Intensity of continuous renal replacement therapies in patients with severe sepsis and septic shock: a systematic review and meta-analysis.
The purpose of this study was to assess the efficacy of continuous
renal replacement therapies in patients with severe sepsis or septic
shock, with or without acute kidney injury. We performed a systematic
search in Medline, Embase, Web of Knowledge, Cochrane Library and
Clinicaltrials.gov and a hand search of the retrieved studies. We
included both randomised controlled clinical trials and subgroups of
randomised trials that assessed the effect of continuous renal
replacement therapies (at traditional or high doses) and reported
clinical outcomes in adult patients with severe sepsis or septic shock.
The study selection and data extraction were performed by duplicate.
Analysis of heterogeneity and meta-analysis was performed according to
the Cochrane Collaboration guidelines for conducting systematic reviews
Twelve studies (1895 patients) met the inclusion criteria. Pooling of all studies resulted in a mortality risk ratio of 0.96 (95% confidence interval 0.83 to 1.12). The studies showed moderate statistical heterogeneity I (2) statistic 52%, P=0.02). The effect on mortality was not modified (interaction P values non significant) by the dose of continuous renal replacement therapies, the severity of illness or the risk of bias. The available evidence suggests that these therapies in patients with severe sepsis or septic shock are not associated with an improvement in other outcomes such as haemodynamics, pulmonary gas exchange, multiple organ dysfunction syndrome or length of stay. The best available evidence does not support the routine use of continuous renal replacement therapies (at traditional or high doses) in patients with severe sepsis or septic shock.
Key Words: sepsis, continuous renal replacement therapy, mortality, review, meta-analysis
|Subject:||Sepsis (Care and treatment)|
|Publication:||Name: Anaesthesia and Intensive Care Publisher: Australian Society of Anaesthetists Audience: Academic Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2011 Australian Society of Anaesthetists ISSN: 0310-057X|
|Issue:||Date: May, 2011 Source Volume: 39 Source Issue: 3|
|Geographic:||Geographic Scope: Australia Geographic Code: 8AUST Australia|
Severe sepsis and septic shock carry a high mortality and account
for a large proportion of patients admitted to intensive care units
It is widely accepted that the release of large amounts of pro- and anti-inflammatory mediators that occurs in severe sepsis contributes to the development of multiple organ dysfunction syndrome (MODS) (5-8), including acute kidney injury (AKI). Theoretically, high-dose continuous renal replacement therapies (CRRT) could remove mediators by convection and/or adsorption (9,10) and reduce mortality, even in the absence of AKI (11). However, most current clinical practice guidelines suggest that the traditional doses of CRRT used in AKI, with or without sepsis, are insufficient to remove these mediators and recommend using at least 35 ml/kg/hour of ultrafiltration (12,13).
Recently, two large randomised clinical trials in patients with AKI (ATN study (14,15) and RENAL study (16,17)) have seriously challenged these recommendations. Additionally, four recent meta-analyses about effectiveness of CRRT in critical patients with AKI (18-21) have described no impact on the mortality or secondary outcomes of these techniques. The uncertainty regarding the effectiveness of CRRT in patients with sepsis without renal failure is even greater.
The object of this review was to assess the effectiveness of CRRT at high or conventional doses in patients with severe sepsis or septic shock, with or without (AKI).
MATERIALS AND METHODS
Studies were included in the review if they met the following criteria: 1) design: controlled clinical trials (including randomised controlled trials and subgroups of randomised trials); 2) patients: studies conducted in adults (16 years old or greater) with a diagnosis of severe sepsis or septic shock, with or without acute kidney failure, according to the authors' definition; 3) intervention: studies evaluating continuous veno-venous haemofiltration or haemodiafiltration (at high or standard doses) compared with continuous veno-venous haemofiltration or haemodiafiltration at standard doses or no CRRT; studies in which combined continuous and intermittent therapies were initially included, and their impact assessed with sensitivity analysis; 4) outcomes: studies that measured short-term mortality (hospital mortality or mortality at 15 to 90 days).
Along with mortality (primary endpoint), other clinical outcomes were analysed (secondary endpoints) whenever possible: haemodynamic response (mean arterial pressure or use of vasopressor drugs using an explicit protocol), pulmonary gas exchange ([P.sub.a][O.sub.2]/Fi[O.sub.2] ratio), incidence and/or evolution of MODS or length of stay in the intensive care unit.
The exclusion criteria were as follows: 1) interventional studies without external control groups (e.g. crossover trials, studies of observed versus expected mortality); 2) studies without sufficient data to assess mortality, 3) studies evaluating other renal replacement therapies (e.g. peritoneal dialysis or coupled plasma filtration immunoadsorption); 4) studies prior to 1995. No a priori language restrictions were established.
