The postural reduction in middle cerebral artery blood velocity is not explained by PaCO2.

In the normocapnic range, middle cerebral artery mean velocity (MCA Vmean) changes approximately 3.5% per mmHg carbon-dioxide tension in arterial blood (PaCO2) and a decrease in PaCO2 will reduce the cerebral blood flow by vasoconstriction (the CO2 reactivity of the brain). When standing up MCA Vmean and the end-tidal carbon-dioxide tension (PETCO2) decrease, suggesting that PaCO2 contributes to the reduction in MCA Vmean. In a fixed body position, PETCO2 tracks changes in the PaCO2 but when assuming the upright position, cardiac output (Q) decreases and its distribution over the lung changes, while ventilation (VE) increases suggesting that PETCO2 decreases more than PaCO2. This study evaluated whether the postural reduction in PaCO2 accounts for the postural decline in MCA Vmean). From the supine to the upright position, VE, Q, PETCO2, PaCO2, MCA Vmean, and the near-infrared spectrophotometry determined cerebral tissue oxygenation (CO2Hb) were followed in seven subjects. When standing up, MCA Vmean (from 65.3+/-3.8 to 54.6+/-3.3 cm s(-1) ; mean +/- SEM; P<0.05) and cO2Hb (-7.2+/-2.2 micromol l(-1) ; P<0.05) decreased. At the same time, the VE/Q ratio increased 49+/-14% (P<0.05) with the postural reduction in PETCO2 overestimating the decline in PaCO2 (-4.8+/-0.9 mmHg vs. -3.0+/-1.1 mmHg; P<0.05). When assuming the upright position, the postural decrease in MCA Vmean seems to be explained by the reduction in PETCO2 but the small decrease in PaCO2 makes it unlikely that the postural decrease in MCA Vmean can be accounted for by the cerebral CO2 reactivity alone.

Abnormal radiological findings and a decreased carbon monoxide transfer factor can persist long after the acute phase of Legionella pneumophila pneumonia.

Pulmonary abnormalities may persist long after the acute phase of legionnaires disease (LD). In a cohort of 122 survivors of an outbreak of LD, 57% were still experiencing an increased number of symptoms associated with dyspnea at a mean of 16 months after recovery from acute-phase LD. For 86 of these patients, additional evaluation involving high-resolution computed tomography (HRCT) of the lung revealed pulmonary abnormalities in 21 (24%); abnormal HRCT findings generally presented as discrete and multiple radiodensities. Residual pulmonary abnormalities were associated with a mean reduction of 20% in the gas transport capacity of the lung. This latter sign could not be used to explain the increased symptoms of dyspnea reported by patients. Receipt of mechanical ventilation during the acute phase of LD, delayed initiation of adequate antibiotic therapy, and chronic obstructive pulmonary disease were identified as risk factors for the persistence of lung abnormalities.

The PlA polymorphism of glycoprotein IIIa functions as a modifier for the effect of estrogen on platelet aggregation.

BACKGROUND: Although estrogen has been shown to contribute to retardation of the development of coronary heart disease in premenopausal women, the efficacy of hormone replacement therapy for coronary heart disease prevention in women with established coronary heart disease remains controversial. Hence, additional research is needed to clarify the effects of hormone replacement therapy on the cardiovascular and clotting systems. We investigated the effect of estrogen on platelet aggregation induced by standard agonists (epinephrine and adenosine diphosphate), with and without the platelet antagonist aspirin. Furthermore, we analyzed our data according to the presence or absence of a prevalent polymorphism of the glycoprotein (GP) IIIa subunit of the platelet fibrinogen receptor GPIIb-IIIa, PlA2. METHODS AND RESULTS: The effect of estrogen on aggregation of platelets was studied in healthy men (n = 20, 10 PlA1/A1 and 10 PlA1/A2) and premenopausal healthy women (n = 10, 5 PlA1/A1 and 5 PlA1/A2). The PlA1/A1 and PlA1/A2 individuals were matched for age and race. Platelet response to agonists was investigated in the presence of (1) estrogen (10(-11) to 10(-8) mol/L), (2) aspirin (0.056 to 56 micromol/L), (3) estrogen plus aspirin, and (4) estrogen plus ICI 182 780 (ICI, 10(-9) mol/L, an inhibitor of the estrogen receptor). We found that physiologic concentrations of estrogen strongly and significantly inhibited the aggregation of PlA1/A2 platelets (P<.005 for epinephrine and P<.05 for adenosine diphosphate, induced aggregation, respectively) in both men and women. Concentrations of estrogen that were 1000-fold greater were required to observe the same level of inhibition with PlA1/A1 platelets. In the presence of aspirin, estrogen failed to provide additional inhibitory effect on aggregation of both PlA1/A1 and PlA1/A2 platelets. The estrogen-specific inhibitor ICI blocked the effect of estrogen on aggregation, suggesting that this effect is mediated by the estrogen receptor. CONCLUSIONS: Estrogen inhibits the aggregation of platelets, but such inhibition is highly dependent on the presence or absence of the PlA2 polymorphism of GPIIIa. However, in the presence of aspirin, the inhibitory effect of estrogen on aggregation was no longer detectable.

