Any person with a suspected or known ingestion of a CA requires immediate evaluation and treatment (Table 71–2). The patient should be attached to a cardiac monitor, and intravenous access should be secured. Early intubation is advised for patients with CNS depression and or hemodynamic instability because of the potential for rapid clinical deterioration. A 12-lead ECG should be obtained for all patients. Laboratory tests, including concentrations of glucose and electrolytes, should be performed for all patients with altered mental status, as well as blood gas analysis to both assess the degree of acidemia and guide alkalinization therapy. Aggressive interventions for maintenance of blood pressure and peripheral perfusion must be performed early to avoid irreversible damage. Both children and adults receiving cardiopulmonary resuscitation have recovered successfully despite periods of asystole exceeding 90 minutes.24,27,79,101 The options for GI decontamination discussed in the following section should then be considered.
TABLE 71–2.Treatment of Cyclic Antidepressant (CA) Toxicity ||Download (.pdf) TABLE 71–2. Treatment of Cyclic Antidepressant (CA) Toxicity
|Toxic Effect ||Treatment |
|Sinus rhythm with a QRS >100 msec || |
Sodium bicarbonate: 1–2 mEq/kg IV boluses at 3 to 5 minute intervals to reverse the abnormality or to a target serum pH ≤ 7.55
Controlled ventilation (if clinically indicated for hypoventilation)
|Wide-complex tachycardia/ventricular tachycardia || |
Sodium bicarbonate: 1–2 mEq/kg IV boluses to reverse the dysrhythmias or to a target serum pH ≤ 7.55
Correct hypoxia, acidemia, hypotension
Consider lidocaine: 1 mg/kg slow IV bolus, followed by infusion of 20–50 μg/kg/min
Consider hypertonic saline (3% sodium chloride)
Consider magnesium sulfate 25–50 mg/kg (maximum 2 g) IV over 2 min
Consider IV fat emulsion therapy 1.5 mL/kg bolus of 20%, repeated every 5 minutes until cardiovascular stability is restored; may consider infusion of 0.25 mL/kg per minute for 30 to 60 minutes with a maximum dose of 12 mL/kg
|Torsade de pointes || |
Overdrive pacing (caution due to rate dependence of CA)
|Hypotension || |
0.9% sodium chloride boluses (up to 30 mL/kg)
Correct hypoxia, acidemia
Sodium bicarbonate: 1–2 mEq/kg IV boluses to a target serum pH of ≤ 7.55
Norepinephrine in standard titrated doses
Consider IV fat emulsion therapy 1.5 mL/kg bolus of 20%, repeated every 5 minutes until cardiovascular stability is restored; may consider infusion of 0.25 mL/kg per minute for 30–60 minutes with a maximum dose of 12 mL/kg
|Seizures || |
Secure airway with intubation if necessary
Correct hypoxia, acidemia
Continuous infusion of midazolam or propofol if barbiturates fail
Consider neuromuscular paralysis/general anesthesia with EEG monitoring if all other measures fail
|Refractory poisoning || |
Consider intravenous fat emulsion in moribund patients
Consider extracorporeal mechanical circulation (extracorporeal membrane oxygenation, cardiopulmonary bypass), no evidence to support hemodialysis or hemoperfusion
Induction of emesis is contraindicated, given the potential for precipitous neurologic and hemodynamic deterioration. Because of the potential lethality of large quantities of CAs, orogastric lavage should be considered in the symptomatic patient with an overdose. Although the benefits of orogastric lavage for CA toxicity are not substantiated by controlled trials, the potential benefits of removing significant quantities of a highly toxic drug must be weighed against the risks of the procedure (Chap. 8).18 Because the anticholinergic actions of some CAs may decrease spontaneous gastric emptying, attempts at orogastric lavage up to 12 hours after ingestion may yield unabsorbed drug. Because of the potential for rapid deterioration of mental status and seizures, orogastric lavage should be performed only after endotracheal intubation has ensured airway protection. Orogastric lavage in young children with unintentional ingestions of CAs may be associated with more risk and impracticalities, such as the inadequate hole size of pediatric tubes, and less benefit given the amount of drug usually ingested. Activated charcoal should be administered in nearly all cases. Irrespective of age, an additional dose of activated charcoal several hours later is reasonable in a seriously poisoned patient in whom unabsorbed drug may still be present in the GI tract or in the case of desorption of CAs from activated charcoal. It is important to monitor for the development of an ileus to prevent abdominal complications from additional doses of activated charcoal.74
Wide-Complex Dysrhythmias, Conduction Delays, and Hypotension
The mainstay therapy for treating wide-complex dysrhythmias and for reversing conduction delays and hypotension is the combination of serum alkalinization and sodium loading. Increasing the extracellular concentration of sodium, or sodium loading, may overwhelm the effective blockade of sodium channels, presumably through gradient effects (Fig. 71–1). Controlled in vitro and in vivo studies in various animal models demonstrate that hypertonic sodium bicarbonate effectively reduces QRS complex prolongation, increases blood pressure, and reverses or suppresses ventricular dysrhythmias caused by CAs.82,92, 93, and 94 These studies showed a clear benefit of hypertonic sodium bicarbonate when compared to hyperventilation, hypertonic sodium chloride, or nonsodium buffer solutions. A systematic review of all animal and human studies published before 2001 revealed that alkalinization therapy was the most beneficial therapy for consequential dysrhythmias and shock16 (Antidotes in Depth: A5).
