Is it safe to use diltiazem or verapamil for treatment of my hospitalized patient with heart failure with reduced ejection fraction (HFrEF) and atrial fibrillation?

Short answer, no! It is generally recommended to avoid the use of diltiazem or verapamil, both a non-dihydropyridine calcium channel blocker (CCB), in patients with HFrEF.  Multiple randomized controlled trials involving patients with HFrEF have shown that use of diltiazem [1] or verapamil [2] is associated with increased cardiovascular mortality and morbidity, especially congestive heart failure (CHF) exacerbations.

Although you might argue that most studies [1,2] on HFrEF on CCBs have been based on patients on chronic (weeks to months) therapy, these agents are also sometimes used in the acute inpatient setting for rate control in atrial fibrillation and even blood pressure control. Even in acute settings, avoidance of these agents–or at least using them with great caution— in patients with HFrEF is prudent. Fortunately, for blood pressure control, another CCB, amlodipine [3] has been deemed safe to use in patients with HFrEF.

Adverse effects of diltiazem and verapamil are often attributed to their negative inotropic effects. As a result, patients with preexisting left ventricular dysfunction may be expected to have worse outcomes. In contrast, amlodipine primarily acts on the peripheral vasculature without significant negative inotropic effect. [4]

What about the use of these agents in patients with heart failure and preserved ejection fraction? Studies to date have found that CCBs are safe in this setting, although no mortality benefit has been shown with their use either [1]

Bonus Pearl: Did you know that use of another CCB, nifedipine, a close cousin of amlodipine (both 1,4- dihydropyridines), has been associated with increased cardiovascular morbidity (worsening CHF and increased hospitalizations) in patients with HFrEF? [5]

Contributed by Fahad Tahir, MD, Mercy Hospital-St. Louis, St. Louis, Missouri

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References:

  1. Goldstein RE, Boccuzzi SJ, Cruess D, Nattel S. Diltiazem increases late-onset congestive heart failure in postinfarction patients with early reduction in ejection fraction. The Adverse Experience Committee; and the Multicenter Diltiazem Postinfarction Research Group. Circulation. 1991 Jan;83(1):52-60. doi: 10.1161/01.cir.83.1.52. PMID: 1984898.https://www.ahajournals.org/doi/epdf/10.1161/01.CIR.83.1.52
  2. Effect of verapamil on mortality and major events after acute myocardial infarction (the Danish Verapamil Infarction Trial II–DAVIT II). Am J Cardiol. 1990 Oct 1;66(10):779-85. doi: 10.1016/0002-9149(90)90351-z. PMID: 2220572.https://www.ajconline.org/article/0002-9149(90)90351-Z/pdf
  3. Packer M, Carson P, Elkayam U, Konstam MA, Moe G, O’Connor C, Rouleau JL, Schocken D, Anderson SA, DeMets DL; PRAISE-2 Study Group. Effect of amlodipine on the survival of patients with severe chronic heart failure due to a nonischemic cardiomyopathy: results of the PRAISE-2 study (prospective randomized amlodipine survival evaluation 2). JACC Heart Fail. 2013 Aug;1(4):308-314. doi: 10.1016/j.jchf.2013.04.004. Epub 2013 Aug 5. PMID: 24621933.https://reader.elsevier.com/reader/sd/pii/S2213177913001844?token=510153852A5AEBBDF5CA9F8B16C671C4E2F4B511B6F723227BA1D2180CDAA4726EC329D5ABC4118738CB1D8B67A3CF6B&originRegion=us-east-1&originCreation=20220316135803
  4. Zamponi, G. W., Striessnig, J., Koschak, A., & Dolphin, A. C. (2015). The Physiology, Pathology, and Pharmacology of Voltage-Gated Calcium Channels and Their Future Therapeutic Potential. Pharmacological reviews, 67(4), 821–870.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4630564/
  5. Elkayam U, Amin J, Mehra A, Vasquez J, Weber L, Rahimtoola SH. A prospective, randomized, double-blind, crossover study to compare the efficacy and safety of chronic nifedipine therapy with that of isosorbide dinitrate and their combination in the treatment of chronic congestive heart failure. Circulation. 1990 Dec;82(6):1954-61. doi: 10.1161/01.cir.82.6.1954. PMID: 2242521.https://www.ahajournals.org/doi/epdf/10.1161/01.CIR.82.6.1954

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis, Massachusetts General Hospital, Harvard Catalyst, Harvard University, their affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

Is it safe to use diltiazem or verapamil for treatment of my hospitalized patient with heart failure with reduced ejection fraction (HFrEF) and atrial fibrillation?

What’s the evidence that REGEN-COV (casirivimab and imdevimab) monoclonal antibody cocktail is effective in the post-exposure prophylaxis of Covid-19?