Decreased lung function associated with perinatal exposure to Dutch background levels of dioxins.

UNLABELLED: Perinatal exposure to Dutch background dioxin levels is rather high. Studies of calamities have shown that dioxins negatively influence the respiratory system. It was hypothesized that perinatal exposure to background dioxin levels leads to lung suboptimality, probably through developmental interference. This study aimed to assess lung function in relation to perinatal dioxin exposure. Spirometry was performed in 41 healthy children (aged 7-12 y. mean 8.2 y) with known perinatal dioxin exposure. The ratio of forced expiratory volume in I s to forced vital capacity (FEV1/FVC ratio) was determined. A complete medical history was taken. The prenatal exposure ranged from 8.74 to 88.8 (mean 34.6) ng TEQ dioxin kg fat(-1), measured in breast milk. The postnatal exposure ranged from 4.34 to 384.51 (mean 75.4) ng TEQ dioxin. Twelve children had to be excluded. A significant decrease in lung function in relation to both prenatal (p = 0.045) and postnatal (p = 0.0002) dioxin exposure was seen in the 29 non-excluded children. A clinical association between chest congestion and perinatal dioxin exposure was seen. CONCLUSION: Perinatal background dioxin exposure may be inversely associated with the FEV1/ FVC ratio.

Changes in peak expiratory flow indices as a proxy for changes in bronchial hyperresponsiveness. Dutch Chronic Non-Specific Lung Disease study group.

Guidelines for asthma management advocate home peak expiratory flow (PEF) monitoring. It is commonly stated that PEF variability is a good proxy of bronchial hyperresponsiveness (BHR), a hallmark of asthma. However, this has hardly been tested longitudinally, as required to monitor asthma. This study assesses which PEF index correlates best with BHR longitudinally and whether the correlation improves when correcting PEF values for the known nonlinearity of mini-Wright PEF meters. Every 6 months, for a period of 2 yrs, PEF diary cards were filled in and BHR to histamine was tested in 104 patients with BHR and reversible airways obstruction, who started treatment with bronchodilators with (n=33) or without (n=71) inhaled corticosteroids. Within each subject, PEF indices and BHR were correlated longitudinally. The highest median correlation coefficients were obtained in the group of patients using inhaled corticosteroids. The PEF indices providing the best correlation with BHR were: mean PEF bronchodilator response (rho=-0.50) and within-day variation (% mean or % maximum) (with postbronchodilator values, rho=-0.50; without postbronchodilator values, rho=-0.40). Using PEF data corrected for the nonlinearity of the PEF meters did not result in higher correlation coefficients. Since current guidelines on asthma management recommend only bronchodilators on demand, the most useful peak expiratory flow index for reflecting bronchial hyperresponsiveness longitudinally is mean within-day peak expiratory flow variation (% mean or % maximum) (without postbronchodilator values). Since the correlation coefficients are not very strong, the authors suggest that peak expiratory flow measurements are not used as a proxy for bronchial hyperresponsiveness longitudinally but as a measurement in its own right. The use of corrections of peak expiratory flows for the nonlinearity of mini-Wright peak expiratory flow meters does not improve the correlation between peak expiratory flow and bronchial hyperresponsiveness.

Methylation of the estrogen receptor-alpha gene promoter is selectively increased in proliferating human aortic smooth muscle cells.

