Using Toxidromes to Assess Poisoned Patients

U s i n g To x i d ro m e s t o A s s e s s Poisoned Patients Mohannad Naheid I. Abu Omar, MDa, John Foxworth, PharmDa,b,* KEYWORDS  Toxidrome  Poisoning  Overdose  Cholinergic  Anticholinergic  Opiate  Sedative  Sympathomimetic

HOSPITAL MEDICINE CLINICS CHECKLIST

1. Five major toxidromes are helpful in identifying a class of drugs with which patients may be poisoned according to their presenting signs and symptoms. 2. Other more specific toxidromes may also be useful; these, for example, are based on laboratory findings and the electrocardiogram as well as some specific drugs. 3. Drug withdrawal presents in opposition to the primary effect of a drug. 4. Familiarity with withdrawal syndromes is also useful. 5. Supportive care must always be paramount in treating poisoned patients. 6. Accessing a poison control center may be extremely helpful; a national contact number is 1-800-222-1222.

Before beginning, it is appropriate to remind the reader that the value of supportive care in managing overdosed and intoxicated patients cannot be overemphasized. Even if one is unable to finally pinpoint the specific agent causing an overdosed patient’s symptoms, most patients will do well if supportive measures are adequate. These supportive measures include considering such issues as the appropriate management of electrolyte disorders, blood pressure, respiratory system disorders (low oxygen tension, hypoventilation, aspiration, pulmonary edema, retention of carbon

Disclosures: The authors have no conflicts of interest and no funding sources to disclose. a Department of Internal Medicine, University of Missouri-Kansas City School of Medicine, 2411 Holmes Street, Kansas City, MO 64108-2792, USA; b Division of Clinical Pharmacology, Department of Medicine, Truman Medical Center, University of Missouri-Kansas City School of Medicine, 2411 Holmes Street, Kansas City, MO 64108-2792, USA * Corresponding author. Division of Clinical Pharmacology, Department of Medicine, Truman Medical Center, University of Missouri-Kansas City School of Medicine, 2411 Holmes Street, Kansas City, MO 64108-2792. E-mail address: [email protected] Hosp Med Clin 3 (2014) e128–e138 http://dx.doi.org/10.1016/j.ehmc.2013.09.001 2211-5943/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.

Toxidromes to Assess Poisoned Patients

dioxide), and correction of hypoglycemia. This principle of supportive care must always be paramount as the caregiver seeks the identification of the poison or poisons to which patients were exposed as well as during the ongoing management of patients. In most cases of poisoning, consultation with a toxicologist will prove instructive. If a toxicology specialist is not readily available locally, a poison control center may be reached at any time by calling 1-800-222-1222. The authors attempt to outline the major clinical toxidromes as well as some laboratory toxidromes, all of which may be useful in identifying a class of drug causing a given patient’s illness. What are the toxidromes, and how does understanding them aid one in managing intoxicated patients? A CASE EXAMPLE

A 19-year-old girl is found by her parents along with a suicide note stemming from a fight with her boyfriend. She is drowsy and lethargic but is able to state that she took the contents of an unlabeled bottle given to her by a classmate. The parents call 911; by the time emergency workers arrive 20 minutes later, the girl has a blood pressure of 60/40 mm Hg, a heart rate of 160 beats per minute, and a respiratory rate of 4 breaths per minute. Her pupils measure 7 mm bilaterally, her skin and mouth are dry, and she has no bowel sounds on physical examination. An electrocardiogram (ECG) performed at the hospital where she is admitted reveals a QRS of 120 ms and a QTc interval of 495 ms. What type of poisoning could cause such a constellation of symptoms? How should one approach such a case? A good diagnostic way to approach such a case is by the application of what are called toxidromes (a neologism derived from the combination of parts of the words toxicology and syndromes).1,2 There are 5 commonly applied general toxidromes: sedative-hypnotic, opioid, sympathomimetic, anticholinergic, and cholinergic (Tables 1 and 2). These toxidromes comprise a constellation of findings from the physical examination as well as other findings. These toxidromes are rather widely encompassing, and there is certainly some overlap between the various toxidromes. More specific, narrower toxidromes are discussed later. How does one undertake the management of such a case? The aforementioned case fits nicely into the application of the anticholinergic toxidrome paradigm. The patient ingested amitriptyline, a first-generation antidepressant. This drug has many physiologic and pharmacologic effects, which provide the clues that are helpful in identifying the ingestion (see Table 1, anticholinergic row). About 10 to 20 mg/kg of this type of drug can cause substantial cardiac and central nervous system manifestations (a therapeutic dose is about 2–4 mg/kg/d). As stated earlier, the hallmark of managing a case like this begins with supportive care (airway, breathing, circulation, dextrose if needed): intravenous (IV) access should be obtained; cardiac monitoring should be provided; intubation might be necessary; vital signs should be monitored; a basic metabolic profile should be drawn; a blood gas should be obtained; and blood pressure and tissue perfusion should be aggressively supported.

