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Role of toxicology assessment in poisoning 

Role of toxicology assessment in poisoning
Chapter:
Role of toxicology assessment in poisoning
Author(s):

Albert Jaeger

DOI:
10.1093/med/9780199600830.003.0315
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date: 21 February 2020

Key points

  • Diagnosis of acute poisoning is based on history, symptoms, biomedical investigations, toxicological analyses, and sometimes therapeutic tests.

  • An accurate and useful toxicological analysis needs good collaboration between the physician and the analytical toxicologist.

  • Toxidromes, electrocardiographic disturbances, and biomedical abnormalities may provide diagnostic clues for specific poisons.

  • Indications for toxicological analysis include assessment of diagnosis, evaluation of severity and prognosis, indication and evaluation of treatments, and medicolegal implications.

  • Interpretation must take into account kinetic and toxicodynamic variation, type of poisoning, and factors such as age and underlying diseases.

Introduction

Diagnosis of acute poisoning is based on history, symptoms, biomedical investigations, toxicological analyses, and sometimes therapeutic tests [1]‌. Toxicological analytical methods are now widely available, but extensive and specific quantitative analyses are expensive. Therefore, the indications should be carefully considered by the physician according to assessment of diagnosis, evaluation of severity and prognosis, indication and evaluation of treatments, and medicolegal implications. The interpretation needs to take several factors into account depending on the poison and the patient.

Methods

Before a toxicological analysis is performed, the physician and the analytical toxicologist should discuss the following points [2]‌:

  • Which substance (the parent compound and/or the metabolite(s)) should be analysed and in what biological sample(s)?

  • What type of analytical method (qualitative or quantitative) and what specificity are needed?

  • Is the analysis useful for the management of the patient?

  • Within what time limit should the results be available for the physician?

A qualitative or semiquantitative analysis of the parent compound (or the active or non-active metabolites) may be adequate for diagnostic assessment. A quantitative analysis of the parent compound is mandatory for kinetic studies. Analysis of the parent compound and the active metabolite(s) is needed for toxicodynamic assessment (symptom–concentration relationship) [2,3]. For instance, in ethylene glycol poisoning, analysis of ethylene glycol concentrations is useful for the diagnosis, but glycolate concentrations are more relevant for the evaluation of the severity and prognosis. Therefore, the analytical toxicologist should be precisely informed about the indications and the objective of the analysis.

Indications

Assessment of diagnosis

The usefulness of systematic toxicological screening in poisoned patients has not been established. In several reports, the concordance between the drug(s) suspected clinically and the drugs detected by toxicological screens ranged from 26 to 96%, and were dependent on the physician, the age of the patient, and the drug ingested [2]‌. The results rarely contributed to the management of the patient. Toxicology screens give qualitative or semiquantitative results for drugs that are frequently involved in poisonings, but they do not usually include toxins that induce severe poisoning, and for which analysis is essential for the prognosis or the treatment (e.g. theophylline, digoxin, lithium, carbon monoxide, methanol, ethylene glycol, etc.) [2,3].

In practice, four different situations may be observed:

  • Poisoning is definite, the toxin(s) is known according to the history, and the symptoms are related to the toxin(s) and dose: a toxicological analysis is not absolutely necessary if it has no prognostic, therapeutic, or medicolegal implications.

  • Poisoning is definite and the toxin(s) is known, but the symptoms are not related to the suspected toxin(s) or to the dose: a toxicological analysis is indicated in order to detect other toxins that may have been ingested.

  • Poisoning is suspected because of symptomatology (toxic symptoms or syndromes), but the toxin(s) is unknown: only a toxicological analysis can confirm or refute poisoning.

  • Poisoning must be excluded by toxicological analysis: in patients presenting with disturbances of the central nervous system (trauma, brain death, in elderly patients), cardiovascular symptoms, or convulsions.

According to the history, the symptoms and biomedical abnormalities, the analysis should be directed towards specific drugs or groups of drugs.

Groups of symptoms (or toxidromes), such as those involving the autonomic nervous system, electrocardiogram (ECG) disturbances, and biomedical abnormalities may provide diagnostic clues for toxins that are not usually included in routine screens. They reflect directly the toxic effects and are often more useful than the measurement of plasma drug concentrations in the management of the patient [1,2]. Some examples of toxidromes, ECG disturbances, and biomedical abnormalities in specific poisonings are given in Tables 315.1, 315.2, and 315.3.

