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AIMS: Meropenem/vaborbactam combination is approved in adults by FDA and EMA for complicated urinary tract infections and by EMA also for other Gram-negative infections. We aimed to characterise the pharmacokinetics of both moieties in an ongoing study in children and use a model-based approach to inform adequate dosing regimens in paediatric patients. METHODS: Over 4196 blood samples of meropenem and vaborbactam (n = 414 subjects) in adults, together with 114 blood samples (n = 39) in paediatric patients aged 3 months to 18 years were available for this analysis. Data were analysed using a population with prior information from a pharmacokinetic model in adults to inform parameter estimation in children. Simulations were performed to assess the suitability of different dosing regimens to achieve adequate probability of target attainment (PTA). RESULTS: Meropenem/vaborbactam PK was described with two-compartment models with first-order elimination. Body weight and CLcr were significant covariates on the disposition of both drugs. A maturation function was evaluated to explore changes in clearance in neonates. PTA ≥90% was derived for children aged ≥3 months after 3.5-h IV infusion of 40 mg/kg Q8h of both meropenem and vaborbactam and 2 g/2 g for those ≥50 kg. Extrapolation of disposition parameters suggest that adequate PTA is achieved after a 3.5-h IV infusion of 20 mg/kg for neonates and infants (3 months). CONCLUSIONS: An integrated analysis of adult and paediatric data allowed accurate description of sparsely sampled meropenem/vaborbactam PK in paediatric patients and provided recommendations for the dosing in neonates and infants (3 months).
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OBJECTIVE: Low cardiac output syndrome complicates recovery after cardiac surgery. We examined the incidence and risk factors for low cardiac output syndrome and its association with postoperative mortality, morbidity, resource use, and cost. METHODS: This cross-sectional retrospective observational study examined patients having cardiac surgery captured in the Premier Healthcare Database. Low cardiac output syndrome was defined as the requirement for postoperative mechanical circulatory support and/or hemodynamic instability requiring prolonged inotropic support. Incidence, risk factors, and association of low cardiac output syndrome with postoperative outcomes, including mortality, hospital and intensive care unit length of stay, hospital readmission, and cost at 30 days, 90 days, and 6 months, were examined. RESULTS: Among 59,810 patients from 164 hospitals having cardiac surgery between July 1, 2012, and June 30, 2014, low cardiac output syndrome developed in 6067 (10.1%) patients. Patients presenting in cardiogenic shock or systolic (± diastolic) heart failure were at greatest risk. Risk-adjusted in-hospital mortality was 12-fold greater with low cardiac output syndrome (odds ratio, 12.0; 95% confidence interval, 10.6-13.5). Risk-adjusted hospital costs (2019$; median [Q1, Q3]) were $64,041 [21,439] in patients who developed low cardiac output syndrome versus $48,086 [16,098] without; P < .001. Increased costs were driven by longer risk-adjusted hospital stay (10.1 [4.5] vs 8.5 [3.8] days); P < .001, intensive care unit (5.5 [2.5] vs 3.3 [1.5] days; P < .001) stay, and all-cause 30-day adjusted hospital readmission rates (mean [SD] 16.6 [8.2]% vs 13.9 [7.2]%; P < .001). CONCLUSIONS: Cardiac surgical patients who develop postoperative low cardiac output syndrome suffer greater mortality and have greater resource use, health care costs, and all-cause readmission, which informs perioperative decision making, and impacts hospital performance metrics and federal priority to reduce health care costs.
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Baixo Débito Cardíaco , Procedimentos Cirúrgicos Cardíacos , Baixo Débito Cardíaco/epidemiologia , Baixo Débito Cardíaco/etiologia , Baixo Débito Cardíaco/terapia , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Estudos Transversais , Humanos , Tempo de Internação , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/terapia , Estudos Retrospectivos , Fatores de RiscoRESUMO
BACKGROUND: We prospectively evaluated efficacy and safety of daptomycin versus active comparator in children with acute hematogenous osteomyelitis (AHO). METHODS: Randomized, controlled, double-blind, global, multicenter, phase 3 trial. Patients 1-17 years of age with suspected/confirmed AHO requiring hospitalization and intravenous therapy were randomized 1:1 to intravenous daptomycin (once-daily, age-adjusted doses) or comparator (vancomycin, nafcillin or equivalent) ≥4 days, followed by oral therapy (14-42 days total). Primary endpoint: protocol-defined clinical improvement by Day 5 in the modified intention-to-treat (MITT) population (confirmed AHO, ≥1 dose of study treatment); differences between study arms were evaluated using a prespecified 15% noninferiority margin for daptomycin. RESULTS: Seventy-three patients per arm received treatment. Pathogens were isolated from 62% of patients (83% methicillin-susceptible Staphylococcus aureus, 9% methicillin-resistant S. aureus [MRSA]). Clinical improvement by Day 5 was observed in 55/71 (78%) daptomycin- and 58/70 (83%) comparator-treated MITT patients (95% confidence interval [CI]: -19.4, 7.4). This difference was not statistically significant; however, daptomycin did not meet the prespecified 15% noninferiority margin, since the lower bound of the 95% CI extended below 15%. Overall, 82% of daptomycin and 87% of comparator patients achieved clinical cure at the test-of-cure visit (secondary endpoint). More comparator patients had treatment-emergent (63% vs. 46%) and treatment-related (18% vs. 7%) adverse events. CONCLUSIONS: Differences between daptomycin and comparator for the primary endpoint were not statistically significant; however, prespecified noninferiority criteria for daptomycin were not met. With insufficient cases of confirmed MRSA, we could not evaluate daptomycin for MRSA AHO. Our nonvalidated protocol design yields valuable information for implementing future trials in AHO (ClinicalTrials.gov NCT01922011).
