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2004 199 Mahè I, Bertrand N, Drouet L, et al Interaction between paracetamol and warfarin in patients: A double-blind, placebo-controlled, randomized study Haematologica 2006;91(12):1621-1627 200 Lovenox (enoxaparin) [package insert] Bridgewater NJ: Aventis Pharmaceuticals; 2004 201 Gonsalves WI, Pruthi RK, Patnaik MM The new oral anticoagulants in clinical practice Mayo Clin Proc 2013;88(5):495-511 202 Kovacs RJ, Flaker GC, Saxonhouse SJ, et al Practical management of anticoagulation in patients with atrial fibrillation J Am Coll Cardiol 2015;65(13):1340-1360 203 del Mar Fernández De Gatta M, Santos-Buelga D, Domínguez-Gil A, et al Immunosuppressive therapy for paediatric transplant e5 patients: pharmacokinetic considerations Clin Pharmacokinet 2002; 41(2):115-135 204 Kronbach T, Fischer V, Meyer UA Cyclosporine metabolism in human liver: identification of a cytochrome P-450III gene family as the major cyclosporine-metabolizing enzyme explains interactions of cyclosporine with other drugs Clin Pharmacol Ther 1988;43(6):630-635 205 Sattler M, Guengerich FP, Yun CH, et al Cytochrome P-450 3A enzymes are responsible for biotransformation of FK506 and rapamycin in man and rat Drug Metab Dispos 1992;20(5):753-761 206 Berkovitch M, Bitzan M, Matsui D, et al Pediatric clinical use of the ketoconazole/cyclosporin interaction Pediatr Nephrol 1994; 8(4):492-493 207 US Center for Drug Evaluation and Research Update Silver Spring, MD: US Department of Health and Human Services; 2004 208 Marty FM, Lowry CM, Cutler CS, et al Voriconazole and sirolimus coadministration after allogeneic hematopoietic stem cell transplantation Biol Blood Marrow Transplant 2006;12(5):552-559 209 Cho E, Chan H, Nguyen HM Management of drug interaction between posaconazole and sirolimus in patients who undergo hematopoietic stem cell transplant Pharmacotherapy 2015;35(6):578-585 210 Kubiak DW, Koo S, Hammond SP, et al Safety of posaconazole and sirolimus coadministration in allogeneic hematopoietic stem cell transplants Biol Blood Marrow Transplant 2012;18(9):1462-1465 211 Kaplan B, Meier-Kriesche HU, Napoli KL, et al The effects of relative timing of sirolimus and cyclosporine microemulsion formulation coadministration on the pharmacokinetics of each agent Clin Pharmacol Ther 1998;63(1):48-53 212 Kovarik JM, Kalbag J, Figueiredo J, et al Differential influence of two cyclosporine formulations on everolimus pharmacokinetics: a clinically relevant pharmacokinetic interaction J Clin Pharmacol 2002;42(1):95-99 213 Baciewicz AM, Chrisman CR, Finch CK, Self TH Update on rifampin, rifabutin, and rifapentine drug interactions Curr Med Res Opin 2013;29(1):1-12 214 Furlan V, Perello L, Jacquemin E, et al Interactions between FK506 and rifampicin or erythromycin in pediatric liver recipients Transplantation 1995;59(8):1217-1218 215 van Gelder T, Klupp J, Barten MJ, et al Comparison of the effects of tacrolimus and cyclosporine on the pharmacokinetics of mycophenolic acid Ther Drug Monit 2001;23(2):119-128 216 Lee PC, Chang SS, Shieh SC, et al Cyclosporine or tacrolimus: which is the better partner for Myfortic or Cellcept? Transplant Proc 2012;44(1):137-139 217 Gearry RB, Barclay ML Azathioprine and 6-mercaptopurine pharmacogenetics and metabolite monitoring in inflammatory bowel disease J Gastroenterol Hepatol 2005;20(8):1149-57 218 Prometheus Laboratories Prescribing information: Imuran (azathioprine) San Diego, CA; 2014 219 Upton A, McCune JS, Kirby KA, et al Fluconazole coadministration concurrent with cyclophosphamide conditioning may reduce regimen-related toxicity postmyeloablative hematopoietic cell transplantation Biol Blood Marrow Transplant 2007;13(7): 760-764 220 Marr KA, Leisenring W, Crippa F, et al Cyclophosphamide metabolism is affected by azole antifungals Blood 2004;103(4): 1557-1559 221 Balk TE, van der Sijs IH, van Gelder T, et al Drug-drug interactions in pediatric oncology patients Pediatr Blood Cancer 2017;64(7) 222 Haidar C, Jeha S Drug interactions in childhood cancer Lancet Oncol 2011;12(1):92-99 223 Smitherman AB, Faircloth CB, Deal A, et al Vincristine toxicity with co-administration of fluconazole during induction therapy for pediatric acute lymphoblastic leukemia Pediatr Blood Cancer 2017;64(10):e26525 224 Crews KR, Stewart CF, Jones-Wallace D, et al Altered irinotecan pharmacokinetics in pediatric high-grade glioma patients receiving enzyme-inducing anticonvulsant therapy Clin Cancer Res 2002;8(7):2202-2209 225 Weintraub M, Adde MA, Venzon DJ, et al Severe atypical neuropathy associated with administration of hematopoietic colonystimulating factors and vincristine J Clin Oncol 1996;14(3):935940 226 Dean R, Nachman J, Lorenzana AN Possible methotrexate-mezlocillin interaction Am J Pediatr Hematol Oncol 1992;14(1):88-89 227 Dawson JK, Abernethy VE, Lynch