Neurologic complications after the frozen elephant trunk procedure: A meta-analysis of more than 3000 patients.

OBJECTIVE: The frozen elephant trunk technique's safety regarding spinal cord ischemia has been questioned. We used a meta-analysis to determine the rates of adverse neurologic events and mortality. METHODS: We searched PubMed/Medline, Embase, Scopus, and Cochrane databases (inception to April 2018) to identify studies of neurologic events after the frozen elephant trunk procedure. Separate meta-analyses were conducted with random-effects models to assess frozen elephant trunk associations with spinal cord ischemia, stroke, operative mortality, and all adverse events combined. Subgroup analyses compared outcomes in patients with acute versus nonacute type A dissection and aneurysm and with different extents of coverage. RESULTS: Thirty-five studies (total N = 3154) met inclusion criteria. The pooled rates of the outcomes of interest were 4.7% (95% confidence interval, 3.5-6.2) for spinal cord ischemia, 7.6% (95% confidence interval, 5.0-11.5) for stroke, and 8.8% (95% confidence interval, 7.0-10.9) for operative mortality. The spinal cord ischemia event rate was higher with stent length 15 cm or greater or coverage to T8 or beyond than with stent length of 10 cm (11.6% vs 2.5%, P < .001). Adverse event rates in patients with acute type A aortic dissection versus nonacute dissection or aneurysm were as follows: mortality 9.2% versus 7.6% (P = .46), stroke 9.3% versus 6.6% (P = .51), and overall adverse events 22.0% versus 16.5% (P = .41). CONCLUSIONS: As the frozen elephant trunk procedure becomes more popular, accurate data regarding outcomes are vital. We associated the frozen elephant trunk technique with (nonsignificantly) more adverse events overall in acute type A dissection cases. Stent length of 10 cm was associated with significantly less risk of spinal cord ischemia. Using a stent 15 cm or greater or coverage extending to T8 or farther should be avoided.

Antithrombin Population Pharmacokinetics in Pediatric Ventricular Assist Device Patients.

OBJECTIVES: Describe the pharmacokinetics of antithrombin in pediatric patients undergoing ventricular assist device therapy and provide dosing recommendations for antithrombin in this population. DESIGN: A retrospective population pharmacokinetic study was designed. SETTING: Large tertiary care children's hospital Subject inclusion criteria consisted of less than 19 years old. PATIENTS: Subjects less than 19 years old undergoing therapy with a HeartWare ventricular assist device (HeartWare, Framingham, MA) or Berlin EXCOR ventricular assist device (Berlin GmbH, Berlin, Germany), who received a dose of antithrombin with a postdose antithrombin activity level from January 1, 2011, to June 30, 2017. INTERVENTIONS: Population pharmacokinetic analysis and simulation using NONMEM v.7.4 (Icon, PLC, Dublin, Ireland). MEASUREMENTS AND MAIN RESULTS: A total of 41 patients met study criteria (median age, 5.8 years [interquartile range, 1.6-9.9 yr]), and 53.7% underwent therapy with the pulsatile Berlin EXCOR pediatric ventricular assist device (Berlin Heart GmbH, Berlin, Germany). All patients received unfractionated heparin continuous infusion at a mean ± SD dose of 29 ± 14 U/kg/hr. A total of 181 antithrombin doses (44.1 ± 24.6 U/kg/dose) were included, and baseline antithrombin activity levels were 77 ± 12 U/dL. Antithrombin activity levels were drawn a median 19.9 hours (interquartile range, 8.8-41.6 hr) after antithrombin dose. A one-compartment proportional error model best fit the data, with allometric scaling of fat-free mass providing a better model fit than actual body weight. Unfractionated heparin and baseline antithrombin were identified as significant covariates. A 50 U/kg dose of antithrombin had a simulated half-life 13.2 ± 6.6 hours. CONCLUSIONS: Antithrombin should be dosed on fat-free mass in pediatric ventricular assist device patients. Unfractionated heparin dose and baseline antithrombin activity level should be considered when dosing antithrombin in pediatric ventricular assist device patients.

A Critical Evaluation of Enoxaparin Dose Adjustment Guidelines in Children.

