1488 SECTION XII I Pediatric Critical Care Pharmacology and Toxicology trained, board certified toxicologists Other resources include pill identification through the National Library of Medicine’s Pil[.]
1488 S E C T I O N X I I I Pediatric Critical Care: Pharmacology and Toxicology TABLE Toxins Reported From 2013–17 as Cause 125.1 of Death in Children ,20 Years Drug Class Examples Alcohols Ethanol, methanol Analgesics Opiates, acetaminophen, ibuprofen, salicylates Anesthetics Local anesthetics Anticholinergic Glycopyrrolate Anticonvulsants Lamotrigine, valproic acid Antidepressants TCAs, SSRIs, SNRIs Antihistamines Diphenhydramine, hydroxyzine Antimicrobials Antibiotics, antiparasitics, antifungals Batteries Disc batteries, other miscellaneous batteries Bites and envenomation Bees, snakes Cardiovascular drugs Antiarrhythmics, calcium channel blockers, clonidine Chemicals Silicone, cyanide, ethylene glycol, nitrates, hydrogen sulfide Cleaning substances, household Disinfectants, laundry detergent, hypochlorite Cold and cough preparations Benzonatate, dextromethorphan Deodorizers Air fresheners Dietary supplements/ herbals/homeopathic Energy drinks Electrolytes and minerals Iron, magnesium hydroxide, cesium chloride Fumes, gases, vapors Carbon dioxide, carbon monoxide, helium Gastrointestinal preparations Antidiarrheals, antacids, antispasmodics, laxatives Hormones and hormone antagonists Hypoglycemics, estrogens, androgens, corticosteroids Hydrocarbons Transmission fluids, power steering fluids, dry cleaning agents, lamp oil, gasoline, kerosene, lighter fluid Narcotic antagonists Naltrexone Pesticides Fumigants, fungicides, herbicides, insecticides Plants Cyanogenic glycoside, cardiac glycoside, hallucinogenic Sedative/hypnotics/ antipsychotics Quetiapine, benzodiazepines Stimulants and street drugs Heroin, MDMA, amphetamines, methamphetamines, cocaine, LSD, 4-acetoxy-N,N- dimethyltryptamine (psilacetin), THC homologs (K2) Tobacco /e-cigarette products Nicotine LSD, Lysergic acid diethylamide; MDMA, 3,4-methylenedioxy-N-methamphetamine; SNRIs, serotonin-norepinephrine reuptake inhibitors; SSRIs, selective serotonin reuptake inhibitors; TCAs, tricyclic antidepressants; THC, tetrahydrocannabinol trained, board-certified toxicologists Other resources include pill identification through the National Library of Medicine’s Pillbox (http://pillbox.nlm.nih.gov/pillimage/search.php), the National Capital Poison Center’s National Battery Ingestion Hotline (http://www.poison.org/battery or 800-498-8666), and the World Health Organization’s world directory of poison centers (http://www.who.int/gho/phe/chemical_safety/poisons_centres/en/).19 These resources are listed in Box 125.3 General Assessment of the Poisoned Patient History When a patient presents with acute onset of symptoms with multiorgan system involvement and/or a puzzling clinical picture, especially within the two common age ranges (less than years old or teenager), poisoning or intoxication should be suspected An accurate history is vitally important in the diagnosis of an unknown poisoning Surprisingly, the physician in the ICU may be the first health professional who can sit with parents and carefully review the circumstances of the exposure Poisonings may occur by various routes, including ingestion, inhalation, ocular exposure, dermal exposure, mucous membrane involvement, or parenteral exposure Once the child’s condition has been stabilized, the clinician should query the family about the incident, with particular attention to the environmental, patient, and toxic agent factors as outlined in Table 125.3 The importance of obtaining precise ingredients or package contents for any known substance cannot be overemphasized Parents should bring the product containers and medication labels Parents may minimize their description of the child’s exposure to a toxin in an attempt to deny the threat of injury or to assuage their guilt that such an episode occurred Therefore, it is prudent to assume a worst-case scenario in calculating the dose exposure of a drug or household product, using the maximum number of missing tablets or amount of liquid, the concentration of the drug or chemical, and the child’s weight The latency between the time of ingestion and onset of symptoms is important The tempo of progression of symptoms