Feasibility and physiological effects of noninvasive neurally adjusted ventilatory assist in preterm infants.

BackgroundNoninvasive neurally adjusted ventilator assist (NIV-NAVA) was introduced to our clinical practice via a pilot and a randomized observational study to assess its safety, feasibility, and short-term physiological effects.MethodsThe pilot protocol applied NIV-NAVA to 11 infants on nasal CPAP, high-flow nasal cannula, or nasal intermittent mandatory ventilation (NIMV), in multiple 2- to 4-h periods of NIV-NAVA for comparison. This provided the necessary data to design a randomized, controlled observational crossover study in eight additional infants to compare the physiological effects of NIV-NAVA with NIMV during 2-h steady-state conditions. We recorded the peak inspiratory pressure (PIP), FiO2, Edi, oxygen saturations (histogram analysis), transcutaneous PCO2, and movement with an Acoustic Respiratory Movement Sensor.ResultsThe NAVA catheter was used for 81 patient days without complications. NIV-NAVA produced significant reductions (as a percentage of measurements on NIMV) in the following: PIP, 13%; FiO2, 13%; frequency of desaturations, 42%; length of desaturations, 32%; and phasic Edi, 19%. Infant movement and caretaker movement were reduced by 42% and 27%, respectively. Neural inspiratory time was increased by 39 ms on NIV-NAVA, possibly due to Head's paradoxical reflex.ConclusionNIV-NAVA was a safe, alternative mode of noninvasive support that produced beneficial short-term physiological effects, especially compared with NIMV.

Evaluation of Ultrasound-Based Sensor to Monitor Respiratory and Nonrespiratory Movement and Timing in Infants.

GOAL: To describe and validate a noncontacting sensor that used reflected ultrasound to separately monitor respiratory, nonrespiratory, and caretaker movements of infants. METHODS: An in-phase and quadrature (I & Q) detection scheme provided adequate bandwidth, in conjunction with postdetection filtering, to separate the three types of movement. The respiratory output was validated by comparing it to the electrical activity of the diaphragm (Edi) obtained from an infant ventilator in 11 infants. The nonrespiratory movement output was compared to movement detected by miniature accelerometers attached to the wrists, ankles, and heads of seven additional infants. Caretaker movement was compared to visual observations annotated in the recordings. RESULTS: The respiratory rate determined by the sensor was equivalent to that from the Edi signal. The sensor could detect the onset of inspiration significantly earlier than the Edi signal (23+/-69 ms). Nonrespiratory movement was identified with an agreement of 0.9 with the accelerometers. It potentially interfered with the respiratory output an average of 4.7+/-4.5% and 14.9+/15% of the time in infants not requiring or on ventilatory support, respectively. Caretaker movements were identified with 98% sensitivity and specificity. The sensor outputs were independent of body coverings or position. CONCLUSION: This single, noncontacting sensor can independently quantify these three types of movement. SIGNIFICANCE: It is feasible to use the sensor as trigger for synchronizing mechanical ventilators to spontaneous breathing, to quantify overall movement, to determine sleep state, to detect seizures, and to document the amount and effects of caretaker activity in infants.

The beryllium bronchoalveolar lavage lymphocyte proliferation test: indicator of beryllium sensitization, inflammation or both?

CONTEXT: We had available records on over 300 workers evaluated with the beryllium bronchoalveolar lavage lymphocyte proliferation test (BeBALLPT) at three expert chronic beryllium disease (CBD) diagnostic centers. OBJECTIVE: The objective was to describe the contribution of the BeBALLPT to classification of workers with respect to beryllium sensitization (BeS) and beryllium-induced lung inflammation. METHODS: Company records were used to identify beryllium workers who had undergone diagnostic bronchoscopy with BeBALLPT. Clinical, work and smoking information was abstracted from electronic and paper databases. We analyzed factors influencing BeBALLPT outcome, and its relation to blood-determined BeS and granulomatous inflammation. RESULTS: Positive BeBALLPTs contributed evidence of BeS in subjects without prior positive beryllium blood lymphocyte proliferation tests (BeBLPTs) and of pulmonary inflammation in persons without granulomata evident on lung biopsy. Positive BeBALLPTs were associated with positive BeBLPTs and more strongly with granulomata. The rate of both positive BeBALLPT and granulomata increased with time worked through 4 years and were lower in smoking subjects. The false negative rate of the BeBALLPT was 20%. CONCLUSION: A positive BeBALLPT is closely linked to the presence of granulomata on lung biopsy and can be considered as an indicator of lung inflammation in addition to BeS. The ability to use BeBALLPT as a substitute for the more risky lung biopsy is limited by the BeBALLPT false negative rate and lack of information on the false positive rate. It is not recommended that a positive BeBALLPT be considered sufficient evidence for both lung inflammation and BeS.

