Thursday, December 5, 2019

A young F is hyperthermic, delirious, and dry: Fever-induced Brugada? Diphenhydramine toxicity? Tricyclic?

Case 1. 

A 30-something with no medical history presented with 1 day of high temperature and delirium.

Her temperature was 106 degrees.

As part of the workup, she underwent an ECG.

I walked into the room and saw this:
What do you think?

There is sinus tachycardia and also a large R-wave in aVR.

V1 and V2 have type 1 Brugada pattern

To determine whether it is indeed Brugada or not, it is important to determine whether the QRS is actually prolonged or not.

If the QRS is prolonged, then the differential includes:
1. Hyperkalemia
2. Drug toxicity, especially diphenhydramine, which has sodium channel blocking effects, and also anticholinergic effects which may result in sinus tachycardia, hyperthermia, delirium, and dry skin.
----Other drugs with sodium channel blockade: Tricyclic antidepressants.  They result in a large R-wave in aVR, but also usually have a wider QRS.
----Other sodium channel blockers, such as flecainide.

However, if the QRS is not prolonged, then Brugada uncovered by fever is the likely culprit.

Here I have drawn a line from the end of the QRS in lead II across the bottom up to V1 and V2.
This shows that much of the apparent R'-wave in V1 and V2 is really a downsloping ST segment.  Thus, Brugada is the likely diagnosis

A very nice explanation of this is given in the document quoted below on current ECG criteria for Brugada pattern.

Bayes de Luna, A et al. Current electrocardiographic criteria for diagnosis of Brugada pattern: a consensus report. J Electrocardiology 45 (2012):433-442.

Full text at Researchgate

Isolated RBBBs

Type 1 Brugada and advanced RBBB are both characterized by a terminal positive wave and a negative T wave in V1-V2.  The distinction between the 2 conditions is straightforward because, usually, in advanced RBBB, the ST segment is not elevated in the right precordial leads, the terminal wave (r' or R') is synchronous with the broad S wave observed in leads I and V6, and the QRS is wider (120 milliseconds). 

In type 1 BrP, however, usually no wide S-wave is present in the left leads because the terminal forces of the ventricular complex in V1-V2 can be recorded only by electrodes placed in proximity of the site where the abnormal electrical activity occurs (the outflow tract of the right ventricle) and not from further away leads. Therefore the QRS in left leads is usually less than 120 milliseconds.

Type 1 Brugada syndrome, which may be baseline or uncovered by fever, and has a normal QRS duration but a wide appearing R'-wave in V1 and V2 because of the downsloping ST segment.

Clinical course:
The patient was diagnosed with pyelonephritis and her fever was reduced with antipyretics.  She was given fluids and she improved and became lucid.  She was able to state she had taken no meds, no drugs, no OTCs, no dietary supplements.

We repeated the ECG:
Brugada pattern is mostly resolved.

Further history later: This patient personally has no further high risk features (syncope / presyncope), but her mother had sudden cardiac arrest in sleep.  

Follow up the next AM:
Brugada pattern is resolved

Below is what the electrophysiologist recommended.

This is based on the Sieira et al, 2017, risk calculator, which gives a borderline risk score (2).    

--Genetic testing could be helpful to confirm the diagnosis and allow for screening of other at-risk family members.   
--EP study to further risk stratify her is recommended, with ICD placement depending on the results.  --Regardless of further evaluation, she should avoid bradycardia, AV nodal blockers, Na channel blockers, and fevers. 
--If she has fever, she should aggressively take acetaminophen and/or ibuprofen and, if not improving, will need to go to ED for further evaluation.  
--If there are any syncopal or presyncopal events, she should be evaluated immediately in the ED.  
--All 1st degree relatives should have 1 time EGG.  


Case 2.

A few days later, this patient presented with influenza:

70-something with fever of 38.0, and was diagnosed with influenza (5523467)
This was read by the computer and overreading physician as:
"Type 3 Brugada Pattern"

Is it?

No!  This is classic type 1 Brugada pattern.

Read more about the types of Brugada syndrome here.  Types 2 and 3 have been merged into Type 2 and look substantially different.

Is this Type 2 Brugada syndrome/ECG pattern?

This was recorded about 30 minutes later:

A previous ECG was obtained and was normal.

The patient denied any chest pain whatsoever, and a troponin at zero and 2 hours were both undetectable. A bedside cardiac ultrasound revealed grossly normal to hyperdynamic systolic function with no obvious areas of wall motion abnormalities. His lab workup was significant for positive influenza A rapid test and hyponatremia.

Patient was advised of the importance of fever control, follow up with primary care and also a cardiologist.

