Severe disease

How common is hyponatremia in patients with Covid-19 and what’s its significance?  

FA Manian MD, MPH, , , , , , , , , , , , , , , , , , , , Leave a comment

Hyponatremia has been reported between 20% and 35% of patients hospitalized for Covid-19, 1-5 with low serum sodium levels on admission often associated with progression to severe illness, mechanical ventilation, increased length of stay and death.1,2,4,5

A 2023 retrospective multicenter study involving over 2,600 hospitalized Covid-19 patients (between February 2020 and August 2022) found hyponatremia in 34.2%: Mild (Na 131-134 mmol/L) 25.1%, moderate (Na 126-130 mmol/L) 7.5% and severe (<126 mmol/L) 1.8%.3 There was a significant association between male sex at birth, hypertension, chronic kidney disease, immunosuppressives, thiazide diuretics and hyponatremia.3

Similarly, another retrospective study of hospitalized Covid-19 patients found an association between hyponatremia and several common chronic diseases, such as diabetes, hypertension, ischemic heart disease, chronic liver disease and chronic kidney disease.4 It’s important to note that since older age has also been found to be a risk factor for hyponatremia in Covid-19, the independent contribution of these conditions to hyponatremia is unclear.3

As with many other infectious diseases, the mechanism of hyponatremia in patients with Covid-19 likely has multiple causes, including hypovolemia, syndrome of inappropriate anti-diuretic hormone secretion (SIADH), diuretic use and corticosteroid deficiency, particularly in the critically ill. 1-4  

Interestingly, a study performed early in the pandemic (March 2020) found that the majority (57%)  of hospitalized Covid-19 patients with hyponatremic were euvolemic and that the administration of isotonic saline to such patients was independently associated with increased hospital mortality (cause unclear).2 The authors suggested closer attention to the volume status of Covid-19 patients with hyponatremia (eg, through closer attention to the jugular venous pressure on physical exam) before considering treatment with isotonic saline.

Last, Covid-19 may be associated with hyponatremia during the post-discharge period as well.  An intriguing 2024 study found nearly 25% of patients with Covid-19 developed hyponatremia (<135 mmol/L) during the 1-year follow-up period after discharge with most not reported to have hyponatremia during their index hospitalization.5 In the same study, hyponatremia was associated with older age, male sex, diabetes, hypertension, heart failure, previous invasive ventilatory support and increased rate of readmission.5

Bonus Pearl: Did you know that there is an inverse relationship between interleukin-6, a key pro-inflammatory cytokine, and plasma sodium levels in Covid-19 and that this association may be stronger than that of other viral or bacterial respiratory infections?2  

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References

  1. Ayus JC, Klantar-Zadeh K, Tantisattamo E, et al. Is hyponatremia a novel marker of inflammation in patients with Covid-19? Nephrol Dial Transplant 2023;38:1921-24. Is hyponatremia a novel marker of inflammation in patients with COVID-19? – PubMed (nih.gov)
  2. Pazos-Guerra M, Ruiz-Sanchez JG, Perez-Candel X, et al. Inappropriate therapy of euvolemic hyponatremia, the most frequent type of hyponatremia in SARS-CoV-2 infection, is associated with increased mortality in COVID-19 patients. Front Endocrinol 2023; 14:1227058. Inappropriate therapy of euvolemic hyponatremia, the most frequent type of hyponatremia in SARS-CoV-2 infection, is associated with increased mortality in COVID-19 patients – PubMed (nih.gov)
  3. De Haan L, ten Wolde, Beudel M, et al. What is the aetiology of dynatreaemia in COVID-19 and how is this related to outcomes in patients admitted during earlier and later COVID-19 waves? A multicentre, restrospective observational study in 11 Dutch hospitals. BMJ Open 2023;13:e075232. Original research: What is the aetiology of dysnatraemia in COVID-19 and how is this related to outcomes in patients admitted during earlier and later COVID-19 waves? A multicentre, retrospective observational study in 11 Dutch hospitals – PMC (nih.gov)
  4. Rehman F, Rehan ST, Rind BJ, et al. Hyponatremia causing factors and its association with disease severity and length of stay in Covid-19 patients: A retrospective study from tertiary care hospital. Medicine 2023; 102:45(e35920) Hyponatremia causing factors and its association with disease severity and length of stay in COVID-19 patients: A retrospective study from tertiary care hospital – PubMed (nih.gov)
  5. Biagetti B, Sanchez-Montalva A, Puig-Perez A, et al. Hyponatremia after COVID-19 is frequent in the first year and increases re-admissions. Scientific Reports 2024:14:595. Hyponatremia after COVID-19 is frequent in the first year and increases re-admissions – PubMed (nih.gov)

 

Disclosures/Disclaimers: 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!

How common is hyponatremia in patients with Covid-19 and what’s its significance?  

How should I generally go about treating my non-ICU hospitalized patient with newly diagnosed Covid-19 and who doesn’t require more than conventional O2?