Source of data and search strategy
An electronic search was performed during October 2009 in the following databases: Medline (using PubMed), Embase (using Embase.com), Cochrane Library (CDSR and Clinical Trials Database), Clinicaltrials.gov and Web of Knowledge. The search strategies are described in Table 1.
This search was supplemented by searching the references of the retrieved full-text articles and the summaries from July to October 2009 in the following journals: New England Journal of Medicine, Lancet, Journal of the American Medical Association, Critical Care, Critical Care Medicine, Intensive Care Medicine, Journal of Critical Care, Medicina Intensiva, REMI, Kidney International, Journal of the American Society of Nephrology, Nefrologia, International Journal of Artificial Organs, Artificial Organs, Blood Purification and Nephrology Dialysis Transplantation.
The authors of potentially relevant studies were occasionally contacted to clarify the inclusion criteria (22,23), but were not used as a primary source of data. The distinction between septic and non-septic patients in three studies (24-26) was provided by a recent meta-analysis (20).
Study selection and data extraction
Studies were selected according to the the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (27). The retrieved studies were assembled into a bibliographic database. After eliminating duplicates, the articles were subjected to a screening process from the title and abstract to exclude irrelevant studies. We obtained full-text versions of the pertinent articles to determine whether they met inclusion and exclusion criteria. The results of the selection process are summarised in Figure 1.
The extracted data included the setting of the study, type of patients, renal replacement techniques, clinical outcomes and methodological quality of the studies (Tables 2 to 4). The doses used were classified as traditional (<35 ml/kg/hour), high (35 to 65 ml/kg/hour) or very high (>65 ml/kg/hour).
The methodological quality of studies was assessed according to the recommendations of the Cochrane Collaboration (28), which considers six domains, coded as 1 (no), 2 (unclear) or 3 (yes): generation of a random list to allocate the study subjects, concealed sequence of randomisation, blinding, attrition and exclusions after randomisation, selective reporting of outcomes and other. The latter domain included the following pre-defined features: study design (primary randomised controlled trial versus sepsis subgroup), early stopping by benefit (29), misbalanced baseline prognostic variables, under-dosage of haemofiltration (in the control or experimental group), observed versus expected mortality, statistical power (to detect a mortality reduction of 20%) and Jadad's scale (30).
[FIGURE 1 OMITTED]
The screening and selection of articles and data extraction were performed in duplicate, and disagreements were resolved by consensus.
Due to the clinical heterogeneity of the studies, the effect of haemofiltration on mortality was analysed using a random effects meta-analysis (DerSimonian-Laird (31)). Statistical heterogeneity was assessed by the Q test, the I (2) statistic (32) and the Galbraith plot (33). The risk of publication bias and/or small study effect was explored by constructing a funnel plot with enhanced contours (34) and Harbord's test (35).
Random effects meta-regression was performed by the residual maximum likelihood method (36). The following pre-selected variables were analysed in the meta-regression model: study design (randomised controlled trial versus randomised trial subgroup), methodological quality of the study (the six domains recommended by the Cochrane Collaboration), renal replacement therapy dose (prescribed or applied), epidemiological design of the study (randomised controlled trial in patients with sepsis versus sepsis subgroup included in a randomised controlled trial), use of renal replacement therapy in the control group, severity of illness (mean Acute Physiology and Chronic Health Evaluation II score in the control group), year of publication and financial support.
Additionally, several exploratory sensitivity analyses were conducted to examine the impact of meta-analysis model (fixed versus random effects), selected association measure (odds ratio vs relative risk) and type of intervention (continuous vs mixed continuous-intermittent techniques).
Given the diversity of measures used, the effects of CRRT on other outcomes (haemodynamics, [P.sub.a][O.sub.2]/ [F.sub.i][O.sub.2] , MODS and length of stay) were analysed using a narrative synthesis of the evidence.
The analyses were performed using the software Stata/IC 11.0, Review Manager 5.0.23, StatsDirect 2.7.7, Reference Manager 12 and GPower 3.0.
Included and excluded studies
Initially, 3776 potentially relevant articles were screened for inclusion in the review. We determined that 3741 of these were not relevant after examination of the title or abstract. After full-text review of the remaining 35 articles, eight studies were excluded because they lacked an external control group (37-44), 10 studies had a control group different from CVVH or no dialysis (45-54) and five additional studies were excluded due to insufficient raw data to assess mortality using a two-by-two table (22,23,55-57). Therefore, 12 studies were finally included in the review (8,9,14,16,24-26,58-62) (Figure 1, Tables 2 and 3).
Three of the included studies (8,58,62) assessed the effect of CVVH versus no CRRT, while the remaining nine studies (9,14,16,24-26,59-61) assessed the effect of higher versus lower doses. Most of these studies included exclusively patients with AKI (9,14,16,24-26,59,61). Only three studies included patients without AKI (8,58,62), two of them (8,58) used low doses of therapy versus standard medical treatment.
