Admission Medication Reconciliations in Pediatric Patients Admitted to an Inpatient Psychiatry Unit.

OBJECTIVE: Medication errors resulting in adverse drug events may occur during transition of care. Most can be prevented with a medication reconciliation. California Senate Bill 1254 requires a pharmacist to perform an admission medication reconciliation (AMR) to obtain an accurate medication list for each high-risk patient upon hospital admission. Adult patient literature reveals that antidepressant, antipsychotic, and mood-stabilizing drugs are high-risk medications likely to cause errors. Therefore, the purpose of this analysis is to determine if pediatric psychiatry inpatients should be considered high risk, meriting an additional AMR by the pharmacy team. METHODS: This was a retrospective, single-center analysis of pediatric patients admitted to the inpatient psychiatry unit at Rady Children's Hospital, San Diego between January 1 and 31, 2021. All newly admitted patients had an AMR performed by the medical team (physician-led AMR). High-risk patients (prescribed a high-risk medication or 3 or more medications of any kind prior to admission) had an additional AMR by the pharmacy team (pharmacy-led AMR). Differences between these 2 AMRs were examined. RESULTS: Of the 58 patients admitted during the study period, 39 (67.2%) were identified as high risk, warranting an AMR by the pharmacy team. From the 170 medications reviewed, 51 differences (30%) were found between physician-led and pharmacy-led AMR, with 4 (2.4%) of the differences involving high-risk medications. No medications were incorrectly ordered, and no adverse drug events occurred. CONCLUSIONS: Given that physician-led and pharmacy-led AMRs of high-risk prescription medications were only marginally different and no medications were incorrectly ordered, the existing AMR methodology used by psychiatrists at our institution is effective at creating a safe medication list.

Intraperitoneal vancomycin for peritoneal dialysis-associated peritonitis in children: Evaluation of loading dose guidelines.

BACKGROUND: Current pediatric International Society for Peritoneal Dialysis guidelines for initial treatment of peritoneal dialysis (PD)-associated peritonitis suggest either monotherapy with cefepime or double therapy with first-generation cephalosporin or glycopeptide and ceftazidime or aminoglycoside. When using vancomycin, the intraperitoneal (IP) recommended pediatric loading dosage is 1000 mg/L of dialysate. This is based on adult pharmacokinetic (PK) studies and roughly translates to the adult recommendation where 30 mg/kg in 2 L is approximately 1000 mg/L. However, since the dialysate volume in pediatric patients is normalized to body surface area and not weight, the current recommended dosing can result in high vancomycin exposure in children. Vancomycin can potentially cause adverse effects. We aimed to determine if the IP vancomycin dosing of 1000 mg/L was causing elevated vancomycin levels and to offer possible dosing recommendations based on PK modeling and simulation. METHODS: Retrospective review of pediatric patients who had been treated with IP vancomycin for PD-associated peritonitis. Vancomycin levels obtained for clinical monitoring were analyzed using NONMEM to generate population and individual (empiric Bayesian) estimates of vancomycin PK parameters and estimated peak levels. Predicted vancomycin peaks were also simulated from virtual pediatrics patients 3-70 kg following various dosing strategies. RESULTS: Six episodes of peritonitis in three patients were analyzed. In the two episodes treated with 1000 mg/L, the first vancomycin levels (h post) were 95.6 ug/mL (3) and 49 (33) and following 500 mg/L were 33.2 (11), 30.2 (11), 23.6 (24), and 22.1 (11). All patients were cured of their peritonitis without the need for catheter removal. Based on our population PK model, a 1000 mg/L IP vancomycin loading dose will typically result in peak > 50 mg/L in patients weighing <35 kg and >60 mg/L in patients <15 kg. Vancomycin levels will remain above 20 mg/L for over 2 days without additional vancomycin dosing. CONCLUSION: The data suggest that a loading dose of vancomycin 1000 mg/L leads to higher than desired vancomycin levels and should be lowered. A 500 mg/L loading dosing appears more appropriate and needs further study.

Intravenous Immunoglobulin Infusion Reactions in Kawasaki Disease Patients Who Undergo Sedation.

