“Seeing little people”… and tachycardia – An intentional ingestion

There are a large number of different substances to consider in the undifferentiated ingestion:

1. Household Items (toxic alcohols, rat poison, drain cleaner, etc.)
2. OTC Drugs consumed in quantities beyond their usual dosages (acetaminophen, NSAIDs, diphenhydramine, etc.)
3. Supplements (vitamins, minerals, weight loss drugs, bodybuilding supplements, etc…)
4. Drugs of abuse (ethanol, cocaine, heroin, MDMA, etc.)
5. Prescription medications (not always prescribed to the patient – opioids, AV nodal blockers, antidepressants, antipsychotics, etc.)

When evaluating these patients, since initial vitals can sometimes be misleading, you should always get a fingerstick glucose and an ECG. The patient’s vital signs are:

• P 132 min-1
• BP 90/50 mm Hg
• RR 22 min-1
• T 38ºC
• SpO2 100% on O2 via NRB

You then get the PCT to get a fingerstick glucose, which is 95 mg/dL, and you order an ECG. Your PCT asks whether it’s really necessary, but you explain that the ECG is an important screening tool for a number of possible toxic substances. This is what you get:

Just like that, you have your answer: tricyclic antidepressant (TCA) overdose. How did you figure that out so quickly? Well, you look at what is colloquially the “toxicology lead,” aVR, the most often ignored lead in cardiology (note: don’t forget to look for proximal LAD and LMCA occlusions here too)(1). Let’s zoom in on aVR:

It can be hard to make sense of what’s going on, especially regarding a baseline, so first you need to remember that aVR normally has negatively (downward) deflected T waves. Once you recognize this, you can more easily see that the QRS is borderline wide (just >120 ms), and there is a terminal R wave >3 mm. These ECG findings, along with the patient’s clinical presentation, are highly suggestive of a TCA overdose, so you will start empiric treatment(2). Had you waited for the patient’s mother to arrive, she would have said that her son doesn’t take any medicines, but upon probing further, she takes amitriptyline for migraine headaches.

Before getting into this more deeply, let’s start with a brief history of antidepressants. In the 1950s, the monoamine theory was developed after observing that reserpine was found to precipitate depression(3). Accordingly, the first monoamine oxidase inhibitor (MAOI), isopropyl-isonicotinyl hydrazide, was found to cause euphoria in tuberculosis patients; however, it was only shortly on the market due to safety concerns regarding tyramine reactions. * TCAs came next. While imipramine, the first TCA, was originally intended for use as an antipsychotic, it was found to have antidepressant rather than antipsychotic properties(3).

TCAs have a diverse side effect profile including antihistaminic, antiadrenergic, and antimuscarinic (“anti HAM”) effects. Additionally, they have a GABA-antagonistic effect through binding to the picrotoxin binding site. For these reasons, newer antidepressants with fewer side effects, like the selective serotonin reuptake inhibitors (SSRIs) and the serotonin and norepinephrine reuptake inhibitors (SNRIs), have supplanted TCAs and MAOIs(3, 4).

The anticholinergic toxidrome, hypotension, and the terminal R wave in aVR are all important clues to our patient’s diagnosis. The most common dysrhythmia of TCA toxicity is sinus tachycardia (due to the antimuscarinic effect) at 120-160/min with an ECG demonstrating QRS widening and a terminal R wave in aVR. Further, it has been shown that patients can be risk stratified based on limb lead QRS interval cutoffs: >100 ms correlates with risk of seizure and >160 correlates with risk of dysrhythmia(4, 5, 6, 7). You can also risk stratify patients by R wave amplitude and R/S ratio in aVR: R amplitude >3mm or R/S ratio of >0.7(6).  As such, a limb lead QRS >100 ms, R amplitude 4 mm, and R/S ratio 1.0 in our patient means that he is at an increased risk for complications.

So how do TCAs work? TCAs are broadly categorized as tertiary and secondary amines(4). Some of the tertiary amines themselves are metabolized into secondary amines(4). Potency varies between the various TCAs, but they generally have a similar side effect profile in therapeutic doses(4). TCAs at therapeutic doses inhibit presynaptic reuptake of norepinephrine and/or serotonin, similar to SNRIs and SSRIs. The tertiary amines are more potent reuptake inhibitors of serotonin, while the secondary amines are more potent reuptake inhibitors of norepinephrine(4). TCAs are all potent antagonists of muscarinic receptors (causing anticholinergic effects and tachycardia), alpha-1 peripheral receptors (causing hypotension), and GABA channels at the picrotoxin binding site (causing seizures).

