Diagnosis and management of common overdose presentations | Lesson

Presentations as a result of acute toxicity to emergency departments and primary care providers are common-place. A major distinction with regard to this problem is that while many cases are as a result of intentional overdose, a substantial number are not. The following outlines some of the common agents seen in the context of acute toxicity. It is obviously essential to assess the psychosocial history, particularly in cases of suspected intentional overdose.

Alcohols

Acute alcohol toxicity and alcohol-related issues probably comprise the majority of toxicological presentations. Obvious inebriation may be evident, however patients also present more insidiously.

Alcohols do not just pertain to ethanol. From a chemical point of view they include the primary, secondary and tertiary alcohols. These include methanol and ethanol, as well as numerous others such as isopropyl alcohol.

Ethanol is absorbed rapidly with peak serum concentrations occurring about 30-60 minutes after ingestion. It exerts its effects via the gamma-aminobutyric acid (GABA) receptor, hence causing central sedative effects similar to those initiated by benzodiazepines. It also works as an N-methyl-D-aspartate (NMDA) glutamate antagonist. Most ethanol is broken down in the liver into acetaldehyde by alcohol dehydrogenase. It is further broken down by acetaldehyde dehydrogenase to acetic acid.

Patients with suspected ethanol toxicity should be fully assessed, with work-up including blood glucose, electrolytes and acid/base assessment. Acute ethanol intoxication does not usually cause significant anion gap metabolic acidosis. Serum ethanol levels must be determined and while metabolism occurs at a fixed rate in an individual, metabolism varies across the population. Serum osmolalities and full toxicology screens should be sent on all such patients.

Hypoglycemia and respiratory compromise are the potentially immediately life threatening sequelae. In general, treatment is supportive and a conservative approach is recommended with respiratory support, glycaemic control and fluid replacement being core components. Attempted emesis should not be induced and forced diuresis is not of benefit as metabolism is predominantly in the liver. Thiamine is an essential coenzyme of carbohydrate metabolism and it should be given to prevent Wernicke’s encephalopathy.

Methanol is a primary alcohol and a common constituent of industrial and commercially available solvents. Methanol serum levels peak at 30-90 minutes but often do not correlate to the time line of symptom presentation. Symptoms often occur 12-24 hours after ingestion. The toxic metabolite, formic acid, is responsible for ocular toxicity and Parkinsonian movement disorders are a recognised complication. Following ingestion, methanol is quickly absorbed and converted to formaldehyde via alcohol dehydrogenase. Aldehyde dehydrogenase then converts formaldehyde into formic acid. Metabolism of formic acid is very slow which results in its accumulation and the resultant metabolic acidosis. A raised anion gap metabolic acidosis occurs with high lactate and ketone levels.

Serum amylase should be tested as haemorrhagic pancreatitis has been described in a large proportion of patients. Initial emphasis of management should be on airway, correcting electrolyte and adequate hydration. Bicarbonate may need to be administered. Antidote therapy using ethanol works on the principle that the affinity of alcohol dehydrogenase for ethanol is 10-20 times greater than it is for methanol. It works by delaying methanol metabolism. Haemodialysis may be required but specialist consultation with neurology, nephrology and ophthalmology should be initiated immediately.

Paracetamol

Paracetamol overdose is an all too common presentation to emergency departments. The vast availability of various different preparations of the drug leads to both intentional and unintentional overdose. In the USA paracetamol has now replaced viral hepatitis as the commonest cause of acute hepatic failure.

Paracetamol is rapidly absorbed from the stomach and small intestine and is primarily metabolised by conjugation in the liver. In the setting of an acute overdose, metabolism via conjugation becomes saturated and excess paracetamol is metabolised by the CYP enzymes to the metabolite NAPQI. NAPQI has an extremely short half-life and is rapidly conjugated with glutathione before being renally excreted. When excess NAPQI is formed or if glutathione stores deplete significantly, NAPQI covalently binds to the cysteinyl sulfhydryl groups of hepatocellular proteins, forming NAPQI protein adducts. These cause a cascade of oxidative damage and mitochondrial dysfunction. Hepatocellular injury and necrosis is caused by the subsequent inflammatory response.

