Dose rationale for the use of meropenem/vaborbactam combination in paediatric patients with Gram-negative bacterial infections.

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.

Risk factors, resource use, and cost of postoperative low cardiac output syndrome.

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.

Daptomycin for Pediatric Gram-Positive Acute Hematogenous Osteomyelitis.

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).

Randomized Multicenter Study Comparing Safety and Efficacy of Daptomycin Versus Standard-of-care in Pediatric Patients With Staphylococcal Bacteremia.

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.

Daptomycin for Complicated Skin Infections: A Randomized Trial.

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.

Levosimendan in patients with left ventricular systolic dysfunction undergoing cardiac surgery on cardiopulmonary bypass: Rationale and study design of the Levosimendan in Patients with Left Ventricular Systolic Dysfunction Undergoing Cardiac Surgery Requiring Cardiopulmonary Bypass (LEVO-CTS) trial.

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 K 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.

Single-dose pharmacokinetics of daptomycin in pediatric patients 3-24 months of age.

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.

A phase 2 prospective, randomized, double-blind trial comparing the effects of tranexamic acid with ecallantide on blood loss from high-risk cardiac surgery with cardiopulmonary bypass (CONSERV-2 Trial).

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.

Delirium duration and mortality in lightly sedated, mechanically ventilated intensive care patients.

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.

A Phase IIIb, randomized, double-blind, placebo-controlled, multicenter study evaluating the safety and efficacy of dexmedetomidine for sedation during awake fiberoptic intubation.

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.

A cost-minimization analysis of dexmedetomidine compared with midazolam for long-term sedation in the intensive care unit.

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.

Monitored anesthesia care with dexmedetomidine: a prospective, randomized, double-blind, multicenter trial.

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.

Dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial.

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.

Perioperative course in 118 infants and children undergoing coarctation repair via a thoracotomy: a prospective, multicenter experience.

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 safety, efficacy, and pharmacokinetics of esmolol for blood pressure control immediately after repair of coarctation of the aorta in infants and children: a multicenter, double-blind, randomized trial.

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.

Dosing of clopidogrel for platelet inhibition in infants and young children: primary results of the Platelet Inhibition in Children On cLOpidogrel (PICOLO) trial.

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.

Clinical outcomes of palliative surgery including a systemic-to-pulmonary artery shunt in infants with cyanotic congenital heart disease: does aspirin make a difference?

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.

Perioperative serum interleukins in neonates with hypoplastic left-heart syndrome and transposition of the great arteries.

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.

NMDA receptor antibodies predict adverse neurological outcome after cardiac surgery in high-risk patients.

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.

Increased transcription factor expression and permeability of the blood brain barrier associated with cardiopulmonary bypass in lambs.

Background: The pathophysiology of neurocognitive dysfunction and developmental delay after cardiopulmonary bypass (CPB) in infants is not known. It is known that head trauma, stroke, and seizures cause dysfunction of the blood brain barrier (BBB) that is associated with increased inducible transcription factor gene expression in the cells of the barrier. The purpose of this study was to determine the effects of CPB and hypothermic circulatory arrest on expression of the transcription factor FOS and the function of the BBB in an infant animal model.

Soluble human complement receptor 1 limits ischemic damage in cardiac surgery patients at high risk requiring cardiopulmonary bypass.

Background: This study was undertaken to determine whether soluble human complement receptor type 1 (TP10), a potent inhibitor of complement activation, would reduce morbidity and mortality in high-risk patients undergoing cardiac surgery on cardiopulmonary bypass (CPB).

Methods: This was a randomized multicenter, prospective, placebo-controlled, double-blind study in which 564 high-risk patients undergoing cardiac surgery on CPB received an intravenous bolus of TP10 (1, 3, 5, 10 mg/kg) or placebo immediately before CPB. The primary endpoint was the composite events of death, myocardial infarction (MI), prolonged (> or =24 hours) intra-aortic balloon pump support (IABP), and prolonged intubation.

Pharmacokinetics and safety of TP10, soluble complement receptor 1, in infants undergoing cardiopulmonary bypass.

Background: Increase in vascular permeability and multiorgan dysfunction after cardiopulmonary bypass (CPB) are barriers to successful cardiac surgery in infants. Complement inhibition with TP10, a C3/C5 convertase inhibitor (AVANT Immunotherapeutics, Needham, Mass), blunts post-CPB organ dysfunction in the neonatal pig. Methods and results The pharmacokinetics and safety of TP10 in infants (age <1 year, n = 15) undergoing CPB were examined in a phase I/II open-label prospective trial.

Serum creatinine and estimated creatinine clearance do not predict perioperatively measured creatinine clearance in neonates undergoing congenital heart surgery.

Objective: To describe changes in creatinine clearance (CrCl) in a small group of neonates who underwent surgery for repair of transposition of the great arteries or palliation of hypoplastic left heart syndrome. To determine whether serum creatinine, urine output, or the Schwartz formula accurately predict measured CrCl in these patients.

Design: Prospective, randomized controlled trial with subsequent extraction of information regarding renal function from the database.

A glial-derived protein, S100B, in neonates and infants with congenital heart disease: evidence for preexisting neurologic injury.

Unlabelled: The glial-derived protein S100B is a serum marker of cerebral ischemia and correlates with negative neurological outcome after cardiopulmonary bypass (CPB) in adults. We sought to characterize the S100B release pattern before and after CPB in neonates and infants with congenital heart disease and correlate it with surgical mortality. Serum was collected before surgery and at 24 postoperative h from 109 neonates and infants with congenital heart disease.