MEDiCATiON SAFETY AND TOxiCOLOGY

Medication Safety and Toxicology Sean O’Neill, Pharm.D. The Children’s Hospital of Philadelphia

Jeanette Trella, Pharm.D. The Poison Control Center at the Children’s Hospital of Philadelphia

Medication Safety and Toxicology

Medication Safety and Toxicology Sean O’Neill, Pharm.D. The Children’s Hospital of Philadelphia

Jeanette Trella, Pharm.D. The Poison Control Center at the Children’s Hospital of Philadelphia

ACCP Updates in Therapeutics® 2015: Pediatric Pharmacy Preparatory Review Course 2-363


Learning Objectives 1. Identify the key vulnerabilities in the pediatric medication use process. 2. Review pediatric-specific considerations in the definition, detection, and mitigation of harm of medication safety events. 3. Describe the U.S. Poison Control Systems structure and the common pediatric poisonings reported. 4. Review the modalities of gastric decontamination and their role in the present-day management of poison ingestion. 5. Recognize the common toxidrome classifications. 6. Understand the pathophysiology and management of select poisonings.

Self-Assessment Questions Answers and explanations to these questions can be found at the end of this chapter. 1. Which of the following organizations released the To Err Is Human report, identifying the magnitude of harm occurring in health care in the United States? A. Institute for Safe Medication Practices. B. The Joint Commission. C. The National Coordinating Council for Medication Error Reporting and Prevention. D. Institute of Medicine. 2. You are a pharmacist member of your organization’s medication safety committee. The committee’s goal in eliminating harm from medications starts with identification of harm events. Which of the following organizations provides a standard for the scoring and classification of medication safety events? A. Institute for Safe Medication Practices. B. The Joint Commission. C. The National Coordinating Council for Medication Error Reporting and Prevention. D. Institute of Medicine. 3. Which of the following error reduction strategies lacks primary literature supporting a decrease in medication safety events in pediatrics? A. Barcode medication administration. B. Smart pump infusion technology. C. Two-clinician independent double-check. D. Computerized physician order entry.

4. You are the pharmacist on a team completing a root cause analysis of a serious medication safety event. When you are reviewing the action items to address the system vulnerabilities, which of the following error reduction strategies offers the highest potential to reduce medication errors in pediatric patients? A. Staff education. B. Policy and procedure development and distribution. C. Checklists. D. Forcing functions. 5. E.K. is a 2-year-old boy who was found with an empty bottle of 100 count chewable multivitamins. Each tablet contained 18 mg iron. He is asymptomatic at time of presentation to the emergency department (ED). Which of the following methods of gastrointestinal decontamination would be most appropriate for E.K.? A. Activated charcoal. B. Multidose activated charcoal. C. Whole bowel irrigation. D. Gastric lavage. 6. J.L. is a 15-year-old girl who presents to the ED with dilated pupils, a heart rate (HR) of 140 beats/ minute, dry mucus membranes, and decreased urine output. She is probably presenting with which type of ingestion? A. Opioid analgesic. B. Anticholinergic. C. Sympathomimetic. D. Cholinergic. 7. Which is the most common reason for exposures of pediatric patients less than 6 years of age reported to U.S. poison control centers? A. Intentional malicious (e.g., Munchausen by proxy). B. Unintentional therapeutic errors (e.g., wrong dose administered). C. Intentional suicide. D. Unintentional general (e.g., exploratory ingestions). 8. Pediatric ingestion of one pill of which of the following would warrant observation in a hospital? A. Glyburide. B. Acetaminophen. C. Furosemide. D. Metformin.



9. K.Y. was found at home minimally responsive. A bottle of metoprolol 100-mg tablets was found empty next to him. He presented to the ED with the following vital signs: HR 35, blood pressure 60/32 mm Hg, and respiratory rate 20 breaths/minute. Within the first 10 minutes he became unresponsive, with no cough or gag reflex. Which of the following is the most appropriate first step in K.Y.’s care? A. Calcium chloride or calcium gluconate. B. Glucagon. C. Intubation. D. Insulin.

Abbreviations AAPCC American Association of Poison Control Centers CPSC Consumer Product Safety Commission NAC N-Acetylcysteine NPDS National Poison Data System SDAC Single Dose Activated Charcoal MDAC Multi-Dose Activated Charcoal WBI Whole Bowel Irrigation APAP Acetaminophen NAPQI N-Acetyl-p-benzo-Quinone Imine

10. C.J. is a 2-year-old boy with a persistent nausea and vomiting and a serum iron level of 700 mg/dL. Which of the following orders for deferoxamine would be most appropriate for C.J.? A. Deferoxamine 15 mg/kg intravenous bolus x 1 dose. B. Deferoxamine 15 mg/kg/hour continuous subcutaneous. C. Deferoxamine is not appropriate for C.J. because his level is not toxic. D. Deferoxamine 15 mg/kg/hour continuous intravenous. 11. Which of the following is considered a toxic blood level of acetaminophen after an acute ingestion? A. 200 mcg/mL at 2 hours after ingestion. B. 230 mcg/mL at 4 hours after ingestion. C. 10 mcg/mL at 12 hours after ingestion. D. 90 mcg/mL at 4 hours after ingestion. 12. R.O. is a 5-year-old boy who presents to the local ED with a wound on his right arm after been bitten by a bat while playing in his backyard. The bat could not be captured. Which of the following is the appropriate management strategy? A. No intervention and monitor for development of rabies symptoms. B. Administer rabies immune globulin 20 units/ kg directly to wound site and human rabies vaccine on days 0, 3, 7, and 14 after exposure. C. Administer rabies immune globulin 20 units/ kg IM × 1 and human rabies vaccine on days 0, 3, 7, and 14 after exposure. D. Administer rabies vaccine at days 0, 3, 7, and 14 after exposure.



I. MEDICATION SAFETY A. Introduction 1. Institute of Medicine (IOM) reports on patient safety events in the health care system. a. To Err Is Human (1999) i. 44,000–98,000 people die in hospitals each year as a result of medical errors. ii. $17–29 billion per year in additional costs related to medical errors iii. Errors are caused by faulty systems, processes, and conditions. b. Crossing the Quality Chasm (2001): Identified the six aims of improvement in care that safe, effective, patient-centered, timely, efficient, and equitable. c. Preventing Medication Errors (2006) i. Medication errors are most common during the prescribing and administration phases of the medication process. ii. 1.5 million preventable adverse drug events (ADEs) occur in the United States per year. iii. The following are recommended error reduction strategies: encouraging patients to become more active in their care, leveraging technology, and improving the labeling and packaging of medications. 2. Landmark pediatric medication safety events a. 2001: Josie King, an 18-month-old girl, dies of severe dehydration and narcotic overdose. b. 2006: Emily Jerry, a 3.5-year-old girl, dies when her chemotherapy is diluted in 23.4% sodium chloride instead of 0.9%. c. 2006: Three premature neonates die after receiving heparin 10,000 units/mL rather than the intended 10 units/mL. d. 2011: An 8-month-old dies in an intensive care unit after receiving 1400 mg of calcium chloride instead of the intended 140 mg. B. Definitions 1. Medication error: The National Coordinating Council for Medication Error Reporting and Prevention (NCC MERP) defines a medication error as any preventable event that may cause or lead to inappropriate medication use or patient harm while the medication is in the control of the health care professional, patient, or consumer. Such events may be related to professional practice, health care products, procedures, and systems, including prescribing, order communication, product labeling, packaging, nomenclature, compounding, dispensing, distribution, administration, education, monitoring, and use. 2. NCC MERP categorization of medication error



Figure 1. NCC MERP index for categorizing medication errors.

3. Adverse drug events (ADEs): Harm caused by the use of a drug. 4. Adverse drug reactions (ADRs): a. The American Society of Health-System Pharmacists (ASHP) defines an ADR as any unexpected, unintended, undesired, or excessive response to a drug that requires discontinuing the drug (therapeutic or diagnostic), requires changing the drug therapy, requires modifying the dose (except for minor dosage adjustments), necessitates admission to a hospital, prolongs stay in a health care facility, necessitates supportive treatment, significantly complicates diagnosis, negatively affects prognosis, or results in temporary or permanent harm, disability, or death. b. The World Health Organization defines an ADR as any response to a drug that is noxious and unintended, which occurs at doses normally used in humans for prophylaxis, diagnosis, or therapy of disease or modification of physiological function.



Patient Cases N.T. is a 10-year-old boy (32 kg) admitted to the surgical inpatient unit after sustaining a femur fracture during a motor vehicle accident. The patient received a 4-mg morphine bolus in the postanesthesia care unit. The patient was transferred to the floor, where he received a 2-mg morphine bolus 15 minutes after the last dose. Shortly after the dose was administered, the patient became apneic and required naloxone and bag/mask ventilation. The patient returned to his baseline 10 minutes later. 1. Which of the following best defines this event? A. Near miss event. B. ADE. C. ADR. D. Both an ADR and ADE. 2. Which NCC MERP classification best categorizes this event? A. Category A. B. Category B. C. Category E. D. Category I.

C. Pediatric Medication Error Incidence and Risk Factors 1. The incidence of medication errors in pediatrics has been reported as 5.7 per 100 medication orders. 2. 79% of potential ADEs occur during the prescribing phase. 3. The most common drug classes include intravenous antibiotics, electrolytes and fluids, and analgesics and sedatives. 4. A 2008 Joint Commission Sentinel Event Alert a. 2.5% of pediatric medication errors led to patient harm. b. The most common types of errors were improper dose or quantity (37.5%), omission errors (19.9%), unauthorized or wrong drug (13.7%), and prescribing error (9.4%). 5. Medication errors in the pediatric population are three times more likely to cause harm than medication errors in adults. 6. Patients less than 2 years old are at greater risk of a prescribing error. 7. Patients less than 1 year old are at greater risk of an administration error. D. Pediatric Vulnerability to Medication Error 1. Developmental pharmacokinetics a. Greater volume of distribution compared with adults b. Lower concentration and affinity of drug binding proteins c. Variable enzymatic capacity during drug metabolism d. Delayed renal elimination in neonates 2. Weight-based dosing: Weight- or body surface area–based dosing increases the need for calculation and potential for error. 3. Off-label use of medications a. Almost 80% of pediatric patients will receive at least one drug for an off-label indication. b. The following patient factors increase the likelihood of off-label medication use: i. Undergoing a surgical procedure ii. Age older than 28 days iii. Greater severity of illness ACCP Updates in Therapeutics® 2015: Pediatric Pharmacy Preparatory Review Course 2-368


iv. All-cause inpatient mortality 4. Communication barriers: Nonverbal patients are unable to communicate about the occurrence and description of potential adverse events, limiting the ability to detect harm. 5. Lack of standardized drug formulations a. Extemporaneously prepared oral suspensions i. Alteration of commercially available products can affect bioavailability, stability, and sterility. ii. All compounding recipes should be based on peer-reviewed sources. b. Intravenous medications manipulation: The need for dilution can increase the risk or potential for error. c. Appropriate references for intravenous dilutions and extemporaneously compounded preparation i. Jew RK, Soo-Hoo W, Erush SC, eds. Extemporaneous Formulations for Pediatric, Geriatric, and Specials Needs Patients. Bethesda, MD: American Society of Health-System Pharmacists, 2010. ii. Nahata MC, Pai VB, Nipple TE, eds. Pediatric Drug Formulations. Cincinnati, OH: Harvey Whitney Books Company, 2004. iii. Institute for Safe Medication Practices. Standard Concentrations of Neonatal Drug Infusions. Available at http://www.ismp.org/Tools/PediatricConcentrations.pdf. Accessed August 26, 2014. Patient Case 3. A pharmacist receives a prescription for captopril 6.25 mg by mouth every 8 hours for a 2-year-old girl (weight 15 kg) for management of her hypertension. The patient is unable to take tablets or pills, and the family is asking about a liquid formulation. Which of the following is the most appropriate next step? A. Review the primary literature to determine whether a recipe with stability data exists. B. Consult with the prescriber to determine whether there is a therapeutic alternative in pediatric formulation. C. Instruct the family to dissolve a 12.5-mg tablet in 2.5 mL of Ora-Sweet and 2.5 of Ora-plus and administer 2.5 mL every 8 hours. D. Instruct the family to dissolve a 12.5-mg tablet in 5 mL of water and administer 2.5 mL every 8 hours.

