Classification

Two types of ADR are recognized.

Type A (augmented) reactions (Table 17.9) are:

Table 17.9 Examples of adverse drug reactions

ACE, angiotensin-converting enzyme; SSRIs, selective serotonin reuptake inhibitors.

a In children and adolescents.

Whilst some such reactions as hypotension with ACE inhibitors may occur after a single dose, others may develop only after months (pulmonary fibrosis with amiodarone) or years (second malignancies with anti-cancer drugs).

Type B (idiosyncratic) reactions (Table 17.9) have no resemblance to the recognized pharmacological or toxicological effects of the drug. They are:

Diagnosis

All ADRs mimic some naturally occurring disease and the distinction between an iatrogenic aetiology, and an event unrelated to the drug, is often difficult. Although some effects are obviously iatrogenic (e.g. acute anaphylaxis occurring a few minutes after intravenous penicillin), many are less so. There are six characteristics that can help distinguish an adverse reaction from an event due to some other cause:

Management

As a general rule, type A reactions can usually be managed by a reduction in dosage whilst type B reactions almost invariably require the drug to be withdrawn (and never re-instituted).

Specific therapy is sometimes required for ADRs such as bleeding with warfarin (vitamin K), acute dystonias (benztropine) or acute anaphylaxis (see Emergency Box 3.1, p. 69).

Randomization

In any RCT the method of randomization should be robust. In particular, the investigator should be unaware of which treatment a patient entering a trial will receive. This avoids selection bias.

Maintaining blindness

Although, ideally, in RCTs neither the investigator nor the patient is aware of the treatment allocation until the end of the study, this is not always possible. Adverse drug reactions, for example, may make it obvious which treatment a patient has been given. Nevertheless maintaining ‘blindness’ is necessary where the outcome is subjective (e.g. relief of pain, alleviation of depression) if bias is to be avoided.

Were the treated and control groups comparable?

Were they similar in their ‘baseline’ characteristics? Were they, for example, of similar age, severity and duration of illness? If not, are the differences likely to influence the results? Has the statistical analysis (using analysis of covariance, or Cox’s proportional hazards model) (see below) tried to adjust for them? Table 17.10 shows some of the baseline characteristics of a trial comparing prednisolone with placebo in the treatment of Bell’s palsy (idiopathic facial paralysis).

Table 17.10 Summary of a multicentre randomized placebo-controlled trial of prednisolone (25 mg twice daily), for 10 days, in the treatment of Bell’s palsy

Outcomes

There are two ways to look at the outcomes of an RCT.

Ideally, there should be no difference but in reality the results of a per protocol analysis are usually more advantageous to a treatment than an intention-to-treat analysis. The reason is that the intention-to-treat analysis will take account of patients who have withdrawn from the trial because of intolerance of the treatment or adverse drug reactions. It is therefore a much more robust approach. The results of the intention-to-treat analysis, in the trial of prednisolone in Bell’s palsy, are shown in Table 17.10. The trial results indicate, with a high probability, that treatment of Bell’s palsy with prednisolone will increase the chances of a full recovery of facial nerve function.

Are the results generalizable?

Were the patients enrolled into the study a reasonable reflection of those likely to be treated in routine clinical practice (a so-called pragmatic trial)? Or were they a selected population that excluded significant patient groups (such as the elderly)? If the latter, view the results with caution.

Analysis of a superiority trial

The analysis of a superiority trial is based on the premise – the ‘null hypothesis’ – that there is no difference between the treatments. The null hypothesis is rejected if the probability of the observed result occurring by chance, the p value, is less than 1 in 20 (i.e. p < 0.05). There are three caveats.

Scrutiny of the magnitude of the effect, and its 95% confidence intervals (CI), is a far better guide than the p value.

Analysis of an equivalence trial

The aim of an equivalence trial is to determine whether two (or possibly more) treatments produce similar benefits. During the design of such trials, it is necessary to decide what difference is unimportant and then to calculate the number of patients needed in order to have an 80% or 90% chance of showing this. In equivalence trials such power calculations show that the number of patients required is invariably greater than those needed for superiority trials. In such studies the comparator itself must, of course, already have been shown to be effective.

Meta-analysis

It is possible to summate all the controlled trials that have been performed in the treatment of a particular condition so as to refine the estimate of effectiveness. This technique minimizes random error in the assessment of the effect size of a treatment because more patients are included than could be accommodated in any single trial. A meta-analysis should be performed (and interpreted) carefully because of the heterogeneity of the individual studies used in it.

Historical controlled trials

Despite the value of the prospective randomized controlled trial there are many treatments that have never been subjected to this technique, yet their efficacy is unquestioned. Examples include insulin in the treatment of diabetic ketoacidosis, thyroxine for hypothyroidism, vitamin B₁₂ in pernicious anaemia and defibrillation for ventricular fibrillation. In a historical controlled trial the outcome in patients treated with the study drug is compared to that of previously untreated people with the same disease. Treatments can be accepted into routine use on the basis of favourable comparisons with historical controls when the following criteria are met:

Case–control studies

This type of study design compares people with a particular condition (the ‘cases’) with those without (the ‘controls’). The approach has predominantly been used to identify epidemiological ‘risk factors’ for specific conditions such as lung cancer (smoking) or sudden infant death syndrome (lying prone); or in the evaluation of potential adverse drug reactions (such as deep venous thrombosis with oral contraceptives).

A case–control design allows an estimation of the odds ratio (OR), which is the ratio of the probability of an event occurring to the probability of the event not occurring (Box 17.1).

An OR that is significantly greater than unity indicates a statistical association that may be causal. The OR for deep venous thrombosis and current use of oral contraceptives equals 2–4 (depending on the preparation): this indicates that the risk of developing a deep venous thrombosis on oral contraceptives is between 2 and 4 times greater than the background rate.

In some studies, the OR for a particular observation has been found to be significantly less than unity, suggesting ‘protection’ from the condition under study. Some studies of women with myocardial infarction indicated protection in those using hormone-replacement therapies but it has been subsequently shown that the result was due to bias. On the other hand, case–control studies have consistently shown that aspirin and other non-steroidal anti-inflammatory drugs are associated with a reduced risk of colon cancer. This seems to be a causal effect.

