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.

Opioid Prescribing Practices in Pediatric Acute Care Settings.

OBJECTIVES: Deaths due to prescription opioid overdoses are at record-high levels. Limiting the amount of opioid prescribed has been suggested as a prevention strategy. The purpose of this study was to describe the opioid prescribing practices in the emergency departments and urgent care sites of a Midwestern tertiary care children's hospital system. METHODS: This retrospective medical record review examined the visits from the 2 pediatric emergency departments and 2 pediatric urgent care sites in the system from June 1, 2012, to May 31, 2013, during which an outpatient opioid prescription was written. The primary outcome was number of days of opioid prescribed. Other data collected included patient demographics, diagnosis, and prescriber information; factors associated with prescriptions written for more than 5 days were identified. RESULTS: A total of 4075 opioid prescriptions were included in the 1-year study period, and 3991 of these had complete data for analysis. The median amount prescribed was 3.3 days with an interquartile range of 2.5 days. Odds of receiving a prescription of more than 5 days' duration were higher for children younger than 1 year (odds ratio [OR], 12.3; 95% confidence interval [CI], 7.3-21.0), 1 to 4 years of age (OR, 7.7; 95% CI, 5.5-10.8), and 5 to 9 years of age (OR, 2.4; 95% CI, 1.7-3.4); for children with noninjury diagnoses (OR, 1.4; 95% CI, 1.2-1.7); or if prescribed by a resident physician (OR, 1.4; 95% CI, 1.1-1.8) or from the urgent care (OR, 1.4; 95% CI, 1.1-1.7). CONCLUSIONS: Opioid prescriptions of more than 5 days were more frequently prescribed for younger patients, noninjury diagnoses, or if prescribed by a resident physician or from the urgent care. We need to focus on medical student, resident, and provider education as well as further opioid research in order to decrease unnecessary prescribing.

Pediatric Pharmaceutical Ingestions.

Pharmaceutical ingestions comprise an important part of pediatric toxicology. Based on the 2015 Annual Report of the American Association of Poison Control Centers' National Poison Data System, coupled with recent epidemiology articles on the topic of pediatric toxicology, it is apparent that poison prevention education has not been completely successful in decreasing exposures to toxic drugs. From the unintentional ingestion in a toddler due to unsafe storage to the intentional adolescent ingestion for misuse and abuse, pharmaceutical medications continue to cause harm. Access to adult prescription drugs in the home accounted for most of the exposures in children age ≤5 years as well as adolescents age 13 to 19 years. Ingestions resulting from more common pharmaceutical exposures are discussed with the hope of increasing awareness about the need for added vigilance. [Pediatr Ann. 2017;46(12):e459-e465.].

Pediatric Environmental Health: Using Data on Toxic Chemical Emissions in Practice.

Children's unique behavioral and physiological characteristics can increase their exposure and susceptibility to environmental chemicals. The link between exposure to environmental chemicals and specific health outcomes, however, is often uncertain. This article introduces several resources to help health practitioners identify potential environmental exposures and risks related to toxic chemicals. It focuses on the U.S. Environmental Protection Agency's (EPA's) free and public environmental data, including the Toxics Release Inventory (TRI) data that contain information about toxics released to the environment. Three hypothetical case studies are presented to demonstrate how these data can help answer environmental exposure questions. The first case study illustrates a scenario where multiple patients in an area exhibit the same symptoms with a suspected link to environmental chemicals. The second case study illustrates a scenario where a patient with a confirmed exposure to a toxic chemical needs assistance with identifying potential environmental sources. And the third case study illustrates a scenario where a patient is concerned about the potential for future exposure to an environmental contaminant in a particular geographic area. Each case study includes contacts for follow-up questions, including the Pediatric Environmental Health Specialty Units (PEHSUs), EPA regional staff, state environmental agencies, and local health departments. These resources can help practitioners access and interpret environmental data, answer questions about potential exposures, and inform next steps if necessary.

Do rapid comprehensive urine drug screens change clinical management in children?

CONTEXT: Multiple studies have concluded that urine drug screens rarely change clinical management. The rapid comprehensive urine drug screen (RCUDS) at our institution detects over 300 substances using a combination of EIA and GC/MS and typically takes 2-5 h for completion. OBJECTIVE: We sought to determine whether this RCUDS altered management in the pediatric population. METHODS: All patients >1 month and <18 years of age in which a RCUDS was completed from 1 January 2012 to 31 December 2012 were eligible for the study. Assuming that clinical management would not be altered in at least 90% of cases with a confidence interval of 95%, an alpha error of 5%, we calculated a sample size of 122 cases to ensure adequate study power. Four board-certified medical toxicologists reviewed 160 cases. Cases were assigned to the toxicologists based on a random-number generator. In addition, each toxicologist reviewed 12 random cases from the other three toxicologist's cases to determine inter-rater reliability. All four toxicologists reviewed any case in which a RCUDS was believed to have changed management. RESULTS: A total of 908 RCUDS were performed during the study period, and 160 were selected for study. Mean age was 10.5 years; male = 83, female = 77. Most were ordered from the ED (101/160 = 63%), followed by the inpatient unit (36/160 = 23%), outpatient (14/160 = 9%), and ICU (9/160 = 6%). 111/160 (69%) had a history of ingestion. Of the 160 randomly chosen cases, only three cases were found in which overall clinical management was altered based on the results of the RCUDS. All three cases were children <3 years old with a RCUDS positive for amfetamines. In all the three cases, police, Division of Family Services (DFS), and social work were involved. In no case did the acute clinical management change occurred due to the results of the RCUDS. CONCLUSIONS: The RCUDS rarely changed management in patients at our institution. Further study is warranted.