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Toxidrome

Signs and Symptoms

Examples of Causative Agents

Comments

Sedative/hypnotic

Sedation, altered mental status, stupor, coma, hypothermia, hypotension, apnea, hyporeflexia

Benzodiazepines, barbiturates, meprobamate, carisoprodol, gluthemide, ethanol

—

Opioid

Miosis, hypoventilation, decreased bowel sounds, apnea, needle scars, noncardiogenic pulmonary edema

Heroin, morphine, oxycodone hydrochloride (OxyContin), fentanyl, hydromorphone, methadone

The classic triad of narcotic overdose includes pinpoint pupils, depressed respiratory rate, and confused or depressed mental status. This finding is probably more sensitive and specific than a response to naloxone.

Sympathomimetic

Tachycardia, diaphoresis, piloerection, hypertension, mydriasis, stroke, chest pain, angina, myocardial infarction, dissecting aortic aneurysm, acute renal injury, hyperthermia, agitation, wide-pulse pressure

Methamphetamine, amphetamines, cocaine, MDMA, some diet medicines, cathinones, ephedrine, caffeine, theophylline

This state is one of exaggerated sympathomimetic (catecholamine-driven) symptoms driven by drugs that accelerate or mimic this system.

Anticholinergic

Dry mouth, skin, and mucous membranes; tachycardia; long QTc; retention of urine; absent or hypoactive bowel sounds; wide QRS; mydriasis; altered mental status and/or sedation; delirium; hallucinations; seizures; slight temperature elevation; opsoclonus

First-generation antihistamines, tricyclic antidepressants, scopolamine, atropine, some anti-Parkinson disease medications, belladonna, jimson weed, cyclobenzaprine

These patients are dry, with urinary retention, absent or diminished bowel sounds, and dry mucous membranes. These patients reflect the opposite of the cholinergic toxidrome presented next.

Cholinergic

Diaphoresis, copious secretions, mydriasis or miosis, bronchospasm, diarrhea, urination, tachycardia or bradycardia, seizures, fasciculations, paralysis

Organophosphates (often found in insecticides), sarin (nerve gas), nicotine poisoning, physostigmine, bethanechol

The hallmark of this toxidrome is the presentation of wet patients (vomiting, diarrhea, urination, lacrimation, diaphoresis, emesis, salivation). The reason for the seeming paradox of possible findings of dilated or constricted pupils, slow or rapid heart rate, and bronchoconstriction or bronchodilation, lies within the degree to which cholinergic poisons to stimulate the adrenal medulla to release catecholamines in a particular case of toxicity.

Abbreviation: MDMA, methylenedioxymethamphetamine.

