Chronic hypoxemia is associated with development of secondary polycythemia. To evaluate effects of transient hypoxemia on serum EPO activity in patients with chronic lung disease, we studied six oxygen-dependent patients who underwent either a 4-h oxygen withdrawal or their routine therapy, in a randomized, blinded fashion, on two separate days. Serum EPO did not differ at baseline between study days. Erythropoietin levels did not change significantly over time during normoxic conditions. Under hypoxic conditions, serum EPO levels rose over 4 h with the change from baseline first becoming significant at 2 h. The log of serum EPO response showed an inverse correlation with the level of arterial oxygen saturation. We conclude that patients with chronic lung disease are able to produce EPO in response to acute hypoxemic stress. Transient episodes of hypoxemia, such as occur during sleep or exercise, may result in increased red blood cell production stimulated by this EPO response.

It has been demonstrated recently that inhaled furosemide inhibits bronchoconstriction induced by cold air, physical exercise, various antigens, and metabisulfite. The goal of the present study was to determine if the inhalation of furosemide would inhibit the bronchoconstriction resulting from the inhalation of lysine-aspirin in aspirin-sensitive asthmatics. Six female subjects with known hypersensitivity to aspirin participated in this crossover study comparing 20 mg of inhaled furosemide and placebo. The volunteers inhaled increasing concentrations of lysine-aspirin after the inhalation of furosemide or placebo. The geometric mean provocative dose causing a 20 percent decrease in the FEV1 (PD20) after the inhalation of placebo was 30.4 mg/ml and the PD20 was equal or below 90 mg/ml in all patients. In contrast, the FEV1 did not decrease by 20 percent in any of the patients pretreated with furosemide when the inhaled concentration was increased to 360 mg/ml. From this study, we conclude that the administration of furosemide blocks the bronchospasm induced by the inhalation of lysine-aspirin in aspirin-sensitive asthmatics.

The treatment of nocturnal asthma remains a challenge. We investigated the use of a pulsed-released albuterol in ten patients with nocturnal symptoms of asthma. In a randomized, double-blind, placebo-controlled, crossover designed study, we tested the use of 8 mg of pulsed-release albuterol sulfate (Proventil Repetabs) vs placebo. The pulsed-release albuterol significantly blunted the overnight drop in FEV1, improved peak flow readings in the morning, and decreased subjective awakenings from sleep. We conclude that pulsed-released albuterol is an effective therapeutic option in patients with nocturnal asthma.

The thresholds used to define a positive result for bronchial provocation challenges (BPC) are arbitrary. Requiring smaller decrements in expired flow to define a positive study would capture more cases of reactive airways (increased sensitivity) but would include some "normal" responses (decreased specificity). To examine the relationship between threshold definition and the ability to correctly classify subjects as either normal or as having airways hyperresponsiveness (AHR), four different BPC tests were administered on different days to 20 patients with a clinical diagnosis of exercise-induced bronchospasm (EIB) and 20 control subjects. The four BPC tests were indoor exercise on a cycle ergometer, methacholine inhalation challenge (MIC), eucapnic voluntary hyperventilation (EVH) with dry gas, and EVH with cold gas. Our results indicate that the thresholds which best separate the two groups are different for each of the four BPC techniques. For methacholine inhalation (MIC), a fall in FEV1 (d%FEV1) of 15 percent or greater at 188 cumulative breath units was 100 percent specific for AHR but had a sensitivity of only 55 percent. Eucapnic voluntary hyperventilation (EVH) with room temperature dry gas was 100 percent specific at a d%FEV1 of 11 percent, but, at that threshold, sensitivity was only 50 percent. EVH with cold air was 100 percent specific at a d%FEV1 of 12 percent but sensitivity was only 35 percent. The bicycle ergometer challenge was far too insensitive to be of value in evaluating AHR. Based on their respective receiver operating characteristic curves, the best separation of the two subject groups occurred at a d%FEV1 of 5 percent and 12 percent for the two EVH techniques and MIC, respectively. An individual's response to one test was highly correlated with the response to either of the other two (r = 0.66, p less than 0.001 for dry vs cold gas EVH; r = 0.56, p less than 0.001 for dry gas EVH vs methacholine; and r = 0.69, p less than 0.001 for cold gas EVH vs methacholine). Thus, MIC and EVH techniques are equally useful in defining AHR and each has its optimal threshold for a positive test result.

