Published Online: 15 DEC 2009
Copyright © 2009 John Wiley & Sons, Ltd. All rights reserved.
General, Applied and Systems Toxicology
How to Cite
Vale, A. and Bradberry, S. 2009. Clinical Toxicology. General, Applied and Systems Toxicology. .
- Published Online: 15 DEC 2009
- Top of page
- Clinical Toxicology
- A Comprehensive Clinical Toxicology Service
This chapter defines the specialty of clinical (or medical) toxicology and the components that should make up a comprehensive clinical toxicology service; it describes the presentation and complications of poisoning and details the general assessment and management of the poisoned patient; the chapter concludes with a discussion of the role of toxicovigilance.
2 Clinical Toxicology
- Top of page
- Clinical Toxicology
- A Comprehensive Clinical Toxicology Service
Clinical toxicology is that discipline within toxicology which is concerned with the impact of drugs and other chemicals on humans. Some define this discipline as medical toxicology. For example, the American College of Medical Toxicology, a nonprofit association of physicians mostly from an emergency-medicine background, defines medical toxicology as a ‘medical subspecialty focusing on the diagnosis, management and prevention of poisoning and other adverse health effects due to medications, occupational and environmental toxins and biological agents’. The present authors, who are physicians who have practised the discipline for several decades, believe the term clinical toxicology should be employed rather than medical toxicology to reflect the fact that clinical toxicology is both a discipline of toxicology and a medical subspecialty. This view also takes account of the fact that in North America in particular, a number of distinguished clinical toxicologists hold a PharmD and offer a professional opinion either via a poisons information centre or at the bedside. It is acknowledged, however, that in Europe most, if not all, clinical toxicologists are medically qualified.
The role of the clinical toxicologist encompasses the traditional therapeutic role, including the development of effective treatment strategies for the management of acute and chronic poisoning, the provision of expert advice via a poisons information service and the evaluation of the adverse effects of drugs and other chemicals on the body. The clinical toxicologist must be able to apply relevant kinetic and biochemical data so that treatment strategies can be developed and refined, based on the likely mechanisms of toxicity (Vale, 1992). In addition, an understanding of pathological appearances is necessary if the results of toxicity tests are to be extrapolated accurately to man and the results of forensic examinations are to be interpreted correctly. The clinical toxicologist will also need to be aware of the limitations of analytical methods, both as regards their sensitivity and specificity.
The increased public awareness and concern regarding the potential effects of pesticides and other chemicals means that a clinical toxicologist must be familiar with the occupational and environmental impact of a wide range of agents. A clinical toxicologist can be expected to be involved in the development of strategies for the management of major chemical disasters, including the chemical contamination of drinking water, the evaluation of antidotes used against chemical warfare agents and in the assessment of the adverse effects of pesticides, whether resulting from a single exposure or chronic low-level exposure.
Thus, clinical toxicologists will need to possess a detailed knowledge and understanding of the clinical, biochemical, kinetic, analytical, forensic, occupational and environmental aspects of toxicology if they are to play the important role that is now expected of them in today's society. They will also need to be committed to research and training.
3 A Comprehensive Clinical Toxicology Service
- Top of page
- Clinical Toxicology
- A Comprehensive Clinical Toxicology Service
It has been suggested previously that poisons centres need to offer a comprehensive clinical toxicology service if they are to survive and meet the challenges of the twenty-first century (Vale and Meredith, 1993). The combination of intensive treatment facilities for poisoned patients and substance abusers, a poisons information service and supporting laboratory is, we believe, the model that should be adopted. A comprehensive clinical toxicology service, embracing a clinical and advisory service, analytical support, research and training, with due emphasis on the occupational and environmental aspects of toxicology is needed if clinical toxicologists are to address adequately current toxicological challenges and opportunities.
3.1 A Poisons Information Service and an Expert Advisory Service to Physicians
A poisons information service must be available 24 hours a day, 365 days a year to provide expert advice to medical and paramedical staff, and, in most countries, to the public, on the toxicity of drugs and other chemicals, plants and animals. Such a service could also serve as a community resource so that health professionals and the general public can be advised both on ways to decrease the risk of poisoning and the measures to take if it occurs.
Physicians using the service must have every confidence that the advice given is evidence-based and up-to-date. To be credible such a service must include those with extensive training in clinical toxicology so that specific advice on the management of cases of poisoning can be given. It is a major advantage if these clinical toxicologists are also directly responsible for the management of patients suffering from the effects of acute or chronic poisoning. Such expertise is necessary if all the available information, circumstantial, clinical, laboratory and from other sources, is to be assessed accurately in relationship to the substances involved and the circumstances of exposure. Only in this way can a detailed plan for clinical management be developed which will maximize the chances of the patient surviving and minimize the risk of short- and long-term sequelae. This expert advice will need to be supported by a comprehensive collection of reference works and original papers, as well as by access to on-line retrieval systems.
3.2 An In-Patient Treatment Service
An in-patient service, of necessity, must be available at all times and be staffed by physicians with extensive training in clinical toxicology, who are respected for their professional competence and authority and who are capable of furnishing reliable opinions, as well as being adept at differential diagnosis. If possible, these physicians should also be responsible clinically, not only for the management of patients suffering from the effects of acute or chronic poisoning, but also for the detoxification of substance abusers. If logistically possible, it is a major advantage if the in-patient beds are in a dedicated area to act as a focus for the provision of expert medical, psychiatric and social care. It is also advantageous if the psychosocial assessments are undertaken by psychiatrists who have a specific commitment to the service.
3.3 An Out-Patient Clinical, Occupational and Environmental Toxicology Service
Many chronic medical problems are alleged to have a toxicological basis, be it occupational or environmental. Patients with such suspected toxicological problems should be assessed by an experienced clinical toxicologist to determine whether the patient's clinical features are due to a toxic exposure or not. In some countries, poisons centres are part of a much larger occupational medicine unit. Where they are not, there should be a close working relationship between clinical toxicologists and occupational physicians, particularly if the former are not appropriately trained in occupational medicine. Only in this way can a first-class occupational toxicology service be offered. A clinical toxicology centre should also play a major role in providing advice on environmental toxicological problems, such as on the chemical contamination of drinking water, the environmental impact of pesticides and on the management of major chemical disasters.
3.4 Advice to Government, Regulatory and International Bodies
Clinical toxicology centres will wish to play a full part in providing advice and support to Government Departments, Regulatory Authorities and Intergovernmental Bodies such as the International Programme on Chemical Safety (IPCS).
3.5 Analytical Support
Whether analytical support is provided ‘in-house’ or by contract with an outside laboratory is less important than the quality and speed of the service offered. In-house facilities allow a close working relationship to develop between clinical and analytical toxicologists, which will strengthen and improve the quality of the overall analytical service even further.
3.6 Research and Training in Toxicology
However outstanding its clinical service, no clinical toxicology centre can have a major impact without being closely involved in toxicological research. It is equally true that without a well-organized and relevant research programme an outstanding clinical service is unlikely to be offered. A commitment to research not only provides a stimulating environment for more senior faculty members, but also helps attract younger colleagues who are highly motivated and committed. Furthermore, a centre which is ‘spearheading’ clinical advances is likely to be widely consulted and have a substantial number of patient referrals.
Training programmes should ensure that those in training are able to apply relevant kinetic and biochemical data, so that treatment strategies can be developed and refined, based on the likely mechanisms of toxicity. Trainees will also need to recognize the limitations of analytical methods and be trained in the occupational and environmental aspects of toxicology.
- Top of page
- Clinical Toxicology
- A Comprehensive Clinical Toxicology Service
Exposure to a substance is often equated with poisoning. However, absorption is necessary for there to be a toxic effect and, even if this occurs, poisoning does not necessarily result, because the amount absorbed may be too small. In developed countries, poisoning causes approximately 10% of acute hospital medical presentations. In such cases poisoning is usually by self-administration (that is the act is deliberate) of prescribed and over-the-counter medicines, or illicit drugs. Rarely, deliberate poisoning may be the result of criminal intent (homicide). Sometimes inappropriate treatment of a patient by a doctor (iatrogenic poisoning) is responsible for the development of poisoning, for example, in the case of digoxin toxicity.