Abu Omar & Foxworth

Table 1 Five major toxidromes as defined by physical findings, with etiologic examples and commentary

Table 2 Clinical signs of intoxication: 5 general toxidromes Vital Signs Toxidrome

BP

Pulse

Respiratory Rate

Temperature

Pupil Size

Mental Status

Moist Mucous Membranes and Diaphoresis

Anticholinergic

4 to [

[

h

[

[

Y to delirium

Y

Decreased bowel sounds, urine retention

Cholinergic

h

h

h

4

h

4 to Y

[

Salivation, lacrimation, urination, diarrhea, gastrointestinal cramping, emesis

Ethanol/sedative hypnotic

Y

Y

Y

4 to Y

h

Y

4

Ataxia

Opioid

Y

Y

Y

4 to Y

Y

Y

4

Hyporeflexia

Sympathomimetic

[

[

[

[

[

Agitated

[

Tremor, seizures, hyperreflexia, chest pain, myocardial infarction, stroke, wide-pulse pressure, tachypnea

Toxidromes to Assess Poisoned Patients

Abbreviations: [, increased; Y, decreased; 4, no change; h, variable; BP, blood pressure.

Other Abnormalities

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Gastrointestinal decontamination should be considered with activated charcoal (especially early in the course, ie, a few hours after the ingestion) keeping in mind the risk of aspiration in sedated patients. Many of these patients will require intubation, which should reduce this risk to some degree. An irony of this type of xenobiotic poisoning is the finding of an increased pulse with a decreased blood pressure. What other tests might be helpful? This sort of patient needs an ECG (with attention to the QRS interval, QTc interval, axis, rate). An abnormal terminal rightward axis on the ECG (greater than 120 ) was found in a retrospective study to be 8.6 times more likely in a tricyclic-poisoned patient than in a patient poisoned with another class of drug.3 This axis deviation occurs because the right bundle is more sensitive to tricyclic poisoning than the left bundle. A blood level of the tricyclic provides little help in managing the case. Is there an antidote for tricyclic poisoning? A major part of the management of this type of overdose is to use serum alkalization therapy using IV sodium bicarbonate. Mechanistically, this treatment may lessen the effect the tricyclic agent has on the cardiac rapid sodium channel. Normally, this channel allows sodium to enter the cell, rapidly depolarizing the cell and causing the upswing of the action potential (phase 0), thereby propagating conduction. The tricyclic agent has the effect of altering the channel’s transportation of sodium by binding to the interior of the channel, substantially slowing the increase of the action potential, producing negative dromotropic and inotropic effects. Raising the pH with sodium bicarbonate suppresses ventricular dysrhythmias associated with tricyclic poisoning. Although one might suppose that hyperventilation would have the same effect by raising the pH through a reduction in systemic carbon dioxide, this does not seem to be as effective.4 The dosage of sodium bicarbonate should be guided by the measurement of blood pH, targeting 7.50 to 7.55 as a goal. The initial dose should be in the range of 1 to 2 mEq/kg, and repeat doses may be given every 3 to 5 minutes and should be guided by the pH and observation of the QRS complex and blood pressure (which should narrow and increase, respectively). If dysrhythmias ensue because of the poisoning, the drugs to be avoided include type 1A agents (eg, procainamide), which block the rapid sodium channel in a manner perhaps similar to the tricyclic agent. Lidocaine is recommended by some reasearchers despite lacking proof of efficacy in humans. What else may be done? Hypotension should be addressed with normal saline in most patients. If patients do not respond appropriately to saline and sodium bicarbonate therapy, one reference suggests norepinephrine at a dosage of 0.1 to 0.2 mg/kg/min.4 Extracorporeal life support might be necessary in those failing to respond to fluids and vasopressors. Seizures might be self-limited and may respond to benzodiazepines. If not, propofol might be considered. Tricyclics characteristically have a very large volume of distribution, extensive protein-binding, and high lipid solubility; thus, elimination will not be enhanced by hemodialysis. Patients with serious tricyclic antidepressant exposure should be monitored carefully as mentioned earlier. Seriously poisoned patients include those presenting with seizures, a heart rate greater than 120 beats per minute, QRS widening, and prolonged QTc.