N-acetylcysteine (NAC) is the antidote to paracetamol and it works by the principle that it is a precursor of glutathione, it enhances sulphate conjugation of unmetabolised drug and acts as an anti-inflammatory and antioxidant. NAC also increase levels of local nitric oxide concentrations which promotes tissue perfusion. It is maximally hepatoprotective when administered within 8 hours of acute ingestion. However, it has benefits beyond this window and has been shown to decrease mortality in late presenting patients with fulminant hepatic failure.

Toxicity from paracetamol is divided into four phases:

• Phase 1 relates to the first 24 hours and patients may be asymptomatic or complain of malaise, nausea. Serum transaminase levels begin to rise approximately 12 hours post ingestion.
• Phase 2 (18-72 hrs) patients develop right hypochondrial pain, nausea, vomiting and anorexia.
• Phase 3 (72-96 hrs) patients deteriorate developing hepatic necrosis with associated jaundice, coagulopathy, hypoglycaemia and hepatic encephalopathy. Acute renal failure develops in some, as does death from multi-organ failure.
• Phase 4 (4 days – 3 weeks) pertains to those who survive phase 3 and have complete resolution of symptoms and organ failure.

Full work-up including FBC, U&E, LFTs, INR, ECG, beta-HCG and blood gas should be carried out. A paracetamol level should be taken 4 or more hours after a single ingestion. Urinalysis may help assess for acute tubular necrosis and patients with an altered mental status may require brain imaging. Gastric lavage has no proven efficacy in isolated cases of paracetamol toxicity which is defined as serum AST or ALT greater than 1,000 IU/l. Prothrombin times and INRs indicate hepatic synthetic function and abnormalities in these parameters are predictive of mortality.

Tricyclic antidepressants

Tricyclic antidepressant overdose is frequently seen in the clinical setting. Symptoms include respiratory depression, seizures and cardiotoxicity, as well as anticholinergic symptoms. Toxic side effects of these drugs are as a result of inhibition of norepinephrine and serotonin reuptake, alpha blockade and anticholinergic action. Salicylate overdose may present with varying symptoms including tachycardia, tachypnea, pyrexia and tinnitus. Differential diagnoses also vary from ARDS to ethylene glycol poisoning.

The main principles of treatment include limiting absorption and correcting metabolic abnormalities. Gastric lavage and activated charcoal are useful in cases of acute ingestion and the biochemical complications involve disruption to enzymes of the Krebs cycle.

Amphetamine

Amphetamine toxicity has a multisystem presentation which includes altered mental status, dyskinesia, palpitations, diarrhoea and vomiting. Varying subclasses of amphetamines exert relative effects depending on their structural chemistry. Effects include agonism of dopaminergic, catecholaminergic and serotonergic receptors.

MDMA (3,4-methylenedioxymethamphetamine), commonly known as ecstasy, is structurally similar to methamphetamine and mescaline. Acute toxicity presents with sympathomimetic effects which are subsequently replaced by feelings of euphoria and relaxation. Autonomic hyperarousal occurs when toxic levels of MDMA are consumed, which is often caused by users attempting to prolong the effects with repeated doses. Tolerance occurs rapidly, with inability to induce the euphoric effects. Sympathomimetic effects predominate instead, which place the user at increased risk of arrhythmias and cardiovascular complications. Seizures and death are recognised outcomes, with growing evidence that MDMA may also cause hepatotoxicity.

Crystal meth is also a member of the amphetamine family and is highly addictive.

Opioids

Cocaine toxicity results in tachyarrhythmias, MI, stroke, and subarachnoid haemorrhage as well as hyperthermia and psychological and behavioural effects. Opioid toxicity occurs in multiple forums in the healthcare environment. Presentations vary from heroin/methadone overdose to abuse of prescribed opioids (e.g. oxycontin) to accidental toxicity as in-patients (e.g. post-operative patients).

Depressed level of consciousness, respiratory depression and miosis are some of the hallmark physical features of opioid toxicity although respiratory depression is the most specific. The unresponsive patients may be difficult to diagnose and so a trial dose of naloxone is often administered in an attempt to restore respiratory function and determine the underlying cause.

