Preferential pulmonary retention of (S)-albuterol after inhalation of racemic albuterol.

The (R)-enantiomer of racemic albuterol produces bronchodilation, whereas the (S)-enantiomer may increase airway reactivity. After oral or intravenous administration of racemic albuterol, the (R)- enantiomer is metabolized several times faster than the (S)-enantiomer; however, enantiomer disposition after inhaling racemic albuterol with a metered-dose inhaler (MDI) is not known. Accordingly, 10 healthy subjects inhaled racemic albuterol with a MDI alone and with a MDI and holding chamber. We measured plasma levels of unchanged (R)- and (S)-albuterol before and up to 4 h after inhalation of racemic albuterol, and determined the unchanged R/S ratio in urine before and at 0.5, 4, 8, and 24 h later. The disposition of albuterol's enantiomers with a MDI and holding chamber was similar to that with a MDI alone. The area under the curve (AUC) of the plasma levels over time was significantly lower for the (S)- than for the (R)-enantiomer-395.5 +/- 141.0 (SE) versus 882.7 +/- 126.4 ng. ml(-)(1). min (p < 0.05)-indicating preferential retention of (S)-albuterol in the lung. The R/S ratio in urine at 0. 5 h after albuterol was > 1, reflecting the higher plasma level of the (R)-enantiomer. In conclusion, preferential retention of the (S)- compared with the (R)-enantiomer in the lung could lead to accumulation of the (S)-enantiomer after long-term use of racemic albuterol.

Reconciling in vitro and in vivo measurements of aerosol delivery from a metered-dose inhaler during mechanical ventilation and defining efficiency-enhancing factors.

We attempted to resolve the discrepancies in reported data on aerosol deposition from a chlorofluorocarbon (CFC)-propelled metered-dose inhaler (MDI) during mechanical ventilation, obtained by in vivo and in vitro methodologies. Albuterol delivery to the lower respiratory tract was decreased in a humidified versus a dry circuit (16.2 versus 30.4%, respectively; p < 0.01). In 10 mechanically ventilated patients, 4.8% of the nominal dose was exhaled. When the exhaled aerosol was subtracted from the in vitro delivery of 16.2% achieved in a humidified ventilator circuit, the resulting value (16.2 - 4.8 = 11.4%) was similar to in vivo estimates of aerosol deposition. Having reconciled in vitro with in vivo findings, we then evaluated factors influencing aerosol delivery. A lower inspiratory flow rate (40 versus 80 L/min; p < 0.001), a longer duty cycle (0.50 versus 0.25; p < 0.04), and a shorter interval between successive MDI actuations (15 versus 60 s; p < 0.02) increased aerosol delivery, whereas use of a hydrofluoroalkane (HFA)-propelled MDI decreased aerosol delivery compared with the CFC-propelled MDI. A MDI and actuator combination other than that designed by the manufacturer altered aerosol particle size and decreased drug delivery. In conclusion, aerosol delivery in an in vitro model accurately reflects in vivo delivery, providing a means for investigating methods to improve the efficiency of aerosol therapy during mechanical ventilation.

Partitioning of lung and chest-wall mechanics before and after lung-volume-reduction surgery.

In the study reported here, we partitioned the mechanics of the respiratory system into lung and chest-wall components, using the rapid occlusion technique in seven patients with severe emphysema before lung-volume-reduction surgery and 3 mo later. Patients showed improvements in 6-min walk (p < 0.01) and dyspnea (p < 0.05). The resistances of the respiratory system and chest wall were not altered by surgery. Ohmic airway resistance did not change, but the component of lung resistance (DeltaRL) due to viscoelastic behavior (stress relaxation) and time-constant inhomogeneities (pendelluft) decreased in six patients (p < 0.03). Dynamic elastance of the lung (Edyn,L) decreased after surgery (p < 0.02), whereas dynamic elastance of the chest wall did not change. The ratio of dynamic intrinsic positive end-expiratory pressure (PEEPi) to static PEEPi, which also reflects viscoelastic properties and time-constant inhomogeneities, increased after surgery (p < 0.05). The decrease in dyspnea was related to the decrease in Edyn,L (r = 0.81, p = 0.03), and tended to be related to the decrease in DeltaRL (r = 0.71, p = 0. 07). In conclusion, lung-volume-reduction surgery decreased dynamic pressure dissipations caused by stress relaxation and time-constant inhomogeneities within lung tissue, and it had no effect on the static mechanical properties of the chest wall.