The optimal dosing and mode of administration of hypertonic sodium bicarbonate and the indications for initiating and terminating this treatment are unsupported by controlled clinical studies. Instead, the information is extrapolated from animal studies, clinical experience, and an understanding of the pathophysiologic mechanisms of CA toxicity. A bolus, or rapid infusion over several minutes, of hypertonic sodium bicarbonate (1–2 mEq/kg) should be administered initially.70,98 Additional boluses every 3 to 5 minutes can be administered until the QRS interval narrows and the hypotension improves (Fig. 71–2). Blood pH should be carefully monitored after several bicarbonate boluses, aiming for a target pH of no greater than 7.50 or 7.55. Because CAs may redistribute from the tissues into the blood over several hours, it may be reasonable to begin a continuous sodium bicarbonate infusion to maintain the pH in this range. Differences in outcomes between repetitive boluses versus bicarbonate infusions are not well studied. Although diluting sodium bicarbonate in 5% dextrose in water and infusing it slowly renders it less able to increase the sodium gradient across the cell, the beneficial effects of pH elevation still warrant its use once the patient is stabilized. No evidence supports prophylactic alkalinization in the absence of cardiovascular toxicity (eg, QRS < 100 msec). In addition, alkalization would inevitably cause a decrease in potassium, which may cause QT prolongation and potentially contribute to other dysrhythmias. Hypertonic sodium chloride (3% NaCl) reverses cardiotoxicity in several animal studies,47,71,82 and numerous reports and extensive clinical experience support its efficacy in humans.16,48,49,73 However, the dose of hypertonic saline for CA poisoning has never been evaluated in humans for safety or efficacy, and the dose suggested by animal studies (up to 15 mEq/kg) exceeds the amount that most clinicians would consider safe (1–2 mEq/kg). Hypertonic sodium chloride is associated with a hyperchloremic metabolic acidosis, an undesired effect that highlights one benefit of hypertonic sodium bicarbonate. However, hypertonic saline could be considered in situations in which alkalinization with sodium bicarbonate is not possible.
Hyperventilation of an intubated patient is a more rapid and easily titratable method of serum alkalinization but is not as effective as sodium bicarbonate in reversing cardiotoxicity.51,70 Simultaneous hyperventilation and sodium bicarbonate administration may result in profound alkalemia and should be performed only with extreme caution and careful monitoring of pH. Hyperventilation without bicarbonate administration may be indicated in patients with ARDS or congestive heart failure in whom administration of large quantities of sodium is contraindicated.
Alkalinization and sodium loading with hypertonic sodium bicarbonate and or hypertonic saline along with controlled ventilation (if clinically indicated) should be administered to all CA overdose patients presenting with major cardiovascular toxicity and altered mental status. Indications include conduction delays (QRS > 100 msec) and hypotension. It is imperative to initiate treatment until CA toxicity can be excluded because of the risk of rapid and precipitous deterioration. Although commonly assumed, it is unclear whether the failure of the QRS complex to narrow with sodium bicarbonate treatment excludes CA toxicity.
It is unclear whether alkalinization and sodium loading is effective for reversing the Brugada pattern. The sparse available literature is equivocal.12,77 It would seem prudent to administer sodium bicarbonate in the presence of a presumed CA-induced Brugada pattern, especially with concomitant signs of other CA toxicity.
Alkalinization may be continued for at least 12 to 24 hours after the ECG has normalized because of the redistribution of the drug from the tissue. However, the time observed for resolution or normalization of conduction abnormalities is extremely variable, ranging from several hours to several days, despite continuous bicarbonate infusion.62 We recommend stopping alkalinization when the patient’s mental status improves and there is improvement, but not necessarily normalization, of abnormal ECG findings.