Twelve patients with stable asthma (mean age, 39 years; asthma duration, 11 years; mean forced expiratory volume in 1 s, 65 percent of predicted; and reversibility, 31 percent) were studied in a double-blind crossover trial. The patients were studied during three test days. Airway resistance and specific airway conductance (Raw and SGaw) were measured using a body plethysmograph and pulse rate, blood pressure, tremor, and subjective effects were recorded before and 1, 3, 5, 10, 15, 30, 60, and 120 min after the test doses. A baseline Raw variability of +/- 20 percent was allowed between the test days. Formoterol 12 micrograms, 24 micrograms, and terbutaline 500 micrograms were given in a spacer (Nebulator) in a randomized double-blind crossover manner as two puffs with a 30-s interval in between. The effect of formoterol 12 micrograms on Raw was significantly better than terbutaline after 3, 5, 10, 60, and 120 min. Formoterol 24 micrograms was significantly better than terbutaline as soon as 3 min after inhalation and at every point in time after that. Formoterol 24 micrograms tended to be better than formoterol 12 micrograms but the differences were not significant at any point in time. All three treatments were well-tolerated. No differences were observed for pulse rate, blood pressure, tremor, or palpitations. The overall onset of bronchodilatation after formoterol 12 and 24 micrograms was faster than after terbutaline 500 micrograms. The tolerability of formoterol was good.

The aim of this study was to investigate whether the administration of prednisone potentiates any of the acute biochemical and cardiovascular effects of high-dose inhaled beta-agonist drugs. These agents are known to cause dose-related changes in plasma potassium and glucose, as well as ECG changes in heart rate, corrected QT interval (QTc), T wave, and U wave. On theoretical grounds, the concomitant use of systemic corticosteroids might enhance these actions. Twenty-four healthy subjects were randomized to receive one of three treatments: salbutamol 5 mg or fenoterol 5 mg or normal saline solution. Each drug was administered twice, 30 min apart by nebulizer, and the procedure was repeated after each subject had received prednisone 30 mg daily for one week. Plasma potassium and glucose levels were measured, and ECGs were obtained after each treatment, together with 12-h Holter monitoring for arrhythmias. Changes in plasma potassium and glucose following nebulized beta-agonist were significantly greater after treatment with prednisone. Baseline potassium level fell from 3.75 mmol/L (95 percent CI 3.61, 3.89) to 3.50 mmol/L (95 percent CI 3.36, 3.64), and thereafter all values were significantly lower at each time point (p = 0.003). The lowest mean plasma potassium was obtained 90 min after fenoterol administration with prednisone pretreatment: 2.78 mmol/L (95 percent CI 2.44, 3.13). Increases in heart rate and QTc interval following both beta-agonist drugs were significant, but T-wave amplitude reductions did not reach significance. Prednisone treatment did not significantly alter the cardiovascular responses. Supraventricular and ventricular ectopic activity was related to beta-agonist use, but no potentiating effect was noted following steroid treatment. We conclude that the acute biochemical effects of beta-agonist administration are augmented by prior treatment with prednisone, but this is not the case for ECG effects. However, the degree of hypokalemia noted as a result of this drug interaction may be of clinical significance in the hypoxic conditions of acute airways obstruction.

The real need for extensive staging at the time of diagnosis is discussed in regard to small cell lung carcinoma. We performed a decisional retrospective analysis on a series of 182 patients, based on three staging steps: the first step included physical examination and routine biologic tests. The second step consisted of liver ultrasonography and needle aspiration of any clinically detectable tumor mass, and the third step included bone marrow examination, radionuclide bone scan, thoracic, abdominal, and brain CT scan. A stepwise multivariate logistic regression performed on 11 variables considered in the first step shows that a four-parameter model can predict the spread of the disease (limited or extensive): weight loss, performance status, and elevated LDH or alkaline phosphatase levels. Limited disease can be predicted in two ways: (1) elevated LDH with normal alkaline phosphatases, no weight loss, and good performance status, or (2) normal LDH and alkaline phosphatases. In this series, 28 percent of patients can be predicted as having extensive disease and can be treated with chemotherapy alone without chest irradiation. After the second step, the probability of disease being extensive is only 25 percent, and only 84 (46.15 percent) patients would need to undergo the third step of staging procedures (brain CT scan, bone marrow aspiration and biopsy, radionuclide bone scan) with this method. We conclude that a multistep approach represents a simple staging method and offers the advantage of harmlessness and lower costs for patients not to be evaluated in prospective clinical trials.

To investigate whether enalapril (E) 10 mg and spironolactone (S) 100 mg attenuate the hypokalemic effect of inhaled terbutaline (T).