Toxidromes to Assess Poisoned Patients

PERHAPS ANOTHER CASE WILL BE OF INTEREST

A 22-year old man is brought to the emergency department after his friends witnessed him having a seizure. He has recently returned from a trip to South America. His vital signs reveal a blood pressure of 190/110 mm Hg, heart rate of 135 beats per minute, respiratory rate of 30 breaths per minute, and temperature of 103 F. He is diaphoretic. His pupils are 8 mm bilaterally. He has a small amount of blood on his tongue, and he seems to have a perforated nasal septum. Bowel sounds are active, and he is agitated. Laboratory reports reveal a hemoglobin of 15 g/dL, white blood cell count of 10,000 cells per cubic millimeter, and 200,000 platelets per cubic millimeter. A blood gas reveals a pH of 7.35; PO2 of 90 mm Hg; PCO2 of 28; and an electrolyte panel shows a sodium of 140 mEq/L, potassium of 4 mEq/L, chloride of 105 mEq/L, and an HCO3– of 13 mEq/L. The serum urea nitrogen (BUN), serum creatinine, blood sugar, and calcium levels are all normal. A urine drug screen is positive for cocaine. A blood alcohol level is zero. An ECG reveals sinus tachycardia and a few premature ventricular contractions, and the rest is normal. A chest film, abdominal film, and urinalysis are all normal. The patient is given IV thiamine and IV normal saline and kept in the emergency department for observation. After 6 hours, he is tremulous and seems to be hallucinating. His vital signs are unchanged from the initial presentation. He is admitted to the hospital for cocaine intoxication; the next day, his vital signs are essentially the same. What is your diagnosis? More history becomes available Some family members appear, who relate that the patient is a heavy user of ethanol and that he occasionally uses street drugs (cocaine included). After his recent return from South America, he began vomiting and has, therefore, been unable to ingest alcohol. Therefore, the most likely diagnosis in this case is ethanol withdrawal. A clue is the long duration of symptoms after his initial presentation, given that the half-life of cocaine is about 1 hour. That would lead one to suspect that after 4 to 5 half-lives, most of the cocaine parent compound (benzoylmethyl ecgonine) would be gone, although some metabolites, such as norcocaine and benzoylecgonine, would be in evidence. How should one manage this case? The management of patients acutely intoxicated with cocaine usually involves supportive care and sedation with a benzodiazepine if necessary. If chest pain or an acute myocardial infarction develop, beta-blockers are contraindicated because of the risk of blocking the vasodilatory beta receptor, thereby increasing the agonism of the vasoconstrictive alpha receptor by norepinephrine whose reuptake is blocked by the action of cocaine. This condition may sometimes lead to hypertension, stroke, or coronary vasoconstriction.5 Labetalol and carvedilol are not good alternatives because they have stronger beta-blocking properties than alpha-blocking properties. Therefore, beta-blockers are not recommended and, in fact, are proscribed by the American Heart Association’s guidelines.6 It is important to recognize the sinister implication of an elevated temperature in cocaine-abusing patients and that an appropriate core temperature must be maintained in such patients using ice-water immersion or other means.7 This patient, however, fits into the sympathomimetic toxidrome pattern not because of current drug exposure to cocaine but because of withdrawal from a depressant (Tables 3–5). The positive urine drug screen never indicates that a person is toxic with that drug at the time the test is positive but might suggest usage a few days prior.

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Table 3 Clinical signs of representative withdrawal scenarios Vital Signs Withdrawn Agent

BP

Pulse

Respiratory Rate

Temperature

Pupil Size

Mental Status

Diaphoresis

Other Abnormalities

Opiates

[

[

4 to [

4

[

4 to anxious

[

Vomiting, flulike syndrome, lacrimation, rhinorrhea, piloerection (cold turkey), lower extremity muscle contractions (kicking the habit), diarrhea, yawning, anxiety

Ethanol/ benzodiazepines

[

[

[

[

[

4 to severe anxiety to hallucinations to delirium

[

Seizures, tremors, hyperreflexia

Sympathomimetic agents

4 to Y

4 to Y

4

4

4

Inability to focus, insomnia to hypersomnia

4

Anhedonia, hyperphagia, irritability

Abbreviations: [, increased; Y, decreased; 4, no change; h, variable; BP, blood pressure.

