RESUMO
BACKGROUND: Thrombosis and inflammation may contribute to morbidity and mortality among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation would improve outcomes in critically ill patients with Covid-19. METHODS: In an open-label, adaptive, multiplatform, randomized clinical trial, critically ill patients with severe Covid-19 were randomly assigned to a pragmatically defined regimen of either therapeutic-dose anticoagulation with heparin or pharmacologic thromboprophylaxis in accordance with local usual care. The primary outcome was organ support-free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of -1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge. RESULTS: The trial was stopped when the prespecified criterion for futility was met for therapeutic-dose anticoagulation. Data on the primary outcome were available for 1098 patients (534 assigned to therapeutic-dose anticoagulation and 564 assigned to usual-care thromboprophylaxis). The median value for organ support-free days was 1 (interquartile range, -1 to 16) among the patients assigned to therapeutic-dose anticoagulation and was 4 (interquartile range, -1 to 16) among the patients assigned to usual-care thromboprophylaxis (adjusted proportional odds ratio, 0.83; 95% credible interval, 0.67 to 1.03; posterior probability of futility [defined as an odds ratio <1.2], 99.9%). The percentage of patients who survived to hospital discharge was similar in the two groups (62.7% and 64.5%, respectively; adjusted odds ratio, 0.84; 95% credible interval, 0.64 to 1.11). Major bleeding occurred in 3.8% of the patients assigned to therapeutic-dose anticoagulation and in 2.3% of those assigned to usual-care pharmacologic thromboprophylaxis. CONCLUSIONS: In critically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin did not result in a greater probability of survival to hospital discharge or a greater number of days free of cardiovascular or respiratory organ support than did usual-care pharmacologic thromboprophylaxis. (REMAP-CAP, ACTIV-4a, and ATTACC ClinicalTrials.gov numbers, NCT02735707, NCT04505774, NCT04359277, and NCT04372589.).
Assuntos
Anticoagulantes/administração & dosagem , Tratamento Farmacológico da COVID-19 , Heparina/administração & dosagem , Trombose/prevenção & controle , Idoso , Anticoagulantes/efeitos adversos , Anticoagulantes/uso terapêutico , COVID-19/mortalidade , Estado Terminal , Feminino , Hemorragia/induzido quimicamente , Heparina/efeitos adversos , Heparina/uso terapêutico , Mortalidade Hospitalar , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Respiração Artificial , Falha de TratamentoRESUMO
BACKGROUND: Thrombosis and inflammation may contribute to the risk of death and complications among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation may improve outcomes in noncritically ill patients who are hospitalized with Covid-19. METHODS: In this open-label, adaptive, multiplatform, controlled trial, we randomly assigned patients who were hospitalized with Covid-19 and who were not critically ill (which was defined as an absence of critical care-level organ support at enrollment) to receive pragmatically defined regimens of either therapeutic-dose anticoagulation with heparin or usual-care pharmacologic thromboprophylaxis. The primary outcome was organ support-free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of -1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge. This outcome was evaluated with the use of a Bayesian statistical model for all patients and according to the baseline d-dimer level. RESULTS: The trial was stopped when prespecified criteria for the superiority of therapeutic-dose anticoagulation were met. Among 2219 patients in the final analysis, the probability that therapeutic-dose anticoagulation increased organ support-free days as compared with usual-care thromboprophylaxis was 98.6% (adjusted odds ratio, 1.27; 95% credible interval, 1.03 to 1.58). The adjusted absolute between-group difference in survival until hospital discharge without organ support favoring therapeutic-dose anticoagulation was 4.0 percentage points (95% credible interval, 0.5 to 7.2). The final probability of the superiority of therapeutic-dose anticoagulation over usual-care thromboprophylaxis was 97.3% in the high d-dimer cohort, 92.9% in the low d-dimer cohort, and 97.3% in the unknown d-dimer cohort. Major bleeding occurred in 1.9% of the patients receiving therapeutic-dose anticoagulation and in 0.9% of those receiving thromboprophylaxis. CONCLUSIONS: In noncritically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin increased the probability of survival to hospital discharge with reduced use of cardiovascular or respiratory organ support as compared with usual-care thromboprophylaxis. (ATTACC, ACTIV-4a, and REMAP-CAP ClinicalTrials.gov numbers, NCT04372589, NCT04505774, NCT04359277, and NCT02735707.).
Assuntos
Anticoagulantes/administração & dosagem , Tratamento Farmacológico da COVID-19 , Heparina/administração & dosagem , Trombose/prevenção & controle , Adulto , Idoso , Anticoagulantes/efeitos adversos , Anticoagulantes/uso terapêutico , COVID-19/mortalidade , Feminino , Hemorragia/induzido quimicamente , Heparina/efeitos adversos , Heparina/uso terapêutico , Heparina de Baixo Peso Molecular/uso terapêutico , Mortalidade Hospitalar , Humanos , Masculino , Pessoa de Meia-Idade , Análise de SobrevidaRESUMO
Iron overload (IO) reflected by elevated ferritin is associated with increased mortality in myelodysplastic syndromes (MDS), however, ferritin is an imperfect metric. Elevated labile plasma iron correlates with clinical outcomes and transferrin saturation (TSAT) >80%, but is not readily measurable. The trajectory of TSAT, and its association with clinical outcomes remain undefined. Canadian MDS registry patients were evaluated. Mean TSAT, mean ferritin and transfusion dose density (TDD) were determined. Survival was evaluated by TSAT and ferritin (<50%, 50-80%, >80%), (≤500 µg/L, 501-800 µg/L, >800 µg/L). In 718 patients, median age was 74 years; 12%, 31%, 29%, 15% and 13% were IPSS-R very low, low, intermediate, high and very high. TSAT and ferritin were moderately correlated (r=0.63, P<0.0001). TSAT increased over time in transfusion- dependent patients (P=0.006). Higher TSAT and ferritin were associated with inferior 5-year overall (OS), progression- free (PFS), and leukemia-free survival (LFS) (P≤0.008) and higher TDD with inferior 5-year OS. TSAT >80% trended with inferior cardiac death-free survival (P=0.053). In univariate analysis, age, IPSS-R, blast percentage by Eastern Cooperative Oncology Group Performance Status, frailty, Charlson Comorbidity Index, iron chelation (Y/N), TDD, TSAT and ferritin were significantly associated with inferior OS. By multivariable analysis, TSAT >80% (P=0.007) remained significant for OS (R2 30.3%). In MDS, TSAT >80% and ferritin >800 µg/L portended inferior OS, PFS and LFS. TSAT may indicate the presence of oxidative stress, and is readily measurable in a clinical setting. The relationship between TSAT and cardiac death-free survival warrants further study.
