Clinical and biochemical endpoints and predictors of response to plasma exchange in septic shock: results from a randomized controlled trial
Critical care (London, England). 2022;26(1):134
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 ).
Therapeutic Plasma Exchange Protects Patients with Sepsis-Associated Disseminated Intravascular Coagulation by Improving Endothelial Function
Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis. 2021;27:10760296211053313
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.
Patients with sepsis-associated disseminated intravascular coagulation (DIC), (n= 112).
Therapeutic plasma exchange (TPE), (n= 40).
Heparin (HP), (n= 36); conventional treatment (n= 36).
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.
The effect of exchange transfusion on mortality in neonatal sepsis: a meta-analysis
European journal of pediatrics. 2021
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.
High dose coupled plasma filtration and adsorption in septic shock patients. Results of the COMPACT-2: a multicentre, adaptive, randomised clinical trial
Intensive care medicine. 2021
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.
Patients aged 14 or more with septic shock, enrolled in the COMPACT-2 multicentre trial (n= 115).
High dose coupled plasma filtration-adsorption (CPFA), (n= 63).
Standard care (n= 52).
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.
The premature closure of ROMPA clinical trial: mortality reduction in septic shock by plasma adsorption
BMJ open. 2019;9(12):e030139
OBJECTIVES Coupled Plasma Filtration and Adsorption (CPFA) use in septic shock remains controversial. The objective is to clarify whether the application of high doses of CPFA in addition to the current clinical practice could reduce hospital mortality in septic shock patients in Intensive Care Units at 28 days and at 90 days follow-up. DESIGN We designed a prospective randomised clinical trial, Reduccion de la Mortalidad Plasma-Adsorcion (ROMPA), to demonstrate an absolute mortality reduction of 20% (alpha=0.05; 1-beta=0.8; n=190 (95x2)). SETTING Being aware of the pitfalls associated with previous medical device trials, we developed a training programme to improve CPFA use (especially clotting problems). The protocol was approved by the ethics committees of all participating centres. Circumstances beyond our control produced a change in recruitment conditions unacceptable to ROMPA researchers and the trial was discontinued. PARTICIPANTS By closure, five centres from an initial 10 fulfilled the necessary trial criteria, with 49 patients included, 30 in the control group (CG) and 19 in the intervention group (IG). INTERVENTION CPFA. MAIN OUTCOME MEASURES Hospital mortality at 28 days and 90 days follow-up. RESULTS After 28 days, 14 patients died (46.7%) from the CG and 11 (57.9%) from the IG, not reaching statistical significance (p=0.444). At 90 days, 19 patients had died (63.3%) from the CG and 11 patients (57.9%) from the IG, (p=0.878). The adjustment by propensity score or the use of the Kaplan-Meier technique failed to achieve statistical difference, neither by Intention to Treat nor by the Actual Intervention Received. CONCLUSION We herewith present the results gained from the prematurely closed trial. The results are inconclusive due to low statistical power but we consider that this data is of interest for the scientific community and potentially necessary for any ensuing debate. REGISTER NCT02357433 in clinicaltrials.gov.
Effect of continuous plasma filtration adsorption on treatment of severely burned patients with sepsis
Zhonghua Shao Shang Za Zhi = Zhonghua Shaoshang Zazhi = Chinese Journal of Burns. 2018;34((6)):370-373.
Objective: To investigate effect of continuous plasma filtration adsorption on treatment of severely burned patients with sepsis. Methods: In January 2014 to September 2017, 86 severely burned patients with sepsis, conforming to the study criteria, were admitted to our hospital and divided into into routine treatment group and continuous plasma filtration group according to the random number table method, with 43 patients in each group. Patients in routine treatment group were treated with routine treatment after admission. Patients in continuous plasma filtration group were treated with blood filter, blood purification machine, and plasma separator for continuous plasma filtration adsorption on the basis of the routine treatment group on the second day after admission. The course of treatment in the 2 groups was 7 d. The total effective treatment rate, changes of leukocyte count (WBC), usea nitrogen, serum creatinine, neutrophile CD64, procalcitonin, and C reactive protein (CRP) before and after treatment, and mortality on 28 days after treatment of patients in 2 groups were analyzed and compared. Results: (1) The total effective treatment rate of patients in continuous plasma filtration group was 88.37% (38/43), which was significantly higher than that of the routine treatment group [65.12% (28/43), chi(2)=6.515, P=0.018]. (2) After treatment, WBC, urea nitrogen, serum creatinine, neutrophils CD64, procalcitonin, and CRP of patients in continuous plasma filtration group were significantly lower those in routine treatment group (t=6.305, 4.420, 18.537, 13.435, 12.975, 14.234, P<0.05). WBC, urea nitrogen, serum creatinine, neutrophile CD64, procalcitonin, and CRP of patients in 2 groups after treatment were significantly lower than those before treatment (t=9.459, 9.130, 25.438, 35.467, 23.471, 23.601, 3.802, 5.662, 12.067, 25.694, 20.720, 12.437, P<0.05). (3) On 28 days after treatment, mortality of patients in continuous plasma filtration group was 6.98% (3/43), which was significantly lower than that in routine treatment group [25.58% (11/43)], chi(2)=5.460, P=0.023. Conclusions: Continuous plasma filtration adsorption is effective in treating severely burned patients with sepsis, which can alleviate inflammatory reaction mediated by inflammatory cytokine with good prognosis.
