Validation of Doppler FloWire for measurement of coronary flow reserve in humans

Previous studies have validated the ¹³³Xenon (¹³³Xe) method to assess regional myocardial blood flow and coronary flow reserve (CFR). Doppler FloWire (DFW) has been used recently for measuring CFR to assess the physiological significance of coronary stenosis. Data obtained by DFW has never been correlated to ¹³³Xe. Our study compared data from DFW measurement of CFR to that obtained by ¹³³Xe in 31 consecutive patients with variable coronary stenosis. Regional myocardial blood flow was measured by assessing the rate constants of ¹³³Xe washout using multicrystal gamma camera after injection (20 millicuries) in the right or left coronary artery. CFR was assessed by measuring resting and hyperemic coronary blood flow by ¹³³Xe and DFW using IV adenosine (140 mcg/k/min × 3 min). CFR was also measured by DFW giving intracoronary (IC) adenosine (12 μg in the right coronary, 18 μg in the left). In both methods—¹³³Xe and DFW—coronary flow reserve was defined as the ratio of maximal hyperemic-to-baseline flow. DFW and ¹³³Xe assessment of CFR correlated highly, whether adenosine was used IC(r = 0.87; P = 0.0001) or IV(r = 0.78; P = 0.0001). CFR obtained by DFW following IC and IV adenosine correlated well (r = 0.79; P = 0.0001). IC adenosine has fewer side effects. Both DFW and ¹³³Xe are comparable in measuring CFR in humans. Cathet. Cardiovasc. Diagn. 45:382–385, 1998. © 1998 Wiley-Liss, Inc.     

Der Nachweis des Verschlusses kleiner Luftwege mit Hilfe einer modifizierten133Xenon-Bolustechnik

A modified bolus technique for the measurement of “closing volume” is described; it involves the use of¹³³Xe as tracer, a pneumotachograph in an open system for control of flow and volume, and a gamma camera for direct registration of the radioactivity over the lung. The results obtained in a group of 11 normal subjects are in good agreement with the predicted values obtained with the original¹³³Xe bolus technique. The disadvantages of the method described are the expensive apparatus and the rather large amounts of radioactivity needed. The advantages are: easy handling of the open system, no dead-space effect compared to methods in which the tracer gas is recorded at the mouth, and regional location of airway closure.     

Interactions of regional respiratory mechanics and pulmonary ventilatory impairment in pulmonary emphysema: assessment with dynamic MRI and xenon-133 single-photon emission CT

STUDY OBJECTIVES: Dynamic MRI and (133)Xe single-photon emission CT (SPECT) were used to directly evaluate the interaction of regional respiratory mechanics and lung ventilatory function in pulmonary emphysema. METHODS: Respiratory diaphragmatic and chest wall (D/CW) motions were analyzed by sequential MRI of fast-gradient echo pulse sequences during two to three respiratory cycles in 28 patients with pulmonary emphysema, including 9 patients undergoing lung volume reduction surgery (LVRS). The extent of air trapping in the regional lung was quantified by the (133)Xe retention index (RI) on three-dimensional (133)Xe SPECT displays. RESULTS: By contrast to healthy subjects (n = 6) with regular, synchronous D/CW motions, pulmonary emphysema patients showed reduced, irregular, or asynchronous motions in the hemithorax or location with greater (133)Xe retention, with significant decreases in the maximal amplitude of D/CW motions (MADM and MACWM; p < 0.0001 and p < 0.05, respectively). The removal of (133)Xe retention sites by LVRS effectively and regionally improved D/CW motions in nine patients, with significant increases in MADM and MACWM (p < 0.01 and p < 0.001, respectively). In a total of 40 studies of the 28 patients including post-LVRS studies, normalized MADM and MACWM correlated with percent predicted FEV(1) (r = 0.881, p < 0.0001; and r = 0.906, p < 0.0001, respectively), and also with (133)Xe RI in each hemithorax (r = -0.871, p < 0 0.0001; and r = -0.901, p < 0 0.0001, respectively.) CONCLUSIONS: This direct comparison of regional respiratory mechanics with lung ventilation demonstrated a close interaction between these impairments in pulmonary emphysema. The present techniques provide additional sensitivity for evaluating pathophysiologic compromises in pulmonary emphysema, and may also be useful for selecting resection targets for LVRS and for monitoring the effects.     

