Production Standard and Stability of Compounded Del Nido Cardioplegia Solution.

Background: The del Nido cardioplegia solution (dNCS) was originally developed for pediatric cardiac surgery, being now also used for adult patients. Hospital pharmacies frequently resort to internal dNCS production which has led to an increase in the need for validated parameters for compounding and storage. Objective: This report defines in-house production standards, as well as the stability of dNCS under optimal storage conditions. Methods: All ingredients were sterile and United States Pharmacopeia (USP)/National Formulary (NF) certified. All final bags were quarantined at 4°C for quality control, when 3 of 33 weekly bags were randomly assayed for potassium content. Each lot was only released if all 3 samples were within ±5% of target. Stability testing was performed per USP 797 guidance. Over a 6-month period, 4 different lots and 4 bags from each lot of dNCS were assayed. Each bag was assessed for physical and chemical stability while refrigerated at 4°C, at 35°C in an incubator, and at 70°C under 80% relative humidity. A light exposure arm was also set up at 25°C under 150 lumens. Calibrators of lidocaine, mannitol, and gluconate were freshly prepared and assayed with the samples by Liquid chromatography/Mass spectrometry (LC/MS). Results: Lidocaine concentrations averaged 0.117 mg/mL (95.8% of theoretical) at 4°C for 30 days. At 35°C, they decayed by 67% in 30 days, while at 70°C nearly 50% was lost after the first day. A first-order kinetics was observed with an Arrhenius activation energy of 25 kcal/mol. Degradation products identified under stress conditions were absent in the stable product. Conclusions: The dNCS is stable for at least 30 days under 4°C refrigeration in ethylene vinyl acetate (EVA) bags.

Use of cidofovir in pediatric patients with adenovirus infection.

Background: Adenoviruses contribute to morbidity and mortality among immunocompromised pediatric patients including stem cell and solid organ transplant recipients. Cidofovir (CDV), an antiviral compound approved by the FDA in 1996, is used for treatment of adenoviral (ADV) infections in immunocompromised patients despite concern of potential nephrotoxicity.   Methods: We conducted a retrospective 5-year review at Boston Children's Hospital of 16 patients (mean age = 6.5 years) receiving 19 courses of CDV. During therapy all pertinent data elements were reviewed to characterize potential response to therapy and incidence of renal dysfunction.   Results: Of the 19 CDV courses prescribed, 16 courses (84%) were in patients who had a positive blood ADV Polymerase chain reaction (PCR) alone or in combination with positive ADV PCR/ Direct Immunofluorescence Assay (DFA) at another site. Respiratory symptoms with or without pneumonia were the most common presentation (10/19, 53%). In the majority of blood positive courses (10/16, 63%), viral clearance was also accompanied by clinical response. This was not the case in four courses where patients expired despite viral clearance, including one in which death was directly attributable to adenovirus. There was reversible renal dysfunction observed during the use of CDV. Conclusions:  CDV appeared safe and reasonably tolerated for treatment of ADV in this pediatric population and was associated with viral response and clinical improvement in the majority of patients but reversible renal dysfunction was a side effect. Further studies of the efficacy of CDV for immunocompromised children with ADV infection are warranted.

Implementing a Distraction-Free Practice With the Red Zone Medication Safety Initiative.

BACKGROUND: The incidence of medication errors remains a continued concern across the spectrum of health care. Approaches to averting medication errors and implementing a culture of safety are key areas of focus for most institutions. We describe our experience of implementing a distraction-free medication safety practice across a large free-standing children's hospital. METHODS: A nurse-led interprofessional group was convened to develop a program-wide quality improvement process for the practice of medication safety. A key driver diagram was developed to guide the Red Zone Medication Safety initiative. Change acceleration process was used to evaluate the implementation and impact of the initiative. RESULTS: Since implementation in 2010, there has been a significant reduction in medication events of 79.2% (P = .00184) and 65.3% (P = .035) (in the cardiac intensive care unit and acute care cardiac unit, respectively), including months with unprecedented zero reportable medication events. There also has been a sustained decrease in the number of events reaching the patient (33.3% in the cardiac intensive care unit and 57.1% in the acute care cardiac unit). CONCLUSIONS: The implementation of a distraction-free practice was found to be feasible and effective, demonstrating a sustained decrease in the overall number of medication events, event rate, and number of events reaching patients. This interprofessional approach was successful in a large inpatient cardiovascular program and then effectively transferred across all hospital inpatient units. Additional sites of implementation include other high-risk patient care areas such as procedure/operative units.

Pediatric heparin-induced thrombocytopenia: prevalence, thrombotic risk, and application of the 4Ts scoring system.

