Elevated Pulmonary Blood Flow Research Articles

Small Airway Function after Repeated Dives with Elevated PO2

Repetitive diving with mildly hyperbaric oxygen pressures (oxygen partial pressure (PO2) approximately 130 kPa) may cause small airway dysfunction, but the relative importance of immersion, PO2, and diver activity has not been elucidated. PURPOSE: To differentiate effects of immersion and elevated PO2 at rest and during exercise, parameters of small airway function were measured in conjunction with five series of dives: rest or cycle ergometer exercise in a 15-foot deep pool with O2 (PO2 = 130 kPa) or air (PO2 = 30 kPa), and rest in a dry hyperbaric chamber with PO2 = 130 kPa. METHODS: Each dive series consisted of five consecutive days with six hours of exposure and 18 hours between dives (same daily starting time). Forced expired volume in 1 second (FEV1), and maximum forced expired flow between 25% and 75% of volume expired (FEF25–75) were measured (CPL, nSpire Medical) the prior week and before and after each dive, plus on the morning after and three days after the fifth dive. The averages of three ATS-valid measures at each time were compared to the baseline average (pre-diving and pre-first dive). The numbers of divers for each condition were wet resting O2:10; wet resting air: 10; dry resting O2:12; wet exercise O2:10; wet exercise air: 14. RESULTS: After surfacing no parameters decreased from baseline. FEV1 and FEF25–75 increased after exercise air dives (Maximum changes: FEV1: 2.3%, FEF25–75: 10.2%, p< 0.001). However, FEV1 and FEF25–75 were low on mornings following resting and exercise O2 dives (Maximum changes: resting: FEV1 -5.2%, FEF25–75: −10.6%, both p< 0.01; exercise: FEV1: −5.2%, p < 0.02; FEF25–75: −15.4%, p< 0.001). Changes resolved after the next dive, but persisted on the third day after the fifth wet O2 dives: resting O2: FEV1 -4.2%, p<0.03; exercise O2: FEV1: −3.9%, p < 0.02; FEF25–75: −10%, p < 0.005. CONCLUSION: Decreases in indices of small airway function appear to follow from a combination of volume shifts (immersion) and elevated PO2. Effects are delayed after the end of exposure, suggesting inflammation. Without a later immersion, small airway function remains depressed for three days following wet O2 at rest or exercise, while volume shifts with elevated pulmonary blood flow (exercise) and minimally- elevated PO2 (air) appear to improve function. Supported by NAVSEA DSBDP and ONR.

Reduced pulmonary blood flow in regions of injury 2 hours after acid aspiration in rats.

BackgroundAspiration-induced lung injury can decrease gas exchange and increase mortality. Acute lung injury following acid aspiration is characterized by elevated pulmonary blood flow (PBF) in damaged lung areas in the early inflammation stage. Knowledge of PBF patterns after acid aspiration is important for targeting intravenous treatments. We examined PBF in an experimental model at a later stage (2 hours after injury).MethodsAnesthetized Wistar-Unilever rats (n = 5) underwent unilateral endobronchial instillation of hydrochloric acid. The PBF distribution was compared between injured and uninjured sides and with that of untreated control animals (n = 6). Changes in lung density after injury were measured using computed tomography (CT). Regional PBF distribution was determined quantitatively in vivo 2 hours after acid instillation by measuring the concentration of [68Ga]-radiolabeled microspheres using positron emission tomography.ResultsCT scans revealed increased lung density in areas of acid aspiration. Lung injury was accompanied by impaired gas exchange. Acid aspiration decreased the arterial pressure of oxygen from 157 mmHg [139;165] to 74 mmHg [67;86] at 20 minutes and tended toward restoration to 109 mmHg [69;114] at 110 minutes (P < 0.001). The PBF ratio of the middle region of the injured versus uninjured lungs of the aspiration group (0.86 [0.7;0.9], median [25%;75%]) was significantly lower than the PBF ratio in the left versus right lung of the control group (1.02 [1.0;1.05]; P = 0.016).ConclusionsThe PBF pattern 2 hours after aspiration-induced lung injury showed a redistribution of PBF away from injured regions that was likely responsible for the partial recovery from hypoxemia over time. Treatments given intravenously 2 hours after acid-induced lung injury may not preferentially reach the injured lung regions, contrary to what occurs during the first hour of inflammation.Please see related article: http://dx.doi.org/10.1186/s12871-015-0014-z.

Invited Commentary

The use of inhaled pulmonary vasodilators to treat pulmonary hypertension (PH) secondary to cardiac disease has revolutionized the management of patients previously thought to be at increased, or in some cases prohibitive, risk for cardiac surgery. For example, children with congenital heart disease categorized by a large left-to-right shunt with the attendant elevated pulmonary blood flow and pressure may also have increased pulmonary vascular resistance (PVR). However, if the PVR in these patients falls to low levels in response to pulmonary vasodilators, such responders will often have a relatively stable postoperative course with the addition of inhaled nitric oxide (iNO) following repair of the defect.

