ADVERSE EFFECTS

Drugs & Aging I (I): 67-89.1991 1170-229X /91 /000I-0067/$ 11.50/0 © Adis International Limited . All rights reserved. ORAl 011

Poisoning in the Elderly

Epidemiological, Clinical and Management Considerations Wendy Klein-Schwartz and Gary M. Oderda Maryland Poison Center. University of Maryland School of Pharmacy. Baltimore. Maryland. USA

Contents 67 68 68 69 69 69 70 70 7/ 7/ 7/ 73 74 74 74 75 76 77 77 78 80 80 81 81 81 84 84 84 86 87 87

Summary I. Introduction 1.I Epidemiology of Poisoning in the Elderly 1.2 Causes of Unintentional Poisonings 1.3 Suicides in the Elderly 1.4 Physiological Changes Affecting Poisoning 2. General Management Considerations 2.1 Assessment 2.2 Treatment 2.2.1 Supportive Care 2.2.2 Prevention of Absorption 2.2.3 Enhancement of Elimination 2.2.4 Administration of Antidotes 3. Psychotherapeutic Drugs 3.1 Antipsychotic Drugs 3.2 Cyclic Antidepressants 3.3 Benzodiazepines 4. Cardiovascular Drugs 4.1 Digoxin 4.2 Nitrates 4.3 Angiotensin Converting Enzyme (ACE) Inhibitors 4.4 I1-Blockers 4.5 Calcium Antagonists 5. Analgesics and Anti-Inflammatory Drugs 5.1 Salicylates 5.2 Nonsteroidal Anti-Inflammatory Drugs 6. Other Drugs 6.1 Oral Hypoglycaemic Agents 6.2 Theophylline 7. Poison Prevention in the Elderly 8. Conclusion

Summary Poisoning is a significant problem in the elderly. The majority of poisonings in older people are unintentional and may result from dementia and confusion, improper use of the product .

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Drugs & Aging 1 (I) 1991

improper storage or mistaken identities. Depression is also common in the elderly and suicide attempts are more likely to be successful in this age group . The elderly patient's recuperative abilities may be inadequate as a result of numerous factors including impaired hepatic or renal function as well as chronic disease processes. General management of poisoning in the elderly parallels management of younger adults, but it is especially im portant to ascertain underlying medical conditions and concurrent medications. In most poisonings, activated charcoal and cathartic are sufficient. Haemodialysis or haemoperfusion may be required at lower plasma drug concentrations in elderly patients. While the specific indications for antidotes are .the same for all age groups, dosage alterations and precautions may need to be considered in the elderly. Drugs most often implicated in poisonings in the elderly include psychotherapeutic drugs, cardiovascular drugs , analgesics and anti-inflammatory drugs, oral hypoglycaemics and theophylline. Cardiovascular and neurological toxicities occur with overdoses of neuroleptic drugs and , more frequently and severely. with cyclic antidepressants. Patients with pre-existing cardiovascular disease are at particular risk of worsening ischaemic heart disease and congestive heart failure. Benzodiazepines onl y appear to produce significant toxicity during long term administration or in combination with other CNS depressants. Digoxin can cause both chronic and acute intoxication, most seriousl y cardiac toxicity including severe ventricular arrhythmias, second or third degree heart block or severe refractory hyperkalaemia. Immune Fab antibody is indicated for the management of digoxin toxicity, although patients dependent on the inotropic effect of digoxin may develop heart failure after digoxin Fab antibody administration. Nitrates can cause toxicity including headache, vomiting, hypotension and tachycardia from excessive sublingual, transdermal or intravenous doses. Conduction disturbances and hypotension occur with overdoses of antihypertensive drugs; these effects are mild with angiotensin converting enzyme (ACE) inhibitors, occasionally severe with {3blockers and of significant concern with calcium channel antagonists. The elderly commonly use aspirin and other salicylates, are more likely to develop chronic intoxications to these agents, and are more susceptible to severe complications such as pulmonary oedema. Salicylate poisoning, recognition of which is often delayed , should be considered in elderly patients with neurological abnormalities or breathing difficulties, especially in the setting of acid-base abnormalities. The clinical effects of NSAID overdose are mild and usually involve the central nervous system and gastrointestinal tract . Elderly patients are also more likely to develop hypoglycaemia when taking sulphonylurea agents even with therapeutic doses. Seizures and arrhythmias occur at lower serum theophylline concentrations in the elderly. Poison prevention efforts aimed at unintentional exposures are primarily focused on preventing toxic exposures from occurring and minimising the consequences of injury should a toxic exposure occur . Several potential poison prevention strategies are outlined below.

1. Introduction Poisoning is a significant problem in the elderly. As with other age groups, many poison exposures are unintentional. However, a significant number are intentional, with suicidal intent, and many are successful. 1.1 Epidemiology of Poisoning in the Elderly Of the I 581 540 human poison exposures reported by the American Association of Poison

Control Centers (AAPCC) National Data Collection System in 1989, 31 536 (2%) involved persons aged at least 60 years, with a predominance in older women (female: male ratio = 1.7: I) [Litovitz et al. 1990]. Accidental poison exposures were more common in the elderly than in younger adults (83.4% vs 64.3%), while intentional exposures occurred less frequently (10.6% vs 30.5%). The 115 fatalities in those 60 years of age and older accounted for 19.4% of the. fatalities reported to the database . Of the 115 fatalities, 70 were intentional

69

Poisoning in the Elderly

Table I. Mortality rates from Maryland Poison Center data in 1989 Age group (years)

Mortality rate (deaths/1000 calls)

