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Home , Paracetamol poisoning, Quinidine

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England and Wales 1960–1997. Br J Cardiovascular effects . T ricyclics retard 2000;176:64–7. phase 0 cardiac depolarisa tion by 3Hawton K, Clements A, Simkin S, inhibiting channels. The delay in Malmberg A. Doctors who kill themselves: a study of the methods used for suicide. propagation of depolarisation in the QJM 2000;93:351–7. atrioventricular (AV) node, His-Purkinje 4Oyefeso A, Ghodse H, Clancy C, Corkery fibres and ventricular myocardium leads HK Ruben Thanacoody MBBS MRCP, JM. Suicide among drug addicts in the UK. to prolongation of the PR and QRS 175 Specialist Registrar Br J Psychiatry 1999; :277–82. interval (Fig 1). A right bundle branch 5Hawton K, Houston K, Shepperd R. Suicide Simon HL Thomas MD FRCP, Senior block pattern may be seen, but second- in young people. Study of 174 cases, aged Lecturer and Consultant Physician under 25 years, based on coroners’ and or third-degree AV block is uncommon. National Poisons Information Service medical records. Br J Psychiatry 1999; In more severe poisoning, ventricular (Newcastle Centre), Wolfson Unit of Clinical 175:271–6. tachycardia can occur, especially in those Pharmacology, University of Newcastle 6Roberts I, Barker M, Li L. Analysis of trends with marked QRS prolongation or in deaths from accidental drug poisoning in , and may degenerate into teenagers, 1985-95. BMJ 1997;315:289. Clin Med 2003;3:114–8 7Townsend E, Hawton K, Harriss L, Bale E, ventricular fibrillation. Bond A. Substances used in deliberate Tricyclic slow repolar- self-poisoning 1985-1997: trends and Antidepressants are involved in about isation and prolong the QT interval, associations with age, gender, repetition one in five cases of overdose. They cause predisposing to torsade de pointes . and suicide intent. Soc Psychiatry Psychiatr Epidemiol 2001;36:228–34. significant morbidity and are the second However this is uncommon; sinus tachy- 8Neeleman J, Wessely S. Drugs taken in fatal most common cause of fatal drug over- cardia is usually the underlying rhythm and non-fatal self-poisoning: a study in dose in the UK. in tricyclic poisoning, whereas torsade south London. Acta Pysychiatr Scand 1997; de pointes is a bradycardia or pause- 95 :283–7. dependent . 9Bateman DN, Bain M, Murphy D, Gorman Tricyclic antidepressants D. Epidemiology of poisoning admissions Hypotension results from a combina- in Scotland 1990– 1999. 2001; Tricyclic antidepress ants account for tion of diminished myocardial contrac- 164:42. most deaths from antidepressant over- tility and peripheral resistance. 10 Fagan E, Wannan G. Reducing dose. and are Refractory hypotension is a common overdoses. BMJ 1996;313:1417–8. particularly toxic. The mechanisms of cause of death. 11 Hickey L, Hawton K, Fagg J, Weitzel H. Deliberate self-harm patients who leave the are summarised in Table 1. accident and emergency department with- Central effects. Severe out a psychiatric assessment: a neglected neurological features include drowsiness, Clinical features population at risk of suicide. J Psychosom ataxia, hypertonia and hyperreflexia with Res 2001;50:87–93. The clinical features of tricyclic anti- extensor plantar responses. Respiratory 12 Thomas SH, Horner JE, Chew K, Connolly J et al. in the north depressants include anticholin ergic, depression and deepening coma may east of England: presentation, early cardiovascular and neurological effects. occur, especially when other CNS management and outcome. Hum Exp depressant substances have also been Toxicol 1997;16:495–500. effects. Serious anti- ingested. Severe agitation and delirium 13 Hawton K, Townsend E, Deeks J, Appleby L effects that may be associated may be present, particular ly during et al. Effects of legislation restricting pack sizes of paracetamol and salicylate on self with poisoning include ileus, urinary recovery. poisoning in the United Kingdom: before retention, confusion, and postural Convulsions occur in more than 5% of and after study. BMJ 2001;322:1203–7. hypertension. cases and are more likely if there is QRS 14 Newsome PN, Bathgate AJ, Henderson NC, prolongation. Seizures may exacerbate MacGilchrist AJ et al. Referral patterns and hypotension and trigger ventricula r social deprivation in paracetamol-induced injury in Scotland. Lancet 2001;358: by worsening and Table 1. Mechanisms of toxicity of 1612–3. hypoxia. tricyclic antidepressants (adapted from 15 Bosse GM, Matyunas NJ. Delayed Ref 1). toxidromes. Review. J Emerg Med 1999; 17:679–90. Investigations l blockade (membrane stabilising action or 1 A 12-lead ECG is essential. ‘quinidine-like’ effect) Prolongation of QRS interval l Anticholinergic activity at autonomic predicts seizures (QRS>0.10 sec) nerve endings and in the brain and ventricular arrhythmias 2 l Inhibition of (QRS>0.16 sec). A terminal R wave reuptake at nerve terminals above 3mm in lead aVR, or an l Vascular - blockade Rwave/Swave ratio of over1.4 may be a better predictor than QRS

