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We aimed to investigate the role of endothelin-mediated vasoconstriction following acute pulmonary thromboembolism (APTE). Thirteen anesthetized piglets (~25 kg) were ventilated with 0 PEEP. Cardiac output (Qt) and wedge pressure (Pw) were measured by a Swan Ganz catheter, along with arterial and venous blood gases. APTE was induced by autologous blood clots (~0.8 g/kg, 12-16 pieces) via a jugular venous catheter at time = 0 minutes until the mean pulmonary arterial pressure (Ppa) was about 2.5 times the baseline at 30 minutes. Eight control animals (Group 1) received only normal saline afterward, while the remaining five (Group 2) received at time = 40-minute saline plus Tezosentan, a nonspecific endothelin antagonist. The drug was initially given as an intravenous bolus (10 mg/kg), followed by an infusion (2 mg/min) until the end of the experiment at 2 hours. Hemodynamic data were measured before APTE and then at 30-minute intervals. Pulmonary vascular resistance index (PVRI) was calculated as (Ppa-Pw)/CI, where CI was cardiac index or Qt/W (body weight). Fluorescent microspheres (FMS) were used to mark regional blood flows and ventilation for cluster analysis. PVRI acutely increased within minutes and remained high despite some recovery over time. With Tezosentan treatment, the results showed that endothelin-mediated vasoconstriction persisted significantly up to 2 hours and accounted for about 25% of the increase in PVRI while clot obstruction accounted for the remaining 75%. CI remained relatively constant throughout. Tezosentan also affected PVRI indirectly by mitigating the shift of regional blood flow back to the embolized areas over time, possibly by attenuating vasoconstriction in the nonembolized areas. We conclude that following APTE, although the increased PVRI is mostly due to mechanical embolic obstruction, secondary factors such as vasoconstriction and pattern of regional blood flow over time also play important roles.

Studies in whole animals, isolated lungs and pulmonary tissue strips have shown that the pulmonary vascular resistance (PVR) to hypoxia is temporally biphasic in nature. We studied the regional temporal response to hypoxia in prone pigs. The animals were ventilated with an FIO2 of 0.21 (control), followed by an FIO2 of 0.12 for 180 min. A biphasic response in P(pa) to hypoxia was seen with the first peak between 10 and 20 min and a second rise in P(pa) starting after 30 min, which was due to an increase in cardiac output. Regional blood flow (Q ) and ventilation (V (A)) were measured using i.v. infusion of 15 microm and inhalation of 1 microm fluorescent microspheres, respectively. We grouped the lung pieces according to their temporal relative flow response to hypoxia. The five groups were each spatially distributed similarly, but not identically, among the animals. The corresponding relative ventilation to each group did not vary much. We conclude that in the prone pig, the PVR response to sustained hypoxia varies among regions of the lungs. Following an initial rise in PVR in most lung pieces, we found unexpectedly that some regions continue to increase PVR progressively and while other regions decrease PVR after the initial increase. The net effect is little change of overall PVR to hypoxia with time. Normoxic control animals had little change in their hemodynamics and the large majority of the lung pieces did not change their resistance over 3h. We speculate that the differential response of regions may be due to a differential role of nitric oxide, endothelin-1 release or K(+) channels.

Study objectives Hypercapnic acidosis has antiinflammatory effects in animal models of acute lung injury (ALI) and improves ventilation-perfusion (V/Q) matching in normal lungs. The effect of hypercapnia on V/Q matching in ALI is conflicting. Hypercapnic acidosis produced by reduced tidal volumes (V t s) was associated with an increased shunt fraction (QS/QT) in patients with ALI compared with control subjects. V t differences between groups make the assessment of hypercapnic acidosis on V/Q matching difficult. Adding CO 2 to the inhaled gas allows the comparison of gas exchange under identical V t conditions. We hypothesized the presence of hypercapnic acidosis from inspired carbon dioxide (ICD) would improve gas exchange in ALI and would be superior to that of low minute ventilation (LV e ) produced by reduced respiratory rate, rather than V t . Design University laboratory study of anesthetized New Zealand White rabbits. Interventions Assessment of V/Q relationships using the multiple inert gas elimination technique was performed in 10 saline solution-lavaged animals, which were ventilated with 6 mL/kg V t s and a positive end-expiratory pressure of 8 cm H 2 O. Each rabbit was studied while it was in eucapnia, followed by hypercapnia (Pa co 2 , 95 to 100 mm Hg) induced by LV e from decreased respiratory rate and by 10% ICD, in random order. Measurements and results The Pa o 2 was greater in ICD and LV e compared to eucapnia, but no significant differences in alveolar-arterial oxygen pressure difference or Pao 2 /fraction of inspired oxygen ratio occurred. LV e statistically reduced the mean V/Q distributions compared with ICD and eucapnia. Log SDs of ventilation and combined retention and excretion curves of the dispersion index were both increased during LV e , indicating the presence of unfavorable changes in ventilation distribution. Neither LV e nor ICD altered the QS/QT. Conclusions LV e slightly impairs overall gas exchange and ventilation distribution, but does not increase QS/QT compared with eucapnia and ICD. While ICD does not significantly improve gas exchange, it may be superior to LV e in achieving the antiinflammatory effects of “therapeutic” hypercapnia, since it does not adversely alter gas exchange and has the potential to make the lung more uniformly acidotic.