Chronic hypercapnia alters lung matrix composition in mouse pups.

RATIONALE: permissive hypercapnia, a stretch-limiting ventilation strategy, often results in high Pa(CO(2)). This strategy is associated with reduced morbidity and mortality in premature infants and its benefits have been attributed to diminished barotrauma. However, little is known about the independent effect of high CO(2) levels during the lung development. METHODS: mice were exposed to 8% CO(2) or room air for 2 wk either from postnatal day 2 through 17 or as adults (approximately 2 mo of age). Lungs were excised and processed for protein, RNA, histology, and total lung volumes. RESULTS: histologic analysis demonstrated that alveolar walls of CO(2)-exposed mouse pups were thinner than those of controls and had twice the total lung volume. Molecular analysis revealed that several matrix proteins in the lung were downregulated in mouse pups exposed to hypercapnia. Interstitial collagen type I alpha1, type III alpha1, elastin and fibronectin protein, and mRNA levels were less than half of controls while collagen IV alpha 5 was unaffected. This decrease in interstitial collagen could thus account for the thinning of the interstitial matrix and the altered lung biomechanics. Matrix metalloproteinase (MMP)-8, a collagenase that has specificity for collagen types I and III, increased in hypercapnic mouse pups, suggesting increased collagen degradation. Moreover, tissue inhibitor of MMP (TIMP)-1, a potent inhibitor of MMP-8, was significantly decreased. However, unlike pups, adult mice exposed to hypercapnia demonstrated only a mild increase in total lung volumes and did not exhibit similar molecular or histologic changes. CONCLUSIONS: although permissive hypercapnia may prevent lung injury from barotrauma, our study revealed that exposure to hypercapnia may be an important factor in lung remodeling and function, especially in early life.

Impulse oscillometry versus spirometry in a long-term study of controller therapy for pediatric asthma.

BACKGROUND: Determination of the benefits and limitations of specific physiologic tests has not been well studied in long-term clinical pediatric trials. OBJECTIVE: We sought to determine the utility of impulse oscillometry in a long-term comparison of 3 controller regimens in children with persistent asthma. METHODS: Children 6 to 14 years of age with mild-to-moderate persistent asthma were characterized with oscillometry and spirometry before entry into a clinical trial and then serially during 48 weeks of therapy with either an inhaled corticosteroid, a combination inhaled corticosteroid with a long-acting beta-agonist, or a leukotriene receptor antagonist. RESULTS: The FEV(1)/forced vital capacity ratio, as well as the forced expiratory flow from 25% to 75% of forced vital capacity in terms of spirometric parameters and the reactance area (XA) from impulse oscillometry, appeared to complement information provided by FEV(1) when comparing the tests and factors that appeared to predict a response to treatment. XA was unique in that it, as distinct from spirometric variables, reflected ongoing improvement during the latter part of the trial. In general, improvements in XA during the latter part of the study occurred independently of indices of atopy and the level of airway responsiveness. CONCLUSION: Assessment of respiratory mechanics over time with oscillometry might offer additional insights into the response of asthmatic patients to therapy. In particular, the pattern of improvement seen in XA over the course of therapy suggests this test might detect alterations in airway mechanics not reflected by spirometry. The possibility that changes in XA reflect ongoing improvement in small airway function deserves additional study.

Tidal volume threshold for colorimetric carbon dioxide detectors available for use in neonates.