E. Error Detection Strategies 1. Voluntary reporting a. Provides greater yield than mandatory reporting systems because of the perceived lack of retribution b. The depth of information contained in error reports leads to more productive outcomes. c. Voluntary reporting systems can be limited by the following: i. Perceived punitive response from colleagues and leaders ii. Poorly designed or arduous reporting systems iii. Lack of awareness that an error occurred iv. Lack of time during regular staffing hours to report the errors 2. ADE trigger tool method a. A retrospective review of a random sample of inpatient hospital records using triggers to identify possible adverse events (Institute for Healthcare Improvement [IHI] white paper). Example: reviewing all naloxone administrations to identify potentially preventable events of oversedation from opioids b. The trigger tool method captures more than 10 times as many detected patient safety events as voluntary reporting. c. Development of consensus pediatric-specific triggers is still warranted. ACCP Updates in Therapeutics® 2015: Pediatric Pharmacy Preparatory Review Course 2-369


3. Continuous quality improvement data from technology (e.g., barcoding, smart pumps) a. Allows capture of compliance with medication use processes b. Identification of errors intercepted by technology (e.g., good catches, near misses) F. Error Reduction Strategies 1. Rank order of error reduction strategies (Institute for Safe Medication Practices [ISMP]) Box 1. Rank Order of Error Reduction Strategies

Forcing functions and Constraints ↓ Automation and Computerization ↓ Standardization and Protocols ↓ Checklists and Redundancies (double check systems) ↓ Rules and Policies ↓ Education and Information Adapted with permission from the Institute for Safe Medication Practices (ISMP).

2. ISMP’s key elements of the medication use system Table 1. ISMP’s Key Elements of the Medication Use System Component

Descriptions

Patient information

Essential information is obtained, readily available in useful form, and considered when prescribing, dispensing, and administering medications

Drug information

Essential drug information is readily available in useful form and considered when ordering, dispensing, and administering medications A controlled formulary system is established to limit choice to essential drugs, minimize the number of drugs with which practitioners must be familiar, and provide adequate time for designing safe processes for the use of new drugs added to the formulary

Communication of drug orders and other drug information

Methods of communicating drug orders and other drug information are standardized and automated to minimize the risk for error

Drug labeling, packaging, and nomenclature

Strategies are undertaken to minimize the possibility of errors with drug products that have similar or confusing manufacturer labeling or packaging or have drug names that look or sound alike Readable labels that clearly identify drugs are on all drug containers, and drugs remain labeled up to the point of administration



Table 1. ISMP’s Key Elements of the Medication Use System (continued) Component

Descriptions

Drug standardization, storage, and distribution

Intravenous solutions, drug concentrations, doses, and administration times are standardized whenever possible Medications are provided to patient care units in a safe and secure manner and available for administration within a time frame that meets essential patient needs Unit-based floor stock is restricted Hazardous chemicals are safely sequestered from patients and not accessible in drug preparation areas

Medication device acquisition, use, and monitoring

The potential for human error is mitigated through careful procurement, maintenance, use, and standardization of devices used to prepare and deliver medications

Environmental factors, workflow, and staffing patterns

Medications are prescribed, transcribed, prepared, dispensed, and administered in a physical environment that offers adequate space and lighting and allows practitioners to remain focused on medication use without distractions The complement of qualified, well-rested practitioners matches the clinical workload without compromising patient safety

Staff competency and education

Practitioners receive sufficient orientation to medication use and undergo baseline and annual competency evaluation of knowledge and skills related to safe medication practices Practitioners involved in medication use are provided with ongoing education about medication error prevention and the safe use of drugs that have the greatest potential to cause harm if misused

Patient education

Patients are included as active partners in their care through education about their medications and ways to avert errors

Quality processes and risk management

A nonpunitive, system-based approach to error reduction is in place and supported by management, senior administration, and the board of trustees or directors Practitioners are motivated to detect and report errors, and interdisciplinary teams regularly analyze errors that have occurred within the organization and in other organizations for the purpose of redesigning systems to best support safe practitioner performance Simple redundancies that support a system of independent double checks or an automated verification process are used for vulnerable parts of the medication system to detect and correct serious errors before they reach patients Proven infection control practices are followed when storing, preparing, and administering medications

Adapted with permission from the Institute for Safe Medication Practices (ISMP).

3. External resource evaluation a. ISMP b. NCC MERP c. IHI d. Agency for Healthcare Research and Quality (AHRQ) e. U.S. Food and Drug Administration MedWatch f. The Joint Commission ACCP Updates in Therapeutics® 2015: Pediatric Pharmacy Preparatory Review Course 2-371


4. High-alert medication identification and error reduction strategies a. Definition: Drugs that bear a high risk of causing significant patient harm when administered in error (available at http://ismp.org/tools/highalertmedicationlists.asp. Accessed August 26, 2014) b. Two-clinician independent double check i. Widely used as an error reduction strategy for high-alert medications, although no data exist demonstrating efficacy in reducing errors. ii. Challenges (a) Requires judicious use to not overwhelm clinicians and devalue the utility (b) Requires clinicians to perform check independently (c) Often used as sole error mitigation strategy when it still relies on human checks (available at http://www.ismp.org/Newsletters/acutecare/issue.aspx?id=51. Accessed August 26, 2014) 5. Technology a. Computerized physician order entry i. Multiple studies in pediatrics have demonstrated a decrease in both prescribing errors and ADEs. ii. Pediatric considerations (a) Customization is required because most vendors do not support pediatric content. (b) A patient’s metric weight (in kilograms) should be required for all orders. (c) Dose range checking should address weight-based dosing as well as adult maximum dosing. b. Barcode medication administration i. Multiple studies in adults have demonstrated 27.3% to 87% reductions in mediation errors. ii. One study in a neonatal intensive care unit demonstrated a 47% reduction in preventable ADEs. iii. Pediatric considerations (a) Challenges exist in barcoding all products, given the degree of dosage form manipulation necessary in pediatrics. (b) Reluctance to wake sleeping or swaddled children can produce workarounds with patient identification. c. Smart pump infusion technology i. One study in pediatrics demonstrated that smart pump technology in conjunction with standard concentrations and medication labels can decrease reported medication errors by 73%. ii. Pediatric considerations (a) Development of a pediatric-specific library should account for dose limit alerting across all pediatric age and weight ranges. (b) Use of standard concentrations can facilitate library use and provide an additional safety feature.

II. TOXICOLOGY A. Poison Control Center Overview 1. There are currently 56 accredited U.S. poison centers, which strive to: a. Provide first aid home management for poisonings b. Save health care dollars by reducing unnecessary emergency department visits c. Prevent poisoning exposures by increasing awareness in the community 2. All certified poison centers submit data to the National Poison Data System (NPDS) ACCP Updates in Therapeutics® 2015: Pediatric Pharmacy Preparatory Review Course 2-372


a. There were 2.3 million human exposures reported to NPDS in 2012. 49% were in children less than 6 years old, 13% in teens, and 38% in adults more than 19 years of age. Table 2. Top 10 Substances in Pediatric and Adult Exposures in 2012 Age Less Than 6 Years

Age More Than 19 Years

Cosmetic & personal care items Analgesics Cleaning substances Foreign bodies Topical preparations Vitamins Antihistamines Pesticides Plants Antimicrobials

Analgesics Sedative hypnotics Antidepressants Cardiovascular drugs Cleaning substances Alcohols Pesticides Bites and envenomations Anticonvulsants Cosmetic and personal care items

b. There were 2937 poison-related fatalities in 2012. i. Only 2% of the fatalities were in children less than 6 years old, so although children represent the largest number of exposures, the nature of their exposures (typically exploratory ingestions of small quantities) make them less likely to lead to serious harm or death. ii. Box 2 shows that the agents most often associated with poison-related fatalities are more closely related to the adult exposure substance list. The reason for these exposures is more likely to be “Intentional exposures” (abuse, misuse, and attempts of suicide) Box 2. Substances Associated with Fatalities in 2012 (All Ages) Sedatives and antipsychotics Cardiovascular drugs Opioids Acetaminophen (combos) Stimulants and street drugs Acetaminophen (only) Alcohols Miscellaneous antidepressants Selective serotonin reuptake inhibitors Antihistamines B. Legislative Changes 1. Poison Prevention Packaging Act (PPPA), 1970 a. Requires child-resistant packaging for many over-the-counter and prescription medications and hazardous household products b. It has been effective at reducing poisoning-related fatalities in children. In the early 1970s there were more than 200 poison-related pediatric deaths per year; in 2012 there were 46 deaths. 2. The Consumer Product Safety Commission administers and enforces federal safety codes, including the PPPA. Safety reports and NPDS data are often used for legislative changes and advocacy efforts for packaging modifications; for example: a. Topical imidazoline derivatives: Any product containing 0.08 mg or more of an imidazoline ACCP Updates in Therapeutics® 2015: Pediatric Pharmacy Preparatory Review Course 2-373


(tetrahydrozoline, naphazoline, oxymetazoline, or xylometazoline) in a single package must be packaged in child-resistant packaging (2012). b. Hydrocarbons (e.g., Tiki Torch fuel): Petition for opaque container submitted; though not officially passed in legislation, many large torch fuel companies have voluntarily changed their products to a dark green or black solution so it does not resemble apple juice (2013). C. Pediatric Poisonings 1. Infants (age less than 1 year) represent only 5% of all exposures. a. Inherently low risk because they are not yet ambulatory b. Consider potential child abuse if exploratory ingestion scenario is described in nonmobile infant, especially in those with underdeveloped pincer grasp movement. c. Unintentional therapeutic errors can also occur in this population because of inadvertent double administrations from multiple caregivers, confusion of medication (e.g., oxymetazoline instead of saline spray), and inappropriate measuring of doses (e.g., 5 teaspoons instead of 5 mL). 2. Toddlers and young children (ages 1–6 years) account for nearly half of all poisoning exposures. a. These children are very curious and constantly exploring their environment. b. They exhibit hand-to-mouth and imitative behaviors, increasing their risk of exposure. 3. Exposure cases are similar in number between children (6–12 years) and teens (13–19 years), both of which account for roughly 6% of all cases. Reason for exposure in teens is more likely to be intentional (e.g., abuse, misuse, suicide attempts). 4. As mentioned before, most pediatric exploratory ingestions do not result in harm; however, there are medications and substances that may cause significant toxicity, even in small amounts. Table 3. Common Medications Harmful to Children in One or Two Dosage Formsa Medication Class