Table 4 Clinical signs of intoxication: some other agents of interest Vital Signs Toxidrome

BP

Pulse

Respiratory Rate

Temperature

Pupil Size

Mental Status

Diaphoresis

Muscle Tone

Serotonin syndrome

[

[

[

[

[

Agitation, coma

[

[

Lower extremity clonus, high temperature (>41.1 C), diarrhea, vomiting, hyperreflexia, may be caused by drug interactions, serotonin receptor blocker excess

Neuroleptic malignant syndrome

[

[

[

[

4

Agitated delirium with confusion

[

[

Lead-pipe rigidity, temperature >41.1 C, associated with dopamine receptor blockade

Malignant hyperthermia

[

[

[

[

—

Agitation

[ and mottling

[

Rigor mortis–like rigidity, caused by inhalational anesthetic, temperature may be as high as 46 C, hyporeflexia

Hallucinogens

—

—

—

—

—

Hallucinations, perceptual distortions, synesthesia, agitation

Nystagmus

4

Ecstasy (MDMA) may induce valvular heart disease with chronic usage

Bath salts (synthetic cathinones)

[

[

4

4

[

Suicidal thoughts, delusions, paranoia, violent behavior, panic attacks, hallucinations

[

4

Tremor, seizures, hyperreflexia, chest pain, myocardial infarction, stroke, tachypnea

Toxidromes to Assess Poisoned Patients

Abbreviations: [, increased; Y, decreased; 4, no change; h, variable; MDMA, methylenedioxymethamphetamine.

Other Abnormalities

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Xenobiotic Causes

Rationale

Wide anion-gap metabolic acidosis

Methanol, ethylene glycol, cyanide exposure, iron overdose, salicylate poisoning, alcoholic ketoacidosis, solvent inhalation, rarely metformin

The anion gap is calculated by subtracting chloride plus bicarbonate from sodium (using the basic metabolic profile as the source). At the authors’ hospital, 95% of the population falls between 3 and 15 (2 standard deviations). Although there is actually electroneutrality, the apparent gap is created from the presence of unmeasured anions. A gap wider than normal when accompanied by metabolic acidosis suggests the presence of an unmeasured anion. For example, this gap could be created by the presence of formic acid when methanol is ingested. Methanol is metabolized by alcohol dehydrogenase to formate and formaldehyde. The formic acid produces protons (H1) that combine with HCO3– to form carbonic acid (H2CO3), which then breaks down to H2O and CO2. This process consumes (or lowers) HCO3–, which creates the gap. Additionally, one should correct for a low albumin (if present) by increasing the gap by 2.5–3.0 mEq for each gram the albumin is less than normal.

Osmolal gap

Many small drug molecules, but of particular interest are isopropyl alcohol, methanol, and ethylene glycol

When suspecting an ingestion of one of the toxic alcohols, it is sometimes useful to compare the calculated osmolality with the true (measured) osmolality. The calculated osmolality is often provided with the patients’ laboratory test results and is calculated by using 2 times the Na1 plus BUN/2.8 1 glucose/18. This calculation estimates the total osmolality provided by the elements in the equation (both effective and ineffective osmoles) and allows a comparison with the true osmolality measured by the laboratory using a freezing point detection method. In the case of an ingestion of ethylene glycol, for example, it will increase the osmolality to a degree dependent on its concentration. If the comparison reveals a substantial difference, and if the measured osmolality and the calculated osmolality are correct, it suggests that a small molecule is present in the blood stream. This finding should not be used as a determinate to rule out ethanol substitute poisoning because if time has passed since the ingestion, and if the ethylene glycol has been converted into metabolites, they will not contribute to osmolality like the parent compound. A useful device to estimate the degree of exposure is to take one-tenth of the molecule weight of the alcohol and multiply it by the omolal gap 10 (minus 10 because 10 is a normal expected gap). The molecular weight for various alcohols are ethanol 46 Da, methanol 32, ethylene glycol 62, and isopropyl alcohol 50. A normal osmolal gap should not be used to rule out an alcohol substitute poisoning.