OBJECTIVE: Colorimetric carbon dioxide detectors are used for confirmation of endotracheal intubation. The colorimetric carbon dioxide detectors that are used for neonates are labeled for use with infants and small children >1 and <15 kg. The objective of this study was to determine the minimal tidal volume that causes a breath-to-breath color change on 2 colorimetric carbon dioxide detectors. METHODS: Using an artificial-lung model, we determined the tidal volume threshold of 2 colorimetric carbon dioxide detectors (Pedi-Cap [Nellcor, Pleasanton, CA] or Mini StatCO(2) [Mercury Medical, Clearwater, FL]) during ventilation with a T-piece resuscitator or neonatal ventilator. Digital video recordings of the colorimetric carbon dioxide detectors were made during 20 seconds of ventilation at each tidal volume. Seven clinicians who were blinded to the tidal volume reviewed the videos in random order and graded the color change to determine adequacy for clinical application. RESULTS: The Mini StatCO(2) tidal volume threshold was 0.83 mL, and the Pedi-Cap tidal volume threshold was 1.08 mL. CONCLUSIONS: The lung model revealed that the tidal volume threshold for the tested colorimetric carbon dioxide detectors is less than the expected tidal volume of a 400-g infant and suggests that these devices are appropriate for use with any neonate to confirm intubation.

A cluster-randomized trial of benchmarking and multimodal quality improvement to improve rates of survival free of bronchopulmonary dysplasia for infants with birth weights of less than 1250 grams.

OBJECTIVE: We tested whether NICU teams trained in benchmarking and quality improvement would change practices and improve rates of survival without bronchopulmonary dysplasia in inborn neonates with birth weights of <1250 g. METHODS: A cluster-randomized trial enrolled 4093 inborn neonates with birth weights of <1250 g at 17 centers of the National Institute of Child Health and Human Development Neonatal Research Network. Three centers were selected as best performers, and the remaining 14 centers were randomized to intervention or control. Changes in rates of survival free of bronchopulmonary dysplasia were compared between study year 1 and year 3. RESULTS: Intervention centers implemented potentially better practices successfully; changes included reduced oxygen saturation targets and reduced exposure to mechanical ventilation. Five of 7 intervention centers and 2 of 7 control centers implemented use of high-saturation alarms to reduce oxygen exposure. Lower oxygen saturation targets reduced oxygen levels in the first week of life. Despite these changes, rates of survival free of bronchopulmonary dysplasia were all similar between intervention and control groups and remained significantly less than the rate achieved in the best-performing centers (73.3%). CONCLUSIONS: In this cluster-randomized trial, benchmarking and multimodal quality improvement changed practices but did not reduce bronchopulmonary dysplasia rates.

Long-term comparison of 3 controller regimens for mild-moderate persistent childhood asthma: the Pediatric Asthma Controller Trial.

BACKGROUND: More evidence is needed on which to base recommendations for treatment of mild-moderate persistent asthma in school-aged children. OBJECTIVE: The Pediatric Asthma Controller Trial (PACT) compared the effectiveness of 3 regimens in achieving asthma control. METHODS: A total of 285 children (ages 6-14 years) with mild-moderate persistent asthma on the basis of symptoms, and with FEV(1) >or= 80% predicted and methacholine FEV(1) PC(20) or= 80% predicted, confirming current guideline recommendations.

Long-term inhaled corticosteroids in preschool children at high risk for asthma.

BACKGROUND: It is unknown whether inhaled corticosteroids can modify the subsequent development of asthma in preschool children at high risk for asthma. METHODS: We randomly assigned 285 participants two or three years of age with a positive asthma predictive index to treatment with fluticasone propionate (at a dose of 88 mug twice daily) or masked placebo for two years, followed by a one-year period without study medication. The primary outcome was the proportion of episode-free days during the observation year. RESULTS: During the observation year, no significant differences were seen between the two groups in the proportion of episode-free days, the number of exacerbations, or lung function. During the treatment period, as compared with placebo use, use of the inhaled corticosteroid was associated with a greater proportion of episode-free days (P=0.006) and a lower rate of exacerbations (P<0.001) and of supplementary use of controller medication (P<0.001). In the inhaled-corticosteroid group, as compared with the placebo group, the mean increase in height was 1.1 cm less at 24 months (P<0.001), but by the end of the trial, the height increase was 0.7 cm less (P=0.008). During treatment, the inhaled corticosteroid reduced symptoms and exacerbations but slowed growth, albeit temporarily and not progressively. CONCLUSIONS: In preschool children at high risk for asthma, two years of inhaled-corticosteroid therapy did not change the development of asthma symptoms or lung function during a third, treatment-free year. These findings do not provide support for a subsequent disease-modifying effect of inhaled corticosteroids after the treatment is discontinued. (ClinicalTrials.gov number, NCT00272441.).

Response profiles to fluticasone and montelukast in mild-to-moderate persistent childhood asthma.