The U.S. FDA has issued an Emergency Use Authorization (EUA) for the emergency use of REGEN-COV in adult and pediatric populations (≥12 years of age and older weighing> 40 kg) who are at high risk* of progression to severe COVID-19— including hospitalization or death— and who are not fully vaccinated or are not expected to mount an adequate immune response to the vaccine (eg, immunocompromised state).1  This recommendation is based on a randomized controlled trial involving individuals enrolled within 96 hours of exposure to a known Covid-19 case (Covid-10 Phase 3 Prevention Trial).2

In this trial, the primary efficacy end point was the development of symptomatic SARS-CoV-2 infection through day 28  in participants who did not have SARS-CoV-2 infection  by PCR or serology at the time of enrollment. Symptomatic SARS-CoV-2 infection developed in 1.5% of treatment group (vs 7.8% in placebo group) with 81.4% relative risk reduction (P<0.001); 66% reduction was observed when symptomatic and asymptomatic infections were combined.  Duration of symptoms and the magnitude and duration of detectable RNA were also lower in the REGEN-COV group compared to placebo. Therapy was well tolerated.2

In the same study, in a subgroup analysis of those who were seropositive at the time of enrollment REGEN-COV lowered the risk of symptomatic disease (0.4% vs 2.3% in the placebo group) with relative risk reduction of 81%, though not statistically significant (P=0.14).  This may be why the FDA EUA extended to certain vaccinated groups as well since to date there are no published trials on the use of REGEN-COV as post-exposure prophylaxis in vaccinated individuals.

*High risk group included ≥65 years of age, BMI≥25 kg/m2, diabetes, immunocompromised state, cardiovascular disease or hypertension, chronic lung disease, sickle cell disease and neurodevelopment disorders.

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References

  1. Fact sheet for health care providers emergency use authorization (EUA) of REGEN-COV. https://www.fda.gov/media/145611/download. Accessed September 15, 2021.
  2. O’Brien MP. Forleo-Neto E, Musser BJ et al. Subcutaneous REGEN-COV antibody combination to prevent Covid-19. N Engl J Med 2021, August 4, 2021. https://www.nejm.org/doi/full/10.1056/NEJMoa2109682

 

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis, Massachusetts General Hospital, Harvard Catalyst, Harvard University, their affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

What’s the evidence that REGEN-COV (casirivimab and imdevimab) monoclonal antibody cocktail is effective in the post-exposure prophylaxis of Covid-19?

Should I treat asymptomatic blood pressure (BP) elevation in my hospitalized patient with well-controlled BP prior to admission?

In contrast to the management of acute symptomatic hypertension in the hospital, evidence-based guidelines on when to treat asymptomatic BP elevation (eg, >160/90 mm Hg without signs of end-organ injury) in patients without acute conditions (eg, acute myocardial infarction [MI] or acute ischemic stroke) are lacking. The literature suggests, however, that a more permissive approach is appropriate in many asymptomatic patients with elevated BPs while hospitalized, particularly in those with well-controlled BPs as outpatient (1-4). 

In a 2018 study involving > 14,000 older adults hospitalized for common non-cardiac conditions, 52% of the cohort with elevated BPs (majority ranging ~160-180 mm Hg) but well-controlled BPs at home were discharged on a more intensive antihypertensive regimen (1). Patients with history of MI or cerebrovascular disease were no more likely and those with limited life expectancy, dementia or metastatic cancer were no less likely to receive antihypertensive intensification which suggests the decision for more aggressive treatment of elevated BP was in large part driven by the BP readings themselves. 

More intensive anti-hypertensive therapy has not only been associated with lack of reduction in cardiac events or improvement in BP control following discharge but also with more adverse events, such as acute kidney injury, MI, falls, syncope and hypotension and increased risk of readmission (2-3). 

Another concern is the frequent use of IV antihypertensives with its attendant risk of overcorrection and adverse events. One study found that about one-third of patients with asymptomatic uncontrolled BP treated with IV antihypertensives had an excessive drop in BP of more than 25% within 6 hours (5).

Since many factors may contribute to transiently elevated inpatient BPs (eg,  acute pain, stress, anxiety, exposure to new drugs and white coat hypertension) (1), the best advice when dealing with an elevated BP in hospitalized patients may be to repeat the BP, gather data on home BPs, contextualize the findings based on likelihood of benefits and risks of more intensive therapy and discuss with the outpatient provider before discharging patients on more intensified anti-hypertensive therapy (4). 

Bonus Pearl: Did you know that nearly one-half of patients with well controlled BPs at home have hypertension during their hospitalization? (1)

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References
1. Anderson TS, Wray CM, Jing B, et al. Intensification of older adults’ outpatient blood pressure treatment at hospital discharge: national retrospective cohort study. BMJ 2018;362:k3503. https://www.bmj.com/content/362/bmj.k3503

2. Anderson TS, Jing B, Auerback A, et al. Clinical outcomes after intensifying antihypertensive medication regimens among older adults at hospital discharge. JAMA Intern Med 2019;170:1528-36. https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2747871

3. Rastogi R, Sheehan MM, Hu B, et al. Treatment and outcomes of inpatient hypertension among adults with noncardiac admissions. JAMA Intern Med. Published online December 28, 2020. https://acphospitalist.org/archives/2021/01/tailor-treatment-for-asymptomatic-inpatient-hypertension.htm

