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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Depressed immunity and impaired proliferation of hematopoietic progenitor cells in patients with complete spinal cord injury.

The bone marrow is supplied with both sensory and autonomic neurons, but their roles in regulating hematopoietic and immunocompetent cells are unknown. Leukocyte growth and activity in patients with stable and complete spinal cord injuries were studied. The innervation of the bone marrow below the injury level lacked normal supraspinal activity, that is, a decentralized bone marrow. Lymphocyte functions were markedly decreased in injured patients. Long-term colony formation of all hematopoietic cell lineages, including dendritic cells, by decentralized bone marrow cells was substantially reduced. It was concluded that nonspecific and adaptive lymphocyte-mediated immunity and growth of early hematopoietic progenitor cells are impaired in patients with spinal cord injuries. Possibly, this reflects cellular defects caused by the malfunctioning neuronal regulation of immune and bone marrow function.

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.

Hypoxia and hyperoxia both transiently affect distribution of pulmonary perfusion but not ventilation in awake sheep.

Despite a remarkable gravity independent heterogeneity in both local pulmonary ventilation and perfusion, the two are closely correlated at rest and during exercise in the normal lung. These observations strongly indicate that there is a mechanism for coupling of the two so that local V/Q-ratio is kept fairly uniform throughout the lung. This is also necessary to achieve adequate gas exchange in the lung. It was recently suggested that oxygen-induced vasoconstriction has a slow and intense component that might contribute to the matching of ventilation and perfusion also under normal conditions (Vejlstrup & Dorrington 1993). We therefore simultaneously determined distribution of local ( approximately 1(1/2) cm3 lung pieces) ventilation and perfusion in eight sheep at normoxia (FiO2 21%) and after 10 min and 2(1/2) h exposure to hypoxia (FiO2 12%; four sheep) or hyperoxia (FiO2 40%; four sheep). We used a approximately 1 microm wet fluorescent aerosol and 15 microm radioactive microspheres i.v. to measure local ventilation and perfusion, respectively. Neither hypoxia nor hyperoxia caused changes in the distribution of ventilation. After 10 min exposure to hypoxia or hyperoxia, distribution of perfusion was altered so that the correlation between values for local ventilation and perfusion decreased. After 2(1/2) h exposure to either hypoxia or hyperoxia, distributions of perfusion and V/Q-ratio had returned to baseline. These results show that distribution of perfusion is influenced by acute changes in oxygen tension, so that local matching of ventilation and perfusion is affected. Apparently, some mechanism restores the matching during extended exposure to the altered oxygen tension.

Minor redistribution of ventilation and perfusion within the lung during exercise in sheep.

Considerable heterogeneity unrelated to the effect of gravity has been demonstrated for both local ventilation (V) and perfusion (Q) in the lung. Local ventilation and perfusion are well matched, so that the heterogeneity of the V/Q ratio is less than for ventilation or perfusion alone (Melsom et aL 1997). We are searching for the mechanisms responsible for the coordinate heterogeneity of ventilation and perfusion. Here, we ask how and to what extent physical exercise induces changes in the distribution of ventilation and perfusion. We measured local (approximately 1.5 cm3 tissue volume) pulmonary ventilation and perfusion simultaneously in six sheep before, during and after running on a treadmill. Local ventilation was determined from the deposition of labelled aerosol particles and local perfusion from trapping of radioactive microspheres. Cardiac output increased approximately 2.5-fold during exercise. V/Q-ratios were not normally distributed and we therefore present the heterogeneity as the interquartile range. At rest, the average interquartile ranges for local ventilation, perfusion and V/Q-ratio were 0.48, 0.51 and 0.39, respectively. During exercise, the corresponding values were 0.44, 0.40 and 0.32. Thus, the distribution of local V/Q-ratio was narrower than for ventilation and perfusion also during exercise. We found a moderate redistribution of relative flow towards the dorsal parts of the lungs when perfusion increased, but the increase in total perfusion and ventilation was for the most part throughout the lung. The results indicate that the coupling between local ventilation and perfusion is at least as potent during exercise as at rest. The correlation (r) between paired values in the two resting periods was 0.93 for ventilation and 0.91 for perfusion and thus indicates time stability for the two variables.

Time course and pattern of pulmonary flow distribution following unilateral airway occlusion in sheep.

