Influence of diluent volume of colistimethate sodium on aerosol characteristics and pharmacokinetics in ventilator-associated pneumonia caused by MDR bacteria.

Objectives: Nebulized colistimethate sodium (CMS) can be used to treat ventilator-associated pneumonia caused by MDR bacteria. The influence of the diluent volume of CMS on aerosol delivery has never been studied. The main objectives of the study were to compare aerosol particle characteristics and plasma and urine pharmacokinetics between two diluent volumes in patients treated with nebulized CMS. Methods: A crossover study was conducted in eight patients receiving nebulized CMS every 8 h. After inclusion, nebulization started with 4 million international units (MIU) of CMS diluted either in 6 mL (experimental dilution) or in 12 mL (recommended dilution) of normal saline in a random order. For each diluent volume, CMS aerosol particle sizes were measured and plasma and urine samples were collected every 2 h. Nebulization time and stability of colistin in normal saline were assessed. Results: The mass median aerodynamic diameters were 1.4 ±âŸ0.2 versus 0.9 ±âŸ0.2 µm (P < 0.001) for 6 and 12 mL diluent volumes, respectively. The plasma area under the concentration-time curve from 0 to 8 h (AUC0-8) of colistinA+B was 6.6 (4.3-17.0) versus 6.7 (3.6-14.0) µg·h/mL (P = 0.461) for each dilution. The total amount of colistin and CMS eliminated in the urine represented, respectively, 17% and 13% of the CMS initially placed in the nebulizer chamber for 6 and 12 mL diluent volumes (P = 0.4). Nebulization time was shorter [66 (58-75) versus 93 (69-136) min, P = 0.042] and colistin stability was better with the 6 mL diluent volume. Conclusions: Nebulization with a higher concentration of CMS in saline (4 MIU in 6 mL) decreases nebulization time and improves colistin stability without changing plasma and urine pharmacokinetics or aerosol particle characteristics for lung deposition.

Exercise intolerance in Glycogen Storage Disease Type III: weakness or energy deficiency?

Myopathic symptoms in Glycogen Storage Disease Type IIIa (GSD IIIa) are generally ascribed to the muscle wasting that these patients suffer in adult life, but an inability to debranch glycogen likely also has an impact on muscle energy metabolism. We hypothesized that patients with GSD IIIa can experience exercise intolerance due to insufficient carbohydrate oxidation in skeletal muscle. Six patients aged 17-36-years were studied. We determined VO 2peak (peak oxygen consumption), the response to forearm exercise, and the metabolic and cardiovascular responses to cycle exercise at 70% of VO 2peak with either a saline or a glucose infusion. VO 2peak was below normal. Glucose improved the work capacity by lowering the heart rate, and increasing the peak work rate by 30% (108 W with glucose vs. 83 W with placebo, p=0.018). The block in muscle glycogenolytic capacity, combined with the liver involvement caused exercise intolerance with dynamic skeletal muscle symptoms (excessive fatigue and muscle pain), and hypoglycemia in 4 subjects. In this study we combined anaerobic and aerobic exercise to systematically study skeletal muscle metabolism and exercise tolerance in patients with GSD IIIa. Exercise capacity was significantly reduced, and our results indicate that this was due to a block in muscle glycogenolytic capacity. Our findings suggest that the general classification of GSD III as a glycogenosis characterized by fixed symptoms related to muscle wasting should be modified to include dynamic exercise-related symptoms of muscle fatigue. A proportion of the skeletal muscle symptoms in GSD IIIa, i.e. weakness and fatigue, may be related to insufficient energy production in muscle.

Long-term outcomes of pandemic 2009 influenza A(H1N1)-associated severe ARDS.

