|Effectiveness of polymyxin B-immobilized fiber column in sepsis: a systematic review
|Cruz D N, Perazella M A, Bellomo R, de Cal M, Polanco N, Corradi V, Lentini P, Nalesso F, Ueno T, Ranieri V M, Ronco C
The authors described the effect of direct haemoperfusion with polymixin B-immobilized fiber column (PMX-F) on clinical outcomes in patients with sepsis. The authors concluded that treatment appeared to have beneficial effects on blood pressure, use of vasoactive drugs, oxygenation and mortality. Limitations of the included studies and the review methodology mean that the results may not be reliable.
To describe the effect of direct haemoperfusion with polymixin B-immobilized fiber column (PMX-F) on blood pressure, use of vasoactive drugs, oxygenation and mortality in patients with sepsis.
PubMed and the Cochrane Collaboration Database (to April 2006) were searched. The search terms used were listed in the review. The search was supplemented by electronic searches of the names of people who had authored relevant papers and handsearches of bibliographies of identified papers, consultation with experts and contact with industry.
Although the authors stated that no language restriction was applied to the search, only papers published in English, Japanese or Italian were eligible for inclusion.
Prospective and retrospective observational studies, pre- and post-intervention design and randomised controlled trials (RCTs) with at least five patients in the intervention group were eligible for inclusion.
Studies of patients treated with PMX-F were eligible for inclusion. In the included parallel group studies, direct haemoperfusion with PMX-F (DHP-PMX) was compared to conventional medical therapy. In the included studies, DHP-PMX contained 5 mg of PMX per gram of polystyrene fiber and with a priming volume of 135 mL DHP-PMX was performed for two hours at a blood flow rate of 50 to 150 mL/minute between one and three times, depending on the patient's response. Subsequent treatments were performed 24 hours after the previous treatment. Where specified, either nafamostat mesylate and unfractionated or low-molecular-weight heparin were used as the anticoagulant. In the included studies, the comparison therapy was one or more of: antibiotic therapy; gamma-globulins; vasopressors; haemodynamic monitoring; organ support in the intensive care unit, including mechanical ventilation; corrective measures for metabolic abnormalities, surgery or renal replacement therapy. For mortality outcomes, studies with any comparable group of patients in an intensive care unit who were not treated with PMX-F were eligible for inclusion.
Participants were patients with sepsis. In the included studies the Acute Physiology and Chronic Health Evaluation (APACHE) score of included patients, where stated, ranged from 8.8 to 28.5. Mean age, where stated, ranged from 39 to 78.5 years. The proportion of males, where stated, ranged from 20 per cent to 85.7 per cent. The proportion of patients with identified gram-negative infection ranged from 37.9 per cent to 100 per cent.
Outcome inclusion criteria were the reporting of at least one of the following outcomes: mean arterial pressure (MAP); doses of vasoactive agents; arterial partial pressure of oxygen/fraction of inspired oxygen (PaO2/FiO2) ratios; endotoxin levels; and mortality. In the included studies, death was determined at the end of follow-up (14 to 60 days).
Three reviewers independently selected the studies to be included in the review. Discrepancies were resolved by discussion.
Assessment of study quality
Three reviewers independently assessed trial quality using the Jadad scale, which measures allocation concealment, randomisation, blinding, withdrawals and dropouts.
Because of the poor reporting of outcomes in the studies, the review authors chose to estimate the change in outcomes following DHP-PMX treatment for all outcomes other than mortality instead of the difference in outcomes between patients treated with DHP-PMX and those treated with placebo. The post-PMX-F outcome measures used in the analysis were those made 24 to 48 hours after the last PMX-F treatment. For mortality outcomes, relative risks were extracted.
Where the data required for inclusion in the meta-analysis could not be extracted from a paper, the authors of the original study were contacted. If the study authors did not respond, the reviewers calculated the mean change and variance from confidence intervals (CIs), standard deviations and p values reported in the manuscript. If the variance of the estimates of change from the primary analysis were missing, this was imputed assuming a correlation of 0.5 between the two periods (where the data were complete, the observed correlation was 0.59; range 0.05 to 0.93).
Three reviewers independently abstracted the data from the included studies. Discrepancies were resolved by discussion.