Assuntos
Ferro , Síndromes Mielodisplásicas , Humanos , Idoso , Canadá , Ferritinas , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/terapia , Transferrinas , TransferrinaRESUMO
INTRODUCTION: Acquired haemophilia A (AHA) is a rare bleeding disorder characterized by autoantibodies against coagulation factor VIII (FVIII). Estimates of AHA incidence are largely based on registry data, which may be prone to referral bias. Population-based studies can enhance our understanding of the epidemiology, presentation and outcomes of AHA. METHODS: We conducted a retrospective, population-based cohort study of all AHA diagnosed and treated in Manitoba, Canada over a 15-year period. Using records from the sole provincial reference laboratory, we identified all patients with FVIII inhibitors who did not have congenital haemophilia. Using a piloted case report form, patient data was ascertained from hospital and bleeding disorder clinic records. RESULTS: From 2006 to 2021, we identified 34 patients with AHA, corresponding to a population-based incidence rate of AHA of 1.78 cases per million per year. The median age at presentation was 76 years and most cases were idiopathic (79%). Almost all patients (97%) presented with bleeding, of which 58% were considered major bleeds and required haemostatic agents in 67%. Longstanding unexplained bleeding symptoms were commonly reported, suggesting delayed diagnosis. Immunosuppressive therapy (IST) was administered in 88% of patients. Remission was achieved in 79% of patients; median time to remission was 2.1 months. There were two deaths due to bleeding. No deaths due to IST were reported. CONCLUSION: The population-based incidence of AHA in Manitoba is 1.78 cases/million/year. Bleeding is common and can be life-threatening. AHA outcomes are encouraging with the use of haemostatic agents and IST. Serious treatment-associated morbidity and mortality is uncommon.
Assuntos
Hemofilia A , Humanos , Hemofilia A/tratamento farmacológico , Hemofilia A/epidemiologia , Incidência , Estudos de Coortes , Estudos Retrospectivos , Resultado do TratamentoRESUMO
PURPOSE: Septic shock is associated with a mortality of 20-40%. The white blood cell count (WBC) at hospital admission correlates with prognosis in septic shock. Here, we explore whether the trajectory of WBC after admission provides further information about outcomes. We aimed to identify groups of patients with different WBC trajectories and the association of WBC trajectory with mortality. METHODS: We included adult patients with septic shock in two academic intensive care units (ICU) in Winnipeg, MB, Canada between 2006 and 2012. We used group-based trajectory analysis to group patients according to their WBC patterns over the first seven days in the ICU. Our primary analysis was the association of WBC trajectory group on 30-day mortality using multivariable Cox proportional hazards regression. RESULTS: We included 917 patients with septic shock. The final model identified seven distinct WBC trajectories. The rising WBC trajectory was independently associated with increased mortality (hazard ratio, 3.41; 95% confidence interval, 1.86 to 6.26; P < 0.001) compared with the stable WBC trajectory. CONCLUSION: In patients with septic shock, distinct and clinically relevant groups can be identified by analyzing WBC trajectories. A rising WBC trajectory was associated with higher mortality.
RéSUMé: OBJECTIF: Le choc septique est associé à une mortalité de 20 à 40 %. La numération leucocytaire à l'admission à l'hôpital est corrélée au pronostic en cas de choc septique. Dans ce manuscrit, nous tentons de déterminer si l'évolution de la numération leucocytaire après l'admission fournit plus d'informations sur les devenirs. Nous avons cherché à identifier des groupes de patients présentant différentes trajectoires d'évolution de numération leucocytaire et l'association entre l'évolution de la numération et la mortalité. MéTHODE: Nous avons inclus des patients adultes atteints d'un choc septique dans deux unités de soins intensifs (USI) universitaires à Winnipeg, Manitoba, Canada entre 2006 et 2012. Nous avons utilisé une analyse de l'évolution basée sur le groupe pour regrouper les patients en fonction du type d'évolution de la numération leucocytaire au cours des sept premiers jours à l'USI. Notre analyse principale consistait à déterminer l'association entre le groupe d'évolution de numération leucocytaire et la mortalité à 30 jours en utilisant une régression multivariable à risque proportionnel de Cox. RéSULTATS: Nous avons inclus 917 patients atteints de choc septique. Le modèle final a identifié sept types de trajectoire d'évolution de numération leucocytaire distincts. Une évolution ascendante de la numération leucocytaire était indépendamment associée à une augmentation de la mortalité (rapport de risque, 3,41; intervalle de confiance à 95 %, 1,86 à 6,26; P < 0,001) par rapport à une évolution de numération leucocytaire stable. CONCLUSION: Chez les patients atteints de choc septique, des groupes distincts et cliniquement pertinents peuvent être identifiés en analysant les trajectoires d'évolution de la numération leucocytaire. Une évolution ascendante de la numération leucocytaire était associée à une mortalité plus élevée.
