data and safety monitoring board, the mem-
replacement therapy.18,19 Indeed, several authorities bers of which were unaware of the study-group
consider an appropriate multicenter, randomized, assignments. An investigator at each center was
controlled trial involving patients with acute kid- responsible for enrolling patients, ensuring adher-
ney injury to be an important research priori- ence to the protocol, and completing the elec-
ty.20,21 To fill this perceived need, in the current tronic case-report form. The first author vouches
trial we compared a strategy of early initiation of for the accuracy and the completeness of the re-
renal-replacement therapy with a strategy of de- ported data and for the adherence of the trial to
layed initiation in patients in the intensive care the protocol. All analyses were performed by the
unit who had acute kidney injury of Kidney Dis- study statistician (the second author) in accor-
ease: Improving Global Outcomes (KDIGO) clas- dance with the International Conference on Har-
sification stage 3 (serum creatinine, 3.0 times the monisation Good Clinical Practice guidelines.
baseline level or 4.0 mg per deciliter [354 mol
per liter]; urine output, <0.3 ml per kilogram of Patients
body weight per hour for 24 or more hours or Patients were eligible if they were adults (18 years
anuria for 12 hours).22 of age or older) who were admitted to the inten-
sive care unit with acute kidney injury that was
compatible with a diagnosis of acute tubular ne-
Me thods
crosis in the context of ischemic or toxic injury
Trial Design and Oversight and were receiving invasive mechanical ventilation,
The Artificial Kidney Initiation in Kidney Injury catecholamine infusion (epinephrine or norepi-
(AKIKI) trial was an institutionally sponsored, nephrine), or both. To undergo randomization,

2 n engl j mednejm.org

The New England Journal of Medicine


Downloaded from nejm.org by ALVARO MONTANEZ on June 26, 2016. For personal use only. No other uses without permission.
Copyright 2016 Massachusetts Medical Society. All rights reserved.
Renal-Replacement Ther apy Initiation in the ICU

patients were required to have KDIGO stage 3 jury. In the delayed-strategy group, renal-replace-
acute kidney injury (see the Supplementary Ap- ment therapy was initiated if one of the labora-
pendix).22 The main exclusion criteria at the time tory abnormalities defined above developed or if
of enrollment were the following severe labora- oliguria or anuria lasted for more than 72 hours
tory abnormalities: a blood urea nitrogen level after randomization (Table S1 in the Supplemen-
higher than 112 mg per deciliter (40 mmol per li- tary Appendix). The choice of the method of re-
ter), a serum potassium concentration greater than nal-replacement therapy (intermittent or contin-
6 mmol per liter (or greater than 5.5 mmol per liter uous technique, duration and interval between
despite medical treatment), a pH below 7.15 in sessions, device setting, and anticoagulation meth-
the context of either pure metabolic acidosis (par- od) was left to the discretion of each study site
tial pressure of arterial carbon dioxide [Paco2] and was prescribed and monitored according to
below 35 mm Hg) or mixed acidosis (Paco2 of national guidelines.24 All centers had extensive
50 mm Hg or more without the possibility of experience in both the management of acute kid-
increasing alveolar ventilation), and acute pul- ney injury and techniques of renal-replacement
monary edema due to fluid overload responsible therapy.
for severe hypoxemia requiring an oxygen flow In both groups, discontinuation of renal-replace-
rate greater than 5 liters per minute to maintain ment therapy was considered if the spontaneous
a peripheral capillary oxygen saturation (Spo2) urine output was 500 ml or higher per 24 hours
greater than 95% or requiring a fraction of in- and was highly recommended if the spontane-
spired oxygen (Fio2) greater than 50% in patients ous urine output was higher than 1000 ml per
receiving mechanical ventilation and despite di- 24 hours in the absence of diuretic therapy or if
uretic therapy. These criteria were later used to urine output was higher than 2000 ml per 24 hours
establish the indication for renal-replacement in patients who were receiving diuretic therapy.
therapy in patients assigned to the delayed strat- Discontinuation of renal-replacement therapy was
egy (i.e., therapy was initiated in that group if any mandatory if diuresis was sufficient to allow for
of these laboratory abnormalities developed af- spontaneous decrease in serum creatinine concen-
ter enrollment). Other exclusion criteria are de- tration. Renal-replacement therapy was resumed if
tailed in the Supplementary Appendix. diuresis appeared to be insufficient to result in
a spontaneous decrease in creatinine level or if
Randomization urine output fell below 1000 ml per 24 hours in
The randomization list was computer-generated, the absence of diuretic therapy (or below 2000 ml
balanced by blocks of variable and undisclosed per 24 hours in patients receiving diuretic therapy).
size, and stratified according to center. Patients
underwent randomization within 5 hours after Outcomes
validation of stage 3 acute kidney injury (which The duration of follow-up for each patient was
left 1 hour to initiate renal-replacement therapy 60 days from randomization. The primary out-
in patients who were assigned to the early strate- come was overall survival measured from the
gy); patients were randomly assigned in a 1:1 ratio date of randomization until death or day 60. For
to either early initiation of renal-replacement ther- patients who were discharged alive from the inten-
apy (early-strategy group) or delayed initiation of sive care unit, information on the primary out-
renal-replacement therapy (delayed-strategy group). come was obtained either directly from the patient
Concealment of the study-group assignments or the patients relatives or from the physician who
was achieved with the use of a centralized, se- was in charge when the patient was still hospi-
cure, interactive, Web-based response system talized. Data from patients who were alive at day
(CleanWeb, Telemedicine Technologies) that was 60 were censored, and data from patients who
accessible from each study center. were lost to follow-up before day 60 were censored
at their last follow-up assessment.
Interventions The secondary outcomes were the receipt of
In the early-strategy group, renal-replacement ther- renal-replacement therapy at least once with the
apy was initiated as soon as possible after random- delayed strategy; the numbers of renal-replacement
ization in order for it to be started within 6 hours therapyfree days, dialysis catheterfree days, me-
after documentation of stage 3 acute kidney in- chanical ventilationfree days, and vasopressor

