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Objectives: The use of neuromuscular blocking agents (NMBAs) in pediatric acute respiratory distress syndrome (PARDS) is common but unsupported by efficacy data. We sought to compare the outcomes between patients with moderate-to-severe PARDS receiving continuous NMBA during the first 48 hours of endotracheal intubation (early NMBA) and those without.Design: Secondary analysis of data from the Randomized Evaluation of Sedation Titration for Respiratory Failure (RESTORE) clinical trial, a pediatric multicenter cluster randomized trial of sedation.Setting: Thirty-one PICUs in the United States.Patients: Children 2 weeks to 17 years receiving invasive mechanical ventilation (MV) for moderate-to-severe PARDS (i.e., oxygenation index >= 8 and bilateral infiltrates on chest radiograph on days 0-1 of endotracheal intubation).Interventions: NMBA for the entire duration of days 1 and 2 after intubation.Measurements and Main Results: Among 1,182 RESTORE patients with moderate-to-severe PARDS, 196 (17%) received early NMBA for a median of 50.0% ventilator days (interquartile range, 33.3-60.7%). The propensity score model predicting the probability of receiving early NMBA included high-frequency oscillatory ventilation on days 0-2 (odds ratio [OR], 7.61; 95% CI, 4.75-12.21) and severe PARDS on days 0-1 (OR, 2.16; 95% CI, 1.50-3.12). After adjusting for risk category, early use of NMBA was associated with a longer duration of MV (hazard ratio, 0.57; 95% CI, 0.48-0.68; p < 0.0001), but not with mortality (OR, 1.62; 95% CI, 0.92-2.85; p = 0.096) compared with no early use of NMBA. Other outcomes including cognitive, functional, and physical impairment at 6 months post-PICU discharge were similar. Outcomes did not differ when comparing high versus low NMBA usage sites or when patients were stratified by baseline PaO2/FIO2 less than 150.Conclusions: Early NMBA use was associated with a longer duration of MV. This propensity score analysis underscores the need for a randomized controlled trial in pediatrics.

OBJECTIVE: We aim to describe current clinical practice, the past decade of experience and factors related to improved outcomes for pediatric patients receiving high-frequency oscillatory ventilation. We have also modeled predictive factors that could help stratify mortality risk and guide future high-frequency oscillatory ventilation practice. DESIGN: Multicenter retrospective, observational questionnaire study. SETTING: Seven PICUs. PATIENTS: Demographic, disease factor, and ventilatory and outcome data were collected, and 328 patients from 2009 to 2010 were included in this analysis. INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: Patients were classified into six cohorts based on underlying diagnosis. We used univariate analysis to identify factors associated with mortality risk and multivariate logistic regression to identify independent predictors of mortality risk. An oxygenation index greater than 35 and immunocompromise exhibited the greatest predictive power (p < 0.0001) for increased mortality risk, and respiratory syncytial virus was associated with lowest mortality risk (p = 0.003). Differences in mortality risk as a function of oxygenation index were highly dependent on primary underlying condition. A trend toward an increase in oscillator amplitude and frequency was observed when compared with historical data. CONCLUSIONS: Given the number of centers and subjects included in the database, these findings provide a robust description of current practice regarding the use of high-frequency oscillatory ventilation for pediatric hypoxic respiratory failure. Patients with severe hypoxic respiratory failure and immunocompromise had the highest mortality risk, and those with respiratory syncytial virus had the lowest. A means of identifying the risk of 30-day mortality for subjects can be obtained by identifying the underlying disease and oxygenation index on conventional ventilation preceding the initiation of high-frequency oscillatory ventilation.

Objective: Electrical impedance tomography measures lung volume in a cross-sectional slice of the lung. Whether these cross-sectional volume changes are representative of the whole lung has only been investigated in adults, showing conflicting results. This study aimed to compare cross-sectional and whole lung volume changes using electrical impedance tomography and respiratory inductive plethysmography. Design: A prospective, single-center, observational, nonrandomized study. Setting: The study was conducted in a neonatal ICU in the Netherlands. Patients: High-frequency ventilated preterm infants with respiratory distress syndrome. Interventions: Cross-sectional and whole lung volume changes were continuously and simultaneously measured by, respectively, electrical impedance tomography and respiratory inductive plethysmography during a stepwise recruitment procedure. End-expiratory lung volume changes were assessed by mapping the inflation and deflation limbs using both the pressure/impedance and pressure/inductance pairs and characterized by calculating the inflection points. In addition, oscillatory tidal volume changes were assessed at each pressure step. Measurements and Main Results: Twenty-three infants were included in the study. Of these, eight infants had to be excluded because the quality of the registration was insufficient for analysis (two electrical impedance tomography and six respiratory inductive plethysmography). In the remaining 15 infants (gestational age 28.0 ± 2.6 wk; birth weight 1,027 ± 514 g), end-expiratory lung volume changes measured by electrical impedance tomography were significantly correlated to respiratory inductive plethysmography measurements in 12 patients (mean r = 0.93 ± 0.05). This was also true for the upper inflection point on the inflation (r = 0.91, p < 0.01) and deflation limb (r = 0.83, p < 0.01). In 13 patients, impedance and inductance data also correlated significantly on oscillatory tidal volume/pressure relationships (mean r = 0.81 ± 0.18). Conclusions: This study shows that cross-sectional lung volume changes measured by electrical impedance tomography are representative for the whole lung and that this concept also applies to newborn infants.