4. Kearney-Strouse J. Tailor treatment for asymptomatic inpatient hypertension. ACP Hospitalist 2021; 15:22-23. https://acphospitalist.org/archives/2021/01/tailor-treatment-for-asymptomatic-inpatient-hypertension.htm

5. Lipari M, Moser LR, Petrovitch EA, et al. As-needed intravenous antihypertensive therapy and blood pressure control. J Hosp Med 2016;11:193-198. https://onlinelibrary.wiley.com/doi/abs/10.1002/jhm.2510

6. Jacobs ZG, Najafi N, Fang MC, et al. Reducing unnecessary treatment of asymptomatic elevated blood pressure with intravenous medications on the general internal medicine wards: a quality improvement initiative. J Hosp Med 2019;14:144-150. https://pubmed.ncbi.nlm.nih.gov/30811319/

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis or its affiliate healthcare centers. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

 

 

 

Should I treat asymptomatic blood pressure (BP) elevation in my hospitalized patient with well-controlled BP prior to admission?

Key clinical pearls on the management of patients suspected of or diagnosed with Covid-19 in the outpatient setting

Here are some key points to remember when managing patients with Covid-19 symptoms in the outpatient setting.  These points are primarily based on the CDC guidelines and the current literature. They may be particularly useful to primary care providers (PCP) who do not have ready access to Covid-19 test kits or radiographic imaging in the diagnosis of patients suspected of or diagnosed with Covid-19.

  • Isolation precautions. 1,6-7 Minimize chances of exposure by placing a facemask on the patient and placing them in an examination room with the door closed. Use standard and transmission-based precautions including contact and airborne protocols when caring for the patient. Put on an isolation gown and N95 filtering facepiece respirator or higher. Use a facemask if a respirator is not available. Put on face shield or goggles if available. Adhere to strict hand hygiene practices with the use of alcohol-based hand rub with greater than 60% ethanol or 70% isopropanol before and after all patient contact. If there is no access to alcohol-based hand sanitizers, the CDC recommends hand washing with soap and water as the next best practice.

 

  • Risk Factors.2-3 Older patients and patients with severe underlying medical conditions seem to be at higher risk for developing more serious complications from Covid-19 illness. Known risk factors for severe Covid-19 include age over 60 years, hypertension, diabetes, cardiovascular disease, chronic respiratory disease, and immunosuppression.

 

  • Symptoms.2,4,8,9 Reported illnesses have ranged from mild symptoms to severe illness and death. These symptoms may appear after a 2- to 14-day incubation period.
    • Fever at any time 88-99%
    • Cough 59-79%
    • Dyspnea 19-55%
    • Fatigue 23-70%
    • Myalgias 15%-44%
    • Sputum production 23-34%
    • Nausea or vomiting 4%-10%
    • Diarrhea 3%-10%
    • Headache 6%-14%
    • Sore throat 14%
    • Rhinorrhea/nasal congestion (4.8%)
    • Anosmia (undocumented percentage)

 

  • Treatment for mild illness.5 Most patients have mild illness and are able to recover at home. Counsel patients suspected to have Covid-19 to begin a home quarantine staying in one room away from other people as much as possible. Patients should drink lots of fluids to stay hydrated and rest. Over the counter medicines may help with symptoms. There is controversy regarding the safety of NSAIDs in Covid-19 (See related P4P pearl). Generally, symptoms last a few days and  patients get better after a week. There is no official guidance from the CDC or other reliable sources on how often a PCP should check in with a patient confirmed with Covid-19 and in quarantine. Please use good judgement and utilize telehealth capabilities via phone call, video call, etc… if possible.

 

  • Treatment for severe illness.3 Patients should be transferred immediately to the nearest hospital. If there is no transfer service available, a family member with appropriate personal protective equipment (PPE) precautions, should drive patient to nearest hospital for critical care services.

 

  • Ending home isolation. 5
    • Without testing: Patients can stop isolation without access to a test result after 3 things have happened. 1) No fever for at least 72 hours. This is 3 full days of no fever and without the use of medication that reduces fever; 2) Respiratory symptoms have improved.; and 3) At least 7 days have passed since symptoms first appeared.
    • With testing. 5 Home isolation may be ended after all of the following 3 criteria have been met: 1) No fever for at least 72 hours. This is 3 full days of no fever and without the use of medication that reduces fever; 2) Respiratory symptoms have improved; and 3) Negative results from at least 2 consecutive nasopharyngeal swab specimens collected more than 24 hours apart.

To all the healthcare providers out there, please be safe and stay healthy!

 

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Contributed by Erica Barnett, Harvard Medical Student, Boston, MA.