Quality of the studies
Whereas all the included studies were described as 'randomised', only six studies described how the random list was generated (8,14,16,25,26,62) (Table 4). The sequence of allocation was concealed in five studies (8,14,16,25,26), and unclear in the remaining seven studies. Due to the nature of the intervention, all of the included studies were non-blinded.
Nine studies were free of significant attrition or exclusions after randomisation (8,14,16,24-26,59,60,62). The risk of bias due to exclusions was considered high in two studies (58,61). One additional study that reported complete follow-up (9) was found later to have excluded patients with septic shock (63), so its risk of bias due to exclusion after randomisation was considered unclear. Four studies had study protocol available and were considered free of selective outcome reporting bias (14,16,26,62). The risk of selective reporting bias was considered high in one study which reported an unusual primary outcome (survival at 15 days after discontinuation of treatment)9 and unclear in the remainder of the studies. Most of the included studies showed other pre-defined limitations, such as the existence of misbalanced groups (58-61), excessive mortality in the control group (9,60), under-dosage in the experimental group (8,26,58) or early stopping by benefit (Saudan et al (25), as reported by Van Wert et al (20)).
[FIGURE 3 OMITTED]
Effect on mortality
There was no evidence of benefit in studies which used renal replacement therapy at traditional doses (less than 35 ml/kg/hour) or high doses (35 to 65 ml/kg/hour) (Figure 2). The relative risk was slightly lower in studies that used more than 65 ml/kg/hour (60,61) (relative risk=0.84, 95% confidence interval 0.59 to 1.19), however there was no statistical interaction between trial group and dose (P=0.237).
Taken as a whole, the included studies showed a moderate degree of statistical heterogeneity (I (2) =52%, P=0.02) (Figure 2) with a pooled risk ratio (random effects) of 0.96 (0.83 to 1.12). The Galbraith plot identified the study of Saudan et al (25) as an outlier. After the exclusion of this study, the heterogeneity was low (I (2) 20%, P=0.25) with a pooled risk ratio of 1.0 (0.90 to 1.11). There was no suggestion of publication bias and/or small studies effect in the funnel plot (Figure 3). These results were robust to the exclusion of the ATN study that used a combination of continuous and intermittent renal replacement therapies (14).
The univariate meta-regression analysis did not detect significant effect of any of the predefined variables including prescribed or applied dose, type of epidemiological study (randomised controlled trials versus subgroups of randomised trials) or risk of bias (Table 5).
In addition to mortality, several of the randomised studies included in the review assessed other clinical outcomes. However, the heterogeneity of measures used did not allow the conducting of a statistical synthesis.
The haemodynamic effect of haemofiltration was assessed in seven randomised studies (8,14,58-62). One (61) reported a higher proportion of 'responders' (defined as a decreased noradrenaline dose of more than 75% in 24 hours) in the high volume haemofiltration group (P=0.004). The remaining six studies did not find any systematic benefit of haemofiltration on the haemodynamic parameters or vasopressor support.
Pulmonary function was examined in five randomised studies (16,24,59,61,62). No association was detected between haemofiltration and [P.sub.a][O.sub.2]/[F.sub.i][O.sub.2] ratio (59,61,62) or duration of mechanical ventilation (16,24). Five studies (8,59-62) reported the effect of haemofiltration on the evolution of MODS. None showed benefit and one reported a more rapid deterioration of the SOFA scores in the experimental group (P=0.027). Length of stay in the intensive care unit or the hospital was reported in six studies (14,16,24,25,61,62) with negative results. The study of Saudan et al (25) reported a tendency (P=0.06) toward a longer intensive care unit stay in the experimental group. Various studies reported adverse effects of the treatment. Payen et al (62) reported a higher incidence and severity of organ failure in the experimental group. The RENAL study (16) reported an increased incidence of hypophosphataemia in the experimental group (P <0.001). The ATN study (14) reported a higher incidence of hypotension requiring vasopressor therapy (P=0.02), hypophosphataemia (P=0.001) and hypokalaemia (P=0.03) in the experimental group.
In contrast to the study of Van Wert (20) which included septic patients with AKI, our study tried to respond to the question of effectiveness of CRRT in relevant clinical outcomes in these patients with or without AKI. Our results suggest that the addition of CRRT or its use at high doses does not improve the clinical outcomes of patients with severe sepsis or septic shock with or without AKI and irrespective of the technique used or the definition of AKI. Albeit conventional haemofiltration, haemofiltration using high cut-off filters, high volume haemofiltration and haemodiafiltration are clearly different, the results are consistent and homogeneous, evidencing a lack of effect. With regard to mortality, only one trial (25) reported a significant reduction in mortality. However this was a small study (based on 28 events) (64), which was stopped early by benefit (28,29,65), which reported an unusual reduction in mortality (risk ratio of 0.31), and that was identified as an outlier in the tree plot (Figure 2) and funnel plot (Figure 3). Therefore, there is a high probability that it was a false positive. After exclusion of this trial, the heterogeneity was greatly reduced and the pooled relative risk was 1.