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Antibacterianos/uso terapêutico , Daptomicina/uso terapêutico , Osteomielite/sangue , Osteomielite/tratamento farmacológico , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos , Doença Aguda/terapia , Administração Intravenosa , Adolescente , Criança , Pré-Escolar , Método Duplo-Cego , Humanos , Lactente , Testes de Sensibilidade Microbiana , Osteomielite/microbiologia , Estudos Prospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Staphylococcus aureus, including community-associated methicillin-resistant S. aureus, is an important cause of pediatric bacteremia. Daptomycin is a well-established treatment option for Gram-positive bacteremia in adults, but its safety and efficacy in children require confirmation. METHODS: This was a randomized (2:1), evaluator-blinded, multicenter, phase 4 clinical trial comparing intravenous daptomycin with standard-of-care (SOC) for treatment of S. aureus bacteremia in 1- to 17-year-old patients (Clinicaltrials.gov: NCT01728376). Total treatment duration (intravenous followed by oral step-down therapy) was 5-42 days. Daptomycin was dosed once daily by patient age: 12-17 years, 7 mg/kg; 7-11 years, 9 mg/kg and 1-6 years, 12 mg/kg. The primary objective was to evaluate daptomycin safety in children who received ≥1 dose; secondary objectives included comparing daptomycin efficacy with SOC (the trial was not designed to confirm noninferiority) and pharmacokinetic analysis. RESULTS: Fifty-five children were randomized to daptomycin and 27 to SOC (primarily vancomycin or cefazolin); 90% had S. aureus. In both groups, 15% of patients had drug-related adverse events, primarily diarrhea (4% daptomycin, 8% SOC) and increased creatine phosphokinase (4% daptomycin, 0% SOC). Clinical success (blinded evaluator-assessed complete/partial resolution of bacteremia signs and symptoms 7-14 days after end-of-treatment) rates were similar for daptomycin (88%) and SOC (77%; 95% confidence interval for difference: -9% to 31%). Daptomycin plasma levels across age groups were comparable with those in adults receiving daptomycin at 6 mg/kg. CONCLUSIONS: Once-daily, age-appropriate daptomycin was well tolerated in children with staphylococcal bacteremia; efficacy was comparable with SOC. Daptomycin in age-adjusted doses is a safe treatment alternative in this setting.
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Antibacterianos/uso terapêutico , Bacteriemia/tratamento farmacológico , Daptomicina/uso terapêutico , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos , Administração Intravenosa , Adolescente , Antibacterianos/efeitos adversos , Criança , Pré-Escolar , Daptomicina/efeitos adversos , Esquema de Medicação , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Humanos , Lactente , Masculino , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Resultado do TratamentoRESUMO
BACKGROUND: Complicated skin and skin structure infections (cSSSI) are common in children. Due to safety and resistance issues with recommended agents, new treatment options would be advantageous. METHODS: Multicenter, evaluator-blinded clinical trial. Patients 1 to 17 years old with cSSSI caused by Gram-positive pathogens were randomized 2:1 to intravenous daptomycin or standard-of-care (SOC) treatment for ≤14 days. Daptomycin was administered once daily with dosing by patient age: 12 to 17 years, 5 mg/kg; 7 to 11 years, 7 mg/kg; 2 to 6 years, 9 mg/kg; 12 to 23 months, 10 mg/kg. The primary objective was to evaluate daptomycin safety. The secondary objective was to assess the efficacy of daptomycin compared with SOC. The intent-to-treat (ITT) population consisted of all randomized patients with any dose of study drug. RESULTS: The ITT population comprised 257 daptomycin and 132 SOC patients (primarily clindamycin or vancomycin); 35% had confirmed methicillin-resistant Staphylococcus aureus. The most common adverse events were diarrhea (7% daptomycin, 5% SOC) and increased creatine phosphokinase (6% daptomycin, 5% SOC). The proportions of safety population patients with treatment-related adverse events were similar between the daptomycin (14%) and SOC (17%) groups. Clinical success rates (blinded evaluator-assessed complete/partial resolution of cSSSI signs and symptoms 7-14 days after end-of-treatment) in the ITT population were also similar for the daptomycin (91%) and SOC groups. CONCLUSIONS: Once-daily daptomycin was well tolerated, with safety and efficacy comparable to SOC in children/adolescents with cSSSI caused by Gram-positive pathogens, including community-acquired methicillin-resistant S aureus.
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Antibacterianos/uso terapêutico , Daptomicina/uso terapêutico , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Dermatopatias Bacterianas/tratamento farmacológico , Adolescente , Criança , Pré-Escolar , Clindamicina/uso terapêutico , Creatina Quinase/sangue , Diarreia/induzido quimicamente , Esquema de Medicação , Feminino , Febre/induzido quimicamente , Humanos , Masculino , Staphylococcus aureus Resistente à Meticilina , Método Simples-Cego , Vancomicina/uso terapêuticoRESUMO
BACKGROUND: Low cardiac output syndrome is associated with increased mortality and occurs in 3% to 14% of patients undergoing cardiac surgery on cardiopulmonary bypass (CPB). Levosimendan, a novel calcium sensitizer and KATP channel activator with inotropic, vasodilatory, and cardioprotective properties, has shown significant promise in reducing the incidence of low cardiac output syndrome and related adverse outcomes in patients undergoing cardiac surgery on CPB. METHODS: LEVO-CTS is a phase 3 randomized, controlled, multicenter study evaluating the efficacy, safety, and cost-effectiveness of levosimendan in reducing morbidity and mortality in high-risk patients with reduced left ventricular ejection fraction (≤35%) undergoing cardiac surgery on CPB. Patients will be randomly assigned to receive either intravenous levosimendan (0.2 µg kg-1 min-1 for the first hour followed by 0.1 µg/kg for 23hours) or matching placebo initiated within 8hours of surgery. The co-primary end points are (1) the composite of death or renal replacement therapy through day 30 or perioperative myocardial infarction, or mechanical assist device use through day 5 (quad end point tested at α<.01), and (2) the composite of death through postoperative day 30 or mechanical assist device use through day 5 (dual end point tested at α<.04). Safety end points include new atrial fibrillation and death through 90days. In addition, an economic analysis will address the cost-effectiveness of levosimendan compared with placebo in high-risk patients undergoing cardiac surgery on CPB. Approximately 880 patients will be enrolled at approximately 60 sites in the United States and Canada between July 2014 and September 2016, with results anticipated in January 2017. CONCLUSION: LEVO-CTS, a large randomized multicenter clinical trial, will evaluate the efficacy, safety, and cost-effectiveness of levosimendan in reducing adverse outcomes in high-risk patients undergoing cardiac surgery on CPB. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (NCT02025621).
