Population Pharmacokinetics of Vancomycin in Pregnant Women.

Objective: Vancomycin is a glycopeptide antibacterial indicated for serious gram-positive infections. Pharmacokinetics (PK) of vancomycin have not been described in pregnant women. This study aims to characterize the PK disposition of vancomycin in pregnant women based on data acquired from a database of routine hospital care for therapeutic drug monitoring to better inform dosing decisions. Methods: In this study, plasma drug concentration data from 34 pregnant hospitalized women who were administered intravenous vancomycin was analyzed. A population pharmacokinetic (PPK) model was developed using non-linear mixed effects modeling. Model selection was based on statistical criterion, graphical analysis, and physiologic relevance. Using the final model AUC0-24 (PK efficacy index of vancomycin) was compared with non-pregnant population. Results: Vancomycin PK in pregnant women were best described by a two-compartment model with first-order elimination and the following parameters: clearance (inter individual variability) of 7.64 L/hr (32%), central volume of 67.35 L, inter-compartmental clearance of 9.06 L/h, and peripheral volume of 37.5 L in a typical patient with 175 ml/min creatinine clearance (CRCL) and 45 kg fat-free mass (FFM). The calculated geometric mean of AUC0-24 for the pregnant population was 223 ug.h/ ml and 226 ug.h/ ml for the non-pregnant population. Conclusion: Our analysis suggests that vancomycin PK in pregnant women is consistent with non-pregnant adults and the dosing regimens used for non-pregnant patients may also be applicable to pregnant patients.

Optimizing Vancomycin Dosing and Monitoring in Neonates and Infants Using Population Pharmacokinetic Modeling.

We determined optimal vancomycin starting dose regimens in infants ≤180 days of age to achieve the highest probability of target attainment with an area under the concentration-time curve for 24 h (AUC24) of ≥400 using population pharmacokinetic (PK) modeling. Secondarily, determination of the relationship between serum creatinine (SCR) and vancomycin clearance in neonates was done. A retrospective population PK study was designed and included pediatric patients ≤180 days old who had received vancomycin and had a serum vancomycin concentration sampled. A population PK model was developed using Pumas (v1.0.5). Simulation was performed with various dosing regimens to evaluate the probability of AUC24 target attainment and probability of trough of ≤20 mg/liter, and comparison to published models was performed. Individual clearance estimates, obtained from the final model, were plotted against SCR and faceted by age quartiles to assess the relationship between SCR and vancomycin clearance. A total of 934 patients were included in the study (58.6% male; median age, 43.6 days [range of 0 to 184]; median number of concentration samples, 1 [range of 1 to 29]). A one-compartment model was developed with body weight (WT), SCR, and postmenstrual age (PMA) identified as significant covariates on clearance. Plotting vancomycin clearance versus SCR demonstrated no clear relationship between the two at <10 days postnatal age (PNA). Dosing regimens to attain AUC24 and trough targets were stratified according to SCR for ≥10 days PNA and PMA for <10 days PNA. A vancomycin population PK model was developed for pediatric patients <180 days of age incorporating WT, SCR, and PMA. The relationship between vancomycin clearance and serum creatinine is not clear at <10 days PNA.

Trajectory of AKI in hospitalized pediatric patients-impact of duration and repeat events.