A specific consideration should be done with respect to three studies comparing conservative treatment versus CVVH or high volume haemofiltration (58,62), or in patients without AKI (8) respectively. Although it is doubtful whether these studies should be analysed together due to differences in design, a subgroup analysis did not reveal any subgroup effect.
One concern with our study could be the mixing of different types of renal replacement therapies, specially continuous and intermittent. Only one study (14) included both types of techniques and this issue was specifically addressed in the meta-regression analysis. The effect on mortality did not change if this study was included or not, showing that the schedule of application of renal replacement therapies was not a factor capable to modifying our conclusions.
With respect to other outcomes such as improvement in haemodynamic status or pulmonary oxygenation, much of the available evidence comes from animal and non-randomised studies (mainly pre-post studies without external control groups (37-39,41)) not included in this review. However, the evidence based on randomised controlled trials is consistent with that of mortality. Only one study with significant methodological limitations reported a reduction in the use of vasopressors in the experimental group (61), and none of the trials reviewed reported an improvement in gas exchange, duration of mechanical ventilation, development of MODS or length of stay. Respect to other outcomes, two recent meta-analyses (18,20) found no effect of high-dose renal replacement therapy on dialysis dependence or length of stay in patients with AKI.
We did not detect any difference of effect of haemofiltration according to the three groups of doses used. However, only two small studies used doses higher than 65 ml/kg/hour. Therefore our study does not preclude the efficacy of these doses in patients with severe sepsis or septic shock. The dose for attaining a sepsis could very likely be different from the dose used for renal support in AKI. Currently there is an ongoing randomised clinical trial (66) addressing this issue. In any case, the results of our review do not support the routine use of doses higher than 35 ml/kg in patients with severe sepsis with or without AKI.
Similarly, this review is limited to studies comparing high-dose haemofiltration-haemodiafiltration or standard haemofiltration-haemodiafiltration versus traditional dosage or no haemofiltration. Thus, the study results cannot be generalised to other haemofiltration techniques with dialysis (e.g. high adsorption filters, filters of high porosity or plasmapheresis).
A further limitation of our study is that six of the 12 studies which met the inclusion criteria were actually not designed to study patients with severe sepsis and septic shock. These studies evaluated patients with AKI and some had very low numbers of septic patients. Furthermore, these groups of septic patients may not have been defined in the same way across studies. Therefore, the external validity of our study is limited by the scarcity of randomised controlled trials addressing specifically clinical outcomes of renal replacement therapies in septic patients. Indeed, almost all the studies that compared high versus low doses were performed in patients with AKI. The effect of high doses in septic patients without acute kidney injury therefore cannot be fully evaluated until well-designed and powered trials are performed.
Finally, the efficacy of haemofiltration in patients with non-infectious systemic inflammatory response syndrome is beyond the scope of this review. It is possible that patients with systemic inflammatoryresponse syndrome (post-cardiac arrest syndrome (67), severe trauma (68,69), pancreatitis (23), severe burns (44)) experience a massive release of mediators and therefore may benefit from early haemofiltration. In contrast, patients with sepsis undergo haemofiltration at a later stage in the course of the disease. It can be hypothesised that the haemofiltration in patients with sepsis is performed outside the therapeuticwindow when organ damage has already occurred. Further research is needed to address this issue.
The best evidence available does not support the routine use of CRRT in patients with sepsis. Further research is necessary regarding the efficacy of early high-dose CRRT in patients with severe systemic inflammatory response syndrome of non-infectious origin.
Web of knowledge
(Sepsis OR SIRS [topic]) AND (haemofiltration OR renal dialysis OR renal replacement therapy [topic]) AND (mortality OR survival OR organ dysfunction OR arterial pressure OR vasoactive drug OR shock reversal OR hypoperfusion OR lactate [topic])
(Sepsis OR SIRS) AND (haemofiltration OR renal dialysis OR renal replacement therapy) AND (mortality OR survival OR organ dysfunction OR arterial pressure OR vasoactive drug OR shock reversal OR hypoperfusion OR lactate)
SIRS=systemic inflammatory response syndrome.
Dr E. Palencia-Herrejon has received financial support from Baxter Laboratories for attending conferences.