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Procedimentos Cirúrgicos Cardíacos , Hidrazonas , Complicações Pós-Operatórias , Piridazinas , Disfunção Ventricular Esquerda/terapia , Administração Intravenosa , Adulto , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Procedimentos Cirúrgicos Cardíacos/métodos , Ponte Cardiopulmonar/métodos , Fármacos Cardiovasculares/administração & dosagem , Fármacos Cardiovasculares/efeitos adversos , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Hidrazonas/administração & dosagem , Hidrazonas/efeitos adversos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/mortalidade , Complicações Pós-Operatórias/prevenção & controle , Piridazinas/administração & dosagem , Piridazinas/efeitos adversos , Simendana , Volume Sistólico , Resultado do Tratamento , Disfunção Ventricular Esquerda/diagnóstico , Disfunção Ventricular Esquerda/fisiopatologiaRESUMO
BACKGROUND: Daptomycin is approved for treatment of complicated skin/skin structure infections and Staphylococcus aureus bloodstream infections (bacteremia) in adults. This study was undertaken to determine the pharmacokinetics of daptomycin in pediatric patients 3-24 months of age with proven/suspected bacterial infection. METHODS: In this phase 1, multicenter, open-label, noncomparative pharmacokinetic and safety study, patients were enrolled in 3 age groups: 3-6, 7-12 and 13-24 months. Intravenous daptomycin (single dose) was infused over 30 minutes at 6 mg/kg in subjects 13-24 months of age and at 4 mg/kg in the younger groups. Blood was collected for analysis of daptomycin concentrations. RESULTS: Twenty-four subjects received daptomycin. Daptomycin exposures (area under the curve0-∞) in children 3-6 and 7-12 months of age receiving 4 mg/kg were similar (215 and 219 µg·h/mL, respectively). Children 13-24 months of age receiving a higher dose, 6 mg/kg, had higher exposures (282 µg·h/mL). Mean maximum plasma concentrations in the age groups were 38.7, 37.1 and 67.0 µg/mL, respectively. Daptomycin exposures based on mg/kg dosing were lower than previously reported for older children and adults, likely because of increased clearance and volume of distribution and decreased apparent elimination half-life. Single-dose daptomycin 4 and 6 mg/kg was well tolerated and was not associated with clinical or laboratory adverse events. CONCLUSIONS: To match known clinically and microbiologically effective exposures in adults, infants require higher mg/kg daptomycin doses. Daptomycin safety and efficacy have not been established in pediatric patients. Pediatric clinical trials are ongoing.
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Antibacterianos/farmacocinética , Infecções Bacterianas/sangue , Daptomicina/farmacocinética , Administração Intravenosa , Antibacterianos/sangue , Área Sob a Curva , Infecções Bacterianas/tratamento farmacológico , Pré-Escolar , Daptomicina/sangue , Feminino , Meia-Vida , Humanos , Lactente , Masculino , Fatores de TempoRESUMO
OBJECTIVE: Ecallantide is a recombinant peptide in the same class as aprotinin that inhibits plasma kallikrein, a major component of the contact coagulation and inflammatory cascades. Therefore, ecallantide was expected to reduce blood loss associated with cardiac surgery requiring cardiopulmonary bypass. METHODS: This prospective multinational, randomized, double-blind trial enrolled patients undergoing cardiac surgery using cardiopulmonary bypass for procedures associated with a high risk of bleeding. Patients were randomly assigned to ecallantide (n = 109) or tranexamic acid (high dose, n = 24; low dose, n = 85). Efficacy was assessed from the volume of packed red blood cells administered within the first 12 hours after surgery. RESULTS: The study was terminated early after the independent data safety and monitoring board observed a statistically significantly higher 30-day mortality in the ecallantide group (12%) than in the tranexamic acid groups (4%, P = .041). Patients receiving ecallantide received more packed red blood cells within 12 hours of surgery than tranexamic acid-treated patients: median = 900 mL (95% confidence interval, 600-1070) versus 300 mL (95% confidence interval, 0-523) (P < .001). Similar differences were seen at 24 hours and at discharge. Patients treated with the higher tranexamic acid dose received less packed red blood cells, 0 mL (95% confidence interval, 280-600), than the group treated with the lower dose, 400 mL (95% confidence interval, 0-400) (P = .008). No deaths occurred in the higher dose tranexamic acid group. CONCLUSIONS: Ecallantide was less effective at reducing perioperative blood loss than tranexamic acid. High-dose tranexamic acid was more effective than the low dose in reducing blood loss.