Case–control studies claiming to demonstrate the efficacy of a drug need to be interpreted with great care: the possibility of bias and confounding is substantial as was seen in the studies of hormone-replacement therapy and myocardial infarction. Confirmation from one or more RCTs is usually essential.

Before-and-after studies

It has sometimes been inferred that observed improvements seen in patients before, and after, the application of a particular treatment is evidence of efficacy. Such an approach is fraught with difficulties: the combination of a placebo effect, as well as regression to the mean, is likely to negate most studies using this type of design. Nevertheless, there are some circumstances where genuine efficacy can be confidently observed with such designs: the consequences of hip replacement, and cataract surgery, are good examples. Such instances can be regarded as special examples of the use of implicit historical controls.

History

More than 80% of adults are conscious on arrival at hospital and the diagnosis of self-poisoning can usually be made from the history (Table 17.12). In the unconscious patient a history from friends or relatives is helpful, and the diagnosis can often be inferred from the medicine containers or a ‘suicide note’ brought by the paramedics. In any patient with an altered level of consciousness, acute poisoning must always be considered in the differential diagnosis.

Table 17.12 Diagnostic process in acute poisoning

Examination

On arrival at hospital, the patient must be assessed urgently (Airways, Breathing and Circulation). The following should be evaluated:

If the patient is unconscious, the following should also be checked:

Some of the physical signs that may aid identification of the agents responsible for poisoning are shown in Table 17.13. The cluster of features on presentation may be distinctive and diagnostic. For example, sinus tachycardia, fixed dilated pupils, exaggerated tendon reflexes, extensor plantar responses and coma suggest tricyclic antidepressant poisoning (Table 17.13 and Table 17.14).

Table 17.13 Some physical signs of poisoning

MDMA, 3,4-methylenedioxymetamfetamine.

Table 17.14 Common feature clusters in acute poisoning

Toxicological investigations

On admission, or at an appropriate time post overdose, a timed blood sample should be taken if it is suspected that aspirin, digoxin, ethylene glycol, iron, lithium, methanol, paracetamol, paraquat, quinine or theophylline has been ingested. The determination of the concentrations of these drugs will be valuable in management. Drug screens on blood and urine are occasionally indicated in severely poisoned patients in whom the cause of coma is unknown. A poison information service will advise.

Non-toxicological investigations (Table 17.17)

Some routine investigations are of value in the differential diagnosis of coma or the detection of poison-induced hypokalaemia, hyperkalaemia, hypoglycaemia, hyperglycaemia, hepatic or renal failure or acid–base disturbances (Table 17.18). Measurement of carboxyhaemoglobin, methaemoglobin and cholinesterase activities are of assistance in the diagnosis and management of cases of poisoning due to carbon monoxide, methaemoglobin-inducing agents such as nitrites and organophosphorus insecticides, respectively.

Table 17.17 Relevant non-toxicological investigations

Table 17.18 Some poisons inducing metabolic acidosis

Clinical features

Amfetamines cause euphoria, extrovert behaviour, a lack of desire to eat or sleep, tremor, dilated pupils, tachycardia and hypertension. More severe intoxication is associated with agitation, paranoid delusions, hallucinations and violent behaviour. Convulsions, rhabdomyolysis, hyperthermia and cardiac arrhythmias may develop in severe poisoning. Rarely, intracerebral and subarachnoid haemorrhage occur and can be fatal.

MDMA poisoning is characterized by agitation, tachycardia, hypertension, widely dilated pupils, trismus and sweating. In more severe cases, hyperthermia, disseminated intravascular coagulation, rhabdomyolysis, acute kidney injury and hyponatraemia (secondary to inappropriate antidiuretic hormone secretion) predominate.

Treatment

Agitation is controlled by diazepam 10–20 mg i.v. or chlorpromazine 50–100 mg i.m. The peripheral sympathomimetic actions of amfetamines are antagonized by β-adrenoceptor blocking drugs. If hyperthermia is present, dantrolene 1 mg/kg body weight i.v. is used.

Clinical features

The clinical features of poisoning with anticonvulsant drugs are summarized in Table 17.19.

Table 17.19 Clinical features of poisoning with anticonvulsant drugs

Treatment

Multiple-dose activated charcoal has been shown to significantly increase elimination of carbamazepine. Early intravenous supplementation with L-carnitine should be used in severe valproate poisoning if hepatotoxicity and encephalopathy are present. Haemodialysis should also be instituted if severe hyperammonaemia and electrolyte and acid–base disturbances occur.

Clinical features

Features after overdose may be delayed for 12–24 hours and include excitement, restlessness, hyperpyrexia, hyper-reflexia, convulsions, opisthotonos, rhabdomyolysis and coma. Sinus tachycardia and either hypo- or hypertension have also been observed.

Treatment

Treatment is supportive with control of convulsions and marked excitement; diazepam 10–20 mg i.v. should be given as necessary and repeated. Dantrolene 1 mg/kg i.v. should be administered if hyperpyrexia develops. Hypotension should be treated with plasma expansion and hypertension by the administration of an α-adrenoceptor blocker such as chlorpromazine.

Clinical features

Even large overdoses of SSRIs appear to be relatively safe unless potentiated by ethanol. Most patients will show no signs of toxicity but drowsiness, nausea, diarrhoea and sinus tachycardia have been reported. Rarely, junctional bradycardia, seizures and hypertension have been encountered and influenza-like symptoms may develop. In contrast, drowsiness, sinus tachycardia, dry mouth, dilated pupils, urinary retention, increased reflexes and extensor plantar responses are the most common features of mild tricyclic antidepressant poisoning. Severe intoxication leads to coma, often with divergent strabismus and convulsions. Plantar, oculocephalic and oculovestibular reflexes may be abolished temporarily. An ECG will often show a wide QRS interval and there is a reasonable correlation between the width of the QRS complex and the severity of poisoning. Metabolic acidosis and cardiorespiratory depression are observed in severe cases.

Treatment

The majority of patients recover with supportive therapy alone (adequate oxygenation, control of convulsions and correction of acidosis), although a small percentage of patients who ingest a tricyclic will require assisted ventilation for 24–48 hours. The onset of supraventricular tachycardia and ventricular tachycardia should be treated with sodium bicarbonate (8.4%) 50 mmol intravenously over 20 min, even if there is no acidosis present. If ventricular tachycardia is compromising cardiac output, amiodarone 300 mg i.v. over 20–60 min should be administered.