In vivo characterization of CYP2D6*12, *29 and *84 using dextromethorphan as a probe drug: a case report.

CYP2D6*84 was first described in a Black South African subject, however, its function remains unknown. Astrolabe, a probabilistic scoring tool developed in our laboratory to call genotypes from whole genome sequence, identified CYP2D6*84 in a trio. The father presented with intermediate metabolism when challenged with the CYP2D6 probe drug dextromethorphan (DM/dextrorphan [DX] = 0.0839). Since his second allele, CYP2D6*12, is nonfunctional, the observed activity is derived by CYP2D6*84. This finding suggests that the allele's hallmark P267H causes decreased activity toward DM and that this allele should receive a value of 0.5 for Activity Score calculations. The mother's DM/DX of 0.0543 was consistent with the decreased activity classification of CYP2D6*29. The child, a critically ill neonate, was not phenotyped, but predicted to be a normal metabolizer.

PCDH19-related epileptic encephalopathy in a male mosaic for a truncating variant.

Variants in the X-linked gene PCDH19 are associated with early infantile epileptic encephalopathy-9. This unusual condition spares hemizygous males except for psychiatric and behavioral abnormalities, and for this reason is also known as female limited epilepsy. Some cases are due to de novo PCDH19 variants, but may also be paternally inherited. Our patient is a 6-year-old male with epileptic encephalopathy. Exome sequencing revealed apparent heterozygosity in PCDH19 for a novel nonsense variant, c.605C>A (p.Ser202*), inconsistent with expectations for a male. Testing of other tissues revealed a mixture of mutant and normal alleles. These results are consistent with somatic mosaicism for p.Ser202*. This is the second male with somatic mosaicism for PCDH19 deficiency, providing further support for cellular interference as the pathogenic mechanism for this condition, which leads to this unusual mode of inheritance in which females are more severely affected than males. © 2016 Wiley Periodicals, Inc.

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.

Unusually Prolonged Presentation of Designer Drug Encephalopathy Responsive to Steroids.

The availability and use of novel psychoactive substances has risen dramatically over the last decade. The unpredictability of their toxicity constitutes a real challenge. We report a case of an adolescent who developed prolonged encephalopathy after ingesting "Hot Molly," which was found to contain the novel psychoactive substance, methylenedioxybenzylpiperazine when analyzed by high resolution mass spectrometry assay. This is the first case of human toxicity from methylenedioxybenzylpiperazine ingestion in the medical literature confirmed by body fluid analysis presenting with significant and prolonged encephalopathy. The prolonged course may be due to CYP2D6 inhibition from a combination of the methylenedioxyphenyl moiety and the patient's ultrarapid metabolizer pharmacokinetics. The response to high dose corticosteroids suggests a possible inflammatory effect that warrants further investigation.

Iodine deficiency, pollutant chemicals, and the thyroid: new information on an old problem.

Many women of reproductive age in the United States are marginally iodine deficient, perhaps because the salt in processed foods is not iodized. Iodine deficiency, per se, can interfere with normal brain development in their offspring; in addition, it increases vulnerability to the effects of certain environmental pollutants, such as nitrate, thiocyanate, and perchlorate. Although pregnant and lactating women should take a supplement containing adequate iodide, only about 15% do so. Such supplements, however, may not contain enough iodide and may not be labeled accurately. The American Thyroid Association recommends that pregnant and lactating women take a supplement with adequate iodide. The American Academy of Pediatrics recommends that pregnant and lactating women also avoid exposure to excess nitrate, which would usually occur from contaminated well water, and thiocyanate, which is in cigarette smoke. Perchlorate is currently a candidate for regulation as a water pollutant. The Environmental Protection Agency should proceed with appropriate regulation, and the Food and Drug Administration should address the mislabeling of the iodine content of prenatal/lactation supplements.

Pediatric Pharmacovigilance: Enhancing Adverse Drug Reaction Reporting in a Tertiary Care Children's Hospital.

