Alveolar macrophages (AMs) may play a key role in human respiratory immune defenses, partially by synthesizing and releasing interleukin 1 (IL = 1). D53 (Ribomunyl), a composite bacterial ribosomal immunostimulant, has been recognized as an efficient prevention of respiratory tract infections. In vitro, D53 enhances the IL-1 production by mouse spleen adherent cells. A thymocyte proliferative response assay was used to evaluate the in vitro IL-1 production by AMs in healthy subjects who received D53 immunostimulant. Twelve nonsmoking healthy subjects took part in a prospective double-blind placebo control study. On day 1, a first bronchoalveolar lavage (BAL) was performed to assess IL-1 production by unstimulated and lipopolysaccharide (LPS) stimulated AM. Then, subjects were randomized to receive D53 (n = 6) or its placebo (n = 6) by both oral and subcutaneous injection routes from day 1 to day 15. On day 15, a second BAL was done and AM IL-1 production was again tested. IL-1 production on day 15 did not significantly differ from day 1 in both D53-treated and placebo groups either when AMs were unstimulated or were stimulated with concentrations of LPS resulting in maximal IL-1 production. However, in the D53-treated group, but not in the placebo group, IL-1 production induced by low LPS concentration (5 mg/L) was significantly higher (mean +/- SEM: 1,238 +/- 287 U/10(6) AM) on day 15 in comparison with day 1 (577 +/- 113 U/10(6) AM; p less than 0.05, Wilcoxon W test) and in comparison with the control group (day 15 IL-1 production induced by 5 mg/L LPS, 758 +/- 175 U/10(6) AM; p less than 0.05, Mann-Whitney U test). Moreover, in the D53-treated group, the optimal LPS concentration (ie, LPS concentration that induced maximal IL-1 production) was significantly lower on day 15 (mean +/- SD: 11 +/- 7 mg/L) than on day 1 (16 +/- 7 mg/L; p less than 0.05 Wilcoxon W test). We conclude that D53 immunostimulant in vivo primes AM to produce IL-1 following low LPS concentration stimulation. This may partially explain the protective effect of D53 immunostimulant against respiratory tract infection.

We studied high intensity, symptom-limited, endurance exercise training in 52 patients with COPD participating in a pulmonary rehabilitation program. The patients had moderate to severe airway obstruction and reduced exercise tolerance with ventilatory limitation. The target workload for endurance exercise testing was 95 percent of the baseline maximum treadmill work load. At training weeks 1, 4 and 8, they were training at 85, 84, and 86 percent respectively, of baseline maximum. After rehabilitation, there was an increase in maximal treadmill work load, VO2max, and endurance exercise time, and a decrease in perceived symptoms. Patients who did not reach anaerobic threshold (group 2) were able to train at a higher percentage of maximum exercise tolerance than patients who reached anaerobic threshold (group 1). The increase in exercise performance of both groups, however, was similar. We conclude that patients with moderate to severe COPD can perform exercise training successfully at intensity targets which represent higher percentages of maximum than typically recommended in normal individuals or other patients.

To describe the frequency of aerosol pentamidine-induced bronchoconstriction, its relationship to non-specific airway responsiveness, and its response to preventive therapy using salbutamol, ipratropium bromide, or sodium cromoglycate.

The effect of two different circuit leaks on the measurement of maximal static inspiratory and expiratory pressures at the mouth (Pimax, Pemax) was assessed in 70 patients with respiratory disease. Patients were divided into three groups with similar anthropometric and spirometric characteristics. The first group (30 patients) had their Pmax measured with a leak of 2.0 mm internal diameter (ID) and 37 mm length (as proposed by T. Ringqvist) and repeated with a second leak of 1.0 mm ID and 15 mm length (as recommended by J. L. Clausen). The two measurements were done in random order. Measurements for the other two groups (20 patients each) were taken with one or another, the two leaks randomly alternated with no leak. Pimax measurements obtained with Ringqvist's leak were 17 percent (p less than 0.005) lower than those with Clausen's leak and 22 percent (p less than 0.005) lower than those with no leak. Pemax measurements performed with Ringqvist's leak in place were 11 percent (p less than 0.005) lower than those with Clausen's leak and 11 percent (p less than 0.005) lower than those obtained with no leak. The comparison between Clausen's leak and no leak showed no statistically significant difference. We conclude that whenever the effect of pressure generated in the mouth is to be avoided in the measurement of respiratory Pmax, a leak of the size proposed by Ringqvist is to be preferred.