 

References:

  1. CDC. Evaluating and Testing Persons for Coronavirus Disease 2019 (COVID-19). https://www.cdc.gov/coronavirus/2019-nCoV/hcp/clinical-criteria.html
  2. CDC. Symptoms and Testing. https://www.cdc.gov/coronavirus/2019-ncov/symptoms-testing/index.html
  3. World Health Organization. Operational Considerations for case management for COVID-19 in health facility and community. https://apps.who.int/iris/bitstream/handle/10665/331492/WHO-2019-nCoV-HCF_operations-2020.1-eng.pdf
  4. Partners in Health. Resource Guide 1: Testing, Tracing, community management. https://www.pih.org/sites/default/files/2020-03/PIH_Guide_COVID_Part_I_Testing_Tracing_Community_Managment_3_28.pdf
  5. CDC. Caring for someone at home. https://www.cdc.gov/coronavirus/2019-ncov/if-you-are-sick/care-for-someone.html
  6. CDC. Using PPE. https://www.cdc.gov/coronavirus/2019-ncov/hcp/using-ppe.html
  7. CDC. Hand Washing. https://www.cdc.gov/coronavirus/2019-ncov/hcp/hand-hygiene.html
  8. Harvard Health Publishing. COVID-19 Basics. https://www.health.harvard.edu/diseases-and-conditions/covid-19-basics
  9. Guan W, Ni Z, Hu Y, et al. Clinical characteristics of Coronavirus disease 2019 in China. N Engl J Med 2020, March 6. DOI:10.1056/NEJM022002032 https://www.ncbi.nlm.nih.gov/pubmed/32109013

 

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Massachusetts General Hospital, Harvard Catalyst, Harvard University, its affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

Key clinical pearls on the management of patients suspected of or diagnosed with Covid-19 in the outpatient setting

Should I continue or discontinue angiotensin converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) in my patients with possible Coronavirus/Covid-19 infection?

The original reports of an association between hypertension and increased risk of mortality in hospitalized patients with Covid-19 infection raised concern over the potential deleterious role of ACEIs or ARBs in such patients.1-4 However, as stated by a joint statement of several cardiology societies, including the American Heart Association, American College of Cardiology and the European Society of Cardiology on March 13, 2020, there is no clinical or scientific evidence that ACEI or ARBS should be routinely discontinued in patients with Covid-19 infection.5

In fact, some have argued for the opposite ie, consideration for the use of ARBs, such as losartan (an angiotensin receptor 1 [AT1R] antagonist), in patients with Covid-19.6,7  Although it is true that Covid-19 appears to use ACE2 as a binding site to infect cells (just as in SARS) and that ACE2 may be upregulated in patients on chronic ACEI or ARBs,8,9 ACE2 may also potentially protect against severe lung injury associated with infections.10,11  

Two complementary mechanisms have been posited for the potential protective effect of ARBs in Covid-19 infection-related lung injury: 1. Blocking the excessive AT1R activation caused by the viral infection; and 2. Upregulation of ACE2, thereby reducing production of angiotensin II and increasing the production of the vasodilator angiotensin 1-7.7

In the absence of proper clinical studies, it is premature, however, to recommend use of losartan or other AT1R antagonists as a means of reducing the likelihood of ARDS in patients with Covid-19 at this time.

Bonus Pearl: Did you know that ARDS is a major cause of death in Covid-19 infection?12

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References

  1. Guan W, Ni Z, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020, March 6. https://www.nejm.org/doi/pdf/10.1056/NEJMoa2002032?articleTools=true
  2. O’Mara GJ. Could ACE inhibitors, and particularly ARBs, increase susceptibility to COVID-19 infection? BMJ 2020;368:m406 ARTICLE
  3. Sommerstein R, Grani C. Preventing a Covid-19 pandemic: ACE inhibitors as a potential risk factor for fatal Covid-19. BMJ2020;368:m810. https://www.bmj.com/content/368/bmj.m810/rr-2
  4. Li X, Geng M, Peng Y, et al. Molecular immune pathogenesis and diagnosis of COVID-19. Journal of Pharmaceutical Analysis 2020, doi htps://doi.org/10.106/j.jpha.2020.03.001. https://www.sciencedirect.com/science/article/pii/S2095177920302045
  5. Cardiology societies recommend patients taking ACE inhibitors, ARBs who contract COVID-19 should continue treatment. March 17, 2020. https://www.healio.com/cardiology/vascular-medicine/news/online/%7Bfe7f0842-aecb-417b-9ecf-3fe7e0ddd991%7D/cardiology-societies-recommend-patients-taking-ace-inhibitors-arbs-who-contract-covid-19-should-continue-treatment
  6. Gurwitz D. Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics. Drug Dev Res 2020;1-4. https://www.ncbi.nlm.nih.gov/pubmed/32129518/
  7. Phadke M, Saunik S. Response to the emerging novel coronavirus outbreak. BMJ 2020;368:m406. https://www.bmj.com/content/368/bmj.m406/rr-2
  8. Zheng YY, Ma YT, Zhang JY, et al. COVID-19 and the cardiovascular system. Nature Reviews/Cardiology 2020; https://doi.org/10.1038/s41569-020-0360-5 .
  9. Ferrario CM, Jessup J, Chappell MC, et al. Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2. Circulation 2005;111:2605-2610. https://www.ahajournals.org/doi/full/10.1161/circulationaha.104.510461
  10. Kuba K, Imai Y, Rao S, et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nature Medicine 2005;11:875-79. Doi:10.1038/nm1267 https://www.nature.com/articles/nm1267?v=1
  11. Tikellis C, Thomas MC. Angiotensin-converting enzyme 2 (ACE2) is a key modulator of the renin angiotensin system in health and disease. International Journal of Peptides. Volume 2012, Article ID 256294, 8 pages. Doi:10.1155/2012/256294. https://research.monash.edu/en/publications/angiotensin-converting-enzyme-2-ace2-is-a-key-modulator-of-the-re