and signs also may help the clinician gauge the severity of the intoxication and the urgency with which intervention is necessary However, there are some exceptions to this rule Patients poisoned by some toxins, such as paraquat and the Amanita mushroom toxin, may have a relatively symptom-free period of 12 hours or more but then manifest life-threatening pulmonary or hepatic toxicity, respectively.20,21 Some drugs, such as sulfonylurea hypoglycemics and valproic acid, can also have similar latency periods before the onset of severe toxicity.22,23 Iron is well known to have a gastrointestinal phase followed by a relatively symptom-free phase known as the latent or quiescent phase, which is then followed by shock and metabolic acidosis.24 Adding another degree of difficulty, some drugs—such as salicylates and carbamazepine—can form bezoars, which can alter when symptoms are present relative to when the drug was ingested.19 Adolescent poisonings are confounded by the intentionality of the episode and unreliability of the adolescent’s history as well as the increased likelihood of a polysubstance ingestion Adolescents in distress may be evasive, misleading, or uncommunicative Their ability to remember or provide a coherent account of what happened may be distorted by the effects of the drugs taken The clinician cannot assume that the time of exposure, dose, or even the toxic agents themselves are accurately recounted CHAPTER 125 Principles of Toxin Assessment and Screening 1489 TABLE a 125.2 Pharmaceuticals Dangerous to Toddlers In 1- to 2-Unit Doses Drug Class Examples Toxicity TCAs Amitriptyline, imipramine, desipramine CNS depression, seizures, arrhythmia, hypotension Antipsychotics (first generation) Thioridazine, chlorpromazine, loxapine Dysrhythmias, hypotension, coma, renal failure, seizures Antipsychotics (second generation) Ziprasidone, clozapine Hypotension, dysrhythmias, CNS depression Antimalarials Chloroquine, hydroxychloroquine, quinine Seizures, arrhythmia, bradycardia, CNS depression Antiarrhythmics Quinidine, disopyramide, procainamide, flecainide ivabradine, propafenone Seizures, arrhythmia Calcium channel blockers Nifedipine, verapamil, diltiazem Bradycardia, hypotension Opioids Codeine, hydrocodone, methadone, morphine, tramadol, oxycodone, fentanyl, buprenorphine Respiratory depression Oral antihyperglycemics Chlorpropamide, glyburide, glipizide, repaglinide, glimepiride, sitagliptin Hypoglycemia Antiplatelets/oral anticoagulants Ticagrelor, prasugrel, clopidogrel, rivaroxaban, dabigatran Hemorrhagic shock Antiepileptics Gabapentin, pregabalin, lamotrigine Hypotension, CNS depression Multiple sclerosis drugs Dalfampridine, fingolimod AMS, seizures, metabolic acidosis, cardiac arrest Bronchodilator Theophylline Seizures, arrhythmia, rhabdomyolysis, hypotension SNRI Venlafaxine Serotonin syndrome, cardiac arrest, seizures, coma, rhabdomyolysis PDE-5 inhibitor Sildenafil Hypotension, CNS depression, cerebral ischemia Antitussive, thermal agent Camphor Seizures, respiratory depression Salicylates Methyl salicylate (oil of wintergreen) Metabolic acidosis, seizures, coma, cerebral edema, pulmonary edema Keratolytic agent Podophyllin Coma, respiratory failure, hypotension a unit dose tablet/capsule or teaspoonful of a liquid formulation AMS, Altered mental status; CNS, central nervous system; PDE-5, phosphodiesterase-5; SNRIs, serotonin-norepinephrine reuptake inhibitor; TCAs, tricyclic antidepressants • BOX 125.3 Resources for the Clinician US Regional poison control center: 800-222-1222 Pill identification: https://pillbox.nlm.nih.gov/index.html Battery ingestion hotline: http://www.poison.org/battery/ or 800-498-8666 World directory of poison centers: http://www.who.int/gho/phe/chemical_safety/poisons_centres/en/ TABLE 125.3 History Taking and Unknown Poisoning in the Pediatric Patient Environment Patient Toxin Witnesses Intentionality Agent(s) involved Time of ingestion Past medical problems Exact ingredients Site of ingestion Current medications Dose (maximum estimated) Illness of family member Known drug allergies Concentration (strength) Medications of family members Time of symptom onset Route of exposure Open containers Prior medical management Formulation (enteric coated or extended release) Substances found in patient’s mouth or hands 1490 S E C