Safety and pharmacokinetics of inhaled morphine delivered using the AERx system in patients with moderate-to-severe asthma.

OBJECTIVE: The safety and pharmacokinetics of inhaled morphine in asthmatic subjects were investigated using the AERx System, a novel aerosol system. METHODS: Twenty subjects with asthma received inhaled placebo and inhaled morphine sulfate, 2.2 mg, 4.4 mg and 8.8 mg, on separate days in a single-blind crossover study. Six of the subjects received an additional open-label dose of 17.6 mg on a separate day. Plasma morphine concentrations and safety evaluations including pulmonary function testing were performed. RESULTS: Mean tmax values were similar following all dose groups at approximately 1-2 minutes. Mean AUC(0-->1) values showed dose proportionality for the first 3 dose groups (6.3, 12.3 and 24.3 ng x h x ml(-1)), the mean AUC(0-->1) for the 17.6 mg dose group was 1.6x that of the 8.8 mg dose group. No statistically significant differences in forced expiratory volume in 1 sec (FEV1) were found for the 2.2 mg, 4.4 mg, or 8.8 mg dose groups; at 17.6 mg, a statistically significant but not clinically meaningful reduction in mean FEV1 (-8.18%) from baseline occurred at 10 minutes compared to placebo, spontaneously returning to baseline by 60 min. Four subjects experienced significant but reversible decreases in FEV1 of > or = 20% compared to baseline and across all dose levels including after placebo, but with no associated increase in dyspnea, wheezing or other adverse events. CONCLUSIONS: Inhaled morphine using the AERx System was absorbed rapidly and demonstrated dose-dependent plasma concentrations. It was well-tolerated and did not cause clinically significant bronchoconstriction in most subjects with moderate-to-severe asthma.

Aerosolized protein delivery in asthma: gamma camera analysis of regional deposition and perfusion.

Bioavailability of an aerosolized anti-inflammatory protein, soluble interleukin-4 receptor (IL-4R), was measured in patients with asthma using two different aerosol delivery systems, a prototype aerosol delivery system (AERx tethered model, Aradigm, Hayward, CA) and PARI LC STAR nebulizer (Pari, Richmond, VA). Regional distribution of the drug in the respiratory tract obtained by planar imaging using gamma camera scintigraphy was utilized to explain the differences in bioavailability. The drug, an experimental protein being developed for asthma, was mixed with radiolabel 99mTechnetium diethylene triaminepentaacetic acid (99mTc-DTPA). Aerosols were characterized in vitro using cascade impaction (mass median aerodynamic diameter [MMAD] and geometric standard deviation [GSD]); the AERx MMAD 2.0 microm (GSD 1.35), the PARI 3.5 microm (GSD 2.5). Four patients with asthma requiring maintenance aerosolized steroids were studied. First, regional volume was determined utilizing equilibrium 133Xe scanning. Then, after a brief period of instruction, patients inhaled four breaths of protein using AERx (0.45 mg in total) followed 1 week later by inhalation via PARI (3.0 mg nebulized until dry). Each deposition image was followed by a measurement of regional perfusion using injected 99mTc albumin macroaggregates. Deposition of 99mTc-DTPA in the subjects was determined by mass balance. Regional analysis was performed using computerized regions of interest. The regional distribution of deposited drug was normalized for regional volume and perfusion. Following each single inhalation, serial blood samples were drawn over a 7-day period to determine area under the curve (AUC) of protein concentration in the blood. Median AUC(AERx)/AUC(PARI) was 7.66/1, based on the amount of drug placed in each device, indicating that AERx was 7.66 times more efficient than PARI. When normalized for total lung deposition (AUC per mg deposited) the ratio decreased to 2.44, indicating that efficiencies of the drug delivery system and deposition were major factors. When normalized for sC/P and (pU/L)xe ratios (central to peripheral and upper to lower ratios are parameters of regional distribution of deposited particles and regional per- fusion ['p']), AUC(AER)x/AUC(PARI) further decreased to 1.35, demonstrating that peripheral sites of deposition with the AERx affected the final blood concentration of the drug. We conclude that inhaled bioavailability of aerosolized protein, as expressed by AUC, is a quantifiable function of lung dose and regional deposition as defined by planar scintigraphy.

Bronchoalveolar lavage and transbronchial lung biopsy during acute rejection and infection in heart-lung transplant patients. Studies of cell counts, lymphocyte phenotypes, and expression of HLA-DR and interleukin-2 receptor.

