随着对危重症患者抢救成功率的提高.docx

1、随着对危重症患者抢救成功率的提高Intensity of Continuous Renal-Replacement Therapy in Critically Ill PatientsThe RENAL Replacement Therapy Study InvestigatorsN Engl J Med 2009; 361:1627-1638October 22, 2009DOI: 10.1056/NEJMoa0902413Share:AbstractArticleReferencesCiting Articles(243)LettersAcute kidney injury is asso

2、ciated with substantial morbidity and mortality.1It is a common finding among patients in the intensive care unit (ICU)2and is an independent predictor of mortality.3Acute kidney injury severe enough to result in the use of renal-replacement therapy affects approximately 5% of patients admitted to t

3、he ICU and is associated with a mortality rate of 60%.4The optimal approach to renal-replacement therapy, as well as the optimal intensity and timing of such therapy, in critically ill patients remains unclear. In one single-center, randomized, controlled study in which continuous renal-replacement

4、therapy was the sole treatment approach, survival improved when the intensity of therapy was increased from an assigned effluent rate of 20 ml per kilogram of body weight per hour to either 35 or 45 ml per kilogram per hour.5However, subsequent single-center studies have had conflicting results.6-8T

5、he recently reported Veterans Affairs/National Institutes of Health Acute Renal Failure Trial Network Study (ClinicalTrials.gov number, NCT00076219)9showed that increasing the intensity of renal-replacement therapy did not decrease mortality among patients with acute kidney injury. In contrast to ot

6、her studies, which used continuous renal-replacement therapy exclusively, this study assigned patients to a protocol of either intermittent or continuous renal-replacement therapy according to whether they were hemodynamically stable or unstable, respectively. This design reflects clinical practice

7、in the United States and elsewhere but makes it difficult to carry out a formal comparison of treatment intensities that would be independent of the particular treatment approach. We conducted a randomized, controlled study to test the hypothesis that increasing the intensity of continuous renal-rep

8、lacement therapy would reduce mortality at 90 days.METHODSStudy DesignThe Randomized Evaluation of Normal versus Augmented Level (RENAL) Replacement Therapy Study was a prospective, randomized, parallel-group trial designed to assess two levels of intensity of continuous renal-replacement therapy in

9、 critically ill patients with acute kidney injury. The study was conducted between December 30, 2005, and November 28, 2008, in 35 ICUs in Australia and New Zealand. The study protocol is outlined in theSupplementary Appendix, available with the full text of this article at NEJM.org. It was approved

10、 by the human research ethics committees of the University of Sydney and all participating institutions. The integrity of data collection was verified by the George Institute for International Health monitoring team. An independent data and safety monitoring committee reviewed safety data and interi

11、m results with the aim of providing advice to the trial management committee should such analyses prove beyond a reasonable doubt that augmented continuous renal-replacement therapy led to a net benefit or harm in terms of mortality.Study PopulationPatients were eligible for enrollment if they were

12、critically ill, were 18 years of age or older, had acute kidney injury, were deemed by the treating clinician to require renal-replacement therapy, and met at least one of the following criteria: oliguria (urine output 100 ml in a 6-hour period) that was unresponsive to fluid resuscitation measures,

13、 a serum potassium concentration exceeding 6.5 mmol per liter, severe acidemia (pH 7.2), a plasma urea nitrogen level above 70 mg per deciliter (25 mmol per liter), a serum creatinine concentration above 3.4 mg per deciliter (300 mol per liter), or the presence of clinically significant organ edema

14、(e.g., pulmonary edema). Written informed consent was obtained from the patient or responsible surrogate by means of either a priori or delayed consent. (For a detailed description of delayed consent, see theSupplementary Appendix.)Patients who had received any previous renal-replacement therapy dur

15、ing the same hospital admission or who were on maintenance dialysis for end-stage kidney disease were ineligible for the study. (For a detailed list of inclusion and exclusion criteria and the criteria for discontinuing the study treatment, see theSupplementary Appendix.)InterventionThe patients in

16、both groups were treated with continuous venovenous hemodiafiltration. Replacement fluid was delivered into the extracorporeal circuit after the filter (i.e., postdilution), with a ratio of dialysate to replacement fluid of 1:1. The effluent flow prescribed was based on the patients body weight at t

17、he time of randomization and was either 40 ml per kilogram per hour (for the higher-intensity group) or 25 ml per kilogram per hour (for the lower-intensity group). Blood flow was kept above 150 ml per minute. Fluid was removed by decreasing the flow of the replacement fluid and of the dialysate in