Effect of lung volume reduction surgery on neuromechanical coupling of the diaphragm.

The mechanisms for symptomatic improvement following lung volume reduction surgery for emphysema are poorly understood. We hypothesized that enhanced neuromechanical coupling of the diaphragm is an important factor in this improvement. We studied seven patients with diffuse emphysema before and 3 mo after surgery. Patients showed improvements in 6-min walking distance (p = 0.002) and dyspnea (p = 0.04). The pressure output of the respiratory muscles, quantified as pressure-time product per minute (PTP/min), decreased after surgery (p = 0.03), as did PaCO2 (p = 0.02). Maximal transdiaphragmatic pressures (Pdi(max)) increased from 80.3 +/- 9.5 (SE) to 110.8 +/- 9.3 cm H2O after surgery (p = 0.03), and the twitch transdiaphragmatic pressure response to phrenic nerve stimulation (Pdi(tw)) increased from 17.2 +/- 2.4 to 25.9 +/- 3.0 cm H2O (p = 0.02); these increases were greater than could be accounted for by a decrease in lung volume. The contribution of the diaphragm to tidal breathing, assessed by relative changes in gastric and transdiaphragmatic pressures, increased after surgery (p = 0.008). Net diaphragmatic neuromechanical coupling, quantified as the quotient of tidal volume (normalized to total lung capacity) to tidal change in Pdi (normalized to Pdi(max)), improved after surgery (p = 0.03) and was related to the increase in 6-min walking distance (r = 0.86, p = 0.03) and decrease in dyspnea (r = 0.76, p = 0.08). In conclusion, lung volume reduction surgery effects an improvement in diaphragmatic function, greater than can be accounted for by a decrease in operating lung volume, and enhances diaphragmatic neuromechanical coupling.

Serum albuterol levels in mechanically ventilated patients and healthy subjects after metered-dose inhaler administration.

In mechanically ventilated patients, systemic blood levels of inhaled drugs reflect absorption from the lower respiratory tract alone since, unlike nonintubated patients, oropharyngeal and gastrointestinal absorption cannot occur. To determine the efficiency of aerosol administration by a metered-dose inhaler (MDI), we measured serum albuterol levels after administration by a MDI and spacer to nine mechanically ventilated patients (10 puffs) and to 10 healthy subjects (six puffs). Serum albuterol levels (+/- SEM) quantitated by high-performance liquid chromatography and electrochemical detection were: 0.09 +/- 0.04 mg/ml/puff at baseline, 0.66 +/- 0.10 at 5 min, 0.98 +/- 0.10 at 10 min, 0.56 +/- 0.08 at 15 min, and 0.37 +/- 0.03 at 30 min in mechanically ventilated patients versus zero at baseline, 0.89 +/- 0.12 at 5 min, 1.27 +/- 0.13 at 10 min, 0.84 +/- 0.09 at 15 min, and 0.53 +/- 0.07 at 30 min in control subjects (p > or = 0.07 at 5, 10, and 30 min; p < or = 0.05 at baseline and at 15 min). Area under the curve (AUC0-30) in the mechanically ventilated patients was 16.8 +/- 1.4 versus 23.4 +/- 1.9 ng/ml/puff x min in control subjects (p = 0.014). In summary, administration of albuterol with a MDI achieved a profile of serum levels in mechanically ventilated patients similar to that in healthy control subjects, but the peak serum level and systemic bioavailability (AUC0-30) were lower in the patients. In conclusion, serum levels reliably assess lower respiratory tract deposition of albuterol, and show that MDIs are more efficient for aerosol delivery in mechanically ventilated patients than was previously reported in studies using radiolabeled aerosols.

Dose-response to bronchodilator delivered by metered-dose inhaler in ventilator-supported patients.