Exhaled acetone is measured to estimate exposure or monitor diabetes and congestive heart failure. Interpreting this measurement depends critically on where acetone exchanges in the lung. Health professionals assume exhaled acetone originates from alveolar gas exchange, but experimental data and theoretical predictions suggest that acetone comes predominantly from airway gas exchange. We measured endogenous acetone in the exhaled breath to evaluate acetone exchange in the lung. The acetone concentration in the exhalate of healthy human subjects was measured dynamically with a quadrupole mass spectrometer and was plotted against exhaled volume. Each subject performed a series of breathing maneuvers in which the steady exhaled flow rate was the only variable. Acetone phase III had a positive slope (0.054 ± 0.016 liter−1) that was statistically independent of flow rate. Exhaled acetone concentration was normalized by acetone concentration in the alveolar air, as estimated by isothermal rebreathing. Acetone concentration in the rebreathed breath ranged from 0.8 to 2.0 parts per million. Normalized end-exhaled acetone concentration was dependent on flow and was 0.79 ± 0.04 and 0.85 ± 0.04 for the slow and fast exhalation rates, respectively. A mathematical model of airway and alveolar gas exchange was used to evaluate acetone transport in the lung. By doubling the connective tissue (epithelium + mucosal tissue) thickness, this model predicted accurately ( R2 = 0.94 ± 0.05) the experimentally measured expirograms and demonstrated that most acetone exchange occurred in the airways of the lung. Therefore, assays using exhaled acetone measurements need to be reevaluated because they may underestimate blood levels.

Hypoxic pulmonary vasoconstriction (HPV) is known to affect regional pulmonary blood flow distribution. It is unknown whether lungs with well-matched ventilation (V̇)/perfusion (Q̇) have regional differences in the HPV response. Five prone pigs were anesthetized and mechanically ventilated (positive end-expiratory pressure = 2 cmH2O). Two hypoxic preconditions [inspired oxygen fraction (FiO2) = 0.13] were completed to stabilize the animal's hypoxic response. Regional pulmonary blood Q̇ and V̇ distribution was determined at various FiO2 (0.21, 0.15, 0.13, 0.11, 0.09) using the fluorescent microsphere technique. Q̇ and V̇ in the lungs were quantified within 2-cm3 lung pieces. Pieces were grouped, or clustered, based on the changes in blood flow when subjected to increasing hypoxia. Unique patterns of Q̇ response to hypoxia were seen within and across animals. The three main patterns (clusters) showed little initial difference in V̇/Q̇ matching at room air where the mean V̇/Q̇ range was 0.92–1.06. The clusters were spatially located in cranial, central, and caudal portions of the lung. With decreasing FiO2, blood flow shifted from the cranial to caudal regions. We determined that pulmonary blood flow changes, caused by HPV, produced distinct response patterns that were seen in similar regions across our prone porcine model.

We studied the spatial distribution of the abnormal ventilation-perfusion (V̇a/Q̇) units in a porcine model of acute pulmonary thromboembolism (APTE), using the fluorescent microsphere (FMS) technique. Four piglets (∼22 kg) were anesthetized and ventilated with room air in the prone position. Each received ∼20 g of preformed blood clots at time t = 0 min via a large-bore central venous catheter, until the mean pulmonary arterial pressure reached 2.5 times baseline. The distributions of regional V̇a and blood flow (Q̇) at five time points ( t = −30, −5, 30, 60, 120 min) were mapped by FMS of 10 distinct colors, i.e., aerosolization of 1-μm FMS for labeling V̇a and intravenous injection of 15-μm FMS for labeling Q̇. Our results showed that, at t = 30 min following APTE, mean V̇a/Q̇ (V̇a/Q̇ = 2.48 ± 1.12) and V̇a/Q̇ heterogeneity (log SD V̇a/Q̇ = 1.76 ± 0.23) were significantly increased. There were also significant increases in physiological dead space (11.2 ± 12.7% at 60 min), but the shunt fraction (V̇a/Q̇ = 0) remained minimal. Cluster analyses showed that the low V̇a/Q̇ units were mainly seen in the least embolized regions, whereas the high V̇a/Q̇ units and dead space were found in the peripheral subpleural regions distal to the clots. At 60 and 120 min, there were modest recoveries in the hemodynamics and gas exchange toward baseline. Redistribution pattern was mostly seen in regional Q̇, whereas V̇a remained relatively unchanged. We concluded that the hypoxemia seen after APTE could be explained by the mechanical diversion of Q̇ to the less embolized regions because of the vascular obstruction by clots elsewhere. These low V̇a/Q̇ units created by high flow, rather than low V̇a, accounted for most of the resultant hypoxemia.