Regional pulmonary function in patients with mitral stenosis in relation to haemodynamic data

Central haemodynamics in 23 patients with mitral stenosis and 7 control subjects were compared with the results of regional lung perfusion studied by (133)Xe, pulmonary scintigraphy with (99)mTc-labelled macro-aggregates of albumin, and regional ventilation by (133)Xe.A close correlation was found between both methods assessing regional pulmonary perfusion, i.e. pulmonary scintigraphy and (133)Xe.The results show that lower lung zones, when compared with upper zones, have both worse perfusion and worse ventilation.The changed distribution of perfusion and the changed distribution of ventilation correlated significantly with central haemodynamics in these patients. The ventilation gradient can be a valuable diagnostic tool for evaluating the severity of mitral stenosis, especially in long and repeated studies, due to its simplicity for the patient.     

Intrapulmonary distribution of 99mtechnetium labelled ultrafine carbon aerosol (Technegas) in severe airflow obstruction

Technegas (TG), an ultrafine dispersion of carbon aggregates labelled with 99mTechnetium (99mTc), has been recently introduced for clinical imaging of lung ventilation. In 12 selected subjects with severe chronic airflow limitation (FEV1 = 0.89 +/- 0.22; mean +/- SD, l) we have studied the regional intrapulmonary distribution of TG and compared it quantitatively with that of 133Xenon (133Xe). A 133Xe equilibration image was acquired for 10-15 s during a breathhold at total lung capacity (TLC). Six subjects (Group 1) inspired 100 ml boli of TG or 133Xe from functional residual capacity (FRC) and another 6 subjects (Group 2) inspired 1.0 l of labelled gas from FRC followed by air to TLC at a constant flow rate less than 0.5 l.s-1. Lung images were then acquired with the chest position rigorously controlled. From the equilibration image, upper, middle, lower, central and peripheral regions were defined. Relative regional fractional concentrations (RFC) were then calculated using the equilibration image to correct for ventilated lung volume. In addition, in four of the Group 2 subjects, each lung image was divided into multiple regions (12-17 per lung). The RFC were then calculated as above (RFCM). The highest and lowest RFC were not significantly different between 133Xe and TG in either Group 1 or Group 2 subjects. Similarly the RFCM analysis showed no systematic difference between 133Xe and TG. The ratio of peripheral to central RFC constitutes a penetration index which for TG was 0.99 +/- 0.23 that of 133Xe. Our results indicate that even in the presence of severe airflow limitation the radiolabelled tracer TG mimics the regional distribution of a real gas.     

Pulmonary function with acute loss of excess lung water by hemodialysis in patients with chronic uremia

We studied lung function in six patients with advanced renal failure who were on a chronic hemodialysis program. With the patients in the seated position, both before and after hemodialysis, we measured lung volumes, maximal mid-expiratory flow rates (MMFR) and alveolar arterial oxygen differences (A-a DO₂). Using xenon 133 (¹³³Xe) we also studied regional lung function and the volume at which “airway closure” began (“closing capacity”). Before dialysis a restrictive pattern was observed, with normal MMFR and reduced lung volumes. With removal of body fluid the residual volume decreased further with a concomitant increase in vital capacity and in MMFR. Before dialysis the majority of patients had an increased residual volume in basal lung regions which decreased after dialysis. In five of six patients the “closing capacities” decreased with dialysis. These results reflected reversible premature airway closure and gas trapping at the lung bases perhaps due to accumulation of edema around small airways.In addition, most of the patients had decreased ventilation and perfusion at the lung bases which improved with dialysis. Little change occurred, however, in the A-a DO₂ with dialysis.     

High-frequency oscillatory ventilation may increase airway closure

In five seated, normal subjects, we measured closing volumes using 133Xe boluses inhaled at residual volume. High frequency oscillatory ventilation (HFOV) (15 Hz, 2 cc/kg) was applied during either inspiration to total lung capacity or the subsequent expiration. Closing volume was increased (P less than 0.001) when HFOV was applied during the latter half of expiration, but not when HFOV was applied during inspiration or the first half of expiration. Subsequently, in seven subjects, we measured the regional distributions of 133Xe boluses delivered during open-glottis breath-hold at 14% vital capacity after equilibration with N2O. HFOV was applied during bolus delivery for about 16 sec. These distributions were compared with those achieved by intravenous injections of 133Xe in saline. Regional perfusion (injected isotope) exceeded regional N2O uptake at the lung bases and this was significantly accentuated by HFOV, compatible with increased basal closure. We conclude that in normal subjects at low lung volumes, HFOV may enhance airway closure, though other explanations are possible.     

