Well-ventilated Lung Research Articles

Functional Lung Avoidance for Individualized Radiation Therapy: Results of a Double-Masked, Randomized Controlled Trial

To determine whether functional lung avoidance based on 3He magnetic resonance imaging (MRI) improves quality of life (QOL) for patients undergoing concurrent chemoradiotherapy (CCRT) for advanced non-small cell lung cancer. Patients with stage III non-small cell lung cancer (or oligometastatic disease treated with curative intent) undergoing CCRT with at least a 10 pack-year smoking history were eligible. Patients underwent pretreatment 3He MRI to measure lung ventilation and had 2 radiation therapy (RT) plans created before randomization: a standard plan, which did not make use of the 3He MRI, and an avoidance plan, preferentially sparing well-ventilated lung. All participants were masked to assignment except the physicist responsible for exporting the selected plan. The primary end point was patient-reported QOL measured at 3-months post-RT by the FACT-L lung cancer subscale (LCS); secondary end points included other QOL metrics, toxicity, and survival outcomes. Target accrual was 64. Twenty-seven patients were randomized before the trial was closed due to slower-than-expected accrual, with 11 randomized to the standard arm and 16 to the avoidance arm. Baseline patient characteristics were well-balanced. At 3 months post-RT, the mean ± SD LCS scores were 17.4 ± 2.8 versus 17.3 ± 6.1 for the standard and avoidance arms, respectively (P = .485). A clinically meaningful, prespecified decline of ≥3 points in the LCS score was observed in 50% (4/8) in the standard arm and 33% (4/12) in the avoidance arm (P = .648). Two patients in each arm developed grade ≥2 radiation pneumonitis, with no grade ≥4 toxicities. Although this trial did not reach full accrual, QOL scores were very similar between arms. Due to the scarcity of 3He MRI, other, more commonly available methods to measure functional lung, such as 4-dimensional computed tomography ventilation mapping, may be considered in the assessment of functional lung avoidance RT, and a larger, multicenter approach would be needed to accrue sufficient patients to test such approaches.

Usage of Inhaled Nitric Oxides in Cases of Eisenmenger Syndrome

Eisenmenger Syndrome is congenital heart disease with pulmonary hypertension and shunting turning from right to left. The resistance of pulmonary vascular more than 7.5 mmHg/L/min. The right ventricle and pulmonary artery always enlarge. Physiological effects of inhaled nitric oxide therapy cause selective pulmonary vasodilation: Hypoxia alveoli causes reversible vasoconstriction, thereby increasing pulmonary wedge pressure. Inhaled nitric oxide can lower it. Moderate cardiac output and systematic arterial pressure are not affected; Selective in pulmonary because it is activated by hemoglobin; Selective vasodilation in the ventilated area, local hypoxia alveoli constricts the surrounding vascular tissue and redistributes blood flow to the ventilated lungs better and higher intraalveolar oxygen pressure. Inhaled nitric oxide enhances this mechanism by increasing blood flow through a well-ventilated lung; Bronchodilators; Pulmonary surfactant, The combination of high concentrations of inspired oxygen and high concentrations of Inhaled nitric oxide reduces the minimum surfactant surface tension.