12 . Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020. https://doi.org/10.1016/S0140-6736(20)30183-5

 

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Massachusetts General Hospital, Harvard Catalyst, Harvard University, its affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

Should I continue or discontinue angiotensin converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) in my patients with possible Coronavirus/Covid-19 infection?

Catch these selected key clinical pearls on coronavirus disease (Covid-19)!

Although the Covid-19 pandemic is continuing to evolve and our knowledge of its epidemiology and pathophysiology is still far from complete, you may find the following pearls based on published literature to date useful when discussing this disease with your colleagues or the public. 1-11

  • Age group: Primarily an adult disease. Children (< 15-year-old) account for only a minority of symptomatic patients (<1%); ~50% of patients are between 15-49 years of age with 15% in the ≥ 65 year group. 1
  • Incubation period: A bit longer than seasonal flu. Median 4.0 days (IQR 2.0-7.0 days); an upper range up to 24 days has also been reported. In contrast, for seasonal flu the median incubation period is shorter (median 2.0 days, 1.0-7.0 days. 1,4,11
  • Transmission: Contact, droplet, and possibly airborne. On average each person may transmit Covid-19 virus to 2-3 other persons (vs <2 people for seasonal flu). Unlike SARS or MERS, but more akin to the seasonal flu, asymptomatic persons may also be able to transmit the disease. 4,5,11
  • Comorbid conditions (eg, diabetes, hypertension, COPD…): Present in about 1/3 of reported patients. 1
  • Symptoms 1,5
    • ~80% of patients may be either asymptomatic or have mild disease
    • Fever may be absent in ~50% of patients on presentation but will eventually develop in ~90% of hospitalized patients
    • Cough (2/3 dry) is present in majority (~80%) of cases
    • Rhinorrhea is uncommon (<10%), in contrast to the seasonal influenza
    • GI symptoms (nausea/vomiting/diarrhea) are uncommon by some reports(<10%), but not by others (>30.0%). 12
    • May take 9-12 days from onset of symptoms to severe disease
  • Labs 1
    • Lymphopenia is common (up to ~80%)
    • Abnormal liver function (AST and ALT) is found in about 1/3 of patients
    • C-reactive protein (CRP) is usually elevated (~80% of severe cases)
    • Procalcitonin is usually normal
  • Treatment: Supportive for now. Candidate drugs include remdesivir, lopinavir/ritonavir, chloroquine phosphate, ribavirin and several others.4
  • Mortality: Reported mortality among mostly symptomatic hospitalized cases is ~2.0% (0.9% without comorbidities, 5-10% in those with comorbidities, 50% among critically ill). Overall mortality rates will likely drop as more patients without symptoms or with mild disease are tested. In contrast, 2 other coronavirus diseases, SARS and MERS, have mortality rates of ~9.0% and 36.0%, respectively. 1,4,5

 

Bonus pearl: Did you know that, Covid-19-infected patients shed the virus in their nasopharyngeal secretions on the average for 12 days, some as long as 24 days?3

 