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Perda Sanguínea Cirúrgica/prevenção & controle , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Ponte Cardiopulmonar/efeitos adversos , Hemostáticos/administração & dosagem , Peptídeos/administração & dosagem , Hemorragia Pós-Operatória/prevenção & controle , Ácido Tranexâmico/administração & dosagem , Idoso , Perda Sanguínea Cirúrgica/mortalidade , Procedimentos Cirúrgicos Cardíacos/mortalidade , Ponte Cardiopulmonar/mortalidade , Método Duplo-Cego , Término Precoce de Ensaios Clínicos , Transfusão de Eritrócitos , Europa (Continente) , Feminino , Hemostáticos/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeos/efeitos adversos , Hemorragia Pós-Operatória/etiologia , Hemorragia Pós-Operatória/mortalidade , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Ácido Tranexâmico/efeitos adversos , Resultado do Tratamento , Estados UnidosRESUMO
OBJECTIVES: To determine the relationship between the number of delirium days experienced by intensive care patients and mortality, ventilation time, and intensive care unit stay. DESIGN: Prospective cohort analysis. SETTING: Patients from 68 intensive care units in five countries. PATIENTS: Three hundred fifty-four medical and surgical intensive care patients enrolled in the SEDCOM (Safety and Efficacy of Dexmedetomidine Compared with Midazolam) trial received a sedative study drug and completed at least one delirium assessment. INTERVENTIONS: Sedative drug interruption and/or titration to maintain light sedation with daily arousal and delirium assessments up to 30 days of mechanical ventilation. MEASUREMENTS AND MAIN RESULTS: The primary outcome was all-cause 30-day mortality. Multivariable analysis using Cox regression incorporating delirium duration as a time-dependent variable and adjusting for eight relevant baseline covariates was conducted to quantify the relationship between number of delirium days and the three main outcomes. Overall, delirium was diagnosed in 228 of 354 patients (64.4%). Mortality was significantly lower in patients without delirium compared to those with delirium (15 of 126 [11.9%] vs. 69 of 228 [30.3%]; p<.001). Similarly, the median time to extubation and intensive care unit discharge were significantly shorter among nondelirious patients (3.6 vs. 10.7 days [p<.001] and 4 vs. 16 days [p<.001], respectively). In multivariable analysis, the duration of delirium exhibited a nonlinear relationship with mortality (p=.02), with the strongest association observed in the early days of delirium. In comparison to 0 days of delirium, an independent dose-response increase in mortality was observed, which increased from 1 day of delirium (hazard ratio, 1.70; 95% confidence interval, 1.27-2.29; p<.001), 2 days of delirium (hazard ratio, 2.69; confidence interval, 1.58-4.57; p<.001), and ≥3 days of delirium (hazard ratio, 3.37; confidence interval, 1.92-7.23; p<.001). Similar independent relationships were observed between delirium duration and ventilation time and intensive care length of stay. CONCLUSIONS: In ventilated and lightly sedated intensive care unit patients, the duration of delirium was the strongest independent predictor of death, ventilation time, and intensive care unit stay after adjusting for relevant covariates.
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Causas de Morte , Delírio/mortalidade , Mortalidade Hospitalar/tendências , Hipnóticos e Sedativos/uso terapêutico , Respiração Artificial/métodos , Idoso , Estudos de Coortes , Sedação Consciente/efeitos adversos , Sedação Consciente/métodos , Cuidados Críticos/métodos , Estado Terminal , Delírio/diagnóstico , Delírio/terapia , Dexmedetomidina/administração & dosagem , Dexmedetomidina/efeitos adversos , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Humanos , Hipnóticos e Sedativos/efeitos adversos , Unidades de Terapia Intensiva , Estimativa de Kaplan-Meier , Tempo de Internação , Masculino , Midazolam/administração & dosagem , Midazolam/efeitos adversos , Pessoa de Meia-Idade , Análise Multivariada , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Estudos Prospectivos , Respiração Artificial/efeitos adversos , Medição de RiscoRESUMO
GABA-mediated sedatives have respiratory depressant properties that may be detrimental in patients with difficult airways. In this randomized, double-blind, multicenter, Phase IIIb Food and Drug Administration study, safety and efficacy of dexmedetomidine compared with placebo were evaluated as the primary sedative for awake fiberoptic intubation (AFOI). Patients were randomized to receive dexmedetomidine or saline. Patients were sedated with dexmedetomidine or rescue midazolam to achieve targeted sedation (Ramsay Sedation Scale ≥ 2) before topicalization and throughout AFOI. Primary efficacy endpoint was percentage of patients requiring rescue midazolam; secondary efficacy endpoints were total dose of rescue midazolam, percentage requiring additional rescue nonmidazolam medications, anesthesiologist's assessment of ease of subject care, and patient recall and satisfaction 24 hours postoperatively. Less rescue midazolam was required to maintain Ramsay Sedation Scale ≥2 (47.3% vs. 86.0%, P < 0.001), and supplemental midazolam dose was lower (1.07 ± 1.5 mg vs. 2.85 ± 3.0 mg, P < 0.001) with dexmedetomidine compared with placebo. More Mallampati Class IV patients treated with dexmedetomidine were successfully intubated without midazolam than with placebo (66.7% vs. 8.3%, P = 0.009). Dexmedetomidine decreased blood pressure and heart rate compared with placebo patients sedated with midazolam. Patients and anesthesiologists showed favorable satisfaction responses in both groups. Adverse events and patient recall were similar in both groups. Dexmedetomidine is effective as the primary sedative in patients undergoing AFOI. Some patients may require small supplemental doses of midazolam, in addition to dexmedetomidine, to achieve sufficient sedation for AFOI. Dexmedetomidine provides another AFOI option for sedation of patients with difficult airways.