In nonintubated patients, metered-dose inhalers (MDIs) are accepted as the most convenient, efficient, and cost effective method of administering inhaled bronchodilators. Recent studies have demonstrated the efficacy of MDIs in ventilator-supported patients; however, the optimal dose of a bronchodilator from a MDI is unknown. We determined the response to increasing doses of albuterol administered by a MDI and cylindrical spacer to 12 mechanically ventilated patients with chronic obstructive pulmonary disease (COPD). Four, eight, and 16 puffs of albuterol were given at 15-min intervals. Rapid airway occlusion were performed before and at 5-min intervals after albuterol for 80 min. Respiratory mechanics were also measured for 60 min in another group of seven patients with COPD who received four puffs of albuterol. Significant decrease in airways resistance occurred after administration of albuterol (p < 0.001). The decrease in airway resistance with four puffs of albuterol was comparable to that observed with cumulative doses of 12 puffs (p = 0.12) and 28 puffs (p = 0.25). Heart rate increased significantly (p < 0.01) after a cumulative dose of 28 puffs. The decrease in airway resistance was sustained for 60 min in the group that received only four puffs of albuterol (p < 0.003). In conclusion, four puffs of albuterol given by a MDI and spacer provided the best combination of bronchodilator effect and safety in stable mechanically ventilated patients with COPD.

The athlete with type I diabetes: managing insulin, diet and exercise.

The numerous benefits of exercise for patients with insulin-dependent (type I) diabetes mellitus include an increase in insulin sensitivity and a reduction of blood glucose levels. However, competitive athletes with type I diabetes must be careful when planning to exercise. The most common potential complications in these athletes include exercise-induced hypoglycemia or hyperglycemia and postexercise hypoglycemia due to increased insulin sensitivity. With proper modifications of insulin dose and diet, plus careful blood glucose monitoring, athletes with type I diabetes can exercise safely and regularly. To prevent hypoglycemia, the insulin dose may need to be reduced by 30 or 50 percent before exercise. Avoiding regular insulin at bedtime and reducing the evening insulin dose may help prevent nocturnal hypoglycemia after exercise. A tailored diet should reduce the chance of hypoglycemia.

Reduced transplant lung volumes after single lung transplantation for chronic obstructive pulmonary disease.

Single lung transplantation is now an extremely successful option for the treatment of end-stage chronic obstructive pulmonary disease (COPD). This procedure involves placing a normal sized lung in a hyperinflated hemithorax. Preliminary observations of these patients suggest that the transplanted lung volume is smaller than expected and often the native (COPD) lung increases in volume. The purpose of this investigation was to quantify the volume contributions of the transplant and native lung to the total lung capacity. In seven patients who underwent single lung transplant for end-stage COPD the transplant and native lung volumes were measured by computer-analyzed planimetry immediately after transplant and the following 6 mo post-transplant. The transplant lung volume was smaller than predicted immediately after transplant at only 33 +/- 5% (mean +/- SD) of predicted TLC. This did not change significantly over the next 6 mo. Native lung volume increased following transplant to 74 +/- 19% predicted TLC at 1 mo and 80 +/- 16% at 6 mo. Five of the seven patients subsequently underwent measurement of pleural pressures at TLC. The mean static pleural pressure at TLC was low at -16 +/- 5.1 cm H2O. In summary, following single lung transplantation for COPD the transplanted lung is significantly restricted. We conclude that the likely mechanism of this restriction is due to low transpulmonary pressure generation.

Dietary prevention and treatment of disease.

Diet is a major factor in five of the 10 leading causes of death in the United States and is a contributing factor in many other diseases and health conditions. Certain diseases can be prevented and general health can be maintained or improved if patients are willing to follow advice about nutrition. Hence, nutrition-related consideration of fiber, cholesterol, carbohydrates and energy should be integral to the management of health conditions.

Declining class size and the decline in graduates choosing family medicine.

In light of the major concern about the marked decline in the numbers of graduates from U.S. medical schools who are entering family medicine, the authors analyzed the effect of declining class size on the numbers of graduates entering family medicine residencies. Data were analyzed from ten years of graduating classes (1981-1990) from the 81 medical schools graduating the most family physicians. The analysis confirmed that declining class size is related to the decline in the production of family physicians. In particular, the 31 schools with the largest declines in the numbers of graduates overall (from the early 1980s compared with the late 1980s and 1990) demonstrated as a group a large fall (nearly 25%) in the production of family physicians. The authors conclude that the large reductions in class size in many medical schools are associated with even larger reductions in the numbers of future family physicians being graduated from U.S. medical schools.

Hypoxemic respiratory failure complicating nosocomial measles in a healthy host.

Since 1983 there has been a steady increase in the number of cases of measles reported to the Centers for Disease Control (CDC), and recent large-scale outbreaks have heightened public awareness. Although mortality from measles is considered rare, systemic complications occur frequently. This case highlights the significant morbidity and potential mortality of measles infection in a normal adult host who did not meet CDC guidelines for measles vaccination.