60

[53 suicides , 17 other (i.e. misuse, abuse or unknown)] and 25 were accidental. The mortality rate from poisoning is much higher in elderly patients than it is in other age groups. While only 1.5% of the calIs received by the Maryland Poison Center in 1989 involved persons of 60 years or older, this age group accounted for 22.6% of alI fatalities (Maryland Poison Center 1989 Statistical Report 1990). The mortality rates from Maryland Poison Center data in 1989 are given in table 1. 1.2 Causes of Unintentional Poisonings Klein-Schwartz and colIeagues (1983) prospectively evaluated poison exposures in 237 persons aged between 60 and 97 (mean 66) years reported to a regional poison centre. Most potential poisonings (63.7%) occurred in the home, folIowed by nursing homes in 14.3% of cases. When compared with adults from 20 to 59 years of age, the elderly were more likely to have taken agents oralIy but less likely to have had exposures to more than one agent. OveralI, 83.1% of exposures were unintentional, 14.8% were suicide attempts, and 1.7%were drug abuse. Four fatalities occurred; 3 were successful suicides and 1 the result of a chronic accidental overdose. A careful examination of the unintentional exposures revealed that the reason for the exposure could be classified into I of 4 groups : I. Dementia and Confusion: Examples include a nursing home resident who for no apparent reason ate or drank substances within his or her reach,

or patients who took inappropriate doses of prescribed medication because they were confused and forgot that they had already taken their dose. 2. Improper Use of the Product: These cases often involved topical or inhalation exposures that occurred while the product was being used for its intended purpose. Examples include inhalation of ammonia fumes while cleaning and topical exposure to a pesticide. 3. Improper Storage ofthe Agent: Medicinal or poisonous products were transferred from the original container to one that was mistaken for a food or drink container and the product consumed. 4. Mistaken Identities: Nonfood items were mistaken for food, and various substances were mistaken for therapeutic agents. Examples included cleaning products mistaken for mouthwashes, ear drops mistaken for eye drops, and agents that were mistaken for topical preparations and applied to the skin. 1.3 Suicides in the Elderly Depression is common in the elderly. Suicide attempts by the elderly are more likely to be successful than suicide attempts by younger adults (Resnik & Cantor 1970; Sendbuehler & Goldstein 1977). Elderly people may have a greater intention to die and use more lethal means . Furthermore, chronic illnesses decrease their ability to recover from injury (Svenson 1987). 1.4 Physiological Changes Affecting Poisoning A number of factors involving drug distribution and pharmacodynamics must be considered in the management of drug therapy in the elderly (Montamat et al. 1989). Table II summarises factors affecting drug disposition in elderly patients. Although these physiological changes are important when making therapeutic decisions in the elderly, they must also be evaluated in overdoses. Alterations in distribution, metabolism and excretion may increase the toxicity of a poison exposure

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Table II. Factors affecting drug disposition in elderly patients [reproduced from Montamat et at, (1989) , with permission) Age-related physiological change Absorption Increased gastric pH Decreased absorptive surface Decreased splanchnic blood flow Decreased gastrointestinal motility Distribution Decreased cardiac output Decreased total body water Decreased lean body mass Decreased serum albumin Increased al -acid glycoprotein Increased body fat Metabolism Decreased hepatic mass Decreased hepatic blood flow

Excretion Decreased renal blood flow Decreased glomerular filtration rate Decreased tubular secret ion

Pathological condition

Therapeutic and environmental factor

Achlorhydria Diarrhoea Postgastrectomy Malabsorption syndromes Pancreatitis

Antacids Anticholinerg ics Cholestyramine Drug interactions Food or meals

Congestive heart failure Dehydration Hepatic failure Malnutr ition Oedema or ascites Renal failure

Drug interactions Protein-binding displacement

Cancer Congestive heart failure Fever Hepatic insufficiency Malnutrition Thyro id-disease Viral infection or immunisation

Dietary composition Drug interactions Insecticides Tobacco (smoking)

Hypovolaemia Renal insufficiency

Drug interactions

significantly in an elderly patient. These factors and the presence of other disease processes may result in inadequate compensatory mechanisms to deal with an acute insult.

1. General Management Considerations Management of the poisoned patient involves gathering information, assessing the situation and developing a management plan. While the general approach to the patient is the same regardless of the person's age, there are a number of aspects which must be considered differently when the patient is elderly. 2.1 Assessment The initial step in treating a potential poisoning in an elderly person is to gather information, including the history, physical findings and, in some

instances, laboratory data. Important components of the history include the name and amount of the agent involved, the route of exposure, the time since exposure, whether the exposure is short or long term, the age and weight of the victim, symptoms or physical findings, pre-existing medical conditions and medications, and any previously administered emergency medical treatment. Elderly persons are more likely to have pre-existing medical conditions than younger adults. Evaluation of the influence of other disease states on the poisoning is essential to assess the potential for toxicity accurately. Older people are usually receiving many medications, both prescription and nonprescription, which may affect their response to an overdose. Concurrent medications may increase the likelihood of an adverse effect or drug interaction, or affect the person's ability to elimi-

71

Poisoning in the Elderl y

nate the toxic substance. A further consideration in obtaining a history of a poisoning in an elderly person is their ability to provide information accurately. If mental capabilities are impaired, it may be necessary to contact a relative or caretaker to obtain or clarify the history. Initial physical examination should focus on those physical findings pertinent to the toxic agent. Positive physical findings may be the result of the intoxication or pre-existing medical conditions. The temporal relationship between the poisoning episode and the onset of symptoms as well as a knowledge of the person's medical history will help to differentiate the aetiology of the physical findings. Depending on the toxic substance, qualitative or quantitative determination of the substance in blood or urine may be necessary to assess the severity of the intoxication. General guidelines for timing of blood sample and plasma concentrations which are considered toxic are independent of age, however aging alters hepatic and renal function, which may decrease elimination of the toxin and prolong the course of the intoxication . This should be considered when using laboratory data to predict the time course of the intoxication and may necessitate obtaining additional plasma concentration measurements to determine whether an individual is handling the drug differently than the reported norm. Another potential ramification of impaired drug elimination is that patients who arrive late at a health care facility may have higher concentrations than expected relative to the amount ingested and the time since ingestion. These factors must be evaluated in conjunction with the history and physical findings in order to utilise the laboratory findings accurately. The next step is to assess the poisoning as nontoxic, mildly toxic, or moderately to severely toxic. Nontoxic exposures require no treatment, and the elderly person or caretaker should be reassured that no problem exists. Mildly toxic poisonings may require treatment, but can often be handled in a nonhealth care facility setting (e.g. irrigation of the skin or eyes, and dilution for an oral ingestion). Poisonings which are classified as moderately toxic to severely toxic must be managed in a health care