Role Of Inhaled Nitric Oxides In Pregnancy With Eisenmenger Syndrome

ABSTRACTEisenmenger Syndrome (ES) is congenital heart disease with pulmonary hypertension and shunting turning from right to left. The resistance of pulmonary vascular more than 7.5 mmHg/L/min. The right ventricle and pulmonary artery always enlarge. During pregnancy, there will be hemodynamic changes that will affect the ES. It can be understood the possible dangers that can occur, like right heart failure; an increase in pulmonary arteries or the aggravation of pulmonary hypertension because there is no decrease in pulmonary resistance; A sudden decrease in venous return in supine hypotension syndrome can cause a relative increase in pulmonary arterial pressure so as to aggravate pulmonary hypertension and reverse shunting.Physiological effects of inhaled nitric oxide (INO) therapy cause selective pulmonary vasodilation: Hypoxia alveoli causes reversible vasoconstriction, thereby increasing pulmonary wedge pressure. INO can lower it. Moderate cardiac output and systematic arterial pressure are not affected; Selective in pulmonary because it is activated by hemoglobin; Selective vasodilation in the ventilated area, local hypoxia alveoli constricts the surrounding vascular tissue and redistributes blood flow to the ventilated lungs better and higher intraalveolar oxygen pressure. INO enhances this mechanism by increasing blood flow through a well-ventilated lung; Bronchodilators; Pulmonary surfactant, The combination of high concentrations of inspired oxygen and high concentrations of INO reduces the minimum surfactant surface tension.Keywords: Inhalation Nitric Oxides, Pregnancy, Eisenmenger Syndrome

Functional Lung Avoidance for Individualized Radiation Therapy (FLAIR): Results of a Randomized, Double-Blind Clinical Trial

To determine if functional lung avoidance based on 3-He MRI improves quality of life (QoL) outcomes for patients with advanced non-small cell lung cancer (NSCLC) undergoing concurrent chemoradiotherapy (CRT). Patients with stage III NSCLC (or stage IV oligometastatic disease treated with curative intent) undergoing CRT who had at least a 10 pack-year smoking history were eligible for this randomized trial (NCT02002052). All patients underwent a pre-treatment 3-He MRI to measure lung ventilation and had two radiotherapy (RT) plans created and approved before randomization: a standard plan, which did not make use of the 3-He MRI, and an avoidance plan, which preferentially spared well-ventilated lung. All participants were blinded to the allocated treatment arm except the physicist responsible for exporting the selected plan. The primary endpoint was patient-reported QoL measured at 3 months post-RT by the FACT-L lung cancer subscale (LCS); secondary QoL endpoints were the FACT-L trial outcome index (TOI), and the FACT-L total score. Additional pre-specified secondary endpoints included toxicity and survival outcomes. Between July 2014 and August 2016, 27 patients were randomized. The trial was closed before reaching the target of 64 patients due to slower-than-expected accrual. Baseline patient characteristics were well-matched between arms (Table 1). Sixteen patients were randomized to the avoidance arm while the remaining 11 received standard RT. At 3 months post-RT, the FACT-L LCS scores (mean ± SD) were 17.4 ± 2.8 and 17.3 ± 6.1 for the standard and avoidance arms (P=0.48) based on 20 patients alive and with complete data. Similarly, the TOI and total scores were 55.2 ± 12.0 / 53.5 ± 13.2 (P=1.00) and 98.0 ± 18.6 / 94.7 ± 17.2 (P=0.85) respectively. A clinically relevant, pre-specified, decline of ≥ 3 points in the FACT-L LCS score was observed in 50% of patients in the standard arm and 33% in the avoidance arm (P=0.65). Median follow-up was 22 months. Two patients in each arm developed grade ≥ 2 pneumonitis while no grade ≥ 4 toxicity of any kind was observed. No statistically significant difference in progression-free or overall survival was observed between the two arms. In this double-blind trial, functional lung avoidance RT was safely delivered, though without any significant improvement in QoL compared to standard RT. Due to the scarcity of 3-He MRI, other, more commonly-available methods to measure functional lung, such as 4D-CT ventilation mapping, may be considered in the assessment of functional lung avoidance RT in the broader multicenter trial setting.Abstract 3201; Table 1Baseline characteristics and questionnaire scoresVariableStandard Arm (n=11)Avoidance Arm (n=16)Age (years) – mean ± SD67 ± 865 ± 8Male – n (%)7 (64)6 (38)Pack-Years – mean ± SD45 ± 1244 ± 26Stage (AJCC version 8) – n (%) IIIA IIIB IVB7 (64)3 (27)1 (9)10 (63)5 (31)1 (6)FACT-L LCS – mean ± SD18 ± 418 ± 5FACT-L TOI – mean ± SD61 ± 1256 ± 15FACT-L total – mean ± SD106 ± 1799 ± 21 Open table in a new tab