OBJECTIVES: Although IVIG infusions are usually well tolerated, reactions can include hypotension, chills, and, rarely, anaphylactic reactions. Risk of adverse reactions correlates with dose and rate of IVIG infusion. An echocardiogram is the preferred imaging modality to detect coronary artery changes in acute Kawasaki disease (KD), but the quality of the study can be compromised if a child moves much during the imaging procedure. Thus, sedation is often required for children younger than 3 years of age. There is concern regarding coadministration of IVIG and sedatives. Therefore, the purpose of this analysis is to determine when the majority of IVIG infusion reactions occur to help find the optimal time to safely perform a sedated echocardiogram in patients with KD. METHODS: This is a retrospective, single-center analysis of patients with KD administered IVIG at Rady Children's Hospital San Diego from November 1, 2013, to October 31, 2016. RESULTS: Of the 260 subjects in this study, 34 (13%) had an IVIG infusion reaction consisting of either chills or hypotension. There were no anaphylactic reactions. All infusion reactions occurred within 4 hours of starting IVIG. No hypotension reactions occurred after 4 hours. All subjects were able to complete their IVIG infusion without any further complications. CONCLUSIONS: Given that the maximum IVIG infusion rate is reached at 1.5 hours per our hospital's policy and that the overwhelming majority of infusion reactions occurred within the first 4 hours, we found it is safe to coadminister IVIG with sedation 4 hours after initiation of IVIG infusion.

Effect of inhaled corticosteroid use on weight (BMI) in pediatric patients with moderate-severe asthma.

OBJECTIVES: Assess the relationship between inhaled corticosteroid use (ICS) and weight (BMI) in pediatric patients with moderate-severe asthma. Assess if the number of emergency department (ED) visits correlates with overall BMI trajectory. Assess the trend of prescribing biologic therapy in pediatric patients with moderate-severe asthma and determine its relationship with weight (BMI). METHODS: A retrospective chart review was performed on 93 pediatric patients with moderate-severe asthma to determine the relationship between ICS use and weight (BMI), biologic therapy and BMI, and number of ED visits and BMI trajectory. A mixed effects model was employed with the correlation between repeated measures accounted for through the random effects. RESULTS: There is a statistically significant increase of 0.369 kg/m2 in BMI trajectory per year in subjects on high-dose steroids compared to an increase of 0.195 kg/m2 in the low dose group (p < 0.05). The BMI of subjects initiated on biologic therapy (omalizumab or mepolizumab) had a statistically significant decrease in BMI trajectory of 0.818 kg/m2 per year (p < 0.05). Subjects with ≥5 ED visits due to asthma exacerbations had a significantly higher BMI trajectory (p < 0.05). CONCLUSIONS: The potency of ICS use in pediatric patients with moderate-severe asthma affects BMI trajectory; the higher the dose, the greater the projected BMI increase per year. Initiation of biologic therapy decreased BMI trajectory over time. Lastly, those with frequent ED visits had a higher BMI trend. Future prospective studies are warranted that further evaluate the potential metabolic impacts of ICS and assess the effects of biologic therapy on BMI.

Effect of Vitamin D Supplementation on Delayed Hyperphosphatemia in Pediatric Acute Lymphoblastic Leukemia Patients During Induction Chemotherapy.

OBJECTIVES: Vitamin D plays a role in maintaining bone health and calcium metabolism, but recent studies cast doubt on vitamin D supplementation's benefits in survivors of acute lymphoblastic leukemia (ALL). Vitamin D supplementation could increase serum phosphate through increased intestinal absorption of phosphate and suppression of parathyroid hormone, which would lead to decreased renal phosphate excretion. Because of the potential for renal injury during induction chemotherapy for ALL, Vitamin D supplementation's potential for increasing hyperphosphatemia could outweigh its suggested but unproven benefits. METHODS: To measure the interaction between vitamin D supplementation and phosphate during chemotherapy induction, a retrospective study was done. Demographic data; clinical information about the diagnosis; laboratory data regarding calcium, phosphate, and vitamin D concentrations; and medication histories were reviewed. RESULTS: A retrospective study of 41 children with ALL showed no statistically significant difference in the final phosphate concentrations that were obtained (4.41 mg/dL vs. 4.53 mg/dL, p = 0.635) with regard to their vitamin D supplementation status. Longitudinal effects with vitamin D and phosphate showed a trend toward increasing phosphate concentrations in patients who received supplemental vitamin D (0.035 vs. 0.010 mg/dL per day; p = 0.102). CONCLUSIONS: Vitamin D potentially poses a risk of hyperphosphatemia in children undergoing induction chemotherapy for ALL.