OBJECTIVES: The purposes of this study are to perform a large-scale evaluation of the standardized dosage adjustment nomogram recommended by the American College of Chest Physicians (CHEST) for the management of enoxaparin in hospitalized pediatric patients and to determine the necessity of routine and repeated anti-factor Xa (anti-Xa) levels. METHODS: A retrospective cohort study was designed, and charts were reviewed in a single tertiary care institution for all patients who received enoxaparin between October 1, 2010, through September 30, 2016. Patients were included if they were receiving treatment doses of enoxaparin according to the pediatric CHEST guidelines, had a subtherapeutic or supratherapeutic anti-Xa level drawn at 3.5 to 6 hours after a dose, had a dose changed in an attempt to attain a therapeutic anti-Xa level, and had a second anti-Xa level drawn 3.5 to 6 hours after the dose change. Descriptive statistical methods were used to characterize the ability of dose adjustment via a nomogram to attain an anti-Xa of 0.5 to 1 unit/mL. RESULTS: A total of 467 patients were identified who received the appropriate initial dose and dosage adjustment and whose levels were drawn according to the CHEST guidelines. In patients who had an initial anti-Xa level of <0.35 units/mL and received the nomogram recommended dose increase of 25% ± 5%, 28 out of 96 patients (29.2%) reached therapeutic levels. Of 197 patients who had an initial anti-Xa level between 0.35 and 0.49 units/mL and who received the nomogram recommended dose increase of 10% ± 5%, 116 (58.9%) reached therapeutic levels. Of 50 patients with an initial anti-Xa level between 1.1 and 1.5 units/mL and who received the nomogram dose decrease of 20% ± 5%, 31 (62%) reached therapeutic levels. CONCLUSIONS: The current dosage adjustment nomogram recommended by the CHEST guidelines does not reliably lead to therapeutic anti-Xa levels when used to adjust enoxaparin doses in pediatric patients.

Vancomycin associated acute kidney injury in pediatric patients.

INTRODUCTION: Vancomycin associated acute kidney injury (vAKI) is a well known complication in pediatric patients. Identification and characterization of the incidence and risk factors for vAKI in the pediatric population would assist clinicians in potentially preventing or mitigating vAKI. METHODS AND MATERIALS: A 6 year retrospective cohort study was designed. Patients were included if they were < 19 years of age, received vancomycin as inpatients, and had a baseline SCr and one other SCr drawn during and up to 72 hours after the discontinuation of vancomycin. Data collection included patient demographics, vancomycin doses and length of therapy, vancomycin serum concentrations, and concomitant medications. The Kidney Disease Improving Global Outcomes (KDIGO) criteria were used to characterize acute kidney injury. Descriptive statistical methods were used and ordinal logistic regression was employed to determine variables significantly associated with vAKI. RESULTS: A total of 7,095 patients met study criteria (55.4% male, median age 4.1 years (IQR 0.67-11.2 years)). Mechanical ventilation was used in 7.9% (n = 563) and mortality was 4.9% (n = 344). A total of 153 concomitant medications were identified. A median of 5 (IQR 3-7) SCr values were obtained and median SCr prior to vancomycin was 0.39 (IQR 0.28-0.57) mg/dL (CrCl 134±58 mL/min/1.73m2). Vancomycin was administered for a median of 2 (IQR 1-3) days (14.9±1.6 mg/kg/dose). vAKI was present in 12.2% (n = 862: KDIGO stage 1 (8.30%, n = 589), KDIGO stage 2 (1.94%, n = 138) KDIGO stage 3 (1.89%, n = 134)). Mean vancomycin serum concentration at 6-8 hours after a dose for patients with vAKI (10.7±8.9 mg/L) was significantly, but not clinically different for patients with no vAKI (7.5±6.3 mg/L). (p<0.05) Ordinal logistic regression identified total dose of vancomycin, vancomycin administration in the intensive care unit, and concomitant medication administration as significant for vAKI. In particular, concomitant administration of several different medications, including nafcillin, clindamycin, and acetazolamide, were noted for strong associations with vAKI. (p<0.05). CONCLUSIONS: Moderate to severe acute kidney injury due to vancomycin is infrequent in children and associated with concomitant medication use and total dose of vancomycin. Serum vancomycin concentrations are not useful predictors of vAKI in the pediatric population.