OBJECTIVES:: During high-frequency oscillatory ventilation, an understanding of the relationship between lung volume and lung mechanics may help clinicians better apply ventilation. The objectives of this study were: 1) to describe the relationship between lung volume and lung function parameters during mapping of the deflation limb of the pressure-volume relationship in infants receiving high-frequency oscillatory ventilation, and 2) to determine whether these parameters might be useful in targeting an optimal volume to apply ventilation. DESIGN:: Observational physiological study. SETTING:: Tertiary neonatal intensive care unit in a pediatric hospital. PATIENTS:: Fifteen infants receiving high-frequency oscillatory ventilation and muscle relaxants. INTERVENTIONS:: The deflation limb of the pressure-volume relationship was mapped in each infant, after recruitment to total lung capacity, using stepwise airway pressure decrements. Total lung capacity and closing volume were defined by oxygenation response. MEASUREMENTS AND MAIN RESULTS:: Lung volume (respiratory inductive plethysmography), oxygen saturation, transcutaneous carbon dioxide, and indicators of lung mechanics were recorded at each pressure. A distinct bell-shaped relationship between lung volume and carbon dioxide, minute ventilation, and tidal volume (both at airway opening and by inductive plethysmography) could be identified on the deflation limb, with an improvement of 21.6 mm Hg (CO2), 168 mL/sec (minute ventilation), 0.25 mL/kg (airway opening tidal volume), and 13.7% (plethysmography tidal volume) compared with total lung capacity levels. The mean (SD) optimal volumes and pressures for these parameters were significantly lower than total lung capacity, occurring at volumes between 38.6 (39.8)% and 62.8 (31.1)% of total lung capacity, and 28 (36.3)% and 41.3 (38.7)% of pressure at total lung capacity (p < 0.05; Bonferroni post-test). These coincided with the lowest pressure and volumes that maintained the oxygenation benefit of recruitment. CONCLUSIONS:: Transcutaneous carbon dioxide, tidal volume, and minute ventilation may assist in refining strategies to identify optimal lung volume. © 2013 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins.

Objectives High-frequency oscillation is used for adults with acute lung injury/acute respiratory distress syndrome. Given the uncertain benefits, our objective was to describe contemporary patient selection, high-frequency oscillation utilization, and outcomes. Design Utilization review. Setting Ten academic centers (Ontario, Canada; January 1, 2005-January 31, 2007). Patients We included 190 consecutive adults treated with high-frequency oscillation and retrospectively abstracted data on patient demographics, gas exchange, hemodynamics, settings during conventional ventilation and high-frequency oscillation, adjunctive therapies, and outcomes. We used logistic regression to explore associations with oxygenation response and hemodynamic and ventilatory complications (2 hrs after high-frequency oscillation initiation) and mortality. Continuous data are reported as mean (sd) or median (quartile 1, quartile 3). Interventions None. Measurements and main results Patients (60.0% male; mean age, 52; sd 17) had predominantly acute lung injury/acute respiratory distress syndrome (89.8%) and were severely ill (mean Acute Physiology and Chronic Health Evaluation II score, 28; sd, 9) and hypoxemic (mean Pao2/Fio2, 80; sd, 42). High-frequency oscillation was started a median of 2 (1, 8) days after intubation and continued for a median of 3 (2, 7) days. During high-frequency oscillation, adjunctive treatments (neuromuscular blockade, 75.6%; recruitment maneuvers, 49.5%; nitric oxide, 34.0%; steroids, 63.1%) and new barotrauma or chest tube placement (23.5%) were common. Ten patients (5.3%) had technical complications; five required a new ventilator. Reasons for stopping high-frequency oscillation included death or withdrawal of life support (39.1%), significant improvement in respiratory failure (37.6%), and inadequate improvement (23.3%). One hundred and twenty-eight of 189 patients died in hospital. Most (62.5%) had a positive oxygenation response after 2 hrs of high-frequency oscillation (mean absolute increase in PaO₂/FiO₂, 22 [SD, 54]; 95% confidence interval of mean 14-31). A minority had lower PaO₂/FiO₂ (32.5%) or a hemodynamic (27.5%) or ventilatory (30.5%) complication. Older age, Acute Physiology and Chronic Health Evaluation II score, and Paco2 before high-frequency oscillation were independently associated with mortality. Conclusions Most patients treated with high-frequency oscillation have acute respiratory distress syndrome and severe hypoxemia that modestly improves 2 hrs after high-frequency oscillation application. However, oxygenation worsens in some patients, complications are common, and mortality is high.

Novel H1N1 swine origin influenza virus has led to a worldwide pandemic. During the pandemic, a significant number of patients became critically ill primarily because of respiratory failure. Most of these patients required intubation and mechanical ventilation and were treated with conventional modes of mechanical ventilation using a lung-protective strategy with low tidal volumes, plateau pressures

Objective Uncertainties about the numerous degrees of freedom in ventilator settings leave many unanswered questions about the biophysical determinants of lung injury. We investigated whether mechanical ventilation with high air flow could yield lung mechanical stress even in normal animals. Design Prospective, randomized, controlled experimental study. Setting University research laboratory. Subjects Thirty normal male Wistar rats (180-230 g). Interventions Rats were ventilated for 2 hrs with tidal volume of 10 mL/kg and either with normal inspiratory air flow (V') of 10 mL/s (F10) or high V' of 30 mL/s (F30). In the control group, animals did not undergo mechanical ventilation. Because high flow led to elevated respiratory rate (200 breaths/min) and airway peak inspiratory pressure (PIP,aw = 17 cm H2O), two additional groups were established to rule out the potential contribution of these variables: a) normal respiratory rate = 100 breaths/min and V' = 30 mL/sec; and b) PIP,aw = 17 cm H2O and V' = 10 mL/sec. Measurements and main results Lung mechanics and histology (light and electron microscopy), arterial blood gas analysis, and type III procollagen messenger RNA expression in lung tissue were analyzed. Ultrastructural microscopy was similar in control and F10 groups. High air flow led to increased lung plateau and peak pressures, hypoxemia, alveolar hyperinflation and collapse, pulmonary neutrophilic infiltration, and augmented type III procollagen messenger RNA expression compared with control rats. The reduction of respiratory rate did not modify the morphofunctional behavior observed in the presence of increased air flow. Even though the increase in peak pressure yielded mechanical and histologic changes, type III procollagen messenger RNA expression remained unaltered. Conclusions Ventilation with high inspiratory air flow may lead to high tensile and shear stresses resulting in lung functional and morphologic compromise and elevation of type III procollagen messenger RNA expression.