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Dexmedetomidina/uso terapêutico , Tecnologia de Fibra Óptica , Hipnóticos e Sedativos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Sedação Consciente , Dexmedetomidina/administração & dosagem , Dexmedetomidina/efeitos adversos , Método Duplo-Cego , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Hipnóticos e Sedativos/administração & dosagem , Hipnóticos e Sedativos/efeitos adversos , Intubação Intratraqueal , Masculino , Midazolam/administração & dosagem , Midazolam/uso terapêutico , Pessoa de Meia-Idade , Satisfação do Paciente , Estudos ProspectivosRESUMO
BACKGROUND: Dexmedetomidine (DEX) is increasingly being used as a sedative for monitored anesthesia care (MAC) because of its analgesic properties, "cooperative sedation," and lack of respiratory depression. In this randomized, multicenter, double-blind, Phase III Food and Drug Administration study, we evaluated the safety and efficacy of two doses of DEX for sedation of patients undergoing a broad range of surgical or diagnostic procedures requiring MAC. METHODS: Three hundred twenty-six patients were randomized 2:2:1 to DEX 0.5 microg/kg, DEX 1 microg/kg, or saline placebo initial loading dose, followed by a maintenance infusion of 0.2-1.0 microg x kg(-1) x h(-1) of DEX (or equivalent volume of saline) titrated to a targeted level of sedation (< or = 4 on the Observer's Assessment of Alertness/Sedation Scale [OAA/S]). Study drug was started at least 15 min before placement of regional or local anesthetic block. Midazolam was given for OAA/S > 4 and fentanyl for pain. The primary end-point was the percentage of patients not requiring rescue midazolam. RESULTS: Significantly fewer patients in the 0.5- and 1-microg/kg DEX groups required supplemental midazolam compared with placebo (59.7% [80/134], 45.7% [59/129] vs 96.8% [61/63], respectively; P < 0.001) and at lower doses to achieve an OAA/S < or = 4 before and during surgery compared with the saline group (1.4 and 0.9 mg vs 4.1 mg, respectively; P < 0.001, each group compared with placebo). Both DEX groups required significantly less fentanyl (84.8 and 83.6 microg vs 144.4 microg, respectively; P < 0.001, for both DEX groups versus placebo) for all surgical subtypes. Anesthesiologists indicated significantly increased ease of achieving and maintaining targeted sedation in both DEX groups compared with placebo with midazolam (P < 0.001). Patient satisfaction was significantly higher with DEX (P < or = 0.009, both groups versus placebo). Common adverse events with DEX were protocol-defined bradycardia and hypotension that were predominately mild to moderate in severity. The incidence of clinically significant respiratory depression (defined as a respiratory rate of < 8 or an oxygen saturation of < 90%) was lower in DEX-treated patients (P = 0.018, for both groups versus placebo). CONCLUSIONS: DEX is an effective baseline sedative for patients undergoing MAC for a broad range of surgical procedures providing better patient satisfaction, less opioid requirements, and less respiratory depression than placebo rescued with midazolam and fentanyl.
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Anestesia , Dexmedetomidina , Hipnóticos e Sedativos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anestesia Intravenosa , Anestésicos Intravenosos , Dexmedetomidina/administração & dosagem , Dexmedetomidina/efeitos adversos , Método Duplo-Cego , Feminino , Fentanila , Hemodinâmica/efeitos dos fármacos , Humanos , Hipnóticos e Sedativos/administração & dosagem , Hipnóticos e Sedativos/efeitos adversos , Masculino , Pessoa de Meia-Idade , Monitorização Intraoperatória , Satisfação do Paciente , Estudos Prospectivos , Adulto JovemRESUMO
OBJECTIVE: To compare the intensive care unit costs and determine factors influencing these costs in mechanically ventilated patients randomized to dexmedetomidine or midazolam by continuous infusion. DESIGN: Cost minimization analysis of a double-blind, multicenter clinical trial randomizing patients 2:1 to receive dexmedetomidine or midazolam from the institutional perspective. SETTING: Sixty-eight intensive care units in the United States, Australia, New Zealand, Brazil, and Argentina. PATIENTS: A total of 366 intubated intensive care unit patients anticipated to require sedation for >24 hrs. MEASUREMENTS AND MAIN RESULTS: Intensive care unit resource use was compared within the two treatment arms, using the U.S. representative costs for these resources. The analyses characterized patient costs from start of study drug until intensive care unit discharge including costs associated with the intensive care unit stay, costs during mechanical ventilation, study drug acquisition cost, and costs of treating adverse drug reactions probably or possibly related to study drugs. Blinded to treatment group, costs were calculated using Medicare reimbursement schedules, average IMS drug costs, expert opinion, and peer-reviewed literature. Censored lengths of intensive care unit stay and mechanical ventilation were imputed, using a nonparametric adjustment algorithm. Crude and multivariate median regressions were performed to relate intensive care unit cost and treatment. Including drug acquisition cost, sedation with dexmedetomidine was associated with a median total intensive care unit cost savings of $9679 (confidence interval, $2314-$17,045) compared with midazolam. The primary cost drivers were reduced costs of intensive care unit stay (median savings, $6584, 95% confidence interval, $727-$12,440) and reduced costs of mechanical ventilation (median savings, $2958, 95% confidence interval, $698-$5219). CONCLUSIONS: Continuous sedation with dexmedetomidine results in significantly lower total intensive care unit costs compared with midazolam infusion for intensive care unit sedation, primarily due to decreased intensive care unit stay costs and reduced mechanical ventilation costs.
