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Effects of Hemorrhage and Resuscitation on Lung Inter-Alveolar Perfusion

Funding:

Department of Veterans Affairs, Merit Review

Principal Investigator:

Robert L. Conhaim, PhD

Project Summary:

PROBLEM: Lung injury caused by surgical or traumatic hemorrhage is an extremely serious clinical problem. Exact estimates of the frequency of hemorrhage-associated lung injury are not known, but the number of acute respiratory distress syndrome (ARDS) patients in the U.S. annually may range from 20,000 to 200,000. Hemorrhage and its consequences -- including transfusion, mechanical ventilation and reperfusion injury -- are known risk factors for ARDS, which implies that hemorrhage-associated lung injury may affect many hospital patients annually.

HYPOTHESIS: We hypothesize that catastrophic lung injury associated with hemorrhage is due to hemorrhage-induced disturbances in alveolar perfusion distribution. We further hypothesize that these disturbances are mediated by thromboxane. We conjecture that degree of perfusion mal-distribution correlates with increase in lung thromboxane concentration, and further conjecture that perfusion mal-distribution and thromboxane concentration correlate with volume of blood loss. We also hypothesize that composition and volume of resuscitation solution infused may exacerbate both perfusion mal-distribution and lung thromboxane concentrations, and that both factors are precursors to lung injury.

AIMS: To determine

  1. how volume and duration of blood loss correlate with perfusion mal-distribution among lung alveoli
  2. how composition and volume of intravenous resuscitation solutions improve or worsen perfusion mal-distribution associated with hemorrhage
  3. how hemorrhage and resuscitation alter lung prostanoid concentrations and distributions
  4. how hemorrhage and resuscitation affect permeability of the vascular-air space barrier (lung injury).

BACKGROUND: Patients experiencing significant blood loss can develop catastrophic lung injury. Patterns of blood volume, hemodynamics, and oxygen transport are physiological events that may precipitate appearance of ARDS, but how these events are connected to ARDS is not known. We hypothesize that the connecting mechanism is the effects of hemorrhage and resuscitation on perfusion distribution among alveoli. We believe that hemorrhage significantly disturbs this distribution and causes ischemia-reperfusion injury within the lung. We further believe that these disturbances cause increases in vascular-air space barrier permeability. Insight into hemorrhage-induced lung injury could be achieved if we could correlate magnitude of blood loss with degree of perfusion mal-distribution, and rise in vascular-air space barrier permeability. Additional insight could be gained if we knew how hemorrhage and resuscitation affected products and mediators of the lung cyclooxygenase pathway. We believe this pathway regulates alveolar perfusion distribution, and that perfusion mal-distribution in hemorrhage is caused by this pathway. Agents that are known to inhibit up-regulation of this pathway might prevent these disturbances. Our proposed studies are designed to address these questions.

METHODS: We will measure inter-alveolar perfusion distribution in the lungs of hemorrhaged and resuscitated rats using analysis of the trapping patterns of small-diameter (4-micron) fluorescent latex particles infused into the pulmonary circulation. These patterns are quantified statistically in digital lung images obtained using a confocal fluorescence microscope. We developed this unique method, and are the only lab in the world that utilizes it. We will measure products and mediators of the lung arachadonic acid cyclooxygenase pathway using radioimmunoassay, immunoblot (western), and immunohistochemistry. We will measure lung epithelial permeability by labeling endogenous plasma albumin with Evans blue dye. We will use confocal microscopy and lung lavage to measure the entry of labeled albumin into the air space, and correlate the volume and concentration of air space albumin with disturbances in perfusion distribution.

SIGNIFICANCE: Patients recovering from traumatic or surgical hemorrhage can experience debilitating pulmonary complications (ARDS and death). Why hemorrhage should lead to such complications is unknown. Perfusion distribution among lung alveoli may be disturbed by hemorrhage, which leads to lung injury. Maintenance of uniform blood flow distribution among uninjured alveoli is essential for efficient gas exchange and patient survival. However, we don't know how hemorrhage and resuscitation affects inter-alveolar perfusion distribution, and how this distribution correlates with lung injury. Our studies could lead to new resuscitation guidelines that might reduce frequency and mortality of this injury

 

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