The total and differential cell counts of 135 bronchoalveolar lavages (BAL) in 48 heart-lung transplant (HLT) patients were compared with the histologic findings in concurrent transbronchial lung biopsies (TBBs). Counts of CD3+, CD4+, and CD8+ lymphocytes were recorded, and a semiquantitative assessment of HLA-DR and interleukin-2 receptor (IL-2R) expression was made on 29 occasions. There were five diagnostic categories: normal (n = 8), acute rejection (ALR) (n = 57), treated rejection (TR) (n = 19), infection (INF) (n = 24), and chronic rejection (CR) (n = 24). Total cell counts in INF were significantly higher than counts in all the other diagnostic groups. The highest BAL lymphocyte counts, significantly higher than in INF, were found in ALR because of increased CD8+ cells, exceeding 15% in 13 of 57 BALs. TBBs in ALR by contrast showed significantly increased numbers of both CD8+ and CD4+ cells. High dose corticosteroid treatment of ALR caused a fall in cellularity of BAL and TBB specimens but not always to values seen when patients were well. During INF and CR, significantly increased numbers of PMNs were seen in the BAL. HLA-DR and IL-2R expression was enhanced in cells of BAL and TBB in all complications. BAL can only supplement at present histologic examination of TBB in the diagnosis of complications after HLT.

Causes of exercise limitation after heart-lung transplantation.

A decade after the first successful human heart-lung transplantation and with improved recipient survival, there is now a growing interest in the quality of life achieved after this procedure. Patients undergoing heart-lung transplantation suffer from diseases that are most protracted and uniformly fatal. Before surgery, they are usually debilitated from the primary disease and long-term inactivity. Therefore several factors contribute to the maximal work capacity achievable after transplantation. They are principally unavoidable complications of allograft transplantation, mainly lung rejection, but include the toxic effects of immunosuppressant therapy. Many, however, are a function of the prolonged incapacitation and deconditioning imposed by the pretransplant illness. The relative roles of these factors in limiting posttransplant exercise tolerance in the various disease groups undergoing heart-lung transplantation are discussed.

Late pulmonary haemodynamic changes in heart-lung transplantation.

As survival improves following heart-lung transplantation (HLT) the importance of obliterative bronchiolitis (OB) as a cause of late death increases. Whilst coronary occlusive disease (COD) may be less common in heart-lung transplant recipients than in patients receiving heart transplants, COD associated with OB can be lethal. We have studied 22 long-term survivors of heart-lung transplantation at an average of 25 months following transplantation during rest and at 50 W supine exercise and with prostacyclin induced vasodilation. Cardiac index increased less with exercise as the physiological measurement of OB using forced expiratory volume in one second (FEV1) fell (P = 0.018). Although resting pulmonary vascular resistance increased with falling FEV1, this increase was still within the normal range. We conclude that a fall in cardiac reserve on exercise accompanies the fall in FEV1 which characterizes OB and may reflect cardiac vascular disease.

High dose nebulized steroid in the treatment of chronic steroid-dependent asthma.

Despite the dramatic success of inhaled steroids in controlling asthma symptoms there remains a small number of patients in whom asthma can only be treated with continuous oral steroids. Eighteen such patients, aged 19-62 years (seven males, 11 females) were followed in an open trial of nebulized budesonide over 12-18 months. All had required at least 7.5 mg or more daily prednisolone to control their symptoms over the preceeding 2 or more years and were taking 1200 micrograms beclomethasone dipropionate or 1600 micrograms budesonide daily. With a daily dose ranging between 4 and 8 mg nebulized budesonide, 14 patients successfully stopped oral steroids while in three the dose was reduced; only one patient failed to benefit. There was an increase in the mean FEV1 from 1.9 (+/- 0.9) to 2.2 (+/- 0.9) l, and in the mean morning PEFR, from 238 (+/- 119) to 286 (+/- 130) l min-1. There was also a significant decrease in the mean number of hospital admissions for acute severe asthma, from 1.5 (+/- 1.8) to 0.9 (+/- 1.1) per year. These findings should encourage a careful and controlled evaluation of nebulized steroids as a substitute for oral steroids in this difficult group of asthmatics.

Giant lymph node hyperplasia of the lung (Castleman's disease) associated with recurrent pleural effusion.