Assuntos
Choque Séptico , Adulto , Estudos de Coortes , Humanos , Unidades de Terapia Intensiva , Contagem de Leucócitos , Prognóstico , Estudos RetrospectivosRESUMO
BACKGROUND: Tranexamic acid (TXA) reduces transfusion in a wide range of surgical populations, although its real-world use in non-cardiac surgeries has not been well described. The objective of this study was to describe prophylactic TXA use in non-cardiac surgeries at high risk for transfusion. METHODS: This is a retrospective cohort study of all adult patients undergoing major non-cardiac surgery at ≥5% risk of perioperative transfusion at five Canadian hospitals between January 2014 and December 2016. Canadian Classification of Health Interventions procedure codes within the Discharge Abstract Database were linked to transfusion and laboratory databases. TXA use was ascertained electronically from The Ottawa Hospital Data Warehouse and via manual chart review for Winnipeg hospitals. For each surgery, we evaluated the percentage of patients who received TXA as well as the specifics of TXA dosing and administration. RESULTS: TXA use was evaluable in 14 300 patients. Overall, 17% of surgeries received TXA, ranging from 0% to 68% among individual surgeries. TXA use was more common in orthopaedic (n = 2043/4942; 41%) and spine surgeries (n = 239/1322; 18%) compared to other surgical domains (n = 109/8036; 1%). TXA was commonly administered as a bolus (n = 2097/2391; 88%). The median TXA dose was 1000 mg (IQR 1000-1000 mg). CONCLUSION: TXA is predominantly used in orthopaedic and spine surgeries, with little uptake in other non-cardiac surgeries at high risk for red blood cell transfusion. Further studies are needed to evaluate the effectiveness and safety of TXA and to understand the barriers to TXA administration in a broad range of non-cardiac surgeries.
Assuntos
Antifibrinolíticos , Ácido Tranexâmico , Perda Sanguínea Cirúrgica/prevenção & controle , Canadá , Humanos , Estudos RetrospectivosRESUMO
PURPOSE: Intravenous immune globulin (IVIG) may improve survival in people with septic shock. Current utilization patterns of IVIG are unknown. We sought to characterize adult patients with septic shock requiring vasopressors who received IVIG, describes IVIG regimens, and evaluate determinants of IVIG use in patients with septic shock. METHODS: We conducted a retrospective database study of adult patients with septic shock admitted to US hospitals in the Premier Healthcare Database (from July 2010 to June 2013). We described the proportion of patients with septic shock receiving IVIG, examined IVIG regimens across sites and employed random-effects multivariable regression techniques to identify predictors of IVIG use. RESULTS: Intravenous immune globulin was administered to 0.3% (n = 685) of patients with septic shock; with a median [interquartile range (IQR)] dose of 1 [0.5-1.8] g·kg-1 for a median [IQR] of 1 [1-2] day. Receipt of IVIG was less likely for Black patients (odds ratio [OR], 0.54; 95% confidence interval [CI] 0.41 to 0.72) and patients without private insurance (Medicare OR, 0.73; 95% CI 0.59 to 0.90; Medicaid OR, 0.41; 95% CI 0.30 to 0.57) and more likely for patients with immunocompromise (OR, 6.83; 95% CI 5.47 to 8.53), necrotizing fasciitis (OR, 9.78; 95% CI 6.97 to 13.72), and toxic shock (OR, 56.9; 95% CI 38.7 to 83.7). CONCLUSIONS: Intravenous immune globulin is used infrequently across the US in patients with septic shock. Regimens of IVIG in septic shock may be less intensive than those associated with a survival benefit in meta-analyses. Observed infrequent use supports apparent clinical equipoise, perhaps secondary to limitations of the primary literature. A clinical trial evaluating the role of IVIG in septic shock is needed.
RéSUMé: OBJECTIF: L'immunoglobuline intraveineuse (IGIV) peut améliorer la survie chez les personnes atteintes de choc septique. Les pratiques actuelles d'utilisation de l'IGIV sont inconnues. Nous avons cherché à caractériser les patients adultes en état de choc septique et nécessitant des vasopresseurs qui ont reçu de l'IGIV, à décrire les dosages administrés d'IGIV, et à évaluer les causes déterminantes d'une utilisation d'IGIV chez ces patients. MéTHODE: Nous avons réalisé une étude rétrospective de base de données portant sur des patients adultes atteints de choc septique admis dans des hôpitaux américains et inclus dans la base de données Premier Healthcare (de juillet 2010 à juin 2013). Nous avons décrit la proportion de patients en choc septique recevant de l'IGIV, examiné les posologies utilisées d'IGIV à travers les sites et employé des techniques de régression multivariable à effets aléatoires pour identifier les prédicteurs de l'utilisation d'IGIV. RéSULTATS: L'IGIV a été administrée à 0,3 % (n = 685) des patients présentant un choc septique, avec une dose médiane [écart interquartile (ÉIQ)] de 1 [0,51,8] g·kg-1 pour une médiane [ÉIQ] de 1 [12] jour. L'administration d'IGIV était moins probable chez les patients noirs (rapport de cotes [RC], 0,54; intervalle de confiance [IC] à 95 %, 0,41 à 0,72) et les patients sans assurance privée (RC Medicare, 0,73; IC 95 %, 0,59 à 0,90; RC Medicaid, 0,41; IC 95 %, 0,30 à 0,57) et plus probable chez les patients immunodéprimés (RC, 6,83; IC 95 %, 5,47 à 8,53), atteints de fasciite nécrosante (RC, 9,78; IC 95 %, 6,97 à 13,72), et en choc toxique (RC, 56,9; IC 95 %, 38,7 à 83,7). CONCLUSION: L'IGIV est rarement utilisée aux États-Unis chez les patients en choc septique. Les dosages d'IGIV utilisés en cas de choc septique pourraient être moins intensifs que ceux associés à un effet bénéfique en matière de survie dans les méta-analyses. L'utilisation peu fréquente observée appuie une équivalence clinique apparente, peut-être secondaire aux limites de la littérature princeps. Une étude clinique évaluant le rôle de l'IGIV dans le choc septique est nécessaire.
