The ECG shows:

• Regular broad complex tachycardia
• Rate 130 bpm
• Right axis deviation (+120 degrees)
• Hidden P waves buried in the ST-segments / T waves (best seen in leads II, aVF). These could be retrograde P waves from a junctional / ventricular rhythm or sinus P waves with an extremely long PR interval (360ms)
• Very broad QRS complexes (160ms)
• Terminal R wave in aVR > 3mm; R/S ratio in aVR > 0.7
• Atypical RBBB pattern in V1-2 (bizarre morphology with left rabbit ear higher than the right)
• QT 400ms with markedly prolonged QTc 590 ms
• Non-specific T wave abnormalities with T-wave inversions in V1-2 & lead III

The combination of tachycardia, QRS and QTc prolongation, right axis deviation and terminal R wave in aVR > 3mm is highly specific for poisoning with sodium-channel blocking drugs, in particular the tricyclic antidepressants.

This patient had attempted suicide by deliberate self-poisoning with around 35mg/kg of Doxepin (a tricyclic antidepressant) an hour prior to presentation.

In overdose, the tricyclics produce rapid onset (within 1-2 hours) of:

• Sedation and coma
• Seizures
• Hypotension
• Tachycardia
• Broad complex dysrhythmias
• Anticholinergic syndrome

Tricyclics mediate their cardiotoxic effects via blockade of myocardial fast sodium channels (QRS prolongation, tall R wave in aVR), inhibition of potassium channels (QTc prolongation) and direct myocardial depression. Other toxic effects are produced by blockade at muscarinic (M1), histamine (H1) and α₁-adenergic receptors.

The degree of QRS broadening on the ECG is correlated with adverse events:

• QRS > 100 ms is predictive of seizures
• QRS > 160 ms is predictive of ventricular arrhythmias (e.g. VT)

The risk assessment for Doxepin ingestion is as follows:

• < 5mg/kg — Minimal symptoms
• 5-10 mg / kg — Drowsiness and mild anticholinergic effects; major toxicity not expected
• > 10 mg / kg — Potential for all major toxic effects to occur within 1-2 h of ingestion
• > 30 mg / kg — Severe toxicity with pH-dependent cardiotoxicity and coma expected to last > 24 h

An overdose of this magnitude (> 30 mg/kg) is likely to be rapidly fatal without intervention.

Management:

• This patient needs to be managed in a monitored area equipped for airway management and resuscitation.
• Secure IV access, adminster high flow oxygen and attach monitoring equipment.
• Administer IV sodium bicarbonate 100 mEq (1-2 mEq / kg); repeat every few minutes until BP improves and QRS complexes begin to narrow.
• Intubate as soon as possible.
• Hyperventilate to maintain a pH of 7.50 – 7.55.
• Once the airway is secure, place a nasogastric tube and give 50g (1g/kg) of activated charcoal.
• Treat further seizures with IV benzodiazepines (e.g. diazepam 5-10mg).
• Treat hypotension with a crystalloid bolus (10-20 mL/kg). If this is unsuccessful in restoring BP then consider starting vasopressors (e.g. noradrenaline infusion).
• If arrhythmias occur, the first step is to give more sodium bicarbonate. Lidocaine (1.5mg/kg) IV is a second line agent once pH is > 7.5.
• Avoid Ia (procainamide) and Ic (flecainide) antiarrhythmics, beta-blockers and amiodarone as they may worsen hypotension and conduction abnormalities.
• Admit the patient to the intensive care unit for ongoing management.

The ingestion of two unidentified tablets by a toddler is a challenging scenario.

With a completely well looking child, it is tempting to be reassured. Indeed most of the time the child will be completely fine. However, depending on whether the tablets were actually ingested, and the nature of the tablets, there is the potential for life-threatening toxicity. If there are tablets left over, these may be identifiable  – but it may not be wise to assume that the ingested tablets were all the same…

Risk assessment in pediatric poisoning can be difficult because ingestion is often unwitnessed, making the determination of dosage and time of ingestion inaccurate, and often the exact agent ingested is uncertain.

