Microbiologic contamination study of nebulizers after aerosol therapy in patients with cystic fibrosis.

BACKGROUND: To evaluate the contamination of delivery systems after an aerosol therapy session in patients with cystic fibrosis who have chronic Pseudomonas aeruginosa infection. METHODS: Fifty-three patients with cystic fibrosis were enrolled in the study from March 1996 to June 1997. All patients were age 7 years or older and had P aeruginosa infection. They also had been treated with recombinant deoxyribonuclease and were capable of producing sputum for culture. RESULTS: Nine devices were excluded for the study. A total of 44 nebulizers were included: 37 from patients with P aeruginosa colonization with a count of 10(6) colony-forming units/mL or more and 7 with a count of between 10(5) colony-forming units/mL and 10(6) colony-forming units/mL. CONCLUSION: This study demonstrates that in the absence of cleaning, nebulizers of patients with cystic fibrosis who are infected with P aeruginosa are likely to be contaminated by a pathogenic flora.

French multicenter randomized double-blind placebo-controlled trial on nebulized amiloride in cystic fibrosis patients. The Amiloride-AFLM Collaborative Study Group.

The effect of amiloride, a sodium channel blocker, has been evaluated in a multicenter randomized double-blind placebo-controlled trial in cystic fibrosis patients more than 5-years-old (n = 137) whose forced vital capacity (FVC), forced expiratory volume in 1 sec (FEV(1)), and forced mid-expiratory flow (FEF(25-75)) were not below 50%, 50%, and 30% of reference values, respectively. Patients were randomly allocated to two parallel groups. Sixty-four patients were chronically colonized with Pseudomonas aeruginosa; they received either amiloride or placebo as a nebulized solution three times daily for 6 months. Routine treatments were continued. Patients chronically colonized with Pseudomonas received nebulized colimycine twice a day for a month during the third and sixth months of treatment. Bronchopulmonary exacerbations were treated in the usual way. The effects of the amiloride treatment were assessed at the end of the 6-month treatment period. The effects on FVC and secondarily on FEV(1), FEF(25-75), the number of days on antibiotic therapy, the Shwachman score, a nutritional index (weight/height(2)), the change in sputum bacterial flora, and nocturnal cough were assessed. For the patients not chronically colonized with Pseudomonas, the effect of the treatment was also evaluated by counting chronic colonizations with pathogens appearing during the trial period. The present study failed to demonstrate any significant benefit of amiloride over placebo on FVC, FEV(1), and the other secondary endpoints in the studied population. Neither the chronically colonized, nor the noncolonized patients benefited. The confidence intervals of the differences between treatment groups indicated small differences that were most likely of no clinical significance. Complementary analyses taking into account the gender, the type of mutation, the subpopulations whose FVC and FEV(1) were below 80% of normal values at the beginning of the study, and also patients less than 10 years old, did not show any statistically or clinically significant improvements following amiloride therapy.

[Comparative study of the performance and ergonomics of nebulizers in cystic fibrosis]. / Etude comparative sur les performances et l'ergonomie de nébuliseurs dans la mucoviscidose.

This study had, as its aim, to test twelve nebulizers (6 jet, 6 ultrasonic) which are used in the treatment of cystic fibrosis. Devices were connected to a respirator in order to mimic the ventilation of a child and of an adult suffering from cystis fibrosis. Three medications: tobramycine, colistine and amiloride were nebulised. The volume of the recommended solution varied between 1.5 and 13 ml according to the manufacturer. During a session of ten minutes the ultrasonic nebulizer delivered an inhaled volume which was significantly greater than the jet (2.72 +/- 0.98 ml vs 1.22 +/- 0.59 ml, p < 0.0001) for the three drugs. Regarding granulometry, the fraction of particles between 0.5 and 5 microns, was higher with ultrasonic than with pneumatic nebulizer for tobramycine (67.1 +/- 10.7 vs 55.5 +/- 11.5%, p < 0.001) and amiloride (66.4 +/- 9.2% vs 58.1 +/- 15%, p < 0.05%). The variation of concentration due to nebulisation were independent of the type of apparatus but influenced by the drug since concentration was increased for tobramycine (+10.5 +/- 18.6%) and amiloride (+13.4 +/- 8/9%). In summary the effective fraction resulting from the inhalable fraction, from granulometry and from changes in concentration was significantly greater for ultrasonic than for jet nebrulizer (17.3 +/- 6.7% vs 9.7 +/- 9.6%, p < 0.001). This study underlines the great variability of the performance of aerosols generators and therefore the need for an accurate evaluation of nebulizer performances in order to prescribe the best nebulizer/drug association in clinical practice.

