Blood Purification and Mortality in Sepsis and Septic Shock

A Systematic Review and Meta-analysis of Randomized Trials

Alessandro Putzu, M.D.; Raoul Schorer, M.D.; Juan Carlos Lopez-Delgado, M.D., Ph.D.; Tiziano Cassina, M.D.; Giovanni Landoni, M.D.

Disclosures

Anesthesiology. 2019;131(3):580-593. 

In This Article

Results

Search Results and Study Characteristics

The search strategy identified 6,933 citations and, after exclusion of inadequate reports (Supplemental Digital Content, table S3, http://links.lww.com/ALN/B977), 37 trials with 2,499 patients were included in the meta-analysis (Figure 1).[17,28–63]

Figure 1.

Flow diagram for the selection of studies. PRISMA, Preferred Reporting Items Systematic Reviews and Meta-Analysis.

The characteristics of the included studies are shown in Table 1 and in the supplement (Supplemental Digital Content, tables S4-S6, http://links.lww.com/ALN/B977). Two trials had four treatment arms.[43,58] Twenty trials used a hemoperfusion technique, 13 used hemofiltration or hemodiafiltration, 4 trials combined hemofiltration with hemoperfusion, and 2 trials used plasma exchange. In three cases we received further information from corresponding authors.[17,59,62]

Three trials were judged to be at low risk of bias,[17,30,46] 20 at unclear risk, and 14 at high risk (Supplemental Digital Content, figs. S1 and S2, http://links.lww.com/ALN/B977). The grading of recommendations assessment, development, and evaluation assessment is reported in table S7 in the Supplemental Digital Content (http://links.lww.com/ALN/B977).

Hemoperfusion Techniques

Hemoperfusion (20 trials and 1,548 patients), which comprises various techniques differing among other things on the presence or absence of polymyxin B in the treatment regimen, was associated with a lower mortality compared to the control group (relative risk = 0.87 [95% CI, 0.78 to 0.98], P = 0.02, trial sequential analysis inconclusive, very low-certainty evidence) the analysis was limited by publication bias, small trial effects, and high heterogeneity (Supplemental Digital Content, figs S3-S5 and table S8, http://links.lww.com/ALN/B977). Subanalyses are reported in the supplement (Supplemental Digital Content, figs. S6—S9 and eResults 1, http://links.lww.com/ALN/B977).

Polymyxin B Immobilized Fiber Column Hemoperfusion. Polymyxin B immobilized fiber column hemoperfusion (13 trials and 1,163 patients) was associated with a lower mortality at longest follow-up available compared to control (relative risk = 0.87 [95% CI, 0.77 to 0.98], P = 0.03, very low-certainty evidence), although the analysis was limited by very high heterogeneity (I2 = 74%, Pheterogeneity < 0.001) (Figure 2). No significant difference in 30-day mortality was found (Supplemental Digital Content, Figure S9, http://links.lww.com/ALN/B977).

Figure 2.

Forest plot of the relative risk of mortality at longest follow up available with polymyxin B-immobilized fiber column hemoperfusion. Various subanalyses are also reported. M-H, Mantel-Haenszel; PMX-HP, polymyxin B immobilized fiber column hemoperfusion.