TH-C-18A-03: Novel Technique for Dynamic Lung Ventilation Imaging Based On Wide Coverage 4D CT

Purpose: An emerging lung ventilation imaging method based on conventional 4D CT has a high translational potential and advantages over other competing modalities, however suffers from binning artifacts and irregular breathing during a scan. We propose a novel technique to compute dynamic ventilation based upon wide coverage 320-slice 4D CT, which provides high spatial and temporal resolution and binning artifact-free images. Methods: Wide coverage 4D CT images were acquired using a commercial 320-slice CT scanner, with 160 mm craniocaudal coverage and 0.35 s rotation time, during tidal breathing for five patients with thoracic cancer. The image at each of 51 time points was deformably registered to a peak-exhalation phase image using B-spline deformable image registration (DIR). For each time-point, the Jacobian determinant of deformation acted as a surrogate for regional ventilation. Dynamic ventilation was then computed by comparing time-resolved ventilation images. The accuracy of DIR was quantified by calculating target registration errors (TREs) of 100 anatomic landmarks per patient. Results: The proposed technique provided regional ventilation information of high spatial and temporal resolution. The average TRE of five patients was 1.4±1.3 mm. Dynamic properties of regional ventilation were found to be spatially heterogeneous. For example, ventilation increased during inhalation and decreased during exhalation in well-ventilated normal lung regions. However, in poorly-ventilated emphysematous regions, ventilation showed relatively minor changes with time around zero. Furthermore, ventilation resolved at this timescale demonstrated a signal that appeared to come from the heartbeat, especially in proximity to the heart. Conclusion: 320-slice 4D CT-based ventilation imaging provides regional ventilation information of high spatial and temporal resolution. Dynamic ventilation information obtained by this technique may be useful in creating a model of dynamic ventilation that could be used to compensate for errors in conventional 4D CT-based ventilation imaging, and may also provide new insights into respiratory physiology. Supported in part by Free to Breathe Young Investigator Research Grant.

Effect of positive end-expiratory pressure on regional ventilation distribution during bronchoconstriction in rabbit studied by synchrotron radiation imaging*

To assess the effects of positive end-expiratory pressure on regional ventilation distribution in normal lung and after histamine-induced bronchoconstriction. Experimental study. International research laboratory. Six healthy New Zealand rabbits weighing 2.5 ± 0.1 kg. Rabbits were anesthetized, tracheostomized, paralyzed, and mechanically ventilated. Synchrotron radiation computed tomography images of tissue density and specific ventilation were acquired using K-edge subtraction imaging with inhaled stable xenon gas in middle and caudal thoracic levels on 0 and 5 cm H(2)O positive end-expiratory pressure at baseline and twice after histamine inhalation. At baseline, a positive end-expiratory pressure of 5 cm H(2)O significantly increased lung volume. Histamine inhalation caused patchy areas of decreased specific ventilation, including some areas with no ventilation. After histamine, positive end-expiratory pressure significantly increased the area of well-ventilated lung regions and decreased the heterogeneity of specific ventilation. This improvement went together with a significant but limited increase in the area of hyperinflated lung zones. The findings of this study suggest that in mechanically ventilated rabbit with severely heterogeneous bronchoconstriction, a positive end-expiratory pressure of 5 cm H(2)O significantly improves regional ventilation homogeneity through dilation of flow-limited airways and recruitment of closed airways.

Feasibility of Image Registration and Intensity-Modulated Radiotherapy Planning With Hyperpolarized Helium-3 Magnetic Resonance Imaging for Non–Small-Cell Lung Cancer