Objective: Ventilator settings typically used for high-frequency oscillatory ventilation (HFO) in adults provide acceptable gas exchange but may not take best advantage of its lung-protective aspects. We provide guidelines for HFO in adults with acute respiratory distress syndrome that should optimize the lungprotective characteristics of this ventilation mode. Design: Roundtable discussions, iterative revisions, and consensus. Setting: Five academic medical centers. Patients: Not applicable. Interventions: Participants addressed how to best maintain ventilation through combinations of oscillation pressure amplitude, frequency, and the use of an endotracheal tube cuff leak, and to maintain oxygenation through combinations of recruitment maneuvers, mean airway pressure, and oxygen concentration. The guiding principles were to provide lung protective ventilation by minimizing the size of tidal volumes, and balance the risks and benefits of lung recruitment and distension. Main Results: HFO may provide smaller tidal volumes and more complete lung recruitment than conventional modes. To optimize these features, we recommend use of the maximum pressureoscillation amplitude coupled with the highest tolerated frequency, targeting a pH of only 7.25‐7.35. This will yield a smaller tidal volume than typical HFO settings where frequency is limited to 6 Hz or less and pressure amplitude is submaximal. Lung recruitment can be achieved with the use of recruitment maneuvers, especially during the first several days of HFO. Recruitment may be augmented or sustained with generous mean airway pressures. These may either be chosen from a table of recommended mean airway pressure and oxygen concentration combinations, or individually titrated based on the oxygenation response of each patient. Conclusions: Modification of the goals and tactics of HFO use may better protect against ventilator-associated lung injury. Further clinical trials are needed to compare the effects on patient outcome of the best use of HFO compared to the most protective use of conventional modes in adult acute respiratory distress syndrome. (Crit Care Med 2007; 35:1649‐1654)

Objective: Randomized controlled trials (RCTs) investigating various lung-protective ventilation modes or strategies in newborn infants have failed to show clear differences in mortality or bronchopulmonary dysplasia. This review tries to identify possible reasons for this observation, applying modern concepts on ventilator-induced lung injury and lung-protective ventilation. Data Source: Published RCTs and systematic reviews on mechanical ventilation in newborn infants were identified by searching PubMed and the Cochrane Library. Data Synthesis: A total of 16 RCTs and four systematic reviews comparing high-frequency ventilation with conventional mechanical ventilation (CMV) failed to show consistent differences in mortality and bronchopulmonary dysplasia. Unfortunately, clear information or data on ventilation and oxygenation targets in the search for optimal lung volumes during high-frequency ventilation or CMV is lacking in many RCTs, questioning the validity of the results and the meta-analytic subgroup analysis. Based on improvement in oxygenation, only three RCTs successfully applied the optimal lung volume strategy during high-frequency ventilation. A total of 24 RCTs and three systematic reviews comparing various CMV modes and settings and two RCTs investigating permissive hypercapnia reported no differences in mortality or bronchopulmonary dysplasia. However, the intervention arms in these RCTs did not differ in tidal volume or positive end-expiratory pressures, variables that are considered important determinants in ventilator-induced lung injury. In fact, no RCT in newborn infants has substantiated so far the experimental finding that avoiding large tidal volumes and low positive end-expiratory pressure during CMV is lung protective in newborn infants. Conclusion: RCTs investigating lung-protective ventilation in neonates have mainly focused on comparing high-frequency ventilation with CMV. Most of these RCTs show weaknesses in the design, which may explain the inconsistent effect of high-frequency ventilation on bronchopulmonary dysplasia. RCTs on CMV only focused on comparing various modes and settings, leaving the important question whether reducing tidal volume or increasing positive end-expiratory pressure is also lung protective in newborn infants unanswered

Objective: The benefits of lung-protective ventilation strategies used for acute respiratory distress syndrome in subjects with normal lungs are uncertain. The purpose of this study was to investigate the hemodynamic effects of conventional lung-protective ventilation (CLPV) and high-frequency oscillatory ventilation (HFOV) in a normal lung animal model. Design: Prospective laboratory investigation. Setting: Animal laboratory in a university medical center. Subjects: Seven landrace pigs (mean weight 41 kg). Interventions: Pigs were ventilated at random conventionally with positive end-expiratory pressure 2-3 cm H 2 O and tidal volume 10-12 mL/kg (control), with CLPV (positive end-expiratory pressure 10 cm H 2 O, tidal volume 6 mL/kg), or with HFOV. Hemodynamics were analyzed after insertion of biventricular conductance catheters and a pulmonary artery catheter. Measurements and Main Results: The protective strategies led to higher mean airway pressures and severe hypercapnia with acidosis, which was only significant with CLPV. Compared with control, oxygenation was worse with CLPV and HFOV. With HFOV and CLPV, mean arterial pressure, cardiac output, and stroke volume decreased significantly; pulmonary arterial elastance increased. The slope of the end-diastolic pressure volume relationship for the left and right ventricle remained unchanged (preserved ventricular function), whereas the intercept increased with both protective strategies (augmented intrathoracic pressure); left and right end-diastolic volumes decreased significantly. Conclusions: In the absence of a fluid resuscitation strategy, CLPV and HFOV caused decreased mean arterial pressure, cardiac output, and stroke volume and worsened oxygenation in this normal lung animal model. This resulted primarily from a biventricular decrease in preload.