Assuntos
Imunoglobulinas Intravenosas , Choque Séptico , Adulto , Atenção à Saúde , Humanos , Medicare , Estudos Retrospectivos , Choque Séptico/tratamento farmacológico , Estados Unidos/epidemiologiaRESUMO
PURPOSE: Tranexamic acid (TXA) reduces red blood cell transfusion in various orthopedic surgeries, yet the degree of practice variation in its use among anesthesiologists and surgeons has not been described. To target future knowledge transfer and implementation strategies, and to better understand determinants of variability in prophylactic TXA use, our primary objective was to evaluate the influence of surgical team members on the variability of prophylactic TXA administration. METHODS: This was a retrospective cohort study of all adult patients undergoing primary total hip arthroplasty (THA), hip fracture surgery, and spine fusion ± vertebrectomy at two Canadian hospitals between January 2014 and December 2016. We used Canadian Classification of Health Interventions procedure codes within the Discharge Abstract Database which we linked to the Ottawa Data Warehouse. We described the percentage of patients that received TXA by individual surgery, the specifics of TXA dosing, and estimated the effect of anesthesiologists and surgeons on prophylactic TXA using multivariable mixed-effects logistic regression analyses. RESULTS: In the 3,900 patients studied, TXA was most commonly used in primary THA (85%; n = 1,344/1,582), with lower use in hip fracture (23%; n = 342/1,506) and spine fusion surgery (23%; n = 186/812). The median [interquartile range] total TXA dose was 1,000 [1,000-1,000] mg, given as a bolus in 92% of cases. Anesthesiologists and surgeons added significant variability to the odds of receiving TXA in hip fracture surgery and spine fusion, but not primary THA. Most of the variability in TXA use was attributed to patient and other factors. CONCLUSION: We confirmed the routine use of TXA in primary THA, while observing lower utilization with more variability in hip fracture and spine fusion surgery. Further study is warranted to understand variations in use and the barriers to TXA implementation in a broader population of orthopedic surgical patients at high risk for transfusion.
RéSUMé: OBJECTIF: L'acide tranexamique (ATX) réduit la transfusion d'érythrocytes dans diverses chirurgies orthopédiques. Cependant, les variations de pratique quant à son utilisation parmi les anesthésiologistes et les chirurgiens n'ont pas été décrites. Afin de cibler les stratégies futures de transfert des connaissances et de mise en Åuvre, et pour mieux comprendre les déterminants de la variabilité dans l'utilisation prophylactique d'ATX, notre objectif principal était d'évaluer l'influence des membres de l'équipe chirurgicale sur la variabilité de l'administration prophylactique d'ATX. MéTHODE: Il s'agissait d'une étude de cohorte rétrospective de tous les patients adultes subissant une arthroplastie totale primaire de la hanche (ATH), une chirurgie de fracture de la hanche et une fusion intervertébrale ± vertébrectomie dans deux hôpitaux canadiens entre janvier 2014 et décembre 2016. Nous avons utilisé les codes de procédure de la Classification canadienne des interventions en santé dans la Base de données sur les congés des patients, que nous avons liée à la banque de données d'Ottawa. Nous avons décrit le pourcentage de patients qui ont reçu de l'ATX par chirurgie individuelle, les détails du dosage de l'ATX, et avons estimé l'effet des anesthésiologistes et des chirurgiens sur l'ATX prophylactique en réalisant des analyses de régression logistique multivariées à effets mixtes. RéSULTATS: Parmi les 3900 patients étudiés, l'ATX était le plus fréquemment utilisé lors d'une ATH primaire (85 %; n = 1344/1582), avec une utilisation plus faible lors de chirurgie de fracture de la hanche (23 %; n = 342/1506) et de chirurgie de fusion intervertébrale (23 %; n = 186/812). La dose totale médiane [écart interquartile] d'ATX était de 1000 mg [1000 à 1000], administrés dans 92 % des cas sous forme de bolus. Les anesthésiologistes et les chirurgiens ont ajouté une variabilité significative aux probabilités de recevoir de l'ATX lors d'une chirurgie de fracture de la hanche et de fusion, mais pas lors d'ATH primaire. La majeure partie de la variabilité dans l'utilisation d'ATX était attribuable aux facteurs liés au patient et à d'autres facteurs. CONCLUSION: Nous avons confirmé l'utilisation de routine de l'ATX dans l'ATH primaire, tout en observant une utilisation moins répandue et plus variable lors de chirurgie de fracture de la hanche et de fusion intervertébrale. Une étude plus approfondie est nécessaire pour comprendre les variations d'utilisation et les obstacles à la mise en Åuvre de l'ATX dans une population plus étendue de patients de chirurgie orthopédique à haut risque de transfusion.
