Principles of toxin assessment and screening









  • Poisoned patients are frequently encountered in the intensive care setting and often pose a diagnostic challenge. Skills in taking a history and performing a thorough physical exam, as well as knowledge of the common toxidromes and the appropriate use of laboratory and/or radiologic studies, are required.



  • Care of poisoned patients is mainly symptomatic and supportive, but some toxins can be treated with a reversal agent or require extracorporeal removal.



  • Some toxins are notable for the delay from time of ingestion to onset of symptoms (e.g., acetaminophen, Amanita mushroom poisoning, valproic acid, sulfonylureas). Others with a long duration of action, such as methadone or naltrexone, can have toxicity recrudescence hours after an apparent good response to an antidote.



  • Intensivists can often predict the severity of poisoning by noting the tempo of progression of a patient’s symptoms and signs of toxicity.



Despite increased public education and preventive measures such as child-safety caps, poisonings in children and adolescents continue to be common occurrences. Children younger than 5 years accounted for 45% of the approximately 2.1 million poison exposure calls taken by poison centers in 2017. The most common categories of products identified during such calls include analgesics, household cleaning substances, cosmetics/personal care products, sedatives/hypnotics/antipsychotics, antidepressants, antihistamines, cardiovascular drugs, foreign bodies, topical agents, cough and cold preparations, vitamins, pesticides, and plants. Among these categories, pharmaceuticals accounted for most of the severe poisoning outcomes. While human exposures with less serious outcomes have decreased 2.48% per year since 2008, those with more serious outcomes (moderate, major, or death) have increased 4.44% per year since 2000. Preschool children and children with developmental delays and pica—as occurs with autistic spectrum disorders—have an increased risk for poisoning. A second peak of serious poisonings occurs in adolescents, when suicide attempts by poisoning or toxicity related to substance abuse become common circumstances. Studies have shown that this latter group tends to be sicker and more frequently requires a higher level of care. Although many exposures are medically trivial, poisonings account for an important number of all pediatric hospital visits and hospitalizations and represent an estimated 3% to 8% of total pediatric intensive care unit (PICU) admissions on an annual basis. , Acute pediatric ingestions—particularly those that may progress to respiratory failure, complex arrhythmias, cardiovascular collapse, and/or status epilepticus—may require PICU admission for close monitoring, early supportive care, and advanced interventions until the drug is eliminated.


There are no current standardized criteria for admission to a PICU for poisoned patients. The exhaustive list of substances that may cause toxic manifestations in pediatric patients encumbers the development of generalizable guidelines. Studies have attempted to determine the percentage of patients admitted to a PICU who received interventions necessitating PICU admission. Only 30% of poisoned patients in one study received one of numerous defined PICU interventions. Factors in this study that were associated with a PICU intervention included (1) higher Pediatric Risk of Mortality III scores, (2) age younger than 2 years or older than 13 years, and (3) intentionality. However, the authors of the study also point out that not all reasons for admission to the PICU could be captured. The study’s investigators subsequently developed and prospectively validated a pediatric scoring model to identify children at low risk of clinically significant ingestions: Reduce Childhood Admissions to the PICU for Poisoning (RECAP2). The RECAP2 model defined clinically significant ingestions requiring PICU admission as those with one or more of the following features: (1) ingestion of clonidine, ethanol, or oral antihyperglycemic agents; (2) exposure to carbon monoxide; (3) onset of symptoms occurring within 2 hours of an immediate-release formulation; and/or (4) onset of symptoms occurring within 4 hours for an extended-release formulation. Real-time application of the RECAP2 model reduced PICU admissions by 32%. , Another pediatric study identified risk factors for a poisoned patient to have an adverse cardiovascular event (ACVE), myocardial injury, shock, ventricular dysrhythmia, or cardiac arrest, or death. This study found that two previously derived predictors of ACVEs in adults also applies to pediatric exposures: QTc of 500 ms or greater or serum bicarbonate concentration less than 20 mEq/L. They also found that adolescent age and exposure to either a cardiovascular drug or to an opioid were independently associated risk factors ( Box 125.1 ). These are additional factors that may indicate a need for an ICU admission.



• BOX 125.1

Predictors for Increased Odds of Adverse Cardiovascular Events in Pediatric Poisonings





  • QTc ≥500 ms



  • Serum bicarbonate <20 mEq/L



  • Opioid drug exposure



  • Cardiovascular drug exposure



  • Adolescent age (≥13 years)