Poisoning in children aged less than six months is most commonly iatrogenic, and less frequently accidental by the parents, and involves over-treatment with, for example, paracetamol. Children between eight months and five years of age also ingest poisons accidentally, or they may be administered deliberately to cause harm, or for financial or sexual gain.
Occupational poisoning as a result of dermal or inhalational exposure to chemicals is a common occurrence in the developing world and still occurs in the developed world. As a result of changes to manufacturing processes, which may be due to criminal intent or incompetence, substantial morbidity and mortality has resulted. A famous example is the outbreak of diethylene glycol poisoning in 1937 due to the contamination of sulfanilamide (Geiling and Cannon, 1938); in recent years other outbreaks of diethylene glycol poisoning have occurred in Australia, Bangladesh, Haiti, India, Nigeria and South Africa following its inappropriate use commercially.
The type of agent taken in overdose is also heavily influenced by availability and culture. In the UK, paracetamol poisoning is responsible for approximately one third of all admissions (Bateman et al., 2006), whereas in Sri Lanka, for example, the agents ingested are more often pesticides or plants such as oleander (Eddleston et al., 2005). In addition, ingestion of heating fuels, antimalarials, antituberculous drugs and traditional medicines are reported frequently in the developing world.
The toxicity of a substance, and therefore the features of poisoning, can generally be predicted from its physicochemical properties, its pharmacological or toxicological actions, the route of exposure and the dose to which an individual has been exposed. The features of poisoning are classified as either local or systemic. Local toxicity is confined to the site of contact of the substance with body surfaces. The route of exposure (eye, skin, respiratory or gastrointestinal (GI) tract) determines the anatomical location of the interaction; the physicochemical characteristics of the substance (solubility, volatility, pH) define its nature and extent. Systemic toxicity depends on the fraction of the dose of the poison that is absorbed into the circulation; systemic toxicity is generally dose related, may be organ-specific, or may involve several organs.
While the pharmacological and toxicological effects of the poison are generally proportional to the amount that has been absorbed, the effects are modulated by variations between individuals. Some individuals react in a non-dose-dependent, idiosyncratic manner to some agents (such as metoclopramide, and some phenothiazines and butyrophenones). The speed with which features appear depends partly on the route of exposure; it is greater with inhalation and injection than with dermal exposure and ingestion.
4.1 Assessment and Management of the Poisoned Patient
The assessment and management of an acutely poisoned patient involves the following approach:
Taking an appropriate history
Assessing vital functions (the level of consciousness, ventilation, circulation and temperature) and correcting any impairment
Identifying complications and treating them:
Fluid, acid–base and electrolyte abnormalities
Requesting appropriate investigations
Assessing the patient psychiatrically and offering appropriate management.
|Constricted pupils (miosis)||Opioids, organophosphorus and carbamate insecticides, nerve agents|
|Dilated pupils (mydriasis)||Tricyclic antidepressants, amphetamines, cocaine, anticholinergic drugs|
|Divergent strabismus||Tricyclic antidepressants|
|Loss of vision||Methanol, quinine|
|Papilloedema||Carbon monoxide, methanol|
|Convulsions||Tricyclic antidepressants, theophylline, opioids, mefenamic acid, isoniazid, amphetamines|
|Dystonic reactions||Metoclopramide, phenothiazines|
|Delirium and hallucinations||Amphetamines, anticholinergic drugs, cannabis, recovery from tricyclic antidepressant poisoning|
|Hypertonia and hyper-reflexia||Tricyclic antidepressants, anticholinergic drugs|
|Tinnitus and deafness||Salicylates, quinine|
|Hyperventilation||Salicylates, phenoxyacetate herbicides, theophylline|
|Hyperthermia||Ecstasy (MDMA), salicylates|
|Blisters||Usually occur in comatose patients|
|Coma, hypertonia, hyper-reflexia, extensor plantar responses, myoclonus, strabismus, mydriasis, sinus tachycardia, convulsions||Tricyclic antidepressants; less commonly antihistamines, orphenadrine, thioridazine|
|Coma, hypotonia, hyporeflexia, flexor or nonelicitable plantar responses, hypotension||Barbiturates, benzodiazepine and alcohol combinations, tricyclic antidepressants|
|Coma, miosis, reduced respiratory rate||Opioid analgesics|
|Nausea, vomiting, tinnitus, deafness, sweating, hyperventilation, vasodilation, tachycardia||Salicylates|
|Hyperthermia, tachycardia, delirium, agitation, mydriasis||MDMA (ecstasy) or other amphetamine|
|Miosis, hypersalivation, bronchorrhoea||Organophosphorus and carbamate insecticides, nerve agents|
Diagnosis is based on the history, circumstantial evidence, the features present (if any) and, occasionally, on the results of haematological, biochemical and toxicological analyses.
4.2 Taking a History
About 80% of adults who have ingested an overdose are conscious on arrival at hospital and the diagnosis of self-poisoning can usually be made from the history. In unconscious patients, a history from friends or relatives is helpful, and the diagnosis can often be inferred from tablet bottles or a ‘suicide note’ brought by the paramedics, or made by exclusion of other causes. Self-poisoning must always be considered in the differential diagnosis in any patient with an altered consciousness level, even if relatives claim that the individual would never take an overdose.
Acutely poisoned patients may be emotionally and psychiatrically distressed, and require competent, sympathetic assessment if essential information is not to be missed. It is pertinent to try to establish the nature of the substance taken, the amount involved, the route (ingestion, injection, inhalation or dermal) and the time of exposure, so that the clinical course can be anticipated and the risk assessed. However, statements about the nature and amount of what has been taken should be regarded with clinical suspicion, because these are often inconsistent with laboratory analysis of blood or urine (Mahoney et al., 1990; Pohjola-Sintonen et al., 2000). When the time of exposure is important (e.g. paracetamol poisoning), the accuracy can be improved by relating events to activities of daily life (e.g. the time of a television programme).
4.3 Assessment of Vital Functions and their Management if Impaired
The level of consciousness, ventilation and circulation should be assessed in all patients.
4.3.1 Level of Consciousness
The Glasgow Coma Scale (GCS) is the most commonly used method to assess the degree of impairment of consciousness. The AVPU (Alert, Voice, Pain, Unresponsiveness) scale is a simplified version of the GCS (alert, responsive to verbal stimulation, responsive to painful stimulation and unresponsive) and corresponds well to GCS scores when assessing level of consciousness in the poisoned patient (Kelly et al., 2004). A GCS score of ≤8 (not obeying commands, not speaking, not eye opening) should prompt careful respiratory assessment, particularly if the laryngeal (gag) reflex is lost.
In any case of poisoning the priority is to assess and, if necessary, treat impairment of respiratory function. Food, vomit, secretions and dentures should be removed from the patient's mouth and pharynx, and the tongue prevented from falling back. The patient should be nursed with their head down in the left lateral position to minimize the risk of aspiration of the gastric contents into the lungs.
Pulse oximetry can be used to measure oxygen saturation. The displayed reading may be inaccurate when the saturation is below 70%, when peripheral perfusion is poor, and in the presence of carboxyhaemoglobin or methaemoglobin. If the patient has an arterial oxygen saturation of less than 95% (by pulse oximetry), is comatose (GCS ≤8) and/or the laryngeal (gag) reflex is absent, arterial blood gases should be measured. Only measurement of arterial blood gases indicates the presence of both hypercapnia (an increase in the arterial partial pressure of carbon dioxide) and hypoxia (a decrease in the arterial partial pressure of oxygen). The presence of ventilatory insufficiency (as determined by arterial partial pressure of oxygen ≤9 kPa on air and/or arterial partial pressure of carbon dioxide ≥6 kPa) should lead to intubation and mechanical ventilation if the central respiratory depression cannot be reversed by administration of a specific antidote, such as naloxone (see Section 188.8.131.52). Even when ventilation is satisfactory on presentation, it must be reassessed periodically because deterioration is well recognized (e.g. after ingestion of a sedative drug).