114 Clinical Medicine Vol 3No 2March/April 2003 CME Poisons

duration but is not commonly but there is no evidence that this alkalaemia (pH >7.55) may precipitate used.3 improves clinical outcome. The current ventricular arrhythmias. 2 Arterial blood gas analysis: metabolic consensus is that activated charcoal acidosis is the most common should be given if a potentially toxic Arrhythmias. Administration of NaHCO 3 abnormality; hypoxia and other amount has been taken within onehour 4 and correction of acidosis, hypoxia and features of respiratory depression and repeated after two hours if central electrolyte abnormalities are the mainstay may also be detected. features are present. 5 of treatment. Antiarrhythmic agents may 3 Electrolytes: it is important to detect should be considered only if a potentially worsen arrhythmias by further blocking and treat hypokalaemia. life-threatening dose has been ingested sodium channels (class I) or delaying within one hour, 6 although there is no cardiac repolarisati on (class III). Measurement of plasma drug concen- clinical evidence of benefit. The airway Beta-blockers can sometimes be useful tration is clinically not useful and is less must be adequately protected. Hypoxia is but may exacerbate hypotension. predictive of complications than QRS likely to occur during the procedure; sulphate has been used in duration. arrhythmias are a significant risk both refractory ventricular fibrillation. during the procedure and for two hours Following cardiac arrest, recovery has Management afterwards. been reported after several hours of Assessment and management of tricyclic cardiopulmonary resuscitation. antidepressant overdose are summarised Sodium bicarbonate. Hypertonic sodium in Tables2 and 3, respectively. bicarbonate (NaHCO 3) is effective in Hypotension. Hypotension may respond treating QRS prolongation, ventricular to simple measures such as raising the Cardiac monitoring. Asymptomatic arrhythmias and hypotension associated foot of the bed and intravenousplasma patients should have continuous cardiac with tricyclic toxicity. 7 Alkalinisation expanders. Inotropic support may be monitoring for at least sixhours. Patients increases plasma protein binding and needed for protracted hypotension and with signs of toxicity should be moni- reduces myocardial binding and car- glucagon has been used successfully. 8 tored until these disappear and the ECG diotoxicity, while the extracellu lar Adrenergic are effective but may has been normal for 12 hours. Late sodium load also improves sodium worsen arrhythmias. Intra-aortic balloon arrhythmias do not occur once cardio- channel function. Intravenous NaHCO 3 pumping may be used in treating refrac- vascular toxicity has resolved. 8.4% in a dose of 50 ml should be given tory hypotension. over 15–20 minutes and can be repeated Gut decontamination. Gut decontamina- until the ECG normalises or the blood Convulsions. Intravenous or tion reduces systemic drug absorption, pH is greater than 7.45. Excessive should be used to control

Fig 1. ECG in severe poisoning demonstrating

I VR V1 V4 widening of the QRS complex.