BACKGROUND: No data on long-term outcomes of survivors of 2009 influenza A(H1N1) (A[H1N1])-associated ARDS are available. The objective of this study was to compare the 1-year outcomes of survivors of A(H1N1)-associated ARDS, according to use or no use of extracorporeal lung assist (ECLA), using its need as an ARDS severity surrogate. METHODS: Survivors of ARDS (12 with ECLA use vs 25 without, corresponding to 75% and 54% of the eligible patients for each group, respectively) selected from the Réseau Européen de Ventilation Artificielle (REVA) registry had previously been healthy, with only pregnancy and/or moderate obesity (BMI ≤ 35 kg/m²) as known risk factors for A(H1N1) infection. Lung function and morphology, health-related quality of life (HRQoL), and psychologic impairment were evaluated. RESULTS: At 1 year post-ICU discharge for the ECLA and no-ECLA groups, respectively, 50% and 40% reported significant exertion dyspnea, 83% and 64% had returned to work, and 75% and 64% had decreased diffusion capacity across the blood-gas barrier, despite their near-normal and similar lung function test results. For both groups, exercise test results showed diminished but comparable exercise capacities, with similar alveolar-arterial oxygen gradients at peak exercise, and CT scans showed minor abnormal findings. HRQoL assessed by the 36-Item Short-Form Health Survey was poorer for both groups than for a sex- and age-matched general population group, but without between-group differences. ECLA and no-ECLA group patients, respectively, had symptoms of anxiety (50% and 56%) and depression (28% and 28%) and were at risk for posttraumatic stress disorder (41% and 44%). CONCLUSIONS: One year post-ICU discharge, a majority of survivors of A(H1N1)-associated ARDS had minor lung disabilities with diminished diffusion capacities across the blood-gas barrier, and most had psychologic impairment and poorer HRQoL than a sex- and age-matched general population group. ECLA and no-ECLA group patients had comparable outcomes. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01271842; URL: www.clinicaltrials.gov

Diaphragm pacing improves sleep in patients with amyotrophic lateral sclerosis.

In amyotrophic lateral sclerosis (ALS) patients, respiratory insufficiency is a major burden. Diaphragm conditioning by electrical stimulation could interfere with lung function decline by promoting the development of type 1 muscle fibres. We describe an ancillary study to a prospective, non-randomized trial (NCT00420719) assessing the effects of diaphragm pacing on forced vital capacity (FVC). Sleep-related disturbances being early clues to diaphragmatic dysfunction, we postulated that they would provide a sensitive marker. Stimulators were implanted laparoscopically in the diaphragm close to the phrenic motor point in 18 ALS patients for daily conditioning. ALS functioning score (ALSFRS), FVC, sniff nasal inspiratory pressure (SNIP), and polysomnographic recordings (PSG, performed with the stimulator turned off) were assessed before implantation and after four months of conditioning (n = 14). Sleep efficiency improved (69 ± 15% to 75 ± 11%, p = 0.0394) with fewer arousals and micro-arousals. This occurred against a background of deterioration as ALSFRS-R, FVC, and SNIP declined. There was, however, no change in NIV status or the ALSFRS respiratory subscore, and the FVC decline was mostly due to impaired expiration. Supporting a better diaphragm function, apnoeas and hypopnoeas during REM sleep decreased. In conclusion, in these severe patients not expected to experience spontaneous improvements, diaphragm conditioning improved sleep and there were hints at diaphragm function changes.

Aerosol delivery and humidification with the Boussignac continuous positive airway pressure device.

BACKGROUND: A simple method for effective bronchodilator aerosol delivery while administering continuing continuous positive airway pressure (CPAP) would be useful in patients with severe bronchial obstruction. OBJECTIVE: To assess the effectiveness of bronchodilator aerosol delivery during CPAP generated by the Boussignac CPAP system and its optimal humidification system. METHODS: First we assessed the relationship between flow and pressure generated in the mask with the Boussignac CPAP system. Next we measured the inspired-gas humidity during CPAP, with several humidification strategies, in 9 healthy volunteers. We then measured the bronchodilator aerosol particle size during CPAP, with and without heat-and-moisture exchanger, in a bench study. Finally, in 7 patients with acute respiratory failure and airway obstruction, we measured work of breathing and gas exchange after a ß(2)-agonist bronchodilator aerosol (terbutaline) delivered during CPAP or via standard nebulization. RESULTS: Optimal humidity was obtained only with the heat-and-moisture exchanger or heated humidifier. The heat-and-moisture exchanger had no influence on bronchodilator aerosol particle size. Work of breathing decreased similarly after bronchodilator via either standard nebulization or CPAP, but P(aO(2)) increased significantly only after CPAP aerosol delivery. CONCLUSIONS: CPAP bronchodilator delivery decreases the work of breathing as effectively as does standard nebulization, but produces a greater oxygenation improvement in patients with airway obstruction. To optimize airway humidification, a heat-and-moisture exchanger could be used with the Boussignac CPAP system, without modifying aerosol delivery.

Nebulized and intravenous colistin in experimental pneumonia caused by Pseudomonas aeruginosa.