OBJECTIVE: To characterize heparin-induced thrombocytopenia (HIT) at a single pediatric center including the prevalence and the accuracy of the 4Ts scoring system as a predictor of HIT. STUDY DESIGN: In this retrospective cohort study, we identified 155 consecutive patients <21 years old with sufficient data for 4Ts scoring. The 4Ts scoring system is a validated pretest tool in adults that predicts the likelihood of HIT using clinical features. Hospital-wide exposure to unfractionated and low molecular weight heparin was determined by querying the hospital pharmacy database. RESULTS: The majority of patients with suspected HIT (61.2%) were on surgical services. Prediction of HIT risk using initial 4Ts scoring found 3 (2%) had high risk 4Ts scores, 114 (73%) had intermediate risk 4Ts scores, and the remaining 38 (25%) had low risk 4Ts scores. HIT was confirmed in 0/38 patients with low risk 4Ts scores, 2/114 patients with intermediate-risk 4Ts scores, and all 3 patients with high-risk 4Ts scores presented with HIT with thrombosis. Of 12 positive HIT screening tests, results were falsely positive in 66.6% of patients with intermediate risk 4Ts scores and 100% of patients with low risk 4Ts scores. The prevalence of HIT was 0.058% and HIT with thrombosis was 0.046% in pediatric patients on unfractionated heparin. CONCLUSIONS: The prevalence of HIT appears significantly lower in pediatric patients compared with adults. Application of the 4Ts system as a pretest tool may reduce laboratory evaluation for HIT in heparin-exposed children with low risk 4Ts scores, decreasing unnecessary further testing, intervention, and cost.

Sterile product compounding using an i.v. compounding workflow management system at a pediatric hospital.

PURPOSE: Patient safety enhancements achieved through the use of an automated i.v. compounding workflow management system are reported. SUMMARY: Automated systems integrating barcode verification of ingredients and the capture of serial images of all steps of the admixture process have the potential to improve the accuracy of parenteral i.v. medication dose preparation. About 18 months after the implementation of such a system at a large pediatric hospital, a retrospective analysis of dose preparation outcomes was conducted to evaluate the effectiveness of the i.v. workflow manager in detecting compounding errors and to categorize detected errors. In verifying the accuracy of 425,683 medication doses prepared during the approximately 13-month evaluation period, dispensing pharmacists detected preparation or documentation errors affecting 2,900 doses (0.68%); 1,223 of those doses (0.29%) required reworking, and 1,677 (0.4%) were rejected and destroyed. Roughly 23% of the detected errors were classified as undetectable via the pharmacy's previous verification practices, with 167 errors judged to pose the potential for adverse drug events resulting in moderate (n=146) or severe (n=21) harm. Among the reworked and rejected doses, 43.8% and 31.3%, respectively, were due to newly emergent problems not seen with traditional paper-based verification systems; however, most of these errors involved blurry or missing images and were not judged to be clinically significant. CONCLUSION: Implementation of an i.v. workflow management system that integrates barcode verification, automated calculations, and image-capture capabilities led to increased detection of errors in the sterile product compounding process.

A randomized controlled trial of a vancomycin loading dose in children.

BACKGROUND: Despite its frequent use, the optimal dosing regimen of intravenous vancomycin remains controversial. Achievement of therapeutic trough early in the course of illness may be beneficial. Our objective was to assess whether a loading dose of vancomycin would increase the proportion of children reaching target trough concentrations 8 hours after initiation of therapy. METHODS: We enrolled hospitalized children aged 2-18 years prescribed vancomycin at Boston Children's Hospital between February 2011 and January 2012. Participants were randomized to receive a loading dose (30 mg/kg) or a conventional initial dose (20 mg/kg). These were followed by a 20 mg/kg/dose every 8 hours in both groups. Serum vancomycin concentrations were measured before the second and third doses. Pharmacokinetic parameters were calculated using individual and population pharmacokinetic models. RESULTS: Two of nineteen (11%) loading dose recipients had a trough 15-20 mg/L before the second dose, compared with 0 of 27 in the conventional dose group (P=0.17). However, the median area under the curve/minimum inhibitory concentration estimates (for a hypothetical minimum inhibitory concentration=1 mg/L) were above 400 in both groups. Red man syndrome incidence was higher in loading dose recipients (48% vs. 24%, P=0.06). CONCLUSIONS: A vancomycin loading dose did not result in earlier achievement of therapeutic trough concentrations in this study. However, the systemic exposure to vancomycin in children administered 60 mg/kg/day was adequate, despite lower than recommended measured trough levels. Therefore, the need for higher target trough concentrations should be questioned.

Pharmacointeraction network models predict unknown drug-drug interactions.