OBJECTIVE: Atherosclerosis is a multigenic process leading to the progressive occlusion of arteries of mid to large caliber. A key step of the atherogenic process is the proliferation and migration of vascular smooth muscle cells into the intimal layer of the arterial conduit. The phenotype of smooth muscle cells, once within the intima, is known to switch from contractile to de-differentiated, yet the regulation of this switch at the genomic level is unknown. Estrogen has been shown to regulate cell proliferation both for cancer cells and for vascular cells. However, methylation of the estrogen receptor-alpha gene (ERalpha) promoter blocks the expression of ERalpha, and thereby can antagonize the regulatory effect of estrogen on cell proliferation. We sought to determine whether methylation of the ERalpha is differentially and selectively regulated in contractile versus de-differentiated arterial smooth muscle cells. METHODS: We used Southern blot assay, combined bisulfite restriction analysis (Cobra) and restriction landmark genome scanning (RLGS-M) to determine the methylation status of ERalpha in human aortic smooth muscle cells, either in situ (normal aortic tissue, contractile phenotype), or the same cells explanted from the aorta and cultured in vitro (de-differentiated phenotype). RESULTS: We provide evidence that methylation of the ERalpha in smooth muscle cells that display a proliferative phenotype is altered relative to the same cells studied within the media of non-atherosclerotic aortas. Thus, the ERalpha promoter does not appear to be methylated in situ (normal aorta), but becomes methylated in proliferating aortic smooth muscle cells. Using a screening technique, RLGS-M, we show that alteration in methylation associated with the smooth muscle cell phenotypic switch does not seem to require heightened activity of the methyltransferase enzyme, and appears to be selective for the ERalpha and a limited pool of genes whose CpG island becomes either demethylated or de novo methylated. CONCLUSIONS: Our data support the concept that the genome of aortic smooth muscle cells is responsive to environmental conditions, and that DNA methylation, in particular methylation of the ERalpha, could contribute to the switch in phenotype observed in these cells.

Nedocromil sodium in obstructive airways disease: effect on symptoms and plasma protein leakage in sputum.

In patients with asthma or chronic obstructive pulmonary disease, there is chronic airway inflammation with increased leakage of plasma proteins into the airway lumen, which can be reduced by inhaled glucocorticosteroids. Nedocromil sodium is an anti-inflammatory drug, and we questioned whether it also affects the leakage of plasma proteins. In a double-blind placebo-controlled study we investigated the effect of 12 weeks of treatment with nedocromil on forced expiratory volume in one second (FEV1), provocative concentration of histamine causing a 20% fall in FEV1 (PC20), peak flow, symptom scores, and plasma protein leakage in sputum, in 31 patients with obstructive airways disease and sputum production (mean (range) FEV1 61% of predicted (42-87%); geometric mean (range) PC20 0.39 (0.04-2.9) mg x mL(-1)). As a measure for plasma protein leakage we calculated the relative coefficients of excretion (RCE) of proteins from serum to the soluble phase of sputum. There was a small increase in morning and evening peak flow (p<0.05) and a decrease in night-time bronchodilator use (p<0.02) in favour of nedocromil. The RCE of alpha2-macroglobulin to albumin significantly decreased after treatment with nedocromil (p=0.03). The results show limited clinical efficacy of nedocromil in our study group. They further suggest that the anti-inflammatory properties of nedocromil extend to inhibition of plasma protein leakage into the airways.

Nitric oxide modulation of pulmonary vascular resistance is red blood cell dependent in isolated rat lungs.