Hypoxic pulmonary vasoconstriction (HPV) is thought to protect gas exchange by decreasing perfusion to hypoxic regions. However, with global hypoxia, non-uniformity in HPV may cause over-perfusion to some regions, leading to high-altitude pulmonary edema. To quantify the spatial distribution of HPV and regional P O 2 ( P R O 2 ) among small lung regions (∼2.0 cm3), five prone beagles (∼8.3 kg) were anesthetized and ventilated (PEEP ∼ 2 cm H2O) with an F I O 2 of 0.21, then 0.50, 0.18, 0.15, and 0.12 in random order. Regional blood perfusion (Q), ventilation (VA) and calculated P R O 2 were obtained using iv infusion of 15 μm and inhalation of 1 μm fluorescent microspheres. Lung pieces were clustered by their relative blood flow response to each F I O 2 . Clusters were shown to be spatially grouped within animals and across animals. Lung piece resistance increased as P R O 2 decreased to 60–70 mmHg but dropped at P R O 2 ’ s 60 mmHg. Regional ventilation changed little with hypoxia. HPV varied more in strength of response, rather than P R O 2 response threshold. In initially homogeneous VA/Q lungs, we conclude that HPV response is heterogeneous and spatially clustered.

Hypoxic pulmonary vasoconstriction (HPV) serves to maintain optimal gas exchange by decreasing perfusion to hypoxic regions. However, global hypoxia and nonuniform HPV may result in overperfusion of poorly constricted regions leading to local edema seen in high-altitude pulmonary edema. To quantify the spatial distribution of HPV and its response to regional Po2 (PrO2) among small lung regions, five pigs were anesthetized and mechanically ventilated in the supine posture. The animals were ventilated with an inspired O2 fraction (FiO2) of 0.50 and 0.21 and then (in random order) 0.15, 0.12, and 0.09. Regional blood flow (Q̇) and alveolar ventilation (V̇a) were measured by using intravenous infusion of 15 μm and inhalation of 1-μm fluorescent microspheres, respectively. PrO2 was calculated for each piece at each FiO2. Lung pieces differed in their Q̇ response to hypoxia in a manner related to their initial V̇a/Q̇ with FiO2 = 0.21. Reducing FiO2 < 0.15 decreased Q̇ to the initially high V̇a/Q̇ (higher PrO2) regions and forced Q̇ into the low V̇a/Q̇ (dorsal-caudal) regions. Resistance increased in most lung pieces as PrO2 decreased, reaching a maximum resistance when PrO2 is between 40 and 50 Torr. Local resistance decreased at Pro2 < 40 Torr. Pieces were statistically clustered with respect to their relative Q̇ response pattern to each FiO2. Some clusters were shown to be spatially organized. We conclude that HPV is spatially heterogeneous. The heterogeneity of Q̇ response may be related, in part, to the heterogeneity of baseline V̇a/Q̇.

Pulmonary arterial occlusion pressure is not thought to reflect left atrial pressure (Pla) when alveolar pressure (PA) exceeds pulmonary venous pressure because alveolar capillaries collapse and the required continuous fluid column between the pulmonary artery and left atrium is interrupted. However, arterial-to-venous flow can occur when PA exceeds both the pulmonary arterial pressure (Ppa) and pulmonary venous pressure (i.e., in Zone 1 conditions), indicating the existence of a continuous patent vascular channel. Accordingly, Ppa should reflect Pla under these conditions. To investigate this connection cannulas were placed in the pulmonary arteries and left atria of eight excised rabbit lungs. Ppa and Pla were set 5 cm H2O above PA, which ranged from 0 to 25 cm H2O. Pla was then reduced in 2 to 4 cm H2O decrements while recording Ppa when arterial-to-venous flow ceased. At all PAs greater than 0 cm H2O, Pla was accurately reflected by the Ppa when both were exceeded by PA. The greater the PA, the lower the Ppa could track Pla below PA. Pla can be accurately measured by a pulmonary arterial catheter under Zone 1 conditions.

