EMERGENCY TREATMENT OF POISONING
Poison and drug information centres
Clinical notes:
General management of acute poisoning
MAJOR POISON AND DRUG INFORMATION CENTRES
D - Drug information centres
P - Specialist poison information centres
T -Tablet identification
Western Cape
Tel: (021) 689 5227
Orange Free State
Gauteng
Tel: (011) 642 2417; 488 3108
Tel: (011) 339-4831
Acute poisoning requires accurate assessment, and prompt therapy may be needed. Hazard is associated not only with the potency of the poison but also with the quantity ingested, the duration of exposure, and the presence of other ingredients in preparations, including solvents.
It should be determined if the poisoning
* is life-threatening and already compromising vital functions;
* poses a potential hazard; or
* is essentially harmless.
Special Prescriber's Points
* It should be borne in mind that up to 50% of histories are incorrect as to the substance, quantity and even actual exposure.
* Early identification of the toxic substance (or ingredients and their potential toxicities) can save time and decrease the risk of toxicity and complications, particularly in instances where a specific antidote could be lifesaving or prevent serious organ damage, e.g. methanol, paracetamol, arsenic, iron poisoning, etc.
* Early collection of blood, urine and other body fluid samples to establish baseline values for monitoring the toxin, glucose, electrolytes, acid/base status and organ damage may be valuable in the management of the poisoned patient.
* Obtaining the original toxic substance or container is more valuable and reliable for rapid and positive identification of the poison than depending on laboratory analysis of blood, urine or other body fluids alone. Medical personnel should be encouraged to obtain and send these to the laboratory as soon as possible. If not initially brought in with the patient, a special effort should be made to send someone to collect them.
* Please note: Standard toxicological screenings cover only the most frequently encountered possibilities. A 'negative' result for a toxicological screening simply means that the screen was negative for the substances tested and not for all possibilities. Communication with the toxicology laboratory is crucial for successful treatment of a poisoning or suspected poisoning.
* Quantitative determinations of toxins are needed for relatively few substances, e.g. paracetamol, salicylates, theophylline, lithium, digoxin and metals. For some of these, and depending on the elimination rate of the substance, two plasma levels, one or more hours apart, may be needed to determine whether concentrations are rising or falling before deciding whether specific therapy is needed or can be discontinued.
* Factors such as age, the presence of other diseases, other drugs and allergy to drugs should also be considered.
Supportive care:
Reliable venous access should be established in comatose patients.
Hypoventilation can be avoided by ensuring an adequate airway with suction, oxygen, insertion of an airway and mechanical ventilation as required. (Most poisons that depress consciousness also impair respiration.)
If opioids are suspected of causing coma and respiratory depression, naloxone may be administered.
An obstructed airway needs immediate attention: dentures and oral secretions should be removed, and the jaw held forward with the patient turned in a left semiprone position.
Volume depletion secondary to vomiting, diarrhoea and sweating is common and should be corrected.
Hypoglycaemia must be excluded in any comatose patient. If present, 50 mL of a 50% dextrose solution should be administered intravenously (adult dose). Hypoglycaemia should be suspected particularly in intoxication with oral hypoglycaemics, salicylates and ethyl alcohol.
Hypotension is most common in severe barbiturate poisoning, and whether due to volume depletion or venous pooling, frequently necessitates monitoring of central venous pressure to determine fluid requirements.
Hypothermia (< 35 C) may develop in comatose patients and may be missed unless a low-reading rectal thermometer is used.
Cardiac conduction defects and arrhythmias may occur in acute poisoning with various substances. ECG monitoring is advisable and attention should be given to aggravating factors such as acidosis, hypoxia and electrolyte/fluid disturbances. Specific treatment will depend on the toxin ingested and the type of arrhythmia.
Convulsions that are single and short-lived do not require immediate anticonvulsive therapy. Diazepam, given slowly intravenously, should be administered if convulsions are protracted or recur frequently, considering, however, that it may produce CNS and, particularly, respiratory depression.
Terminating topical exposure to poisons:
Contaminated clothing should be removed and the skin washed with soap and water. If contaminated, the hair should be shampooed.
Terminating exposure to ingested toxins:
The stomach should be emptied after the ingestion of most poisons, (there are some notable exceptions, e.g. corrosives, volatile hydrocarbons and convulsants). Gastric emptying is clearly unnecessary if the risk of toxicity is small, or if the patient presents too late. Emptying the stomach more than 4 hours after ingestion is of questionable value, although worthwhile recovery of tricyclic antidepressants (and other drugs which delay gastric emptying, e.g. anticholinergics, opiates, antihistamines and sympathomimetic amines) can be achieved 4-12 hours after ingestion.
Induced emesis may be preferred to lavage in alert patients with an active gag reflex and is usually more efficient than lavage especially when large tablets or capsules have been swallowed. Emesis is best induced with ipecacuanha.
Gastric lavage via a large-bore orogastric tube (32-40 F in adults and 16-28 F in children) is preferred in patients with a depressed level of consciousness, but only after a cuffed endotracheal tube has been inserted to prevent aspiration.
Stomach emptying should be followed by the administration of activated charcoal, which reduces absorption of many substances.
Osmotic laxatives e.g. saline purgatives (such as sodium sulphate), sorbitol 70% or lactulose may usefully assist in clearing the bowel of potentially absorbable poisonous material.
Rough estimates of the dose, the time elapsed since exposure, and the physical state of the patient determine whether emesis, gastric lavage, supportive care, or specific therapy is required, as well as the sequence of such interventions.
MANAGEMENT OF POISONING WITH SPECIFIC SUBSTANCES
Aspirin and other salicylates
Toxic doses disturb the acid/base balance and uncouple oxidative phosphorylation which may result in metabolic acidosis or compensated respiratory alkalosis. In overdose, salicylates may be retained in the stomach for 4-8 hours or longer. Ingestion of large amounts may form concretions in the stomach which may delay absorption.
Oil of wintergreen is 98% methyl salicylate. 1 mL is equivalent to 1.4 g salicylate. It is particularly hazardous in children.
Clinical features: These may include restlessness, hyperventilation, tinnitus, deafness, tachycardia, nausea, vomiting, sweating, hyperthermia, dehydration, pulmonary oedema, acute renal failure, hypokalaemia, hypoglycaemia and hypoprothrombinaemia. Stupor and coma indicate severe poisoning.
Management depends on the severity of toxicity.
* Severity can be determined by measuring blood salicylate levels 6 or more hours after acute ingestion, but may be misleading in severe acidosis.
* Therapeutic plasma salicylate level lies between 0.7-2.2 mmol/L, or 100-300 mcg/mL.
* Emesis or lavage should be followed by activated charcoal; studies have indicated that repeated doses, 50-100 g every 4 hours, increase clearance significantly by a process termed `gastrointestinal dialysis'.
* Dehydration, acidosis, hypoglycaemia and electrolyte disturbances should be corrected.
* Hyperthermia is managed by external cooling.
* Alkalinisation of the urine (pH 7.5-8.5) by administering sodium bicarbonate orally or by infusion, is recommended to increase excretion of salicylates.
* Care must be taken to avoid fluid overload and renal function closely monitored.
* In severe poisoning with decreased urinary flow, pulmonary oedema or progressive deterioration, charcoal haemoperfusion or haemodialysis should be considered.
* Antacids may be administered to counteract gastric irritation and vitamin K to correct deranged coagulation mechanisms.
Other non-steroidal anti-inflammatory agents
Clinical features: Acute poisoning may produce few specific clinical findings, but symptoms may include nausea, vomiting, epigastric pain, tinnitus, deafness, drowsiness, dizziness, headache, sweating and oliguria. Apnoea and near coma have been reported. Overdose of the potentially more toxic mefenamic acid preparations can cause convulsions.
Management
* The stomach should be emptied within 4 hours.
* This is followed by activated charcoal.
* Regular antacids such as magnesium- and aluminium hydroxide should be given for gastrointestinal irritation.