The influence of positive expiratory pressure (PEP) applied during inhalation of a beta 2-agonist in treatment of bronchial asthma was investigated in a randomized crossover study with two-week treatment periods. In one period, two puffs (0.5 mg) of terbutaline was given from a metered dose inhaler and inhaled through a device consisting of a conespacer connected to a facemask giving PEP (10 to 15 cm H2O). In a second period, terbutaline 0.5 mg was inhaled similarly but without PEP, and in a third period placebo spray was inhaled with PEP. Treatments were given three times daily. Peak expiratory flow (PEF) was measured before and after each inhalation and symptom scores for dyspnea, cough, and mucus production were noted in a diary. All treatments increased PEF significantly (p less than 0.0001). The mean increase was 32 L/min during treatment with terbutaline and PEP. This was greater than the increase of 25 L/min during terbutaline treatment (p = 0.005). The increase in PEF during terbutaline treatment was significantly higher than the achieved 18 L/min during PEP (p = 0.026). The study showed improved bronchodilation when PEP was combined with inhalation of beta 2-agonist compared with beta 2-agonist alone.

Methacholine challenges were performed in ten subjects with mild asthma at 2 h before and 20 min after placebo or 5, 10, 20, 40, 80, and 160 mg of inhaled verapamil given in a single-blind randomized crossover manner on different days. While verapamil did not have a bronchodilator effect, the 10-mg dose modestly increased the concentration of methacholine required to decrease FEV1 by 20 percent (PC20). The mean (+/- SEM) increase in PC20 from baseline was 2.1 +/- 0.2 times baseline after 10 mg of verapamil, compared to 1.1 +/- 0.1 times baseline after placebo (p less than 0.001). Unexpectedly, bronchoconstriction (greater than 10 percent decrease in FEV1) associated with cough or wheezing was observed in seven of ten subjects at doses of 20 mg or more. This adverse effect was not related to the osmolarity of the nebulized solutions. Thirty minutes before a standardized exercise challenge, 13 subjects inhaled placebo, 10 mg, or the highest dose of verapamil tolerated during the methacholine study (20 to 160 mg) in a double-blind randomized crossover manner. The exercise challenge was aborted in three subjects because of bronchospasm that occurred after administration of the higher dose. The mean (+/- SEM) maximum change in FEV1 after exercise in the ten subjects completing all three regimens of treatment was -17.1 +/- 4.0 percent after placebo, -12.7 +/- 4.3 percent after 10 mg (p less than 0.05), and -6.4 +/- 3.6 percent after the highest dose (p less than 0.05). We conclude that increasing the dose of verapamil above 10 mg did not provide greater benefit but, paradoxically, induced bronchoconstriction in most of the subjects. Because of this potential bronchoconstrictor effect, high doses of oral or intravenous verapamil should be used with caution in asthmatic subjects.

Adequate humidification of inspired gases with HMEs during long-term MV remains controversial. In this study, a comparison is made between tracheal secretions during long-term MV either with HME or conventional HH. Both the HME and HH groups were similar with respect to age, sex, diagnosis, duration of MV, SAPS and mortality. Temperature of gases in the tracheal tube was lower and the amount of tracheal instillations was greater in the HME group than in the HH group. Tracheal secretions became thicker between day 1 (control) and day 5, in the HME group than in the HH group. Four and two tube occlusions occurred in HME and HH groups, respectively. Tracheal bacterial colonization was similar in the two groups. Given the advantages of HME (reduced nurses' work and financial cost), HME could be routinely used under cautious surveillance and replaced by HH if difficulty in suctioning occurs.