BACKGROUND: Adverse drug reactions (ADRs) are notoriously underreported within health care facilities. In 2009-2010, ADRs were detected in only 0.5% of patients at the authors' institution, a pediatric hospital in the Midwestern United States. Additionally, historical ADRs were often inaccurately or incompletely documented in the medical record. An integrative Drug Safety Service (DSS) was implemented to improve the detection and accurate documentation of ADRs. METHODS: The DSS incorporated standardized ADR terminology, computerized triggers to identify ADRs, and a simplified voluntary reporting system within the facility. The DSS staff provided extensive hospital staff education on ADR reporting and the role of the DSS. The primary aim of this report was to assess the impact of the DSS on the number of ADRs reported at the authors' institution. The secondary aims were to evaluate the mechanisms by which patients with ADRs were identified and to assess the accuracy of ADR documentation after implementation of the DSS. RESULTS: A significant increase was observed (slope, 6.01; P < .001) in ADR detection after implementation of the DSS, with a greater than 4-fold increase from 10 cases per 10,000 admissions before initiation to 41 cases per 10,000 admissions after DSS implementation. Computerized triggers, International Classification of Diseases, 9th Edition (ICD-9) codes associated with ADRs, and the DSS identified 33%, 33%, and 24% of ADRs, respectively, while voluntary reporting only detected 9% of ADRs. CONCLUSIONS: Implementation of a multifaceted, interdisciplinary DSS was more effective in detecting ADRs than voluntary reporting alone. A proactive approach to ADR detection resulted in a significant increase in the identification and evaluation of ADRs.

Use of ultrasound to locate retained testes in dogs and cats.

Ultrasound was used to locate undescended testes in 30 dogs and 4 cats where the final testicular location was determined surgically. Time between ultrasound and surgery ranged between 0 and 17 days. Forty-three testes (63.2%) were retained and 42/43 (97.7%) were detected ultrasonographically. Retained testes were located in the abdomen (n = 28) and inguinal region (n = 14). One retained testis could not be identified with use of ultrasound. Locations of retained testes ranged from the caudal pole of the kidney to the inguinal region. Descriptions of testicular echogenicity and size were not available for all testes. A 100% positive predictive value was found for all testes with use of ultrasound in both abdominal and inguinal regions. The sensitivity of ultrasound was 96.6% for abdominal and 100% for inguinal testes. Ultrasound is a sensitive test for location of retained testes, and supports the opinion that preoperative ultrasound can help facilitate location of retained testes prior to surgical exploration or laparoscopy. © 2012 Veterinary Radiology & Ultrasound.

Chronic amitriptyline overdose in a child.

Amitriptyline, a tricyclic antidepressant, has a well-described toxicity profile, and acute ingestions are common in the pediatric toxicology world. However, little can be found in the literature regarding chronic overdose. We describe a case of a 6-year-old girl who was prescribed amitriptyline 30 mg nightly for sleep problems, but was mistakenly given 300 mg (15 mg/kg) nightly for over a month. She was noted to have mental status changes and difficulty reading several days after starting the medication. She presented to the local children's hospital in status epilepticus with significant cardiac conduction abnormalities on ECG. Her total amitriptyline/nortriptyline level was found to be 1676 ng/mL (normal therapeutic level 50-300 ng/mL). She was treated for several days with sodium bicarbonate. Within 24 h, her neurologic status improved and had returned to baseline within several days. Her ECG normalized, and she was discharged home, without apparent sequelae. A brief discussion of possible protective mechanisms (including pharmacogenomic) is presented.

Serum concentrations in three children with unintentional tetrahydrozoline overdose.

BACKGROUND: Major symptoms can occur from tetrahydrozoline (THZ) overdoses in young children, requiring intensive care management. We report three cases that presented with CNS depression and cardiovascular effects where serum concentrations were performed. CASE REPORT: Case 1 ingested an unknown amount of eye drops containing THZ, resulting in altered mental status, bradycardia, hypothermia, and hypotension. Cases 2 and 3 ingested 7.5 mL of eye drops containing THZ. Case 2 presented to the emergency department (ED) without symptoms but became lethargic and bradycardic 90 min after ingestion. By contrast, Case 3 became lethargic 15 min after ingestion and required intubation on arrival to the ED. All children were admitted to ICU for observation and improved within 24 h of ingestion. Urine obtained for drug screening was positive for THZ. Blood was obtained to assess level using gas-chromatography mass-spectrometry (GC-MS). CASE DISCUSSION: Case 1 had plasma levels of 51.4 and 23.6 ng/mL at 7 and 12 h, respectively, after ingestion, revealing a half-life of 4.4 h. Numerous case reports have been published documenting the dangers of ingesting these topical over-the-counter (OTC) products. However, human PK data are not available to help in our understanding of THZ toxicokinetics and disposition in humans after ingestion. CONCLUSION: We report three pediatric cases after ingestion of THZ where plasma concentrations were obtained with a calculated half-life of 4.4 h in one case.