n engl j mednejm.org 3
The New England Journal of Medicine
Downloaded from nejm.org by ALVARO MONTANEZ on June 26, 2016. For personal use only. No other uses without permission.
Copyright 2016 Massachusetts Medical Society. All rights reserved.
The n e w e ng l a n d j o u r na l of m e dic i n e

therapyfree days (i.e., days alive and without the cacy analyses were planned, after the observation
intervention; a value of 0 days was assigned for of 90 and 180 deaths. To maintain an overall type
patients who died) between randomization and I error rate of 5%, the significance level of each
day 28; the Sepsis-related Organ Failure Assess- analysis was adjusted with the use of the OBrien
ment (SOFA) score25 at day 3 and day 7; the vital and Fleming approach.29 To maintain a power of
status at day 28; the length of stay in the inten- 90%, this approach also necessitated an increase
sive care unit and in the hospital; the proportion in the planned number of patients, to 560. To
of patients with treatment limitations (i.e., with- take into account a potential loss to follow-up of
holding or withdrawal of treatment); the occur- 10%, enrollment of 620 patients was planned.
rence of nosocomial infections; and complications Baseline characteristics in each study group
potentially related to acute kidney injury or renal- were analyzed as frequencies and percentages for
replacement therapy (see the Supplementary Ap- categorical variables and as means and standard
pendix). deviations or medians and interquartile ranges
Other prespecified outcomes included the for continuous variables, as appropriate. The over-
time between randomization and the initiation all survival (primary outcome), estimated by the
of renal-replacement therapy, the time between KaplanMeier method, was analyzed in the inten-
the occurrence of at least one of the criteria that tion-to-treat population and compared between
mandated renal-replacement therapy in the de- the two groups with the use of a log-rank test.
layed-strategy group and actual initiation of ther- Further stratification according to center, adjust-
apy, the number of sessions of renal-replacement ment for baseline prognostic factors (Simplified
therapy, and dependence on renal-replacement Acute Physiology Score [SAPS] III, treatment or
therapy at days 28 and 60. Because diuresis was no treatment with vasopressors, receipt or no
closely monitored, we also noted the number of receipt of mechanical ventilation, presence or
patients who, for at least 1 day, had urine output absence of septic shock, and time between admis-
of more than 1000 ml per 24 hours in the absence sion to the intensive care unit and development of
of diuretic therapy or of more than 2000 ml per acute kidney injury of <7 days vs. 7 days), and
24 hours with diuretic therapy and who did not determination of baseline predictors of renal-
require initiation or resumption of renal-replace- replacement therapy in the delayed-strategy group
ment therapy for at least 7 days. The total numbers were also performed with a Cox semiparametric
of units of red cells transfused was also compared. proportional-hazards model.
These outcomes had not been prespecified in the Categorical variables were compared with the
protocol when the trial was being designed. use of the chi-square test or Fishers exact test,
and continuous variables were compared with
Statistical Analysis the use of Students t-test or Wilcoxon test, as
This trial was designed as a sequential study appropriate. The time to recovery of renal func-
(with two interim analyses)26 (see the Supplemen- tion, as marked by diuresis, was described by
tary Appendix). On the basis of published data, means of the KaplanMeier method and com-
death at day 60 was expected in 55%6,7,9,27 of pared with a log-rank test. For this analysis, data
patients requiring renal-replacement therapy in from all patients were censored at the time of
the intensive care unit. At the time that the trial death or at day 28.
was being designed, indirect evidence13,14,28 sug- With the exception of the primary outcome
gested that mortality might be expected to be (for which the type I error rate was adapted for
15 percentage points lower in association with interim analyses), all analyses were performed at
delayed renal-replacement therapy. We calculat- a two-sided alpha level of 5%. All analyses were
ed that with a total sample size of 546 patients, performed with R software, version 3.2.3 (R Foun-
the study would have 90% power to show a dation for Statistical Computing).
15-percentage-point lower mortality with the
delayed strategy than with the early strategy R e sult s
(corresponding to a relative risk of 0.65 in favor
of the delayed strategy, under an assumption of Patients
an exponential distribution of survival times), at A total of 5528 patients were eligible for inclusion
a two-sided alpha level of 5%. Two interim effi- in the trial, and 620 patients underwent random-

4 n engl j mednejm.org

The New England Journal of Medicine


Downloaded from nejm.org by ALVARO MONTANEZ on June 26, 2016. For personal use only. No other uses without permission.
Copyright 2016 Massachusetts Medical Society. All rights reserved.
Renal-Replacement Ther apy Initiation in the ICU