II VL V2 V5

III VP V3 V6

II

Clinical Medicine Vol 3No 2March/April 2003 115 CME Poisons convulsions, avoiding which tricyclic antidepressants. Drug-specific develop within this period. Those who worsens sodium channel blockade and ovine antibody Fab fragments have given develop convulsions should be treated may exacerbate arrhythmias. Anaes- promising results but are not yet with a and have their thesia, neuromuscu lar paralysis and routinely available. 9 renal function and creatine kinase moni- mechanical ventilation should be tored. considered for refractory seizures. Selective serotonin re-uptake inhibitors Newer antidepressants Agitation. Drug-induced agitation and psychosis are common and may require The use of selective serotonin reuptake high doses of . Major inhibitors (SSRIs) in has tranquillisers should be avoided since increased markedly in line with their Mirtazapine has presynaptic alpha 2- these may exacerbate hypotension, increased prescribing . They are safer antagonist and H 1- antagonist arrhythmias and fits. than tricyclics in overdose, but occasion- activity. Limited information is available, ally cause significant toxicity. , but it appears relatively safe in overdose, Drug elimination techniques. Haemo- and drowsiness are the most its principal effect being sedation. It is dialysis, haemoperfu sion and forced common features, but convulsions, unlikely to cause convulsions. do not increase clearance due to hypotension, respiratory depression and the large volume of distribution of ECG abnormalities can occur. 10 Citalo- pram may cause prolongation of the QTinterval and QRS complex. The selective noradrena line reuptake Table 2. Assessment of tricyclic The 11 (Table 4) inhibitor reboxetine is thought to be rel- 1 antidepressant overdose. occurs occasionally. Patients taking a atively safe in overdose but human data are scarce. Hypotension, tachycardia and l Airway, breathing and circulation combination of an SSRI and tricyclic urinary retention may occur. l Intravenous access antidepressant or monoamine oxidase l Cardiac monitoring inhibitor (MAOI) are at particular risk. l ECG l U&Es Management Use of the selective serotonin and nora- l Arterial blood gas analysis Patients should not be discharged from drenaline reuptake inhibitor venlafaxine is increasing. Overdose causes sedation U&E = urea and electrolyte. hospital until six hours has elapsed since overdose because complicatio ns may and occasionally convulsions. QT interval prolongation has been reported.

1 Table 3. Management of tricyclic antidepressant overdose. Gastric decontamination (within 1 hour) Overdose of trazodone, an atypical Correct Hypoxia antidepressant, commonly causes Acidosis Electrolyte abnormalities drowsiness, nausea and vomiting. Rare complications are hypotension, respira- Hypertonic NaHCO 3 If any of the following is present: (50 ml of 8.4%) l acidosis tory failure, hyponatraemia, convulsions l widened QRS, especially if >0.16sec and prolongation of the QT interval l arrhythmias leading to torsade de pointes and cardiac l hypotension arrest. Arrhythmias Give NaHCO3 as above Avoid antiarrhythmic drugs especially class IA, IC, III Correct hypoxia, acidosis, electrolyte abnormalities Monoamine oxidase inhibitors Hypotension NaHCO3 Intravenous fluids After an MAOI overdose there is an Glucagon asymptomatic period lasting up to Consider (eg norepinephrine for non-responders) 12 hours. This is followed by sympathetic Intra-aortic balloon pumping for refractory hypotension and neuromuscular hyperactivity char- Convulsions Airway protection acterised by agitation, tremor, hyper- Benzodiazepines reflexia, hyperther mia, rigidity and Cardiac arrest Continue CPR seizures. Finally, central nervous system Magnesium for refractory VF depression and cardiovascular collapse may occur. CPR = cardiopulmonary resuscitation; NaHCO 3 = sodium bicarbonate; VF = ventricular fibrillation. Moclobemide, a reversible MAOI,