Select Examples Antiarrhythmic Agents

Class IA

Quinidine, procainamide

Class IC

Flecainide, propafenone

Class III

Amiodarone

Other

Digoxin Antihypertensive Agents

α-2 Agonists

Clonidine

β-Blockers

Atenolol, metoprolol, propranolol

Calcium channel blockers

Amlodipine, diltiazem, nifedipine, verapamil Antidepressant Agents

Tricyclic antidepressants

Amitriptyline, desipramine, imipramine Oral Antidiabetic Agents

Sulfonylureas

Amitriptyline, desipramine, imipramine



Table 3. Common Medications Harmful to Children in One or Two Dosage Formsa (continued) Medication Class

Select Examples Gastrointestinal Agents

Antidiarrheals

Lomotil Analgesics and Opioids

Opioids

Buprenorphine, fentanyl, hydrocodone, oxycodone, methadone

Salicylates

Aspirin, methyl salicylates, oil of wintergreen

Please note, this list highlights some of the most commonly prescribed medications and does not include all medications and substances that can be harmful to children in small amounts. a

D. General Toxicology 1. Toxidromes is a term combining toxic and syndromes. a. A classification system to determine substances probably involved in the poisoning of a patient based on his or her clinical findings b. Can be used as a guide, but full past medical history, history of present illness, and physical examination and laboratory test results are critical in assessing a patient exposed to toxins

Oral Secretions

Respiratory Rate

Lung Secretions

Heart Rate and Blood Pressure

Gastrointestinal Motility

Urine Output

Muscle and Temperature

Cholinergic Organophosphates, physostigmine, donepezil

Agitation, seizures

↓

↑

↑

↑

↓

↑

↑

Fasciculations, paralysis

↑

Sympathomimetic Amphetamines, cocaine, pseudoephedrine

Agitation, aggression, seizures

↑

—

↑

↓

↑

↑ or ↓

—

↑ Temperature

↑

Antimuscarinic Diphenhydramine, atropine, scopolamine

Delirium, altered mental state

↑

↓

±

↓

↑

↓

↓

↑ Temperature

↓

Sedative/Hypnotic Benzodiazepines, barbiturates

↓ Mental state, ataxia, delirium

↑ or ↓

—

↓

—

↑ or ↓

—

—

↓ Temperature

—

Substance Class Examples


Sweat

Pupils

Central Nervous System

Table 4. Toxidromes


Respiratory Rate

Lung Secretions

Heart Rate and Blood Pressure

Gastrointestinal Motility

Urine Output

Muscle and Temperature

Sweat

↓ mental state, lethargy coma

Oral Secretions

Opioid Oxycodone, fentanyl, morphine

Pupils

Substance Class Examples

Central Nervous System

Table 4. Toxidromes (continued)

↓

—

↓

—

↑ or ↓

↓

—

↓ Temperature

—

2. General management of poisoned patients: Poisoned patients are managed similar to any other patient, in the sense that the ABCs (airway, breathing, and circulation) are the top priority. Unfortunately, the number of poisonous substances far outweighs the number of antidotes, and “supportive care” (management of the ABCs) is often the treatment modality used. However, there are occasions when supportive care is not enough, and specific antidotes and decontamination measures must be used, along with consultation of a toxicologist. a. A: Airway: Gag and cough reflex b. B: Breathing i. Respiratory rate ii. Blood gas c. C: Circulation i. Heart rate ii. Blood pressure iii. Electrocardiogram d. A: Altered neurologic status i. Coma or stupor ii. Agitation iii. Seizure e. D: Diagnosis of poisoning i. Decontamination (e.g., removal of contaminated clothing, gastric decontamination by way of activated charcoal) ii. Enhanced elimination (e.g., dialysis) 3. Gastric decontamination: Use of gastric decontamination measures in the management of poisoned patients has dropped tremendously over the last 20 years. Typically, all measures below are avoided if the patient has a compromised, unprotected airway (e.g., absent gag or decreased mental status and not intubated) because nearly all have an associated risk of aspiration. a. Syrup of ipecac i. Role in management of poisoning cases: As of 2003, the American Academy of Pediatrics no longer recommends routine use of ipecac in the home management of ingestions of a potentially poisonous substance. Because of decreased demands, syrup of ipecac is no longer manufactured. ii. Mechanism of action: Direct stimulation of chemoreceptor trigger zone, induces vomiting within 20 minutes iii. Adverse effects: excessive vomiting, vagal bradycardia, persistent vomiting may lead to esophageal tears b. Single-dose activated charcoal ACCP Updates in Therapeutics® 2015: Pediatric Pharmacy Preparatory Review Course 2-376


i.

Role in management of poisoning cases: May be considered in asymptomatic patients who present within an hour after ingestion of a potentially toxic dose of a substance. Cases of serious adverse events (e.g., aspiration, death) have resulted in decreased use. In 2012, it was used nearly one-third less than it was 20 years before. ii. Mechanism of action: Adsorbs toxins while in stomach to lessen the extent of absorption; should use within 1 hour after ingestion. Does not adsorb all materials; for example, iron, lithium, and alcohols are not likely to be adsorbed. iii. Adverse effects: vomiting, constipation, aspiration c. Multidose activated charcoal i. Role in management of poisoning cases: Like single-dose activated charcoal, it adsorbs toxins; however, when used in multiple doses, it is thought to adsorb toxins that undergo extensive enterohepatic recirculation. Carbamazepine, dapsone, phenobarbital, quinine, and theophylline have all shown enhanced elimination in volunteer studies. Clinical benefit may not correlate. Do not use activated charcoal preparation containing sorbitol for repeat doses because electrolyte abnormalities and fluid shifts may occur. ii. Mechanism of action: Adsorbing toxins to decrease absorption or reabsorption as in case of enterohepatic recirculation. iii. Adverse effects: vomiting, constipation, aspiration d. Whole bowel irrigation (WBI) i. Role in management of poisoning cases: May be considered in exposures to long-acting substances, body stuffers or packers, fentanyl patch ingestions, and ingestion of agents not well adsorbed by charcoal. Do not use in patients with absent bowel sounds. Consider gastrointestinal (GI) stimulant (e.g., bisacodyl) to assist with evacuation of bowels. ii. Mechanism of action: Concentrated polyethylene glycol with electrolytes decreases GI transit time by producing osmotic-induced diarrhea. Dose is 0.5 L per hour in children 9 months to 6 years old, 1 L per hour in children 6–12 years old, and 1.5–2 L per hour in adults. iii. Adverse effects: GI discomfort, diarrhea, aspiration, colonic perforation e. Gastric lavage i. Role in management of poisoning cases: May be considered in patients who present less than 1–4 hours after ingestion, who are already intubated, and who have ingested a toxin that may result in significant toxicity for which there is no safe and effective antidote. That said, the invasiveness of this procedure and the lack of consistent evidence supporting its efficacy have led to a very limited number of gastric lavage attempts per year. ii. Mechanism of action: Large-bore orogastric tube inserted while patient is on his or her side 10–15 mL/kg of warm water is instilled in the tube and then removed. This method cannot remove larger pills or objects. iii. Adverse effects: esophageal injury, airway trauma, electrolyte disturbances, hypoxia Patient Cases C.Y. is an 8-month-old boy who presents to the emergency department with episodes of severe irritability. His vitals were heart rate (HR) 170 beats/minute, blood pressure (BP) 110/70 mm Hg, and respiratory rate (RR) 30 breaths/minute, temperature 39°F. His mucous membranes were dry, and he had decreased bowel sounds. Blood culture and cerebrospinal fluid tests were negative. A reactive respiratory panel was sent and was positive for rhinovirus. He has no significant past medical history. C.Y. is not on any prescription medications, but after further questioning his mother admits to giving him several doses of a liquid over-the-counter medication for a cold in the last 48 hours.



Patient Cases (continued) 4. Which of the following medications is most likely to be responsible for C.Y.’s clinical presentation? A. Acetaminophen. B. Diphenhydramine. C. Dextromethorphan. D. No medications could be causing his symptoms; his presentation is consistent with a rhinovirus infection. 5. If C.Y.’s symptoms were associated with exposure to a medication, which gastric decontamination measure should be considered? A. Gastric lavage. B. Single-dose activated charcoal. C. Whole bowel irrigation. D. No gastric decontamination measures are warranted.

E. Management of Select Agents 1. All cases of suspected self-harm or malicious administration of any substance would be referred to a hospital for evaluation, regardless of substance or exposure amount. In addition, such patients should undergo routine toxicology screening (e.g., urine drug screen, acetaminophen, aspirin) because history is often unreliable. 2. Acetaminophen a. Epidemiology: Acetaminophen is a widely used over-the-counter analgesic and is in the analgesic class that is among the top 10 reported exposures to poison centers. Despite availability of an antidote, it is also one of the top 10 substances involved in poison-related deaths. b. Mechanism of toxicity: Acetaminophen is metabolized via three pathways: 90% sulfation and glucuronidation and 5% by CYP2E1 to N-acetyl-p-benzo-quinone imine (NAPQI). i. NAPQI is a toxic metabolite that binds to hepatocytes, leading to cell death. ii. NAPQI is deactivated by glutathione. iii. In an overdose, glutathione stores become depleted and NAPQI builds up.