facility. In some instances, mildly toxic exposures require treatment in a health care facility because the elderly person or their caretaker is incapable of handling the situation at home. 2.2 Treatment The various strategies available to manage commonly encountered poisonings are summarised in table III. 2.2.1 Supportive Care The most important component of therapy of the poisoned elderly patient is supportive care. Attention should be focused on identification ofCNS and cardiovascular toxicities including coma and respiratory depression, seizures, cerebral oedema, hypotension or hypertension and arrhythmias. Other potential complications include altered body temperature, pulmonary oedema, acid-base disturbances and long term complications of coma such as pneumonia and decubitus ulcers. 2.2.2 Prevention ofAbsorption Acute oral toxic ingestions can be treated by inducing vomiting with ipecac syrup 30ml or performing lavage and administering activated charcoal and a cathartic. Gastric emptying with an emetic or lavage can be considered for recent ingestions. CNS depression, seizures or the ingestion of caustics are absolute contraindications to an emetic. Although controversy has surrounded the use of emetics in hydrocarbon or antiemetic ingestions, these are no longer considered contraindications to inducing vomiting (Manoguerra & Krenzelok 1978; Ng et aJ. 1974; Thoman & Verhulst 1966). An alternative method of gastric emptying is lavage. Lavage can be performed in patients with seizures once the seizures have been controlled and in comatose patients once a cuffed endotracheal tube has been inserted to protect the airway. Lavage is contraindicated in caustic ingestions. Whether ipecac syrup or lavage is preferable in adults is unclear. Although two studies in adults demonstrated significantly more returned with lav-

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Table III. Summary of appropriate strategies to manage poisonings with drugs commonly used in the elderly Drug class

Lavagea

Activated charcoal

Antipsychotics Cyclic antidepressants Benzodiazepines Digoxin

v v

v v

v

v v

Nitrates ACE inhibitors fj-Blockers Calcium antagonists Salicylates NSAIDs

v v v v

v v v v

v v

v v

v

v

v

v

Oral hypoglycaemics Theophylline a b

Multiple-dose activated charcoal

Urine alkalinisation

Haemodialysis

Haemoperfusion

Specific antidote

Sodium bicarbonate Flumazenil Digoxin Fab antibodies Methylene blue Glucagon Calcium chloride

v v b vb

Glucose

If patient presents early. Depends on agent within category .

age than ipecac, problems with these studies relating to methodology leave this issue unresolved (Auerbach et al. 1986; Tandberg et al. 1986). An intracerebral bleed temporally related to ipecac administration in an elderly woman suggests the need for caution when considering ipecac syrup in patients with prior cerebrovascular or cardiovascular disease (Klein-Schwartz et al. 1984). These questions are becoming less relevant as the role of gastric emptying itself is being questioned and the use of activated charcoal assumes greater importance in gastrointestinal decontamination. Activated charcoal has a large surface area which adsorbs many drugs and chemicals. The charcoal dose of 60 to 100g in adults is administered as a slurry and can be drunk or poured down a lavage tube. Saline cathartics (e.g. magnesium sulphate, magnesium citrate) or hyperosmotic cathartics (e.g, sorbitol) are recommended to decrease the transit time of the activated charcoal-toxin complex through the gastrointestinal tract. Although cathartics are routinely administered with activated charcoal and many commercially available acti-

vated charcoal preparations are formulated with sorbitol, an additional effect of cathartics of decreasing drug absorption has only been demonstrated for sustained release products (Goldberg et al. 1987). The questionable efficacy of cathartics is an important consideration since the elderly are particularly susceptible to the potential adverse effects of fluid and electrolyte disturbances. Magnesium-containing cathartics pose the additional risk of hypermagnesaemia; a 77-year-old woman with poor renal function developed hypermagnesaemia following a single 17.5g dose of magnesium citrate in a chronic theophylline intoxication (Weber & Santiago 1989) [see also section 2.2.3]. Two studies in human volunteers found charcoal to be more effective than ipecac syrup as the primary gastrointestinal decontamination procedure (Curtis et al. 1984; Neuvonen et al. 1983). Therapeutic doses of study drugs were used which may not apply to overdoses (Curtis et al. 1984; Neuvonen et al. 1983), but in a third study utilising an ampicillin overdose model the reductions in absorption for ipecac or activated charcoal were sig-

Poisoning in the Elderl y

nificantly different from control but not from each other (Tennenbein et al. 1987). A prospective randomised study of overdose patients in an emergency room demonstrated no advantage in combining ipecac syrup or lavage with activated charcoal and magnesium sulphate, unless the patient was obtunded and presented within I hour of ingestion, in which case lavage was beneficial (Kulig et al. 1985). To summarise, in elderly patients the primary method of gastrointestinal decontamination is activated charcoal and cathartic. Healthy patients over 60 years of age may be able to tolerate ipecacinduced vomiting, but this should be avoided in those with pre-existing medical problems. Lavage would be preferred in these patients if gastric emptying is indicated . 2.2.3 Enhan cement of Elimination Enhancement of elimination of the drug may prevent or minimise toxicity. Forced diuresis and alteration of urine pH will increase the urinary excretion of some drugs and chemicals. Increasing urine output to 2 to 4 mljkgJh by administering fluids and a diuretic such as furosemide (frusemide) or mannitol will enhance the elimination of amphetamines, bromides, ethanol, isoniazid, phencyclidine, phenobarbital, salicylates and strychnine. Potential complications include cerebral and pulmonary oedema. Alkalinisation of the urine to pH 7 or greater with intravenous sodium bicarbonate will also increase the elimination of phenobarbital , salicylates and isoniazid. Urinary acidification will increase the renal clearance of amphetamines, phencyclidine or strychnine but is not recommended because of the high risk for rhabdomyolysis with myoglobinuria which, in the presence of a decreased urine pH, can precipitate acute renal failure. Procedures to augment urinary elimination of drugs may not be effective in elderly patients with impaired renal function. Elderly patients on long term diuretic treatment may be hypokalaemic, making urine alkalinisation impossible. Since fluid and electrolyte balance may be precarious in the elderly, close monitoring of fluid input and output,

