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Survival Benefits of Therapeutic Plasma Exchange in Severe Sepsis and Septic Shock: A Systematic Review and Meta-analysis
Lee OPE, Kanesan N, Leow EH, Sultana R, Chor YK, Gan CS, Lee JH
Journal of intensive care medicine. 2023;:8850666231170775
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Editor's Choice
Abstract
OBJECTIVES To summarize the role of therapeutic plasma exchange (TPE) in critically ill adults and children with severe sepsis. DATA COLLECTION A systematic search was performed using the following databases: Medline, EMBASE, CINAHL, and Cochrane from January 1990 till December 2022. Comparative studies of TPE in severe sepsis were selected. Adult and pediatric data were analyzed separately. DATA SYNTHESIS Eight randomized control trials and 6 observational studies (n = 50,142 patients) were included. Centrifugal TPE was the most common modality (209/280, 74.6% adults and 952/1026, 92.7% children). Every TPE study utilized different volume exchanges. Most TPE sessions (1173/1306, 89.8%) employed fresh frozen plasma (FFP) as replacement fluid and heparin as anticoagulant. Adults with severe sepsis supported with TPE using FFP had lower mortality (risk ratio, RR: 0.64 [95% confidence interval, CI: 0.49, 0.84]) compared to those who did not. In contrast, TPE was associated with increased mortality in septic children without thrombocytopenia-associated multiorgan failure (RR: 2.23, 95% CI: 1.93, 2.57). There was no difference in outcomes in patients supported with centrifugal and membrane TPE. In both populations, patients supported on TPE as a continuous regime had poorer outcome. CONCLUSION Current evidence indicates that TPE is a potential adjunct therapy in adults with severe sepsis but not in children.
PICO Summary
Population
Critically ill adults and children with severe sepsis or septic shock (14 studies, n= 50,142).
Intervention
Therapeutic plasma exchange (TPE) alone, or in combination with hemofiltration, hemadsorption, or conventional treatment of sepsis.
Comparison
Various comparators, including: other forms of blood purification therapy, immunomodulation and conventional treatment.
Outcome
Centrifugal TPE was the most common modality (209/280, 74.6% adults and 952/1,026, 92.7% children). Every TPE study utilized different volume exchanges. Most TPE sessions (1,173/1,306, 89.8%) employed fresh frozen plasma (FFP) as replacement fluid and heparin as anticoagulant. Adults with severe sepsis supported with TPE using FFP had lower mortality (risk ratio (RR), 0.64 [95% confidence interval (CI) [0.49, 0.84]) compared to those who did not. In contrast, TPE was associated with increased mortality in septic children without thrombocytopenia-associated multiorgan failure (RR, 2.23; 95% CI [1.93, 2.57]). There was no difference in outcomes in patients supported with centrifugal and membrane TPE. In both populations, patients supported on TPE as a continuous regime had poorer outcome.
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Blood Purification for Adult Patients With Severe Infection or Sepsis/Septic Shock: A Network Meta-Analysis of Randomized Controlled Trials
Chen, J. J., Lai, P. C., Lee, T. H., Huang, Y. T.
Critical care medicine. 2023
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Abstract
OBJECTIVES This study aimed to conduct a comprehensive and updated systematic review with network meta-analysis (NMA) to assess the outcome benefits of various blood purification modalities for adult patients with severe infection or sepsis. DATA SOURCES We conducted a search of PubMed, MEDLINE, clinical trial registries, Cochrane Library, and Embase databases with no language restrictions. STUDY SELECTION Only randomized controlled trials (RCTs) were selected. DATA EXTRACTION The primary outcome was overall mortality. The secondary outcomes were the length of mechanical ventilation (MV) days and ICU stay, incidence of acute kidney injury (AKI), and kidney replacement therapy requirement. DATA SYNTHESIS We included a total of 60 RCTs with 4,595 participants, comparing 16 blood purification modalities with 17 interventions. Polymyxin-B hemoperfusion (relative risk [RR]: 0.70; 95% CI, 0.57-0.86) and plasma exchange (RR: 0.61; 95% CI, 0.42-0.91) were associated with low mortality (very low and low certainty of evidence, respectively). Because of the presence of high clinical heterogeneity and intransitivity, the potential benefit of polymyxin-B hemoperfusion remained inconclusive. The analysis of secondary outcomes was limited by the scarcity of available studies. HA330 with high-volume continuous venovenous hemofiltration (CVVH), HA330, and standard-volume CVVH were associated with shorter ICU stay. HA330 with high-volume CVVH, HA330, and standard-volume CVVH were beneficial in reducing MV days. None of the interventions showed a significant reduction in the incidence of AKI or the need for kidney replacement therapy. CONCLUSIONS Our NMA suggests that plasma exchange and polymyxin-B hemoperfusion may provide potential benefits for adult patients with severe infection or sepsis/septic shock when compared with standard care alone, but most comparisons were based on low or very low certainty evidence. The therapeutic effect of polymyxin-B hemoperfusion remains uncertain. Further RCTs are required to identify the specific patient population that may benefit from extracorporeal blood purification.
