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One-year follow-up of the CAPSID randomized trial for high-dose convalescent plasma in severe COVID-19 patients
Körper S, Grüner B, Zickler D, Wiesmann T, Wuchter P, Blasczyk R, Zacharowski K, Spieth P, Tonn T, Rosenberger P, et al
The Journal of clinical investigation. 2022
Abstract
BACKGROUND Results of many randomized trials on COVID-19 convalescent plasma (CCP) have been reported but information on long-term outcome after CCP treatment is limited. The objectives of this extended observation of the randomized CAPSID trial are to assess long-term outcome and disease burden in patients initially treated with or without CCP. METHODS Of 105 randomized patients, 50 participated in the extended observation. Quality of life (QoL) was assessed by questionnaires and a structured interview. CCP-donors (n=113) with asymptomatic to moderate COVID-19 were included as a reference group. RESULTS The median follow-up of patients was 396 days, the estimated 1-year survival was 78.7% in the CCP and 60.2% in the control group (p=0.08). The subgroup treated with a higher cumulative amount of neutralizing antibodies showed a better 1-year survival compared to the control group (91.5% versus 60.2%; p=0.01). Medical events and QoL assessments showed a consistent trend for better results in the CCP group without reaching statistical significance. There was no difference in the increase of neutralizing antibodies after vaccination between CCP and the control group. CONCLUSION The trial demonstrated a trend towards better outcome in the CCP group without reaching statistical significance. A pre-defined subgroup analysis showed a significant better outcome (long-term survival; time to discharge from ICU and time to hospital discharge) among those who received a higher amount of neutralizing antibodies compared to the control group. A substantial long-term disease burden remains after severe COVID-19. TRIAL REGISTRATION EudraCT number 2020-001310-38FUNDING. Bundesministerium für Gesundheit (German Federal Ministry of Health): ZMVI1-2520COR802/ZMI1-2521COR802.
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Use of Thromboelastography in the Evaluation and Management of Patients With Traumatic Brain Injury: A Systematic Review and Meta-Analysis
Cannon JW, Dias JD, Kumar MA, Walsh M, Thomas SG, Cotton BA, Schuster JM, Evans SL, Schreiber MA, Adam EH, et al
Critical care explorations. 2021;3(9):e0526
Abstract
Traumatic brain injury is associated with coagulopathy that increases mortality risk. Viscoelastic hemostatic assays such as thromboelastography (Haemonetics SA, Signy, Switzerland) provide rapid coagulopathy assessment and may be particularly useful for goal-directed treatment of traumatic brain injury patients. We conducted a systematic review to assess thromboelastography in the evaluation and management of coagulopathy in traumatic brain injury patients. DATA SOURCES MEDLINE, PubMed Central, Embase, and CENTRAL. STUDY SELECTION Clinical studies of adult patients with traumatic brain injury (isolated or polytrauma) who were assessed by either standard thromboelastography or thromboelastography with platelet mapping plus either conventional coagulation assays or platelet function assays from January 1999 to June 2021. DATA EXTRACTION Demographics, injury mechanism and severity, diagnostic, laboratory data, therapies, and outcome data were extracted for analysis and comparison. DATA SYNTHESIS Database search revealed 1,169 sources; eight additional articles were identified by the authors. After review, 31 publications were used for qualitative analysis, and of these, 16 were used for quantitative analysis. Qualitative and quantitative analysis found unique patterns of thromboelastography and thromboelastography with platelet mapping parameters in traumatic brain injury patients. Patterns were distinct compared with healthy controls, nontraumatic brain injury trauma patients, and traumatic brain injury subpopulations including those with severe traumatic brain injury or penetrating traumatic brain injury. Abnormal thromboelastography K-time and adenosine diphosphate % inhibition on thromboelastography with platelet mapping are associated with decreased survival after traumatic brain injury. Subgroup meta-analysis of severe traumatic brain injury patients from two randomized controlled trials demonstrated improved survival when using a viscoelastic hemostatic assay-guided resuscitation strategy (odds ratio, 0.39; 95% CI, 0.17-0.91; p = 0.030). CONCLUSIONS Thromboelastography and thromboelastography with platelet mapping characterize coagulopathy patterns in traumatic brain injury patients. Abnormal thromboelastography profiles are associated with poor outcomes. Conversely, treatment protocols designed to normalize abnormal parameters may be associated with improved traumatic brain injury patient outcomes. Current quality of evidence in this population is low; so future efforts should evaluate viscoelastic hemostatic assay-guided hemostatic resuscitation in larger numbers of traumatic brain injury patients with specific focus on those with traumatic brain injury-associated coagulopathy.