However, some of the most serious consequences of TCA overdose are related to their cardiac effects. TCAs are myocardial fast sodium channel blockers and selectively block the right bundle branch due to its relatively longer refractory period(4). This action slows phase 0 depolarization of the action potential manifesting as QRS widening, right bundle branch block (RBBB) pattern, and a terminal R wave in aVR (which only indicates TCA ingestion and not necessarily toxicity). This often leads to wide complex tachycardia from aberrantly conducted sinus tachycardia, but can also lead to reentrant ventricular tachycardia due to prolongation of anterograde conduction with resultant nonuniform ventricular conduction(4).

TCA toxicity presents with tachycardia from the antimuscarinic effects and hypotension from direct myocardial dysfunction due to altered sodium channel function and peripheral vasodilation due to alpha-1 antagonism(4). TCAs are weak bases and likely bind the cardiac sodium channels in their ionized form; this chemical property has important ramifications for treatment of TCA toxicity, as will be seen below(4). Some patients will actually demonstrate a Brugada-like pattern from TCA binding to cardiac sodium channels, mimicking the effect of defective sodium channels that characterizes the syndrome(8).

Of course, always address the ABCs. Protect the airway by intubating early if there is CNS depression or hemodynamic instability. You should always contact and consult your local poison control center, both for epidemiological reasons and for getting speedy pointed advice and recommendations.

The mainstay of management/treatment is sodium bicarbonate – don’t just say “bicarb” because both the sodium and the bicarbonate are important components to treating TCA toxicity and its effects on cardiac sodium channels. It is theorized that the sodium component increases the sodium gradient and overwhelms the sodium channel blockade, therefore reducing QRS widening, increasing blood pressure, and preventing ventricular dysrhythmias(4). The bicarbonate component alkalinizes the serum and increases the proportion of the TCA in its non-ionized state; this reduces binding at the fast sodium channels(4).

GI decontamination is also an important element of treatment. While one should never induce emesis, one should consider performing orogastric lavage, particularly because TCA’s anticholinergic properties will delay gastric emptying. Lavage should only be performed after intubation, any patient sick enough to get intubated for his/her TCA overdose should get lavaged(4). In the intubated patient, activated charcoal (AC) should be given after lavage. It should also be considered in patients who are awake with intact sensorium and able to cooperate and don’t have an aspiration risk, multidose AC however is not recommended, a second dose can be considered for CNS symptoms(4).

Dosing of sodium bicarbonate is done generally in hypertonic concentrations. Sodium bicarbonate should be dosed 1-2 mEq/kg as a bolus every 3-5 minutes until the QRS interval has narrowed, and then a bicarbonate infusion should be started to alkalinize the serum and maintain the serum pH as close to 7.55 as possible(4, 9). An ECG should be repeated immediately after the bolus, otherwise the effect on the QRS may be missed. Hypertonic sodium chloride may be considered if the QRS interval continues to widen despite a serum pH of 7.55, but its use has not been supported by clinical trials(4). Mechanical hyperventilation is another option and often preferable in patients who develop ARDS in whom large fluid boluses would be contraindicated(4).

For the patient who develops dysrhythmias despite sodium bicarbonate, you should consider lidocaine, a class IB antidysrhythmic that will displace the more toxic TCA from the sodium channel. However, class IA and IC antidysrhythmic are absolutely contraindicated – they act almost identically to TCAs on sodium channels(4, 10). Class IIIs have only limitedly been studied, but due to their QT prolongation properties, it is generally thought that they should be avoided(4).

Hypotension should first be managed with volume expansion with crystalloids (sodium bicarbonate or hypertonic saline as mentioned above), but in the patient who is not fluid-responsive, direct-acting vasoconstrictors (norepinephrine and phenylephrine) are next line, based on the premise that neurotransmitters have been exhausted by TCA effect. However, at present, no high quality study has been performed to compare different classes of vasopressor for this indication.

For seizures, use benzodiazepines as first line agents, and barbiturates and propofol as second line. Phenytoin is ineffective for terminating toxic seizures(4), and experimental data has suggested enhanced cardiovascular toxicity, possibly due to its class IB sodium channel blocking effects(11). If seizures cannot be controlled, then neuromuscular paralysis with a paralytic agent and general anesthesia with continuous EEG monitoring should be performed(4, 11, 12).