ization (Fig. S1 in the Supplementary Appendix); replacement therapy in the delayed-strategy group
312 were assigned to the early-strategy group and are provided in the Supplementary Appendix.
308 were assigned to the delayed-strategy group.
One patient in the early-strategy group subse- Primary and Secondary Outcomes
quently withdrew consent for the use of his data, Follow-up data at 60 days were available for 614
leaving a total of 619 patients in the analysis. patients (99%); a total of 303 deaths had been
The characteristics of the patients were well observed by day 60 (150 in the early-strategy
balanced between the two study groups, with group and 153 in the delayed-strategy group).
the exception of the prothrombin ratio (i.e., the The mortality rates in our analysis were esti-
ratio of a patients prothrombin time to that in a mated with the use of the KaplanMeier meth-
control sample, expressed as a percentage), which od. The KaplanMeier estimate of the overall
was significantly lower in the delayed-strategy mortality at day 60 was 49.1% (95% confidence
group (Table1, and Table S2 in the Supplemen- interval [CI], 45.0 to 52.9). Mortality did not dif-
tary Appendix). Sepsis was present in 494 patients fer significantly between the two study groups:
(80%), and 389 patients (63%) had been exposed 48.5% (95% CI, 42.6 to 53.8) in the early-strategy
to nephrotoxic agents. group and 49.7% (95% CI, 43.8 to 55.0) in the
delayed-strategy group (P=0.79) (Fig.1). Further
Renal-Replacement Therapy stratification according to center and adjustment
The patients in the early-strategy group under- for important prognostic factors did not materi-
went their first renal-replacement therapy session ally change the results.
within a median of 2 hours (interquartile range, A post hoc exploratory analysis was per-
1 to 3) after randomization and within a median formed to compare patients who never received
of 4.3 hours (interquartile range, 2.7 to 5.9) after renal-replacement therapy with those who re-
documentation of stage 3 acute kidney injury ceived it either early or late. The lowest mortal-
and of the fulfillment of other inclusion criteria. ity at day 60 (37.1%) was found among patients
In this group, six patients did not receive renal- who never received renal-replacement therapy,
replacement therapy (see the Supplementary Ap- and the highest mortality (61.8%) was found
pendix). among patients who received therapy late, whereas
A total of 157 patients (51%) received renal- intermediate mortality (48.5%) was found among
replacement therapy in the delayed-strategy group patients who received therapy early (P<0.001).
within a median of 57 hours (interquartile range, Patients who never received renal-replacement
25 to 83) after randomization (Fig.1). The medi- therapy were less ill at baseline, and patients who
an interval between the occurrence of at least one received it late were the most severely ill patients
criterion mandating renal-replacement therapy at baseline. The differences in mortality became
and its initiation was 4.7 hours (interquartile nonsignificant after adjustment for baseline se-
range, 1.7 to 10.0). Five patients received renal- verity of illness, which suggests that these ob-
replacement therapy without meeting the initia- served differences were markedly confounded
tion criteria. Persistence of oliguria or anuria for (see the Supplementary Appendix).
more than 72 hours after randomization and a In the delayed-strategy group, 95 patients
blood urea nitrogen level higher than 112 mg per (61%) of the 155 who were alive at day 60 had
deciliter (40 mmol per liter) were the two most not received renal-replacement therapy, and the
common reasons for renal-replacement therapy total number of therapy sessions differed sub-
(Table S3 in the Supplementary Appendix). stantially between the study groups (Table S5 in
Patient characteristics at the time of initiation the Supplementary Appendix). Mortality at day
of renal-replacement therapy are provided in 28, numbers of mechanical ventilationfree and
Table S4 in the Supplementary Appendix. Meta- vasopressor-free days, length of stay in intensive
bolic abnormalities were more marked in the care unit and in the hospital, and dependence on
delayed-strategy group than in the early-strategy renal-replacement therapy at day 28 and 60 did
group. Details regarding the methods used for not differ significantly between the two study
renal-replacement therapy, the changes in blood groups (Table2). However, the number of days
urea nitrogen and serum creatinine levels during free from renal-replacement therapy was signifi-
follow-up, and the baseline predictors of renal- cantly higher, and the rate of catheter-related

n engl j mednejm.org 5
The New England Journal of Medicine
Downloaded from nejm.org by ALVARO MONTANEZ on June 26, 2016. For personal use only. No other uses without permission.
Copyright 2016 Massachusetts Medical Society. All rights reserved.
The n e w e ng l a n d j o u r na l of m e dic i n e

Table 1. Characteristics of the Patients at Baseline.*

Early Strategy Delayed Strategy


Characteristic (N=311) (N=308)
Age yr 64.814.2 67.413.4
Serum creatinine before ICU admission mg/dl 0.950.26 0.970.31
Coexisting conditions no. (%)
Chronic renal failure 22 (7) 38 (12)
Hypertension 161 (52) 167 (54)
Diabetes mellitus 82 (26) 81 (26)
Congestive heart failure 24 (8) 32 (10)
Ischemic heart disease 30 (10) 32 (10)
SAPS III at enrollment 72.614.4 73.714.2
SOFA score at enrollment 10.93.2 10.83.1
Exposure to at least one nephrotoxic agent in past 2 days no./total no. (%) 194/311 (62) 195/308 (63)
Intravenous contrast 66/194 (34) 71/195 (36)
Aminoglycoside 106/194 (55) 106/195 (54)
Vancomycin 26/194 (13) 29/195 (15)
Physiological support no. (%)
Invasive mechanical ventilation 266 (86) 267 (87)
Vasopressor support with epinephrine or norepinephrine 265 (85) 263 (85)
Sepsis status no. (%)
Sepsis 25 (8) 21 (7)
Severe sepsis 16 (5) 19 (6)
Septic shock 209 (67) 204 (66)
Patients with oliguria or anuria no. (%) 202 (65) 191 (62)
Serum creatinine mg/dl 3.251.40 3.201.32
Blood urea nitrogen mg/dl 5324 5424
Serum potassium mmol/liter 4.40.7 4.40.7
Serum bicarbonate mmol/liter 18.75.1 18.85.5