Risk assessment, at least initially should be based on the ‘worst case scenario’:

• assume the time of ingestion is the latest time possible.
• assume all agents that are unaccounted for or missing were ingested.
• spillage is difficult to estimate – do not try to account for it.
• when more than one child is involved, assume that each child ingested all of the unaccounted for agent(s).

Consulting the Poison information Centre is always a good idea!

The exact drugs on the ‘two pills can kill’ list will vary from place to place. In Australia they includes:

• Sodium channel blockers
  • chloroquine (and hydroxychloroquine)
  • dextropropoxyphene
  • propanolol
  • tricyclic antidepressants
  • diphenoxylate/ atropine
• Calcium channel blockers
  • verapamil, diltiazem
• Theophylline SR
• Sulfonylureas
• Recreational sympathomimetic drugs
  • amphetamines and ecstasy
• Opiates
  • methadone
  • morphine
  • oxycodone

Early toxicity (within a few hours)

• Sodium channel blockers:
• tricyclics, chloroquine, dextropropoxyphene, propanolol
• Amphetamines and ecstasy

Delayed toxicity

• Up to 8 hours for hypoglycemia from sulfonylurea toxicity
• Up to 12 hours for slow release formulations of:
  • Calcium channel blockers
  • Opioids
  • Theophylline SR

• Amphetamines and ecstasy
  • agitation, confusion, hypertension, hyperthermia
• Calcium channel blockers
  • delayed onset of bradycardia, hypotension, conduction defects, refractory shock
  • see Toxicology Conundrum #028: Verapamil and high-dose insulin euglycemic therapy
• Chloroquine
  • rapid onset of coma, seizures and cardiovascular collapse
• Dextropropoxyphene
  • ventricular tachycardia
• Opioids
  • coma, respiratory depression. May be delayed with controlled-release morphine or diphenoxylate/ atropine
  • see Toxicology Conundrum #006: Buprenorphine
• Propanolol
  • coma, seizures, ventricular dysrhythmias, hypoglycemia
• Sulfonylureas
  • hypoglycemia
• Theophylline SR
  • seizures, supraventricular tachycardia, vomiting
  • see Toxicology Conundrum #014: Theophyline
• Tricyclic antidepressants
  • coma, seizures, hypotension, ventricular dysrhythmias
  • see Toxicology Conundrum #022: Tricyclic antidepressant

If there are no immediate life-threats or resuscitation issues then the following management principles apply:

• Admit for at least 12 hours observation.
• Admit to a health facility that has the appropriate resources to observe, resuscitate and treat the child if evidence of toxicity occurs
• IV access can be deferred until early evidence of toxicity is apparent
• Check bedside glucose level:
  • on presentation
  • if there is any clinical evidence of hypoglycemia
  • and at discharge
• Staff looking after the patient should be briefed on the clinical features for which the patient is being observed
• Monitor the following:
  • level of consciousness
  • vital signs (pulse rate, blood pressure and respiratory rate)
  • early clinical features of hypoglycemia
• Perform an ECG and institute cardiac monitoring if there is any abnormality of conscious state or vital signs, or the child appears unwell
• Only discharge the patient during the day

In this case, I would not perform decontamination at this stage.

Decontamination in pediatric poisonings should never be a routine procedure. The decision to decontaminate should only be made if the benefits are thought to outweigh the risks. It is rarely indicated in asymptomatic children with normal vital signs, even if the risk assessment is based on the ‘worst case scenario’.

However decontamination should be performed if there is clinical evidence of early toxicity that may be life-threatening, or if the risk assessment indicates that supportive care and antidotal therapy alone will not be sufficient to ensure a good outcome.

Tricyclic antidepressants (TCAs) overdoses are Australia’s major cause of drug ingestion fatality.