* Further therapy is supportive with correction of electrolyte, acid/base and hydration imbalance, and attention to organ function.
* Seizures may be managed with slow, careful administration of intravenous diazepam.
* All NSAIDs are highly protein-bound and are probably not accessible for removal by dialysis.
Opioid analgesics
Respiratory depression is the most important toxic effect of the opioid analgesics. Death from morphine poisoning is nearly always due to respiratory arrest.
Clinical features: Poisoning with morphine and other opioids produces central nervous system depression ranging from drowsiness to deep coma, respiratory depression with shallow respiration or apnoea, cyanosis, miosis (pin-point pupils), hypotension and hypothermia. If hypoxia is severe, the pupils may be dilated. In some cases there is spasticity, muscle twitching, convulsions and non-cardiogenic pulmonary oedema. The onset of pulmonary oedema may be rapid, but in the comatose patient it may be delayed for up to 24 hours after recovery from coma (following administration of an opioid antagonist).
Management
* Stomach emptying - gastric lavage should be performed in the comatose patient via an orogastric tube after a cuffed endotracheal tube has been inserted to prevent aspiration. (Gastric emptying may be delayed because of opioid-induced pylorospasm.)
* Activated charcoal should be administered to adsorb opioid in the intestine and may be followed by a saline cathartic such as sodium sulphate, magnesium citrate or magnesium sulphate. Sorbitol 70% or lactulose are also useful cathartics.
* Immediate attention to an adequate airway, and artificial ventilation, may be indicated.
* Naloxone, an opioid antagonist, is administered intravenously or intramuscularly (preferably IV). The initial adult dose is 0.4-2 mg. If improvement does not occur immediately with IV administration, it may be repeated at 2-3 minute intervals to a maximum of 10 mg. The diagnosis should be reconsidered if 2-3 doses fail to produce a response. In children, the initial dose is 0.01 mg/kg, followed if necessary by a dose of 0.1 mg/kg.
* Naloxone may precipitate a severe withdrawal syndrome in an addict, that cannot be readily suppressed during the period of action of the antagonist.
* The duration of action of naloxone is shorter than that of most opioids. Patients should be observed carefully; repeated doses may be required after initial improvement.
* Opioid-induced pulmonary oedema should be treated with positive- pressure ventilation using positive end expiratory pressure (PEEP).
* Dialysis is unsuccessful in increasing opioid clearance due to the large volume of distribution and low blood concentrations.
Paracetamol
The liver is the main target organ in paracetamol poisoning. Doses of 7.5-15 g in an adult may cause severe centrilobular hepatic necrosis. Renal tubular necrosis may also develop. Hepatic and renal failure typically manifest only after 3-5 days.
Clinical features: Within a few hours after the overdose (0.5-24 hours) patients experience symptoms of gastrointestinal irritability with anorexia, nausea, vomiting, abdominal pain, as well as pallor, malaise and increased sweating. During this phase the patient may, however, appear normal or asymptomatic. During the next 24-48 hours symptoms and signs may become less pronounced, but the blood chemistry starts to become abnormal. In the typical case of severe intoxication, the clinical picture of progressive liver failure develops within 3-5 days.
Management
* Emesis or gastric lavage is indicated if less than 6 hours have elapsed since ingestion. Activated charcoal should be administered if the specific antidote is given by the IV route, but is contraindicated if the antidote is given orally.
* Acetylcysteine is the antidote of choice and is usually given intravenously. (Profile and dosage under ANTIDOTES.) Although more effective when administered within 8-12 hours of ingestion of paracetamol, recent studies have indicated benefit if antidote therapy is initiated up to 96 hours after the overdose. Acetylcysteine has not been shown to contribute to hepatic injury that is already present.
* Paracetamol plasma levels should be obtained 4 hours after ingestion or as soon as possible thereafter.
* In substantial overdoses (> 125 mg/kg or > 7.5 g in an adult) administration of the antidote should be initiated immediately, without waiting for plasma levels. The antidote may be discontinued if the levels are found to be in the non-toxic range.
* If the initial paracetamol level is in the toxic range, full antidote therapy is necessary.
* Patients with plasma levels above the predictive graph line joining 150-200 mcg/mL at 4 h and 20-30 mcg/mL at 15 h after ingestion should be treated with the specific antidote.
* Liver damage is likely to occur in 90% of patients with paracetamol levels > 300 mcg/mL at 4 hours or > 45 mcg/mL at 15 hours post ingestion. Levels below 120 mcg/mL at 4 hours are unlikely to cause hepatotoxicity. For reliable hepatotoxicity risk assessment, blood for plasma levels must be drawn after the drug has peaked (at least 4 hours post ingestion).
* Patients presenting 24 hours or later after an overdose of paracetamol and having detectable plasma levels or biochemical evidence of hepatotoxicity must be given acetylcysteine.
* Patients taking drugs that induce hepatic enzymes, e.g. barbiturates, phenytoin, carbamazepine, rifampicin and meprobamate, or alcohol abusers may develop paracetamol toxicity at lower plasma concentrations; a lower threshold for instituting specific antidote therapy should be used (50-70% of the potential toxic levels).
* If paracetamol levels are in the potentially toxic range, liver and kidney function tests should be performed daily.
* An alternative to the IV acetylcysteine regimen is oral acetylcysteine. Carbocysteine and methionine have also been used. See under ANTIDOTES for recommended dosages .
* The disadvantage of oral preparations is that they cause nausea and patients have difficulty retaining them. However, they may be the only alternative in patients presenting with severe reactions to IV acetylcysteine. If vomiting is persistent, an anti-emetic is indicated.
Cardiovascular and haematological
agents
Carbon monoxide
Carbon monoxide is produced via incomplete combustion processes and is tasteless, colourless, odourless and non-irritating. It has a > 200 times greater affinity for haemoglobin than oxygen, forming carboxyhaemoglobin and shifting the oxyhaemoglobin dissociation curve to the left which reduces unloading of oxygen to the tissues.
Clinical features: Carbon monoxide causes injury by hypoxia, with symptoms referable to tissues with greatest oxygen consumption, notably the brain and myocardium. Clinical features include headache, fatigue, nausea, vomiting, mental confusion, chest pain, dyspnoea, palpitations, visual disturbances, syncope, increased respiration, coma, convulsions and eventually compromised cardiorespiratory function and death. The outcome will depend on the degree and duration of peripheral tissue hypoxia. A cherry-red skin and mucous membranes is characteristic of non-survivors; it is an autopsy finding.
Although COHb levels can be used to confirm exposure and establish severity, they correlate only roughly with clinical features.
Management
* Treatment consists of 100% oxygen to increase the dissociation of the carbon monoxide-haemoglobin complex.
* A tight-fitting mask that does not permit inhalation of atmospheric air should be used with high-flow oxygen.
* Hyperbaric oxygen is preferred if available, especially when carboxyhaemoglobin levels are greater than 40% or with coma secondary to carbon monoxide poisoning.
* Intubation and ventilation may be necessary in severe cases.
* Supportive care should include continuous cardiac monitoring, treatment of arrhythmias and correction of acid/base and electrolyte abnormalities.
* Brain hypoxia may result in cerebral oedema.
* Creatinine phosphokinase and urine myoglobin levels should be monitored to detect rhabdomyolysis. With rhabdomyolysis, urinary output should be maintained at 50 mL/hour to protect renal function, provided cerebral oedema is not precipitated/aggravated.
Sympathomimetic agents
These agents include amphetamines, adrenaline, ephedrine, naphazoline and related drugs such as pseudoephedrine, phenylpropanolamine, phenylephrine, commonly used in 'cold and flu' preparations, decongestants, cough mixtures and various appetite suppressants; also methylphenidate.