Assuntos
Cuidados Críticos/economia , Dexmedetomidina/economia , Hipnóticos e Sedativos/economia , Midazolam/economia , Redução de Custos/economia , Análise Custo-Benefício , Cuidados Críticos/métodos , Dexmedetomidina/efeitos adversos , Dexmedetomidina/uso terapêutico , Método Duplo-Cego , Feminino , Humanos , Hipnóticos e Sedativos/efeitos adversos , Hipnóticos e Sedativos/uso terapêutico , Unidades de Terapia Intensiva/economia , Assistência de Longa Duração/economia , Assistência de Longa Duração/métodos , Masculino , Midazolam/efeitos adversos , Midazolam/uso terapêutico , Respiração Artificial/economia , Respiração Artificial/métodos , Resultado do Tratamento , Estados UnidosRESUMO
CONTEXT: Gamma-aminobutyric acid receptor agonist medications are the most commonly used sedatives for intensive care unit (ICU) patients, yet preliminary evidence indicates that the alpha(2) agonist dexmedetomidine may have distinct advantages. OBJECTIVE: To compare the efficacy and safety of prolonged sedation with dexmedetomidine vs midazolam for mechanically ventilated patients. DESIGN, SETTING, AND PATIENTS: Prospective, double-blind, randomized trial conducted in 68 centers in 5 countries between March 2005 and August 2007 among 375 medical/surgical ICU patients with expected mechanical ventilation for more than 24 hours. Sedation level and delirium were assessed using the Richmond Agitation-Sedation Scale (RASS) and the Confusion Assessment Method for the ICU. INTERVENTIONS: Dexmedetomidine (0.2-1.4 microg/kg per hour [n = 244]) or midazolam (0.02-0.1 mg/kg per hour [n = 122]) titrated to achieve light sedation (RASS scores between -2 and +1) from enrollment until extubation or 30 days. MAIN OUTCOME MEASURES: Percentage of time within target RASS range. Secondary end points included prevalence and duration of delirium, use of fentanyl and open-label midazolam, and nursing assessments. Additional outcomes included duration of mechanical ventilation, ICU length of stay, and adverse events. RESULTS: There was no difference in percentage of time within the target RASS range (77.3% for dexmedetomidine group vs 75.1% for midazolam group; difference, 2.2% [95% confidence interval {CI}, -3.2% to 7.5%]; P = .18). The prevalence of delirium during treatment was 54% (n = 132/244) in dexmedetomidine-treated patients vs 76.6% (n = 93/122) in midazolam-treated patients (difference, 22.6% [95% CI, 14% to 33%]; P < .001). Median time to extubation was 1.9 days shorter in dexmedetomidine-treated patients (3.7 days [95% CI, 3.1 to 4.0] vs 5.6 days [95% CI, 4.6 to 5.9]; P = .01), and ICU length of stay was similar (5.9 days [95% CI, 5.7 to 7.0] vs 7.6 days [95% CI, 6.7 to 8.6]; P = .24). Dexmedetomidine-treated patients were more likely to develop bradycardia (42.2% [103/244] vs 18.9% [23/122]; P < .001), with a nonsignificant increase in the proportion requiring treatment (4.9% [12/244] vs 0.8% [1/122]; P = .07), but had a lower likelihood of tachycardia (25.4% [62/244] vs 44.3% [54/122]; P < .001) or hypertension requiring treatment (18.9% [46/244] vs 29.5% [36/122]; P = .02). CONCLUSIONS: There was no difference between dexmedetomidine and midazolam in time at targeted sedation level in mechanically ventilated ICU patients. At comparable sedation levels, dexmedetomidine-treated patients spent less time on the ventilator, experienced less delirium, and developed less tachycardia and hypertension. The most notable adverse effect of dexmedetomidine was bradycardia. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00216190 Published online February 2, 2009 (doi:10.1001/jama.2009.56).
Assuntos
Agonistas alfa-Adrenérgicos , Sedação Consciente , Estado Terminal , Dexmedetomidina , Moduladores GABAérgicos , Hipnóticos e Sedativos , Midazolam , Respiração Artificial , APACHE , Agonistas alfa-Adrenérgicos/administração & dosagem , Agonistas alfa-Adrenérgicos/efeitos adversos , Idoso , Sedação Consciente/métodos , Delírio/epidemiologia , Dexmedetomidina/administração & dosagem , Dexmedetomidina/efeitos adversos , Método Duplo-Cego , Feminino , Moduladores GABAérgicos/administração & dosagem , Moduladores GABAérgicos/efeitos adversos , Humanos , Hipnóticos e Sedativos/administração & dosagem , Hipnóticos e Sedativos/efeitos adversos , Unidades de Terapia Intensiva , Estimativa de Kaplan-Meier , Tempo de Internação , Masculino , Midazolam/administração & dosagem , Midazolam/efeitos adversos , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
OBJECTIVE: The hospital course for pediatric coarctation repair has not been described. We had 4 aims: (1) to determine the influence of age, anatomy, and type of repair on aortic crossclamp time, (2) to determine the impact of age or aortic crossclamp time on postoperative morbidity, (3) to describe current antihypertensive strategies, and (4) to describe antihypertensive medications at hospital discharge. METHODS: Data were obtained from a prospective randomized multicenter esmolol safety and efficacy trial. The study included patients who were scheduled for a coarctation repair receiving esmolol as their first-line antihypertensive medication in the operating room (n = 118; weight > or = 2.5 kg and age < 6 years). RESULTS: (1) Patient age and type of coarctation did not affect the aortic crossclamp time. (2) Younger age, but not aortic crossclamp time, was associated with a significantly longer time to extubation and longer hospital length of stay. (3) A combination of esmolol and sodium nitroprusside (Nipride, Roche, Basel, Switzerland) provided excellent early blood pressure control. (4) At discharge, 64% of patients were receiving antihypertensive medications. Older patients were more likely to be discharged with antihypertensive medication (91% of patients aged 2-6 years, P < .0002). CONCLUSION: The study describes a multi-institutional approach to the repair of isolated coarctation in infants and children. Patients repaired by end-to-end anastomosis had shorter aortic crossclamp time, younger patients had longer hospital length of stay, a majority of patients had sodium nitroprusside (Nipride) added to esmolol for early blood pressure control, and older patients were more likely to be discharged with antihypertensive medication.
Assuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Coartação Aórtica/cirurgia , Propanolaminas/uso terapêutico , Toracotomia , Antagonistas Adrenérgicos beta/administração & dosagem , Fatores Etários , Anti-Hipertensivos/administração & dosagem , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Tempo de Internação , Masculino , Nitroprussiato/administração & dosagem , Propanolaminas/administração & dosagem , Estudos ProspectivosRESUMO
OBJECTIVES: Blood pressure control is important after repair of coarctation of the aorta. We report the first prospective multi-institutional trial addressing the safety and efficacy of esmolol after repair of coarctation of the aorta in infants and children. METHODS: The primary objective of this phase IIIb, multicenter, double-blind, randomized, dose-ranging trial was the efficacy of esmolol to control hypertension. Candidates included subjects younger than 6 years and weighing 2.5 kg or more who underwent surgical intervention for coarctation of the aorta and required therapy for systemic hypertension. One hundred sixteen subjects received esmolol: 36 received a low dose (125 microg/kg), 43 received a medium dose (250 microg/kg), and 37 received a high dose (500 microg/kg). The primary outcomes were the change in systolic blood pressure and the need for additional antihypertensive rescue medication 5 minutes after the initiation of esmolol. RESULTS: All dose groups showed a significant decrease from baseline in systolic blood pressure (-9.6 +/- 16.3 mm Hg, P < .001). There were no differences in systolic blood pressure response at 5 minutes between dose groups (high, medium, or low) or age groups. The need for rescue medication at 5 minutes was not different between dose groups. All dose groups showed similar incidences of adverse events. There were no serious adverse events. DISCUSSION: Esmolol can be administered safely to patients younger than 6 years after repair of coarctation of the aorta. In the dose range of 125 to 500 microg/kg, esmolol significantly decreased systolic blood pressure.
Assuntos
Antagonistas Adrenérgicos beta/administração & dosagem , Anti-Hipertensivos/administração & dosagem , Coartação Aórtica/cirurgia , Pressão Sanguínea/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Complicações Pós-Operatórias , Propanolaminas/administração & dosagem , Antagonistas Adrenérgicos beta/efeitos adversos , Antagonistas Adrenérgicos beta/farmacocinética , Anti-Hipertensivos/efeitos adversos , Anti-Hipertensivos/farmacocinética , Coartação Aórtica/fisiopatologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Hipertensão/etiologia , Lactente , Recém-Nascido , Masculino , Propanolaminas/efeitos adversos , Propanolaminas/farmacocinéticaRESUMO
BACKGROUND: Infants and young children with certain types of heart disease are at increased risk for thromboses. Clopidogrel 75 mg/d is used in adults to prevent thrombotic events. The dose to achieve similar platelet inhibition in children is unknown. The objectives of the present study were (1) to determine the dose of clopidogrel needed in infants and young children to achieve a mean 30% to 50% inhibition of 5-micromol/L ADP-induced platelet aggregation (ie, inhibition similar to that observed with 75 mg in adults) and (2) to assess the safety and tolerability of clopidogrel in infants and young children. METHODS AND RESULTS: We performed a prospective, multicenter, randomized, placebo-controlled trial evaluating the pharmacodynamics of clopidogrel in children (0 to 24 months) with a cardiac condition at risk for arterial thrombosis. Patients were randomized to clopidogrel versus placebo in a 3:1 ratio in 4 sequential groups (0.01, 0.10, 0.20, and 0.15 mg/kg) for > or = 7 and < or = 28 days. Platelet aggregation was assessed at baseline and steady state by light-transmission aggregometry. Of 116 patients enrolled, 92 (50% neonates, 50% infants/toddlers) were randomized, and 73 completed the study. A total of 79% of the randomized and treated patients were taking aspirin. Compared with placebo, clopidogrel 0.20 mg x kg(-1) x d(-1) resulted in a mean 49.3% (95% confidence interval 25.7% to 72.8%) inhibition of the maximum extent of platelet aggregation and a mean 43.9% (95% confidence interval 18.6% to 69.2%) inhibition of the rate of platelet aggregation. There was marked interpatient variability in the degree of platelet aggregation inhibition within each treatment-dose group and age group. No serious bleeding events occurred. CONCLUSIONS: Clopidogrel 0.20 mg x kg(-1) x d(-1) in children 0 to 24 months of age achieves a platelet inhibition level similar to that in adults taking 75 mg/d. Clopidogrel is well tolerated in infants and young children at this dose.
Assuntos
Agregação Plaquetária/efeitos dos fármacos , Ticlopidina/análogos & derivados , Aspirina/uso terapêutico , Clopidogrel , Relação Dose-Resposta a Droga , Hemorragia/induzido quimicamente , Humanos , Lactente , Recém-Nascido , Inibidores da Agregação Plaquetária/uso terapêutico , Ticlopidina/administração & dosagem , Ticlopidina/efeitos adversosRESUMO
BACKGROUND: Aspirin (ASA) often is used to prevent thrombosis in infants with congenital heart disease after placement of a systemic-to-pulmonary artery shunt, but its effect on outcomes is unknown. METHODS AND RESULTS: The present multicenter study prospectively collected data on 1-year postoperative rates of death, shunt thrombosis, or hospitalization age <4 months for bidirectional Glenn/hemi-Fontan surgery in 1004 infants. The use and dose of ASA were recorded. Kaplan-Meier event rates were calculated for each event and the composite outcome, and a Cox regression model was constructed for time to event. Model terms were ASA use and type of surgery, with adjustment for age at surgery. Diagnoses were hypoplastic left heart syndrome (n=346), tricuspid atresia (n=103), tetralogy of Fallot (n=127), pulmonary atresia (n=177), heterotaxy syndrome (n=38), and other (n=213). There were 344 shunts placed without cardiopulmonary bypass (closed shunt), 287 shunts with bypass (open shunt), 323 Norwood procedures, and 50 Sano procedures. Overall, 80% of patients received ASA. One-year postoperative events rates were high: 38% for the composite end point, 26% for death, and 12% for shunt thrombosis. After the exclusion of patients with early mortality, patients receiving ASA had a lower risk of shunt thrombosis (hazard ratio, 0.13; P=0.008) and death (closed shunt: hazard ratio, 0.41, P=0.057; open shunt: hazard ratio, 0.10, P<0.001; Norwood: hazard ratio, 0.34, P<0.001; Sano: hazard ratio, 0.68, P=NS) compared with those not receiving ASA. CONCLUSIONS: The morbidity and mortality for infants after surgical placement of a systemic-to-pulmonary artery shunt are high. ASA appears to lower the risk of death and shunt thrombosis in the present observational study.