Pulse, blood pressure and temperature (core and peripheral) should be measured to assess cardiovascular function. An electrocardiogram (ECG) should be undertaken in moderately or severely poisoned patients, particularly when a drug with a cardiotoxic action (e.g. a tricyclic antidepressant that produces QRS prolongation) has been ingested (Thanacoody and Thomas, 2005). Although hypotension (systolic blood pressure ≤80 mmHg) is a recognized feature of acute poisoning, the classical features of shock (tachycardia and pale, cold skin) are seen rarely, because only a minority of patients are severely poisoned.
Hypotension and shock may be caused by:
Vasodilation and venous pooling in the lower limbs (e.g. angiotensin-converting enzyme (ACE) inhibitors [Lip and Ferner, 1995], phenothiazines);
A decrease in circulating blood volume because of GI losses (e.g. profuse vomiting in theophylline poisoning [Vale, 2007b]), increased insensible losses (e.g. salicylate poisoning [Chapman and Proudfoot, 1989]), increased renal losses (e.g. poisoning due to diuretics) and increased capillary permeability.
Hypotension may be exacerbated by coexisting hypoxia, acidosis and dysrhythmias. Young patients are generally not at risk of cerebral or renal damage unless their systolic blood pressure falls below 80 mmHg. In older patients, it is preferable to maintain systolic blood pressure above 90 mmHg. As a first step, the patient should be placed in a head-down position by elevating the foot of the bed by 15 cm. If this measure fails to produce improvement, plasma volume should be expanded by infusion of a crystalloid such as sodium chloride solution 0.9%. Invasive haemodynamic monitoring to confirm that adequate volume replacement has been administered may be appropriate. Dobutamine 2.5–10 µg kg−1 min−1, or epinephrine 0.5–2.0 µg kg−1 min−1, is indicated if hypotension is resistant to these measures; dopamine 2–5 µg kg−1min−1 is an alternative. A vasoconstrictor sympathomimetic drug (e.g. norepinephrine) may be necessary in severe cases, but it must be recognized that blood pressure may be raised at the expense of perfusion of vital organs, such as the kidneys.
A few drugs when taken in overdose may produce systemic hypertension. If this is mild and associated with agitation, a benzodiazepine such as diazepam may suffice. In more severe cases, for example, those due to a monoamine oxidase inhibitor, there may be a risk of arterial rupture, particularly intracranially. To prevent this, intravenous (iv) isosorbide dinitrate 2–10 mg h−1 up to 20 mg h−1 if necessary, or an α-adrenergic blocking agent (e.g. phentolamine, 5 mg iv every 10–15 minutes), or sodium nitroprusside 0.5–1.5 µg kg−1 min−1 by iv infusion, may be administered until blood pressure elevation is controlled.
4.3.4 Abnormalities of Temperature
A core (rectal) temperature below 35 °C is often present in older patients who are comatose, particularly if they have been exposed to cold temperatures for several hours. Placing the patient in a room with moistened air at a temperature of 27–29 °C and covering him or her with a foil space blanket to minimize heat loss is the best way to treat hypothermia. In addition, iv and intragastric fluids at normal body temperature may be used. Local radiant heat should not be used.
Rarely, body temperature may increase to potentially fatal levels after poisoning with central nervous system (CNS) stimulants such as cocaine, amphetamines, including 3,4-methylenedioxymethamp-hetamine (MDMA) (ecstasy) (Freedman et al., 2005), monoamine oxidase inhibitors or theophylline. In such cases, muscle tone is often increased (hypertonia) and convulsions (see Section (4.5.3)) and rhabdomyolysis (see Section (4.5.4)) are common. Cooling measures should be instituted, sedation with diazepam should be given and, in severe cases, dantrolene 1 mg (kg body weight)−1 should be administered intravenously.
4.4 Examination and Identification of Poison-Induced Features
Physical signs (features) are particularly important when trying to elucidate the cause of unexplained coma. A diagnosis of acute poisoning can only rarely be made on the basis of a single physical sign, but there are clusters of features that make a diagnosis of poisoning with specific drugs very likely (Table 1). General observations may also reveal useful information. For example, solvents or alcohol may be smelt on the breath, track marks may reveal undisclosed illicit substance abuse, atypical bruising may warn of domestic or other violence, and the signs of alcoholic liver disease may be revealed.
Inequality of the pupils is not uncommon in poisoned patients. Widely dilated pupils that react poorly to light may be caused by poisons with anticholinergic actions (e.g. tricyclic antidepressants) or sympathomimetic effects (e.g. amphetamines). Miosis (constricted pupils) is usually caused by opioid analgesics or poisons with cholinergic or anticholinesterase actions (e.g. organophosphorus or carbamate insecticides, nerve agents). Visual impairment (blindness) is associated most commonly with quinine (Mackie et al., 1997) and methanol (Barceloux et al., 2002) poisoning.
Strabismus (squint), internuclear ophthalmoplegia (paralysis of the muscles inside the eye that control the iris and ciliary body) and total external ophthalmoplegia (paralysis of the muscles that control eye movements) have been described in poisoning by various drugs (Hotson and Sachdev, 1982). Transient and variable strabismus (usually with the optic axes divergent in the horizontal plane) has been attributed to phenytoin, carbamazepine and tricyclic antidepressants. Although loss of oculocephalic and oculovestibular reflexes is usually regarded as evidence of severe brain-stem damage, poisoning with carbamazepine, phenytoin and tricyclic antidepressants can be associated with loss of these reflexes, but patients recover completely.
Hypertonia, hyper-reflexia and extensor plantar responses are commonly found in tricyclic antidepressant poisoning, and with other drugs with marked anticholinergic actions (e.g. the older antihistamines). However, all of these signs may be abolished in deep coma. Decerebrate and decorticate movements of the limbs often occur in unconscious poisoned patients but, in most cases, there is no irreversible brain damage and the patient recovers fully. Acute dystonic movements (muscle dysfunction characterized by spasm) are also observed in poisoning due to metoclopramide (Bateman et al., 1985), or less commonly haloperidol, droperidol, prochlorperazine or trifluoperazine.
4.5 Complications of Poisoning and their Management
4.5.1 Fluid, Acid–Base and Electrolyte Imbalance
Patients who are vomiting, sweating excessively or passing large quantities of urine should be given fluids intravenously to replace GI, dermal and renal losses.
Acid–base abnormalities, particularly respiratory and metabolic acidoses, are common presentations in acute poisoning. Respiratory acidosis due to CNS depression or pulmonary toxicity, and metabolic acidosis due to lactic acidaemia or derangements of intermediary metabolism are common features of poisoning (Jones, 2007). Respiratory alkalosis is a feature of early salicylate poisoning (Chapman and Proudfoot, 1989). Some common poisons that cause metabolic acidosis are shown in Table 3. After correction of hypoxia and hypotension, metabolic acidosis should be treated by the administration of sodium bicarbonate 50–100 ml as a bolus dose with further boluses being given as required.
Information about the nature of poisons ingested can occasionally be obtained from standard haematological and biochemical investigations, and from arterial blood gas analysis (Table 4). Measurement of a full blood count is generally of little diagnostic value, though prolongation of the prothrombin time (international normalized ratio (INR)) may be caused by anticoagulants or by liver necrosis in paracetamol or hepatotoxic mushroom poisoning. Routine biochemistry and arterial blood-gas analysis are of value in the differential diagnosis of coma or the detection of poison-induced hypokalaemia, hyperkalaemia, hypoglycaemia, hyperglycaemia and hepatic and renal failure or of acid–base disturbances. Measurement of carboxyhaemoglobin, methaemoglobin and cholinesterase activities are of assistance in the diagnosis and management respectively of cases of poisoning due to carbon monoxide, methaemoglobin-inducing agents such as nitrites, and organophosphorus or carbamate insecticides.