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An inquiry into the treatment of sepsis using plasma exchange therapy: A systematic review and meta-analysis
Zhang L, Zhao XY, Guo SY, Jiang J, Wang G, Weng YB
International wound journal. 2023
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Abstract
Sepsis is a potentially lethal condition that occurs when the body's response to infection damages tissue and organs. The production of inflammatory mediators typically assists in defending the body against infection; however, an overreaction to inflammation can cause coagulation problems, vascular endothelial damage, and organ hypoperfusion. Blood purification methods, such as plasmapheresis, can effectively remove inflammatory mediators from plasma. The purpose of this meta-analysis was to explore the efficacy of plasma exchange for sepsis treatment as noted in recent studies. The authors searched the Pubmed (Medline), Cochrane Central Register of Controlled Trials (The Cochrane Library), Embase (Ovid), and Scopus databases and included controlled clinical studies that compared plasmapheresis or plasma filtration with conventional treatment in patients with severe sepsis. The Newcastle-Ottawa Scale literature quality assessment tool was used to assess the risk of bias. The primary study outcome was all-cause mortality. The random effects model was adopted for conducting the meta-analysis. Among the 1013 records found, the study included 5 trials, all of which carried a low risk of bias. The use of plasmapheresis was associated with a longer stay in the intensive care unit (odds ratio [OR], 0.85, 95% confidence interval [CI], 0.39-1.32, heterogeneity [I(2) ] = 0%), a significant reduction in all-cause mortality (OR, 0.54, 95% CI, 0.33-0.89, I(2) = 70%), and reduced mortality (OR, 0.29, 95% CI, 0.13-0.67, I(2) = 0%) in adults; the results for children differed from this (OR, 0.79, 95% CI, 0.36-1.72, I(2) = 89%). Four trials reported no adverse events; one trial reported an adverse event related to plasma exchange, including an instance of hypotension in one patient. Plasmapheresis appeared to be an effective treatment for patients suffering from sepsis. A large number of additional randomised controlled trials are needed to confirm this finding.
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Efficacy and safety of nafamostat mesilate anticoagulation in blood purification treatment of critically ill patients: a systematic review and meta-analysis
Lin Y, Shao Y, Liu Y, Yang R, Liao S, Yang S, Xu M, He J
Renal failure. 2022;44(1):1263-1279
Abstract
BACKGROUND Nafamostat mesilate (NM), a broad-spectrum and potent serine protease inhibitor, can be used as an anticoagulant during extracorporeal circulation, as well as a promising drug effective against coronavirus disease 2019 (COVID-19). We conducted a systematic meta-analysis to evaluate the safety and efficacy of NM administration in critically ill patients who underwent blood purification therapy (BPT). METHODS The Cochrane Library, Web of Science and PubMed were comprehensively searched from inception to August 20, 2021, for potential studies. RESULTS Four randomized controlled trials (RCTs) and seven observational studies with 2723 patients met the inclusion criteria. The meta-analysis demonstrated that conventional therapy (CT) significantly increased hospital mortality compared with NM administration (RR = 1.25, p = 0.0007). In subgroup analyses, the in-hospital mortality of the NM group was significantly lower than that of the anticoagulant-free (NA) group (RR = 1.31, p = 0.002). The CT interventions markedly elevated the risk ratio of bleeding complications by 45% (RR = 1.45, p = 0.010) compared with NM interventions. In another subgroup analysis, NM used exhibited a significantly lower risk of bleeding complications than those of the low-molecular-weight heparin (LMWH) used (RR = 4.58, p = 0.020). The filter lifespan was decreased significantly (MD = -10.59, p < 0.0001) in the NA groups compared with the NM groups. Due to the poor quality of the included RCTs, these results should be interpreted with caution. CONCLUSION Given the better survival outcomes, lower risk of bleeding, NM anticoagulation seems to be a safe and efficient approach for BPT patients and could yield a favorable filter lifespan. More multi-center RCTs with large samples are required for further validation of this study.