Assuntos
Antifibrinolíticos , Artroplastia de Quadril , Cirurgiões , Ácido Tranexâmico , Adulto , Anestesiologistas , Perda Sanguínea Cirúrgica/prevenção & controle , Canadá , Humanos , Estudos RetrospectivosRESUMO
PURPOSE: This national survey evaluated the perceived efficacy and safety of intravenous immune globulin (IVIG) in septic shock, self-reported utilization patterns, barriers to use, the population of interest for further trials and willingness to participate in future research of IVIG in septic shock. METHODS: We conducted a cross-sectional survey of critical care and infectious diseases physicians across Canada. We summarized categorical item responses as counts and proportions. We developed a multivariable logistic regression model to identify physician-level predictors of IVIG use in septic shock. RESULTS: Our survey was disseminated to 674 eligible respondents with a final response rate of 60%. Most (91%) respondents reported having prescribed IVIG to patients with septic shock at least once, 86% for septic shock due to necrotizing fasciitis, 52% for other bacterial toxin-mediated causes of septic shock, and 5% for undifferentiated septic shock. The majority of respondents expressed uncertainty regarding the impact of IVIG on mortality (97%) and safety (95%) in septic shock. Respondents were willing to participate in further IVIG research with 98% stating they would consider enrolling their patients into a trial of IVIG in septic shock. Familiarity with published evidence was the single greatest predictor of IVIG use in septic shock (odds ratio, 10.2; 95% confidence interval, 3.4 to 30.5; P < 0.001). CONCLUSIONS: Most Canadian critical care and infectious diseases specialist physicians reported previous experience using IVIG in septic shock. Respondents identified inadequacy of existing research as the greatest barrier to routine use of IVIG in septic shock. Most respondents support the need for further studies on IVIG in septic shock, and would consider enrolling their own patients into a trial of IVIG in septic shock.
RéSUMé: OBJECTIF : Cette enquête nationale a évalué l'efficacité et l'innocuité perçues des immunoglobulines intraveineuses (IgIV) dans le contexte du choc septique, les habitudes d'utilisation autodéclarées, les obstacles à l'utilisation de cette modalité, les populations à explorer pour des études futures et la volonté de participer aux recherches futures sur les IgIV et le choc septique. MéTHODE : Nous avons mené une enquête transversale auprès de médecins intensivistes et spécialistes des maladies infectieuses au Canada. Nous avons résumé les réponses de chaque point catégorique en tant que dénombrement et proportions. Nous avons mis au point un modèle de régression logistique multivariée afin d'identifier les prédicteurs, au niveau des médecins, d'une utilisation des IgIV en cas de choc septique. RéSULTATS : Notre sondage a été acheminé à 674 médecins admissibles et nous avons obtenu un taux de réponse final de 60 %. La plupart (91%) des répondants ont indiqué avoir prescrit des IgIV aux patients en choc septique au moins une fois, 86 % pour un choc septique dû à une fasciite nécrosante, 52 % pour des chocs septiques d'autres étiologies médiées par des toxines bactériennes, et 5 % dans des cas de choc septique non différencié. La majorité des répondants ont exprimé de l'incertitude quant à l'incidence des IgIV sur la mortalité (97 %) et l'innocuité (95 %) lors de choc septique. Les répondants étaient disposés à participer à d'autres recherches sur les IgIV, 98 % déclarant qu'ils envisageraient d'inscrire leurs patients à une étude sur les IgIV et le choc septique. La familiarité avec les données probantes publiées était le plus grand prédicteur d'utilisation d'IgIV dans un contexte de choc septique (rapport de cotes, 10,2; intervalle de confiance à 95 %, 3,4 à 30,5; P < 0,001). CONCLUSION : La plupart des médecins intensivistes et spécialistes des maladies infectieuses canadiens ont rapporté avoir une expérience antérieure d'utilisation d'IgIV en cas de choc septique. Les répondants ont identifié l'insuffisance de la recherche existante comme le plus grand obstacle à l'utilisation systématique d'IgIV dans les cas de choc septique. La plupart des répondants appuient la nécessité d'études plus approfondies sur les IgIV et le choc septique et envisageraient d'inscrire leurs propres patients à une étude sur les IgIV dans un contexte de choc septique.
Assuntos
Doenças Transmissíveis , Médicos , Sepse , Choque Séptico , Canadá , Cuidados Críticos , Estudos Transversais , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Choque Séptico/tratamento farmacológicoRESUMO
BACKGROUND: Mortality from COVID-19 is high among hospitalized patients and effective therapeutics are lacking. Hypercoagulability, thrombosis and hyperinflammation occur in COVID-19 and may contribute to severe complications. Therapeutic anticoagulation may improve clinical outcomes through anti-thrombotic, anti-inflammatory and anti-viral mechanisms. Our primary objective is to evaluate whether therapeutic-dose anticoagulation with low-molecular-weight heparin or unfractionated heparin prevents mechanical ventilation and/or death in patients hospitalized with COVID-19 compared to usual care. METHODS: An international, open-label, adaptive randomized controlled trial. Using a Bayesian framework, the trial will declare results as soon as pre-specified posterior probabilities for superiority, futility, or harm are reached. The trial uses response-adaptive randomization to maximize the probability that patients will receive the more beneficial treatment approach, as treatment effect information accumulates within the trial. By leveraging a common data safety monitoring board and pooling data with a second similar international Bayesian adaptive trial (REMAP-COVID anticoagulation domain), treatment efficacy and safety will be evaluated as efficiently as possible. The primary outcome is an ordinal endpoint with three possible outcomes based on the worst status of each patient through day 30: no requirement for invasive mechanical ventilation, invasive mechanical ventilation or death. CONCLUSION: Using an adaptive trial design, the Anti-Thrombotic Therapy To Ameliorate Complications of COVID-19 trial will establish whether therapeutic anticoagulation can reduce mortality and/or avoid the need for mechanical ventilation in patients hospitalized with COVID-19. Leveraging existing networks to recruit sites will increase enrollment and mitigate enrollment risk in sites with declining COVID-19 cases.