T I O N X I I I Pediatric Critical Care: Pharmacology and Toxicology Physical Examination The physical examination is crucial for assessment of the patient’s medical stability and for identification of the unknown poison As with any critically ill patient, the first priority is assessment and stabilization of the airway, breathing, and circulation (ABCs) Once completed, attention can be turned to observations that may lead to a diagnosis Specific changes in vital signs and symptoms can be associated with likely toxins or groups of toxins Such characteristic clinical patterns of illness are sometimes termed toxidromes Table 125.4 lists some of the more common toxidromes One should bear in mind that the patient presentation may not exactly follow one of these toxidromes owing to variabilities in individual response to a drug, especially in cases of polysubstance exposure The gastrointestinal tract is often involved early in a poisoning, with findings such as nausea, vomiting, abdominal pain, and diarrhea Many times an elevated temperature is associated with overdoses involving cocaine, phenothiazines, atropine, or salicylates Table 125.5 lists examples of drugs and toxic agents associated with specific effects on the cardiovascular system Toxins may cause hypertension or hypotension by direct effects on vascular smooth muscle, neurogenic effects on autonomic nervous centers governing vascular innervation, direct effects on the heart, or renal effects Specific agents that can cause hypertension include adrenergic stimulants, such as amphetamines, cocaine, phencyclidine, phenylpropanolamine, ephedrine, and phenylephrine Although the hypertension caused by sympathomimetics frequently lasts only a few hours, it may be associated with acute encephalopathy and/or intracranial hemorrhage Acute hypotension may be the result of poisoning by aconite, antiarrhythmic agents, antihypertensive agents, b-adrenergic antagonists, calcium channel antagonists, clonidine, tricyclic antidepressants (severe), iron (severe), opiates, or phenothiazines Tachycardia may be induced by ingestion of any of the sympathetic nervous system stimulants listed in Table 125.5 Tachycardia is also associated with ingestion of exogenous thyroid hormone preparations, the early phase of poisoning with tricyclic antidepressants, theophylline overdoses, and caffeine or nicotine intoxications Bradycardia may accompany exaggerated vagal responses to some compounds or direct negative chronotropic effects on the heart Interference with the cardiac conduction system may also cause bradycardia Cardiac drugs associated with bradyarrhythmias include the calcium channel antagonists, digitalis, and b-adrenergic antagonists Antiarrhythmic agents, such as quinidine and procainamide, can also cause bradycardia Aconite, an herbal remedy, binds to site of the open state of TABLE 125.4 Common Toxidromes in Pediatric Poisonings Signs and Symptoms Agent Dilated pupils, tachycardia, tachypnea, arrhythmias, hypertension, warm moist skin, pallor, sweating, agitation, nausea, vomiting, abdominal pain, delirium Sympathomimetic syndrome Miosis, salivation, vomiting, diarrhea, wheezing, bronchorrhea, lacrimation, seizures, weakness, tremors, coma, respiratory failure, bradycardia, urinary frequency Organophosphate insecticides (cholinergic toxidrome) Fever, tachypnea, hyperpnea, sweating, lethargy, metabolic acidosis (late), nausea, vomiting, tinnitus, seizures (late), coma (late) Salicylates Seizures, metabolic acidosis, history of tuberculosis, hyperglycemia Isoniazid Dry mouth and skin, flushed appearance, dilated pupils, fever, ileus, urinary retention, disorientation Anticholinergic syndrome Oculogyric crises, dystonia, opisthotonus Phenothiazines Severe metabolic acidosis, sluggish pupils, hyperemic retina, blurred vision Methanol Hypoglycemia, lethargy, ataxia, seizures, characteristic breath odor Ethanol Lethargy or coma, metabolic acidosis, active urinary sediment, crystalluria Ethylene glycol Headache, flulike symptoms, lethargy, dizziness, coma Carbon monoxide Pinpoint pupils, coma, respiratory depression, hypothermia, pulmonary edema, constipation Opiate Hyperthermia, akathisia, mydriasis, diarrhea, hyperreflexia, clonus, seizures, autonomic dysfunction, agitation, delirium, rhabdomyolysis Serotonin syndrome Metabolic