Usefulness of nasal provocation tests in occupational rhinitis.

OBJECTIVE: The aim of the study was to determine whether Nasal Provocation Tests (NPT) could help in the diagnosis of occupational rhinitis (OR). METHODS: Changes in nasal airway resistance (NAR), measured by posterior rhinomanometry during specific nasal challenge associated with per and post test clinical scores, were compared to a prior probability, based on the patient's history, determined by occupational physicians, in 41 hairdressers and 33 bakers referred for suspected OR. RESULTS: A DeltaNAR >or= 150% defined the positivity of the NPT. DeltaNAR demonstrated 50% sensitivity and a 86% specificity in hairdressers and a 95% sensitivity with 100 % specificity in bakers. DeltaNAR presented significant positive correlations with both per (p = 0.0003, r = 0.48) and post test clinical scores (p < 0.005, r = 0.39). The addition of clinical scores increased the sensitivity to 100% in hairdressers with 81% specificity. CONCLUSIONS: The NPT constitutes a safe procedure of nasal reactivity with good levels of sensitivity and specificity in both hairdressers and bakers when nasal resistance and clinical scores are taken into account.

Impairment of nitric oxide output of conducting airways in primary ciliary dyskinesia.

Nasal nitric oxide (NO) concentration is dramatically reduced in primary ciliary dyskinesia (PCD). The aims of this study were to apply a multiple-flow NO analysis to investigate whether NO output from the bronchial tree was affected in a similar way to nasal NO output, and to search for a relationship between flow-independent exchange parameters and airflow limitation. Multiple flow rate analysis of exhaled NO, allowing the calculation of maximum airway wall flux and alveolar NO concentration, was performed in 17 PCD patients (median age, 25-75th percentiles: 13.5, 12.1-17.6) with documented ultrastructural cilia abnormalities and 28 healthy subjects (16.0, 11.0-21.0). Median maximum airway wall flux and median alveolar NO concentration were significantly reduced in PCD patients compared to healthy subjects: 16.0, 7.5-29.5, vs. 25.0, 15.0-32.5 nl/min (P<0.05) and 2.5, 1.6-3.3, vs. 5.0, 3.6-6.5 ppb (P<0.01), respectively. Significant correlations between maximum airway wall flux and airflow limitation were found, i.e., resistance of respiratory system (rho=0.74, P<0.005), forced expiratory volume in one second (FEV(1))/VC (rho= -0.61, P<0.05), FEV(1) (rho=-0.52, P< 0.05), mid expiratory flow between 25 and 75% of forced vital capacity (MEF(25-75)) (rho=-0.54, P<0.05), and maximal instantaneous expiratory flow at 50% of the vital capacity (MEF(50)) (rho=-0.55, P<0.05). In conclusion, the impairment of NO output is less pronounced in the lower than in the upper (nasal) respiratory tract in PCD. A decrease in maximal NO output from conducting airways is associated with limited airflow impairment.

Alveolar nitric oxide and effect of deep inspiration during methacholine challenge.

STUDY OBJECTIVES: To assess whether the dual anatomic origin of exhaled nitric oxide (NO), namely alveolar and bronchial, could explain the link between exhaled NO and airway responsiveness, and could participate in the bronchodilatory effect of deep inspiration (DI) that may be evidenced during methacholine challenge. DESIGN AND SETTING: Prospective study in a laboratory performing pulmonary function tests of an academic hospital. PATIENTS AND INTERVENTIONS: Patients underwent multiple flow analysis of exhaled NO, allowing calculation of total maximum airway NO flux (J'awno) and NO concentration of expansible compartment (CAno), and received a cumulative methacholine dose of 2,000 microg. DI effect was assessed by continuous measurement of the resistance of respiratory system using the forced oscillation technique before and after DI. RESULTS: In a first phase involving 23 patients, a positive correlation between log values of J'awno and CAno was demonstrated with the degree of airway responsiveness (percentage of FEV(1) decrease). In a second phase involving 38 patients, only log CAno was correlated with responsiveness, and no significant relationship was demonstrated between J'awno or CAno and the effect of DI. Patients with smaller airways and/or distal airflow limitation exhibited a constrictive response to DI. CONCLUSION: Airway responsiveness is mainly associated with an increase in distal origin of NO output, and no relationship between exhaled NO and the effect of DI was evidenced.

