An electronic medical records-based approach to identify idiosyncratic drug-induced liver injury in children.

Drug-induced liver injury (DILI) is the leading cause of liver failure in the United States and the most common cause of drug recall. As opposed to the recognized direct toxicity of super-therapeutic acetaminophen or chemotherapeutic agents in children, limited data exists for pediatric populations on the incidence of idiosyncratic DILI (iDILI) that may develop independently of drug dose or duration of administration. To improve the detection of adverse drug reactions at our hospital, we utilized electronic medical records-based automated trigger tools to alert providers of potential iDILI. Clinical criteria concerning for iDILI were defined as serum ALT > 5x or serum bilirubin > 1.5x upper limit of normal in the setting of medication exposure. Over a two year period, 12 patients were identified as having possible or probable iDILI. Out of the identified patients, three were males, and the mean age was 10.8 years. Implicated agents included eight antibiotics, two anti-epileptics, one anti-psychotic, and one anti-inflammatory medication. Roussel-Uclaf Causality Assessment Methods identified one "possible" case, 11 "probable" cases, and one "highly probable" case of iDILI. Improved awareness and more vigilant programming can generate better data on iDILI and improve our understanding of the condition and its incidence in children.

Description of an Innovative Pediatric Individualized Therapeutics Clinic: Working toward Precision Drug Therapy.

The GOLDILOKs® (Genomic and Ontogeny-Linked Dose Individualization and cLinical Optimization for KidS) Clinic aims to provide families and physicians with data to make more informed decisions with regard to pharmacological therapy by using innovative therapy and genomic technologies. The objectives are two-fold: (1) To describe the utility of the GOLDILOKs® Clinic to referring prescribers by evaluating the type of referrals made to the GOLDILOKs® Clinic and (2) to assess the most often utilized technologies (e.g., genotyping) completed to formulate therapy recommendations. Patient data from July 2010 to June 2016 was retrospectively reviewed following Institutional Review Board (IRB) approval. The GOLDILOKs® Clinic evaluated 306 patients and had increases in annual referrals from 14 in 2010⁻2011 to 84 in 2016⁻2017. The children that were referred were predominately Caucasian (82%) and male (59%) with an average age of 12.4 ± 5.9 years. Subspecialty versus primary care referrals accounted for 82% and 18% of referrals, respectively. Adverse drug reactions (n = 166) and poor medication response (n = 179) were the major reasons for referral. However, it must be noted that patients could have multiple reasons for referral. Pharmacogenetic results were extensively used to provide guidance for future therapy in patients with medication-related problems. Genotyping of drug metabolizing enzymes and drug target receptors was performed in 221 patients (72.2%). Recommendations were fully accepted by 63% and partially accepted by 22% of internal provider referrals.

Comparison of Arginine Hydrochloride and Acetazolamide for the Correction of Metabolic Alkalosis in Pediatric Patients.

Metabolic alkalosis is a common acid-base disturbance occurring in critically ill pediatric patients. Acetazolamide and arginine hydrochloride are pharmacologic agents used at our institution for patients refractory to first-line therapy or those unable to tolerate fluid replacement. The objective of this retrospective review was to determine if a course of arginine hydrochloride or acetazolamide was more effective at correcting metabolic alkalosis within a 24-hour period. Patients included received a course of acetazolamide or arginine hydrochloride for metabolic alkalosis with a repeat metabolic panel 18-30 hours after treatment initiation. Exclusion criteria consisted of previous treatment with either drug within 24 hours or a documented metabolic disorder. Efficacy was determined by proportion of patients achieving resolution of metabolic alkalosis (treatment success: serum CO2 <30 mmol/L and Cl >96 mmol/L). Additionally, mean change in serum bicarbonate and chloride concentrations was assessed. Thirty-four patients met inclusion criteria, 19 patients received acetazolamide and 15 patients received arginine hydrochloride. Treatment success was similar in patients receiving acetazolamide and arginine hydrochloride (37% vs. 7%, P = 0.053). Correction of serum bicarbonate was observed in more patients treated with acetazolamide (42% vs. 7%, P = 0.047). Both groups had a similar increase in mean serum chloride concentration (5.7 ± 5.3 vs. 4.4 ± 4.4 mmol/L, P = 0.458). Mean decrease in serum bicarbonate concentration was equivalent between groups (5.6 ± 5.2 vs. 2.8 ± 4.7, mmol/L, P = 0.110). Acetazolamide and arginine hydrochloride appear to be equally effective in correcting metabolic alkalosis in critically ill pediatric patients.

