32: Toxicology and Drug Reactions


CHAPTER 32
Toxicology and Drug Reactions


Neha N. Goel1, Stephanie Hernandez1, and Lisa Rho2


1 Icahn School of Medicine at Mount Sinai, New York, NY, USA


2 Reid Health, Richmond, IN, USA


Background


Definition of disease



  • Specific toxic syndromes or toxidromes are a symptom complex of a specific poisoning.
  • Given the similarities of the pharmacology of many toxins, treatment can be tailored to various toxidromes based on clinical presentation.

Incidence/prevalence



  • In its 2014 annual report, the American Association of Poison Control Centers compiled data from 56 poison centers in the USA, which reported a total of 2 165 142 human toxin exposure cases, 58% of which were adult exposures.
  • The five substance classes most frequently involved in all human exposures were analgesics (11.3%), cosmetics/personal care products (7.7%), household cleaning substances (7.7%), sedatives/hypnotics/antipsychotics (5.9%), and antidepressants (4.4%).

Etiology



  • The etiology of a poisoning is variable and can be from intentional drug overdose, illicit drug abuse, unintentional drug interactions, or environmental or occupational toxin exposures.

Prevention


Primary prevention



  • Community, family, and school‐based programs implemented in early childhood can help mitigate the risk of drug and alcohol abuse.
  • Educate patients regarding safe use, storage, side effects, and interactions of all prescription and over‐the‐counter medications.

Secondary prevention



  • Drug and alcohol rehabilitation as well as psychiatric evaluation should be considered when appropriate.

Diagnosis


Differential diagnosis


It is important to consider alternative or coexisting conditions for altered mental status other than toxin and drug ingestion such as sepsis, stroke, and seizures.


Typical presentation


The typical presentation of an intoxicated patient involves altered mental status as well as alteration of vital signs and physical exam findings specific for each toxidrome. Detailed presentations of the different toxidromes and associated drugs are listed in Table 32.1.


Clinical diagnosis


History



  • A history from an altered patient is usually unreliable. Efforts should be made to obtain the types and quantities of prescribed, over‐the‐counter, or illicit drugs that the patient may have ingested.
  • Emergency responders, friends, family members, and outpatient pharmacists can help provide information.

Physical examination:


See Table 32.1 for the typical presentations and different physical exam findings for different toxidromes.


Useful clinical decision rules and calculators



  • The Rumack–Matthew nomogram for acetaminophen ingestion uses time from ingestion and acetaminophen level to determine if N‐acetylcysteine should be administered (https://www.mdcalc.com/acetaminophen‐overdose‐nac‐dosing).

    Table 32.1 Presentation of common toxidromes.




























































































    Toxidrome Temp BP/HR Resp rate Mentalstatus Pupils Mucousmembranes Reflexes Other common findings Associateddrugs/toxins
    Anticholinergic Delirium Mydriasis Dry ‘Hot as a hare, dry as a bone, red as a beet, mad as a hatter, blind as a bat’ Antihistamines
    Atropine
    Benztropine
    TCA
    Scopolamine
    Phenothiazines
    Cholinergic ↑− Variable Miosis Wet SLUDGE: salivation, lacrimation, urination, defecation,GI diarrhea, emesis, bronchorrhea Organophosphates
    Carbamates
    Physostigmine
    Pilocarpine
    Edrophonium
    Nicotine alkaloids
    Neuroleptic malignant syndrome ↑− Variable Diaphoretic Lead pipe rigidity, bradykinesia Haloperidol
    Phenothiazines
    Risperidone
    Olanzapine
    Chlorpromazine
    Opiate ↓− ↓− ↓↓ Decreased LOC Miosis ↓− Respiratory arrest Heroin
    Morphine
    Fentanyl
    Methadone
    Meperidine
    Sedative‐hypnotic ↓− ↓− ↓− Decreased LOC Miosis to no change ↓− Respiratory arrest Benzodiazepines
    Alcohols
    Barbiturates
    Serotonin syndrome ↑− ↑− Variable Mydriasis Diaphoretic ↑↑ Tremor, shivering, diarrhea, clonus, lower extremity rigidity Antidepressants
    Meperidine
    Trazadone
    Triptans
    Sympathomimetic Activating Mydriasis Diaphoretic Hypokalemia, metabolic acidosis, agitation, hallucinations Cocaine
    Amphetamines
    Ephedrine
    Pseudoephedrine
    Theophylline

Laboratory diagnosis


List of diagnostic tests



  • Initial laboratory tests should include a comprehensive metabolic panel, complete blood count, and arterial blood gas. Serum levels of acetaminophen, salicylates, and ethanol should be assessed.
  • Serum and urine drug assays can help identify exposures to different drugs or their metabolites but cannot confirm that they are the reason for the poisoning. It is important to identify the specific toxin through history, physical exam, and clinical toxidrome and use these assays as validating tests.
  • The serum anion gap, osmolal gap, and oxygen saturation gap can help narrow down specific toxins:

    • Serum anion gap = [Na+] – ([Cl] + [HCO3 ]).

