Toxidromes
Identification of the constellation of signs and symptoms that define a specific toxicologic syndrome, or "toxidrome", may narrow a differential diagnosis to a specific class of poisons [
3]. Descriptions of selected toxidromes may be found in Table
1. Many toxidromes have several overlapping features. For example, anticholinergic findings are highly similar to sympathomimetic findings, with one exception being the effects on sweat glands: anticholinergic agents produce warm, flushed dry skin, while sympathomimetic produce diaphoresis. Toxidrome findings may also be affected by individual variability, co-morbid conditions, and co-ingestants. For example, tachycardia associated with sympathomimetic or anticholinergic toxidromes may be absent in a patient who is concurrently taking beta antagonist medications. Additionally, while toxidromes may be applied to classes of drugs, some individual agents within these classes may have one or more toxidrome findings absent. For instance, meperidine is an opiate analgesic, but does not induce miosis that helps define the "classic" opiate toxidrome. When accurately identified, the toxidrome may provide invaluable information for diagnosis and subsequent treatment, although the many limitations impeding acute toxidrome diagnosis must be carefully considered.
Opioid | opioid receptor | sedation, miosis, decreased bowel sounds, decreased respirations |
Anticholinergic | muscurinic acetylcholine receptors | altered mental status, sedation, hallucinations, mydriasis, dry skin, dry mucous membranes, decreased bowel sounds and urinary retention |
Sedative-hypnotic | gamma-aminobutyric acid receptors | sedation, normal pupils, decreased respirations |
Sympathomimetic | alpha and beta adrenergic receptors | agitation, mydriasis, tachycardia, hypertension, hyperthermia, diaphoresis |
Cholinergic | nicotinic and muscurinic acetylcholine receptors | altered mental status, seizures, miosis, lacrimation, diaphoresis, bronchospasm, bronchorrhea, vomiting, diarrhea, bradycardia |
Serotonin syndrome | serotonin receptors | altered mental status, tachycardia, hypertension, hyperreflexia, clonus, hyperthermia |
Hyperthermic syndromes
Toxin induced hyperthermia syndromes include sympathomimetic fever, uncoupling syndrome, serotonin syndrome, neuroleptic malignant syndrome, malignant hyperthermia, and anticholinergic poisonings [
4]. Sympathomimetics, such as amphetamines and cocaine, may produce hyperthermia due excess serotonin and dopamine resulting in thermal deregulation [
5]. Treatment is primarily supportive and may include active cooling and administration of benzodiazepine agents. Uncoupling syndrome occurs when the process of oxidative phosphorylation is disrupted leading to heat generation and a reduced ability to aerobically generate Adenosine-5'-triphosphate (ATP). Severe salicylate poisoning is a characteristic toxin that has been associated with uncoupling [
6]. The development of hyperthermia in the salicylate poisoned patient is an indicator of advanced poisoning that will likely require dialysis. Serotonin syndrome occurs when there is a relative excess of serotonin at both peripheral and central serotonergic receptors [
7]. Patients may present with hyperthermia, alterations in mental status and neuromuscular abnormalities (rigidity, hyperreflexia, clonus) although there may be individual variability in these findings. It is associated with drug interactions such as the combination of monoamine oxidase inhibitors and meperidine, but may also occur with single agent therapeutic dosing or overdose of serotonergic agents. The serotonin antagonist cyproheptadine has been advocated to treat serotonin syndrome in conjunction with benzodiazepines and other supportive treatments such as active cooling. However, cyproheptadine may only be administered orally and its true efficacy is not well known which limits its overall utility. Neuroleptic malignant syndrome is a condition caused by relative deficiency of dopamine within the central nervous system [
8]. It has been associated with dopamine receptor antagonists and the withdrawal of dopamine agonists such as levodopa/carbidopa products. Clinically it may be difficult to distinguish from serotonin syndrome and other hyperthermic emergencies. Bromocriptine, amantadine, and dantrolene have been utilized in some reports, but true efficacy has not been fully delineated. Malignant hyperthermia occurs when genetically susceptible individuals are exposed to depolarizing neuromuscular blocking agents or volatile general anesthetics [
9]. Treatment consists of removing the inciting agent, supportive care, and dantrolene administration. Finally, anticholinergic poisoning may result in hyperthermia through impairment of normal cooling mechanisms such as sweating. Supportive care including active cooling and benzodiazepines are the primary treatments for this condition. Overall, differentiating between the toxic hyperthermic syndromes may be challenging and additional causes of hyperthermia such as heat stroke/exhaustion and infection should also be explored. In most toxin induced hyperthermic syndromes, treatment includes benzodiazepine administration, active cooling and general supportive care. Antidotes may be attempted if the specific diagnosis is evident.