acidosis, prolonged QRS interval, coma, seizures, dilated pupils, dysrhythmias Tricyclic antidepressants Protracted vomiting, tremors, tachycardia, anxiety, seizures, hypotension Theophylline Feeling of impending doom, sudden coma, metabolic acidosis, hypotension, almond odor Cyanide Rotatory nystagmus, delirium; “4 Cs”—combative, catatonia, convulsions, coma Phencyclidine Fever, “lead-pipe” rigidity, mental status changes, autonomic instability (tachycardia, tachypnea, labile or high blood pressure, dysrhythmias, diaphoresis) Neuroleptic malignant syndrome: antipsychotics, antiemetics Anxiety, agitation, insomnia, tremor, diaphoresis, palpitations, headache, loss of appetite, nausea/vomiting, tachycardia, seizures, hallucinations or other psychotic symptoms, autonomic hyperactivity (fever, tachycardia, hypertension, drenching sweats) Withdrawal syndromes: ethanol, sedative hypnotics (benzodiazepines or barbiturates), baclofen, GHB (g-hydroxybutyrate) Anxiety, restlessness, tachycardia, diaphoresis, gastrointestinal distress Opioid withdrawal CHAPTER 125 Principles of Toxin Assessment and Screening TABLE 125.5 Toxins Associated With Cardiovascular Findings Sign Agents Tachycardia Amphetamines Antihistamines Anticholinergics, atropine, belladonna Aconite Caffeine Cocaine Cardiac glycosides b-Adrenergic agonists (albuterol, terbutaline) Nicotine Sympathomimetic agents Theophylline Bradycardia Aconite Antiarrhythmics b-Adrenergic blockers Calcium channel blockers Cardiac glycosides Clonidine Ergotamine Opiates Organophosphate pesticides Phenylpropanolamine Quinidine Sedatives/hypnotics Torsades des pointes Amantadine Antiarrhythmics Amiodarone Arsenic Astemizole Chloral hydrate Chloroquine Cisapride Cyclic antidepressants Disopyramide Encainide Fluoride Lidocaine Mexiletine Organophosphates Terfenadine Quinidine Procainamide Pentamidine Phenothiazines Prenylamine Suxamethonium Ventricular tachycardia Aconite Amphetamines Antiarrhythmics (e.g., quinidine, flecainide) Carbamazepine Chloral hydrate Chlorinated hydrocarbons Cocaine Cyclic antidepressants Digitalis Theophylline Thioridazine 1491 voltage-sensitive sodium channels, which then become refractory to excitation and cause arrhythmias.25 Drugs with cardiotoxic effects are among those most associated with life-threatening toxicity In one 10-year retrospective study, 15 out of 17 poisoned patients requiring extracorporeal life support measures for refractory shock or prolonged cardiac arrest had overdosed on a cardiotoxic agent.26 Many drugs and chemicals depress a patient’s consciousness either directly or through hypoxia due to decreased respiratory drive or asphyxia The dynamic nature of a poisoning mandates serial assessments of consciousness using an objective scoring system, such as the Glasgow Coma Scale (GCS), to gauge accurately whether the patient’s overall condition is deteriorating or improving In many serious intoxications, such as carbon monoxide or cyanide poisoning, the state of consciousness may be the single best indicator of the patient’s overall prognosis Pupil size depends on the balance between dilating and constricting fibers and is under complex autonomic nervous system control Both sympathetic and parasympathetic nerves regulate the iris and can be affected by a variety of toxins Anticholinergic drugs—such as tricyclic antidepressants, antihistamines, and belladonna— paralyze the parasympathetic fibers leading to pupillary dilation Conversely, agents that inactivate cholinesterase, leading to accumulations of acetylcholine (e.g., organophosphate pesticides, physostigmine), constrict the pupil Ethanol, phenothiazines, and barbiturates also constrict the pupils Opiates act centrally to cause extreme pupillary constriction (miosis) Sympathomimetics, such as amphetamines and cocaine, cause extreme pupillary dilation (mydriasis) Pilocarpine directly stimulates the sphincter muscle of the iris, causing constriction Toxins can also be responsible for unequal pupil size Instillation of atropine to the eye causes ipsilateral pupillary dilation Polydrug overdoses may include agents with opposite pupillary actions; thus, overreliance on pupil size alone in deciding which poison is responsible for the patient’s condition may lead to a misdiagnosis Closed head trauma or central nervous system (CNS) hemorrhage, sometimes