FA Manian MD, MPH, , , , , , , , , , , , , , , Leave a comment

Much of the management of Covid-19 hospitalized patients who don’t require ICU care and need no more than conventional 02 (ie, high-flow or mechanical/non-mechanical ventilatory support) depends on the severity of their disease: “mild/moderate” (eg, SpO2≥94% on room air) vs “severe” (eg, Sp02<94% on room air) disease; respiration rate ≥30/min and lung infiltrates on chest radiograph>50% may also be considered, but I personally find these parameters less reliable.  Generally, patients hospitalized with Covid-19-related symptoms (respiratory or otherwise) require specific treatment to keep them from progressing or succumbing to their disease (see Figure below). 1-5

In patients with mild/moderate Covid-19, the first step is to determine whether they are at low risk (ie, NO risk factors) or high risk (ie, ≥1 risk factors) of progression to severe disease.  Recall that there are numerous risk factors for progression, including age (eg, ≥50 y) and many comorbidities, such as diabetes, chronic kidney disease, obesity, smoking (current or former), disability (eg, wheelchair dependence), and mental health disorders (eg, depression), just to name a few.1 If your patient with mild/moderate Covid-19 has ANY Covid-related symptoms and ANY risk factors for progression, you should strongly consider IV remdesivir. If your patient’s admission has nothing to do with Covid-19 but qualify for anti-Covid treatment, an oral anti-viral regimen (eg, nirmatrelvir-ritonavir [Paxlovid]) used for ambulatory patients may also be considered (see related pearl on P4P). If your patient has NO risk factors for progression to severe disease, symptomatic treatment is all that’s needed.

If your patient has severe disease but no need for 02 supplementation, IV remdesivir and prophylactic heparin (either fractionated [eg, enoxaparin] or unfractionated) should be considered; no need for dexamethasone or systemic steroids in this situation.

If your patient has severe Covid-19 and needs supplemental 02, you should consider initiation of remdesivir, dexamethasone and, at the minimum, prophylactic anticoagulation with either a fractionated or unfractionated heparin product as soon as possible.  Use of therapeutic anticoagulation in this setting (ie, outside of ICU) is controversial with NIH guidelines recommending therapeutic heparin for those with elevated D-dimer without increased bleeding risk (CIIa, “weak” with moderate supportive evidence).2,6,7  You may also be able to forgo systemic steroids in your patient with minimal 02 requirement (ie, 1-2 L) per NIH, particularly if immunocompromised, as hypoxia in such patients may be more related to viral infection itself and not significant inflammatory reaction.

If your patient with severe Covid-19 gets progressively worse requiring high-flow oxygen or non-invasive ventilation outside of ICU, you should consider adding baricitinib as a first line immunomodulator (tocilizumab or others in NIH guidelines as an alternative)2 in patients who are not already immunocompromised or do not already have and are not at high risk of secondary infections.

The duration of remdesivir treatment in hospitalized patients is usually 5 days (or until discharge) for severe Covid-19, and 3 days for those with mild/moderate disease. The ultimate duration should be individualized in patients at risk of ongoing viral replication.  One retrospective study in immunocompromised patients hospitalized for Covid-19 found remdesivir to be effective in reducing hospitalization and mortality when initiated within 2 days of hospitalization and given for a median of 5 days, even among those not requiring 02 supplementation or requiring only low flow 02.

Couple more things to keep in mind when managing severe Covid-19. When indicated, remdesivir should be given ideally as early as possible and no later than 10 days after onset of symptoms and dexamethasone should be given for up to 10 days or until discharge.  Anticoagulation, prophylactic or therapeutic, should only be prescribed in the absence of any contraindications for bleeding (see Figure footnote) and continued until discharge for no more than 14 days total.

As with all drugs, please make sure you are thoroughly familiar with the dosing, adverse effects and contraindications to above-referenced medications before prescribing them.

Figure. Management of SARS-CoV-2 positive hospitalized patients requiring no or only conventional 02 due to Covid-19

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References

  1. CDC. Interim Clinical Considerations for COVID-19 Treatment in Outpatients | CDC. Accessed Feb 1, 2024
  2. NIH. Clinical Spectrum | COVID-19 Treatment Guidelines (nih.gov). Accessed Feb 1, 2024
  3. Uptodate. Coived-19 management in hospitalized patients. https://www.uptodate.com/contents/covid-19-management-in-hospitalized-adults. Accessed Feb 5, 2024.
  4. Bash K, Sacha G, Latifi M. Covid-19: A management update. Clev Clin J Med 2023;90:677-683. https://www.ccjm.org/content/90/11/677
  5. Mozaffari E, Chandak A, Gottlieb RL, et al. Remdesivir reduced mortality in immunocompromised patients hospitalized for Covid-19 across variant waves: Findings from routine clinical practice. Clin Infect Dis 2023; 77;1626-34. https://pubmed.ncbi.nlm.nih.gov/37556727/
  6. Merz LE, Fogerty AE. The conundrum of anticoagulation for hospitalized patient with Covid-19. NEJM Evidence 2023;2 (2).  https://evidence.nejm.org/doi/full/10.1056/EVIDe2200329
  7. ATTACC, CTIV-4a, REMAP-CAP Investigators. Therapeutic anticoagulation with heparin in noncritically patients with Covid-19. N Engl J Med 2021; 385:790-802. https://pubmed.ncbi.nlm.nih.gov/34351721/

Disclosures/Disclaimers: 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!