      • An elevated serum anion gap of >12 mEq/L is usually seen with ingestions of salicylates, methanol, ethylene glycol, isoniazid, paraldehyde, formaldehyde, NSAIDs, and metformin.
      • A low serum anion gap of <7 mEq/L is seen with ingestion of lithium.

    • An osmolal gap reflects the presence of an osmotically active substance, usually an alcohol, that has been ingested. It is the difference between the measured and the calculated osmolality of a serum.

      • Calculated osmolality (Osmcalculated) = 2[Na+ (mmol/L)] + [urea (mg/dL)]/2.8 + [glucose (mg/dL)]/18 + [ethanol (mg/dL)]/4.6.
      • Osmolal gap (normal <10) = Osmmeasured – Osmcalculated.
      • Causes of an elevated osmolal gap are acetone, isopropanol, mannitol, methanol, ethylene glycol, formaldehyde, and paraldehyde.

    • Winter’s formula can be used to calculate the expected PCO2 compensation in a pure metabolic acidosis.

      • PCO2 = 1.5 × HCO3 + 8 ± 2.
      • It identifies a mixed acid–base disorder, often a respiratory acidosis, reflecting inadequate respiratory compensation for the metabolic acidosis. This signifies the patient’s need for non‐invasive or invasive positive pressure ventilation.
      • Salicylate toxicity usually produces a mixed metabolic acidosis and respiratory alkalosis.

    • The oxygen saturation gap is the difference between the percentage oxygen saturation on an arterial blood gas and the percentage saturation measured by multi‐wavelength co‐oximetry.

      • The oxygen saturation gap is usually elevated from the presence of carboxyhemoglobin, methemoglobin, or sulfhemoglobin.
      • Cyanide poisoning does not result in an elevated oxygen saturation gap.

List of imaging techniques



  • Imaging techniques should be guided by clinical presentation and physical examination; this can include brain imaging for altered mental status and chest imaging for hypoxemia or respiratory insufficiency.
  • Abdominal X‐rays may help in certain toxicities, such as body packers, ingestion of radio‐opaque iron pills or leaded foreign bodies, and caustic ingestions.

Potential pitfalls/common errors made regarding diagnosis of disease



  • It is important to consider complications related to toxin ingestion as well as coexisting conditions when treating patients. For example, patients can come in with both an acute MI as well as cocaine intoxication and both should be treated appropriately.
  • Some drug assays may result in false positive results, false negative results, or reflect the patient’s drug exposure rather than the drug poisoning. History, physical exam, and clinical toxidrome must be used to diagnose and treat the drug poisoning.
  • All intentional drug overdoses should be screened for an acetaminophen concentration since it is a common ingestion, it may not be disclosed in the history, and there is no clinical toxidrome to identify the acute ingestion.
  • Be aware that several newer synthetic drugs such as synthetic cannabinoids and bath salts can have a varied presentation depending on their composition.

Treatment


Treatment rationale



  • Initial treatment of all toxin ingestions should focus on managing airway, breathing, circulation, and neurologic deficits (the ABCDs) of toxicology.
  • Reverse the toxin if possible with specific antidotes (Table 32.2).
  • Consider therapies that will reduce absorption (GI decontamination) or enhance elimination (urine alkalization, hemodialysis, intravenous lipid emulsion):

    • Activated charcoal is most effective within 1–2 hours of ingestion and can help reduce GI absorption by binding the toxin. Activated charcoal is not recommended in heavy metals, caustic agents, hydrocarbon, and toxic alcohol ingestion. Multiple‐dose activated charcoal is most effective for ingestions with theophylline, quinine, carbamazepine, dapsone, and phenobarbital, among others. It is contraindicated in patients at risk for bowel obstruction or perforation, or at risk of aspiration due to vomiting, altered mental status, or an unprotected airway.
    • Whole bowel irrigation is used for lithium, iron, sustained‐release or enteric‐coated medication overdose, or in cases of body packing. It is contraindicated with bowel obstruction, perforation, ileus, nausea/vomiting, or an unprotected airway.
    • Routine use of gastric lavage or induced emesis is not recommended.

  • Once toxin reversal and elimination have been attempted, supportive care should be the basis of treatment.