Transdiaphragmatic pressure control of airway pressure support in healthy subjects.

We designed a new servoventilator that proportionally adjusts airway pressure to transdiaphragmatic pressure (Pdi) generated by the subject during inspiration. Each cycle is triggered by either a preset Pdi increase or a preset inspiratory flow value (whichever is reached first), whereas cycling-off is flow-dependent. We evaluated the servoventilator in seven healthy subjects at normocapnia and three levels of hypercapnia (normocapnia + 3, + 6, and + 9 mm Hg) comparatively with spontaneous breathing. Triggering was by Pdi in six subjects and flow in one. At all end-tidal carbon dioxide pressure levels, time from onset of diaphragm electromyographic activity to inspiratory flow was similar with and without the servoventilator. Airway pressure increased proportionally to Pdi variation during servoventilator breathing. Flow, tidal volume, respiratory rate, intrinsic positive end-expiratory pressure, and esophageal and transdiaphragmatic pressure-time products increased significantly with hypercapnia with and without the servoventilator. Breathing pattern parameters were similar in the two breathing modes, and no differences were found for intrinsic positive end-expiratory pressure or gastric pressure variation during exhalation. Esophageal and transdiaphragmatic pressure-time products were lower with than without the servoventilator. The Pdi-driven servoventilator was well synchronized to the subjects effort, delivering a pressure proportional to Pdi and reducing respiratory effort at normocapnia and hypercapnia.

Effect of intratracheal adenoviral vector administration on lung development in newborn rats.

Local overexpression of genes that promote lung defense or repair may be helpful in protecting the immature neonatal lung from injuries, but whether the vectors used to administer these genes affect physiological postnatal lung growth has not been investigated. We explored the effect on alveolarization of E1-deleted Adnull vector (Ad5-LMP-null) given intratracheally to 3-day-old rats. Three Adnull doses were evaluated 10(8), 5 x 10(8), and 10(9) TCID(50). Lung morphometry on day 21 showed significant growth disorders with the two higher doses. With 5 x 10(8) TCID(50), absolute lung volume increased significantly (+16%), as did absolute (+20%) and specific (+32%) alveolar airspace volumes, whereas alveolar surface density decreased by 13% (p < 0.009 for all parameters). Lung inflammation was mild, nonsignificant, and occurred mainly with the highest Adnull dose, indicating that it was unlikely to contribute to our results. Adnull instillation induced a significant#10; decrease in terminal bronchiolar cell proliferation as evaluated by proliferating cell nuclear antigen immunostaining (p = 0.02), as well as a 23% decrease in absolute parenchyma elastic fiber length (p = 0.02). Furthermore, lung tropoelastin mRNA content decreased by 25% (p < 0.02). In conclusion, E1-deleted adenoviral vectors can induce lung growth disorders when instilled into the airways of neonatal rats. Interactions with lung matrix turnover may be the main explanation to these deleterious effects.

Distribution of ventilation/perfusion ratios in pulmonary embolism: an adjunct to the interpretation of ventilation/perfusion lung scans.

UNLABELLED: Diagnosis of pulmonary embolism (PE) by visual interpretation of ventilation/perfusion (V/Q) scans is limited by the high percentages of patients classified in the intermediate- and low-probability categories. This study proposes a quantitative analysis of the distribution of V/Q ratios to better identify patients with PE. METHODS: We studied 99 consecutive patients who underwent dual-isotope (81m)Kr/(99m)Tc-macroaggregate V/Q scanning and arterial blood gas analysis within 48 h. The 8-view V/Q scans were visually analyzed by 2 observers according to the revised criteria of the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) (normal scan or low, intermediate, or high probability of PE). Quantitative analysis of the posterior-view distribution histogram of V/Q ratios was performed using dedicated software. Briefly, regions of interest were drawn around the lungs on the matched V/Q images, smooth filtering was applied, normalized regional V/Q ratios were calculated within each pixel, and a distribution histogram was built. RESULTS: Patients with normal scans (n = 16) had a predominance of V/Q ratios (63.3% +/- 13.0%) between 0.8 and 1.2. They had only 9.8% +/- 5.8% of ratios > 1.2, and the remaining 26.9% +/- 7.5% of ratios were <0.8. By contrast, patients with PE (n = 34) were characterized by a significant increase (15.5 +/- 10.0%, P = 0.04) in high V/Q ratios (>1.2) and a significant increase (34.5% +/- 8.2%, P = 0.003) in low V/Q ratios (<0.8). Interestingly, a similar pattern was found in patients with a high PIOPED probability of PE, 21.3% +/- 11.0% and 37.5% +/- 9.2%, respectively. Within the nondiagnostic group (intermediate- + low-probability scans, n = 58), 17 patients were finally diagnosed with PE. Analysis of the distribution histogram in this group allowed the identification of 5 patients with PE (specificity, 78%). CONCLUSION: A quantitative approach to lung scan interpretation, based on the distribution histogram of V/Q ratios, may be helpful for categorizing patients with suspected PE.

