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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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Adjuvant therapy in neonatal sepsis to prevent mortality - A systematic review and network meta-analysis
Abiramalatha T, Ramaswamy VV, Bandyopadhyay T, Somanath SH, Shaik NB, Kallem VR, Pullattayil AK, Kaushal M
Journal of neonatal-perinatal medicine. 2022
Abstract
BACKGROUND Despite appropriate antibiotic therapy, the risk of mortality in neonatal sepsis still remains high. We conducted a systematic review to comprehensively evaluate different adjuvant therapies in neonatal sepsis in a network meta-analysis. METHODS We included randomized controlled trials (RCTs) and quasi-RCTs that evaluated adjuvant therapies in neonatal sepsis. Neonates of all gestational and postnatal ages, who were diagnosed with sepsis based on blood culture or sepsis screen were included. We searched MEDLINE, CENTRAL, EMBASE and CINAHL until 12th April 2021 and reference lists. Data extraction and risk of bias assessment were performed in duplicate. A network meta-analysis with bayesian random-effects model was used for data synthesis. Certainty of evidence (CoE) was assessed using GRADE. RESULTS We included 45 studies involving 6,566 neonates. Moderate CoE showed IVIG [Relative Risk (RR); 95% Credible Interval (CrI): 1.00; (0.67-1.53)] as an adjunctive therapy probably does not reduce all-cause mortality before discharge, compared to standard care. Melatonin [0.12 (0-0.08)] and granulocyte transfusion [0.39 (0.19-0.76)] may reduce mortality before discharge, but CoE is very low. The evidence is also very uncertain regarding other adjunctive therapies to reduce mortality before discharge. Pentoxifylline may decrease the duration of hospital stay [Mean difference; 95% CrI: -7.48 days (-14.50-0.37)], but CoE is very low. CONCLUSION Given the biological plausibility for possible efficacy of these adjuvant therapies and that the CoE from the available trials is very low to low except for IVIG, we need large adequately powered RCTs to evaluate these therapies in sepsis in neonates.
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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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Recombinant human activated protein C for severe sepsis in neonates
Kylat RI, Ohlsson A
Cochrane Database of Systematic Reviews.. 2012;:CD005385.
Abstract
BACKGROUND Sepsis is a common problem in preterm and term infants. The incidence of neonatal sepsis has declined, but mortality remains high. Recombinant human activated protein C (rhAPC) possess a broad spectrum of activity modulating coagulation and inflammation. In septic adults it may reduce mortality, but no significant benefit has been reported in children with severe sepsis. OBJECTIVES To determine whether treatment with rhAPC reduces mortality and/or morbidity in neonatal sepsis. SEARCH METHODS For this update searches were carried out in May 2011 of the Cochrane Central Register of Controlled Trials (The Cochrane Library), MEDLINE, EMBASE, CINAHL, and abstracts of annual meetings of the Pediatric Academic Societies. Doctoral dissertations, theses and the Science Citation Index for articles on activated protein C were searched. No language restriction was applied. SELECTION CRITERIA Randomized or quasi-randomized trials, assessing the efficacy of rhAPC compared to placebo or no intervention as an adjunct to antibiotic therapy of suspected or confirmed severe sepsis in term and preterm infants less than 28 days old. Eligible trials should report at least one of the following outcomes: mortality during initial hospital stay, neurodevelopmental assessment at two years of age or later, length of hospital stay, duration of ventilation, chronic lung disease, periventricular leukomalacia, intraventricular haemorrhage, necrotizing enterocolitis, bleeding, and any other adverse events. DATA COLLECTION AND ANALYSIS Review authors were to independently evaluate the articles for inclusion criteria and quality, and abstract information for the outcomes of interest. Differences were to be resolved by consensus. The statistical methods were to include relative risk, risk difference, number needed to treat to benefit or number needed to treat to harm for dichotomous and weighed mean difference for continuous outcomes reported with 95% confidence intervals. A fixed effect model was to be used for meta-analysis. Heterogeneity tests, including the I(2) statistic, were to be performed to assess the appropriateness of pooling the data. MAIN RESULTS No eligible trials were identified. In October 2011 rhAPC (Xigris[REGISTERED]) was withdrawn from the market by Eli Lilly due to a higher mortality in a trial among adults. Xigris[REGISTERED] (DrotAA)( rhAPC) should no longer be used in any age category and the product should be returned to the distributor. AUTHORS' CONCLUSIONS Despite the scientific rationale for its use, there is insufficient data to use rhAPC for the management of severe sepsis in newborn infants. Due to the results among adults with lack of efficacy, an increase in bleeding and resulting withdrawal of rhAPC from the market, neonates should not be treated with rhAPC and further trials should not be conducted.
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Granulocyte transfusions for neonates with confirmed or suspected sepsis and neutropenia
Pammi M, Brocklehurst P
Cochrane Database of Systematic Reviews. 2011;((10):):CD003956.
Abstract
BACKGROUND Neonates have immature granulopoiesis, which frequently results in neutropenia after sepsis. Neutropaenic septic neonates have a higher mortality than non-neutropenic septic neonates. Therefore, granulocyte transfusion to septic neutropenic neonates may improve outcomes. OBJECTIVES The primary objective was to determine the effect of granulocyte or buffy coat transfusions as adjuncts to antibiotics, after confirmed or suspected sepsis in neutropenic neonates, on all-cause mortality during hospital stay and neurological outcome at >= year of age. Secondary objectives were to determine the effects of granulocyte transfusions on length of hospital stay in survivors to discharge, adverse effects and immunologic outcomes at >= year of age. SEARCH STRATEGY The Cochrane Central Register of Controlled Trials (The Cochrane Library), MEDLINE, EMBASE and CINAHL, proceedings of the PAS conferences and ongoing trials at clinicaltrials.gov and clinical-trials.com were searched in July 2011. SELECTION CRITERIA Studies where neutropenic neonates with suspected or confirmed sepsis were randomised or quasi-randomised to granulocyte or buffy coat transfusions at any dose or duration, and reporting any outcome of interest were included. DATA COLLECTION AND ANALYSIS Relative risk (RR) and risk difference (RD) with 95% confidence intervals using the fixed effects model were reported for dichotomous outcomes. Pre-specified subgroup analyses were performed. MAIN RESULTS Four trials were eligible for inclusion. Forty-four infants with sepsis and neutropenia were randomised in three trials to granulocyte transfusions or placebo/no transfusion. In another trial, 35 infants with sepsis and neutropenia on antibiotics were randomised to granulocyte transfusion or IVIG.When granulocyte transfusion was compared with placebo or no transfusion, there was no significant difference in 'all-cause mortality' (three trials; typical RR 0.89, 95% CI 0.43 to 1.86; typical RD -0.05, 95% CI -0.31 to 0.21).When granulocyte transfusion was compared with intravenous immunoglobulin (one trial), there was a reduction in 'all-cause mortality' of borderline statistical significance (RR 0.06, 95% CI 0.00 to 1.04; RD -0.34, 95% CI -0.60 to -0.09; NNT 2.7, 95% CI 1.6 to 9.1).Pulmonary complications were the only adverse effect reported in the trials that used buffy coat transfusions. None of the trials reported on neurological outcome at one year of age or later, length of hospital stay in survivors to discharge or immunological outcome at one year of age or later. AUTHORS' CONCLUSIONS Currently, there is inconclusive evidence from randomised controlled trials (RCTs) to support or refute the routine use of granulocyte transfusions in neutropenic, septic neonates. Researchers are encouraged to conduct adequately powered multi-centre trials of granulocyte transfusions in neutropenic septic neonates.