Clinical features: Sympathetic overactivity with irritability, agitation, hyperactivity, sweating, dilated pupils, hyperpyrexia, tachycardia, hypertension and hyperreflexia. Presentation may be confused with thyrotoxicosis, or if delusions and hallucinations are present, with acute psychosis. Seizures, hypertension and ventricular arrhythmias may occur in severe overdose, and marked pyrexia may lead to a heatstroke-like syndrome and possibly death. Severe hypertension may cause intracranial haemorrhage, cardiac failure and pulmonary oedema.
Management
* Emesis or lavage should be performed, but is probably ineffective more than 4-6 hours after ingestion.
* Stomach emptying should be followed by activated charcoal and a saline cathartic such as magnesium sulphate or sodium sulphate.
* General and supportive care should include ECG monitoring.
* Hyperthermia should be treated with cooling.
* For hypertensive reactions, nifedipine, 10 mg sublingually, may be used. Beta blocking agents are contraindicated because of unopposed alpha- adrenergic effects.
* Diazepam is useful for treating hyperactivity and convulsions.
Barbiturates and other sedatives
Short-acting barbiturates such as hexobarbitone, pentobarbitone and secobarbitone are more lipid soluble, more potent and relatively more toxic than the long-acting compounds such as phenobarbitone and barbitone. Symptoms and signs develop more rapidly (15-30 minutes) with short-acting barbiturate overdose, with a peak effect in 2-4 hours. With phenobarbitone overdose, symptoms begin at 1-2 hours and peak at 6-18 hours.
Therapeutic phenobarbitone blood levels lie between 40-160 mcmol/L (10-40 mcg/mL). When interpreting values cognisance should be taken of concomitant CNS depressants and habituation.
Clinical features: The characteristic signs and symptoms are due to depression of the central nervous, respiratory and cardiovascular systems, and include drowsiness, ataxia, confusion, stupor, coma, hypoventilation, hypotension and hypothermia - ingestion of other central nervous system depressants such as alcohol will potentiate these toxic effects. Other features may be acute renal failure, and bullous skin lesions (in 6% of patients). Early fatalities from overdose result from cardiorespiratory arrest. Late causes include circulatory failure, pneumonia, and pulmonary and cerebral oedema.
Management
* Gastric emptying should be performed within 4-8 hours after ingestion of the above agents.
* This should be followed by activated charcoal to decrease absorption. After the initial charcoal dose, repeated doses, 50-100 g every 4 hours, have been shown to increase body clearance significantly.
* Careful attention should be paid to adequate ventilation; patients often require intubation and mechanical respiration.
* Blood gases should be monitored and acidosis treated.
* Hypotension may be corrected by volume expansion, but vasoactive agents such as dopamine or dobutamine may be needed in severe cases.
* A low-reading rectal thermometer should be used to detect hypothermia.
* Urinary alkalinisation increases phenobarbitone excretion. Alkaline diuresis is of no value in the treatment of short-acting barbiturate intoxication.
* Patients severely poisoned with any of the barbiturates should be considered for charcoal haemoperfusion.
Benzodiazepines
These agents are generally of a low order of toxicity unless ingested with alcohol or other CNS depressants. In small children and the elderly, however, the danger of respiratory depression with overdose exists.
Clinical features: Toxicity may be manifested by impaired level of consciousness, ataxia, dysarthria and respiratory depression.
Management
* Treat by gastric emptying followed by oral activated charcoal.
* When there is respiratory compromise, attention should be paid to the airways and ventilation.
* In rare instances, where poisoning is unusually severe, with marked respiratory depression or deep coma, e.g. in the elderly or patients with obstructive airways disease, the benzodiazepine antagonist, flumazenil, may be considered, bearing in mind its relatively short half-life, high cost, and the potential for precipitating an acute withdrawal syndrome in patients who have been taking benzodiazepines regularly for longer than 4-6 weeks. Judicious use of this antidote may reduce morbidity and the level of intensive care. (Section N01.)
Lithium
Most cases of lithium toxicity occur with chronic therapy and may be caused by decreased excretion of the drug due to renal deterioration, dehydration or concomitant thiazide diuretic therapy. With acute overdose, symptoms may be delayed (12 hours or more) due to delayed entry of lithium into the tissues.
Therapeutic lithium concentrations lie between 0.4-1.2 mmol/L.
Clinical features: Changes in mental status are common in lithium toxicity. Features of toxicity include nausea, vomiting, diarrhoea, apathy, restlessness, tremor, fasciculations, ataxia, confusion, dysarthria, renal dysfunction, electrolyte imbalance, convulsions and coma. Serious ECG changes, similar to those seen in hypokalaemia, occur in advanced intoxication.
Management
* Gastric emesis or lavage is indicated in acute overdose situations.
* Hydration and electrolyte status (especially potassium levels), as well as lithium blood levels, should be meticulously monitored.
* Plasma lithium concentrations in excess of 2.5-3 mmol/L require haemodialysis which is the treatment of choice for severe lithium intoxication (due to its small molecular weight and negligible protein binding, lithium is the most dialysable toxin known). Rebound in plasma levels may occur due to redistribution and/or continued gastrointestinal absorption - repeat dialysis may be needed.
* It should be noted that sodium and water loss may continue for days or weeks after lithium intoxication.
* Forced diuresis fails to enhance lithium clearance significantly, and has resulted in serious problems with electrolyte imbalance.
* Lithium is not adsorbed to charcoal.
Phenothiazines (and most other neuroleptics)
Clinical features: Neuroleptic overdose can produce a depressed level of consciousness, extrapyramidal signs (such as rigidity, tremor, hyperreflexia and dyskinesia), marked restlessness, hypotension and cardiac arrhythmias. True convulsions are uncommon and should be differentiated from acute dystonic reactions. In severe poisoning, or with concomitant alcohol or sedative/hypnotic intake, respiratory depression may occur. Malignant neuroleptic syndrome may develop.
Management
* An airway to maintain respiration should be established.
* Gastric lavage should be performed even if several hours have elapsed since ingestion, as phenothiazines may inhibit gastric emptying and suppress vomiting.
* Repeated doses of activated charcoal (every 2-4 hours) are recommendable.
* ECG monitoring is necessary to detect arrhythmias; hypoxia, acid/base and electrolyte abnormalities must be corrected.
* Hypotension can be treated by giving IV fluids.
* The use of sympathomimetic amines is contraindicated.
* Dialysis and haemoperfusion have no role in the management since phenothiazines are highly protein-bound and widely distributed.
* Phenytoin may be used for ventricular arrhythmias such as ventricular tachycardia or fibrillation, but quinidine and procainamide are contraindicated.
* Acute dystonic reactions are best managed with an anticholinergic agent such as biperiden (Akineton®), 5 mg given slowly intravenously, or with carefully titrated intravenous diazepam.
Note: Some phenothiazines cross-react weakly with the tricyclic antidepressant laboratory assay.
Tricyclic antidepressants (TCAs)
Cardiovascular toxicity is the principal cause of fatalities from TCA overdose. It is caused by the blockade of noradrenaline uptake as well as the anticholinergic, membrane stabilising and alpha-blocking effects of TCAs.
Clinical features: Overdosage can produce central nervous system, anticholinergic and cardiovascular effects.
Nervous system toxic effects include drowsiness, agitation, hallucinations, hyperactive reflexes, myoclonus, choreoathetosis, muscle twitching and rigidity, convulsions, respiratory depression and coma.
Anticholinergic effects include flushing, dry mouth, dilated pupils, hyperpyrexia, and bladder and bowel paralysis.
Cardiovascular toxic effects include sinus tachycardia, hypotension, conduction abnormalities and arrhythmias, e.g. PR and QRS prolongation, ST and T wave changes, heart block, atypical and regular ventricular tachycardia, and ventricular fibrillation. Patients may develop respiratory complications similar to those seen in barbiturate overdose, which may include respiratory depression, aspiration pneumonia, adult respiratory distress syndrome and pulmonary oedema.
Management
* This entails cardiac monitoring and attention to adequate ventilation.
* Gastric lavage is useful as late as 8 hours after ingestion (gastric emptying is delayed by the TCAs).