Lidocaine is the antidysrhythmic most commonly advocated for treatment of CA-induced dysrhythmias, although no controlled human studies demonstrate its efficacy.86 Because lidocaine has sodium channel blocking properties, some investigators argue against its use in CA poisoning.1 These theoretical concerns are not well supported in the literature, and the class IB antidysrhythmic channel binding kinetics may prove favorable. Although limited data also suggest that the IB antidysrhythmic phenytoin prevents or reverses conduction abnormalities,43,69 these data were poorly controlled for other confounding factors, such as blood pH and sodium bicarbonate administration; they had very small numbers; and, in some, the cardiotoxicity was not severe. Since phenytoin exacerbates ventricular dysrhythmias in animals21 and fails to protect against seizures,10 its use is no longer recommended.
The use of class IA (quinidine, procainamide, disopyramide, and moricizine) and class IC (flecainide, propafenone) antidysrhythmics is absolutely contraindicated because they have similar pharmacologic actions to CAs and thus may worsen the sodium channel inhibition and exacerbate cardiotoxicity. Class III antidysrhythmics (amiodarone, bretylium, and sotalol) prolong the QT interval and, although unstudied, may be contraindicated as well (Chap. 64).
Because magnesium sulfate has antidysrhythmic properties, it may be beneficial in the treatment of ventricular dysrhythmias. Animal studies of the effects of magnesium on CA-induced dysrhythmias yield conflicting results.52,53 However, successful use of magnesium sulfate in the treatment of refractory ventricular fibrillation after TCA overdose is reported.24,27,54,91 A case control study suggested that magnesium sulfate and sodium bicarbonate resulted in lower fatality incidence and shorter intensive care unit stay compared to sodium bicarbonate alone.29 When dysrhythmias fail to reverse after alkalinization, sodium loading, and a trial of lidocaine, or magnesium sulfate may be warranted.
Slowing the heart rate in the presence of CAs may allow more time during diastole for CA unbinding from sodium channels and result in an improvement in ventricular conduction.3,92 This may abolish the reentry mechanism for dysrhythmias and was one rationale for the past use of physostigmine and propranolol. Thus, decreasing the sinus rate may itself be effective in abolishing ventricular dysrhythmias by eliminating rate-dependent conduction slowing. Propranolol terminated ventricular tachycardia in an animal model but also caused significant hypotension and death.94 In one case series, patients developed severe hypotension or had a cardiac arrest shortly after receiving a β-adrenergic antagonist.36 Other animal studies suggest that preventing or abolishing tachycardia by sinus node destruction, or by using bradycardic agents that impede sinus node automaticity without affecting myocardial repolarization or contractility, may successfully prevent CA-induced ventricular dysrhythmias.3,4 The combined negative inotropic effects of β-adrenergic antagonists and CAs, along with the significant cardiac and CNS effects reported with physostigmine use, do not support their routine use in the management of CA-induced tachydysrhythmias.
Standard initial treatment for hypotension should include volume expansion with isotonic saline or sodium bicarbonate. Hypotension unresponsive to these therapeutic interventions necessitates the use of inotropic or vasopressor support and possibly extracorporeal cardiovascular support.
No controlled human trials are available to guide the use of vasopressor therapy. The pharmacologic properties of CAs complicate the choice of a specific agent. Specifically, CA blockade of neurotransmitter reuptake theoretically could result in depletion of intracellular catecholamines. This could blunt the effect of dopamine, which is dependent on the release of endogenous norepinephrine for its inotropic activity. This suggests that a direct-acting vasopressor such as norepinephrine is more efficacious than an indirect-acting catecholamine such as dopamine.
In fact, limited clinical data suggest that norepinephrine is more efficacious than dopamine.109 In a retrospective study of 26 adult hypotensive patients receiving nonstandardized therapy, response rates to norepinephrine (5–53 μg/min) were significantly better than response rates to dopamine (5–10 μg/kg/min).110 Patients who did not respond to dopamine at vasopressor doses (10–50 μg/kg/min) responded to norepinephrine (5–74 μg/min). Animal data comparing various treatments are conflicting, and their direct applicability to clinical human poisoning is limited.32,111 Both norepinephrine and epinephrine increased the survival rate in CA-poisoned rats. In addition, epinephrine was superior to norepinephrine when used both with and without sodium bicarbonate, and the most effective treatment regimen in this study was epinephrine plus sodium bicarbonate; neither precipitated dysrhythmias. The authors propose that epinephrine is more efficacious because it augments myocardial perfusion more than norepinephrine and improves the recovery of CA sodium channel blockade by hyperpolarization of the membrane potential through its stimulation of increased potassium intracellular transport.
