Aerosolized anticoagulants ameliorate acute lung injury in sheep after exposure to burn and smoke inhalation

Texas A&M University - Galveston, Galveston, Texas, United States
Critical Care Medicine (Impact Factor: 6.31). 01/2008; 35(12):2805-10. DOI: 10.1097/01.CCM.0000291647.18329.83
Source: PubMed


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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    • "The primary mechanism is thought to be a combination of mucolysis by the N-acetylcysteine component, bronchodilation by the albuterol, and inhibition of fibrin clot formation within the airways by the anticoagulant heparin. Herndon and Traber’s7 laboratory reported the effects of aerosolized recombinant human antithrombin and heparin in an ovine model of acute lung injury induced by smoke inhalation and cutaneous flame burn. The results of this study strongly suggest that aerosolized recombinant human antithrombin and heparin in combination may be a novel therapeutic approach for airway management of 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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    • "At present, therapy for inhalation trauma is merely supportive [10]. Animal models of smoke injury [6,7,9] and clinical trials of burn patients with inhalation trauma suggest that local treatment with heparin has beneficial effects [11,12]. The objective of the present trial is to determine the clinical efficacy and safety of frequent nebulizations of heparin in burn patients with inhalation trauma. "
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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 · 1.73 Impact Factor
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    • "They found that the two agents in combination resulted in better lung compliance, less pulmonary edema, and less airway obstruction than controls. Interestingly, neither agent used alone had the same ameliorating effect [110]. "
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    ABSTRACT: Lung injury resulting from inhalation of smoke or chemical products of combustion continues to be associated with significant morbidity and mortality. Combined with cutaneous burns, inhalation injury increases fluid resuscitation requirements, incidence of pulmonary complications and overall mortality of thermal injury. While many products and techniques have been developed to manage cutaneous thermal trauma, relatively few diagnosis-specific therapeutic options have been identified for patients with inhalation injury. Several factors explain slower progress for improvement in management of patients with inhalation injury. Inhalation injury is a more complex clinical problem. Burned cutaneous tissue may be excised and replaced with skin grafts. Injured pulmonary tissue must be protected from secondary injury due to resuscitation, mechanical ventilation and infection while host repair mechanisms receive appropriate support. Many of the consequences of smoke inhalation result from an inflammatory response involving mediators whose number and role remain incompletely understood despite improved tools for processing of clinical material. Improvements in mortality from inhalation injury are mostly due to widespread improvements in critical care rather than focused interventions for smoke inhalation. Morbidity associated with inhalation injury is produced by heat exposure and inhaled toxins. Management of toxin exposure in smoke inhalation remains controversial, particularly as related to carbon monoxide and cyanide. Hyperbaric oxygen treatment has been evaluated in multiple trials to manage neurologic sequelae of carbon monoxide exposure. Unfortunately, data to date do not support application of hyperbaric oxygen in this population outside the context of clinical trials. Cyanide is another toxin produced by combustion of natural or synthetic materials. A number of antidote strategies have been evaluated to address tissue hypoxia associated with cyanide exposure. Data from European centers supports application of specific antidotes for cyanide toxicity. Consistent international support for this therapy is lacking. Even diagnostic criteria are not consistently applied though bronchoscopy is one diagnostic and therapeutic tool. Medical strategies under investigation for specific treatment of smoke inhalation include beta-agonists, pulmonary blood flow modifiers, anticoagulants and antiinflammatory strategies. Until the value of these and other approaches is confirmed, however, the clinical approach to inhalation injury is supportive.
    Scandinavian Journal of Trauma Resuscitation and Emergency Medicine 04/2013; 21(1):31. DOI:10.1186/1757-7241-21-31 · 2.03 Impact Factor
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