Effect of net gas volume changes on alveolar and arterial gas partial pressures in the presence of ventilation-perfusion mismatch.

The second gas effect (SGE) occurs when nitrous oxide enhances the uptake of volatile anesthetics administered simultaneously. Recent work shows that the SGE is greater in blood than in the gas phase, that this is due to ventilation-perfusion mismatch, that as mismatch increases, the SGE increases in blood but is diminished in the gas phase, and that these effects persist well into the period of nitrous oxide maintenance anesthesia. These modifications of the SGE are most pronounced with the low soluble agents in current use. We investigate further the effect of net gas volume loss during nitrous oxide uptake on low concentrations of other gases present using partial pressure-solubility diagrams. The steady-state equations of gas exchange were solved assuming a log-normal distribution of ventilation-perfusion ratios using Lebesgue-Stieltjes integration. It was shown that under these conditions the classical partial pressure-solubility diagram must be modified, that for currently used volatile anesthetic agents the alveolar-arterial partial pressure difference is less than that predicted in the past, and that the alveolar-arterial partial pressure difference may even be reversed during uptake in the case of highly insoluble gases such as sulfur hexafluoride. Comparing this with the situation described previously for nitrogen in steady-state air breathing, we show that for nitrogen, the direction of the alveolar-arterial gradient is opposite to the direction of net gas volume movement. Although gas uptake with ventilation-perfusion inequality exceeding that when matching is optimal is shown to be possible, it is less likely than alveolar-arterial partial pressure reversal. NEW & NOTEWORTHY Net uptake of gases administered with nitrous oxide may proceed against an alveolar-arterial partial pressure gradient. The alveolar-arterial gradient for nitrogen in the steady-state breathing air depends not only on the existence of a distribution of ventilation-perfusion ratios in the lung but also on the presence of a net change in gas volume and is opposite in direction to the direction of net gas volume uptake.

Can Mathematical Modeling Explain the Measured Magnitude of the Second Gas Effect?

BACKGROUND: Recent clinical studies suggest that the magnitude of the second gas effect is considerably greater on arterial blood partial pressures of volatile agents than on end-expired partial pressures, and a significant second gas effect on blood partial pressures of oxygen and volatile agents occurs even at relatively low rates of nitrous oxide uptake. We set out to further investigate the mechanism of this phenomenon with the help of mathematical modeling. METHODS: Log-normal distributions of ventilation and blood flow were generated representing the range of ventilation-perfusion scatter seen in patients during general anesthesia. Mixtures of nominal delivered concentrations of volatile agents (desflurane, isoflurane and diethyl ether) with and without 70% nitrous oxide were mathematically modeled using steady state mass-balance principles, and the magnitude of the second gas effect calculated as an augmentation ratio for the volatile agent, defined as the partial pressure in the presence to that in the absence of nitrous oxide. RESULTS: Increasing the degree of mismatch increased the second gas effect in blood. Simultaneously, the second gas effect decreased in the gas phase. The increase in blood was greatest for the least soluble gas, desflurane, and least for the most soluble gas, diethyl ether, while opposite results applied in the gas phase. CONCLUSIONS: Modeling of ventilation-perfusion inhomogeneity confirms that the second gas effect is greater in blood than in expired gas. Gas-based minimum alveolar concentration readings may therefore underestimate the depth of anesthesia during nitrous oxide anesthesia with volatile agents. The effect on minimum alveolar concentration is likely to be most pronounced for the less soluble volatile agents in current use.

Riociguat versus sildenafil on hypoxic pulmonary vasoconstriction and ventilation/perfusion matching.

INTRODUCTION: Current treatment with vasodilators for pulmonary hypertension associated with respiratory diseases is limited by their inhibitory effect on hypoxic pulmonary vasoconstriction (HPV) and uncoupling effects on ventilation-perfusion (V'/Q'). Hypoxia is also a well-known modulator of the nitric oxide (NO) pathway, and may therefore differentially affect the responses to phosphodiesterase 5 (PDE5) inhibitors and soluble guanylyl cyclase (sGC) stimulators. So far, the effects of the sGC stimulator riociguat on HPV have been poorly characterized. MATERIALS AND METHODS: Contraction was recorded in pulmonary arteries (PA) in a wire myograph. Anesthetized rats were catheterized to record PA pressure. Ventilation and perfusion were analyzed by micro-CT-SPECT images in rats with pulmonary fibrosis induced by bleomycin. RESULTS: The PDE5 inhibitor sildenafil and the sGC stimulator riociguat similarly inhibited HPV in vitro and in vivo. Riociguat was more effective as vasodilator in isolated rat and human PA than sildenafil. Riociguat was ≈3-fold more potent under hypoxic conditions and it markedly inhibited HPV in vivo at a dose that barely affected the thromboxane A2 (TXA2) mimetic U46619-induced pressor responses. Pulmonary fibrosis was associated with V'/Q' uncoupling and riociguat did not affect the V'/Q' ratio. CONCLUSION: PDE5 inhibitors and sGC stimulators show a different vasodilator profile. Riociguat was highly effective and potentiated by hypoxia in rat and human PA. In vivo, riociguat preferentially inhibited hypoxic than non-hypoxic vasoconstriction. However, it did not worsen V'/Q' coupling in a rat model of pulmonary fibrosis.

