Nebulized Heparin for Post-COVID-19-Related Hypoxia

To the editor

The pulmonary manifestations of coronavirus disease 2019 (COVID-19) may require a long time follow-up and a special therapeutic approach (such as pulmonary rehabilitation, supplementary oxygens, etc.).[1] [2] [3] This may end with pulmonary fibrosis that necessitates long time oxygen therapy.[4] Most of these patients are hospitalized because of oxygen supply need that exceeds the capacity of portable or home oxygen concentrator devices.[5] Nebulized and/or inhaled unfractionated heparin is investigated in some disease conditions. Some examples of these are smoke inhalation-related lung injuries, adult respiratory distress syndrome (ARDS), and pulmonary fibrosis. These trials were all safe and successful somewhat.[6] [7] [8] Here, we report two cases of post-COVID-19-related disabling respiratory distress conditions that were treated with nebulized unfractionated heparin administration.

The first case was that of an 81-year-old female COVID-19 patient. She was admitted to our hospital's intensive care unit (ICU) for mechanical ventilation support. A three day pulse 250 mg and 80 mg maintenance dose of IV methylprednisolone was started. Also, she had received diuretics and different antibiotics. After 24 days of ICU unit care, she has been transmitted to our medical world with a 10 L O₂ supply using a non-rebreather (NRB) facemask. Her ICU maintenance treatment of subcutaneous low molecular weight heparin (LMWH) enoxaparin sodium 0.6 mL twice daily, methylprednisolone 40 mg PO daily continued. During her seventh day of follow-up at our medical ward, N-acetylcysteine 300 mg IV thrice daily was also initiated. Despite these maintenance therapies, her O₂ need was not decreased. On the 14th day of medical ward follow-up, still, her O₂ requirement was 8 to 10 L (to keep pulse oxymetry oxygen saturation [sO₂] at 92%). The ground glass appearances, bronchial dilatations, and cardiomegaly are evident in her chest CT ([Fig. 1]). Her insistence on home discharge was continued even at this critical level of O₂ supply need. After a thorough search for possible nonharmful therapeutic approaches at these conditions, the suggestion of using nebulized heparin was made by the first author. In addition to the COVID-19 inpatient written consent form, this treatment was discussed with the patient and her first-degree kin. After a positive response, the first dose of 10,000 IU UFH (Koparin [Kocak Farma Ltd. Co.]) was administered by nebulizer for 1 hour (diluted in 3 mL of 0.9% NaCl solution). At the next day of this treatment, her oxygen need was decreased to 5 L (sO₂ was 92%) (without any noted side effects). So, the dose of nebulized UFH increased to twice daily thereafter. At the end of third day of nebulized UFH treatment, her sO₂ became 94% (with only a 4 L nasal O₂ supply). Because of her insistence, she was discharged home with a portable O₂ concentrator treatment support. On the 10th day of discharge, she has contacted by phone. She claimed that she is doing well. Her sO₂ is approximately 95% (with a 3–4 L O₂ supply) ([Table 1] for the progress).

Table 1 Pre- and post-nebulized unfractionated heparin (UFH) treatment days cases' oxygen saturation and need

Days		−1	0	1	2	3	4	5	10
Nebulized UFH	Case 1	−	+	+	+	+	−	−	−
	Case 2	−	+	+	+	+	+	−	−
O2 need (L)	Case 1	8–10	8–10	5	5	4	−	−	3–4
	Case 2	10	10	8	8	8	8	7–8	4
sO2 (%)	Case 1	92	92	92	94	94			94
	Case 2	90–91	90	93	93	93	92–93	93	94

Fig. 1 Views from chest computed tomography of the cases (A = Case1, and B = Case 2).