Nebulizer performance: AFLM study. Association Française de Lutte contre la Mucoviscidose.

This study was conducted by the AFLM order to determine the performance characteristics of 12 commercially available nebulizers (6 ultrasonic and 6 jet) used in the treatment of cystic fibrosis (CF). The nebulizers were connected to a circuit which simulated the ventilation of a CF child and CF adult, and were tested using three drug solutions: tobramycin (T), colistin (C), and amiloride (A). Nebulizer performance was evaluated according to the volume of drug solution delivered in 10 min during the simulated inspiratory phase (VI), drug granulometry (G%), drug concentration modification in the nebulizer reservoir (delta C), and percentage of efficiently aerosolized drug EA%). The ultrasonic devices delivered a significantly higher VI than the jet nebulizers (p < 0.0001) for all three study drug. Ventilation rate did not influence VI. Regarding granulometry, higher percentages of T and A were found to be contained in droplets ranging from 0.5 to 5.0 micron following ultrasonic nebulization. Drug concentration modifications were independent of the nebulizer used but were influenced by drug type; overconcentrations of T and A were observed (delta C = +10.5 +/- 18.6 and +13.4 +/- 8.9%, respectively). On average, the ultrasonic devices achieved a higher EA% than the jet nebulizers (17.3 +/- 6.7 and 9.7 +/- 9.6%, respectively). This study highlights the significant variability in performance of different nebulizer types and empahsizes the importance of accurately testing nebulizers prior to clinical use so that the most efficacious nebulizer/drug combinations may be prescribed.

[The quality of oxygen therapy delivery systems using oxygen-saving valves. A multicenter study. The ANTADIR Medico-Technical Commission]. / Qualité de l'oxygénothérapie délivrée avec les valves économiseuses d'oxygène. Une étude multicentrique. Commission médico-technique ANTADIR.

The saturation of oxygen (SaO2) using oxygen therapy with an oxygen saving system, Optimox (CFPO) or COS 5 (Puritan, Bennett) has been compared to the SaO2 using continuous oxygen therapy. The oxygen output using the oxygen saving system was regulated in such a way as to be equivalent to the oxygen flow without the economiser. Three situations were studied: the day, the night and during effort. Ninety four patients (84 men and 10 women), aged 65.3 +/- 9.7), who were hypoxaemic (SaO2: 84.5 +/- 6.4%) coming from twelve pneumology units were included in the study. The percentage of time spent above SaO2 (T greater than 90) was used to judge the criteria of the efficacy of the oxygen therapy. T greater than 90 without (SSECO) and with the oxygen saving system (AVECO) were compared in each subject. T greater than 90 AVECO was below T greater than 90 SSECO in 52% of patients and was greater in 23% of subjects. The nasal, auditory and respiratory comfort was good whatever the period of examination for more than half of the subjects. In conclusion for an equivalent oxygen flow the addition of an oxygen saving device significantly alters the quality of diurnal and nocturnal oxygen therapy in one patient out of two.

Preserved CO2 response in cerebral and muscular blood vessels during cimetidine treatment.

It is known that cimetidine inhibits the hypoxia-induced increase in cerebral blood flow (CFB) in dogs, but the mechanism of this inhibition is not fully understood. Since the accepted mechanisms explaining the increase in CBF during hypercapnia are very different from those active during hypoxia, acute hypercapnia was induced in 12 conscious dogs in order to study the cimetidine effect in this condition. Six dogs were given i.v. saline (control group) and the other six, i.v. cimetidine (4 mg kg-1). After 15 min, CBF and various muscular blood flow measurements were performed, using the microspheres technique under two conditions: (1) breathing air and (2) after 2 h inhalation of a gas mixture with FiCO2 0.10, FiO2 0.21 in nitrogen. The CBF increase was similar in both series with or without cimetidine. The changes in muscular blood flow were unaffected by the H2-blocker. We conclude that cimetidine has no effect on the CBF and on muscular blood flow during acute hypercapnia.

The inotropic effect of digoxin on an isolated rat heart in hypercapnia and (or) hypoxia.

