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OBJECTIVE: To characterize surface-bound proteins and to measure the thickness of fibrin fibers bound to extracorporeal membrane oxygenation (ECMO) circuits used in children. DESIGN: Single-center observational prospective study, April to November 2021. SETTING: PICU, Royal Children's Hospital, Melbourne, Australia. PATIENTS: Patients aged less than 18 years on venoarterial ECMO and without preexisting disorder. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: ECMO circuits were collected from six patients. Circuit samples were collected from five different sites, and subsequently processed for proteomic and scanning electron microscopy (SEM) studies. The concentration of proteins bound to ECMO circuit samples was measured using a bicinchoninic acid protein assay, whereas characterization of the bound proteome was performed using data-independent acquisition mass spectrometry. The Reactome Over-representation Pathway Analyses tool was used to identify functional pathways related to bound proteins. For the SEM studies, ECMO circuit samples were prepared and imaged, and the thickness of bound fibrin fibers was measured using the Fiji ImageJ software, version 1.53c (https://imagej.net/software/fiji/). Protein binding to ECMO circuit samples and fibrin networks showed significant intra-circuit and interpatient variation. The median (range) total protein concentration was 19.0 (0-76.9) µg/mL, and the median total number of proteins was 2011 (1435-2777). A total of 933 proteins were commonly bound to ECMO circuit samples from all patients and were functionally involved in 212 pathways, with signal transduction, cell cycle, and metabolism of proteins being the top three pathway categories. The median intra-circuit fibrin fiber thickness was 0.20 (0.15-0.24) µm, whereas the median interpatient fibrin fiber thickness was 0.18 (0.15-0.21) µm. CONCLUSIONS: In this report, we have characterized proteins and fiber fibrin thickness bound to ECMO circuits in six children. The techniques and approaches may be useful for investigating interactions between blood, coagulation, and the ECMO circuit and have the potential for circuit design.
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OBJECTIVES: To investigate changes in von Willebrand factor (VWF) concentration, function, and multimers during pediatric extracorporeal membrane oxygenation (ECMO) and determine whether routine monitoring of VWF during ECMO would be useful in predicting bleeding. DESIGN: Prospective observational study of pediatric ECMO patients from April 2017 to May 2019. SETTING: The PICU in a large, tertiary referral pediatric ECMO center. PATIENTS: Twenty-five neonates and children (< 18 yr) supported by venoarterial ECMO. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Arterial blood samples were collected within 24 hours pre-ECMO, daily for the first 5 days of ECMO, every second day until decannulation, and 24 hours post-ECMO. The STA R Max analyzer was used to measure VWF antigen (VWF:Ag) and ristocetin cofactor (VWF:RCo) activity. VWF collagen binding (VWF:CB) was measured using an enzyme-linked immunosorbent assay. VWF multimers were measured using the semi-automated Hydragel 11 VWF Multimer assay. Corresponding clinical data for each patient was also recorded. A total of 25 venoarterial ECMO patients were recruited (median age, 73 d; interquartile range [IQR], 3 d to 1 yr). The median ECMO duration was 4 days (IQR, 3-8 d) and 15 patients had at least one major bleed during ECMO. The percentage of high molecular weight multimers (HMWM) decreased and intermediate molecular weight multimers increased while patients were on ECMO, irrespective of a bleeding status. VWF:Ag increased and the VWF:RCo/VWF:Ag and VWF:CB/VWF:Ag ratios decreased while patients were on ECMO compared with the baseline pre-ECMO samples and healthy children. CONCLUSIONS: Neonates and children on ECMO exhibited a loss of HMWM and lower VWF:CB/VWF:Ag and VWF:RCo/VWF:Ag ratios compared with healthy children, irrespective of major bleeding occurring. Therefore, monitoring VWF during ECMO would not be useful in predicting bleeding in these patients and changes to other hemostatic factors should be investigated to further understand bleeding during ECMO.