Septic shock is characterized by hypoperfusion and tissue energy defects. We prospectively evaluated the therapeutic benefit of augmenting cardiac output and therefore oxygen delivery (DO2) on mortality in patients with septic shock. Twenty-five patients were randomized to a normal treatment (NT) group and 26 patients were randomized to an optimal treatment (OT) group. All patients had a clinically evident site of infection, sepsis as defined by a systemic response to the infection, and shock indicated by systemic hypoperfusion. Patients were treated during the initial 72 h by an algorithm differing only in the end point of resuscitation. The cardiac index (CI) was increased to 3.0 L/min/m2 in the NT group and to 6 L/min/m2 in the OT group. There were no significant differences in cardiorespiratory parameters in the NT and OT groups on entrance into the study. During treatment, CI averaged 3.6 +/- 0.2 L/min/m2 and DO2 averaged 8.6 +/- 0.8 ml/min/kg in the NT group and CI averaged 5.1 +/- 0.2 L/min/m2 and DO2 averaged 12.2 +/- 0.7 ml/min/kg in the OT group (p less than 0.01). A significant correlation between DO2 and survival was observed. Seventy-two percent of the OT patients died vs 50 percent of the NT patients (p = 0.14). Surviving NT patients stayed 13.7 +/- 3 days in the ICU vs 7.4 +/- 0.6 days (p less than 0.05) for the OT patients. Since some of the NT patients were spontaneously hyperdynamic and some of the OT patients did not achieve their desired end point, patients were arbitrarily subsetted using a midpoint CI of 4.5 L/min/m2. The NT less than 4.5 group had a CI of 3.1 +/- 0.2 L/min/m2 and DO2 of 10.9 +/- 1.0 ml/min/kg while the OT group greater than 4.5 L/min/m2 had a CI of 5.7 +/- 0.2 L/min/m2 and a DO2 of 13.8 +/- 0.7 ml/min/kg (p less than 0.01). Mortality in the NT less than 4.5 group was 74 percent as compared with 40 percent in the OT greater than 4.5 group (p less than 0.05).

In a series of 253 high-risk surgical patients, we measured the oxygen consumption (VO2) at frequent intervals before, during, and immediately after surgical operations and calculated the rate of VO2 deficit from the measured VO2 minus the VO2 need estimated from the patient's own resting preoperative control values corrected for both temperature and anesthesia. The calculated oxygen deficit was related to multiple organ failure, complications, and outcome. The 64 patients who died all had organ failure; their cumulative VO2 deficit averaged 33.2 +/- 4.0 L/m2 (+/- SEM) at its maximum, which occurred 17.8 +/- 2.2 h after surgery. In the 31 survivors with organ failure, the cumulative VO2 deficit averaged 21.6 +/- 3.7 L/m2 at its maximum, which occurred 10.1 +/- 2.7 h after surgery (p less than 0.05). In the 158 survivors without organ failure or major complications, the maximum cumulative VO2 deficit averaged 9.2 +/- 1.3 L/m2 at 4.1 +/- 0.6 h after surgery (p less than 0.05). In a prospective randomized clinical trial, a protocol group maintained at supranormal hemodynamic and oxygen transport values had significantly reduced oxygen debt (7.6 +/- 3.4 L/m2 vs 17.3 +/- 6.8 L/m2; p less than 0.05), fewer organ failures, and lower mortality (4 percent vs 33 percent; p less than 0.05) compared with a control group maintained at normal hemodynamic values. The data demonstrate a strong relationship between the magnitude and duration of the VO2 deficit in the intraoperative and early postoperative period and the subsequent appearance of organ failure and death. The latter may be reduced when oxygen debts were prevented or minimized by augmenting naturally occurring compensations that increased oxygen delivery.

To investigate the effect of nedocromil sodium on changes in airway reactivity to methacholine induced by platelet activating factor, we studied 12 nonasthmatic, nonatopic subjects (24 to 41 years) in a double-blind trial. The FEV1 and airflow at 30 percent of vital capacity from a partial forced expiration (V30p) were used to assess changes in airway caliber. Two concentration-response curves to doubling concentrations of MCh (from 0.3 mg/ml) were performed 48 h apart. The concentrations of MCh causing a 20 percent fall in FEV1 (PC20FEV1) or a 40 percent fall in V30p (PC40V30p) were calculated. After the first MCh challenge, subjects were matched by airway reactivity and randomly assigned to nedocromil sodium (two puffs qid 2 mg/puff) or placebo treatment. Two days after the second MCh challenge, PAF was inhaled, and changes in airway caliber were recorded. Administration of either nedocromil sodium or placebo was ended at this time and airway response to MCh was assessed two days after PAF. The two concentration-response curves to MCh obtained before PAF exposure were superimposable. The PAF caused a dose-related bronchoconstriction in both groups; the maximal fall in V30p was 27.6 +/- 6.6 percent (mean +/- SE) in the nedocromil sodium group and 37.4 +/- 4.6 percent in the placebo group. Two days after PAF, the PC20FEV1 did not change in subjects who received nedocromil sodium (4.86 vs 4.32 mg/ml; geometric mean), but it fell from 6.59 to 1.12 mg/ml (p less than 0.05) in placebo-treated subjects. These results indicate that nedocromil sodium inhibits PAF-induced increase in airway reactivity.