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J. LATOUR-PEREZ *, E. PALENCIA-HERREJON ([dagger]), V. GOMEZ-TELLO([dagger])([dagger]), A. BAEZA-ROMAN ([section]), M. A. GARCIA-GARCIA **, B. SANCHEZ-ARTOLA ([dagger])([dagger])
Intensive Care Unit, Elche University General Hospital, Elche, Spain
* M.D., Ph.D., Specialist in Intensive Care Medicine and Clinical Head.
([dagger]) M.D., Ph.D., Specialist in Intensive Care Medicine and Clinical Head, Intensive Care Unit, Hospital Infanta Leonor, Madrid.
([dagger])([dagger])M.D., Ph.D., Intensivist, Intensive Care Unit, Hospital Moncloa.
([section]) M.D., Resident in Intensive Care Medicine.
** M.D., Specialist in Intensive Care Medicine and Consultant, Intensive Care Unit, Hospital de Sagunt, Sagunto.
([dagger])([dagger]) M.D., Specialist in Intensive Care Medicine and Consultant, Department of Internal Medicine, Hospital Infanta Leonor.
Address for correspondence: Dr V. Gomez-Tello, Hospital Moncloa, Unidad de Cuidados Intensivos, Av. Valladolid, 83 28008 Madrid, Spain.
Accepted for publication on December 2, 2010.
TABLE 1 Search strategy PubMed #1 (SIRS OR systemic inflammatory response syndrome OR infection OR sepsis OR septic shock OR shock) #2 (cardiac arrest OR trauma OR acute pancreatitis OR burns OR acute renal failure) #3 (#1) OR (#2) #4 (renal dialysis OR renal replacement therapy OR haemofiltration OR haemodiafiltration) #5 (mortality OR survival OR organ dysfunction OR arterial pressure OR vasoactive drug OR shock reversal OR hypoperfusion OR lactate) #6 ((#3) AND (#4) AND (#5)) #7 "1995" [pdat] : "2009" [pdat] #8 (Clinical Trial [ptyp] OR Meta-Analysis [ptyp] OR Randomised Controlled Trial [ptyp] OR Comparative Study [ptyp]) #9 ("humans"[MeSH Terms]) #10 (# 6 AND #7 AND #8 AND #9) Embase #1 SIRS OR systemic AND inflammatory AND response AND ("syndrome"/exp OR syndrome) OR "infection"/exp OR infection OR "sepsis"/exp OR sepsis OR septic AND ("shock"/exp OR shock) OR "shock"/exp OR shock OR (cardiac AND arrest OR "trauma"/exp OR trauma OR acute AND ("pancreatitis"/exp OR pancreatitis) OR "burns"/ exp OR burns OR acute AND renal AND failure) AND [1995-2009]/py #2 renal AND ("dialysis"/exp OR dialysis) OR renal AND replacement AND ("therapy"/exp OR therapy) OR "haemofiltration"/exp OR haemofiltration OR "haemodiafiltration"/exp OR haemodiafiltration OR "dialysis'/exp OR dialysis OR "haemodialysis"/exp OR haemodialysis OR dialytic AND [1995-2009]/py #3 "mortality"/exp OR mortality OR "survival"/exp OR survival OR "organ"/exp OR organ AND dysfunction OR arterial AND ("pressure"/exp OR pressure) OR vasoactive AND ("drug"/exp OR drug) OR "shock"/ exp OR shock AND reversal OR "hypoperfusion"/ exp OR hypoperfusion OR "lactate"/exp OR lactate AND [1995-2009]/py #4 #1 AND #2 AND #3 Web of knowledge TABLE 2 Included studies (patients and setting) Study, Patients Country, number year of centres Sander, Surgical Germany, 1 1997 (58) Ronco, AKI (sepsis subgroup) Italy, 1 2000 (9) Bouman, ICU patients with AKI Netherlands, 2 2002 (24) (predominant post- cardiac surgery) (sepsis subgroup) Cole, Sepsis Australia, 1 2002 (8) Morgera, Sepsis Germany, 1 2004 (59) Ghani, Sepsis Malaysia, 1 2006 (60) Saudan, ICU patients with AKI Switzerland, 1 2006 (25) (sepsis subgroup) Tolwani, ICU patients with AKI USA, 1 2008 (26) (sepsis subgroup) ATN, AKI (sepsis subgroup) USA, 27 2008 (14) Boussekey, Septic shock France, 1 2008 (61) Payen, Sepsis France, 12 2009 (62) RENAL, AKI (sepsis subgroup) Australia and 2009 (16) New Zealand, 35 Study, Financial Inclusion criteria year support Sander, Not Sepsis 1997 (58) reported Ronco, Not AKI 2000 (9) reported Bouman, Not