Cost-effectiveness of alpha-1 antitrypsin replacement therapy in treatment of congenital chronic obstructive pulmonary disease.

BACKGROUND: Alpha 1-antitrypsin (AAT) replacement therapy is an expensive intervention ($20,000-$30,000 per patient annually) which may slow or arrest the progression of chronic obstructive pulmonary disease (COPD) in AAT-deficient patients. While FDA-approved, therapy efficacy is unknown. The costs and benefits of AAT replacement therapy were evaluated for patients with congenital COPD. METHODS: Epidemiological and disease cost data were taken from published sources. A discrete-time model of disease stage probability transition was developed to calculate the present-value expected cost of disease treatment, under a range of possible therapy efficacy and other parameter values. RESULTS: At an efficacy of 70 percent, the cost per life year saved with AAT replacement therapy would be between $28,000 and $72,000 (1990 US dollars), depending on patient age, sex, and smoking status. At 30 percent efficacy, the cost per life year saved range would be between $50,000 and $128,000. A controlled efficacy study would cost $53 million or less, if the true efficacy were 50 percent or better. CONCLUSIONS: With efficacy of 30 percent or higher, therapy cost-effectiveness would be comparable to other widely used medical interventions. The economic assessment methodology was used to evaluate both the therapeutic innovation and the value of additional clinical research.

Bronchial responsiveness after human heart-lung transplantation.

We evaluated bronchial responsiveness to inhaled albuterol (salbutamol), ipratropium bromide, methacholine, and propranolol in eight heart-lung transplant (HLT) recipients 2.3 +/- 1.5 months (mean +/- SD) (range, 1 to 4.5 months) after HLT. All patients had a restrictive ventilatory defect but none had airflow limitation (FEV1/FVC = 0.93 +/- 0.05) (range, 0.86 to 0.97). Specific airway conductance (sGaw) improved significantly with both albuterol (p less than 0.01) and ipratropium bromide (p less than 0.01) but FEV1 did not. Only one HLT patient had bronchoconstriction with propranolol, whereas all but one were hyperresponsive to methacholine. Prior inhalation of ipratropium bromide blocked the response to methacholine (p less than 0.005). Serial methacholine provocation tests performed in seven long-term survivors of HLT 24.6 +/- 16.0 months (range, 12 to 51 months) after HLT revealed no time-dependent evolution of bronchial hyperresponsiveness to methacholine. Limited maximal airway narrowing to methacholine was seen in five HLT recipients who showed a 29 +/- 4 percent (range, 23 to 35 percent) fall in FEV1 compared with two patients who did not achieve a plateau with a 47 percent and 63 percent fall in FEV1, respectively. These results further our understanding of bronchial responsiveness in the denervated transplanted lung. The findings of stable hyperresponsiveness to methacholine over a prolonged time interval, limited maximal airway narrowing to methacholine, and blockade of methacholine hyperresponsiveness by ipratropium bromide support the concept of denervation hypersensitivity of muscarinic receptors.

Effect of acute respiratory acidosis on multimodality sensory evoked potentials of Long-Evans rats.

Auditory, visual and somatosensory evoked potentials (EPs), recorded epidurally from 31 chronically implanted male Long-Evans rats, were studied to examine the pattern of sensory effects caused by hypercapnia. Recordings were obtained before exposures, 10-20 min after the beginning of exposure to CO2 in synthetic air, and 30 min after the end of exposure. Previous recordings revealed no substantial effects of the extended recording period itself. Blood pH during an average exposure of 18.8% CO2 was about 7.1. During this level of CO2 exposure the somatosensory response was almost completely abolished, but the latencies of early detectable components were not affected. In contrast, the latencies of all brainstem auditory evoked response components and the 1-5 interwave time increased, whereas amplitudes were only slightly affected. Amplitudes and latencies of early and late components of the flash EP were decreased and lengthened, but the after-discharge components appeared to be most sensitive to CO2. Concentration-response relationships were examined by exposure of rats to 8 and 16% CO2. The most sensitive EP parameter was average amplitude of the late somatosensory EP components. These results suggest that EPs might be useful for assessing acute metabolic disturbances as well as more commonly assessed neurologic disorders.

Unexpected, unexplained sudden death in young asthmatic subjects.

The clinical course of asthma in four patients younger than 25 years was considered. Three died unexpectedly of their disease, and the fourth was successfully resuscitated after cardiopulmonary arrest. None of these patients met the criteria for status asthmaticus in the period preceding their death. The time course of the illness from apparent wellness to death was documented as seconds to minutes. No obvious cause of the severe disease was found at postmortem in two patients or by clinical analysis in all four. Patients with bronchial asthma may die with this disease unexpectedly, rapidly and with no obvious cause for the severity of this process.