BACKGROUND: Peak severity of acute kidney injury (AKI) is associated with mortality in hospitalized pediatric patients. Other factors associated with AKI, such as number of AKI events, severity of AKI events and time spent in AKI, may also have associations with mortality. Characterization of these events could help to evaluate patient outcomes. METHODS: Pediatric inpatients (<19 years of age) from 2011 to 2019 who were not on maintenance renal replacement therapy and had least one serum creatinine (SCr) obtained during hospital admission were included. Percent change in SCr from the minimum value in the prior 7 days was used for AKI staging according to Kidney Disease: Improving Global Outcomes (KDIGO) criteria. Maximum value for age appropriate normal was used for patients with only one SCr. Repeat AKI events were classified in patients if KDIGO criteria were met more than once with at least one SCr value between episodes that did not meet KDIGO criteria. Patient demographics were summarized and incidence of AKI was determined along with associations with mortality. AKI characterizations for the admission were developed including: AKI, repeat (more than one) AKI, AKI severity (maximum KDIGO stage) and total number of AKI events. AKI duration as percent admission days in a KDIGO stage and AKI percent velocity were determined. Kaplan-Meier analysis was performed for time to 30-day survival by AKI characterization. A mixed-effects logistic regression model with mortality as the dependent variable nested in patients was developed incorporating patient variables and AKI characterizations. RESULTS: A total of 184 297 inpatient encounters met study criteria [male 51.7%, age 7.8 years (interquartile range 2.5-13.8) and mortality 0.56%]. Hospital length of stay was 1.9 days (IQR 0.37, 4.8 days), 15.4% had an intensive care unit admission and 12.2% underwent mechanical ventilation. AKI occurred in 5.6% (n = 10 246) of admissions [Stage 1, 4.5% (n = 8310); Stage 2, 1.3% (n = 2363); Stage 3, 0.77% (n = 1423)] and repeat AKI events occurred in 1.92% (n = 3558). AKI was associated with mortality (odds ratio 6.0, 95% confidence interval 4.8-7.6; P < 0.001) and increasing severity (KDIGO maximum stage) was associated with increased mortality. Multiple AKI events were also associated with mortality (P < 0.001). Duration of AKI was associated with mortality (P < 0.001) but AKI velocity was not (P > 0.05). CONCLUSIONS: AKI occurs in 5.6% of the pediatric inpatient population and multiple AKI events occur in ∼30% of these patients. Maximum KDIGO stage is most strongly associated with mortality. Multiple AKI events and AKI duration should also be considered when evaluating patient outcomes.

Reassessing the Pediatric Dosing Recommendations for Unfractionated Heparin Using Real-World Data: A Pharmacokinetic-Pharmacodynamic Modeling Approach.

Optimal pediatric dosing of unfractionated heparin (UFH) is challenging because of the paucity of clinical outcome and pharmacokinetic-pharmacodynamic (PK/PD) studies in pediatrics. This study aimed to: (i) develop a PK/PD model for UFH, quantified by anti-factor Xa assay, and the UFH effect, measured by activated partial thromboplastin time (aPTT); and (ii) use simulations to evaluate pediatric UFH infusions for achieving the anti-factor Xa (0.3-0.7 IU/mL) therapeutic target. Electronic health record data were retrospectively collected from 633 patients aged <19 years admitted to Texas Children's Hospital. The PK/PD model was developed using a 70% (training)/30% (testing) split-sample approach. A 1-compartment PK model with linear elimination adequately described the UFH PK. An allometrically scaled body weight on clearance (CL) and volume of distribution (Vd) with an age-dependent maturation function of extracellular water on Vd were the covariates identified. Comparable with literature, the typical values for CL and Vd were 3.28 L/(h·50 kg) and 8.83 L/50 kg, respectively. A linear model adequately described the UFH-aPTT relationship with an estimated slope of 150 seconds/(IU/mL). Simulations of the currently recommended starting infusions (28 IU/h/kg for pediatrics <1 year old or 20 IU/h/kg for pediatrics >1 year old) showed that the anti-factor Xa therapeutic target was achieved only in 15.3%, 14.6%, 36.9%, and 45.11% of subjects in the age groups of <1 year, 1-6 years, 6-12 years, and 12-19 years, respectively. In conclusion, the UFH anti-factor Xa target is not achieved initially, especially in young pediatrics, suggesting the need to optimize UFH dosing to achieve higher therapeutic success.

Characterization of drug-drug interactions on the pharmacokinetic disposition of busulfan in paediatric patients during haematopoietic stem cell transplantation conditioning.

