For every thing (turn...turn...turn....)
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Humans↗
Biomedical subjects
R K Albert
Publications and source records attributed to R K Albert.
Influence of the route of allergen administration and genetic background on the murine allergic pulmonary response.
We used various ovalbumin sensitization and challenge protocols to determine the importance of the route of allergen administration and the genetic background in modulating the physiologic, inflammatory, and immunologic features characteristic of allergen-induced asthma. In BALB/c mice, induction of maximal airway hyperresponsiveness and airspace eosinophilia required administration of ovalbumin by both the intraperitoneal and the intranasal routes (combination protocol), whereas intraperitoneal immunization alone resulted in maximal ovalbumin-specific IgE plasma levels. Thus, a systemic immune response to allergen, in addition to, or independent of IgE production, as well as local allergen challenge were necessary for maximal induction of pulmonary disease. BALB/c mice treated with ovalbumin by the combination protocol had increased Th2-type cytokine mRNA levels in bronchial lymph node tissue compared with control mice. In contrast, C57BL/6 mice treated with ovalbumin by the combination protocol had significantly decreased responses compared with BALB/c mice for all parameters of allergic pulmonary disease examined, with the exception of airspace eosinophilia. Genetic background has a striking and selective effect on the phenotype of murine allergic pulmonary disease. Further analysis of this murine model should be useful in helping define the critical pathogenetic events in allergen-induced asthma.
Administration, Intranasal↗
Is pulmonary rehabilitation an effective treatment for chronic obstructive pulmonary disease? No.
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Exercise Therapy↗
Lung volume reduction surgery improves maximal O2 consumption, maximal minute ventilation, O2 pulse, and dead space-to-tidal volume ratio during leg cycle ergometry.
Early experience suggests that lung volume reduction surgery improves exercise tolerance as measured by the 6-min walk distance in patients with emphysema. To identify the physiologic mechanism(s) by which lung volume reduction surgery improved exercise, we performed progressive cardiopulmonary exercise testing, including rest and peak exercise blood gas determinations, on 21 consecutive patients before and 3 mo after lung volume reduction surgery. Maximal work (median, range, % change) increased 17.5 watts (-13 to +44 watts, 46%, p < 0.05), maximal oxygen consumption increased 0.16 L/min (-0.17 to +0.48, 25%, p < 0.05), maximal ventilation increased 6.6 L/min (-7 to +26 L/min, 27%, p < 0.05), and the dead space/tidal volume ratio at peak exercise decreased 0.07 (-0.22 to +0.09, 12%, p < 0.05), exclusively as a result of an increase in the tidal volume. After lung volume reduction surgery heart rate decreased at the point of isowatt exercise, from 115 to 111 beats/min (p < 0.05). No difference was observed in the other physiologic variables measured at isowatt exercise. In 13 patients exercised while breathing room air, the alveolar-to-arterial O2 difference increased, and the arterial O2 tension decreased from rest to peak exercise both before and after the operation, but significant changes in this response were not observed after surgery. The primary problem limiting exercise performance in these patients was the limited ventilatory capacity as 16 and 13 of the 21 subjects developed acute respiratory acidemia at peak exercise before and after surgery, respectively. Lung volume reduction surgery in patients with severe emphysema improved maximal ventilation, thereby improving maximal exercise performance.
Exercise Test↗
The importance of leukotrienes in airway inflammation in a mouse model of asthma.
Inhalation of antigen in immunized mice induces an infiltration of eosinophils into the airways and increased bronchial hyperreactivity as are observed in human asthma. We employed a model of late-phase allergic pulmonary inflammation in mice to address the role of leukotrienes (LT) in mediating airway eosinophilia and hyperreactivity to methacholine. Allergen intranasal challenge in OVA-sensitized mice induced LTB4 and LTC4 release into the airspace, widespread mucus occlusion of the airways, leukocytic infiltration of the airway tissue and broncho-alveolar lavage fluid that was predominantly eosinophils, and bronchial hyperreactivity to methacholine. Specific inhibitors of 5-lipoxygenase and 5-lipoxygenase-activating protein (FLAP) blocked airway mucus release and infiltration by eosinophils indicating a key role for leukotrienes in these features of allergic pulmonary inflammation. The role of leukotrienes or eosinophils in mediating airway hyperresponsiveness to aeroallergen could not be established, however, in this murine model.
5-Lipoxygenase-Activating Proteins↗
Airway hyperreactivity is associated with specific leukocyte subset infiltration in a mouse model of allergic airway inflammation.
