Dear Editor:
We have read with great interest the article published by Sarvazad et al. [1], where they found that hyponatremia was present in 38% of patients (22/58); also it was more common in outpatients than in patients in Intensive Care Units. However, Zhang et al. found that in patients hospitalized by SARS-CoV-2 infection, hyponatremia was closely related to the severity of infection [2]. It is known that hyponatremia is an electrolyte disorder associated with high morbidity, and his correction decreases the risk of mortality regardless of the cause [3].
In this manuscript, we describe our hospital experience with the diagnosis and management of an important cause of hyponatremia in times of the COVID-19 pandemic: the syndrome of inappropriate antidiuretic hormone secretion (SIADH), which occurs in response to the continuous release of antidiuretic hormone (ADH) despite low serum osmolality and has multifactorial etiology.
The pathogenesis of SIADH in patients with COVID-19 pneumonia involves the production of proinflammatory cytokines, mainly interleukin-6 (IL-6), which directly stimulate the nonosmotic release of ADH and cause direct damage to the alveolar basement membrane; this triggers the activation of the hypoxic pulmonary vasoconstriction pathway, leading to increased ADH production [4]. This was evidenced in a retrospective study of a case series of 52 patients with COVID-19, wherein an inverse correlation was found between sodium concentration and IL-6 levels [5].
The diagnosis is made on the basis of serum sodium levels indicating euvolemic hypoosmolar hyponatremia after ruling out renal disease, adrenal insufficiency, and hypothyroidism, as well as diuretic use. Treatment in our country, due to unavailability of vasopressin receptor antagonists (vaptans), is based on water restriction. However, this therapeutic measure involves high risk of failure due to the requirement of time to be effective; the response not being stable and varying on a daily basis; poor compliance to the indications; and the requirement of renal function monitoring [6], especially in the elderly population.
In our clinical experience in a COVID-19 Unit of a Social Security Hospital in Peru (Table 1), we identified and treated two elderly patients without contributory medical history, who were diagnosed with severe COVID-19 pneumonia confirmed via reverse transcription polymerase chain reaction and who developed euvolemic hypoosmolar hyponatremia. These patients did not respond to hydration with normal saline solution. On examining laboratory results, their biochemical findings were found to be compatible with SIADH. Both patients underwent water restriction, which was individualized and consisted of a fluid restriction of 500 ml/day less than the urinary volume of 24 h, with appropriate renal function monitoring, which contributed to the management of COVID-19, and achieved an improvement in serum sodium levels.
Table 1.
Demographic and laboratory characteristics of patients with COVID-19 and SIADH
| Case 01 | Case 02 | |
|---|---|---|
| Age (years) | 89 | 70 |
| Gender | Female | Male |
| Chronic disease | none | None |
| Symptoms | Cough, shortness of breath, and drowsiness | Cough, fever, and shortness of breath |
| Chest CT without contrast on admission | Ground-glass pattern involving 50% of both lungs | Ground-glass pattern involving 45% of both lungs |
| CBC on admission | ||
| Hemoglobin (Hb): 12.9–18.4 g/dl | Hb: 12.5 | Hb: 14.1 |
| Platelets (PLT): 150–450 × 103/ul | PLT: 269 | PLT: 548 |
| White blood cells (WBC): 5–10 × 103/ul | WBC: 8540 | WBC: 12,060 |
| Band neutrophils (AB): 0–5% | AB: 0 | AB: 2 |
| Lymphocytes (LT): 20–40% | LT: 6 | LT:4 |
| Ferritin level on admission | ||
| Male: 28–365 ng/ml | 1664 | 951 |
| Female: 5–148 ng/ml | ||
| C-reactive protein on admission | ||
| Normal < 10 mg/l | 39 | 112 |
| Serum electrolyte on admission | ||
| Na: 135–145 mEq/L | Na: 128 | Na: 124 |
| K: 3.5–5 mEq/L | K: 3.7 | K:5.1 |
| Serum osmolarity | ||
| Normal range: 285–295 mmol/kg | 262 | 254 |
| Biochemical profile | ||
| Glucose (Glu): 70–100 mg/dl | Glu: 122 | Glu: 119 |
| Creatinine (Cr): 0.5–1.2 mg/dl | Cr:0.5 | Cr: 0.6 |
| ALT: 10–49 U/l | ALT:57 | ALT:66 |
| AST: 0–34 U/l | AST:54 | AST:65 |
| GGT: 0–38 U/l | GGT:56 | GGT:43 |
| ALP: 45–129 U/l | ALP: 115 | ALP: 80 |
| Volemia | Euvolemia | Euvolemia |
| Use of diuretics | No | No |
| Response to normal saline | No | No |
| Initial diagnostic | Euvolemic hypoosmolar hyponatremia. Severe COVID-19 pneumonia | Euvolemic hypoosmolar hyponatremia. Severe COVID-19 pneumonia |
| Basal cortisol-8:00 h | ||
| Normal range: 5–25 ug/dl | 26 | 15 |
| Thyroid profile | ||
| TSH: 0.55–4.78 uUI/ml | TSH:2.06 | TSH: 2.30 |
| fT4: 0.89–1.76 ng/dl | fT4: 1.09 | fT4: 1.4 |
| Serum uric acid | ||
| Male: 3.7–9.2 mg/dl | 1.8 | 1.4 |
| Female: 3.1–7.8 mg/dl | ||
| Urine specific gravity | ||
| Normal range: 1.005–1.030 | 1.010 | 1.010 |
| Urine sodium level | ||
| Normal range: 40–220 mEq/day | 165 | 175 |
| FENa (%) | > 0.5 | > 0.5 |
| Urinary osmolality | ||
| Normal range: 50–1200 mOsm/Kg | 350 | 372 |
| Treatment | Initially hypertonic saline, after water restriction. Management of COVID-19 infection | Initially hypertonic saline, after water restriction. Management of COVID-19 infection |
| Final serum electrolytes | ||
| Na (mEq/L), K (mEq/L) | 23 days after admission: Na:132, K:4.3 | 25 days after admission: Na: 136, K:3.8 |
Data obtained from the Division of Neumology of Hospital Nacional Guillermo Almenara Irigoyen
ALT Alanine transaminase, ALP Alkaline phosphatase, AST Aspartate transaminase, CBC Complete blood count, FENa fractional excretion of sodium, fT4 free thyroxine, GGT Gamma-glutamyltransferase, TSH thyroid-stimulating hormone
As in other patients with unstable hemodynamics, patients with severe COVID-19 require fluid administration as a mainstay of treatment. Extravascular volume overload is an unintended consequence of intensive fluid therapy. It makes the administration of it careful in these patients [7], especially in patients with advanced age. During the treatment of COVID-19 infection, it is important to highlight the effects of corticosteroid use in these patients, such as water and sodium retention, especially those with mineralocorticoid action and when high doses are administered [8]. Some corticoids have minimal mineralocorticoid effects, such as dexamethasone, which it's used in patients who require mechanical ventilation or oxygen because it showed a decrease in mortality according to the RECOVERY study [9]. The indirect effects of glucocorticoids in the proximal tubule increase the cellular response of angiotensin II-stimulated sodium transporters; in the distal tubule, their effect appears to be related to cross-binding to mineralocorticoid receptors. As a result, there is an increase in sodium and water retention, and circulating volume increases [10].