Changes in blood flow and permeability of vessels to protein preceding the development of cutaneous ulcers in the hind limb of the rabbit

The effect of sciatic nerve transection on the cutaneous and muscle nutritive blood flow in the hind limb of rabbits was studied. Vessel permeability to albumin was measured with ¹²⁵I-labeled human serum albumin periodically during the 2 weeks after transection. Cutaneous blood flow was measured with the ¹³³Xe washout technique. Two days after transection a decrease of blood flow was observed. The maximum drop in the blood flow occurred on the seventh day. A sharp increase in permeability to albumin was observed in the denervated leg starting on the fourth day after transection. Microscopic examination shows that peripheral nerve injury is responsible for structure disorders corresponding to the decrease of cutaneous blood flow and increase in the permeability to albumin.     

Reversible ventilation and perfusion abnormalities in unilateral obstructed lung

An intraluminal carcinoid tumor obstructing the left mainstem bronchus produced hypoxemia through alteration in ventilation/perfusion matching. Studies of regional lung function using 133-xenon (133Xe) and a multiprobe computerized instrumentation system documented a reduction of perfusion to 22 percent and ventilation to 6 percent of the total. There was negligible washout of intravenously injected 133Xe from the left lung consistent with air trapping. Four days after left mainstem bronchial sleeve resection, perfusion, ventilation and washout of injected xenon had significantly improved and by four months postresection, all measurements were virtually normal, although complete restoration of perfusion in relation to ventilation was delayed. Regional lung function studied with a multiprobe system in this patient provided a clinical model for the study of ventilation and perfusion inter-relationships in large airway obstruction and demonstrated that a prolonged time may be required for return of perfusion to normal.     

The effect of vagal stimulation on the distribution of inspired gas in the lungs.

We investigated the direct effects of efferent vagal activity on the distribution of inspired gas by stimulating the vagus nerve of one lung and measuring the topographic distribution of a radioactive tracer (133Xe) to both lungs. The distribution of inspired (133Xe) boli was measured with NaI scintillation detectors placed apex-base over each posterior lung of intubated, paralyzed, anesthetized dogs. In 7 supine dogs vagal stimulation reduced the distribution of rapidly insufflated 133Xe boli (flow greater than 2.5 L/s) to the test lung (P less than 0.02), but not when boli were insufflated slowly (flow less than 0.5 L/s), suggesting that vagal stimulation affects pulmonary gas distribution primarily by increasing airway resistance and not through changes in lung compliance. The effect of vagal stimulation on the regional apex-base distribution of inspired gas (greater than 2.5 L/s) was measured in 7 supine and 5 upright dogs. In the supine position, vagal stimulation did not change the uniform apex-base bolus distribution, whereas in the upright position less of the bolus was distributed to the middle and lower lung regions (P less than 0.043), compared to control measurements. This indicates that the regional effects of vagal stimulation on the distribution of inspired gas are uniform in the supine position, but that vagal stimulation alters the distribution of inspired gas when the apex-base pleural pressure gradient is increased.     

Topographical ventilation and perfusion distribution during IPPB in the lateral posture.

We measured topographical ventilation and perfusion distribution in the gravity field using 133Xe in 5 normal subjects either during natural breathing or during intermittent positive pressure ventilation (IPPB) in the lateral decubitus posture. The ratio of ventilation of upper regions to that of lower regions increased from 0.61 +/- 0.10 (mean +/- SE) during natural breathing to 0.95 +/- 0.08 during IPPB. In contrast, the ratio of regional perfusion was unchanged in the 2 conditions. Consequently, distribution of regional ventilation-perfusion ratios became less homogeneous during IPPB. Whereas during natural breathing the ratio of ventilation-perfusion of upper regions to that of lower regions was 1.09 +/- 0.18, during IPPB this ratio was 1.52 +/- 0.14. Despite the differences in regional ventilation distribution between natural breathing and IPPB, analysis of multiple-breath 133Xe washouts measured at the mouth did not reveal any difference. The results are consistent with the hypothesis that the magnitude of diaphragmatic tension is the main determinant of topographical ventilation distribution in the lateral posture.     

Impaired autoregulation of blood flow in skeletal muscle and subcutaneous tissue in long-term type 1 (insulin-dependent) diabetic patients with microangiopathy

Summary Autoregulation of blood flow was studied in skeletal muscle and subcutaneous tissue in seven Type 1 (insulindependent) diabetic patients (median age: 36 years) with nephropathy and retinopathy and in eight normal subjects of the same age. Blood flow was measured by the local ¹³³Xe washout technique. Reduction in arterial perfusion pressure was produced by elevating the limb 20 and 40 cm above heart level. Blood flow remained within 10% of control values when the limb was elevated in normal subjects. In five of the seven diabetic subjects blood flow fell significantly in both tissues when the limb was elevated 40 cm indicating impaired autoregulation. The results suggest that intrinsic vascular (arteriolar) mechanisms (myogenic and/or metabolic) underlying the normal autoregulatory response are defective in some diabetic patients with microangiopathy.     