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References

  1. Guan W, Ni Z, Hu Y, et al. Clinical characteristics of Coronavirus disease 2019 in China. N Engl J Med 2020. First published Feb 28, 220, last updated March 6, 2020. https://www.nejm.org/doi/10.1056/NEJMoa2002032
  2. Holshue ML, DeBolt C, Lindquist S, et al. First case of 2019 novel Coronavirus in the United States. N Engl J Med 2020; 382:929-36. https://www.nejm.org/doi/full/10.1056/NEJMoa2001191
  3. Young BE, Ong SWX, Kalimuddin S, et al. Epidemiologic features and clinical course of patients infected with SARS-CoV-2 in Singapore. JAMA. Doi:10.1001/jama.2020.3204. Published online March 3, 2020. https://jamanetwork.com/journals/jama/fullarticle/2762688
  4. Wang Y, Wang Y, Chen Y, et al. Unique epidemiological and clinical features of the emerging 2019 novel coronavirus pneumonia (COVID-19) implicate special control measures. J Med Virol 2020. Doi: 10.1002/jmv.25748. https://www.ncbi.nlm.nih.gov/pubmed/32134116
  5. Fauci AS, Lane HC, Redfield RR. Covid-19—Navigating the uncharted. N Eng J Med 2020. DOI:10.1056/NEJMe2002387. https://www.nejm.org/doi/full/10.1056/NEJMe2002387
  6. Del Rio C, Malani PN. 2019 novel coronavirus—important information for clinicians. JAMA 2020, Feb 5. https://www.ncbi.nlm.nih.gov/pubmed/32022836
  7. Lipsitch M, Swerdlow DL, Finelli L. Defining the epidemiology of Covid-19—studies needed. N Engl J Med 2020. Feb 19. DOI:10.1056/NEJMp2002125. https://www.ncbi.nlm.nih.gov/pubmed/32074416/
  8. Morens DM, Daszak P, Taubenberger JK. Escaping Pandora’s box—another novel coronavirus. N Eng J Med 2020. Feb 26. DOI:10.1056/NEJMp2002106. https://www.nejm.org/doi/full/10.1056/NEJMp2002106
  9. She J, Jiang J, Ye L, et al. 2019 novel coronavirus of pneumonia in Wuhan, China: merging attack and management strategies. Clin Trans Med 2020;9:19. https://clintransmed.springeropen.com/articles/10.1186/s40169-020-00271-z
  10. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395: 497-506. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30183-5/fulltext
  11. Bai Y, Yao L, Wei T, et al. Presumed asymptomatic carrier transmission of COVID-19. JAMA 2020. Feb 21. https://jamanetwork.com/journals/jama/fullarticle/2762028
  12. Pan L, Mu M, Yang P, et al. Clinical characteristics of COVID-19 patients with digestive symptoms in Hubei, China: a descriptive, cross-sectional, multicenter study. Am j Gastroenterol 2020. https://journals.lww.com/ajg/Documents/COVID_Digestive_Symptoms_AJG_Preproof.pdf
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Is my patient with gout at higher risk of cancer?

Although the association of gout with cardiovascular disease, chronic kidney disease, hypertension, diabetes mellitus or obesity is well known, increasingly number of epidemiologic studies support the association of gout with higher risk of malignancy. 1,2

A 2015 meta-analysis of 3 studies involving over 50,000 persons concluded that gout was an independent risk factor for cancer, particularly urological, gastrointestinal and lung cancers. 1

A population-based study of comorbidities in over 2 million persons in Sweden found that in addition to an increased risk of diabetes mellitus, hypertension, chronic heart failure, chronic kidney disease and alcohol abuse, gout was associated with increased risk of malignancy: odds ratio 1.3 (1.2-1.5) in men and 1.1 (1.1-1.2) in women. 2

Although serum uric acid has been considered to have anti-oxidant properties, a prospective study of over 28,000 women followed over a median of 15.2 years did not find high serum acid levels to be protective of cancer.3 In fact, uric acid levels > 5.4 mg/dL at the time of subject enrollment was independently associated with increased risk of total cancer mortality and deaths from a variety of malignant neoplasms, including those of breast, female genital organs, and nervous systems. 3 In a similar prospective study involving men, high uric acid levels (>6.7 mg/dL) were associated with increased risk of mortality from gastrointestinal, respiratory and intrathoracic organ malignancies. 4

Whether the observed association between gout and higher risk of malignancy is causal or due to the company that gout often keeps (eg, lifestyle) is unclear.

Fun fact: Did you know that among mammals, only humans, great apes and certain breeds of dogs (eg, Dalmation) produce elevated levels of uric acid in the urine and blood? 5

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References

  1. Wang W, Xu D, Wang B, et al. Increased risk of cancer in relation to gout: a review of three prospective cohort studies with 50,358 subjects. Mediators of Inflammation 2015, Article ID 680853, 6 pages. https://www.ncbi.nlm.nih.gov/pubmed/26504360
  2. Wandell P. Gout and its comorbidities in the total population of Stockholm. Preventive Medicine 2015; 81:387-91. ISSN 0091-7435. https://www.ncbi.nlm.nih.gov/pubmed/26500085
  3. Strasak AM, Rapp K, Hilbe W, et al. The role of serum uric acid as an antioxidant protecting against cancer: prospective study in more than 28000 older Austrian women. Ann Onc 2007;18:1893-97. https://www.ncbi.nlm.nih.gov/pubmed/17785768
  4. Strasak Am, Hilbe RK, Oberaingner W, et al. Serum uric acid and risk of cancer mortality in a large prospective male cohort. Cancer Causes Control 2007;18:1021-9. https://www.ncbi.nlm.nih.gov/pubmed/17665312
  5. Bannasch D, Safra N, Young A, et al. Mutations in the SLC2A9 gene cause hyperuriosuria and hyperuricemia in the dog. PLOS Genet 2008;4:e1000246. https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1000246&type=printable
Is my patient with gout at higher risk of cancer?

Why is my patient with diabetic ketoacidosis (DKA) and hypovolemia hypertensive?

Although we may expect patients with DKA to present with hypotension due to hypovolemia, many patients with DKA may actually be hypertensive. This finding is particularly intriguing because hyperinsulinemia, not insulinopenia as found in DKA, has been associated with hypertension. 1,2

Though not proven, potential explanations for hypertension in DKA include elevated serum levels of catecholamines, pro-inflammatory cytokines, renin, angiotension II and aldosterone.3-5 Hyperosmolality may also lead to the release of antidiuretic hormone (ADH) which increases blood pressure via V2 receptors.  Another possibility is that the high insulin levels associated with the treatment of DKA suppress the catecholamine-stimulated production of vasodilative eicosanoids (eg, prostaglandins) by adipose tissue. 1 It’s possible that in any given patient, 1 or more of these mechanisms may be enough to override the potential hypotensive effect of insulin deficiency in DKA.