Figure 2. Acetaminophen metabolism. ACCP Updates in Therapeutics® 2015: Pediatric Pharmacy Preparatory Review Course 2-378


c. Signs and symptoms of toxicity i. Early (less than 24 hours): Possibly asymptomatic, or with mild symptoms such as nausea, vomiting, diarrhea, decreased appetite, abdominal pain; possible altered mental status with larger doses ii. Late (more than 24 hours): abdominal pain, jaundice, and coma d. Management i. Acute ingestions exceeding 200 mg/kg or 6.5 g, or chronic ingestions of 150 mg/kg/day or 6 g/day × 2 days require hospital management. ii. Obtain a 4-hour acetaminophen level, liver function tests (LFTs), prothrombin time (PT) and international normalized ratio (INR), basic metabolic panel (BMP), and lactate (for severe overdoses). iii. Plot levels on the Rumack nomogram (Figure 3) to determine whether N-acetylcysteine (NAC) is indicated. Initiate NAC therapy if 4-hour level is greater than 150 mg/dL. (a) See Select Antidotes section for more information. (b) In cases of chronic toxicity, or unknown time of ingestion, consider empiric NAC therapy until LFTs and APAP laboratory test results have returned and are reassuring. (c) NAC is available in two forms: intravenous and oral (the oral formulation is the inhaled form given by mouth). There is essentially no difference in efficacy between the two forms, but the poor palatability and extended duration of time have caused the oral form to fall out of favor. iv. Dosing (see Select Antidotes section below) e. Management pitfalls: NAC must be continued until acetaminophen levels are undetectable and LFTs are trending down. i. It is recommended to obtain repeat laboratory tests 2 hours before end of third bag. ii. If no time has lapsed between decision to continue therapy and end of third bag, then there is no need to rebolus; continue with rate of last bag for an additional 16 hours. Patient Case P.W. is a 16-year-old girl who presented to the ED at 8 a.m. with nausea, vomiting, and abdominal pain. She admitted to ingesting an entire bottle of extra-strength acetaminophen the night before in an attempt to harm herself after a breakup with her boyfriend. Laboratory test results were as follows: Na 142/ K 4.2/ Cl 110/ CO2 20/ BUN 10/ SCr 0.6; aspartate aminotransferase 1700 IU/L and alanine aminotransferase 1650 IU/L. Her acetaminophen level was undetectable. 6. Which of the following is the most appropriate course of action for P.W.? A. Withhold NAC therapy, because her acetaminophen level is undetectable, and history in patients who try to commit suicide is unreliable. B. Initiate NAC therapy because LFTs are elevated. C. Send the patient to a psychiatric unit; no additional laboratory tests are necessary. D. Withhold NAC therapy at the moment but continue to monitor LFTs.



Figure 3. Rumack nomogram.

Adapted with permission from Rumack BH, Matthew H. Acetaminophen poisoning and toxicity. Pediatrics 1975;55:871-6.

Nomogram: Acetaminophen plasma concentration versus time after acetaminophen ingestion. The nomogram has been developed to estimate the probability of whether an acetaminophen level (in relation to the interval after ingestion) will result in hepatotoxicity and therefore whether acetylcysteine therapy should be administered. Values above the Rumack-Matthew line connecting 200 mcg/mL at 4 hours with 50 mcg/mL at 12 hours are reported to be associated with a potentially increased risk of hepatotoxicity if acetylcysteine is not administered. In order to err on the side of safety, a treatment line has been established that is 25% below the Rumack-Matthew line. Cautions for Use of This Chart 1. Time coordinates refer to time after ingestion. 2. Graph relates only to plasma (or serum) concentrations after a single, acute overdose ingestion. 3. The treatment line is plotted 25% below the Rumack-Matthew line to allow for potential errors in acetaminophen assays and estimated time from ingestion of an overdose (Rumack BH, Peterson RC, Koch GG, Amara IA. Acetaminophen Overdose: 662 Cases With Evaluation of Oral Acetylcysteine Treatment. Arch Intern Med. 1981;141(3):380-385). Reprinted with permission from McNeil Consumer Products Inc.



3. Aspirin a. Epidemiology: Patients poisoned by salicylates tend to decompensate quickly, potentially progressing to metabolic acidosis, renal failure, and death. Salicylates include aspirin, bismuth subsalicylates, methyl salicylates, and oil of wintergreen (which is also methyl salicylate). b. Mechanism of toxicity: Central stimulation of the respiratory center causes hyperventilation, which may lead to dehydration and compensatory metabolic acidosis. In addition, uncoupling of oxidative phosphorylation, glucose, and fatty acid metabolism give rise to metabolic acidosis. c. Signs and symptoms of toxicity i. Early: tachypnea, hyperpnea, respiratory alkalosis, gastritis, dehydration, tinnitus, fever, elevated heart rate, agitation, confusion ii. Late: metabolic acidosis, noncardiogenic pulmonary edema, renal insufficiency, hepatotoxicity, coma, and seizure d. Management i. Patients who ingest more than 150 mg/kg (6.5 g) or 100 mg/kg/day × 2 days should be monitored for a minimum of 6 hours. ii. Obtain baseline salicylate level, basic metabolic panel, and, for severe cases, a blood gas. iii. Sodium bicarbonate bolus or infusion to maintain serum pH above 7.4 (or urine pH 7.5–8) (a) Urinary excretion is enhanced with alkaline urine. (b) Bicarbonate also keeps salicylates ionized, thus decreasing ability to distribute into tissue. iv. Dialysis if patient has detectable levels and one of the following: severe metabolic acidosis, unresponsive hypotension, significant altered mental status with no other identifiable cause, evidence of end-organ injury (e.g., renal, cerebral, pulmonary), or level greater than 100 mg/dL v. Monitor salicylate levels and BMPs every 2 hours until a peak and decline is observed. e. Management pitfalls i. Be sure to communicate units when discussing salicylate levels to avoid potential for inappropriate treatment. ii. Use caution with mechanically ventilated patients because the need for respiratory compensation through respiratory hyperventilation must be considered. iii. Monitor and replete potassium levels to help kidneys excrete hydrogen ions. iv. Pharmacobezoars (mass of clumped-up pills) may form in the stomach. A rise or plateau in levels could indicate a pharmacobezoar. Patient Case 7. A.J., a 3-year-old boy, was found by parents with a bottle of 100-count chewable baby aspirin. It was a full bottle, and roughly ¼ of the tablets remain. The parents brought the child and the bottle to the ED within 30 minutes of the ingestion occurring. He weighs 17 kg. Upon examination he was found to be tachypneic, at 50 breaths/minute, but otherwise normal vitals. He had some guarding upon abdominal examination and had vomited several times before arrival. A BMP and venous blood gas (VBG) were obtained and were reported back within normal range. His salicylate level was 10 mg/dL. Which of the following should be the next step in the management of A.J.? A. His salicylate level was low and his VBG was normal, so he may be sent home. B. Renal should be consulted because he should undergo dialysis immediately. C. A salicylate level, BMP, and VBG should be repeated in 2 hours. D. He ingested a potentially toxic dose of aspirin and should be given activated charcoal. 4. β-Blockers a. Epidemiology: Cardiovascular drugs remain among the top 10 exposures for adults and also in fatalities in poison center data. ACCP Updates in Therapeutics® 2015: Pediatric Pharmacy Preparatory Review Course 2-381


b. Mechanism of toxicity: β-receptor blockade. Receptor selectivity is dose dependent and is diminished in the setting of an overdose. c. Signs and symptoms of toxicity i. Bradycardia ii. Hypotension iii. QRS widening with agents that have sodium channel blockade activity (e.g., propranolol) iv. Prolonged QT with agents that cause potassium channel blockade activity (e.g., sotalol) v. Sinoatrial and atrioventricular node blockade vi. Hyperkalemia vii. Hypoglycemia (especially in children and patients with diabetes) viii. Seizures with lipid soluble agents (e.g., propranolol) ix. Bronchospasm x. Possible coma and death with severe overdoses d. Management: Ingestions of more than a maximum single therapeutic dose must be monitored at a health care facility i. Supportive care ii. Glucagon, considered first line for β-blocker–induced bradycardia (see Select Antidotes section below for dosing) iii. Vasopressors (e.g., norepinephrine, epinephrine, dopamine) iv. Calcium for hypotension Patient Cases 8. K.W. is a 2-year-old girl who was found with her grandmother’s pill reminder box. Her grandmother takes lisinopril, a multivitamin without iron, metoprolol, metformin, melatonin, and warfarin. There were 3 days left in the box, and there are no pills remaining. Which of the grandmother’s medications is likely to be the most harmful to K.W.? A. Warfarin. B. Metformin. C. Metoprolol. D. Melatonin. 9. If K.W. developed hypotension and bradycardia, what would be the most logical treatment algorithm to consider A. Fluids, then glucagon, then calcium, then epinephrine. B. Fluids, then glucagon, then epinephrine, then high-dose insulin euglycemic therapy. C. Epinephrine, then glucagon, then fluids, then high-dose insulin euglycemic therapy. D. Fluids, then epinephrine, then lipid emulsion therapy. v. Consider high-dose insulin euglycemic therapy (off-label use) for refractory cases (see Select Antidotes section below for dosing). vi. May also consider lipid emulsion therapy (off-label use) for refractory cases e. Management pitfalls: Sotalol and extended-release β-blockers may have delayed toxicity and should be monitored for at least 24 hours. Monitor serum glucose and potassium closely if using high-dose insulin, euglycemic therapy. 5. Calcium channel blockers a. Epidemiology: Cardiovascular drugs remain among the top 10 exposures for adults and also in fatalities in poison center data. b. Mechanism of toxicity: Direct antagonism of L-type calcium channels of the heart and vascular smooth muscle, leading to decreased calcium influx and resultant reduction of cardiac contractility, ACCP Updates in Therapeutics® 2015: Pediatric Pharmacy Preparatory Review Course 2-382


loss in vascular tone, and slowed atrioventricular and sinoatrial node activity. Also inhibits insulin release from pancreatic islet cells. c. Signs and symptoms of toxicity: bradycardia (more with nondihydropyridines), hypotension, second- or third-degree atrioventricular block, hyperglycemia, stupor, confusion, and possible coma and death with severe overdoses. d. Management: Ingestions of more than a maximum single therapeutic dose must be monitored at a health care facility. i. Supportive care ii. Calcium iii. Vasopressors (e.g., norepinephrine, epinephrine, dopamine) iv. High-dose insulin euglycemic therapy (off-label use) (see Select Antidotes section below for dosing) v. Glucagon for bradycardia (see Select Antidotes section below for dosing) vi. May consider lipid emulsion therapy (off-label use) for refractory cases e. Management pitfalls: Avoid administration of calcium chloride through peripheral lines (may cause venous sclerosis). 6. Caustics a. Epidemiology: Caustic agents account for a broad class of substances (alkali and acids) that can be found throughout the home setting. Since passage of the PPPA in the 1970s, which requires childresistant packaging for all caustics at a concentration of 2% and above, the incidence and severity of caustic exposures in children have dramatically decreased. b. Mechanism of toxicity: Acids (pH less than 3) tend to cause coagulation necrosis, resulting in eschar formation that protects from deeper penetrating burns. Alkalis (pH greater than 11) cause liquefactive necrosis, which typically results in more extensive damage. c. Signs and symptoms of toxicity: Severe pain on lips, mouth, tongue, throat, chest, abdomen, excess drooling, dysphagia, odynophagia, hematemesis, hoarseness, stridor, and respiratory distress may occur in the event of inhalation or aspiration of the substance. d. Management i. Supportive care ii. Decontamination of the skin and eyes should be performed as appropriate. iii. If intubation necessary, should be done with laryngoscope to avoid inadvertent perforation of pharynx or larynx iv. Gastric decontamination is rarely indicated. Oral dilution (water or milk) should not be forced. v. Endoscopy may be necessary to determine extent of damage; further treatment and follow-up (for stricture formation) are determined based on grading of damage. (a) Grade I esophageal injuries typically lack ulcer formation and do not develop strictures. (b) Grade II burns have ulcerations of submucosal layer (IIa are noncircumferential, IIb are circumferential). (c) Grade III are defined as having deep ulcerations and necrosis and are at greatest risk for strictures, which may develop over weeks to months after injury. vi. Intravenous steroids and antibiotics may be considered in severe cases; however, data on their efficacy are limited. In addition, studies show that steroids may actually worsen outcomes of grade III esophageal burns through increased risk of infection and thinning of tissue; therefore, steroids should be avoided in that group. However, there is some evidence that they may be considered in grade IIb burns. e. Management pitfalls i. Do not attempt to use neutralization methods in the management of caustic ingestions. An exothermic reaction may occur that could worsen the extent of the injury. ii. Do not use gastric decontamination measures because they may increase additional esophageal injury and risk of aspiration or airway damage. ACCP Updates in Therapeutics® 2015: Pediatric Pharmacy Preparatory Review Course 2-383