73

electrolytes (including serum sodium and potassium) and blood pH is essential. Haemodialysis and haemoperfusion can effectively enhance the elimination of some drugs. Haemodialysis should be considered in severe poisonings with substances such as ethylene glycol, lithium, methanol , phenobarbital and salicylates, while haemoperfusion will effectively remove phenobarbital and theophylline. For a given drug or chemical there are specific indications for these procedures related to plasma concentration of the substance and the severity of signs and symptoms. In the elderly patient haemodialysis or haemoperfusion may be required at lower plasma drug concentrations because of more serious symptomatol ogy resulting from pre-existing medical conditions or impaired ability to compensate for toxic effects. Drug overdoses in the elderly during long term therapy with, for example, salicylates, theophylline and lithium , often exhibit more serious signs and symptoms at lower plasma drug concentrations than with acute overdoses. Impaired elimination of drugs secondary to age-related changes in hepatic and renal function may necessitate utilisation of haemodialysis or haemoperfusion more frequently in the elderly. In some instances of renal impairment, haemodialysis may be required after antidote administration to remove the renally excreted complex formed. For example, ferrioxamine - which is formed when deferoxamine complexes with iron - is renally eliminated and can be removed by haemodialysis in patients with renal failure (Whitten et al. 1966). Multiple-dose activated charcoal enhances the clearance of drugs (e.g. carbamazepine, cyclic antidepressants, digoxin, phenobarbital , phenytoin and theophylline) which are secreted from the blood into the stomach or that undergo enterohepatic recirculation, but the effectiveness of this procedure on the time course of intoxication and medical outcome is unclear (Pond et al. 1984). Activated charcoal is administered every 4 to 6 hours until the plasma concentration is in the therapeutic range or until major signs of toxicity resolve. Cathartics are administered with the first dose and then every 12 to 24 hours. However, multiple-dose activated

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charcoal should be used with caution in elderly patients with poor gastrointestinal motility , since there is an increasing incidence of constipation with age. Similarly, toxicity from cathartics in a multiple-dose regimen may be more likely in elderly patients with decreased or absent gastrointestinal motility, because the increase in transit time may increase the absorption of magnesium . Hypermagnesaemia with evidence of clinical toxicity following the use of magnesium-containing cathartics has been reported in elderly patients receiving multiple-dose charcoal regimens for theophylline intoxications (Garrelts et al. 1989; Weber & Santiago 1989). 2.2.4 Administration ofAntidotes The final component of the management plan is antidote administration, usually as an adjunct to supportive care. Only a few of the substances most commonly involved in poisonings have specific antidotes. In general, the specific indications are the same for all age groups. Dosage changes may need to be considered for some antidotes, particularly if there is hepatic or renal impairment. Another important consideration is whether pre-existing medical conditions predispose the elderly patient to adverse effects of the antidotes. For example, the use of digoxin Fab antibody in managing intoxication in patients receiving digoxin therapy can precipitate congestive heart failure and render the patient unresponsive to further digoxin. Similarly, in patients on long term oral anticoagulant treatment who require absolute anticoagulation and are given phytomenadione (vitamin Kj), caution is necessary since temporary resistance to anticoagulation may result.

3. Psychotherapeutic Drugs The prevalence of organic brain syndrome and functional disorders increases with age. Since the aetiology of mental disorders in the elderly is often multifactorial, social therapy, psychotherapy and psychoactive drug therapy are all essential for the effective management of these problems (Lamy 1980). Drugs for behaviour disorders , depression,

anxiety and apprehension , cognitive and memory impairment and sleep disturbance are commonly prescribed for the elderly. The elderly experience numerous adverse effects with therapeutic doses of psychotherapeutic drugs. Poisonings, either from unintentional misuse or suicide attempts, also occur with these drugs. 3.1 Antipsychotic Drugs Phenothiazines, thioxanthenes and butyrophenones are used for the management of psychosis. In therapeutic doses the drugs in these classes differ mainly in potency and adverse effects, including sedation , anticholinergic effects, extrapyramidal effects and orthostatic hypotension. Overdoses produce neurological and cardiovascular toxicities similar to those of cyclic antidepressant overdoses (see section 3.2) but complications are less frequent and less severe. However, elderly patients with preexisting cardiac disease are potentially at risk from significant cardiovascular toxicity. In overdose, initial CNS stimulation with agitation, delirium, disorientation and confusion is followed by depression ranging from sedation to coma. In 43 cases of phenothiazine poisoning, respiratory depression requiring intubation did not occur in overdoses with phenothiazines only, but was reported in 6 of 17 cases of mixed drug overdose (Barry et at. 1973). Since phenothiazines lower the seizure threshold, convulsions may occur but are infrequent. Ventricular arrhythmias and conduction disturbances are most frequently associated with thioridazine and mesoridazine (Crane 1970; Marrs-Simon et at. 1988). Complete heart block and bundle branch block have also been reported (Elkayam & Frishman 1980). Diastolic hypotension is most common, occurring in 12 of 26 patients in one series (Barry et at. 1973). Hypothermia or hyperthermia , miosis and anticholinergic effects may also be noted with overdoses (Barry et at. 1973). Acute dystonic reactions, including torticoIlis, trismus , oculogyric crisis, fixed facial grimacing, tongue spasms or protrusion and opisthotonos, are more common with haloperidol and the piperazine

Poisoning in the Elderly

group (prochlorperazine, trifluoperazine, fluphenazine) [Corre et al. 1984]. These reactions may occur within the first few hours after an ingestion or may be delayed many hours and can occur after only I tablet (Corre et al. 1984). The phenothiazines and other antipsychotics are considered relatively safe in an overdose. In adults, significant morbidity is associated with mixed overdoses with cyclic antidepressants or sedativehypnotics. Fatalities are uncommon with acute overdoses. Of 7 fatalities reported to the AAPCC National Data Collection System in 1989 in which a phenothiazine was considered the primary responsible agent, 4 involved people of 60 years of age or greater (Litovitz et al. 1990). Initial evaluation of an overdose should include an ECG and monitoring of vital signs as well as cardiac monitoring . Treatment consists of supportive care and gastrointestinal decontamination, which may be effective up to 12 hours after ingestion since phenothiazines delay gastric emptying. Acute dystonic reactions are treated with diphenhydramine 50mg intravenously over 2 minutes or benztropine mesylate 2mg intramuscularly or intravenously. Dystonias may recur because the half-lives of the phenothiazines and other antipsychotics are long, so treatment should continue with oral diphenhydramine 50mg 3 times daily for 2 to 3 days (Corre et al. 1984). 3.2 Cyclic Antidepressants The cyclic antidepressants are effective for managing endogenous depression in the elderly. Since suicide is a potential consequence of depression and the onset of antidepressant activity is several weeks, there is a high risk of overdoses with these drugs. There is a disproportionately high incidence of fatalities with cyclic antidepressants compared with the incidence of overdoses (Litovitz et al. 1990). The elderly are potentially at risk for cardiac toxicity from therapeutic doses as well as overdoses of cyclic antidepressants because of underlying disease (Davenport 1988)and altered elimination. The management of cyclic antidepressant poisoning is outlined in figure I. .