Evaluation of an Alternative Intravenous N-Acetylcysteine Regimen in Pediatric Patients.

OBJECTIVE: Conventionally, intravenous N-acetylcysteine (IV-NAC) administration is a 3-bag regimen administered over the course of 21 hours, which increases the risk of reconstitution and administration errors. To minimize errors, an alternative IV-NAC regimen consists of a loading dose (150 mg/kg) followed by a maintenance infusion (15 mg/kg/hr) until termination criteria are met. The aim was to determine the clinical outcomes of an alternative IV-NAC regimen in pediatric patients. METHODS: A retrospective review of pharmacy dispensing records and diagnostic codes at a pediatric hospital identified patients who received alternative IV-NAC dosing from March 1, 2008, to September 10, 2012, for acetaminophen overdoses. Exclusion criteria included chronic liver disease, initiation of oral or other IV-NAC regimens, and initiation of standard IV-NAC infusion prior to facility transfer. Clinical and laboratory data were abstracted from the electronic medical record. Descriptive statistics were utilized. Clinical outcomes and adverse drug reaction incidences were compared between the alternative and Food and Drug Administration (FDA)-approved IV-NAC regimens. RESULTS: Fifty-nine patients (mean age 13.4 ± 4.3 years; range: 2 months-18 years) with acetaminophen overdoses were identified. Upon IV-NAC discontinuation, 45 patients had normal alanine transaminase (ALT) concentrations, while 14 patients' ALT concentrations remained elevated (median 140 units/L) but were trending downward. Two patients (3.4%) developed hepatotoxicity (aspartate transaminase/ALT > 1000 units/L). No patients developed hepatic failure, were listed for a liver transplant, were intubated, underwent hemodialysis, or died. Two patients (3.4%) developed anaphylactoid reactions. No known medication or administration errors occurred. Clinical outcome incidences of the studied endpoints with the alternative IV-NAC regimen are at the lower end of published incidence ranges compared to the FDA IV-NAC regimen for acetaminophen overdoses. CONCLUSIONS: This alternative IV-NAC regimen appears to be effective and well tolerated among pediatric patients when compared to the FDA-approved regimen. It may also result in fewer reconstitution and administration errors, leading to improved patient safety.

Development of criteria for gentamicin monitoring in a neonatal intensive care unit.

PURPOSE: The results of a study to identify factors associated with serum gentamicin levels outside the therapeutic range in a neonatal population are reported. METHODS: A single-center retrospective chart review was conducted to identify cases involving gentamicin use in the neonatal intensive care unit; a sample of cases sufficient for risk-factor analysis (n = 225) was selected for evaluation. In all evaluated cases, gentamicin was administered according to a standardized dosing protocol based on gestational age and weight. Selected clinical factors and laboratory values potentially associated with undesirably high or low serum drug levels were analyzed. RESULTS: Of the 225 patient cases included in the analysis, 184 (82%) involved appropriate (i.e., per protocol) gentamicin dosing. Of the 41 doses classified as inappropriate, 33 were higher and 8 were lower than those recommended by the protocol. Six (18%) of the newborns who received doses classified as inappropriately high had supratherapeutic serum trough concentrations, and 3 (9%) had subtherapeutic trough values. Among the neonates with supratherapeutic peak values, none had an elevated trough value and only 1 received a gentamicin dose deemed to be inappropriately high. Factors associated with an increased relative risk (RR) of a supratherapeutic trough included inappropriate dosing (RR, 2.9; 95% confidence interval [CI], 1.18-6.9), an elevated serum creatinine (SCr) concentration (>0.8 mg/dL) on the day of blood sampling for drug level assessment (RR, 25.6; 95% CI, 9.1-71.4), low urine output (<1 mL/kg/hr) on the day of blood sampling (RR, 7.8; 95% CI, 3.0-15.4), and shock (RR, 3.16; 95% CI, 1.32-7.57). CONCLUSION: When adhering to a weight-based gentamicin dosing protocol, the SCr level and urine output are the best indicators for identifying neonatal patients at risk for supratherapeutic gentamicin trough levels. Shock and inappropriate dosing strategies also put patients at increased risk for supratherapeutic troughs.