AIM: The study objective was to develop a population pharmacokinetic model for busulfan to comprehensively examine drug-drug interactions in paediatric patients undergoing haematopoietic stem cell transplantation. Currently, there is limited evidence to substantiate potential drug-drug interactions with busulfan. METHODS: This retrospective study population was comprised of 250 patients receiving, on average, 0.8 mg/kg intravenous busulfan as pretreatment. All model analyses were conducted using nonlinear mixed effects modelling in Pumas v2.0. The metabolic pathways of primary interest were glutathione conjugation and cytochrome P450 (CYP) activity. Concomitant medications were categorized as CYP inhibitors, inducers or glutathione S-transferase depleters, and included in the model as conditional covariates. A bootstrap simulation and visual predictive check were conducted to qualify the final model. RESULTS: The final 1-compartment model incorporates covariates of weight and age in relation to their effects on both total body clearance and volume of distribution. The estimated typical values of clearance and volume were 1.138 L/h (CI: 1.095-1.179 L/h) and 3.527 L (CI: 3.418-3.621 L), respectively. No significant changes in clearance were observed when medications that alter proposed hepatic and metabolic pathways of busulfan were coadministered. CONCLUSION: To the best of our knowledge, this is the largest single centre study of busulfan in children and the first to quantify the maturation effect of both clearance and volume. This study could not demonstrate a difference in busulfan clearance when comparing patients who received medications that alter the glutathione S-transferase, CYP3A4 or CYP2C9 pathway to those who did not.

Acetazolamide-Associated Acute Kidney Injury in Critically Ill Pediatric Patients.

OBJECTIVE: Our objective was to determine the incidence and risk factors for intravenous acetazolamide-associated acute kidney injury (AKI). METHODS: We utilized a retrospective cohort study including patients <19 years of age initiated on intravenous acetazolamide while admitted to an ICU. Data collection included patient demographics, clinical variables, acetazolamide dosing, and serum creatinine (SCr) values. Incidence of AKI was assessed per Kidney Disease Improving Global Outcomes criteria. Descriptive statistical analysis and ordinal logistic regression analysis were performed to determine the incidence of AKI and variables associated with AKI. RESULTS: A total of 868 patients met study criteria (male 55.8%, median age 0.66 years [IQR 0.19, 3.0 years]). Intravenous acetazolamide was administered at 5.1 ± 2.8 mg/kg/dose for a median of 4 doses (IQR 2, 6). Median baseline SCr was 0.28 mg/dL (IQR 0.22, 0.37), corresponding to a creatinine clearance of 115 ± 55 mL/min/1.73 m2. Acute kidney injury occurred in 26.8% (n = 233) of patients (stage I = 20.1%, stage II = 3.7%, stage III 3.1%), and no patients received renal replacement therapy. An ordinal logistic regression model identified an increased odds of AKI with cyclosporine, ethacrynic acid, and piperacillin-tazobactam administration. CONCLUSIONS: Acute kidney injury occurs frequently in critically ill pediatric patients receiving intravenous acetazolamide.

Understanding the Role of Pharmacometrics-Based Clinical Decision Support Systems in Pediatric Patient Management: A Case Study Using Lyv Software.

Pharmacometrics could play a key role in shifting pediatric pharmacotherapy from dosing for an average patient to individualizing dosing. Clinicians can have these quantitative tools at their disposal without requiring significant training through the development of clinical decision support systems with easy-to-use interfaces that have a back-end analysis engine or pharmacometric model that uses extensive electronic health record data to predict an individualized dose for each patient. There has been increased development of these clinical decision support systems recently, and for these tools to make the proper breakthrough into clinical practice, it is of utmost importance to perform rigorous testing to ensure adequate predictive performance. In this article, we walk through the components of a decision support tool and the testing required to determine its robustness using an example of a decision support tool we developed for vancomycin dosing in pediatrics.

"Second line medications" for supraventricular arrhythmias in children: In-hospital efficacy and adverse events during treatment initiation of sotalol and flecainide.