Nitric oxide (NO) or endothelium-derived relaxing factor may play an important role in modulating pulmonary vascular resistance (PVR), although previous studies have produced conflicting results. Endogenous NO inhibition causes an increase in PVR in intact animals but not in saline-perfused isolated lungs. We hypothesized that blood is essential for NO to serve as a modulator of PVR. Therefore, the effects of endogenous NO inhibition (N omega-nitro-L-arginine methyl ester [L-NAME]) were determined in isolated rat lungs as related to the presence of different blood components under normoxic conditions and after 1 wk of hypoxia (fraction of inspired oxygen [FIO2] = 10%). Exogenously administered inhaled NO was evaluated in isolated lungs from normoxic and hypoxic rats. In normoxic rats, L-NAME (10-100 microM) caused a dose-dependent increase in PVR in whole (hematocrit [Hct] 40%) and diluted (Hct 12%) blood-perfused lungs. L-NAME (10-800 microM) had no effect in isolated lungs perfused with a modified salt solution of equal viscosity to blood either alone, or containing plasma (50%) or free oxyhemoglobin (10 microM). In whole blood perfused lungs, L-NAME (100 microM) increased PVR more in hypoxic versus normoxic isolated lungs (141% vs 100%). Inhaled NO decreased PVR in isolated lungs from hypoxic rats and partially reversed the effects of L-NAME, but had no effect in normoxic lungs. In conclusion, endogenous and inhaled NO modulate PVR in isolated rat lungs and this role is increased by prolonged hypoxia. The response to inhibition of endogenous NO is dependent on the presence of red blood cells and is independent of the changes in viscosity or the presence of oxyhemoglobin or plasma.

Endotoxin alters hypoxic pulmonary vasoconstriction in isolated rat lungs.

Hypoxic pulmonary vasoconstriction (HPV) is an important mechanism for maintaining oxygenation, which may be altered by endotoxin. We determined that acute endotoxemia alters the HPV response secondary to changes in endothelium-derived vasoactive products. Rats were treated with Salmonella typhimurium lipopolysaccharide (LPS; 15 mg/kg i.p.) either 1 to 6 h before lung isolation and compared with control rats (no LPS). Additional 6-h LPS-treated and control rats were pretreated with either indomethacin (15 mg/kg i.p.), a cyclooxygenase inhibitor, or bosentan (10 mg/kg po), a nonselective endothelin-receptor antagonist. The rats lungs were isolated and challenged with 3% O2 for 10 min to elicit HPV responses before and after nitric oxide (NO) synthase inhibition with N omega-nitro-L-arginine methyl ester (L-NAME; 100 microM). LPS (6 h) significantly increased the peak HPV responses by 108%. L-NAME had no significant effect in LPS-treated lungs but increased the peak HPV response in control lungs to levels equal to LPS-treated lungs. Bosentan increased the peak HPV response in all lungs, and indomethacin increased the peak HPV in LPS-treated lungs. The HPV response was sustained in control lungs at 10 min and in additional 20-min studies. In contrast, in LPS-treated lungs the HPV response faded after 10 min to levels equal to control, and in 20-min studies it faded by 82% to levels significantly less than in control lungs. The 10-min fade in LPS-treated lungs was attenuated by indomethacin (51%) and bosentan (80%) but not by L-NAME. In conclusion, acute endotoxemia with LPS increased the peak HPV response, but this effect was not sustained and by 20 min was nearly abolished. Inhibition of endogenous NO by LPS may explain the increased peak HPV response, but NO is not involved in the fade. The fade is at least partially due to increased vasodilating cyclooxygenase products and endothelins.

Chronic inhaled nitric oxide: effects on pulmonary vascular endothelial function and pathology in rats.

Nitric oxide (NO) is a potent endogenous vasodilator produced in endothelial cells. Inhaled NO selectively vasodilates the pulmonary circulation. We determined the effects of chronic inhaled NO on hypoxic pulmonary vascular remodeling and endothelium NO-dependent and -independent vasodilation during normoxic and hypoxic conditions in rats. Rats were exposed to 3 wk of normoxia (N), normoxia + 20 ppm inhaled NO (N+NO), chronic hypoxia with 10% normobaric oxygen (CH), or CH and 20 ppm inhaled NO (CH+NO). Inhaled NO decreased the number of muscular pulmonary arteries, the medial smooth muscle thickness, and the right ventricular hypertrophy associated with chronic hypoxia but had no effect on these parameters in normoxic rats. All groups were evaluated with isolated perfused lungs. The pulmonary artery pressure increased by the same amount in the CH and CH+NO rats compared with N rats. Inhibition of NO synthase with N omega-nitro-L-arginine methyl ester (L-NAME) caused greater pulmonary vasoconstriction in CH (19.2 +/- 3.7 mmHg) vs. N (7.8 +/- 3.0 mmHg) and less in CH+NO (9.1 +/- 0.8 mmHg) vs. CH rats. Bradykinin (3 micrograms) caused greater vasodilation in CH (76 +/- 12%) vs. N (29 +/- 5%) but significantly less in CH+NO (41 +/- 11%) vs. CH rats. Vasodilation with acute inhaled NO (40 ppm) was no different in CH vs. N rats but was lower in CH+NO (19 +/- 5%) vs. CH (34 +/- 6%) rats. This study demonstrates that chronic inhaled NO attenuates hypoxic pulmonary vascular remodeling. Furthermore, these results suggest that chronic inhaled NO decreases endothelium NO-dependent and -independent vasodilation.