Population Pharmacokinetics of Vancomycin in Pediatric Extracorporeal Membrane Oxygenation.

OBJECTIVES: Describe the pharmacokinetics of vancomycin in pediatric patients undergoing extracorporeal membrane oxygenation and provide dosing recommendations to attain an area under the curve for 24 hours greater than 400 in this population. DESIGN: Retrospective, population pharmacokinetic analysis. SETTING: PICU of a large tertiary care children's hospital. INTERVENTIONS: Population pharmacokinetic analysis and simulation were performed with NONMEM v7.3 (Icon, PLC, Dublin, Ireland). PATIENTS: Patients less than 19 years old who received IV vancomycin and had serum vancomycin concentration monitoring while undergoing extracorporeal membrane oxygenation from January 1, 2011, to June 30, 2017. MEASUREMENTS AND MAIN RESULTS: A total of 93 patients met study criteria (male 51%, median age 0.64 yr [interquartile range 0.07-6.7 yr]). Mean estimated creatinine clearance was 65 ± 47 mL/min/1.73 m. Patients received 1,116 vancomycin doses (14.6 ± 1.9 mg/kg/dose) and had 433 vancomycin serum concentrations (13.6 ± 6.9 mg/L) at 13.2 ± 10.7 hours after a dose. A two-compartment pharmacokinetic model with allometrically scaled weight on clearance (0.75) and volumes of distribution (1) was developed. Serum creatinine, postmenstrual age were significant covariates for clearance, patient age for central volume of distribution, and albumin for peripheral volume of distribution. Simulation identified a doses of 25-30 mg/kg/dose every 12-24 hours as having the highest percentage of patients with an area under the curve for 24 hours greater than 400 with the highest percentage trough concentrations in the less than 15 mg/L range. CONCLUSIONS: A vancomycin dose of 25-30 mg/kg/dose every 12-24 hours with serum concentration monitoring is a reasonable empiric dosing strategy to obtain an area under the curve for 24 hours greater than 400 in pediatric extracorporeal membrane oxygenation patients.

Population Pharmacokinetic Analysis of Gentamicin in Pediatric Extracorporeal Membrane Oxygenation.

BACKGROUND: Gentamicin pharmacokinetics may be altered in pediatric patients undergoing extracorporeal membrane oxygenation (ECMO). Description of gentamicin pharmacokinetics and relevant variables can improve dosing. METHODS: A retrospective population pharmacokinetic study was designed, and pediatric patients who received gentamicin while undergoing ECMO therapy over a period of 6 1/2 years were included. Data collection included the following: patient demographics, serum creatinine, albumin, hematocrit, gentamicin dosing and serum concentrations, urine output, and ECMO circuit parameters. Descriptive statistics were used to characterize the patient population. Population pharmacokinetic analysis was performed with NONMEM, and simulation was performed to identify empiric doses to achieve therapeutic serum concentrations. RESULTS: A total of 37 patients met study criteria (75.7% male patients), with a median age of 0.17 [interquartile range (IQR) 0.12-0.82] years. Primary indications for ECMO included the following: congenital diaphragmatic hernia (n = 17), persistent pulmonary hypertension (n = 5), and septic shock (n = 4). Patients received a total of 117 gentamicin doses [median 1.8 (IQR 1.4-2.9) mg/kg/dose] and had 125 serum concentrations measured at a median of 22.8 (IQR 15.8-25.5) hours after a dose. Population pharmacokinetic analysis identified a 2-compartment model with additive error as the best fit. Covariates included the following: allometrically scaled fat-free mass on clearance, central and peripheral volume of distribution (VDcentral and VDperipheral), and intercompartmental clearance; serum creatinine on clearance; ultrafiltration rate on central volume of distribution. Simulation identified dosage of 4-5 mg/kg/dose every 24 hours for neonates and infants as an acceptable empiric dosing regimen. Children and adolescents had elevated trough concentrations when dosed according to traditional dosing methods. CONCLUSIONS: Fat-free mass should be used to dose gentamicin in pediatric ECMO patients. Serum creatinine is a marker of gentamicin clearance and should be used to adjust gentamicin dosing in pediatric ECMO patients.