Methods of synthesis
Data from parallel and before/after studies were combined using random-effects meta-analysis, with each study weighted by the inverse of the variance of the effect estimate. The outcome measures were weighted mean differences for continuous outcome data and pooled relative risks for dichotomous outcome data. Statistical heterogeneity between studies was estimated by Χ2 test.
Sensitivity analyses were used to investigate the effects of study design, sample size, type of infection (gram-positive or gram-negative), imputed values for the correlation coefficient, study centre and the baseline outcome measures.
Funnel plots were used to assess the possibility of publication bias.
Results of the review
Twenty eight studies (1,425 participants) were included in the review. There were nine RCTs (474 participants), seven non-RCT parallel studies (566 participants) and 12 before/after studies (385 participants).
The overall quality of the included studies was judged by the reviewers as poor. The funnel plots showed some evidence of publication bias for mean arterial pressure and mortality.
Effect on mean arterial pressure (12 studies): PMX-F was associated with a significant increase in mean arterial pressure (weighted mean difference was 19 mmHg, 95% CI: 15 to 22 mmHg, p<0.001). There was significant heterogeneity between studies (p<0.001).
Effect on dose of vasoactive agents (four studies): PMX-F was associated with a significant decrease in dopamine/dobutamine dose (weighted mean difference was 1.8 μg/kg/minute, 95% CI: 0.4 to 3.3 μg/kg/minute, p=0.01).
Effect on PaO2/FiO2 ratio (seven studies): PMX-F was associated with an increase in PaO2/FiO2 ratio (weighted mean difference was 32 units, 95% CI: 23 to 41 units, p<0.001).
Effect on endotoxin level (17 studies): PMX-F was associated with a decrease in endotoxin level (weighted mean difference was -21.2 pg/mL, 95% CI: -24.9 to -17.5 pg/mL, p<0.001). There was significant heterogeneity between studies (p<0.001).
Effect on mortality (15 studies): PMX-F was associated with a reduction in mortality risk (relative risk was 0.53, 95% CI: 0.43 to 0.65).
Two studies reported adverse events associated with PMX-F: clotting of the device in 4/21 filter cartridges; and hypersensitivity (erythema) in 2/35 patients. No adverse events relating to nephrotoxicity or neurotoxicity were reported in any of the studies.
Sensitivity analyses showed that the results were robust to the assumed before/after correlation of outcomes.
Direct haemoperfusion with PMX-F appeared to have beneficial effects on mean arterial pressure, dopamine use, PaO2/FiO2 ratio and mortality.
The review addressed a clearly defined study question. The authors appeared to make changes to the eligibility of studies after the search was completed (such as the comparison group for the studies on mortality). This could have lead to subjective decisions being made, and hence reduced the reliability of the results. The authors conducted a validity assessment using the Jadad scale, which was appropriate only for RCTs and yet they appeared to use the same scale for observational studies. Therefore, the statement that the included studies were of poor quality was not fully justified.
The decision by the review authors to analyse before/after differences in outcomes from studies that were designed as controlled parallel studies was unusual, and rendered the results of the review questionable. The authors pooled results from different study designs, which was not appropriate. Given that the almost all the studies were conducted in Japan, the generalisability of the results to other countries was questionable.
The limitations of the review mean that the results may not be reliable.
Implications of the review for practice and research
Practice: The authors did not state any implications for practice.
Research: An adequately powered clinical trial was required to confirm the results of the review. Specific questions to be addressed were whether patients with MRSA infections benefited from PMX-F and the optimal timing of treatment. Further investigation was required of the possible benefit in adult respiratory distress syndrome or acute lung injury, the effect of PMX-F on acute kidney injury and the need for renal replacement therapy.
The work was funded through a fellowship from the International Society of Nephrology.
Cruz D N, Perazella M A, Bellomo R, de Cal M, Polanco N, Corradi V, Lentini P, Nalesso F, Ueno T, Ranieri V M, Ronco C. Effectiveness of polymyxin B-immobilized fiber column in sepsis: a systematic review. Critical Care 2007; 11(2): R47
Subject indexing assigned by CRD
Adult; Aged; Cardiotonic Agents /administration & Dobutamine /administration & Dopamine /administration & Endotoxins /blood; Hemoperfusion /adverse effects /instrumentation /methods; Humans; Middle Aged; Polymyxin B; Sepsis /blood /mortality /therapy; Survival Rate; Treatment Outcome; dosage; dosage; dosage
Date bibliographic record published
Date abstract record published
This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.