* Plusminus values are means SD. A total of 620 patients underwent randomization, and 1 patient subsequently with
drew permission for the use of his data. To convert values for creatinine to micromoles per liter, multiply by 88.4. To
convert values for blood urea nitrogen to millimoles per liter, multiply by 0.357. Additional data on baseline characteris
tics are provided in Table S2 in the Supplementary Appendix. ARDS denotes acute respiratory distress syndrome, and
ICU intensive care unit.
The serum creatinine concentration before ICU admission was either determined with the use of values measured in
the 12 months preceding the ICU stay or was estimated.22
The Simplified Acute Physiology Score (SAPS) III ranges from 0 to 146, with higher scores indicating more severe dis
ease and a higher risk of death.
The Sepsis-related Organ Failure Assessment (SOFA) score ranges from 0 to 24, with higher scores indicating more se
vere organ failure.25
Some patients were exposed to more than one nephrotoxic agent.
Sepsis was defined as suspected or confirmed infection, with at least two of four signs of a systemic inflammatory re
sponse. Severe sepsis was defined as sepsis with evidence of organ dysfunction. Septic shock was defined as sepsis-
induced hypotension despite fluid resuscitation of at least 30 ml per kilogram of body weight of intravenous fluid ad
ministered within the period spanning the 4 hours before and 4 hours after initiation of vasopressor therapy.

bloodstream infections was significantly lower, tially related to acute kidney injury or renal-
in the delayed-strategy group than in the early- replacement therapy did not differ significantly
strategy group (Table2). between the two study groups, with the excep-
The rate of complications that were poten- tion of hypophosphatemia, which was more

6 n engl j mednejm.org

The New England Journal of Medicine


Downloaded from nejm.org by ALVARO MONTANEZ on June 26, 2016. For personal use only. No other uses without permission.
Copyright 2016 Massachusetts Medical Society. All rights reserved.
Renal-Replacement Ther apy Initiation in the ICU

common in the early-strategy group (Table2).


A
The overall rate of hemorrhage did not differ 1.0
significantly between the study groups (Table2). 0.9
Whereas there was no significant difference be- 0.8

Proportion Surviving
tween the groups in the rate of either dialysis 0.7
catheterrelated or digestive-tract blood loss, 0.6 Early strategy
blood loss from other causes was significantly 0.5
Delayed strategy
more common in the delayed-strategy group 0.4
(Table S8 in the Supplementary Appendix). The 0.3
P=0.79
numbers of patients who received red cells and 0.2
the amount of red cells received per patient did 0.1
not differ significantly between the groups (Ta- 0.0
0 7 14 21 28 35 42 49 56 60
ble2). Adequate diuresis together with no need
Days
for renal-replacement therapy were observed earlier
No. at Risk
in the delayed-strategy group than in the early- Early strategy 311 241 207 194 179 172 167 161 158 157
strategy group (P<0.001) (Fig.2). Delayed strategy 308 239 204 191 178 165 161 156 156 155

B
Discussion 1.0
0.9
In this trial, a strategy of delayed initiation of
Proportion Free from Renal-
0.8
renal-replacement therapy in critically ill pa-
Replacement Therapy
0.7
tients with severe acute kidney injury obviated the 0.6
need for renal-replacement therapy in almost 0.5 Delayed strategy
50% of cases (resulting in a considerable differ- 0.4
ence in the total number of renal-replacement 0.3
therapy sessions). Mortality at day 60 did not dif- 0.2
P<0.001

fer significantly between the early-strategy group 0.1


Early strategy
and the delayed-strategy group. 0.0
0 1 2 3 4 5 6 7 8 12 16 20 24 28
The available knowledge about the initiation
of renal-replacement therapy during acute kid- Days

ney injury derives predominantly from observa- No. at Risk


Early strategy 311 7 4 4 4 4 3 3 3 1 1 0 0 0
tional studies.31-33 Meta-analyses have suggested Delayed strategy 308 268 229 192 153 135 118 105 92 61 39 28 21 13
that a survival advantage is associated with early
renal-replacement therapy.34,35 A major pitfall of Figure 1. Probability of Survival and Timing of Renal-Replacement Therapy.
such observational studies is that all patients Panel A shows KaplanMeier curves of the probability of survival from ran
received renal-replacement therapy that is, domization to day 60. Panel B shows the time from randomization to the
initiation of renal-replacement therapy, stratified according to study group.
there was no control group, and the possibility
Some patients in the early-strategy group received renal-replacement thera
that delaying renal-replacement therapy might py after 6 hours because of other emergencies resulting in postponement
provide time for spontaneous renal recovery was of the initiation of therapy by the medical team, a lack of availability of the
not explored. Two small, single-center, random- renal-replacement therapy machine, or difficulties with catheter insertion.
ized, controlled trials have addressed this is- Other reasons for delay included situations such as a surgical procedure or
radiologic examinations that needed to be performed before the initiation
sue,27,36 but they showed no difference in mortal-
of renal-replacement therapy.
ity. The current results address the timing of
renal-replacement therapy.23 Two other large mul-
ticenter studies are in progress,37,38 and we specu-
late that the results of those studies will confirm nant with the rate in other studies.5,7-9 Patients in
our findings, particularly because a pilot study the current study received renal-replacement ther-
showed that a delayed strategy averted the need apy at a median of 2 hours after randomization
for renal-replacement therapy in an appreciable with the early strategy and at a median of 57 hours
number of patients.39 with the delayed strategy. Contrary to our hypoth-
The 50% mortality among patients in our trial esis, no survival benefit was observed with the
was close to our working hypothesis and conso- delayed strategy of renal-replacement therapy.