Table 315.1 Toxidromes involving the autonomic nervous system

Syndrome

Mechanism

Symptoms

Toxins

Cholinergic Muscarinic

  • Stimulation of cholinergic receptors

  • ↑ acetylcholine production or

  • ↓ acetylcholine degradation

Sweating, hypersalivation, bronchorrhea, diarrhoea, vomiting, miosis, bradycardia

Acetylcholine, pilocarpine, mushrooms (Clitocybe), organophosphate and carbamate insecticides

Nicotinic

Tachycardia, hypertension, fasciculation, paralysis

Nicotine, nicotinic, and organophosphate insecticides

Anticholinergic (or atropinic)

Cholinergic receptors blockade

Dry skin, hyperthermia, mydriasis, tachycardia, confusion, hallucinations, hyperventilation, agitation

Atropine, Atropa belladonna, Datura, mushrooms (Amanita muscaria, A. pantherina), TCA, antihistamines, antiparkinson-drugs

Sympathomimetic (or adrenergic)

Stimulation of α‎ and β‎-adrenergic receptors

Agitation, convulsion, hypertension, tachycardia, hyperglycaemia, hypokalaemia, leucocytosis, hyperlactataemia

Caffeine, xanthines, theophylline, amphetamines, cocaine, LSD, phencyclidine

Narcotic (or opioid)

Opiate receptors agonist effect

CNS depression, hypoventilation, hypotension, miosis

Heroin, morphine, codeine, dextropropoxyphene

Withdrawal

Adrenergic stimulation

Insomnia, hallucinations, agitation (convulsion), diarrhoea, mydriasis, sweating, tachycardia, cramps

Withdrawal of alcohol, benzodiazepines, opiates

Antabuse

Acetaldehyde accumulation

Cutaneous flush, tachycardia, headache, hypotension, hyperventilation

Disulfiram, dithiocarbamates, mushrooms (Coprinus), dimethylformamide

Serotoninergic

↑ Serotoninergic brain activity, increased activity of 5-HT1A réceptors

Hyperthermia, dysautonomia, tachycardia, consciouness disturbances, hypertonia, hyperreflexia, myoclonia

Serotonin reuptake inhibitors, serotonin receptor agonists

Neuroleptic malignant

Dopaminergic receptors antagonism, acute depletion of dopamine

Hyperthermia, dysautonomia, tachycardia, consciousness disturbances, hypertonia, rhabdomyolysis, hyperleucocytosis

Piperazine-type neuroleptics

Ecstasy (MDMA)

Disturbances of dopaminergic and serotoninergic neurones, ↑ production of serotonin

Hyperthermia, dysautonomia, tachycardia, consciousness disturbances, hypertonia, disseminated intravascular coagulation, rhabdomyolysis, renal failure

MDMA

LSD, lysergic acid diethylamide; CNS, central nervous system; MDMA, 3-4-methylene dioxymethamphetamine.

Table 315.2 ECG disturbances induced by poisons

Disturbances

Effects

Toxins

Tachycardia

  • Anticholinergic

  • Betamimetic

  • Alphamimetic

  • Atropine, A. belladona, Datura, anti-H1 histaminines, TCA, quinidine, disopyramide

  • Salbutamol, theophylline, xanthines, caffeine

  • Amphetamines, cocaine, ephedrine

Bradycardia

  • Cholinergic

  • Beta-blockade

  • Na-K-ATPase inhibition

  • Ca channel blockade

  • Na channel blockade

  • Alphalytic

  • Acetylcholine, some opiates, organophosphates

  • Beta-blockers

  • Digoxin, digitoxin

  • Class IV AAR

  • Class I AAR, chloroquine, TCA, some beta-blockers

  • Clonidine, methyldopa

Ventricular dysrhythmias (VES, VT, VF, torsades de pointes)

  • Betamimetic

  • Alphamimetic

  • Na-K-ATPase inhibition

  • Na channel blockade

  • Salbutamol, theophylline

  • Amphetaminines, cocaine, ephedrine, trichloroethylene

  • Digoxin, digitoxin

  • Class I AAR, chloroquine, TCA, some beta-blockers

Atrioventricular block

  • Na-K-ATPase inhibition

  • Na channel blockade

  • Digoxin, digitoxin

  • Class I AAR, chloroquine, TCA, some beta-blockers, ciguatoxin, tetrodotoxin

Intraventricular block (QRS > 0,10 s)