Prophylactic intravenous calcium therapy for exchange blood transfusion in the newborn
The Cochrane Database of Systematic Reviews. 2017;((10)):CD011048.
BACKGROUND Exchange blood transfusion (EBT) is a form of whole blood transfusion in which the total blood volume is replaced within a few hours. In perinatal and neonatal medicine, EBT is most often used in the management of severe anaemia or severe hyperbilirubinaemia in the first week of life. Hypocalcaemia, one of the common morbidities associated with EBT, is thought to arise from the chelating effects of the citrate commonly used as an anticoagulant in the donor's blood. This disorder manifests with muscular and nervous irritability and cardiac arrhythmias. OBJECTIVES To determine whether the use of prophylactic calcium reduces the risk of hypocalcaemia-related morbidities and death among newborn infants receiving EBT. SEARCH METHODS We used the standard search strategy of the Cochrane Neonatal Review group to search the Cochrane Central Register of Controlled Trials (CENTRAL 2016, Issue 5), MEDLINE via PubMed (1966 to 29 June 2016), Embase (1980 to 29 June 2016), and CINAHL (1982 to 29 June 2016). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. SELECTION CRITERIA All randomised and quasi-randomised trials of prophylactic intravenous calcium in EBT for newborns. DATA COLLECTION AND ANALYSIS Two review authors independently assessed and extracted data on methods, participants, interventions, and outcomes (mean total and ionised serum calcium before and after EBT and the presence of adverse events such as hypoglycaemia, apnoea, cardiac arrest, and death immediately after EBT). We reported results as means difference (MD) with 95% confidence intervals (CI) for continuous outcomes and risk ratio (RR) and risk differences (RD) and 95% CIs for dichotomous outcomes. We assessed quality using the Cochrane 'Risk of bias' assessment tool and the GRADE system. MAIN RESULTS We found only one quasi-randomised trial with 30 participants that met our inclusion criteria. In the small trial, total and ionised serum calcium levels were measured immediately before and immediately after EBT. All the participants were included in the final analysis and all the important outcomes were reported. Primary outcomesThere was one death in each group (RR 1.00, 95% CI 0.07 to 14.55; RD 0.00, 95% CI -0.18 to 0.18; participants = 30; studies = 1). The study did not report the presence of cardiac arrhythmias within one week of EBT and the number of infants with serum calcium levels (total less than 8 mg/dL (2 mmol/L) or ionised less than 4.4 mg/dL (1.1 mmol/L)).Pair-wise comparison of EBT with intravenous 10% calcium gluconate versus EBT without intravenous calcium (change from baseline) showed mean total serum calcium was raised in the intervention group compared to the control group (MD -0.46, 95% CI -0.81 to -0.11; participants = 30; studies = 1). Very low-quality evidence also indicated an increase in the levels of mean ionised serum calcium in the intervention group compared to the control group (MD -0.22, 95% CI -0.33 to -0.11; participants = 30; studies = 1). Secondary outcomesAdverse reactions to intravenous calcium therapy included cardiac arrest in one neonate in the intervention arm (RR 3.00, 95% CI 0.13 to 68.26; RD 0.07, 95% CI -0.10 to 0.23; participants = 30; studies = 1). There was apnoea and hypoglycaemia (RR 1.00, 95% CI 0.07 to 14.55; RD 0.00, 95% CI -0.18 to 0.18; participants = 30; studies = 1) in the two neonates who died. Data were not available for other major secondary outcomes such as the number of infants with reduced serum magnesium, reduced parathormone, increased calcitonin, presence of seizures, carpopedal spasm, jitteriness and prolonged QTc interval on electrocardiography within one week of EBT. AUTHORS' CONCLUSIONS Very low-quality data from one quasi-randomised controlled trial suggested that the mean serum total and ionised calcium increased in the study group but decreased in the control group immediately after EBT. However, the mean values of total and ionised cal
The effect of plasmapheresis on treating disseminated intravascular coagulation (DIC) caused by a Hemiscorpius lepturus (Gadim) sting
Clinical Toxicology (Philadelphia, Pa.). 2017;:1-6.