INTRODUCTION: Sotalol and flecainide are used as second line agents in children for the treatment of supraventricular arrhythmias (SA) refractory to anti-beta adrenergic antiarrhythmics or digoxin. Efficacy and adverse events in this cohort have not been well described. Here, we report our institutional experience of second line treatment initiation for SA in children. METHODS AND RESULTS: Utilizing an institutional database, 247 patients initiated on sotalol and 81 patients initiated on flecainide were identified. Congenital heart disease (CHD) was present in 40% of patients. Arrhythmia-free discharge on single or dual agent therapy (in combination with other antiarrhythmics) was 87% for sotalol and 91% for flecainide. Neither age, sex, dosing, presence of CHD nor arrhythmia subtype were associated with alterations in in-hospital efficacy. Compared to baseline, QTc intervals in sotalol patients (436 [416-452 ms] vs. 415 [400-431 ms], p < .01) and QRS intervals in flecainide patients (75 [68-88 ms] vs. 62 [56-71 ms], p < .01) were prolonged. Dose reduction or discontinuation due to QRS prolongation occurred in 9% of patients on flecainide. QTc prolongation resulting in dose reduction/discontinuation of sotalol was encountered in 9 patients (4%) and death with documented torsade de pointes in 2 patients (1%), with 9 of 11 patients having underlying CHD. CONCLUSION: In children requiring second line agents for treatment of SA, both sotalol and flecainide appear to be highly efficacious. Although predominantly safe in otherwise healthy patients, electrocardiogram changes can occur and children with underlying cardiac disease may have an increased risk of adverse events and rhythm-related side effects during initiation.

Impact of Body Habitus on the Outcomes of Pediatric Patients With Diabetic Ketoacidosis.

OBJECTIVE: To determine whether obese and overweight pediatric patients with new onset diabetic ketoacidosis (DKA) treated with continuous infusion insulin have increased time to subcutaneous insulin initiation or adverse events as compared with patients with normal body habitus. METHODS: A retrospective, cohort study was designed that included patients 2 to 18 years of age admitted with new onset DKA who received continuous infusion insulin from January 1, 2011, to December 31, 2017. Patients were stratified according to BMI percentile with the primary outcome of time to initiation of subcutaneous insulin. Secondary endpoints included time to minimum beta-hydroxybutyrate, and incidence of hypoglycemia or other adverse events. RESULTS: A total of 337 patients (46.6% male, 9.6 ± 3.8 years of age) met study criteria. Patients were classified by body habitus as obese (7.7%, n = 26), overweight (7.1%, n = 24), normal body weight (58.8%, n = 198), or underweight (26.4%, n = 89), based on BMI percentile. Most patients were initiated on insulin at 0.1 unit/kg/hr (86.7%) for 16.7 ± 7.0 hours. Time from continuous infusion insulin initiation to subcutaneous insulin was not different between body habitus groups, nor was hypoglycemia or the use of mannitol (p > 0.05). Median time to lowest beta-hydroxybutyrate was greater for obese (26.4, IQR [13.9, 41.9]) and overweight (32.4, IQR [18.3, 47.0]) groups than for normal body habitus patients (16.5, IQR [12.3, 23.8]) (p < 0.05). CONCLUSIONS: Time to subcutaneous insulin and adverse events was not associated with body habitus, but obese and overweight patients may have delayed beta-hydroxybutyrate clearance.

Neighborhoods matter; but for whom? Heterogeneity of neighborhood disadvantage on child obesity by sex.

Although evidence suggests that neighborhood context, particularly socioeconomic context, influences child obesity, little is known about how these neighborhood factors may be heterogeneous rather than monolithic. Using a novel dataset comprised of the electronic medical records for over 250,000 children aged 2-17 nested within 992 neighborhoods in the greater Houston area, we assessed whether neighborhoods influenced the obesity of children differently based on sex. Results indicated that neighborhood disadvantage, assessed using a comprehensive, multidimensional, latent profile analysis-generated measure, had a strong, positive association with the odds of obesity for both boys and girls. Interactions revealed that the relationship between disadvantage and obesity was stronger for girls, relative to boys. Our findings demonstrated the complex dynamics underlying the influence of residential neighborhood context on obesity for specific subgroups of children.

Efficacy of Low-Dose Epinephrine Continuous Infusion in Neonatal Intensive Care Unit Patients.