Airway hyperreactivity is defined as an increased bronchoconstrictor response to physical, pharmacological, or other stimuli. Patients with asthma develop airway hyperreactivity as well as peribronchial inflammation. We employed an established schistosome soluble egg antigen (SEA)-induced murine model of allergic inflammation to examine the temporal relationship between airway hyperreactivity and leukocyte subset infiltration. Dose response curves of intravenous methacholine were used in mice to characterize airway reactivity at various time points after intranasal SEA rechallenge. Cellular infiltration into the airspace was assessed by bronchoalveolar lavage. Airway hyperreactivity increased as early as 1 h postchallenge. Peak hyperreactivity occurred at 8 h postchallenge. Subsequently, reactivity decreased at 24 h and fell to the level observed in controls by 48 h. Neutrophil influx correlated directly with the increase in airway reactivity, as neutrophils were observed as early as 1 h, peaked at 8 h, diminished by 24 h and were not detected at 48 h post-SEA challenge. In contrast, eosinophil infiltration was not observed until 24 h and peaked at 48 h post-SEA rechallenge when increases in airway reactivity were not detected. Airway resistance induced by methacholine correlated with neutrophil (r2 = 0.90) but not eosinophil (r2 = 0.1) infiltration. These results suggest that the airway hyperreactivity observed during allergic airway inflammation correlates with airways neutrophilia and weakly eosinophil accumulation.
Animals↗
Clinical experimentation. Lessons from lung volume reduction surgery.
Although the advancement of medical science can occur only with the systematic evaluation of new interventions, novel therapies continue to be introduced and accepted prior to thorough study. The recent development of lung volume reduction surgery for emphysema provides an illustration of the unwillingness or the inability of the medical community, unconstrained by legal or reimbursement limitations, to assure the safety and efficacy of a new procedure prior to widespread utilization. Medical practitioners must learn to recognize the experimental nature of new procedures independent of the courts and third-party payers. The nature of the informed consent that must be obtained for an experimental therapy is different from that which is required for standard medical practice and this difference can provide a test of whether a new treatment is experimental. A comparison between the introduction of lung volume reduction surgery and the rigorous scrutiny required of any pharmacologic interventions for emphysema underscores the double standard that exists for evaluating new surgical (and some medical) innovations. Such a double standard cannot be defended on ethical or scientific grounds. Specific changes in the way experimental therapies are introduced and disseminated are suggested. Until all new medical and surgical interventions are required to undergo a thorough evaluation prior to becoming standard of case, the promise of evidence-based medicine can never be fulfilled.
Ethics, Medical↗
Economic aspects of lung volume reduction surgery.
OBJECTIVE: To investigate the economics of lung volume reduction surgery. DESIGN: Medical center and physician charges obtained from billing records. SETTING: Academic health center. PATIENTS: Twenty-three consecutive patients undergoing lung volume reduction surgery at a single institution who were discharged from the hospital prior to November 1, 1995. OUTCOME MEASURES: Length of hospital stay, mortality, medical center charges and professional fees, and sponsor reimbursement. RESULTS: Median hospital stay was 8.0 days and there were no deaths. The median charge was $26,669 (range, $20,032 to $75,561) of which 73% was for medical center services and 27% was for physician services. Fees for medical center rooms and operating suite time accounted for 71% of medical center charges. Charges by surgeons and anesthesiologists accounted for 77% of professional fees. Total charges were directly related to length of stay (r2 = 0.95). Median reimbursement for medical center services was $22,264 (114%; range, $13,333 to $123,362) and for physician services was $2,783 (34%; range, $2,597 to $11,265), resulting in a median total reimbursement that represented 94% of total charges. The median reimbursement-to-cost ratio was 1.22, compared with 1.05 for all medical services in fiscal year 1995. CONCLUSIONS: These data must now be assessed relative to outcomes such as quality of life, patient function, and long-term survival to determine cost-effectiveness of lung volume reduction surgery.
Cost Savings↗
Efficacy of a 6-week prophylactic ganciclovir regimen and the role of serial cytomegalovirus antibody testing in lung transplant recipients.
CMV is a frequently occurring pathogen in recipients of solid organ transplants, and those receiving lung transplants seem to be affected more frequently and more severely. Because the duration of prophylactic ganciclovir may influence the incidence of CMV disease in solid organ transplant recipients, we evaluated the efficacy of a 6-week prophylactic regimen in lung transplant recipients. We also evaluated the ability of a fourfold rise in CMV antibody titer to predict the development of CMV disease. Twenty-one consecutive lung transplant recipients were enrolled: 15 were CMV antibody-positive at the time of transplantation, and six were CMV antibody-negative and received a lung transplant from CMV-positive donors. Mean +/- SD follow-up was 430 +/- 157 days (range 178-730 days, median 449 days). The 6-week ganciclovir regimen prevented neither CMV infection (which occurred in 17/21 patients, 81%) nor CMV disease (seen in 8/21 patients, 38%). A fourfold rise in CMV antibody titer only preceded the onset of CMV disease in 3/13 instances (23%). We conclude that a 6-week regimen of ganciclovir prophylaxis does not prevent CMV infection or disease in lung transplant recipients and that a rise in serially obtained CMV antibody titers rarely precedes the development of CMV disease.
