Jacob Hildebrandt

Increased surface tension favors pulmonary edema formation in anesthetized dogs' lungs.

The possibility that surface tension may affect the hydrostatic transmural pressure of pulmonary vessels and the development of pulmonary edema was studied in anesthetized, open-chested dogs. Isogravimetric pressure (the static intravascular pressure at which transmural osmotic and hydrostatic pressures are balanced such that net fluid flux is zero and lung weight is constant) was measured in nine animals under three conditions: (a) control, normal surface tension, at an alveolar pressure of 30 cm H2O with the apenic lung at room temperature; (b) after increasing surface tension by cooling and ventilating at a low functional residual capacity, at an alveolar pressure sufficient to produce the same lung volume present during control measurements; and (c) after restoring surface tension by rewarming while holding the lung at a high inflation volume, again at the control lung volume. Lung volumes were established from external dimensions and confirmed +/- 10% by deflation spirometry. The isogravimetric pressure (relative to alveolar pressure) was significantly less with increased surface tension than during either the initial control condition (P less than 0.01), or when the surface tension has been restored (P less than 0.01). Similar changes occurred in each of three additional studies performed with control alveolar pressures of 10 cm H2O. Thus, increased surface tension favors fluid leakage presumably because it increases the microvascular transmural pressure.

Thromboxane A2 mediates lung vasoconstriction but not permeability after endotoxin.

The effect of dazoxiben, a selective thromboxane (Tx) synthetase inhibitor, on systemic and pulmonary hemodynamics, eicosanoids, and lung permeability was assessed in awake goats with lung lymph fistulae following infusion of Escherichia coli endotoxin (1 microgram/kg). Animals received endotoxin either with no treatment or pretreatment with a bolus (25 mg/kg) followed by a maintenance infusion (10 mg/kg per h) of dazoxiben. In untreated animals, the peak rise of 26.8 cm H2O in pulmonary artery (Ppa) and of 13.5 cm H2O in wedge (Pw) pressures occurred at the same time as the peak elevations in plasma thromboxane B2 (T X B2). Maximum reduction in cardiac output (Qt) also occurred at the same time. Lung lymph flow (QL) increased during this period and remained elevated for at least 6 h after endotoxin. T X B2 levels had returned from a peak of 13.1 to 0.7 ng/ml by 2 h. In dazoxiben-treated animals, plasma concentrations of T X B2 were never significantly elevated. Increases in Ppa and Pw were markedly reduced and decreased Qt was transient. QL in treated animals began to increase by 30 min after endotoxin and reached a peak by 2 h. Increased QL in treated animals was not as great as in the untreated animals. Moreover, lymph-plasma protein ratios increased significantly in treated animals. Plasma prostaglandin (PG)F2 alpha and 6-keto-PGF1 alpha concentrations were elevated in both groups after endotoxin with values significantly greater in treated animals. We conclude that selective inhibition of Tx ameliorates many adverse hemodynamic consequences of endotoxemia but does not prevent lung permeability changes.

Lung Volume Reduction by Bronchoscopic Administration of Steam

RATIONALE At present, bronchoscopic approaches to lung volume reduction (LVR) create airway obstruction to achieve parenchyma collapse, avoiding many risks of surgical LVR. However, LVR by these methods is limited by temporary or incomplete collapse and/or residual atelectatic and scarred tissue volumes. Heat-induced ablation of lung tissue is currently under investigation as an alternative LVR methodology. OBJECTIVES We hypothesized that bronchoscopic steam injection can produce safe and effective LVR, and explored potential mechanisms for the effects. METHODS Steam treatments were applied bilaterally to six cranial lobe segments of large dogs. For series 1, 14 dogs received one of three target heat dose levels (1, 4, or 8 cal · ml⁻¹ segment volume), and then 3 months of follow-up including pulmonary function testing and monitoring for complications. For series 2, 12 dogs received a single target dose (4 cal · ml⁻¹) or sham, similar follow-up, and then assessment of lobar mass, volume, and blood flow. Vapor content of series 2 steam was 40% greater than for series 1 (similar heat dose) to attempt more peripheral heat delivery. MEASUREMENTS AND MAIN RESULTS Nineteen of 20 treatment animals survived with minimal evidence of serious risks or reduced pulmonary function testing volumes, but 1 died from pneumothorax 5 days post-treatment. Postmortem processing of animals that survived as planned revealed obvious dose-dependent lobe reductions, additional evidence of risks, and blood flow reduction that occurred immediately post-treatment. CONCLUSIONS Bronchoscopic administration of steam is a potentially safe means to achieve LVR, but substantial risks are present and further research is recommended.

Respiratory gas exchange and inert gas retention during partial liquid ventilation

Perfluorocarbon (PFC) fluids have been used as ventilatory media due to their unique combination of low toxicity, low solubility in body fluids, ability to lower interfacial tensions, and high oxygen and carbon dioxide carrying capacities12. Cardiorespiratory support has been achieved during liquid ventilation with a variety of perfluorinated chemicals in a range of experimental animals1,2,7,8,9,18. In animal models of respiratory distress syndrome, introduction of PFC to the lungs has been shown to improve both compliance and gas exchange11,13,14,15,16 However, the presence of fluid in the gas exchange regions of the lung should impede convective and diffusive mass transport and have a deleterious effect on gas exchange. Indeed, while it is possible to achieve adequate oxygenation during liquid ventilation, CO2 retention and acidosis can be problematic7. In order to maximize the benefits of this mode of ventilation while minimizing the side effects of CO2 retention, acidosis, and O2 toxicity due to high FIO2, a clearer understanding of the determinants of gas exchange through a fluorocarbon medium is necessary.