Pressure-volume analysis of the lung with an exponential and linear-exponential model in asthma and COPD. Dutch CNSLD Study Group.

The prevalence of abnormalities in lung elasticity in patients with asthma or chronic obstructive pulmonary disease (COPD) is still unclear. This might be due to uncertainties concerning the method of analysis of quasistatic deflation lung pressure-volume curves. Pressure-volume curves were obtained in 99 patients with moderately severe asthma or COPD. These patients were a subgroup from a Dutch multicentre trial; the entire group was selected on the basis of a moderately lowered % predicted forced expiratory volume in one second (FEV1), and a provocative concentration of histamine producing a 20% decrease in FEV1 (PC20) < 8 mg.mL-1 obtained with the 2 min tidal breathing technique. The curves were fitted with an exponential (E) model and an exponential model which took the linear appearance in the mid vital capacity range into account (linear-exponential (LE)). The linear-exponential model showed a markedly better fit ability, yielding additional parameters, such as the compliance at functional residual capacity (FRC) level as slope of the linear part (b), and the volume at which the linear part changed into the exponential part of the curve (transition volume (Vtr)). Vtr (mean value Vtr/total lung capacity (TLC) = 0.79 (SD 0.07)) showed a close positive linear correlation with obstruction and hyperinflation variables, which might be due to airway closure, already starting at elevated lung volumes. The exponential shape factor K was closely correlated with b and mean values (K = 1.32 (SD 0.05) kPa-1; b = 2.96 (SD 1.16) L,kPa-1) and the relationship with age was comparable with data reported in healthy individuals. The shape factor of the linear-exponential fit showed no correlation with any elasticity related variable. Neither the elastic recoil at 90% TLC, as obtained from the linear-exponential fit, nor its relationship with age were significantly different from healthy individuals. We conclude that, for a more accurate description of the lung pressure-volume curve, a linear-exponential fit is preferable to an exponential model. However, the physiological relevance of the shape parameter (KLE) is still unclear. These results indicate that patients with moderately severe asthma or COPD had, on average, no appreciable loss of elastic lung recoil as compared with healthy individuals.

Analysis of plasma-protein leakage and local secretion in sputum from patients with asthma and chronic obstructive pulmonary disease.

In order to assess the usefulness of sputum analysis in studying plasma-protein exudation and local secretion of proteins in the airways, we measured specific proteins in the sputum sol phase (SSP) and sputum gel phase (SGP) from patients with stable asthma or chronic obstructive pulmonary disease (COPD). Protein levels in SSP showed relatively small variations between two subsequent visits of each patient (n = 22), as also reflected by intraclass correlation coefficients above 0.79. Protein levels differed between SSP and SGP, but inclusion of the SGP data did not affect the variation of protein levels in sputum. The degree of plasma-protein leakage was estimated from the relative coefficients of excretion (RCE) of alpha 2-macroglobulin and albumin (QA2M/QALB), and of alpha 2-macroglobulin and ceruloplasmin (QA2M/QCP), which do not depend on variable dilution of sputum. Despite the heterogeneity of the study group of 26 patients with asthma (atopic [13] smokers [13], including five patients using inhaled steroids), QA2M/QALB and QA2M/QCP correlated both with bronchial hyperreactivity (Spearman rank: r = -0.45 and r = -0.36, p < 0.05) and with blood eosinophil counts (r = 0.37 and 0.56, p < 0.05). We conclude that protein levels in SSP are relatively constant in patients with stable asthma or COPD; in patients with asthma, the plasma-protein leakage, as measured with the RCE in SSP, appears to correlate with indirect indices of airway inflammation.