A case of giant lymph node hyperplasia (Castleman's disease) of the lung presented with pleural effusion (which was recurrent), an unusual complication. The patient was treated with pneumonectomy and has survived for three years without relapse. This is the first report of the disease from black Africa.

Natural history of chronic rejection in heart-lung transplant recipients.

Chronic rejection is the major cause of death of long-term survivors of heart-lung transplantation. Of our 61 patients who have received heart-lung transplants, 29 have been followed up for a year or longer. Seven patients had clinical evidence of chronic rejection within 15 months of transplantations of these seven, four died with postmortem confirmation of extensive obliterative bronchiolitis, interstitial and pleural fibrosis, and vascular sclerosis in the heart and lungs. All seven patients had evidence on transbronchial biopsy specimens of submucosal fibrosis and vascular sclerosis. Twelve of our remaining patients have shown similar areas of lung fibrosis on transbronchial biopsy specimens, and the other 10 are well and without fibrosis seen on transbronchial biopsy specimens. Studies of the 201 biopsy specimens obtained from 29 patients confirmed rejection on 130 occasions, with more frequent, more persistent, and more severe rejection in the chronic-rejection group than in the without-fibrosis or lung-fibrosis group. Opportunistic infections resulted in pneumonia on 19 occasions, and these were most commonly found in patients with lung fibrosis. We conclude that chronic lung rejection is the likely outcome in patients with early, poorly controlled, severe rejection.

Lung function associated with histologically diagnosed acute lung rejection and pulmonary infection in heart-lung transplant patients.

A group of 34 heart-lung transplant patients were studied with serial pulmonary function measurements, chest radiographs, and transbronchial biopsies from the time of surgery. These investigations were carried out routinely at 3 and 6 months and then annually after transplantation as well as on clinical suspicion of acute lung rejection or infection. A total of 61 transbronchial biopsies and concurrent lung function and chest radiographs were obtained. Of the biopsies, 30 (49.2%) showed histologic evidence of lung rejection, 12 (19.7%) demonstrated various opportunistic infections, and 19 (31.1%) were normal. Compared to during episodes of normal biopsies, FEV1 decreased significantly with lung rejection (p less than 0.001) and with infection (p less than 0.01). Vital capacity (VC) and DLCO also fell with these acute lung complications. Using histologic diagnosis as a standard, lung function testing had a sensitivity of 86% in detecting lung rejection in the first 3 months postoperation and 75% in the subsequent period. Its sensitivity for detecting lung infection was 75%. Although not distinguishing between these two complications, lung function had a specificity of 84% for detecting occurrence of an acute lung complication. Chest radiographs, although of similar sensitivity in the first 3 months postsurgery, had a sensitivity of only 19% for rejection in subsequent months and 58% for infection. Its specificity was 100%. Lung function testing changes in a predictable fashion with lung rejection and infection, offers an improvement over chest radiographs, and provides a quantitative measurement to aid the decision of when to undertake transbronchial lung biopsy.

Transplantation of the lung.

The introduction of cyclosporine as a highly effective immunosuppressive agent and the development of new techniques for heart-lung and lung transplantation have led to a new treatment for a wide range of fatal cardiopulmonary diseases. Indications for surgery are now becoming clear, together with major contra-indications. Suppurative lung disease, such as cystic fibrosis, can be effectively treated by heart-lung transplant (HLT). A whole new field of pulmonary medicine is emerging to provide the physiological monitoring and diagnostic techniques for major complications such as opportunistic lung infection and pulmonary rejection. Obliterative bronchiolitis, a consequence of frequent and severe rejection, still provides a major challenge to the immunological scientist and respiratory physician. Lung transplantation, by disrupting the vascular supply and innervation of the lung, is raising major questions about the generally accepted beliefs of regulation of breathing and pulmonary mechanics. Finally, as the survival rate improves beyond the current 50% at 3 yrs, lung transplantation will perhaps present further challenges to our understanding of the pathogenesis of various diseases such as asthma and cystic fibrosis.

Histologic prognostic indicators for the lung allografts of heart-lung transplants.