Assuntos
Antivirais/uso terapêutico , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Heparina/administração & dosagem , Pneumonia Viral/tratamento farmacológico , Trombose/prevenção & controle , Adolescente , Adulto , Anticoagulantes/administração & dosagem , COVID-19 , Infecções por Coronavirus/complicações , Infecções por Coronavirus/epidemiologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/epidemiologia , SARS-CoV-2 , Trombose/etiologia , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVES: To characterize the prevalence, incidence, and temporal evolution of thrombocytopenia (platelets < 100 × 10/L) in septic shock and to investigate the independent association of thrombocytopenia on clinical outcomes. DESIGN: Retrospective, propensity-matched, cohort study. SETTING: Two academic ICUs in Winnipeg, Canada. PATIENTS: Nine-hundred eighty adult patients diagnosed with septic shock between 2007 and 2012. INTERVENTIONS: Propensity-matched cohort analysis and Cox proportional hazard model evaluating thrombocytopenia over time. MEASUREMENTS AND MAIN RESULTS: Of 980 adults, 165 patients (16.8%) had thrombocytopenia at ICU admission (prevalent), whereas 271 (27.7%) developed thrombocytopenia during ICU admission (incident). Among patients with incident thrombocytopenia, the median time from ICU admission to thrombocytopenia was 2 days (interquartile range, 1-3 d). Among survivors, the median time from incident thrombocytopenia to platelet recovery was 6 days (interquartile range, 4-8 d). The median time from liberation of vasopressors to recovery of platelets concentration (≥ 100 × 10/L) was 2 days (interquartile range, 0-4 d). In a propensity-matched analysis, thrombocytopenia was associated with increased durations of ICU length of stay (9 vs 6 d; p < 0.01), mechanical ventilation (7 vs 4 d; p < 0.01), and vasopressor use (4 vs 3 d; p < 0.01), as well as increased major bleeding events (41% vs 18%; p < 0.01). In an adjusted Cox proportional hazards model, thrombocytopenia was significantly associated with both increased ICU mortality (hazard ratio, 1.99; 95% CI, 1.51-2.63) and hospital mortality (hazard ratio, 1.93; 95% CI, 1.48-2.51). CONCLUSIONS: Both the prevalence and incidence of thrombocytopenia are high in septic shock. Incident thrombocytopenia occurs early in septic shock, and platelet recovery lags behind clinical recovery. In septic shock, thrombocytopenia is associated with increased length of stay, longer duration of organ support, major bleeding events, and mortality.
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Cuidados Críticos/estatística & dados numéricos , Índice de Gravidade de Doença , Choque Séptico/epidemiologia , Trombocitopenia/epidemiologia , Estudos de Coortes , Feminino , Humanos , Tempo de Internação/estatística & dados numéricos , Masculino , Prevalência , Estudos RetrospectivosRESUMO
PURPOSE: Statistical approaches have been developed to detect bias in individual trials, but guidance on how to detect systematic differences at a meta-analytical level is lacking. In this paper, we elucidate whether author bias can be detected in a cohort of randomized trials included in a meta-analysis. METHODS: We utilized mortality data from 35 trials (10,880 patients) included in our previously published meta-analysis. First, we linked each author with their trial (or trials). Then we calculated author-specific odds ratios using univariate cross table methods. Finally, we tested the effect of authorship by comparing each author's estimated odds ratio with all other pooled estimated odds ratios using meta-regression. RESULTS: The median number of investigators named as authors on the primary trial reports was six (interquartile range: 5-8, range: 2-32). The results showed that the slope of author effect for mortality ranged from - 1.35 to 0.71. We identified only one author team showing a marginally significant effect (- 0.39; 95% confidence interval, - 0.78 to 0.00). This author team has a history of retractions due to data manipulations and ethical violations. CONCLUSION: When combining trial-level data to produce a pooled effect estimate, investigators must consider sources of potential bias. Our results suggest that systematic errors can be detected using meta-regression, although further research is needed to examine the sensitivity of this model. Systematic reviewers will benefit from the availability of methods to guard against the dissemination of results with the potential to mislead decision-making.
RéSUMé: OBJECTIF: Des approches statistiques ont été élaborées pour détecter les biais dans les essais individuels, mais nous manquons d'orientations sur les méthodes à utiliser pour les détecter au niveau des méta-analyses. Dans cet article, nous étudions s'il est possible de détecter des biais liés à l'auteur dans un ensemble d'essais randomisés inclus dans une méta-analyse. MéTHODES: Nous avons utilisé les données sur la mortalité tirées de 35 essais (10 880 patients) inclus dans notre méta-analyse publiée antérieurement. Nous avons tout d'abord lié chaque auteur à son étude (ou à ses études). Nous avons ensuite calculé des rapports de cotes (odds ratios) spécifiques utilisant des méthodes de tableaux unifactoriels croisés. Enfin, nous avons testé l'effet « auteur ¼ en comparant les rapports de cotes estimés de chaque auteur avec le rapport de cotes groupé de tous les autres auteurs au moyen d'une métarégression. RéSULTATS: Le nombre médian d'investigateurs cité comme auteurs dans les publications principales des essais était de six (plage interquartile : 5 à 8, limites : 2 à 32). Les résultats ont montré que la pente de l'effet « auteur ¼ pour la mortalité allait de -1,35 à 0,71. Nous n'avons identifié qu'une seule équipe d'auteurs ayant un effet peu à la limite de la significativité (-0,39; intervalle de confiance à 95 % : -0,78 à 0,00). Cette équipe a un historique de rétractions de publications en raison de manipulations des données et de violations de l'éthique. CONCLUSION: Lorsqu'ils combinent les données des essais pour produire une estimation groupée de l'effet, les investigateurs doivent envisager les sources de biais potentiels. Nos résultats suggèrent que des erreurs systématiques peuvent être détectées en utilisant une métarégression bien qu'il soit nécessaire de poursuivre les recherches pour évaluer la sensibilité de ce modèle. Les réviseurs systématiques tireront parti de la disponibilité de méthodes les protégeant de la dissémination de résultats susceptibles de fausser des prises de décision potentielles.