Hyperventilation with mixtures of O2 and CO2 has long been known to enhance carbon monoxide (CO) elimination at low HbCO levels in animals and humans. The effect of this therapy on oxygen delivery (DO2) has not been studied. Isocapnic hyperventilation utilizing mechanical ventilation may decrease cardiac output and therefore decrease DO2 while increasing CO elimination. We studied the effects of isocapnic hyperventilation on five adult mechanically ventilated sheep exposed to multiple episodes of severe CO poisoning. Five ventilatory patterns were studied: baseline minute ventilation (RR. VT), twice (2. RR) and four times (4. RR) baseline respiratory rate, and twice (2. VT) and four times (4. VT) baseline tidal volume. The mean carboxyhemoglobin (HbCO) washout half-time (t1/2) was 14.3 +/- 1.6 min for RR. VT, decreasing to 9.5 +/- 0.9 min for 2. RR, 8.0 +/- 0.5 min for 2. VT, 6.2 +/- 0.5 min for 4. RR, and 5.2 +/- 0.5 min for 4. VT. DO2 was increased during hyperventilation compared with baseline ventilation for 2. VT, 4. RR, and 4. VT ventilatory patterns. Isocapnic hyperventilation, in our animal model, did not alter arterial or pulmonary blood pressures, arterial pH, or cardiac output. Isocapnic hyperventilation is a promising therapy for CO poisoning.

The microsphere method has been used extensively to measure regional blood flow in large laboratory animals. A fundamental premise of the method is that microspheres do not alter regional flow or vascular tone. Whereas this assumption is accepted in large animals, it may not be valid in the pulmonary circulation of smaller animals. Three studies were performed to determine the hemodynamic effects of microspheres on the rat pulmonary circulation. Increasing numbers of 15-μm-diameter microspheres were injected into a fully dilated, isolated-lung preparation. Vascular resistance increased 0.8% for every 100,000 microspheres injected. Microspheres were also injected into an isolated-lung preparation in which vascular tone was increased with hypoxia. Microspheres did not induce vasodilatation, as reported in other vascular beds. Fluorescent microspheres were injected via tail veins into awake rats, and the spatial locations of the microspheres were determined. Regional distributions remained highly correlated when microspheres of one color were injected after microspheres of another color. This indicates that the initial injection did not alter regional perfusion. We conclude that, when used in appropriate numbers, 15-μm-diameter microspheres do not alter regional flow or vascular tone in the rat pulmonary circulation.

Prior studies exploring the spatial distributions of ventilation and perfusion have partitioned the lung into discrete regions not constrained by anatomical boundaries and may blur regional differences in perfusion and ventilation. To characterize the anatomical heterogeneity of regional ventilation and perfusion, we administered fluorescent microspheres to mark regional ventilation and perfusion in five Sprague–Dawley rats and then using highly automated computer algorithms, partitioned the lungs into regions defined by anatomical structures identified in the images. The anatomical regions ranged in size from the near-acinar to the lobar level. Ventilation and perfusion were well correlated at the smallest anatomical level. Perfusion and ventilation heterogeneity were relatively less in rats compared to data previously published in larger animals. The more uniform distributions may be due to a smaller gravitational gradient and/or the fewer number of generations in the distribution trees before reaching the level of gas exchange, making regional matching of ventilation and perfusion less extensive in small animals.

Total liquid ventilation (LV) lowers airway pressures and potentially reduces barotrauma in models of hyaline membrane disease. LV eliminates surface tension by eliminating the air-perfluorochemicals (PFC) interface but does not eliminate interfacial tension (IT) at the lung/PFC interface. We hypothesized that pretreatment with exogenous surfactant before LV would shift the overall pressure-volume (PV) curve to the left, compared with LV without surfactant. Sequential quasi-static PV curves were obtained in 10 excised lungs (saline, air, PFC), with one-half randomized to exogenous surfactant replacement before LV. Analysis revealed that maximal inflation pressures were reduced during LV compared with baseline air curves. Addition of exogenous surfactant to LV further reduced maximal inflation pressures. A novel approach was used to transform these PV curves to estimates of in situ IT-volume curves. Estimated maximal IT at 20 ml/kg in preterm lamb lungs on air inflation after surfactant was 51 mN/m, compared with 40 mN/m for LV alone and with 27 mN/m for the combination of surfactant and LV. We conclude that the IT-reducing properties of the PFC studied (perflubron) can be augmented through the use of exogenous surfactant.