Electrocardiogram
Electrocardiographic (ECG) changes in the poisoned patient are commonly encountered [
10]. Despite the fact that medications have widely varying indications for therapeutic use, many unrelated drugs share common cardiac electrocardiographic effects if taken in overdose. Toxins can be placed into broad classes based on their electrocardiographic effects (Table
2). The recognition of specific ECG changes associated with other clinical data (toxidromes) can lead clinicians to specific therapies that can be potentially life saving. Therefore, all seriously poisoned patients, particularly exposure to one of these agents is suspected, should have a minimum of an initial ECG. Repeat ECGs and cardiac monitoring would also be indicated if an ECG abnormality is identified or if the patient is at risk for delayed toxicity.
Table 2
Toxin Induced ECG Effects
Antihistamines | Amantadine |
Astemizole | Carbamazepine |
Clarithromycin | Chloroquine |
Diphenhydramine | Class IA antiarrhythmics |
Loratidine | Disopyramide |
Terfenadine | Quinidine |
Antipsychotics | Procainamide |
Chlorpromazine | Class IC antiarrhythmics |
Droperidol | Encainide |
Haloperidol | Flecainide |
Mesoridazine | Propafenone |
Pimozide | Citalopram |
Quetiapine | Cocaine |
Risperidone | Cyclic Antidepressants |
Thioridazine | Amitriptyline |
Ziprasidone | Amoxapine |
Arsenic trioxide | Desipramine |
Bepridil | Doxepin |
Chloroquine | Imipramine |
Cisapride | Nortriptyline |
Citalopram | Maprotiline |
Clarithromycin | Diltiazem |
Class IA antiarrhythmics | Diphenhydramine |
Disopyramide | Hydroxychloroquine |
Quinidine | Loxapine |
Procainamide | Orphenadrine |
Class IC antiarrhythmics | Phenothiazines |
Encainide | Medoridazine |
Flecainide | Thioridazine |
Moricizine | Propranolol |
Propafenone | Propoxyphene |
Class III antiarrhythmics | Quinine |
Amiodarone | Verapamil |
Dofetilide | |
Ibutilide | |
Sotalol | |
Cyclic Antidepressants | |
Erythomycin | |
Fluoroquinolones | |
Halofantrine | |
Hydroxychloroquine | |
Levomethadyl | |
Methadone | |
Pentamidine | |
Quinine | |
Tacrolimus | |
Venlafaxine | |
Studies suggest that approximately 3% of all non-cardiac prescriptions are associated with the potential for QT prolongation [
11]. This drug induced QT prolongation may lead polymorphic ventricular tachycardia, most often as the torsades de pointes variant [
12]. QT prolongation is considered to occur when the QTc interval is greater than 440 ms in men and 460 ms in women. The potential for an arrhythmia for a given QT interval will vary depending on the specific drug [
13]. For example, venlafaxine is associated with QT prolongation, but rarely causes torsades due to venlafaxine-induced tachycardia. However, sotalol, on the other hand, induces bradycardia that increases the risk of torsades. Toxins may also inhibit fast cardiac sodium channels and thereby prolong the QRS complex [
14]. The Na
+ channel blockers can cause slowed intraventricular conduction, unidirectional block, the development of a re-entrant circuit, and a resulting ventricular tachycardia or ventricular fibrillation. Myocardial Na
+ channel blocking drugs comprise a diverse group of pharmaceutical agents. There are multiple agents that can result in human cardiotoxicity and resultant ECG changes which may be treated through the administration of sodium bicarbonate. Physicians managing patients who have taken overdoses on medications should be aware of the various electrocardiographic changes that can potentially occur in the overdose setting.