Dose-effect relations for local functional and structural changes of the lung after irradiation for malignant lymphoma.

PURPOSE: To estimate the dose-effect relations for local functional (ventilation and perfusion) and structural (density) changes of the lung, 3-4 months after irradiation. METHODS: Twenty-five patients with malignant lymphoma were irradiated with a (modified) mantle field to an average dose of 38 Gy, given in 21 fractions. Single photon emission computed tomography (SPECT) ventilation (V) and perfusion (Q) scans, and CT scans were performed before and 3-4 months after radiation treatment. The three-dimensional dose distribution was calculated using the CT data. After correlation of SPECT and CT data sets, the average post-treatment value of V, Q and lung density per voxel was calculated relative to the pre-treatment value, per dose interval of 4 Gy. Subsequently, the dose-effect relations in each patient were normalized to the average value per voxel in the dose interval of 0-12 Gy. In addition, in each dose interval of 4 Gy the fraction of patients with changes larger than 20% was calculated for all three parameters. The dose-effect relations for perfusion and ventilation normalized to the low-dose regions, and the dose-incidence curves for the fraction of patients with changes larger than 20% were fitted for all three parameters, using a logistic model. RESULTS: Marked changes in the distribution of V and Q were found after irradiation. Prior to normalization to the low-dose regions, a change in V and Q was found in most patients in the dose interval of 0-12 Gy, varying from an increase of 37% to a decrease of 10%, which was followed by a decreasing trend at higher doses. The increase in the low-dose regions indicated a redistribution phenomenon, the magnitude of which was dependent of the irradiated volume. The logistic fit of the dose-effect relations for Q and V, normalized to the low-dose regions, resulted in values for D50 of 51 Gy and 54 Gy (given in 21 fractions on average), respectively, and for the steepness parameter k of 4.2 and 4.0, respectively. The logistic fit for the dose-incidence curves for Q, V and lung density resulted in values for D50 and k of 38 Gy, 37 Gy, 44 Gy and 10.3, 7.8 and 9.4, respectively. CONCLUSIONS: With the combined use of SPECT and CT scans, we have obtained dose-effect relations for local functional and structural damage in the lung, 3-4 months after irradiation.

Sites of vasodilation by inhaled nitric oxide vs. sodium nitroprusside in endothelin-constricted isolated rat lungs.

We localized the sites of vasodilation of inhaled nitric oxide (NO), a selective pulmonary vasodilator, and sodium nitroprusside (SNP) in isolated rat lungs. The sites were determined by analyzing the arterial, venous, and double-occlusion data with a two-resistor (small arteries and veins) three-capacitor (large arteries, large veins, and capillaries) model of the pulmonary vascular bed. Inhaled NO (170 and 670 ppm) and SNP (22.5 and 45.0 micrograms) decreased the small-artery resistance by 7.4 +/- 1.6, 17.2 +/- 2.2, 14.2 +/- 2.8, and 21.4 +/- 3.4% and the small-vein resistance by 13.5 +/- 3.2, 20.3 +/- 3.4 (SNP of 22.5 micrograms not significant), and 9.3 +/- 3.3%, respectively, in blood-perfused lungs (n = 12). Similar results were observed in Krebs-perfused lungs (n = 12). Capillary compliance was unaffected by inhaled NO and SNP. SNP increased the large-artery capacitance by 40.0 +/- 8.6 and 69.3 +/- 9.7%, whereas inhaled NO had no effect. SNP increased the large-vein capacitance by 31.0 +/- 8.7 and 48.0 +/- 10.7%, whereas inhaled NO had no effect in blood-perfused lungs. However, in Krebs-perfused lungs inhaled NO and SNP (45.0 micrograms only) increased the large-vein capacitance by 43.3 +/- 11.9, 41.4 +/- 14.2, and 44.2 +/- 11.0%. In conclusion, in blood-perfused isolated rat lungs inhaled NO and SNP dilate small-resistance arteries and veins, whereas SNP but not inhaled NO dilates larger capacitance arteries and veins. Furthermore, blood appears to prevent the downstream vasodilation by inhaled NO on larger capacitance pulmonary veins.

Direct effects of intravenous anesthetics on pulmonary vascular resistance in the isolated rat lung.

