Roberts, James R. MD
Learning Objectives: After reading this article, the physician should be able to:
1. Discuss the classic EKG findings of tricyclic antidepressant cardiotoxicity (TCA).
2. Formulate an empiric treatment regimen based on EKG findings.
3. Summarize the relevance of EKG findings in the overdosed patient.
Release Date: September 2009
Brugada and Wellens' syndromes are not your everyday EKG findings, and even when present, emergency clinicians may not detect them. If you're perceptive enough to spot either, you will certainly look like a pro. This month's EKG standout is tricyclic antidepressant toxicity. This tracing routinely baffles the computer, many residents, and even the cardiology fellow.
Electrocardiographic Criteria for Tricyclic Antidepressant Cardiotoxicity
Niemann JT, et al
Am J Cardiol
This is an older but classic article written during the heyday of TCA cardiotoxicity. It evaluated 25 patients with suspected TCA overdose and analyzed EKG findings. Subjects negative for TCAs by urine testing were considered controls. This study reported the then-obscure now well known EKG findings that excessive TCAs can induce. In its time, that was cutting-edge information, but now is standard knowledge and well described in the emergency medicine literature.
The authors found a significant increase in heart rate and increased duration of the QRS and QTc intervals in TCA-ingesting patients vs. controls. A curious but consistent rightward change in the frontal plane QRS vector also was reported. This latter finding is otherwise known as a large R wave in AVR, and not much else causes such striking changes in this lead. This EKG vector is apparently quite sensitive for TCA toxicity, and is more sensitive than the more nonspecific tachycardia or prolonged QRS or QTc. The EKG findings in TCA overdose vs. controls are highlighted in the table. Via a Bayesian probability analysis, the diagnostic efficiency of the EKG was 97 percent. Interestingly, all TCA-positive patients had a sinus tachycardia. This is one of the first papers stating that an EKG has diagnostic sensitivity in unknown or suspected TCA overdose. As a footnote, these patients had minor changes when compared with critically ill patients who have similar but much more impressive changes.
Comment: Taking a bottle of one of the many tricyclic antidepressants used to be a death sentence and often still is. Not even the best toxicologist in the world can save a patient once his TCA overdose precipitates ventricular fibrillation, severe hypotension, or seizures. The majority of deaths occur in the prehospital phase or in less than a few hours, and toxicity progresses with almost unprecedented speed when compared with other cardiovascular toxins. Most patients who survive the first six to eight hours of a TCA overdose can be saved, but there may be significant morbidity with the best of care.
Figure. An EKG can p...Image Tools
An unconscious patient rarely telegraphs much information concerning his overdose. Seasoned clinicians use subtle clues to hone their diagnostic acumen. While the novice eagerly awaits the arrival of the offending pill bottles or drug screen, the erudite EP uses the EKG. An EKG is useful in evaluating many drug overdoses. One can be a medical celebrity by picking up a prolonged QTc in an opioid overdose secondary to methadone or bidirectional ventricular tachycardia in a clandestine digoxin overdose. The EKG of TCA toxicity is quite striking, and should be etched in the mind of all acute care physicians. One can initiate aggressive empiric therapy, which is benign if mistaken, based on EKG findings alone. Perhaps one might snatch the patient from the jaws of death with proper and aggressive intervention. One need not know the specific overdose, but empiric therapy for TCA poisoning is supported by the EKG findings if one is astute enough to consider those pernicious squiggles emanating from the EKG machine.
There is no true antidote for TCA overdose, but this EKG screams for intravenous sodium bicarbonate, alkalinization of the serum, aggressive sedation for seizure control (huge doses of benzodiazepines are probably best), and avoiding medications such as procainamide that can make the situation worse.
One word of caution: Hyperkalemia also can widen the QRS complex and is life-threatening, but significant hyperkalemia rarely produces tachycardia. A serious propoxyphene or fluoride overdose can mimic a TCA EKG. And cocaine is a sodium channel blocker as well. Before disaster intervenes, the initial subtle TCA toxicity findings also can be gleaned by the clinician on top of his game. Just look for a prolonged QTc/QRS interval, the ubiquitous tachycardia, and especially the once-seen-never-forgotten, impossible-to-ignore ARV lead findings.