75

Cardiovascular and CNS toxicities predominate in cyclic antidepressant overdoses. Cardiac effects include arrhythmias, conduction disturbances and hypotension . Myocardial infarction is a potential complication in patients with pre-existing cardiac disease because anticholinergic and adrenergic effects increase cardiac work. Patients with intrinsically poor cardiac function may develop heart failure from a direct myocardial depressant action which decreases myocardial contractility. Cardiac toxicity is the major cause of morbidity and mortality with amitriptyline , desipramine, doxepin, imipramine, nortriptyline, protriptyline and trimipramine. Amoxapine and maprotiline overdoses are associated with a higher risk of seizures than the other drugs (Kulig et al. 1982; Litovitz & Troutman 1983; North et al. 1983; Wedin et al. 1986),but amoxapine may be less cardiotoxic (Kulig et al. 1982). The potential for serious toxicity in a cyclic antidepressant overdose can be assessed early in the intoxication . Major signs of toxicity including CNS depression, respiratory depression, seizures, arrhythmias, conduction blocks and hypotension should be evident during a 6-hour observation period in an emergency department (Callaham & Kassel 1985; Foulke et al. 1986). Cardiac monitoring, monitoring of vital signs and ECG should be performed. Prolongation of the QRS interval is considered a predictor of serious toxicity, including seizures and ventricular arrhythmias (Boehnert & Lovejoy 1985). Supportive care is critical in cyclic antidepressant overdoses. Rapid control of seizures is important since seizures increase cardiac workload which may precipitate cardiac toxicity. This is especially important in elderly patients with compromised cardiac function. Alkalinisation of the plasma, either by hyperventilation or sodium bicarbonate administration, will decrease the risk of arrhythmias, conduction disturbances and hypotension (Hoffman & McElroy 1981;Kingston 1979). Lidocaine (lignocaine), phenytoin, intracardiac pacing and cardioversion can be used to manage arrhythmias, with fluids, Trendelenburg position

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Drugs & Aging / (I) / 99/

• •

Suspec ted cyclic antidepressant overdose

Establish IV line. Place patient on card iac monitor.Check consc iousness , airway protect ion, ECG

History and clinical presentation, clinical laboratory tests (arterial blood gases . pH) monitor CRS interval

•

Lavage (if early ), multiple doses of activated charcoal , cathart ic every 12-24 hours

•

I

Patient conscious with stab le haemodynamic parameters

Monitor CNS and cardiovascular status (inclUding ECG). and bowel sounds . Observe for 6 hours

•

+

Patient has major signs of toxicity (obtunded, comatose. seizures . hypotens ion, arrhythmias . conduction blocks)

.......

......

...

Major signs of toxicity prolonged CRS interval (:1: 0. 1 sec). JII"'" diminished or absent bowel sounds

+

Continue sodium bicarbona te. cardiac monitorin g until ECG is norma l for at least 12 hours

Asymptomatic or resolving lethargy and/or tachycardia. normal CRS interval. active bowe l sounds

I

• Establish adequate airway and ventilation with supplemental oxygen • Admin ister appropriate medication for cardiovascular abnormalities and seizures (see section 3.2) • Admin ister sodium bicarbonate or hyperventilate patient to alkalinise plasma to pH 7.45-7 .5

...

..... Discharge .....

.....

Fig. 1. Man agement of cyclic antide pressant poisoning in the elderly.

and vasopressors with direct a-agonist actions [e.g. norepinephr ine (noradrenaline)] for hypotension. Lavage, followed by activated charcoal and cathartic should be performed. Ipecac syrup is contraindicated because of the potential for rapid deteriorat ion of e N S status.

3.3 Benzodia zepines Benzod iazepines are the most frequentl y prescribed sedative hypnotics in the elderly. Long term adm inistration, particularly of long acting agents, commonly produ ces toxic effects in the elderly (such as excess sedation) which can lead to falls

Poisoning in th e Eld erl y

(Ray et al. 1987). Adverse effects tend to be dose related rather than idiosyncratic. The elderly are more prone to these ad verse drug reactions as a result of altered pharmacodynamics and pharma cokinetics (Montamat et al. 1989). Man y acute benzodiazepine overdoses occur each year, but most do not produce significant toxicity (Litovitz et al. 1990). Of 2 980 643 poison exposure cases reported to the AAPCC National Data Collection System over a 4-year period, 51 326 ( 1.7%) inv o lved benzodiazepines (Litovitz 1987). Of 11 22 fatal ities during this period 65 (5.8%) involved benzodiazepines. In 5 of these cases, a benzod iazepine alone was implicated ; alprazolam in 3 instances, temazepam in I, and triazolam in 1. In the elderly a number offactors may alter the response to benzodiazep ines. A decrease in seru m albumin levels in the elderl y ma y increase the percentage of unbound, and thus pharmacologically active, drug for agents such as chlordiazepo xide, diaz epam, lora zepam , temazepam , and triazolam. An increased volume of distribution has been correlated with increa sing age for chlordiazepoxide and diaz epam, while a decreased volume of distribution has been correlated with increasing age for lorazepam (M ontarnat et al. 1989). The elde rly have decreased hepatic enzyme acti vity responsible for phas e I preox idation reactions (Everitt & Avorn 1986) and thus longer active agents which undergo hepatic oxidation (such as flura zepam and diazepam ) ma y ha ve even longer half-lives in the elderly (Everitt & Avorn 1986). As in oth er age groups, ingest ions in th e elderly ofbenzodiazepines alone usuall y produce minimal to xicity. Grade 0 or I coma with no difficulty ma intaining blood pressure or spontaneous respirat ions occurs. Combinations of benzodiazepines and oth er CNS depressants, such as ethanol, ma y produce life-threaten ing effects in the elderl y (G reenblatt et al. 1977). F1umazen il, a benzodiazepine antagonist, is currentl y undergoing clinical trials in the US and is available in other countries. The primary application of the drug appears to be in reversing benzodiazepine effects after anaesthesia, but it may also be useful in the elderly to reverse prolonged ben-

77

zodiazepine to xicit y or in overdoses combining benzodiazepines and other drugs which cause cardiovascular or respiratory compromise (see review by Brogden & Goa 1988).