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Results of the CAPSID randomized trial for high-dose convalescent plasma in severe COVID-19 patients
Körper S, Weiss M, Zickler D, Wiesmann T, Zacharowski K, Corman VM, Grüner B, Ernst L, Spieth P, Lepper PM, et al
The Journal of Clinical Investigation. 2021
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Abstract
BACKGROUND COVID-19 convalescent plasma (CCP) has been considered a treatment option in COVID-19. This trial assessed the efficacy of neutralizing antibody containing high-dose CCP in hospitalized adults with COVID-19 requiring respiratory support or intensive care treatment. METHODS Patients (n=105) were randomized 1:1 to either receive standard treatment and 3 units of CCP or standard treatment alone. Control group patients with progress on day 14 could cross over to the CCP group. Primary outcome was a dichotomous composite outcome of survival and no longer fulfilling criteria for severe COVID-19 on day 21. RESULTS The primary outcome occurred in 43.4% of patients in the CCP and 32.7% in the control group (p=0.32). The median time to clinical improvement was 26 days in the CCP group and 66 days in the control group (p=0.27). Median time to discharge from hospital was 31 days in the CCP and 51 days in the control group (p=0.24). In the subgroup that received a higher cumulative amount of neutralizing antibodies the primary outcome occurred in 56.0% (versus 32.1%), with significantly shorter intervals to clinical improvement (20 versus 66 days)(p<0.05), and to hospital discharge (21 versus 51 days, p=0.03) and better survival (day-60 probability of survival 91.6% versus 68.1%; p=0.02) compared to the control group. CONCLUSION CCP added to standard treatment was not associated with significant improvement in the primary and secondary outcomes. A pre-defined subgroup analysis showed a significant benefit for CCP among those who received a larger amount of neutralizing antibodies. TRIAL REGISTRATION ClinicalTrials.gov, NCT04433910FUNDING. German Federal Ministry of Health.
PICO Summary
Population
Hospitalized adults with COVID-19 in centres in Germany, enrolled in the CAPSID trial (n= 105).
Intervention
Convalescent plasma (CCP), (n= 53).
Comparison
Standard care (n= 52).
Outcome
The primary outcome occurred in 43.4% of patients in the CCP and 32.7% in the control group. The median time to clinical improvement was 26 days in the CCP group and 66 days in the control group. Median time to discharge from hospital was 31 days in the CCP and 51 days in the control group. In the subgroup that received a higher cumulative amount of neutralizing antibodies the primary outcome occurred in 56.0% (vs. 32.1%), with significantly shorter intervals to clinical improvement (20 vs. 66 days), and to hospital discharge (21 vs. 51 days) and better survival (day-60 probability of survival 91.6% vs. 68.1%) compared to the control group.