Clinical features

Features of severe hypoglycaemia include drowsiness, coma, convulsions, depressed limb reflexes, extensor plantar responses and cerebral oedema. Hypokalaemia may be associated. Neurogenic diabetes insipidus and persistent vegetative states are possible long-term complications if hypoglycaemia is prolonged. Cholestatic jaundice has been described as a late complication of chlorpropamide poisoning.

Treatment

The blood or plasma glucose concentration should be measured urgently and intravenous glucose given, if necessary. Glucagon produces only a slight rise in blood glucose, although it can reduce the amount of glucose required (see p. 1001).

Severe insulin poisoning. A continuous infusion of 10–20% glucose (with K⁺ 10–20 mmol/L) together with carbohydrate-rich meals are required, though there may be difficulty in maintaining normoglycaemia.

Sulfonylurea poisoning. The administration of glucose increases already high circulating insulin concentrations. Octreotide (50 µg i.v.), which inhibits insulin release, should be given as well as glucose.

Clinical features

Chloroquine. Hypotension is often the first clinical manifestation of chloroquine poisoning. It may progress to acute heart failure, pulmonary oedema and cardiac arrest. Agitation and acute psychosis, convulsions and coma may ensue. Hypokalaemia is common and is due to chloroquine-induced potassium channel blockade. Bradyarrhythmias and tachyarrhythmias are common and ECG conduction abnormalities are similar to those seen in quinine poisoning.

Quinine. Cinchonism (tinnitus, deafness, vertigo, nausea, headache and diarrhoea) is common. In more severe poisoning, convulsions, hypotension, pulmonary oedema and cardiorespiratory arrest is seen (due to ventricular arrhythmias which are often preceded by ECG conduction abnormalities, particularly QT prolongation). Quinine cardiotoxicity is due to sodium channel blockade. Patients may also develop ocular features, including blindness, which can be permanent.

Primaquine. The main concern regarding primaquine is its propensity to cause methaemoglobinaemia and haemolytic anaemia.

Treatment

Multiple-dose oral activated charcoal increases quinine and probably chloroquine clearance. Hypokalaemia should be corrected. Sodium bicarbonate 50–100 mmol i.v. is given if the ECG shows intraventricular block but will exacerbate hypokalaemia, which should be corrected first. Mechanical ventilation, the administration of an inotrope and high doses of diazepam (1 mg/kg as a loading dose and 0.25–0.4 mg/kg per hour maintenance) may reduce the mortality in severe chloroquine poisoning. Overdrive pacing may be required if torsades de pointes (p. 710) occurs in quinine poisoning and does not respond to magnesium sulphate infusion. If clinically significant methaemoglobinaemia (generally above 30%) develops in primaquine poisoning, methylthioninium (methylene blue) 1–2 mg/kg body weight should be administered.

Clinical features

In mild poisoning, sinus bradycardia is the only feature, but if a substantial amount has been ingested, coma, convulsions and hypotension develop. Less commonly, delirium, hallucinations and cardiac arrest supervene.

Treatment

Glucagon 50–150 µg/kg (typically 5–10 mg in an adult) followed by an infusion of 1–5 mg/h is the most effective agent. It acts by by-passing the blocked beta-receptor thus activating adenyl cyclase and promoting formation of cyclic AMP from ATP; cyclic AMP in turn exerts a direct beta-stimulant effect on the heart. Atropine 0.6–1.2 mg i.v. can be used to treat bradycardia but is usually less effective.

Clinical features

Benzodiazepines produce drowsiness, ataxia, dysarthria and nystagmus. Coma and respiratory depression develop in severe intoxication.

Treatment

If respiratory depression is present in patients who have severe benzodiazepine poisoning, flumazenil 0.5–1.0 mg i.v. is given in an adult and this dose often needs repeating. Flumazenil use often avoids ventilation. It is contraindicated in mixed tricyclic antidepressant (TCA)/benzodiazepine poisoning and in those with a history of epilepsy because it may cause convulsions.

Clinical features

Hypotension occurs due to peripheral vasodilatation, myocardial depression and conduction block. The electrocardiogram may progress from sinus bradycardia through first, then higher, degrees of block, to asystole. Cardiac and non-cardiac pulmonary oedema may ensue in severely poisoned patients. Other features include nausea, vomiting, seizures and a lactic acidosis. When a sustained-release preparation has been ingested the onset of severe features is delayed, sometimes for more than 12 hours. Overdose with even small amounts can have profound effects.

Treatment

Intravenous atropine 0.6–1.2 mg, repeated as required, should be given for bradycardia and heart block. The initial dose can be repeated every 3–5 min but if there is no response in pulse rate or blood pressure after three such doses it is unlikely that further boluses will be helpful. The response to atropine is sometimes improved following intravenous 10% calcium chloride, 5–10 mL (at 1–2 mL/min). If there is an initial response to calcium, a continuous infusion is warranted; this is given as 10% calcium chloride, 1–10 mL/h.

Cardiac pacing has a role if there is evidence of AV conduction delay but failure to capture occurs.

Treat hypotension initially with intravenous crystalloid. If significant hypotension persists despite volume replacement, administer glucagon (see p. 409) as it activates myosin kinase independent of calcium. Give i.v. glucagon 10 mg (150 µg/kg) as a slow bolus and repeat. If there is a favourable response in blood pressure, an infusion of 5–10 mg/h can be commenced; if there is no response after the initial boluses, discontinue.

Insulin–glucose euglycaemia has been shown to improve myocardial contractility and systemic perfusion. If hypotension persists despite the above measures, insulin is given as a bolus dose of 1 U/kg, followed by an infusion of 1–10 U/kg per hour with 10% glucose and frequent monitoring of blood glucose and potassium.

Acidosis impairs L-type channel function (see p. 708) and is corrected by the administration of sodium bicarbonate, which has been shown experimentally to improve myocardial contractility and cardiac output.

Clinical features

Initially there is euphoria, followed by distorted and heightened images, colours and sounds, altered tactile sensations and sinus tachycardia. Visual and auditory hallucinations and acute psychosis are particularly likely to occur after substantial ingestion in naive cannabis users. Intravenous injection leads to watery diarrhoea, tachycardia, hypotension and arthralgia.