4. Cardiovascular Drugs Cardiovascular disease is responsible for significant morbidity and mortality in the elderly. Impaired clearance of cardiovascular drugs such as d igoxin can result in long term intoxication in elderl y patients. Acute toxicity can develop fro m inappropriate dosing, drug interactions or intentional overdoses of cardiac drugs. 4.1 Digoxin Digoxin is ind icated for the management of supraventricular tachycardia and congestive heart failure in the elderly. Digoxin poisoning results from either acute overdose or chronic therapeutic intoxication. The elderly are at high risk for chronic digoxin toxicity because of decreased renal function and lower volumes of distribution. Other risk factors for digoxin toxicity such as electrolyte disturbances, hypothyroidism, ischaemi c heart disease and pulmonary disease (Bresnahan & Vlietstra 1979) are common in the elderly. Of 14 fatalities reported to the AAPCC National Data Collection System in 1989 in which digoxin was considered the primary responsible agent , 12 involved persons over 60 years of age (Litovitz et al. 1990); 8 of which were the resu lt of chronic intoxication. Cardiac to xicit y is responsible for the most serious morbidity and mortality in digoxin poisoning and mayor may not be preceded by other signs of toxicity (Cole & Smith 1986). Common arrhythmias and conduction disturbances include paroxysm al atrial tachycardia with block, sustained j unctional tachycardia, premature ventricular contra ctions, bigeminy, ventricular tachycardia, ventricular fibrillation, type I second degree AV block , AV junctional exit block , complete AV block and bundle branch block. Noncardiac toxicities include gastrointestinal, CNS and visual disturbances. The diagnosis of chronic digoxin intoxicat ion in the el-

78

derly may be delayed because some of these effects such as anorexia, muscle weakness, headache , disorientation, confusion, and depression may not be initially attributed to digoxin toxicity. Initial management of digoxin poisoning includes stopping digoxin in chronic intoxication and gastrointestinal decontamination in acute overdose (fig. 2). Multiple-dose activated charcoal is recommended to increase digoxin clearance (Boldy et al. 1985; Lalonde et al. 1985). Atropine, lidocaine, phenytoin and pacemaker insertion are suitable treatment modalities for cardiac toxicity. Digoxin immune Fab antibody is indicated for the management of life-threatening digoxin toxicity, including severe ventricular arrhythmias (e.g. ventricular tachycardia or fibrillation , or progressive bradyarrhythmias), second or third degree heart block unresponsive to atropine, and severe refractory hyperkalaemia (i.e. > 5 mmol/L) [Cole & Smith 1986; Smith et al. 1982; Wenger et al. 1985]. Digoxin immune Fab reversed digoxin toxicity in 21 of 26 patients in one study (Smith et al. 1982) and 53 of 56 patients in another (Wenger et al. 1985). Patients with poor cardiac function receiving digoxin who are dependent on the inotropic effect of the drug may develop heart failure after digoxin immune Fab (Smith et al. 1982). Elderly patients with chronic digoxin intoxication who are treated with digoxin immune Fab may be at risk for this adverse reaction . 4.2 Nitrates Ischaemic heart disease, the most important cardiovascular disease of the elderly, is usually managed with nitroglycerin (glyceryl trin itrate) or isosorbide dinitrate, or less commonly pentaerithrityl (pentaerythritol) and eritrityl (erythrityl) tetranitrates. Adverse effects with therapeutic doses include headache , flushing, dizziness and syncope from postural hypotension. Acute overdose, in addition, produces nausea, vomiting, palpitations and reflex tachycardia. Elderly patients with compromised cerebral blood flow, pulmonary disease and/ or pre-existing coronary artery disease may be more susceptible to serious complications such as myo-

Drugs & Agi ng 1 (I) 1991

cardial infarction or congestive heart failure at lower doses of nitrates than younger adults . Nitrates have a wide therapeutic index, and thus acute, oral ingestions usually produce no or minimal toxicity. Poisonings more commonly result from excessive sublingual, transdermal or intravenous doses. Although clinical trials suggest that elevations in methaemoglobin levels are not clinically significant (Buenger & Mauro 1989), several cases of significant methaemoglobinaemia have been reported with intravenous infusion of nitroglycerin ~ 10 JLg/kg/min (Buenger & Mauro 1989). Methaemoglobinaemia occurs less commonly than the other clinical manifestations of nitrate overdose, but is a potentially life-threatening effect in some patients. For example, an 80-year-old man with angina died after taking 100 nitroglycerin O.4mg tablets over a 36-hour period. Other medications included sublingual isosorbide dinitrate 10mg 4 times daily and nitroglycerin 2% ointment. He developed a methaemoglobin concentration of 7% which in the presence of a severely compromised cardiovascular status was believed to have contributed to his death (Marshall & Ecklund 1980). Patients are usually asymptomatic at methaemoglobin concentrations less than 15%. Clinical cyanosis and a 'chocolate brown' appearance of the blood is evident with methaemoglobin concentrations between 15 and 30%. At 30 to 50% methaemoglobin, headache, fatigue, weakness, dizziness, tachypnoea and tachycardia occur. Lethargy, stupor, respiratory depression, coma, convulsions, arrhythmias and cardiovascular collapse are noted at 50 to 70% methaemoglobin, with death at levels greater than 70% (Ellenhom & Barceloux 1988). Cyanosis and the chocolate brown appearance of blood strongly suggest methaemoglobinaemia. The diagnosis is further strengthened by the persistence of cyanosis when administering oxygen. In addition to measuring methaemoglobin concentrations, arterial blood gases will show normal p02 and normal calculated oxygen saturation with a reduced measured oxygen saturation. Gastrointestinal decontamination should be performed following acute oral nitrate overdoses. Supportive care including administration of 100%

79

Po isoning i n the Elderl y

Suspected digoxin or digitoxin PO'SOf1llJg

+

Ensure presence of adequate vital signs . Check consciousness , airway protection , ECG. Start IV fluids

•

History and clinical presentation , clinical laboratory tests (blood glucose, electrolytes, arterial blood gases , pH, serum digoxin level)

• 'Ir

I

Lavage, activated charcoal and cathartic

I

I

I

I ,Ir Monitor ECG continuously for arrhythm ias and potassium imbalances

+

Stable haemodynamic parameters and normokalaemic

+

I

•

If hyperkalaem ic administer glucose, insulin, sodium bicarbonate . If arrhythmias are present administer appropriate therapy (atropine . phenytoin, lidocaine, transvenous pacemaker . cardioversion) . Amiodarone or brelylium should be used for ventricular arrhythmias unresponsive to above. Administer multiple-dose activated charcoa l

"

Hyperkalaem ia and cardiovascular abnormalities corrected . Continue monitoring. Adequate vital signs established

."

