Carol Marshall

Influence of isoflurane on hypoxic pulmonary vasoconstriction in dogs

The authors studied the influence of locally administered isoflurane anesthesia on the pulmonary vascular response to regional alveolar hypoxia (hypoxic pulmonary vasoconstriction [HPV]) over a range of cardiac outputs (COs) in seven mechanically ventilated, closed-chest dogs. The right lung was ventilated with 100% O2 throughout the study. The left lung was ventilated with either 100% O2 (normoxia) or an hypoxic gas mixture (hypoxia). Different alveolar concentrations of isoflurane (0, 1, and 2.5 MAC) were administered to the left lung in a randomized sequence. The CO was altered by opening and closing surgically produced arteriovenous fistulae, at all isoflurane concentrations, and by hemorrhage at 0 MAC isoflurane. The magnitude of the HPV response was measured by differential CO2 elimination in the absence of isoflurane and by venous admixtures in all phases. During normoxia, the left lung effective flow (&OV0422;L%) measured from differential CO2 excretion was 39.9 ± 1.2% of the total blood flow and decreased to 18.8 ± 2.6% when ventilated with the hypoxic gas mixture. Venous admixture (&OV0422;VA/&OV0422;T%) was significantly correlated with &OV0422;L% during hypoxic ventilation in the absence of isoflurane. &OV0422;VA/&OV0422;T% was 22.3 ± 2.7% during hypoxia with normal CO, and it increased significantly to 27.7 ± 1.1% when the CO was increased 43%. It was not significantly altered (23.6 ± 3.6%) when the CO was decreased by 54%. Isoflurane 2.5 MAC significantly increased &OV0422;VA/QT% during hypoxic ventilation of the left lung to 33.9 ± 2.6% with low CO and 35.4 ± 1.7% with normal CO. Isoflurane 1 MAC increased &OV0422;VA/QT% to 27.2 ± 2.7% with normal CO and 28.1 ± 2.6% with high CO. Comparing the effects of the different concentrations of isoflurane on &OV0422;VA/&OV0422;T% during left lung hypoxia under the same conditions of CO, mixed venous and alveolar oxygen tension, and pulmonary artery and pulmonary artery occlusion pressures revealed a significant direct effect of isoflurane dose such that: (% depression of HPV) = [22.8(% alveolar isoflurane) – 5.3]. The ED50 for this response was 2.4% alveolar isoflurane. The authors conclude that isoflurane directly depresses HPV and that secondary influences of the anesthetic action should be considered in the interpretation of the action of inhalational agents on this response in vivo.

Effects of Halothane, Enflurane, and Isoflurane on Hypoxic Pulmonary Vasoconstriction in Rat Lungs In Vitro

Rat lungs were ventilated and perfused at a constant rate in vitro. The maximal hypoxic pulmonary vasoconstrictor (HPV) response was recorded by measuring the pulmonary artery pressure change when the inspired oxygen concentration was changed from 21% to 3% (with 5.5% carbon dioxide) in the absence of anesthetic vapor.In different experimental groups, the effects of halothane, enflurane, and isoflurane on HPV were examined. In random order the anesthetics were added to the inspired gas in concentrations of 0.25, 0.5, 1, 1.5, and 2 or 2.5 MAC units. The HPV pressor response to 3% oxygen in the presence of anesthetic agent was expressed as a per cent of the pressure response observed in the absence of anesthetic (R%MAX).All three agents depressed HPV in a dose-related manner. The concentrations in MAC units at which 50% depression of HPV (ED50) occurred was 0.47, 0.60, and 0.56 for halothane, isoflurane, and enflurane, respectively, and neither the ED50 values nor the slopes of these dose response curves were significantly different.It was concluded that these halogenated general anesthetics inhibit HPV with essentially the same potency.