In untreated patients with uncomplicated essential hypertension, exercise induces an abnormal increase in blood pressure; the influences of this increase on exercise were evaluated by a cardiopulmonary exercise test (CPX) performed in control conditions (step 1) and during acute blood pressure reduction (step 2). Patients were classified as (1) normotensive (resting diastolic blood pressure [BPd] less than 90 mm Hg; n = 14), (2) mildly hypertensive (BPd of 90 to 104 mm Hg; n = 9), and (3) moderately to severely hypertensive (BPd greater than or equal to 105 mm Hg; n = 16). For the three groups, peak mean blood pressure during exercise was 125 +/- 5 mm Hg (mean +/- SEM), 144 +/- 3 mm Hg (p less than 0.01 vs normotensive), and 161 +/- 4 mm Hg (p less than 0.01 vs normotensive and p less than 0.01 vs mild hypertension), respectively. Oxygen consumption (VO2) at peak exercise and at ventilatory anaerobic threshold was 26.1 +/- 1.1 and 17.2 +/- 0.5 ml/min/kg, 25.4 +/- 1.1 and 16.9 +/- 0.8 ml/min/kg, and 26.4 +/- 1.3 and 17.5 +/- 1.2 ml/min/kg in normotensive subjects, those with mild hypertension, and those with moderate to severe hypertension, respectively. Fourteen normotensive subjects, six with mild hypertension, and nine with moderate to severe hypertension participated to step 2 (nifedipine vs placebo, double-blind crossover). Nifedipine reduced blood pressure at rest and at peak exercise in those with hypertension. Peak exercise VO2 was unaffected by nifedipine in both normotensive subjects and those with hypertension. With nifedipine, ventilatory anaerobic threshold occurred earlier and at a lower VO2 in mild and in moderate to severe hypertension (delta VO2 = -1.9 and -2.4 ml/min/kg, respectively). These findings might be due to nifedipine-induced redistribution of blood flow during exercise and might be the reason for the complaint of weakness after blood pressure reduction in hypertensive subjects.

A survey of four inhaled beta-agonist agents was evaluated as a means of selecting the optimum agent for chronic therapy in patients with stable COPD. Eighteen patients completed as protocol of prebronchodilator and postbronchodilator spirometry utilizing albuterol, metaproterenol, pirbuterol, and terbutaline daily in random order. Subsequently, each patient received treatment with either the greatest or least response-invoking agent for four weeks, followed by a second interval with the opposite agent. At the end of each interval, the results of repeat spirometry, arterial blood gas determinations, 12-min walks, dyspnea questionnaires, and self-monitored peak expiratory flow rates were recorded. Use of the greatest response-invoking agent resulted in significantly larger prebronchodilator and postbronchodilator FEV1 and FVC. No other study factor was significantly different. Acute bronchodilator surveys may have a role in medication selection in view of the improvement in spirometric volumes.

Our objective was to compare the differential effects of age and drug type on bronchodilator response.

Survival rates for persons receiving intensive care for Pneumocystis carinii pneumonia have improved. However, the utility of prolonged intensive care for patients who do not show initial improvement remains unclear. We assessed survival in a nested cohort study of patients receiving intensive care while participating in a randomized trial of early adjunctive corticosteroids for Pneumocystis pneumonia. Twenty-eight of 251 (11 percent) participants were admitted to an intensive care unit. Fourteen (50 percent) of these were discharged alive from the intensive care unit and 11 (39 percent) were discharged alive from the hospital. Survivors and nonsurvivors were similar demographically and with respect to treatment received but differed in the mean days of intensive care received (4.5 vs 8.6 [p = 0.02]). The conditional probability surviving to hospital discharge after intensive care dropped steadily from 39 percent at intensive care unit admission to 17 percent after one week and to 0 percent after two weeks.

