Long-term treatment of plastic bronchitis with aerosolized tissue plasminogen activator in a Fontan patient

Wakeham, Martin K.; Bergen, Andrew H. Van; Torero, Luis E.; Akhter, Javeed

doi:10.1097/01.pcc.0000149320.06424.1d

Cited by 51 publications

(47 citation statements)

References 13 publications

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“…tPA can also be useful in animal models for treating a variety of extravascular fibrin deposition disorders, including prevention of intra-abdominal adhesions (49) and clearance of airways after burns and smoke inhalation (50). In addition, it has been reported anecdotally as beneficial therapy for patients with plastic bronchitis after Fontan procedure in congenital heart disease (7,8,10). …”

Section: Discussionmentioning

confidence: 99%

Tissue Plasminogen Activator Prevents Mortality from Sulfur Mustard Analog–Induced Airway Obstruction

Veress

Hendry‐Hofer²,

Loader³

et al. 2013

Am J Respir Cell Mol Biol

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Sulfur mustard (SM) inhalation causes the rare but life-threatening disorder of plastic bronchitis, characterized by bronchial cast formation, resulting in severe airway obstruction that can lead to respiratory failure and death. Mortality in those requiring intubation is greater than 80%. To date, no antidote exists for SM toxicity. In addition, therapies for plastic bronchitis are solely anecdotal, due to lack of systematic research available to assess drug efficacy in improving mortality and/or morbidity. Adult rats exposed to SM analog were treated with intratracheal tissue plasminogen activator (tPA) (0.15-0.7 mg/kg, 5.5 and 6.5 h), compared with controls (no treatment, isoflurane, and placebo). Respiratory distress and pulse oximetry were assessed (for 12 or 48 h), and arterial blood gases were obtained at study termination (12 h). Microdissection of fixed lungs was done to assess airway obstruction by casts. Optimal intratracheal tPA treatment (0.7 mg/kg) completely eliminated mortality (0% at 48 h), and greatly improved morbidity in this nearly uniformly fatal disease model (90-100% mortality at 48 h). tPA normalized plastic bronchitis-associated hypoxemia, hypercarbia, and lactic acidosis, and improved respiratory distress (i.e., clinical scores) while decreasing airway fibrin casts. Intratracheal tPA diminished airwayobstructive fibrin-containing casts while improving clinical respiratory distress, pulmonary gas exchange, tissue oxygenation, and oxygen utilization in our model of severe chemically induced plastic bronchitis. Most importantly, mortality, which was associated with hypoxemia and clinical respiratory distress, was eliminated.Keywords: plastic bronchitis; tissue plasminogen activator; airway obstruction; sulfur mustard; fibrin Sulfur mustard (bis(2-chloroethyl)sulfide; SM) is a vesicant and chemical weapon used in warfare during much of the twentieth century, and which remains in the stockpiles of multiple nations today (Syria, Iran, North Korea, Libya, the United States, and possibly others). SM exposure affects the eyes, skin, upper airways, and lungs. After a brief latent period, respiratory failure and death can develop within 12 to 48 hours. Despite a century of study, the mechanisms responsible for SM's toxic effects remain unsolved, and clinically effective rescue therapies or antidotes are not available.Initial reports of human SM inhalation toxicity in the early 1900s described the presence of airway-obstructive necrotic debris/ mucosa, or "pseudomembranes," in the large airways of victims, and these were more recently confirmed in the victims of the IranIraq war (1, 2). Such severe lesions have been reported to lead to respiratory compromise, with need for artificial ventilation, and death in 80% of those needing intubation (2). Furthermore, chronic conducting airway lesions, such as bronchiolitis obliterans, tracheal/bronchial stenosis, and chronic bronchitis, are commonly found in survivors of SM inhalation months to years after exposure (2, 3), whereas chronic alveolar or paren...

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Section: Discussionmentioning

confidence: 99%

Tissue Plasminogen Activator Prevents Mortality from Sulfur Mustard Analog–Induced Airway Obstruction

Veress

Hendry‐Hofer²,

Loader³

et al. 2013

Am J Respir Cell Mol Biol

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“…Fibrinolytics have proven useful in treating children affected by plastic bronchitis, suggesting that it is the fibrin component that is largely responsible for the obstruction (39)(40)(41). These and other studies (42) were the first to document fibrinogenolysis occurring on a large scale in the airways of asthma patients, but their results still provide little insight into why this harmful phenomenon occurs.…”

Section: Crabs and Clots Provide A Cluementioning

confidence: 96%

Airway Fibrinogenolysis and the Initiation of Allergic Inflammation

Millien

Lu²,

Mak³

et al. 2014

Annals ATS

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The past 15 years of allergic disease research have produced extraordinary improvements in our understanding of the pathogenesis of airway allergic diseases such as asthma. Whereas it was previously viewed as largely an immunoglobulin E-mediated process, the gradual recognition that T cells, especially Type 2 T helper (Th2) cells and Th17 cells, play a major role in asthma and related afflictions has inspired clinical trials targeting cytokine-based inflammatory pathways that show great promise. What has yet to be clarified about the pathogenesis of allergic inflammatory disorders, however, are the fundamental initiating factors, both exogenous and endogenous, that drive and sustain B-and T-cell responses that underlie the expression of chronic disease. Here we review how proteinases derived from diverse sources drive allergic responses. A central discovery supporting the proteinase hypothesis of allergic disease pathophysiology is the role played by airway fibrinogen, which in part appears to serve as a sensor of unregulated proteinase activity and which, when cleaved, both participates in a novel allergic signaling pathway through Toll-like receptor 4 and forms fibrin clots that contribute to airway obstruction. Unresolved at present is the ultimate source of airway allergenic proteinases. From among many potential candidates, perhaps the most intriguing is the possibility such enzymes derive from airway fungi. Together, these new findings expand both our knowledge of allergic disease pathophysiology and options for therapeutic intervention.

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“…Whereas long-term, inhaled mucolytic therapy has been relatively safe to use as demonstrated in cystic fibrosis, prolonged inhaled tPA has only been demonstrated without complications in one human case study [63] and therefore should be used with caution. Incubation of removed bronchial casts in solution in vitro with various therapeutic agents and analyzing their efficacy may allow the clinician to individually tailor therapy.…”

Section: Chronic Therapymentioning

confidence: 97%

“…Quasney et al [56] 123 benefit for use of tPA in plastic bronchitis [36,61]. However, there has been reported effective use of inhaled tPA [55,62], and Wakeham et al [63] showed long-term and efficacious therapy over the course of 18 months without any adverse complications. A murine model studied the safety of prolonged, repeated administration of inhaled pulmonary formulation tPA [64].…”

Section: Acute Managementmentioning

confidence: 99%

Successful Management of Plastic Bronchitis in a Child Post Fontan: Case Report and Literature Review

Randhawa

Chin

et al. 2012

Lung

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Long-term treatment of plastic bronchitis with aerosolized tissue plasminogen activator in a Fontan patient

Abstract: Treatment of plastic bronchitis with aerosolized tissue plasminogen activator may benefit patients in whom other therapies have failed.

Cited by 51 publications

References 13 publications

Tissue Plasminogen Activator Prevents Mortality from Sulfur Mustard Analog–Induced Airway Obstruction

Tissue Plasminogen Activator Prevents Mortality from Sulfur Mustard Analog–Induced Airway Obstruction

Airway Fibrinogenolysis and the Initiation of Allergic Inflammation

Successful Management of Plastic Bronchitis in a Child Post Fontan: Case Report and Literature Review

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