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Autoria/normas , Viés , Metanálise como Assunto , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Análise de Regressão , Revisões Sistemáticas como AssuntoRESUMO
Prediction of response to erythropoietin stimulating agents (ESAs) in anemic MDS patients is often based on the Nordic score. We wished to validate the Nordic score (IWG 2006 response criteria) in a larger cohort and determine if other variables such as IPSS/IPSS-R, ferritin, LDH, and a novel European ESA response score (Santini 2013) were of prognostic importance. We analyzed 208 ESA-treated MDS patients (WHO 2008 criteria) from a prospective registry. Ninety-four and 93% had lower risk scores by IPSS (low/int - 1) and IPSS-R (low/very low), respectively. Erythroid response was achieved in 94 patients (47%); responses were similar with erythropoietin (50%) and darbepoetin (39%; p = 0.2). The Nordic and European scores were both validated on univariate analysis. Variables independently predictive of response in multivariate analysis were low-risk IPSS score (OR 0.1, p = 0.0016) and serum EPO level < 100 mIU/mL (OR 8.7, p < 0.0001). We propose a new ESA response score, consisting of (a) IPSS low score (1 point) and (b) serum EPO levels < 100 mIU/ml (2 points), yielding scores ranging from 0 to 3, with response rates varying from 17 to 81%. The Nordic score has validity but we observed lower than the expected response rates in the best risk group. Our proposed scoring system appears more discriminating but needs validation.
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Eritropoetina/sangue , Hematínicos/administração & dosagem , Modelos Biológicos , Síndromes Mielodisplásicas , Sistema de Registros , Canadá , Feminino , Ferritinas/sangue , Humanos , Lactente , Recém-Nascido , L-Lactato Desidrogenase/sangue , Masculino , Síndromes Mielodisplásicas/sangue , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/mortalidade , Estudos ProspectivosRESUMO
BACKGROUND: In 'real-life', the Nordic score guides Erythropoietic stimulating agent (ESA) use in lower-risk myelodysplastic syndrome (MDS) with predicted response rates of 25% or 74%. As new treatments emerge, a more discriminating score is needed. OBJECTIVES: To validate existing ESA predictive scores and develop a new score that identifies non-responders. METHODS: ESA-treated patients were identified in 3 MDS registries in Italy and Canada (FISM 555, GROM 233, and MDS-CAN 208). Clinical and disease-related variables were captured. Nordic, MDS-CAN, and IPSS-R-based ESA scores were calculated and documented ESA responses compared. RESULTS: 996 ESA-treated patients were identified. Overall response rate (ORR) was 59%. The database was randomly divided into balanced derivation (n = 463) and validation (n = 462) cohorts. By multivariate analysis, transfusion independence, erythropoietin (EPO) level <100 IU/L, and IPSS low-risk were independently predictive of response. Assigning a score of 1 to each resulted in a scoring system of 0-3 with response rates of 23%, 43%, 67%, and 85%. ORR was concordant in the validation cohort. The 'ITACA' score had the highest discriminating power of response. CONCLUSION: ITACA is an internally-validated predictive SS of ESA response in real-life 'good risk' MDS patients derived from a large international dataset that surpasses others. The incorporation of biologic markers to better identify non-responders is still needed.
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Hematínicos/uso terapêutico , Síndromes Mielodisplásicas , Idoso , Idoso de 80 Anos ou mais , Canadá/epidemiologia , Bases de Dados Factuais , Feminino , Humanos , Cooperação Internacional , Itália/epidemiologia , Modelos Logísticos , Masculino , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/mortalidade , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Sistema de Registros , Taxa de SobrevidaRESUMO
BACKGROUND: Extracorporeal photopheresis (ECP) culls pathogenic T lymphocytes, be these the clones of cutaneous T-cell lymphoma, or mediators of chronic graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (BMT-GVHD). Whether or not ECP may have an effect in the rarer instances of solid organ transplantation-associated GVHD (SOT-GVHD) is unclear. Mortality rates in SOT-GVHD rival those of transfusion-associated GVHD, with fatalities preceded by pancytopenia and peripheral blood chimerism (PBC) levels exceeding 20%. ECP has been described in two SOT-GVHD cases to date, with one surviving. STUDY DESIGN AND METHODS: Clinicolaboratory features (including HLA relationships) in a case of multivisceral transplantation were reviewed from the time of surgery to the onset and progression of SOT-GVHD. ECP, which was introduced as a less immunosuppressive and more selective intervention, was assessed for its effect on serial PBC (as measured by short-tandem-repeat analysis) and clinical outcome. RESULTS: Multivisceral SOT-GVHD manifested with erythroderma, neutropenic sepsis, and PBC increasing from 6% on Posttransplant Day (PTD) 38 to 78% by PTD 60 (at a doubling time of 6 days despite corticosteroids). ECP was administered on PTDs 62 and 67 and was associated with the first evidence of PBC decay to 67% on PTD 69. Death nevertheless ensued on the last day of salvage antithymocyte globulin (PTDs 69-73) despite further PBC reduction to 41%. CONCLUSION: Further study is needed to determine if the sooner or more frequent application of ECP might attenuate the high case fatality rates of SOT-GVHD.