INTRODUCTION The highest mortality from scorpion stings in Iran is due to the stings of a particular type of scorpion known as Hemiscorpius lepturus (H. lepturus, Gadim in local language). The present study aimed at investigating the use of plasmapheresis to treat severe cases of H. lepturus stings. METHOD This pilot study was a randomized clinical trial conducted from June 2015 to June 2016 in Razi hospital of Ahvaz, Iran. Twenty-nine patients who had been stung by H. lepturus and admitted to ICU because of disseminated intravascular coagulation (DIC) were randomly assigned into control (15 patients, supportive treatments) and plasmapheresis (14 patients, supportive treatments + plasmapheresis) groups, and the patient outcomes were compared between the two groups. FINDINGS Eighteen patients were female (62%), and the mean of patient age was 24 +/- 7. Most of the sting cases had occurred in the torso (15 patients, 52%). Only 10 patients (34%) arrived in the hospital within 12 h of being stung. There was no significant difference between the two groups in terms of the demographic and sting features. In the plasmapheresis group, hemoglobin level was significantly lower, while the PT and INR were measurably higher. In total, the plasmapheresis group experienced 29 sessions of treatment (an average of two sessions for each patient). Overall, 19 patients (66%) expired, whereas 10 patients (34%) experienced recovery with or without complications. The rate of recovery was significantly higher in the plasmapheresis group compared with controls, with eight patients (57%) in the plasmapheresis group surviving compared with two (14%) in the control group (p=.045). The duration of hospitalization was higher in the plasmaphersis group (p < .001). A comparison of the dead and recovered patients' features indicated that the dead patients arrived in the hospital significantly later than the recovered ones, and they also had lower platelet counts. CONCLUSIONS The findings of this small-scale pilot study show that using plasmapheresis in treating DIC in patients stung by H. lepturus can prevent death and encourage recovery. However, prior to using plasmapheresis as a routine treatment for severe cases of people stung by this scorpion or other similar ones, further controlled studies with a larger sample size are needed.
Double volume exchange transfusion in severe neonatal sepsis
Indian Journal of Pediatrics. 2016;83((2)):107-13.
OBJECTIVES To study the efficacy and safety of double volume exchange transfusion (DVET) in neonates>1000 g birth weight with severe sepsis. METHODS Eighty-three neonates weighing >1000 g with severe sepsis were randomly assigned to DVET or standard therapy (ST) group. Primary outcome was mortality by 14 d from enrollment. RESULTS A 21 % reduction in mortality, albeit non-significant, by 14 d from enrollment was observed in DVET group in comparison to ST group [RR: 0.79 (95 % C.I 0.45-1.3); p 0.4]. A similar trend in mortality reduction was observed with early mortality and mortality by discharge in DVET group. No difference was observed in normalization of dysfunctional organs by 14 d. Cardiovascular and hematological system benefitted the most, followed by renal dysfunction with DVET. A significant improvement in post DVET IgG, IgA, IgM, C3 and base deficit was observed. No serious adverse effects occurred following DVET. CONCLUSIONS In neonates >1000 g with severe sepsis, DVET was associated with a trend towards decrease in mortality by 14 d from enrollment. A significant improvement in immunoglobulin and complement C3 levels and acid base status were observed following DVET. DVET is a safe procedure in severely sick and septic neonates.
The efficacy and safety of plasma exchange in patients with sepsis and septic shock: a systematic review and meta-analysis
Critical Care (London, England). 2014;18((6):):699.
INTRODUCTION Sepsis and septic shock are leading causes of intensive care unit (ICU) mortality. They are characterized by excessive inflammation, upregulation of procoagulant proteins and depletion of natural anticoagulants. Plasma exchange has the potential to improve survival in sepsis by removing inflammatory cytokines and restoring deficient plasma proteins. The objective of this study is to evaluate the efficacy and safety of plasma exchange in patients with sepsis. METHODS We searched MEDLINE, EMBASE, CENTRAL, Scopus, reference lists of relevant articles, and grey literature for relevant citations. We included randomized controlled trials comparing plasma exchange or plasma filtration with usual care in critically ill patients with sepsis or septic shock. Two reviewers independently identified trials, extracted trial-level data and performed risk of bias assessments using the Cochrane Risk of Bias tool. The primary outcome was all-cause mortality reported at longest follow-up. Meta-analysis was performed using a random-effects model. RESULTS Of 1,957 records identified, we included four unique trials enrolling a total of 194 patients (one enrolling adults only, two enrolling children only, one enrolling adults and children). The mean age of adult patients ranged from 38 to 53 years (n=128) and the mean age of children ranged from 0.9 to 18 years (n=66). All trials were at unclear to high risk of bias. The use of plasma exchange was not associated with a significant reduction in all-cause mortality (risk ratio (RR) 0.83, 95% confidence interval (CI) 0.45 to 1.52, I(2) 60%). In adults, plasma exchange was associated with reduced mortality (RR 0.63, 95% CI 0.42 to 0.96; I(2) 0%), but was not in children (RR 0.96, 95% CI 0.28 to 3.38; I(2) 60%). None of the trials reported ICU or hospital lengths of stay. Only one trial reported adverse events associated with plasma exchange including six episodes of hypotension and one allergic reaction to fresh frozen plasma. CONCLUSIONS Insufficient evidence exists to recommend plasma exchange as an adjunctive therapy for patients with sepsis or septic shock. Rigorous randomized controlled trials evaluating clinically relevant patient-centered outcomes are required to evaluate the impact of plasma exchange in this condition.