Na channel blockade

Class I AAR, chloroquine, TCA, some beta-blockers, thioridazine

Increased QT interval

  • K channel blockade

  • Na channel blockade

  • Amiodarone

  • Class I AAR, chloroquine, TCA, some beta-blockers

TCA, tri-tetracyclic antidepressants; AAR, anti-arrhythmics; VES, ventricular extrasystoles; VT, ventricular tachycardia; VF, ventricular fibrillation

Table 315.3 Biomedical disturbances in specific poisonings

Disturbances

Toxin

  • Anion gap

  • Osmolal gap

  • Hypoglycaemia

  • Hypokalaemia

  • Hyperkalaemia

  • Hypocalcaemia

  • Pseudohyperchloraemia

  • Decreased prothombin level

  • Methaemoglobinaemia

  • Decreased plasma or erythocyte cholinesterase level

  • Oxalate crystals in urine

  • Gastric opacities on radiographs

  • Methanol, ethylene glycols, acetone

  • Ethanol, methanol, ethylene glycols, acetone

  • Insulin, oral antidiabetics

  • Chloroquine, theophylline

  • Digoxin, digitoxin

  • Fluoride

  • Bromine and bromide

  • Oral anticoagulants, rodenticides, snake venoms

  • Methaemoglobin-forming agents

  • Organophosphate and carbamet insecticides

  • Ethylene glycol

  • Metals, halogenated hydrocarbons

Therapeutic tests, such as naloxone in opiate and flumazenil in benzodiazepine poisoning, may also confirm the diagnosis [1]‌.

Evaluation of severity and prognosis

In order to establish the relationship between the severity and the blood/plasma concentrations, the analysis must be specific and quantitative and sometimes include the active metabolites. The relationship is dependent on the mechanism of toxicity [3]‌.

Functional toxins (e.g. barbiturates, benzodiazepines, meprobamate, cardiotropic drugs, lithium, theophylline, etc.) impair the function of one or more organs. Patients recover without sequelae if no complications occur during the poisoning. Their toxicity is directly related to the concentration at the target organ or receptor, Symptoms appear when the plasma concentration exceeds a threshold level, and the severity increases with the concentration (Fig. 315.1). The duration of the toxicity is dependent on the plasma half-life and the decrease of the concentration at the target organ. For instance, in barbiturate, meprobamate, or ethanol poisoning, the severity of disturbances of the central nervous system and coma is closely related to the plasma concentration. In acute theophylline poisoning, toxicity is minor at concentrations between 20 and 40 mg/L, moderate at concentrations between 40 and 100 mg/L, and severe at concentrations above 100 mg/L. If the parent compound is metabolized into active metabolites that have not been analysed, there is not usually a relationship between plasma parent drug concentrations and symptoms [3]‌.

Fig. 315.1. Toxicokinetic–toxicodynamic relationship for a functional poison (monocompartment kinetics).

Fig. 315.1. Toxicokinetic–toxicodynamic relationship for a functional poison (monocompartment kinetics).

Curve A, concentration; curve B, toxic effect.

Lesional toxins (paraquat, paracetamol (acetaminophen), colchicine, amatoxins, heavy metals, etc.) induce cellular or organ damage. The severity depends on the maximum concentration that has been (or will be) reached at the target organ. If cellular damage has occurred, symptoms may not improve even though the toxin has been eliminated from the target organ. The interpretation has to take into account the plasma concentration and the time at which this concentration has been measured. Depending on the delay following ingestion, the same plasma concentration may be non-toxic, toxic, or lethal (Fig. 315.2). In these poisonings, plasma concentrations have a prognostic value: risk of lethal outcome in paraquat poisoning [4]‌, and risk of hepatitis in acetaminophen poisoning [5].

Fig. 315.2. Toxicokinetic–toxicodynamic relationship for a lesional poison.

Fig. 315.2. Toxicokinetic–toxicodynamic relationship for a lesional poison.

Curve A, concentration; curve B, toxic effect.

Some toxins act by both mechanisms: the parent compound is a functional toxin, but after a delay cellular damage due to prolonged cellular hypoxia (carbon monoxide, cyanide) or to the accumulation of cytotoxic metabolites (methanol, ethylene glycol) may occur. The interpretation is based on the kinetic data (plasma concentrations of the parent compound and metabolites) and on the time after ingestion or the duration of the exposure [3]‌. In acute short exposure to carbon monoxide, the symptoms correlate well with carboxyhaemoglobinaemia levels. In prolonged exposure, the severity depends not only on the carboxyhaemoglobin level, but also on the duration of the cerebral hypoxia. The potential toxicity of methanol is related to the methanol concentration measured in the early phase of the poisoning. The real toxicity depends on the concentrations of the toxic metabolites. If the patient is seen in a later phase, severe symptoms may be present despite low methanol concentrations.