Abu Omar & Foxworth

Table 5 Laboratory toxidromes

Long QTc syndrome

Myriad of possibilities; refer to crediblemeds.org for listing (last accessed 8/12/13); some examples include some fluoroquinolones, ondansetron, macrolides, arsenic, many psychiatric medications (haloperidol, aripiprazole, citalopram, tricyclic antidepressants, trazodone), methadone, cocaine, many antiarrthymic drugs (amiodarone, flecainide, ibutilide). This list is not intended to be all inclusive.

Drugs causing this disorder seem to decrease egress of potassium from the myocardial cell during repolarization through a pore controlled genetically by the gene HERG, thereby creating a repolarization disorder (failure to decrease the transmembrane electrical potential to the appropriate resting membrane potential). This disorder may then deteriorate into torsades de pointes, ventricular tachycardia, and ventricular fibrillation.

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Regarding withdrawal, the principle is that drug withdrawal presents in opposition to the primary effect of a drug. In the case of ethanol withdrawal, the hyperactive sympathetic system is driven by glutamate (an excitatory amino acid), levels of which are high in compensating for the constant presence of the sedative ethanol. When ethanol is withdrawn, the glutamate influence is no longer offset by a depressant (alcohol). Therefore, this patient should be managed for alcohol withdrawal with benzodiazepines, thiamine, supportive care, electrolyte management, and counseling. In summary, many toxicology experts consider and recommend that others assess and consider the categorization of poisonings into general types of toxic substances by using the presenting clinical features to sort poisoned patients into toxidromes. This technique is often helpful in determining a drug class most compatible with the clinical findings. Of course, clinical medicine is often complicated, and patients may confound things by taking several different kinds of drugs that may conflict with each other pharmacologically. So, for example, if a patient overdoses on a betablocker and a tricyclic, will they be more likely to present with bradycardia, normal rate, or tachycardia? Patients may also present soon after an ingestion and still have a normal clinical examination at least until they absorb pharmacologically active amounts of a substance. Or a patient might become intoxicated with ethanol, then ingest ethylene glycol, and present without an anion-gap acidosis because (at least temporarily) ethanol prevents the conversion of ethylene glycol into the acids that normally create a wide anion-gap acidosis in this type of ingestion. Nevertheless, the application of the toxidromes can help point the clinician in the right direction and/or help direct attention to diagnostic tests, which can help unravel a clinical poisoning enigma. REFERENCES

1. Mofenson DM, Greensher J. The unknown poison. Pediatrics 1974;54:336–42. 2. Kulig K. Initial management of ingestions of toxic substances. N Engl J Med 1992;326:1677–81. 3. Wolfe TR, Caravati EM, Rollins DE, et al. Terminal 40-ms frontal plane QRS axis as a marker for trycyclic antidepressant overdose. Ann Emerg Med 1989;18:348–51. 4. Liebelt EL. Cyclic antidepressants. In: Nelson LS, Hoffman RS, Lewin NA, et al, editors. Goldfrank’s toxicologic emergencies. New York: McGraw-Hill; 2011. p. 1055. 5. Lange RA, Cigarroa RG, Flores ED, et al. Potentiation of cocaine-induced coronary vasoconstriction by beta-adrenergic blockade. Ann Intern Med 1990;112: 897–903. 6. McCord J, Jneid H, Hollander JE, et al. Management of cocaine-associated chest pain and myocardial infarction: a scientific statement from the American Heart Association Acute Care Committee of the Council on Clinical Cardiology. Circulation 2008;117:1897–907. 7. Marzuk PM, Tardiff K, Leon AC, et al. Ambient temperature and mortality from unintentional cocaine overdose. JAMA 1998;279:1795–800.