Impact of elevated pulmonary blood flow and capillary pressure on lung responsiveness

Since alterations in pulmonary hemodynamics may lead to airway hyperreactivity, the consequences of individual changes in pulmonary blood flow (Qp) and capillary pressure (Pc) on lung responsiveness were investigated. During maintenance of a steady-state Pc of 5, 10, or 15 mmHg (groups 1-3), acute increases of Qp were generated in isolated, perfused rat lungs by simultaneous pulmonary arterial pressure elevation and venous pressure lowering. Conversely, at constant low (groups 4 and 5) or high Qp (groups 6 and 7), Pc was lowered or elevated by changing, in parallel, the pulmonary arterial and venous pressures. Pulmonary input impedance was measured under baseline conditions and during methacholine provocation (2-18 microg*kg(-1)*min(-1)), whereas the pulmonary hemodynamics were altered in accordance with the group allocation. The airway resistance and constant-phase parenchymal model parameters were identified from the pulmonary input impedance spectra. Increases of Qp at constant Pc had no effect on the basal lung mechanics, whereas they enhanced the lung reactivity to methacholine, particularly when high Pc was maintained [peak airway resistance increases of 299 +/- 99% (SE) vs. 609 +/- 217% at Qp levels of 5 and 10 ml/min, respectively, P < 0.05]. In contrast, the change of Pc at constant Qp slightly deteriorated the basal parenchymal mechanics without affecting the lung responsiveness. These findings suggest that increases in Qp per se may lead to the development of airway hyperreactivity. This phenomenon may contribute to the airway susceptibility under conditions associated with simultaneous elevations in pulmonary vascular pressures and Qp, such as exercise-induced asthma and the situation in children with congenital heart diseases.

Development of a device for transcatheter pulmonary artery banding: evaluation in animals

Pulmonary artery banding (PAB) is the first palliation in infants with complex congenital heart disease and elevated pulmonary blood flow. In older patients with corrected transposition of the great arteries, it may be used to re-train the left ventricle. To date, the only option is surgical. We report the development and the evaluation of a device for transcatheter PAB. We intended to implant a pulmonary artery (PA) reducer percutaneously between the native pulmonic valve and the pulmonary bifurcation. Immediately following its insertion, we planned to implant a balloon expandable stent inside the restriction to calibrate the banding. Sheep were sacrificed acutely (group 1, n=6) and after 1 month of follow-up (group 2, n=6), the reducer was implanted successfully in all animals. It allowed the PA diameter to be reduced from 25 to 10.5 mm. Bare stents were successfully delivered inside the reducer. No paraprosthetic leak was found by injecting contrast dye. After the insertion procedure, signs of intolerance to obstruction were present in all animals and prompted us to dilate the stents from 12 to 16 mm. One animal from group 1 died before a balloon dilatation could be achieved. In the animals from group 2, the mean systolic gradient was 19 and 34.8 mmHg, respectively, at early and late evaluation. Implantation of a PA reducer is possible in sheep, through a transcatheter approach allowing intravascular PAB. Miniaturization of the device is necessary to enlarge its use from adulthood to childhood.

Pulmonary vascular K+ channel expression and vasoreactivity in a model of congenital heart disease.

K+ channels play an important role in mediating pulmonary vasodilation caused by increased oxygen tension, nitric oxide, alkalosis, and shear stress. To test the hypothesis that lung K+ channel gene expression may be altered by chronic increases in pulmonary blood flow, we measured gene and protein expression of calcium-sensitive (K Ca ) and voltage-gated (Kv2.1) K+ channels, and a pH-sensitive K+ channel (TASK), in distal lung from fetal lambs in which an aortopulmonary shunt was placed at 139 days gestation. Under baseline conditions, animals with an aortopulmonary shunt showed elevated pulmonary artery pressure and pulmonary blood flow compared with twin controls. Hypoxia caused a greater increase in pulmonary vascular tone in shunt animals compared with controls. Alkalosis caused pulmonary vasodilation in control but not shunt animals. To determine lung K+ channel mRNA levels, we performed quantitative RT-PCR. In comparison with control animals, lung K Ca channel mRNA content was increased in shunt animals, whereas TASK mRNA levels were decreased. There was no difference in Kv2.1 mRNA levels. Channel protein expression was consistent with these findings. We conclude that, in the presence of elevated pulmonary blood flow, K Ca channel expression is increased and TASK is decreased.