PURPOSE: Emergence of multidrug-resistant strains in intensive care units has renewed interest in colistin, which often remains the only available antimicrobial agent active against resistant Pseudomonas aeruginosa. The aim of this study is to compare lung tissue deposition and antibacterial efficiency between nebulized and intravenous administration of colistin in piglets with pneumonia caused by P. aeruginosa. METHODS: In ventilated piglets, colistimethate was administered 24 h following bronchial inoculation of Pseudomonas aeruginosa (minimum inhibitory concentration of colistin = 2 microg ml(-1)) either by nebulization (8 mg kg(-1) every 12 h, n = 6) or by intravenous infusion (3.2 mg kg(-1) every 8 h, n = 6). All piglets were killed 49 h after inoculation. Colistin peak lung tissue concentrations and lung bacterial burden were assessed on multiple post mortem subpleural lung specimens. RESULTS: Median colistin peak lung concentration following nebulization was 2.8 microg g(-1) (25-75% interquartile range = 0.8-13.7 microg g(-1)). Colistin was undetected in lung tissue following intravenous infusion. In the aerosol group, peak lung tissue concentrations were significantly greater in lung segments with mild pneumonia (median = 10.0 microg g(-1), 25-75% interquartile range = 1.8-16.1 microg g(-1)) than in lung segments with severe pneumonia (median = 1.2 microg g(-1), 25-75% interquartile range = 0.5-3.3 microg g(-1)) (p < 0.01). After 24 h of treatment, 67% of pulmonary segments had bacterial counts <10(2) cfu g(-1) following nebulization and 28% following intravenous administration (p < 0.001). In control animals, 12% of lung segments had bacterial counts <10(2) cfu g(-1) 49 h following bronchial inoculation. CONCLUSION: Nebulized colistin provides rapid and efficient bacterial killing in ventilated piglets with inoculation pneumonia caused by Pseudomonas aeruginosa.

Chemosensitivity recovery in Ondine's curse syndrome under treatment with desogestrel.

Congenital central hypoventilation syndrome (CCHS), or Ondine's curse syndrome, is a rare genetic disorder associated with mutations of the PHOX2B gene. It is characterized by sleep-related life-threatening hypoventilation that requires mechanical ventilation. The ventilatory response to hypercapnia and hypoxia is absent or dramatically reduced. Spontaneous or pharmacologically induced recovery has never been reported. We have fortuitously observed a case of CO(2)-chemosensitivity recovery in a woman with CCHS who took a progestin contraceptive - desogestrel. We hypothesized that the desogestrel could be responsible for this effect. We tested this hypothesis in a second adult patient. Her lack of CO(2)-chemosensitivity was documented 5 months before she was prescribed desogestrel. Three weeks after initiation of the treatment she exhibited a ventilatory and sensory response to hypercapnia. This response persisted 3 weeks later. This is the first documented case of pharmacologically restored chemosensitivity in CCHS. It suggests that a very potent progestin such as desogestrel could unveil latent chemosensitive neural circuits.

Comparison of lung tissue concentrations of nebulized ceftazidime in ventilated piglets: ultrasonic versus vibrating plate nebulizers.

OBJECTIVE: To compare the efficiency of an Aeroneb Pro vibrating plate and an Atomisor MegaHertz ultrasonic nebulizer for providing ceftazidime distal lung deposition. DESIGN: In vitro experiments. One gram of cetazidime was nebulized in respiratory circuits and mass median aerodynamic diameter of particles generated by ultrasonic and vibrating plate nebulizers was compared using a laser velocimeter. In vivo experiments. Lung tissue concentrations and extrapulmonary depositions were measured in ten anesthetized ventilated piglets with healthy lungs that received 1 g of ceftazidime by nebulization with either an ultrasonic (n = 5), or a vibrating plate (n = 5) nebulizer. SETTING: A two-bed Experimental Intensive Care Unit of a University School of Medicine. INTERVENTION: Following sacrifice, 5 subpleural specimens were sampled in dependent and nondependent lung regions for measuring ceftazidime lung tissue concentrations by high-performance liquid chromatography. MEASUREMENTS AND RESULTS: Mass median aerodynamic diameters generated by both nebulizers were similar with more than 95% of the particles between 0.5 and 5 microm. Lung tissue concentrations were 553 +/- 123 [95% confidence interval: 514-638] microg g(-1) using ultrasonic nebulizer, and 452 +/- 172 [95% confidence interval: 376-528] microg g(-1) using vibrating plate nebulizers (NS). Extrapulmonary depositions were, respectively, of 38 +/- 5% (ultrasonic) and 34 +/- 4% (vibrating plate) (NS). CONCLUSIONS: Vibrating plate nebulizer is comparable to ultrasonic nebulizers for ceftazidime nebulization. It may represent a new attractive technology for inhaled antibiotic therapy.