Heavy users suffer impairment of memory and attention and poor academic performance. There is an increased risk of anxiety and depression. Regular users are at risk of dependence. Cannabis use results in an overall increase in the relative risk for later schizophrenia and psychotic episodes (see p. 1185). Cannabis smoke is probably carcinogenic.

Treatment

Reassurance is usually the only treatment required, although sedation with intravenous diazepam 10–20 mg i.v. in an adult or chlorpromazine 50–100 mg i.m. in an adult is sometimes required. Hypotension requires i.v. fluids.

Clinical features

After initial euphoria, cocaine produces agitation, tachycardia, hypertension, sweating, hallucinations, convulsions, metabolic acidosis, hyperthermia, rhabdomyolysis and ventricular arrhythmias. Dissection of the aorta, myocarditis, myocardial infarction, dilated cardiomyopathy, subarachnoid haemorrhage, and cerebral haemorrhage and infarction also occur. If a young person presents with a stroke or myocardial infarction, cocaine poisoning, because of its vasoconstrictor effect, is a possible diagnosis.

Treatment

Diazepam 10–20 mg i.v. is used to control agitation and convulsions. Active external cooling should be used for hyperthermia. Hypertension and tachycardia usually respond to sedation and cooling. If hypertension persists, give i.v. nitrates such as glyceryl trinitrate starting at 1–2 mg/h and gradually increase the dose (maximum 12 mg/h) until BP is controlled. Calcium channel blockers such as nifedipine, verapamil or diltiazem are an alternative as second-line therapy. The use of beta-blockers is controversial. Early use of a benzodiazepine is often effective in relieving cocaine-associated non-cardiac chest pain. Aspirin and nitrates should be given to all people with chest pain suspected of being cardiac in origin. Treat myocardial ischaemia/infarction conventionally.

Clinical features

These include nausea, vomiting, dizziness, anorexia and drowsiness. Rarely, confusion, visual disturbances and hallucinations occur. Sinus bradycardia is often marked and may be followed by supraventricular arrhythmias with or without heart block, ventricular premature beats and ventricular tachycardia. Hyperkalaemia occurs due to the inhibition of the sodium-potassium activated ATPase pump.

Treatment

Sinus bradycardia, atrioventricular block and sinoatrial standstill are often reduced or even abolished by atropine 1.2–2.4 mg i.v. If cardiac output is compromised, however, digoxin-specific antibody fragments (digoxin-Fab) should be administered. In both acute and chronic poisoning, only half the estimated dose (calculated from amount of drug taken or serum digoxin concentration) required for full neutralization need be given initially; a further dose is given if clinically indicated.

Clinical features

Poisoning with GHB is characterized by aggressive behaviour, ataxia, amnesia, vomiting, drowsiness, bradycardia, respiratory depression and apnoea, seizures and characteristically coma, which is short-lived.

Management

In a patient who is breathing spontaneously, the management of GHB poisoning is primarily supportive with oxygen supplementation and the administration of atropine for persistent bradycardia, as necessary. Those who are severely poisoned will require mechanical ventilation, although recovery is usually complete within 6–8 hours.

Clinical features

The initial features are characterized by nausea, vomiting (the vomit may be grey or black in colour), abdominal pain and diarrhoea. Severely poisoned patients develop haematemesis, hypotension, coma and shock at an early stage. Usually, however, most patients only suffer mild gastrointestinal symptoms. A small minority deteriorate 12–48 hours after ingestion and develop shock, metabolic acidosis, acute tubular necrosis and hepatocellular necrosis. Rarely, up to 6 weeks after ingestion, intestinal strictures due to corrosive damage occur. The serum iron concentration should be measured some 4 hours after ingestion and if the concentration exceeds the predicted normal iron binding capacity (usually >5 mg/L; 90 µmol/L), free iron is circulating and treatment with desferrioxamine is required.

Treatment

The majority of patients ingesting iron do not require desferrioxamine therapy. If a patient develops coma or shock, desferrioxamine should be given without delay in a dose of 15 mg/kg per hour i.v. (total amount of infusion usually not to exceed 80 mg/kg in 24 hours). If the recommended rate of administration is continued for several days, adverse effects including pulmonary oedema and ARDS have been reported.

Clinical features

Features of intoxication include thirst, polyuria, diarrhoea and vomiting and in more serious cases impairment of consciousness, hypertonia and convulsions; irreversible neurological damage occurs. Measurement of the serum lithium concentration confirms the diagnosis. Acute massive overdose may produce concentrations of 5 mmol/L (34.7 mg/L) without causing toxic features, whereas chronic toxicity is associated with neurological features at concentrations >1.5 mmol/L (6.94 mg/L).

Treatment

Forced diuresis with sodium chloride 0.9% is effective in increasing elimination of lithium, though haemodialysis is far superior and should be undertaken particularly if neurological features are present, if renal function is impaired and if chronic toxicity or acute on chronic toxicity are the modes of presentation.

Clinical features

These include impaired consciousness, hypotension, respiratory depression, hypothermia or hyperthermia, antimuscarinic effects such as tachycardia, dry mouth and blurred vision, occasionally seizures, rhabdomyolysis, cardiac arrhythmias (both atrial and ventricular) and acute respiratory distress syndrome. Extrapyramidal effects, including acute dystonic reactions, occur but are not dose related. Most ‘atypical’ antipsychotics have less profound sedative actions than the older neuroleptics. Q–T interval prolongation and subsequent ventricular arrhythmias (including torsades de pointes) have occurred following overdose with the atypical neuroleptics. Unpredictable fluctuations in conscious level, with variations between agitation and marked somnolence, have been particularly associated with olanzapine overdose.

Treatment

Procyclidine 5–10 mg i.v. in an adult is occasionally required for the treatment of dyskinesia and oculogyric crisis. If hypotension is severe and does not respond to intravenous fluids, a sympathomimetic amine such as noradrenaline (norepinephrine) is used. After correcting acidosis with sodium bicarbonate, the preferred treatment for arrhythmias caused by antipsychotic drugs (usually torsades de pointes) is intravenous magnesium or cardiac pacing. Amiodarone is used if multifocal ventricular arrhythmias occur.