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Oxigenação por Membrana Extracorpórea , Doenças de von Willebrand , Criança , Humanos , Recém-Nascido , Oxigenação por Membrana Extracorpórea/efeitos adversos , Hemorragia , Estudos Prospectivos , Fator de von Willebrand , Lactente , Pré-Escolar , AdolescenteRESUMO
OBJECTIVES: To investigate platelet pathophysiology associated with pediatric extracorporeal membrane oxygenation (ECMO). DESIGN: Prospective observational study of neonatal and pediatric ECMO patients from September 1, 2016, to December 31, 2019. SETTING: The PICU in a large tertiary referral pediatric ECMO center. PATIENTS: Eighty-seven neonates and children (< 18 yr) supported by ECMO. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Arterial blood samples were collected on days 1, 2, and 5 of ECMO and were analyzed by whole blood flow cytometry. Corresponding clinical data for each patient was also recorded. A total of 87 patients were recruited (median age, 65 d; interquartile range [IQR], 7 d to 4 yr). The median duration of ECMO was 5 days (IQR, 3-8 d) with a median length of stay in PICU and hospital of 18 days (IQR, 10-29 d) and 35 days (IQR, 19-75 d), respectively. Forty-two patients (48%) had at least one major bleed according to a priori determined definitions, and 12 patients (14%) had at least one thrombotic event during ECMO. Platelet fibrinogen receptor expression decreased (median fluorescence intensity [MFI], 29,256 vs 26,544; p = 0.0005), while von Willebrand Factor expression increased (MFI: 7,620 vs 8,829; p = 0.0459) from day 2 to day 5 of ECMO. Platelet response to agonist, Thrombin Receptor Activator Peptide 6, also decreased from day 2 to day 5 of ECMO, as measured by binding with anti-P-selectin, PAC-1 (binds activated GPIIb/IIIa), and anti-CD63 monoclonal antibodies (P-selectin area under the curve [AUC]: 63.46 vs 42.82, respectively, p = 0.0022; PAC-1 AUC: 93.75 vs 74.46, p = 0.0191; CD63 AUC: 55.69 vs 41.76, p = 0.0020). CONCLUSIONS: The loss of platelet response over time may contribute to bleeding during ECMO. These novel insights may be useful in understanding mechanisms of bleeding in pediatric ECMO and monitoring platelet markers clinically could allow for prediction or early detection of bleeding and thrombosis.
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Oxigenação por Membrana Extracorpórea , Trombose , Plaquetas , Oxigenação por Membrana Extracorpórea/efeitos adversos , Hemorragia , Humanos , Fenótipo , SelectinasRESUMO
Pharmaceutic products designed to perturb the function of epigenetic modulators have been approved by regulatory authorities for treatment of advanced cancer. While the predominant effort in epigenetic drug development continues to be in oncology, non-oncology indications are also garnering interest. A survey of pharmaceutical companies was conducted to assess the interest and concerns for developing small molecule direct epigenetic effectors (EEs) as medicines. Survey themes addressed (1) general levels of interest and activity with EEs as therapeutic agents, (2) potential safety concerns, and (3) possible future efforts to develop targeted strategies for nonclinical safety assessment of EEs. Thirteen companies contributed data to the survey. Overall, the survey data indicate the consensus opinion that existing ICH guidelines are effective and appropriate for nonclinical safety assessment activities with EEs. Attention in the framework of study design should, on a case by case basis, be considered for delayed or latent toxicities, carcinogenicity, reproductive toxicity, and the theoretical potential for transgenerational effects. While current guidelines have been appropriate for the nonclinical safety assessments of epigenetic targets, broader experience with a wide range of epigenetic targets will provide information to assess the potential need for new or revised risk assessment strategies for EE drugs.
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Indústria Farmacêutica/normas , Controle de Medicamentos e Entorpecentes , Epigênese Genética/efeitos dos fármacos , Preparações Farmacêuticas/normas , Inquéritos e Questionários , Animais , Avaliação Pré-Clínica de Medicamentos/normas , Avaliação Pré-Clínica de Medicamentos/tendências , Indústria Farmacêutica/tendências , Controle de Medicamentos e Entorpecentes/tendências , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Epigênese Genética/genética , Humanos , Preparações Farmacêuticas/administração & dosagem , Medição de Risco/normas , Medição de Risco/tendênciasRESUMO
Kawasaki disease is usually a limited illness of early childhood. However, life-threatening cardiac manifestations can occur, either at acute presentation or as a consequence of coronary arterial involvement. We report the successful use of veno-arterial (VA) extracorporeal membrane oxygenation (ECMO) for cardiac support in two children with Kawasaki disease: one with acute Kawasaki disease shock syndrome, the other with complications of coronary arteritis and subsequent surgery. We also reviewed the reported experience in the ELSO database and available literature.