Antibodies, Viral↗
Mechanisms of the adult respiratory distress syndrome: selectins.
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Adult↗
Flow pulsatility does not increase mean microvascular pressure or filtration in zone 3 rabbit lungs.
We previously reported that mean pulmonary arterial pressure (Ppa) during pulsatile flow exceeded that for steady flow when flow was greater than the normal resting value and speculated that this was due to irregularities of the flow profiles in precapillary vessels, mainly the larger arteries. From this we hypothesized that neither mean microvascular pressure nor the rate of fluid filtration would be affected by flow pulsatility. We therefore compared the effects of steady vs. pulsatile flow on the double-occlusion pressure (Pdo) and on edema formation (rate of weight gain) in zone 3 rabbit lungs. Excised left lungs (n = 19) were perfused with Tyrode solution and ventilated with an end-expiratory pressure of 2.5 cmH2O. A diaphragm pump generated pulsatile flow with a stroke volume of 1.0 ml (approximately 0.8 the normal resting value for rabbit left lung). Nonpulsatile flow was generated by raising an arterial reservoir. Flow rate was set at 100 or 400 ml/min (approximately 0.4 or 1.6 x the normal resting cardiac output, respectively). Vascular pressures (referenced to the bottom of the lung) were measured after ventilation, at end expiration, was interrupted. Pdo values were obtained in random order at 15 time points that were evenly distributed within the pulse cycle, averaged across pulses to obtain the mean capillary pressure profile, and then averaged over time. At the lower flow of 100 ml/min, mean Ppa and Pdo were slightly lower (3-4%) during pulsatile compared with nonpulsatile conditions. At the higher flow of 400 ml/min, mean Ppa was higher under pulsatile conditions (13%), whereas downstream the mean Pdo values were equal.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Perfusion through vessels open in zone 1 contributes to gas exchange in rabbit lungs in situ.
We previously found that up to 15% of the normal cardiac output can flow through lungs that are entirely in zone 1 and that the zone 1 pathway utilizes alveolar corner vessels. Because of the proximity of these vessels to alveoli, we hypothesized that lungs perfused under zone 1 conditions would exchange gas. We used the multiple inert gas elimination technique to assess the ventilation-perfusion (VA/Q) distribution under zones 1 and 2 in six rabbit lungs perfused with tris(hydroxymethyl)aminomethane-buffered Tyrode solution containing 1% albumin, 4% dextran, and papaverine (25 mg/l). High-frequency oscillation (tidal volume = 2.8 ml at 20 Hz, bias flow = 1 l/min) kept alveolar pressure (PA) nearly constant at 10 or 20 cmH2O. Pulmonary arterial pressure was set 2.5 cmH2O below or 5 cmH2O above PA (zones 1 and 2, respectively). Pulmonary venous pressure was kept at 0 cmH2O, with zero reference being the bottom of the lung. At PA of 10 cmH2O, flow was 64 +/- 40 and 5 +/- 3 ml/min (P < 0.05) and the mean VA/Q for perfusion was 1.1 +/- 0.4 and > 5 (P < 0.05) in zones 2 and 1, respectively. At PA of 20 cmH2O, flow was 89 +/- 36 and 22 +/- 13 ml/min (P < 0.05) and the mean VA/Q for perfusion was 0.8 +/- 0.3 and 3.7 +/- 2.4 (P < 0.05) in zones 2 and 1, respectively. Shunt averaged < 5% of total flow in all conditions. Blood flowing through vessels remaining open under zone 1 conditions 1) exchanges gas, 2) does not occur through anatomic or physiological shunts, and 3) may explain the high VA/Q seen with positive end-expiratory pressure.
Albumins↗
Lung reduction surgery. Great expectations and a cautionary note.
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Humans↗
The cost-effectiveness of lung transplantation. A pilot study. University of Washington Medical Center Lung Transplant Study Group.
OBJECTIVE: Lung transplantation is one of the fastest-growing solid organ transplant procedures in the world, yet its cost-effectiveness is unknown. We compared the costs and outcomes of the first 25 patients who received lung transplants at the University of Washington with 24 patients currently on the lung transplant waiting list. DESIGN: Inpatient and outpatient charges were obtained from the hospital billing service and home health agencies. Quality-adjusted life year scores (QALYs) were computed from the following: (1) utility scores obtained through standard gamble interviews, and (2) published survival data from an international lung transplant registry and from studies of patients on lung transplant waiting lists. RESULTS: Transplantation charges averaged $164,989 (median, $152,071). Average monthly charges posttransplant were $11,917 in year 1 and $4,525 thereafter, vs $3,395 for waiting-list patients. Posttransplant utility scores were significantly higher than waiting-list scores (0.80 vs 0.68; p < 0.001). Life expectancy was not greater for lung transplant vs waiting-list patients (5.89 vs 5.32 years; p > 0.05), although quality-adjusted life expectancy did improve significantly. After converting charges to costs, the incremental cost per QALY gained for posttransplant compared with waiting-list patients was $176,817. CONCLUSIONS: Lung transplantation is very expensive, although it can substantially improve quality of life. Two-thirds of care costs are incurred after transplantation. The principal barriers to cost-effectiveness at present are the high cost of postrecovery care and marginal gains in life expectancy compared with conservative care.