Effect of Bronchoconstriction-induced Ventilation-Perfusion Mismatch on Uptake and Elimination of Isoflurane and Desflurane.

BACKGROUND: Increasing numbers of patients with obstructive lung diseases need anesthesia for surgery. These conditions are associated with pulmonary ventilation/perfusion (VA/Q) mismatch affecting kinetics of volatile anesthetics. Pure shunt might delay uptake of less soluble anesthetic agents but other forms of VA/Q scatter have not yet been examined. Volatile anesthetics with higher blood solubility would be less affected by VA/Q mismatch. We therefore compared uptake and elimination of higher soluble isoflurane and less soluble desflurane in a piglet model. METHODS: Juvenile piglets (26.7 ± 1.5 kg) received either isoflurane (n = 7) or desflurane (n = 7). Arterial and mixed venous blood samples were obtained during wash-in and wash-out of volatile anesthetics before and during bronchoconstriction by methacholine inhalation (100 µg/ml). Total uptake and elimination were calculated based on partial pressure measurements by micropore membrane inlet mass spectrometry and literature-derived partition coefficients and assumed end-expired to arterial gradients to be negligible. VA/Q distribution was assessed by the multiple inert gas elimination technique. RESULTS: Before methacholine inhalation, isoflurane arterial partial pressures reached 90% of final plateau within 16 min and decreased to 10% after 28 min. By methacholine nebulization, arterial uptake and elimination delayed to 35 and 44 min. Desflurane needed 4 min during wash-in and 6 min during wash-out, but with bronchoconstriction 90% of both uptake and elimination was reached within 15 min. CONCLUSIONS: Inhaled methacholine induced bronchoconstriction and inhomogeneous VA/Q distribution. Solubility of inhalational anesthetics significantly influenced pharmacokinetics: higher soluble isoflurane is less affected than fairly insoluble desflurane, indicating different uptake and elimination during bronchoconstriction.

Phosphodiesterase 5 inhibition with sildenafil reverses exercise oscillatory breathing in chronic heart failure: a long-term cardiopulmonary exercise testing placebo-controlled study.

AIMS: Exercise oscillatory breathing (EOB) is a ventilatory abnormality that occurs in ∼20% of heart failure (HF) patients and carries a very unfavourable prognosis. Pulmonary vasoconstriction has been suggested to be involved in this disorder. We hypothesized that modulation of pulmonary vascular hypertone by oversignalling of the nitric oxide pathway with phosphodiesterase 5 (PDE5) inhibition might be beneficial. Accordingly, we performed a 1-year pilot trial with sildenafil in patients with HF and EOB. METHODS AND RESULTS: Among 122 HF cases, 32 presented with EOB during cardiopulmonary exercise testing (CPX) and were randomized to receive placebo (n = 16) or sildenafil (n = 16) at the dose of 50 mg three times a day, in addition to their current antifailure treatment. CPX-derived variables and pulmonary haemodynamics were assessed at 6 and 12 months. Sildenafil reversed EOB in 87% of patients at 6 months and 93% at 1 year, respectively (P < 0.01). This effect was accompanied by an improvement in functional performance (peak VO(2); from 9.6 to 12.4 and 13.2 mL/min/kg; P < 0.01) and exercise ventilation efficiency (ventilation to CO(2) production slope; from 41.1 to 32.7 and 31.5; P < 0.01). Chronic treatment with PDE5 inhibition significantly decreased pulmonary capillary wedge pressure (from 21 to 14 and 14 mmHg), mean pulmonary artery pressure (PAP; from 34.8 to 23 and 24 mmHg), and pulmonary vascular resistance (PVR; from 360 to 270 and 266 dyne/s/cm(5)) compared with placebo (P < 0.01 for each comparison). On exploratory analysis, there was a correlation between PAP and PVR and the decrease in EOB in the treatment group. Placebo did not alter any of the aforementioned variables. CONCLUSIONS: PDE5 inhibition in HF patients with EOB offers the dual advantage of improving functional capacity and modulating the EOB pattern. PAP and PVR reduction seem to underlie the correction of the breathing disorder. Whether reversal of this unfavourable prognostic signal can affect survival remains unconfirmed at the moment.