Laboratory analysis
When evaluating the intoxicated patient, there is no substitute for a thorough history and physical exam. Samples cannot be simply processed by the lab with the correct diagnosis to a clinical mystery returning on a computer printout. Analytical capabilities vary significantly between regional care facilities and may limit the time in which results for analytical studies may be obtained which limits the use for direction of care in the acute setting [
15]. When used appropriately, diagnostic tests may be of help in the management of the intoxicated patient. In the patient whose history is generally unreliable or in the unresponsive patient where no history is available, the clinician may gain further clues as to the etiology of a poisoning by responsible diagnostic testing. When a specific toxin or even class of toxins is suspected, requesting qualitative or quantitative levels may be appropriate if deemed necessary for diagnosis and treatment.
An acetaminophen (paracetamol) level drawn after a single, acute overdose is one of the few examples where a diagnostic laboratory result independent of clinical findings can be used to make treatment decisions [
16‐
18]. Considering previous published studies, the authors recommended universal screening of all intentional overdose patients for the presence of acetaminophen. Because products containing salicylates are readily available, clinical effects of salicylate toxicity are non-specific, and a lack of metabolic acidosis does not rule out the potential for salicylate toxicity, clinicians should have a low threshold for also obtaining serum salicylate levels in potentially toxic patients [
19].
The serum osmol gap is a common laboratory test that may be useful when evaluating poisoned patients. This test is most often discussed in the context of evaluating the patient suspected of toxic alcohol (
e.g. ethylene glycol, methanol, and isopropanol) intoxication. Though this test may have utility in such situations, it has many pitfalls and limitations which limit its effectiveness. A calculated serum osmolarity (Osm
C) may be obtained by any of a number of equations, involving the patient's glucose, sodium, and urea which contribute to almost all of the normally measured osmolality [
20,
21]. The most commonly utilized equation in the United States and Europe are noted below:
The difference between the measured (Osm
M) and calculated (Osm
C) is the osmol gap (OG): OG = Osm
M - Osm
C. If a significant osmol gap is discovered, the difference in the two values may represent the presence of foreign substances in the blood [
22]. A list of possible causes of an elevated osmol gap is listed in Table
3. Traditionally, a normal gap has been defined as ≤ 10 mOsm/kg [
23]. Unfortunately, what constitutes a normal osmol gap is widely debated [
24‐
27]. There are several concerns in regard to utilizing the osmol gap as a screening tool in the evaluation of the potentially toxic-alcohol poisoned patient. If a patient's ingestion of a toxic alcohol occurred at a time distant from the actual blood sampling, the osmotically active parent compound may have been metabolized to acidic metabolites. The subsequent metabolites have no osmotic activity of their own and hence no osmol gap will be detected [
20,
28]. Therefore, it is possible that a patient may present at a point after ingestion with only a moderate rise in their osmol gap and anion gap [
29,
30]. However, recent research has found that an OG of 10 has a sensitivity of >85% and a specificity of <50% with a high negative predictive value (0.92) for identifying poisoned patients in which an antidote may be administered.(Lynd 08) Still, the osmol gap should be used with caution as an adjunct to clinical decision making and not as a primary determinant to rule out toxic alcohol ingestion. A "normal" osmol should be interpreted with caution; a negative study may, in fact, not rule out the presence of such an ingestion – the test result must be interpreted within the context of the clinical presentation. If such a poisoning is suspected, appropriate therapy should be initiated presumptively (
i.e. ethanol infusion, 4-methyl-pyrazole, hemodialysis,
etc.) while confirmation from serum levels of the suspected toxin are pending.