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Table 4. Clinical features of the serotonin syndrome. result of more complete distribution in body water. Altered mental status Agitation, delirium, hallucinations, drowsiness, coma) Autonomic instability Tachycardia, hyperpyrexia, hypertension or Investigations hypotension Plasma lithium concentration should be Neuromuscular hyperactivity Shivering, tremor, teeth grinding, myoclonus, hyperreflexia measured immediately in patients with Flushing symptoms or suspected chronic toxicity. Measurement should be delayed for Gastrointestinal features Diarrhoea, vomiting sixhours in asymptoma tic patients Rhabdomyolysis and renal failure following acute overdose. If severe poisoning is present or a sustained- release preparation has been taken, the measurement should be repeated every appears less toxic in overdose. It may It is important to differentiate the three 6–12 hours until the level begins to fall. cause vomiting, blood pressure changes, types of because the type The therapeutic range for lithium is typ- tachycardia and drowsiness. affects the interpretatio n of plasma ically 0.4– 1.2 mmol/l but may vary All MAOIs may give rise to the sero- lithium concentrations, prognosis and between laboratories. The ECG should tonin syndrome when taken in combina- management: be monitored in symptomatic patients. tion with an SSRI or . • acute (ieoverdose taken by patients not previously receiving lithium) Management Management • acute-on-chronic (ieacute overdose by patients already on lithium Hydration and correction of electrolyte Activated charcoal should be given by treatment), or imbalances are important. Hypotension mouth if the patient presents within chronic. and fits should be treated conventionally. onehour. Convulsions, agitation and • muscular spasm should be managed Gut decontamination . Activated charcoal with benzodiazepines. Cooling measures Clinical features is not useful. Gastric lavage may be and dantrolene can be used for hyper- These are summarised in T able 5. The considered if the patient presents within thermia. For persistent hypertensio n, correlation between serum lithium con- onehour of a potentially life-threatening a short-acting beta-blocker such as centration and the development of overdose. Sodium polystyrene or may be used. symptoms of toxicity is poor. 13 Single sulphonate and whole-bowel irrigation acute overdoses usually produce only reduce lithium absorption, but there is Lithium mild symptoms, despite high plasma no evidence that clinical outcome is lithium concentratio ns. Patients with affected by any of these interventions. Lithium is mainly used in the treatment chronic or acute-on- chronic toxicity of bipolar depressive illness, usually as a commonly develop symptoms at lower Elimination. Haemodialysis is the treat- slow-release preparation of lithium car- plasma lithium concentrations because ment of choice in serious lithium intoxi- bonate. It has a low therapeutic index tissue concentrations are higher as a cation; it is indicated when severe clinical and needs regular monitoring. Lithium is cleared from the body by the kidney (half-life 18–36 hours); it is filtered at Table 5. Clinical features of lithium toxicity. theglomerulus and reabsorbed in the Poisoning proximal tubule and loop of Henle. Lithium toxicity 12 may be provoked by System Mild/moderate Severe excessive dosing, dehydration or by drugs that affect lithium . GastrointestinalNausea, vomiting, diarrhoea Important examples are non-steroidal NeurologicalApathy , lethargy, drowsiness, Myoclonic movements, ataxia, tremor, muscle fasciculations, chorea, confusion, mania, hyper anti-inflammatory agents, diuretics blurred vision reflexia, agitation, stupor, seizures, and angiotensin-converting enzyme coma inhibitors. Lithium-induced neurotoxi- CardiovascularQT prolongation Arrhythmias ( torsade de pointes , city may occur at lower plasma concen- sinus arrest asystole), hypotension trations in the presence of SSRIs, Renal/metabolicPolyuria, hypernatraemia Acute renal failure antidepressants, , pheny- Respiratory Adult respiratory distress syndrome toin, and antipsychotic HaematologicalNeutrophil leucocytosis drugs.