n engl j mednejm.org 7
The New England Journal of Medicine
Downloaded from nejm.org by ALVARO MONTANEZ on June 26, 2016. For personal use only. No other uses without permission.
Copyright 2016 Massachusetts Medical Society. All rights reserved.
8
Table 2. Primary and Secondary Outcomes and Adverse Events.*

Early Strategy Delayed Strategy Hazard Ratio


Outcome (N=311) (N=308) P Value (95% CI)
Death no. (% [95% CI])
Day 28 129 (41.6 [35.946.9]) 134 (43.5 [37.748.8])
Day 60 150 (48.5 [42.653.8]) 153 (49.7 [43.855.0]) 0.79 1.03 (0.821.29)
Adjusted analysis 0.84 1.02 (0.811.29)
Patients with treatment limitation in ICU no. (%) 71 (23) 73 (24) 0.78
Median study day on which a treatment limitation first occurred 6 (212.5) 8 (314) 0.23
(IQR)
Patients who received renal-replacement therapy no. (%) 305 (98) 157 (51) <0.001
The

Median renal-replacement therapyfree days (IQR) 17 (226) 19 (529) <0.001


Median mechanical ventilationfree days (IQR) 7 (022) 6 (021) 0.76
Median vasopressor-free days (IQR) 20 (126) 20 (026) 0.67
SOFA score
Day 3 104 104 0.14
Day 7 84 84 0.63
SOFA score without renal component
Day 3 84 84 0.62
Day 7 64 63 0.94
n e w e ng l a n d j o u r na l

The New England Journal of Medicine


n engl j mednejm.org
of

Median length of ICU stay (IQR)


Survivors 13 (823) 13 (723) 0.87
Nonsurvivors 6 (214) 6 (213) 0.92
Median length of hospital stay (IQR)

Copyright 2016 Massachusetts Medical Society. All rights reserved.


m e dic i n e

Survivors 29 (1751) 32 (2051) 0.58


Nonsurvivors 6 (214) 6 (213) 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 (2.34.6) 2.1 (1.13.1) 0.09
Unexplained bloodstream infection no. (%) 21 (7) 26 (8) 0.43

Downloaded from nejm.org by ALVARO MONTANEZ on June 26, 2016. For personal use only. No other uses without permission.
Ventilator-associated pneumonia no. (%) 50 (16) 37 (12) 0.15
Complications potentially related to acute kidney injury or renal-re
placement therapy no. (%)
Hemorrhage 27 (9) 36 (12) 0.21
Thrombocytopenia 172 (55) 165 (54) 0.70
Thrombosis 11 (4) 16 (5) 0.31
Hypokalemia 69 (22) 67 (22) 0.95
Hypophosphatemia 69 (22) 46 (15) 0.03
Hyperkalemia 16 (5) 18 (6) 0.68
Cardiac rhythm disorders no. (%)
Severe 29 (9) 35 (11) 0.40
Moderate 49 (16) 48 (16) 0.77
Transfusion
Patients who received transfusion no. (%) 146 (47) 152 (49) 0.57
Units of red cells transfused per patient 2.44.1 2.44.3 0.75
Dependence on renal-replacement therapy no./total no. (%)
Day 28 22/179 (12) 17/178 (10) 0.51

n engl j mednejm.org
Day 60 3/157 (2) 8/155 (5) 0.12

* Plusminus values are means SD. The numbers of days free from renal-replacement therapy, mechanical ventilation, and vasopressor therapy was defined as the number of days alive

The New England Journal of Medicine


without the intervention at day 28; for patients who died, a value of 0 days was assigned. IQR denotes interquartile range.
Mortality rates were estimated with the use of the KaplanMeier method. The vital status at day 60 was not available for 7 patients (see the Supplementary Appendix).
This analysis was stratified according to center and adjusted for the following baseline characteristics: receipt or no receipt of mechanical ventilation, SAPS III, presence or absence of
septic shock, treatment or no treatment with vasopressors, and time between admission and acute kidney injury.
Renal-Replacement Ther apy Initiation in the ICU

Treatment limitations (withholding or withdrawal of treatment) could involve any treatment used during the ICU stay.
Catheter-related bloodstream infections were defined according to the 2009 guidelines from the Infectious Diseases Society of America.30

Copyright 2016 Massachusetts Medical Society. All rights reserved.


Definitions are provided in the Supplementary Appendix.

Downloaded from nejm.org by ALVARO MONTANEZ on June 26, 2016. For personal use only. No other uses without permission.
9
The n e w e ng l a n d j o u r na l of m e dic i n e