The explanation for the increased frequency of troubles with digoxin therapy in patients with chronic pulmonary diseases is debated. The reported effects of hypoxia in vivo on myocardial levels of digoxin are contradictory, and there have been few studies on the effects of hypercapnia. In the past, it has been shown in rat myocardial tissue at rest in vitro that hypoxia decreased and hypercapnic acidosis increased the digoxin uptake. We performed a new study in vitro in an isolated beating rat heart perfused at constant flow (37 degrees C) and stimulated at a constant frequency (6 Hz). The performances were recorded with an intraventricular balloon equipped with a tip-manometer catheter. The action of digoxin was studied by recording systolic pressure (PS) and diastolic pressure (PD), the left ventricular developed pressure (LVDP = PS - PD), the (dP/dt)max, and the ratio (dP/dt)max/PS. First, the heart was perfused for 30 min with a modified Tyrode's solution perfusate aerated with carbogen (pH = 7.40; PCO2 = 37 mmHg; PO2 = 530 mmHg) (1 mmHg = 133.32 Pa). Various parameters of contractions were recorded (initial control values). Then the heart was perfused for 15 min with Tyrode's solution aerated either with a hypoxic gas mixture (pH = 7.41; PCO2 = 36 mmHg; PO2 = 122 mmHg), a hypercapnic gas mixture (pH = 7.08; PCO2 75 mmHg; PO2 = 485 mmHg), or a hypoxic-hypercapnic gas mixture (pH = 7.09; PCO2 = 73 mmHg; PO2 = 124 mmHg). Control hearts were continuously perfused with Tyrode's solution aerated with carbogen.(ABSTRACT TRUNCATED AT 250 WORDS)

Theophylline disposition in patients with COLD with and without hypoxemia.

This study aimed to assess the effect of hypoxemia on theophylline disposition. Ten patients with a mean (+/- SEM) of 58 +/- 3 years with COLD (PaO2 55 +/- 1 mm Hg, PaCO2 46 +/- 2 mm Hg, and pH of 7.39 +/- 0.01) were hospitalized to have oxygen therapy. Before starting O2, they received intravenously, 4 mg/kg of theophylline over a 20-minute period; blood samples and urine were collected for six hours. The results suggested that hypoxia does not influence the disposition of theophylline or its metabolites.

Effect of moderate hypoxemia on atrial natriuretic factor and arginine vasopressin in normal man.

The object of this study was to assess the effect of moderate acute hypoxemia on plasma concentrations of atrial natriuretic factor (ANF), arginine vasopressin (AVP), plasma renin activity (PRA) and urinary excretion of prostaglandin E2 (UPGE2V). Eight volunteers were exposed for 2 hours to a gas mixture containing 10% O2, 4.5% CO2 and 85.5% N2. Hypoxia increased diastolic blood pressure and free water clearance. Hypoxia did not change the AVP, PRA or UPG2V, although increased ANF from 17.7 +/- 3.4 pg/mL to 27.2 +/- 1.7 pg/mL (p less than 0.005) at 120 minutes. ANF changes were closely associated with the rise in blood pressure.

Theophylline disposition during acute and chronic hypoxia in the conscious dog.

It has been reported in experimental models that acute hypoxia reduced the activity of the hepatic cytochrome P-450. The objective of the present study was to investigate in conscious dogs whether acute and chronic hypoxia will influence the disposition of theophylline. To this purpose 6 beagle dogs received 8 mg/kg i.v. of theophylline while breathing air, after acute hypoxia (PaO2 of 48.5 +/- 0.3 mmHg) and after 96 hours of hypoxia. Theophylline and metabolites, 3-methylxanthine and 1,3-dimethyluric acid, were assayed by HPLC. Theophylline volume of distribution, while breathing air, was 0.51 +/- 0.03 L/kg and was not affected by hypoxia. Theophylline metabolic and renal clearances were 1.53 +/- 0.24 and 0.18 +/- 0.04 mL/min/kg and remained constant when the dogs were hypoxic. The urinary recovery of theophylline and metabolites was not affected by acute or chronic hypoxia. It is concluded, that in the dog hypoxia does not affect the disposition of theophylline.

Role of the mechanical impairment on the ventilatory response to CO2 in chronic airway obstruction.