Efficacy of Anticholinergic and

Cholinergically induced bronchoconstriction is thought to be a major cause of bronchospasm during anesthesia. We used tracheally intubated rabbits (4-mm endotracheal tube) stimulated with methacholine to assess the efficacy of β-adrenergic agonist and anticholinergic treatment in reversing the increases in respiratory system resistance. Four groups were compared: (a) inhaled metaproterenol, 20 puffs via metered dose inhaler (0.65 mg/puff); (b) inhaled ipratropium bromide, 20 puffs from a metered dose inhaler (18 μg/puff); (c) 2 mg of intravenous atropine; and (d) no treatment after methacholine challenge as a control group. Methacholine increased respiratory system resistance from 0.041 ± 0.001 (mean ± SEM) to 0.098 ± 0.006 cm H2O mL-1 s-1 (P < 0.001). Whereas β-adrenergic agonist treatment was ineffective in ameliorating bronchoconstriction, inhaled ipratropium bromide and atropine were highly effective, causing an 86%-88% reversal in the methacholine-induced increase in respiratory system resistance. Both these agents were also effective in improving dynamic compliance. We conclude that inhaled ipratropium bromide is effective in treating cholinergic bronchospasm even when administered via a small endotracheal tube and that the β-adrenergic agonist metaproterenol is ineffective in rabbits in the face of maximal cholinergic stimulation.

bt-adrenergic Agonist Treatment of Maximal Cholinergic Bronchospasm in Tracheally Intubated Rabbits

In the course of studying gas exchange during partial liquid ventilation (PLV) in healthy and injured piglets, we noted a reversal in the profile of exhaled CO2 (PECO2) versus time. Rather than a positive slope, the CO2 expirogram often reached a peak early in expiration and fell toward the end of the breath. In addition to a change in sign, the absolute value of the slope was very large. The change in profile led us to question the generally accepted practice of using “end-tidal” PECO2 to represent average alveolar PACO2 during PLV. Given the steep rate of change of PECO2 over a breath, the use of a single point on the CO2 expirogram to represent alveolar gas during PLV seemed in error. We hypothesized that a combination of increased ventilation heterogeneity and diffusion limitation could account for the reversal in sign and exaggeration of the slopes. To further investigate this problem we explicitly measured PECO2 vs. exhaled volume in two additional experiments and compared these findings to 40 previously studied animals.

Negative Slope of Exhaled CO2 Profile

Evidence from liquid-filled rat lungs supported the presence of CO2-dependent, active relaxation of parenchyma under normoxia by unknown mechanisms (Emery et al., 2007). This response may improve matching of alveolar ventilation (V˙A) to perfusion (Q˙) by increasing compliance and V˙A in overperfused (high CO2) regions, and decrease V˙A in underperfused regions. Here, we have more directly studied CO2-dependent parenchymal relaxation and tested a hypothesized role for actin-myosin interaction in this effect. Lung parenchymal strips (∼1.5mm×1.5mm×15mm) from 16 rats were alternately exposed to normoxic hypocapnia ( [Formula: see text] ) or hypercapnia ( [Formula: see text] ). Seven specimens were used to construct length-tension curves, and nine were tested with and without the myosin blocker 2,3-butanedione monoxime (BDM). The results demonstrate substantial, reversible CO2-dependent changes in parenchyma strip recoil (up to 23%) and BDM eliminates this effect, supporting a potentially important role for parenchymal myosin in V˙A/Q˙ matching.

CO2 relaxation of the rat lung parenchymal strip

VERTICAL DISTRIBUTION OF INSPIRED VOLUME DURING LIQUID VENTILATION WITH PERFLUOROCHEMICAL (PFC) LIQUID. ▴ 312

VERTICAL DISTRIBUTION OF INSPIRED VOLUME DURING LIQUID VENTILATION WITH PERFLUOROCHEMICAL (PFC) LIQUID. ▴ 312

Liquid Ventilation with perfluorochemicals (PFC) violates many of our long-held assumptions about how the lung functions. However, the technique has been so successful in animal models of lung disease that it is currently being tested in clinical trials for the treatment of infant and acute (“adult”) respiratory distress syndrome in newborns, children, and adults. A common feature of both infant and acute respiratory distress syndromes is an inability of the lungs surfactant system to adequately lower surface tension, leading to regions of atelectasis. Liquid ventilation with PFC appears to ameliorate the disease process by lowering interfacial tension in the lung, opening regions of atelectasis, and improving gas exchange. To understand how gas exchange is successful during liquid ventilation requires careful re-evaluation of the assumptions underlying our current models of gas exchange physiology during normal gas ventilation. These assumptions must then be examined in light of the alterations in pulmonary physiology during liquid ventilation.

Gas Exchange during Gas and Liquid Ventilation

In the majority of clinical cases, smoke inhalation results in a self-limited lung injury mostly confined to the airways. In this study, an animal model of inhalation injury was developed that reflected similar pathophysiology. Cardiopulmonary parameters were studied in awake, instrumented goats following spontaneous inhalation of characterized Douglas fir smoke. Peak carboxyhemoglobin levels averaged 37% during a mean exposure time of 33 minutes. All animals survived the 24-hour study period, and showed only transient abnormalities in lung fluid balance and gas exchange, with no change in lung mechanics or plasma eicosanoid (TxB2 and 6-keto-PGF1 alpha) levels. However, extravascular lung water at 24 hours was increased 33%, suggesting the presence of some airway edema and retained secretions. We feel this model fairly represents the majority of clinical smoke inhalation cases. This model is compared to other large animal inhalation injury models producing more severe lung injury.