Drug-drug interactions (DDIs) can lead to serious and potentially lethal adverse events. In recent years, several drugs have been withdrawn from the market due to interaction-related adverse events (AEs). Current methods for detecting DDIs rely on the accumulation of sufficient clinical evidence in the post-market stage - a lengthy process that often takes years, during which time numerous patients may suffer from the adverse effects of the DDI. Detection methods are further hindered by the extremely large combinatoric space of possible drug-drug-AE combinations. There is therefore a practical need for predictive tools that can identify potential DDIs years in advance, enabling drug safety professionals to better prioritize their limited investigative resources and take appropriate regulatory action. To meet this need, we describe Predictive Pharmacointeraction Networks (PPINs) - a novel approach that predicts unknown DDIs by exploiting the network structure of all known DDIs, together with other intrinsic and taxonomic properties of drugs and AEs. We constructed an 856-drug DDI network from a 2009 snapshot of a widely-used drug safety database, and used it to develop PPIN models for predicting future DDIs. We compared the DDIs predicted based solely on these 2009 data, with newly reported DDIs that appeared in a 2012 snapshot of the same database. Using a standard multivariate approach to combine predictors, the PPIN model achieved an AUROC (area under the receiver operating characteristic curve) of 0.81 with a sensitivity of 48% given a specificity of 90%. An analysis of DDIs by severity level revealed that the model was most effective for predicting "contraindicated" DDIs (AUROC = 0.92) and less effective for "minor" DDIs (AUROC = 0.63). These results indicate that network based methods can be useful for predicting unknown drug-drug interactions.

Predicting adverse drug events using pharmacological network models.

Early and accurate identification of adverse drug events (ADEs) is critically important for public health. We have developed a novel approach for predicting ADEs, called predictive pharmacosafety networks (PPNs). PPNs integrate the network structure formed by known drug-ADE relationships with information on specific drugs and adverse events to predict likely unknown ADEs. Rather than waiting for sufficient post-market evidence to accumulate for a given ADE, this predictive approach relies on leveraging existing, contextual drug safety information, thereby having the potential to identify certain ADEs earlier. We constructed a network representation of drug-ADE associations for 809 drugs and 852 ADEs on the basis of a snapshot of a widely used drug safety database from 2005 and supplemented these data with additional pharmacological information. We trained a logistic regression model to predict unknown drug-ADE associations that were not listed in the 2005 snapshot. We evaluated the model's performance by comparing these predictions with the new drug-ADE associations that appeared in a 2010 snapshot of the same drug safety database. The proposed model achieved an AUROC (area under the receiver operating characteristic curve) statistic of 0.87, with a sensitivity of 0.42 given a specificity of 0.95. These findings suggest that predictive network methods can be useful for predicting unknown ADEs.

Neonatal babesiosis: case report and review of the literature.

A case of transfusion-associated neonatal babesiosis is presented. Jaundice, hepatosplenomegaly, anemia and conjugated hyperbilirubinemia developed in this preterm infant. The diagnosis was eventually made by blood smear, serology and polymerase chain reaction. The patient was treated with clindamycin and quinine and made a favorable recovery. Of neonatal babesiosis reported in the literature, 9 other cases are reviewed, including 6 that were transfusion-associated, 2 congenital and 2 tick transmitted.

An antibiotic order form intervention does not improve or reduce vancomycin use.

OBJECTIVES: To determine whether a paper-based antibiotic ordering system is an effective antibiotic stewardship measure. METHODS: An antibiotic order form (AOF) was introduced in July 2001 at a pediatric tertiary care hospital. Vancomycin courses prescribed before and after the AOF introduction were retrospectively reviewed based on Hospital Infection Control Practices Advisory Committee guidelines. The impact of the AOF on the appropriateness of vancomycin prescribing was evaluated in univariate and multivariable analyses that adjusted for other factors associated with appropriateness of vancomycin use. The density of vancomycin use after introduction of the AOF was also assessed. RESULTS: Compliance with the AOF was poor (<50%) during the planned study period; therefore an additional 2 months of improved compliance (70-80%) were included. Rates of inappropriate vancomycin use increased during the study periods: 35% before AOF; 39% post-AOF; and 51% during the improved compliance period. On adjusted analysis, vancomycin utilization was significantly more inappropriate after introduction of the AOF. Vancomycin doses per 1000 patient days increased after introduction of the AOF. CONCLUSIONS: Inappropriate vancomycin use and vancomycin use overall increased after the introduction of an AOF. An AOF intervention did not have its intended effect of improving and reducing vancomycin use.

Evaluating vancomycin use at a pediatric hospital: new approaches and insights.