Purpose: To demonstrate the feasibility of registering hyperpolarized helium-3 magnetic resonance images (3He-MRI) to X-ray computed tomography (CT) for functionally weighted intensity-modulated radiotherapy (IMRT) planning.Methods and Materials: Six patients with non–small-cell lung cancer underwent 3He ventilation MRI, which was fused with radiotherapy planning CT using rigid registration. Registration accuracy was assessed using an overlap coefficient, calculated as the proportion of the segmented 3He-MR volume (VMRI) that intersects the segmented CT lung volume expressed as a percentage of VMRI. For each patient, an IMRT plan that minimized the volume of total lung receiving a dose ≥20 Gy (V20) was compared with a plan that minimized the V20 to well-ventilated lung defined by the registered 3He-MRI.Results: The 3He-MRI and CT were registered with sufficient accuracy to enable functionally guided IMRT planning (median overlap, 89%; range, 72–97%). In comparison with the total lung IMRT plans, IMRT constrained with 3He-MRI reduced the V20 not only for the well-ventilated lung (median reduction, 3.1%; range, 0.4–5.1%; p = 0.028) but also for the total lung volume (median reduction, 1.6%; range, 0.2–3.7%; p = 0.028).Conclusions: Statistically significant improvements to IMRT plans are possible using functional information provided by 3He-MRI that has been registered to radiotherapy planning CT.

Low concentrations of inhaled nitric oxide do not improve oxygenation in patients with very severe chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is characterized by airway narrowing that is most frequently inhomogeneously distributed. Ventilation/perfusion (V/Q) mismatch may explain much of the hypoxemia in patients with advanced disease. A potential treatment strategy would be to redistribute blood flow to well-ventilated lung regions in order to decrease V/Q mismatch. It has been suggested that inhaled nitric oxide (iNO) in physiologic concentrations ( approximately 100 p.p.b.) could act as a local vasodilating agent in well-ventilated lung regions. To test this, we included 10 volunteer patients with very severe COPD in this study. NO was mixed with O(2) and N(2) and administered through a face mask. The partial pressure of inspired oxygen (P(i)o(2)) did not change by more than +/- 0.5 kPa from the room air value. NO was given in 15-min periods at concentrations of approximately 0, approximately 40, approximately 400, approximately 4000 and approximately 40,000 p.p.b. (random order). During each NO exposure, arterial blood gases, methemoglobin and systemic blood pressure were measured every fifth minute. None of the patients reported subjective effects of the different gas mixtures. The partial pressure of oxygen in arterial blood (P(a)o(2)) did not change by more than +/- 1.2 kPa from the baseline value, and there was no correlation between the change in P(a)o(2) and iNO concentration. No significant changes were found in blood pressure or methemoglobin during iNO. No significant effect of iNO at concentrations up to 40,000 p.p.b. in inspired gas was found on arterial blood gases. This indicates that neither low nor high concentrations of iNO improve oxygenation in patients with very severe COPD.

5-Lipoxygenase Deficiency Prevents Respiratory Failure during Ventilator-induced Lung Injury

Mechanical ventilation with high VT (HVT) progressively leads to lung injury and decreased efficiency of gas exchange. Hypoxic pulmonary vasoconstriction (HPV) directs blood flow to well-ventilated lung regions, preserving systemic oxygenation during pulmonary injury. Recent experimental studies have revealed an important role for leukotriene (LT) biosynthesis by 5-lipoxygenase (5LO) in the impairment of HPV by endotoxin. To investigate whether or not impairment of HPV contributes to the hypoxemia associated with HVT and to evaluate the role of LTs in ventilator-induced lung injury. We studied wild-type and 5LO-deficient mice ventilated for up to 10 hours with low VT (LVT) or HVT. In wild-type mice, HVT, but not LVT, increased pulmonary vascular permeability and edema formation, impaired systemic oxygenation, and reduced survival. HPV, as reflected by the increase in left pulmonary vascular resistance induced by left mainstem bronchus occlusion, was markedly impaired in animals ventilated with HVT. HVT ventilation increased bronchoalveolar lavage levels of LTs and neutrophils. In 5LO-deficient mice, the HVT-induced increase of pulmonary vascular permeability and worsening of respiratory mechanics were markedly attenuated, systemic oxygenation was preserved, and survival increased. Moreover, in 5LO-deficient mice, HVT ventilation did not impair the ability of left mainstem bronchus occlusion to increase left pulmonary vascular resistance. Administration of MK886, a 5LO-activity inhibitor, or MK571, a selective cysteinyl-LT(1) receptor antagonist, largely prevented ventilator-induced lung injury. These results indicate that LTs play a central role in the lung injury and impaired oxygenation induced by HVT ventilation.