OBJECTIVES: Although epinephrine is used in the neonatal intensive care unit, few data exist on efficacy of doses <0.05 mcg/kg/min. This study evaluates the efficacy and safety of low-dose epinephrine continuous infusion at doses <0.05 mcg/kg/min in infants. METHODS: Single-center, retrospective review of hypotensive infants from 2011-2018. Charts were reviewed for initial and maximum epinephrine doses, additional vasoactive agents, short-term efficacy, and adverse effects. The primary outcome was percentage of patients initiated on low-dose epinephrine whose dose did not require titration to ≥0.05 mcg/kg/min. RESULTS: A total of 115 patients met study criteria with 131 distinct occurrences of low-dose epinephrine initiation. Most patients were unresponsive to other vasopressors at the time of epinephrine initiation. The median (IQR) starting dose of low-dose epinephrine was 0.01 (0.01-0.04) mcg/kg/min and median (IQR) maximum dose was 0.04 (0.02-0.08) mcg/kg/min. Fifty-five percent were responders. Patients in this cohort demonstrated significant improvement of blood pressure and urine output (p < 0.001) without adverse effects. CONCLUSIONS: Low-dose epinephrine infusion may be considered as an alternative treatment to standard starting doses in hypotensive neonatal intensive care unit patients.

Evaluation of Antimicrobial Utilization in the Pediatric Drowning Population.

BACKGROUND: Management of pediatric drowning often includes evaluation and treatment of infectious disease. There are few data describing the infections associated with pediatric drowning. METHODS: A descriptive retrospective study was designed, and patients aged < 19 years admitted for > 24 hours to our institution after a drowning were included from January 2011 through June 30, 2017. Data collection included patient demographics, submersion injury details, resuscitation details, patient admission details, chest radiograph on admission, use of intubation and mechanical ventilation, hospital length of stay, culture data, antimicrobial use, and mortality. Descriptive statistical methods (mean and standard deviation, median and range, percentage) were used to characterize the patient population, and Fisher exact test was used to evaluate the association between antimicrobial use in the first 72 hours of admission and mortality. RESULTS: A total of 114 patients met study criteria (male, 59.7%; median age, 3.7 years [range, 0.15-17.79 years]). Median hospital length of stay was 2 days (range, 1-60 days). Intensive care unit admission occurred in 80.7%, intubation occurred in 46.5%, and mortality was 18.4%. The most common submersion location was a pool (76.3% [n = 87]) with water primarily characterized as freshwater (82.5% [n = 94]). Reported submersion time for the majority of patients was < 5 minutes (54.4%) with cardiopulmonary resuscitation in 78.1%. In the first 72 hours after admission, culture were obtained in 40 patients (35.1%), and 27.5% of these cultures were positive. The primary organisms identified were consistent oropharyngeal flora. Antimicrobials were initiated in 50% of the patient population with clindamycin as most common. There was not a significant association between antimicrobial use in the first 72 hours after admission and mortality (17.2% vs 19.6%, P = .81). CONCLUSIONS: Infectious disease associated with pediatric drowning in pools is uncommon. Empiric use of antimicrobials does not appear to affect outcomes.

Hospital outcomes for pediatric heart transplant recipients undergoing tracheostomy: A multi-institutional analysis.

Tracheostomy is associated with increased mortality and resource utilization in children with CHD. However, the prevalence and hospital outcomes of tracheostomy in children with HTx are not known. We describe the prevalence and compare the post-HTx hospital outcomes of pediatric patients with Pre-TT and Post-TT to those without tracheostomy. A multi-institutional retrospective cohort study was performed using the Pediatric Health Information System database. Hospital mortality, mediastinitis, LOS, and costs were compared among patients with Pre-TT, Post-TT, and no tracheostomy. Pre-TT was identified in 29 (1.1%) and Post-TT was identified in 41 (1.6%) of 2603 index HTx hospitalizations. Patients with Pre-TT were younger and more likely to have CHD, a non-cardiac birth defect, or an airway anomaly compared to those without Pre-TT. Pre-TT was not independently associated with increased post-HTx in-hospital mortality. Age at HTx < 1 year, CHD, and Post-TT were associated with increased in-hospital mortality. Pre-TT that occurred during the HTx hospitalization and Post-TT were associated with increased resource utilization. Tracheostomy was not associated with mediastinitis.

Chloral Hydrate Sedation in a Dexmedetomidine Era.