Modelo experimental de perfusão pulmonar ex vivo em ratos: avaliação de desempenho de pulmões submetidos à administração de prostaciclina inalada versus parenteral / An experimental rat model of ex vivo lung perfusion for the assessment of lungs after prostacyclin administration: inhaled versus parenteral routes

OBJETIVO: Apresentar um modelo experimental de administração de prostaglandina I2 (PGI2) por via inalatória vs. parenteral e avaliar o desempenho funcional dos pulmões em um sistema de perfusão pulmonar ex vivo. MÉTODOS: Quarenta ratos Wistar foram anestesiados, ventilados, submetidos a laparotomia com ressecção do esterno e anticoagulados. O tronco da artéria pulmonar foi canulado. Todos os animais foram submetidos a ventilação mecânica. Os animais foram randomizados em quatro grupos (10 ratos/grupo): salina nebulizada (SN); salina parenteral (SP); PGI2 nebulizada (PGI2N); e PGI2 parenteral (PGI2P). A dose de PGI2 nos grupos PGI2N e PGI2P foi de 20 e 10 µg/kg, respectivamente. Os blocos cardiopulmonares foram submetidos in situ a perfusão anterógrada com solução de baixo potássio e dextrana a 4ºC via artéria pulmonar, extraídos em bloco e armazenados a 4ºC por 6 h. Os blocos foram ventilados e perfundidos em um sistema ex vivo por 50 min, sendo obtidas medidas de mecânica ventilatória, hemodinâmica e trocas gasosas. RESULTADOS: Houve redução da pressão arterial pulmonar média após a nebulização em todos os grupos (p < 0,001), sem diferença entre os grupos. Na perfusão ex vivo, a mecânica ventilatória não diferiu entre os grupos. Houve redução da capacidade relativa de oxigenação ao longo da perfusão nos grupos SN e SP (p = 0,04), e houve aumento significativo da pressão arterial pulmonar no grupo SN. CONCLUSÕES: O modelo experimental de administração de PGI2 na extração pulmonar é exequível e confiável. Na reperfusão, os resultados de hemodinâmica e de trocas gasosas demonstraram tendência a um melhor desempenho com o uso de PGI2 do que com solução salina.

OBJECTIVE:To present a model of prostaglandin I2 (PGI2) administration (inhaled vs. parenteral) and to assess the functional performance of the lungs in an ex vivo lung perfusion system. METHODS: Forty Wistar rats were anesthetized and placed on mechanical ventilation followed by median sterno-laparotomy and anticoagulation. The main pulmonary artery was cannulated. All animals were maintained on mechanical ventilation and were randomized into four groups (10 rats/group): inhaled saline (IS); parenteral saline (PS); inhaled PGI2 (IPGI2); and parenteral PGI2 (PPGI2). The dose of PGI2 used in the IPGI2 and PPGI2 groups was 20 and 10 µg/kg, respectively. The heart-lung blocks were submitted to antegrade perfusion with a low potassium and dextran solution via the pulmonary artery, followed by en bloc extraction and storage at 4ºC for 6 h. The heart-lung blocks were then ventilated and perfused in an ex vivo lung perfusion system for 50 min. Respiratory mechanics, hemodynamics, and gas exchange were assessed. RESULTS: Mean pulmonary artery pressure following nebulization decreased in all groups (p < 0.001), with no significant differences among the groups. During the ex vivo perfusion, respiratory mechanics did not differ among the groups, although relative oxygenation capacity decreased significantly in the IS and PS groups (p = 0.04), whereas mean pulmonary artery pressure increased significantly in the IS group. CONCLUSIONS: The experimental model of inhaled PGI2 administration during lung extraction is feasible and reliable. During reperfusion, hemodynamics and gas exchange trended toward better performance with the use of PGI2 than that with the use of saline.

Recombinant angiotensin-converting enzyme 2 improves pulmonary blood flow and oxygenation in lipopolysaccharide-induced lung injury in piglets.