Clinical features and treatment

In most cases minor gastrointestinal disturbance is the only feature but, in more severe cases, coma, convulsions and acute kidney injury have occurred. Transient renal impairment is common after ibuprofen overdose. Poisoning with mefenamic acid commonly results in convulsions though these are usually short-lived.

Treatment is symptomatic and supportive.

Clinical features

Cardinal signs of opiate poisoning are pinpoint pupils, reduced respiratory rate and coma. Hypothermia, hypoglycaemia and convulsions are occasionally observed in severe cases. In severe heroin overdose, non-cardiogenic pulmonary oedema has been reported.

Treatment

Naloxone 1.2–2.0 mg i.v. will reverse at least partially severe respiratory depression and coma. In severe poisoning larger initial doses or repeat doses will be required. The duration of action of naloxone is often less than the drug taken in overdose, e.g. methadone, which has a very long half-life. For this reason an infusion of naloxone is often required. Non-cardiogenic pulmonary oedema should be treated with mechanical ventilation.

Clinical features

Following the ingestion of an overdose of paracetamol, patients usually remain asymptomatic for the first 24 hours or at the most develop anorexia, nausea and vomiting. Liver damage is not usually detectable by routine liver function tests until at least 18 hours after ingestion of the drug. Liver damage usually reaches a peak, as assessed by measurement of alanine transferase (ALT) activity and prothrombin time (INR), at 72–96 hours after ingestion. Without treatment, a small percentage of patients will develop fulminant hepatic failure. Acute kidney injury due to acute tubular necrosis occurs in 25% of patients who have severe hepatic damage and in a few without evidence of serious disturbance of liver function.

Treatment

The treatment protocol is dependent on the time of presentation and this is summarized in Table 17.20. Acetylcysteine has emerged as an effective protective agent provided that it is administered within 8–10 hours of ingestion of the overdose. It acts by replenishing cellular glutathione stores, though it may also repair oxidation damage caused by NAPQI. The treatment regimen is shown in Table 17.21. If a staggered overdose has been taken (multiple ingestions over several hours), acetylcysteine should be given when the paracetamol dose exceeds 150 mg/kg body weight in any one 24-hour period or 75 mg/kg body weight in those at high risk (see above).

Table 17.20 Management of people with paracetamol poisoning

Table 17.21 Regimen for acetylcysteine

Up to 15% of patients treated with intravenous acetylcysteine (20.25-h regimen) develop rash, angio-oedema, hypotension and bronchospasm. These reactions, which are related to the initial bolus, are seldom serious and discontinuing the infusion is usually all that is required. In more severe cases, chlorphenamine 10–20 mg i.v. in an adult should be given.

If liver or renal failure ensues, this should be treated conventionally though there is evidence that a continuing infusion of acetylcysteine (continue 16-h infusion until recovery) will improve the morbidity and mortality. Liver transplantation has been performed successfully in patients who have paracetamol-induced fulminant hepatic failure (see p. 316).

Clinical features

Salicylates stimulate the respiratory centre, increase the depth and rate of respiration, and induce a respiratory alkalosis. Compensatory mechanisms, including renal excretion of bicarbonate and potassium, result in a metabolic acidosis. Salicylates also interfere with carbohydrate, fat and protein metabolism, and disrupt oxidative phosphorylation, producing increased concentrations of lactate, pyruvate and ketone bodies, all of which contribute to the acidosis.

Thus, tachypnoea, sweating, vomiting, epigastric pain, tinnitus and deafness develop. Respiratory alkalosis and metabolic acidosis supervene and a mixed acid–base disturbance is observed commonly. Rarely, in severe poisoning, non-cardiogenic pulmonary oedema, coma and convulsions ensue.

The severity of salicylate toxicity is dose-related.

Treatment

Fluid and electrolyte replacement is required and special attention should be paid to potassium supplementation. Severe metabolic acidosis requires at least partial correction with the administration of sodium bicarbonate intravenously. Mild cases of salicylate poisoning are managed with parenteral fluid and electrolyte replacement only. Patients whose plasma salicylate concentrations are in excess of 500 mg/L (3.62 mmol/L) should receive urine alkalinization (see p. 913). Haemodialysis is the treatment of choice for severely poisoned patients (plasma salicylate concentration >700 mg/L; >5.07 mmol/L), particularly those with coma and metabolic acidosis.

Clinical features

Nausea, vomiting, hyperventilation, haematemesis, abdominal pain, diarrhoea, sinus tachycardia, supraventricular and ventricular arrhythmias, hypotension, restlessness, irritability, headache, hyperreflexia, tremors and convulsions have been observed. Hypokalaemia probably results from activation of Na⁺/K⁺ ATPase. A mixed acid–base disturbance is common. Most symptomatic patients have plasma theophylline concentrations in excess of 25 mg/L (430 µmol/L). Convulsions are seen more commonly when concentrations are >50 mg/L (>860 µmol/L). Plasma potassium concentrations of <2.6 mmol/L, metabolic acidosis, hypotension, seizures and arrhythmias are indications of severe poisoning.

Treatment

There is good evidence that multiple-dose (12.5 g/h) activated charcoal enhances the elimination of theophylline. However, protracted theophylline-induced vomiting may mitigate the benefit of this therapy, unless vomiting is suppressed by a 5HT₃ antagonist such as ondansetron 4–8 mg i.v. Correction of hypokalaemia to prevent or treat tachyarrhythmias is of great importance. A non-selective β-adrenoceptor blocking drug, such as propranolol, is also useful in the treatment of tachyarrhythmias secondary to hypokalaemia, but should not be given if the patient has severe airways disease. Convulsions should be treated with diazepam 10–20 mg i.v. in an adult.

Clinical features

Symptoms of mild to moderate exposure to carbon monoxide may be mistaken for a viral illness. A peak carboxyhaemoglobin (COHb) concentration of less than 10% is not normally associated with symptoms and peak COHb concentrations of 10–30% usually result only in headache and mild exertional dyspnoea. Higher concentrations of COHb are associated with coma, convulsions and cardiorespiratory arrest. Metabolic acidosis, myocardial ischaemia, hypertonia, extensor plantar responses, retinal haemorrhages and papilloedema also occur. Neuropsychiatric features may develop after apparent recovery from carbon monoxide exposure.