Hypernatraemia can be caused by ingestion of salt and is well recognized as a nonaccidental injury in children. Urine sodium concentration is elevated in salt poisoning, but this finding does not exclude hypernatraemia caused by dehydration; measurement of the fractional excretion of sodium and water is needed to distinguish the two causes (Coulthard and Haycock, 2003). Hyponatraemia is a recognized complication of the use of MDMA (‘Ecstasy’). It is caused by inappropriate secretion of antidiuretic hormone (ADH) (Henry et al., 1998), which impairs renal water excretion. This is often exacerbated by such patients drinking large amounts of water. It is managed by restricting the amount of fluid given to the patient.
Unless renal function is impaired or rhabdomyolysis is severe, hyperkalaemia is a relatively uncommon metabolic complication of poisoning. In contrast, marked hypokalaemia is a more common problem and may have serious sequelae. Most potassium disturbances in acute poisoning are due to disruption of extrarenal control mechanisms, notably the activity of Na+/K+ ATPase (adenosine triphosphatase) and potassium channels.
Hypokalaemia occurs because of increased Na+/K+ ATPase activity (e.g. β2- agonist, theophylline or insulin poisoning), competitive blockade of potassium channels (e.g. barium or chloroquine poisoning), GI losses and/or alkalosis. Hypokalaemia results in generalized muscle weakness, paralytic ileus, ECG changes (flat or inverted T waves, prominent U waves, ST segment depression) and cardiac arrhythmias (atrial tachycardia ± block, atrioventricular (AV) dissociation, ventricular tachycardia (VT), ventricular fibrillation (VF)). Severe and clinically significant hypokalaemia (e.g. that caused by theophylline (Vale, 2007b) or β2-agonist poisoning (Vale, 2007c) should be corrected by infusing potassium to prevent arrhythmias (Bradberry and Vale, 1995).
Hyperkalaemia follows inhibition of Na+/K+ ATPase activity (e.g. by digoxin), increased uptake of potassium salts, disruption of intermediary metabolism (e.g. cyanide poisoning), activation of potassium channels (e.g. fluoride poisoning) and the presence of acidosis and rhabdomyolysis, particularly if the latter is complicated by renal failure. Hyperkalaemia is associated with abdominal pain, diarrhoea, muscle pain and weakness, ECG changes (tall peaked T waves, ST segment depression, prolonged PR interval, QRS prolongation) and cardiac arrhythmias (VT, VF).
Hypocalcaemia is a specific feature of ethylene glycol and hydrogen fluoride poisoning, in which calcium is deposited as insoluble oxalate and hydroxyapatite crystals, respectively.
Hypophosphataemia may contribute to morbidity and mortality in paracetamol poisoning by inducing mental confusion, irritability and coma (Jones et al., 1989; Schmidt and Dalhoff, 2002). Phosphaturia appears to be the principal cause of hypophosphataemia in paracetamol poisoning; it may occur in the absence of fulminant hepatic failure and indicates paracetamol-induced renal tubular damage (Jones et al., 1989; Florkowski et al., 1994). More recently, hyperphosphataemia has been shown to be a highly specific and sensitive predictor of nonsurvival in patients with severe paracetamol poisoning (Schmidt and Dalhoff, 2002). It has been suggested that hyperphosphataemia is caused by renal dysfunction in the absence of hepatic regeneration (Schmidt and Dalhoff, 2002).
Hypoglycaemia may follow an overdose of insulin, sulfonylureas or ethanol, and may occur in paracetamol-induced liver failure. It is corrected by infusing 10% dextrose, if necessary, after a bolus injection of 50% dextrose (50 ml).
4.5.2 Skin Blisters
Skin blisters may be found in poisoned patients who are, or have been, unconscious (Beveridge and Lawson, 1965; Hoffbrand and Ridley, 1972). Such lesions are not diagnostic of specific poisons, but are sufficiently common in poisoned patients (and sufficiently uncommon in patients unconscious from other causes) to be of diagnostic value. Unconscious patients should be turned at least every 2 hours. Bullous lesions should be left intact until they burst, to reduce the risk of infection. Deroofing should be performed when the blister bursts; a nonadhesive dressing is then applied.
These may occur, for example, in poisoning due to tricyclic antidepressants (Bateman, 2005), mefenamic acid or opioids. Usually the seizures are short-lived but, if they are prolonged, diazepam 10–20 mg iv or lorazepam 4 mg iv should be administered. Persistent fits must be controlled rapidly to prevent severe hypoxia and brain damage and should be treated with a loading dose of phenytoin 18 mg kg−1 administered intravenously at a rate not more than 50 mg min−1, with ECG monitoring. Theoretically, phenytoin is contraindicated in poisoning due to tricyclic antidepressants as it may exacerbate sodium-channel blockade and increase the risk of cardiac arrhythmias. Rarely, muscle relaxation and mechanical ventilation are required in addition to phenytoin.
Rhabdomyolysis is a condition in which there is dissolution of striated muscle fibres, with leakage of muscle cell contents (enzymes, myoglobin, potassium and phosphate) (Vale, 2007a). In patients who are poisoned, nontraumatic rhabdomyolysis may be caused by a direct insult to the cell membrane, affecting its ability to maintain ion gradients or be secondary to local muscle compression as a result of coma or seizures. Two clinically important complications are observed: acute renal failure (which may be nonoliguric) and peripheral nerve damage (secondary to compartment syndrome), resulting predominantly in wrist or foot drop.
Rhabdomyolysis accounts for 5–9% of all cases of acute renal failure (Grossman et al., 1974; Thomas and Ibels, 1985) and 5–30% of patients with rhabdomyolysis develop acute renal failure (Gabow et al., 1982; Ward, 1988). Three main mechanisms are involved (Holt and Moore, 2001). First, tubular necrosis occurs by free-radical-mediated lipid peroxidation. This involves redox cycling between two oxidation states of myoglobin haem: Fe3+ (ferric) and Fe4+ (ferryl) (Holt and Moore, 2000). The formation of ferryl myoglobin requires the presence of lipid hydroperoxides (LOOH). Once formed, the ferryl species reacts with lipids and LOOH to form lipid alkyl (LOO) and lipid peroxyl (L) radicals that progressively damage renal tubular membranes. Thus, ferryl myoglobin can initiate lipid peroxidation.
Secondly, renal vasoconstriction occurs due to activation of the sympathetic nervous system and the renin–angiotensin system in response to reduced effective circulating blood volume, scavenging of the vasodilator nitric oxide (NO) by myoglobin and release of isoprostanes (particularly 15-F2t and 15-E2t, which are potent vasoconstrictors), formed as a result of free-radical damage to phospholipid membranes.
Thirdly, tubular obstruction occurs due to the formation of tubular casts formed by binding of free myoglobin to Tamm–Horsfall protein (uromodulin), a renal glycoprotein (Zager, 1989), and as a result of urate crystal deposition.
Experimentally, urine alkalinization (see Section (184.108.40.206)) has been shown to suppress the rate of conversion of ferryl (Fe4+) myoglobin to ferric (Fe3+) myoglobin. Thus, alkalinization inhibits the cyclical formation of lipid peroxide radicals and limits lipid peroxidation (Moore et al., 1998), so reducing tubular damage. Isoprostane release is also reduced by alkalinization, thereby lessening vasoconstriction. In addition, binding of myoglobin to Tamm–Horsfall protein is reduced under alkaline conditions, so that tubular casts are not formed (Zager, 1989). The administration of 8.4% sodium bicarbonate 225 ml should produce urine alkalinization; further boluses of sodium bicarbonate will be required to maintain the urine pH greater than 7.5. However, limited experimental and clinical data (Eneas et al., 1979; Homsi et al., 1997; Brown et al., 2004) suggest that early volume replacement is more important than urine alkalinization in preventing rhabdomyolysis-induced renal failure.