The effect of severe generalized edema on respiratory system mechanics is not well described. We measured airway pressure, gastric pressure, and four vertical pleural pressures in 13 anesthetized paralyzed pigs ventilated in the upright position. Pressure-volume relationships of the respiratory system, chest wall, and lung were measured on deflation from total lung capacity to residual volume and during tidal breathing both before (control) and 50 min after one of two interventions. In one series of experiments, a volume equal to 15–20% of the pig's body weight was infused intravenously. In a second series, a balloon was placed in the peritoneal space to distend the abdomen to the same gastric pressures as achieved in the first series. Measurements were compared before and after either abdominal balloon inflation or volume infusion. Volume infusion increased the pleural pressure in dependent lung regions, decreased both total lung capacity (34%) and functional residual capacity (62%) (both P less than 0.05), and markedly shifted the respiratory system and chest wall pressure-volume curves to the right, but it only moderately affected the lung deflation curve. Tidal compliances of the respiratory system, chest wall, and lung decreased 36, 31, and 49%, respectively (all P less than 0.05). The effect of abdominal balloon inflation on respiratory system mechanics was similar to that of volume infusion. We conclude that infusing large volumes of fluid markedly alters chest wall mechanics, mainly by causing abdominal distension that prohibits descent of the diaphragm.

Previous studies reported that regional CO2tension might affect regional ventilation (V̇) following acute pulmonary thromboembolism (APTE). We investigated the pathophysiology and magnitude of these changes. Eight anesthetized and ventilated piglets received autologous clots at time = 0 min until mean pulmonary artery pressure was 2.5 times baseline. The distribution of V̇ and perfusion (Q̇) at four different times (−5, 30, 60, 120 min) was mapped by fluorescent microspheres. Regional V̇ and Q̇ were examined postmortem by sectioning the air-dried lung into 900–1,000 samples of ∼2 cm3each. After the redistribution of regional Q̇ by APTE, but in the scenario assuming that no V̇ shift had yet occurred, CO2tension in different lung regions at 30 min post-APTE (PXCO2) was estimated from the V̇/Q̇ data and divided into four distinct clusters: i.e., PXCO2< 10 Torr; 10 < PXCO2< 25 Torr; 25 < PXCO2< 50 Torr; PXCO2> 50 Torr. Our data showed that the clusters in higher V̇/Q̇ regions (with a PXCO2< 25 Torr) received ∼35% less V̇ when measured within 30 min of APTE, whereas, in contrast, the lower V̇/Q̇ regions showed no statistically significant increases in their V̇. However, after 30 min, there was minimal further redistribution of V̇. We conclude that there are significant compensatory V̇ shifts out of regions of low CO2tension soon following APTE, and that these variations in regional CO2tension, which initiate CO2-dependent changes in airway resistance and lung parenchymal compliance, can lead to improved gas exchange.

Abdominal distension (AD) occurs in pregnancy and is also commonly seen in patients with ascites from various causes. Because the abdomen forms part of the "chest wall," the purpose of this study was to clarify the effects of AD on ventilatory mechanics. Airway pressure, four (vertical) regional pleural pressures, and abdominal pressure were measured in five anesthetized, paralyzed, and ventilated upright pigs. The effects of AD on the lung and chest wall were studied by inflating a liquid-filled balloon placed in the abdominal cavity. Respiratory system, chest wall, and lung pressure-volume (PV) relationships were measured on deflation from total lung capacity to residual volume, as well as in the tidal breathing range, before and 15 min after abdominal pressure was raised. Increasing abdominal pressure from 3 to 15 cmH2O decreased total lung capacity and functional residual capacity by approximately 40% and shifted the respiratory system and chest wall PV curves downward and to the right. Much smaller downward shifts in lung deflation curves were seen, with no change in the transdiaphragmatic PV relationship. All regional pleural pressures increased (became less negative) and, in the dependent region, approached 0 cmH2O at functional residual capacity. Tidal compliances of the respiratory system, chest wall, and lung were decreased 43, 42, and 48%, respectively. AD markedly alters respiratory system mechanics primarily by "stiffening" the diaphragm/abdomen part of the chest wall and secondarily by restricting lung expansion, thus shifting the lung PV curve as seen after chest strapping. The less negative pleural pressures in the dependent lung regions suggest that nonuniformities of ventilation could also be accentuated and gas exchange impaired by AD.