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Association of Intravenous Tranexamic Acid With Thromboembolic Events and Mortality: A Systematic Review, Meta-analysis, and Meta-regression
Taeuber I, Weibel S, Herrmann E, Neef V, Schlesinger T, Kranke P, Messroghli L, Zacharowski K, Choorapoikayil S, Meybohm P
JAMA surgery. 2021;:e210884
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Abstract
IMPORTANCE Tranexamic acid (TXA) is an efficient antifibrinolytic agent; however, concerns remain about the potential adverse effects, particularly vascular occlusive events, that may be associated with its use. OBJECTIVE To examine the association between intravenous TXA and total thromboembolic events (TEs) and mortality in patients of all ages and of any medical disciplines. DATA SOURCE Cochrane Central Register of Controlled Trials and MEDLINE were searched for eligible studies investigating intravenous TXA and postinterventional outcome published between 1976 and 2020. STUDY SELECTION Randomized clinical trials comparing intravenous TXA with placebo/no treatment. The electronic database search yielded a total of 782 studies, and 381 were considered for full-text review. Included studies were published in English, German, French, and Spanish. Studies with only oral or topical tranexamic administration were excluded. DATA EXTRACTION AND SYNTHESIS Meta-analysis, subgroup and sensitivity analysis, and meta-regression were performed. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. MAIN OUTCOMES AND MEASURES Vascular occlusive events and mortality. RESULTS A total of 216 eligible trials including 125 550 patients were analyzed. Total TEs were found in 1020 (2.1%) in the group receiving TXA and 900 (2.0%) in the control group. This study found no association between TXA and risk for total TEs (risk difference = 0.001; 95% CI, -0.001 to 0.002; P = .49) for venous thrombosis, pulmonary embolism, venous TEs, myocardial infarction or ischemia, and cerebral infarction or ischemia. Sensitivity analysis using the risk ratio as an effect measure with (risk ratio = 1.02; 95% CI, 0.94-1.11; P = .56) and without (risk ratio = 1.03; 95% CI, 0.95-1.12; P = .52) studies with double-zero events revealed robust effect size estimates. Sensitivity analysis with studies judged at low risk for selection bias showed similar results. Administration of TXA was associated with a significant reduction in overall mortality and bleeding mortality but not with nonbleeding mortality. In addition, an increased risk for vascular occlusive events was not found in studies including patients with a history of thromboembolism. Comparison of studies with sample sizes of less than or equal to 99 (risk difference = 0.004; 95% CI, -0.006 to 0.014; P = .40), 100 to 999 (risk difference = 0.004; 95% CI, -0.003 to 0.011; P = .26), and greater than or equal to 1000 (risk difference = -0.001; 95% CI, -0.003 to 0.001; P = .44) showed no association between TXA and incidence of total TEs. Meta-regression of 143 intervention groups showed no association between TXA dosing and risk for venous TEs (risk difference, -0.005; 95% CI, -0.021 to 0.011; P = .53). CONCLUSIONS AND RELEVANCE Findings from this systematic review and meta-analysis of 216 studies suggested that intravenous TXA, irrespective of dosing, is not associated with increased risk of any TE. These results help clarify the incidence of adverse events associated with administration of intravenous TXA and suggest that TXA is safe for use with undetermined utility for patients receiving neurological care.
PICO Summary
Population
Patients of all ages and of any medical disciplines (216 studies, n= 125,550).
Intervention
Intravenous tranexamic acid (TXA).
Comparison
Placebo/no treatment.
Outcome
Total thromboembolic events (TEs) were found in 1020 (2.1%) in the group receiving TXA and 900 (2.0%) in the control group. No association was found between TXA and risk for total TEs for venous thrombosis, pulmonary embolism, venous TEs, myocardial infarction or ischemia, and cerebral infarction or ischemia. Administration of TXA was associated with a significant reduction in overall mortality and bleeding mortality but not with non-bleeding mortality. An increased risk for vascular occlusive events was not found in studies including patients with a history of thromboembolism. Comparison of studies with sample sizes ranging between less than or equal to 99 and greater than or equal to 1000 showed no association between TXA and incidence of total TEs. Meta-regression of 143 intervention groups showed no association between TXA dosing and risk for venous TEs.