Beneficial effect of an inhibitor of leukocyte elastase (EPI-hNE-4) in presence of repeated lung injuries.

Persistence of alveolar neutrophil influx and activation may enhance the fibrotic process after acute lung injury. On the other hand, elastase has an antimicrobial activity and could participate in neutrophil migration, both events being critically important in host defense, explaining the controversial issue of therapeutic elastase inhibition in the setting of acute lung injury. We assessed the effect of a neutrophil elastase inhibitor, EPI-hNE-4, in single (bleomycin, 1.2 mg/rat intratracheally) and repeated (bleomycin, 1.2 mg/rat plus endotoxin and 1 mg/kg intratracheally 24 h later) lung injuries to assess the role of neutrophil in fibrosis. Subsequently, the effect of EPI-hNE-4 on bacterial clearance was evaluated during Pseudomonas aeruginosa-induced pneumonia. In the single injury model, despite a dramatic reduction of alveolar neutrophil influx with EPI-hNE-4 treatment, no significant inhibition of the decrease in respiratory system compliance, an index of lung fibrosis, was demonstrated at day 14. In the repeated injury model, EPI-hNE-4 treatment afforded a significant protective effect on compliance and alveolar inflammation at day 14. During bacterial pneumonia, EPI-hNE4 did not modify alveolar neutrophil recruitment or bacterial clearance from bronchoalveolar lavage fluid and lung homogenate. In conclusion, EPI-hNE-4, a specific inhibitor of leukocyte elastase, afforded a partial protective effect on the respiratory system compliance during repeated lung injuries, and had no detrimental effect during a gram-negative bacterial pneumonia.

Increase in alveolar nitric oxide in the presence of symptoms in childhood asthma.

STUDY OBJECTIVES: To determine respective contributions of alveolar and proximal airway compartments in exhaled nitric oxide (NO) output (QNO) in pediatric patients with asthma and to correlate their variations with mild symptoms or bronchial obstruction. PATIENTS AND DESIGN: In 15 asthmatic children with recent mild symptoms, 30 asymptomatic asthmatic children, and 15 healthy children, exhaled NO concentration was measured at multiple expiratory flow (V) rates allowing the calculation of alveolar and proximal airway contributions in QNO, using two approaches, ie, linear and nonlinear models. MEASUREMENTS AND RESULTS: Asymptomatic and recently symptomatic patients were not significantly different regarding FEV(1) and maximum V between 25% and 75% of FVC (MEF(25-75)): FEV(1), 93.3 +/- 13.4% vs 90 +/- 7.5%; MEF(25-75), 70 +/- 22% vs 68 +/- 28% of predicted values, respectively (mean +/- SD). Maximal airway QNO output was significantly higher in recently symptomatic vs asymptomatic patients (p < 0.0001), and in asymptomatic patients vs healthy children (p < 0.02): 134 +/- 7 nl/min, 55 +/- 43 nl/min, and 19 +/- 8 nl/min, respectively. In a multiple regression analysis, variables that influenced airway QNO output were symptoms (p < 0.0001) and distal airway obstruction as assessed by MEF(25-75) (p < 0.05). Alveolar NO concentration (FANO) was significantly (p < 0.03) higher in recently symptomatic than in patients without symptoms, whereas it was not significantly different between asymptomatic patients and healthy children: 7.2 +/- 2.4 parts per billion (ppb), 5.5 +/- 2.7 ppb, and 4.2 +/- 2.0 ppb, respectively. CONCLUSIONS: An increase in FANO was observed in the presence of symptoms, and proximal airway NO output was correlated with distal obstruction during asthma.