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Oxigenação por Membrana Extracorpórea/métodos , Síndrome de Linfonodos Mucocutâneos/terapia , Pré-Escolar , História do Século XX , História do Século XXI , Humanos , Lactente , Masculino , Síndrome de Linfonodos Mucocutâneos/patologia , Resultado do TratamentoRESUMO
OBJECTIVES: To investigate whether the use of continuous renal replacement therapy is independently associated with increased in-hospital mortality in children on extracorporeal membrane oxygenation. DESIGN: Retrospective, 1:1 propensity-matched cohort study. SETTING: Tertiary PICU. PATIENTS: Eighty-six children on extracorporeal membrane oxygenation, 43 of whom also received hemofiltration. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Demographics, pre-extracorporeal membrane oxygenation hemodynamic data, fluid status, and biochemistry tests were collected, as well as duration of extracorporeal membrane oxygenation, blood product use, complications, and mortality. Forty-three children receiving extracorporeal membrane oxygenation and continuous renal replacement therapy were matched to a cohort of 43 children on extracorporeal membrane oxygenation not receiving continuous renal replacement therapy. The main indication for hemofiltration was fluid overload in 29 patients (67.4%), renal failure in nine patients (20.9%), and electrolyte abnormalities in five patients (11.6%). The median duration of hemofiltration was 108 hours (47-209 hr). Patients receiving hemofiltration had a longer duration of extracorporeal membrane oxygenation (127 hr [94-302 hr] vs 121 hr [67-182 hr]; p = 0.05) and received more platelet transfusions (0.91 mL/kg/hr [0.43-1.58 mL/kg/hr] vs 0.63 mL/kg/hr [0.30-0.79 mL/kg/hr]; p = 0.01). There were otherwise no differences in mechanical or patient-related complications between both groups. There was no difference in the proportion of patients who were successfully decannulated (81.4% vs 74.4%; p = 0.44), survived to ICU discharge (65.1% vs 55.8%; p = 0.38), or survived to hospital discharge (62.8% vs 48.8%; p = 0.19) in the controls versus the hemofiltration group. CONCLUSIONS: In-hospital mortality was similar between children on extracorporeal membrane oxygenation with and without hemofiltration although hemofiltration appeared to be associated with a slight increase in the duration of extracorporeal membrane oxygenation and more liberal platelet transfusions.
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Injúria Renal Aguda/terapia , Oxigenação por Membrana Extracorpórea/mortalidade , Hemofiltração/mortalidade , Mortalidade Hospitalar , Insuficiência Respiratória/terapia , Injúria Renal Aguda/complicações , Injúria Renal Aguda/mortalidade , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Recém-Nascido , Modelos Logísticos , Masculino , Prognóstico , Pontuação de Propensão , Insuficiência Respiratória/complicações , Insuficiência Respiratória/mortalidade , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do TratamentoRESUMO
OBJECTIVES: To evaluate the relationship between glucose derangement, insulin administration, and mortality among children on extracorporeal membrane oxygenation. DESIGN: Retrospective cohort. SETTING: Tertiary PICU. PATIENTS: Two hundred nine children receiving extracorporeal membrane oxygenation, including 97 neonates. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Hyperglycemia and severe hyperglycemia were defined as a single blood glucose level greater than 15 mmol/L (270 mg/dL) and greater than 20 mmol/L (360 mg/dL), respectively. Hypoglycemia and severe hypoglycemia were defined as any single glucose level less than 3.3 mmol/L (60 mg/dL) and less than 2.2 mmol/L (40 mg/dL), respectively. A total of 15,912 glucose values were recorded. The median number of glucose values was 59 per patient, corresponding to a mean 0.53 ± 0.12 tests per hour. Sixty-nine patients (33.0%) without dysglycemia and who received no insulin were defined as the control group. Eighty-nine (42.6%) and 26 (12.4%) patients developed hyperglycemia and severe hyperglycemia, respectively. Sixty-three (30.1%) and 17 (8.1%) patients developed hypoglycemia and severe hypoglycemia, respectively. Sixty-one patients (29.2%) received IV insulin during extracorporeal membrane oxygenation. Both hyperglycemia and hypoglycemia were associated with increased mortality on extracorporeal membrane oxygenation (46% and 48%, respectively, vs 29% of controls; p = 0.03). However, after adjusting for severity of illness and extracorporeal membrane oxygenation complications, abnormal glucose levels were not independently related to mortality. CONCLUSIONS: Dysglycemia in children on extracorporeal membrane oxygenation was common but not independently associated with increased mortality. The optimal glucose range for this high-risk population requires further investigation.
