The bronchodilator effect of nebulized AMN, albuterol and their combination was evaluated in 16 steroid-dependent asthmatic children. In phase 1, maximal bronchodilation was determined by dose-response studies on separate days. Maximal bronchodilator dose of each drug was administered either alone or in combination during phase 2. In phase 1, 0.11 +/- 0.01 mg/kg of albuterol and 0.03 mg/kg of AMN produced maximum bronchodilation. In phase 2, the peak response to albuterol occurred within 30 min and to AMN, at 60 min. Maximal FEV1 achieved after AMN was 90 percent of the maximal achieved after albuterol. AMN FEV1 response was better than for placebo for 3 h; that for albuterol was better for 4 h. Combination therapy produced a peak response similar to that of albuterol but was better than albuterol by 6 h. Thus, the maximum bronchodilator effect of AMN is less than that of albuterol in asthmatic children, but the combination may extend the period of bronchodilatation.

The effect of four weeks of treatment with beclomethasone dipropionate (BDP, 500 micrograms twice daily) on the bronchial responsiveness to propranolol was examined in 16 patients with mild asthma in a placebo-controlled, double-blind crossover study. Propranolol was inhaled in doubling concentrations and the results were expressed as the cumulative dose producing a 20 percent fall in FEV1 (PC20). After four weeks of treatment with BDP, the mean FEV1 increased from 82.0 percent predicted to 88.1 percent predicted. The difference was significant (p less than 0.001). Treatment with BDP did not significantly change the responsiveness to propranolol, the geometric mean PC20 being 3.17 mg/ml before and 3.64 mg/ml after BDP treatment. The recovery of FEV1 was faster after 60 minutes of BDP treatment in comparison with placebo treatment (beyond 90 minutes). This study suggests that BDP treatment is unable to reduce bronchial responsiveness to propranolol but can accelerate the recovery of bronchoconstriction induced by propranolol in asthmatic patients.

We wanted to determine the long-term effects of a continuous infusion of PGE1 on DO2 and VO2 in patients with ARDS. Data were obtained from a randomized double-blind multicenter trial, which evaluated the effects of PGE1 on survival in patients with ARDS. Patients were stratified according to treatment and outcome: placebo-died (n = 8); PGE1-died (n = 12); placebo-survived (n = 9); and PGE1-survived (n = 8). In the placebo-died group, elevations occurred in VO2, which were associated with increases in O2ext and a constant DO2. In contrast, in the PGE1-died group, elevations in VO2 were associated with increases in DO2 and an unchanged O2ext. In the placebo-survived group, VO2 and DO2 decreased, whereas in the PGE1-survived group, VO2 and DO2 increased; however, O2ext decreased in both of these groups. Since impaired O2ext occurs in ARDS, PGE1-induced elevations in DO2, rather than compensatory increases in O2ext, may achieve better tissue oxygenation. We conclude that although the recently completed multicenter trial failed to show an enhancing effect of PGE1 on survival in patients with advanced ARDS, PGE1 may have important effects on oxygen transport and, therefore, may still have a role in the treatment of early manifestations of ARDS, either alone or in combination with other agents.

Nasal CPAP is presently accepted as first-line therapy for obstructive sleep apnea, but a significant minority of patients do not tolerate nasal CPAP. The purpose of this study was to compare the benefits of nasal CPAP, nasal oxygen (O2), and placebo (air) using patients as their own controls. We studied eight men, aged 33 to 72 (mean 57 years), who had mild obstructive sleep apnea. To be eligible for study, patients had to have an apnea plus hypopnea index greater than or equal to 5, plus one or more of the following: blood pressure greater than 150/95 mm Hg, multiple sleep latency test mean score less than or equal to 10 minutes, or significant nocturnal cardiac ectopy. After a baseline study, patients received a month each of nocturnal O2 at 4 LPM and air at 4 LPM, presented in random order. The third month of treatment consisted of nasal CPAP (range 2.5 to 12.5 cm H2O). Patients underwent evaluation at baseline and after each month of treatment. It was concluded that oxygen was more effective in improving oxygenation and hypopneas than is nasal CPAP. However, oxygen did not reduce apneas or improve daytime hypersomnolence as well as nasal CPAP in patients with mild OSA. Oxygen might be considered as an alternate form of treatment for patients who are not hypersomnolent, or as an adjunct to nasal CPAP.