Structural change of the thorax in chronic obstructive pulmonary disease.

This study examines structural changes of the thorax in hyperinflated subjects with chronic obstructive pulmonary disease (COPD). Age-matched normal subjects were used for comparison. Thoracic dimensions were determined using anteroposterior and lateral chest radiographs performed at total lung capacity, functional residual capacity, and residual volume. Rib cage dimensions (lateral diameter, rib angle, anteroposterior diameter) and diaphragm position were determined at each lung volume. There were no significant differences in rib cage dimension between the COPD and normal subjects for all lung volumes. In contrast, the diaphragm was significantly lower in the COPD subjects. The change of rib cage dimensions in the COPD subjects (for a similar volume change) was not different from that in normal subjects, whereas the change of diaphragm position in the COPD subjects (for a similar volume change) was reduced. In conclusion, the primary structural change of the thorax in COPD with chronic hyperinflation is confined to the diaphragm, with no appreciable structural change in the rib cage.

Pulmonary lymphangioleiomyomatosis associated with pulmonary parenchymal, hilar, and mediastinal noncaseating granulomas.

A young nonsmoking woman presented with severe dyspnea, exercise desaturation, and chest discomfort. Pathologic and histochemical findings revealed pulmonary lymphangioleiomyomatosis (LAM) as the primary abnormality. In addition, there were multiple noncaseating granulomas with special stains and cultures negative for organisms. This highly unusual combination of pathologic findings might suggest the presence of coexistent sarcoidosis in our patient with LAM.

Accuracy and precision of HDL cholesterol measurements using an office chemistry analyzer.

BACKGROUND: A physician can obtain a patient's complete lipoprotein profile at the time of the office visit including assays of the total serum cholesterol, high-density lipoprotein cholesterol (HDL-C), and fasting triglyceride concentrations, and then calculate the low-density lipoprotein cholesterol (LDL-C). Until recently, this was not possible. Instruments are currently available that provide reliable rapid total serum cholesterol and fasting triglyceride measurements. METHODS: This study evaluated the accuracy and precision of a recently developed analytical method for the rapid measurement of HDL-C (Seralyzer Cholesterol System) as compared with a reference clinical laboratory method (Kodak Ektachem 700 XR). Blood specimens were taken from 90 participants and were analyzed in duplicate for HDL-C concentrations and total cholesterol using the Seralyzer and a standard Ektachem 700 XR. RESULTS: Nearly all (98.9%) of the initial Seralyzer HDL-C measures were within +/- 0.08 mmol/L (+/- 3 mg/dL) of the duplicate Seralyzer values. Most (98.3%) of the Seralyzer HDL-C results were within +/- 0.16 mmol/L (+/- 6 mg/dL) of the Kodak HDL-C values. CONCLUSIONS: The Seralyzer HDL-C test provides a reliable and accurate measure of the HDL-C concentration.

Lung weight in vivo measured with computed tomography and rebreathing of soluble gases.

In nine anesthetized dogs, accuracy of noninvasive measurements of lung weight (W) and gas volume in vivo was determined from volume and density determined by computed tomography (CT) and by rebreathing helium and the soluble gases dimethyl ether (WDME) and acetylene (WC2H2). Reference standards were obtained from the postmortem scale weight of the frozen lungs (Wscale) and compared with the CT lung weights measured in the living dog (WCT-38) and the frozen carcass (WCT-cold). WCT-cold did not significantly differ from Wscale [-2 +/- 9% (SD), P = 0.7]. WCT-cold was 10% greater than WCT-38 (0.10 greater than P greater than 0.05), suggesting an increase in lung weight despite immediately commencing freezing after death. WDME measured 64 +/- 6% and WC2H2 56 +/- 12% of WCT-38. Serial multiple measurements in three dogs over 14 wk showed a coefficient of variation (CV) of 10 +/- 2% for WDME, 18 +/- 2% for WC2H2, 4.1 +/- 0.9% for WCT, 2.6 +/- 0.8% for CT density, and 3.5 +/- 1.6% for functional residual capacity (FRC) by CT. FRC calculated from CT consistently underestimated FRC measured by rebreathing helium by 18 +/- 8% (P less than 0.005). This error, despite good agreement between WCT and Wscale, was explained by underestimation of CT total lung volume and overestimation of lung density by factors known to affect CT readings, such as partial volume effects, beam hardening, and limited number of input signals. These data show that CT scanning can provide serial measurement of the mass, density, and volume of the lungs with a CV in the order of 5%, but the rebreathing of soluble gases gives more than double this variability. Measurements of WDME performed on the same day had a CV of 3 +/- 1%, so that WDME provides a precise noninvasive means to measure lung weight in acute studies.