Fortunately, many depressed patients now benefit from SSRIs and other non-TCA antidepressants so the nascent physician may not be quite as familiar as the seasoned veteran with the classic EKG changes. Once recognized and treated, I have been amazed by the alacrity with which the QRS complex narrows. It's important to continue the bicarbonate drip to maintain the serum pH around 7.5. This may not always be possible. Just remember that it's not alkalinization of the urine, the approach for salicylate or phenobarbital poisoning, it's alkalinization of the serum when it comes to TCA poisoning. The benefit of sodium bicarbonate is probably a combination of sodium channel blockade override and increased protein binding of free drug. Regardless of the obscure pathophysiology, sodium bicarbonate seems to work like a charm. There is no proven benefit of other antiarrhythmics, many of which can exacerbate EKG manifestations. The sodium channel blockade is reminiscent of quinidine toxicity, demonstrating this drug's effectiveness of blocking sodium channels and adversely affecting phase O of the cardiac cell depolarization.
You will not see these findings with SSRI overdose or even a massive overdose with the newer atypical antipsychotics. Parenthetically, quetiapine (Seroquel) overdose is almost always associated with a sinus tachycardia, but not the serendipitous QTc-, QRS-, AVR-, and TCA-related changes.
I can't emphasize enough the rapid deterioration one sees with a TCA overdose. This is one of the few overdoses that can progress from a merely anxious yet still talking and oriented individual who just downed a bottle of Elavil to one who suddenly becomes very agitated, has a grand mal seizure, and then dies right in front of you, all in minutes. Severe agitation or a seizure is common prior to cardiac arrest, probably worsening acidosis that subsequently increases free TCA in the serum. Agitation should be approached aggressively with appropriate sedation. Benzodiazepines are safe and usually effective if you give enough.
A QRS of more than 100 msec and a rightward terminal 40 ms AVR lead seem to be sensitive harbingers of cardiovascular toxicity, although they are only moderately sensitive and specific for predicting final outcome. When this article was published in 1986, TCA toxicity accounted for almost 40 percent of all poison-related ICU admissions. Today, EM residents may see only a few dramatic cases during training. Even the experienced attending needs to be vigilant, ensuring that the occasional symptomatic TCA OD garners his full and immediate attention.
Table. EKG Criteria ...Image Tools
In my experience as a toxicologist and having seen countless patients with severe and even fatal TCA overdoses in the 1980s and 1990s, a tall R wave in AVR is almost a sentinel event for making a clinical diagnosis of TCA poisoning. Once recognized as a prognosticator of bad things to come, it's one of the first things to look for in a symptomatic overdose patient. Tachycardia and prolonged QTc are universal with many medical conditions and drug effects, but this unusual AVR vector change was a relatively new finding when this study was presented. Before that observation, most of us totally ignored the lowly AVR lead.
The diagnosis of TCA toxicity is relatively straightforward when confirmed by a simple immunoassay drug screen. Even a single therapeutic dose will produce a positive TCA analysis for 24 to 48 hours. Of course, a drug screen is only qualitative, and does not define overdose versus therapeutic effect. Many false positives crop up for TCA analysis on the routine immunoassay urine drug screen (e.g., various antihistamines, cyclobenzaprine [Flexeril], quetiapine, and carbamazepine [Tegretol]). One does not need the drug screen, however, to consider a clinical diagnosis.
The mean heart rate in this study was only 117±13 beats per minute, although heart rates from 140 to 160 are not uncommon in severe overdose. I know of no way to decrease heart rate, and because it's a sinus tachycardia, there seems to be no need to try to alter the rate by itself. When the QRS widens and the rate increases, a TCA-poisoned patient with a sinus tachycardia can be misdiagnosed as having ventricular tachycardia. I have seen cardiologists look at this tracing and the EKG computer, and diagnose it as VT due to the rapid wide complex tachycardia.
Figure. Note that th...Image Tools
It is likely that the anticholinergic effects of TCAs produce the tachycardia, but I have seen some rather toxic TCA overdoses that did not manifest severe tachycardia.
Value of the QRS Duration versus the Serum Drug Level in Predicting Seizures and Ventricular Arrhythmias after an Acute Overdose of Tricyclic Antidepressants
Boehnert M, Lovejoy FH
New Engl J Med
Although quantitative serum TCA levels are never available to real clinicians, have no diagnostic significance anyway, and have essentially no value in directing intervention, it is generally concluded that the higher the serum level, the greater the toxicity. This is considered a classic article, and these authors relate serum TCA levels to ventricular arrhythmias and seizures following TCA overdose. As with almost any other academic attempt to predict toxicity from drug levels, the authors were unable to assign a useful predictive value of serum TCA levels.
