Nebulized Heparin in 2025: at the Interface between Promising Benefits and the Need for Further Research

In the contemporary era of anticoagulation, when direct oral anticoagulants (DOACs) dominate the market,[1] heparin remains an indispensable therapeutic agent in some clinical scenarios due to its unique pharmacokinetic properties.[2] The primary applications of heparin include acute and critical care settings, where its rapid onset and reversibility make it the preferred choice for immediate anticoagulation, such as in unstable patients with pulmonary embolism (PE) or those undergoing cardiopulmonary bypass surgery.[3] Heparin is also widely used in patients with severe kidney failure, as its metabolism is not significantly influenced by renal function, also playing a key role in bridging therapy for patients transitioning on or off DOACs or warfarin, in anticoagulation during pregnancy and breastfeeding, in patients undergoing hemodialysis and extracorporeal circulation, and in severe cases of coronavirus disease 2019 (COVID-19), particularly among those requiring intensive care and/or mechanical ventilation.[3] [4]

In these clinical contexts, unfractionated heparin (UFH) and low-molecular-weight heparin are typically administered parenterally, either intravenously (especially UFH) or subcutaneously. The invasive nature of these administration routes has been a major driving force behind the development of DOACs, which offer the advantage of oral administration, potentially improving patient compliance.[5]

To overcome this limitation and, indeed, to provide targeted anticoagulant therapy to the lung to aid COVID-19/PE therapy, recent research has explored alternative formulations of heparin, particularly intranasal and nebulized delivery systems. Preliminary trials have yielded encouraging results, as summarized in an article published 3 years ago in this journal.[6] Since then, additional studies have assessed the clinical efficacy and therapeutic potential of nebulized heparin, generating notable findings, so we felt that a Commentary on this topic would be of interest to the readership.

In 2023, Zhang et al. conducted a systematic review and meta-analysis summarizing the evidence on nebulized heparin in mechanically ventilated patients.[7] Their analysis included eight randomized clinical trials (RCTs) with a total of 651 patients. Comparisons were made between nebulized heparin (between 5,000 IU every 12 hours and 25,000 IU every 4 hours) and various controls, including no treatment (n = 1 study), nebulized water (n = 1 study), nebulized salbutamol (n = 1 study), and nebulized sodium chloride (NaCl) at different concentrations (n = 5 studies). Overall, nebulized heparin was associated with significantly reduced length of stay in the intensive care unit (ICU; six studies; mean difference: −1.10 days, 95% confidence interval [CI]: −1.87 to −0.33), shorter duration of mechanical ventilation (two studies; mean difference: −2.63 days, 95% CI: −3.68 to −1.58), prolonged ventilator-free days (two studies; mean difference: 4.22 days; 95% CI: 1.10–7.35), and reduced overall hospital stay (three studies; mean difference: −1.00 days; 95% CI: −2.90 to −0.90). However, in-hospital mortality remained unchanged (five studies; odds ratio [OR]: 1.10; 95% CI: 0.69–1.77). Importantly, these benefits were not associated with increased incidence of adverse events, particularly bleeding. Additional studies have been published following this meta-analysis.

In the same year, Gupta et al. conducted a systematic literature review to evaluate the efficacy of nebulized heparin in COVID-19 patients presenting with respiratory symptoms.[8] Their analysis included five studies, that is, two prospective observational, two RCTs, and one case report, encompassing a total of 286 patients, 209 of whom received nebulized heparin at doses ranging from 4,000 IU every 12 hours to 25,000 IU every 6 hours. Although a formal meta-analysis was not performed, the authors reported that patients receiving nebulized heparin showed improved oxygen saturation, reduced concentrations of inflammatory biomarkers, and potentially shorter hospital stays.

Semigolovskii et al. published an observational study to explore the impact of ultrasound nebulized UFH on hospital mortality in patients with hemodynamically insignificant PE.[9] The authors analyzed the clinical outcomes in 713 patients admitted to a cardiac ICU, with nebulized UFH administered at a dose of 5,000 IU twice daily starting from the year 2004, later supplemented with apixaban (10 mg twice daily for 7 days, followed by 5 mg twice daily) from 2014 onward. Although no formal statistical analysis was conducted, the study reported a nearly three-fold reduction in PE-related mortality following the introduction of nebulized heparin, decreasing from 40–45% to 10–15%. Scintigraphic imaging demonstrated a reduction in perfusion abnormalities within 7 days of treatment start. No clinically significant bleeding events or cases of heparin-induced thrombocytopenia were reported.