Fosphenytoin Population Pharmacokinetics in the Acutely Ill Pediatric Population.

OBJECTIVE: The purpose of this study is to describe the pharmacokinetics of phenytoin in pediatric patients receiving fosphenytoin. DESIGN: Retrospective, population pharmacokinetic analysis. SETTING: Emergency department or PICU of a large tertiary care children's hospital. PATIENTS: Patients less than 19 years old who received fosphenytoin in the PICU or emergency center for treatment of seizures from January 2011 to June 2017 were included. INTERVENTIONS: Population pharmacokinetic analysis was performed with NONMEM v7.3 (Icon Plc, Dublin, Ireland). Simulation was performed to determine optimal loading dose and maintenance dosing regimens. MEASUREMENTS AND MAIN RESULTS: A total of 536 patients (55.4% male; median age, 3.4 yr [interquartile range, 0.92-8.5 yr]) met study criteria. Fosphenytoin was administered at median 15.1 mg/kg/dose (interquartile range, 6.3-20.7 mg/kg/dose). Mean serum concentrations of 17.5 ± 7.8 mg/L were at a median 4.2 hours (interquartile range, 2.5-7.8 hr) after a dose. A pharmacokinetic model with two compartments, allometrically scaled fat-free mass on all parameters, and serum creatinine and concomitant phenobarbital use on clearance had the best fit. Simulation demonstrated that a 20 mg/kg loading dose followed by 6 mg/kg/dose every 8 hours had the greatest percentage of concentrations in the 10-20 mg/L range, with reduced doses to achieve therapeutic in patients with reduced kidney function. CONCLUSIONS: A loading dose of 20 mg/kg followed by 6 mg/kg/dose every 8 hours based on fat-free mass is a reasonable empiric strategy for attainment and maintenance of therapeutic trough concentrations. Concomitant phenobarbital use may increase clearance of phenytoin and fosphenytoin dose reductions should occur in patients with reduced kidney function.

Phenobarbital population pharmacokinetics across the pediatric age spectrum.

OBJECTIVE: Phenobarbital is frequently used in pediatric patients for treatment and prophylaxis of seizures. Pharmacokinetic data for this patient population is lacking and would assist in dosing decisions. METHODS: A retrospective population pharmacokinetic analysis was designed for all pediatric patients <19 years of age initiated on phenobarbital at our institution from January 2011 to June 2017. Patients were included if they were initiated on intravenous or enteral phenobarbital for treatment or prophylaxis of seizures and had a serum phenobarbital concentration monitored while an inpatient. Data collection included the following: age, weight, height, gestational age, core body temperature, serum creatinine, blood urea nitrogen, aspartase aminotransferase, alanine aminotransferase, urine output over the prior 12 hours, phenobarbital doses and serum concentrations, and potential drug-drug interactions. Descriptive statistical methods were used to summarize the data. Pharmacokinetic analysis was performed with NONMEM and simulation was performed for doses of 10, 20, 30, and 40 mg kg-1  dose-1 , iv, followed by enteral doses of 3, 4, 5, and 6 mg kg-1  d-1 . RESULTS: A total of 355 patients (50.3% male, median gestational age 39 weeks (interquartile range [IQR] 35, 40), median age 0.28 years (IQR 0.06, 0.82). Median phenobarbital dose was enteral = 2.6 (IQR 1.9, 3.9) mg kg-1  dose-1 ; intravenous = 2.6 (IQR 2.2, 4.9) mg kg-1  dose-1 ) and mean serum concentration was 41.1 ± 23.9 mg/L at median 6.5 (IQR 2.9, 11.1) hours after a dose. A one-compartment proportional error model best fit the data where clearance and volume of distribution were allometrically scaled using fat-free mass. Significant covariates included serum creatinine, postmenstrual age, and drug-drug interactions on clearance, and age in years on volume of distribution. SIGNIFICANCE: Phenobarbital dosing of 30 mg kg-1  dose-1 ,iv, followed by 4 mg kg-1  d-1 had the highest probability of attaining a therapeutic concentration at 7 days. Postmenstrual age and drug-drug interactions should be incorporated into dosing decisions.