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Comparison of common perioperative blood loss estimation techniques: a systematic review and meta-analysis
Gerdessen L, Meybohm P, Choorapoikayil S, Herrmann E, Taeuber I, Neef V, Raimann FJ, Zacharowski K, Piekarski F
Journal of clinical monitoring and computing. 2020
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Abstract
Estimating intraoperative blood loss is one of the daily challenges for clinicians. Despite the knowledge of the inaccuracy of visual estimation by anaesthetists and surgeons, this is still the mainstay to estimate surgical blood loss. This review aims at highlighting the strengths and weaknesses of currently used measurement methods. A systematic review of studies on estimation of blood loss was carried out. Studies were included investigating the accuracy of techniques for quantifying blood loss in vivo and in vitro. We excluded nonhuman trials and studies using only monitoring parameters to estimate blood loss. A meta-analysis was performed to evaluate systematic measurement errors of the different methods. Only studies that were compared with a validated reference e.g. Haemoglobin extraction assay were included. 90 studies met the inclusion criteria for systematic review and were analyzed. Six studies were included in the meta-analysis, as only these were conducted with a validated reference. The mixed effect meta-analysis showed the highest correlation to the reference for colorimetric methods (0.93 95% CI 0.91-0.96), followed by gravimetric (0.77 95% CI 0.61-0.93) and finally visual methods (0.61 95% CI 0.40-0.82). The bias for estimated blood loss (ml) was lowest for colorimetric methods (57.59 95% CI 23.88-91.3) compared to the reference, followed by gravimetric (326.36 95% CI 201.65-450.86) and visual methods (456.51 95% CI 395.19-517.83). Of the many studies included, only a few were compared with a validated reference. The majority of the studies chose known imprecise procedures as the method of comparison. Colorimetric methods offer the highest degree of accuracy in blood loss estimation. Systems that use colorimetric techniques have a significant advantage in the real-time assessment of blood loss.
PICO Summary
Population
Adult surgery and obstetric patients (90 in vitro and in vivo studies).
Intervention
Visual blood loss estimation methods.
Comparison
Several methods including: gravimetric and colorimetric methods.
Outcome
The mixed effect meta-analysis showed the highest correlation to the reference for colorimetric methods (0.93), followed by gravimetric (0.77) and finally visual methods (0.61). The bias for estimated blood loss (ml) was lowest for colorimetric methods (57.59) compared to the reference, followed by gravimetric (326.36) and visual methods (456.51). Colorimetric methods offer the highest degree of accuracy in blood loss estimation.
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Health economics of Patient Blood Management: a cost-benefit analysis based on a meta-analysis
Meybohm P, Straub N, Fullenbach C, Judd L, Kleineruschkamp A, Taeuber I, Zacharowski K, Choorapoikayil S
Vox sanguinis. 2019
Abstract
BACKGROUND AND OBJECTIVES Patient Blood Management (PBM) is the timely application of evidence-based medical and surgical concepts designed to improve haemoglobin concentration, optimize haemostasis and minimize blood loss in an effort to improve patient outcomes. The focus of this cost-benefit analysis is to analyse the economic benefit of widespread implementation of a multimodal PBM programme. MATERIALS AND METHODS Based on a recent meta-analysis including 17 studies (>235 000 patients) comparing PBM with control care and data from the University Hospital Frankfurt, a cost-benefit analysis was performed. Outcome data were red blood cell (RBC) transfusion rate, number of transfused RBC units, and length of hospital stay (LOS). Costs were considered for the following three PBM interventions as examples: anaemia management including therapy of iron deficiency, use of cell salvage and tranexamic acid. For sensitivity analysis, a Monte Carlo simulation was performed. RESULTS Iron supplementation was applied in 3.1%, cell salvage in 65% and tranexamic acid in 89% of the PBM patients. In total, applying these three PBM interventions costs euro129.04 per patient. However, PBM was associated with a reduction in transfusion rate, transfused RBC units per patient, and LOS which yielded to mean savings of euro150.64 per patient. Thus, the overall benefit of PBM implementation was euro21.60 per patient. In the Monte Carlo simulation, the cost savings on the outcome side exceeded the PBM costs in approximately 2/3 of all repetitions and the total benefit was euro1 878 000 in 100.000 simulated patients. CONCLUSION Resources to implement a multimodal PBM concept optimizing patient care and safety can be cost-effectively.