In a subsequent investigation,[10] Borsi et al. conducted a double-blind clinical trial including 40 intubated ICU patients with pneumonia, randomly assigned to receive either nebulized heparin (5,000 IU every 8 hours) or normal saline. The incidence of emergency tracheal tube replacement due to blockage was significantly lower in the nebulized heparin group compared with the saline group (60% vs. 75%; p = 0.013). Moreover, nebulized heparin was associated with a significant reduction in the number of emergency suctions or tracheal tube occlusion removals (5.5 vs. 6.5; p = 0.01).

Ismail et al. conducted an RCT involving 100 COVID-19 patients[11] to assess the efficacy of prophylactic nebulized heparin in mitigating acute lung injury. Participants were randomized to receive either nebulized heparin at a dose of 1,000 IU/kg every 6 hours or placebo (saline). The authors found that the nebulized heparin group showed a significantly improved hypoxic index after 3 to 4 days (346 vs. 329; p = 0.040) and 5 to 7 days (350 vs. 324; p = 0.014) of prophylaxis. Additionally, the increase in D-dimer levels after 3 days of treatment was lower in the heparin group compared with the placebo group (221 vs. 252 ng/mL; p = 0.016). Importantly, no bleeding complications were reported in the heparin group.

In a randomized, triple-blind, placebo-controlled Phase I/II clinical trial,[12] Ramos da Silva Grillo et al. investigated the anticoagulant, antiviral, and anti-inflammatory profiles, as well as the respiratory outcomes, of inhaled heparin in hospitalized COVID-19 patients. Patients were randomized to receive inhalations of enriched heparin (n = 13; 12.5 mg diluted in 5 ml of 0.9% saline) or placebo (n = 14; saline) every 4 hours for 7 days. Among the secondary outcomes, the heparin inhalation group demonstrated a reduced need for supplemental oxygen therapy (p < 0.001 for trend) and an earlier increase in the ratio between partial fraction of inspired oxygen and partial pressure of oxygen (PaO₂/FiO₂) ratio (p = 0.032 for trend).

Hakim et al. conducted a subsequent RCT involving 88 adult patients with smoke inhalation injury.[13] Participants were assigned to receive either 5,000 IU of nebulized heparin or nebulized normal saline every 4 hours for up to 14 days. The study found that the mean PaO₂/FiO₂ ratio was significantly higher in the nebulized heparin group (p < 0.001), but there were no statistically significant differences between groups regarding the development of acute respiratory distress syndrome (p = 0.23), mortality (p = 0.35), or reintubation rates (p = 0.42).

Further research was conducted by Cosgrave et al. in a phase Ib/IIa open-label, multicenter RCT.[14] This study included 40 COVID-19 patients with acute lung opacities requiring high-flow nasal oxygen (>30 L/min), positive pressure ventilatory support, or invasive mechanical ventilation in the ICU for less than 48 hours. Patients were randomized to receive nebulized heparin (n = 20; 5,000 IU every 6 hours) or standard of care (n = 19, following the exclusion of one patient). No significant differences were observed in D-dimer concentration changes after 10 days of treatment (mean change: −316.5 ng/mL in the heparin group vs. −321.7 ng/mL in the standard of care group; p = 0.996). Moreover, respiratory improvement appeared 10 days was significantly greater in the standard of care group, while there were no significant differences in time to separation from advanced respiratory support, ICU/hospital discharge, or mortality between groups. However, given the small sample size, the low number of clinical outcome events (e.g., two deaths in the nebulized heparin cohort vs. three in the standard of care group), and the low therapeutic dosage of nebulized heparin compared with other studies, these findings should be interpreted with caution.

In conclusion, current evidence suggest that nebulized heparin has shown some potential clinical benefits in patients with acute respiratory conditions, offering a more comfortable administration route that may enhance patient compliance to the therapy without significantly increasing the bleeding risk. Nevertheless, further large-scale, well-designed clinical trials are necessary to fully establish the efficacy and safety of nebulized heparin across diverse patient populations.

Publication History

Received: 11 February 2025

Accepted: 05 March 2025

Accepted Manuscript online:
06 March 2025

Article published online:
28 March 2025

• References

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