We performed a multicenter study to test the hypothesis that tidal liquid ventilation (TLV) would improve cardiopulmonary, lung histomorphological, and inflammatory profiles compared with conventional mechanical gas ventilation (CMV). Sheep were studied using the same volume-controlled, pressure-limited ventilator systems, protocols, and treatment strategies in three independent laboratories. Following baseline measurements, oleic acid lung injury was induced and animals were randomized to 4 hours of CMV or TLV targeted to "best PaO2" and PaCO2 35 to 60 mm Hg. The following were significantly higher (p < 0.01) during TLV than CMV: PaO2, venous oxygen saturation, respiratory compliance, cardiac output, stroke volume, oxygen delivery, ventilatory efficiency index; alveolar area, lung % gas exchange space, and expansion index. The following were lower (p < 0.01) during TLV compared with CMV: inspiratory and expiratory pause pressures, mean airway pressure, minute ventilation, physiologic shunt, plasma lactate, lung interleukin-6, interleukin-8, myeloperoxidase, and composite total injury score. No significant laboratories by treatment group interactions were found. In summary, TLV resulted in improved cardiopulmonary physiology at lower ventilatory requirements with more favorable histological and inflammatory profiles than CMV. As such, TLV offers a feasible ventilatory alternative as a lung protective strategy in this model of acute lung injury.

SUMMARY We tested the hypothesis that surfactant replacement would be beneficial In the acld­ aspiration model of acute lung Injury. HCI (0.1 N, 2 mllkg) was Injected Into the trachea of excised rabbit lungs (n = 8). Control lungs (n = 4) had no Intervention. All were perfused with lYrode's solution mixed 1:1 with autologous whole blood at 40 mllmin/kg for 30 min, and then degassed. A modified natural surfactant (Survanta@, Ross Laboratories) was then Injected Into the trachea of four lungs Injured with HCI (100 mg/kg at 25 mg/ml). lWo quasi-static pressure-volume curves were determined. The mean alveolar pressures at 50,60,70,80, and 90% of TLC were greater In the HCI group than In the control group (p < 0.05). However, no difference was observed between the control lungs and thosethat received HCI + Survanta. In 13 anesthetized, paralyzed, and venti­ lated rabbits, deflation pressure-volume curvas were determined from TLC to FRC (measured by helium dilution). Then, 0.1 N HCI (3 ml/kg) was Injected into the trachea and, in seven, Survanta was Instilled 5 min later. The mean alveolar pressures at 60, 70, 80, and 90% TLC were higher at 15 and 60 min In the HCI group compared with their pre-HCI time point (p < 0.05). In the HCI + Survanta group, no differences were seen at 15 min, and only slight Increased were seen at 60 min. No effect of surfactant replacement on arterial blood gases was observed. HCI aspiration Increased recoil In both excised and in "i"o lungs, and surfactant replacement with Survanta returned recoil to normal. AM REV RESPIR DIS 1990; 142:1279-1283

We studied the roles of endothelins in determining ventilation (V̇a) and perfusion (Q̇) mismatch in a porcine model of acute pulmonary thromboembolism (APTE), using a nonspecific endothelin antagonist, tezosentan. Nine anesthetized piglets (∼23 kg) received autologous clots (∼20 g) via a central venous catheter at time = 0 min. The distribution of V̇a and Q̇ at five different time points (−30, −5, 30, 60, 120 min) was mapped by fluorescent microspheres of 10 different colors. Five piglets ( group 1) received tezosentan (courtesy of Actelion) starting at time = 40 min for 2 h, and four piglets ( group 2) received only saline and served as control. Our results showed that, in all of the animals at 30 min following APTE but before tezosentan, the mean V̇a/Q̇ was increased, as was V̇a/Q̇ heterogeneity (log SD V̇a/Q̇), which represented a widening of its main peak. Afterwards, tezosentan attenuated the pulmonary hypertension in group 1 but also produced moderate systemic hypotension. However, it did not improve arterial Po2 or V̇a/Q̇ mismatch. We concluded that endothelin antagonism had minimal impact on gas exchange following APTE and confirmed our earlier observation that the main mechanism for hypoxemia in APTE was due to the mechanical redistribution of pulmonary regional blood flow away from the embolized vessels, resulting in the creation of many divergent low and high V̇a/Q̇ regions.