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Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/terapia , Transplante de Órgãos/efeitos adversos , Fotoferese/métodos , Doença Aguda , Adulto , Evolução Fatal , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Insuficiência de Múltiplos Órgãos/etiologiaRESUMO
OBJECTIVE: To evaluate the efficacy and safety of heparin in patients with sepsis, septic shock, or disseminated intravascular coagulation associated with infection. DESIGN: Systematic review and metaanalysis. DATA SOURCES: Randomized controlled trials from MEDLINE, EMBASE, CENTRAL, Global Health, Scopus, Web of Science, the International Clinical Trials Registry Platform (inception to April 2014), conference proceedings, and reference lists of relevant articles. STUDY SELECTION AND DATA EXTRACTION: Two reviewers independently identified and extracted trial-level data from randomized trials investigating unfractionated or low molecular heparin administered to patients with sepsis, severe sepsis, septic shock, or disseminated intravascular coagulation associated with infection. Internal validity was assessed in duplicate using the Risk of Bias tool. The strength of evidence was assessed in duplicate using Grading of Recommendations Assessment, Development, and Evaluation methodology. Our primary outcome was mortality. Safety outcomes included hemorrhage, transfusion, and thrombocytopenia. MEASUREMENTS AND MAIN RESULTS: We included nine trials enrolling 2,637 patients. Eight trials were of unclear risk of bias and one was classified as having low risk of bias. In trials comparing heparin to placebo or usual care, the risk ratio for death associated with heparin was 0.88 (95% CI, 0.77-1.00; I2 = 0%; 2,477 patients; six trials; moderate strength of evidence). In trials comparing heparin to other anticoagulants, the risk ratio for death was 1.30 (95% CI, 0.78-2.18; I2 = 0%; 160 patients; three trials; low strength of evidence). In trials comparing heparin to placebo or usual care, major hemorrhage was not statistically significantly increased (risk ratio, 0.79; 95% CI, 0.53-1.17; I2 = 0%; 2,392 patients; three trials). In one small trial of heparin compared with other anticoagulants, the risk of major hemorrhage was significantly increased (2.14; 95% CI, 1.07-4.30; 48 patients). Important secondary and safety outcomes, including minor bleeding, were sparsely reported. CONCLUSIONS: Heparin in patients with sepsis, septic shock, and disseminated intravascular coagulation associated with infection may be associated with decreased mortality; however, the overall impact remains uncertain. Safety outcomes have been underreported and require further study. Increased major bleeding with heparin administration cannot be excluded. Large rigorous randomized trials are needed to evaluate more carefully the efficacy and safety of heparin in patients with sepsis, severe sepsis, and septic shock.
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Anticoagulantes/uso terapêutico , Coagulação Intravascular Disseminada/tratamento farmacológico , Heparina de Baixo Peso Molecular/uso terapêutico , Heparina/uso terapêutico , Sepse/tratamento farmacológico , Anticoagulantes/efeitos adversos , Transfusão de Sangue/estatística & dados numéricos , Coagulação Intravascular Disseminada/mortalidade , Hemorragia/induzido quimicamente , Heparina/efeitos adversos , Heparina de Baixo Peso Molecular/efeitos adversos , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Sepse/mortalidade , Choque Séptico/tratamento farmacológico , Choque Séptico/mortalidade , Trombocitopenia/induzido quimicamenteRESUMO
Rh alloimmunization remains a potentially devastating complication of pregnancy, with fetal anemia causing hydrops and intrauterine death. Intrauterine transfusion is the standard treatment, but is particularly dangerous before 20 weeks gestation. When the need for intrauterine transfusion is anticipated early in pregnancy, immune-modulating therapies such as plasmapheresis and IVIG have been used to delay transfusion to a later gestational age. We report a 35-year-old G5P1 Rh(D)-negative woman with severe Rh alloimmunization managed successfully with sequential plasmapheresis, intravenous immune globulin and intrauterine transfusion. The optimal plasmapheresis treatment protocol and incremental benefit of IVIG remains unknown.
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Transfusão de Sangue Intrauterina , Eritroblastose Fetal/terapia , Imunoglobulinas Intravenosas/administração & dosagem , Plasmaferese , Isoimunização Rh/terapia , Adulto , Eritroblastose Fetal/sangue , Feminino , Humanos , Gravidez , Isoimunização Rh/sangueRESUMO
Hereditary xerocytosis (HX, MIM 194380) is an autosomal dominant hemolytic anemia characterized by primary erythrocyte dehydration. Copy number analyses, linkage studies, and exome sequencing were used to identify novel mutations affecting PIEZO1, encoded by the FAM38A gene, in 2 multigenerational HX kindreds. Segregation analyses confirmed transmission of the PIEZO1 mutations and cosegregation with the disease phenotype in all affected persons in both kindreds. All patients were heterozygous for FAM38A mutations, except for 3 patients predicted to be homozygous by clinical and physiologic studies who were also homozygous at the DNA level. The FAM38A mutations were both in residues highly conserved across species and within members of the Piezo family of proteins. PIEZO proteins are the recently identified pore-forming subunits of channels that mediate mechanotransduction in mammalian cells. FAM38A transcripts were identified in human erythroid cell mRNA, and discovery proteomics identified PIEZO1 peptides in human erythrocyte membranes. These findings, the first report of mutation in a mammalian mechanosensory transduction channel-associated with genetic disease, suggest that PIEZO proteins play an important role in maintaining erythrocyte volume homeostasis.