Methaemoglobin is formed when ferrous haemoglobin iron (II) is oxidized to ferric iron (III), which cannot participate in oxygen transport. Methaemoglobin concentrations are normally maintained at around 1% total haemoglobin by the action of a nicotinamide adenine dinucleotide (NADH)-dependent methaemoglobin reductase for which the physiological electron carrier is cytochrome b5 (Bunn and Forget, 1986). Excess methaemoglobin causes tissue hypoxia, not only because methaemoglobin is incapable of binding oxygen, but also because the oxidation of one or more iron atoms in the haem tetramer distorts the tetramer structure, so that the remaining nonoxidized haem subunits bind oxygen avidly, but release it less efficiently (Bunn and Forget, 1986).
Poisoning with a number of oxidizing drugs and chemicals may be complicated by methaemoglobinaemia (Bradberry et al., 1994a; Bradberry et al., 1994b; Bradberry et al., 2001; Bradberry, 2003). Two important chemical groups in this regard are organic nitrites (e.g. amyl and isobutyl nitrite) and amino or nitro derivatives of benzene (e.g. aniline, dapsone and lidocaine). Organic nitrites are sold as ‘room odourizers’. Inhalation causes profound, though transient, vasodilatation with the intent of enhancing sexual pleasure or inducing a transient ‘high’. Substantial absorption, which may occur after prolonged inhalation or ingestion, precipitates methaemoglobin formation. Amino and nitro derivatives of benzene are particularly potent methaemoglobin-formers because once absorbed they are activated to a metabolite that enters a cyclical process of methaemoglobin production such that even small exposures can result in clinically significant methaemoglobinaemia (Bradberry, 2007).
Even though methaemoglobin cannot bind oxygen, it is appropriate to administer high-flow oxygen to symptomatic patients with methaemoglobinaemia to maximize oxygen saturation of residual normal ferrous haemoglobin. In addition, methylthioninium chloride (methylene blue), which acts as an electron donor to reduce methaemoglobin, should be employed. In otherwise healthy individuals, methaemoglobin concentrations less than 30% usually do not require specific therapy, since such patients have only minor or no symptoms and methaemoglobin will be reduced over several hours by the intrinsic activity of methaemoglobin reductase. However, an anaemic patient may experience symptoms of hypoxia at methaemoglobin concentrations below 30%, since even in the absence of methaemoglobinaemia their overall oxygen transporting capacity is reduced. Such patients, or otherwise healthy individuals with methaemoglobin concentrations greater than 30%, warrant treatment with methylthioninium chloride 1–2 mg kg−1 (the dose depending on the severity of features) intravenously over 5–10 minutes as a 1% solution. If the methaemoglobin concentration is greater than 50%, methylthioninium chloride 2 mg kg−1 should be administered. Symptomatic improvement usually occurs within 30 minutes.
If there is evidence of continuing chemical absorption or prolonged methaemoglobin formation, a second dose of methylthioninium chloride 1–2 mg kg−1 may be required. High doses (typically in excess of 20 mg kg−1) of methylthioninium chloride can initiate severe intravascular haemolysis and doses as low as 4 mg kg−1 may exacerbate the haemolytic effect of oxidizing chemicals. Severe renal impairment is an absolute contraindication to methylthioninium chloride administration, since it is eliminated predominantly renally. Methylthioninium chloride will also be less effective where nicotinamide adenine dinucleotide phosphate (NADPH) availability is reduced, as occurs in the presence of glucose-6-phosphate dehydrogenase (G-6-PD) deficiency and haemolysis, and when the chemical initiating methaemoglobin formation itself utilizes NADPH in cyclical methaemoglobin production, as occurs with, for example, dapsone and aniline.
4.5.6 Serotonin Syndrome
Serotonin toxicity results from an excess of serotonin in the CNS, which can be due to inhibition of the metabolism of serotonin (monoamine oxidase inhibitors), prevention of the reuptake of serotonin in nerve terminals (serotonin reuptake inhibitors), increased serotonin precursors (tryptophan) or increased serotonin release (serotonin-releasing agents such as amphetamines, fenfluramine, MDMA) (Isbister et al., 2007).
Serotonin toxicity occurs insidiously and is characterized by the development, within hours, of a triad of altered mental status (approximately 40% of patients), neuromuscular hyperactivity (approximately 50% of patients) and autonomic instability (approximately 40% of patients), though diagnosis does not depend on all parts of the triad being present (Sternbach, 1991; Isbister and Buckley, 2005; Boyer and Shannon, 2005; Thanacoody, 2007; Isbister et al., 2007). Features of altered mental status include agitation, confusion, delirium and hallucinations. Drowsiness and coma may occur in severe cases. Neuromuscular features include profound shivering, tremor, teeth grinding, myoclonus and hyper-reflexia. Features of autonomic instability include dilated pupils, sinus tachycardia, fever and hypertension or hypotension. Flushing, diarrhoea and vomiting are also common. In severe cases seizures, hyperthermia, rhabdomyolysis, renal failure and coagulopathies may develop.
The Hunter Serotonin Toxicity Criteria (Dunkley et al., 2008) have refined Sternbach's criteria and proposed seven features which are considered to be more sensitive and specific in making the diagnosis: clonus (spontaneous, inducible and ocular), agitation, diaphoresis, tremor, hyper-reflexia, hypertonicity and hyperthermia (T0 > 38 °C). Clonus is the most important diagnostic sign.
The precipitating drug(s) should be discontinued and supportive care instituted. The control of agitation with benzodiazepines is essential. If hyperthermia supervenes, cooled iv fluids, tepid sponging and use of fans may help; paralysis and assisted ventilation should be employed if these measures do not to reduce muscle activity (Boyer and Shannon, 2005). Seizures should be controlled with diazepam 10–20 mg in an adult. Myoclonic jerks may be helped by clonazepam 1 mg intravenously over 2 minutes. The 5HT2A (5-hydroxytryptamine (serotonin) receptor 2A) antagonists, cyproheptadine 4–12 mg orally (up to 12–32 mg has been proposed during a 24 hour period (Boyer and Shannon, 2005)) and chlorpromazine 50 mg parenterally, have been used to treat serotonin syndrome following overdose, but there are no controlled trials to support the use of either agent (Isbister et al., 2007).
Measurement of the concentration of a specific poison in the blood, or toxicological screening of blood or urine, can be used to establish a diagnosis of poisoning, particularly in severely poisoned patients in whom the cause of coma is unknown. However, although identification of a poison may reassure the clinician, this is not a good reason for the request. Before proceeding, the clinician should consider how the result of a screen will alter management. The pattern of drugs involved in poisoning in most developed countries is such that specific treatment is unlikely to be available and management will therefore be supportive. There are a small number of cases where emergency measurement of the plasma concentration will assist clinical management and/or help to determine prognosis: aspirin (salicylate), carbamazepine, digoxin, ethylene glycol, iron, lithium, methanol, paracetamol, paraquat, phenobarbital, quinine and theophylline.
Routine radiology is of little diagnostic value. It can be used to confirm ingestion of metallic objects (e.g. coins, button batteries) or injection of globules of metallic mercury. Rarely, hydrocarbon solvents may be seen as a slightly opaque layer floating on the top of the gastric contents with the patient upright, or outlining the small bowel. Some enteric coated or sustained-release drug formulations may be seen on plain abdominal radiographs, but, with the exception of iron salts, ordinary formulations are seldom seen. Ingested packets of illicit substances may be discernible on a plain radiograph, but computed tomography (CT) or magnetic resonance imaging (MRI) is more reliably able to detect such objects. Radiology may be particularly helpful in confirming some of the complications of poisoning, for example, aspiration pneumonia, noncardiogenic pulmonary oedema (salicylates), bronchiolitis obliterans (nitrogen oxides), acute respiratory distress syndrome (ARDS) and lung fibrosis (paraquat).