Brief Overview: The use of chloral hydrate as the primary sedation agent has declined across the nation after commercial production of the liquid formulation ceased. Although alternative sedatives have gained popularity, some pharmacies have continued to provide oral chloral hydrate by compounding it from raw ingredients. Thus, oral chloral hydrate use has continued in children despite the availability of alternative effective agents. Objective: The purpose of this investigation was to evaluate institutional chloral hydrate utilization as the primary agent for procedural sedation. Design/Methods: We conducted a retrospective study of patients given chloral hydrate for procedural sedation from October 2010 to December 2016. The hospital pharmacy database of chloral hydrate use at our 2 free-standing children's hospitals was reviewed and matched to procedure billing data. Results: There were 5874 chloral hydrate administrations for procedural sedation during the study period. The highest rates of use occurred in 2014, when there were 1420 chloral hydrate orders within our hospital. The large majority of sedations were for cardiac studies/procedures (n = 4250, 72.4%). Conclusions: Despite significant declines in use of chloral hydrate for procedural sedation across the country, local utilization of oral chloral hydrate remains high. Recent declines may be due to high-use clinical sites transitioning to alternative sedatives such as intranasal dexmedetomidine.

Population Pharmacokinetics of Vancomycin in the Pediatric Ventricular Assist Device Population.

OBJECTIVES: Determine the pharmacokinetic disposition of vancomycin in the pediatric ventricular assist device population. DESIGN: A retrospective, population pharmacokinetic study. SETTING: Large, quaternary care children's hospital. PATIENTS: Less than 19 years old initiated on vancomycin while undergoing ventricular assist device therapy from 2011 to 2018 in our institution. INTERVENTIONS: Patient data were summarized by using descriptive statistical methods, and population pharmacokinetic analysis was performed by using NONMEM (Icon, PLC, Dublin, Ireland). Simulation was performed to identify a vancomycin dosing strategy that resulted in a trough concentration less than 15 mg/L and an area under the curve0-24:minimum inhibitory concentration ratio of greater than 400. MEASUREMENTS AND MAIN RESULTS: A total of 69 patients (male 50.7%, median age 7.1 years [interquartile range, 2.4-11.9]) met study criteria (HeartWare [Framingham, MA] = 37, Berlin Heart [Berlin, Germany] = 22, Impella [Abiomed, Danvers, MA] = 4, RotaFlow [Maquet, Hirrlingen, Germany] right ventricular assist device = 3, HeartMate II [Abbott Laboratories, Abbott Park, IL] = 2, Berlin Heart biventricular assist device = 1). Patients received a median of 21 doses (interquartile range, 13-44 doses) of IV vancomycin (14.8 ± 1.8 mg/kg/dose) along with vancomycin as an intrathoracic irrigation (n = 48; 69.6%). The mean serum concentration was 12.2 ± 5.2 mg/L at 11.2 ± 6.9 hours after a dose. A one-compartment pharmacokinetic model best fit the data with allometric scaling on clearance and volume of distribution. Clearance was characterized by total body weight and serum creatinine, and volume of distribution was characterized by total body weight. Simulation identified doses greater than 15 mg/kg/dose with extended intervals were necessary to achieve endpoints. CONCLUSIONS: Vancomycin dosing in pediatric ventricular assist device patients should be altered in comparison to nonventricular assist device patients and should be accompanied with frequent serum concentration monitoring.

Characteristics and outcomes of children with congenital heart disease needing diaphragm plication.

BACKGROUND: Diaphragm dysfunction following surgery for congenital heart disease is a known complication leading to delays in recovery and increased post-operative morbidity and mortality. We aimed to determine the incidence of and risk factors associated with diaphragm plication in children undergoing cardiac surgery and evaluate timing to repair and effects on hospital cost and length of stay. METHODS: We conducted a multi-institutional retrospective observational cohort study. Forty-three hospitals from the Pediatric Health Information System database were included, and a total of 112,110 patients admitted between January 2004 and December 2014 were analysed. RESULTS: Patients less than 18 years of age who underwent cardiac surgery were included. Risk Adjustment for Congenital Heart Surgery was utilized to determine procedure complexity. The overall incidence of diaphragm dysfunction was 2.2% (n = 2513 out of 112,110). Of these, 24.0% (603 patients) underwent diaphragm plication. Higher complexity cardiac surgery (Risk Adjustment for Congenital Heart Surgery 5-6) and age less than 4 weeks were associated with a higher likelihood of diaphragm plication (p-value < 0.01). Diaphragmatic plication was associated with increased hospital length of stay (p-value < 0.01) and increased medical cost. CONCLUSIONS: Diaphragm plication after surgery for congenital heart disease is associated with longer hospital length of stay and increased cost. There is a strong correlation of prolonged time to plication with increased length of stay and medical cost. The likelihood of plication increases with younger age and higher procedure complexity. Methods to improve early recognition and treatment of diaphragm dysfunction should be developed.