7. Foreign bodies, coins, or button batteries a. Epidemiology: Foreign bodies (toys) are among the top 10 ingestions in pediatric patients reported to poison centers each year. Fortunately, most foreign body ingestions are not likely to cause complications. However, we pay special attention to the following ingestions: button batteries, coins, lead-based objects, magnets, sharp objects, and expand-in-water toys. b. Mechanism of toxicity i. Button batteries: Ingestions are very serious. Can cause tissue damage as soon as 2 hours after ingestion. ii. Coins: Not typically problematic, but there have been cases of asymptomatic esophageal or airway entrapment. iii. Lead-based objects: Can lead to systemic toxicity iv. Magnets: When more than one is swallowed, the attraction of magnets in adjacent loops of bowel may cause bowel wall necrosis. v. Sharp objects: May cause direct tissue damage vi. Expand-in-water toys: Although unlikely, may lead to bowel obstruction c. Signs and symptoms of toxicity: Depend on the foreign body. However, many of the symptoms are a result of airway or GI obstruction or damage. d. Management i. Button batteries: Radiograph to confirm that the battery is not lodged in the esophagus and follow-up radiograph to make sure the battery has cleared within 4–10 days. Potential emergent endoscopic removal is necessary if not past pylorus. ii. Coins: Radiograph to confirm coin is not lodged in the esophagus, should pass without intervention. Potential endoscopic removal is necessary if not past pylorus. iii. Lead-based objects: Radiograph to confirm location, consider WBI to increase GI transit time and decrease opportunity for absorption and systemic toxicity. May also consider use of acid neutralizer, which may help decrease extent of absorption but is not likely to be beneficial in setting of WBI. iv. Magnets: Radiograph to determine whether multiple magnets were swallowed. If multiple magnets ingested and are past the stomach, and patient is asymptotic, may consider WBI for prompt expulsion from GI tract. If multiple magnets are in esophagus or stomach, or if patient is symptomatic, may consider endoscopic removal. v. Sharp objects: Radiograph and potential endoscopic or surgical removal. vi. Expand-in-water toys: Although unlikely, may lead to bowel obstruction. Radiolucent imaging is not helpful. Monitor for signs of bowel obstruction, and if evident, surgical intervention may be necessary. e. Management pitfalls: Delayed recognition and treatment of button battery ingestions have been deadly. 8. Iron a. Epidemiology: Fortunately, packaging regulations and education on the harm that iron can cause have greatly reduced the incidence of iron poisoning in children. However, significant poisonings still occur and must be managed promptly and appropriately. b. Mechanism of toxicity: Iron is a GI irritant and can result in significant mucosal irritation and injury. Systemic toxicity manifests as lactic acidosis and organ failure. It is thought that iron’s cellular toxicity is a result of oxidative and free radical injury. c. Signs and symptoms of toxicity: Nausea, vomiting, diarrhea, corrosive injury and hematemesis, blood loss, coma, shock, seizures, metabolic acidosis, hepatic failure, coagulopathy, and death. Iron overdose has been described in five stages (not all are experienced by every patient): i. 0.5–2 hours: Vomiting, hematemesis, diarrhea, shock, acidosis, death; absence of symptoms in first 6 hours probably eliminates likelihood of severe iron toxicity ACCP Updates in Therapeutics® 2015: Pediatric Pharmacy Preparatory Review Course 2-384


ii. iii. iv. v.

Latent phase 6–24 hours: Potentially symptom free 2–12 hours: Shock, severe acidosis, fever, coma, death 2–3 days: Hepatic failure 2–8 weeks: Delayed symptoms associated with initial caustic injury (e.g., strictures, intestinal obstructions) d. Management: Patients who have ingested more than 40 mg/kg or who are experiencing moderate to severe symptoms should be evaluated in the hospital. i. Consider abdominal radiograph to determine potential for GI decontamination in setting of potentially toxic tablet ingestion. Liquid and chewable tablets are not typically radiopaque; therefore, lack of visual of iron on radiograph does not rule out iron ingestion. Charcoal not effective; consider WBI if situation appropriate. ii. Initiate deferoxamine therapy at 15 mg/kg/hour intravenously if patient has severe symptoms or if serum Fe level is greater than 500 µg/mL (a) Deferoxamine binds with ferric iron to produce a ferrioxamine complex that is excreted in the urine. (b) This complex is excreted renally and will cause the urine to turn a reddish-brown color. (c) If iron is not present, then the complex will not form and the urine color will remain unchanged, indicating that therapy can probably be terminated. e. Management pitfalls i. In the setting of acute iron toxicity, use intravenous route for deferoxamine administration, especially in patients with poor hemoperfusion, because absorption and distribution of intramuscular and subcutaneous routes may be altered. ii. Stage 2 may provide a false sense of reassurance that the patient is out of the woods, but significant morbidity and mortality can result, especially with early discharge. iii. Patients with chronic iron overload are at an increased risk for Yersinia enterocolitica sepsis because this organism requires iron stores for growth. This risk is thought to be worsened by deferoxamine therapy because it fosters the growth of Yersinia. 9. Lead a. Epidemiology: Despite the dramatic reduction in prevalence and severity of lead poisoning since the removal of lead from gasoline and paint in the 1970s, lead remains an important environmental health concern for young children, especially in poor families. Therefore, it is recommended that children undergo routine lead screens at 1 and 2 years of age, especially those whose families participate in poverty assistance programs. Goal level is less than 5 µg/ dL. Antidotes used in lead poisoning are British anti-lewisite (BAL, or dimercaprol), edetate calcium disodium, and succimer. BAL is a metal chelator that crosses the blood-brain barrier. It is manufactured in peanut oil and administered intramuscularly. Its administration can be very painful, and it cannot be used as a single therapy in lead poisonings. Edetate calcium disodium is also a metal chelator, but it is administered intravenously and does not cross the blood-brain barrier. b. Mechanism of toxicity: Lead toxicity affects many organ systems through a variety of complex mechanisms, through its affinity for electronic donor ligands, interference with calciummediated metabolic pathways, and mutagenic and myogenic effects in mammalian cells. c. Signs and symptoms of toxicity (in children) i. Level greater than 70 µg/dL: encephalopathy, persistent vomiting, anemia ii. Level 50–70 µg/dL: hyperirritable behavior, intermittent lethargy, vomiting, and abdominal pain iii. Level 20–69 µg/dL: impaired cognition, behavior, balance, impaired growth and hearing d. Management i. GI decontamination should be considered in acute ingestions. ACCP Updates in Therapeutics® 2015: Pediatric Pharmacy Preparatory Review Course 2-385


ii. Encephalopathy: Treat with BAL and intravenous edetate calcium disodium given 4 hours after BAL; continue to overlap therapy at least 3–5 days. Studies suggest that the combination of BAL and edetate calcium disodium is more effective than the latter alone. iii. Symptomatic without encephalopathy: May try oral succimer or intravenous edetate calcium disodium if intolerant to succimer iv. Asymptomatic (a) Level 5–45 µg/dL: Review home and school environment, educate, and follow levels closely. (b) Level greater than 45 µg/dL: Consider treating with oral succimer. e. Management pitfalls i. Patients typical exhibit difficulty with compliance to succimer because of its poor palatability. ii. Succimer is available only as capsules, may be opened and mixed with soft foods or juice; use chilled food or beverage may improve palatability. iii. Edetate calcium disodium has many aliases (e.g., calcium disodium versenate or calcium EDTA). Avoid use of abbreviation EDTA so as to avoid confusion with disodium EDTA (which could result in life-threatening hypocalcemia). iv. BAL is administered intramuscularly and is very painful. Avoid giving to patients with a peanut allergy. Patient Case 10. L.N. is a 4-year-old girl who presented to the ED with new-onset seizures, one witnessed by ED triage staff. She recently moved with her family from India to the United States. Her mother reported that L.N. has been showing signs of impaired cognition and worsening, aggressive behavior over the last several months. An abdominal radiograph was unremarkable. Computed tomography scan was consistent for encephalopathy. A serum lead level was obtained and reported back as 90 mcg/dL. Which of the following would be the most appropriate course of therapy for L.N.? A. Oral succimer alone. B. WBI followed by edetate calcium disodium. C. Edetate calcium disodium followed by BAL. D. BAL followed by continuous edetate calcium disodium. 10. Rabies a. Epidemiology i. Cases of rabies have been on a steady decline since 1950 because of the widespread immunization of dogs and available prophylaxis regimen. ii. Potential sources of wildlife exposure include bats, raccoons, skunks, foxes, coyotes, and bobcats. iii. The incubation period in humans averages 1 to 3 months. b. Mechanism of toxicity i. The rabies virus can be spread only via salvia and brain or nervous tissue. ii. The most common mode of transmission is bite from a virus-containing host. c. Signs and symptoms of toxicity: anxiety, radicular pain, dysesthesia or pruritus, hydrophobia, and dysautonomia d. Management i. Postexposure prophylaxis: Rabies is 100% preventable with appropriate medical care. Ideally, prophylaxis should be initiated within 24 hours of exposure. (a) Recommended for all patients bitten by a high-risk animal (b) Recommended for all sleeping people and unattended children present in a room with a bat presence, because bat bites may be painless and are difficult to detect. ACCP Updates in Therapeutics® 2015: Pediatric Pharmacy Preparatory Review Course 2-386