have voiced concern about the potentially delete-


1.0 rious effects of intermittent hemodialysis in pa-
Probability of Adequate Urine Output with
No Need for Renal-Replacement Therapy
Delayed strategy
0.9 tients whose condition is unstable.40
0.8 Our trial has potential limitations. First, the
0.7
Early strategy power of our study to distinguish a significant
0.6 difference in mortality could be questioned.
0.5 However, to detect an effect size of 1.2 percent-
0.4
age points (i.e., the difference in mortality that
we found between the two groups in our study)
0.3
with a power of 90%, a sample of more than
0.2
P<0.001 70,000 patients would be required. Second, al-
0.1
though we did not use Kt/V (a measure of the
0.0
0 7 14 21 28
clearance of urea in which K represents the rate
Days
of urea clearance by the dialyzer, t is the dura-
tion of dialysis, and V is the volume of distribu-
No. at Risk
Early strategy 311 99 42 27 10 tion of urea in the patient) to evaluate the dose
Delayed strategy 308 68 29 14 7 of renal-replacement therapy, low urea levels in
serum were maintained during therapy. Third,
Figure 2. Probability of Adequate Urine Output without the Need the patients in the trial population had advanced
for Renal-Replacement Therapy.
acute kidney injury, and therefore our results
Shown are the KaplanMeier curves of the probability of a patient having
may not be generalizable to patients with differ-
urine output, for at least 1 day, of more than 1000 ml per 24 hours in the
absence of diuretic treatment or more than 2000 ml per 24 hours with di ent KDIGO stages of acute kidney injury. Finally,
uretic treatment and not requiring initiation or resumption of renal-replace some could interpret the finding of higher mor-
ment therapy for at least 7 days, from randomization to day 28 (see also tality among patients who received late renal-
Fig. S3 in the Supplementary Appendix). replacement therapy as a deleterious effect of
this strategy. However, the patients who received
late renal-replacement therapy obviously had more
Although the survival curves were similar in severe illness than those who did not, and fur-
the two groups, the recovery of renal function, as ther adjustment according to baseline severity
marked by diuresis, was more rapid and catheter- suggests that this observed crude difference was
related infections occurred less frequently in the confounded (see the Supplementary Appendix).
delayed-strategy group than in the early-strategy Our study should not be interpreted as sug-
group. Subtle or undetected circulatory altera- gesting that a wait and see approach is safe for
tions might have slowed the apparent recovery of all patients. Indeed, careful surveillance is man-
renal function in the early-strategy group. The datory when deciding to delay renal-replacement
rate of gastrointestinal bleeding did not differ sig- therapy in patients with severe acute kidney injury
nificantly between the groups. Finally, the lengths so that any complication will be detected and re-
of stay in the intensive care unit and in the hospital nal-replacement therapy initiated without delay.
were similar in the two groups, which indicates In our trial, delaying the initiation of therapy al-
that allowing time for renal function recovery lowed many patients to recover from acute kidney
did not lead to prolongation of the stay in the injury without embarking on such a treatment
intensive care unit. course.
Our findings may not be generalizable, be- In conclusion, our trial involving critically ill
cause more than 50% of the patients in our trial patients with severe acute kidney injury showed
received intermittent hemodialysis as the first no significant difference in mortality with a strat-
method of therapy and only 30% of the patients egy of delayed initiation as compared with early
received continuous renal-replacement therapy initiation of renal-replacement therapy.
as the sole method (with no intermittent dialysis
at any time). Although a previously published Supported by a grant from the Programme Hospitalier de
large, randomized, controlled trial did not show Recherche Clinique National, 2012 (AOM12456), funded by the
French Ministry of Health.
differences in mortality according to the method Disclosure forms provided by the authors are available with
of renal-replacement therapy,9 some investigators the full text of this article at NEJM.org.

10 n engl j mednejm.org

The New England Journal of Medicine


Downloaded from nejm.org by ALVARO MONTANEZ on June 26, 2016. For personal use only. No other uses without permission.
Copyright 2016 Massachusetts Medical Society. All rights reserved.
Renal-Replacement Ther apy Initiation in the ICU

We thank Laurent Brochard (Critical Care Saint Michaels versit Pierre et Marie Curie, Paris) for their participation in the
Hospital, University of Toronto, Toronto), Christian Melot independent data and safety monitoring board of the trial; the
(Erasme University Hospital, Emergency Department, Universit doctors and nurses from all the study sites; and Isabelle Hoff-
Libre de Bruxelles, Brussels), and Alexandre Hertig (Hpital mann, Nadia Ettalhaoui, and Emeline Dubief for assistance in
Tenon, Urgences nphrologiques et transplantation rnale, Uni- monitoring and study management.

Appendix
The authors affiliations are as follows: Assistance PubliqueHpitaux de Paris (APHP), Hpital Louis Mourier, Service de Ranimation
Mdico-Chirurgicale, Colombes (S.G., J.-D.R., D.D.), Universite Paris Diderot, Sorbonne Paris Cit, Epidmiologie Clinique-valuation
conomique Appliqu aux Populations Vulnrables (ECEVE) (S.G., D.H., F.T.), Institut National de la Sant et de la Recherche Mdicale
(INSERM), ECEVE, Centre dinvestigation CliniqueEpidmiologie Clinique (CIC-EC) 1425 (S.G., D.H., F.T.), APHP, Hpital Louis
Mourier, Dpartement dEpidmiologie et Recherche Clinique, CIC-EC 1425 (D.H.), Service de Pneumologie et Ranimation Mdicale,
APHP, Groupe Hospitalier PitiSalptrire (J. Mayaux), Ranimation Mdicale et Toxicologique, Hpital Lariboisire, INSERM Unit
1144, Universit Paris Diderot (B.M.), APHP, Hpital Bichat, Dpartement dEpidmiologie et Recherche Clinique, CIC-EC 1425 (F.T.),
and Universit Paris Diderot, Infection, Antimicrobiens, Modlisation, Evolution (IAME), Unit Mixte de Recherche (UMR) 1137, Sor-
bonne Paris Cit (J.-D.R., D.D.), Paris, APHP, Hpitaux Universitaires Henri Mondor, Service de Ranimation Mdicale (F.S.), and
APHP, Hpitaux Universitaires Henri Mondor, Dpartement Hospitalo-Universitaire Ageing Thorax-Vessels-Blood, Service de Ranima-
tion Mdicale, Cardiovascular and Respiratory Manifestations of Acute Lung Injury and Sepsis (CARMAS) Research Group and Univer-
sit Paris-Est Crteil Val de Marne (N.P.), Crteil, Ranimation Mdico-Chirurgicale, Centre Hospitalier Gnral, La Roche-sur-Yon
(L.M.-L.), Service de Ranimation, Centre Hospitalier Universitaire (CHU) de Pointe PitreAbymes, Guadeloupe (B.P., G.T.), Ranima-
tion Polyvalente, CH Ren Dubos, Pontoise (E.B.), Ranimation Mdicale CHU Bordeaux, Hpital Pellegrin, Bordeaux (A. Boyer), Service
de Ranimation, CH Sud Francilien, Corbeil Essonne (G.C.), Dpartement de Ranimation Mdicale et Mdecine Hyperbare, CHU
Angers, Universit dAngers, Angers (N.L.), Ranimation Mdicale, CHU Rouen, Rouen (D.C.), Ranimation Mdicale, Hpital Gabriel
Montpied, CHU de Clermont-Ferrand, Clermont-Ferrand (A.L.), Ranimation Mdico-Chirurgicale, Hpital de La Source, Centre Hos-
pitalier Rgional dOrlans, Orleans (A. Bretagnol), Centre de Ranimation, CHU de Lille, Facult de Mdecine, Universit de Lille, Lille
(S.N.); Ranimation Polyvalente, CH Victor Dupouy, Argenteuil (M.T.), Service de Ranimation des Dtresses Respiratoires Aigus et
Infections Svres, Hpital Nord, Marseille (J.-M.F.), Service de Ranimation Mdicale INSERM Unit 1088, CHU de Picardie, Amiens
(J. Maizel), Ranimation Mdicale, Hpital de la Croix Rousse, Lyon (H.Y.), and Ranimation, CH Cholet, Cholet (P.M.) all in France.