The purpose of this study was to assess the relationship between the breathing pattern response to CO2 and the severity of mechanical impairment in twenty patients with COLD. The CO2 response was compared to that of a control group of twelve normal subjects. All patients had airway obstruction (FEV1 = 40 +/- 14% of predicted; means +/- SD) and hyperinflation (FRC = 154 +/- 23% of predicted). Tidal volume (VT), inspiratory and total cycle duration (TI, TT), occlusion pressure (P0.1) and endtidal PCO2 were measured at rest and during hyperoxic CO2 rebreathing. On the same day, in all patients, arterial blood gas analysis, spirometric and plethysmographic measurements were made. The slope (S) of the P0.1 response (SP 0.1) to increasing endtidal PCO2 was negatively correlated with airway resistance (r = -0.59; p less than 0.01). Although the flow response, S(VT/TI), was positively and closely correlated with SP 0.1 (r = 0.88; p less than 0.001), it also appeared to be independently influenced by obstruction (p less than 0.01). The tidal volume response, SVT, was principally correlated with inspiratory capacity (r = 0.90; p less than 0.001) and also, independently, with Vmax50 (p less than 0.01). SVT was diminished in seventeen patients, ten of whom only had a decreased S(VT/TI). The shortening in TI during hypercapnia was most marked in patients with the greatest S(P0.1), who did not have arterial hypercapnia at rest. These results suggest: that the poor VT response to CO2 in COLD patients is principally caused by a limitation in inspiratory volume expansion.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison between ventilatory and mouth occlusion pressure responses to hypoxia and hypercapnia in healthy sleeping man.

Ventilatory and mouth occlusion pressure (P0.1) responses to progressive isocapnic-hypoxia and hyperoxic-hypercapnia were compared in eleven healthy sleeping men during the same night. Hypoxic and hypercapnic responses were determined during wakefulness, non-rapid and rapid-eye-movement sleep. The following parameters were measured: minute ventilation (VE), tidal volume (VT), 'duty cycle' (TI/TT), mean inspiratory flow rate (VT/TI) and P0.1, an index of the neuromuscular inspiratory drive. To allow a direct comparison between the two types of chemostimuli, responses were characterized by the value of the different parameters at 'equivalent' levels of hypoxia and hypercapnia, i.e., at levels which produced the same P0.1 during wakefulness: an oxyhaemoglobin saturation (Sao2) of 94% during the isocapnic-hypoxic tests (PETCO2 = 42.5 +/- 1.2 mmHg) was found to be equivalent to a PETCO2 of 47.4 +/- 3.7 mmHg during hypoxic-hypercapnic tests. For both tests, the arousal levels of the stimulus and of P0.1 were similar in all sleep stages. Sleep did not significantly modify P0.1 or breathing pattern responses to hypoxia (Sao2 = 94%). In contrast, at the 'equivalent' level of hypercapnic stimulation, P0.1 (P less than 0.05) and VE (P less than 0.01) responses were significantly impaired, particularly in REM sleep, with a decrease in VT (P less than 0.01) and VT/TI (P less than 0.05) responses. The results suggest that CO2 intracranial receptor mechanisms are more affected by sleep than the O2 peripheral receptor activity.

Cimetidine inhibits cerebral and hepatic mitochondrial respiration in rat.

The presence of cimetidine in the incubation medium of rat brain mitochondria caused decreased oxygen uptake, especially during oxidative phosphorylation (state 3). This inhibition of the respiratory control and of ATP synthesis was dose-dependent. The same observations were made for hepatic mitochondria. The significance of these results is discussed in terms of both the neurological side-effects of cimetidine and its effect on regulatory mechanisms of cerebral or hepatic blood flow.

[A multicenter trial of a device for treating obstructive sleep apnea by continuous positive pressure]. / Essai multicentrique d'un dispositif de traitement des apnées obstructives du sommeil par la pression positive continue.

The efficacy and tolerance of a nasal CPAP device marketed in France (Pression +, Sefam) for the treatment of obstructive sleep apnoea syndromes have been evaluated in a co-operative trial including 12 patients. This study confirmed the efficacy of nasal CPAP on sleep parameters: total sleep time was increased; light non-REM sleep was diminished; slow-wave sleep and REM sleep were augmented; sleep apnoeas were eliminated completely or almost completely; oxygen saturation was markedly improved. At one month follow-up, most clinical features were improved; daytime blood gases showed little change but the number of red cells was decreased. On the whole, the tolerance was good in this highly motivated group of patients: eleven patients (92%) were willing to continue their home treatment with the same device. Most difficulties were due to the making of a tailored molded nasal mask and its use during sleep.

Long-term oxygen therapy can reverse the progression of pulmonary hypertension in patients with chronic obstructive pulmonary disease.