* Lavage should be followed by activated charcoal and further doses, given e.g. every 4-6 hours, may effectively remove enterorecycling drug.
* Blood pH must be checked and acidosis adequately corrected with bicarbonate to enhance protein binding and decrease the concentration of free drug in the plasma.
* Forced diuresis, dialysis, and haemoperfusion have no role in the management of poisoning with tricyclic or heterocyclic compounds, (because of the marked protein binding and large volume of distribution of these drugs).
* Seizures may be treated with diazepam.
* Alkalinisation (with sodium bicarbonate) will usually benefit both convulsive activity and cardiotoxicity - 0.5-2 mEq/kg IV bolus followed by IV infusion to maintain blood pH of 7.5 has been suggested. Both sodium and potassium levels should be monitored closely.
* Cardiac arrhythmias may be particularly difficult to manage. Phenytoin and lignocaine are the antiarrhythmic drugs of choice. Propranolol should be used with caution. Disopyramide, procainamide and quinidine are contraindicated because of their additive cardiac depressant effect.
* Physostigmine has been used for delirium, coma, choreo-athetosis, myoclonus and some resistant cardiotoxic effects, but must be used with caution because of potentially serious cholinergic effects. It should always be administered under close ECG control.
* Prolonged monitoring is needed in severe poisoning as the half-lives of the TCAs vary from 24-72 hours, and may be increased in overdose.
Hydrocarbons
- paraffin
Most of the hydrocarbons are petroleum distillates, derived from crude oil and coal, which contain varying amounts of saturated and unsaturated aliphatic (open chain) and aromatic (cyclic) hydrocarbons.
The aliphatics are not readily absorbed from the GI tract and therefore cause minimal systemic toxic effects. They are, however, inclined to be aspirated causing respiratory complications. The aromatic hydrocarbons are well absorbed, and may therefore induce systemic toxic effects but are less inclined to cause aspiration related complications.
Viscosity is the most important physical property determining the aspiration hazard of the hydrocarbons. The lower the viscosity, the higher the substance's ability to 'migrate' into the tracheo-bronchial tree upon ingestion. The aspirated hydrocarbons inhibit surfactant and also cause direct broncheo-alveolar injury, leading to chemical pneumonitis characterised by ventilation/perfusion imbalance and hypoxia. As little as 1 mL can result in chemical pneumonitis.
The low viscosity aliphatic-based petroleum distillates widely available include paraffin (lamp oil, 'lampolie' or kerosene), power paraffin, mineral turpentine, thinners, petrol (gasoline), diesel, and 'benzine' (to be distinguished from benzene). Although they have a high propensity to cause chemical pneumonitis, they have a low potential to cause systemic toxicity. The acute ingestion of small amounts of petrol will not cause acute lead poisoning.
Lubricating oil, mineral oil (liquid paraffin), baby oil, suntan oils, petroleum jelly (vaseline), grease and paraffin wax have a high viscosity and are unlikely to cause chemical pneumonitis.
The pure aromatic hydrocarbons, like benzene and its derivatives - toluene (methylbenzene) and xylene (dimethylbenzene) - are well absorbed from the GI tract. Delirium, loss of consciousness and convulsions may develop after severe exposure. Kidney and liver damage may also occur. Exposure to these highly volatile compounds occurs more commonly through inhalation than ingestion. Following ingestion, the risk of aspiration is lower than with the aliphatic hydrocarbons. Fortunately, these compounds are not readily available to the general public.
Turpentine (to be distinguished from mineral turpentine) is a volatile oil distilled from pine wood. Ingestion is characterised by gastrointestinal and central nervous system toxic effects. It is also potentially nephrotoxic and can cause chemical pneumonitis. Since it has a limited distribution through dealers in fine art materials, exposure is uncommon.
The halogenated hydrocarbons, such as carbon tetrachloride, are not traditionally classified under the hydrocarbons. They possess a relatively high inherent toxicity, and are especially toxic to the central nervous system, liver, kidneys and blood vessels. Toxicity appears to result from the intracellular biotransformation of these compounds to toxic intermediates, including epoxides, in the liver.
Hydrocarbons are often used as carrying agents or solvents for other more toxic substances, such as pesticides, camphor and heavy metals. In cases where these compounds or substantial amounts of hydrocarbons with a high inherent toxicity e.g. benzene and carbon tetrachloride, have been ingested, evacuation of the stomach must be considered. Attempting to intubate an alert or semiconscious patient with a cuffed endotracheal tube to protect the airway, as is often recommended under these circumstances, is difficult and potentially hazardous. The passage of a nasogastric tube and aspiration of the gastric contents may be a safer procedure.
Paraffin is often sold or stored in soft drink or wine bottles or other unlabelled containers which are left around the house or garage, making it easily accessible to children.
The most serious toxic effect following ingestion of paraffin is aspiration pneumonitis which occurs in 12-40% of patients. After ingestion, the child usually experiences a burning sensation in the mouth. Because of this and its bad taste, the volume ingested is usually small. Nausea and vomiting are common. Respiratory symptoms and signs generally appear within 30-60 minutes after ingestion, but may be delayed for 6-8 hours. A non-productive cough, tachypnoea and tachycardia are indicative of the development of a chemical pneumonitis. Bronchospasm with wheezes and coarse crackles, as well as intercostal and subcostal retraction are common clinical findings. Cyanosis may be present in severe cases. Central nervous system symptoms and signs include lethargy and irritability. A fever frequently develops in patients with pulmonary involvement. The pathogenesis of this is not known. The clinical picture generally deteriorates over the first 24 hours. The persistence or the development of a fever after 24-48 hours usually suggests secondary infection. Pulmonary oedema or haemoptysis may develop in severe cases. Convulsions and coma may also occur, but are not frequently encountered.
Common radiological findings of chemical pneumonitis include bilateral perihilar infiltrates, which gradually progress to form areas of patchy infiltrates, and finally large areas of consolidation. Pleural effusions, pneumothorax and pneumotocoeles have been reported in a minority of cases.
Abnormalities on the chest X-ray may be seen within 30 minutes of aspiration, even in the absence of symptoms and signs of chemical pneumonitis.
Management: (A similar approach is recommended in the management of ingestion of the hydrocarbons with a low viscosity and low inherent toxicity.)
* Asymptomatic patients must be physically examined for any pulmonary involvement. A chest X-ray at 5 to 6 hours post ingestion is recommended and the patient should be observed for 8 hours. If asymptomatic after 8 hours and if the chest X-ray is normal, the patient can be discharged.
* Symptomatic patients should be X-rayed on admission.
* Induced emesis or gastric lavage, is not recommended as it increases the risk of aspiration and chemical pneumonitis.
* The administration of mineral oil (liquid paraffin) or plant oils in an attempt to increase the viscosity of the ingested hydrocarbon, is contraindicated. It has been shown to increase the incidence of pulmonary complications. The use of milk is also not recommended. The administration of clear fluids by mouth is, however, not contraindicated.
* The administration of activated charcoal is not recommended as its efficacy in hydrocarbon ingestion is questionable and it may induced vomiting.
* In patients with pulmonary involvement, the respiratory and central nervous system functions should be carefully assessed. Arterial blood gases and electrolytes should be obtained where possible.
* Oxygen therapy should be provided to all patients with symptoms and signs of chemical pneumonitis. Other respiratory treatment modalities, such as ventilation and PEEP should be employed according to standard indications.
* Corticosteroid therapy has never been shown to be of any benefit in hydrocarbon pneumonitis and may increase the risk of secondary bacterial infection.
* The use of antibiotics prophylactically in hydrocarbon pneumonitis is not advocated since it has not been shown to prevent secondary infection. However, some experts do feel that there is a place for prophylactic antibiotic use in these cases.
* A persistent fever or a fever which develops 1-3 days post ingestion probably indicates a secondary infection requiring specific antimicrobial therapy.
Iron
A dose in excess of 20 mg/kg of elemental iron is considered potentially toxic, while the estimated lethal dose is 180-300 mg/kg. (Ferrous sulphate, crystalline form, contains about 20% elemental iron, ferrous fumarate 33% and ferrous gluconate 12%.)