How should I generally go about treating my non-ICU hospitalized patient with newly diagnosed Covid-19 and who doesn’t require more than conventional O2?

When should I consider treating my adult ambulatory patient with newly diagnosed Covid-19 with an antiviral drug?

FA Manian MD, MPH, , , , , , , , , , , , , , , 1 Comment

You should seriously consider prescribing an antiviral agent either oral nirmatrelvir-ritonavir (Paxlovid) (within 5 days of onset of symptoms) or IV remdesivir (within 7 days of onset of symptoms) in all your ambulatory patients with mild/moderate Covid-19 at high risk of progression (ie, ≥1 risk factors) to severe disease (Figure). 1-3 Both of these drugs reduce hospitalization and mortality from Covid-19 by over 85%!1 Oral molnupiravir may be prescribed as a second-line agent (within 5 days of onset of symptoms), if neither Paxlovid or remdesivir is an option and the patient is not pregnant. There is no indication for the use of  dexamethasone or systemic steroids in the treatment of Covid-19 in ambulatory settings. As with all drugs, you should be familiar with adverse-effects and contraindications of these anti-viral agents before prescribing them. 

Couple of questions to ask when managing a patient with newly diagnosed Covid-19 in ambulatory setting:

  1. Does your patient truly have mild/moderate disease (eg, Sp02 on room air ≥94% on room air and not tachypneic) or severe disease (eg, Sp02 on room air <94%)?4 If severe disease is likely, you should refer your patient to a hospital for evaluation and treatment as soon as possible. If your patient is not symptomatic from Covid-19, no antiviral treatment is indicated. 
  2. Once you decide your patient has mild/moderate disease and doesn’t need to go to hospital, ask whether your patient has any risk factor associated with progression to severe Covid-19.2 Recall that there are numerous risk factors, including age over 50 and many physical disabilities, smoking (current or former) and mental health disorders, such as depression, ADHD, autism and depression that may be present even in the younger population.2
    • In the absence of any risk factor for progression, no antiviral therapy is indicated.

In the presence of 1 or more risk factors for progression or contraindications, you should consider initiation of Paxlovid x 5 days, if within 5 days of onset of Covid-19 symptoms or IV remdesivir x 3 days, if within 7 days of onset of Covid-19 symptoms.  

  • Remember that although Paxlovid may potentially interact with numerous drugs, fewer such drugs are absolutely contraindicated. Convenient online resources are available to help you decide if your patient can still receive Paxlovid safely.
  • Also don’t forget that remdesivir can now be given without dosage adjustment in renal insufficiency, including those on dialysis. 

If for some reason neither Paxlovid nor remdesivir is an option, oral molnupiravir can be considered with some caveats, including recommendations against its use during pregnancy and use of effective contraception during and following treatment in people who engage in sexual activity that may result in conception. 

Irrespective of treatment, it is prudent to monitor for any deterioration of sp02 at home when managing patients with mild/moderate Covid-19.  

Bonus pearl: Did you know that despite its high efficacy (89% reduction in hospitalization and death) against Covid-19,1,5 Paxlovid is severely underutilized in the outpatient setting with fewer than 25% of eligible patients with Covid-19 receiving it?6

Figure: Covid-19 management in ambulatory adult patients

 

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References

  1. Rubin R. Paxlovid Is Effective but Underused—Here’s What the Latest Research Says About Rebound and More | Infectious Diseases | JAMA | JAMA Network Published online January 31, 2024. doi:10.1001/jama.2023.28254
  2. Interim Clinical Considerations for COVID-19 Treatment in Outpatients | CDC. Accessed Feb 1, 2024
  3. Molnupiravir | COVID-19 Treatment Guidelines (nih.gov). Accessed Feb 1, 2024.
  4. Clinical Spectrum | COVID-19 Treatment Guidelines (nih.gov). Accessed Feb 1, 2024
  5. Appaneal HJ, LaPlante KL, Lopes VV, et al. Nirmatrelvir/ritonavir utilization for the treatment of non-hospitalized adults with Covid-10 in the National Veterans Affairs (VA) Healthcare System. Infectious Diseases and Therapy 204;13:155-172. Nirmatrelvir/Ritonavir Utilization for the Treatment of Non-hospitalized Adults with COVID-19 in the National Veterans Affairs (VA) Healthcare System | Infectious Diseases and Therapy (springer.com)
  6. Hammond J, Leister-Tebbe H, Gardner A, et al. Oral Nirmatrelvir for high-risk, nonhospitalized adults with Covid-19. N Engl J Med 2022; 386:397-408. Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19 – PubMed (nih.gov)

 

Disclosures/Disclaimers: 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!

 

 

When should I consider treating my adult ambulatory patient with newly diagnosed Covid-19 with an antiviral drug?