Influence of Mixed Venous Oxygen Tension (PVO2) on Blood Flow to Atelectatic Lung

The influence of mixed venous oxygen tension (PVO2) on blood flow to the atelectatic left lung was studied at normal and reduced cardiac outputs (CO) using extracorporeal veno-venous bypass in six pentobarbital anesthetized, mechanically ventilated dogs. Aortic and left pulmonary artery flows; airway, left atrial, central venous, pulmonary, and systemic arterial pressures; hemoglobin, arterial, and mixed venous blood gases were measured. The blood flow reduction observed in atelectasis was altered by the PVO2. Approximately 50% of blood flow was diverted away from atelectatic lung when PVO2 was low (24 ± 2 mmHg) or normal (46 ± 2 mmHg) (mean left lung blood flow [VL] was 23.2 ± 4.6% with low PVO2 and 19.0 ± 3.4%, with normal PVO2). When PVO2I was increased to greater than 100 mmHg, diversion of blood flow away from atelectatic lung did not occur and VL% was nearly the flow expected for normoxic ventilated left lung (mean VL% = 40.4 ± 5.9%). Shunt (VS/VT%) was significantly greater when PVO2 was high than when it was normal or low (mean VS/VT% = 51.7 ± 5.6%, 31.0 ± 3.1%, 26.0 ± 3.4% with high, normal, and low PVO2, respectively). Mean PVO2 was significantly greater when PVO22 was high than when PVO2 was normal or low, despite the increase in VL% and VS/VT% (PVO2 = 327 ± 25 mmHg, 220 ± 32 mmHg, 115 + 21 mmHg with high, normal, and low PVO2, respectively). A 40% reduction in cardiac output significantly decreased transmural pulmonary artery pressure but did not affect PVO2, VS/VT%i or VL%- The mechanism of blood-flow reduction to atelectatic lung is therefore hypoxic pulmonary vasoconstriction, determined by the PVO2. The contribution of mechanical factors in reducing blood flow to atelectatic lung in the open chest is small

Endothelin-1 is elevated in monocrotaline pulmonary hypertension.

These studies document striking pulmonary vasoconstrictor response to nitric oxide synthase (NOS) inhibition in monocrotaline (MCT) pulmonary hypertension in rats. This constriction is caused by elevated endothelin (ET)-1 production acting on ETA receptors. Isolated, red blood cell plus buffer-perfused lungs from rats were studied 3 wk after MCT (60 mg/kg) or saline injection. MCT-injected rats developed pulmonary hypertension, right ventricular hypertrophy, and heightened pulmonary vasoconstriction to ANG II and the NOS inhibitor N G-monomethyl-l-arginine (l-NMMA). In MCT-injected lungs, the magnitude of the pulmonary pressor response to NOS inhibition correlated strongly with the extent of pulmonary hypertension. Pretreatment of isolated MCT-injected lungs with combined ETA (BQ-123) plus ETB (BQ-788) antagonists or ETA antagonist alone prevented thel-NMMA-induced constriction. Addition of ETA antagonist reversed establishedl-NMMA-induced constriction; ETB antagonist did not. ET-1 concentrations were elevated in MCT-injected lung perfusate compared with sham-injected lung perfusate, but ET-1 levels did not differ before and after NOS inhibition. NOS inhibition enhanced hypoxic pulmonary vasoconstriction in both sham- and MCT-injected lungs, but the enhancement was greater in MCT-injected lungs. Results suggest that in MCT pulmonary hypertension, elevated endogenous ET-1 production acting through ETA receptors causes pulmonary vasoconstriction that is normally masked by endogenous NO production.These studies document striking pulmonary vasoconstrictor response to nitric oxide synthase (NOS) inhibition in monocrotaline (MCT) pulmonary hypertension in rats. This constriction is caused by elevated endothelin (ET)-1 production acting on ETA receptors. Isolated, red blood cell plus buffer-perfused lungs from rats were studied 3 wk after MCT (60 mg/kg) or saline injection. MCT-injected rats developed pulmonary hypertension, right ventricular hypertrophy, and heightened pulmonary vasoconstriction to ANG II and the NOS inhibitor NG-monomethyl-L-arginine (L-NMMA). In MCT-injected lungs, the magnitude of the pulmonary pressor response to NOS inhibition correlated strongly with the extent of pulmonary hypertension. Pretreatment of isolated MCT-injected lungs with combined ETA (BQ-123) plus ETB (BQ-788) antagonists or ETA antagonist alone prevented the L-NMMA-induced constriction. Addition of ETA antagonist reversed established L-NMMA-induced constriction; ETB antagonist did not. ET-1 concentrations were elevated in MCT-injected lung perfusate compared with sham-injected lung perfusate, but ET-1 levels did not differ before and after NOS inhibition. NOS inhibition enhanced hypoxic pulmonary vasoconstriction in both sham- and MCT-injected lungs, but the enhancement was greater in MCT-injected lungs. Results suggest that in MCT pulmonary hypertension, elevated endogenous ET-1 production acting through ETA receptors causes pulmonary vasoconstriction that is normally masked by endogenous NO production.