Both prone position and high-frequency oscillatory ventilation (HFOV) have the potential to facilitate lung recruitment, and their combined use could thus be synergetic on gas exchange. Keeping the lung open could also potentially be lung protective. The aim of this study was to compare physiologic and proinflammatory effects of HFOV, prone positioning, or their combination in severe acute respiratory distress syndrome (ARDS).: Prospective, comparative randomized study.A medical intensive care unit.Thirty-nine ARDS patients with a Pao2/Fio2 ratio150 mm Hg at positive end-expiratory pressureor =5 cm H2O.After 12 hrs on conventional lung-protective mechanical ventilation (tidal volume 6 mL/kg of ideal body weight, plateau pressure not exceeding the upper inflection point, and a maximum of 35 cm H2O; supine-CV), 39 patients were randomized to receive one of the following 12-hr periods: conventional lung-protective mechanical ventilation in prone position (prone-CV), HFOV in supine position (supine-HFOV), or HFOV in prone position (prone-HFOV).Prone-CV (from 138 +/- 58 mm Hg to 217 +/- 110 mm Hg, p.0001) and prone-HFOV (from 126 +/- 40 mm Hg to 227 +/- 64 mm Hg, p0.0001) improved the Pao2/Fio2 ratio whereas supine-HFOV did not alter the Pao2/Fio2 ratio (from 134 +/- 57 mm Hg to 138 +/- 48 mm Hg). The oxygenation index ({mean airway pressure x Fio2 x 100}/Pao2) decreased in the prone-CV and prone-HFOV groups and was lower than in the supine-HFOV group. Interleukin-8 increased significantly in the bronchoalveolar lavage fluid (BALF) in supine-HFOV and prone-HFOV groups compared with prone-CV and supine-CV. Neutrophil counts were higher in the supine-HFOV group than in the prone-CV group.Although HFOV in the supine position does not improve oxygenation or lung inflammation, the prone position increases oxygenation and reduces lung inflammation in ARDS patients. Prone-HFOV produced similar improvement in oxygenation like prone-CV but was associated with higher BALF indexes of inflammation. In contrast, supine-HFOV did not improve gas exchange and was associated with enhanced lung inflammation.

Overview of the mechanisms governing gas transport, mechanical factors influencing the transmission of pressure and flow to the lung, and the measurement of lung mechanics during high-frequency oscillatory ventilation (HFOV) in acute respiratory distress syndrome.Studies indexed in PubMed illustrating key concepts relevant to the manuscript objectives. Pressure transmission during HFOV in the adult lung was simulated using a published theoretical model.Gas transport during HFOV is complex and involves a range of different mechanisms, including bulk convection, turbulence, asymmetric velocity profiles, pendelluft, cardiogenic mixing, laminar flow with Taylor dispersion, collateral ventilation, and molecular diffusion. Except for molecular diffusion, each mechanism involves generation of convective fluid motion, and is influenced by the mechanical characteristics of the intubated respiratory system and the ventilatory settings. These factors have important consequences for the damping of the oscillatory pressure waveform and the drop in mean pressure from the airway opening to the lung. New techniques enabling partitioning of airway and tissue properties are being developed for measurement of lung mechanics during HFOV.Awareness of the different mechanisms governing gas transport and the prevailing lung mechanics during HFOV represents essential background for the physician planning to use this mode of ventilation in the adult patient. Monitoring of lung volume, respiratory mechanics, and ventilation homogeneity may facilitate individual optimization of HFOV ventilatory settings in the future.

Efforts to minimize ventilator-induced lung injury in adults with hypoxemic respiratory failure have recently focused on the potential role of high-frequency oscillatory ventilation (HFOV). However, HFOV has been studied in newborns with hypoxemic respiratory failure for nearly 3 decades. In this brief review, we attempt to summarize key physiological principles learned from this cumulative neonatal/pediatric experience with HFOV.

To determine the safety, feasibility, and lung-recruitment efficacy of an explicit ventilation protocol combining high-frequency oscillatory ventilation and recruitment maneuvers.Prospective, multiple-center, single-intervention pilot study.Four university-affiliated intensive care units.Twenty-five patients with early acute respiratory distress syndrome and severe oxygenation failure.Patients were transitioned from standardized conventional ventilation to high-frequency oscillatory ventilation beginning with an initial cycle of up to three sustained inflation recruitment maneuvers (40 cm H2O x 40 secs), followed by a decremental titration of Fio2 and then mean airway pressure. Recruitment maneuvers were repeated for hypoxemia and routinely at least twice daily if the Fio2 was0.4. A specific protocol was used for weaning high-frequency oscillatory ventilation, for transitioning to conventional ventilation, and for judging intolerance of conventional ventilation whereby patients should be put back on high-frequency oscillatory ventilation.Patients (median [interquartile range] Acute Physiology and Chronic Health Evaluation II, 24 [19-32]; age, 50 [41-64]) were enrolled after 13 (range, 6-51) hrs of conventional ventilation. Following the initial cycle of recruitment, the mean (+/-sd) Pao2/Fio2 increased significantly compared with standardized conventional ventilation (200 +/- 117 vs. 92 +/- 36 mm Hg, p.001). After a mean of 12 hrs of high-frequency oscillatory ventilation, the mean Fio2 was significantly reduced compared with prestudy levels (0.5 +/- 0.2 vs. 0.9 +/- 0.1, p.001). A median of seven (four to 11) recruitment maneuvers was performed per patient over the study period, with only eight of 244 (3.3%) being aborted. Six of 19 patients transitioned to conventional ventilation (32%) were deemed intolerant and were switched back to high-frequency oscillatory ventilation. Protocol adherence was excellent with documented rates90%.The combination of high-frequency oscillatory ventilation and recruitment maneuvers resulted in rapid and sustained improvement in oxygenation, likely through lung recruitment. This explicit high-frequency oscillatory ventilation protocol appears well tolerated, feasible, and physiologically sound.