Oliguric acute kidney 2002 (24) reported failure plus mechanical ventilation Cole, Mixed Severe sepsis or septic 2002 (8) public- shock private Morgera, Not Sepsis plus acute kidney 2004 (59) reported failure and MODS Ghani, Private Severe sepsis or septic 2006 (60) shock Saudan, Not Clinical diagnosis of acute 2006 (25) reported renal failure Tolwani, Mixed Clinical diagnosis of acute 2008 (26) public- renal failure private ATN, Public Adult patients with AKI 2008 (14) and failure of one or more non-renal organ systems (SOFA score [greater than or equal to] 2) or sepsis Boussekey, Hospital Septic shock with AKI 2008 (61) Payen, Private Severe sepsis or septic 2009 (62) shock <24 h and SAPS score 35-63 RENAL, Mixed Critical adult patients 2009 (16) public- AKI and need for renal private replacement therapy Study, Main exclusion criteria Mean APACHE-II year (predicted mortality) Sander, 1) Age <18 or >80; 2) pregnancy; 14 (18.6%) 1997 (58) 3) recent sepsis; 4) chronic renal failure; 5) contraindications against systemic anticoagulation; 6) immunosuppression or immunodeficiency Ronco, No informed consent; septic 23 (46.0%) 2000 (9) shock (63) Bouman, 1) Previous renal failure; 2) 23 (46.0 %) 2002 (24) renal failure not secondary to acute tubular necrosis; 3) severe comorbidity (post-cardiac arrest encephalopathy, AIDS, grade-C cirrhosis) Cole, 1) End-stage renal failure; 2) 22 (42.4%) 2002 (8) malignancy; 3) AIDS; 4) life expectancy <6 months; 5) possible life support withdrawal Morgera, Not reported 31 (%) 2004 (59) Ghani, 1) end-stage renal disease; 2) Not reported 2006 (60) malign neoplasm; 3) AIDS; 4) life expectancy <6 months Saudan, 1) Pre-or post-renal failure; 2) 25 (53.3%) 2006 (25) Suspicion of glomerular disease; 3) end-stage renal failure; 4) patients on angiotensin- converting enzyme inhibitors Tolwani, 1) End-stage renal disease; 2) 26 (56.9%) 2008 (26) previous intermittent haemodialysis; 3) >24 h of CRRT at time of enrollment; 4) Body weight >125 kg or <50 kg ATN, 1) advanced nephropathy; 2) 26 (56.9%) 2008 (14) acute kidney failure not due to acute tubular necrosis; 3) >72 h from the beginning of the AKI and BUN >100 mg/dl Boussekey, 1) Severe chronic renal failure; 32 (76.0%) 2008 (61) 2) patients included in another study; 3) severe immunosuppression; 4) moribund; limitation of therapy; septic shock or renal failure >5 days after ICU admission; 5) absence of written consent; 6) patients who died within the first day after randomisation Payen, 1) Pregnancy; 2) age <18; 3) Not reported 2009 (62) moribund; 4) chronic renal failure; 5) immunosuppression RENAL, Previous dialysis, chronic APACHE-III 102 2009 (16) dialysis, moribund, weight <60 (approximate or >100-120 kg mortality 70-80%) APACHE=Acute Physiology and Chronic Health Evaluation score, AKI=acute kidney injury, ICU=intensive care unit, AIDS=acquired immune deficiency syndrome, MODS=multiple organ dysfunction syndrome, CRRT=continuous renal replacement therapies, SOFA=sequential organ failure assessment, BUN=blood urea nitrogen, SAPS=Simplified Acute Physiology Score. TABLE 3 Renal replacement techniques Study, Renal replacement Blood flow year therapy (ml/min) Sander, CVVH vs no 150 1997 (58) haemofiltration Ronco, HVHF vs CVVH 120-240 2000 (9) Bouman, HVHF vs CVVH 100-200 2002 (24) Cole, CVVH vs no 200 2002 (8) haemofiltration Morgera, CVVHDF vs CVVH Not reported 2004 (59) Ghani, HVHF vs CVVH 250-350 2006 (60) Saudan, CVVHDF vs CVVH 100-125 200625 Tolwani, CVVHDF 100-150 2008 (26) ATN, IHD+SLED (each day) 360 (IHD)/ 2008 (14) + CVVHDF-CVVH 220-210 (CRRT) (high dose) vs IHD + SLED (alternate days) + CVVHDF-CVVH (standard dose) Boussekey, HVHF (very high dose) vs 180-300 2008 (61) CVVH (high dose) Payen, CVVH vs no 150 2009 (62) haemofiltration RENAL, CVVHDF >150 2009 (16) Study, Dose prescribed Dose applied year Sander, 1 l/h Not recorded 1997 (58) Ronco, 35/45 vs 20 ml/kg/h 33, 6/42, 4 vs 18, 2000 (9) 9 ml/kg/h Bouman, 72/96 vs 24/36 l/24 h 48.2 vs 19.5 ml/kg/h 2002 (24) Cole, 2 l/h Not reported 2002 (8) Morgera, 2.5 vs 1 l/h Not reported 2004 (59) Ghani, 100 ml/kg/h (or 6 l/h) Not reported 2006 (60) 6 h vs 2 l/h (35 ml/kg/h approx) Saudan, 42 ml/kg/h (CVVHDF) 34.9 vs 21.8 ml/kg/h 200625 vs 25 ml/kg/h (CVVH) Tolwani, 35 ml/kg/h 29 vs 17 ml/kg/h 2008 (26) ATN, Kt/V >1.2 (IHD) + 36, Kt/V 1, 32 (IHD) + 35, 2008 (14) 2 ml/kg/h (CRRT) vs 8 ml/kg/h (CRRT) vs Kt/V >1.2 (IHD) + 21, Kt/V 1, 31 (IHD) + 22, 5 ml/kg/h (CRRT) 0 ml/kg/h (CRRT) Boussekey, 65 vs 35 ml/kg/h 62 vs 32 ml/kg/h 2008 (61) Payen, 25 ml/kg/h 24, 7 ml/kg/h 2009 (62) RENAL, 40 vs 25 ml/kg/h 33.4 vs 22.0 ml/kg/h 2009 (16) Study, Filter ([m.sup.2]) Anticoagulation year Sander, PAN (0.6 [m.sup.2]) Heparin 1997 (58) Ronco, Polysulfone Heparin 2000 (9) (0.7-1.3 [m.sup.2]) Bouman, Cellulose Heparin/nadroparin/no 2002 (24) triacetate (1.9 [m.sup.2]) Cole, PAN (1.2 [m.sup.2]) Heparin (regional) 2002 (8) Morgera, Polyamide Heparin 2004 (59) (1.1 [m.sup.2]) Ghani, Polysulfone Heparin/no 2006 (60) (1.4 [m.sup.2]) Saudan, PAN (0.9 [m.sup.2]) Not reported 200625 Tolwani, PAN (0.9 [m.sup.2]) No/citrate 2008 (26) ATN, Various No/heparin/citrate 2008 (14) (polysulfone, PAN) Boussekey, Polysulfone No/heparin 2008 (61) (1.4 [m.sup.2]) Payen, Polysulfone Heparin 2009 (62) (1.2 [m.sup.2]) RENAL, PAN 48% heparin 2009 (16) prefilter, 19% heparin+protamine, 49% no anticoagulation Study, Reposition Substitution year fluid Sander, Not reported Ringer 1997 (58) Ronco, Postdilution Lactate 2000 (9) Bouman, Postdilution Bicarbonate 2002 (24) Cole, Predilution Lactate 2002 (8) Morgera, Postdilution Bicarbonate 2004 (59) Ghani, Pre and Bicarbonate 2006 (60) postdilution (1/2) Saudan, Predilution Bicarbonate 200625 Tolwani, Predilution Not 2008 (26) reported ATN, Predilution Bicarbonate 2008 (14) dominant (except citrate) Boussekey, Pre (1/3) or Bicarbonate 2008 (61) postdilution (2/3) Payen, Not recorded Bicarbonate 2009 (62) RENAL, Postdilution Bicarbonate 2009 (16) CVVH=continuous veno-venous haemofiltration, PAN=polyacrylonitrile, HVHF=high-volume haemofiltration, CVVHDF=continuous veno-venous haemodiafiltration, IHD=intermittent haemodialysis, SLED=sustained low-efficiency dialysis, CRRT=continuous renal replacement therapy. TABLE 4 Included studies (risk of bias) * Study Design Random Concealed list randomisation generation Sander, Randomised Unclear Unclear 1997 (58) study Ronco, Subgroup of Unclear Unclear 2000 (9) randomised controlled trial Bouman, Subgroup of Unclear Unclear 2002 (24) randomised controlled trial Cole, Randomised Yes Yes 2002 (8) study Morgera, Randomised Unclear Unclear 2004 (59) study Ghani, Randomised Unclear Unclear 2006 (60) study Saudan, Subgroup of Yes Yes 2006 (25) randomised controlled trial Tolwani, Subgroup of Yes Yes 2008 (26) randomised controlled trial ATN, Subgroup of Yes Yes 2008 (14) randomised controlled trial Boussekey, Randomised Unclear Unclear 200861 study Payen, Randomised Yes Unclear 2009 (62) study RENAL, Subgroup of Yes Yes 2009 (16) randomised controlled trial Study Attritions- Other domains exclusions addressed Sander, No # No: baseline misbalance favouring 1997 (58) experimental group. High control group mortality (92%). Sub-dosage in the experimental group Ronco, Unclear No: undefined population. 