If hypokalaemic replace potassium

Patient is hyperkalaem ic and/or arrhythmias present

IObserve for 6 hours

I Discharge ~

•

IChronic"poisoning I

I Acute poisoning I

•

~~

Arrhythmia·free , normokalaemic . asymptomatic

Fig. 2. Management of cardiac glycoside po i so n ing in the elderly.

Life-threaten ing arrhythmias or severe refractory hyperkalaemia .

•

I Administer digoxin immune I Fab antibodies

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Drugs & Aging / (I) /99/

oxygen, intubation and ventilation, intravenous fluids, dopamine for hypotension and diazepam for convulsions should be provided as needed. The specific antidote for methaemoglobinaemia (> 30%) is methylene blue which increases the nonenzymatic reduction of methaemoglobin to oxyhaemoglobin (Ellenhorn & Barceloux 1988). It should also be given to patients with methaemoglobin levels less than 30% who are symptomatic. The elderly frequently fall into this category because of pre-existing medical conditions which predispose them to toxicity at lower methaemoglobin levels. 4.3 Angiotensin Converting Enzyme Inhibitors Angiotensin converting enzyme (ACE) inhibitors are frequently used in the elderly for the treatment of hypertension and congestive heart failure. The introduction of ACE inhibitors into the therapeutic market in the US is relatively recent, and to date there have been few serious overdoses. The major concern in elderly patients who take overdoses of ACE inhibitors is the possibility that profound hypotension may develop. Mild or severe hypotension responsive to dopamine and/or fluids has been reported in 4 younger women (aged between 33 and 56 years) after overdoses with enalapril 300 or 440mg (Lau 1986; Waeber et al. 1984), and captopril 750mg or 5g (Augenstein et al. 1988; Turhan et al. 1984). Renal effects of ACE inhibitors include proteinuria, nephrotic syndrome, acute renal failure, acute tubular necrosis, and reversible acute-on-chronic renal failure. Although these effects have not been reported in acute overdoses, renal function should be monitored in elderly patients. Treatment of ACE inhibitor overdose in the elderly parallels that in younger patients and includes gastrointestinal decontamination and supportive care. Monitoring parameters focus on blood pressure and renal function.

4.4 {3-Blockers Elderly patients are treated with {3-blockers for numerous indications including hypertension , arrhythmias, ischaemic heart disease and glaucoma. Cardiovascular effects of {3-blocker overdoses include bradycardia, conduction disturbances and severe hypotension . First-degree atrioventricular block may progress to complete heart block and asystole. Patients with underlying cardiac disease are particularly susceptible to toxicity from {3blocker overdose including complications such as pulmonary oedema, congestive heart failure and cardiovascular collapse (Critchley & Ungar 1989). Because of the partial agonist activity of pindolol, overdoses with this drug more commonly exhibit hypertension and tachycardia. Lethargy, coma and respiratory depression may occur. Seizures are associated with overdoses of the more highly lipophilic drugs such as propranolol and oxprenolol (Buiumsohn et al. 1979; Weinstein 1984). Other toxicities include vomiting, bronchospasm and hypoglycaemia. {3-Blockers have a wide therapeutic index. Compromised cardiac or pulmonary function narrows the therapeutic index, placing elderly patients with pre-existing cardiac disease, chronic obstructive pulmonary disease or asthma at higher risk of serious toxicity. The {3-blockers vary in the relative contribution of renal elimination or hepatic metabolism to their clearance from the body. Therefore, impaired renal or hepatic function will influence the pharmacokinetic profile of different {3blockers to different extents. Accumulation of the {3-blocker or active metabolites predisposes the patient with renal failure to toxicity (Critchley & Ungar 1989). This has a potential impact on the development and time course of {3-blocker intoxication in some elderly patients. Management of a {3-blocker overdose includes gastrointestinal decontamination and close observation for respiratory depression and seizures. Patients should be on a cardiac monitor. Glucagon, atropine, {3-adrenergic agonists and transvenous cardiac pacing are potential treatment modalities for bradycardia and/or severe hypotension (Critch-

Poisoning in the Elderly

ley & Ungar 1989), although atropine's effectiveness is questionable (Weinstein 1984). Glucagon, considered the drug of choice for hypotension and bradycardia, has often proven effective when added to other previously ineffective drug regimens. The response to isoprenaline (isoproterenol) varies and high doses (up to 200 IJg/min) may be required in ,B-blocker overdose (Agura et al. 1986; Hurwitz et al. 1986). Prenalterol, a cardioselective ,BI-agonist, has been advocated for ,B-blocker poisoning (Critchley & Ungar 1989). Cardiac pacing may be required for profound bradycardia and heart block. 4.5 Calcium Antagonists Of 3647 calcium antagonist poisonings reported to the AAPCC data base in 1989, 2038 were in adults 18 years of age or older, and 867 were intentional overdoses. Treatment in health care facilities was required in 2025 cases with major complications in 96 cases and 26 deaths. Diltiazem, nifedipine, or an unknown calcium antagonist were each responsible for I death; the remaining 23 deaths were from verapamil - 8 of the deaths were in patients 60 years of age or older and all but I were intentional (Litovitz et al. 1990). The cardiovascular effects of overdose with calcium antagonists are of significant concern in the elderly. Atrioventricular conduction is affected more by verapamil and diltiazem and to a lesser degree by nifedipine. Verapamil and diltiazem frequently produce bradycardia while nifedipine produces tachycardia. Further hypotension can occur with all calcium antagonists. Asystole occurred in a 74-year-old man who mistakenly took diltiazem 1500mg (Snover & Bocchino 1986) and in a digitalised patient after intravenous administration of verapamil 5mg (Kounis 1980). Elderly patients should be monitored for arrhythmias and conduction disturbances including heart block, atrioventricular dissociation, and asystole. CNS effects , such as drowsiness and lightheadedness, may be seen in elderly patients with therapeutic doses of calcium antagonists as well as with overdoses. For example, a 59-year-old patient developed mental confusion after ingestion of nifed-