1. Unilateral bronchial occlusion causes ipsilateral hypoxic pulmonary vasoconstriction, which shifts blood flow towards the other lung. We studied the time course of flow diversion following acute bronchial occlusion, and the temporal effect of the latter on blood gases and vertical distribution of blood flow within the two lungs. 2. Serial infusion of radioactive or fluorescent microspheres were given to each of seven adult standing sheep before, during occlusion of the left mainstem bronchus for up to 6 min, and after release of occlusion. Pulmonary and systemic arterial pressures were recorded continuously and arterial and mixed venous blood gases were determined intermittently. Post-mortem, the lungs were inflated, dried and cut into slices. Relative blood flow at the time of infusion was expressed as the weight-normalized intensity of each tracer in each slice or lung divided by the weight-normalized intensity in the two lungs. 3. Within 30 s, 1 min and 2 min after onset of occlusion, flow in the occluded lung had decreased to 68-84% (range), 51-78% and 43-79% respectively, of the initial value. In the contralateral lung, flow increased by 10-24%, 14-37% and 23-39% respectively. The distribution of flow along the gravitational axis within each lung varied widely between animals, both before and during occlusion. The during-occlusion profiles in the occluded lung differed from those in the non-occluded lung. In either lung, during-occlusion profiles could not be predicted with certainty from the pre-occlusion profiles. Two minutes post-occlusion, inter- and intra-lung flow distribution were nearly the same as before occlusion. Arterial oxygen tension fell in the first minute of occlusion, but never below 7.5 kPa, and increased slowly thereafter. Arterial carbon dioxide tension increased slightly throughout the occlusion period. No appreciable changes in systemic or pulmonary artery pressure were observed. Post-occlusion, arterial oxygen tension was still sub-normal, while carbon dioxide tension continued to increase. 4. We conclude that acute unilateral bronchial occlusion diverts blood flow within 30 s towards the contralateral lung. This rapidly occurring flow diversion prevents the development of severe arterial hypoxaemia. The variable and largely unpredictable distribution of blood flow in the hyperfused non-occluded lung might explain some of the gas-exchange abnormalities observed in physiologically hyperfused lungs and in patients with one hyperfused lung.

Lymph flow pattern in the intact thoracic duct in sheep.

1. To study the lymph flow dynamics in the intact thoracic duct, we applied an ultrasound transit-time flow probe in seven anaesthetized and four unanaesthetized adult sheep (approximately 60 kg). In unanaesthetized non-fasting animals we found that lymph flow in the thoracic duct was always regular pulsatile (pulsation frequency, 5.2 +/- 0.8 min-1) with no relation to heart or respiratory activity. At baseline the peak level of the thoracic duct pulse flow was 11.6-20.7 ml min-1 with a nadir of 0-3.6 ml min-1. Mean lymph flow was 5.4 +/- 3.1 ml min-1. The flow pattern of lymph in the thoracic duct was essentially the same in the anaesthetized animals. 2. In both the anaesthetized and unanaesthetized animals, the lymph flow response to a stepwise increase in the outflow venous pressure showed interindividual variation. Some were sensitive to any increase in outflow venous pressure, but others were resistant in that lymph flow did not decrease until outflow venous pressure was increased to higher levels. This resistance was also observed in the high lymph flow condition produced by fluid infusion in the anaesthetized animal and mechanical constriction of the caudal vena cava in the unaesthetized animals. Pulsation frequency of the thoracic duct flow initially increased and then decreased with a stepwise increase in the outflow venous pressure. This initial increase might be a compensatory response to maintain lymph flow against elevated outflow venous pressure. 3. To test the effect of long-term outflow venous pressure elevation in unanaesthetized sheep, outflow venous pressure was increased by inflation of a cuff around the cranial vena cava for 1, 5 or 25 h. The cuff was inflated to a level where lymph flow was reduced. Lymph flow remained low or decreased further during the entire cuff-inflation period. We calculated the lymph debt caused by the outflow venous pressure elevation and the amount 'repaid' when venous pressure returned to normal. Lymph debt for 25 h was 6400 ml but only 200 ml was repaid. Since we observed no visible oedema formation in the lower body of the sheep, the non-colloidal components of the lymph must have been reabsorbed into the bloodstream, most likely in the lymph nodes.

Distribution of pulmonary ventilation and perfusion measured simultaneously in awake goats.