Low risk of bias trials (three trials and 745 patients) found no difference in mortality with polymyxin B immobilized fiber column hemoperfusion versus control (relative risk = 1.14 [95% CI, 0.96 to 1.36], P = 0.12, moderate-certainty evidence; Figure 2). Recent trials published after 2010 (three trials and 740 patients) showed that polymyxin B immobilized fiber column hemoperfusion was associated with higher mortality than conventional therapy (relative risk = 1.22 [95% CI, 1.03 to 1.45], P = 0.02, I2 = 0%, low-certainty evidence), while trials published before 2011 were associated with a mortality benefit (relative risk = 0.58 [95% CI, 0.49 to 0.69], P < 0.001, I2 = 8%; Pgroups < 0.001). Studies conducted in Asia (seven trials in Japan and one in Thailand, with a total of 367 patients) showed that polymyxin B immobilized fiber column hemoperfusion decreased mortality (relative risk = 0.62 [95% CI, 0.52 to 0.75], P < 0.001, I2 = 57%, Pheterogeneity = 0.02), while aggregate data from trials conducted in the United States and Europe (five trials and 796 patients) found no difference (relative risk = 1.11 [95% CI, 0.94 to 1.32], P = 0.21, I2 = 50%, Pheterogeneity = 0.09), (Pgroups < 0.001). Similarly, when excluding trials performed in Japan by the Nakamura group (five trials and 162 overall patients), polymyxin B immobilized fiber column hemoperfusion was associated with no difference in mortality compared to conventional therapy (relative risk = 0.98 [95% CI, 0.86 to 1.12], P = 0.80; Supplemental Digital Content, figs. S10-S13, http://links.lww.com/ALN/B977).

Hemoperfusion with Other Devices. Hemoperfusion with devices other than polymyxin B–immobilized filter column (seven trials and 385 patients) was not associated with a difference in mortality compared to conventional therapy (relative risk = 0.81 [95% CI, 0.53 to 1.21], P = 0.30, very low-certainty evidence). The hemoperfusion devices included were Adsorba-300 filter (one trial, relative risk = 0.50 [95% CI, 0.22 to 1.14], P = 0.10); Alteco endotoxin hemoadsorber (one trial, relative risk = 0.57 [95% CI, 0.06 to 5.03], P = 0.61); CytoSorb (two trials, relative risk = 0.94 [95% CI, 0.14 to 6.49], P = 0.95); HA330 resin cartridge (two trials, relative risk = 0.61 [95% CI, 0.31 to 1.19], P = 0.15); and Matisse EN 500 endotoxin adsorber (one trial, relative risk = 1.13 [95% CI, 0.66 to 1.96], P = 0.65; Supplemental Digital Content, Figure S3, http://links.lww.com/ALN/B977).

Hemofiltration Techniques

The use of hemofiltration with a blood purification aim was associated with lower mortality compared to control (relative risk = 0.79 [95% CI, 0.63, 1.00], P = 0.05, trial sequential analysis inconclusive, very low-certainty evidence) in 13 trials and 596 patients without acute kidney injury requiring renal replacement therapy (Figure 3 and Supplemental Digital Content, Figure S14, http://links.lww.com/ALN/B977). On subgroup analysis, hemofiltration was not associated with a difference in mortality in trials conducted in Europe and the United States (relative risk = 0.94 [95% CI, 0.74 to 1.19], P = 0.61, I2 = 0%, five trials and 223 patients) but was associated with a decrease in mortality in trials conducted in Asia (relative risk = 0.58 [95% CI, 0.40 to 0.82], P = 0.002, I2 = 0%, eight trials and 373 patients; Pgroups = 0.02); other analyses are reported in the supplement (Supplemental Digital Content, figs. S15-S18, table S9 and eResults 2, http://links.lww.com/ALN/B977).

Figure 3.

Forest plot of the relative risk of mortality at the longest follow-up available with hemofiltration, combined hemofiltration and hemoperfusion, or plasmapheresis. Blood purif., blood purification; M-H, Mantel-Haenszel.

Combined Hemofiltration and Hemoperfusion Techniques

The association of hemoperfusion and hemofiltration was not associated with a significant difference in mortality compared to control (relative risk = 0.63 [95% CI, 0.36 to 1.13], P = 0.12, trial sequential analysis inconclusive, very low-certainty evidence) in four trials including a total of 247 patients without acute kidney injury requiring renal replacement therapy (Figure 3).

Plasmapheresis Techniques

Plasmapheresis was associated with a lower mortality compared to standard treatment (relative risk = 0.63 [95% CI, 0.42 to 0.96], P = 0.03, trial sequential analysis inconclusive, very low-certainty evidence) with two trials and 128 patients included (Figure 3).

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