TCAs are weak bases (typically with pKa of ~8.5) that act as noradrenaline and serotonin reuptake inhibitors and GABA-A receptor blockers.

Cardiotoxic effects primarily result from blockade of inactivated fast sodium channels in a use-dependent manner (blockade is higher at faster heart rates).

This can result in life-threatening dysrhythmias. Of secondary importance is reversible inhibition of potassium channels and direct myocardial depression.

Other toxic effects result from blockade of muscarinic (M1), histaminergic (H1), and peripheral alpha1-adrenergic receptors.

Sodium channel activation states

The patient has ingested 50 mg/kg of amitriptyline.

• >10 mg/kg is potentially life-threatening.
• >30 mg/kg is expected to result in severe toxicity with pH-dependent cardiotoxicity and coma lasting >24 hours.

Expected clinical manifestations of 50 mg/kg amitriptyline include:

rapid deterioration within 1-2 hours of ingestion – even if the patient is alert with a normal ECG on arrival.

• Delayed effects may result from anticholinergic-mediated delayed gastric emptying or extended release amitriptyline.

central nervous system

• sedation and coma tend to precede cardiotoxicity
• seizures
• delirium (anticholinergic)

cardiovascular

• sinus tachycardia and possible mild hypertension initially
• hypotension (alpha-blocking effects and myocardial depression)
• broad complex tacydysrrhythmia
• broad complex bradycardia occurs pre-arrest

anticholinergic effects

• may occur on present or may be delayed and prolonged
• agitation, restlessness, delirium
• mydriasis
• dry, warm flushed skin
• urinary retention
• tachycardia
• ileus
• myoclonic jerks

The important ECG findings suggestive of TCA toxicity are:

QRS widening (>100 ms)  and right axis deviation of the terminal QRS

In combination, these findings are almost pathognomic of sodium channel blockade:

• Right axis deviation of the terminal QRS is defined by:
  • terminal R wave >3 mm in aVR, or
  • R/S ratio >0.7 in AVR
• QRS widening
  • >100 ms is associated with seizures
  • >160 ms is associated with cardiac dysrhythmias

A right bundle branch block pattern may be found. Tachycardia is often present as a result of the anticholinergic effects of TCAs or as a reflex response to alpha1-blockade mediated hypotension. Bradycardia in the context of a massive TCA overdose is generally a pre-terminal event.

Finally, the ECG can be normal if the dose ingested was sub-toxic or if the patient has presented early.

Learn more:

LITFL ECG Library — Tricyclic antidepressant overdose

Sodium bicarbonate

• most conveniently used as 50 mmol/50 mL single use pre-filled syringes for rapid administration.
• also available as 100 mmol/ 100 mL vials.

The mechanisms for the therapeutic effect are multifactorial and poorly understood. Any or all of the following mechanisms may have role:

1. Plasma alkalinization and TCA plasma protein binding
2. Intracellular alkalosis and TCA receptor binding
3. Intracellular hypopolarization
4. Sodium load
5. Correction of metabolic acidosis
6. Volume loading
7. Other pharmacokinetic effects

These potential mechanisms are discussed in (exhaust-ive/ing!) detail below:

1. Plasma alkalinization and TCA plasma protein binding

Plasma alkalinization promotes TCA protein binding (especially to alpha1-acid glycoprotein (AAG)), reducing the concentration of free drug available to cause sodium blockade.

• As up to 95% of the drug is protein bound (varies for different TCAs), sodium bicarbonate can make a large difference to its unbound fraction and hence its toxicity.

• Thus plasma proteins can act as a “sink” that sequesters TCAs away from the sites of toxicity (the sodium channels), until they can be redistributed to peripheral tissues.

The capacity for plasma protein binding to TCAs in an overdose setting depends on many factors but their clinical significance is unknown:

• The amount of TCA to bind.
• The amount of TCA that binds to each AAG protein (up to 2 to 14 times the AAG concentration)
• The amount of AAG there is in the circulation.
• The degree to which the binding capacity (and the affinity of different binding sites) changes with change in pH.