Based on the available data, pharmacologic effects, theoretical concerns, and experience, norepinephrine (0.1–0.2 μg/kg/min) is recommended for hypotension that is unresponsive to volume expansion and hypertonic sodium bicarbonate therapy. Central venous pressure and or pulmonary artery catheterization may be necessary to guide the choice of additional vasopressor or inotropic agents, especially in the presence of other cardiodepressant drugs.
If these measures fail to correct hypotension, extracorporeal life support measures should be considered. Extracorporeal membrane oxygenation, extracorporeal circulation, and cardiopulmonary bypass are successful adjuncts for refractory hypotension and life support when maximum therapeutic interventions fail.42,101,113 These modalities can provide critical perfusion to the heart and brain and maintain metabolic function while giving the body time to metabolize and eliminate the CA by maintaining hepatorenal blood flow.
Vasopressin is increasingly being used in the setting of vasodilatory shock with successful increases in arterial blood pressure based on its vasoconstrictive actions from several mechanisms. Its successful use for intractable hypotension due to CA toxicity, unresponsive to α-receptor agonists and pH manipulation, has been described and warrants further investigation.9
Intravenous fat emulsion is reported to be effective in reversing cardiovascular toxicity due to several lipophilic drugs including amitriptyline and clomipramine. Its utilization and effectiveness appears logical given their pharmacological properties—Log D and Log P—octanol/water partition coefficient discussed previously.
Several controlled animal studies have demonstrated improved survival in clomipramine-induced cardiovascular collapse when intravenous lipid emulsion is given either as pretreatment or resuscitation in comparison with saline controls and sodium bicarbonate infusion.44 Other animal studies failed to demonstrate any benefit.7,64 Specifically, one failed to demonstrate a statistically significant benefit in amitriptyline-poisoned rats pretreated with intravenous fat emulsion.7 Case series and case reports demonstrate clinical improvement when lipids have been administered for cardiovascular collapse or instability refractory to other therapies.38,44,50,58,99 The dosing and timing of administration are variable as well as other concomitant therapies, making it difficult to reach any definitive conclusions regarding its effectiveness. In addition, significant adverse reactions and complications have been noted including ARDS and pancreatitis. More data is emerging allowing more evidence-based criteria for its use and dosing. Certainly for patients with refractory hypotension and or ventricular dysrhythmias, fat emulsion therapy should be strongly considered, given the high mortality rate with these medications (Antidotes in Depth: A20).
Central Nervous System Toxicity
Seizures caused by CAs usually are brief and may stop before treatment can be initiated. Recurrent seizures, prolonged seizures (>2 minutes), and status epilepticus require prompt treatment to prevent worsening acidosis, hypoxia, and development of hyperthermia and rhabdomyolysis. Benzodiazepines are effective as first-line therapy for seizures. If this therapy fails, barbiturates or propofol should be administered. Propofol controlled refractory seizures resulting from amoxapine toxicity.75 Failure to respond to barbiturates or propofol should lead to consideration of neuromuscular paralysis and general anesthesia with continuous electroencephalographic monitoring. Phenytoin is not recommended for seizures because data not only demonstrate a failure to terminate seizures but also suggest enhanced cardiovascular toxicity.9,21
Use of flumazenil in a patient with known or suspected CA ingestion is contraindicated. Several case reports of patients with CA overdoses describe seizures following administration of flumazenil59 (Antidotes in Depth: A27). Physostigmine was used in the past to reverse the acute CNS toxicity of CAs (Antidotes in Depth: A9). However, physostigmine is not recommended because it may increase the risk of cardiac toxicity, cause bradycardia and asystole, and precipitate seizures in acutely CA-poisoned patients.84
No specific treatment modalities have demonstrated clinical significant efficacy in enhancing the elimination of CAs. Some investigators propose multiple doses of activated charcoal to enhance CA elimination because of their small enterohepatic and enterogastric circulation.67 Human volunteer studies and case series of patients with CA overdoses suggest that the half-life of CAs may be decreased by multiple-dose activated charcoal (MDAC).107 Activated charcoal reduced the apparent half-life of amitriptyline to 4 to 40 hours in overdose patients, compared to previously published values of 30 to more than 60 hours.107 Changes in the severity or duration of clinical toxicity, however, were not reported. Other investigators showed that in human volunteers MDAC reduced the half-life of therapeutic doses of amitriptyline approximately 20% compared with no activated charcoal administration. However, the methodologic flaws and equivocal findings of these studies and the lack of any positive outcome data for this intervention from additional studies do not provide evidence supporting its use in this setting.23,40 Pharmacokinetic properties of CAs (large volumes of distribution, high plasma protein binding) weighed against the small increases in clearance and the potential complications of MDAC, such as impaction, intestinal infarction, and perforation, do not warrant its routine use.23,74 One additional dose of activated charcoal may be given to decrease GI absorption in patients with evidence of significant CNS and cardiovascular toxicity if bowel sounds are present.