INTRODUCTION Although mechanical ventilation is lifesaving for patients with acute respiratory distress syndrome, it can cause ventilator-induced lung injury. To minimize ventilator-induced lung injury, different ventilatory strategies have been developed. One of the strategies is the use of high-frequency oscillatory ventilation (HFOV). THEORETICAL BACKGROUNDS OF VENTILATOR-INDUCED LUNG INJURY AND HFOV: Because of the novel gas exchange mechanisms, HFOV can provide adequate gas exchange using extremely small tidal volumes and maintain high end-expiratory lung volume without inducing overdistension, which should result in minimization of ventilator-induced lung injury. STUDIES OF HFOV AND LUNG INJURY There are convincing clinical and animal data indicating that HFOV is an ideal lung-protective ventilatory strategy, particularly in the setting of neonatal respiratory failure, if lung volume recruitment is performed. CLINICAL IMPLICATION OF HFOV IN ADULT ACUTE RESPIRATORY DISTRESS SYNDROME A recent clinical trial demonstrated early (

Objective: To evaluate whether hypercapnic acidosis attenuates acute alterations of pulmonary capillary permeability due to high lung stretch in rats using a simple, noninvasive, scintigraphic method. Design: Prospective, randomized, controlled animal study. Setting: University research laboratory. Subjects: Male adult Wistar rats weighing 291 ± 7.5 g. Interventions: Three groups of rats were studied: controls ventilated with a low (6 mUkg body weight) tidal volume and rats ventilated with a high (38 mUkg body weight) tidal volume under normocapnic (Paco 2 = 35.2 ± 1.65 mm Hg) or hypercapnic (Paco 2 = 102.5 ± 5.63 mm Hg) conditions. Measurements and Main Results: Pulmonary capillary permeability alterations were assessed by monitoring the rate of 111 In-transferrin accumulation in lung tissue. Respiratory system pressure-volume curves were registered and analyzed. High tidal volume ventilation increased 111 In-transferrin plasma to lung flux in such a way that 111 In-transferrin behaved like a marker of water. The rate of initial (first 30 mins of high tidal volume ventilation) lung transferrin accumulation measured by scintigraphy (standardized lung/heart ratio) was steady, correlated with the percent decrease in respiratory system compliance (a marker of edema progression), and did not differ between normocapnic and hypercapnic groups (18.9 ± 3.97 vs. 14.2 ± 2.89%/hr, not significant). However, lung 111 In-tranferrin accumulation rate was highly scattered due to variable interindividual mechanical properties of the respiratory system. This rate was correlated with initial values of volume of the upper inflection point of the pressure-volume curve (r = -.53, p

To investigate the value of electrical impedance tomography for the assessment of regional lung mechanics during high-frequency oscillatory ventilation (HFOV).Prospective, interventional animal study.University research laboratory.Eight pigs with lavage-induced lung injury.Electrical impedance tomography measurements were performed during a pressure-volume maneuver and during a recruitment-derecruitment maneuver on HFOV by stepwise variation of continuous distending pressure (CDP).Lung volume was estimated by calibrated strain-gauge plethysmography; regional lung volume changes were assessed by electrical impedance tomography in various regions of interest. We found that inflation during the pressure-volume maneuver was distributed nonhomogeneously, whereas deflation was homogeneous. During HFOV, no major regional differences were found during either inflation or deflation. The upper inflection point on the deflation limb was at a slightly higher continuous distending pressure (26+/-3 cm H2O) than the minimal physiologic shunt fraction (at continuous distending pressure of 23+/-7), where there were hemodynamic signs of overdistension. Maximal compliance on the deflation limb (at continuous distending pressure of 13+/-3 cm H2O) agreed well with the minimal continuous distending pressure, where shunt fraction was just below 0.1 (14+/-2 cm H2O).HFOV has a homogenizing effect on lung volume distribution. Regional lung volume distribution can be assessed using electrical impedance tomography. However, thoracic fluid accumulation may complicate its interpretation.

Objective: Previous studies failed to show clear benefits of high-frequency ventilation compared with conventional positive pressure ventilation (PPVCON) in experimental meconium aspiration syndrome. However, none of these studies applied an open lung ventilation strategy (OLC), which aims to reduce intrapulmonary shunt due to alveolar collapse. We hypothesized that, if combined with an open lung strategy, both high-frequency oscillatory ventilation (HFOVOLC) and positive pressure ventilation (PPVOLC) would improve gas exchange and attenuate ventilator-induced lung injury in experimental meconium aspiration syndrome. Design: Prospective, randomized animal study. Setting: Research laboratory of a large university. Subjects: Forty-two newborn piglets. Interventions: Thirty minutes after intratracheal meconium instillation, 36 newborn piglets were assigned to one of three ventilation groups - PPVOLC, HFOVOLC, or PPV CON - and ventilated for 5 hrs. In both OLC groups, collapsed alveoli were actively recruited and thereafter stabilized using the lowest possible airway pressures. During PPVCON, ventilator settings were adjusted to prevent critical hypoxia (PaO2 CON group, arterial oxygenation and lung mechanics were superior in both OLC groups and the saline controls. Analysis of the bronchoalveolar lavage fluid obtained after 5 hrs of ventilation showed increased myeloperoxidase activity in the PPVCON group compared with both OLC groups and saline controls. Alveolar protein influx was not different between the groups. Histologic analysis revealed a higher lung injury score in the PPVCON group compared with the PPVOLC and the HFOVOLC groups. Conclusions: Application of the OLC during PPV and HFOV is feasible in experimental meconium aspiration syndrome and results in superior oxygenation and less ventilator-induced lung injury compared with PPVCON.

Objective: To evaluate the effects of high-frequency oscillation on the response to exogenous surfactant in lung-injured adult sheep. Design: A prospective, controlled, in vivo, animal laboratory study. Setting: Animal research facility of a health sciences university. Subjects: Twenty-eight adult sheep. Interventions: Animals were anesthetized and instrumented with a tracheostomy and vascular catheters. Following whole lung saline lavage, animals were randomized to one of four groups: Group S-CMV received surfactant and was ventilated for 4 hrs using a conventional mechanical ventilation strategy, group S-HFOV/CMV received surfactant and was ventilated with a high-frequency oscillation technique for 2 hrs and a conventional mechanical strategy for 2 hrs, group HFOV/CMV underwent the latter ventilatory strategies without receiving surfactant, and group HFOV was ventilated with high-frequency oscillation only for 4 hrs. At the end of the ventilatory period, the distributions of ventilation and surfactant were evaluated in animals that received surfactant. Measurements and Main Results: Animals in the S-CMV group had a significantly greater mean Pao 2 value at the end of the experimental period than animals in the S-HFOV/CMV or HFOV/ CMV groups. Evaluation of the distribution of ventilation relative to surfactant demonstrated that animals ventilated with high-frequency oscillation followed by conventional mechanical ventilation had a significantly greater disproportionate distribution of ventilation relative to surfactant compared with the CMV-only group. Conclusions: A period of high-frequency oscillation, as used in this study, immediately following exogenous surfactant administration mitigates the host's response to surfactant when subsequently switched to conventional mechanical ventilation.