Single dose studies have assessed the utility of ipratropium bromide alone or with beta agonists in the short- and long-term management of chronic obstructive lung disease and asthma. We performed a randomized, double-blind trial to assess the incremental benefit over 24 hours of adding ipratropium vs placebo to a standardized regimen of medications commonly used in the acute and subsequent hospital management of COPD and asthma. Sixty-eight subjects received nebulized salbutamol, intravenous methylprednisolone, intravenous aminophylline, and antibiotics and were randomized to receive either 80 micrograms of ipratropium or placebo via metered dose inhaler and spacing device with each salbutamol treatment (6 to 8 times per day). Among the 50 patients who completed the study, there were no significant differences between ipratropium and placebo groups with respect to baseline FEV1, FVC, and PaCO2. The improvement of FEV1 from baseline to 24 hours was 294 (SD = 568) ml in the ipratropium group vs 393 (SD = 622) ml in placebo group. Adjusting FEV1 by age, gender, and smoking did not significantly alter the findings. Those with an admission diagnosis of asthma showed larger 24 hour FEV1 responses (487 ml in ipratropium vs 801 ml in placebo) than those with COPD (149 ml ipratropium vs 102 ml in placebo). However, within these two strata, there were no significant differences in FEV1 improvement between ipratropium and placebo groups. This study suggests that if ipratropium is used in the initial emergency treatment of COPD or asthma, it could safely be discontinued by 24 hours in order to reduce the cost and complexity of therapy.

To compare conventional versus ultrasound-guided internal jugular vein cannulation techniques.

Continuous positive-pressure ventilation and PSV were compared prospectively in patients at a surgical intensive care unit. All patients suffered from mild to moderate ARI (PaO2/FIO2 of 125 to 350 mm Hg). The patients were randomly assigned to a PSV group (n = 28) or a control group with continued CPPV (n = 27). The usual hemodynamic and oxygenation variables, ITBV, and extravascular lung water (ETV) were assessed before and six hours after switching to PSV. The changes (d) of PaO2/FIO2, RI, and P(A-a)O2 were used for evaluation of the effect of PSV. Significant correlations were found between the ETV(CPPV) and dPaO2/FIO2 (r = -0.672), ETV(CPPV) and dRI (r = 0.722), and ETV(CPPV) and dP(A-a)O2 (r = 0.601), which led to the conclusion that the level of ETV determined the efficacy of PSV. In the subgroup with ETV less than 11 ml/kg (n = 15), PSV significantly improved PaO2/FIO2 (248 to 286 mm Hg), RI (1.55 to 1.22), ITBV (801 to 888 ml/m2), cardiac index (4.21 to 4.76 L/min.m2), stroke index (42.2 to 48.1 ml/m2), and oxygen delivery (735 to 833 ml/min.m2). In the subgroup with ETV greater than 11 ml/kg (n = 13), PSV caused a significant deterioration of PaO2/FIO2, RI, and intrapulmonary shunt. It is concluded that in patients with moderate ARI in whom ETV is almost normal, PSV is superior to CPPV, and the efficacy of PSV is independent of the level of oxygenation during CPPV.

To determine the efficacy of nedocromil sodium in adult asthma patients using bronchodilators alone to control their disease, a consecutive sample of 127 patients with long-term asthma was studied for 16 weeks. The patients were maintained on sustained release theophylline preparations (SRT) and inhaled and oral beta-adrenergic bronchodilators (beta 2). One hundred sixteen patients (90 percent) completed the study; one placebo-treated patient withdrew owing to throat irritation and wheezing. Nedocromil sodium provided an additional benefit to adult patients receiving SRT and inhaled beta 2-agonists. With the exception of night-time asthma, nedocromil sodium maintained this improvement for the final 12 weeks of the study despite a reduction in concomitant bronchodilator therapy.