The "Ideal" Body Weight for Pediatric Gentamicin Dosing in the Era of Obesity: A Population Pharmacokinetic Analysis.

BACKGROUND: Obese pediatric patients often require dose reductions when initiating gentamicin therapy. An appropriate method for calculating ideal body weight for dosing gentamicin in pediatric patients has not been validated. METHODS: A retrospective population pharmacokinetic study was designed and included non-intensive care pediatric patients who received gentamicin and had serum gentamicin concentrations sampled. Actual body weight (ABW), adjusted body weight, and fat-free mass (FFM) were used to describe the pharmacokinetic variables. Descriptive statistical methods were used for the population, and pharmacokinetic analysis occurred with NONMEM (ICON Plc, Dublin, Ireland). Simulation was performed to estimate dosing based on adjustments in body weight. RESULTS: A total of 520 patients met inclusion criteria (male 57.3%, mean age 9.6 ± 4.9 years, ABW 38.0 ± 24.3 kg). Obesity was present in 21.3% of the patients and overweight in 15.8%. Gentamicin was administered at 2.17 ± 0.86 mg/kg per dose. A median of 2 (interquartile range, 1-3) gentamicin serum concentrations were sampled at a median 1.8 (interquartile range, 1.1-7.8) hours after a dose. Population pharmacokinetic analysis demonstrated a 2-compartment model with allometrically scaled FFM providing the best fit. Other significant covariates included serum creatinine and age. Simulation demonstrated increased doses per body weight for traditional and once-daily dosing when using FFM for gentamicin dosing. CONCLUSIONS: FFM should be used to adjust ABW for empirically dosing gentamicin in pediatric patients aged 2-18 years.

Population Pharmacokinetics of Enoxaparin in Pediatric Patients.

BACKGROUND: There are no studies evaluating the pharmacokinetics of enoxaparin in the hospitalized pediatric patient population. OBJECTIVE: To characterize the pharmacokinetics of enoxaparin in pediatric patients. METHODS: A retrospective review of inpatients 1 to 18 years of age admitted to our institution who received enoxaparin with anti-factor Xa activity level monitoring was performed. Demographic variables, enoxaparin dosing, and anti-factor Xa activity levels were collected. Population pharmacokinetic analysis was performed with bootstrap analysis. Simulation (n = 10 000) was performed to determine the percentage who achieved targeted anti-Xa levels at various doses. RESULTS: A total of 853 patients (male 52.1%, median age = 12.2 years; interquartile range [IQR] = 4.6-15.8 years) received a mean enoxaparin dose of 0.86 ± 0.31 mg/kg/dose. A median of 3 (IQR = 1-5) anti-factor Xa levels were sampled at 4.4 ± 1.3 hours after a dose, with a mean anti-factor Xa level of 0.52 ± 0.23 U/mL. A 1-compartment model best fit the data, and significant covariates included allometrically scaled weight, serum creatinine, and hematocrit on clearance, and platelets on volume of distribution. Simulations were run for patients both without and with reduced kidney function (creatinine clearance of ≤30 mL/min/1.73 m2). A dose of 1 mg/kg/dose every 12 hours had the highest probability (72.3%) of achieving an anti-Xa level within the target range (0.5-1 U/mL), whereas a dose reduction of ~30% achieved the same result in patients with reduced kidney function. CONCLUSIONS: Pediatric patients should initially be dosed at 1-mg/kg/dose subcutaneously every 12 hours for treatment of thromboembolism followed by anti-Xa activity monitoring. Dose reductions of ~30% for creatinine clearance ≤30 mL/min/1.73 m2 are required.

Enhancement of diuresis with metolazone in infant paediatric cardiac intensive care patients.

