Nebulized Heparin in Burn Patients with Inhalation Trauma—Safety and Feasibility

Abstract

Background: Pulmonary hypercoagulopathy is intrinsic to inhalation trauma. Nebulized heparin could theoretically be beneficial in patients with inhalation injury, but current data are conflicting. We aimed to investigate the safety, feasibility, and effectiveness of nebulized heparin. Methods: International multicenter, double-blind, placebo-controlled randomized clinical trial in specialized burn care centers. Adult patients with inhalation trauma received nebulizations of unfractionated heparin (25,000 international unit (IU), 5 mL) or placebo (0.9% NaCl, 5 mL) every four hours for 14 days or until extubation. The primary outcome was the number of ventilator-free days at day 28 post-admission. Here, we report on the secondary outcomes related to safety and feasibility. Results: The study was prematurely stopped after inclusion of 13 patients (heparin N = 7, placebo N = 6) due to low recruitment and high costs associated with the trial medication. Therefore, no analyses on effectiveness were performed. In the heparin group, serious respiratory problems occurred due to saturation of the expiratory filter following nebulizations. In total, 129 out of 427 scheduled nebulizations were withheld in the heparin group (in 3 patients) and 45 out of 299 scheduled nebulizations were withheld in the placebo group (in 2 patients). Blood-stained sputum or expected increased bleeding risks were the most frequent reasons to withhold nebulizations. Conclusion: In this prematurely stopped trial, we encountered important safety and feasibility issues related to frequent heparin nebulizations in burn patients with inhalation trauma. This should be taken into account when heparin nebulizations are considered in these patients.

Nebulized Heparin for Adult Patients With Smoke Inhalation Injury: A Review of the Literature

“…The majority of these studies were retrospective and observational (6 studies), 1,12,[26][27][28]33 with only 2 prospective, randomized controlled trials. 34,35 One of the retrospective, observational studies reported only safety data. 33 No additional studies were identified through the review of reference lists.…”

“…Six of the 7 included studies comparing nebulized heparin with a control group reported rates of pneumonia, with 2 reporting statistically higher rates of pneumonia with nebulized heparin. 12,[26][27][28]33,35 Holt and colleagues were the first to report a higher incidence of pneumonia in patients receiving heparin, although this finding was not statistically significant (63% vs 50%, P = .12). 12 Yip and colleagues reported no difference in the incidence of pneumonia (17.3% vs 18.2%).…”

“…The final prospective evaluation of nebulized heparin was published by Glas and colleagues in 2020. 35 However, this multicenter, randomized, double-blind, placebo-controlled trial was stopped early due to slow recruitment and high cost of blinded placebo medication. Patients were randomized to receive either 25 000 units nebulized heparin every 4 hours or placebo within 36 hours of IHI, and therapy was continued for 14 days or until extubation or death.…”

“…There was 1 patient in the treatment arm of this study who had an aPTT greater than 150 seconds; however, this normalized after discontinuation of the heparin nebulization. 35 Most studies evaluating coagulopathy associated with nebulized heparin excluded patients with hypersensitivity to heparin and those with bleeding disorders or platelet counts less than 50 000/µL. 1,26,33 Nebulized heparin has not been shown to increase the rates of clinically significant bleeding at doses of up to 25 000 units in patients not meeting the aforementioned exclusion criteria.…”

“…27 Glas and colleagues found the incidence of pneumonia to be similar between heparin and placebo groups (2 vs 1 patient); however, these findings are limited by the premature cessation of the trial due to low enrollment and were not statistically analyzed. 35…”