COX and the control of the pulmonary circulation

The lung possesses a low resistance circulation that must, at all times, accommodate the entire cardiac output. Moreover, to ensure proper oxygenation of hemoglobin, blood flow must be directed to well-ventilated lung units, i.e., ventilation and perfusion must be matched.Cyclooxygenase (COX)-mediated arachidonic acid (AA) metabolites can influence both pulmonary vascular resistance and ventilation–perfusion matching. In isolated dog and rabbit lungs, ventilation of the right lung with oxygen (O2) and the left lung with nitrogen (N2) resulted in normal perfusion pressures and blood gas tensions. In both species, administration of COX inhibitors resulted in redistribution of blood flow from hypoxic alveoli (N2-ventilated lung) to the well-oxygenated alveoli (O2-ventilated lung) and an increase in arterial oxygen tension, i.e., a COX-mediated AA metabolite or metabolites opposed hypoxic pulmonary vasoconstriction (HPV), but, by virtue of this activity, prevented optimal matching of ventilation with perfusion. The effects of COX inhibition were reversed by prostacyclin (PGI2).These findings are consistent with the hypothesis that COX-derived products of AA metabolism can influence ventilation–perfusion matching in the lung. Moreover, the results of studies in dogs suggest that one such metabolite of AA is PGI2.

Management of pulmonary hypertension: physiological and pharmacological considerations for anesthesiologists.

For decades the pulmonary circulation was not considered as important as the systemic (“greater”) circulation. However, pulmonary hypertension can arise because of many diseases of the heart and lung. Therefore, increasing efforts in research have been undertaken leading to a profound increase in un

Administration of nitric oxide into open lung regions: delivery and monitoring

Pulsed administration of nitric oxide has proven effective in relieving pulmonary hypertension and in improving oxygenation. With this delivery method the nitric oxide administration to low ventilated lung regions is avoided with subsequent enhancement in oxygenation. This study presents (i) pulsed administration technique for nitric oxide during artificial ventilation, (ii) evaluation of the delivery in an animal model, and (iii) validation of the delivery device in a laboratory setting. Nitric oxide was delivered in four different pulse volumes synchronously with inspiration. The delivery was monitored with a fast responding high sensitivity nitric oxide monitor and nitric oxide uptake was calculated. Pulse delivery dose range, accuracy of the delivered dose, and stability of successive doses were analysed in a laboratory setting. Uptake of the delivered nitric oxide was 87-92%. Measured nitric oxide pulse concentration was 1.6-fold the delivery concentration, calculated as the ratio of nitric oxide flow to inspiration flow. Dose accuracy and stability were both 5% or 3 nmol in the validated range of 3-1000 nmol. With pulsed administration nitric oxide therapy can be directed to well-ventilated lung regions. Avoiding administration to the anatomic dead space eliminates nitric oxide exhalation effectively, which makes the method optimal for nitric oxide therapy in a rebreathing circuit. The required dose range from paediatric to adult is covered by the delivery device with a single nitric oxide gas supply.

The use of ECG and respiratory triggering to improve the sensitivity of oxygen-enhanced proton MRI of lung ventilation.