Additionally, some patients may require positive pressure ventilation, which can contribute to fluid retention, because it raises intrathoracic pressure, which in turn leads to a decrease in central arterial blood volume. Finally, the activation of baroreceptors increases vasomotor tone and the reabsorption of sodium and water destined to increase blood volume [11].
In conclusion, we highlight the importance of identifying the underlying etiological hyponatremia in patients with COVID-19, with SIADH being a diagnostic and therapeutic challenge, especially in the elderly population, as well as emphasizing appropriate clinical judgment when deciding between fluid restriction and fluid therapy to avoid complications.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Consent for publication
Written informed consent was obtained from study participants for participation in the study and for publication of this report. Consent and approval for publication was also obtained from the Ethics Committee of the Guillermo Almenara Irigoyen Hospital-Lima, Peru.
Footnotes
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References
- 1.Sarvazad H, Cahngaripour S, Roozbahani NE, Izadi B. Evaluation of electrolytes status of sodium, potassium, magnesium, and fasting blood sugar at the initial admission of COVID-19 patients without underlying disease in Golestan Hospital. Kermanshah New Microbes New Infect. 2020 doi: 10.1016/j.nmni.2020.100807. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Zhang W, Lu S, Zhang M, et al. Zhonghuaweizhongbingjijiuyixue. 2020;32(7):774–778. doi: 10.3760/cma.j.cn121430-20200331-00417. [DOI] [Google Scholar]
- 3.Corona G, Giuliani C, Verbalis JG, et al. Hyponatremia improvement is associated with a reduced risk of mortality: evidence from a meta-analysis. PLoS ONE. 2015;10(4):e0124105. doi: 10.1371/journal.pone.0124105. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Mastorakos G, Weber JS, Magiakou MA, et al. Hypothalamic-pituitary-adrenal axis activation and stimulation of systemic vasopressin secretion by recombinant interleukin-6 in humans: potential implications for the syndrome of inappropriate vasopressin secretion. J ClinEndocrinolMetab. 1994;79(4):934–939. doi: 10.1210/jcem.79.4.7962300. [DOI] [PubMed] [Google Scholar]
- 5.Berni A, Malandrino D, Parenti G, et al. Hyponatremia, IL-6, and SARS-CoV-2 (COVID-19) infection: may all fit together? J Endocrinol Invest. 2020;43(8):1137–1139. doi: 10.1007/s40618-020-01301-w. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Mentrasti G, Scortichini L, Torniai M, et al. Syndrome of inappropriate antidiuretic hormone secretion (SIADH): optimal management. TherClin Risk Manag. 2020;16:663–672. doi: 10.2147/TCRM.S206066. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Kazory A, Ronco C, McCullough PA. SARS-CoV-2 (COVID-19) and intravascular volume management strategies in the critically ill. Proceedings (Baylor University. Medical Center) 2020 doi: 10.1080/08998280.2020.1754700. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Alessi J, de Oliveira GB, Schaan BD, et al. Dexamethasone in the era of COVID-19: friend or foe? An essay on the effects of dexamethasone and the potential risks of its inadvertent use in patients with diabetes. DiabetolMetabSyndr. 2020;12:80. doi: 10.1186/s13098-020-00583-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.RECOVERY Collaborative Group, Horby P, Lim W. S. et al Dexamethasone in Hospitalized Patients with Covid-19—preliminary report. The New England J Med NEJMoa2021436 Adv Online Publ. 2020 doi: 10.1056/NEJMoa2021436. [DOI] [Google Scholar]
- 10.Weinstein RS. Glucocorticoid-induced osteoporosis and osteonecrosis. EndocrinolMetabClin North Am. 2012;41(3):595–611. doi: 10.1016/j.ecl.2012.04.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Vignon P, Evrard B, Asfar P, et al. Fluid administration and monitoring in ARDS: which management? Intensive Care Med. 2020;46(12):2252–2264. doi: 10.1007/s00134-020-06310-0. [DOI] [PMC free article] [PubMed] [Google Scholar]