The second case was that of a 67-year-old male COVID-19 patient. His chest CT shows consolidations, ground-glass appearance, and bronchial dilations ([Fig. 1]). On the 17th day of admission, NRB facemask O₂ support was not successful in keeping his sO₂ levels above 92%. So, heated and humidified high-flow nasal oxygen support was started. Supportive maintenance steroid and LMWH were all given. On the 29th day of hospital admission, O₂ needs were settled at 10 L (with sO₂ levels of 90–91%). With the courage of positive results of our nebulized UFH therapy in the above first case, we discussed this treatment option with this patient too. After a positive response, as in the above previous patient, this UFH treatment was initiated as 10,000 IU twice daily. On the day of starting this treatment, the sO₂ level was 91% (with a 10 L NRB facemask O₂ supply). The day after starting this therapy, his sO₂ was raised to 93% (with an 8 L O₂ supply). As in the first case, this patient was discharged on the fifth day of completion of UFH therapy with a 2 to 3 L O₂ supply need only (sO₂ = 94%) ([Table 1]).

Publication History

Received: 04 May 2021

Accepted: 16 June 2021

Article published online:
30 July 2021

• References

• 1 Greenhalgh T, Knight M, A'Court C, Buxton M, Husain L. Management of post-acute COVID-19 in primary care. BMJ 2020; 370: m3026
• 2 van de Veerdonk FL, Kouijzer IJE, de Nooijer AH. et al. Outcomes associated with use of a Kinin B2 receptor antagonist among patients with COVID-19. JAMA Netw Open 2020; 3 (08) e2017708
• 3 Recognizing happy hypoxia syndrome as a new symptom of COVID-19 | Universitas Gadjah Mada. Access December 20, 2020 at: https://www.ugm.ac.id/en/news/19993-recognizing-happy-hypoxia-syndrome-as-a-new-symptom-of-covid-19
• 4 Rai DK, Sharma P, Kumar R. Post COVID-19 pulmonary fibrosis. Is it real threat?. Indian J Tuberc 2021; 68 (03) 330-333
• 5 Sardesai I, Grover J, Garg M. et al. Short term home oxygen therapy COVID-19 patients: the COVID-HOT algorithm. J Family Med Prim Care 2020; 9 (07) 3209-3219
• 6 Yildiz-Pekoz A, Ozsoy Y. Inhaled heparin: therapeutic efficacy and recent formulations. J Aerosol Med Pulm Drug Deliv 2017; 30 (03) 143-156
• 7 Ashraf U, Bajantri B, Roa-Gomez G, Venkatram S, Cantin A, Diaz-Fuentes G. Nebulized heparin and N-acetylcysteine for smoke inhalational injury: a case report. Medicine (Baltimore) 2018; 97 (19) e0638
• 8 Abdelaal Ahmed Mahmoud A, Mahmoud HE, Mahran MA, Khaled M. Streptokinase versus unfractionated heparin nebulization in patients with severe acute respiratory distress syndrome (ARDS): a randomized controlled trial with observational controls. J Cardiothorac Vasc Anesth 2020; 34 (02) 436-443
• 9 Seeds EAM, Page CP. Heparin inhibits allergen-induced eosinophil infiltration into guinea-pig lung via a mechanism unrelated to its anticoagulant activity. Pulm Pharmacol Ther 2001; 14 (02) 111-119
• 10 Vancheri C, Mastruzzo C, Armato F. et al. Intranasal heparin reduces eosinophil recruitment after nasal allergen challenge in patients with allergic rhinitis. J Allergy Clin Immunol 2001; 108 (05) 703-708
• 11 van Haren FMP, Page C, Laffey JG. et al. Nebulised heparin as a treatment for COVID-19: scientific rationale and a call for randomised evidence. Crit Care 24 454;2020 https://doi.org/10.1186/s13054-020-03148-2
• 12 Dixon B, Smith RJ, Campbell DJ. et al; CHARLI Study Group. Nebulised heparin for patients with or at risk of acute respiratory distress syndrome: a multicentre, randomised, double-blind, placebo-controlled phase 3 trial. Lancet Respir Med 2021; 9 (04) 360-372