We have shown previously that inspired CO2 (3-5%) improves ventilation-perfusion (V̇a/Q̇) matching but with the consequence of mild arterial hypercapnia and respiratory acidosis. We hypothesized that adding CO2 only late in inspiration to limit its effects to the conducting airways would enhance V̇a/Q̇ matching and improve oxygenation without arterial hypercapnia. CO2 was added in the latter half of inspiration in a volume aimed to reach a concentration of 5% in the conducting airways throughout the respiratory cycle. Ten mixed-breed dogs were anesthetized and, in a randomized order, ventilated with room air, 5% CO2 throughout inspiration, and CO2 added only to the latter half of inspiration. The multiple inert-gas elimination technique was used to assess V̇a/Q̇ heterogeneity. Late-inspired CO2 produced only very small changes in arterial pH (7.38 vs. 7.40) and arterial CO2 (40.6 vs. 39.4 Torr). Compared with baseline, late-inspired CO2 significantly improved arterial oxygenation (97.5 vs. 94.2 Torr), decreased the alveolar-arterial Po2 difference (10.4 vs. 15.7 Torr) and decreased the multiple inert-gas elimination technique-derived arterial-alveolar inert gas area difference, a global measurement of V̇a/Q̇ heterogeneity (0.36 vs. 0.22). These changes were equal to those with 5% CO2 throughout inspiration (arterial Po2, 102.5 Torr; alveolar-arterial Po2 difference, 10.1 Torr; and arterial-alveolar inert gas area difference, 0.21). In conclusion, we have established that the majority of the improvement in gas exchange efficiency with inspired CO2 can be achieved by limiting its application to the conducting airways and does not require systemic acidosis.

To investigate whether hypercapnic acidosis protects against ventilator-induced lung injury (VILI) in vivo, we subjected 12 anesthetized, paralyzed rabbits to high tidal volume ventilation (25 cc/kg) at 32 breaths per minute and zero positive end-expiratory pressure for 4 hours. Each rabbit was randomized to receive either an FI(CO(2)) to achieve eucapnia (Pa(CO(2)) approximately 40 mm Hg; n = 6) or hypercapnic acidosis (Pa(CO(2)) 80-100 mm Hg; n = 6). Injury was assessed by measuring differences between the two groups' respiratory mechanics, gas exchange, wet:dry weight, bronchoalveolar lavage fluid protein concentration and cell count, and injury score. The eucapnic group showed significantly higher plateau pressures (27.0 +/- 2.5 versus 20.9 +/- 3.0; p = 0.016), change in Pa(O(2)) (165.2 +/- 19.4 versus 77.3 +/- 87.9 mm Hg; p = 0.02), wet:dry weight (9.7 +/- 2.3 versus 6.6 +/- 1.8; p = 0.04), bronchoalveolar lavage protein concentration (1,350 +/- 228 versus 656 +/- 511 micro g/ml; p = 0.03), cell count (6.86 x 10(5) +/- 0.18 x 10(5) versus 2.84 x 10(5) +/- 0.28 x 10(5) nucleated cells/ml; p = 0.021), and injury score (7.0 +/- 3.3 versus 0.7 +/- 0.9; p < 0.0001). We conclude that hypercapnic acidosis is protective against VILI in this model.

The mechanism by which oxygenation improves when patients with ARDS are turned from supine to prone position is not known. From results of our previous studies we reasoned that (1) when supine, in the setting of lung injury, transpulmonary pressure will be less than airway opening pressure and (2) atelectasis will develop preferentially in dorsal lung areas, and (3) both ventilation and ventilation/perfusion ratios would improve in these regions on turning prone. To study this directly, we measured regional ventilation and perfusion using 81mKr and 99mTc-MAA, respectively, and single photon emission computed tomography, both prone and supine, in four control animals and four given oleic acid. After oleic acid, the prone position improved (1) oxygenation (mean +/- SD PaO2 = 140 +/- 112 versus 453 +/- 54 mm Hg), (2) median ventilation/perfusion ratios (0.77 versus 0.95), (3) ventilation/perfusion heterogeneity (coefficient of variation 86 +/- 15 versus 61 +/- 6), and (4) the gravitational ventilation/perfusion gradient (dependent to non-dependent slopes of 0.22 versus -0.02, all p0.05). The prone position generates a transpulmonary pressure sufficient to exceed airway opening pressure in dorsal lung regions, i.e., in regions where atelectasis, shunt, and ventilation/perfusion heterogeneity are most severe, without adversely affecting ventral lung regions.