Development of Tolerance to Chronic Intermittent Furosemide Therapy in Pediatric Patients.

OBJECTIVES: The purpose of this study is to describe whether tolerance develops in pediatric patients receiving chronic intermittent furosemide therapy, to characterize when it occurs and whether age-related variations exist. The effects of increasing total daily dose of furosemide and concurrent diuretics and vasopressors were assessed as secondary aims. METHODS: Charts from patients receiving intravenous or oral furosemide for at least 3 consecutive days of therapy between June 1, 2013, and December 31, 2013, were reviewed retrospectively. Daily net fluid balance was used as the objective marker for development of tolerance. Net fluid balance (mL/kg/mg) was defined as the difference in a patient's daily intake and urine output (mL), normalized by weight (kg) and total daily dose of furosemide (mg). RESULTS: Sixty-one patients, aged 2 days to 20 years (median 3 years), were included in this study. Median daily dose of furosemide was 1.96 mg/kg/day (range, 0-13.7 mg/kg/day). Average net fluid balance for all patients on the first day and last day of therapy was 6.83 and 26.66 mL/kg/mg, respectively (p = 0.011). Linear regression and Spearman's correlation found no significant relationship between age and difference in net fluid balance between the first and last day. Linear mixed-effects model for net fluid balance with day as covariate found that net fluid balance increases over time (p = 0.002). CONCLUSIONS: Pediatric patients appear to develop tolerance to chronic intermittent furosemide therapy.

Pharmacodynamic Characteristics of Nephrotoxicity Associated With Vancomycin Use in Children.

BACKGROUND: Limited studies incorporating population-based pharmacokinetic modeling have been conducted to determine pharmacodynamic indices associated with nephrotoxicity during vancomycin exposure in children. METHODS: A retrospective cohort analysis was conducted from September 2003 to December 2011 at 2 hospitals. Nephrotoxicity was defined as an increase in serum creatinine concentration (SCr) by ≥0.5 mg/dL, or ≥50% increase in baseline SCr, either persisting for ≥2 consecutive days. A 1-compartment model with first-order kinetics was used in NONMEM 7.2 to estimate trough concentrations (Cmin) and area under the curve over 24 hours (AUC). Univariate, classification and regression tree (CART), and multivariate analyses were conducted to identify factors contributing to nephrotoxicity. RESULTS: The analyses included 680 pediatric subjects with 1576 vancomycin serum concentrations. Based on univariate analysis, median Cmin (14.2 [interquartile range, IQR, 7.1-25.4] vs 8.4 [IQR, 5.5-12.4] mcg/mL; P = .001) and AUC (544 [IQR, 359-801] vs 378 [IQR, 304-494]; P < .001) were significantly higher in the nephrotoxic group compared with the non-nephrotoxic group. Using CART, we discovered that subjects with doses ≥60 mg/kg per day and AUC >1063 mg-h/L had a significantly higher occurrence of nephrotoxicity (P = .005). Adjusting for intensive care unit stay and concomitant nephrotoxic drugs, steady-state vancomycin Cmin ≥15 mcg/mL (adjusted odds ratio [aOR], 2.5; 95% confidence interval [CI], 1.1-5.8; P = .028) and AUC ≥800 mg-h/L (aOR, 3.7; 95% CI, 1.2-11.0; P = .018) were associated with increased risk of nephrotoxicity. CONCLUSIONS: Our study describes the pediatric exposure-nephrotoxicity relationships for vancomycin. Vancomycin Cmin ≥15 mcg/mL and AUC ≥800 mg-h/L in children are independently associated with a > 2.5-fold increased risk of nephrotoxicity and may provide justification for use of alternative antibiotics in selected situations.

Bayesian Estimation of Vancomycin Pharmacokinetics in Obese Children: Matched Case-Control Study.