They did not verify resolution of Brugada pattern with control of fever.  This would be advisable.


Here are more cases of Fever and Brugada:

--Hyperthermia and ST Elevation 

    -- The syndrome of Brugada and Fever was discussed at length

--A Patient with Syncope 

     -- a very subtle case of syncope due to Brugada that was missed on the first presentation and not diagnosed until he had recurrent syncope 3 years later.

     -- in this case, the computer diagnosed STEMI but the patient had Fever with Brugada


Fever and Brugada--Important articles

The literature below shows that fever-induced Brugada is indeed a high risk for an arrhythmic event.

This article is on Brugada in general, not just fever-induced:

A score model to predict risk of events in patients with Brugada Syndrome

Here is full text:

This was a single center cohort of 400 patients with Brugada syndrome.  78 patients had spontaneous type I ECG.  Clinical presentation was aborted sudden death in 20 patients, syncope in 111, and asymptomatic in 269 patients.  Familial syncope or sudden death was found in 184 patients, 31 of these in first degree relatives under 35 years of age.  ICD was placed in 176.  During a mean follow-up of 80.7 months, 34 arrhythmic events occurred (event rate: 1.4% year). Variables significantly associated to events were: presentation as aborted SCD (Hazard risk [HR] 20.0), syncope (HR 3.7), spontaneous type I (HR 2.7), male gender (HR 2.7), early SCD in first-degree relatives (HR 2.9), SND (HR 5.0), inducible VA (HR 4.7) and proband status (HR 2.1). A score including ECG pattern, early familial SCD antecedents, inducible electrophysiological study, presentation as syncope or as aborted SCD and SND had a predictive performance of 0.82. A score greater than 2 conferred a 5-year event probability of 9.2%.

These are specifically on fever-induced Brugada

Arrhythmic events in Brugada syndrome patients induced by fever.  Annals of Noninvasive Electrocardiology 2019.

These authors analyzed all the reports of fever with Brugada which are available and found that the incidence of arrhythmic events in patients with active fever and Brugada was 38% (very high!).  (This has a high risk of selection bias, as all are reported cases.)

This study references experimental evidence that higher temperature alters Na conduction through the membrane in patients with SNC5A mutation.

Studies have shown a higher prevalence of BrS in febrile patients compared to nonfebrile ones.  Fever not only unmasks a Brugada-type electrocardiogram (ECG) but also increases the risk of ventricular tachyarrhythmias such as ventricular fibrillation (VF) or sudden cardiac death.  The underlying mechanism of this finding might involve a decrease of the sodium current during a rise in temperature which has been recently described using human cardiomyocytes from induced pluripotent stem cells.

They emphasize that further analysis has to be executed in order to find a common way as how to treat patients that present with fever-induced BrS as well as to establish the risk of arrhythmic events that might threaten those patients with next fever episode. 

Conclusion of this paper: Fever is a great risk factor for arrhythmia events in Brugada Syndrome patients. Patients with known fever-triggered Brugada syndrome should be surveilled closely during fever and be started on antipyretic therapy as soon as possible.  There are limited data regarding the impact of EP study in BrS patients triggered by fever.  An EP study might be helpful in symptomatic patients (Sroubek et al., 2016) in the presence of spontaneous BrS ECG or drug-induced ECG.

Eighty-eight asymptomatic patients with fever induced Type 1 Brugada syndrome had a mean age of 45.8 ± 18.7 years and 71.6% (67 of 88) were men. Twenty-one percent (18 of 88) had a family history of sudden cardiac death and 26.4% (14 of 53) carried a pathogenic SCN5A mutation. Drug-challenge was positive in 29 of 36 patients tested (80.6%). The risk of ventricular fibrillation in asymptomatic patients was 0.9%/y (3 of 88, 43.6 ± 37.4 months).

Fever-related arrhythmic events in the multicenter Survey on Arrhythmic Events in Brugada Syndrome.  Heart Rhythm 2018.  In 588 patients with known Brugada syndrome and first arrhythmic event, 35 were during fever.  Family history of sudden death,  history of syncope, and spontaneous type 1 Brugada ECG were noted in 17%, 40%, and 71% of patients, respectively. VF was induced at EP study in 9 of 19 patients (47%). An SCN5A mutation was found in 14 of 28 patients (50%). The highest proportion of fever-related AE was observed in the pediatric population (age less than 16 years) with a disproportionally higher event rate in the very young (age 0–5 years) (65%). 