Toxic effects result from the corrosive action of iron in the gastrointestinal tract, and from the presence of unbound iron in the serum. Corrosive mucosal lesions, haemorrhagic necrosis of the stomach and small bowel, or segmental infarction of the distal small bowel may occur. Other pathological changes include acute hepatic necrosis, shock, acute renal failure, severe acidosis, pancreatic injury and pulmonary oedema or haemorrhage.
Clinical features: Although not clear in some cases, severe iron intoxication can be divided into phases. The early phase (0.5-2 hours) is characterised by vomiting, haematemesis, abdominal pain, diarrhoea, lethargy, shock, acidosis and coagulopathy. This is followed by a quiescent period (variable up to 12 hours) during which a deceptive recovery and stabilisation occur. In severe intoxication this period may be brief. This is followed by a potentially life-threatening period (12-48 hours) characterised by haematemesis, melaena, possible gastrointestinal perforation, vascular collapse, severe acidosis, hypoglycaemia, cyanosis, pulmonary oedema, convulsions and coma. Towards the end of this phase, hepatorenal failure develops.
Management
* The stomach should be emptied by gastric lavage.
* Iron is radiopaque and an abdominal X-ray will help to determine the success or failure of gastrointestinal evacuation. Iron tablets may form concretions in the stomach.
* Blood samples should be taken for determination of haemoglobin, haematocrit, white cell count, blood glucose, electrolytes, acid/base status, blood-typing and iron levels.
* Shock and acidosis should be appropriately managed with careful attention to fluid balance to avoid pulmonary oedema.
* Patients with iron levels below 54 mmol/L (< 300 mcg/dL) and/or who remain asymptomatic 6 hours after the overdose would not be expected to develop significant toxicity, and require no active treatment.
* A provocative chelation challenge can be used to detect excess iron: up to 1 g of desferrioxamine is given intramuscularly; a `vin rose' appearance of the urine is indicative of excess iron, which requires chelation therapy.
* Patients who present with spontaneous vomiting and diarrhoea, leucocytosis (> 15x109/L) and hyperglycaemia (> 8.3 mmol/L) within 6 hours of ingestion probably have iron levels > 54 mcmol/L (> 300 mcg/dL) and should receive chelation therapy.
* Patients with iron levels between 54-90 mcmol/L (300-500 mcg/dL) require brief chelation therapy; those with levels between 90-180 mcmol/L (500-1000 mcg/dL) require chelation and supportive treatment. Patients with levels > 180 mmol/L require vigorous supportive treatment and prolonged chelation therapy.
* In significant poisoning, if the patient is normotensive, give desferrioxamine intramuscularly.
* In seriously ill patients, or those already in shock, an intravenous infusion of desferrioxamine, administered at a rate not exceeding 15 mg/kg/hour is preferable. The iron chelate is excreted entirely by the renal route.
* Consider exchange transfusion in severely symptomatic cases or those with iron levels > 180 mcmol/L.
* Therapy should be continued until the `vin rose' colouring of the urine clears, until the patient is free of symptoms, or until plasma iron levels are satisfactory (< 20 mcmol/L).
Profile of deferoxamine (syn. desferrioxamine) appears under ANTIDOTES.
The potentially fatal human dose of methanol is 30 mL of a 40% solution, although fatalities have been reported with 15 mL.
Clinical features: Initially symptoms include those of minor inebriation followed by a latent period of 12-30 hours when methanol is metabolised to the toxic products formaldehyde and formic acid. Co-ingestion of alcohol delays the toxic effects. Severe acidosis is due to formic acid and lactic acidosis and the severe retinal toxicity is caused by formaldehyde. Further symptoms and signs include headache, confusion, vertigo, nausea, vomiting, abdominal pain, blurred vision, blindness, Kussmaul's respiration, restlessness, delirium, convulsions and coma.
Management:
* Gastric lavage or emesis as early as possible. (Charcoal does not absorb methanol well and is of little value.)
* Ethanol in all cases, while awaiting methanol determination. To maintain a blood level of 100 mg/dL of ethanol begin with a loading dose of 0.6 g/kg, followed by an ethanol infusion of 66 mg/kg/hour (for non-drinkers) to 154 mg/kg/hour (for chronic ethanol drinkers).
* Particular attention should be directed towards the correction of metabolic acidosis with sodium bicarbonate.
* Haemodialysis, if the blood-methanol level is greater than 50 mg/dL, continued until the level is in the range of 20 mg/dL.
* The administration of folate, in the form of leucovorin, may have a therapeutic advantage (1 mg/kg, up to 50 mg/dose, followed by the same dose 4 hourly for 6 doses).
Special Prescriber's Points
* Methanol, formic acid and formaldehyde are effectively removed by haemodialysis which is about 8 times more effective than peritoneal dialysis.
* Other indications for haemodialysis include any visual impairment, metabolic acidosis not correctable with bicarbonate, and renal failure.
* Ethanol is also removed by dialysis and must be replaced by increasing the ethanol infusion rate or by adding ethanol to the dialysate.
* Ethanol blood levels should be maintained between 100-150 mg/dL.
* Note that ethanol prolongs the elimination half-life of methanol to 24-30 hours so that several days may be required to reduce methanol levels to < 20 mg/dL if haemodialysis is not used.
Paraquat and diquat herbicides
Paraquat is the most toxic herbicide known, producing multiorgan toxicity. Prominent toxic effects following oral ingestion include oral, oesophageal and gastric corrosions with severe gastroenteritis. Multiple organ failure rapidly develops within 1-3 days, depending on the dose. Those who survive the initial phase develop pulmonary fibrosis and respiratory failure.
* Any oral exposure should be considered serious and potentially fatal.
* Pulmonary fibrosis has not been reported following diquat exposure. A higher incidence of severe acute renal failure occurs with diquat than with paraquat poisoning.
Management
* Immediate treatment entails oral administration of Fuller's earth. 240-500 mL of the following mixture should be given every 2-4 hours for 2 or 3 days: Fuller's earth 300 g and magnesium sulphate 50 g per 1 litre water.
* Activated charcoal is equally effective and may be used if Fuller's earth is not available. Mix with a saline cathartic or sorbitol or lactulose to prevent constipation. Repeat every 4 hours until paraquat is no longer detected in the urine.
* If neither is available, emesis should be induced and gastric lavage performed cautiously in view of possible ulceration of the pharynx and oesophagus.
* Charcoal haemoperfusion or, if not available, haemodialysis, must be started as soon as possible, without waiting for paraquat levels.
* Pulmonary complications should be managed appropriately, but it should be remembered that a high inspiratory oxygen concentration (FiO2) worsens pulmonary toxicity. The use of low FiO2 mixtures with positive end- expiratory pressure and continuous positive pressure breathing is preferable.
Cyanide
Cyanide is one of the most rapidly-acting of all poisons. (Death may occur within minutes.) It inhibits enzymes controlling oxidative processes, resulting in cellular oxygen utilisation defects.
Clinical features: As cyanides are rapidly absorbed from the skin, mucosal surfaces and lungs, features of poisoning usually appear within seconds to minutes after exposure. Symptoms include giddiness, headache, palpitations, dyspnoea, loss of consciousness, followed by convulsions and death. Note that cyanosis is not present, the skin colour may be 'brick-red', and there is typically an odour of bitter almonds.
Management
* Establish an airway, with intubation and ventilation if necessary. Avoid mouth-to-mouth resuscitation to prevent self-poisoning.
* Administer 100% oxygen immediately.
* Avoid direct dermal contact with contaminated clothing which should be removed and the skin washed with soap and water.
* Adequate ventilation, administration of 100% oxygen and good supportive care is essential and has led to patient survival even in the absence of antidotal therapy. Oxygen therapy contributes to the reversal of the cyanide- cytochrome complex.