Effect of the humidification device on the work of breathing during noninvasive ventilation.

OBJECTIVE: Heat and moisture exchangers (HME) increase circuitry deadspace compared to heated humidifiers (HH). This study compared the effect of HH and HME during noninvasive ventilation (NIV) on arterial blood gases and patient's effort assessed by respiratory muscles pressure-time product and by work of breathing (WOB). DESIGN AND SETTING: Randomized cross-over study in a medical intensive care unit. PATIENTS: Nine patients receiving NIV for moderate to severe acute hypercapnic respiratory failure. MEASUREMENTS: HME was randomly compared to HH during periods of 20 min. Each device was studied without (ZEEP) and with a PEEP of 5 cmH(2)O. At the end of each period arterial blood gases, ventilatory parameters, oesophageal and gastric pressures were recorded and indexes of patient's effort calculated. RESULTS: Minute ventilation was significantly higher with HME than with HH (ZEEP: 15.8+/-3.7 vs. 12.8+/-3.6 l/min) despite a similar PaCO(2) (60+/-16 vs. 57+/-16 mmHg). HME was associated with a greater increase in WOB (ZEEP: 15.5+/-7.7 vs. 8.4+/-4.5 J/min and PEEP: 11.3+/-5.7 vs. 7.3+/-3.8 J/min) and indexes of patient effort. NIV with HME failed to decrease WOB compared to baseline. Addition of PEEP reduced the level of effort, but similar differences between HME and HH were observed. CONCLUSIONS: In patients receiving NIV for moderate to severe acute hypercapnic respiratory failure, the use of HME lessens the efficacy of NIV in reducing effort compared to HH.

Effect of partial liquid ventilation on bacterial clearance during Pseudomonas aeruginosa-induced lung injury in rats.

OBJECTIVE: Partial liquid ventilation (PLV) has been shown to exhibit anti-inflammatory properties during non-infectious models of acute lung injury. The aim of this experimental study was to assess the effects of PLV on bacterial clearance during Pseudomonas aeruginosa-induced pneumonia in rats. DESIGN: The rats were assigned to four groups 4 h after bacterial challenge according to the kind of mechanical ventilation [gas ventilation (GV) or PLV, 6 ml/kg perflubron plus 2 ml/kg per h] and to the level of PEEP used (3 or 8 cm of water). Physiologic measures were recorded during anesthesia (arterial blood gases, airway and blood pressures) for 4 subsequent hours until sacrifice. RESULTS: No improvement of oxygenation was demonstrated in any group. The bacterial counts were higher in PLV-PEEP 8 rats compared to GV-PEEP 8 rats: median, 1.7.10(4) cfu (25th-75th percentiles, 1.2.10(4)-1.8.10(4)) versus 1.1.10(4) (8.7.10(3)-1.3.10(4))/ml of BAL fluid and 4.0.10(6) cfu (2.0.10(6)-5.5.10(6)) versus 1.7.10(6) cfu (9.7.10(5)-3.2.10(6))/ml of lung homogenate, respectively ( P<0.05, n=8/10 surviving rats per group). PEEP 8 was associated with a significant decrease in neutrophil recruitment in BAL fluid compared to PEEP 3 in both GV and PLV groups. Additional in vitro experiments demonstrated that perflubron induced a decrease in phagocytosis of P. aeruginosa by alveolar neutrophils. CONCLUSIONS: These results demonstrate that PLV is associated with an impaired bacterial clearance during early pneumonia in rats, which could have been favored by decreased bacterial phagocytosis by neutrophils.

Bactericidal activity response of blood neutrophils from critically ill patients to in vitro granulocyte colony-stimulating factor stimulation.