Treatment

In addition to removing the patient from carbon monoxide exposure, high flow oxygen should be administered using a tightly fitting face mask. Endotracheal intubation and mechanical ventilation is required in those who are unconscious. Several controlled studies of hyperbaric oxygen have been published but none have shown long-term clinical benefit.

Clinical features

Inhalation of hydrogen cyanide produces symptoms within seconds and death within minutes. By contrast, the ingestion of a cyanide salt may not produce features for 1 hour. After exposure initial symptoms are non-specific and include a feeling of constriction in the chest and dyspnoea. Coma, convulsions and metabolic acidosis may then supervene.

Treatment

Oxygen should be administered and, if available, dicobalt edetate 300 mg should be administered intravenously; the dose is repeated in severe cases. Dicobalt edetate (and the free cobalt contained in the preparation) complexes free cyanide. An alternative but expensive antidote is hydroxocobalamin, which enhances endogenous cyanide detoxification mechanisms: 5 g i.v. is administered, and a second dose may be required in severe cases. If these two antidotes are not available sodium thiosulphate 12.5 g i.v., which acts by enhancing endogenous detoxification, and sodium nitrite 300 mg i.v. should be administered. Sodium nitrite produces methaemoglobinaemia; methaemoglobin combines with cyanide to form cyanmethaemoglobin.

Clinical features

In children in particular severe hypoglycaemia may accompany alcohol intoxication due to inhibition of gluconeogenesis. Hypoglycaemia is also observed in those who are malnourished or who have fasted in the previous 24 hours. In severe cases of intoxication, coma and hypothermia are often present and lactic acidosis, ketoacidosis and acute kidney injury have been reported.

Treatment

As ethanol-induced hypoglycaemia is not responsive to glucagon, i.v. glucose 10–20% should be infused at a rate determined by the blood sugar. Haemodialysis is used if the blood ethanol concentration exceeds 7500 mg/L and if a severe metabolic acidosis is present, which has not been corrected by i.v. fluids and bicarbonate.

Clinical features

Initially, the features of ethylene glycol poisoning are similar to ethanol intoxication (though there is no ethanol on the breath). Coma and convulsions follow and a variety of neurological abnormalities, including nystagmus and ophthalmoplegias, are seen. Severe metabolic acidosis, hypocalcaemia and acute kidney disease are well-recognized complications. In diethylene glycol poisoning nausea and vomiting, headache, abdominal pain, coma, seizures, metabolic acidosis and acute kidney injury commonly occur. Pancreatitis and hepatitis, together with cranial neuropathies and demyelinating peripheral neuropathy, are also seen.

Treatment

If the patient presents early after ingestion, the first priority is to inhibit metabolism using either intravenous fomepizole or ethanol; the former does not require monitoring. Fomepizole 15 mg/kg body weight should be administered followed by four 12-hourly doses of 10 mg/kg, then 15 mg/kg every 12 hours until glycol concentrations are not detectable. Following a substantial ingestion, haemodialysis or haemodialfiltration should be employed to remove the glycol and metabolites. If dialysis is employed the frequency of fomepizole dosing should be increased to 4-hourly because fomepizole is dialysable. Alternatively, a loading dose of ethanol 50 g should be administered followed by an i.v. infusion of ethanol 10–12 g/h to produce blood ethanol concentrations of 500–1000 mg/L (11–22 mmol/L). The infusion is continued until the glycol is no longer detectable in the blood. If haemodialysis is employed, the rate of ethanol administration will need to be increased to 17–22 g/h as ethanol is dialysable. Supportive measures to combat shock, hypocalcaemia and metabolic acidosis should be instituted.

Clinical features

If the ingestion is accidental, features very rarely occur except in the case of petroleum distillates where aspiration is a recognized complication because of their low surface tension. Powder detergents, sterilizing tablets, denture cleaning tablets and industrial bleaches (which contain high concentrations of sodium hypochlorite) are corrosive to the mouth and pharynx if ingested. Nail polish and nail polish remover contain acetone that may produce coma if ingested in substantial quantities. Inhalation by small children of substantial quantities of talcum powder has occasionally given rise to severe pulmonary oedema and death.

Clinical features

Mild intoxication may result in no more than lethargy and occasional abdominal discomfort, though abdominal pain, vomiting, constipation and encephalopathy (seizures, delirium, coma) may develop in more severe cases. Encephalopathy is more common in children than in adults but is now rare in the developed world. Typically, though very rarely, lead poisoning results in foot drop attributable to peripheral motor neuropathy. A bluish discoloration of the gum margins due to the deposition of lead sulphide is observed occasionally.

The characteristic haematological features include:

Treatment

The social and occupational dimensions of lead poisoning must be recognized. Simply giving the patient chelation therapy and then returning them to a contaminated environment is of no value.

The decision to use chelation therapy is based not only on the blood lead concentration but on the presence of symptoms. Parenteral sodium calcium edetate 75 mg/kg per day has been the chelating agent of choice for over 50 years, but there is now evidence to suggest that oral DMSA 30 mg/kg per day is of similar efficacy. At least 5 days’ treatment is usually required.

Clinical features

Inhalation of acute mercury vapour causes headache, nausea, cough, chest pain, bronchitis and occasionally pneumonia. Proteinuria and nephrotic syndrome are observed rarely. In addition a fine tremor and neurobehavioural impairment occurs and peripheral nerve involvement has also been observed. Ingestion of inorganic and organic mercury compounds causes an irritant gastroenteritis with corrosive ulceration, bloody diarrhoea and abdominal cramps and may lead to circulatory collapse and shock. Mercurous compounds are less corrosive and toxic than mercuric salts.

Treatment

Dimercaptopropanesulphonate (DMPS) is the antidote of choice and is given intravenously in a dose of 30 mg/kg per day. At least 5 days’ treatment is usually required.

Clinical features

Methanol causes inebriation and drowsiness. After a latent period coma supervenes. Blurred vision and diminished visual acuity occur due to formate accumulation. The presence of dilated pupils that are unreactive to light suggests that permanent blindness is likely to ensue. A severe metabolic acidosis may develop and be accompanied by hyperglycaemia and a raised serum amylase activity. A blood methanol concentration of 500 mg/L (15.63 mmol/L) confirms severe poisoning. The mortality correlates well with the severity and duration of metabolic acidosis. Survivors may show permanent neurological sequelae including parkinsonian-like signs as well as blindness.