Early changes in capillary flow and transport following missile wounds

The local hemodynamic response to missile wounds in soft tissue has been studied on 31 mongrel dogs with a double isotope clearance technique using sodium iodide (Na¹³¹I) and xenon (¹³³Xe). Three different impact velocities with a small spherical projectile were used to vary the amount of energy absorbed by the tissues. The isotope was injected at a constant depth but at varying distances from the wound site. The flow responses (i.e., xenon clearance) were quite variable, but there was a tendency toward greater responses between 35 and 45 mm from the wound channel after high-velocity missile wounds. The same tendency was seen more clearly for iodide clearance values. The size of the damage by missiles hitting with the three velocities used is discussed. Because of irregularities in the volume of tissue absorbing the energy, variations in individual animals could be expected. However, the flow pattern recorded with the isotope clearance technique coincides in both time and localization with the hemodynamic and angiographic findings after wounds caused in a similar way and reported previously.     

Effect of perfusion pressure and hematocrit on capillary flow and transport in hyperemic skeletal muscle of the dog

The local tissue clearances of two radioactive tracers with different transport characteristics, one lipid soluble and highly diffusible ¹³³Xe and one water-soluble presumably extracellular ¹³¹Iodide, have been compared in vasodilated skeletal muscle of the dog at different flows and perfusion pressures. The transport of iodide was diffusion-limited except perhaps at the lowest flow values. The capillary diffusion capacity or permeability-surface area product PS of iodide was flow-dependent and thus decreased considerably at flow values below 10–15 ml/min/100 g and perfusion pressures below 40–50 mm Hg. This behavior is interpreted as due to greater non-homogeneous distribution of flow through an open capillary bed at lowered pressures and flows. It is independent of the mode of vasodilation either of the whole muscle (ischemic work) or locally (papaverine in the injectate), and also independent of hematocrit and changes in transmural pressure.     

Participation of the arterial and portal drainage in the calculation of total hepatic blood flow in guinea pigs

Experiments were performed on partly isolated livers of guinea pigs. The hepatic outflow (HOF) was measured by an electromagnetic flowmeter placed on the inferior vena cava. Nutritive hepatic blood flow (HBF) was measured with ¹³³Xe bolus technique with the tracer injected into the portal vein or hepatic artery. Under unchanged perfusion conditions, three exponents could be demonstrated irrespective of the site of injection. Two of them observed during the first 5 min represent the intrahepatic, the third (slowest one) the extrahepatic blood flow. Occlusion of either the portal vein or the hepatic artery results in a monoexponential decrease during the first 5 min. Calculation of the HBF was based on an equation including both components of the washout curves obtained after arterial and portal application. The calculated HBF was equal to the value of the directly measured total outflow but overestimated HBF_f calculated from the first exponent of the washout curve obtained after intraportal tracer application.     

Intra-bullous ventilation of giant bulla: does slow ventilation space on multi-breath nitrogen washout test mean that giant bulla is present?]

Intra-bullous ventilation and uneven ventilation in patients with giant bulla were studied by the multi-breath nitrogen washout and 133Xe washout tests. Fourteen patients underwent the nitrogen washout test before and after bullectomy; 2 of them also underwent the 133Xe washout test before surgery. After bullectomy, pulmonary nitrogen clearance delay and alveolar dilution rate (ADR) of slow ventilation space improved significantly (p less than 0.01) from 202.5% to 51.5%, and from 0.98 to 0.95, respectively. The dilution rate of 133Xe in the bullous region, based on the 133Xe clearance curve, showed the same values as the nitrogen washout test. Therefore, we considered that bullous ventilation could be estimated by the ADR of the nitrogen washout test and that uneven ventilation resulted from the ADR difference between the giant bulla and the nonbullous lung. When the nonbullous lung region was emphysematous, however, it was impossible to estimate the intra-bullous ventilation from the nitrogen washout test.     