The mainstay of therapy for most poisoned patients is supportive care, which can range from administration of intravenous fluids and close cardiorespiratory monitoring to extracorporeal removal and support. If the patient is critically ill and a specific toxic syndrome with a known antidote is not identified, the intensivist may consider a mode of enhanced elimination, the most common being hemodialysis. A list of toxins for which hemodialysis may be indicated is included in Box 125.2 . , Recently, there has been more examination of the use of extracorporeal treatments in the management of poisoned patients. The Extracorporeal Treatments in Poisoning (EXTRIP) work group consists of experts from the fields of nephrology, clinical toxicology, critical care, and pharmacology. This group has convened to provide uniform recommendations on when such treatments should be used for acetaminophen, barbiturates, carbamazepine, digoxin, lithium, metformin, methanol, phenytoin, salicylates, thallium, theophylline, tricyclic antidepressants, and valproic acid. Both specific toxins and plasma concentrations for these toxins are included in these recommendations. While not all toxins have been explored by this work group to date, future toxins to be explored include baclofen, ethylene glycol, methotrexate, isoniazid, calcium channel blockers, β-blockers, dabigatran, gabapentin/pregabalin, quinine/chloroquine, and amatoxins. , In severe poisonings refractory to extracorporeal removal, extracorporeal membrane oxygenation (ECMO) is a supportive treatment modality that has been used when cardiac arrest or refractory hypotension develops after poisoning. The use of ECMO for toxicologic exposures was described in a 2010 to 2013 retrospective analysis of the Toxicology Investigators Consortium (ToxIC) database of the American College of Medical Toxicology. ECMO was used with an 80% survival rate by supporting cardiovascular hemodynamics and oxygenation while the xenobiotic was metabolized and/or eliminated for the following toxicologic exposures: carbon monoxide/smoke inhalation, metformin, flecainide, methanol, diphenhydramine + quetiapine, bitter almonds (cyanide), verapamil + citalopram, metformin + trazodone + clonazepam, and diphenhydramine + tramadol. This study showed that although used rarely (<1% of 26,271 exposures), ECMO may be an effective treatment modality for severe poisonings. In another series of 12,021 children with acute ingestions admitted to a PICU setting, the most frequent PICU intervention was airway and respiratory support, accounting for 63% of all PICU interventions.



• BOX 125.2

Toxins Removable Via Hemodialysis





  • Acetaminophen



  • Barbiturates



  • Carbamazepine



  • Ethylene glycol



  • Lithium



  • Metformin



  • Methanol



  • Salicylates



  • Isopropanol



  • Theophylline



  • Valproic acid



  • Thallium



  • Digoxin




Common agents involved in serious pediatric poisonings


The agents most frequently involved in serious pediatric poisonings include prescription medications (e.g., cyclic antidepressants, anticonvulsants, cardiovascular-acting drugs, opiates), alcohols, carbon monoxide, caustic agents, and hydrocarbon-based household products. See Table 125.1 for a list of the toxins reported as the cause of death in children age younger than 20 years in the last 5 years. , The types of medications to which children and adolescents are frequently exposed have shifted concordantly with the rise in the opiate epidemic and legalization of marijuana in some states. , Children may be more susceptible than adults to opiate-induced respiratory depression as a result of a developmental age-related increase in the activity of P-glycoprotein, a transporter at the blood-brain barrier responsible for removal of some opiates and their metabolites. Clinicians should ask caretakers about the types and doses of any medications, including those available over the counter (e.g., cough and cold preparations and gastrointestinal preparations, such as loperamide), herbs, vitamins, diet supplements, or ethnic remedies being given to their child. Such therapies may interact with the toxins responsible for the poisoning or otherwise contribute to the child’s toxicity. Families are using herbs and diet supplements with increasing frequency to treat their children’s illnesses or simply to promote their general well-being, and serious poisonings in which herbs and dietary supplements are implicated are appearing in the medical literature. Clinicians should keep in mind that some pharmaceutical agents can be life-threatening to toddlers in only one or two doses. For a list of these drugs, see Table 125.2 . If a patient is known or suspected to have ingested one of these drugs, supportive care and close observation as well as a possible specific treatment can be instituted sooner. Additional attention should be paid when the patient is an international adoptee or a child immigrating to the United States as these patients may have been exposed to lead, arsenic, or other toxins in a polluted environment in their home country or by their family’s use of poorly regulated remedies.



TABLE 125.1

Toxins Reported From 2013–17 as Cause 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.


TABLE 125.2

Pharmaceuticals Dangerous to Toddlers In 1- to 2-Unit Doses a












































































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

AMS, Altered mental status; CNS, central nervous system; PDE-5, phosphodiesterase-5; SNRIs, serotonin-norepinephrine reuptake inhibitor; TCAs, tricyclic antidepressants.

a 1 unit dose = 1 tablet/capsule or 1 teaspoonful of a liquid formulation.



Resources for the clinician


In making the diagnosis of an unknown poisoning, one must often rely on clues obtained from a thorough history and physical examination. Laboratory analyses and radiographic findings are sometimes helpful. The regional poison control center (US telephone: 800-222-1222) can provide consultative services by medically trained, board-certified toxicologists. Other resources include pill identification through the National Library of Medicine’s Pillbox ( pillbox.nlm.nih.gov.easyaccess1.lib.cuhk.edu.hk/pillimage/search.php ), the National Capital Poison Center’s National Battery Ingestion Hotline ( www.poison.org/battery or 800-498-8666), and the World Health Organization’s world directory of poison centers ( www.who.int.easyaccess1.lib.cuhk.edu.hk/gho/phe/chemical_safety/poisons_centres/en/ ). These resources are listed in Box 125.3 .



• BOX 125.3

Resources for the Clinician






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 5 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.



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

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Jun 26, 2021 | Posted by in CRITICAL CARE | Comments Off on Principles of toxin assessment and screening
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