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A model-based cost-effectiveness analysis of patient blood management
Kleineruschkamp A, Meybohm P, Straub N, Zacharowski K, Choorapoikayil S
Blood Transfusion = Trasfusione Del Sangue. 2018;:1-17.
Abstract
BACKGROUND Patient blood management (PBM) is a multidisciplinary concept focused on the management of anaemia, minimisation of iatrogenic blood loss and rational use of allogeneic blood products. The aims of this study were: (i) to analyse post-operative outcome in patients with liberal vs restrictive exposure to allogeneic blood products and (ii) to evaluate the cost-effectiveness of PBM in patients undergoing surgery. MATERIALS AND METHODS A systematic literature review and meta-analysis were performed to compare post-operative complications in predominantly non-transfused patients (restrictive transfusion group) and patients who received one to three units of red blood cells (liberal transfusion group). Outcome measures included sepsis with/without pneumonia, acute renal failure, acute myocardial infarction and acute stroke. In a second step, a health economic model was developed to calculate cost-effectiveness of PBM (PBM-arm vs control-arm) for simulated cohorts of 10,000 cardiac and non-cardiac surgical patients based on the results of the meta-analysis and costs. RESULTS Out of 478 search results, 22 studies were analysed in the meta-analysis. The pooled relative risk of any complication in the restrictive transfusion group was 0.43 for non-cardiac and 0.34 for cardiac surgical patients. In the simulation model, PBM was related to reduced complications (1,768 vs 1,245) and complication-related deaths (411 vs 304) compared to standard care. PBM-related costs of therapy exceeded costs of the control arm by euro 150 per patient. However, total costs, including hospitalisation, were higher in the control-arm for both non-cardiac (euro 2,885.11) and cardiac surgery patients (euro 1,760.69). The incremental cost-effectiveness ratio including hospitalisation showed savings of euro 30,458 (non-cardiac and cardiac surgery patients) for preventing one complication and euro 128,023 (non-cardiac and cardiac surgery patients) for prevention of one complication-related death in the PBM-arm. DISCUSSION Our results indicate that PBM may be associated with fewer adverse clinical outcomes compared to control management and may, thereby, be cost-effective.
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Multimodal Patient Blood Management Program Based on a Three-pillar Strategy: A Systematic Review and Meta-analysis
Althoff FC, Neb H, Herrmann E, Trentino KM, Vernich L, Fullenbach C, Freedman J, Waters JH, Farmer S, Leahy MF, et al
Annals of Surgery. 2018
Abstract
OBJECTIVES To determine whether a multidisciplinary, multimodal Patient Blood Management (PBM) program for patients undergoing surgery is effective in reducing perioperative complication rate, and thereby is effective in improving clinical outcome. BACKGROUND PBM is a medical concept with the focus on a comprehensive anemia management, to minimize iatrogenic (unnecessary) blood loss, and to harness and optimize patient-specific physiological tolerance of anemia. METHODS A systematic review and meta-analysis was performed. Eligible studies had to address each of the 3 PBM pillars with at least 1 measure per pillar, for example, preoperative anemia management plus cell salvage plus rational transfusion strategy. The study protocol has been registered with PROSPERO (CRD42017079217). RESULTS Seventeen studies comprising 235,779 surgical patients were included in this meta-analysis (100,886 pre-PBM group and 134,893 PBM group). Implementation of PBM significantly reduced transfusion rates by 39% [risk ratio (RR) 0.61, 95% confidence interval (CI) 0.55-0.68, P < 0.00001], 0.43 red blood cell units per patient (mean difference -0.43, 95% CI -0.54 to -0.31, P < 0.00001), hospital length of stay (mean difference -0.45, 95% CI -0.65 to -0.25, P < 0,00001), total number of complications (RR 0.80, 95% CI 0.74-0.88, P <0.00001), and mortality rate (RR 0.89, 95% CI 0.80-0.98, P = 0.02). CONCLUSIONS Overall, a comprehensive PBM program addressing all 3 PBM pillars is associated with reduced transfusion need of red blood cell units, lower complication and mortality rate, and thereby improving clinical outcome. Thus, this first meta-analysis investigating a multimodal approach should motivate all executives and health care providers to support further PBM activities.This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0.