seen in the context of a poisoning with hypertension-inducing drugs such as phenylpropanolamine or ephedrine, can themselves cause pupillary effects.27 When treating a disoriented, delirious pediatric patient, the clinician must consider which intoxications may be responsible Because of their central anticholinergic effects and common availability, antihistamines (e.g., chlorpheniramine, diphenhydramine) must be considered Alcohol-containing household products or liquor may be responsible In the adolescent, substances of abuse may cause delirium or hallucinations Jimsonweed (Datura stramonium) plant seeds containing atropine and other anticholinergic chemicals can be intentionally chewed by adolescents for their euphoric (and delirium-producing) effects caused by a central anticholinergic syndrome Hallucinogens include lysergic acid diethylamide (LSD), psilocybin (“magic mushrooms”), mescaline, and some amphetamine congeners (“designer drugs,” e.g., 3-methoxy 4,5-methylenedioxyamphetamine [MMDA], 3,4-methylenedioxyN-methamphetamine [MDMA, “ecstasy”], or 3,4-methylenedioxyN-ethylamphetamine [MDEA]) Both cocaine and amphetamines can cause an acute psychosis Smokable forms of methamphetamine (known as “crystal” or “ice”) and phencyclidine (PCP) cause symptoms of agitation, aggression, and combativeness Additionally, intensivists should be alert for abstinence syndromes in adolescents suffering from chronic substance abuse Drug withdrawal from opiates, benzodiazepines, or alcohol (delirium tremens) often causes agitation, irritability, or even delusional thinking in affected patients Withdrawal from chronic use of g-hydroxybutyrate (GHB; a popular “designer drug”) is 1492 S E C T I O N X I I I Pediatric Critical Care: Pharmacology and Toxicology characterized by anxiety, insomnia, tremor, confusion, delirium, hallucinations, cardiovascular changes, nausea, vomiting, and diaphoresis.28 Other neurologic findings may be found depending on the drug or toxin Phenytoin and PCP frequently cause nystagmus Opsoclonus (saccadic eye movements) can be caused by lithium Tinnitus is associated with ingestions of ergot, quinine, salicylates, or streptomycin Changes in color vision may be seen in chronic digitalis overdose or cinchonism (quinidine) Many poisonings cause cutaneous manifestations These displays can be especially important when differentiating between anticholinergic and sympathomimetic ingestions, which cause dry/flushed skin or diaphoretic/pale skin, respectively Abusers of intravenous narcotics or other drugs may have needle tracks, characteristic tattoos, or scarring from “skin popping.” The latter are round papules and plaques typically found on the extremities as a result of injecting illicit drugs into the skin.29 Those suffering from inhalant abuse frequently have rashes around the nose and mouth as a result of defatting and irritative effects of inhaled solvents Methemoglobinemia can cause an acute cyanotic appearance despite relatively normal blood gas values A variety of rashes can be seen with adverse drug reactions and allergic responses to drugs, plants, or chemicals Typical chemical burns may result from dermal exposure to caustics Alopecia is associated with exposures to antimetabolite medications and other antineoplastic agents or with overdoses of chemicals such as arsenic, thallium, and selenium Jaundice may result from exposure to hepatotoxins such as carbon tetrachloride, aniline dyes, quinacrine, or phenothiazines The clinician must be alert to characteristic odors in containers found at the scene of the exposure, of substances spilled on the patient’s skin or clothing, or on the patient’s breath Organophosphate insecticides and thallium impart the strong odor of garlic Cyanide exposures have the characteristic aroma of bitter almond (although 50% of the population is of the genotype that cannot detect the odor) Ethanol, kerosene, camphor, and gasoline impart their strong odors to the breath Adolescents abusing glues or volatile organic compounds by inhalation may have a solvent smell on their breath and clothes Table 125.6 lists typical intoxications that can be diagnosed by the patient’s breath odors Laboratory Tests and Toxin Screens Specific drug identification by laboratory testing often does not change the medical management of a patient but can