We have shown that in patients with COPD, myocardial efficiency during exercise is enhanced following acute elevations of plasma phosphate (Pi). A decrease in Hb-O2 affinity (increase in P50) was not responsible for the improvement. We postulated that the physiologic benefit was due to the acute reversal of a subclinical myocardial Pi depletion. To further test this hypothesis in a chronic state, we studied nine stable hypoxemic (PaO2 = 64 +/- 2 mm Hg [+/- SEM]) patients with COPD over five weeks: two weeks at normal plasma Pi; and three weeks at elevated plasma Pi, induced by etidronate disodium (Didronel; 750 mg orally daily). Administration of etidronate disodium increased (p less than 0.05) plasma level of Pi (4.4 +/- 0.2 to 5.8 +/- 0.1 mg/dl), RBC level of Pi (3.1 +/- 0.2 to 4.1 +/- 0.2 mg/dl), RBC level of 2,3-DPG (16.2 +/- 1.1 to 21.3 g+/- 1.3 mumol/g of Hb) and P50 (23.7 +/- 0.5 to 26.0 +/- 0.8 mm Hg). At the end of the treatment, the widening of the C(a-v)O2 with exercise (7.1 +/- 0.8 to 8.9 +/- 0.6 ml/dl) was less pronounced than under control conditions (6.9 +/- 0.4 to 10.1 +/- 0.6 ml/dl; p less than 0.02); concomitantly, the crossover point (COP; the PaO2 below which a rightward-shifted Hb-O2 curve causes the C(a-v)O2 to become narrower rather than wider) increased (37 +/- 2 to 49 +/- 1 mm Hg). Indicators of myocardial work efficiency were not affected by etidronate disodium at rest or during exercise. We postulate that during exercise the potential beneficial effect of the rightward shift of the Hb-O2 curve upon cardiac function was negated by the fall of PaO2 to or below the COP level, a situation which would limit increases in tissue O2 extraction.

To examine the differential effect of drugs used for stress ulcer prophylaxis on nosocomial pneumonia in critically ill patients.

To determine whether caffeine consumption affects bronchoprovocation challenge (BPC).

In a randomized, double-blind, crossover cumulative study, the individual maximal bronchodilator dosages for formoterol (F) and salbutamol (S) were assessed for their respective influence on ECG, pulse rate, and serum potassium levels in 13 patients with stable and reversible asthma. The following dosages were administered with an interval of 1 h: 12-24-48-(48)-(48) micrograms for F and 100-200-400-400-(400)-(400) micrograms for S. The study day was discontinued if pulse rate was above 140 beats min-1, a flattening of T wave on the ECG was recorded, or a maximal bronchodilation in FEV1 was observed (above 110 percent of the predicted value or an increase in FEV1 in the last two measurements below 5 percent). The maximal individual dose of F administered was 84 micrograms in six patients, 132 micrograms in three patients, 180 micrograms in three patients, and 228 micrograms in one patient. For S, the maximal individual dose was 400 micrograms in three patients, 2,200 micrograms in eight patients, 3,000 micrograms in one patient, and 3,800 micrograms in one patient. The mean maximal increase in FEV1 was 36.0 percent after F and 35.1 percent after S. Pulse rate increased from 73 to S3 beats.min-1 after F and from 75 to 84 beats.min-1 after S (both statistically significant). No pulse rate above 140 beats.min-1 was observed. In the high-therapeutic range (up to 36 micrograms of F and 6,090 micrograms of S), no changes in potassium level were observed. In still higher dosages, mean potassium level decreased from 4.16 to 3.78 mmol.L-1 after F and from 4.02 to 3.88 mmol.L-1 after S (not clinically relevant). The lowest individual potassium level recorded was 3.1 mmol.L-1. No clinically important changes in ECG were observed. In conclusion, very high doses of F and S administered from a metered dose inhaler proved to be safe for patients.