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Clinical and biochemical endpoints and predictors of response to plasma exchange in septic shock: results from a randomized controlled trial
Stahl K, Wand P, Seeliger B, Wendel-Garcia PD, Schmidt JJ, Schmidt BMW, Sauer A, Lehmann F, Budde U, Busch M, et al
Critical care (London, England). 2022;26(1):134
Abstract
BACKGROUND Recently, a randomized controlled trial (RCT) demonstrated rapid but individually variable hemodynamic improvement with therapeutic plasma exchange (TPE) in patients with septic shock. Prediction of clinical efficacy in specific sepsis treatments is fundamental for individualized sepsis therapy. METHODS In the original RCT, patients with septic shock of < 24 h duration and norepinephrine (NE) requirement ≥ 0.4 μg/kg/min received standard of care (SOC) or SOC + one single TPE. Here, we report all clinical and biological endpoints of this study. Multivariate mixed-effects modeling of NE reduction was performed to investigate characteristics that could be associated with clinical response to TPE. RESULTS A continuous effect of TPE on the reduction in NE doses over the initial 24 h was observed (SOC group: estimated NE dose reduction of 0.005 µg/kg/min per hour; TPE group: 0.018 µg/kg/min per hour, p = 0.004). Similarly, under TPE, serum lactate levels, continuously decreased over the initial 24 h in the TPE group, whereas lactate levels increased under SOC (p = 0.001). A reduction in biomarkers and disease mediators (such as PCT (p = 0.037), vWF:Ag (p < 0.001), Angpt-2 (p = 0.009), sTie-2 (p = 0.005)) along with a repletion of exhausted protective factors (such as AT-III (p = 0.026), Protein C (p = 0.012), ADAMTS-13 (p = 0.008)) could be observed in the TPE but not in the SOC group. In a multivariate mixed effects model, increasing baseline lactate levels led to greater NE dose reduction effects with TPE as opposed to SOC (p = 0.004). CONCLUSIONS Adjunctive TPE is associated with the removal of injurious mediators and repletion of consumed protective factors altogether leading to preserved hemodynamic stabilization in refractory septic shock. We identified that baseline lactate concentration as a potential response predictor might guide future designing of large RCTs that will further evaluate TPE with regard to hard endpoints. Trial registration Retrospectively registered 18th January 2020 at clinicaltrials.gov (Identifier: NCT04231994 ).
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Coupled plasma filtration adsorption for the treatment of sepsis or septic shock: a systematic review and meta-analysis
Li, Y., Li, H., Guo, J., Wang, Y., Zhang, D.
BMC infectious diseases. 2022;22(1):714
Abstract
BACKGROUND The effect of coupled plasma filtration adsorption (CPFA) for the treatment of sepsis or septic shock is controversial. A systematic review and meta-analysis was performed to evaluate the impact of CPFA on all-cause mortality in patients with sepsis or septic shock. METHODS We searched the PubMed, Cochrane, and Embase databases for randomized controlled trials (RCTs) and cohort studies from inception to the 1st of May 2022. We included studies involving patients (˃ 14 years) with sepsis or septic shock. All authors reported our primary outcome of all-cause mortality (hospital mortality, 28-day mortality or 30-day mortality). Results were expressed as odds ratio (OR) with accompanying 95% confidence interval (CI). RESULTS Six studies including 537 patients were included. The primary outcome of this meta-analysis showed that the all-cause mortality was about 54.2% (119/243 in the CPFA group and 172/294 in the control group). There was no statistically significant difference in the all-cause mortality between two groups (odds ratio [OR] = 0.75; 95% CI 0.53 to 1.06; P = 0.11; Chi(2) = 14.04; I(2) = 64%). CONCLUSIONS The treatment of CPFA failed to decrease all-cause mortality of sepsis or septic shock patients. Further large-scale randomized controlled trials (RCTs) evaluating the ability of this therapy to improve clinical outcomes are still required to confirm these results.
