Advantages and pitfalls of combining intravenous antithrombin with nebulized heparin and tissue plasminogen activator in acute respiratory distress syndrome

Sebastian Rehberg, Yusuke Yamamoto, Linda Sousse, Collette Jonkam, Robert A. Cox, Donald Prough, Perenlei Enkhbaatar

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

BACKGROUND: 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 antiinflammatory properties of rhAT in ARDS. Therefore, the present prospective, randomized experiment was conducted using an established ovine model. METHODS: 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. RESULTS: 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. CONCLUSION: Combining intravenous rhATwith 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.

Original languageEnglish (US)
Pages (from-to)126-133
Number of pages8
JournalJournal of Trauma and Acute Care Surgery
Volume76
Issue number1
DOIs
StatePublished - Jan 2014

Fingerprint

Antithrombins
Adult Respiratory Distress Syndrome
Tissue Plasminogen Activator
Heparin
Pulmonary Gas Exchange
Lung
Anti-Inflammatory Agents
Lymph
Sheep
Wounds and Injuries
Smoke Inhalation Injury
Neutrophil Activation
Water-Electrolyte Balance
Body Surface Area
Therapeutics
Group Psychotherapy
Smoke
Anticoagulants
Blood Vessels
Neutrophils

Keywords

  • Acute lung injury
  • Anticoagulants
  • Burn and smoke inhalation
  • Vascular leakage

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine
  • Surgery

Cite this

Advantages and pitfalls of combining intravenous antithrombin with nebulized heparin and tissue plasminogen activator in acute respiratory distress syndrome. / Rehberg, Sebastian; Yamamoto, Yusuke; Sousse, Linda; Jonkam, Collette; Cox, Robert A.; Prough, Donald; Enkhbaatar, Perenlei.

In: Journal of Trauma and Acute Care Surgery, Vol. 76, No. 1, 01.2014, p. 126-133.

Research output: Contribution to journalArticle

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abstract = "BACKGROUND: 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 antiinflammatory properties of rhAT in ARDS. Therefore, the present prospective, randomized experiment was conducted using an established ovine model. METHODS: 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. RESULTS: 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. CONCLUSION: Combining intravenous rhATwith 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.",
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AU - Cox, Robert A.

AU - Prough, Donald

AU - Enkhbaatar, Perenlei

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N2 - BACKGROUND: 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 antiinflammatory properties of rhAT in ARDS. Therefore, the present prospective, randomized experiment was conducted using an established ovine model. METHODS: 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. RESULTS: 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. CONCLUSION: Combining intravenous rhATwith 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.

AB - BACKGROUND: 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 antiinflammatory properties of rhAT in ARDS. Therefore, the present prospective, randomized experiment was conducted using an established ovine model. METHODS: 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. RESULTS: 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. CONCLUSION: Combining intravenous rhATwith 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.

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