Patients with artificial airways frequently need aerosol or humidity therapy. For this study, we used aerosols generated from a heated Puritan all-purpose nebulizer and humidity generated from a heated Bennett cascade humidifier to determine the effects of these therapies in spontaneously breathing neurosurgical patients with nasal endotracheal tubes and normal lungs. Crossover comparison of oxygenation status before and after aerosol or humidity therapy was done by analyzing P(A-a)O2 in these patients. We found that aerosols have a detrimental effect on the patient's oxygenation status, suggesting that humidity is preferable in maintaining adequate oxygenation in a patient with a normal lung plus artificial airway. The arterial pH and PaCO2 were not affected by aerosol therapy. Care should be exercised with regard to the adverse hypoxemic effect of bland aerosols when a large-reservoir jet nebulizer is used in an intubated patient who already has impaired cardiopulmonary function or borderline PaO2.

Patients presenting to a chest clinic because of adult-onset wheezing with no history of allergy had a 90 percent prevalence of gastroesophageal reflux, even though reflux symptoms were mild or absent. Ninety patients were randomly assigned to receive cimetidine or an identical placebo or to undergo antireflux surgery. During a six-month period, all groups improved clinically; the cimetidine and surgical groups improved more than the placebo group. The intake of pulmonary medication decreased significantly in both cimetidine and surgical groups. Pulmonary function test results improved in the cimetidine- and surgically treated patients; improvement was not statistically significant. At long-term follow-up, the surgical group maintained clinical improvement and decreased pulmonary medication intake, whereas the placebo group worsened. We conclude that gastroesophageal reflux can play a significant role in some patients with nonallergic pulmonary disease and that its treatment can improve pulmonary symptoms and objective measurements of pulmonary function.

The adverse effects of prolonged immobility are due primarily to gravitational effects on blood flow and ventilation, impairment of the normal mucociliary escalator and possibly an increase in extravascular lung water. However, CLRT theoretically should reverse these abnormalities. The sequence of events that culminate in LRTI or pneumonia is unclear; however, low tidal volumes, increased extravascular lung water and the accumulation of bronchopulmonary secretions may lead to atelectasis, a well-known precursor of pneumonia. Three prospective, randomized studies evaluating patients with acute head trauma, orthopedic injuries requiring traction and blunt chest trauma all showed a decreased incidence of LRTI or pneumonia with CLRT compared with those treated in a conventional bed and turned every 2 h by the nursing staff. In general, the methodology was sound with early randomization, use of precise criteria to define LRTI and pneumonia and appropriate observation. The fourth study performed in a medical ICU with a heterogeneous group of patients did not show a difference in incidence of nosocomial pneumonia between treatment in CLRT and a conventional bed, but did show a decreased length of ICU stay for patients with pneumonia treated with CLRT. It appears that if CLRT is to be effective, it needs to be instituted early in the patient's illness. The length of time that CLRT should be utilized is unknown; however, intuitively, as long as the patient is at risk, the therapy should be continued. It is also unclear whether CLRT should be started at full rotation immediately or begun at lesser degrees of rotation and advanced serially over several hours. Another unknown is the minimum time that CLRT should be administered per day. In the studies discussed, most patients were rotated for 10 to 16 h/day. The minimum degree of rotation necessary for an effect is also unknown; in the studies cited, rotations from 40 degrees to 62 degrees in each direction were used. Based on the current data, the early use of CLRT in comatose or otherwise immobile patients decreases the incidence of LRTI including pneumonia over the first 7 to 14 days of ICU care. The prevention of pneumonia and more rapid transfer from the ICU should offset the additional expense of a specialized bed. The data suggest that a multicenter study with accrual of a large number of patients to evaluate this form of therapy in a prospective, randomized study is necessary. If the hypothesis that CLRT decreases the incidence of nosocomial pneumonia in the ICU is proven, the impact on critical care in the 90s would be substantial.

To test whether propranolol may influence the progression of coronary atherosclerosis.