We should note that reports of frequent hypertension in DKA have primarily involved pediatric patients. A 2011 study found that 82% of pediatric patients with DKA had hypertension during the first 6 hours of admission with no patient having hypotension.3  

On the other extreme, refractory hypotension without obvious cause (eg, sepsis, acute adrenal insufficiency, cardiogenic causes) has also been reported in DKA.5Because insulin inhibits the production of vasodilative prostaglandins (eg, PGI2 and PGE2), severe insulin deficiency in DKA can also contribute to hypotension along with volume depletion. 

Potential genetic polymorphism in the synthesis and metabolism of prostaglandins may at least partially explain the varied blood pressure response and whether a patient with DKA presents with hypertension or hypotension. 5  

The author would like to acknowledge the valuable contribution of Lloyd Axelrod MD, Massachusetts General Hospital, to this post.

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References

  1. Axelrod L. Insulin, prostaglandins, and the pathogenesis of hypertension. Diabetes 1991;40:1223-1227. https://diabetes.diabetesjournals.org/content/40/10/1223&nbsp;
  2. Chatzipantelli K, Head C, Megerman J, et al. The relationship between plasma insulin level, prostaglandin productin by adipose tissue and blood pressure in normal rats and rats with diabetes mellitus and diabetic ketoacidosis. Metabolism 1996;45:691-98. https://www.sciencedirect.com/science/article/abs/pii/S002604959690133X&nbsp;
  3. Deeter KH, Roberts JS, Bradford H, et al. Hypertension despite dehydration during severe pediatric diabetic ketoacidosis. Pediatr Diabetes 2011;12:295-301. https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1399-5448.2010.00695.x&nbsp;
  4. Ferris JB, O’Hare JA, Kelleher CM, et al. Diabetic control and the renin-angiotensin system, catecholamines and blood pressure. Hypertension 1985 7(Suppl II):II-58-II-63. https://www.ahajournals.org/doi/abs/10.1161/01.HYP.7.6_Pt_2.II58  
  5. Singh D, Cantu M, Marx MHM, et al. Diabetic ketoacidosis and fluid refractory hypotension. Clin Pediatrics 2016;55:182-84. https://journals.sagepub.com/doi/abs/10.1177/0009922815584549?journalCode=cpja&nbsp;

 

Why is my patient with diabetic ketoacidosis (DKA) and hypovolemia hypertensive?

Of the commonly used drugs for benign prostatic hypertrophy (BPH), which ones may be the least likely to cause hypotension in my hospitalized patient with borderline systolic blood pressures?

5-alpha-reductase inhibitors (RIs) (eg, finasteride and dutasteride) are less likely to cause hypotension than alpha-1-adrenergic antagonists (AAs) (eg, tamsulosin, doxazocin, terazocin, and alfuzocin), the other major class of drugs commonly used for treatment of signs and symptoms of benign prostatic hypertrophy (BPH).

A Cochrane systematic review found that finasteride, an RI, has a lower risk of postural hypotension compared to doxazosin, an AA. 1 In fact, there’s no solid evidence that RIs exacerbate hypotension on their own. 2,3 Unfortunately, RIs take longer to achieve benefit because they work by reducing prostate size over time, while AAs work much faster by reducing prostate smooth muscle tone.4 So, while it’s reasonable to choose an RI over an AA in our patient with soft pressures, it’s also reasonable to expect it won’t work quite as well during his hospital stay and you may still be forced to choose an AA.  

Among AAs, tamsulosin is the least likely to be associated with hypotension when compared to others in the same class (eg, doxazocin and terazocin) which are also sometimes used for treatment of hypertension. Thus, tamsulosin may be the best choice for patients at risk of  hypotension.5 However, even tamsulosin is not totally safe in this regard, especially in the first 4 weeks after starting or re-starting treatment when its risk of hospital admission for hypotension is about double that of RIs.6

Bonus pearl: Did you know that prazocin was the first promising selective AA investigated for BPH but likely because of its availability in generic form and the general notion at the time that medical therapy of BPH would not be widely accepted by urologists, larger randomized-controlled trials were never pursued!7