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Glicemia/efeitos dos fármacos , Oxigenação por Membrana Extracorpórea/efeitos adversos , Hiperglicemia/epidemiologia , Hipoglicemia/epidemiologia , Criança , Pré-Escolar , Oxigenação por Membrana Extracorpórea/mortalidade , Feminino , Humanos , Hiperglicemia/tratamento farmacológico , Hiperglicemia/mortalidade , Hipoglicemia/mortalidade , Lactente , Recém-Nascido , Insulina/administração & dosagem , Insulina/efeitos adversos , Insulina/uso terapêutico , Unidades de Terapia Intensiva Pediátrica , Masculino , Prevalência , Estudos Retrospectivos , Resultado do TratamentoRESUMO
We aimed to determine the effect of elective left heart decompression at the time of initiation of central venoarterial extracorporeal membrane oxygenation (VA ECMO) on VA ECMO duration and clinical outcomes in children in a single tertiary ECMO referral center with a large pediatric population from a national referral center for pediatric cardiac surgery. We studied 51 episodes of VA ECMO in a historical cohort of 49 pediatric patients treated between the years 1990 and 2013 in the Paediatric Intensive Care Unit (PICU) of the Royal Children's Hospital, Melbourne. The cases had a variety of diagnoses including congenital cardiac abnormalities, sepsis, myocarditis, and cardiomyopathy. Left heart decompression as an elective treatment or an emergency intervention for left heart distension was effectively achieved by a number of methods, including left atrial venting, blade atrial septostomy, and left ventricular cannulation. Elective left heart decompression was associated with a reduction in time on ECMO (128 h) when compared with emergency decompression (236 h) (P = 0.013). Subgroup analysis showed that ECMO duration was greatest in noncardiac patients (elective 138 h, emergency 295 h; P = 0.02) and in patients who died despite both emergency decompression and ECMO (elective 133 h, emergency 354 h; P = 0.002). As the emergency cases had a lower pH, a higher PaCO2 , and a lower oxygenation index and were treated with a higher mean airway pressure, positive end-expiratory pressure, and respiratory rate prior to receiving VA ECMO, we undertook multivariate linear regression modeling to show that only PaCO2 and the timing of left heart decompression were associated with ECMO duration. However, elective left heart decompression was not associated with a reduction in length of PICU stay, duration of mechanical ventilation, or duration of oxygen therapy. Elective left heart decompression was not associated with improved ECMO survival or survival to PICU discharge. Elective left heart decompression may reduce ECMO duration and has therefore the potential to reduce ECMO-related complications. A prospective, randomized controlled trial is indicated to study this intervention further.
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Descompressão Cirúrgica/métodos , Oxigenação por Membrana Extracorpórea/métodos , Ventrículos do Coração/cirurgia , Função Ventricular Esquerda , Fatores Etários , Descompressão Cirúrgica/efeitos adversos , Descompressão Cirúrgica/mortalidade , Procedimentos Cirúrgicos Eletivos , Emergências , Oxigenação por Membrana Extracorpórea/efeitos adversos , Oxigenação por Membrana Extracorpórea/mortalidade , Feminino , Ventrículos do Coração/fisiopatologia , Mortalidade Hospitalar , Hospitais Pediátricos , Humanos , Lactente , Unidades de Terapia Intensiva Pediátrica , Tempo de Internação , Modelos Lineares , Masculino , Análise Multivariada , Oxigenoterapia , Complicações Pós-Operatórias/mortalidade , Complicações Pós-Operatórias/terapia , Respiração Artificial , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , VitóriaRESUMO
OBJECTIVE: The aim of this study was to evaluate whether the use of therapeutic hypothermia in patients receiving extracorporeal membrane oxygenation after paediatric cardiac surgery is associated with increased complication rates. METHODS: We undertook a retrospective study to compare the complication rates and clinical course of children after cardiac surgery in two groups extracorporeal membrane oxygenation without therapeutic hypothermia (group 1) and extracorporeal membrane oxygenation with therapeutic hypothermia (group 2). Therapeutic hypothermia was performed via the extracorporeal membrane oxygenation circuit heater-cooler device. RESULTS: A total of 96 patients were included in this study (59 in group 1 and 37 in group 2). Complications were comparable between group 1 and group 2, except that more patients with therapeutic hypothermia had hypertension while on extracorporeal membrane oxygenation. Therapeutic hypothermia was not independently associated with in-hospital mortality (adjusted odds ratio 1.16, 95% CI: 0.33-4.03; p=0.82). CONCLUSION: Therapeutic hypothermia can be safely provided to children on extracorporeal membrane oxygenation after cardiac surgery without an increase in complication rates.