To prospectively evaluate the oxygenation effect of inhaled nitric oxide (INO) delivered during high-frequency oscillatory ventilation in adult patients with the acute respiratory distress syndrome and oxygenation failure. DESIGN Prospective, clinical study.Intensive care unit of a university teaching hospital.A total of 23 adults (14 women, 9 men, 44.9 +/- 17.5 yrs, Acute Physiology and Chronic Health Evaluation II score of 28.6 +/- 7.1) with acute respiratory distress syndrome (lung injury score, 3.5 +/- 0.4) with Fio2 ofor = 0.6 and mean airway pressure ofor=28 cm H2O.INO was initiated at a dose of 5 ppm, and subsequently titrated according to a protocol, to determine the dose (5, 10, or 20 ppm) resulting in the greatest increase in Pao2/Fio2. Blood gas measurements were obtained 10-15 mins after initiation or any increase in INO dosage to assess the effect on Pao2/Fio2.Arterial blood gases and ventilator settings were recorded at four time points: during conventional ventilation just before initiating high-frequency oscillatory ventilation, during high-frequency oscillatory ventilation just before initiating INO, after 30 mins on the optimal dose of INO, and 8-12 hrs after starting INO. Oxygenation index ([Fio2 x mean airway pressure x 100]/Pao2) and Pao2/Fio2 ratios were calculated at the same time intervals. At 30 mins after INO initiation, 83% of patients had a significant increase in blood oxygen tension, defined asor = 20% increase in Pao2/Fio2. The mean change in Pao2/Fio2 at 30 mins was 38%. In these 19 patients, Pao2/Fio2 was highest at 20 ppm in four patients, at 10 ppm in eight patients, and at 5 ppm in seven patients. Compared with baseline measurements, Pao2/Fio2 improved significantly at both 30 mins (112 +/- 59 vs. 75 +/- 32, p=.01) and 8-12 hrs after INO initiation (146 +/- 52 vs. 75 +/- 32, p.0001). In addition, oxygenation index was reduced at 8-12 hrs compared with baseline measurements (26 +/- 13 vs. 40 +/- 17, p=.08).INO delivered at doses of 5 to 20 ppm during high-frequency oscillatory ventilation increases Pao2/Fio2 and may be a safe and effective rescue therapy for patients with severe oxygenation failure.

High-frequency oscillatory ventilation (HFOV) and inhaled nitric oxide (iNO) have been reported to improve oxygenation in children with acute hypoxemic respiratory failure (AHRF), but their roles in the treatment of AHRF remains unknown. The use of HFOV improves oxygenation by increasing lung recruitment. iNO can improve oxygenation in AHRF, but it may have limited efficacy in patients with poor lung inflation. Based on these findings, we hypothesized that the combined treatment of HFOV and inhalation of low-dose NO would improve oxygenation and survival in children with severe AHRF compared with children treated with conventional mechanical ventilation (CMV) or either treatment alone.Tertiary pediatric intensive care units at seven academic centers.Post hoc analysis of data from children enrolled in a multicenter, randomized, masked study of the use of iNO in the treatment of AHRF.A total of 108 pediatric patients with AHRF defined as an oxygenation index of15 twice within 6 hrs. Mode of ventilation (HFOV or CMV) was determined by the patient's physician based on guidelines to maximize oxygenation. The patient was then randomized to treatment with or without iNO. Comparisons were made between patients who were treated with HFOV plus iNO (n = 14), HFOV alone (n = 12), CMV plus iNO (n = 35), and CMV alone (n = 38).Ventilation with CMV or HFOV with or without iNO.We found that the change in Pao /Fio ratio was greatest in the HFOV plus iNO group compared with the other treatment groups at 4 hrs (p =.02) and 12 hrs (p =.01). After 24 hrs of treatment, both HFOV plus iNO and HFOV alone resulted in greater improvement in Pao2/Fio2 ratio than either CMV alone or CMV plus iNO (p =.005). After 72 hrs, treatment with HFOV alone resulted in a greater improvement in Pao2/Fio2 ratio than either CMV alone or CMV plus iNO (p =.03). There was no difference in predefined treatment failures between treatment groups.We conclude that the combination of HFOV with iNO causes a greater improvement in oxygenation than either treatment strategy alone in children with severe AHRF. We speculate that the enhanced lung recruitment by HFOV enhances the effects of low dose iNO on gas exchange.

We report a case of an infant delivered before the completion of 26 wks' gestation, weighing 300 g at birth, and treated with high-frequency oscillatory ventilation for respiratory distress syndrome. Her neurologic examination at 18 months of age is compatible with mild delay in gross and fine motor skills.