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Therapeutic Plasma Exchange Protects Patients with Sepsis-Associated Disseminated Intravascular Coagulation by Improving Endothelial Function
Weng J, Chen M, Fang D, Liu D, Guo R, Yang S
Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis. 2021;27:10760296211053313
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Editor's Choice
Abstract
The mortality rate of sepsis-associated disseminated intravascular coagulation (DIC) is high. This study aimed to explore the efficacy of therapeutic plasma exchange (TPE) in sepsis-associated DIC patients by improving endothelial function. A total of 112 sepsis-associated DIC patients were randomly divided into the TPE group (n = 40), the heparin (HP) group (n = 36), and the SHAM group (n = 36). The SHAM group received conventional treatment; the HP group was treated with HP based on conventional treatment; and the TPE group received conventional treatment plus TPE. The differences in thromboelastogram (TEG), platelet (PLT), coagulation function, and the endothelial cell (EC) injury biomarkers at 6 h, 24 h, 48 h, 72 h, and 7 days after TPE were compared among the three groups, and the three groups were compared in terms of Acute Physiology and Chronic Health Evaluation II (APACHE II) score, Sepsis-Related Organ Failure Assessment (SOFA) score, the length of intensive care unit (ICU) hospitalization, 28-day mortality rate, 28-day cumulative survival rate, the incidence of bleeding events, the incidence of acute kidney injury (AKI), and acute respiratory distress syndrome (ARDS). The efficacy of TPE is superior to the HP in increasing PLT, improving coagulation function, increasing the 28-day cumulative survival rate, and reducing the length of ICU hospitalization, 28-day mortality, and the incidence of bleeding events, AKI, and ARDS with statistically significant differences (P < .05). Moreover, the effect of TPE outperforms HP on the EC injury biomarkers with statistically significant differences (P < .05). Our results suggest that TPE may be more effective than HP in the treatment of patients with sepsis-associated DIC. The possible mechanism is via improving endothelial function.
PICO Summary
Population
Patients with sepsis-associated disseminated intravascular coagulation (DIC), (n= 112).
Intervention
Therapeutic plasma exchange (TPE), (n= 40).
Comparison
Heparin (HP), (n= 36); conventional treatment (n= 36).
Outcome
The efficacy of TPE was superior to the HP in increasing platelet, improving coagulation function, increasing the 28-day cumulative survival rate, and reducing the length of intensive care unit hospitalization, 28-day mortality, and the incidence of bleeding events, acute kidney injury and acute respiratory distress syndrome with statistically significant differences. The effect of TPE outperformed HP on the endothelial cell injury biomarkers with statistically significant differences.
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High dose coupled plasma filtration and adsorption in septic shock patients. Results of the COMPACT-2: a multicentre, adaptive, randomised clinical trial
Garbero E, Livigni S, Ferrari F, Finazzi S, Langer M, Malacarne P, Meca MCC, Mosca S, Olivieri C, Pozzato M, et al
Intensive care medicine. 2021
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Editor's Choice
Abstract
PURPOSE This study aimed at evaluating the efficacy and safety of high-dose (> 0.2 L/kg of treated plasma per day) coupled plasma filtration-adsorption (CPFA) in treating patients with septic shock. METHODS Multicentre, randomised, adaptive trial, performed in 12 Italian intensive care units (ICUs). Patients aged 14 or more, admitted to the ICU with septic shock, or had developed it during the stay were eligible. The final outcome was mortality at discharge from the last hospital at which the patient received care. RESULTS Between May 2015, and October 2017, 115 patients were randomised. The first interim analysis revealed a number of early deaths, prompting an unplanned analysis. Last hospital mortality was non-significantly higher in the CPFA (55.6%) than in the control group (46.2%, p = 0.35). The 90-day survival curves diverged in favour of the controls early after randomisation and remained separated afterwards (p = 0.100). An unplanned analysis showed higher mortality in CPFA compared to controls among patients without severe renal failure (p = 0.025); a dose-response relationship was observed between treated plasma volume and mortality (p = 0.010). CONCLUSION The COMPACT-2 trial was stopped due to the possible harmful effect of CPFA in patients with septic shock. The harmful effect, if present, was particularly marked in the early phase of septic shock. Patients not requiring renal replacement therapy seemed most exposed to the possible harm, with evidence of a dose-response effect. Until the mechanisms behind these results are fully understood, the use of CPFA for the treatment of patients with septic shock is not recommended.
PICO Summary
Population
Patients aged 14 or more with septic shock, enrolled in the COMPACT-2 multicentre trial (n= 115).
Intervention
High dose coupled plasma filtration-adsorption (CPFA), (n= 63).
Comparison
Standard care (n= 52).
Outcome
The first interim analysis revealed a number of early deaths, prompting an unplanned analysis. Last hospital mortality was non-significantly higher in the CPFA (55.6%) than in the control group (46.2%). The 90-day survival curves diverged in favour of the controls early after randomisation and remained separated afterwards. An unplanned analysis showed higher mortality in CPFA compared to controls among patients without severe renal failure; a dose-response relationship was observed between treated plasma volume and mortality. The COMPACT-2 trial was stopped due to the possible harmful effect of CPFA in patients with septic shock.