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Procedimentos Cirúrgicos Cardíacos/métodos , Oxigenação por Membrana Extracorpórea/métodos , Hipotermia Induzida/efeitos adversos , Complicações Pós-Operatórias , Adolescente , Criança , Pré-Escolar , Feminino , Mortalidade Hospitalar , Humanos , Lactente , Recém-Nascido , Modelos Logísticos , Masculino , Razão de Chances , Estudos Retrospectivos , Resultado do TratamentoRESUMO
OBJECTIVE: There are limited data on the outcomes of children receiving delayed (≥7 days) extracorporeal membrane oxygenation after cardiac surgery. The primary aim of this project is to identify the aetiology and outcomes of extracorporeal membrane oxygenation in children receiving delayed (≥7 days) extracorporeal membrane oxygenation after cardiac surgery. PATIENTS AND METHODS: We conducted a retrospective review of all children ≤18 years supported with delayed extracorporeal membrane oxygenation after cardiac surgery between the period January, 2001 and March, 2012 at the Arkansas Children's Hospital, United States of America, and Royal Children's Hospital, Australia. The data collected in our study included patient demographic information, diagnoses, extracorporeal membrane oxygenation indication, extracorporeal membrane oxygenation support details, medical and surgical history, laboratory, microbiological, and radiographic data, information on organ dysfunction, complications, and patient outcomes. The outcome variables evaluated in this report included: survival to hospital discharge and current survival with emphasis on neurological, renal, pulmonary, and other end-organ function. RESULTS: During the study period, 423 patients undergoing cardiac surgery were supported with extracorporeal membrane oxygenation at two institutions, with a survival of 232 patients (55%). Of these, 371 patients received extracorporeal membrane oxygenation <7 days after cardiac surgery, with a survival of 205 (55%) patients, and 52 patients received extracorporeal membrane oxygenation ≥7 days after cardiac surgery, with a survival of 27 (52%) patients. The median duration of extracorporeal membrane oxygenation run for the study cohort was 5 days (interquartile range: 3, 10). In all, 14 patients (25%) received extracorporeal membrane oxygenation during active cardiopulmonary resuscitation with chest compressions. There were 24 patients (44%) who received dialysis while being on extracorporeal membrane oxygenation. There were eight patients (15%) who had positive blood cultures and four patients (7%) who had positive urine cultures while being on extracorporeal membrane oxygenation. There were nine patients (16%) who had bleeding complications associated with extracorporeal membrane oxygenation runs. There were 10 patients (18%) who had cerebrovascular thromboembolic events associated with extracorporeal membrane oxygenation runs. Of these, 19 patients are still alive with significant comorbidities. CONCLUSIONS: This study demonstrates that mortality outcomes are comparable among children receiving extracorporeal membrane oxygenation ≥7 days and <7 days after cardiac surgery. The proportion of patients receiving extracorporeal membrane oxygenation ≥7 days is small and the aetiology diverse.
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Baixo Débito Cardíaco/terapia , Procedimentos Cirúrgicos Cardíacos , Oxigenação por Membrana Extracorpórea/estatística & dados numéricos , Parada Cardíaca/terapia , Cardiopatias Congênitas/cirurgia , Complicações Pós-Operatórias/terapia , Insuficiência Respiratória/terapia , Bacteriemia/epidemiologia , Bacteriemia/terapia , Baixo Débito Cardíaco/epidemiologia , Reanimação Cardiopulmonar , Estudos de Coortes , Feminino , Parada Cardíaca/epidemiologia , Humanos , Lactente , Recém-Nascido , Masculino , Complicações Pós-Operatórias/epidemiologia , Insuficiência Respiratória/epidemiologia , Estudos Retrospectivos , Choque/epidemiologia , Choque/terapiaRESUMO
OBJECTIVES: To explore the prevalence and risk factors for hemolysis in children receiving extracorporeal membrane oxygenation and examine the relationship between hemolysis and adverse outcomes. DESIGN: Retrospective, single-center study. SETTING: Tertiary PICU. PATIENTS: Two hundred seven children receiving extracorporeal membrane oxygenation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Plasma-free hemoglobin was tested daily and hemolysis was diagnosed based on peak plasma-free hemoglobin as mild (< 0.5 g/L), moderate (0.5-1.0 g/L), or severe (> 1.0 g/L). Gender, age, weight, diagnosis, oxygenator type, cannulation site, mean venous inlet pressure, mean pump speed, mean flow, and visible clots in the extracorporeal membrane oxygenation circuit were entered into the ordered logistic regression model to identify risk factors of hemolysis. Complications and clinical outcomes were compared across four hemolysis groups. Of the 207 patients, 69 patients (33.3%; 95% CI, 27.0-40.2%) did not have hemolysis, 98 patients (47.3%; 95% CI, 40.4-54.4%) had mild hemolysis, 26 patients (12.5%; 95% CI, 8.4-17.9%) had moderate hemolysis, and 14 patients (6.8%; 95% CI, 3.7-11.1%) had severe hemolysis with a median peak plasma-free hemoglobin of 1.51 g/L (1.18-2.05 g/L). The independent risk factors for hemolysis during extracorporeal membrane oxygenation were use of Quadrox D (odds ratio, 7.25; 95% CI, 3.10-16.95; p < 0.001) or Lilliput (odds ratio, 37.32; 95% CI, 8.95-155.56; p < 0.001) oxygenators, mean venous inlet pressure (odds ratio, 0.95; 95% CI, 0.91-0.98; p = 0.002), and mean pump speed (odds ratio, 2.89; 95% CI, 1.36-6.14; p = 0.006). Patients with hemolysis were more likely to experience a longer extracorporeal membrane oxygenation run and require more blood products. After controlling for age, weight, pediatric index of mortality 2, and diagnosis, patients with severe hemolysis were more likely to die in the ICU (odds ratio, 5.93; 95% CI, 1.64-21.43; p = 0.007) and in hospital (odds ratio, 6.34; 95% CI, 1.71-23.54; p = 0.006). CONCLUSIONS: Hemolysis during extracorporeal membrane oxygenation with centrifugal pumps was common and associated with a number of adverse outcomes. Risk factors for hemolysis included oxygenator types, mean venous inlet pressure, and mean pump speed. Further studies are warranted comparing pump types while controlling both physical and nonphysical confounders.