BACKGROUND: Outcome data are needed to base recommendations for controller asthma medication use in school-aged children. OBJECTIVE: We sought to determine intraindividual and interindividual response profiles and predictors of response to an inhaled corticosteroid (ICS) and a leukotriene receptor antagonist (LTRA). METHODS: An ICS, fluticasone propionate (100 mug twice daily), and an LTRA, montelukast (5-10 mg nightly, age dependent), were administered to children ages 6 to 17 years with mild-to-moderate persistent asthma using only as-needed bronchodilators in a multicenter, double-masked, 2-sequence, 16-week crossover trial. Clinical, pulmonary, and inflammatory responses to these controllers were evaluated. RESULTS: Improvements in most clinical asthma control measures occurred with both controllers. However, clinical outcomes (asthma control days [ACDs], the validated Asthma Control Questionnaire, and albuterol use), pulmonary responses (FEV(1)/forced vital capacity, peak expiratory flow variability, morning peak expiratory flow, and measures of impedance), and inflammatory biomarkers (exhaled nitric oxide [eNO]) improved significantly more with fluticasone than with montelukast treatment. eNO was both a predictor of ACDs (P = .011) and a response indicator (P = .003) in discriminating the difference in ACD response between fluticasone and montelukast. CONCLUSIONS: The more favorable clinical, pulmonary, and inflammatory responses to an ICS than to an LTRA provide pediatric-based group evidence to support ICSs as the preferred first-line therapy for mild-to-moderate persistent asthma in children. eNO, as a predictor of response, might help to identify individual children not receiving controller medication who achieve a greater improvement in ACDs with an ICS compared with an LTRA.

Virulence role of group B Streptococcus beta-hemolysin/cytolysin in a neonatal rabbit model of early-onset pulmonary infection.

We examined the virulence role of group B Streptococcus (GBS) beta-hemolysin/cytolysin (beta h/c) in a neonatal-rabbit model of GBS pulmonary infection. Rabbits infected intratracheally with wild-type (wt) GBS developed focal pneumonia and, by 18 h after infection, had 100-fold more bacteria in lung tissue than did rabbits infected with a delta beta h/c mutant. Mortality (40% vs. 0%), development of bacteremia, and mean bacterial blood counts were all significantly higher in the rabbits challenged with wt GBS than in those challenged with the delta beta h/c mutant. Lung compliance during mechanical ventilation was impaired after injection of wt GBS but not after injection of the Delta beta h/c mutant strain. This work, to our knowledge, provides the first in vivo evidence for a critical role of the beta h/c toxin in GBS neonatal pneumonia and in the breakdown of the pulmonary barrier to systemic infection.

Characterization of within-subject responses to fluticasone and montelukast in childhood asthma.

BACKGROUND: Responses to inhaled corticosteroids (ICSs) and leukotriene receptor antagonists (LTRAs) vary among asthmatic patients. OBJECTIVE: We sought to determine whether responses to ICSs and LTRAs are concordant for individuals or whether asthmatic patients who do not respond to one medication respond to the other. METHODS: Children 6 to 17 years of age with mild-to-moderate persistent asthma were randomized to one of 2 crossover sequences, including 8 weeks of an ICS, fluticasone propionate (100 microg twice daily), and 8 weeks of an LTRA, montelukast (5-10 mg nightly depending on age), in a multicenter, double-masked, 18-week trial. Response was assessed on the basis of improvement in FEV 1 and assessed for relationships to baseline asthma phenotype-associated biomarkers. RESULTS: Defining response as improvement in FEV 1 of 7.5% or greater, 17% of 126 participants responded to both medications, 23% responded to fluticasone alone, 5% responded to montelukast alone, and 55% responded to neither medication. Compared with those who responded to neither medication, favorable response to fluticasone alone was associated with higher levels of exhaled nitric oxide, total eosinophil counts, levels of serum IgE, and levels of serum eosinophil cationic protein and lower levels of methacholine PC(20) and pulmonary function; favorable response to montelukast alone was associated with younger age and shorter disease duration. Greater differential response to fluticasone over montelukast was associated with higher bronchodilator use, bronchodilator response, exhaled nitric oxide levels, and eosinophil cationic protein levels and lower methacholine PC(20) and pulmonary function values. CONCLUSIONS: Response to fluticasone and montelukast vary considerably. Children with low pulmonary function or high levels of markers associated with allergic inflammation should receive ICS therapy. Other children could receive either ICSs or LTRAs.