References
1. Hoste EA, Bagshaw SM, Bellomo R, et afiltration versus intermittent haemodi- 16. Wald R, Bagshaw SM. The timing of
al. Epidemiology of acute kidney injury in alysis for acute renal failure in patients renal replacement therapy initiation in
critically ill patients: the multinational with multiple-organ dysfunction syn- acute kidney injury: is earlier truly better?
AKI-EPI study. Intensive Care Med 2015; drome: a multicentre randomised trial. Crit Care Med 2014;42:1933-4.
41:1411-23. Lancet 2006;368:379-85. 17. Shingarev R, Wille K, Tolwani A. Man-
2. Bonventre JV. Dialysis in acute kidney 10. Vaara ST, Reinikainen M, Wald R, agement of complications in renal replace-
injury more is not better. N Engl J Med Bagshaw SM, Pettil V. Timing of RRT ment therapy. Semin Dial 2011;24:164-8.
2008;359:82-4. based on the presence of conventional in- 18. Clark E, Wald R, Walsh M, Bagshaw
3. Bonventre JV, Basile D, Liu KD, et al. dications. Clin J Am Soc Nephrol 2014;9: SM. Timing of initiation of renal replace-
AKI: a path forward. Clin J Am Soc 1577-85. ment therapy for acute kidney injury: a
Nephrol 2013;8:1606-8. 11. Gibney N, Hoste E, Burdmann EA, et survey of nephrologists and intensivists
4. Mehta RL, Cerd J, Burdmann EA, et al. Timing of initiation and discontinua- in Canada. Nephrol Dial Transplant 2012;
al. International Society of Nephrologys tion of renal replacement therapy in AKI: 27:2761-7.
0by25 initiative for acute kidney injury unanswered key questions. Clin J Am Soc 19. Legrand M, Darmon M, Joannidis M,
(zero preventable deaths by 2025): a hu- Nephrol 2008;3:876-80. Payen D. Management of renal replace-
man rights case for nephrology. Lancet 12. Bagshaw SM, Uchino S, Bellomo R, et ment therapy in ICU patients: an interna-
2015;385:2616-43. al. Timing of renal replacement therapy tional survey. Intensive Care Med 2013;39:
5. The VA/NIH Acute Renal Failure Trial and clinical outcomes in critically ill pa- 101-8.
Network. Intensity of renal support in tients with severe acute kidney injury. 20. Section 5: dialysis interventions for
critically ill patients with acute kidney in- J Crit Care 2009;24:129-40. treatment of AKI. Kidney Int Suppl (2011)
jury. N Engl J Med 2008;359:7-20. 13. Schneider AG, Uchino S, Bellomo R. 2012;2:89-115.
6. Uchino S, Kellum JA, Bellomo R, et al. Severe acute kidney injury not treated 21. Brochard L, Abroug F, Brenner M, et
Acute renal failure in critically ill pa- with renal replacement therapy: charac- al. An official ATS/ERS/ESICM/SCCM/
tients: a multinational, multicenter study. teristics and outcome. Nephrol Dial SRLF statement: prevention and manage-
JAMA 2005;294:813-8. Transplant 2012;27:947-52. ment of acute renal failure in the ICU pa-
7. The RENAL Replacement Therapy 14. Elseviers MM, Lins RL, Van der tient: an international consensus confer-
Study Investigators. Intensity of continu- Niepen P, et al. Renal replacement therapy ence in intensive care medicine. Am J
ous renal-replacement therapy in critical- is an independent risk factor for mortality Respir Crit Care Med 2010;181:1128-55.
ly ill patients. N Engl J Med 2009; 361: in critically ill patients with acute kidney 22. Section 2: AKI definition. Kidney Int
1627-38. injury. Crit Care 2010;14(6):R221. Suppl (2011) 2012;2:19-36.
8. Schiffl H, Lang SM, Fischer R. Daily 15. Payen D, Mateo J, Cavaillon JM, et al. 23. Gaudry S, Hajage D, Schortgen F, et
hemodialysis and the outcome of acute Impact of continuous venovenous hemo- al. Comparison of two strategies for initi-
renal failure. N Engl J Med 2002;346:305- filtration on organ failure during the ating renal replacement therapy in the
10. early phase of severe sepsis: a randomized intensive care unit: study protocol for a
9. Vinsonneau C, Camus C, Combes A, controlled trial. Crit Care Med 2009;37: randomized controlled trial (AKIKI). Tri-
et al. Continuous venovenous haemodi- 803-10. als 2015;16:170.