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Oxigenação por Membrana Extracorpórea/efeitos adversos , Hemoglobina A/análise , Hemólise/fisiologia , Fatores Etários , Peso Corporal , Pré-Escolar , Oxigenação por Membrana Extracorpórea/instrumentação , Feminino , Humanos , Lactente , Recém-Nascido , Unidades de Terapia Intensiva Pediátrica , Modelos Logísticos , Masculino , Razão de Chances , Prevalência , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Fatores Sexuais , Resultado do TratamentoRESUMO
Cardiovascular safety pharmacology and toxicology studies include vehicle control animals in most studies. Electrocardiogram data on common vehicles is accumulated relatively quickly. In the interests of the 3Rs principles it may be useful to use this historical information to reduce the use of animals or to refine the sensitivity of studies. We used implanted telemetry data from a large nonhuman primate (NHP) cardiovascular study (n = 48) evaluating the effect of moxifloxacin. We extracted 24 animals to conduct a n = 3/sex/group analysis. The remaining 24 animals were used to generate 1000 unique combinations of 3 male and 3 female NHP to act as control groups for the three treated groups in the n = 3/sex/group analysis. The distribution of treatment effects, median minimum detectable difference (MDD) values were gathered from the 1000 studies. These represent contemporary controls. Data were available from 42 NHP from 3 other studies in the same laboratory using the same technology. These were used to generate 1000 unique combinations of 6, 12, 18, 24 and 36 NHP to act as historical control animals for the 18 animals in the treated groups of the moxifloxacin study. Data from an additional laboratory were also available for 20 NHP. The QT, RR and QT-RR data from the three sources were comparable. However, differences in the time course of QTc effect in the vehicle data from the two laboratories meant that it was not possible to use cross-lab controls. In the case of historical controls from the same laboratory, these could be used in place of the contemporary controls in determining a treatment's effect. There appeared to be an advantage in using larger (≥18) group sizes for historical controls. These data support the opportunity of using historical controls to reduce the number of animals used in new cardiovascular studies.
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Eletrocardiografia , Fluoroquinolonas , Moxifloxacina , Telemetria , Animais , Feminino , Eletrocardiografia/métodos , Eletrocardiografia/efeitos dos fármacos , Masculino , Telemetria/métodos , Síndrome do QT Longo/induzido quimicamente , Síndrome do QT Longo/fisiopatologia , Grupos Controle , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Estado de Consciência/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos/métodosRESUMO
Nitric oxide (NO) can be safely delivered through the sweep gas to the oxygenator of an extracorporeal membrane oxygenation (ECMO) circuit. It has theoretical benefits such as preventing platelet adhesion to surfaces, mitigating inflammatory response and protection against ischemia-reperfusion injury. In this uncontrolled before-after study of children on ECMO, the outcomes of those who received NO were compared with those who did not. Among 393 ECMO runs (from 337 patients), 192 of 393 (49%) received NO and 201 of 393 (51%) did not. The use of NO was associated with a 37% reduction in circuit change (adjusted risk ratio [aRR]: 0.63, 95% confidence interval [CI]: 0.42-0.93). The aRR (95% CI) for risk of neurologic injury was 0.72 (0.47-1.11). We observed potential heterogeneity of treatment effect for the risk of neurologic injury in children who had cardiac surgery: the risk with NO was lower in those who had cardiac surgery (aRR: 0.50, 95% CI: 0.26-0.96). There was no difference in survival between the study groups. In children managed with NO delivered through the ECMO circuit, we report a reduction in observed rate of circuit change and lower risk of neurologic injury in children who underwent cardiac surgery. Nitric oxide therapy on ECMO warrants prospective evaluation in children.