The Prevention of Early Asthma in Kids study: design, rationale and methods for the Childhood Asthma Research and Education network.

Pediatric asthma remains an important public health concern as its prevalence and cost to the health care system is rising. In order to promote innovative research in asthma therapies, the National Heart, Lung and Blood Institute created the Childhood Asthma Research and Education Network in 1999. As its first study, the steering committee of the Childhood Asthma Research and Education Network designed a randomized clinical trial to determine if persistent asthma could be prevented in children at a high risk to develop the disease. This communication presents the design of its first clinical trial, the Prevention of Asthma in Kids (PEAK) trial and the organization of the Childhood Asthma Research and Education Network that developed and implemented this trial. Studies of the natural history of asthma have shown that, in persistent asthma, the initial asthma-like symptoms and loss of lung function occur predominately during the first years of life. Therefore, in the Prevention of Asthma in Kids study, children 2 and 3 years old with a positive asthma predictive index were randomized to twice daily treatment with fluticasone 88 microg or placebo via metered-dose inhaler and Aerochamber for 2 years. The double blind treatment period was followed by a 1-year observational period. Lung function was measured by spirometry and oscillometry technique at 4-month intervals throughout the study. Bronchodilator reversibility and exhaled nitric oxide (ENO) studies were performed at the end of the treatment and observation periods. The primary outcome measure was the number of asthma-free days. Other secondary outcomes included number of exacerbations, use of asthma medications and lung function. These measures were chosen to reflect the progression of the disease from intermittent wheezing to persistent asthma and measurement of the extent of airflow limitation and airway reactivity.

Increased fragility of pulmonary capillaries in newborn rabbit.

The pulmonary capillaries of neonatal lungs are potentially vulnerable to stress failure because of the complex changes in the pulmonary circulation that occur at birth. We perfusion fixed the lungs from nine anesthetized newborn rabbits at capillary transmural pressures (P(tm)) of 5 +/- 5, 10 +/- 5, and 15 +/- 5 cmH(2)O. Normal microscopic appearances were seen at P(tm) values of 5 +/- 5 and 10 +/- 5 cmH(2)O, but massive airway edema was observed in lungs perfused at a P(tm) of 15 +/- 5 cmH(2)O. Consistent with this, no disruptions of the alveolar epithelium were observed at P(tm) values of 5 +/- 5 cmH(2)O, but mean values of 0.11 and 1.22 breaks/mm epithelium were found at P(tm) of 10 +/- 5 and 15 +/- 5 cmH(2)O, respectively (P < 0.05 for 5 +/- 5 vs. 15 +/- 5 cmH(2)O). These pressures are in striking contrast to those in the adult rabbit in which, by a similar procedure, a P(tm) of 52.5 cmH(2)O, is required before stress failure is consistently seen. We conclude that stress failure of pulmonary capillaries in newborn rabbit lungs can occur at P(tm) values of less than one-third of those that are required in adult lungs.

Thickness of the blood-gas barrier in premature and 1-day-old newborn rabbit lungs.

The pulmonary capillaries of neonatal lungs are potentially vulnerable to stress failure because of the complex changes in the pulmonary circulation that occur at birth. We studied the ultrastructure of the blood-gas barrier (BGB) in premature and 1-day-old rabbit lungs and compared it with the ultrastructure of adult lungs. Normal gestation of rabbits is 30 days. After extensive pilot measurements, three premature (27 days gestation) and three newborn (1 day old) rabbit lungs were perfusion-fixed at arterial, venous, and airway pressures of 25, 0, and 10 cmH2O, respectively, and the measurements were compared with those of three adult lungs. The thickness of the capillary endothelium, alveolar epithelium, and interstitium of the BGB was measured at right angles to the barrier at random points. A striking finding was the large number of measurements of the interstitial thickness in 1-day-old lungs that were very thin (0-0.1 microm). The percentages of occurrence of very thin interstitium in premature, 1-day-old, and adult lungs were 35.3 +/- 9.4, 71.7 +/- 5.2, and 43.0 +/- 2.6, respectively (P < 0.02 for 1 day old vs. premature and adult). Given the previously found relationship between stress failure and interstitial thickness, this large proportion of very thin interstitial layers in the capillaries of 1-day-old lungs is a reasonable explanation for their previously demonstrated vulnerability to stress failure.