PURPOSE: The study objective was to compare different body size descriptors that best estimate vancomycin Vd and clearance (CL). METHODS: Patients between 3 months and 21 years old who received vancomycin for ≥48 hours from 2003 to 2011 were evaluated in this matched case-control study. Cases had body mass index in the ≥85th percentile; controls were nonobese individuals who were matched by age and baseline serum creatinine (SCr). Using a 1-compartment model with first-order kinetics, Bayesian post hoc individual Vd and CL were estimated. FINDINGS: Analysis included 87 matched pairs with 389 vancomycin serum concentrations. Median ages were 10.0 (interquartile range [IQR], 4.8-15.2) years for cases (overweight and obese children) and 10.2 (IQR, 4.5-14.8) years for controls (normal-weight children). Median weights were 44.0 (IQR, 23.4-78.1) kg for cases and 31.3 (IQR, 16.8-47.1) kg for controls. Mean (SD) for the baseline SCr values were also similar between the groups: 0.51 (0.22) (IQR, 0.34-0.67) mg/dL and 0.48 (0.20) (IQR, 0.30-0.60) mg/dL for the cases and controls, respectively. Actual weight and allometric weight (ie, weight(0.75)) were used in the final model to estimate Vd and CL, respectively. The mean Vd and CL, based on weight, for cases were lower than controls by 0.012 L/kg and 0.014 L/kg/h, respectively. IMPLICATIONS: In obese children, actual weight and allometric weight are reasonable, convenient estimations of body fat to use for estimating vancomycin Vd and CL, respectively. However, these pharmacokinetic differences between obese children and those with normal weights are small and may not likely to be clinically relevant in dose variation.

Population-Based Pharmacokinetic Modeling of Vancomycin in Children with Renal Insufficiency.

BACKGROUND: Vancomycin dosing to achieve the area-under-the-curve to minimum inhibitory concentration (AUC/MIC) target of ≥ 400 in children with renal insufficiency is unknown. Our objectives were to compare vancomycin clearance (CL) and initial dosing in children with normal and impaired renal function. METHODS: Using a matched case-control study in subjects ≥ 3 months old who received vancomycin ≥ 48 hr, we performed population-based modeling with empiric Bayesian post-hoc individual parameter estimations and Monte Carlo simulations. Cases, defined by baseline serum creatinine (SCr) ≥ 0.9 mg/dL, were matched 1:1 to controls by age and weight. RESULTS: Analysis included 63 matched pairs with 319 serum concentrations. Mean age (± SD) was 13 ± 6 yr and weight, 51 ± 25 kg. Mean baseline SCr was 0.6 ± 0.2 mg/dL for controls, and 1.3 ± 0.5 for cases. Age, SCr, and weight were independent covariates for CL. Final model parameters and inter-subject variability (ISV) were: CL(L/hr) = 0.235*Weight0.75*(0.64/SCr)0.497*(ln(DOL)/8.6)1.19 ISV=39%, where DOL is day of life. Target AUC/MIC ≥ 400 was achieved in 80% of cases at vancomycin 45 mg/kg/day, but required 60 mg/kg/day for controls. Drug CL improved in 87% of cases due to recovery of renal function. CONCLUSION: Due to reduced CL, a less frequent dosing at 15 mg/kg every 8 hr (i.e., 45 mg/kg/day) may be appropriate for some children with renal impairment. Close monitoring of renal function and drug concentrations is prudent to ensure adequate drug exposure, especially in those with renal impairment since recovery of renal function may occur during therapy.

Vancomycin monitoring in children using bayesian estimation.

BACKGROUND: Optimal monitoring of vancomycin in children needs evaluation using the exposure target with area under the curve (AUC) of the serum concentrations versus time over 24 hours. Our study objectives were to: (1) compare the accuracy and precision of vancomycin AUC estimations using 2 sampling strategies-1 serum concentration sample (1S, near trough) versus 2 samples (2S, near peak and trough) against the rich sample (RS) method; and (2) determine the performance of these strategies in predicting future AUC against an internal validation sample (VS). METHODS: This was a retrospective cohort study using population-based pharmacokinetic modeling with Bayesian post hoc individual estimations in nonlinear mixed effects modeling (version 7.2). Pediatric subjects 3 months-21 years of age who received vancomycin ≥48 hours and had more than 3 drug samples within the first ≤96 hours of therapy were enrolled. Outcome measures were the accuracy, precision, and internal predictive performance of AUC estimations using 2 monitoring strategies (ie, 1S versus 2S) against the RS (which was derived from modeling all serum vancomycin concentrations obtained anytime during therapy) and VS (from serum concentrations obtained after 96 hours of therapy). RESULTS: Analysis included 138 subjects with 712 vancomycin serum concentrations. Median age was 6.1 (interquartile range, 2.2-12.2) years, weight 22 (13-38) kg, and baseline serum creatinine 0.37 (0.30-0.50) mg/dL. Both accuracy and precision were improved with the 2S, compared with 1S, for AUC estimations (-2.0% versus -7.6% and 10.3% versus 12.8%, respectively) against the RS. Improved accuracy and precision were also observed for 2S when evaluated against VS in predicting future AUC. CONCLUSIONS: Compared with 1S, the 2S sampling strategy for vancomycin monitoring improved accuracy and precision in estimating and predicting future AUC. Evaluating 2 drug concentrations in children may be prudent to ensure adequate drug exposure.