To determine if ammonium ion plays a role in the lactate and ventilatory thresholds of incremental exercise, we investigated the effects on blood lactate and ventilation of NH(4+)-buffering by monosodium glutamate. Six normal volunteers underwent intravenous loading with MSG, 9 g, in a randomized, double-blind, saline placebo controlled crossover study. Four of the six subjects had a greater than 10 percent fall in peak (NH4+) following MSG (37 +/- 2.0 vs 25 +/- 4.3 micrograms/dl p = 0.003, PLB vs MSG). When MSG blunted the rise in venous (NH4+) during exercise, uncoupling of the LT and VT was observed. Specifically, with suppression of peak exercise (NH4+) by MSG, the LT was delayed (r = -0.84, p = 0.03), the VT was earlier (r = 0.86, p = 0.02), and the VO2 difference between the LT and VT widened (r = -0.90, p = 0.02). We conclude that NH4+ plays a role in determining the LT and VT of incremental exercise and that the VT may not be exclusively dependent on blood lactate.

We evaluated nasal anesthesia regimens by comparing, in seven normal men, four drug regimens: 1) 1 percent phenylephrine; 2) 4 percent lidocaine; 3) 1 percent phenylephrine + 4 percent lidocaine; and 4) 5 percent cocaine. After spraying each drug into the anterior nares, vasoconstriction, decongestion, and nasal anesthesia (measured as transnasal depth of nasogastric (NG) tube insertion before discomfort) were assessed. There were no significant differences in NG tube insertion depth between the regimens (p = 0.54). Insertion depth was significantly increased after 10 ml of 2 percent viscous lidocaine were sniffed (p less than 0.004), but again, differences between regimens were not significant (p = 0.051). One hundred bronchoscoped patients received one of the following sprayed into the nose: 1) placebo (P); 2) 1 percent phenylephrine + P; 3) 1 percent phenylephrine + 4 percent lidocaine; or 4) 5 percent cocaine + P. Each patient then sniffed viscous lidocaine. There were no significant differences between regimens for any of the following: 1) nasal resistance to bronchoscope insertion, 2) patient's nasal discomfort, or 3) bronchoscopist's perception of patient discomfort. We conclude that sprayed anesthetics contribute little to nasal anesthesia and any regimen appears acceptable when viscous lidocaine is used.

To evaluate the effect of long-term bronchodilator therapy in CF patients with demonstrated bronchial hyperresponsiveness, we first performed methacholine challenges to determine responsiveness, then entered 27 patients (16 methacholine responders and 11 nonresponders) into a two-month double-blind crossover trial of albuterol, 90 micrograms by inhalation four times a day vs placebo. Among the responders, daily PEFR measures improved significantly more during treatment with albuterol (12 +/- 32 L/min) than with placebo (-0.4 +/- 19 L/min; p less than 0.05). In addition, a clinically important level of improvement in PEFR (15 percent increase) was reached significantly more frequently in the responders. Methacholine nonresponders had no change in PEFR on either albuterol or placebo. Daily symptom scores as well as spirometry measurements at biweekly visits did not show significant changes. We conclude that long-term therapy with inhaled albuterol improves lung function in CF patients, but only in those with bronchial hyperresponsiveness as demonstrated by methacholine challenge.

Conflicting reports have appeared concerning the role of anticholinergic agents in the treatment of acute asthma. This study was designed to determine whether atropine sulfate, the only anticholinergic agent currently available in the United States for nebulization, increases bronchodilation when added to an inhaled beta-adrenergic agonist during the initial treatment of an acute asthma attack. Adults asthmatics (n = 40) with acute asthma attacks were randomized to receive metaproterenol (5 percent solution, 0.3 ml) either alone or with atropine sulfate (2.5 mg), by nebulization. Spirometry, vital signs, and the presence of side effects 0, 30, 60, and 120 minutes after treatment were determined. There were no significant differences between the metaproterenol alone and metaproterenol plus atropine sulfate groups in regard to age, duration of asthma, baseline spirometry, or side effects. No differences were noted between the two groups regarding changes in FEV1 and FVC from baseline (expressed in milliliters or as a percentage of baseline) during the observation period. We conclude that nebulized atropine sulfate yields no additional benefit when added to metaproterenol during the initial treatment of an acute asthma attack.