Other factors may play a role such as variation in the distribution of different TCAs between RBCs and the plasma, the effects of age and disease-states on AAG concentration, and perhaps even lipid levels in the blood.

However, pH change is effective in the absence of protein in experimental models, so mechanisms other than the effects of protein binding must be important.

2. Intracellular alkalosis and TCA receptor binding

Intracellular alkalosis increases the unbinding rate of TCAs from the sodium channel receptor as a result of increased lipid solubility. This promotes dissociation of the neutral form of the drug from the TCA receptor site in the sodium channel.

• The ionized form of TCAs binds the inactivated voltage-depended sodium channel and is trapped in the channel; this leads to sodium channel blockade.
• Alkalinisation favours the nonionized state which does not become bound and trapped in the sodium channel and can thus diffuse through the plasma membrane.
• Presumably the TCA must enter the intracellular space prior to binding the sodium channel as much of the effect of bicarbonate is lost if the cellular bicarbonate pump is blocked to prevent the intracellular accumulation of bicarbonate (Wang’s protein-free perfused heart model).

3. Intracellular hypopolarization

High bicarbonate leads to high extracellular pH. This, in turn, results in proton-potassium exchange across plasma membranes leading to low extracellular potassium concentration/ high intracellular potassium concentration and hypopolarization that decreases sodium channel blockade by voltage-dependent drug-binding changes.

4. Sodium load

Sodium load has a secondary positive effect by over-riding sodium channel blockade due to an increased sodium concentration gradient  across the cell membrane.

• Hypertonic saline was  more efficacious than alkalinization at improving cardiac conduction and hypotension in a swine model.
• There are case reports of good responses to rapidly administered boluses of hypertonic saline in TCA toxicity, whereas in a case report of a slow infusion there was no effect.

5. Correction of metabolic acidosis

Plasma alkalinisation also counters the metabolic acidosis caused by TCAs. Severe metabolic acidosis is potentially fatal on its own if severe. This may also help reduce tachycardia, and thus decrease use-dependent Na channel blockade.

6. Volume loading

The volume effects of sodium bicarbonate may have benefit in the shocked patient, by ameliorating the consequences of shock and allowing more widespread distribution of TCAs to tissues other than the heart and CNS.

7. Metabolism, tissue distribution, excretion, and urinary alkalinization

The effects of alkalinization on hepatic metabolism and tissue distribution are not well understood.

In the context of sodium bicarbonate use, tissue distribution is likely to be important (as alluded to above).

• The early toxicity of TCAs results from the initially high plasma concentrations (rapid oral absorption leads to peak levels within 2 hours) and rapid distribution to highly perfused organs (brain and heart).
• Increased protein binding may allow time for redistribution to other peripheral organs such as skeletal muscle and adipose tissue.

Metabolism and elimination are probably much less important.

• TCAs are cytochrome P450 metabolized and undergo saturation in an overdose settling, leading to a prolonged half-life.
• Similarly they are highly lipid-soluble and widely distributed leading to a high volume of distribution and thus a long elimination half-life.

TCAs typically undergo some degree of enterohepatic circulation.

Urine alkalinization does not confer any therapeutic benefit.

• Renal excretion of TCAs is typically <10% as the active molecules are highly lipid-soluble and undergo extensive metabolism.
• High pH will DECREASE ionization of TCAs, the opposite of what would be necessary to trap TCAs in the urine (and I don’t think trying to acidify the urine is a good idea!)