OBJECTIVE: To study angiotensin-converting enzyme 2 in a piglet model with acute respiratory distress syndrome and to evaluate the therapeutic potential of this substance in a preclinical setting, as this model allows the assessment of the same parameters required for monitoring the disease in human intensive care medicine. The acute respiratory distress syndrome is the most severe form of acute lung injury with a high mortality rate. As yet, there is no specific therapy for improving the clinical outcome. Recently, angiotensin-converting enzyme 2, which inactivates angiotensin II, has been shown to ameliorate acute lung injury in mice. DESIGN: Prospective, randomized, double-blinded animal study. SETTING: Animal research laboratory. SUBJECTS: Fifteen anesthetized and mechanically ventilated piglets. INTERVENTIONS: Acute respiratory distress syndrome was induced by lipopolysaccharide infusion. Thereafter, six animals were assigned randomly into angiotensin-converting enzyme 2 group, whereas another six animals served as control. Three animals received angiotensin-converting enzyme 2 without lipopolysaccharide pretreatment. MEASUREMENTS AND MAIN RESULTS: Systemic and pulmonary hemodynamics, blood gas exchange parameters, tumor necrosis factor-alpha, and angiotensin II levels were examined before acute respiratory distress syndrome induction and at various time points after administering angiotensin-converting enzyme 2 or saline. In addition, ventilation-perfusion distribution of the lung tissue was assessed by the multiple inert gas elimination technique. Animals treated with angiotensin-converting enzyme 2 maintained significantly higher PaO2 than the control group, and pulmonary hypertension was less pronounced. Furthermore, angiotensin II and tumor necrosis factor-alpha levels, both of which were substantially increased, returned to basal values. Multiple inert gas elimination technique revealed a more homogeneous pulmonary blood flow after treatment with angiotensin-converting enzyme 2. In intergroup comparisons, there were no differences in pulmonary blood flow to lung units with subnormal ventilation/perfusion ratios. CONCLUSIONS: Angiotensin-converting enzyme 2 attenuates arterial hypoxemia, pulmonary hypertension, and redistribution of pulmonary blood flow in a piglet model of acute respiratory distress syndrome, and may be a promising substance for clinical use.

Effect of sedation with detomidine and butorphanol on pulmonary gas exchange in the horse.

BACKGROUND: Sedation with alpha2-agonists in the horse is reported to be accompanied by impairment of arterial oxygenation. The present study was undertaken to investigate pulmonary gas exchange using the Multiple Inert Gas Elimination Technique (MIGET), during sedation with the alpha2-agonist detomidine alone and in combination with the opioid butorphanol. METHODS: Seven Standardbred trotter horses aged 3-7 years and weighing 380-520 kg, were studied. The protocol consisted of three consecutive measurements; in the unsedated horse, after intravenous administration of detomidine (0.02 mg/kg) and after subsequent butorphanol administration (0.025 mg/kg). Pulmonary function and haemodynamic effects were investigated. The distribution of ventilation-perfusion ratios (VA/Q) was estimated with MIGET. RESULTS: During detomidine sedation, arterial oxygen tension (PaO2) decreased (12.8 +/- 0.7 to 10.8 +/- 1.2 kPa) and arterial carbon dioxide tension (PaCO2) increased (5.9 +/- 0.3 to 6.1 +/- 0.2 kPa) compared to measurements in the unsedated horse. Mismatch between ventilation and perfusion in the lungs was evident, but no increase in intrapulmonary shunt could be detected. Respiratory rate and minute ventilation did not change. Heart rate and cardiac output decreased, while pulmonary and systemic blood pressure and vascular resistance increased. Addition of butorphanol resulted in a significant decrease in ventilation and increase in PaCO2. Alveolar-arterial oxygen content difference P(A-a)O2 remained impaired after butorphanol administration, the VA/Q distribution improved as the decreased ventilation and persistent low blood flow was well matched. Also after subsequent butorphanol no increase in intrapulmonary shunt was evident. CONCLUSION: The results of the present study suggest that both pulmonary and cardiovascular factors contribute to the impaired pulmonary gas exchange during detomidine and butorphanol sedation in the horse.

Cardiopulmonary effects of intravenous prostaglandin E1 during experimental one-lung ventilation.

BACKGROUND: One-lung ventilation greatly improves operating conditions during thoracic surgery. Serious disadvantages of one-lung ventilation are hypoxaemia and increased pulmonary vascular resistance. Prostaglandins, like prostaglandin I2 (PGI2), are potent pulmonary vasodilators but may also influence venous admixture and systemic circulation. Since the lung is capable of extensive degradation of prostaglandin E1 (PGE1) but not of PGI2, PGE1 might affect systemic circulation to a lesser degree. Hence, we studied the effects of intravenous PGE1 on systemic and pulmonary circulation and on oxygenation during one-lung ventilation. METHODS: Lateral thoracotomy and cross-clamping of the left main stem bronchus was performed in twelve anaesthetised and ventilated pigs. Animals were cannulated with arterial, central venous and fast response thermodilution pulmonary artery catheters for haemodynamic measurements. PGE1 was administered with infusion rates of 25, 50, and 100 ng x kg (-1) x min (-1) during one-lung ventilation. RESULTS: All doses of PGE1 significantly decreased pulmonary vascular resistance and mean pulmonary artery pressure. However, a comparable significant reduction in systemic vascular resistance and mean arterial pressure was found. Arterial oxygen tension and venous admixture showed a slight but significant deterioration. Oxygen delivery remained unchanged or increased since the cardiac index increased. CONCLUSION: During one-lung ventilation in the pig, infusion of PGE1 significantly decreased pulmonary vascular resistance and pulmonary artery pressure but failed to achieve selective pulmonary vasodilation.