Adult↗
Sequelae of the adult respiratory distress syndrome.
Most survivors of ARDS have persistent mild reductions of TLCO even as long as a year after their episode. The lung volumes and flows return to normal in most instances, although a subset of patients will have persistent impairment. Both obstructive and restrictive deficits may be seen. This group may be predicted by the degree of acute lung injury assessed by the level of FIO2, PEEP, and gas exchange abnormality that exists in the first few days. In the first year after ARDS most physiological abnormalities will improve, but if deficits persist at one year further improvement is unlikely. Although many patients report dyspnoea following ARDS, the symptom does not correlate with abnormalities of pulmonary function. The possibility that conventional management may augment the degree of acute injury and worsen outcome must be considered. The effects of chronic hyperoxia in humans with acute lung injury or those of high levels of PEEP compared with low levels are not known. Exploring new ventilator management strategies while we await more specific treatment directed at the primary problem of acute lung inflammation will hopefully reduce acute mortality as well as acute and chronic morbidity.
Forced Expiratory Volume↗
Pulsatile and nonpulsatile pressure-flow relationships in zone 3 excised rabbit lungs.
We compared the effects of pulsatile vs. nonpulsatile flow (Q) on pulmonary arterial pressure (Ppa)-Q relationships in zone 3 over wide ranges of pulse rate, stroke volume (SV), and Q. Excised left lungs of rabbits (n = 15) were perfused with tris(hydroxymethyl)aminomethane-buffered Tyrode solution containing 4% dextran, 1% albumin, and 10 mg/l of indomethacin and were ventilated with room air. Pulsatile Q was generated by a diaphragm pump delivering SV of 0.5, 1, or 2 ml (representing approximately 0.3, 0.6, and 1.2 times, respectively, the normal resting SV for rabbit left lung) and adjusting the pump frequency. Nonpulsatile Q was generated by raising an arterial reservoir to the required height. Mean pulmonary arterial (Ppa) and left atrial pressures were measured at end exhalation (positive end-expiratory pressure = 2.5 cmH2O) near the tips of the perfusion cannulas and were referenced to the lung base. Left atrial pressure was held constant at 7 cmH2O.Q was alternated between pulsatile and nonpulsatile, increasing Q stepwise from 100 to 600 ml/min (Q from approximately 0.3 to 2 times the normal resting Q for rabbit left lung), after which Q was reduced stepwise back to initial values. For the smallest SV there were no differences between Ppa-Q curves under pulsatile and nonpulsatile conditions. At the largest SV, Ppa was greater during pulsatile than nonpulsatile Q at Q > 100 ml/min. The slopes of the Ppa-Q curves were greater during pulsatile Q at the two larger SV values. These results can be explained by increasing Q turbulence and less ideal velocity profiles at higher peak Q resulting from the effects of rapidly changing inertial forces.
Animals↗
Mechanism by which the prone position improves oxygenation in acute lung injury.
The mechanism by which oxygenation improves when patients with ARDS are turned from supine to prone position is not known. From results of our previous studies we reasoned that (1) when supine, in the setting of lung injury, transpulmonary pressure will be less than airway opening pressure and (2) atelectasis will develop preferentially in dorsal lung areas, and (3) both ventilation and ventilation/perfusion ratios would improve in these regions on turning prone. To study this directly, we measured regional ventilation and perfusion using 81mKr and 99mTc-MAA, respectively, and single photon emission computed tomography, both prone and supine, in four control animals and four given oleic acid. After oleic acid, the prone position improved (1) oxygenation (mean +/- SD PaO2 = 140 +/- 112 versus 453 +/- 54 mm Hg), (2) median ventilation/perfusion ratios (0.77 versus 0.95), (3) ventilation/perfusion heterogeneity (coefficient of variation 86 +/- 15 versus 61 +/- 6), and (4) the gravitational ventilation/perfusion gradient (dependent to non-dependent slopes of 0.22 versus -0.02, all p < 0.05). The prone position generates a transpulmonary pressure sufficient to exceed airway opening pressure in dorsal lung regions, i.e., in regions where atelectasis, shunt, and ventilation/perfusion heterogeneity are most severe, without adversely affecting ventral lung regions.
Animals↗