Pulmonary Blood Pressure and Flow during Atelectasis in the Dog

The purpose of the study was to measure the time course, direction, and magnitude of the hypoxic pulmonary vasoconstriction (HPV) response to atelectasis. Six dogs were anesthetized with pentobarbital. With the chest open, each lung was ventilated separately, Pulmonary blood flow was measured with electromagnetic flow probes. Pulmonary arterial, left atrial, and systemic arterial pressures were measured via indwelling catheters. The right lung was ventilated continuously with 100% O2, while the left lung was either ventilated with 100% O2, (control phase), unventilated (4 hours of atelectasis), or ventilated with a gas mixture containing 4% O2, 3% CO2, and 93% N2 (hypoxia phase). Left lung atelectasis resulted in a reduction of the per cent left lung blood flow from 43 ± 4% (mean ± SE) to 25 ± 7% at 15 min and to 12 ± 1% at 60 min which persisted for the remaining four-hour period. The per cent left lung blood flow was significantly lower (8 ± 1%) and the Pao2 significantly higher (356 ± 38 mmHg) during the maximal response to atelectasis as compared to 15 min of hypoxic ventilation (23 ± 5%; 211 ± 21 mmHg). With atelectasis or hypoxic ventilation, pulmonary perfusion pressure was increased significantly from the control value of 7.9 ± 0.8 mmHg to approximately 11 mmHg.The present study demonstrated that in the open chest model without systemic hypoxemia, the response to acute atelectasis is a regional increase in pulmonary vascular resistance which develops quickly (15 min) and is maximal by 60 min and is maintained thereafter. As a result, there is a sustained diversion of blood flow away from the atelectatic lung and a generalized increase of pulmonary perfusion pressure.

Improvement in Oxygenation by Phenylephrine and Nitric Oxide in Patients with Adult Respiratory Distress Syndrome

Background: Inhaled nitric oxide (NO), a selective vasodilator, improves oxygenation in many patients with adult respiratory distress syndrome (ARDS). Vasoconstrictors may also improve oxygenation, possibly by enhancing hypoxic pulmonary vasoconstriction. This study compared the effects of phenylephrine, NO, and their combination in patients with ARDS. Methods: Twelve patients with ARDS (PaO2 /FIO2 180; Murray score 2) were studied. Each patient received three treatments in random order: intravenous phenylephrine, 50–200 micro gram/min, titrated to a 20% increase in mean arterial blood pressure; inhaled NO, 40 ppm; and the combination (phenylephrine + NO). Hemodynamics and blood gas measurements were made during each treatment and at pre‐ and posttreatment baselines. Results: All three treatments improved PaO2 overall. Six patients were “phenylephrine‐responders” (Delta PaO2 > 10 mmHg), and six were “phenylephrine‐nonresponders.” In phenylephrine‐responders, the effect of phenylephrine was comparable with that of NO (PaO2 from 105 +/‐ 10 to 132 +/‐ 14 mmHg with phenylephrine, and from 110 +/‐ 14 to 143 +/‐ 19 mmHg with NO), and the effect of phenylephrine + NO was greater than that of either treatment alone (PaO2 from 123 +/‐ 13 to 178 +/‐ 23 mmHg). In phenylephrine‐nonresponders, phenylephrine did not affect Pa sub O2, and the effect of phenylephrine + NO was not statistically different from that of NO alone (PaO2 from 82 +/‐ 12 to 138 +/‐ 28 mmHg with NO; from 84 +/‐ 12 to 127 +/‐ 23 mmHg with phenylephrine + NO). Data are mean +/‐ SEM. Conclusions: Phenylephrine alone can improve PaO2 in patients with ARDS. In phenylephrine‐responsive patients, phenylephrine augments the improvement in PaO2 seen with inhaled NO. These results may reflect selective enhancement of hypoxic pulmonary vasoconstriction by phenylephrine, which complements selective vasodilation by NO.