Sixteen patients with severe chronic obstructive pulmonary disease (COPD) (average values at the onset of O2 therapy: FEV1, 891 +/- 284 ml; PaO2, 50.2 +/- 6.6 mmHg; PaCO2, 51.0 +/- 6.4 mmHg) underwent 3 consecutive right heart catheterizations. The first was performed 47 +/- 28 months (T0) before the onset of long-term O2 therapy (LTO2). The second was performed just before the onset of LTO2 (T1). The third was performed after 31 +/- 19 months of LTO2 (T2). Oxygen therapy (15 to 18 h/day) was prescribed on the basis of usual criteria. From T0 to T1, PaO2 decreased from 59.3 +/- 9.4 to 50.2 +/- 6.6 mmHg, and mean pulmonary arterial pressure (Ppa) worsened from 23.3 +/- 6.8 to 28.0 +/- 7.4 mmHg (p less than 0.005). From T1 to T2, PaO2 was stable, whereas Ppa decreased from 28.0 +/- 7.4 to 23.9 +/- 6.6 mmHg (p less than 0.05). Pulmonary hypertension improved in 12 of the 16 patients. Before the onset of LTO2 (from T0 to T1), there was a yearly increase in Ppa of 1.47 +/- 2.3 mmHg, whereas during LTO2 a yearly decrease of 2.15 +/- 4.4 mmHg was observed, and the difference between these 2 values was highly significant. The changes in Ppa either from T0 to T1 or from T1 to T2 were not associated with concomitant changes in cardiac output or pulmonary capillary wedge pressure but were related to changes in pulmonary vascular resistance. These results suggest that LTO2 for 15 to 18 h/day can reverse the progression of pulmonary hypertension in a high percentage of patients with severe COPD, but that normalization of Ppa is rarely observed.

In vitro effects of hypoxia and (or) hypercapnic acidosis on the myocardial uptake of digoxin.

A recent study has shown in the conscious dog that hypoxia associated with respiratory acidosis could increase the in vivo distribution of digoxin in the myocardium. The aim of the present study was to evaluate in vitro the effects of hypoxia and (or) hypercapnic acidosis on the digoxin uptake. For this purpose, rat myocardium was incubated for 180 min with radiolabelled [3H]digoxin. The uptake of digoxin which was expressed in nanograms of digoxin bound per 100 mg of myocardium was decreased by hypoxia and increased by hypercapnic acidosis. The association of hypoxia and hypercapnic acidosis had no effect on the digoxin uptake, suggesting that in vitro hypoxia acts in an opposite way to hypercapnia.

[Continuous positive pressure in the treatment of sleep apnea syndromes]. / La pression positive continue dans le traitement des syndromes d'apnées du sommeil.

Continuous positive airway pressure as a long-term home treatment for sleep apnea syndromes would seem to present irreconcilable requirements; it must be simple and comfortable to use during sleep and it must be relatively inexpensive. The device described in this paper includes a compressor, an individually molded nose-mask and a water column. Improvements are still in progress, but, as it stands, it enables sleep apnea patients to be successfully treated at home.

Long-term course of pulmonary arterial pressure in chronic obstructive pulmonary disease.

Ninety-three patients with severe chronic obstructive pulmonary disease (COPD) of the bronchitic (n = 74) or emphysematous type (n = 19), who all had arterial hypoxemia, underwent 2 right cardiac catheterizations in a clinical steady state, with a delay of 5 yr or more between the first and the last catheterization. No patients received long-term O2 therapy or pulmonary vasodilator drugs. Patients were divided into 2 groups according to the initial level of mean pulmonary artery pressure (Pap). Group 1 included 61 patients without initial pulmonary arterial hypertension (PAH), Pap being less than 20 mmHg; the average delay between the 2 catheterizations was 93.4 +/- 26.8 months. Group 2 included 32 patients with initial PAH (Pap greater than or equal to 20 mmHg), and the average delay was 85.0 +/- 26.0 months. The changes in Pap were small. They ranged from 15.5 +/- 2.4 to 19.6 +/- 7.0 mmHg in Group 1 (p less than 0.001) and from 25.8 +/- 5.6 to 27.8 +/- 9.5 mmHg in Group 2 (NS). The average increase in Pap was 0.65 mmHg/yr in Group 1 and 0.39 mmHg/yr in Group 2 (no statistical difference between the 2 groups). The other hemodynamic parameters (pulmonary capillary wedge pressure, right ventricle filling pressure, cardiac output) did not change. Hemodynamic "worsening," which was defined by an increase in Pap by greater than or equal to 5 mm Hg, was observed in 29% of the patients (n = 27). In these patients, there was a marked worsening of hypoxemia, which was not observed in the remaining 66 patients.(ABSTRACT TRUNCATED AT 250 WORDS)