Clinical Medicine Vol 3No 2March/April 2003 117 CME Poisons effects are associated with a high plasma European Association of Poisons Centres 15 Menghini VV, Albright RC Jr. Treatment of lithium concentrati on. Haemodialysi s and Clinical Toxicologists. J Toxicol Clin lithium intoxication with continuous veno- 35 should be used in all patients with severe Toxicol 1997; :721–41. venous hemodiafiltration. Am J Kidney Dis 5TOXBASE internet database, 2002. 2000;36:E21. neurotoxicity, but patients with lithium http://www.spib.axl.co.uk concentrations below 2.5 mmol/l or 6Vale JA. Position statement: gastric lavage. those without neurotoxicity and concen- Review. American Academy of Clinical trations below 4.0 mmol/l can usually be Toxicology; European Association of treated conservatively. Following dialysis, Poisons Centres and Clinical Toxicologists. JToxicol Clin Toxicol 1997;35:711–9. a rebound rise in serum lithium concen- 7Hoffman JR, Votey SR, Bayer M, Silver L. tration may occur due to redistribution Effect of hypertonic sodium bicarbonate in from tissues. High-volume continuous the treatment of moderate-to-severe cyclic venovenous haemofiltr ation has also antidepressant overdose. Am J Emerg Med 11 been used successfully and may avoid 1993; :336–41. 8Sensky PR, Olczak SA. High-dose intra- haemodynamic instability and rebound venous glucagon in severe tricyclic increases in lithium concentration after poisoning. Postgrad Med J 1999;75:611–12. dialysis.14,15 9Heard K, O’Malley GF, Dart RC. Treatment of amitriptyline poisoning with ovine anti- body to tricyclic antidepressants. Lancet References 1999;354:1614–5. 10 Barbey JT, Roose SP. SSRI safety in over- 1Kerr GW, McGuffie AC, Wilkie S. Tricyclic dose. Review. J Clin Psychiatry 1998; antidepressant overdose: a review. Emerg 59(Suppl15):42– 8. Med J 2001;18:236–41. 11 Mason PJ, Morris VA, Balcezak TJ. 2Boehnert MT, Lovejoy FH Jr. Value of the Serotonin syndrome. Presentation of 2 cases QRS duration versus the serum drug level in and review of the literature. Medicine predicting seizures and ventricular arrhyth- (Baltimore) 2000;79:201–9. mias after an acute overdose of tricyclic 12 Timmer RT, Sands JM. Lithium intoxica- antidepressants. N Engl J Med 1985;313: tion. Review. J Am Soc Nephrol 1999; 10: 474–9. 666–74. 3Liebelt EL, Francis PD, Woolf AD. ECG lead 13 Bailey B, McGuigan M. Lithium poisoning aVR versus QRS interval in predicting from a control center perspective. seizures and arrhythmias in acute tricyclic Ther Drug Monit 2000;22:650–5. antidepressant toxicity. Ann Emerg Med 14 van Bommel EF , Kalmeijer MD, Ponssen 1996;26:195–201. HH. T reatment of life-threatening lithium 4Chyka PA, Seger D. Position statement: toxicity with high-volume continuous veno- single-dose activated charcoal. Review. venous hemofiltration. Am J Nephrol 2000; American Academy of Clinical Toxicology; 20:408–11.

Key Points

Overdose with antidepressants is common and may cause significant morbidity, particularly when tricyclics, monoamine oxidase inhibitors or lithium are involved

Patients admitted with tricyclic antidepressant poisoning must have continuous cardiac monitoring. Sodium bicarbonate is important for preventing and treating complications

Selective serotonin reuptake inhibitors are relatively safe in overdose but occasionally cause convulsions, ECG abnormalities and the serotonin syndrome

Newer antidepressants are increasingly used in self-poisoning. Although safer than tricyclics in overdose, the available evidence is limited. Venlafaxine is commonly used and may cause convulsions

Lithium has a narrow therapeutic ratio and chronic toxicity may arise from drug interactions. Haemodialysis is indicated for patients with severe effects, especially neurotoxicity. Rebound increase in lithium may occur following haemodialysis

KEY WORDS: antidepressants, lithium, mirtazapine, monoamine oxidase inhibitors, overdose, poisoning, raboxetine, selective serotonin reuptake inhibitors, trazodone, tricyclic antidepressants, venlafaxine

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