Measures to enhance urinary CA excretion have a minimal effect on total clearance. Urinary alkalinization does not enhance, and may reduce, urinary clearance due to passive reabsorption of the unionized CA from an alkaline urine. Hemodialysis is ineffective in enhancing the elimination of CAs because of their large volumes of distribution, high lipid solubility, and extensive protein binding.45 Hemoperfusion overcomes some of the limitations of hemodialysis but may not be effective because of the large volumes of distributions of CAs. Although several uncontrolled case reports and a case series described improvement in cardiotoxicity during hemoperfusion, this finding may be coincidental.13,24,35
Hospital Admission Criteria
All patients who present with known or suspected CA ingestion should undergo continuous cardiac monitoring and serial ECG for a minimum of 6 hours. Recommendations in the older literature for 48 to 72 hours of intensive care unit monitoring even for patients with minor CA ingestions stem from isolated case reports of late-onset dysrhythmias, CNS effects, and sudden deaths.83 However, review of these cases shows inadequate GI decontamination, inadequate therapeutic interventions, and significant ongoing complications of overdose. Several retrospective studies demonstrate that late, unexpected complications in CA overdoses such as seizures, dysrhythmias, and death did not occur in patients who had few or no major signs of toxicity at presentation or a normal level of consciousness and a normal ECG for 24 hours.20,27,30,85 A disposition algorithm has been proposed based on clinical signs and symptoms.6,108 If the patient is asymptomatic at presentation, undergoes GI decontamination, has normal ECGs, or has sinus tachycardia (with normal QRS complexes) that resolves, and the patient remains asymptomatic in the health care facility for a minimum of 6 hours without any treatment interventions, the patient may be medically cleared for psychiatric evaluation (if appropriate) or discharged home as appropriate.
A prospective study of 67 patients used the Antidepressant Overdose Risk Assessment (ADORA) criteria to identify patients who were at high risk for developing serious toxicity and proposed criteria for hospitalization.33 In this study, the presence of QRS interval greater than 100 msec, cardiac dysrhythmias, altered mental status, seizures, respiratory depression, or hypotension on presentation to the ED (or within 6 hours of ingestion, if the time was known) was 100% sensitive in identifying patients with significant toxicity and subsequent complications. Criteria specific for intensive care unit admission (other than patients requiring ventilatory and or blood pressure support), versus an inpatient bed with continuous cardiac monitoring, are less clear and probably are institution dependent.103
The disposition of patients with persistent isolated sinus tachycardia, prolonged QT interval with no concomitant altered mental status, or blood pressure changes, is not clearly defined. Previous studies demonstrate that these two parameters alone are not predictive of subsequent clinical toxicity or complications.33,34 In addition, the sinus tachycardia may persist for up to one week following ingestion. However, a study of isolated CA overdose patients reported that a heart rate greater than 120 beats/min and QT interval greater than 480 msec were associated with an increased likelihood of major toxicity.22 These patients are candidates for observation units with continuous ECG monitoring and serial ECGs for 24 hours.
Inpatient Cardiac Monitoring
The duration of cardiac monitoring in any patient initially exhibiting signs of major clinical toxicity depends on many factors. Certainly the duration of CA cardiotoxicity and neurotoxicity may be prolonged, and using normalization of ECG abnormalities as an end point for therapy and discharge is problematic. Some studies document the variable resolution and normalization of QRS prolongation and T40-msec axis rotation.81,97 Based on the available literature, it is reasonable to recommend that after the mental status and blood pressure normalize, and the ECG improves, patients who exhibited significant poisoning should be monitored for another 24 hours off of all of therapy, including alkalinization, antidysrhythmics, and inotropics/vasopressors.