be very important when considering the social and legal aspects of cases involving children.30 However, it is also important to be aware of the limitations of laboratory testing Although laboratory testing of the blood or urine occasionally reveals an unanticipated toxin involved in an overdose, more frequently it confirms the physician’s clinical diagnosis on the basis of a careful history and physical examination The pediatric intensivist is well advised to know which compounds are included in the toxicology screen performed by their institution because this is variable and frequently based on cost, ease of detection, available technical equipment, and relative frequency of the overdose in the community, among other considerations Most hospitals include the following compounds on a toxicology screen: acetaminophen, ethanol, barbiturates, opiates, anticonvulsants, some benzodiazepines, phenothiazines, and salicylates Toxicology screens may or may not include certain drugs of abuse (e.g., amphetamines, cocaine, tetrahydrocannabinol), older tricyclic antidepressants (e.g., amitriptyline, imipramine), and methanol Many common toxic agents—including carbon monoxide, cyanide, methemoglobin, iron, lithium, heavy metals such as lead or arsenic, and ethylene TABLE Toxins Associated With Characteristic 125.6 Breath Odors Toxin Characteristic Odor Acetone Ketones Arsenic Garlic Camphor Mothballs Chloroform Sweet Cyanide Bitter almond Ethanol Fruity, alcohol Hydrogen sulfide Rotten eggs Isopropanol Ketones Methyl salicylate Wintergreen Nicotine Stale tobacco Organophosphates Garlic N-3-pyridylmethyl-N’-p-nitrophenyl urea Peanuts Paraldehyde, chloral hydrate Pears Phenol, cresol Phenolic Phosphorus, organophosphate pesticides Garlic Salicylates Acetone Selenium Garlic Thallium Garlic Turpentine Violets glycol—are never included in a routine toxicology screen and must be ordered specifically For these reasons, a “negative” toxicology screen does not rule out the diagnosis of a poisoning Similarly, it is important to keep in mind the possibility of a falsepositive result and the potential need for confirmatory testing using mass spectrometry.30a The more specific a clinician is in communicating with laboratory personnel about which toxins are suspected clinically, the more directed laboratory personnel can be in seeking specific answers through laboratory methods Because some toxins (e.g., cocaine, other drugs of abuse, some heavy metals) are detected more easily in urine than in the blood, both specimens should be submitted when the toxicology screen is ordered Reliability in the screening for drugs or toxins requires not only a sound analytic technique but also adequate sample collection, chain of custody, and timely reporting of the results Sources of error include delay in the time between sample collection and assay; problems with sample collection (wrong patient, wrong tube, loss of fluid, poor labeling); natural chemical reactions (volatilization, enzymatic degradation); purposeful sample alteration; technical limits on the detection threshold of the assay used; and misinterpretation of the units in reporting the results Other limits of laboratory testing should also be kept in mind For example, an ingestion of clonazepam or lorazepam may have a negative benzodiazepine screen on urine drug analysis because these two benzodiazepines not form the metabolite oxazepam for which urine drug screens test.31 Although not as frequently used in ICUs as blood and urine samples, it is still important for intensivists to be aware of the use of hair testing, as this is frequently encountered outside of the ICU.32 Blood concentrations of acetaminophen, aspirin, barbiturates, carbamazepine, carbon ... quinacrine, or phenothiazines The clinician must be alert to characteristic odors in containers found at the scene of the exposure, of substances spilled on the patient’s skin or clothing, or on the... any critically ill patient, the first priority is assessment and stabilization of the airway, breathing, and circulation (ABCs) Once completed, attention can be turned to observations that may lead... diarrhea Many times an elevated temperature is associated with overdoses involving cocaine, phenothiazines, atropine, or salicylates Table 125.5 lists examples of drugs and toxic agents associated