Invited commentary

Invited commentary

Determinants Of The Pulmonary Input Impedance Spectrum: Theoretical Considerations Based On A Mathematical Model

The determinants of the shape of the pulmonary input impedance spectrum were investigated using a mathematical model based on Womersley’s equations for pulsatile flow in constrained viscoelastic tubes and structural data (morphometry, elasticity, and rheology) provided for the entire cat lung by Zhuang et al. Mean distending pressures and diameters of vessels were determined from the struc-tured data and four independent variables: cardiac output and left atrial, pleural, and alveolar pressures. Studies were performed in a control model and a model whose structure was designed to imitate that of a subject with pulmonary vascular impairment. Model simplifications were investigated. Increasing left atrial pressure or cardiac output caused passive distention of vessels that increased total blood volume and decreased vascular resistance, creating a slight spectral shift downward and to the right. Increasing pleural pressure decreased total blood volume and increased vascular resistance, creating a spectral shift upward and to the right. Increasing levels of alveolar pressure resulted in increased vascular resistance and pressures find a shift in blood volume from the capillaries to the arteries without significant change in total blood volume, creating a spectral shift that was slightly downward and to the right. Model simplification studies demonstrated that (1) all vessels distal to the tenth generation (arteries with zero distending pressure diameters < 50 μM) can be modelled as a simple resistor or (2) all vessels distal to the fourth generation can be modelled as a modified Windkessel. Results obtained from the passive studies were consistent with those obtained from normal lambs and lam be with chronically elevated pulmonary blood flow. To model a hypertensive state created by ifljury to the lung microvasculature, the number and size of small vessels and the compliance constants of all arteries were decreased and the viscoelastic constant was increased, which created the requisite shift to the right and upward. To better match the modulus fluctuation and negative phase angles at higher frequencies in the hypertensive animals, the development of a major reflection site between the main and branch arteries was hypothesized.

Pulmonary blood velocity patterns in lamb models of pulmonary vascular impairment

To provide a comprehensive picture of the interaction between abnormal pulmonary hemodynamics and pulmonary blood velocity patterns in the young, we have developed infant animal models of pulmonary hypertension and/or elevated pulmonary blood flow. This report focuses on relationships between selected velocity waveform shape-dependent variables — i.e., the time between the onset of systole and peak velocity (rise time), the time during which velocity remains at >90% of that peak (90% time), and flow reversal patterns — and traditional hemodynamic indications of pulmonary vascular impairment, i.e., elevated pulmonary artery pressure and pulmonary vascular resistance. Studies were performed on 36 anesthetized, open-chest, one-month-old lambs with normal pulmonary circulations or with abnormal conditions that had been initiated during the first few days of life via (1) a central venous injection of monocrotaline pyrrole (hypertension) or (2) a side-to-side anastomosis between the common carotid artery and jugular vein (elevated flow). Animals with large shunts (shunt open cardiac output/shunt closed cardiac output >2.1) had both elevated pressures and flows. The tightest correlations (linear and log-linear) were found between unindexed pulmonary vascular resistance and waveform variables, the most reliable being 90% time (r = −0.838), 90% time + rise time (r = −0.838), and 90% time × rise time (r = −0.824). The best correlate to mean pulmonary artery pressure was 90% time + rise time (r = −0.713). Combined rise time and 90% time variables yielded results that exceeded 90% sensitivity and specificity levels in diagnosing elevated pulmonary vascular resistance (>700 dyne-sec/cm5). Absence of flow reversal in central and anterior regions was an indicator of markedly elevated pulmonary artery pressures (mean >28mmHg). The findings of this report (1) demonstrate the successful development of animal models that mimic a broad spectrum of relevant pulmonary hemodynamics in infants and children with compromised pulmonary circulations and (2) point to shape variables that should improve noninvasive assessment of elevated pulmonary vascular resistance.

Pulmonary blood velocity profile variability in open-chest dogs: influence of acutely altered hemodynamic states on profiles, and influence of profiles on the accuracy of techniques for cardiac output determination.

Clinical investigations focused on finding characteristics of noninvasively obtained measurements of pulmonary blood velocity that can be used to quantitate pulmonary blood flow and/or pulmonary pressure have often yielded results whose imprecision has been attributed to flow pattern variability. To determine flow pattern variability in an in vivo animal model in varying hemodynamic states, main pulmonary artery blood velocity waveforms were recorded in 17 dogs at 2-mm intervals along an anterior to posterior wall-oriented axis using a 20-MHz pulsed Doppler needle probe. Control data were obtained before the animals were subjected to altered flow (atrial level shunts) and pressure (10% O2 inhalation) states. Instantaneous velocity profiles were computed throughout the cardiac cycle. Estimates of pulmonary blood flow were obtained assuming an elliptical model of the pulmonary artery which allowed computation of velocity at all points in the cross section, based on the measured values along the axis. Model-based estimates were compared to measured values and estimates obtained in the traditional fashion, i.e., the product of centerline velocity and cross-sectional area. Results clearly showed marked interanimal variability, even in control states. Reverse flow in the posterior half of the vessel, which tended to become more pronounced with increased pulmonary artery pressure, was observed during late systole and early diastole. Elevated pulmonary blood flow tended to increase the maximum velocities along the anterior wall relative to midline velocities. Neither estimate of cardiac output yielded consistently accurate results (r = 0.77 for model-based method, r = 0.80 for area times central velocity method). Findings of this study, which highlight the dependency of waveform characteristics on sampling site, the large degree of intersubject variability, and the need for large or multiple sample volumes for pulmonary blood flow determination, help clarify inconsistencies observed by clinicians and suggest that future work with animal models will facilitate a greater understanding of the determinants of human pulmonary velocity waveforms.