MY Comment by KEN GRAUER, MD (12/5/2019):
We have previously discussed Brugada ECG patterns and Brugada Syndrome on multiple occasions in Dr. Smith’s ECG Blog (Sept. 8, 2019) — (Jan. 30, 2019) — many others ...
  • In today’s post — Dr. Smith emphasizes the potential for high fever to precipitate a Brugada-1 ECG pattern, with associated increased risk for an arrhythmic event.

Review of relevant literature is provided by Dr. Smith (above). I limit my comments to the following synthesizing thoughts:
  • The ECG picture of a Brugada-1 pattern (as shown in the initial ECG of this case) should be instantly recognized. Emergency providers need to be comfortable recognizing this ECG pattern.
  • Acute febrile illness may “unmask” previously undiagnosed Brugada Syndrome. Treatment of the underlying cause of the fever (which was acute pyelonephritis in Case #1 above) — may resolve (or greatly diminish) the abnormal ECG pattern (as it did in Case #1).
  • What is clear — is that patients with spontaneous or induced (including induced by fever) Brugada-1 ECG patterns are at greatly increased risk of a future malignant arrhythmia event IF there is: i) A positive family history of sudden death — and/or — ii) A spontaneous Brugada-1 ECG pattern in a 1st-degree relative — and/or — iii) A previous history in the patient of syncope, presyncope, seizures or nocturnal agonal respiration — and/or — iv) A positive sodium channel-blocker challenge test after resolution of the acute precipitating problem.
  • What is less clear — is how much risk an asymptomatic and otherwise healthy patient with a structurally normal heart faces, especially IF the Brugada-1 ECG pattern resolves after resolution of the precipitating event. KEY QUESTION: Does the previously healthy, 30-something young woman in Case #1, whose Brugada-1 ECG pattern largely resolved with treatment of her acute febrile illness — Does she truly need an ICD? (Implantable Cardioverter-Defibrillator), with long-term potential for device-related complications from the ICD, including inappropriate shocks?
BOTTOM LINE: Whereas decision-making is clear for symptomatic patients with a Brugada-1 ECG pattern — it is complex, and continues to be a bit of a “moving target” for asymptomatic individuals without persistent ECG abnormality. I'd be happy to refer these patients to EP cardiology for formal evaluation.

P.S. (which I am writing the next day, on 12/6/2019): I missed the "Further History gotten Later" at the time I wrote my initial comment on 12/5. This further History adds that although this patient personally had no syncope/presyncope — her mother had sudden cardiac arrest during sleep ==> Therefore, a positive Family History that for this young woman clearly merits full evaluation by EP cardiology!


  1. Great case once again! Question is, why 2 points on the risk score. This is not spontaneous but rather “provoked” Type 1 so 1 point for FHx? No?

    1. Thanks for your question Andy! I have not used the risk score that you refer to — so I will refer your question to Dr. Smith for his input on this. That said, the “P.S.” ( = very last paragraph) in My Comment above reflects my concern, namely SUDDEN DEATH in the mother during sleep (ie, presumably cause unknown, but potentially arrhythmic in nature) — in addition to the decidedly positive Brugada-1 ECG pattern that this previously healthy 30-something y.o. woman developed (even though induced by fever) — would seem more than ENOUGH to justify full evaluation by EP Cardiology, regardless of any numerical risk score her case may have generated. Dr. Smith cites lots of literature (above) indicating increased risk posed by febrile induction of Brugada-1 ECG patterns.

    2. Brugada ECG is spontaneous. Fever does not qualify as provoked (an EP study with Na channel blockade would) + sudden death in mother. This is my understanding. And this is the score that the EP doc gave too.

  2. I do agree with Dr Grauer, an EP cardiology evaluation seems to be warranted. On the other hand, what worries me more is the frequently diagnosed "Febrile benign convulsion" in kids that present to the E.D (at least in our country) with fever and an apparent convulsion. We are trying to educate our Pediatric specialists on this topic and obtain a detailed family Hx in every case and keep in mind all those red flags.
    Thanks again to Dr Smith and Dr Grauer
    H Munoz, MD Caracas Venezuela

    1. Gracias otra vez, Hector. Although when I was Attending, the thought of a Brugada Syndrome-induced arrhythmia in a pediatric patient who presented with a clear febrile seizure was not something that passed my mind — But, your question, and this case study makes one reconsider … — — I would think routine ECGs in the very young with what appears to be a clear febrile seizure are not generally indicated — but — IF there is a positive family history of sudden death in a close blood relative to such a child (as you suggest) — then Brugada Syndrome merits consideration. THANKS again for your comment, Hector. Input from others (Any pediatric cardiologists out there?) on this question is welcomed! — :)


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