Evaluation of Intravenous Ranitidine on Gastric pH in Critically Ill Pediatric Patients.

OBJECTIVE: To determine the dosing regimen of intravenous ranitidine (IVR) most likely to achieve a gastric pH of ≥4 in critically ill pediatric patients. METHODS: A retrospective cohort study was designed and included patients younger than 19 years with gastric pH samples taken from a nasogastric tube within 24 hours after a dose of IVR in an intensive care unit. Data collection included patient demographics, clinical variables, IVR dosing, and gastric pH samples. Descriptive statistical analysis and multivariable logistic regression analysis with clustering of patients was performed to determine variables associated with odds of obtaining a pH of ≥4. RESULTS: A total of 628 patients (1356 nasogastric samples) met study criteria (median age 1.3 years [IQR, 0.33, 5.7 years]; 53% male). The IVR dose was 0.90 ± 0.30 mg/kg per dose every 8.1 ± 2.9 hours, and 60.9% of patients (n = 383) had a pH ≥4. Patients with a pH value ≥4 had gastric pH samples taken earlier after a dose of IVR (6.7 ± 5.0 vs. 5.9 ± 4.7 hours, p < 0.001) but had no difference in IVR dose per kilogram (0.88 ± 0.31 vs. 0.88 ± 0.26, p = 0.86) or frequency of dosing (7.9 ± 3.2 vs. 7.9 ± 3.2 hours, p = 0.89). A multivariable logistic regression model identified increasing age, decreased kidney function, and decreased time to pH sample after an IVR dose with significantly greater odds of pH ≥4. CONCLUSIONS: The IVR dosing to maintain a gastric pH ≥4 in critically ill pediatric patients should occur more frequently than every 8 hours. Gastric pH evaluation may be necessary to assess IVR efficacy.

Antipyretic Efficacy of Acetaminophen and Ibuprofen in Critically Ill Pediatric Patients.

OBJECTIVES: To determine the antipyretic efficacy of acetaminophen (IV, enteral, rectal) and ibuprofen (enteral) in critically ill febrile pediatric patients. DESIGN: Retrospective cohort study. SETTING: Quaternary care pediatric hospital ICUs. PATIENTS: Pediatric patients less than 19 years old who were febrile (≥ 38.0°C), received a dose of IV acetaminophen, enteral acetaminophen, rectal acetaminophen, or enteral ibuprofen and had at least one temperature measurement in the following 6 hours. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 3,341 patients (55.8% male, median age 2.5 yr [interquartile range, 0.63-9.2 yr]) met study criteria. Baseline temperature was median 38.6°C (interquartile range, 38.3-38.9°C) measured via axillary (76.9%) route. Patients became afebrile (87.5%) at median 1.4 hours (interquartile range, 0.77-2.3 hr) after the first dose of medication, a -2.9 ± 1.6% change in temperature. Antipyretic medications included as follows: enteral acetaminophen (n = 1,664), IV acetaminophen (n = 682), rectal acetaminophen (n = 637), and enteral ibuprofen (n = 358). Enteral ibuprofen had a significantly greater odds of defervescence on multivariable logistic regression analysis (p = 0.04) with a decrease of -1.97 ± 0.89°C while IV acetaminophen was significant for a decreased time to defervescence at median 1.5 hours (interquartile range 0.8-2.3 hr) after a dose (p = 0.03). Patient age, presence of obesity, and baseline temperature were significant for decreased antipyretic efficacy (p < 0.05). CONCLUSIONS: Enteral ibuprofen was the most efficacious antipyretic and IV acetaminophen had the shortest time to defervescence.

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.