When to hospitalize


Patient who present with acute intoxication should be hospitalized or placed under observation for monitoring since the severity of ingestion can be unknown at the time of presentation.


Table of treatment


















































































Toxin Treatment and antidotes
Acetaminophen N‐acetylcysteine:


  • PO: 140 mg/kg load then 70 mg/kg every 4 hours × 17 doses
  • IV: 150 mg/kg over 60 minutes; then 50 mg/kg over 4 hours; then 100 mg/kg over 16 hours

Treatment should not be delayed while waiting for levels if known acetaminophen ingestion
Rumack–Matthew nomogram uses time from ingestion and the acetaminophen level to determine if N‐acetylcysteine is necessary
Referral to liver transplant center if patient is at risk for developing fulminant hepatic failure
Potential list for transplant according to King’s College Criteria:


  • Arterial pH <7.3 after adequate fluid resuscitation OR
  • Creatinine >3.4 mg/dL, INR> 6.5, and grade III hepatic encephalopathy or worse within 24 hour period
Anticholinergics Physostigmine 0.5–2 mg IV over 5 minutes
May repeat in 5–10 minutes
Benzodiazepines Flumazenil 0.2 mg IV over 2 minutes
Repeat 0.2 mg dose at 1 minute intervals to desired level of consciousness (max. dose 1 mg)
Caution with patient on chronic benzodiazepines as flumazenil can precipitate withdrawal or possible seizures
Beta‐blockers Glucagon 5–10 mg IV bolus over 1 minute then infusion of 1–10 mg/h titrated to symptom response
Consider cardiac pacing
Hyperinsulinemia–euglycemia therapy:


  • Insulin 1 U/kg IV bolus
  • Then, 0.5–1 U/kg/h IV drip
  • Monitor glucose every 30 minutes
  • If BG ≤250, give dextrose 25–50 g IV bolus then 0.5 g/kg/h IV infusion
  • Monitor potassium for hypokalemia
Botulinum Botulinum antitoxin 1 vial IV; repeat every 2–4 hours PRN
Epinephrine at bedside
Calcium channel blockers 2–3 g calcium gluconate or 1 g calcium chloride every 10 minutes
Monitor serum calcium for hypercalcemia
Glucagon 5–10 mg IV bolus over 1 minute then infusion of 1–10 mg/h can reduce vasopressor requirements
Hyperinsulinemia–euglycemia therapy:


  • Insulin 1 U/kg IV bolus
  • Then, 0.5–1 U/kg/h IV drip
  • Monitor glucose every 30 minutes
  • If BG ≤250, give dextrose 25–50 g IV bolus then 0.5 g/kg/h IV infusion
  • Monitor potassium for hypokalemia
Carbon monoxide 100% supplemental O2 with 4.5–4.8% CO2
Hyperbaric O2 therapy for severe symptoms such as COHgb ≥25% (≥15% in pregnancy), coma, syncope, altered mental status, seizure, fetal distress, myocardial ischemia
Cocaine Supportive therapy:

  • Benzodiazepines for agitation
  • Active and passive cooling for hyperthermia
  • Calcium channel blockers and nitrates for hypertension
Cyanide 100% oxygen
Amyl nitrate 1 amp inhalation for 15–30 seconds every 30 seconds
Sodium thiosulfate 12.5 g IV over 10–30 minutes; can repeat half dose in 2 hours or if symptoms reappear
Hydroxycobalamin 5 g IV over 30 minutes
Sodium nitrite 300 mg IV over 3 minutes; can repeat half dose if symptoms reappear
Digoxin Digibind or digifab
Acute ingestion: 10 vials:


  • No. of vials = [amount ingested (mg)] × 0.8/0.5 mg

Chronic ingestion: 3–6 vials:


  • No. of vials = [digoxin level (ng/mL)] × [weight (kg)]/100
Ethylene glycol Goal: treat until levels <20 mg/dL:


  • Fomepizole 15 mg/kg IV load over 30 minutes, then 10 mg/kg IV every 12 hours × 4 doses
  • Continue 15 mg/kg IV bolus every 12 hours as needed

Thiamine 50–100 mg daily
Pyridoxine 100 mg daily
Hemodialysis in severe organ dysfunction
Ethanol infusion (less preferred)
Iron Deferoxamine 5 mg/kg/h IV and titrate to 15 mg/kg/h IV; max. dose 68 g. Limit to 24 hours
Isoniazid Pyridoxine 1 g IV for every gram of isoniazid
For unknown quantities, 5 g IV at 0.5 g/min until seizures stop
Lead Succimer 10 mg/kg PO every 8 hours × 5 days; then 10 mg/kg PO every 12 hours × 14 days
For lead encephalopathy:


  • Dimercaprol 75 mg/m2 deep IM every 4 hours x 5 days; first dose precedes EDTA by 4 hours
  • Followed by edetate calcium disodium 1500 mg/m2/day continuous IV or IM divided twice to four times a day
Lithium Renal replacement therapy for serum lithium levels >3.5 mEq/L in acute ingestion and >2.5 mEq/L in chronic ingestion
Monitor for rebound increase in lithium levels when using hemodialysis as it does not affect intracellular lithium
Methanol Goal: treat until levels <25 mg/dL:


  • Fomepizole 15 mg/kg IV loading dose over 30 minutes, then 10 mg/kg IV bolus every 12 hours × 48 hours
  • Followed by 15 mg/kg IV bolus every 12 hours as needed

Folate 1–2 mg/kg (50–75 mg) IV every 4 hours × 24 hours. Extra dose at completion of hemodialysis
Hemodialysis in severe organ dysfunction or levels >50 mg/dL
Ethanol infusion (less preferred)
Methemoglobinemia Methylene blue 1–2 mg/kg or 0.1–0.2 mL/kg of 1% solution over 5 minutes
Neuroleptic malignant syndrome Bromocriptine 2.5–10 mg PO three to four times a day
Opiates Naloxone 0.04–0.05 mg IV initial dose, can increase to 1–2 mg IV if no response after 2–3 minutes to max. dose of 10 mg
If repeated boluses are required, consider naloxone infusion with hourly rate two‐thirds of IV bolus dose given
Goal: adequate ventilation or respiratory rate ≥12. Do not titrate to normal level of consciousness
Caution in patients with chronic opiate use as high doses of naloxone can induce withdrawal
Organophosphates/cholinergic toxidrome For respiratory symptoms the goal is atropinization (mydriasis, dry mouth, tachycardia): atropine 1–2 mg IV push initially with subsequent doses doubled every 2–3 minutes until symptoms resolve
Glycopyrrolate 1–2 mg IV if atropine dose required is high enough to cause additional CNS toxicity
For severe toxicity, muscle fasciculation, and weakness: pralidoxime 1–2 g or 25–50 mg/kg IV over 30 minutes, then 200–500 mg/h or 10–20 mg/kg/h infusion
Benzodiazepines such as diazepam 10–20 mg IV can be used for seizures, anxiety, or fasciculation
Salicylates Multiple dose activated charcoal
NaHCO3 150 mEq in 1 L D5W IV infusion: goal is urine pH to 8.1 or plasma pH 7.45–7.50
Hemodialysis:


  • Acute ingestion: serum salicylate level >120 mg/dL or levels >100 mg/dL 6 hours post‐ingestion
  • Chronic ingestion: serum salicylate level >60 mg/dL or for symptomatic patient
Serotonin toxidrome Cyproheptidine 4–12 mg PO initial dose then 2 mg every 2 hours until clinical response
Maintenance dose 4–8 mg every 6 hours (max. 32 mg/day)
Sulfonylureas 25 g of 50% dextrose (D50W) IV
Octreotide 50–150 μg IM/SQ every 6 hours
Tricyclic antidepressants NaHCO3 1–2 mEq/kg IV bolus for QRS widening
NaHCO3 150 mEq in 1 L D5W IV at 1–3 mEq/mg/h to target serum pH 7.45–7.50
Lidocaine for ventricular arrhythmias
200 mL of 3% NaCl hypertonic saline for refractory arrhythmias despite pH >7.55
Valproic acid l‐carnitine:


  • Symptomatic: 100 mg/kg IV (max. 6 g) load over 30 minutes; then 15 mg/kg IV every 4 hours over 10–30 minutes
  • Asymptomatic: 100 mg/kg/day (max. 3 g) PO divided over 6 hours

Prevention/management of complications



  • Some patients presenting with severe intoxications can require prolonged ventilation or ICU support. It is important to ensure that measures be taken to avoid complications related to supportive therapy, such as minimizing sedation, providing daily spontaneous awakening trials, and mobilizing patients.
  • Once the patient is recovering, psychiatric evaluation is necessary for intentional ingestions, and drug and alcohol rehabilitation should be considered to prevent readmissions and relapse.

Management/treatment algorithm (Algorithm 32.1)

Schematic illustration of managing the hospitalized patient.

Algorithm 32.1 Managing the hospitalized overdose patient

Nov 20, 2022 | Posted by in ANESTHESIA | Comments Off on 32: Toxicology and Drug Reactions

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