Indication and evaluation of treatments

The management of the poisoned patient is mostly supportive and based on anamnestic, clinical, and biological data. Toxicological quantitative analyses are mandatory for some treatments [3]‌. Depending on the analytical results and clinical data, the physician will estimate the indication of the following:

  • Alkaline diuresis in salicylate poisoning.

  • Repeated dose of oral activated charcoal in phenobarbital or theophylline poisoning.

  • Haemodialysis in lithium, methanol, ethylene glycol, and salicylate poisoning, and haemoperfusion in carbamate or theophylline poisoning.

  • Ethanol or 4-methylpyrazole in ethylene glycol or methanol poisoning, N-acetyl cysteine in acetaminophen poisoning.

  • Chelating agents in metal poisoning or deferoxamine (desferrioxamine) in iron poisoning.

In digitalis poisoning, the indication for Fab fragments is essentially based on clinical and biochemical (hyperkalaemia) criteria, but previous confirmation of the diagnosis by measurement of digitalis plasma concentration is recommended.

Evaluation of the methods used for decontamination or enhancing elimination must be based not only on clinical improvement but also on precise kinetic data which vary depending on the technique used.

Medicolegal implications

Quantitative and specific analyses are indicated if the poisoning may have medicolegal consequences (e.g. occupational or criminal poisoning).

Interpretation

Apart from the mechanism of toxicity, other factors must be taken into account in the interpretation of analytical and kinetic data [2,3].

Type of poisoning

Similar plasma concentrations may be associated with different severity, depending on the type of poisoning: acute, acute on chronic, or chronic. Toxic symptoms appear at lower plasma concentrations in chronic theophylline poisoning than in acute poisoning; convulsions and severe dysrhythmias may appear at concentrations between 40 and 70 mg/L, and the probability of developing convulsions is 50% when the peak concentration exceeds 40 mg/L whereas in acute poisoning the same probability is only observed if the peak concentration is above 120 mg/L. In chronic lithium poisoning, severe disturbances of the central nervous system may appear at supratherapeutic plasma concentrations (>1.2 mmol/L), whereas in acute poisoning no toxicity has been reported at concentrations ranging up to 8 mmol/L [3]‌. Similar severity of digoxin poisoning is observed at lower plasma digoxin concentrations in chronic overdose than in acute poisoning.

With some toxins (barbiturates, ethanol), a tolerance may be observed in patients treated or poisoned chronically. In acute ethanol poisoning with similar blood ethanol levels, symptoms are less severe in chronic alcoholics than in non-tolerant individuals. Patients treated chronically with barbiturates are more tolerant to acute barbiturate toxicity and the duration of coma is often shorter because of an increase in hepatic elimination by enzyme induction.

Age

In chronic theophylline overdoses with the same plasma concentrations, symptoms and prognosis are more severe in elderly patients than in young adults. For a given plasma concentration, the cardiotoxic effects of digoxin are more severe in adults than in children.

Underlying diseases and toxic symptoms

An underlying disease or toxic symptoms, such as hypoxaemia and shock, may strongly modify the toxicodynamics [3]‌. In theophylline poisoning, the risk of toxicity and the plasma half-life are increased in patients with congestive heart failure because of impaired elimination by hepatic metabolism. Patients with epilepsy are at higher risk of developing convulsions in poisoning with drugs that may induce convulsions. In poisoning with cardiotropic drugs, the toxicity is increased in patients with chronic heart diseases. In acute meprobamate overdoses, the plasma half-life is increased in patients with shock.

Concurrent ingestion of other drugs

The ingestion of drugs with anticholinergic effects may prolong the gastrointestinal absorption of other drugs. In poisoning with several cardiotoxic drugs with synergistic effects severe symptoms may appear even if the plasma concentration of each drug individually is at a therapeutic level.

Dose ingested

Dose-dependent kinetics, with a change from first-order to zero-order kinetics, have been reported in massive theophylline and salicylate poisoning.

Acknowledgements

The editors were saddened to hear of the death of Dr Albert Jaeger since writing this chapter of the book.

References

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