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Intensity of continuous renal replacement therapies in
patients with severe sepsis and septic shock: a systematic review and
meta-analysis.
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| Abstract: |
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
of interventions. 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 |
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| Article Type: | Report |
| Subject: | Sepsis (Care and treatment) |
| Authors: |
Latour-Perez, J. Palencia-Herrejon, E. Gomez-Tello, V. Baeza-Roman, A. Garcia-Garcia, M.A. Sanchez-Artola, B. |
| Pub Date: | 05/01/2011 |
| 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 |
| Accession Number: | 260691509 |
| Full Text: |
Severe sepsis and septic shock carry a high mortality and account
for a large proportion of patients admitted to intensive care units
(1-4). 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. Statistical methods 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. RESULTS 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). Other outcomes 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. DISCUSSION 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. CONCLUSION 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]) Clinicaltrials.gov (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. FINANCIAL DECLARATION Dr E. Palencia-Herrejon has received financial support from Baxter Laboratories for attending conferences. REFERENCES (1.) 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Hemofiltration increases IL-6 clearance in early systemic inflammatory response syndrome but does not alter IL-6 and TNF alpha plasma concentrations. Intensive Care Med 1997; 23: 878-884. (59.) Morgera S, Slowinski T, Melzer C, Sobottke V, Vargas-Hein O, Volk T et al. Renal replacement therapy with high-cutoff hemofilters: impact of convection and diffusion on cytokine clearances and protein status. Am J Kidney Dis 2004; 43: 444-453. (60.) Ghani RA, Zainudin S, Ctkong N, Rahman AFA, Wafa SRWSH, Mohamad M et al. Serum IL-6 and IL-1-ra with sequential organ failure assessment scores in septic patients receiving high-volume haemofiltration and continuous venovenous haemofiltration. Nephrology (Carlton) 2006; 11: 386-393. (61.) Boussekey N, Chiche A, Faure K, Devos P, Guery B, d'Escrivan T et al. A pilot randomized study comparing high and low volume hemofiltration on vasopressor use in septic shock. Intensive Care Med 2008; 34: 1646-1653. (62.) Payen D, Mateo J, Cavaillon JM, Fraisse F, Floriot C, Vicaut E. Impact of continuous venovenous hemofiltration on organ failure during the early phase of severe sepsis: a randomized controlled trial. Crit Care Med 2009; 37: 803-810. (63.) Piccinni P, Ronco C. Early isovolemic hemofiltration in oliguric patients with septic shock [author reply]. Intensive Care Med 2006; 32: 1097. (64.) Pogue J, Yusuf S. Overcoming the limitations of current meta-analysis of randomised controlled trials. Lancet 1998; 351: 47-52. (65.) Bassler D, Briel M, Montori VM, Lane M, Glasziou P, Zhou Q et al. Stopping randomized trials early for benefit and estimation of treatment effects: systematic review and meta regression analysis. JAMA 2010; 303: 1180-1187. (66.) Haemofiltration Study: IVOIRE (High Volume in Intensive Care). From http://www.clinicaltrials.gov/ct2/show/ NCT00241228?term = IVOIRE&rank=1 Accessed August 2010. (67.) Laurent I, Adrie C, Vinsonneau C, Cariou A, Chiche J-D, Ohanessian A et al. High-volume hemofiltration after out-of-hospital cardiac arrest: a randomized study. J Am Coll Cardiol 2005; 46: 432-437. (68.) Sanchez-Izquierdo JA, Perez Vela JL, Lozano Quintana MJ, Alted Lopez E, Ortuno de Solo B, Ambros Checa A. Cytokines clearance during venovenous hemofiltration in the trauma patient. Am J Kidney Dis 1997; 30: 483-488. (69.) Sanchez-Izquierdo RJA, Alted E, Lozano MJ, Perez JL, Ambros A, Caballero R. Influence of continuous hemofiltration on the hemodynamics of trauma patients. Surgery 1997; 122: 902-908. 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. Email: vgtello@gmail.com 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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