Treatment

Treatment is similar to that of ethylene glycol poisoning (see p. 921) with the addition of folinic acid 30 mg i.v. 6-hourly, which accelerates formate metabolism thereby reducing ocular toxicity.

Clinical features

Systemic features include increased salivation, rhinorrhoea, bronchorrhoea, miosis and eye pain, abdominal pain, nausea, vomiting and diarrhoea, involuntary micturition and defecation, muscle weakness and fasciculation, tremor, restlessness, ataxia and convulsions. Bradycardia, tachycardia and hypotension occur, dependent on whether muscarinic or nicotinic effects predominate. Death occurs from respiratory failure within minutes but mild or moderately exposed individuals usually recover completely. Diagnosis is confirmed by measuring the erythrocyte cholinesterase activity

Treatment

The administration of atropine 2 mg i.v. repeated every 3–5 min as necessary to patients presenting with rhinorrhoea and bronchorrhoea may be life-saving. In addition, an oxime should be given to all patients requiring atropine as soon as possible after exposure before ‘ageing’ has occurred. For example, pralidoxime chloride 30 mg/kg i.v., followed by an infusion of pralidoxime chloride 8–10 mg/kg per hour; alternatively boluses of pralidoxime chloride 30 mg/kg may be given 4- to 6-hourly. Intravenous diazepam 10–20 mg, repeated as required, is useful in controlling apprehension, agitation, fasciculation and convulsions.

Clinical features

Poisoning is characterized by anxiety, restlessness, tiredness, headache, and muscarinic (cholinergic) features such as nausea, vomiting, abdominal colic, diarrhoea, tenesmus, sweating, hypersalivation and chest tightness. Miosis may be present. Nicotinic effects include muscle fasciculation and flaccid paresis of limb muscles, respiratory muscles, and, occasionally of extraocular muscles. Respiratory failure will ensue in severe cases and is exacerbated by the development of bronchorrhoea and pulmonary oedema. Coma and convulsions occur in severe poisoning. Diagnosis is confirmed by measuring the erythrocyte cholinesterase activity; plasma cholinesterase activity is less specific but may also be depressed. Delayed polyneuropathy is a rare complication of acute exposure to some OP insecticides not marketed in most countries. It is initiated by phosphorylation and subsequent ageing of at least 70% of neuropathy target esterase (NTE) in peripheral nerves.

The intermediate syndrome usually becomes established 2–4 days after exposure when the symptoms and signs of the acute cholinergic syndrome are no longer obvious. The characteristic features of the syndrome are weakness of the muscles of respiration (diaphragm, intercostal muscles and accessory muscles including neck muscles) and of proximal limb muscles. Accompanying features often include weakness of muscles innervated by some cranial nerves.

Treatment

Mild cases require no specific treatment other than the removal of soiled clothing. Atropine 2 mg i.v. should be given every 3–5 min if necessary to reduce increased secretions, rhinorrhoea and bronchorrhoea. Symptomatic patients should also be given an oxime (pralidoxime, obidoxime or HI-6) to reactivate inhibited acetylcholinesterase: for example, pralidoxime chloride 30 mg/kg by slow i.v. injection followed by an infusion of pralidoxime mesylate 8–10 mg/kg per hour.

Clinical features

Ingestion causes vomiting, epigastric pain, peripheral circulatory failure, severe metabolic acidosis, acute kidney injury and disseminated intravascular coagulation, in addition to the features induced by phosphine. Exposure to phosphine causes lacrimation, rhinorrhoea, productive cough, breathlessness, chest tightness, dizziness, headache, nausea and drowsiness. Acute pulmonary oedema, hypertension, cardiac arrhythmias, convulsions and jaundice have been described in severe cases. Ataxia, intention tremor and diplopia are found on examination.

Treatment

Treatment is symptomatic and supportive. Gastric lavage should not be used as it can increase the rate of disintegration of the product ingested and increase toxicity. Activated charcoal may bind metal phosphides. The mortality is high despite supportive care.

Clinical features and treatment

The most common symptoms are nausea, vomiting, abdominal cramps, headache, diarrhoea and short-term memory loss. Axonal sensory motor neuropathy, seizures, coma and death have also been reported. Treatment is symptomatic and supportive.

Clinical features and treatment

The predominant symptoms are diarrhoea, nausea, vomiting and abdominal pain. Symptoms tend to occur between 30 minutes and a few hours after shellfish consumption, with patients recovering within 2–3 days. Treatment is symptomatic and supportive.

Clinical features and treatment

The symptoms of neurotoxic shellfish poisoning occur within 30 minutes to 3 hours, last a few days and include nausea, vomiting, diarrhoea, chills, sweats, reversal of temperature, hypotension, arrhythmias, numbness, tingling, paraesthesiae of the lips, face and extremities, cramps, bronchoconstriction, paralysis, seizures and coma. Treatment is symptomatic and supportive.

Clinical features and treatment

Symptoms develop within 30 minutes. The illness is characterized by paraesthesiae of the mouth, lips, face and extremities and is often accompanied by nausea, vomiting and diarrhoea. In more severe cases, dystonia, dysphagia, muscle weakness, paralysis, ataxia and respiratory depression occur. In one outbreak involving 187 cases, there were 26 deaths. Treatment is symptomatic and supportive.

Clinical features and treatment

The onset of symptoms occurs from a few minutes to 30 hours after ingestion of toxic fish. Typically features appear between one and six hours and include abdominal cramps, nausea, vomiting and watery diarrhoea. In some cases, numbness and paraesthesiae of the lips, tongue and throat occur. Other features described include malaise, dry mouth, metallic taste, myalgia, arthralgia, blurred vision, photophobia and transient blindness. In more severe cases, hypotension, cranial nerve palsies and respiratory paralysis have been reported. Treatment is symptomatic and supportive. Recovery takes from 48 hours to 1 week in the mild form and from 1 to several weeks in the severe form. The mortality in severe cases may be as high as 12%.