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The effect of exchange transfusion on mortality in neonatal sepsis: a meta-analysis
Mathias S, Balachander B, Bosco A, Britto C, Rao S
European journal of pediatrics. 2021
Abstract
Although antimicrobials are the cornerstone of neonatal sepsis management, adjunctive therapies are required to improve outcomes. The aim of our study was to evaluate the effect of exchange transfusion (ET) on mortality (primary outcome) in neonatal sepsis, as well as on immunoglobulin, complement and neutrophil levels and assess its complications (secondary outcomes). Databases searched include PubMed, NCBI, Google Scholar, CINHAL, Ovid and Scopus. Randomized controlled trials (RCTs), controlled observational studies (COSs) and uncontrolled observational studies (UOSs) reporting mortality data from using ET in neonatal sepsis were included. Studies with additional interventions, non-septic ET indications and populations aged > 28 days were excluded. Data extracted include demographics, features of study, sepsis and ET, as well as mortality rates, immunological and laboratory changes and complications. Data was meta-analysed and displayed using forest plots. The meta-analysis of 14 studies (3 RCTs, 11 COSs) revealed a mortality benefit in septic neonates who underwent ET-RR 0.72 (CI 0.61-0.86, p = 0.01) and a significant increase in pooled immunological parameters (immunoglobulin, complement levels) (SMD 1.13, [0.25, 2.02], p = 0.02) and neutrophil levels (SMD 1.07 [0.04, 2.11], p = 0.03) compared to controls. The descriptive analysis of 9 UOSs revealed thrombocytopenia as the most frequently reported complication (n = 48). Moderate-high risk of bias was largely due to inadequate sample sizes and follow-up durations.Conclusion: Currently, the use of ET in neonatal sepsis is not directly recommended due to low certainty of evidence, inadequate power and moderate-high risk of bias and heterogeneity.Trial registration: PROSPERO (CRD42020176629) ( https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=176629 ) What is Known: • Exchange transfusion is one of the adjunctive methods for treatment of neonatal sepsis. What is New: • The pooled analysis of all studies shows that exchange transfusion has a low certainty of evidence in the context of neonatal mortality. However, at this point, this intervention cannot be refuted or recommended due to heterogeneity of studies and inadequate power.
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Effect of Extracorporeal Blood Purification on Mortality in Sepsis: A Meta-Analysis and Trial Sequential Analysis
Snow TAC, Littlewood S, Corredor C, Singer M, Arulkumaran N
Blood purification. 2020;:1-11
Abstract
OBJECTIVE The objective of this study was to conduct a meta-analysis and trial sequential analysis (TSA) of published randomized controlled trials (RCTs) to determine whether mortality benefit exists for extracorporeal blood purification techniques in sepsis. DATA SOURCES A systematic search on MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials for RCTs was performed. STUDY SELECTION RCTs investigating the effect of extracorporeal blood purification device use on mortality among critically ill septic patients were selected. DATA EXTRACTION Mortality was assessed using Mantel-Haenszel models, and I2 was used for heterogeneity. Data are presented as odds ratios (OR); 95% confidence intervals (CIs); p values; I2. Using the control event mortality proportion, we performed a TSA and calculated the required information size using an anticipated intervention effect of a 14% relative reduction in mortality. DATA SYNTHESIS Thirty-nine RCTs were identified, with 2,729 patients. Fourteen studies used hemofiltration (n = 789), 17 used endotoxin adsorption devices (n = 1,363), 3 used nonspecific adsorption (n = 110), 2 were cytokine removal devices (n = 117), 2 used coupled plasma filtration adsorption (CPFA) (n = 207), 2 combined hemofiltration and perfusion (n = 40), and 1 used plasma exchange (n = 106). On conventional meta-analysis, hemofiltration (OR 0.56 [0.40-0.79]; p < 0.001; I2 = 0%), endotoxin removal devices (OR 0.40 [0.23-0.67], p < 0.001; I2 = 71%), and nonspecific adsorption devices (OR 0.32 [0.13-0.82]; p = 0.02; I2 = 23%) were associated with mortality benefit, but not cytokine removal (OR 0.99 [0.07-13.42], p = 0.99; I2 = 64%), CPFA (OR 0.50 [0.10-2.47]; p = 0.40; I2 = 64%), or combined hemofiltration and adsorption (OR 0.71 [0.13-3.79]; p = 0.69; I2 = 0%). TSA however revealed that based on the number of existing patients recruited for RCTs, neither hemofiltration (TSA-adjusted CI 0.29-1.10), endotoxin removal devices (CI 0.05-3.40), nor nonspecific adsorption devices (CI 0.01-14.31) were associated with mortality benefit. CONCLUSION There are inadequate data at present to conclude that the use of extracorporeal blood purification techniques in sepsis is beneficial. Further adequately powered RCTs are required to confirm any potential mortality benefit, which may be most evident in patients at greatest risk of death.