MP Methotrexate and penicillin interaction Br J Rheumatol 1998;37(7):807 228 Ronchera CL, Hernández T, Peris JE, et al Pharmacokinetic interaction between high-dose methotrexate and amoxycillin Ther Drug Monit 1993;15(5):375-9 229 Cassano WF Serious methotrexate toxicity caused by interaction with ibuprofen Am J Pediatr Hematol Oncol 1989;11(4):481-482 230 Daly H, Boyle J, Roberts C, Scott G Interaction between methotrexate and non-steroidal anti-inflammatory drugs Lancet 1986;1(8480):557 231 Dupuis LL, Koren G, Shore A, Silverman ED, Laxer RM Methotrexate-nonsteroidal antiinflammatory drug interaction in children with arthritis J Rheumatol 1990;17(11):1469-73 232 Suzuki K, Doki K, Homma M, et al Co-administration of proton pump inhibitors delays elimination of plasma methotrexate in high-dose methotrexate therapy Br J Clin Pharmacol 2009;67(1):44-49 233 Richmond R, McRorie ER, Ogden DA, Lambert CM Methotrexate and triamterene: a potentially fatal combination? Ann Rheum Dis 1997;56(3):209-10 234 Segal EM, Flood MR, Mancini RS, et al Oral chemotherapy food and drug interactions: a comprehensive review of the literature J Oncol Pract 2014;10(4):e255-e268 e6 Abstract: Adverse drug events (ADEs) are defined as any injury resulting from the use of a drug ADEs are common in the pediatric intensive care unit (PICU), leading to significant morbidity, mortality, and economic impact Polypharmacy and potential drug-drug interactions (DDIs), severity of illness, use of high-risk medications, and the need for nonstandard dosage forms increase the risk of ADEs This chapter reviews drug-induced ADEs affecting all major organ systems and includes expert analysis of the biochemical properties associated with DDIs commonly found in the PICU It also provides detailed explanation of the recognition and management of DDIs by drug class Key words: adverse drug reaction, adverse drug event, drug-drug interaction, pediatric, intensive care 125 Principles of Toxin Assessment and Screening APRIL CLAWSON AND LAWRENCE QUANG Despite increased public education and preventive measures such as child-safety caps, poisonings in children and adolescents continue to be common occurrences Children younger than years accounted for 45% of the approximately 2.1 million poison exposure calls taken by poison centers in 2017.1 The most common categories of products identified during such calls include analgesics, household cleaning substances, cosmetics/personal care products, sedatives/hypnotics/antipsychotics, antidepressants, antihistamines, cardiovascular drugs, foreign bodies, topical agents, cough and cold preparations, vitamins, pesticides, and plants Among these categories, pharmaceuticals accounted for most of the severe poisoning outcomes While human exposures with less serious outcomes have decreased 2.48% per year since 2008, those with more serious outcomes (moderate, major, or death) have increased 4.44% per year since 2000.1 Preschool children and children with developmental delays and pica—as occurs with autistic spectrum disorders—have an increased risk for poisoning A second peak of serious poisonings occurs in adolescents, when suicide attempts by poisoning or toxicity related to substance abuse become common circumstances Studies have shown that this latter group tends to be sicker and more frequently requires a higher level of care.2 Although many exposures are medically trivial, poisonings account for an important number of all pediatric hospital visits and hospitalizations and represent an estimated 3% to 8% of total pediatric intensive care unit (PICU) admissions on an annual basis.2,3 Acute pediatric ingestions—particularly those that may progress to respiratory failure, complex arrhythmias, 1486 • Poisoned patients are frequently encountered in the intensive care setting and often pose a diagnostic challenge Skills in taking a history and performing a thorough physical exam, as well as knowledge of the common toxidromes and the appropriate use of laboratory and/or radiologic studies, are required Care of poisoned patients is mainly symptomatic and supportive, but some toxins can be treated with a reversal agent or require extracorporeal removal • • • PEARLS Some toxins are notable for the delay from time of ingestion to onset of symptoms (e.g., acetaminophen, Amanita mushroom poisoning, valproic acid, sulfonylureas) Others with a long duration of action, such as methadone or naltrexone, can have toxicity recrudescence hours after an apparent good response to an antidote Intensivists can often predict the severity of poisoning by noting the tempo of progression of a patient’s symptoms and signs of toxicity cardiovascular collapse, and/or status epilepticus—may require PICU admission for close monitoring, early supportive care, and advanced interventions until the drug is eliminated There are no current standardized