The effect of caffeine on exercise-induced bronchoconstriction was examined in ten patients with bronchial asthma. Placebo and caffeine 3.5 mg/kg and 7 mg/kg were given two hours before exercise. Spirometry was taken at one and two hours following caffeine and at 5, 15, and 30 minutes following exercise. Caffeine significantly improved baseline FEV1 and prevented exercise-induced bronchoconstriction only at a dose of 7 mg/kg. Caffeine was well tolerated by the patients. These data suggest that only high doses of caffeine significantly prevent a postexercise drop in FEV1.

We designed a randomized controlled study to evaluate the benefit of upper-limb exercise training, alone and in combination with walking training, in patients with severe CAO. In an outpatient department supervised by a physiotherapist, we evaluated 28 patients with severe stable CAO (FEV1, 32 percent of predicted). Patients were randomly allocated to either a control (eight), upper-limb (six), lower-limb (seven), or combined (seven) exercise group. The upper-limb group trained with a circuit of upper-limb exercises, the lower-limb group by walking, and the combined group with both. Exercise was for one hour three times per week for eight weeks. Assessment before and after training included pulmonary function, mouth pressures, respiratory muscle endurance, maximal bicycle exercise test, maximal and submaximal arm ergometer, six-minute walking distance, and a scale of well-being (Bandura scale). Twenty-six patients completed the program. There was a significant improvement (Wilcoxon rank sum test) in the following: six-minute walking distance in the lower-limb (p less than 0.005) and combined (p less than 0.003) groups; arm ergometer in the upper-limb (p less than 0.005) and combined (p less than 0.04) groups; and the scale of well-being in the combined (p less than 0.005) group. There was no significant change in any other parameter measured. We conclude that exercise training improves exercise performance in severe CAO, that the training is specific for the muscle group trained, and that upper-limb exercises should be included in training programs for these patients.

This prospective study was done to determine whether immediate echocardiography, to implicate or exclude a cardiac basis for breathlessness, can improve the management of acute dyspnea. One hundred ninety-six consecutive patients admitted to the hospital with a chief complaint of dyspnea were randomized to receive or not receive an echocardiogram within 24 hours of admission. Most patients randomized to echo and control groups had cardiac or pulmonary disease and were comparable in their other clinical characteristics. Predefined study end points included the following: change in diagnosis or treatment; performance of additional diagnostic cardiopulmonary studies; and duration of hospitalization (the principal end point). Changes in diagnosis or treatment during hospitalization were as infrequent among patients randomized to echo as among control patients. Echocardiography independently confirmed the clinical diagnosis in 72 percent of echo-randomized patients. Even when echo findings conflicted with the clinical diagnosis, the diagnosis and management plan rarely changed. Additional cardiac or pulmonary studies were ordered as frequently among patients randomized to echocardiography as among those randomized to control. The mean duration of hospital stay also did not differ between the two groups, and no clinical parameter served to predict which subgroup of patients might benefit from echocardiography. Although echocardiography can be expeditiously obtained during respiratory exacerbations of cardiopulmonary disease, indiscriminate echo does not necessarily hasten or alter the treatment of such patients.