2000 (9) ([dagger]) Misbalanced groups. High control group mortality (expected 42%, observed 75%). Unusual definition of mortality Bouman, Yes Unclear: misbalanced groups 2002 (24) Cole, Yes Unclear: small study. Sub-dosage 2002 (8) in the experimental group Morgera, Yes Unclear: misbalanced groups 2004 (59) Ghani, Yes No: misbalanced groups. High 2006 (60) control group mortality Saudan, Yes No: early stopped by benefit 2006 (25) Tolwani, Yes No: misbalanced groups (higher 2008 (26) proportion of mechanical ventilation in the experimental group); sub-dosage in both arms ATN, Yes Unclear: late initiation of 2008 (14) haemofiltration. Low renal recovery rate. Relative high doses in the experimental group Boussekey, No No: misbalanced groups. Relative 200861 low mortality in the experimental group Payen, Yes Unclear: early stopped by harm 2009 (62) RENAL, Yes Yes 2009 (16) Study Statistical power Jadad's (to detect a scale 20% mortality score reduction) Sander, 26% 2 1997 (58) Ronco, 19% 2 2000 (9) Bouman, 14% 2 2002 (24) Cole, 6% 3 2002 (8) Morgera, 8% 2 2004 (59) Ghani, 18% 2 2006 (60) Saudan, 39% 3 2006 (25) Tolwani, 36% 3 2008 (26) ATN, 80% 3 2008 (14) Boussekey, 8% 2 200861 Payen, 15% 2 2009 (62) RENAL, 79% 3 2009 (16) * All the studies were non-blinded. No serious selective reporting was detected. # Results analysed in this review as intention to treat. ([dagger]) No-specified exclusion of septic shock patients: see Piccinni 2006 (63). TABLE 5 Subgroup effect (meta-regression analysis) Relative odds Residual Variable ratio P [I.sup.2] CRRT dose experimental group 0.576 0.237 55.3% (prescribed) (>65/35-65/<35 ml/kg/h) CRRT dose experimental group 0.998 0.955 60.5% (prescribed) (continuous variable) CRRT dose experimental group (applied) 0.982 0.644 70.4% (continuous variable) CRRT control group (yes vs no) 0.868 0.840 59.7% APACHE-II score control group 1.065 0.514 65.7% (continuous variable) Type of study (RCT sepsis subgroup) 0.879 0.824 60.0% (yes vs no) Random list generation 0.899 0.856 60.3% (yes/unclear/no) Concealed randomisation 0.697 0.515 59.3% (yes/unclear/no) No post/randomisation exclusions 1.795 0.196 55.5% (yes/unclear/no) Other (yes/unclear/no) 1.686 0.185 60.3% Jadad's scale (continuous variable) 0.697 0.515 59.3% Year of publication 1.02 0.791 60.1% (continuous variable) Financial support 1.38 0.551 51.9% (disclosed/not disclosed) CRRT=continuous renal replacement therapy, APACHE=Acute Physiology and Chronic Health Evaluation, RCT=randomised controlled trial. FIGURE 2: Forest plot (all studies). RR=relative risk, CI=confidence interval. Events, Events, Study Year RR (95% CI) treatment control % weight Traditional dose 0.79 (0.56, 1.12) 11/15 12/13 10.40 (<35 ml/kg/h) 1997 Sander Cole 2002 1.00 (0.32, 3.10) 4/12 4/12 1.67 Payen 2009 1.29 (0.82, 2.03) 22/39 17/39 7.51 Sub-total 0.99 (0.66, 1.48) 37/66 33/64 19.57 ([I.sup.2]=44.2%, P=0.167) High dose (35-65 ml/kg/h) Ronco 2000 092 (0.65, 1.29) 22/32 15/20 10.36 Bauman 2002 2.00 (0.78, 5.14) 8/14 4/14 2.32 Morgera 2004 2.00 (0.82, 4.89) 8/12 4/12 2.56 Saudan 2006 0.31 (0.15, 0.63) 7/37 21/34 3.74 Tolwani 2008 1.09 (0.83, 1.43) 37/54 34/54 12.90 ATN 2008 1.08 (0.95, 1.24) 204/358 184/350 18.83 RENAL 2009 0.91 (0.79, 1.06) 168/359 186/363 18.20 Sub-total 0.98 (0.80, 1.21) 454/866 448/847 68.90 ([I.sup.2]=67.3%, P=0.005) Very high dose (>65 ml/kg/h) Ghani 2006 0.88 (0.61, 1.27) 11/15 15/18 9.62 Boussekey 2008 0.56 (0.19, 1.59) 3/9 6/10 1.91 Sub-total 0.84 (0.59, 1.19) 14/24 21/28 11.52 ([I.sup.2]=0.0%, P=0.376) Sub-total 0.96 (0.83, 1.12) 505/956 502/939 100.00 ([I.sup.2]=51.7%, P=0.019)
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