Changes in lung signal between normal breathing and breathing pure oxygen is the basis for oxygen-enhanced ventilation MRI. An optimal technique guarantees a significant response to pure oxygen in well-ventilated lung tissue. To improve the sensitivity, we investigated the effect of ECG and respiratory triggering. Centric reordered single-shot rapid acquisition relaxation enhancement sequences (TE 4.2 ms, echo spacing 4.2 ms, bandwidth 650 Hz/pixel), with an inversion recovery preparation pulse (TI 700 ms), were used. Series of 20 measurements were performed with and without ECG and respiratory triggering in five young volunteers. Subsequently, series of 100 images were acquired during breathing normal air and pure oxygen (as "stimulus"). Ventilation maps showed by means of the z-score how far the response deviates from the signal intensities during the normal air condition. The standard deviation of the lung signal intensities was lowest for the cardiac-triggered series. In the ventilation maps, on the other hand, signal changes were statistically more significant in the respiratory than in the cardiac-triggered series. The average z-scores in the right (left) cranial part of the lung were 12.4 (13.0) and 9.2 (9.7) for respiratory and ECG-triggered acquisitions. We propose to use respiratory triggering as a means to improve the sensitivity of MR ventilation studies.

Regional VA, Q, and VA/Q during PLV: effects of nitroprusside and inhaled nitric oxide.

Partial liquid ventilation (PLV) with high-specific-weight perfluorocarbon liquids has been shown to improve oxygenation in acute lung injury, possibly by redistributing perfusion from dependent, injured regions to nondependent, less injured regions of the lung. Our hypothesis was that during PLV in normal lungs, a shift in perfusion away from dependent lung zones might, in part, be due to vasoconstriction that could be reversed by infusing sodium nitroprusside (NTP). In addition, delivering inhaled NO during PLV should improve gas exchange by further redistributing blood flow to well-ventilated lung regions. To examine this, we used a single transverse-slice positron emission tomography camera to image regional ventilation and perfusion at the level of the heart apex in six supine mechanically ventilated sheep during five conditions: control, PLV, PLV + NTP, and PLV + NO at 10 and 80 ppm. We found that PLV shifted perfusion from dependent to middle regions, and the dependent region demonstrated marked hypoventilation. The vertical distribution of perfusion changed little when high-dose intravenous NTP was added during PLV, and inhaled NO tended to shift perfusion toward better ventilated middle regions. We conclude that PLV shifts perfusion to the middle regions of the lung because of the high specific weight of perflubron rather than vasoconstriction.

L-Arginine in lung graft preservation and reperfusion

Background Inhaled nitric oxide has been shown to ameliorate early lung graft dysfunction. It improves oxygenation by inducing pulmonary vasodilatation in well-ventilated lung areas, and it also modulates leukocyte–endothelium interactions. We used a porcine, single lung transplantation model to evaluate whether the benefits of exogenously administered gas could be achieved easier by adding L-arginine, the substrate of endogenous nitric oxide synthesis, as an additive to the flush solution and intravenously during reperfusion. Methods Six pig lungs were flushed with modified Euro-Collins solutions containing L-arginine (2 g/liter). After cold (4° C) storage, the left lung was transplanted. Ischemic time was 260 minutes. The recipients received intravenous boluses of L-arginine (30 mg/kg), followed by infusion (20 mg/kg/min) during the first 30 minutes of reperfusion. Six control animals received saline as placebo. We measured the blood flow and pulmonary vascular resistance (PVR) in the transplanted and in the native lung using a right heart bypass model. We measured blood gases, leukocyte counts, plasma free-radical trapping capacity, and diene conjugates in pulmonary venous blood and myeloperoxidase activity of the lung tissue. Results Pulmonary vascular resistance was 4 to 5-fold higher in the transplanted lung than in the native lung, which received 80% of the total blood flow. L-arginine reduced PVR by 30% in the native lung ( p < 0.001), but not in the transplanted lung. L-arginine had no effect on oxygenation or carbon dioxide exchange of the transplanted lung. Nor did L-arginine treatment have any effect on leukocyte sequestration or myeloperoxidase activity in the transplanted lung. The plasma antioxidant capacity in venous blood of the transplanted lung almost doubled shortly during early reperfusion without influence of L-arginine. Conclusions L-arginine reduced PVR in the native lung but did not improve pulmonary hemodynamics, gas exchange, or reduce leukocyte sequestration of the transplanted lung.

No apparent effect of nitric oxide on the local matching of pulmonary perfusion and ventilation in awake sheep.