Leukotriene D4-induced hypoxaemia in asthma is mediated by the cys-leukotriene1 receptor.

Bronchoprovocation with cysteinyl-leukotrienes (LTs) induces airflow obstruction and gas exchange abnormalities, namely ventilation-perfusion ratio (V'(A)/Q') imbalance. However, it is unknown which of the two different receptors for cysteinyl-LTs mediate these V'(A)/Q' disturbances. In a double-blinded, crossover design, 10 patients with mild asthma were randomised to receive an oral single dose of the selective cysteinyl-LT1 receptor antagonist montelukast (40 mg) or placebo before leukotriene (LT)D4 inhalation challenge. Gas exchange, including V'(A)/Q' descriptors were measured at baseline, 3 h after montelukast/placebo pretreatment and 5, 15 and 45 min after the LTD4 challenge. Compared with montelukast, inhalation of LTD(4) induced a marked fall in forced expiratory volume in one second (mean+/-se 33+/-2%) and profound V'(A)/Q' mismatching, reflected by a decreased arterial oxygen tension (from 100+/-4 to 75+/-3 mmHg) and an increased overall index of V'(A)/Q' heterogeneity dispersion of retention minus excretion inert gases corrected for dead space (from 4.9+/-1.2 to 8.4+/-1.1; normal< or =3.0; dimensionless), 5 min after placebo. Following montelukast, LTD4 produced no significant changes in any of the variables. In conclusion, these findings point to the view that leukotriene D4)-induced gas exchange disturbances and bronchoconstriction are both mediated by the cysteinyl-leukotriene1 receptor.

Inhaled prostacyclin is safe, effective, and affordable in patients with pulmonary hypertension, right heart dysfunction, and refractory hypoxemia after cardiothoracic surgery.

BACKGROUND: The purpose of this study was to describe our institutional experience in using inhaled prostacyclin as a selective pulmonary vasodilator in patients with pulmonary hypertension, refractory hypoxemia, and right heart dysfunction after cardiothoracic surgery. METHODS: Between February 2001 and March 2003, cardiothoracic surgical patients with pulmonary hypertension (mean pulmonary artery pressure >30 mm Hg or systolic pulmonary artery pressure >40 mm Hg), hypoxemia (PaO(2)/fraction of inspired oxygen <150 mm Hg), or right heart dysfunction (central venous pressure >16 mm Hg and cardiac index <2.2 L.min(-1).m(-2)) were prospectively administered inhaled prostacyclin at an initial concentration of 20,000 ng/mL and then weaned per protocol. Hemodynamic variables were measured before the initiation of inhaled prostacyclin, 30 to 60 minutes after initiation, and again 4 to 6 hours later. RESULTS: One hundred twenty-six patients were enrolled during the study period. At both time points, inhaled prostacyclin significantly decreased the mean pulmonary artery pressure without altering the mean arterial pressure. The average length of time on inhaled prostacyclin was 45.6 hours. There were no adverse events attributable to inhaled prostacyclin. The average cost for inhaled prostacyclin was 150 US dollars per day. Compared with nitric oxide, which costs 3000 US dollars per day, the potential cost savings over this period were 681,686 US dollars. CONCLUSIONS: Inhaled prostacyclin seems to be a safe and effective pulmonary vasodilator for cardiothoracic surgical patients with pulmonary hypertension, refractory hypoxemia, or right heart dysfunction. Overall, inhaled prostacyclin significantly decreases mean pulmonary artery pressures without altering the mean arterial pressure. Compared with nitric oxide, there is no special equipment required for administration or toxicity monitoring, and the cost savings are substantial.

Comparative effects of helium-oxygen and external positive end-expiratory pressure on respiratory mechanics, gas exchange, and ventilation-perfusion relationships in mechanically ventilated patients with chronic obstructive pulmonary disease.