n engl j mednejm.org 11
The New England Journal of Medicine
Downloaded from nejm.org by ALVARO MONTANEZ on June 26, 2016. For personal use only. No other uses without permission.
Copyright 2016 Massachusetts Medical Society. All rights reserved.
The n e w e ng l a n d j o u r na l of m e dic i n e

24. Vinsonneau C, Allain-Launay E, Blay- sign for randomized clinical trials. Con- 36. Jamale TE, Hase NK, Kulkarni M, et
au C, et al. Renal replacement therapy in trol Clin Trials 2003;24:506-22. al. Earlier-start versus usual-start dialysis
adult and pediatric intensive care: recom- 30. Mermel LA, Allon M, Bouza E, et al. in patients with community-acquired
mendations by an expert panel from the Clinical practice guidelines for the diag- acute kidney injury: a randomized con-
French Intensive Care Society (SRLF) with nosis and management of intravascular trolled trial. Am J Kidney Dis 2013; 62:
the French Society of Anesthesia Intensive catheter-related infection: 2009 update by 1116-21.
Care (SFAR) French Group for Pediatric the Infectious Diseases Society of Ameri- 37. Smith OM, Wald R, Adhikari NK, et
Intensive Care Emergencies (GFRUP) the ca. Clin Infect Dis 2009;49:1-45. al. Standard versus Accelerated Initiation
French Dialysis Society (SFD). Ann Inten- 31. Chou YH, Huang TM, Wu VC, et al. Im- of Renal Replacement Therapy in Acute
sive Care 2015;5:58. pact of timing of renal replacement thera- Kidney Injury (STARRT-AKI): study pro-
25. Vincent JL, Moreno R, Takala J, et al. py initiation on outcome of septic acute tocol for a randomized controlled trial.
The SOFA (Sepsis-related Organ Failure kidney injury. Crit Care 2011;15:R134. Trials 2013;14:320.
Assessment) score to describe organ dys- 32. Guerin C, Girard R, Selli J-M, Perdrix 38. Barbar SD, Binquet C, Monchi M, Bru-
function/failure: on behalf of the Working J-P, Ayzac L. Initial versus delayed acute yre R, Quenot JP. Impact on mortality of
Group on Sepsis-Related Problems of the renal failure in the intensive care unit: a the timing of renal replacement therapy
European Society of Intensive Care Medi- multicenter prospective epidemiological in patients with severe acute kidney injury
cine. Intensive Care Med 1996;22:707-10. study. Am J Respir Crit Care Med 2000; in septic shock: the IDEAL-ICU study (Ini-
26. Whitehead J. A unified theory for se- 161:872-9. tiation of Dialysis Early versus Delayed in
quential clinical trials. Stat Med 1999;18: 33. Kleinknecht D, Jungers P, Chanard J, the Intensive Care Unit): study protocol
2271-86. Barbanel C, Ganeval D. Uremic and non- for a randomized controlled trial. Trials
27. Bouman CS, Oudemans-Van Straaten uremic complications in acute renal fail- 2014;15:270.
HM, Tijssen JG, Zandstra DF, Kesecioglu ure: evaluation of early and frequent dialy- 39. Wald R, Adhikari NK, Smith OM, et
J. Effects of early high-volume continuous sis on prognosis. Kidney Int 1972;1:190-6. al. Comparison of standard and acceler-
venovenous hemofiltration on survival 34. Seabra VF, Balk EM, Liangos O, Sosa ated initiation of renal replacement thera-
and recovery of renal function in intensive MA, Cendoroglo M, Jaber BL. Timing of py in acute kidney injury. Kidney Int 2015;
care patients with acute renal failure: a renal replacement therapy initiation in 88:897-904.
prospective, randomized trial. Crit Care acute renal failure: a meta-analysis. Am J 40. Schneider AG, Bellomo R, Bagshaw
Med 2002;30:2205-11. Kidney Dis 2008;52:272-84. SM, et al. Choice of renal replacement
28. Gaudry S, Ricard JD, Leclaire C, et al. 35. Karvellas CJ, Farhat MR, Sajjad I, et al. therapy modality and dialysis dependence
Acute kidney injury in critical care: expe- A comparison of early versus late initia- after acute kidney injury: a systematic re-
rience of a conservative strategy. J Crit tion of renal replacement therapy in criti- view and meta-analysis. Intensive Care
Care 2014;29:1022-7. cally ill patients with acute kidney injury: Med 2013;39:987-97.
29. Karrison TG, Huo D, Chappell R. A a systematic review and meta-analysis. Copyright 2016 Massachusetts Medical Society.
group sequential, response-adaptive de- Crit Care 2011;15:R72.

12 n engl j mednejm.org

The New England Journal of Medicine


Downloaded from nejm.org by ALVARO MONTANEZ on June 26, 2016. For personal use only. No other uses without permission.
Copyright 2016 Massachusetts Medical Society. All rights reserved.