Indications for sodium bicarbonate in tricyclic antidepressant overdose:

Severe cardiotoxicity

• cardiac arrest
• ventricular dysrhythmias
• hypotension resistant to fluid challenge

Consider for prevention of severe cardiotoxicity resulting from:

• seizure – leads to metabolic acidosis
• prolonged intubation attempts – leads to respiratory acidosis

Administration of sodium bicarbonate:

If cardiac arrest or arrhythmia and haemodynamically unstable(hypotension) then:

• sodium bicarbonate 100 mmol (2 mmmol/kg) bolus every few minutes while monitoring the effect on ECG until haemodynamically stable
• the optimal total dose is “enough” (to reverse cardiotoxicity)

Once stable after resuscitation:

• consider further sodium bicarbonate to maintain pH 7.5- 7.55 based on hourly ABGs and QRS width (aim for <100 ms)

if there is ongoing arrhythmia, QRS >140 ms, or hypotensionthen options include:

• repeat sodium bicarbonate boluses or
• sodium bicarbonate infusion(100 mmol in 1L normal saline at 250 mL/h) and adjust the rate based on hourly ABGs
  • Boluses of sodium bicarbonate are likely to be more effective than infusions because they will lead to rapid shifts in the concentration of free drug
  • Sodium bicarbonate infusions may lead to renal compensation for metabolic alkalosis reducing their effectiveness

It is often prudent to consider a bolus of sodium bicarbonate prior to intubation to counter the effects of increased acidosis while ventilation is ceased.

Most patients with severe toxicity will be intubated and sodium bicarbonate infusions may be unnecessary if the patient can be hyperventilated to a target of pH 7.5-7.55.

Plasma alkalinization can be stopped once the ECG and haemodynamic parameters have normalized.

• There may be a theoretical risk of relapse of cardiotoxicity as a result of further TCA unloading from plasma proteins if sufficient time has not been given to allow TCA redistribution to the more poorly perfused tissues
• Ongoing monitoring is essential, although the precise duration is uncertain and requires clinical judgment

• Resuscitation -
  Manage patient in an area equipped for cardiorespiratory monitoring and resuscitation.

Potential life threats are:

• coma
• respiratory acidosis
• seizures
• cardiac dysrhythmia
• cardiac arrest

Do not stop resuscitation until intubated, treated with sodium bicarbonate, and pH >7.5 (or until the change of shift…)
Consider extreme measures such as extracorporeal membrane oxygenation and circulatory assist devices in extremis.
Good neurological outcome can be achieved even after many hours of cardiac arrest with effective CPR.

Ventricular dysrhythmias

• treat with sodium bicarbonate
• cardioversion and defibrillation are unlikely to be successful
• type 1a antiarrhythmics (e.g. procainimide), amiodarone, and beta-blockers are contra-indicated.
• hypertonic saline, intralipid and even high-dose insulin euglycemic therapy (HIET) are unproven therapeutic measures that should be considered in refractory cases.

Seizures

• benzodiazepines (e.g. diazepam 5-10 mg IV)
• sodium bicarbonate (seizure-induced metabolic acidosis may worsen TCA cardiotoxicity)
• rapid sequence intubation and ventilation

Hypotension

• IV crystalloid (10-20 ml/kg) boluses
• vasopressors such as noradrenaline (if alpha-blockade is thought to be contributing)
• sodium bicarbonate

CNS depression

• prompt intubation at the onset of CNS depression (e.g. GCS<12) – consider a bolus of sodium bicarbonate prior to intubation to guard against worsening acidosis.
• Hyperventilate intubated patients to pH 7.50-7.55

• Supportive care and monitoring -
  general measures, including indwelling urinary catheterisation and continuous cardiac monitoring.
• Investigations -
  Screening tests in deliberate self-poisoning – ECG, glucose, paracetamol level
  Other investigations may be indicated according to progress/ comorbidities/ possible complications (e.g. chest radiograph, ABG)
• Decontamination -
  Activated charcoal can be given in TCA ingestions >10 mg/kg, but only after the airway is secured by endotracheal intubation.
• Enhanced elimination – nil
• Antidotes -
  sodium bicarbonate (see Q3-5)
• Disposition -
  This patient will need intubation and ventilation and should be admitted to ICU.