We determined the direct effects of thiopental, ketamine, midazolam, etomidate, and propofol on pulmonary vascular resistance (PVR), the relationship of the direct effects to the baseline PVR, and the possible interaction with functional endothelium. The intravenous anesthetics were injected randomly into 1) endothelium-intact isolated rat lungs which were either unconstricted or constricted with angiotensin II (n = 10), and 2) lungs with endothelial injury produced by electrolysis (n = 10). In endothelium-intact lungs thiopental (0.5 and 5.0 mg/kg) and etomidate (3.0 mg/kg) significantly (P < 0.05) increased PVR by 3% +/- 1%, 30% +/- 7%, and 29% +/- 5%, respectively. Ketamine (3.0 and 100 mg/kg) and propofol (20 mg/kg) significantly (P < 0.05) decreased the PVR by 6% +/- 1%, 15% +/- 1%, and 8% +/- 1%, respectively. Midazolam (0.3 and 3.0 mg/kg) and smaller doses of etomidate (0.3 mg/kg) and propofol (2.0 mg/kg) did not affect PVR. These responses did not vary with the baseline PVR over a twofold range. The effects of thiopental, ketamine, etomidate, and midazolam were not altered by endothelial injury. In contrast to the vasodilation produced by propofol in normal lungs, propofol (20 mg/kg) significantly (P < 0.05) increased the PVR by 8% +/- 2% after endothelial injury. In conclusion, this study demonstrates that thiopental and etomidate are direct pulmonary vasoconstrictors, ketamine and propofol are direct pulmonary vasodilators, and midazolam has no direct effects in the isolated rat lung. Further, these effects on pulmonary vasculature do not vary with baseline PVR, and only propofol appears to have endothelium-dependent effects.

A new method to determine dose-effect relations for local lung-function changes using correlated SPECT and CT data.

PURPOSE: To determine dose-effect relations for regional lung-function changes after radiotherapy. METHODS: Single Photon Emission Computed Tomography (SPECT) was performed to quantify regional ventilation and perfusion. CT scans were used to calculate the three-dimensional (3-D) dose distribution. Both SPECT and CT scans were performed prior to radiotherapy and 5 months after the start of the treatment. To obtain combined 3-D information on ventilation, perfusion and dose, the SPECT data were correlated with the corresponding CT data. The relative changes in ventilation and perfusion were calculated in each SPECT voxel (voxel size about 6 x 6 x 6 mm) and related to the dose in that voxel. The average relative changes were determined per dose interval of 4 Gy. This procedure was evaluated using the data from five patients treated for Hodgkin's disease with mantle field irradiation with a prescribed total dose of 40-42 Gy. RESULTS: Dose-effect relations for perfusion were observed in all patients, while in four of the five patients, a dose-effect relation was found for ventilation. The maximal uncertainty of the calculated radiation dose was 11%: a difference between the position of the patient during treatment and during CT scanning caused a maximal dose uncertainty of 6%, while the accuracy of the dose calculation algorithm itself was estimated to be within 5%. CONCLUSION: The results indicate that the combined use of SPECT and CT information is an effective method for determining dose-effect relations for regional lung function parameters in each individual patient.

Inhaled nitric oxide: dose response and the effects of blood in the isolated rat lung.

Inhaled nitric oxide (NO) is a vasodilator selective to the pulmonary circulation. Using isolated rat lungs, we determined the dose-response relationship of NO and the role of blood in mediating pulmonary vasodilation and selectivity. Inhaled 20, 50, 100, and 1,000 ppm NO attenuated (P < 0.001) hypoxic pulmonary vasoconstriction by 16.1 +/- 4.9, 22.6 +/- 6.8, 28.4 +/- 3.5, and 69.3 +/- 4.2%, respectively. Inhaled 13, 34, 67, and 670 ppm NO attenuated the increase in pulmonary arterial pressure secondary to angiotensin II more (P < 0.001) in Greenberg-Bohr buffer- (GB) than in blood-perfused lungs (51.7 +/- 9.9, 71.9 +/- 8.9, 78.2 +/- 5.3, and 91.9 +/- 2.1% vs. 14.3 +/- 4.1, 23.8 +/- 4.6, 28.4 +/- 3.8, and 55.5 +/- 5.9%, respectively). Samples from GB- but not blood-perfused lungs contained NO (93.0 +/- 26.3 nM). Intravascular NO attenuated the response to angiotensin II more (P < 0.001) in GB- (with and without plasma) than in blood- (hematocrit = 41 and 5%) perfused lungs (75.6 +/- 6.4 and 70.9 +/- 4.8% vs. 22.2 +/- 2.4 and 39.4 +/- 7.6%). In conclusion, inhaled NO produces reversible dose-dependent pulmonary vasodilation over a large range of concentrations. Inhaled NO enters the circulation, but red blood cells prevent systemic vasodilation and also a significant amount of pulmonary vasodilation.