OBJECTIVE: Neutrophil function impairment is common in nonneutropenic critically ill patients. Whether granulocyte colony-stimulating factor (G-CSF) may be useful for preventing nosocomial infection in these patients is debated. The response of blood neutrophils from critically ill patients to G-CSF was investigated in vitro. DESIGN AND SETTING: Prospective study, laboratory investigation in two intensive care units. PATIENTS: 52 critically ill patients without immunosuppression. MEASUREMENTS: Neutrophils obtained from 52 patients on the 5th day of their intensive care unit stay were incubated with and without G-CSF (1, 10, 100 ng/ml). Reactive oxygen species (ROS) release and bactericidal activity against Staphylococcus aureus and Pseudomonas aeruginosa were evaluated. Plasma cytokines (interleukin 10, tumor necrosis factor alpha, and G-CSF) were measured. RESULTS: Median values (25th-75th percentiles) indicated no stimulatory effect of G-CSF on neutrophil bactericidal activity against either organism: S. aureus, 100% (95-109) of the unstimulated condition with 1 ng/ml G-CSF, and P. aeruginosa, 102% (98-109) with 1 ng/ml G-CSF. However, wide interindividual variability was found, ranging from marked inhibition to marked stimulation. Similar variability was found for ROS release. No correlations were found between ROS release and bactericidal activities against either bacterial strain. Inhibition of neutrophil bactericidal activity by G-CSF was associated with significantly higher plasma interleukin 10 concentrations. Plasma G-CSF levels were significantly higher in patients whose neutrophil bactericidal activity was unresponsive to G-CSF, suggesting G-CSF receptor downregulation. CONCLUSIONS: The effect of G-CSF on in vitro neutrophil bactericidal activity varied widely, depending on endogenous levels of G-CSF and was not predictable based on severity scores.

Granulocyte colony-stimulating factor enhances alpha-naphthylthiourea-induced pulmonary hypertension.

Physiopathological discrepancies exist between the most widely used models of pulmonary hypertension (PH), namely monocrotaline- and hypoxia-induced PH. The development of a new model could help in the understanding of underlying mechanisms. Repeated alpha-naphthylthiourea (ANTU) injections (5 mg/kg weekly, 3 wk) induced pulmonary vascular remodeling, which was associated with development of PH and right ventricular hypertrophy. ANTU followed by granulocyte colony-stimulating factor (G-CSF; 25 microgram. kg(-1). day(-1) subcutaneously, 3 days/wk) induced higher pulmonary arterial pressures and right ventricular hypertrophy than ANTU alone. Lidocaine, which inhibits neutrophil functions, inhibited PH exacerbation by G-CSF. Endothelial nitric oxide synthase expression, measured to assess ANTU-related endothelial toxicity, decreased significantly in ANTU-treated rats and fell even more sharply when G-CSF was given. This occurred despite a significant increase in vascular endothelial cell growth factor expression in lung and right ventricle in rats given ANTU alone and even more in rats given ANTU plus G-CSF. Repeated ANTU administration induces PH with vascular remodeling that can be further aggravated by the neutrophil activator G-CSF.

Quantitative lung perfusion scan as a predictor of aerosol distribution heterogeneity and disease severity in children with cystic fibrosis.

BACKGROUND: The assessment of lung ventilation by radionuclide imaging has proved useful for the optimization of aerosol therapy in children with cystic fibrosis. Further analysis of lung perfusion may provide additional information. METHODS: Quantitative analysis of regional lung aerosol distribution (Tc phytates) and perfusion (Tc macroaggregates) homogeneity was performed in 18 children with cystic fibrosis, using the third and fourth spatial moments (skew and Kurtosis) of count distribution. Patients were chosen from a prospective study whose goal was to compare the efficacy of two nebulization methods of a radiolabelled aerosol: one session involved a nebulizer activated by patient inspiratory flow (control session), whereas the other involved a nebulizer powered by a pressure support device (PS session). RESULTS: Quantitative regional distribution of perfusion was similar to aerosol distribution, although skew and Kurtosis were lower, indicating better homogeneity. Perfusion skew was inversely correlated with pulmonary volumes and Shwachman score, even more significantly than ventilation skew. Using receiver operating characteristic curve analysis, a perfusion skew threshold of 0.67 was predictive of disease severity (FEV1 > or =60% or FEV1 <60%) with 86% sensitivity and 91% specificity. Furthermore, same skew threshold allowed the identification of patients who were 'PS responders' (greater amount of radioactivity deposited after the PS session) or 'PS non-responders' with 80% sensitivity and 77% specificity. CONCLUSION: Quantification of regional lung perfusion is easy to perform and heterogeneity of the distribution is closely correlated to disease severity. Moreover, perfusion skew can identify patients who are likely to benefit from pressure support (to optimize aerosol therapy) and may be helpful for orienting potential non-responders towards alternative therapies.