81

ipine 900mg (Herrington et al. 1986), and seizures were seen following ingestion of diltiazem 10.8g in a 58-year-old man with a history of epilepsy (Rumack 1990). Seizures in elderly patients could have significant cardiovascular repercussions. Supportive care is the major component of treatment of overdoses with calcium channel antagonists. Because of the potential adverse cardiovascular consequences of seizures in the elderly, aggressive management is important. Diazepam (5 to 10mg over 2 to 3 minutes) followed by phenytoin (15 to 18 rug/kg loading dose , not to exceed 0.5 rug/kg/min) and phenobarbital (10 to 20 mg/ kg given at 25 to 50 mg/rnin) are recommended for treating calcium antagonist-induced seizures. Intravenous calcium is indicated for hypotension, bradycardia and conduction disturbances. Calcium chloride is preferred over calcium gluconate, since it provides more calcium per volume and has a greater inotropic effect (White et al. 1976). Blood pressure, ECG, and plasma calcium levels should be monitored. In addition, close attention to fluid administration is essential particularly in the elderly, because of possible pulmonary oedema. Dopamine or epinephrine (adrenaline) can be added to calcium and fluids to reverse hypotension. Glucagon, atropine, isoprenaline and ventricular pacing have been shown to be effective in some cases of heart block (Rumack 1990). Since the volumes of distribution of calcium antagonists are large, it is unlikely that haemoperfusion or haemodialysis will remove a sufficient amount of drug to be clinically useful (Rumack 1990). Nevertheless a 49year-old woman improved clinically with haemoperfusion after overdosing on diltiazem 1200mg, metoprolol 500mg and ethanol (Anthony et al. 1986).

5. Analgesics and Anti-Inflammatory Drugs Elderly patients are often afflicted with pain associated with musculoskeletal conditions including gout , osteoarthritis and rheumatoid arthritis (Lamy 1980). Analgesics and anti-inflammatory drugs are therefore commonly used in the elderly for man-

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Drugs & Aging 1 (I) 199/

aging both acute and chronic pain. These medications have been associated with toxicity during long term therapeutic use as well as with acute intentional overdose. 5.1 Salicylates Aspirin and other salicylates are widely used in the elderly. While the frequency of acute salicylate poisoning has decreased since the 1960s, chronic or therapeutic overdoses are associated with serious morb idity and mortality . Long term salicylate intoxication occurs in older patients with a high frequency of associated medical problems (Anderson et al. 1976). Elderly people with chronic salicylate intoxications may be more susceptible to severe complications such as pulmonary oedema (Heffner & Sahn 1981). Failure to recognise chronic salicylate poisoning results in delays in stopping the drug and instituting treatment for the overdose. It is particularly important to consider the diagnosis of salicylate intoxication in elderly patients with neurological abnormalities or dyspnoea or tachypnoea, especially in the setting of acid-base abnormalities (Anderson et al. 1976). Of 35 fatalities reported to the AAPCC National Data Collection System in 1989 in which aspirin or methylsalicylate was considered the primary agent responsible for the death, 9 (7 of 31 with aspirin, 2 of 4 with methylsalicylate) involved people 60 years of age or older (Litovitz et al. 1990). Salicylate intoxication produces multisystem involvement including gastrointestinal, neurological, metabolic, pulmonary and cardiac complications. Nausea and vomiting, dizziness, tinnitus, confusion, drowsiness and hyperventilation with a concomitant respiratory alkalosis are common initial manifestations. In more serious intoxications, agitation , amnesia, bizarre behaviour, hallucinations, generalised seizures, stupor, coma and tremor or movement disorders are evident. Many of these serious neurological effects are more common in chronic than in acute salicylate intoxications (Anderson et al. 1976; Greer et al. 1965). Metabolic acidosis, resulting from accumulation of pyruvate, lactate and ketoacids, is a later manifestation of

salicylate poisoning. Hypokalaemia, hyper- or hypoglycaemia, coagulation abnormalities, fever and dehydration also occur. Noncardiogenic pulmonary oedema and adult respiratory distress syndrome are potential life-threatening complications of salicylate intoxication (Heffner & Sahn 1981; Hormaechea et al. 1979; Sorensen 1979). Similarly, congestive heart failure and cardiorespiratory arrest are uncommon but potentially fatal. Acute aspirin ingestions of 150 mg/kg or greater are potentially toxic, with ingestions above 300 mg/ kg requiring treatment in a health care facility (fig. 3). Those taking more than 100 mg/kg of aspirin daily are at risk of chronic intoxication especially in the presence of impaired renal function and dehydration: elderly people with impaired hepatic and renal function are therefore at greater risk from chronic intoxication. While serum salicylate concentrations are helpful in evaluating the severity of acute poisoning, interpretation in chronic poisoning is difficult, since adults with chronic intoxications may have higher morbidity and mortality than those with acute intoxications at similar serum salicylate concentrations (Anderson et al. 1976). Gastrointestinal decontamination can be considered up to 12 hours after ingestion since large .doses delay gastric emptying. Acid-base, dehydration, blood glucose and electrolyte status should be evaluated and corrected with intravenous fluid therapy. Therapeutic interventions include phytomenadione for coagulation abnormalities; ventilatory support, positive end-expiratory pressure (PEEP) or continuous positive airway pressure (CPAP) and diuretics for pulmonary complications; and sponging with tepid water or cooling blankets for fever. Alkalinisation of blood with sodium bicarbonate decreases salicylate concentration in the brain and other tissues (Done 1978)and may alkalinise the urine, which increases renal salicylate clearance. Severely intoxicated patients with a 6-hour serum salicylate concentration of greater than 8.69 mmol/L for an acute overdose, or refractory acidosis, progressive clinical deterioration despite therapy, or renal failure are candidates for haemodialysis. Haemodialysis will remove salicylate and correct acid-base and electrolyte abnor-

83

Po ison ing in the Elderl y

I Suspected salicylateoverdose I

I

~

Acute overdose of ~150 mglkg aspirin equivalent

I

~

I

Lavage, activated charcoal and cathartic

• •

Salicylatedose