OBJECTIVE: To compare the effects of He/O(2) and external PEEP (PEEPe) on intrinsic PEEP (PEEPi), respiratory mechanics, gas exchange, and ventilation/perfusion (V(A)/Q) in mechanically ventilated COPD patients. DESIGN AND SETTING: Prospective, interventional study in the intensive care unit of a university hospital. INTERVENTIONS: Ten intubated, sedated, paralyzed, mechanically ventilated COPD patients studied in the following conditions: (a) baseline settings made by clinician in charge, air/O(2), ZEEP; (b) He/O(2), ZEEP; (c) air/O(2), ZEEP; (d) air/O(2), PEEPe 80% of PEEPi. Measurements at each condition included V(A)/Q by the multiple inert gas elimination technique (MIGET). RESULTS: PEEPi and trapped gas volume were comparably reduced by He/O(2) (4.2+/-4 vs. 7.7+/-4 cmH(2)O and 98+/-82 vs. 217+/-124 ml, respectively) and PEEPe (4.4+/-1.3 vs. 7.8+/-3.6 cmH(2)O and 120+/-107 vs. 216+/-115 ml, respectively). He/O(2) reduced inspiratory and expiratory respiratory system resistance (15.5+/-4.4 vs. 20.7+/-6.9 and 19+/-9 vs. 28.8+/-15 cmH(2)O l(-1)s(-1), respectively) and plateau pressure (13+/-4 vs. 17+/-6 cmH(2)O). PEEPe increased airway pressures, including total PEEP, and elastance. PaO(2)/FIO(2) was slightly reduced by He/O(2) (225+/-83 vs. 245+/-82) without significant V(A)/Q change. CONCLUSIONS: He/O(2) and PEEPe comparably reduced PEEPi and trapped gas volume. However, He/O(2) decreased airway resistance and intrathoracic pressures, at a small cost in arterial oxygenation. He/O(2) could offer an attractive option in COPD patients with PEEPi/dynamic hyperinflation.

Combination of nonspecific PDE inhibitors with inhaled prostacyclin in experimental pulmonary hypertension.

Inhalation of aerosolized prostacyclin (PGI(2)) exerts selective pulmonary vasodilation, but its effect is rapidly lost after termination of nebulization. Amplification of the vasodilatory response to inhaled PGI(2) might be achieved by phosphodiesterase (PDE) inhibitors to stabilize its second messenger, cAMP. We established stable pulmonary hypertension in perfused rabbit lungs by continuous infusion of U-46619. Short-term (10-min) aerosolization maneuvers of PGI(2) effected a rapid, moderate decrease in pulmonary arterial pressure, with post-PGI(2) vasorelaxation being lost within 10-15 min, accompanied by a marginal reduction in shunt flow. Preceding administration of subthreshold doses of the PDE inhibitors theophylline, dipyridamole, and pentoxifylline via the intravascular or inhalational route, which per se did not influence pulmonary hemodynamics, caused more than doubling of the immediate pulmonary arterial pressure drop in response to PGI(2) and marked prolongation of the post-PGI(2) vasorelaxation to >60 min (all PDE inhibitors via both routes of application). This was accompanied by a reduction in shunt flow in the case of aerosolized theophylline (27.5%), pentoxifylline (30.5%), and dipyridamole (33.4%). Coaerosolization of PGI(2) and PDE inhibitors may be considered as a therapeutic strategy in pulmonary hypertension.

Conebulization of surfactant and urokinase restores gas exchange in perfused lungs with alveolar fibrin formation.

Alveolar fibrin generation has been suggested to possess strong surfactant-inhibitory potency. In perfused rabbit lungs, fibrin formation in the alveolar space was induced by sequential ultrasonic aerosolization of fibrinogen and thrombin, and the efficacy of rescue administration of surfactant and urokinase was investigated. Ventilation-perfusion (VA/Q) distribution was assessed by the multiple inert gas elimination technique. Aerosolization of fibrinogen (approximately 20 mg/kg body wt) increased shunt flow to approximately 7%. Sequential nebulization of fibrinogen and thrombin (1.3 U/kg body wt) caused alveolar fibrin deposition, documented immunohistologically, and provoked marked shunt flow, progressing to approximately 22% at the end of the experiments. The hemodynamics were virtually unchanged. Rescue aerosolization of natural bovine surfactant (15 mg/kg body wt) or urokinase-type plasminogen activator (4,500 U/kg body wt), undertaken after fibrin formation, improved gas exchange but progressive shunt flow still occurred (efficacy, surfactant > urokinase). In contrast, conebulization of surfactant and urokinase reversed shunt flow to approximately 7%, with an increased appearance of normal VA/Q matching. We conclude that alveolar fibrin formation is a potent surfactant-inhibitory mechanism in intact lungs, provoking severe VA/Q mismatch with a predominance of shunt flow, and that rescue aerosolization of surfactant plus urokinase may offer restoration of gas exchange under these conditions.

