Aerosolized anticoagulants ameliorate acute lung injury in sheep after exposure to burn and smoke inhalation
ABSTRACT Acute lung injury is a detrimental complication for victims of burn accidents. Airway obstruction plays an important role in pulmonary dysfunction in these patients. In this study, we tested the hypothesis that aerosolized anticoagulants will reduce the degree of airway obstruction and improve pulmonary function in sheep with severe combined burn and smoke inhalation injury by preventing the formation of airway fibrin clots.
Prospective, randomized, controlled, experimental animal study.
Investigational intensive care unit at a university hospital.
Adult female sheep.
After 7 days of surgical recovery, sheep were given a cutaneous burn (40% of total body surface, third degree) and insufflated with cotton smoke (48 breaths, <40 degrees C) under halothane anesthesia. After injury, sheep were placed on ventilators and resuscitated with lactated Ringer's solution. Sheep were randomly divided into five groups: sham, noninjured and nontreated (n = 6); control, injured and aerosolized with saline (n = 6); recombinant human antithrombin (rhAT) + heparin, injured and aerosolized with rhAT (290 units for each) and heparin (10,000 units for each) (n = 6); rhAT, injured and aerosolized with rhAT alone (290 units for each; n = 5); and heparin, injured and aerosolized with heparin alone (10,000 units for each; n = 5). rhAT and heparin were aerosolized every 4 hrs, starting at 2 hrs postinjury.
Cardiopulmonary hemodynamics were monitored during a 48-hr experimental time period. Control sheep developed multiple signs of acute lung injury. This pathophysiology included decreased pulmonary gas exchange and lung compliance, increased pulmonary edema, and extensive airway obstruction. These variables were stable in sham animals. The aerosolization of rhAT or heparin alone did not significantly improve deteriorated pulmonary gas exchange. However, aerosolization of these anticoagulants in combination significantly attenuated all the observed pulmonary pathophysiology.
The results provide definitive evidence that aerosolized rhAT and heparin in combination may be a novel treatment strategy for pulmonary pathology in burn victims with smoke inhalation injury.
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ABSTRACT: Background: Smoke inhalation is a major source of morbidity and mortality. Heparin and N-acetylcysteine treatment has potential efficacy in inhalation injury. We investigated the impact of a heparin/N-acetylcysteine/albuterol nebulization protocol in adult patients with inhalation injury. Methods: A retrospective review was performed of adult inhalation injury patients, admitted to a regional burn center between January 2011 and July 2012, who underwent a protocol of alternating treatments of heparin and N-acetylcysteine/albuterol nebulization every 4 hours. The study cohort was matched 1:1 by age, sex, and burn size to a control cohort admitted within 5 years before protocol implementation. Results: The study (n = 20) and control cohorts (n = 20) were well matched, with nearly identical age (50 vs 49 years), sex distribution (70% male), burn size (total body surface area, 22% vs 21%), and inhalation injury, except grade I injuries (79% vs 47%, P = 0.01). The protocol did not change mortality (30% vs 25%, P = 0.72) or duration of mechanical ventilation (8.5 vs 8.8 days, P = 0.9). There was no difference in development of sepsis (40% vs 33%, P = 0.7) or acute respiratory distress syndrome (15% vs 10%, P = 1); however, those who received the protocol were more likely to develop pneumonia (45% vs 11%, P = 0.03). Conclusions: The implementation of a heparin/N-acetylcysteine/albuterol protocol did not reduce mortality or duration of mechanical ventilation in this cohort of adults with inhalation injury and resulted in a significant increase in pneumonia rates. Larger prospective studies are necessary, with close attention paid to minimizing the infection risk incurred from frequent administration of nebulized medications.06/2014; 2(6):e165. DOI:10.1097/GOX.0000000000000121
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ABSTRACT: Pulmonary coagulopathy is a hallmark of lung injury following inhalation trauma. Locally applied heparin attenuates lung injury in animal models of smoke inhalation. Whether local treatment with heparin benefits patients with inhalation trauma is uncertain. The present trial aims at comparing a strategy using frequent nebulizations of heparin with standard care in intubated and ventilated burn patients with bronchoscopically confirmed inhalation trauma. The Randomized Controlled Trial Investigating the Efficacy and Safety of Nebulized HEParin versus Placebo in BURN Patients with Inhalation Trauma (HEPBURN) is an international multi-center, double-blind, placebo-controlled, two-arm study. One hundred and sixteen intubated and ventilated burn patients with confirmed inhalation trauma are randomized to nebulizations of heparin (the nebulized heparin strategy) or nebulizations of normal saline (the control strategy) every four hours for 14 days or until extubation, whichever comes first. The primary endpoint is the number of ventilator-free days, defined as days alive and breathing without assistance during the first 28 days, if the period of unassisted breathing lasts for at least 24 consecutive hours. As far as the authors know, HEPBURN is the first randomized, placebo-controlled trial, powered to investigate whether local treatment with heparin shortens duration of ventilation of intubated and ventilated burn patients with inhalation trauma.Trial registration: NCT01773083, registered on 16 January 2013.Recruiting. Randomisation commenced on 1 January 2014.Trials 03/2014; 15(1):91. DOI:10.1186/1745-6215-15-91 · 2.12 Impact Factor
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ABSTRACT: Pulmonary coagulopathy has become an important therapeutic target in adult respiratory distress syndrome (ARDS). We hypothesized that combining intravenous recombinant human antithrombin (rhAT), nebulized heparin, and nebulized tissue plasminogen activator (TPA) more effectively improves pulmonary gas exchange compared with a single rhAT infusion, while maintaining the anti-inflammatory properties of rhAT in ARDS. Therefore, the present prospective, randomized experiment was conducted using an established ovine model. Following burn and smoke inhalation injury (40% of total body surface area, third-degree flame burn, and 4 × 12 breaths of cold cotton smoke), 18 chronically instrumented sheep were randomly assigned to receive intravenous saline plus saline nebulization (control), intravenous rhAT (6 IU/kg/h) started 1 hour after injury plus saline nebulization (AT i.v.) or intravenous rhAT combined with nebulized heparin (10,000 IU every 4 hours, started 2 hours after injury), and nebulized TPA (2 mg every 4 hours, started 4 hours after injury) (triple therapy, n = 6 each). All animals were mechanically ventilated and fluid resuscitated according to standard protocols during the 48-hour study period. Both treatment approaches attenuated ARDS compared with control animals. Notably, triple therapy was associated with an improved PaO2/FiO2 ratio (p = 0.007), attenuated pulmonary obstruction (p = 0.02) and shunting (p = 0.025), as well as reduced ventilatory pressures (p < 0.05 each) versus AT i.v. at 48 hours. However, the anti-inflammatory effects of sole AT i.v., namely, the inhibition of neutrophil activation (neutrophil count in the lymph and pulmonary polymorphonuclear cells, p < 0.05 vs. control each), pulmonary transvascular fluid flux (lymph flow, p = 0.004 vs. control), and systemic vascular leakage (cumulative net fluid balance, p < 0.001 vs. control), were abolished in the triple therapy group. Combining intravenous rhAT with nebulized heparin and nebulized TPA more effectively restores pulmonary gas exchange, but the anti-inflammatory effects of sole rhAT are abolished with the triple therapy. Interferences between the different anticoagulants may represent a potential explanation for these findings.01/2014; 76(1):126-33. DOI:10.1097/TA.0b013e3182ab0785