* Specific therapy is with:
* dicobalt edetate (Kelocyanor®) or
* amyl nitrite, sodium nitrite and sodium thiosulphate solution (Trypac-Cyano®).
* Supportive measures for complications such as lactic acidosis, pulmonary oedema and arrhythmias may be needed.
* If the cyanide was taken by mouth, gastric lavage should be carried out until the odour of almonds can no longer be detected, and activated charcoal administered (although considered by some not to be very effective).
Organophosphates and carbamates
The organophosphates and carbamates are cholinesterase inhibitors, indirectly causing a stimulation of muscarinic and nicotinic receptors. They can be absorbed by ingestion, inhalation or via the skin. While the organophosphates form an irreversible complex with cholinesterase, the carbamyl-enzyme complex is reversible, leading to a less severe intoxication with a much shorter duration (± 24 hours). The carbamates also penetrate the blood-brain barrier poorly, producing fewer CNS effects.
Clinical features include:
Muscarinic effects - hypersecretion (increased sweating, salivation and bronchial secretions), constricted pupils, bradycardia and hypotension, bronchoconstriction, vomiting, diarrhoea and urinary incontinence.
Nicotinic effects - muscular weakness, fasciculations and weakness of respiratory muscles. (In certain cases the nicotinic effects override the muscarinic effects and the patient may present with tachycardia, hypertension and mydriasis.)
Central nervous system effects - restlessness, anxiety, headaches, convulsions and coma (with accompanying depression of the respiratory centre).
Management
* First, an adequate airway should be ensured and if necessary the patient should be intubated (avoiding succinylcholine).
* The stomach should be emptied by inducing emesis or by gastric lavage, followed by activated charcoal (to prevent further absorption of ingested organophosphate).
* All contaminated clothing should be removed and the patient washed thoroughly with soap and water.
* Atropine administration should be initiated as soon as possible.
* An initial intravenous 'test dose' of 1 mg in adults and 0.01 mg/kg in children provides a measure of severity. The dose of atropine in organophosphate poisoning is 0.05 mg/kg (2-4 mg in adults) every 15 minutes until full atropinisation is reached. For maintenance therapy, an intermittent or continuous intravenous infusion of 0.05 mg/kg/hr may be given. High doses of atropine are sometimes required initially (4-5 mg every 15 minutes).
* The criterion of adequate therapy is control of excessive bronchial and oral secretions.
* As the patient improves, the dose of atropine should be tapered slowly, usually over 24 hours or longer. It is important that atropine therapy should not be stopped abruptly.
* Close observation during this stage is essential, as rebound effects of organophosphate toxicity (due to their lipid solubility) may occur.
Parameters to monitor: Presence of hypersecretion, ECG, pupil size, blood pressure and pulse, serial measurement of vital capacity (preferred to peak flow measurements) to detect respiratory insufficiency, and plasma cholinesterase. Normal levels of plasma cholinesterase are 3000-8500 U/L in adults.
* Although cholinesterase reactivators such as obidoxime are widely regarded as valuable adjuvants in the early management of moderate to severe organophosphate poisoning (if given within 24 hours of exposure), it is not clear if their use alters the outcome. Therapy should be in conjunction with atropine and other supportive measures.
* Cholinesterase reactivators, e.g. obidoxime, are contraindicated in carbamate poisoning.
* Several complications may follow organophosphate poisoning:
* Since most of these substances have a petroleum base, aspiration may cause a chemical aspiration pneumonitis.
* Potential toxicity of the vehicle should be taken into account.
* Ventricular arrhythmias (with a prolonged QT interval) may occur.
* Confusion and convulsions, due to the effects of the organophosphate or to excess atropine, are best controlled with diazepam.
* Aminoglycosides and succinylcholine should be avoided in organophosphate poisoning because of their blocking effect on the neuromuscular junction.
* Phenothiazines, reserpine and theophylline are also contraindicated.
Theophylline and related
drugs
Theophylline
Drug levels are a useful guide to the severity of the overdose. The therapeutic range of theophylline is 55-110 mcmol/L (10-20 mcg/mL) in plasma/serum, but sustained-release preparations will not reflect accurately the degree of intoxication if levels are taken early (levels may continue to rise dramatically until at least 8 hours after ingestion).
Clinical features: Nausea and vomiting (which may be severe and intractable), abdominal pain, gastrointestinal haemorrhage with severe toxicity, agitation, restlessness, dilated pupils, convulsions, tachycardia and supraventricular and ventricular arrhythmias. Profound hypokalaemia commonly occurs and may be a major factor in the genesis of arrythmias.
Management
* The stomach should be emptied as soon as possible and followed by 100 g activated charcoal orally.
* If vomiting can be controlled, this should be followed by regular administration of activated charcoal (e.g. 50 g every 4 hours for 6-8 doses); multiple doses result in substantial decrease in theophylline elimination half-life, with rapid fall in serum concentration.
* Hydration should be assessed, electrolytes monitored frequently, and hypokalaemia corrected with an IV infusion of potassium chloride (section A12).
* A cardiac monitor should be used to detect arrhythmias. Beta blocking agents (except in asthmatics), lidocaine or calcium channel blockers (e.g. verapamil) may be drugs of choice for treating arrhythmias.
* Convulsions can usually be controlled with slow IV administration of diazepam.
* Although most patients with theophylline overdose can be treated satisfactorily with supportive measures, charcoal haemoperfusion should be considered in severe poisoning, refractory seizures, cardiovascular compromise, and patients with delayed theophylline clearance including the elderly and those with significant liver disease or cardiac failure.
(syn. N-acetylcysteine)
A derivative of the naturally-occurring amino acid L-cysteine, indicated for treating paracetamol overdose. It is converted to cysteine in vivo and acts by stimulating hepatic glutathione synthesis.
Special Prescriber's Points
* Use with caution in patients with asthma or a history of asthma.
* Patients should be observed carefully for the emergence of hypersensitivity reactions. Skin rashes, anaphylactoid reactions and anaphylactic shock have been reported.
* The hypersensitivity-type adverse reactions often tend to be due to histamine release and are not necessarily true allergic reactions. Therefore, acetylcysteine may not need to be discontinued in mild reactions. These reactions may be overcome by temporary cessation of the infusion, IV administration of an antihistamine, followed by a slower infusion rate of acetylcysteine.
* Acetylcysteine is incompatible with rubber and metals; silicone rubber and plastic should be used.
* Plasma potassium should be monitored; hypokalaemia and ECG changes have been associated with paracetamol overdosage irrespective of the treatment.
* Considered to be relatively safe during pregnancy and breast- feeding.
Adult dose: IV infusion, initially 150 mg/kg in 200 mL 5% dextrose over 15 minutes; then 50 mg/kg in 500 mL 5% dextrose over the next 4 hours by continuous infusion; followed by 100 mg/kg in 1 litre 5% dextrose over 16 hours.
* Although there are no clear guidelines with regard to the duration of IV acetylcysteine therapy, there are strong indications that a 48-hour regimen is superior to the 24-hour regimen, especially in seriously intoxicated patients and in cases where therapy is started late. The manufacturer's dosage regimen covers only the first 20-24 hours. The recommended dose for the second 24 hours is 150 mg/kg in 1 litre 5% dextrose water over 24 hours. The above represents a minimum dosage requirement and is exceeded in some investigational regimens.
Paediatric dose: As adult dose.
Preparations include:
Acetylcysteine [INN] [V03AB23]
Parvolex® Glaxo [S2]
inject, 200 mg/mL (2 g/10 mL)
Oral antidotes in paracetamol poisoning
Activated charcoal should not be given if an oral antidote is used.
Acetylcysteine
Oral acetylcysteine is proven to be effective in the treatment of paracetamol overdose; it has recently become available in South Africa.
Dose: Oral, loading dose of 140 mg/kg followed by 70 mg/kg 4 hourly for 17 doses (over a period of 72 hours).
* Solutions should be diluted to 5% in water or fruit juice/soft drink. Capsules or powder should be taken with adequate amounts of fluid (250 mL).