(c) Passive prophylaxis: Rabies immune globulin (RIG), 20 units/kg locally infiltrated around wound if possible. If not possible or no visible wound, RIG should be administered intramuscularly at a site distant from the vaccine administration site. (d) Active prophylaxis: Human rabies vaccine, 1 mL intramuscularly on days 0, 3, 7, and 14 after exposure ii. Treatment (a) Neither the human rabies vaccine nor rabies immune globulin improves outcome once symptoms have manifested. (b) Supportive care (c) Survival from a rabies infection is very rare. Patient Case 11. A.O. is a 3-month-old girl who was sleeping in her parents’ bedroom. A.O.’s father awoke in the middle of the night to find a bat flying around in the bedroom. Upon examination, there is no evident bite mark or wound. Which statement describes the most appropriate management strategy? A. No prophylaxis is necessary because there is no visible bite. B. Initiate prophylaxis with RIG and human rabies vaccine within 24 hours. C. Initiate prophylaxis with RIG and human rabies vaccine within 7 days. D. Initiate just the human rabies vaccine. RIG is not necessary because there is no visible bite. 11. Snake bites a. Epidemiology: The majority of venomous snakes in the United States are in the Viperidae family (subfamily Crotalinae), which includes the eastern and western diamondback rattlesnakes, copperheads, and cottonmouths (water moccasins). b. Mechanism of toxicity: Venom contains enzymes, peptides, amino acids, metallic ions, lipids, and carbohydrates. Clinical manifestation from envenomation depends on the snake species and the amount of venom injected. c. Signs and symptoms of toxicity (varies depending on species of snake): intense pain, weakness, dizziness, altered mental status, paresthesia, muscle fasciculations, tachycardia, visual disturbances, coagulopathy, pulmonary edema, cardiovascular collapse d. Management i. Frequently monitor local swelling, muscle strength, complete blood cell count, and PT, activated partial thromboplastin time, and INR ii. Administer tetanus vaccine or antibiotics as indicated iii. Call the poison control center (1-800-222-1222 in the United States) to determine whether administration of antivenin is necessary and to help coordinate procurement of such (especially in the case of exotic, venomous snake bites) (a) Bites from venomous snakes native to the United States can be treated with Crotalinae polyvalent immune Fab (ovine) (CroFabTM). (b) Antivenom exerts its action by binding to the venom. Therefore, dosing is not based on size of patient; rather, a flat dose of 4–6 vials is repeated in 1-hour increments until clinical improvement noted. (c) Although not approved for use in children, it has been used successfully in pediatric cases. e. Management pitfalls i. Patients need to be monitored (physical examination, complete blood cell count) 2–4 days and up to 2 weeks after discharge for recurrence of symptoms. ii. Most U.S. hospitals carry Crotalinae polyvalent immune Fab (ovine); however, it covers only the Crotalinae subfamily. If suspected snake is exotic or not within that subfamily (e.g., the ACCP Updates in Therapeutics® 2015: Pediatric Pharmacy Preparatory Review Course 2-387


coral snakes, which are in the Elapidae subfamily), then contact the poison control center for assistance in locating appropriate antivenom, if available. 12. Tricyclic antidepressants (TCAs) a. Epidemiology: Although the use of TCAs has decreased with the advent of newer medications, such as the selective serotonin reuptake inhibitors, the severity of clinical manifestations associated with inadvertent exposures and with intentional overdoses continues to be alarming. b. Mechanism of toxicity: Central and peripheral antagonisms at muscarinic receptors cause anticholinergic syndrome (see Table 4), blocking of fast sodium channels leads to arrhythmias, and antagonist activity at the α1-adrenergic receptors leads to a decrease in preload and vascular resistance. c. Signs and symptoms of toxicity: Anticholinergic syndrome, tachycardia, prolonged QRS, prolonged QT, arrhythmias, convulsions, coma, and death d. Management i. Infants and children who ingest TCAs should be referred to a health care facility for evaluation if they exceed a dose of 5 mg/kg, except for desipramine (more than 2.5 mg/kg), nortriptyline (more than 2.5 mg/kg), or trimipramine (more than 2.5 mg/kg). ii. Any adult who ingests an amount of TCAs exceeding the maximum therapeutic dose should be referred to the hospital. iii. Supportive care (a) Seizures: Benzodiazepines; paralysis will help with muscular involvement and help with temperature regulation, however, will not affect central nervous system activity, so continuous electroencephalography is recommended. (b) Hyperthermia: cooling protocols (antipyretics not likely to have much effect) (c) Prolonged QRS greater than 100 milliseconds: Treat with sodium bicarbonate 1–2 mEq/ kg intravenously as needed to maintain serum pH between 7.45 and 7.55, consider lidocaine if refractory despite appropriate management with sodium bicarbonate. (d) Hypotension: fluids and sodium bicarbonate e. Management pitfalls i. Do not use physostigmine to reverse the anticholinergic effects; it may aggravate cardiac complications and lower seizure threshold. ii. Do not use class Ia or Ib antiarrhythmics because they further block sodium channels and can aggravate cardiotoxicity. F. Select Antidotes 1. Flumazenil a. Indication: reversal of benzodiazepine overdose. However, because benzodiazepine overdoses do not typically result in depressed respiratory status, reversal is often not necessary. Flumazenil is used frequently as a reversal agent in general anesthesia or conscious sedation but less often in the overdose setting. b. Mechanism of action: competitive inhibition at the benzodiazepine subtype of the γ-aminobutyric acid receptor c. Dosing: 0.01 mg/kg/dose (maximum 0.2 mg) given over 30 seconds; may repeat every minute until optimal response (maximum dose 3 mg in 60 minutes) d. Adverse reactions: flushing, palpitations, agitation; may potentiate seizures or withdrawal in susceptible people 2. Fomepizole a. Indication: Ethanol or methanol poisoning. It may be initiated in the following circumstances: i. Methanol or ethylene glycol concentration more than 20 mcg/dL ii. Reliable history with blood concentrations pending ACCP Updates in Therapeutics® 2015: Pediatric Pharmacy Preparatory Review Course 2-388


3.

4.

5.

6.

iii. Metabolic acidosis with unexplained osmolar gap (early) or anion gap (delayed-2–4 hours after ingestion) b. Mechanism of action: Inhibition of alcohol dehydrogenase, preventing the metabolism of methanol and ethylene glycol to their toxic metabolites, formic acid for methanol and oxalic and glycolic acid for ethylene glycol c. Dosing: 15 mg/kg (up to 1.5 g) intravenously × 1, followed by 10 mg/kg every 12 hours; increase dose to 15 mg/kg every 12 hours if therapy needs to continue beyond 4 doses (can undergo autoinduction of metabolism after 4 or more doses). Drug is dialyzable; modify frequency of dosing (manufacturer recommends increase to every 4 hours during dialysis). d. Adverse reactions: headache, nausea, vomiting, phlebitis, transient elevations of transaminases or triglycerides with repeat dosing Glucagon a. Indication: β-blocker or calcium channel blocker overdose b. Mechanism of action: Improves chronotrophy and inotrophy by increasing cardiac cyclic adenosine monophosphate, independent of the β-adrenergic receptor or calcium channel’s antagonized state. c. Dosing: Administer bolus over 3–5 minutes; titrate infusion to achieve adequate hemodynamic response. i. Children: 0.03–0.15 mg/kg, then infusion of 0.07 mg/kg/hour (maximum 5 mg/hour) ii. Adolescents: 5–10 mg, 1–5 mg/hour iii. Adults: 3–10 mg, then 3–5 mg/hour d. Adverse reactions: nausea, vomiting, hypertension, tachycardia, hyperglycemia, hypersensitivity reaction, anaphylaxis High-dose regular insulin (hyperinsulinemia-euglycemia [HIE] therapy) a. Indication: To improve hemodynamics in β-blocker and calcium channel antagonist overdoses that are unresponsive to conventional therapy for hypotension. Used in conjunction with dextrose (offlabel use). Usually third line behind vasopressors and glucagon b. Mechanism of action: Improves inotropy and increases peripheral vascular resistance. Specific pharmacologic rationale is not well established. c. Dosing: Use concentrated insulin product (500 units). Must be diluted before use; stability not known i. Bolus: 1 unit/kg, followed by an infusion at 0.1 unit/kg/hour to 1 unit/kg/hour ii. All patients should also be initiated on a dextrose infusion at 0.5 g/kg/hour (if patient has blood glucose less than 200 before starting, he or she should be loaded first then initiated on infusion). d. Adverse reactions: hypoglycemia, hypokalemia, fluid overload, hyponatremia Lipid emulsion therapy a. Indication: Potential improvement in hemodynamic measures in overdose situations, after all other measures have failed (off-label use) b. Mechanism of action: Not fully understood. Primary thought is the “lipid sink theory,” which is that the lipids bind to lipid-soluble agents, inhibiting their ability to bind to receptors, thus decreasing severity of toxic effects. c. Dosing: 1.5 mL/kg bolus (maximum 100 mL) over 2–3 minutes; if clinical response may start infusion at 0.25–0.5 mL/kg/minute for up to 60 minutes (maximum 1L over 60 minutes) d. Adverse reactions: Pancreatitis, increased LFTs, cyanosis, lipid overloading syndrome (focal seizures, fever, leukocytosis, hepatomegaly, splenomegaly, and shock), potential laboratory interference N-Acetylcysteine a. Indication: Use in acetaminophen overdose. Oral and intravenous are considered equivalent from an efficacy perspective. ACCP Updates in Therapeutics® 2015: Pediatric Pharmacy Preparatory Review Course 2-389


b. Mechanism of action: Acts as a glutathione precursor to help reduce the amount of NAPQI available, thereby reducing cellular damage. Studies have shown that it is most effective when initiated within 8–10 hours after ingestion; however, there have been cases in which NAC therapy appeared to be efficacious even with delayed initiation. c. Dosing Route

Intravenous

Oral

First dose

150 mg/kg every 1 in 200 mL

140 mg/kg every 1

Repeat doses

12.5 mg/kg/hour every 4 hours 6.25 mg/kg/hour every 16 hours

70 mg/kg every 4 hours

Total duration

21 hours

72 hours

i.

Intravenous dosing (a) Dilute as per package insert or acetadote.net (b) To accommodate standardized concentration for dispensing and to simplify preparation and administration, you may consider establishing an institution-wide standard concentration and dosing of a 3% solution at a rate of 150 mg/kg/hour × 1 hour, 12.5 mg/ kg/hour × 4 hours, then 6.25 mg/kg/hour × 16 hours. ii. Oral dosing: Dilute to 5% solution before administration. Cola is best to mask flavor. Ice cold, with lid, through straw also may help. iii. Reminder: Do not stop infusion or oral dosing until it has been documented that the patient has an undetectable acetaminophen level and the LFTs are trending down. d. Adverse reactions i. Oral: nausea, vomiting, diarrhea ii. Intravenous: flushing, rash, nausea, vomiting, rarely anaphylaxis 7. Naloxone a. Indication: Reversal of respiratory suppressant effects of opioids and possible reversal of the effects of clonidine overdose. b. Mechanism of action: Competes and displaces opioids from m opioid receptors c. Dosing (intramuscular, intraosseous, intravenous, intranasal; off label) i. Full reversal: 0.1 mg/kg/dose (maximum 2 mg), repeat every 2–3 minutes as needed. Full reversal dose appropriate for most pediatric exploratory ingestions, unless past medical history indicates a likely tolerance to medications. ii. Partial reversal: 0.001–0.01 mg/kg/dose (maximum 0.04–0.4 mg); repeat every 2–3 minutes as needed. iii. Continuous infusion may be considered in the setting of long-acting opioid ingestion (e.g., methadone, extended-release oxycodone, fentanyl patch ingestion). Dose by the amount in milligrams of effective intermittent dose administered hourly (e.g., if it took 2 mg to reverse patient, consider a rate of 2 mg/hour). d. Adverse reactions: Significant withdrawal symptoms may occur in patients tolerant to opioid agonists. 8. Octreotide a. Indication: Treatment of sulfonylurea-induced hypoglycemia refractory to glucose therapy. Treatment with intravenous dextrose should continue throughout therapy (off-label use). b. Mechanism of action: Reduces insulin release from pancreatic β-cells c. Dosing i. Adult: 50–100 mcg subcutaneously or intravenously, every 6–12 hours as needed. ii. Children: 1–2 mcg/kg (maximum 50 mcg) subcutaneously or intravenously, every 6–12 hours as needed. ACCP Updates in Therapeutics® 2015: Pediatric Pharmacy Preparatory Review Course 2-390