The respiratory tissue in the lung receives nitric oxide (NO) from two sources; NO produced in upper airways, and NO produced in lung parenchyma. It has been hypothesized that optimal local matching of ventilation and perfusion (which is necessary for effective gas exchange) is ensured because well-ventilated lung tissue has a higher concentration of NO and thereby higher blood flow owing to the vasodilatory effect of NO. To test this hypothesis, we simultaneously measured the distributions of local (regions of approximately 1.5 cm3) blood flow (radioactive microspheres) and local ventilation (fluorescent aerosol) in five tracheostomized, awake and standing sheep. Tracers for perfusion and ventilation were administered (1) at baseline, (2) during endogenous NO production blockage (L-NAME 25 mg kg-1) and administration of NO free air, and (3) when the sheep received exogenous NO ( approximately 30 p.p.m.), but having its endogenous NO production blocked. The intrapulmonary distribution of ventilation was similar in all three situations. Within horizontal levels of the lung, distribution of perfusion was not affected by variable access to NO, but along the gravitational axis perfusion was more evenly distributed when the sheep had no access to NO. Exogenous NO tended to restore the baseline vertical profile. These changes in vertical distribution of perfusion can be explained by the effect of variable NO concentrations on pulmonary arterial pressure and cardiac output. Variable access to NO had no effect on arterial blood gases. We conclude that NO is important for the vertical distribution of pulmonary perfusion, but has no apparent effect on the local matching of ventilation and perfusion within horizontal layers of the lung.

Inhaled and exhaled nitric oxide.

. Inhaled nitric oxide (NO) is used to treat various cardiopulmonary disorders associated with pulmonary hypertension. The rationale is based on the fact that NO, given by inhalation, only dilates those pulmonary vessels that perfuse well-ventilated lung units. As a result, pulmonary gas exchange is improved while pulmonary vascular resistance is reduced and pulmonary blood flow is increased. Inhaled NO has been succesfully applied to treat persistent pulmonary hypertension of the newborn, reducing the need for extracorporeal life support. Although pulmonary hypertension and altered vasoreactivity contribute to profound hypoxaemia in adult and paediatric acute respiratory distress syndrome (ARDS), the benefit of inhaled NO still remains to be established in patients with ARDS. ARDS is a complex response of the lung to direct or indirect insults, leading to pulmonary vasoconstriction and various inflammatory responses. Recent randomized trials suggest that inhaled NO only causes a transient improvement in oxygenation. Whether this effect is important in the long-term management of ARDS remains to be established. NO, measured in the exhaled breath, is an elegant and non-invasive means to monitor inflammation of the upper and lower respiratory tract. In the normal upper airways, the bulk of exhaled NO originates from the paranasal sinuses. Exhaled NO is increased in nasal allergy and decreased in cystic fibrosis, nasal polyposis and chronic sinusitis. That NO production is increased in asthmatic airways is also well established. However, several questions still need to be addressed, in particular evaluation of the sensitivity and specificity of the measurement techniques, and assessment of the bronchodilator action of endogenous NO.

Inhaled nitric oxide in the treatment of hypoxemic respiratory failure.

Inhaled nitric oxide (iNO) is a pulmonary vasodilator that recruits blood flow to well-ventilated lung areas in the presence of lung disease. iNO may improve oxygenation by decreasing intrapulmonary shunt or may worsen oxygenation by reversing hypoxic pulmonary vasoconstriction, therapy increasing ventilation-perfusion mismatch. Recent studies have examined the mechanisms for gas exchange alterations with iNO. Moreover, several randomized controlled trials have explored the magnitude of the effect on oxygenation and the beneficial influence on clinical outcome in neonatal patients with hypoxemic respiratory failure. It is not known to what extent an increase in oxygenation affects clinical outcome in older patients. The potential benefit of iNO therapy must be weighed against the potential risks of inactivating surfactant and platelet function as well as influencing endogenous pulmonary vasoregulation. Well-designed studies will be important to determine whether the improvement in oxygenation outweighs these as well as unknown risks.