Clinical features and treatment

Clinically, the mean incubation period is 30 min. The illness is characterized by flushing, headache, sweating, dizziness, burning of the mouth and throat, abdominal cramps, nausea, vomiting and diarrhoea and is usually short-lived; the mean duration is 4 hours. Treatment is symptomatic and supportive. Antihistamines may alleviate the symptoms.

Clinical features and treatment

Local pain occurs followed by myalgia, nausea, griping abdominal pain, dyspnoea and even death. The cluster of severe systemic symptoms that constitute the Irukandji syndrome occur some 30 min after the jellyfish sting. The symptoms include severe low back pain, excruciating muscle cramps in all four limbs, the abdomen and chest, sweating, anxiety, restlessness, nausea, vomiting, headache, palpitations, life-threatening hypertension, pulmonary oedema and toxic global heart dilatation.

Adhesive tape may be used to remove any tentacles still adherent to the bather. Local application of 5% acetic acid is said to prevent stinging cells adherent to the skin discharging. Local analgesia and antihistamine creams provide symptomatic relief. Other features should be treated symptomatically and supportively.

Clinical features and treatment

Severe pain occurs immediately at the site of puncture, followed by swelling. Signs of systemic involvement, which may be delayed for 24 hours, include vomiting, sweating, piloerection, abdominal colic, diarrhoea. In some cases, depending on the species, shock, respiratory depression and pulmonary oedema may develop.

Local infiltration with anaesthetic or a ring block will usually alleviate local pain, though systemic analgesia may be required. Specific antivenom, if available, should be administered as soon as possible.

Clinical features and treatment

The bite quickly becomes painful and generalized muscle pain, sweating, headache and shock may occur. No systemic treatment is required except in cases of severe systemic toxicity, when specific antivenom should be given, if this is available.

Clinical features

Viperidae (Viperinae and Crotalinae)

Russell’s viper causes most of the snake-bite mortality in India, Pakistan and Myanmar. There is local swelling at the site of the bite (Fig. 17.7) which may become massive. Local tissue necrosis may occur. Evidence of systemic involvement (envenomation) occurs within 30 minutes, including vomiting, evidence of shock and hypotension. Haemorrhage due to incoagulable blood can be fatal.

Figure 17.7 Snake bite showing swelling at site.

Treatment

As a first aid measure, a firm pressure bandage should be placed over the bite and the limb immobilized. This may delay the spread of the venom. Arterial tourniquets should not be used, and incision or excision of the bite area should not be performed. Local wounds often require little treatment. If necrosis is present, antibiotics should be given. Skin grafting may be required later. Antitetanus prophylaxis must be given. The type of snake should be identified if possible.

In about 50% of cases, no venom has been injected by the bite. Nevertheless, careful observation for 12–24 hours is necessary in case envenomation develops. General supportive measures should be given, as necessary. These include intravenous fluids with volume expanders for hypotension and diazepam for anxiety. Treatment of acute respiratory, cardiac and kidney injury is instituted as necessary.

Antivenoms are not generally indicated unless envenomation is present, as they can cause severe allergic reactions. Antivenoms can rapidly neutralize venom, but only if an amount in excess of the amount of venom is given. Large quantities of antivenom may be required. As antivenoms cannot reverse the effects of the venom, they must be given early to minimize some of the local effects and may prevent necrosis at the site of the bite. Antivenoms should be administered intravenously by slow infusion, the same dose being given to children and adults.

Allergic reactions are frequent, and adrenaline (epinephrine) 1 in 1000 solution should be available. In severe cases, the antivenom infusion should be continued even if an allergic reaction occurs, with subcutaneous injections of adrenaline being given as necessary. Some forms of neurotoxicity, such as those induced by the death adder, respond to anticholinesterase therapy with neostigmine and atropine.

Clinical features and treatment

Intense watery diarrhoea starts 8–24 hours after ingestion and persists for 24 hours or longer. Patients often become severely dehydrated. Signs of liver damage appear during the 2nd day and hepatic failure may ensue. Impaired kidney function is often seen both because of fluid loss and as a result of direct kidney injury. In all patients, fluid, electrolyte and acid–base disturbances should be corrected and renal and hepatic function supported. The value of silibinin and benzylpenicillin is not proven. Occasionally, liver transplantation is necessary.

Clinical features and treatment

Vapours from the mushrooms are irritating to the eyes and respiratory tract. Gastrointestinal symptoms appear 5–8 hours after exposure. Vertigo, sweating, diplopia, headache, dysarthria, incoordination and ataxia may follow. Symptomatic and supportive care are required. Pyridoxine 25 mg/kg as an infusion over 30 min, should be given if severe CNS toxicity develops; repeat doses may be required.

Clinical features and treatment

Symptoms occur within 20–60 min. Effects include altered time and space sense, depersonalization, hallucinations, derealization and euphoria. Symptoms are usually maximal within 2 hours and disappear within 4–6 hours, though ‘flashbacks’ may recur after weeks or months. Anxiety and agitation should be treated with diazepam, 10–20 mg i.v., repeated if necessary.

Clinical features and treatment

Nausea, vomiting, inebriation, euphoria, confusion, anxiety, visual disturbances and hallucinations occur often within 30 minutes. Severe agitation and violent behaviour are occasionally seen. Other features include myoclonic jerks, muscle fasciculation, seizures and coma. Symptomatic and supportive care should be given as necessary. Diazepam, 10–20 mg, repeated as required, should be administered for anxiety, agitation and seizures.

Clinical features and treatment

Diarrhoea, abdominal pain, diaphoresis, salivation, lacrimation, miosis, bronchorrhoea, bronchospasm, bradycardia and hypotension occur. Atropine, 0.6–2 mg i.v. should be given to manage the cholinergic syndrome.

Clinical features and treatment

Symptoms are typically delayed for 2–4 days. Some patients suffer a mild gastrointestinal disturbance before developing signs of renal impairment, headache, fatigue, intense thirst, chills, muscular discomfort, and abdominal, lumbar and flank pain. Transient polyuria with proteinuria, haematuria and, characteristically, leucocyturia is followed by oliguria and then anuria. Renal function may recover only partially; chronic kidney disease is reported in about 10–40% of cases. Management involves careful monitoring and haemodialysis/haemofiltration if renal failure supervenes. Renal transplantation may be required.