Performing an ECG is also of limited diagnostic value, though it should be undertaken in those ingesting potentially cardiotoxic drugs; continuous ECG monitoring may be appropriate in such patients. Sinus tachycardia with prolongation of the PR and QRS intervals in an unconscious patient should prompt consideration of tricyclic antidepressant poisoning. With increasing cardiotoxicity, VT may supervene. ECG changes in association with poison-induced potassium disturbances are discussed in Section (4.5.1). QT interval prolongation is a recognized adverse effect of several drugs in overdose (e.g. quetiapine, terfenadine and quinine) and predisposes to ventricular arrhythmias, notably torsade de pointes.
4.6.1 Psychiatric Assessment and Management
In adults, self-poisoning is commonly a ‘cry for help’. Common precipitants include relationship problems, often in the context of depression and alcohol abuse. Those involved are most often females under the age of 35 who are in good physical health. They take an overdose in circumstances where they are likely to be found, or in the presence of others. In those older than 55 years of age, men predominate and the overdose is usually taken in the course of a depressive illness or because of poor physical health. The risks of repetition of self-harm and of suicide following self-poisoning are substantial (Hawton, 2007).
All patients require a sympathetic and caring approach, a psychiatric and social assessment and, sometimes, psychiatric treatment. Psychosocial assessment should include investigation of the events and problems preceding the act, suicidal intent and other motives for the act, psychiatric disorders, personality traits and disorders, family and personal history, psychiatric history, including of self-harm, risk of further self-harm and suicide, and coping resources and support (Hawton, 2007).
4.7 Management of the Poisoned Patient
As explained above, initial management involves the treatment of any potentially life-threatening conditions, such as airway compromise, breathing difficulties, haemodynamic instability, serious dysrhythmias and convulsions. Thereafter, fluid, acid–base and electrolyte abnormalities should be corrected and temperature disturbances treated appropriately.
Further management is aimed at:
Reducing absorption of the chemical(s) to which the individual has been exposed;
Employing a specific antidote, if appropriate;
Using methods to increase the elimination of the poison, if relevant.
Expert advice can always be obtained from a poisons information service.
4.7.1 Reduction of Poison Absorption
Poisons may be absorbed through the lungs, skin or from the GI tract. To reduce absorption through the lungs and skin, the exposed individual should be moved from the contaminated area, contaminated clothing should be removed and the skin thoroughly washed with soap and water.
While it appears logical to assume that removal of unabsorbed drug from the GI tract (‘gut decontamination’) will be beneficial, the efficacy of current methods remains unproven and efforts to remove small amounts of ‘safe’ drugs are clearly not worthwhile or appropriate.
220.127.116.11 Activated Charcoal
Activated charcoal adsorbs a wide variety of drugs and toxic agents; the exceptions are acids and alkalis, ethanol, ethylene glycol, iron, lithium and methanol. In studies in volunteers given 50 g activated charcoal, the mean reduction in absorption was 40, 16 and 21% at 60, 120 and 180 minutes, respectively, after ingestion (Chyka et al., 2005). Based on these studies, activated charcoal should be considered in those who have ingested a potentially toxic amount of a poison (known to be adsorbed by charcoal) up to one hour previously. There are insufficient data to support or exclude its use after one hour. There is no evidence that administration of activated charcoal improves the clinical outcome.
18.104.22.168 Gastric Lavage
Gastric-emptying studies in volunteers provide no support for the use of gastric lavage. In the single clinical study in which benefit was claimed for lavage within one hour of overdose, patients also received activated charcoal (Kulig et al., 1985). There was also selection bias, and hence conclusions based on these data are limited. Thus, gastric lavage should not be used routinely in the management of poisoned patients, as there is no evidence that it improves outcome, and it may cause significant morbidity (Kulig and Vale, 2004). The efficacy with which lavage removes gastric contents decreases with time. Therefore, lavage should be considered only in patients who have ingested life-threatening amounts of a toxic agent up to one hour previously.
22.214.171.124 Emesis with Syrup of Ipecacuanha
Syrup of ipecacuanha is derived from the dried roots of Cephaelis ipecacuanha and C. acuminata and contains the active alkaloids emetine and cephaeline. Emetine has a direct irritant action on the gastric mucosa, which causes vomiting within 30 minutes of administration; subsequent vomiting results from the central action of both alkaloids. Although syrup of ipecacuanha is an effective emetic, there is little evidence that its use prevents significant absorption of toxic material and, moreover, its adverse effects (e.g. persistent vomiting, diarrhoea, lethargy, drowsiness) may complicate diagnosis (Krenzelok et al., 2004). It should be abandoned.
126.96.36.199 Whole-Bowel Irrigation
Theoretically, the more quickly a poison passes through the gut, the less it is absorbed. Whole-bowel irrigation using polyethylene glycol electrolyte solutions does not result in absorption of fluid and electrolytes, even though large volumes are administered rapidly via a nasogastric tube. Some volunteer studies have shown substantial decreases in the bioavailability of ingested drugs, but no controlled clinical trials have been conducted and there is no evidence that whole-bowel irrigation improves outcome (Tenenbein and Lheureux, 2004). Based on volunteer studies, whole-bowel irrigation may be considered following potentially toxic ingestion of sustained-release or enteric-coated drugs and in body-packers (Hoffman et al., 1990).
Cathartics have been used alone and with activated charcoal. Two general types of osmotic cathartics have been used: saccharide cathartics (sorbitol) and saline cathartics (magnesium citrate, magnesium sulfate, sodium sulfate). Cathartics are intended to decrease the absorption of substances by accelerating the expulsion of the poison from the GI tract. Since most drug absorption occurs rapidly in the upper GI tract, the use of cathartics is most likely to benefit patients who have ingested drugs that are absorbed slowly. In volunteers, cathartics did not alter significantly the serum concentrations of lithium and salicylate when administered 30 minutes after dosing (Sørensen and Lindkær-Jensen, 1975) or change significantly the urine recovery of the metabolites of paracetamol (Galinsky and Levy, 1984) or salicylate (Mayersohn et al., 1977). In other studies, there was no difference in the mean area under the curve (AUC) of theophylline between the sorbitol-treated and control groups. No clinical studies have been published to investigate the ability of a cathartic, with or without activated charcoal, to reduce the bioavailability of drugs or to improve the outcome of poisoned patients. For these reasons it has been concluded that cathartics alone have no role in the management of poisoned patients. In addition, based on available data, routine use of a cathartic with activated charcoal has not been endorsed either (Barceloux et al., 2004).
There is no generally agreed definition of an antidote. The Shorter Oxford English Dictionary 2007 defines an antidote as a ‘medicine given to counteract the action of a poison’. A WHO Working Party suggested an antidote was a ‘therapeutic substance used to counteract the toxic action(s) of a specified xenobiotic’ (Meredith et al., 1993), which could include substances such as activated charcoal. Flanagan and Jones 2001 have defined an antidote as a ‘substance used to treat poisoning which has a specific action depending on the poison’. Bateman and Marrs (see Antidotal Studies) have adopted a similar definition.
Antidotes exert their beneficial effects by a variety of mechanisms, including forming an inert complex with the poison, accelerating detoxification of the poison, reducing the rate of conversion of the poison to a more toxic compound, competing with the poison for essential receptor sites, blocking essential receptors through which the toxic effects are mediated and bypassing the effect of the poison. These actions are described more fully in Antidotal Studies.