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Oxigenação por Membrana Extracorpórea , Óxido Nítrico , Humanos , Oxigenação por Membrana Extracorpórea/métodos , Oxigenação por Membrana Extracorpórea/efeitos adversos , Oxigenação por Membrana Extracorpórea/instrumentação , Óxido Nítrico/administração & dosagem , Lactente , Masculino , Feminino , Pré-Escolar , Estudos de Coortes , Criança , Recém-Nascido , Resultado do Tratamento , OxigenadoresRESUMO
The continuous contact between blood and the foreign surface of the extracorporeal membrane oxygenation (ECMO) circuit contributes to hemostatic, inflammatory, and other physiological disturbances observed during ECMO. Although previous studies have extensively investigated blood samples from patients on ECMO, cell adsorption to the ECMO circuit as an additional factor that could potentially influence clinical outcomes, has largely been overlooked. Here we provide a detailed immunofluorescence (IF) protocol designed to characterize cellular binding on ECMO circuits collected from patients. Extracorporeal membrane oxygenation circuits were collected from three pediatric patients and an albumin primed-only ECMO circuit was used as control. Circuit samples from five different sites within each ECMO circuit were collected and processed for the IF protocol. CD14 and CD42a antibodies were used to identify platelets and leukocytes bound to each ECMO circuit sample and images captured using inverted fluorescence microscopy. The protocol enables the comprehensive characterization of platelet and leukocyte binding to ECMO circuits collected from patients, which could in turn extend our knowledge of the characteristics of circuit binding and may provide guidance for improved ECMO circuit design.
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The cardiovascular safety pharmacology (SP) study conducted to satisfy ICH S7A and S7B has commonly used a cross-over study design where each animal receives all treatments. In an increasing number of cases, cross-over designs are not possible and parallel studies have to be used. These can seldom be as large as 8 animals/treatment to match an n = 8 cross-over. Animals in parallel designs receive only one treatment. Parallel studies will have a different sensitivity to detect changes. This sensitivity is a critical question in using nonclinical QTc evaluations to support an integrated proarrhythmic risk assessment under the newly released ICH E14/S7B Q&As. The current analysis used a study large enough (n = 48) to be analyzed both as a parallel and as a cross-over design to directly compare the performance of the two experimental designs coupled to different statistical models, while all other study conduct aspects were the same. A total of 48 nonhuman primates (NHP) received 2 different treatments twice: vehicle, moxifloxacin (80 mg/kg), vehicle, moxifloxacin (80 mg/kg). Post-dose QTc interval data were recorded for 48 h for each treatment. Data were analyzed using 12 animals randomly selected for each treatment in a parallel design or as an n = 48 animal cross-over study. Different statistical models were used. The primary endpoint was the residual deviation (sigma) from the models applied to hourly time intervals. The sigma was used to determine the minimal detectable difference (MDD) for the study design-statistical model combination. Two statistical models were applicable to either study design. They gave similar sigma and resulting MDD values. In cross-over designs, the individual animal identification (ID) can be used in the statistical model. This enabled the smallest MDD value. Simple statistical models for analysis were identified: Treatment + Baseline for parallel designs and Treatment + ID for cross-over designs. The statistical sensitivity of NHP parallel study designs is reasonable (MDD for n = 6 of 12.7 ms), and in combination with testing exposures higher than likely to be necessary in man could be used in an integrated risk assessment. Where sensitivity of the NHP in vivo QTc assessment is critical, the cross-over design enabled a higher sensitivity (MDD 12.2 ms for n = 4; 8 ms for n = 8).