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Washed cell salvage in surgical patients: a review and meta-analysis of prospective randomized trials under PRISMA
Meybohm P, Choorapoikayil S, Wessels A, Herrmann E, Zacharowski K, Spahn DR
Medicine. 2016;95((31)):e4490.
Abstract
BACKGROUND Cell salvage is commonly used as part of a blood conservation strategy. However concerns among clinicians exist about the efficacy of transfusion of washed cell salvage. METHODS We performed a meta-analysis of randomized controlled trials in which patients, scheduled for all types of surgery, were randomized to washed cell salvage or to a control group with no cell salvage. Data were independently extracted, risk ratio (RR), and weighted mean differences (WMD) with 95% confidence intervals (CIs) were calculated. Data were pooled using a random effects model. The primary endpoint was the number of patients exposed to allogeneic red blood cell (RBC) transfusion. RESULTS Out of 1140 search results, a total of 47 trials were included. Overall, the use of washed cell salvage reduced the rate of exposure to allogeneic RBC transfusion by a relative 39% (RR = 0.61; 95% CI 0.57 to 0.65; P < 0.001), resulting in an average saving of 0.20 units of allogeneic RBC per patient (weighted mean differences [WMD] = -0.20; 95% CI -0.22 to -0.18; P < 0.001), reduced risk of infection by 28% (RR = 0.72; 95% CI 0.54 to 0.97; P = 0.03), reduced length of hospital stay by 2.31 days (WMD = -2.31; 95% CI -2.50 to -2.11; P < 0.001), but did not significantly affect risk of mortality (RR = 0.92; 95% CI 0.63 to 1.34; P = 0.66). No statistical difference could be observed in the number of patients exposed to re-operation, plasma, platelets, or rate of myocardial infarction and stroke. CONCLUSIONS Washed cell salvage is efficacious in reducing the need for allogeneic RBC transfusion and risk of infection in surgery.
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Aprotinin may increase mortality in low and intermediate risk but not in high risk cardiac surgical patients compared to tranexamic acid and -aminocaproic acid - a meta-analysis of randomised and observational trials of over 30.000 patients
Meybohm P, Herrmann E, Nierhoff J, Zacharowski K
PLoS ONE. 2013;8((3):):e58009.
Abstract
BACKGROUND To compare the effect of aprotinin with the effect of lysine analogues (tranexamic acid and -aminocaproic acid) on early mortality in three subgroups of patients: low, intermediate and high risk of cardiac surgery. METHODS AND FINDINGS We performed a meta-analysis of randomised controlled trials and observational with the following data sources: Medline, Cochrane Library, and reference lists of identified articles. The primary outcome measure was early (in-hospital/30-day) mortality. The secondary outcome measures were any transfusion of packed red blood cells within 24 hours after surgery, any re-operation for bleeding or massive bleeding, and acute renal dysfunction or failure within the selected cited publications, respectively. Out of 328 search results, 31 studies (15 trials and 16 observational studies) included 33,501 patients. Early mortality was significantly increased after aprotinin vs. lysine analogues with a pooled risk ratio (95% CI) of 1.58 (1.13-2.21), p<0.001 in the low (n=14,297) and in the intermediate risk subgroup (1.42 (1.09-1.84), p<0.001; n=14,427), respectively. Contrarily, in the subgroup of high risk patients (n=4,777), the risk for mortality did not differ significantly between aprotinin and lysine analogues (1.03 (0.67-1.58), p=0.90). CONCLUSION Aprotinin may be associated with an increased risk of mortality in low and intermediate risk cardiac surgery, but presumably may has no effect on early mortality in a subgroup of high risk cardiac surgery compared to lysine analogues. Thus, decisions to re-license aprotinin in lower risk patients should critically be debated. In contrast, aprotinin might probably be beneficial in high risk cardiac surgery as it reduces risk of transfusion and bleeding complications.