Optimizing pediatric esmolol dosing using computerized practitioner order entry.

OBJECTIVES: The aims of this study were to 1) describe the cardiovascular dose-response of esmolol and dose-limiting adverse effects in pediatric patients; 2) assess an institutional guideline for protocol adherence, efficacy, and achievement of therapeutic targets for pediatric patients with tachyarrhythmias or systemic hypertension; and 3) revise the protocol accordingly. METHODS: In this prospective study, pediatric/neonatal subjects were identified using a medication utilization report in the electronic medical record and treated with esmolol for blood pressure or rhythm control at Rady Children's Hospital San Diego between November 1, 2012, and February 28, 2013. Inclusion criteria required subjects to be under intensive care and have bedside telemetry monitoring. Data collection consisted of patient demographic information, administration history of esmolol, concurrent administration of other cardiovascular medications, patient cardiovascular goals, and vital signs. RESULTS: A total of 8 subjects representing 10 administrations of esmolol were included in the study. Whereas esmolol was found to be safe and effective overall for control of hypertension and tachyarrhythmia, protocol adherence was poor, leading to subtherapeutic dosing schemes, dose changes prior to achievement of presumed steady-state pharmacokinetics, and erratic dosing to target effect. CONCLUSIONS: After the review, the data were revealed at a program-wide conference and consensus was reached on a new, data-driven protocol. As a result of this quality improvement initiative, the new protocol provides more precise dosing and clearly delineated therapeutic targets and is designed to reflect specific esmolol pharmacokinetics. The effort emphasizes the need to construct foundations for follow-up quality improvement efforts in intensive care pharmacology.

Improved vancomycin dosing in children using area under the curve exposure.

BACKGROUND: : Our objectives were to (1) determine the pharmacokinetic indices of vancomycin in pediatric patients; and (2) compare attainment of 2 target exposures: area under curve (AUC) / minimum inhibitory concentration (MIC) ≥400 and trough concentration ≥15 mcg/mL. METHODS: : The population-based pharmacokinetic modeling was performed using NONMEM 7.2 for children ≥3 months old who received vancomycin for ≥48 hours from 2003 to 2011. A 1-compartment model with first-order kinetics was used to estimate clearance, volume of distribution and AUC. Empiric Bayesian post hoc individual parameters and Monte Carlo simulations (N = 11,000) were performed. RESULTS: : Analysis included 702 patients with 1660 vancomycin serum concentrations. Median age was 6.6 (interquartile range 2.2-13.4) years, weight 22.7 (12.6-46) kg and baseline serum creatinine 0.40 (0.30-0.60) mg/dL. Final model pharmacokinetic indices were clearance (L/h) = 0.248 * Wt * (0.48/serum creatinine) * (ln(age)/7.8) and volume of distribution (L) = 0.636 * Wt. Using these parameters and the observed MIC distribution, Monte Carlo simulation indicated that the initial median dose of 44 (39-52) mg/kg/day was inadequate in most subjects. Regimens of 60 mg/kg/day for subjects ≥12 years old and 70 mg/kg/day for those <12 years old achieved target AUC/MIC in ~75% and trough concentrations ≥15 in ~45% of virtual subjects. An AUC/MIC ~400 corresponded to trough concentration ~8 to 9 mcg/mL. CONCLUSIONS: : Targeted exposure using vancomycin AUC/MIC, compared with trough concentrations, is a more realistic target in children. Depending on age, serum creatinine and MIC distribution, vancomycin in a dosage of 60 to 70 mg/kg/day was necessary to achieve AUC/MIC ≥ 400 in 75% of patients.