criteria for admission to a PICU for poisoned patients The exhaustive list of substances that may cause toxic manifestations in pediatric patients encumbers the development of generalizable guidelines Studies have attempted to determine the percentage of patients admitted to a PICU who received interventions necessitating PICU admission Only 30% of poisoned patients in one study received one of numerous defined PICU interventions Factors in this study that were associated with a PICU intervention included (1) higher Pediatric Risk of Mortality III scores, (2) age younger than years or older than 13 years, and (3) intentionality However, the authors of the study also point out that not all reasons for admission to the PICU could be captured.4–6 The study’s investigators subsequently developed and prospectively validated a pediatric scoring model to identify children at low risk of clinically significant ingestions: Reduce Childhood Admissions to the PICU for Poisoning (RECAP2) The RECAP2 model defined clinically significant ingestions requiring PICU admission as those with one or more of the following features: (1) ingestion of clonidine, ethanol, or oral antihyperglycemic agents; (2) exposure to carbon monoxide; (3) onset of symptoms occurring within hours of an immediaterelease formulation; and/or (4) onset of symptoms occurring within hours for an extended-release formulation Real-time application of the RECAP2 model reduced PICU admissions by 32%.5,6 CHAPTER 125 Principles of Toxin Assessment and Screening • BOX 125.1 Predictors for Increased Odds of Adverse Cardiovascular Events in Pediatric Poisonings QTc 500 ms Serum bicarbonate ,20 mEq/L Opioid drug exposure Cardiovascular drug exposure Adolescent age (13 years) • BOX 125.2 Toxins Removable Via Hemodialysis Acetaminophen Barbiturates Carbamazepine Ethylene glycol Lithium Metformin Methanol Salicylates Isopropanol Theophylline Valproic acid Thallium Digoxin Another pediatric study identified risk factors for a poisoned patient to have an adverse cardiovascular event (ACVE), myocardial injury, shock, ventricular dysrhythmia, or cardiac arrest, or death This study found that two previously derived predictors of ACVEs in adults also applies to pediatric exposures: QTc of 500 ms or greater or serum bicarbonate concentration less than 20 mEq/L They also found that adolescent age and exposure to either a cardiovascular drug or to an opioid were independently associated risk factors (Box 125.1).7 These are additional factors that may indicate a need for an ICU admission The mainstay of therapy for most poisoned patients is supportive care, which can range from administration of intravenous fluids and close cardiorespiratory monitoring to extracorporeal removal and support.8 If the patient is critically ill and a specific toxic syndrome with a known antidote is not identified, the intensivist may consider a mode of enhanced elimination, the most common being hemodialysis A list of toxins for which hemodialysis may be indicated is included in Box 125.2.9,10 Recently, there has been more examination of the use of extracorporeal treatments in the management of poisoned patients The Extracorporeal Treatments in Poisoning (EXTRIP) work group consists of experts from the fields of nephrology, clinical toxicology, critical care, and pharmacology This group has convened to provide uniform recommendations on when such treatments should be used for acetaminophen, barbiturates, carbamazepine, digoxin, lithium, metformin, methanol, phenytoin, salicylates, thallium, theophylline, tricyclic antidepressants, and valproic acid Both specific toxins and plasma concentrations for these toxins are included in these recommendations While not all toxins have been explored by this work group to date, future toxins to be explored include baclofen, ethylene glycol, methotrexate, isoniazid, calcium channel blockers, b-blockers, dabigatran, gabapentin/pregabalin, quinine/chloroquine, and amatoxins.8,10 In severe poisonings refractory to extracorporeal removal, extracorporeal membrane oxygenation (ECMO) is a supportive treatment modality that has been used when cardiac arrest or refractory hypotension develops after poisoning The use of ECMO for toxicologic exposures was described in a 2010 to 2013 retrospective analysis of the Toxicology Investigators Consortium (ToxIC) 1487 database of the American College of Medical Toxicology ECMO was used with an 80% survival rate by supporting cardiovascular hemodynamics and oxygenation while the xenobiotic was metabolized and/or eliminated for the following toxicologic exposures: carbon monoxide/smoke inhalation, metformin, flecainide, methanol, diphenhydramine quetiapine, bitter almonds (cyanide), verapamil citalopram, metformin trazodone clonazepam, and diphenhydramine tramadol This study showed that although used rarely (