Preparations include:
Solmucol® Lagamed [S2]
sachets, 200 mg, 400 mg
Although carbocisteine is used by some centres in mild or less severe paracetamol intoxication, animal studies have indicated that it does not offer adequate protection against liver damage. The safety of late or prolonged administration (> 24 hours) has not been sufficiently explored.
Dose: Oral, 150 mg/kg (3 mL/kg of 250 mg/5 mL or 1 mL/kg of 750 mg/5 mL syrup) every 4 hours for 24 hours.
* For a short profile and preparations available see section R05.
Methionine (syn. dl-methionine, racemethionine)
Methionine is not readily available.
The safety of late (> 15 hours post ingestion) or prolonged administration (> 16 hours) has not been sufficiently explored.
Dose: Oral, 2.5 g 4 hourly for a total of 4 doses, started within 10-12 hours after paracetamol ingestion.
* May be mixed in orange juice/soft drink.
Preparations include:
Methionine [INN] [V03AB26]
(WHO essential therapeutic group)
Antamon Ped® Protea Pharm.
powder, 200 mg/2 g
(WHO essential therapeutic group)
Activated charcoal is a powerful adsorbent of a wide spectrum of drugs and poisonous substances thereby reducing absorption from the gut. It is used in cases of overdosage or accidental poisoning by drugs and other non-corrosive substances, usually after the stomach has been emptied by lavage or emesis, and plays a very important role in the management of poisoning.
Special Prescriber's Points
* It is essential that the activated charcoal used is of a grade that is documented and proven to be an adequate absorbent/adsorbent.
* Since charcoal adsorbs ipecacuanha it should not be given before the emetic.
* Current opinion favours the use of larger and more frequent doses of charcoal in all instances where a potential for adsorbing intoxicants exists.
* Binding of drugs in the lumen also creates a concentration gradient so that the drug or poison passes continuously from the circulation into the gut lumen. There are indications that this 'gastrointestinal dialysis' is valuable in hastening the elimination of numerous drugs or toxins that have already been absorbed into the bloodstream.
* It is recommended that 2-4 additional doses of 20-50 g be administered in severely poisoned patients, in cases where slow release tablets have been ingested (e.g. theophylline), in poisoning with drugs that are excreted into the bile, undergoing entero-hepatic recycling (e.g. tricyclic antidepressants, oestrogens and progestogens, digitoxin), as well as those secreted into the intestine (e.g. digoxin, pethidine).
* It is of no value in poisoning with strong acids or alkalis, iron salts, lithium, petroleum products (including kerosene), and of questionable value in cyanide ingestion.
* Activated charcoal may be mildly constipating, but is essentially safe and innocuous. Mixing the suspended dose with 20 mL lactulose and 50% syrup (or sorbitol 70%) makes it more palatable and prevents the constipating effect.
Adult dose: Usually oral or via gastric tube, 50-100 g, prepared as a thick slurry in 200-500 mL water.
Paediatric dose: Under 6 years, 10 g in 50-100 mL water; older children, 20-50 g in 100-300 mL water.
(syn. desferrioxamine)
(WHO essential agent)
Deferoxamine chelates several metal ions, e.g. iron and aluminium. It has a much greater affinity for trivalent (ferric) iron than for ferrous iron. It removes depot iron from ferritin and haemosiderin, but only when excess concentrations are present. It does not significantly enhance elimination of iron in normal individuals.
Deferoxamine is used in the management of acute iron poisoning, as well as in the long-term treatment of pathological iron overload, e.g. idiopathic haemochromatosis and transfusion haemosiderosis. It is also used in aluminium- related encephalopathy and in aluminium-related bone disease in chronic dialysis patients.
It is poorly absorbed from the GI tract if the mucosa is intact - for systemic effects it has to be given parenterally. Although metabolised by plasma enzymes, the pathways have not been defined. The complex formed with iron (ferrioxamine) is water-soluble, readily excreted in the urine and responsible for a characteristic reddish colouring.
Special Prescriber's Points
* Avoid in severe renal disease or anuria, and use with caution in renal impairment.
* Patients on prolonged therapy should have regular ophthalmological and audiological evaluations since the most serious adverse effects involve hearing and vision.
* Adverse effects following rapid intravenous administration include flushing, urticaria, tachycardia and severe hypotension. Hypersensitivity reactions e.g. rash, fever and anaphylactic shock may occur. Other effects include dysuria, diarrhoea, headache, blurred vision, and pain and induration at injection sites.
* Deferoxamine is teratogenic in animals; during pregnancy, it should be used only if essential, with the benefits outweighing the potential harm to the fetus. It is considered to be relatively safe during breast-feeding.
* Considered safe in porphyria.
Adult dose: Acute iron poisoning: IM, 1-2 g every 3-12 hours to a maximum of 6 g every 24 hours. (500 mg is dissolved in 5 mL water for injection.)
IV therapy should be reserved for patients who are in shock: 1 g, by slow infusion at a rate not exceeding 15 mg/kg/hour, every 4-6 hours (max. 80 mg/kg in 24 hours).
Continuous IV infusions (12-24 hours) have been shown to be more effective in iron overdose than intermittent dosing. It is recommended that the average total daily dose (1.5-4 g) be given as a slow intravenous infusion over 12 hours.
Oral doses, e.g. 5 g in water, may be given in an attempt to bind unabsorbed iron still present in the GI tract.
Elimination of pathological iron overload: Initially, IM, 1 g daily in a single or 2 divided doses. Maintenance therapy, 500 mg daily.
* Iron excretion should preferably be monitored, initially every day and periodically later in the course of therapy.
Paediatric dose: IM or by slow IV infusion, 20 mg/kg, followed by 10-15 mg/kg every 4-12 hours. (Rate of IV infusion up to 15 mg/kg/hour; max. 80 mg/kg in 24 hours).
Preparations include:
Deferoxamine [INN] [V03AC01]
Desferal® Ciba-Geigy [S4]
inject, 500 mg (mesylate)
(syn. cobalt edetate; cobalt tetracemate)
Dicobalt edetate is used in the treatment of severe cyanide poisoning. It chelates cyanide, forming a stable complex.
Special Prescriber's Points
* Cobalt is toxic (complex-formation with cyanide reduces the potential toxicity of the cobalt itself) and should only be used in patients with known severe cyanide poisoning. This product should not be used as a precautionary measure.
* Adverse effects include facial oedema, vomiting, sweating, retro- sternal chest pain, ventricular tachycardia and hypotension. Skin rashes, laryngeal oedema and anaphylactoid reactions have been reported.
Adult dose: IV injection, 300 mg over 1 minute, followed immediately by 50 mL 50% dextrose, using the same needle.
* If there is no immediate response, a second injection of 300 mg, followed by dextrose, may be given, and repeated for the third time if there is still no response after 5 minutes, again followed by dextrose.
* It is recommended that the IV injection be given steadily, over about 1 minute.
* Consult the package insert before use.
Preparations include:
Dicobalt edetate [INN] [V03AB03]
Kelocyanor® Restan [S1]
inject, 300 mg/20 mL
(WHO essential agent)
The sulfhydryl groups in dimercaprol form chelation complexes with certain metals and these stable complexes are excreted in the urine. It is the antidote of choice in treating acute mercury, arsenic and gold poisoning; it may also be useful as an adjunct to calcium disodium edetate in the treatment of lead poisoning (especially lead encephalopathy in children). Although it has been used successfully in copper, thallium, bismuth and antimony poisoning, the role is less well established.
Only administered by deep intramuscular injection, as a 10% solution in oil. The dimercaprol not chelated to metal is rapidly metabolised, and excreted in urine and faeces (often completely within 4 hours).
Special Prescriber's Points
* The drug is most effective when administered early after poisoning has occurred.
* Adverse effects may be minimised by allowing at least 4-hour intervals between doses.
* Contraindicated in iron, cadmium, selenium and uranium poisoning. The complexes formed with these metals are more toxic to the kidney than the free metals.