OBJECTIVES: To characterize vancomycin use at a pediatric tertiary-care hospital, to discriminate between initial (< or = 72 hours) and prolonged (> 72 hours) inappropriate use, and to define patient characteristics associated with inappropriate use. DESIGN: Vancomycin courses were retrospectively reviewed using an algorithm modeled on HICPAC guidelines. Data were collected regarding patient demographics, comorbidities, other medication use, and nosocomial infections. The association between each variable and the outcome of inappropriate use was determined by longitudinal regression analysis. A multivariable model was constructed to assess risk factors for inappropriate initial and prolonged vancomycin use. SETTING: A pediatric tertiary-care medical center. PATIENTS: Children older than 1 year who received intravenous vancomycin from November 2000 to June 2001. RESULTS: Three hundred twenty-seven vancomycin courses administered to 260 patients were evaluated for appropriateness. Of initial courses, 114 (35%) were considered inappropriate. Of 143 prolonged courses, 103 (72%) were considered inappropriate. Multivariable risk factor analysis identified the following variables as significantly associated with inappropriate initial use: admission to the surgery service, having a malignancy, receipt of a stem cell transplant, and having received a prior inappropriate course of vancomycin. No variables were identified as significant risk factors for inappropriate prolonged use. CONCLUSIONS: Substantial inappropriate use of vancomycin was identified. Prolonged inappropriate use was a particular problem. This risk factor analysis suggests that interventions targeting patients admitted to certain services or receiving multiple courses of vancomycin could reduce inappropriate use.

Antibiotic desensitization for the allergic patient: 5 years of experience and practice.

BACKGROUND: Antibiotic desensitization is an option for patients with suspected IgE-mediated antibiotic allergy when no other alternative exists for treating life-threatening bacterial infections. However, there are limited data describing the outcomes of this procedure with newer, commonly used antibiotics. OBJECTIVE: To evaluate the safety and utility of antibiotic desensitization. METHODS: We retrospectively reviewed the medical records of all patients undergoing antibiotic desensitization in our institution between November 1996 and November 2001. RESULTS: There were a total of 57 desensitizations performed in 21 patients. The mean age of the patients was 22.8 years (range, 1.9-44.5 years) and 15 (71%) were female. Nineteen (90%) of the 21 patients had been diagnosed as having cystic fibrosis. In 33 (100%) of 33 desensitizations to unique antibiotics that occurred during the study period, the indication for desensitization was a history suggestive of an IgE-mediated reaction to the antibiotic and/or a positive skin test result to the antibiotic or a known cross-reactive antibiotic. Desensitizations were performed to 12 different antibiotics. Successful outcomes were achieved in 43 desensitizations (75%). Of the 11 cases (19%) that were terminated due to an allergic reaction, there were no fatalities, intubations, or other aggressive interventions besides the use of epinephrine, antihistamines, and corticosteroids. In 7 of 11 unsuccessful desensitizations, a non-IgE mechanism appeared to be responsible for the allergic reaction. CONCLUSIONS: Antibiotic desensitization is a useful option when treating patients with life-threatening infections who must receive antibiotics to which they have an IgE-mediated allergy. These data indicate that in most cases, patients with presumed IgE-mediated antibiotic allergy may safely receive antibiotics after desensitization.

Once-daily gentamicin dosing for the preterm and term newborn: proposal for a simple regimen that achieves target levels.

OBJECTIVE: Based on recent safety and efficacy data, combined with the known pharmacokinetic parameters of aminoglycosides in the newborn, once-daily gentamicin should be preferable to the many other dosing regimens currently in use. Although there are growing data to support its use in term newborns, experience with preterm infants is more limited. In our Neonatal Intensive Care Unit, we experienced difficulties regarding complicated dosing regimens, actual dosing errors, and the tendency to check trough and peak levels around the third dose for infants receiving only a 48 hour course. Therefore, we conducted a quality improvement initiative in which we developed and tested a clinical practice guideline for the use of once-daily gentamicin for preterm and term infants that we hoped would yield trough and peak levels in our target range. METHODS: We combined a review of the published English language literature with pharmacokinetic analysis of our own data prior to initiation of this new regimen to design the following dosing regimen: <35 weeks gestation: 3 mg/kg q 24 hours, > or =35 weeks gestation: 4 mg/kg q 24 hours. Our goal serum levels were a trough < or =2 microg/ml and a peak between 6 and 12 microg/ml. We collected and analyzed trough and peak levels from all infants receiving this dosing regimen in the first week of life for at least 72 hours between 3/1/99 and 12/31/00. RESULTS: In total, 214 babies met our inclusion criteria, 75 of whom were <35 weeks gestation. 100% of babies of all gestational ages had a nontoxic trough level. For infants <35 weeks gestation, 79% had a therapeutic peak level, with a mean value of 6.8 microg/ml. For infants of at least 35 weeks gestation, 93% had a therapeutic peak level, with a mean value of 8.4 microg/ml. 92% of nontherapeutic peaks were too low. CONCLUSION: This study of once-daily gentamicin represents the largest sample size of pre-term infants published to date. The proposed regimen is simple and yields a high proportion of desirable levels. We recommend it for use in preterm and term newborns.