iii. Most patients require one to three doses for adequate management. d. Adverse reactions: Injection site pain is the most common when used for this indication because the well-known adverse effect profile is associated more with chronic administration. For other indications (longer term), its use can result in gallbladder disease, gastrointestinal effects, and cardiovascular complications. Patient Cases 12. R.V. is a 15-year-old, 100-kg boy found down in his bathroom. His grandfather’s verapamil pill bottle, filled the day before, was found empty next to him. He was brought to the ED, where he was noted to have systolic blood pressure in the 70s mm Hg, HR 30 beats/minute. Electrocardiogram showed sinus bradycardia. He was given fluid and calcium gluconate boluses, BP improved to 90/50 mm Hg, and HR improved to 50 beats/minute. Serum calcium level after bolus was 7.5 mg/dL. What is the most appropriate next step in the management of R.V.? A. Do nothing; his vital signs have stabilized. B. Give another calcium bolus, then consider epinephrine infusion, then consider initiation of high-dose insulin euglycemic protocol. C. Give another calcium bolus, then consider epinephrine infusion, then consider lipid emulsion therapy. D. Initiate high-dose insulin euglycemic protocol, then lipid emulsion therapy. 13. High-dose insulin euglycemic therapy is initiated at some point in R.V.’s course at a rate of 1 unit/kg/hour, with a dextrose 25% infusion running at 0.5 g/kg/hour. His hypotension has resolved and remained stable for the last 12 hours; however, he has required two dextrose 50% boluses to treat a blood glucose level less than 50 mg/dL. His blood glucose drops below 50 mg/dL for a third time. Which is the best strategy to manage R.V.’s recurring hypoglycemic episodes? A. Stop his high-dose insulin euglycemic therapy. B. Continue with the high-dose insulin euglycemic therapy, but increase the infusion rate of the dextrose 25% bag. C. Use dextrose 50% boluses as needed with no change to the high-dose insulin euglycemic therapy. D. Continue with the high-dose insulin euglycemic therapy but consider decreasing the insulin rate.



REFERENCES Medication Safety 1. Institute of Medicine; Kohn LT, Corrigan JM, Donaldson MS, eds. To Err Is Human: Building a Safer Health System. Washington, DC: National Academy Press, 2000. 2. Institute of Medicine. Crossing the Quality Chasm: A New Health System for the 21st Century. Washington, DC: National Academy Press, 2001. 3. Institute of Medicine. Preventing Medication Error: Quality Chasm Series. Washington, DC: National Academy Press, 2006. Available at www.iom.edu/ Reports/2006/Preventing-Medication-Errors-Quality-Chasm-Series.aspx. Accessed August 24, 2014. 4. National Coordinating Council for Medication Error Reporting and Prevention. About medication errors. Available at http://www.nccmerp.org/aboutMedErrors.html. Accessed August 24, 2014. 5. National Coordinating Council for Medication Error Reporting and Prevention. About medication errors. Available at http://www.nccmerp.org/medErrorCatIndex.html. Accessed August 24, 2014. 6. Nebeker JR, Barach P, Samore MH. Clarifying adverse drug events: a clinician’s guide to terminology, documentation, and reporting. Ann Intern Med 2004;140:795-801. 7. American Society of Health-System Pharmacists. ASHP guidelines on adverse drug reaction monitoring and reporting. Am J Health Syst Pharm 1995;52:417-9. 8. Fortescue EB, Kaushal R, Landrigan CP, et al. Prioritizing strategies for preventing medication errors and adverse drug events in pediatric inpatients. Pediatrics 2003;111:722-9. 9. Otero P, Leyton A, Mariani G, et al. Medication errors in pediatric inpatients: prevalence and results of a prevention program. Pediatrics 2008;122:e737-43. 10. Kaushal R, Bates DW, Landrigan C, et al. Medication errors and adverse events in pediatric inpatients. JAMA 2001;285:2114-20. 11. Sentinel Event Alert: Preventing Pediatric Medication Errors. Available at www.jointcommission.org. Accessed August 24, 2014.

12. Kearns GL, Abdel-Rahman SM, Alander SW, et al. Developmental pharmacology: drug disposition, action, and therapy in infants and children. N Engl J Med 2003;349:1157-67. 13. Shah SS, Hall M, Goodman DM, et al. Off label drug use in hospitalized children. Arch Pediatr Adolesc Med 2007;161:282-90. 14. Levine SR, Cohen MR, Blanchard NR. Guidelines for preventing medication errors in pediatrics. J Pediatr Pharmacol Ther 2001;6:426-42. 15. Cohen MR. Why error reporting systems should be voluntary: they provide better information for reducing errors. BMJ 2000;320:728-9. 16. Griffin FA, Resar RK. IHI global trigger tool for measuring adverse events, 2nd ed. IHI innovation series white paper. Cambridge, MA: Institute for Healthcare Improvement, 2009. 17. Classen DC, Resar R, Griffin F, et al. Global trigger tool shows that adverse events in hospitals may be ten times greater than previously. Health Aff 2011;40:581-9. 18. Institute for Safe Medication Practices. ISMP HighAlert Medications. Available at http://ismp.org/ Tools/highAlertMedicationLists.asp. Accessed August 26, 2014. 19. Institute for Safe Medication Practices. Independent double checks: undervalued and misused: selective use of the strategy can play an important role in medication safety. Available at http://www.ismp. org/newsletters/acutecare/showarticle.aspx?id=51. Accessed August 26, 2014. 20. Potts AL, Barr FE, Gregory DF, et al. Computerized physician order entry and medication errors in a pediatric critical care unit. Pediatrics 2004;113:59-63. 21. Van Rosse F, Maat B, Rademaker CM, et al. The effect of computerized physician order entry on medication prescription errors and clinical outcome in pediatric and intensive care. Pediatrics 2009;123:1184-90. 22. Walsh KE, Landrigan CP, Adams WG, et al. Effect of computer order entry on prevention of serious medication errors in hospitalized children. Pediatrics 2008;121:e421-7.



23. Miller DF, Fortier CR, Garrison KL. Barcode medication administration technology: characterization of high-alert medication triggers and clinician workarounds. Ann Pharmacother 2011;45:162-8. 24. Morris FH, Abramowitz PW, Nelson SP, et al. Effectiveness of a barcode medication administration system in reducing preventable adverse drug events in a neonatal intensive care unit: a prospective cohort study. J Pediatr 2009;154:363-8. 25. Larsen GY, Parker HB, Cash J, et al. Standard drug concentrations and smart-pump technology reduce continuous medication infusion errors in pediatric patients. Pediatrics 2005;116:e21-5. Toxicology Poison Control Center Overview 1. Mowry JB, Spyker DA, Cantilena LR, et al. 2012 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 30th Annual Report. Clin Toxicol 2013;51:949-1229. Legislative Changes 1. Poison Prevention Packaging Act of 1972. Available at http://www.ecfr.gov/cgi-bin/text-idx?c=ecfr&tpl=/ ecfrbrowse/Title16/16cfr1700_main_02.tpl. Accessed August 15, 2014. Pediatric Poisonings 1. Matteucci MJ. One pill can kill: assessing the potential for fatal poisonings in children. Pediatr Ann 2005;34:964-8. General Toxicology 1. American Academy of Clinical Toxicology and European Association of Poisons Centres and Clinical Toxicologists. Position paper update: ipecac syrup for gastrointestinal decontamination. Clin Tox. 2013;51(3):134-9. 2. American Academy of Clinical Toxicology and European Association of Poisons Centres and Clinical Toxicologists. Position paper: single-dose activated charcoal. Clin Toxicol 2005;43:61-87.

3. American Academy of Clinical Toxicology and European Association of Poisons Centres and Clinical Toxicologists. Position paper update: MDAC for gastrointestinal decontamination. Clin Toxicol 1999;37(6):731-51. 4. American Academy of Clinical Toxicology and European Association of Poisons Centres and Clinical Toxicologists. Position paper update: whole bowel for gastrointestinal decontamination. Clin Toxicol 2013;42(6):843-54. 5. American Academy of Clinical Toxicology and European Association of Poisons Centres and Clinical Toxicologists. Position paper update: gastric lavage for gastrointestinal decontamination. Clin Toxicol 2013;51(3):140-46. Management of Select Agents 1. Rumack BH, Matthew H. Acetaminophen poisoning and toxicity. Pediatrics 1975;55(6):871-6. 2. Smilkstein MJ, Knapp GL, Kulig KW, et al. Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose. Analysis of the national multicenter study (1976–1985). N Engl J Med 1988;319(24):1557-62. 3. Rumack BH, Bateman DN. Acetaminophen and acetylcysteine dose and duration: past, present, and future. Clin Toxicol 2012;50(2):91-98. 4. Dart RC, Erdman AR, Olson KR, et al. Acetaminophen poisoning: an evidence-based consensus guideline for out-of-hospital management. Clin Toxicol 2006;44:1-18. 5. Trella J, Osterhoudt KC. Use of a “single bag” system for intravenous N-acetylcysteine at a children’s hospital. Clin Toxicol 2009;47(7):745. 6. Chyka PA, Erdman AR, Christianson G, et al. Salicylate poisoning: an evidence-based consensus guideline for out-of-hospital management. Clin Toxicol 1006;44:1–18. 7. Dargan P, Wallace C, Jones A. An evidence based flowchart guide to the management of acute salicylate (aspirin) overdose. Emerg Med 2002;19:206-9. 8. Higgins RM, Higgins RM, Connolly JO, Hendry BM. Alkalinization and hemodialysis in severe salicylate poisoning: comparison of elimination techniques in same patient. Clin Nephrol 1998;50(3):178-83.