Effects of crocetin on pulmonary gas exchange in foxhounds during hypoxic exercise.

The carotenoid compound crocetin has been hypothesized to enhance the diffusion of O(2) through plasma, and observations in the rat and rabbit have revealed improvement in arterial PO(2) when crocetin is given. To determine whether crocetin enhances diffusion of O(2) between alveolar gas and the red blood cell in the pulmonary capillary in vivo, five foxhounds, two previously subjected to sham and three to actual lobectomy or pneumonectomy, were studied while breathing 14% O(2) at rest and during moderate and heavy exercise before and within 10 min after injection of a single dose of crocetin as the trans isomer of sodium crocetinate (TSC) at 100 microg/kg iv. This dose is equivalent to that used in previous studies and would yield an initial plasma concentration of 0.7-1.0 microg/ml. Ventilation-perfusion inequality and pulmonary diffusion limitation were assessed by the multiple inert gas elimination technique in concert with conventional measurements of arterial and mixed venous O(2) and CO(2). TSC had no effect on ventilation, cardiac output, O(2) consumption, arterial PO(2)/saturation, or pulmonary O(2) diffusing capacity. There were minor reductions in ventilation-perfusion mismatching (logarithm of the standard deviation of perfusion fell from 0.48 to 0.43, P = 0.001) and in CO(2) output and respiratory exchange ratio (P = 0.05), which may have been due to TSC or to persisting effects of the first exercise bout. Spectrophotometry revealed that TSC disappeared from plasma with a half time of approximately 10 min. We conclude that, in this model of extensive pulmonary O(2) diffusion limitation, TSC as given has no effect on O(2) exchange or transport. Whether the original hypothesis is invalid, the dose of TSC was too low, or plasma diffusion of O(2) is not rate limiting without TSC cannot be discerned from the present study.

Effect of inhaled nitric oxide in combination with almitrine on ventilation-perfusion distributions in experimental lung injury.

OBJECTIVE: To investigate a possible additive effect of combined nitric oxide (NO) and almitrine bismesylate (ALM) on pulmonary ventilation-perfusion (V(A)/Q) ratio. DESIGN: Prospective, controlled animal study. SETTING: Animal research facility of a university hospital. INTERVENTIONS: Three conditions were studied in ten female pigs with experimental acute lung injury (ALI) induced by repeated lung lavage: 1) 10 ppm NO, 2) 10 ppm NO with 1 microg/kg per min ALM, 3) 1 microg/ kg per min ALM. For each condition, gas exchange, hemodynamics and V(A)/Q distributions were analyzed using the multiple inert gas elimination technique (MIGET). MEASUREMENT AND RESULTS: With NO + ALM, arterial oxygen partial pressure (PaO2) increased from 63 +/- 18 mmHg to 202 +/- 97 mmHg while intrapulmonary shunt decreased from 50 +/- 15 % to 26 +/- 12% and blood flow to regions with a normal V(A)/Q ratio increased from 49 +/- 16 % to 72 +/- 15 %. These changes were significant when compared to untreated ALI (p < 0.05) and NO or ALM alone (p < 0.05), although improvements due to NO or ALM also reached statistical significance compared to ALI values (p < 0.05). CONCLUSIONS: We conclude that NO + ALM results in an additive improvement of pulmonary gas exchange in an experimental model of ALI by diverting additional blood flow from non-ventilated lung regions towards those with normal V(A)/Q relationships.

Gas exchange response to a PAF receptor antagonist, SR 27417A, in acute asthma: a pilot study.