Effects of inhaled versus intravenous vasodilators in experimental pulmonary hypertension.

Inhaled nitric oxide (NO) causes selective pulmonary vasodilation and improves gas exchange in acute lung failure. In experimental pulmonary hypertension, we compared the influence of the aerosolized vasodilatory prostaglandins (PG) PGI2 and PGE1 on vascular tone and gas exchange to that of infused prostanoids (PGI2, PGE1) and inhaled NO. An increase of pulmonary artery pressure (Ppa) from 8 to approximately 34 mmHg was provoked by continuous infusion of U-46619 (thromboxane A2 (TxA2) analogue) in blood-free perfused rabbit lungs. This was accompanied by formation of moderate lung oedema and severe ventilation-perfusion (V'/Q') mismatch, with predominance of shunt flow (>50%, assessed by the multiple inert gas elimination technique). When standardized to reduce the Pps by approximately 10 mmHg, inhaled NO (200 ppm), aerosolized PGI2 (4 ng x kg(-1) x min(-1)) and nebulized PGE1 (8 ng x kg(-1) x min(-1)) all reduced both pre- and postcapillary vascular resistance, but did not affect formation of lung oedema. All inhalative agents improved the V'/Q' mismatch and reduced shunt flow, the rank order of this capacity being NO > PGI2 > PGE1. In contrast, lowering of Ppa by intravascular administration of PGI2 and PGE1 did not improve gas exchange. "Supratherapeutic" doses of inhaled vasodilators in control lungs (400 ppm NO, 30 ng x kg(-1) x min(-1) of PGI2 or PGE1) did not provoke vascular leakage or affect the physiological V'/Q' matching. We conclude that aerosolization of prostaglandins I2 and E1 is as effective as inhalation of nitric oxide in relieving pulmonary hypertension. When administered via this route instead of being infused intravascularly, the prostanoids are capable of improving ventilation-perfusion matching, suggesting selective vasodilation in well-ventilated lung areas.

Combined effects of NO inhalation and intravenous PGF2 alpha on pulmonary circulation and gas exchange in an ovine ARDS model.

Inhalation of nitric oxide (NO) selectively dilates pulmonary vessels in well-ventilated regions. Prostaglandin F2 alpha (PGF2 alpha) is a vasoconstrictor and is reported to enhance hypoxic pulmonary vasoconstriction. The objective of this study was to examine whether the combination of intravenous PGF2 alpha and inhaled NO in ARDS lungs has a beneficial effect on oxygenation. We investigated the effect of intravenous PGF2 alpha infusion (0.05-10.0 micrograms/kg per min) with and without NO inhalation (60 ppm) on the hemodynamics and gas exchange in an ovine ARDS model, examining the pulmonary artery pressure versus the flow plot by varying cardiac output. After lung lavage, NO inhalation reduced the mean pulmonary arterial pressure (MPAP) by decreasing the zero-flow pressure intercept from 10.6 +/- 3.8 (mean +/- SD) to 8.5 +/- 3.8 mmHg (p < 0.05) with no significant change in slope. NO inhalation improved PaO2 from 56 +/- 12 to 84 +/- 38 mmHg (p < 0.005) and reduced pulmonary shunt from 65 +/- 5 to 53 +/- 8% (Qs/Qt) (p < 0.001). The dose-dependent effects of PGF2 alpha infusion were: (1) increased MPAP attributed to an increased slope in pulmonary artery pressure-flow plot; (2) decreased cardiac index; (3) decreased Qs/Qt with unchanged PaO2. The dose-dependent decrease in Qs/Qt after PGF2 alpha infusion was attributed to the decreased cardiac output. It is suggested that inhalation of NO reduced the critical vascular pressure near alveoli without affecting upstream vessels, while infused PGF2 alpha constricted the larger upstream pulmonary artery vessels without appreciably affecting the critical pressure. Inhalation of NO into well-ventilated lung areas shifted perfusion to well-oxygenated areas, and there was no supplemental shift in blood flow by adding an infusion of PGF2 alpha.