Oxygenation improves in patients with adult respiratory distress syndrome and in animals with oleic acid-induced lung injury when they are turned from the supine to the prone position. Dependent and nondependent pleural pressures (Ppl) were measured in six pigs ventilated in the supine and prone positions before and after volume infusion (VI). Before VI the mean +/- SEM AaPO2 difference was 26 +/- 8 mm Hg when the animals were supine and 10 +/- 2 mm Hg when they were prone (p > 0.05). After VI the AaPO2 was 64 +/- 6 mm Hg when the animals were supine (p < 0.05) and 43 +/- 7 mm Hg when they were prone (p < 0.05). VI increased the Ppl gradient from 0.53 +/- 0.1 to 0.71 +/- 0.1 cm H2O/cm when the animals were supine (p < 0.05) and from 0.17 +/- 0.1 to 0.27 +/- 0.1 cm H2O/cm when they were prone (p < 0.05). Dependent Ppl at FRC was much less positive when the animals were prone versus supine (0.9 +/- 0.3 versus 3.0 +/- 0.5 cm H2O, p < 0.05), suggesting that the airways in these dependent regions would narrow and/or close and that ventilation to these regions would diminish as a result of VI.

Fluid leaking from arterial and venous extra-alveolar vessels (EAV's) may account for up to 60% of the total transvascular fluid flux when edema occurs in the setting of normal vascular permeability. We determined if the permeability and relative contribution of EAV's was altered after inducing acute lung injury in rabbits by administering oleic acid (0.1 ml/kg) into the pulmonary artery, HCl (5 ml/kg of 0.1 N) into the trachea, or air emboli (0.03 ml.kg-1.min-1) into the right atrium for 90 min. Subsequently, the lungs were excised and continuously weighed while they were maintained in a warmed, humidified chamber with alveolar and pulmonary vascular pressures controlled and the lungs either ventilated or distended with 5% CO2 in air. The vascular system was filled with autologous blood and saline (1:1) to which papaverine (0.1 mg/ml) was added to inhibit vasospasm. Vascular pressures were referenced to the lung base. After a transient hydrostatic stress to maximize recruitment, vascular pressures were set at 5 cmH2O, and lungs were allowed to become isogravimetric (30-60 min). A fluid filtration coefficient (Kf) was determined by the use of a modification of the method of Drake and colleagues [Am. J. Physiol. 234 (Heart Circ. Physiol. 3): H266-H274, 1978]. EAV's were isolated by zoning techniques. In control preparations arterial and venous EAV's accounted for 26% (n = 9) and 38% (n = 11) of the total leakage, respectively. In all three models Kf increased two- to fourfold when the lungs were in zone 3 (alveolar vessels and arterial and venous EAV's contributing to the leakage).(ABSTRACT TRUNCATED AT 250 WORDS)

Because of conflicting data in the literature, we studied the effect of positive-pressure inflation on transvascular fluid filtration in zone 1 lungs. Lungs from New Zealand White rabbits (n = 10) were excised, perfused with saline and autologous whole blood (1:1), ventilated, and continuously weighed. Pulmonary arterial and venous pressures (Pvas) were referenced to the most dependent part of the lung. A change in vascular volume (delta Vvas) and a fluid filtration rate (FFR) were calculated from the change in lung weight that occurred from 0 to 30 s and from 3 to 5 and 5 to 10 min, respectively, after changing alveolar pressure (PA). FFR's and delta Vvas's were measured with Pvas equal to 2 or 10 cmH2O and PA changing from 15 to 30 cmH2O when the lungs were normal and after they were made edematous. When Pvas = 2 cmH2O, increasing PA increased the Vvas and the FFR in both normal and edematous lungs. However, when Pvas = 10 cmH2O, increasing PA only slightly changed the Vvas and reduced the FFR in the normal lungs, and decreased Vvas and markedly decreased the FFR in the presence of edema. Inflating zone 1 lungs by positive pressure has an effect on transvascular fluid flux that depends on the Pvas. The results suggest that the sites of leakage in zone 1 also vary depending on Pvas and PA.

Leukotrienes (LTs) C4 and D4 are vasoconstrictors and are thought to increase both systemic and pulmonary vascular permeability. However, we and others have observed that LTC4 and LTD4 cause pulmonary vasoconstriction but do not increase the fluid filtration coefficient of excised guinea pig lungs perfused with a cell-depleted perfusate. To determine what vascular segments were exposed to an LT-induced increase in intravascular hydrostatic pressure we measured pulmonary arterial (Ppa), pulmonary arterial occlusion (Po,a), venous (Po,v) and double occlusion (Pdo) pressures in isolated guinea pig lungs perfused with a cell-depleted buffered salt solution before and after injecting 4 micrograms of LTB4, LTC4, or LTD4 into the pulmonary artery. All three LTs increased airway pressures and also increased Ppa, Po,a, and Pdo. Histamine (15 micrograms) as well as serotonin (20 or 200 micrograms) had the same effect. In excised rabbit lungs, histamine and serotonin increased only Ppa, and Po,a. LTC4 had no vasoactivity. There are marked species variations with regard to the activity and site of action of histamine, serotonin, and LTC4 on the pulmonary circulation.