Effect of granulocyte colony-stimulating factor on bleomycin-induced acute lung injury and pulmonary fibrosis.

OBJECTIVE: Potentially fatal pulmonary toxicity is a dreaded complication of bleomycin. Increased use of granulocyte colony-stimulating factor in patients receiving chemotherapy has been paralleled by an increased incidence of bleomycin-induced pulmonary toxicity. We investigated whether granulocyte colony-stimulating factor (25 microg x kg(-1) x day(-1), 4 days) enhanced endotracheal bleomycin-induced (5 mg/kg) acute lung injury and fibrosis in rats. SETTING: University laboratory. SUBJECTS: Sprague-Dawley rats. INTERVENTIONS: We compared the effects of alveolar instillation of bleomycin in rats treated with either granulocyte colony-stimulating factor or saline. MEASUREMENTS AND MAIN RESULTS: Mortality was 25% with bleomycin only and 50% with bleomycin + granulocyte colony-stimulating factor. Granulocyte colony-stimulating factor increased alveolar neutrophil recruitment, pulmonary edema, and lung myeloperoxidase activity on day 4. Lung static compliance on day 15 was severely decreased with bleomycin alone and showed a further significant decrease when granulocyte colony-stimulating factor was added (controls, 3.85 +/- 0.14 mL/kPa; bleomycin, 1.44 +/- 0.06 mL/kPa; and bleomycin + granulocyte colony-stimulating factor, 0.65 +/- 0.09 mL/kPa; control vs. bleomycin, p <.0001; and bleomycin vs. bleomycin + granulocyte colony-stimulating factor, p =.0003). Lung morphology with bleomycin + granulocyte colony-stimulating factor showed, in addition to the changes observed with bleomycin alone, four patterns indicating more severe disease: honeycomb foci, pleural thickening with hyaline fibrosis, interstitial granuloma with increased number of macrophages but not neutrophils, and established interstitial fibrosis. Lidocaine, which prevents neutrophil adhesion to endothelial cells, inhibited granulocyte colony-stimulating factor-related exacerbation of acute lung injury (bronchoalveolar lavage fluid cells and pulmonary edema) and pulmonary fibrosis (lung static compliance and morphologic changes). CONCLUSIONS: Granulocyte colony-stimulating factor enhances bleomycin-induced lung toxicity by a mechanism that probably involves neutrophils.

Mechanism of respiratory insufficiency in pure or mixed drug-induced coma involving benzodiazepines.

OBJECTIVE: We tested the hypothesis that the mechanism of respiratory insufficiency in drug-induced coma involving benzodiazepines is an increase in upper airway resistance. METHODS: Eighteen nonintubated and seven intubated (control) patients were poisoned with hypnotic sedatives involving benzodiazepines. Neurological and respiratory parameters were measured by polysomnography before and after flumazenil. Flumazenil was administered as escalating bolus doses followed by a continuous infusion. RESULTS: Upon entry, Glasgow Coma Score was 7 +/- 1 in nonintubated and 5 +/- 1 in intubated patients. Snoring with flow limitation and obstructive apnea were recorded in 16 and 5 among the 18 nonintubated patients, respectively. Central apnea was not observed. Total pulmonary resistance was 2.5-fold higher in nonintubated patients than in intubated patients. Total and resistive work of breathing (WOB) was significantly greater in the nonintubated group. Flumazenil bolus administration was associated with an improvement in Glasgow Coma Score from 7 +/- 1 to 13 +/- 1 in the nonintubatedpatients, and from 5 +/- 1 to 11 +/- in the intubated patients. Mean effective bolus doses were 0.3 +/- 0.1 mg in nonintubated patients and 0.6 +/- 0.1 mg in intubated patients. Tidal and minute volumes increased significantly, and WOB decreased significantly in nonintubated patients. In nonintubated patients, the decrease in total WOB resulted from a significant decrease in resistive WOB. CONCLUSION: Drug-induced coma involving benzodiazepines is characterized by snoring with flow limitation and obstructive apnea. The mechanism of respiratory insufficiency in nonintubated patients with drug-induced coma involving benzodiazepines is an increase in upper airway resistance and WOB.