18、equal proportion, so that effluent exceeded them both by any amount prescribed by the clinician. Filters with the AN69 membrane (Gambro) were used. Hemosol BO fluid (Gambro) was used as the dialysate and replacement fluid. Gambro had no role in the initiation, design, analysis, or reporting of the s

19、tudy.Study OutcomesThe primary study outcome was death from any cause within 90 days after randomization. Secondary and tertiary outcomes included death within 28 days after randomization, death in the ICU, in-hospital death, cessation of renal-replacement therapy, duration of ICU and hospital stays

20、, duration of mechanical ventilation and renal-replacement therapy, dialysis status at day 90, and any new organ failures.Statistical AnalysisAll statistical analyses were conducted according to a predefined plan.10,11The target enrollment was 1500 patients, which provided 90% power to detect an 8.5

21、% absolute reduction in 90-day mortality from a baseline of 60% (alpha level, 0.05). Two interim analyses were performed and reviewed by an independent data and safety monitoring committee. Since the HaybittlePeto rule with a maximum of three analyses was used to limit the overall probability of a t

22、ype I error to 0.05, the final analysis was conducted at an alpha level of 0.048.All analyses were performed according to the intention-to-treat principle, with no imputation for missing values. Data from patients who were lost to follow-up were not analyzed. Proportions were compared with the use o

23、f the chi-square test, and continuous variables were analyzed with the use of Students t-test. MantelHaenszel adjusted odds ratios and their corresponding 95% confidence intervals were calculated. Analysis of the primary outcome for the two groups was also performed by means of the log-rank test, wi

24、th the results presented as a KaplanMeier cumulative-incidence plot.Prespecified subgroup analyses were performed according to the presence or absence of sepsis; failure of one or more nonrenal organs; a Sequential Organ Failure Assessment (SOFA) cardiovascular score of 3 or 4 at baseline (on a scal

25、e ranging from 0 to 4, with a higher score indicating more severe organ dysfunction); and an estimated glomerular filtration rate of less than 60 ml per minute within 6 months prior to randomization. We assessed subgroups for heterogeneity of treatment effect according to accepted clinical guideline

26、s.12Statistical analyses were performed, independently checked, and replicated with the use of SAS software, version 9.1.RESULTSEnrollmentBetween December 1, 2005, and August 31, 2008, we enrolled 1508 patients, of whom 747 were assigned to the higher-intensity treatment group and 761 to the lower-i

27、ntensity treatment group (Figure 1FIGURE 1Numbers of Patients Enrolled in the Study, Randomly Assigned to a Treatment Group, and Included in the Analysis.). Consent was subsequently withheld or withdrawn for 43 patients (2.9%), 25 of whom had been assigned to higher-intensity therapy and 18 to lower

28、-intensity therapy; only 1 patient was lost to follow-up, thus the primary outcome was available for 1464 patients (97.1%).Baseline CharacteristicsAll baseline characteristics were similar between the two groups (Table 1TABLE 1Baseline Characteristics of the Study Patients.). The serum creatinine co

29、ncentrations before randomization in the higher-intensity and lower-intensity treatment groups were 3.8 mg per deciliter (338 mol per liter) and 3.7 mg per deciliter (330 mol per liter), respectively. In all, 73.9% of patients were receiving mechanical ventilation, 49.4% had severe sepsis, and 82.5%

30、 were receiving vasoactive drugs.Study and Supportive TreatmentsTable 2TABLE 2Characteristics of Study Treatments and Subsequent Use of Renal-Replacement Therapy.lists the characteristics of the study therapy. The mean duration of treatment in the two groups was similar, but during therapy, they had

31、 significantly different mean daily serum creatinine concentrations (1.9 mg per deciliter 170 mol per liter in the higher-intensity group vs. 2.3 mg per deciliter 204 mol per liter in the lower-intensity group, P0.001) and blood urea nitrogen levels (35.6 mg per deciliter 12.7 mmol per liter vs. 44.

32、5 mg per deciliter 15.9 mmol per liter, P0.001). These differences were consistent with the difference in the intensity of the delivered treatment (mean effluent rate, 33.4 ml per kilogram of body weight per hour in the higher-intensity group vs. 22.0 in the lower-intensity group; P0.001). Patients receiving higher-intensity continuous renal-replacement therapy were more likely to receive regional extracorporeal-circuit anticoagulation with heparin and protamine (P=0.007) and required more filters per day (0.93 vs. 0.84, P0.001). Only 7.6% and 7.0% of the patients in the higher-in