The pathogenic role of platelet-activating factor (PAF) in asthma has been questioned due to the limited or negative efficacy of PAF antagonists; however, in acute asthma (AA), where the endogenous release of PAF may be enhanced, the effects of PAF antagonist receptors have not been investigated. It was postulated that inhaled PAF provokes gas exchange defects in mild asthma likely to be related to airway vascular leakage. The response to a potent, selective PAF receptor antagonist, SR 27471A, on pulmonary gas exchange was studied, more specifically ventilation-perfusion (VA'/Q') distributions, in patients with AA within 48 h of hospitalization. A randomized, double-blind, placebo-controlled, parallel group (n=6, each) design was used. After baseline measurements, either placebo or SR 27417A (20 mg, orally) was administered and measurements were repeated 3 h later. Conventional anti-asthma medication was not interrupted. Despite a near-complete inhibition of the in vitro, platelet aggregation tests by 40 nM PAF (mean+/-SEM from 72+/-9 to 6+/-2%) and 80 nM PAF (from 81+/-7 to 6+/-3% both p<0.01) by SR 27471A indicating a good bioactivity of the compound, no significant changes in baseline forced expiratory volume in one second, (40+/-6%), respiratory system resistance (6.2+/-0.7 cmH2O x L(-1) x s), alveolar-arterial pressure difference for oxygen (5.2+/-0.4 kPa), arterial oxygen tension (9.0+/-0.5 kPa) or VA'/Q' distributions, as expressed by the dispersion of pulmonary blood flow (LogSD Q, 1.07+/-0.09; normal values <0.60), were observed. It is concluded that SR 27417A has limited value when added to the conventional treatment of acute asthma. These findings minimize the potential pathogenic role of endogenous platelet-activating factor as a relevant mediator of airway inflammation during acute asthma.

Pulmonary gas exchange in cystic fibrosis: basal status and the effect of i.v. antibiotics and inhaled amiloride.

In order to evaluate the degree and type of gas exchange impairment in cystic fibrosis, ventilation/perfusion relationships in ten patients (mean age 26 yrs, mean Shwachman score 86) were examined. Pulmonary gas exchange was studied using the multiple inert gas elimination technique. High-resolution computed tomography (HRCT) and spirometry, including diffusing capacity, were performed after each gas exchange study for comparison. Examinations were done before and after home i.v. antibiotic treatment (HIVAT, 14 days) and after inhaled amiloride and placebo (14 days), in crossover fashion, clinical status after HIVAT serving as the baseline for the crossover study. Before HIVAT, the mean residual volume was 182% of the predicted value, the mean vital capacity 72% pred and the mean forced expiratory volume in one second 53% pred (p<0.001). The dispersion of pulmonary blood flow at different ventilation/perfusion ratios (V'/Q') ((logarithmic SD of the perfusion distribution (log SDQ)), used as an index for gas exchange impairment, was increased to a mean of 0.72. No linear correlation was seen between ventilation/perfusion inequality, spirometry and HRCT (p>0.05). After HIVAT, log SDQ was significantly improved to 0.66 (p<0.05). After placebo, but not after amiloride, log SDQ, arterial oxygen tension, alveolar-arterial oxygen tension difference and maximal expiratory flows when 50% and 25% of the forced vital capacity tension remain to be exhaled were significantly worse (p<0.05, respectively). Areas with a low V'/Q' were significantly lower after amiloride compared to after the placebo period (p<0.05). Moderate ventilation/perfusion inequality was present in the majority of the studied cystic fibrosis patients. The degree of ventilation/perfusion inequality cannot be estimated from spirometry or high-resolution computed tomography. The low proportion of low ventilation/perfusion ratios indicates that the regular treatment directed towards mucus plugging of small airways is beneficial. An improvement in the ventilation/perfusion relationship was seen after home i.v. antibiotic treatment and inhaled amiloride may possibly have a further positive effect on gas exchange.

[Inhalation administration of nitric oxide during selective pulmonary ventilation decreases the intrapulmonary shunt]. / La administración inhalatoria de óxido nítrico durante la ventilación pulmonar selectiva disminuye el shunt intrapulmonar.

OBJECTIVE: To assess the effects of inhaled nitric oxide (NO) on oxygenation and hemodynamics in patients undergoing lung resection surgery during one-lung ventilation (OPV). PATIENTS AND METHODS: Prospective study of 16 patients aged 62 +/- 10 years scheduled for chest surgery under combined general and epidural anesthesia. During ventilation of only one lung, NO was administered for 15 minutes. Arterial blood and mixed venous blood samples were taken for analysis of blood gases and the calculation of intrapulmonary shunt. Pulmonary and systemic hemodynamic variables were also recorded using a Swan-Ganz catheter at three times: baseline (ventilation of both lungs), OLV, and with OLV plus NO (OLV NO). RESULTS: The most relevant data consisted of a significant decrease in shunt after start of NO inhalation in comparison with the level during OLV (31.1 +/- 0.5% versus 36 +/- 0.6%; p < 0.05). Arterial oxygen pressure decreased significantly during OLV and increased after start of NO (118.9 +/- 53.6 versus 155.4 +/- 78.5 mmHg; p < 0.05). Mean pulmonary artery pressure, pulmonary and systemic vascular resistances, and cardiac index did not change with inhalation of NO. CONCLUSIONS: Inhalational administration of NO during OLV significantly improves arterial oxygenation and decreases intrapulmonary shunt during OLV, without causing hemodynamic or systemic effects.