To determine the effect of frequency, amplitude, inspiratory time, and mean airway pressure on gas flow through a chest tube in an animal model of pneumothorax treated with high-frequency oscillatory ventilation (HFOV).Observational study.Animal laboratory.Neonatal piglets (n = 12).After saline lavage, a model of experimental pneumothorax was created by selective right mainstem intubation and manual ventilation at high-peak inspiratory pressure. A chest tube was placed, and gas flow through the chest tube was measured with a pneumotachometer during HFOV with the SensorMedics 3100A. The effects of frequency, inspiratory time, amplitude, and mean airway pressure on chest tube gas flow were determined.Gas flow through the chest tube was significantly higher (p.001) at 5 Hz (601 +/- 23 mL/min) than at 10 Hz (464 +/- 64 mL/min) or 15 Hz (400 +/- 11 mL/min), while mean airway pressure, inspiratory time, and PaCO2 were kept constant. Gas flow was higher at an inspiratory time of 50% compared with one of 30% (645 +/- 49 vs. 436 +/- 36 mL/min, respectively). Gas flow was directly related to amplitude (284 mL/min at an amplitude of 10 cm H2O, increasing to 877 mL/min at an amplitude of 80 cm H2O) when a 3.5-mm endotracheal tube was used; however, gas flow was attenuated at amplitudes of40 cm H2O when smaller endotracheal tubes were used. Gas flow increased significantly with the increase of mean airway pressure from 92 mL/min at 15 cm H2O to 1433 mL/min at 30 cm H2O.In a neonatal piglet model of pneumothorax treated with HFOV, with amplitude adjusted to maintain constant alveolar ventilation, gas flow through the chest tube was significantly lower at 15 Hz compared with either 10 Hz or 5 Hz. Chest tube gas flow increased with increasing inspiratory time, amplitude, and mean airway pressure. These findings support the use of higher frequencies, short inspiratory times, low amplitudes, and low mean airway pressures for healing air leak with HFOV.

Objective: Enrollment of individual patients into more than one study has been poorly evaluated. The objective of this study was to describe the characteristics of patients, researchers and centers involved in coenrollment, studies precluding coenrollment, and the prevalence, patterns, predictors, and outcomes of coenrollment in a randomized clinical trial. Design, Setting, Methods: We conducted an observational study nested within the OSCILLation for Acute Respiratory Distress Syndrome Treated Early Trial, which compared high-frequency oscillatory ventilation to conventional ventilation. We collected patient, center, and study data on coenrollment in randomized patients. Multilevel regression examined factors independently associated with coenrollment, considering clustering within centers. We examined the effect of coenrollment on safety and the trial outcome. Interventions None. Measurements and Main Results: Overall, 127 of 548 randomized patients (23.2%) were coenrolled in 25 unique studies. Coenrollment was reported in 17 of 39 centers (43.6%). Patients were most commonly coenrolled in one additional randomized clinical trial (76; 59.8%). Coenrollment was less likely in older patients (odds ratio, 0.87; 95% CI, 0.76–0.997), and in ICUs with greater than 26 beds (odds ratio, 0.56; 95% CI, 0.34–0.94), and more likely by investigators with more than 11 years of experience (odds ratio, 1.73; 95% CI, 1.06–2.82), by research coordinators with more than 8 years of experience (odds ratio, 1.87; 95% CI, 1.11–3.18) and in Canada (odds ratio, 4.66; 95% CI, 1.43–15.15). Serious adverse events were similar between coenrolled high-frequency oscillatory ventilation and control patients. Coenrollment did not modify the treatment effect of high-frequency oscillatory ventilation on hospital mortality. Conclusions: Coenrollment occurred in 23% of patients, commonly in younger patients, in smaller centers with more research infrastructure, and in Canada. Coenrollment did not influence patient safety or trial results.

OBJECTIVE To examine dose-response relationships regarding the efficiency of gas exchange and hemodynamic function during high-frequency oscillation and partial liquid ventilation (HFO-PLV) of the perfluorocarbon (PFC)-treated lung in a model of acute lung injury. SETTING An animal research laboratory in a university medical center. DESIGN A prospective, randomized study comparing animals receiving varying doses (0, 5, 15, and 20 mL/kg) of perflubron during high-frequency oscillatory ventilation (HFOV) with mean airway pressure (Paw) optimized to achieve a minimal percutaneous oxygen saturation (Spo2). SUBJECTS Nineteen healthy swine (mean weight 28.9 kg) with saline lavage-induced acute lung injury. METHODS Animals were treated with repetitive saline lavage to achieve a uniform degree of acute lung injury (Spo2 < or =90% on an Fio2 of 1.0). After lung injury, subjects were converted to HFOV, and lung volume was optimized. HFO-PLV was initiated by instillation of perflubron at a rate of 0.5 mL.kg-1.min-1 to achieve total doses of 5, 15, and 20 mL/kg. After PFC dosing, the only experimental manipulation consisted of adjustment of Paw to achieve an Spo2 of 90% +/- 2% with Fio2 of 0.6. Gas exchange, hemodynamic variables, and pulmonary mechanics data were collected over a 1-hr period. Five control animals were not dosed with perflubron and remained on HFOV for the 1-hr period of data collection. MEASUREMENTS AND MAIN RESULTS After lung volume recruitment with HFOV, the initiation of HFO-PLV was best tolerated with the two lower doses in our protocol. There were essentially no changes in Paco2 or pH between groups over the dosing interval. After dosing, analysis of variance demonstrated a PFC dose-dependent effect for oxygenation index (p =.01) only; the lowest oxygenation index was found in the 15 mL/kg group (p =.01). In the 15 mL/kg group, the Paw decreased steadily from 20.6 +/- 3.4 cm H2O at the end of dosing to 18.0 +/- 4.9 cm H2O at 60 mins. The Pao2 increased from 113 +/- 51 torr (15.06 +/- 6.79 kPa) to 134 +/- 49 torr (17.86 +/- 6.53 kPa) during this period and was associated with a decreasing oxygenation index (from 11.4 +/- 2.0 to 9.3 +/- 1.5). The cardiac index and pulmonary vascular resistance did not change significantly during the dosing period and were relatively stable after the completion of dosing. CONCLUSIONS The combination of HFOV and perflubron administration was well tolerated hemodynamically and was not associated with deterioration of gas exchange during dosing. Our data suggest that the optimal dose of perflubron to achieve the lowest oxygenation index during HFO-PLV is between 5 and 15 mL/kg. The combination of HFOV and perflubron administration is a novel strategy in the treatment of acute lung injury that shows some promise and merits additional investigation. We hope in future studies to address the histopathologic effects of varying perflubron doses during HFOV in a long-term study of the lung-protective effects of HFO-PLV.