Long-term effects of different humidification systems on endotracheal tube patency: evaluation by the acoustic reflection method.

BACKGROUND: Accumulation of mucous secretions in an endotracheal tube (ETT) increases its resistance, and the amount of deposit may be affected by the quality of humidification and heating of the inspired gas. METHODS: The authors assessed the impact of two humidification systems, a heated humidifier (HH) and a hygroscopic-hydrophobic heat and moisture exchanger (HME), on the ETT patency in patients selected to require mechanical ventilation for more than 48 h. This comparison was performed over two consecutive periods and used the acoustic reflection method, which characterizes the amount and site of ETT obstruction and allows estimating ETT inner volume and resistance. Measurements were performed three times a week over the period of mechanical ventilation. Comparisons were performed at mid duration and at the end of the mechanical ventilation period. RESULTS: The HH was used in 34 patients, and the HME was used in 26 patients. The two groups had similar severity and duration of mechanical ventilation. At mid duration of mechanical ventilation (5.5 +/- 3.3 vs. 4.8 +/- 3.3 days; P = 0.4), no difference was observed in ETT volume and resistance between the two groups. At the end of the study period (10.5 +/- 5.8 vs. 9.6 +/- 6.3 days of mechanical ventilation; P = 0.4), ETT volume was reduced to a greater extent with HME than with HH (-3.3 +/- 2.9 vs. -5.1 +/- 2.5%; P = 0.008), and ETT resistance increased significantly more with the HME than with the HH (8.4 +/- 12.2 vs. 19.4 +/- 17.7%; P = 0.001). CONCLUSION: Prolonged use of humidification systems results in progressive reduction of ETT patency, and to a greater extent with HMEs than with HHs.

LPS-induced lung injury in neonatal rats: changes in gelatinase activities and consequences on lung growth.

Postnatal lung growth disorders may involve imbalance between metalloproteinases and their inhibitors. Inflammatory cell 92-kDa gelatinase overactivity has been reported in adults with lung injury but has not been looked for in neonates. We compared gelatinase activity in neonatal and adult rats and evaluated postnatal lung growth after lipopolysaccharide (LPS)-induced lung injury. Significant intra-alveolar inflammatory cell recruitment occurred in adults and neonates; cell counts increased 16-fold in adults and 2.7-fold in neonates. Total 92-kDa gelatinase activity was increased in neonates and adults and was significantly correlated to inflammatory cell counts. For a given cell count, 92-kDa gelatinase increased more in neonates than in adults. Morphometric neonatal lung analysis showed that LPS-injured lungs had decreases in absolute values of lung volume (P < 0.03), alveolar surface (P < 0.004), and air space volume (P < 0.03). Doxycycline, a nonspecific metalloproteinase inhibitor, partly inhibited LPS-induced 92-kDa gelatinase overactivity but did not improve LPS-induced alveolar growth disorders. LPS-mediated lung injury in neonatal rats induced both gelatinase B overactivity and alveolar growth disorders, although no causal link between these two effects was demonstrated.

Protection against acute lung injury by intravenous or intratracheal pretreatment with EPI-HNE-4, a new potent neutrophil elastase inhibitor.

Excessive accumulation of active neutrophil elastase (NE) in pulmonary fluids and tissues of patients with cystic fibrosis (CF) is thought to act on the lungs, compromising their structure and function. The aim of this study was to investigate the in vitro and in vivo protective effect of a new, rapidly acting, potent (Ki = 5.45 x 10(-12) M and Kon = 8 x 10(6) M(-1) s(-1)) and specific human NE inhibitor, EPI-HNE-4, engineered from the Kunitz domain. The results demonstrated that this inhibitor was able to (i) effectively inhibit in vitro the high levels of active NE present in a medium as complex as sputum from children with CF, with a measured IC(50) equal or close to the calculated IC(50) in 60% of cases, and (ii) almost completely block (91%) the N-formyl-methionine-leucine-phenylalanine-induced migration of purified human neutrophils across a Matrigel basement membrane. Intratracheal administration (250, 175, or 100 microg per rat) of the inhibitor 5 min before instillation of pure human NE (HNE) (150 microg per rat) to rats induced effective, dose-dependent protection of the lungs, 4 h later, from hemorrhage, serum albumin leakage, residual active NE, and discrete neutrophil influx in air spaces induced by instillation of pure HNE. Intravenous administration (3 mg per rat) of EPI-HNE-4, 15 min before instillation of the soluble fraction of pooled sputum (delivering 120 microg of active NE per rat) from children with CF, effectively reduced (64%), 4 h later, the massive neutrophil influx induced by sputum instillation. Overall, these data strongly suggest that associated aerosol and systemic administration of EPI-HNE-4 would be beneficial in the treatment of CF.