9. Fertel BS, Nelson LS, Goldfarb DS. The underutilization of hemodialysis in patients with salicylate poisoning. Kidney Int 2009;75:1349-53. 10. Wax PM, Erman AR, Chyka PA, et al. β-blocker ingestion: an evidence-based consensus guideline for out-of-hospital management. Clin Toxicol 2005; 43:131-46. 11. Olsen KR, Erdman AR, Woolf AD, et al. Calcium channel blocker ingestion: an evidence-based consensus guideline for out-of-hospital management. Clin Toxicol 2005;43(7):797-822. 12. Peclova D, Navratil T. Corrosive ingestion: the evidence base. Are steroids still indicated in secondand third-degree corrosive burns of the oesophagus? Clin Toxicol 2004;42:414-6. 13. Usta M, Erkan T, Cokugras FC, et al. High doses of methylprednisolone in the management of caustic esophageal burns. Pediatrics 2014;133(6):E1518-24. 14. Litovitz T, Whitaker N, Clark L, White NC, Marsolek M. Emerging battery ingestion hazards: clinical implications. Pediatrics 2010;125:1168-77. 15. Waltzman ML, Baskin M, Wypij D, et al. A randomized clinical trial of the management of esophageal coins in children. Pediatrics 2005;116;614-19. 16. Fergusson, J., Malecky, G. and Simpson, E. Lead foreign body ingestion in children. J Pediatric Child Health 1997;33:542-4. 17. Moon JS, Bliss D, Hunter CJ. An unusual case of small bowel obstruction in a child caused by ingestion of water-storing gel beads. J Pediatr Surg 2012;47:E19-22. 18. Zamora IJ, Vu LT, Larimer, EL et al. Water-absorbing balls: a “growing” problem. Pediatrics 2012;130:e1011–4. 19. Osterhoudt KO, Peranteau WH, Shaw KN, Flake AW. A 2-year old girl with abdominal pain after an action sure to attract attention. Pediatr Emerg Care 2012;28(12):1406-8. 20. Silverman JA, Brown JC, Willis MM, Ebel BE. Increase in pediatric magnet-related foreign bodies requiring emergency care. Ann Emerg Med 2013;62(6):e1-6.

21. Manoguerra AS, Erdman AR, Booze LL, et al. Iron ingestion: an evidence-based consensus guideline for out-of-hospital management. Clin Toxicol 2005;43:553-70. 22. Warniment C, Tsang K, Galazka SS. Lead poisoning in children. Am Fam Physician 2010;81(6):751-57. 23. Wheeler W, Brown MJ. Blood lead levels in children aged 1–5 years: United States, 1999–2010. MMWR 2013;62(13):245-48. 24. Chisolm JJ. The use of chelating agents in the treatment of acute and chronic lead intoxication in childhood. J Pediatr 1968;73:1-38. 25. American Academy of Pediatrics. Red book: 2012 Report of the Committee on Infectious Diseases. Pickering LK, ed. 29th ed. Elk Grove Village, IL: American Academy of Pediatrics, 2012. 26. Centers for Disease Control and Prevention. Rabies. Available at http://www.cdc.gov/rabies/index.html. Accessed August 28, 2014. 27. Juckutt G, Hancox JG. Venomous snakebites in the United States: management, review, and update. Am Fam Physician 2002:1367-74. 28. CroFab [package insert]. West Conshohocken, PA: BTG International Inc., March 2012. 29. Pizon AF, Riley BD, LoVecchio F, Gill R. Safety and efficacy of crotalidae polyvalent immune Fab in pediatric crotaline envenomations. Acad Emerg Med 2007;14(4):373-76. 30. Woolf AD, Erdman AR, Nelson LS, et al. Tricyclic antidepressant poisoning: an evidence-based consensus guideline for out-of-hospital management. Clin Toxicol 2007;45(3):203-33. Select Antidotes 1. Marraffa JM, Cohen V, Howland MA. Antidotes for toxicological emergencies: a practical review. Am J Health Syst Pharm 2012;69(3):199-212. 2. American College of Medical Toxicology. ACMT position statement: interim guidance for the use of lipid resuscitation therapy. J Med Toxicol 2011;7:8182.



ANSWERS AND EXPLANATIONS TO PATIENT CASES 1. Answer: D This event is both an ADE and an ADR according to the ASHP and WHO definitions. This is not a near miss because the event reached the patient. 2. Answer: C This event would be classified as a category E event because it reached the patient and required an intervention mitigate harm. Categories A and B are for events that do not reach the patient. Category I is for events resulting in patient death. 3. Answer: B It is also recommend to use medications with manufacturerproduced dosage forms when clinically appropriate. Use of primary literature–based extemporaneously compounded formulation should occur only when there is no therapeutic alternative. The use of non–evidencebased formulations should be prohibited. 4. Answer: B C.Y.’s symptoms were consistent with an anticholinergic toxidrome, so diphenhydramine is very likely to be involved. He was tachycardiac, hypertensive, and hyperthermic and had dry mucous membranes and decreased bowel sounds. The anticholinergic symptoms with the report of recent exposure to an over-the-counter medication should lead us to suspect diphenhydramine. 5. Answer: D No gastric decontamination measures are warranted because C.Y. is already displaying symptoms, which indicates that absorption has already occurred, and his mother reports giving several doses of the medication over the last 48 hours. 6. Answer: B Given that ingestion of a toxic dose of acetaminophen was relayed in the patient’s history and that LFTs indicate hepatic injury, it is important to initiate NAC therapy immediately (Answer C is incorrect). Although histories can be unreliable, the clinical evidence of hepatic injury indicates that NAC is warranted (Answer A is incorrect). It is prudent to start the NAC as soon as possible because its efficacy will decrease further out from the time of ingestion (Answer D is incorrect). That said, there have been reports that the initiation of NAC therapy more than 24 hours after ingestion appeared to have been of benefit.

7. Answer: C The patient ingested a potentially toxic dose of aspirin and is mildly symptomatic upon presentation. Repeat salicylate levels should be obtained and repeated every 2 hours until a peak and decline is noted. The level and clinical presentation of A.J. do not warrant dialysis at this time. The patient is tachypneic on admission, so he might be at higher risk of aspiration. Activated charcoal probably should be avoided for this reason. 8. Answer: C Metoprolol is on the list of agents that can cause serious harm in one or two doses. Although warfarin is of concern, an antidote is available, and significant clinical effects are not expected. Metformin may cause lactic acidosis in an overdose setting, but bradycardia and hypotension can be caused by β-blockers, which have more immediate implications. 9. Answer: B As with any patient (except in cases of severe cardiac failure), fluid boluses should be the first step in the management of bradycardia (Answer C is incorrect). However, because β-blockade is occurring, glucagon is a best next step over epinephrine for more efficient and effective improvement in heart rate and hypotension (Answer D is incorrect). Although calcium may be used in the setting of a β-blocker overdose, its use is not likely to precede that of at vasopressor such as epinephrine (Answer A is incorrect). 10. Answer: D Given that the patient had an elevated lead level and was encephalopathic, the best option would be BAL (which will cross the blood-brain barrier) followed by edetate calcium disodium. Oral succimer is probably not a good option at this point because the patient is displaying severe symptoms. WBI is not necessary because the lead poisoning in this case is probably from chronic exposure. 11. Answer: B Both RIG and vaccine are recommended for all sleeping people and unattended children present in a room with a bat because bat bites may be painless and difficult to detect. The Centers for Disease Control and Prevention also recommends prompt response and treatment within 24 hours.



12. Answer: B Because R.V.’s serum calcium was a little low, he should receive another bolus. From there, a vasopressor infusion (such as epinephrine) should be considered. Although high-dose insulin euglycemic therapy has been shown to be effective in the management of calcium channel blocker overdoses, it is unlikely that it will supersede calcium in the setting of low serum calcium. Likewise, lipid emulsion therapy should be considered a last resort. 13. Answer: D HIE therapy has been reported to be effective at a range of 0.1–1 unit/kg/hour. R.V. is at the higher end of the range and has been stable from a cardiovascular perspective for a number of hours. One could consider abrupt discontinuation of HIE therapy, but it is preferable to wean the rate of insulin infusion over time; therefore, bluntly stopping the HIE therapy is not ideal. He is already receiving a large amount of fluid with his dextrose 25% , so if it were decided to increase dextrose amount, then an increase in dextrose concentration should be considered.



ANSWERS AND EXPLANATIONS TO SELF-ASSESSMENT QUESTIONS 1. Answer: D The Institute of Medicine released the To Err Is Human report in 1999. 2. Answer: C The National Coordinating Council for Medication Error Reporting and Prevention provides the standard scoring and classification system for medication safety events. 3. Answer: C There is no primary literature supporting the two-clinician independent double-check decreasing medication errors. 4. Answer: D See ISMP’s rank order of error reduction strategies in the text. 5. Answer: C If the patient and scenario indicate that it is appropriate to perform gastric decontamination, WBI is the most likely gastric decontamination measure to be used in iron overdoses. Charcoal does not bind to iron, and because of the invasiveness of gastric lavage, there is no role for its use in poisoned patients. 6. Answer: B The patient has an elevated heart rate, mydriasis, dry mucous membranes, and decreased urine output. The last two symptoms (dry membranes and decreased urine output) help differentiate anticholinergics from sympathomimetics, so an anticholinergic medication is most likely to be involved in this patient’s symptoms. 7. Answer: D Children less than 6 years of age account for the most exposures reported to poison control centers, most of whom are children age 1–3 years. Because of their oral exploration of their surroundings and desire to emulate adults, these exposures are often unintentional general (e.g., exploratory ingestions). Unintentional therapeutic exposures and malicious exposures also occur, but not to the same extent as unintentional general exposures. 8. Answer: A Glyburide is on the list of medications that could harm a child in a single dose. Profound hypoglycemia can occur, especially in children, who have decreased glycogen stores and are at high risk for severe, persistent hypogly-

cemia. There is no role for home management of pediatric ingestions of glyburide. 9. Answer: C The first steps in managing any patient are the ABCs (airway, breathing, and circulation). The patient is exhibiting signs of potential airway compromise from his unresponsive state, so he should be intubated. His cardiovascular system also needs to be addressed, but at present he does have a pulse and a blood pressure (Answers A, B, and D are incorrect). He will need to receive a fluid bolus, then specific treatments for b-blocker overdoses (glucagon, then catecholamines, then calcium or high-dose insulin). 10. Answer: D A level greater than 500 mg/dL is considered toxic and warrants treatment (Answer C is incorrect). Deferoxamine can be administered intravenously, subcutaneously, or intramuscularly. It is thought that intravenous administration is preferred over subcutaneous or intramuscular in severely poisoned patients because it is more reliable, eliminating the need for absorption before distribution (Answer B is incorrect). Deferoxamine is administered as a continuous infusion (Answer A is incorrect); therefore, 15 mg/kg/hour intravenous continuous (Answer D) is the most appropriate. 11. Answer: B According to the Rumack nomogram, levels greater than 150 mcg/mL at 4 hours after ingestion warrant NAC therapy (Answer D is incorrect). Obtaining a level before 4 hours will not capture the peak with certainty and therefore will not be useful with assessing risk with the Rumack nomogram (Answer A is incorrect). The level of 90 mcg/mL at 4 hours and 10 mcg/mL at 12 hours fall below the treatment line on the nomogram (Answers C and D are incorrect). The most difficult part of using the Rumack nomogram is being able to trust the time since ingestion, so it is best to also check LFTs to monitor for hepatic damage. It is also important to remember that the nomogram does not apply to chronic ingestions and to patients with underlying hepatic impairment. 12. Answer: B The Centers for Disease Control and Prevention recommends both active and passive immunity for bat bites if the bat cannot be captured to rule out rabies. For patients with open wounds, RIG is recommended to be administered directly into the wound.