* Avoid in patients with severe hepatic function insufficiency. Use with caution in patients with hypertension; doses should be reduced in renal impairment.
* The most frequent adverse effect is hypertension, accompanied by tachycardia. Other effects include nausea and vomiting, sweating, burning of the eyes, lips, mouth and throat; lacrimation, conjunctivitis, salivation; muscle spasm and pain, abdominal pain, tingling of the extremities, headache, tightness of the throat and chest.
* Injections are often painful and sterile abscesses may form.
* Considered safe in porphyria.
Adult dose: Deep IM injection, 400-800 mg in divided doses on the first day; 200-400 mg in divided doses on the second and third days; 100-200 mg in divided doses on subsequent days.
* Within this range individual doses should be adjusted according to body-weight, the causative agent, the severity of the condition, and the severity of the adverse effects of the drug.
* As a general guide single doses should not exceed 3 mg/kg; however, in severe acute poisoning single doses of 5 mg/kg may be required initially. The duration of therapy may be 7-10 days, depending on the response and the reduction of the metal in blood and urine.
Paediatric dose: 2.5-4 mg/kg 4-12 hourly.
Preparations include:
Dimercaprol [INN] [V03AB09]
Dimercaprol Injection B.P.® Boots
inject, 50 mg/mL
(syn. ipecac)
(WHO essential agent)
Ipecacuanha contains two alkaloids, emetine and cephaeline, prepared from the roots of the plants Cephaelis ipecacuanha and C.acuminata. It is used to induce vomiting following recent ingestion of toxic substances and overdosage of drugs. It acts by stimulation of the chemoreceptor trigger zone (CTZ) as well as by a local irritant effect on the GI mucosa. Emesis produced by ipecac is favoured in children but may also be effective in adults. It is available without prescription, and sufficiently safe to be kept and administered at home in an emergency situation.
Contraindications:
* Ingestion of corrosive agents, e.g. strong acids or alkalis.
* Ingestion of volatile organic solvents or petroleum distillates, e.g. paraffins, gasoline, paint thinners.
* Ingestion of CNS stimulants, e.g. camphor oil. Stimulation associated with vomiting may trigger convulsions with the danger of aspiration.
* Impaired level of consciousness.
Special Prescriber's Points
* Emergency use is justified during pregnancy and lactation.
* Although ipecac may be less effective in patients who have ingested agents with strong antiemetic properties, this is not a common finding in clinical practice.
* The dose may be repeated once if emesis has not occurred within 20-30 minutes.
Adult dose: Oral, 15-30 mL, followed by a copious drink of water or fruit juice
Paediatric dose: Infants 6-18 months, 5-15 mL; older children, 15 mL, with a glass of tepid water or fruit juice.
Preparations include:
Ipecacuanha [V03AB01]
Ipecac Syrup (U.S.P.)
Powdered Ipecac (U.S.P.) 7 g, glycerol 10 mL, syrup to 100 mL
Paediatric Ipecacuanha Emetic Mixture (B.P.)
Ipecacuanha Liquid Extract (B.P.) 7 mL, hydrochloric acid 0.25 mL, glycerol 10 mL, Syrup (B.P.) to 100 mL
Ipekakuanha-Tinktuur® Lennon [S1]
Ipecacuanha Liquid Extract 5 mL, glacial acetic acid 0.1 mL per 100 mL. Contains alcohol (100%) 18.9% v/v.
Obidoxime is a cholinesterase reactivator used in the treatment of organophosphate poisoning. It restores cholinesterase activity by reversal of phosphorylation of the enzyme. Cholinesterase reactivators should only be used in conjunction with atropine and other supportive measures in moderate to severe organophosphate poisoning.
Obidoxime is administered parenterally. It crosses the blood-brain barrier and is rapidly excreted in urine, partly unchanged and partly as a metabolite.
Special Prescriber's Points
* Obidoxime is of doubtful value if administration is commenced later than 24 hours after exposure.
* Therapy should be started about 5 minutes after the first administration of atropine sulphate.
* Inadvertent intra-arterial administration may lead to irritation; careful intravenous injection should be assured.
* Adverse effects include flushing of the face, 5-10 minutes after injection and lasting for 2-3 hours; pain at the injection site, mild to moderate hypertension and tachycardia, transient paraesthesia and decreased pain sensitivity.
* In carbamate poisoning the use of cholinesterase reactivators is contraindicated. There is a possibility of the obidoxime attaching itself to the anionic site of cholinesterase, thus inhibiting uninhibited enzyme and potentiating toxicity.
Adult dose: IV, initially 250 mg (3-5 mg/kg). If a satisfactory response is obtained after the first injection, a further dose should be given once or twice at intervals of 2 hours.
* May also be given IM.
Paediatric dose: A single dose of 4-8 mg/kg is recommended.
Preparations include:
Obidoxime chloride [INN] [V03AB13]
Toxogonin® Merck [S4]
inject, 250 mg/mL
(WHO essential agent)
Indicated for the treatment of copper, mercury, arsenic, lead and zinc poisoning, Wilson's disease and cystinuria. For a profile, and the use as a remittive agent in the management of rheumatoid arthritis, see section M01.
Adult dose: Chelation therapy: Oral, usually 0.5-1.5 g daily in 4 divided doses.
Paediatric dose: Oral, 20-40 mg/kg daily in 4 divided doses.
Preparations include:
Penicillamine [INN] [M01CC01]
Metalcaptase® Knoll [S4]
film coated tablets, 150 mg, 300 mg
Penicillamine® Dista (Eli Lilly)
tablets, 125 mg
Nitrite/sodium thiosulphate regimen
(WHO essential agents)
Cyanide combines with cytochrome oxidase, thus inhibiting cellular respiration. Antidotes are amyl nitrite, sodium nitrite and sodium thiosulphate. The amyl nitrite is used initially for rapid response until the sodium nitrite is ready for injection.
The nitrites oxidise haemoglobin (Fe2+) to methaemoglobin (Fe3+), which has a much higher affinity for cyanide, leading to a dissociation of the cyanide- cytochrome complex. The cyanide is strongly bound within the erythrocyte in the form of cyanmethaemoglobin, lowering the plasma cyanide. The methaemoglobin thus acts as a 'mopping-up' agent for cyanide. Because drug-induced methaemoglobin and cyanmethaemoglobin are dissociable complexes, there is a risk of the release of free cyanide. Sodium thiosulphate is therefore administered. Thiosulphate serves as a substrate for the enzyme rhodanese which mediates the conversion of any free cyanide to the much less toxic thiocyanate which is readily excreted in the urine. Methaemoglobin is eventually restored to haemoglobin by the intracellular reductase systems.
Special Prescriber's Points
* All cyanide antidotes are potentially toxic.
* Dicobalt edetate is the preferred treatment.
* 100% oxygenation is important and should be ensured during therapy.
* Adverse effects of nitrites include hypotension, headache, nausea, vomiting and syncope.
* Nitrites must be used with caution in patients with severe cardiovascular or cerebral vascular disease.
* The danger of the above regimen is an overdose of the methaemoglobin inducer, which may lead to a severe lowering of the oxygen- carrying capacity of the blood leading to hypoxia. Although methylene blue (2 mg/kg) may be given to reverse the methaemoglobinaemia in an emergency situation, this may induce cyanide release.
Adult dose: Treatment is started by the inhalation of 0.3 mL amyl nitrite, emptied on a gauze swab, followed by 10 mL intravenous sodium nitrite, over 3 minutes. After 5 minutes, 50 mL intravenous sodium thiosulphate 50% should be given over 10 minutes. The two injections may be repeated after 2 hours if necessary.
Preparations include:
Amyl nitrite, sodium nitrite, sodium thiosulphate
Tripac-Cyano® Covan [S1]
kit containing: 6x0.3 mL amyl nitrite for inhalation; 2x10 mL sodium nitrite 3% injection; 4x25 mL sodium thiosulphate 50% injection