Beneficial effects of nitric oxide inhalation on pulmonary bacterial clearance.

OBJECTIVE: The beneficial effects of nitric oxide inhalation on oxygenation during acute respiratory distress syndrome are well described. In contrast, the effects of nitric oxide on pulmonary inflammatory response are much less known in vivo. The objectives of this study were to evaluate the effects of nitric oxide inhalation on bacterial clearance during bacterial pneumonia and on alveolar neutrophil functions. DESIGN: Controlled animal study. SETTING: Research laboratory of an academic institution. SUBJECTS: Male Sprague-Dawley rats. INTERVENTIONS: Severe pneumonia was induced by alveolar instillation of live Pseudomonas aeruginosa (1.5 x 10(8) colony-forming units/kg) in rats. After instillation, rats were exposed to oxygen alone (FIO(2) 100%) or to oxygen (FIO(2) approximately 100%) plus nitric oxide (10 ppm) during 24 hrs. MEASUREMENTS AND MAIN RESULTS: Oxygen plus nitric oxide inhalation compared with oxygen alone increased recruitment of alveolar neutrophils (32.5 +/- 4.6 x 10(6) cells/mL vs. 23.4 +/- 1.9 x 10(6) cells/mL, p <.05) and improved bacterial clearance in the bronchoalveolar lavage fluid (8.1 +/- 4.2 x 10(2) vs. 1.6 +/- 1.0 x 10(5) colony-forming units/mL, p <.05) and in the pulmonary parenchyma (1.7 +/- 1.14 x 10(7) vs. 3.4 +/- 1.5 x 10(8) colony-forming units/mL, p <.05). However, neither protein concentration in the bronchoalveolar lavage fluid nor mortality rates were modified by nitric oxide inhalation. The ex vivo alveolar neutrophil functions were similar regardless of whether rats previously inhaled nitric oxide. In vitro experiments demonstrated that nitric oxide donor had a direct bactericidal effect against P. aeruginosa and did not modify alveolar neutrophil functions. CONCLUSIONS: These results suggest a beneficial effect of nitric oxide inhalation on bacterial clearance of P. aeruginosa attributable to both a direct bactericidal effect and an influx of alveolar neutrophils with preserved functions.

Gelatinase activities in the airways of premature infants and development of bronchopulmonary dysplasia.

Matrix-degrading metalloproteinases may play a role in the pathophysiology of bronchopulmonary dysplasia (BDP). We, therefore, evaluated correlations between gelatinase activities [metalloproteinase (MMP)-2 and MMP-9] or tissue inhibitor of metalloproteinase (TIMP)-1 levels present in the airways during the initial phase of hyaline membrane disease and the onset of BPD. Tracheal aspirates were obtained within 6 h of birth (day 0) from 64 intubated neonates with a gestational age < or =30 wk. Forty-five neonates were resampled on day 3 or 5. Total MMP-2 level measured by zymography fell with time, whereas total MMP-9 level and TIMP-1 levels, assayed by ELISA, increased; the MMP-9 increase correlated with the increase in airway inflammatory cell numbers. Among the parameters measured on day 0, 3, or 5, lower total MMP-2 level, lower birth weight, and higher fraction of inspired oxygen on day 0 were significantly and independently associated with the development of BPD. In conclusion, MMP-9 level and TIMP-1 levels increased after birth but are not linked to BPD outcome. In contrast, low MMP-2 level at birth is strongly associated with the development of BPD.