Inhaled nitric oxide. Selective pulmonary vasodilation in cardiac surgical patients.

BACKGROUND: Inhaled nitric oxide (NO), an endothelium-derived relaxing factor, is a selective pulmonary vasodilator. The authors investigated whether the pulmonary vasodilation resulting from 20 ppm inhaled NO is related to the degree of pulmonary hypertension or affected by cardiopulmonary bypass (CPB) or the presence of intravenous nitrates. METHODS: In patients undergoing cardiac surgery (n = 20) or in whom the circulation was supported with a ventricular assist device (VAD; n = 5), the lungs were ventilated with 80% O2 and 20% N2 followed by the same gas concentrations containing 20 ppm NO for 6 min. RESULTS: Inhaled NO decreased (P < 0.05) the pulmonary artery pressure from 36 +/- 3 to 29 +/- 2 mmHg and 32 +/- 2 to 27 +/- 1 mmHg, before and after CPB, respectively, and from 68 +/- 12 to 55 +/- 9 mmHg in patients with a VAD. Similarly, the pulmonary vascular resistance (PVR) decreased (P < 0.05) from 387 +/- 44 to 253 +/- 26 dyne.cm.s-5 and 260 +/- 27 to 182 +/- 18 dyne.cm.s-5, before and after CPB, respectively, and from 1,085 +/- 229 to 752 +/- 130 dyne.cm.s-5 in patients with a VAD. Central venous pressure, cardiac output, systemic hemodynamics, and blood gases did not change after inhalation of NO before or after CPB, whereas arterial oxygen tension, mixed venous hemoglobin saturation, and mean arterial pressure increased (P < 0.05) in patients supported with a VAD. All hemodynamic and laboratory data returned to control 6 min after discontinuation of NO. The decrease in PVR was proportional to baseline PVR (delta PVR = -0.45 PVRb + 39.9) before CPB. The pre- and post-CPB slopes were identical despite possible damage to the endothelium resulting from CPB and the post-CPB presence of intravenous nitroglycerin (17 of 20 patients). CONCLUSIONS: This study demonstrates that 20 ppm inhaled NO is a selective pulmonary vasodilator in cardiac surgical patients before and after CPB and in patients in whom the circulation is supported with a VAD. Furthermore, NO-induced pulmonary vasodilation is proportional to PVRb and does not appear to be altered by CPB, the presence of a VAD, or infusion of nitrates.

Standardized quantitative 67Ga scintigraphy in relation to carbon monoxide diffusion capacity in pulmonary sarcoidosis.

67Ga lung uptake, obtained by a standardized computer-assisted quantitative method of 67Ga scintigraphy, was compared to carbon monoxide diffusion capacity (DLCO) in 45 patients with biopsy proven pulmonary sarcoidosis. Increased 67Ga lung uptake was found in 24 (53%) patients and DLCO was decreased in only 16 (36%) patients. An inverse relationship (r = -0.53; p < 0.001) was demonstrated between 67Ga lung uptake and DLCO. Eleven patients had an increased 67Ga lung uptake whereas the DLCO values were normal. There was no correlation between 67Ga lung uptake or DLCO and either chest radiographic stage or mode of clinical presentation. On the basis of the normal limits for 67Ga lung uptake and DLCO, 4 subgroups of patients could be identified. The use of the combined investigations may open an opportunity for an early identification of those patients who require therapy. An increased 67Ga accumulation within the lung seems to be considered as a factor indicating risk for pulmonary disability, which is supported by the follow-up of the 4 subgroups of patients.