As others have noted, all patients with a seizure or ventricular arrhythmia had characteristic TCA toxic manifestation within six hours of ingestion or not at all. The QRS duration likewise peaked within six hours. After 24 hours, all patients remained stable even with continued serum TCA levels in excess of 1000 ng/ml. There was poor correlation between serum TCA levels and serious symptoms over a wide range (329-4873 ng/ml). In this report, the QRS duration was much more predictive of toxicity than serum levels. Based on the QRS complex, the authors stratify risk as:
▪ Negligible: QRS less than 100 msec.
▪ Moderate: 100–160 msec
▪ High risk for seizures and ventricular arrhythmias: greater than 160 msec.
Importantly, this prognostic value seems to diminish after 24 hours.
There are many TCAs currently available, and one size does not fit all, but total TCA levels (parent drug plus active metabolite) greater than 1000 ng/ml were generally associated with toxicity in this report. It's a waste of time to send such levels in the ED, and they appear to be only of interest to the pathologist who unfortunately misinterprets them frequently and fails to account for the massive and unpredictable post-mortem redistribution that occurs with TCAs. The vagaries and vicissitudes of post-mortem drug testing do not allow for an accurate autopsy determination of pre-mortem levels, let alone assign a specific cause of death in all but the most straightforward cases. Nonetheless, the medical examiners continue to pontificate.
As an example, the classic textbook, Disposition of Toxic Drug and Chemicals in Man (Randall C. Baselt, ed., Foster City, CA: Chemical Toxicology Institute; 1994), describes the toxicology of amitriptyline (Elavil, Endep) with so-called toxic levels that are all over the map. One must interpret “fatal blood levels” of any drug found at autopsy with great caution. The true toxicologist deems post-mortem drug analysis an interesting finding that must be correlated with many parameters and a modicum of voodoo, but it is basically a toxicology nightmare. While some simple correlations do hold true, interpreting post-mortem drug levels is a difficult task and hardly an exact science.
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Dr. Roberts: Your article on Brugada syndrome (EMN 2009;31:9) was eye-opening and informative. My question pertaining to the article rests in what to do with these patients. As you mentioned, most bureaucrats say syncope is an outpatient diagnosis, and I tend to agree for young healthy patients.
I diagnose “incomplete RBBB” all the time! Should I be consulting cardiology on all these patients for Brugada pattern? Can these patients be discharged with cardiology followup for a work-up of Brugada pattern and not call them all the time? These lead to sticky situations because this is something we see all the time. I'd appreciate any advice you have. — Scott Goldstein, DO, Hershey, PA
Dr. Roberts: As usual, a fascinating article on Brugada syndrome. With regard to the incidence, the numbers quoted are not consistent with your statements that it appears much more commonly in Asian populations and that the incidence is much lower in Europe and the United States. Twelve of 10,000 people in Japan (0.12%) would seem to be about equal to the 0.1 percent to 0.2 percent quoted for the U.S. Caucasian and Hispanic populations. Perhaps the U.S. incidence is less or the Asian incidence is greater?
The EKG characteristics of this syndrome are so nonspecific it would seem that the diagnosis may almost never be made by EKG alone (although that Type I EKG is pretty attention-grabbing), but rather will only be made when one of the other manifestations occurs or has occurred, and an astute physician puts a new EKG together with that item of past medical history, quite a challenge but potentially life-saving if it can be done. In a 30-year career seeing 5000 patients a year, a moderately busy EP might cross paths with 150 to 300 patients with the defect, if the 0.1 to 0.2 percent incidence is true, and that's not an insignificant number.
It is always a pleasure to read your articles. — Peter Utas, MD, Glendale, CA
Dr. Roberts responds: Drs. Utas and Goldstein seem to get it, with a firm grasp of the obvious interrogatories. This is a quandary, and downright befuddles us all. Rule 1: Scrutinize the EKG with gusto, and think long and hard about a young person with an RBBB, especially with ST elevation, who has truly unexplained syncope or serious palpitations. As with chest pain and no obvious explanation in a low-risk patient, you are simply feeling lucky if you send him home without at least alacritous follow-up (the next day) for an outpatient workup. If your gut tells you something is amiss, admit to telemetry, and argue with the annoyed attending and with insurance for the denied days later.
Hence, Rule 2: Be cautious, proactive, think some more, keep the patient in the ED another six to eight hours, and more importantly, share the liability. Get a consultant personally involved while the patient is in the ED, and show him a copy of EMN if he seems similarly baffled; the article is on the web site (http://bit.ly/Brugada). Forget statistics. It's always 50 percent with any given patient for anything; either they have it or they don't. As for the statistics, Dr. Utas is correct. In any event, reports are all over the map, and the data are too sparse to reach a firm conclusion about the true incidence.
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