The histologic changes in transbronchial lung biopsy specimens of heart-lung transplant patients were graded during episodes of acute rejection and when patients were well. Infection was strictly excluded from all episodes studied. Grade of severity of rejection was determined by the magnitude and extent of the inflammatory infiltrate. Biopsy specimens, obtained 1 year after the initial biopsies, were examined for histologic evidence of airway submucosal fibrosis, and each patient's clinical status at this time was recorded. The biopsy material from 22 long-term survivors was studied. On 16 occasions the specimens showed no evidence of rejection (grade 0). Twelve of these sets of specimens were from clinically well patients, and four were from the patients who had clinical evidence of rejection. The other six sets of specimens, from clinically well patients, showed evidence of rejection: three grade 1 and three grade 2. One year later, the clinically well patients had normal biopsy histology without fibrosis and normal lung function. Bronchiolitis obliterans had not developed in any patient. There were 27 episodes of rejection in the 22 patients, of which 23 were confirmed histologically. Eleven sets of specimens had grade 1 acute rejection, eight grade 2, and four grade 3. Three of these patients died, and bronchiolitis obliterans was confirmed at necropsy. Lung fibrosis was more common in specimens taken after 1 year, and lung function was depressed in these patients. The histologic grading of transbronchial lung biopsy material, although still in the early stages of development, provides some predictive value to the long-term outcome of the lung transplant patient, in development of both bronchiolitis obliterans and lesser fibrotic changes.

The use of home spirometry in detecting acute lung rejection and infection following heart-lung transplantation.

The value of home spirometry in detecting acute lung rejection and opportunistic infections was studied in 15 heart-lung transplant recipients over a six-month period. The patients measured their FEV1 and FVC twice daily at home using a portable turbine spirometer. The records were then reviewed in relation to the results of transbronchial lung biopsy carried out during occurrences of respiratory symptoms and during routine posttransplant assessment. FEV1 and FVC fell by a mean (+/- SD) of 10.4 +/- 6.9 percent and 9.3 +/- 7.9 percent, respectively, during 20 episodes of lung rejection. The corresponding figures during opportunistic infections were 12.8 +/- 10.1 percent and 12.5 +/- 14.3 percent. No such change was observed during routine normal biopsies. Regular home spirometry offered early detection of these complications allowing early transbronchial lung biopsy as well as assessing efficacy of their therapy. Above all, measurements can be made daily, which is unique in the assessment of solid organ transplants.

The effect of recipient lung size on lung physiology after heart-lung transplantation.

We studied the postoperative course of lung volumes in 32 heart-lung transplant recipients relative to the predicted total lung capacity of the individual donors, to assess the degree of inaccuracy likely to result from the radiological method of matching of donor and recipient lung sizes. There was a tendency for recipients with large preoperative lung volumes--from, for example, emphysema--to receive smaller lungs, while those with smaller volumes from pulmonary vascular disease received bigger donor lungs, but no immediate problems were incurred. After an initial fall in total lung capacity, the postoperative value of the total lung capacity approached the recipients' pretransplant value about one year after the operation irrespective of the size of the donor lungs. This suggests that chest wall compliance is the major determinant of postoperative lung volume and not the donor lung size or compliance. Exact matching of donors' and recipients' lung sizes may not be necessary, and if required can be simply achieved by comparing the measured total lung capacity in the recipient with the predicted value of the donor based on sex, age, and height.

The role of physiological deadspace and shunt in the gas exchange of patients with pulmonary hypertension: a study of exercise and prostacyclin infusion.

Haemodynamic and gas exchange measurements were made at rest, on supine exercise and on acute vasodilatation with intravenous prostacyclin in eight patients with pulmonary hypertension. This enabled an assessment of the contribution of V/Q imbalance to the abnormal gas exchange on the condition. At rest arterial oxygen tension, PaO2 (mean 8.1 +/- 1.7 kPa) and mixed venous oxygen tension, PVO2 (3.6 +/- 0.4) were reduced. The physiological shunt, Qs/Qt (15 +/- 17%) and the dead space, Vd/Vt (0.47 +/- 0.11) were elevated above normal. Exercise produced an increase in cardiac index, a fall in PVO2, no significant change in PaO2 and also no appreciable changes in the Vd/Vt and Qs/Qt. Intravenous prostacyclin increased the cardiac index and raised the PVO2 and the PaO2 but again with no significant changes in Vd/Vt and Qs/Qt. We conclude that ventilation-perfusion imbalance as shown by increased Vd/Vt and Qs/Qt, contributes significantly to the abnormal gas exchange in pulmonary hypertension. But neither index was altered by exercise or vasodilation; the latter improves the hypoxemia by increasing the PVO2 from an increase in the cardiac output.