There are only a small number of poisons for which there is a specific antidote (Table 5) and few antidotes are employed regularly in clinical practice. Those that are include N-acetylcysteine, naloxone and flumazenil, and these are described below.
|Aluminium (aluminum)||Desferrioxamine (deferoxamine)|
|Arsenic||Dimercaprol, succimer (DMSAa)|
|β-Adrenoceptor blocking drugs||Atropine, glucagon|
|Calcium channel blockers||Atropine|
|Copper||d-Penicillamine, unithiol (DMPSb)|
|Cyanide||Dicobalt edetate, hydroxocobalamin, oxygen, sodium nitrite, sodium thiosulfate|
|Diethylene glycol||Ethanol, fomepizole|
|Digoxin and digitoxin||Atropine, digoxin-specific antibody fragments|
|Ethylene glycol||Ethanol, fomepizole|
|Iron salts||Desferrioxamine (deferoxamine)|
|Lead (inorganic)||Sodium calcium edetate, succimer (DMSAa)|
|Methaemoglobinaemia||Methylthioninium chloride (Methylene blue)|
|Mercury (inorganic)||Unithiol (DMPSb)|
|Nerve agents||Atropine, HI-6, obidoxime, pralidoxime,|
|Oleander||Digoxin-specific antibody fragments|
|Organophosphorus insecticides||Atropine, obidoxime, pralidoxime,|
|Thallium||Prussian (Berlin) blue|
|Warfarin and other anticoagulants||Phytomenadione (Vitamin K)|
Acetylcysteine acts by replenishing cellular glutathione stores. Acetylcysteine may also repair oxidation damage caused by N-acetyl-p-benzoquinone imine (NAPQI), either directly or, more probably, through the generation of cysteine and/or glutathione, and may also act as a source of sulfate and thereby ‘unsaturate’ sulfate conjugation (Jones, 1998). IV therapy with acetylcysteine is preferred, if available, because in overdose paracetamol induces vomiting and oral therapy may not be absorbed. The iv regimen employed involves a 20 hour 15 min to 21 hour regimen (Prescott et al., 1979a; Buckley et al., 1999; Kerr et al., 2005) and involves the administration of acetylcysteine 150 mg kg−1 over 15–60 minutes, then 50 mg/kg over the next four hours and 100 mg kg−1 over the next 16 hours; (total dose, 300 mg kg−1 over 20 hours 15 min to 21 hours). An oral regimen (Smilkstein et al., 1988) used only in the USA and now largely superseded by the iv preparation involved the administration of acetylcysteine 1330 mg kg−1 over 72 hours. Acetylcysteine must be administered within 8–10 hours of ingestion if hepatic damage is to be minimized or prevented (Vale and Proudfoot, 1995; Kerr et al., 2005; Prescott, 2005).
Approximately 10% of patients treated with iv acetylcysteine (20 hour 15 min regimen) develop rash and bronchospasm within the first hour of commencing treatment; the reaction is probably the result of histamine release caused by acetylcysteine in a concentration-dependent manner (Dawson et al., 1989; Sandilands and Bateman 2009). These reactions are seldom serious, but infusion of acetylcysteine should be discontinued for 30–60 minutes. Antihistamines are not usually required.
Naloxone is a pure opioid antagonist and has been used to make a rapid clinical diagnosis of opioid poisoning in those whose clinical presentation suggests inadequate ventilation caused by an opiate. It causes no adverse effects when given in opioid-naive individuals, though even in small doses may produce withdrawal symptoms in addicts. The dose of naloxone is titrated until the effects of the opioid have been reversed to a clinically detectable extent within 1–2 minutes. Typically, this dose of naloxone is 1.2 mg intravenously, followed by naloxone 2 mg if the response is only partial; a further 2 mg may be given 2–5 minutes later, if full resuscitation is not achieved. In patients who have not responded to naloxone 4 mg, the diagnosis of opioid poisoning should be reconsidered.
As naloxone has a half-life of some 45 and 90 minutes, which is much shorter than the half-life of opioids, repeat doses of naloxone are often required to maintain opioid reversal (Meredith et al., 1993). Alternatively, an infusion of naloxone may be commenced with the dose infused over one hour being 60–100% of the resuscitative dose. For slow-onset acting agents, such as methadone, the patient will need careful monitoring for several hours after the start of the infusion to ensure that appropriate levels of reversal are achieved.
Since naloxone reverses the effect of opioids on the gut there may be an increase in absorption of an orally ingested compound which leads to unexpected increases in opioid effects.
Flumazenil is the specific antidote for benzodiazepines and may be given to avoid ventilation in patients with chronic obstructive pulmonary disease. Although flumazenil will reverse the respiratory and CNS depressant actions of a benzodiazepine, caution should be exercised in patients who have coingested a tricyclic antidepressant and in those known to suffer from epilepsy, because seizures and arrhythmias could be precipitated by its use. Flumazenil has a short half-life (about one hour) (Meredith et al., 1993). Therefore, patients with severe poisoning in whom it is indicated should be administered flumazenil 0.5 mg intravenously over one minute; flumazenil 1.0 mg should be given if there is no response or only a partial response. Once the patient has been resuscitated fully, an iv infusion (0.5–1.0 mg h−1) may be commenced, if necessary, to maintain reversal of the respiratory and CNS depressant actions of the benzodiazepine. Flumazenil is also effective, though less so, in reversing sedation in overdose from the nonbenzodiazepine hypnotics zopiclone, zolpidem and zaleplon.
4.7.3 Methods to Increase Elimination
188.8.131.52 Multiple-Dose Activated Charcoal
Multiple-dose activated charcoal is thought to produce its beneficial effect by interrupting the enteroenteric and, in some cases, the enterohepatic and the enterogastric circulation of drugs. In addition, any unabsorbed drug still present in the gut will be adsorbed onto the activated charcoal, thereby reducing drug absorption. Human volunteer studies have demonstrated that multiple-dose activated charcoal increases the elimination of many drugs, the most important clinically being carbamazepine (Neuvonen and Elonen, 1980), dapsone (Neuvonen et al., 1980), phenobarbital (Neuvonen and Elonen, 1980), quinine (Lockey and Bateman, 1989) and theophylline (Berlinger et al., 1983; Mahutte et al., 1983). Clinical studies have confirmed these volunteer studies and shown that the elimination of carbamazepine (Boldy et al., 1987; Montoya-Cabrera et al., 1996), dapsone (Neuvonen et al., 1980; Neuvonen et al., 1983), phenobarbital (Pond et al., 1984; Boldy et al., 1986), quinine (Prescott et al., 1989) and theophylline (Mahutte et al., 1983; True et al., 1984; Amitai et al., 1986) is enhanced by multiple-dose activated charcoal. Based on these studies, multiple-dose activated charcoal should be considered if a patient has ingested a life-threatening amount of carbamazepine, dapsone, phenobarbital, quinine or theophylline. However, this therapy has not yet been shown in a controlled study in poisoned patients to reduce morbidity and mortality (Vale et al., 1999). Further studies are required to establish the role of multiple-dose activated charcoal and the optimal dosage regimen of charcoal to be administered. It is suggested that, after an initial dose of 50–100 g given to an adult, charcoal be administered hourly, every two hours or every four hours at a dose equivalent to 12.5 g h−1 (Vale et al., 1999).
184.108.40.206 Urine Alkalinization
Urine alkalinization is a treatment regimen that increases poison elimination by the administration of iv sodium bicarbonate to produce urine with a pH ≥ 7.5 (Proudfoot et al., 2003; Proudfoot et al., 2004). The administration of 8.4% sodium bicarbonate 225 ml should produce alkalinization; further boluses of sodium bicarbonate will be required to maintain the urine pH greater than 7.5. The term urine alkalinization emphasizes that urine pH manipulation rather than a diuresis is the prime objective of treatment. Administration of bicarbonate to alkalinize the urine may rarely result in alkalaemia (an increase in blood pH or reduction in its hydrogen ion concentration), but there is no evidence to suggest that relatively short-duration alkalaemia (no more than a few hours) poses a risk to life in normal individuals. Hypokalaemia is the most common complication of urine alkalinization but can be corrected by giving potassium supplements. Alkalotic tetany occurs occasionally, but hypocalcaemia is rare.