The first Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto (GISSI) study showed striking evidence of the effectiveness and safety of intravenous thrombolytic treatment in acute myocardial infarction (MI). Since publication in The Lancet, the original report has become a reference work for every paper which deals with thrombolysis. In addition to GISSI's scientific value, these studies applied formal research to routine clinical practice outside of referral centers. Nearly all Italian CCUs took part in the GISSI projects, so that the results provide a profile of the patient who seeks care for acute MI in Italy. This wide data base allowed GISSI investigators to look into some relevant clinical events, eg, primary ventricular fibrillation, stroke, and in-hospital reinfarction. The GISSI-2 trial followed the GISSI-1 philosophy. The package of treatments recommended after extensive discussion with all the investigators (beta-blocker, aspirin, nitrates) was widely adopted. Now, only five years after the start of the GISSI-1, the overall mortality of Italian patients with acute MI has decreased from 13.0 percent to about 9 percent, and the number of patients with acute MI arriving in hospital within 1 h of the onset of symptoms has increased 50 percent. It is the wish of the GISSI investigators that this approach to treating acute MI will be regarded and acknowledged as their major contribution to the problem.

We studied the treatment of multiple rib fractures in NIC, comparing ventilatory with nonventilatory methods in 69 patients who were randomly allocated to one of the following two treatments: (1) a CPAP mask combined with regional analgesia (n = 36); or (2) endotracheal intubation and mechanical ventilation with PEEP (n = 33). Clinical outcome was as follows: mean duration of treatment, 4.5 +/- 2.3 days for the group with CPAP and 7.3 +/- 3.7 days for the intubated group (p = 0.0003); mean number of days spent in intensive care, 5.3 +/- 2.9 days and 9.5 +/- 4.4 days, respectively (p = less than 0.0001); mean period of hospitalization, 8.4 +/- 7.1 days and 14.6 +/- 8.6 days, respectively (p = 0.0019); and patients developing complications: 28 percent (10/36) and 73 percent (24/33), respectively. Infections caused the difference in complications, primarily pneumonias, which occurred in 14 percent (5/36) of the group with CPAP but in 48 percent (16/33) of the intubated group. We conclude that treatment with a CPAP mask combined with regional analgesia can shorten and simplify treatment in these patients, mainly through a decreased infection rate, when compared with intubation and mechanical ventilation, and we recommend this treatment in patients similar to our sample.

In a double-blind, crossover study, nebulized ketanserin, a 5-HT2 receptor antagonist, and a placebo were given to eight patients with moderate to severe nonasthmatic COPD. Intravenous ketanserin had rapid onset of action and induced a longer lasting bronchial response than inhaled ketanserin. These results confirm that ketanserin acts as a mild bronchodilator in patients with COPD and demonstrate that the inhaled route has no advantage over the intravenous route in terms of effectiveness. Thus, 5-HT may play a role in bronchomotor tone, at least in patients with chronic airway obstruction.

Two promising novel recombinant tissue-type plasminogen activator (rt-PA) regimens for pulmonary embolism (PE) are being actively investigated: 100 mg/2 h as a continuous peripheral intravenous infusion, and bolus rt-PA, adjusted to weight, as a 2-min infusion. For deep venous thrombosis (DVT), less progress has been made in finding an optimal dosing regimen of rt-PA. Our mandate for the 1990s is to use the best possible thrombolytic dosing regimens in large clinical trials of PE and DVT. The primary objective of these planned clinical studies is to determine which patients with PE and DVT will benefit the most from thrombolysis followed by anticoagulation rather than anticoagulation alone.

We performed a randomized trial comparing two dosing regimens of recombinant tissue plasminogen activator (rt-PA) plus heparin vs heparin alone in the treatment of acute proximal deep vein thrombosis in 83 patients. Of 12 patients who received 0.5 mg/kg rt-PA plus heparin over 4 h, seven (58 percent) had greater than 50 percent lysis of the thrombus, compared with none of 12 who received placebo plus heparin (p = 0.002). Of 28 patients who received 0.5 mg/kg rt-PA over 8 h, repeated in 24 h, six (21 percent) had greater than 50 percent lysis, compared with two (7 percent) of 30 patients who received placebo plus heparin (p = 0.11). The 4-h infusion of rt-PA produced a 40 percent reduction and the 8-h infusion an 11 percent reduction in plasma fibrinogen concentration. At long-term follow-up, three (25 percent) of 12 patients in whom greater than 50 percent lysis was achieved had symptoms of the postphlebitic syndrome, compared with 19 (56 percent) of 34 patients in whom lysis was less than 50 percent (p = 0.07).