CD133 allows elaborated discrimination and quantification of haematopoietic progenitor subsets in human haematopoietic stem cell transplants

The success of haematopoietic stem cell (HSC) transplantation largely depends on numbers of transplanted HSCs, which reside in the CD34⁺ populations of bone marrow (BM), peripheral blood stem cells (PBSC) and umbilical cord blood (UCB). More specifically HSCs reside in the CD38^low/? subpopulation, which cannot be objectively discriminated from mature CD34⁺ CD38⁺ progenitors. Thus, better marker combinations for the quantification of more primitive haematopoietic stem and progenitor cells in transplants are required. Recently, by combining CD34 and CD133 we could clearly distinguish CD133⁺ CD34⁺ multipotent and lympho‐myeloid from CD133^low CD34⁺ erythro‐myeloid progenitors in UCB samples. To qualify the assessment of CD133 for routine quality control of adult HSC sources, we analysed the developmental potentials of CD133⁺ and CD133^low subpopulations in BM and PBSC. Similar to UCB, CD133 expression objectively discriminated functionally distinct subpopulations in adult HSC sources. By implementing anti‐CD45RA staining, which separates multipotent (CD133⁺ CD34⁺ CD45RA^?) from lympho‐myeloid (CD133⁺ CD34⁺ CD45RA⁺) progenitor fractions, UCB was found to contain 2–3 times higher multipotent progenitor frequencies than BM and PBSC. To test for the consistency of CD133 expression, we compared CD133⁺ CD34⁺ contents of 128 UCB samples with maternal and obstetrical factors and obtained similar correlations to related studies focusing on CD34⁺ cell contents. In conclusion, implementation of anti‐CD133 staining into existing routine panels will improve the quality control analyses for HSC transplants.     

133Xe clearance estimates the effect of vasopressin on peritoneal blood flow in rats

BACKGROUND/AIMS: When assessing the peritoneal microcirculation with invasive methods, interference with the mechanisms of vaso-regulation may occur. The 133Xe clearance technique renders the possibility, by minimal invasiveness, to estimate the influence of a vasoactive agent on the peritoneal microcirculation. METHODOLOGY: Ten to 15MBq of 133Xe were injected in the abdominal cavity in thirty-eight Wistar-FU (W-FU) rats and 35 Lister-Hooded (LH) rats. A NaI (Tl)-scintillation detector registered activity before and during vasopressin infusion. Gamma camera imaging confirmed the washout from the abdominal cavity. The laser Doppler flowmetry technique was used as a comparison. RESULTS: Vasopressin at 0.07 IU/kg/min IV significantly reduced 133Xe-clearance by 37% (p = 0.029) and 52% (p=0.036) and laser Doppler flowmetry by 69% (p=0.0019) and 44% (p=0.0039) in W-FU and LH rats, respectively. A linear correlation between dose of vasopressin and relative decrease in 133Xe clearance was demonstrated in the W-FU rat model (r2=0.98, p=0.023). The 133Xe clearance from the abdominal cavity in rat using a single-compartment model or the slow compartment in a double-compartment model gave reproducible information. CONCLUSIONS: The usefulness of this mini-invasive technique for sequential measurements before and during intervention will render the 133Xe clearance suitable for assessment of blood flow changes in the abdominal cavity.     

Possibilities, limitations, and technique for the study of regional myocardial perfusion in man by Xenon-133.

The theoretical possibilities and the practical limitations of the Xenon-133 (133Xe) method for the study of regional myocardial perfusion in man are discussed. The techniques for data acqusition and processing developed over the past 5 years are described in detail. Illustrative examples of experimental findings are reported. The practical interpretation of the data, at the light of the influence of injection site, initial tracer distribution, constancy of counting geometry, spatial resolution, and Xenon retention in fat, is presented.     

In vivo magnetic resonance vascular imaging using laser-polarized 3He microbubbles

Laser-polarized gases (³He and ¹²⁹Xe) are currently being used in magnetic resonance imaging as strong signal sources that can be safely introduced into the lung. Recently, researchers have been investigating other tissues using ¹²⁹Xe. These studies use xenon dissolved in a carrier such as lipid vesicles or blood. Since helium is much less soluble than xenon in these materials, ³He has been used exclusively for imaging air spaces. However, considering that the signal of ³He is more than 10 times greater than that of ¹²⁹Xe for presently attainable polarization levels, this work has focused on generating a method to introduce ³He into the vascular system. We addressed the low solubility issue by producing suspensions of ³He microbubbles. Here, we provide the first vascular images obtained with laser-polarized ³He. The potential increase in signal and absence of background should allow this technique to produce high-resolution angiographic images. In addition, quantitative measurements of blood flow velocity and tissue perfusion will be feasible.