Assuntos
Aspirina/uso terapêutico , Procedimentos Cirúrgicos Cardíacos , Cardiopatias Congênitas/tratamento farmacológico , Cardiopatias Congênitas/cirurgia , Cuidados Paliativos , Artéria Pulmonar/cirurgia , Aspirina/farmacologia , Procedimentos Cirúrgicos Cardíacos/métodos , Cardiopatias Congênitas/mortalidade , Humanos , Lactente , Cuidados Paliativos/métodos , Estudos Prospectivos , Artéria Pulmonar/efeitos dos fármacos , Resultado do TratamentoRESUMO
OBJECTIVE: The primary study objective was to examine the impact of diagnosis on the inflammatory response in neonates with congenital heart disease undergoing cardiac surgery. The secondary objective was to study the impact of the inflammatory response on postoperative outcome in these neonates. DESIGN: Observational study. SETTING: Tertiary care children's hospital heart center. PATIENTS: Neonates with hypoplastic left-heart syndrome (HLHS) undergoing stage I repair and patients with transposition of the great arteries (TGA) undergoing arterial switch operation. MEASUREMENTS AND MAIN RESULTS: There were 24 neonates with HLHS and 21 neonates with TGA. Serum samples to measure interleukin (IL)-6 and -10 were obtained before and after CPB at 1, 3, 6, and 24 hours postoperatively. Time to extubation, intensive care unit (ICU) length of stay, and peritoneal fluid drainage were compared between the groups. Serum IL-6 and IL-10 concentrations increased after CPB when compared to the preoperative concentration. Preoperative concentrations of IL-6 were significantly elevated in the HLHS group (HLHS: 32 [21.1, 69.6] pg/mL v TGA: 7.2 [3.6, 22.5] pg/mL [median, 25th, and 75th percentile], p = 0.003) and remained elevated immediately after CPB, and at 3 and 6 hours postoperatively. The IL-10 to IL-6 ratio was lower in the HLHS group preoperatively and immediately after CPB. ICU length of stay was significantly longer in the HLHS group (TGA 4 [3-6] days v HLHS 6 [5-8] days, p = 0.031). Mortality in the HLHS group (4/24) was associated with significantly higher IL-6 postoperatively (IL-6 immediately postoperatively: HLHS survivors 59.9 [34.3, 65.7] pg/mL v nonsurvivors 98.7 [94.4, 104.5] pg/mL, p < 0.011). CONCLUSIONS: All neonates with TGA or HLHS have a significant inflammatory response after CPB. Neonates with HLHS have evidence of an activated inflammatory response before CPB, which remains significant in the postoperative period. Accelerated interleukin expression and an abnormal cytokine balance correlate with longer time to extubation, longer ICU length of stay, and increased peritoneal fluid volume.
Assuntos
Procedimentos Cirúrgicos Cardíacos , Síndrome do Coração Esquerdo Hipoplásico/sangue , Síndrome do Coração Esquerdo Hipoplásico/cirurgia , Interleucina-10/sangue , Interleucina-6/sangue , Transposição dos Grandes Vasos/sangue , Transposição dos Grandes Vasos/cirurgia , Biomarcadores/sangue , Ponte Cardiopulmonar , Parada Circulatória Induzida por Hipotermia Profunda , Humanos , Recém-Nascido , Mediadores da Inflamação/sangue , Unidades de Terapia Intensiva Neonatal , Tempo de Internação , Período Pós-Operatório , Projetos de Pesquisa , Análise de Sobrevida , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND AND PURPOSE: The goal of this study was to compare the predictive ability of S100B, N-methyl-D-aspartate (NMDA) receptor antibodies (NR2Ab) and C-reactive protein (CRP) for neurological deficits after cardiac surgery with cardiopulmonary bypass (CPB). METHODS: We investigated 557 high-risk adult patients who underwent coronary artery or valve replacement surgery using CPB as a substudy of a prospective, blinded, multicenter clinical trial. Serum concentrations of S100B (n=513 patients), NR2Ab (n=398) and CRP (n=510) were measured preoperatively, 24 and 48 hours after CPB. Neurological adverse events were assessed at baseline and postoperative days 1 and 2; neurocognitive function (mini-mental status examination) was assessed at baseline and on postoperative days 1, 7 and 28. RESULTS: Fifty-five (9.9%) patients had moderate or severe neurological adverse events (confusion/delirium, transient ischemic attack, or stroke) within 48 hours of CPB. Women had significantly more neurological complications than men (15.5% versus 7.8%; P=0.007). Ninety-six percent (24/25) of patients with NR2Ab concentrations > or =2.0 ng/mL preoperatively had neurological complications within 48 hours post-CPB, versus only 5.4% (20/373) of patients with NR2Ab concentrations <2.0 ng/mL, resulting in a 17.9-fold increase (95% CI, 11.6 to 27.6) in postoperative neurological complications for patients with high levels of NR2A antibodies. Preoperative serum S100B and CRP did not predict neurological complications from CPB. Decreased mini-mental status examination scores for orientation, attention and recall were associated with neurological adverse events early after CPB. CONCLUSIONS: Preoperative serum concentrations of NR2Ab, but not S100B or CRP, are predictive of severe neurological adverse events after CPB. Patients with a positive NR2Ab test (> or =2.0 ng/mL) preoperatively were nearly 18 times more likely to experience a postoperative neurological event than patients with a negative test (<2.0 ng/mL).