Gravity has been regarded as the major determinant for local pulmonary perfusion and ventilation. Recent reports, describing major gravity independent heterogeneity in both variables, have questioned the importance of gravity. We asked to what extent ventilation and perfusion were related, and if they showed similar distributions along the vertical axis in the lung. We gave 99mTc-aerosols as tracers for ventilation and radioactive microspheres as blood flow tracers in five awake goats over 4 min. Ventilation and perfusion were determined in approximately 1.5 cm3 pieces of the lung. For both variables the vertical distribution could vary considerably from lung to lung, but within each lung the two distributions were similar. Both ventilation and perfusion were heterogeneously distributed (CV approximately 40% for both), they were highly correlated (r = 0.81) and the average 25-75-interpercentile interval for ventilation to perfusion ratio (0.84-1.13) was significantly less wide than for both ventilation (0.76-1.38) and perfusion (0.76-1.40). Some pieces were considerably overventilated while a few were correspondingly underventilated. This could indicate that perfusion is adjusted to ventilation in normoxic lungs with a low sensitivity to overventilation.

Both gravity and non-gravity dependent factors determine regional blood flow within the goat lung.

Distribution of pulmonary blood flow has traditionally been regarded as determined by gravity. This view has been challenged recently by reports describing marked gravity-independent distribution of flow. These reports were based on experiments in which local blood flow was measured by methods that have not been thoroughly evaluated. In the present study, we showed that in the goat lung regional trapping of i.v. infused microspheres (O = 15 microns) correlated to endothelial uptake of a simultaneously i.v. infused diamine (r = 0.99, region size approximately 1.5 cm3, dry weight approximately 40 mg). This indicates that the deposition of microspheres reflects true regional pulmonary blood flow. Using the microsphere method, we found a marked gravity-independent heterogeneity in blood flow (coefficient of variation approximately 40%) in the awake goat. We could find no pattern related to anatomy that could account for this variability. We re-examined the influence of gravity by analysing the distribution of pulmonary blood flow in anaesthetized goats both in prone and supine positions. The dorsal to sternal distribution of flow appeared to be inverted when the animals were turned from prone to supine recumbency, indicating that gravity influenced the distribution of pulmonary blood flow along this axis. However, along the gravitational axis, distribution of blood flow varied considerably from lung to lung. It appears that in awake goats the distribution of pulmonary blood flow is the result of several different determinants.

Regional heterogeneity of myocardial blood flow within the rabbit left ventricle during haemorrhagic hypotension.

Several studies have reported an extensive regional heterogeneity in myocardial blood flow. The reported coefficients of variation for regional myocardial perfusion range from about 0.2 to 0.4 in normotensive animals. The spatial distribution of myocardial perfusion during haemorrhagic hypotension seems not to have been assessed. The goal of the present study was to determine the regional heterogeneity in myocardial blood flow within the rabbit left ventricle during normal conditions and after haemorrhagic hypotension. Radioactive microspheres were infused into the left ventricle in barbiturate anaesthetized rabbits over either 30 or 120 sec. The haemorrhagic hypotension was induced by bleeding, so that mean arterial blood pressure was reduced to about 50% of control. The left ventricles were divided into samples of about 0.025 g each. Regional heterogeneity in the blood flow was expressed as the coefficient of variation corrected for the Poisson distribution of microspheres (CVc). The CVc was 0.37 +/- 0.09 (mean +/- SD) during control and 0.41 +/- 0.11 after bleeding, the CVc obtained after bleeding being somewhat higher than during control (P < 0.05). We obtained a high correlation coefficient (tau about 0.68) between regional perfusion values at control and after bleeding which indicates a stable perfusion pattern within the myocardium. We conclude that the regional distribution of coronary blood flow within the left ventricle is markedly heterogenous during control condition and that this pattern is not changed during haemorrhagic hypotension.

Uneven perfusion within single cat muscles: nitric oxide and citrate synthase play no role.

There is an unexplained, marked regional heterogeneity in perfusion within single skeletal muscles both in dogs and rabbits. We asked if a similar distribution of perfusion was present within cat muscles. If present, we wanted to assess the possible roles of nitric oxide (NO) mediated vasodilation and citrate synthase (CS) activity for the regulation of this perfusion pattern. Perfusion was determined in 0.25 g regions within the gastrocnemius muscles by trapping of microspheres. We studied awake or anesthetized cats before and during inhibition of NO-formation using N-monomethyl-L-arginine. The CS activity was determined in homogenates of these regions. The coefficient of variation corrected for the Poisson distribution of microspheres (CVc) for the regional perfusion averaged 0.39. Despite a 25% reduction in perfusion to the whole muscles as compared to control, the uneven distribution of perfusion was not affected by blocking NO formation. Regional perfusion was not correlated to regional CS activity. Even if the regional distribution of CS activity also showed a scatter, mean coefficient of variation corrected for methodological error = 0.20, it was markedly less than that for perfusion. We conclude that neither NO vasodilation nor CS activity play an important role in the regulation of the regional perfusion pattern within single cat muscles.