Table 3
Toxic causes of an elevated osmol gap
Toxic alcohols
| Ethanol |
| Isopropanol |
| Methanol |
| Ethylene Glycol |
Drugs/Additives
| Isoniazid |
| Mannitol |
| Propylene glycol |
| Glycerol |
| Osmotic contrast dyes |
Other Chemicals
| Ethyl ether |
| Acetone |
| Trichloroethane |
Obtaining a basic metabolic panel in all poisoned patients is generally recommended. When low serum bicarbonate is discovered on a metabolic panel, the clinician should determine if an elevated anion gap exists. The formula most commonly used for the anion gap calculation is: [Na
+] - [Cl
- + HCO
3]. This equation allows one to determine if serum electroneutrality is being maintained. The primary cation (sodium) and anions (chloride and bicarbonate) are represented in the equation [
31]. There are other contributors to this equation that are "unmeasured" [
32]. The normal range for this anion gap is accepted to be 8–16 mEq/L. Practically speaking, an increase in the anion gap beyond an accepted normal range, accompanied by a metabolic acidosis, represents an increase in unmeasured endogenous (
e.g. lactate) or exogenous(
e.g. salicylates) anions [
33]. A list of the more common causes of this phenomenon are organized in the classic MUDILES pneumonic (Table
4). It is imperative that clinicians who admit poisoned patients initially presenting with an increased anion gap metabolic acidosis investigate the etiology of that acidosis. Many symptomatic poisoned patients may have an initial mild metabolic acidosis upon presentation due to the processes resulting in the elevation of serum lactate. However, with adequate supportive care including hydration and oxygenation, the anion gap acidosis should improve. If, despite adequate supportive care, an anion gap metabolic acidosis worsens in a poisoned patient, the clinician should consider either toxins that form acidic metabolites (i.e. ethylene glycol, methanol, or ibuprofen) or toxins which cause lactic acidosis by interfering with aerobic energy production (i.e. cyanide or iron) [
34‐
36].
Table 4
Potential causes of increased anion gap metabolic acidosis
Methanol |
Uremia |
Diabetic ketoacidosis |
Iron, Inhalants (i.e. carbon monoxide, cyanide, toluene), Isoniazid, Ibuprofen |
Lactic acidosis |
Ethylene glycol, Ethanol ketoacidosis |
Salicylates, Starvation ketoacidosis, Sympathomimetics |
Many clinicians regularly obtain urine drug screening (UDS) on altered patients or on those suspected of ingestion. Such routine urine drug testing, however, is of questionable benefit for overdose and trauma in the emergency setting [
37‐
40]. Most of the therapy is supportive and directed at the clinical scenario (i.e. mental status, cardiovascular function, respiratory condition), therefore the impact of such routine UDS is low. Interpretation of the results can be difficult even when the objective for ordering a comprehensive urine screen is adequately defined. Agents with very short half-lives such as gamma hydroxybutyrate (GHB) may be undetectable by laboratory analysis even in the acute setting. In contrast, when testing for agents with long half-lives, detection is possible but acuity may be difficult to predict. Most assays rely on antibody detection of drug metabolites with some drugs remaining positive days after use and thus may not be related to the patient's current clinical picture. The positive identification of drug metabolites is likewise influenced by chronicity of ingestion, fat solubility, and co-ingestions [
41,
42]. Conversely, many drugs of abuse are not detected on most urine drug screens, including GHB, fentanyl, and ketamine. The utility of ordering urine drug screens is fraught with significant testing limitations, including false-positive and false-negative results. Urine drug immunoscreening assays utilize monocolonal antibodies to detect structural conformations found in drugs belonging to a specific drug classes. Unfortunately, these antibodies have variable sensitivity and specificity [
43]. Physicians need to be fully aware of the scope of drugs being detected and the sensitivity and specificity for the tests they are ordering. Many authors have shown that the test results rarely affect management decisions [
15].