Dr. Tharp’s Research

Impaired Lung Mechanics and Intraoperative Ventilator Induced Lung Injury

Post-operative pulmonary complications are common, costly, and difficult to predict. Impaired intraoperative lung mechanics may lead to alveolar injuries arising from combinations of patient or procedural factors. The magnitude at which impaired lung mechanics leads to pathological damage is not known. Concerted clinical trial efforts at refining lung protective ventilation have yielded marginal improvement in patient outcomes. Human biological data on intraoperative lung injury are nearly absent.

Previously we found a high degree of impairment in lung mechanics during robotic assisted laparoscopic surgery. The data suggested regionally heterogenous ventilation and potential for atelectrauma. The impairment was increasingly severe in subjects with obesity, leading us to speculate about the potential for subclinical lung injury.

This integrated respiratory physiology study aims to determine the relationships between impaired lung mechanics, regional alveolar damage, and obesity. We will first collect blood and bronchoalveolar lavage before and after surgery and measure intraoperative pulmonary mechanics in a cross-sectional study. We will assay for markers of alveolarcapillary disruption and examine their association with lung mechanics and patient factors. We will then conduct a proof-of concept interventional trial, using transpulmonary pressure guided ventilation to improve intraoperative lung mechanics and look for changes in markers of alveolar-capillary damage in blood and bronchoalveolar lavage.

This research is designed to address important, unanswered questions about intraoperative ventilation, lung injury, and obesity. The data from this study will potentially provide biochemical targets and mechanical ventilation parameters useful in refining lung protective ventilation methods. The results will be relevant to a wide audience ranging from basic scientists to clinical anesthesiologists.

Related Publications

The bronchoalveolar proteome changes in obesity
William G. Tharp, et al.

Obesity contributes to pulmonary dysfunction through poorly understood biochemical mechanisms. Chronic inflammation and altered cellular metabolism have emerged as pathological changes across organ systems in obesity, but whether similar changes occur in lungs with obesity is unknown as data in humans is lacking.  The authors measured the alveolar proteome in bronchoalveolar lavages from subjects with a wide range of body mass index and no lung disease. Utilizing 14 subjects (7 males/7 females) the researchers found changes in proteins and pathways associated with increasing body mass index that are similar to pathological changes observed in other tissues and may constitute mechanisms of pulmonary dysfunction in obesity.  Their data support the theory that the biochemical changes in organ systems in obesity exhibit conserved molecular or pathway alterations, which form a mechanistic foundation for the pathophysiological consequences of obesity.

Magnitude of obesity alone does not alter the alveolar lipidome
William G. Tharp, et al.

Obesity may lead to pulmonary dysfunction through complex and incompletely understood cellular and biochemical effects.  Altered lung lipid metabolism has been identified as a potential mechanism of lung dysfunction in obesity, but data in humans are lacking.  The authors measured the alveolar lipidome in bronchoalveolar lavages from subjects (14 adult subjects, 7 males and 7 females, with body mass indexes (BMIs) ranging from 24.3 to 50.9 kg/m² ) with healthy lungs with a wide range of body mass index.  Findings show that though a small number of lipid species were associated with BMI in multivariate analyses, no robust differences in lipidome composition or specific lipid species were identified over the range of body habitus. The magnitude of obesity alone did not substantially alter the alveolar lipidome in patients without lung disease. Differences in lung function in patients with obesity and no lung disease were unlikely related to changes in alveolar lipid composition.

Effects of obesity, pneumoperitoneum, and body position on mechanical power of intraoperative ventilation: an observational study. 
William G. Tharp, et al.

Mechanical power can describe the complex interaction between the respiratory system and the ventilator and may predict lung injury or pulmonary complications, but the power associated with injury of healthy human lungs is unknown. Body habitus and surgical conditions may alter mechanical power but the effects have not been measured. In a secondary analysis of an observational study of obesity and lung mechanics during robotic laparoscopic surgery, researchers comprehensively quantified the static elastic, dynamic elastic, and resistive energies comprising mechanical power of ventilation. They stratified by body mass index (BMI) and examined power at four surgical stages: level after intubation, with pneumoperitoneum, in Trendelenburg, and level after releasing the pneumoperitoneum. Esophageal manometry was used to estimate transpulmonary pressures. Mechanical power of ventilation and its bioenergetic components increased over BMI categories. Respiratory system and lung power were nearly doubled in subjects with class 3 obesity compared with lean at all stages. Power dissipated into the respiratory system was increased with class 2 or 3 obesity compared with lean. Increased power of ventilation was associated with decreasing transpulmonary pressures. Body habitus is a prime determinant of increased intraoperative mechanical power. Results indicate that obesity and surgical conditions increase the energies dissipated into the respiratory system during ventilation. The observed elevations in power may be related to tidal recruitment or atelectasis, and point to specific energetic features of mechanical ventilation of patients with obesity that may be controlled with individualized ventilator settings.