The optimal antibiotic dosage in serious chest infections is not established and commonly used regimens may well be excessive. We have compared the efficacy of a low dose of cefotaxime (2 g every 12 h) with a more usual dose (2 g every 8 h) in a prospective, randomized study of the treatment of chest infections in the seriously ill. Fifty intensive care unit patients received either regimen for five days. The two groups appeared demographically comparable. Clinical resolution occurred in 86 percent, no change occurred in 4 percent, and deterioration occurred in 10 percent. Microbiologic clearance occurred in 52 percent of those in whom a pathogen was isolated (46 percent of patients). There was no significant difference in clinical or microbiologic response between the two regimens. It is concluded that cefotaxime in a dose of 2 g twice daily is effective in the treatment of serious chest infections.

We compared the bronchodilator effects and systemic tolerability of 12, 24 and 48 micrograms formoterol DP capsules with 12 micrograms formoterol MDI and placebo in 30 patients with reversible obstructive airway disease. Pulmonary function tests were done and pulse rate and blood pressure were recorded. We observed significant differences between all active substances vs placebo regarding peak effect, duration of effect and AUC value. No significant difference was observed between either 12 or 24 micrograms formoterol DP and 12 micrograms from MDI in all mentioned parameters. With 48 micrograms DP, increased peak effect, AUC and duration of effect were noted. Heart rate Holter monitoring showed a slightly more pronounced effect with 48 micrograms. We conclude that 12 to 24 micrograms formoterol DP capsules are equivalent to 12 micrograms of formoterol MDI regarding efficacy and tolerability, while 48 micrograms formoterol DP capsules cause more profound effects in bronchodilation and on the heart rate.

Astemizole, administered for seven days to asthmatic subjects, had an effect of bronchoconstriction induced by inhaled histamine for a mean period of 42 days. This study evaluates whether a single dose of astemizole would have the same effect.

A study to assess the effect of the long-term use of triamcinolone acetonide (TA) on adrenal function was conducted with 143 male and female patients with asthma who were randomly assigned to receive 800, 1200, or 1,600 micrograms of TA daily for six months. Adrenal function was assessed prior to treatment and after two weeks and one, three, and six months of TA use. The effect of TA was evaluated by measuring plasma cortisol levels just prior to and 30 min after a bolus IV injection of 0.25 mg cosyntropin. Adrenal suppression was assumed if the plasma concentration of cortisol did not increase by at least 7 micrograms/dl from the prestimulation value, and remained below 18 micrograms/dl 30 min after the cosyntropin injection. Urine collected for 24 h prior to each cosyntropin stimulation was assayed for free cortisol and related metabolites to confirm suppression. Although all treatment regimens caused some reduction in the 24-h excretion of corticosteroid products, none of the mean values was below the normal ranges. The mean data indicate that TA had no significant effect on adrenal function at any dose or at any time for the patients overall. Individually, three patients exhibited some reduction in adrenal function.

A validation study was performed on the MESAM 4, a digital recording device developed to monitor oxygen saturation, heart rate (HR), snoring, and body position in order to screen subjects for obstructive sleep apnea syndrome (OSAS). MESAM 4 recordings were scored with the computer-based automatic scoring system provided with the equipment. Nocturnal polysomnography (PSG) and MESAM 4 recordings were run simultaneously on 56 subjects presenting with any type of sleep complaint, including those secondary to OSAS. Patients were assigned to one room by hospital administration and were monitored consecutively. The polygraphic equipment and MESAM 4 equipment were placed on the subjects by separate teams. Records of PSG and MESAM 4 were analyzed in double-blind fashion. With the MESAM 4 computerized analysis, three indices based on SaO2 (ODI), on heart rate (HVI), and on snoring (ISI) were obtained, and the number of abnormal respiratory events occurring during the time selected for analysis (TAT) were determined. Polysomnographic records were scored by 30-s epochs following the American Sleep Disorders Association standards for sleep states and stages and for sleep-related events, including sleep apneas, hypopneas, and periodic leg movements. Following independent scoring, 26 subjects were identified with OSAS by PSG, while MESAM 4 identified 25 subjects with OSAS using oxygen algorithm; all had a respiratory disturbance index greater than or equal to 10 with PSG. Results of each polysomnogram and each MESAM 4 analysis were compared. With the polysomnogram used as a standard, the degree of error for each variable with the MESAM 4 was calculated. Specificity and sensitivity of the most accurate index of the MESAM 4, the ODI, were 97 percent and 92 percent, respectively. The other two indices, HVI and ISI, were less accurate: specificity and sensitivity were 32 percent and 58 percent for HVI and 27 percent and 96 percent for ISI. Nevertheless, a combination of all three indices (ODI, HVI, ISI) would have prevented the two false-positive cases we observed. The results of this validation study show that MESAM 4 can be helpful to general practitioners, clinicians, and epidemiologists as a low-cost screening device for subjects with OSAS and habitual snoring.