Many have hypothesized that lipid emulsion may be a reasonable choice for treating a TCA overdose, as TCAs are highly lipophilic. Animal studies have been inconclusive(14, 15). There has been only one unpublished human RCT(13) that showed no difference in clinically meaningful outcomes with iv lipid emulsion as an adjunct to standard therapy. The study randomized 108 patients to receive sodium bicarbonate or sodium bicarbonate with intravenous lipid emulsion and showed no significant change in time needed for ECG reversal, blood pressure at the time of ECG reversal, mortality, or in length of hospitalization(14). Based on this limited data, Toxbase, the clinical toxicology database of the UK National Poisons Information Service, recommends IV lipid emulsion in patients who have failed sodium bicarbonate therapy(15). This can be be dosed 1.5ml/kg of 20% repeated every 5 minutes until cardiovascular stability restored, or an infusion of 0.25ml kg-1 min-1 for 30-60 minutes at a maximum of 12 ml kg-1.

Your patient is given sodium bicarbonate boluses immediately. He is somewhat altered, and although presently protecting his airway, he is uncooperative. His QRS is greater than 100 ms and his R/S ratio is greater than 0.7, indicating a high likelihood of seizures. In consultation with the local poison control center, you decide to intubate the patient for airway protection and start propofol for sedation and seizure prophylaxis. This also allows you to place an orogastric tube for gastric lavage and afterwards, activated charcoal. You place an arterial line for continuous hemodynamic monitoring and frequent blood gas collection. Your patient’s BP improves to 105/70 after sodium bicarbonate administration, and repeat ECG shows a normal QRS interval.

The current recommendation is at least 6 hours of continuous cardiac monitoring and serial ECGs after boluses of sodium bicarbonate until a stable QRS interval is established and can be maintained on a drip(4). People who die from TCA overdose generally do so within 6 hours of ingestion. Several retrospective studies have demonstrated that when patients have normal mental status or no signs of toxicity on presentation and normal ECG for 24 hours, they don’t develop the late, unexpected complications of dysrhythmia, seizure, and death.

The intentional overdose may be managed differently than the unintentional ingestion. Most often children or older patients mixing up their medications can go home once medically cleared. The intentional overdose typically will require admission to a psychiatric facility after medical clearance(4, 16, 17, 18). A patient should be admitted for any of the following upon presentation or within 6 hours of ingestion(19, 20).

• QRS >100 ms
• Dysrhythmia
• AMS
• Seizures
• respiratory depression
• hypotension

Your patient is resuscitated and admitted to the ICU. His perfusion remains adequate, pH is maintained between 7.50 and 7.55, and after 24 hours, the ECG is normal upon discontinuing sodium bicarbonate. The patient is extubated and transferred to the psychiatric unit. His mother has consulted her neurologist for a new medication to treat her migraines.

1. Maintain a broad differential for the agitated patient, particularly those with a possible ingestion
2. Always get a fingerstick glucose and an ECG
3. Though not indicative alone of a TCA overdose, be sure to pay attention to aVR and look out for a terminal R and QRS prolongation, particularly when coupled with anticholinergic (antimuscarinic) toxicity:
   1. Dry
   2. Non-reactive dilated pupils
   3. Febrile
   4. Tachycardia
   5. Hallucinations, often lilliputian hallucinations
   6. Agitation
4. Risk stratify your patient using QRS (seizures when QRS >100 ms, dysrhythmias when QRS >160 ms) and the R:S ratio (>0.7 predicts morbidity)
5. Treat with sodium bicarbonate 1-2 mEq/kg q3-5 minutes until the QRS narrows; consider hypertonic sodium chloride for the non-responsive patient
6. Use lidocaine as your antidysrhythmic in the event that your patient’s dysrhythmia does not respond to sodium bicarbonate,
7. Treat hypotension with volume expansion then direct-acting vasopressors
8. Treat seizures with benzodiazepines and propofol
9. Intubate patients when high risk for airway compromise, then lavage and administer activated charcoal
10. For patients unresponsive despite sodium bicarbonate infusion, consider IV lipid emulsion
11. In the unintentional ingestion, you can medically clear a patient if he/she is symptom-free for 6 hours, has normal vital signs, and has a normal QRS