References

  1. Tacklind J, Fink HA, MacDonald R, et al. Finasteride for benign prostatic hyperplasia. Cochrane Database of Systematic Reviews, 2010 Oct 6. https://www.ncbi.nlm.nih.gov/pubmed/20927745
  2. Finasteride prescribing information: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020180s037lbl.pdf
  3. Dutasteride prescribing information: https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021319s014lbl.pdf
  4. Rigatti P, Brausi M, Scarpa RM, et al. A comparison of the efficacy and tolerability of tamsulosin and finasteride in patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia. Prostate Cancer and Prostatic Diseases 2003; 6:315–323. https://www.ncbi.nlm.nih.gov/pubmed/14663474
  5. Tewari A and Narayan P. Alpha-adrenergic blocking drugs in the management of benign prostatic hyperplasia: interactions with antihypertensive therapy. Urology 1999 Mar;53:14-20. https://www.ncbi.nlm.nih.gov/pubmed/10094096
  6. Bird ST, Delaney JAC, Brophy JM, et al. Tamsulosin treatment for benign prostatic hyperplasia and risk of severe hypotension in men aged 40-85 years in the United States: risk window analyses using between and within patient methodology. BMJ 2013; 347 :f6320. https://www.ncbi.nlm.nih.gov/pubmed/24192967
  7. Lepor H. Alpha blockers for the treatment of benign prostatic hyperplasia. Rev Urol 2007;9:181-90.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2213889/

Contributed by Nick Bodnar, Harvard medical student, Boston, MA.

 

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Of the commonly used drugs for benign prostatic hypertrophy (BPH), which ones may be the least likely to cause hypotension in my hospitalized patient with borderline systolic blood pressures?

How does excess licorice consumption cause hypertension and hypokalemia?

The active ingredient of licorice, glycyrrhizic acid or glycyrrhizin, is first converted to glycyrrhetinic acid (GRA) in the bowel which is then absorbed. Once in the circulation, GRA inhibits activation of 11 β-hydroxysteroid dehydrogenase 2 (11 β-HSD2), an enzyme in renal tissue that converts active cortisol to inactive cortisone. Without the full action of this enzyme, proper sodium and potassium homeostasis would be difficult because cortisol is just as effective in stimulating mineralocorticoid receptors as aldosterone but with 100-1000 times higher concentration than that of aldosterone! 1-3

Other ways that GRA may cause hypertension and hypokalemia include inhibition of 5 β-reductase in the liver, an enzyme that metabolizes aldosterone and direct stimulation of mineralocorticoid receptors, though overall these mechanisms may not be as important as the effect of GRA on cortisol metabolism in renal tissue.1,2

Besides causing fluid retention, licorice ingestion has also been found to increase systemic vascular resistance possibly by increasing vascular tone and remodeling of the vascular wall, potentiating the vasoconstrictor actions of angiotensin II and catecholamines in smooth muscle, and suppressing vasodilatory systems, including endothelial nitric oxide synthase and prostacyclin synthesis.

It’s no wonder that the FDA issued a statement in 2017: “If you’re 40 or older, eating 2 ounces of black licorice a day for a day for at least two weeks could land you in the hospital with an irregular heart rhythm or arrhythmia.” 5

Bonus Pearl: Did you know that as early as 1951, extract of licorice was reported for treatment of Addison’s disease, a combination of licorice and soy sauce has been reported to be “life-saving” in a patient with Addison’s disease (2007), and GRA food supplementation may lower serum potassium in chronic hemodialysis patients (2009)? 6,7

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References

  1. Sontia B, Mooney J, Gaudet L, et al. Pseudohyperaldosteronism, liquorice and hypertension. J Clin Hypertens (Greenwich) 2008; 10:153-57. https://www.ncbi.nlm.nih.gov/pubmed/18256580
  2. Omar HR, Komarova I, El-Ghonemi M, et al. Licorice abuse: time to send a warning message. The Adv Endocrinol Metab 2012;3:125-138. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3498851/
  3. Penninkilampi R, Eslick EM, Eslick GD. The association between consistent licorice ingestion, hypertension and hypokalaemia: as systematic review and meta-analysis. Journal of Human Hypertension 2017;31:699-707. https://www.ncbi.nlm.nih.gov/pubmed/28660884
  4. Black licorice: trik or treat? https://www.fda.gov/ForConsumers/ConsumerUpdates/ucm 277152.htm
  5. Hautaniemi EJ, Tahvanainen AM, Koskela JK, et al. Voluntary liquorice ingestion increases blood pressure via increased volume load, elevated peripheral arterial resistance, and decreased aortic compliance. Sci Rep 2017;7:10947. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5591274/
  6. Groen J, Pelser H, Willebrands AF, et al. Extract of licorice for the treatment of Addison’s disease. N Engl J Med 1951;244:471-75. https://www.ncbi.nlm.nih.gov/pubmed/14806786
  7. Cooper H, Bhattacharya B, Verma V, et al. Liquorice and soy sauce, a life-saving concoction in a patient with Addison’s disease. Ann Clin Biochem 2007;44:397-99. https://www.ncbi.nlm.nih.gov/pubmed/17594790
  8. Farese S, Kruse Anja, Pasch A, et al. Glycyrrhetinic acid food supplementation lowers serum potassium concentration in chronic hemodialysis patients. Kidney International 2009;76:877-84. https://www.ncbi.nlm.nih.gov/pubmed/19641483

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis or its affiliate healthcare centers, Mass General Hospital, Harvard Medical School or its affiliated institutions. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

How does excess licorice consumption cause hypertension and hypokalemia?