Mechanical Factors Do Not Influence Blood Flow Distribution in Atelectasis

The contribution of mechanical factors to the vascular resistance of the atelectatic lung has been studied in vivo in the anesthetized open-chest dog. When the left lung was ventilated with an hypoxic gas mixture (while the right lung was ventilated with 100% O2), left lung blood flow decreased from 0.99 +/- 0.11 1.min-1 to 0.40 +/- 0.08 1.min-1 due to hypoxic pulmonary vasoconstriction (hypoxic stimulus PSO2 = 36.1 +/- 0.8 mmHg). When the left lung was made atelectatic, blood flow decreased to 0.65 +/- 0.11 1.min-1, consistent with a weaker hypoxic stimulus (PSO2 = 54.0 +/- 3.2 mmHg). With the addition of sodium nitroprusside infused intravenously, left lung blood flow increased to 1.05 +/- 0.14 1.min-1 during atelectasis, and to 0.61 +/- 0.09 1.min-1 during hypoxic ventilation, while flow remained at 0.94 +/- 0.18 1.min-1 during hyperoxic ventilation. When the results were plotted on pressure-flow diagrams, the hyperoxic, hypoxic, and atelectatic lung points fell on the same pressure-flow line in the presence of nitroprusside. It is concluded that hypoxic pulmonary vasoconstriction is the major (but not necessarily only) determinant of increased vascular resistance in the atelectatic lung, and that passive mechanical factors do not measurably affect blood flow distribution during open-chest atelectasis.

High-dose almitrine bismesylate inhibits hypoxic pulmonary vasoconstriction in closed-chest dogs

The effect of almitrine bismesylate on the hypoxic pulmonary vasoconstrictor (HPV) response was studied in seven closed-chest dogs anesthetized with pentobarbital and paralyzed with pancuronium. The right lung was ventilated continuously with 100% O2, while the left lung was ventilated with either 100% O2 (“hyperoxia”) or with an hypoxic gas mixture (“hypoxia”: end-tidal Po2 = 50.1 ± 0.1 mmHg). Cardiac output (CO) was altered from a “normal” value of 3.10 ± 0.18 1 · min-1 to a “high” value of 3.92 ± 0.16 1 · min-1 by opening arteriovenous fistulae which allowed measurements of two points along a pressure-flow line. These four phases of left lung hypoxia or hyperoxia with normal and high cardiac output were repeated in the presence and absence of almitrine. Almitrine bismesylate was administered as a constant infusion of 14.3 μg · kg-1 · min-1 for a mean plasma concentration of 219.5 ± 26.4 ng · ml-1. Relative blood (low to each lung was measured with a differential CO2 excretion (VCO2) method corrected for the Haldane effect. With both lungs hyperoxic, the percent left lung blood flow (%QL-VCO2) was 44 ± 1%. When the left lung was exposed to hypoxia, the %QL-VCO2 decreased significantly to 22 ±1%- However, with the administration of almitrine, the %QL-VCO2 during left lung hypoxia increased significantly to 36 ± 2%. The arterial oxygen tension decreased significantly between hyperoxia (Pao2 = 633 ± 6 mmHg) and hypoxia (271 ± 31 mmHg). With the addition of almitrine, there was no change during hyperoxia; however, during hypoxia, the Pao2 decreased significantly to 124 ± 15 mmHg. Cardiac output did not influence these findings. The pulmonary vascular conductance (G) is the slope of the pressure-flow line. The pulmonary vascular conductance of the right lung (GR × 103) (1.6 ± 0.1 dyn-1 8 cm5 · s-1) did not change significantly during hyperoxia or hypoxia when no drug was given. With the administration of almitrine, GR decreased significantly to 1.0±0.1 dyn-1 · cm5 · s-1 during both hyperoxia and hypoxia. The same was true at normal and high cardiac output. The pulmonary vascular conductance of the left lung (GL) decreased significantly between hyperoxia (1.24 ± 0.1 dyn-1 · cm5 · s-1) and hypoxia (0.7 ± 0.1 dyn-1 · cm5 · s-1). However, with the addition of almitrine, GL decreased significantly during hyperoxia (0.8 ± 0.1 dyn-1 · cm-1 · s-1), but not during hypoxia (0.8 ± 0.1 dyn-1 · cm5 · s-1). The same was true at normal and high cardiac output. It is concluded that almitrine bismesylate caused nonspecific pulmonary vasoconstriction that was greater in the 100% O2 ventilated lung than in the hypoxic lung regions. Therefore, blood flow was diverted from the hyperoxic back to the hypoxic lung causing a reduction of the HPV response.