Bronchial responsiveness to exercise after human cardiopulmonary transplantation.

Heart-lung transplant (HLT) recipients characteristically display marked bronchial hyperresponsiveness (BHR) to inhaled methacholine, but their bronchial responsiveness (BR) to exercise has not been reported. We measured BR to exercise in 13 stable HLT recipients, 13 normal control (NC) subjects and 13 asthmatic patients (AS). All subjects exercised for eight minutes on a bicycle ergometer at a work level designed to obtain and maintain 80 percent maximum heart rate, or to tolerance. The postexercise fall in FEV1 was equivalent in the HLT group and the NC group (0 +/- 0.2 L vs 0 +/- 0.2 L:p = NS) in contrast to the AS group (-0.6 +/- 0.5 L:p less than 0.01). Stable HLT recipients do not exhibit BHR to exercise at tolerable work loads. This observation supports the hypothesis that BHR to methacholine after HLT is due to denervation hypersensitivity of muscarinic receptors rather than other causes.

The distribution of MHC class I and II antigens on bronchial epithelium.

The distribution and degree of expression of Class I and Class II major histocompatibility (MHC) antigens on human lower respiratory tract epithelium were evaluated in five freshly obtained pneumonectomy and lobectomy specimens using an immunoperoxidase technique. Multiple sites were examined from each specimen, and two independent observers graded each sample as positive, equivocal, or negative compared with control slides. Interobserver agreement was high. From a total of 120 grade determinations, 114 showed complete concordance and only one showed a positive/negative discordance. Both Class I (HLA-A,B,C) and Class II (HLA-DR) antigens were uniformly and strongly expressed throughout the major, lobar, and segmental bronchi of each sample, the bronchiolar epithelium, and the alveolar epithelium. Paired samples of adjacent lower respiratory tract epithelium harvested with the fiberoptic bronchoscope and during pathologic examination, respectively, revealed an identical staining pattern for these antigens. Staining for HLA-DQ expression (a subset of MHC Class II antigens) was generally weaker and appeared more variable, with four negative, six equivocal, and 30 positive samples. Our observations demonstrate the widespread expression of Class I antigens on airway epithelium and reveal for the first time the ubiquitous nature of Class II MHC antigen (HLA-DR) expression throughout the lower respiratory tract. Furthermore, they attest to the adequacy of bronchoscopically obtained samples for immunologic staining. These results provide a basis for both a putative mechanism of bronchocentric rejection phenomena after human heart-lung transplantation and for the means to monitor it prospectively.

Increased lung water and ascites after massive cocaine overdosage in mice and improved survival related to beta-adrenergic blockage.

STUDY OBJECTIVE: To determine the effect of massive cocaine intoxication on lung water and ascites accumulation and the effect of beta- and alpha-adrenergic blockade on survival in massive cocaine intoxication in the mouse. DESIGN: The effect of massive cocaine intoxication on lung water, ascitic fluid accumulation, and survival following LD 100 doses of intravenous cocaine with and without alpha- and beta-adrenergic blockade was determined. INTERVENTIONS: Cocaine hydrochloride (0.15 mg/g body weight) was administered intravenously with no other interventions; with propranolol hydrochloride intravenously (0.5 mg per mouse) before and after cocaine; and with phentolamine intravenously (10.5 micrograms per mouse) before cocaine. MEASUREMENTS AND MAIN RESULTS: Intravenous cocaine hydrochloride resulted in an increase in lung water (saline controls, 4.17 +/- 1.3 [standard deviation] mg water per g mouse; cocaine hydrochloride, 5.94 +/- 0.9 mg water per g mouse; P less than 0.002). Cocaine hydrochloride always resulted in the accumulation of transudative ascitic fluid (saline controls, no measurable ascitic fluid; cocaine administration, 20.2 +/- 12.9 micrograms per mouse; ascitic fluid protein concentration, 23.5 +/- 8.5 g/L). Propranolol hydrochloride administered before or after intravenous cocaine hydrochloride resulted in a striking reduction in mortality (84 of 84 mice without propranolol died [mortality = 100%]; 7 of 39 mice with propranolol died [mortality = 18%]; P less than 0.001). CONCLUSIONS: Massive cocaine intoxication is associated with increased lung water and transudative ascites. Fluid accumulation is not prevented by either alpha- or beta-adrenergic blockers. Propranolol, administered either before or after cocaine, sharply reduces mortality. The results should be extrapolated to treatment in humans with caution.