Assuntos
Fluoroquinolonas , Síndrome do QT Longo , Humanos , Animais , Moxifloxacina/uso terapêutico , Estudos Cross-Over , Síndrome do QT Longo/tratamento farmacológico , Eletrocardiografia , Primatas , Frequência Cardíaca , Relação Dose-Resposta a DrogaRESUMO
The number of animals used in a nonhuman primate (NHP) in vivo QTc assessment conducted as part of the safety pharmacology (SP) studies on a potential new drug is relatively small (4-8 subjects). The number is much smaller than the number of healthy volunteers in a conventional thorough QT (TQT) study (40-60 volunteers). How is it possible that such small studies could offer an equivalent sensitivity in an integrated nonclinical and clinical cardiac repolarization risk assessment? This study provided the opportunity to empirically demonstrate in a large number of NHPs the performance of a nonclinical evaluation at a similar size to a TQT study. By contrasting an analysis mimicking the sampling and aggregation of QTc interval data in a manner which is TQT-like with a more conventional SP-like analysis it was demonstrated that the SP-like analysis was more sensitive. In prospective power calculations 80% power at p = 0.05 can be achieved for a 5 ms QTc change with only n = 8 NHPs using the SP-like analysis and in a group of only 4 NHPs 80% power to detect 10 ms could be achieved. By contrast groups of 24 NHPs would be required to achieve 80% power to detect 5 ms using the TQT-like sampling and aggregation approach. Overall, this study has demonstrated that smaller safety pharmacology in vivo QTc assessments using all the available data in larger data aggregates can achieve sensitivity comparable to a human TQT study.
Assuntos
Eletrocardiografia , Síndrome do QT Longo , Animais , Humanos , Estudos Prospectivos , Voluntários Saudáveis , Síndrome do QT Longo/induzido quimicamente , Síndrome do QT Longo/diagnóstico , Primatas , Relação Dose-Resposta a Droga , Frequência CardíacaRESUMO
Background: Extracorporeal membrane oxygenation (ECMO) is used in children with cardiopulmonary failure. While the majority of ECMO centers use unfractionated heparin, other anticoagulants, including factor XI and factor XII inhibitors are emerging, which may prove suitable for ECMO patients. However, before these anticoagulants can be applied in these patients, baseline data of FXI and FXII changes need to be acquired. Objectives: This study aimed to describe the longitudinal profile of FXI and FXII antigenic levels and function before, during, and after ECMO in children. Methods: This is a prospective observational study in neonatal and pediatric patients with ECMO (<18 years). All patients with venoarterial ECMO and with sufficient plasma volume collected before ECMO, on day 1 and day 3, and 24 hours postdecannulation were included. Antigenic levels and functional activity of FXI and FXII were determined in these samples. Longitudinal profiles of these values were created using a linear mixed model. Results: Sixteen patients were included in this study. Mean FXI and FXII antigenic levels (U/mL) changed from 7.9 and 53.2 before ECMO to 6.0 and 34.5 on day 3 and they recovered to 8.8 and 39.4, respectively, after stopping ECMO. Function (%) of FXI and FXII decreased from 59.1 and 59.0 to 49.0 and 50.7 on day 3 and recovered to 66.0 and 54.4, respectively. Conclusion: This study provides the first insights into changes of the contact pathway in children undergoing ECMO. FXI and FXII antigen and function change during ECMO. Results from this study can be used as starting point for future contact pathway anticoagulant studies in pediatric patients with ECMO.
RESUMO
OBJECTIVE: To demonstrate positive outcome, to achieve higher flow rates, and to reverse shock more quickly by implementing central extracorporeal membrane oxygenation (ECMO) in children with refractory septic shock. Children hospitalized with sepsis have significant mortality rates. The development of shock is the most important risk factor for death. For children with septic shock refractory to all other forms of therapy, ECMO has been recommended but estimated survival is <50% and the best method of applying the technology is unknown. In recent years, our institutional practice has been to cannulate children with refractory septic shock directly through the chest (central, atrioaortic ECMO) to achieve higher blood flow rates. DESIGN: Retrospective case series. SETTING: Intensive care unit of a tertiary referral pediatric hospital. PATIENTS: Twenty-three children with refractory septic shock who received central ECMO primarily as circulatory support. INTERVENTIONS: Central ECMO. MEASUREMENTS AND MAIN RESULTS: The primary outcome measure was survival to hospital discharge. Pre-ECMO circulatory and ventilatory parameters, infecting organism, duration and complications of ECMO and length of hospital stay were also collected. Twenty-three patients (median: age, 6 yrs; weight, 20 kg) over a 9-yr period were included. All patients had microbiological evidence of infection, and meningococcemia was the most common diagnosis. Twenty-two (96%) patients had failure of at least three organ systems, and all patients received at least two inotropes with a mean inotrope score of 82.2 (sd, 115.6). Eight (35%) patients suffered cardiac arrest and required external cardiac massage before ECMO. Eighteen (78%) patients survived to be decannulated off ECMO, and 17 (74%) children survived to hospital discharge. Higher pre-ECMO arterial lactate levels were associated with increased mortality (11.7 mmol/L in nonsurvivors vs. 6.0 mmol/L in survivors, p = .007). CONCLUSIONS: Central ECMO seems to be associated with better survival than conventional ECMO and should be considered by clinicians as a viable strategy in children with refractory septic shock.