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| Typical Bradycardia - Credit Wikipedia |
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A week scarcely goes by without our learning of another unusual aspect or feature of COVID-19 disease, impacting everything from blood vessels, to blood chemistry, to CNS function. A short list of examples includes:
The Lancet: Yet Another Study On Neurological Manifestations In Severe COVID-19 Patients
WHO Scientific Brief: Multisystem Inflammatory Syndrome in Children & Adolescents with COVID-19
EID Journal: Two Reports On Thrombotic Events In COVID-19 Patients
EID Journal: Pulmonary Embolism and Increased Levels of d-Dimer in COVID-19 Patients
Large-Vessel Stroke as a Presenting Feature of Covid-19 in the Young
Much has been written about The Cardiovascular Impact of COVID-19, and last May the American Heart Association's journal Circulation published:
(Excerpt)
Among patients with COVID-19, there is a high prevalence of cardiovascular disease, and >7% of patients experience myocardial injury from the infection (22% of critically ill patients). Although angiotensin-converting enzyme 2 serves as the portal for infection, the role of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers requires further investigation. COVID-19 poses a challenge for heart transplantation, affecting donor selection, immunosuppression, and posttransplant management. There are a number of promising therapies under active investigation to treat and prevent COVID-19.
Recently, JAMA published an original investigation which found a 3-fold increase in out-of-hospital cardiac arrests in New York City during the peak of their COVID-19 epidemic, finding:
From March 1 to April 25, 2020, New York City, New York (NYC), reported 17 118 COVID-19–related deaths. On April 6, 2020, out-of-hospital cardiac arrests peaked at 305 cases, nearly a 10-fold increase from the prior year.
While many of these cases already had underlying cardiac problems, COVID-19 appears to have a direct, and often serious impact on cardiac function.
Today, in a study published in the EID Journal, we have another example of an unexpected cardiac manifestation - Relative Bradycardia (Faget's sign) - which has been observed in younger COVID-19 patients without evidence of cardiac disease.
Bradycardia is typically defined as a resting heart rate < 60 , while `normal' is considered anywhere from 60 to 100 BPM. Above 100 BPM, and the rhythm is considered to be a Tachycardia.
Relative Bradycardia (RB) doesn't have to be < 60 BPM, but it does have to be lower than expected given a patient's condition. And since it is normal for someone to have an elevated pulse when they have a fever (typically 10 BPM for each degree over normal), someone with a high fever and a normal pulse rate can be considered to have `Relative Bradycardia'.
The mechanism behind relative bradycardia isn't known, although it is associated with certain types of bacterial and viral infections (e.g. typhoid fever, Legionnaire's disease, Yellow Fever, etc.).
In 2018's The Clinical Significance of Relative Bradycardia by Fan Ye MD, PhD; Mohamad Hatahet, MD; Mohamed A. Youniss, MD; Hale Z. Toklu, PhD; Joseph J. Mazza, MD; Steven Yale, MD, the authors wrote:
Abstract
Introduction: Relative bradycardia is a poorly understood paradoxical phenomenon that refers to a clinical sign whereby the pulse rate is lower than expected for a given body temperature.
Conclusions: Relative bradycardia is a sensitive but nonspecific clinical sign that may be an important bedside tool for narrowing the differential diagnosis of potential infectious and noninfectious etiologies. Recognizing this relationship may assist the clinician by providing bedside clinical clues into potential etiologies of disease, particularly in the setting of infectious diseases and in circumstances when other stigma of disease is absent.
While not necessarily an ominous sign, relative bradycardia is unusual - and often disease specific enough - to warrant further study.
All of which brings us to today's EID Journal article, which finds relative bradycardia common in a number of younger COVID-19 patients with no history of cardiac disease, and suggests it may be a potential diagnostic sign.
Research LetterKazuhiko Ikeuchi, Makoto Saito, Shinya Yamamoto, Hiroyuki Nagai, and Eisuke AdachiAuthor affiliations: The University of Tokyo, Tokyo, JapanAbstractCoronavirus disease is reported to affect the cardiovascular system. We showed that relative bradycardia was a common characteristic for 54 patients with PCR-confirmed mild-to-moderate coronavirus disease in Japan. This clinical sign could help clinicians to diagnose this disease.Pulse rate usually increases 10 beats/min for each 1°C increase in body temperature (1). However, in some specific infectious diseases, pulse rate does not increase as expected, a condition called relative bradycardia. High fever (temperature >39°C) for patients with coronavirus disease (COVID-19) has been reported (2,3), but the association between fever and pulse rate has not been investigated. We investigated relative bradycardia as a characteristic clinical feature in patients with mild-to-moderate COVID-19.(SNIP)
We performed computed tomography and electrocardiography for all patients: no patients were given a diagnosis of cardiac disease. Computed tomography showed pneumonia for 49 (90.7%) patients, and 11 (20.4%) patients required oxygen therapy without intubation. A total of 24 patients received COVID-19–specific treatment (favipiravir, n = 15; hydroxychloroquine, n = 10; both drugs, n = 1); no patients received vasopressors, or corticosteroids for COVID-19. All patients improved and were discharged.Body temperature, respiratory rate, systolic blood pressure, and time after the first symptoms (in days) were associated with pulse rate by univariable analysis (Appendix Table). However, only body temperature was independently associated with pulse rate by multivariable analysis. The predicted change in pulse rate (was 7.37 (95% CI 5.92–8.82) beats/min for each 1°C increase in body temperature (Figure).Relative bradycardia is a characteristic physical finding in some intracellular bacterial infections, viral infections, and noninfectious diseases (4). Our data showed that a predicted change in pulse rate was <10 beats/min for each 1°C increase in patients with COVID-19. Furthermore, all patients with high fever also met another criterion of relative bradycardia (i.e., body temperature >38.9°C with pulse rate <120 beats/min) (1).Although the mechanism of relative bradycardia is not known, a hypothesis is that increased levels of inflammatory cytokines, such as interleukin-6, which was reported for patients with COVID-19, can increase vagal tone and decrease heart rate variability (4–6). Another hypothesis is that the toxic effect on the nervous system caused by SARS-CoV-2 (7) disturbs autonomic control of heart rate.Angiotensin-converting enzyme 2, which is the receptor for SARS-CoV-2, is known to be expressed on cardiac cells (8). Therefore, relative bradycardia might reflect a characteristic inflammatory response to COVID-19, directly or indirectly affecting cardiovascular system.There are several limitations in our study. First, 34 patients received antipyretic medicines during their hospitalization (acetaminophen, n = 33; loxoprofen, n = 1), and 1 patient received prednisolone (5 mg/day) for myasthenia gravis. Because fever was underestimated for patients who received these medications, relative bradycardia might be a more common clinical sign. In our cohort, body temperature decreased over time. Although there was a relationship between pulse rate and time after first symptom in a univariable model, this finding was probably confounded by body temperature and thus not significant when adjusted. Second, our data did not include patients who were intubated. Additional research on patients with severe respiratory dysfunction is needed.In summary, relative bradycardia was a characteristic clinical finding in patients who had mild-to-moderate COVID-19 in Japan. This clinical sign could help clinicians diagnose COVID-19.Dr. Ikeuchi is a graduate student at the Institute of Medical Science, University of Tokyo, Tokyo, Japan. His primary research interest is HIV.