Cardiac asthma in elderly patients: incidence, clinical presentation and outcome.

BACKGROUND: Cardiac asthma is common, but has been poorly investigated. The objective was to compare the characteristics and outcome of cardiac asthma with that of classical congestive heart failure (CHF) in elderly patients. METHODS: Prospective study in an 1,800-bed teaching hospital. RESULTS: Two hundred and twelve consecutive patients aged > or = 65 years presenting with dyspnea due to CHF (mean age of 82 +/- 8 years) were included. Findings of cardiac echocardiography and natriuretic peptides levels were used to confirm CHF. Cardiac asthma patients were defined as a patient with CHF and wheezing reported by attending physician upon admission to the emergency department. The CHF group (n = 137) and the cardiac asthma group (n = 75), differed for tobacco use (34% vs. 59%, p < 0.05), history of chronic obstructive pulmonary disease (16% vs. 47%, p < 0.05), peripheral arterial disease (10% vs. 24%, p < 0.05). Patients with cardiac asthma had a significantly lower pH (7.38 +/- 0.08 vs. 7.43 +/- 0.06, p < 0.05), and a higher PaCO2 (47 +/- 15 vs. 41 +/- 11 mmHg, p < 0.05) at admission. In the cardiac asthma group, patients had greater distal airway obstruction: forced expiratory volume in 1 second of 1.09 vs. 1.33 Liter (p < 0.05), and a forced expiratory flow at 25% to 75% of vital capacity of 0.76 vs. 0.99 Liter (p < 0.05). The in-hospital (23% vs. 19%) and one year mortality (48% vs. 43%) rates were similar. CONCLUSION: Patients with cardiac asthma represented one third of CHF in elderly patients. They were more hypercapnic and experienced more distal airway obstruction. However, outcomes were similar.

Telemetric monitoring of pulmonary function after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Late-onset noninfectious pulmonary complications (LONIPC) are both frequent and severe after allogeneic hematopoietic stem cell transplantation (HSCT). The high mortality rate (40-80%) may be related to delayed diagnosis. We assessed the use of telemetric home surveillance of pulmonary function for early diagnosis of LONIPC in transplant recipients. METHODS: This prospective study monitored pulmonary function in 37 allogeneic HSCT recipients. About 3 months after HSCT, they received a portable spirometer that measured forced vital capacity, forced expiratory volume per second, and midexpiratory flow 25-75 (MEF25-75). Data were transmitted twice weekly by telephone. Conventional plethysmography confirmed any significant deterioration (>20%). RESULTS: Thirteen episodes of spirometric deterioration were detected by telemetry in 11 patients during a median 17-month (4-41) follow-up period after transplantation. In these cases, examinations including spirometry, high-resolution thoracic computed tomography and bronchoalveolar lavage diagnosed LONIPC in eight episodes in seven patients (cumulative incidence 23.4%, SE 0.08, at month 24 after transplant): bronchiolitis obliterans (BO, n=3), interstitial pneumonia (IP, n=4), or both BO and IP (n=1). Five episodes improved and three were stabilized with increased immunosuppressive therapy. At the last follow-up, of the seven patients with LONIPC, one successfully stopped immunosuppressive therapy, two were receiving low-dose mycophenolate mofetil, and four were receiving low-dose corticosteroid therapy. There were no cases of respiratory failure and no patient died from LONIPC. CONCLUSION: Telemetric home monitoring of pulmonary function is a useful procedure for early diagnosis of LONIPC before clinical pulmonary symptoms and may improve outcome after allogeneic HSCT.

Acute respiratory failure in the elderly: etiology, emergency diagnosis and prognosis.