Paraquat

Paraquat dichloride is a highly toxic herbicide used primarily to control weeds and grass. Its name is derived as a result of the para positioning of the quaternary nitrogens as per the chemical structure of the molecule. Some preparations of paraquat have an added dye, pungent odour and a pro-emetic agent to induce immediate vomiting in case of ingestion. Modalities of poisoning in order of decreasing toxicity are inhalation, ingestion and skin exposure. Damage is conferred directly to gastrointestinal mucosa on contact while cells in the lung selectively accumulate paraquat probably by active transport. It essentially interferes with electron transfer and as a herbicide it inhibits photosynthesis. It is highly toxic by the inhaled route in particular and only very small quantities are required to induce death. Multi-organ dysfunction occurs with even small or medium amounts of exposure while survival is unlikely in those who ingest a large quantity.

Prehospital treatment includes administration of activated charcoal, immediate removal of contaminated clothing, thorough washing and rinsing eyes with plain water for ten to fifteen minutes. In the emergency department setting nasogastric suction may be considered if ingestion has occurred within an hour. There is no proven antidote for paraquat poisoning so treatment is mainly supportive. Excessive oxygen should not be administered as it may worsen paraquat toxicity.  Studies have suggested a link between paraquat dichloride exposure and the development of Parkinson’s disease.

Organophosphates

Organophosphates are man-made poisons used in agriculture and home and garden environments. They include malathion, parathion, and diazinon as well as others. Nerve gas derivatives include soman, sarin tabun and VX. Other toxic preparations include organophosphate (OP) based herbicides. Organophosphates exert their effects by irreversibly inhibiting acetylchoninesterase (AChE). This leads to the accumulation of acetylcholine (ACh) which leads to muscle over-stimulation causing disruption across the cholinergic synapses. When ACh accumulates at autonomic ganglia this leads to overstimulation of nicotinic expression in the sympathetic system.  Again direct contact, ingestion or inhalation results in toxic effects. Symptoms occur during or after exposure and include headache, dizziness, weakness, diarrhoea, salivation, vomiting etc. Certain symptoms are attributable to overstimulation of nicotinic acetylcholine receptors while others such as visual symptoms, wheezing and salivation/lacrimation are caused by muscarinic overstimulation.

Treatment of OP poisoning includes carbamates to protect AChE from inhibition and anti-cholinergic drugs. Atropine may be used as an antidote as it is a muscarinic antagonist and therefore blocks the action of ACh in the periphery. Currently there is debate as to whether drugs such as pralidoxime should be used at all in this setting. While there is no evidence to demonstrate that exposure to organophosphates causes cancer, studies in rats have demonstrated higher incidence of pancreatic, adrenal and thyroid tumours.

Cyanide

Cyanide exists in various forms including hydrogen cyanide, cyanogen chloride, sodium cyanide and potassium cyanide. It exists in certain foods such as lima beans and almonds while cyanide precursors exist in the pits and seeds of apricots and apples. It exists in cigarette smoke and is used in many guises in the manufacturing industry. In nature cyanides are produced by certain bacteria, algae and fungi as well as certain plants. Once absorbed cyanide is distributed to all organs and tissue. Cyanide exerts its potentially lethal effect because the cyanide anion inhibits cytochrome c oxidase in the electron transport chain, as a result, uncoupling mitochondrial oxidative phosphorylation and inhibiting cellular respiration. This occurs even when there are adequate oxygen stores. The result is the cell being unable to aerobically produce ATP. Hydrogen cyanide is the most hazardous cyanide compound and was weaponised by the Nazis as the genocidal agent Zyklon B in World War II.

The FDA approved a cyanide antidote, the Cyanokit in 2006. In this context hydroxocobalamin reacts with cyanide to form cyanocobalmin which is eliminated by the kidneys. Older antidotes involved administration of amyl nitrite pearls, sodium nitrite and sodium thiosulfate. Within the hospital setting it is worth remembering that intensive treatment with sodium nitroprusside is a possible source of cyanide poisoning. It’s structure comprises an octahedral iron (II) centre surrounded by five tightly bound cyanide ligands and one linear nitric oxide ligand.