BACKGROUND: Few data are available regarding the use of metolazone in infants in cardiac intensive care. Researchers need to carry out further evaluation to characterise the effects of this treatment in this population. METHODS: This is a descriptive, retrospective study carried out in patients less than a year old. These infants had received metolazone over a 2-year period in the paediatric cardiac intensive care unit at our institution. The primary goal was to measure the change in urine output from 24 hours before the start of metolazone therapy to 24 hours after. Patient demographic variables, laboratory data, and fluid-balance data were analysed. RESULTS: The study identified 97 infants with a mean age of 0.32±0.25 years. Their mean weight was 4.9±1.5 kg, and 58% of the participants were male. An overall 63% of them had undergone cardiovascular surgery. The baseline estimated creatinine clearance was 93±37 ml/minute/1.73 m2. Initially, the participants had received a metolazone dose of 0.27±0.10 mg/kg/day, the maximum dose being 0.43 mg/kg/day. They had also received other diuretics during metolazone initiation, such as furosemide (87.6%), spironolactone (58.8%), acetazolamide (11.3%), bumetanide (7.2%), and ethacrynic acid (1%). The median change in urine output after metolazone was 0.9 ml/kg/hour (interquartile range 0.15-1.9). The study categorised a total of 66 patients (68.0%) as responders. Multivariable analysis identified acetazolamide use (p=0.002) and increased fluid input in the 24 hours after metolazone initiation (p0.05). CONCLUSIONS: Metolazone increased urine output in a select group of patients. Efficacy can be maximised by strategic selection of patients.

Enoxaparin Population Pharmacokinetics in the First Year of Life.

AIMS: Enoxaparin dosing requirements in the first year of life can be highly variable. Characterization of pharmacokinetics in this patient population can assist in dosing. METHODS: Patients less than 1 year postnatal age who received enoxaparin and had an anti-factor Xa activity level drawn as inpatients were identified through the pharmacy database over a 5-year period. Patients on renal replacement therapy or with hyperbilirubinemia were excluded. Data collection included demographic variables, indication for enoxaparin, enoxaparin doses, anti-factor Xa activity levels, serum creatinine, hemoglobin, hematocrit, platelet count, and urine output over the previous 24 hours. Population pharmacokinetic analysis was performed with NONMEM. RESULTS: A total of 182 patients [male 50%, median 100 days postnatal age (range: 4-353 days)] met the study criteria. Patients received median 22 doses (range: 1-526) at a mean starting dose of 1.38 ± 0.43 mg/kg with median 5 (range: 1-56) anti-factor Xa activity levels measured. A 1-compartment proportional and additive error model best fits the data. Allometrically scaled weight significantly decreased the objective function value, as did serum creatinine on clearance, and postmenstrual age (PMA) on volume of distribution. When evaluated graphically, dosing based on PMA appeared to have less variability as compared to postnatal age-based dosing. CONCLUSIONS: Dosing of enoxaparin in infants younger than 1 year should incorporate PMA.

Population pharmacokinetics of human antithrombin concentrate in paediatric patients.

AIMS: Antithrombin is increasingly used in paediatric patients, yet there are few age-specific pharmacokinetic data to guide dosing. We aimed to describe the pharmacokinetic profile of human (plasma-derived) antithrombin concentrate in paediatric patients. METHODS: A 5-year retrospective review was performed of patients <19 years of age admitted to our institution who received antithrombin concentrate, were not on mechanical circulatory support and had baseline (predose) and postdose plasma antithrombin activity levels available for analysis. Demographic and laboratory variables, antithrombin dosing information and data on the use of continuous infusion unfractionated heparin were collected. Population pharmacokinetic analysis was performed with bootstrap analysis. The model developed was tested against a validation dataset from a cohort of similar patients, and a predictive value was calculated. RESULTS: A total 184 patients met the study criteria {46.7% male, median age [years] 0.35 [interquartile range (IQR) 0.07-3.9]}. A median of two antithrombin doses (IQR 1-4) were given to patients (at a dose of 46.3 ± 13.6 units kg-1 ), with median of three (IQR 2-7) postdose levels per patient. Continuous infusion unfractionated heparin was administered in 87.5% of patients, at a mean dose of 34.1 ± 22.7 units kg-1 h-1 . A one-compartment exponential error model best fit the data, and significant covariates included allometrically scaled weight on clearance and volume of distribution, unfractionated heparin dose on clearance, and baseline antithrombin activity level on volume of distribution. The model resulted in a median -1.75% prediction error (IQR -11.75% to 6.5%) when applied to the validation dataset (n = 30). CONCLUSIONS: Antithrombin pharmacokinetics are significantly influenced by the concurrent use of unfractionated heparin and baseline antithrombin activity.