Thrombolytic therapy has been shown to limit infarct size, improve ventricular function, and decrease mortality in suspected evolving myocardial infarction (MI). Aspirin therapy also decreases mortality as well as stroke and reinfarction in suspected evolving MI. The combined ability of both agents to lyse as well as to prevent clots yields a greater benefit than either alone. The use of aspirin with thrombolysis also protects against the increase in reinfarction observed when thrombolytic therapy is given alone. While ongoing research is evaluating the optimal thrombolytic agent as well as the possible role of heparin, it is already clear that the use of aspirin with thrombolytic therapy will significantly decrease reinfarction, stroke, and vascular mortality in suspected evolving MI.

We studied the safety and efficacy of albuterol (salbutamol) delivered by continuous nebulization (CN) in the initial emergency department treatment of asthma. In a randomized fashion 21 patients received 5 mg of albuterol by bolus nebulization (BN) at time 0 and again 60 minutes later. Twenty-one others received albuterol (0.2 mg/ml) by CN using a calibrated nebulizer with a known output of 25 ml/h. Thus, each patient had received 10 mg of albuterol over two hours. FEV1, blood pressure (BP), heart rate (HR), respiratory rate (RR), and hand tremor were recorded at 30-minute intervals. The FEV1 was 1.48 +/- 0.64 L prior to BN and increased to a maximum of 2.20 +/- 0.94 L (p less than 0.05) 90 minutes later. The FEV1 prior to CN was 1.13 +/- 0.51 L and improved to 2.20 +/- 1.02 L (p less than 0.05) at 120 minutes. The FEV1 did not differ significantly between regimens over the 2-hour period. Both modes of therapy were well tolerated. There was a slight but significant increase in HR at 30 and 90 minutes in the BN group when compared with CN. There was no significant difference in BP, RR, or tremor between the groups. Thus, albuterol by CN was found to be equally effective as the same medication by BN in the early treatment of asthma in patients seen in the emergency department.

Pentoxifylline is a xanthine derivative with hemorrheologic and vascular properties that may improve gas exchange in patients with chronic obstructive pulmonary disease (COPD). We tested this hypothesis in 12 patients with COPD (mean FEV1 = 40 percent predicted; mean DCO, 8.6 ml/min/mm Hg) randomly divided into a treatment and control group and six healthy volunteers. Following establishment of baseline DCO and maximum expiratory flow volume (MEFV) curve values, each subject in the treatment and healthy groups took 400 mg of pentoxifylline three times a day for 12 weeks. Weekly DCO and MEFV curves were measured before treadmill exercise in both COPD groups and before and after exercise in the healthy group. The MEFV curve parameters from the final three weeks of therapy did not differ significantly from baseline values. During this time, however, the treatment COPD group's resting DCO rose by 8.2 +/- 2.4 percent over baseline level (p less than 0.01). Treadmill walk time increased from 17.7 +/- 2.9 minutes to 23.2 +/- 2.9 minutes (p less than 0.02). This was accompanied by improved exercise oxygen saturation measured by oximetry (SoxiO2). Premedication SoxiO2 fell from 92.8 +/- 1.2 percent to 88.6 +/- 2.5 percent during exercise, and from 94.4 +/- 1.1 percent to only 91.8 +/- 1.0 percent after 12 weeks of medication (p less than 0.05). No such improvement was noted in the control COPD group. Although the healthy group's resting SoxiO2 and DCO did not change during treatment, their exercise DCO increased significantly from 36.3 +/- 3.1 ml/min/mm Hg to 41.8 +/- 3.5 ml/min/mm Hg (p less than 0.001). These data demonstrate that pentoxifylline improves gas exchange, possibly by increasing cardiac output, and/or by raising mixed venous PO2, and/or by improving blood flow to underperfused alveoli.