INTRODUCTION: Our objectives were to determine the causes of acute respiratory failure (ARF) in elderly patients and to assess the accuracy of the initial diagnosis by the emergency physician, and that of the prognosis. METHOD: In this prospective observational study, patients were included if they were admitted to our emergency department, aged 65 years or more with dyspnea, and fulfilled at least one of the following criteria of ARF: respiratory rate at least 25 minute-1; arterial partial pressure of oxygen (PaO2) 70 mmHg or less, or peripheral oxygen saturation 92% or less in breathing room air; arterial partial pressure of CO2 (PaCO2) > or = 45 mmHg, with pH < or = 7.35. The final diagnoses were determined by an expert panel from the completed medical chart. RESULTS: A total of 514 patients (aged (mean +/- standard deviation) 80 +/- 9 years) were included. The main causes of ARF were cardiogenic pulmonary edema (43%), community-acquired pneumonia (35%), acute exacerbation of chronic respiratory disease (32%), pulmonary embolism (18%), and acute asthma (3%); 47% had more than two diagnoses. In-hospital mortality was 16%. A missed diagnosis in the emergency department was noted in 101 (20%) patients. The accuracy of the diagnosis of the emergency physician ranged from 0.76 for cardiogenic pulmonary edema to 0.96 for asthma. An inappropriate treatment occurred in 162 (32%) patients, and lead to a higher mortality (25% versus 11%; p < 0.001). In a multivariate analysis, inappropriate initial treatment (odds ratio 2.83, p < 0.002), hypercapnia > 45 mmHg (odds ratio 2.79, p < 0.004), clearance of creatinine < 50 ml minute-1 (odds ratio 2.37, p < 0.013), elevated NT-pro-B-type natriuretic peptide or B-type natriuretic peptide (odds ratio 2.06, p < 0.046), and clinical signs of acute ventilatory failure (odds ratio 1.98, p < 0.047) were predictive of death. CONCLUSION: Inappropriate initial treatment in the emergency room was associated with increased mortality in elderly patients with ARF.

Mild intermittent asthma: CT assessment of bronchial cross-sectional area and lung attenuation at controlled lung volume.

PURPOSE: To evaluate, with thin-section computed tomography (CT), changes in bronchial cross-sectional area and lung attenuation induced by bronchial stimulation in patients with mild intermittent asthma, at a given lung volume monitored with pneumotachography. MATERIALS AND METHODS: Twelve patients with mild intermittent asthma who were nonsmokers (National Institutes of Health staging) and six nonsmoking healthy volunteers, age and sex ratio-matched, were examined by using helical thin-collimation CT at the level of basal bronchi at 65% of total lung capacity. Three sets of acquisitions were obtained: at baseline and after inhalation of methacholine and then salbutamol. Cross-sectional areas of bronchi greater than 4 mm(2) were segmented and calculated from CT images. Lung attenuation was measured in the anterior, lateral, and posterior areas of the right lung parenchyma. Gas trapping was evaluated by using thin-section CT at residual volume in six of the patients with asthma. Statistical analysis included two factors repeated-measurement analysis of variance and Mann-Whitney and Kruskal-Wallis nonparametric tests. RESULTS: Bronchial cross-sectional areas and lung attenuation did not vary significantly compared with baseline values following bronchial challenge in healthy volunteers or patients with asthma. However, in patients with asthma, bronchial cross-sectional areas were significantly smaller than in healthy volunteers, except after inhalation of salbutamol. Lung attenuation and anteroposterior attenuation gradient were significantly higher in patients with asthma than in healthy patients (P <.001). Air-trapping scores were significantly higher after methacholine challenge. CONCLUSION: Helical thin-collimation CT at controlled lung volume and at full expiration associated with bronchial challenge may help evaluate bronchoreactivity and inflammation in mild intermittent asthma.

Lung tissue concentrations of nebulized amikacin during mechanical ventilation in piglets with healthy lungs.

The tissue concentration of aminoglycosides in lung parenchyma is the main determinant of bactericidal efficiency. The aim of the study was to compare the lung deposition of amikacin administered either by an ultrasonic nebulizer or by intravenous infusion during mechanical ventilation. Eighteen healthy ventilated piglets received a single daily dose of amikacin by intravenous infusion (15 mg. kg(-1)) and 18 by aerosol (1 g in 12 ml). The amount of aerosolized amikacin reaching the tracheobronchial tree represented 40 +/- 5% of the initial dose with an aerodynamic size distribution showing 50% of particles ranging between 0.5 and 5 microm mass median diameter. Animals were killed at different time intervals after the second dose. Tissue concentrations of amikacin were determined on cryomixed multiple lung specimen by an immunoenzymatic method. The lung concentrations of nebulized amikacin, peaking at 208 +/- 76 microg. g(-1), were more than 10-fold higher than the lung concentrations of intravenous amikacin and were homogeneously distributed throughout the lung parenchyma. Amikacin plasma concentrations lower than 5 mmol. l(-1) were measured after the sixth hour after the nebulization. In conclusion, the ultrasonic nebulization of amikacin resulted in high tissue concentrations, far above the minimal inhibitory concentrations of most gram-negative strains.