Unsuspected hemodynamic alterations during endotracheal suctioning.

Endotracheal suctioning of intubated patients is associated with hemodynamic complications including arterial hypoxemia, cardiac arrhythmias, hypotension and even death. Prior investigations of this subject focus primarily on arterial hypoxemia. Our observations of ETS revealed significant falls in the mixed SvO2 and we postulated that alterations in VO2 or CO must be occurring. This study was then designed to determine the alterations in CO, VO2, SaO2 and the resulting effect on SvO2 during ETS. Ten critically ill intubated patients with pulmonary artery catheters in place, were studied during routine ETS by the nursing staff. We found that ETS produced a significant decrease in SvO2 which was predominantly due to an increased VO2 accompanied by an inadequate rise or even fall in CO. Alterations in SaO2 appeared to be modest and were insensitive indicators of alterations in SvO2.

Reduction of pulmonary capillary blood volume following cold exposure in patients with Raynaud's phenomenon.

In a previous study we induced digital vasospasm with cold pressor stimulus, and an acute decrease in the lung diffusing capacity for carbon monoxide (Dsb) resulted. We hypothesized its cause to be spasm occurring simultaneously in the pulmonary vasculature and the digital arteries. We measured in this study the Dsb, the diffusing capacity of the pulmonary membrane (Dm), and the volume of blood in the pulmonary capillaries (Vc) after cold-induced digital vasospasm in patients with Raynaud's phenomenon. Control subjects showed no significant decrease in Dsb, Dm, or Vc after cold exposure. Eight of 12 subjects with Raynaud's phenomenon had a significant decrease in Dsb 60 min after testing (25.3 +/- 6.6 vs 19.8 +/- 6.1 ml/min/mm Hg, p less than 0.01). The acute decrease in Dsb was due to a significant decrease in Vc (54 +/- 20 vs 39 +/- 10 ml, p less than 0.05), while Dm was unchanged (52 +/- 17 vs 51 +/- 20 ml/min). Four subjects who had a decrease in Dsb after cold challenge had repeated studies later after pretreatment with sublingual nifedipine. The magnitude of change in Dsb was similar to that observed in the untreated state (23.6 +/- 10.6 vs 20.9 +/- 9.6 ml/min/mm Hg). We conclude that digital vasospasm is accompanied by an acute reduction in Vc in both primary and secondary Raynaud's phenomenon and indicates concurrent vasoconstriction within the pulmonary vaculature.

Office-based assessment of pulmonary function.

PFT is a valuable tool for evaluating the patient with respiratory complaints and for screening the high-risk population. It is no longer only a hospital-based test, but, with current technology, is an efficient, practical procedure that can be performed in an office at minimal cost to the patient. In addition, serial spirometry can be used to identify high-risk populations and gauge response to bronchodilator therapy. Spirometry should be performed routinely in all smokers older than 40.

Key issues in nutrition. Disease prevention through adulthood and old age.

Certain dietary practices are valid methods of lowering the risk of disease. Others, while popular, have unproven benefits or may even be associated with risks of their own. Careful evaluation of hypercholesterolemia is necessary. Persons with a high level of low-density lipoprotein (LDL) cholesterol and a low level of high-density lipoprotein (HDL) cholesterol need diet therapy, because they are at increased risk of cardiovascular disease. Weight reduction and fat restriction can lower blood pressure, help control hyperglycemia, and improve the LDL cholesterol-HDL cholesterol ratio. Some evidence indicates a protective role of beta carotene against cancer in animals. However, hypervitaminosis A is dangerous and relatively easy to accomplish, so supplementation beyond a multivitamin tablet is discouraged. Data about inhibition of cancer in humans through use of high doses of vitamin E or C or selenium are inconclusive, and studies of effects of long-term ingestion are not available. In general, megadoses of even healthy substances are thought to be dangerous. Decreased consumption of fat, increased consumption of foods high in fiber, and elimination of alcohol and tobacco are sensible recommendations. Consumption of cruciferous vegetables has not been proven to reduce the incidence of cancer, but a moderate amount of them in the diet would seem reasonable.