Urine alkalinization increases the urine elimination of chlorpropamide, 2,4-dichlorophenoxyacetic acid, diflunisal, fluoride, mecoprop, methotrexate, phenobarbital and salicylate (Proudfoot et al., 2004). Based on volunteer and clinical studies, urine alkalinization should be considered as first-line treatment for patients with moderately severe salicylate poisoning (Prescott et al., 1982) who do not meet the criteria for haemodialysis. Urine alkalinization cannot be recommended as first-line treatment in cases of phenobarbital poisoning, as multiple-dose activated charcoal is superior (Ebid and Abdel-Rahman, 2001). Supportive care, including the infusion of dextrose, is invariably adequate in chlorpropamide poisoning. A substantial diuresis (approximately 600 ml h−1) is required in addition to urine alkalinization if the chlorophenoxy herbicides, 2,4-dichlorophenoxyacetic acid and mecoprop, are to have their elimination enhanced in a clinically significant way (Prescott et al., 1979b).
220.127.116.11 Haemodialysis, Haemodialfiltration and Haemoperfusion
Haemodialysis, haemodialfiltration and haemoperfusion are of little value in patients poisoned with drugs with large volumes of distribution (e.g. tricyclic antidepressants), because the plasma contains only a small proportion of the total amount of drug in the body. These methods to increase poison elimination are indicated in patients with both severe clinical features and high plasma toxin concentrations.
Haemodialysis significantly increases elimination of ethanol, ethylene glycol, isopropanol, lithium, methanol and salicylate, and is the treatment of choice in all cases of severe poisoning with these agents (Vale, 1990). Haemodialfiltration is more widely and readily available and increases elimination of poisons such as ethylene glycol and methanol, though it is less efficient than haemodialysis. Charcoal haemoperfusion can significantly reduce the body burden of phenobarbital, carbamazepine and theophylline, but multiple-dose activated charcoal is as effective and simpler to use.
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The concept of toxicovigilance encompasses the active detection, validation and follow-up of clinical adverse events related to toxic exposures in human beings (Descotes and Testud, 2005). WHO has defined toxicovigilance as the ‘active process of identifying and evaluating toxic risks in a community in order to reduce or remove them’ (IPCS, 1997). Descotes and Testud 2005 have extended this definition and proposed that toxicovigilance ‘primarily encompasses the active detection, validation and follow-up of clinical adverse events related to toxic exposures via household, occupational or environmental chemicals and products’. Drug-induced clinical adverse events are dealt with by a related process of pharmacovigilance (postmarketing drug surveillance).
Descotes and Testud 2005 believe that, ‘Toxicovigilance is essentially based on the medical assessment of acute or chronic intoxications on an individual basis, which requires validated information that epidemiologists either do not look for or cannot analyse as comprehensively on a large scale’. Toxicovigilance primarily involves the collection of medically validated data from case reports, preferably using a consistent structured format to allow for the aggregation of information for global risk assessment. Thus, toxicovigilance ‘generates signals that can be used to elaborate pathogenic hypotheses, and this in turn can serve as an impetus for epidemiological studies’ (Descotes and Testud, 2005).
The IPCS has stated that the main goal of toxicovigilance is prevention. ‘Toxicovigilance consists of the active observation and evaluation of toxic risks and phenomena in the community—an activity that should result in measures aimed to reduce or remove risks’ (IPCS, 1997).
The IPCS believes that the role of poisons information centres in toxicovigilance includes (IPCS, 1997):
Identifying serious poisoning risks in the local community, and the substances, circumstances and population groups involved;
Identifying changes in the incidence of poisoning, for example, different substances of abuse, application of new pesticides and seasonal variations in the incidence of poisoning, such as carbon monoxide poisoning from heating appliances;
Monitoring the toxicity of commercial products, such as household, industrial and agricultural chemicals, as well as pharmaceuticals (by any route of administration), for acute, medium-term and chronic effects, with particular regard to new products and formulations (e.g. overuse of analgesics, occupational exposure to solvents);
Monitoring the toxic effects of drug overdosage;
Identifying substances that cause significant morbidity and mortality, and specific effects on organs (e.g. high incidence of renal insufficiency, foetal malformations);
Reporting to health authorities and other relevant bodies situations that demand preventative corrective action, and, where appropriate, calling an alert;
Monitoring the effectiveness of preventative measures.
Similarly, Volans et al. 2007 have suggested that, ‘In practise, toxicovigilance is achieved through a range of activities, undertaken mainly, although not exclusively, by poisons centres. Clinical adverse events and hazards can be identified by a retrospective analysis of detailed case reports from poison centre databases to identify new patterns in cases of poisoning, or by prospective observation studies designed to answer specific questions, for example, to identify hazards associated with products and their use that can result in recommendations to improve drug safety’.
The most well-developed national poisons surveillance system is that coordinated by the American Association of Poisons Control Centers (AAPCC). It was formerly called the Toxic Exposure Surveillance System (TESS) but is now referred to as the AAPCC National Poison Data System (NPDS). Automated, real-time toxicovigilance of the database was initiated in March 2003 as a surveillance process to identify exposures that may have public health and safety implications (Watson et al., 2005). The goal was to provide early identification of new product hazards, water, food or product contamination, chemical/biological terrorism incidents and emerging substances of abuse. Watson et al. 2005 have suggested that the methods were designed to detect:
Increases in total or human exposure case volume at each poison center;
Increases in national reporting of individual toxic (clinical) effects;
Cases that meet a surveillance-case definition.
These toxicovigilance tools were applied to incoming data on both real-time and near-real-time (1 to 24 hour interval) basis (Watson et al., 2005). The results were reviewed by clinical toxicologists with public health expertise to determine if further investigation or dissemination of findings was necessary. Clinical (toxic) effect data were collected using a list of 131 unique clinical effects, laboratory and diagnostic findings (Watson et al., 2005). Medical outcomes were categorized as no effect, minor effect, moderate effect, major effect and death using standardized definitions.
The medical outcomes of TESS/NDPS cases have been used to calculate a hazard factor (serious outcomes per 1000 poison exposure cases) (Watson et al., 2005). Hazard factor analysis provides a method for comparisons of the relative toxicity of products. An early use of hazard analysis compared the relative toxicity, defined as the rate of either major outcome or death associated with different poison exposure substance categories in children (Litovitz and Manoguerra, 1992). The hazard factor was calculated as the number of major medical outcomes and deaths per 1000 poison exposures with a documented medical outcome. This analysis showed that the three categories of substances most commonly involved in unintentional paediatric poisoning exposures, cosmetics and personal-care products, cleaning products and plants, had low hazard factors, indicating that the most common exposures were associated with minimal toxicity. Hazard-factor analysis identified a number of less frequently reported poisoning exposures that had more significant toxicity. Exposures with high hazard factors included hydrocarbons and pesticides. It was found that products containing yohimbe or ephedra were more likely to be associated with severe medical outcomes than other botanical products when risk ratios were compared (Watson et al., 2005).
The TESS/NDPS database has also been utilized for product safety assessment and to identify changes in substance-reporting patterns (Litovitz, 1998). Data have been used to support regulatory actions such as child-resistant closures on ethanol-containing mouthwashes, topical preparations of dibucaine and lidocaine, and acetonitrile-containing cosmetics. TESS/NDPS data have supported the reclassification of prescription medications to over-the-counter status and the cancellation of the registration of relatively more toxic pesticides, such as mevinphos and arsenical ant baits (Watson et al., 2005).
As Descotes and Testud 2005 have concluded, ‘So far very few countries have set up structured toxicovigilance systems and it is hoped that in the future, national and international initiatives will help bridge this gap in our knowledge of the toxicity of many chemicals and commercial products to human beings’.
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- 1986). Repetitive oral activated charcoal and control of emesis in severe theophylline toxicity. Annals of Internal Medicine, 105, 386–387. , , and (
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