Time Course and Responses of Sustained Hypoxic Pulmonary Vasoconstriction in the Dog

The stability of the pulmonary blood pressure and flow response to alveolar hypoxia (hypoxic pulmonary vasoconstriction or HPV) was studied in six pentobarbital anesthetized, mechanically ventilated open-chested dogs. Aortic and left pulmonary artery blood flows; systemic and pulmonary arterial, central venous, left atrial, and airway pressures; hemoglobin; arterial and mixed venous blood gases were measured. The right lung was ventilated continuously with 100% oxygen, while the left lung was ventilated alternately with 100% O2 (prehypoxia control phase), an hypoxic gas mixture containing 4% O2, 3% CO2, balance N2 for 4 h, or 100% O2 (post-hypoxia control phase). Hypoxic ventilation of the left lung resulted in an immediate and sustained decrease in left lung blood flow (&OV0422;L%) from 39.0 ± 1.8% (mean ± SE) to 9.9 ± 3.6% at 15 min of hypoxic ventilation. &OV0422;L% remained decreased and did not vary significantly during the 4 h of hypoxia. Venous admixture correspondingly was increased and Pao2 decreased by hypoxic ventilation and did not vary significantly during the 4 h of hypoxia. All variables returned to control levels upon reestablishing ventilation with 100% O2.While the maximal reduction in &OV0422;L% with left lung hypoxic ventilation was identical to that observed during atelectasis previously in our laboratory, the time course of the response was different. The response to hypoxia was maximal by 15 min, however, &OV0422;L% decreased more slowly during atelectasis, where the maximal reduction was observed by 60 min. The present study therefore demonstrated that hypoxic ventilation of the left lung yielded an immediate and sustained decrease in left lung blood flow for 4 h. The stability of the HPV response probably was accounted for by the lack of such confounding factors as respiratory alkalosis, severe systemic hypoxemia, and increased cardiac output.

Role of wall tension in hypoxic responses of isolated rat pulmonary arteries

The changes in force developed during 40-min exposures to hypoxia (37 +/- 1 mmHg) were recorded in large (0.84 +/- 0.02-mm-diameter) and small (0.39 +/- 0.01-mm-diameter) intrapulmonary arteries during combinations of mechanical wall stretch tensions (passive + active myogenic components), equivalent to transmural vascular pressures of 5, 15, 30, 50, and 100 mmHg, and active (vasoconstriction) tensions, stimulated by PGF2alpha in doses of 0, 25, 50, and 75% effective concentrations. Constriction was observed in all arteries during the first minute; however, at any active tension, the pattern of the subsequent response was a function of the stretch tension. At 5, 15, and 30 mmHg, the constriction decreased slightly at 5 min and then increased again to remain constrictor throughout. At 50 and 100 mmHg, the initial constriction was followed by persistent dilation. Hypoxic constrictor responses, most resembling those observed in lungs in vivo and in vitro, were observed when the mechanical stretch wall tension was equivalent to 15 or 30 mmHg and the dose of PGF2alpha was 25 or 50% effective concentration. These observations reconcile many apparently contradictory results reported previously.The changes in force developed during 40-min exposures to hypoxia (37 ± 1 mmHg) were recorded in large (0.84 ± 0.02-mm-diameter) and small (0.39 ± 0.01-mm-diameter) intrapulmonary arteries during combinations of mechanical wall stretch tensions (passive + active myogenic components), equivalent to transmural vascular pressures of 5, 15, 30, 50, and 100 mmHg, and active (vasoconstriction) tensions, stimulated by PGF2α in doses of 0, 25, 50, and 75% effective concentrations. Constriction was observed in all arteries during the first minute; however, at any active tension, the pattern of the subsequent response was a function of the stretch tension. At 5, 15, and 30 mmHg, the constriction decreased slightly at 5 min and then increased again to remain constrictor throughout. At 50 and 100 mmHg, the initial constriction was followed by persistent dilation. Hypoxic constrictor responses, most resembling those observed in lungs in vivo and in vitro, were observed when the mechanical stretch wall tension was equivalent to 15 or 30 mmHg and the dose of PGF2α was 25 or 50% effective concentration. These observations reconcile many apparently contradictory results reported previously.