Objective: Partial liquid ventilation with the perfluorochemical, perflubron, has been shown to improve lung mechanics and enhance gas exchange in the treatment of severe acute lung injury. However, the most effective strategy to provide optimal intrapulmonary distribution of perflubron has not been fully accessed. The objective of this study was to examine the effect of body position (supine vs. rotational) and mode of ventilation (conventional mechanical ventilation [CMV] vs. high-frequency oscillatory ventilation [HFOV]) on perflubron distribution and oxygenation improvement. Design: Prospective, randomized, animal trial. Setting: Research laboratory at a university medical center. Subjects: Twenty healthy piglets (4.5-6.6 kg). Interventions: Subjects underwent repetitive saline lavage to achieve a uniform degree of lung injury and then were randomized to either CMV or were converted to HFOV. Within each ventilator group, animals were randomized to supine positioning (S) or rotational positioning with alternation between supine and prone position (R) during incremental dosing of three 5-mUkg doses of perflubron. Measurements and Main Results: Arterial blood gas tensions, hemodynamic variables, and the oxygenation index were recorded after each dose of 5 mUkg. Lateral cinefluoroscopic images after each dose were digitized for computer analysis of density. A density index was calculated for a 2-cm 2 window in three dorsal and three ventral lung regions. Uniformity of distribution was calculated by comparing the mean density among the six regions. Oxygenation improvements were compared between groups. There were no significant differences in hemodynamic variables or gas exchange after lung injury in the four groups. Rotational positioning produced significantly more uniform perflubron distribution during both CMV and HFOV. This effect was independent of the mode of ventilation. The mean ventral density index was affected by rotating position and HFOV mode of ventilation after 10 mUkg of perflubron, and rotating position was affected only after 15 mUkg of perflubron. There was a significant reduction in the oxygenation index from baseline to end lavage in both CMV groups, as well as all of the animals that were rotated. Conclusion: Perflubron is more uniformly dispersed when dosed in a rotational fashion with alternation between supine and prone position during incremental dosing. This effect is independent of mode of ventilation. There was no relationship between oxygenation improvements and nondependent perflubron distribution. CMV and rotating dosing both led to a significant decrease in the oxygenation index after a 15 mUkg dose of perflubron. This information has important impact on the future development of dosing strategies and clinical trial design.

We previously reported improved oxygenation, but no change, in rates of extracorporeal membrane oxygenation (ECMO) use or death among infants with persistent pulmonary hypertension of the newborn who received inhaled nitric oxide (NO) with conventional ventilation, irrespective of lung disease. The goal of our study was to determine whether treatment with inhaled NO improves oxygenation and clinical outcomes in infants with persistent pulmonary hypertension of the newborn and associated lung disease who are ventilated with high-frequency oscillatory ventilation (HFOV).Single-center, prospective, randomized, controlled trial.Newborn intensive care unit of a tertiary care teaching hospital.We studied infants with a gestational age ofor =34 wks who were receiving mechanical ventilatory support and had echocardiographic and clinical evidence of pulmonary hypertension and hypoxemia (PaO2or =100 mm Hg on FIO2 = 1.0), despite optimal medical management Infants with congenital heart disease, diaphragmatic hernia, or other major anomalies were excluded.The treatment group received inhaled NO, whereas the control group did not. Adjunct therapies and ECMO criteria were the same in the two groups of patients. Investigators and clinicians were not masked as to treatment assignment, and no crossover of patients was permitted.Primary outcome variables were mortality and use of ECMO. Secondary outcomes included change in oxygenation and duration of mechanical ventilatory support and supplemental oxygen therapy. Forty-two patients were enrolled. Baseline oxygenation and clinical characteristics were similar in the two groups of patients. Infants in the inhaled NO group (n = 21) had improved measures of oxygenation at 15 mins and 1 hr after enrollment compared with infants in the control group (n = 20). Fewer infants in the inhaled NO group compared with the control group were treated with ECMO (14% vs. 55%, respectively; p = .007). Mortality did not differ with treatment assignment.Among infants ventilated by HFOV, those receiving inhaled NO had a reduced need for ECMO. We speculate that HFOV enhances the effectiveness of inhaled NO treatment in infants with persistent pulmonary hypertension of the newborn and associated lung disease.

Objective: We conducted a prospective study to assess the hemodynamic effects of conventional mechanical ventilation (CMV) compared with high-frequency oscillation (HFO) in newborn babies with respiratory distress syndrome. Methods: A total of 18 consecutive term and preterm infants were examined by two-dimensional M-mode and pulsed Doppler echocardiography. Results: Five patients had to be excluded, three of them because of increasing cardiovascular support after initiation of HFO. The remaining 13 infants (seven males, six females) had a median gestational age of 33 wks (range, 25-40) and a birth weight of 2350 g (range, 790-3600). Patients entered the study at 21 hrs (range, 5-69) of life, receiving total maintenance fluid of 90 mL/kg/day (range, 60-120). Five babies (38%) needed continuous inotropic support. HFO was used as a rescue therapy in infants who failed with CMV. In all 13 patients, HFO significantly impaired cardiac performance compared with CMV by decreasing aortic velocity-time integral: median, 10.2 cm (range, 6.0-14.6) vs. 8.3 cm (range, 5.3-12.4; p

Other than relapse, pulmonary complications are the most common cause of mortality in patients who undergo bone marrow transplantation (BMT). Diffuse alveolar hemorrhage (DAH) is one noninfectious pulmonary complication of BMT. Presenting clinical findings include nonproductive cough usually without hemoptysis, dyspnea, hypoxemia, a decrease in hematocrit, and diffuse infiltrates on chest radiograph.We report a case of DAH after allogeneic BMT in a 6-yr-old female patient. Although a chest radiograph revealed patchy bilateral alveolar densities and large volumes of bright red blood were suctioned from the endotracheal tube, there was no evidence of coagulopathy and no infectious agent was identified on examination of bronchoalveolar lavage fluid, blood, and urine.The child was treated with high-dose corticosteroids and high-frequency oscillatory ventilation and experienced a complete clinical recovery from her pulmonary disease.The definition, presenting symptoms, findings and timing, and associated risk factors of DAH after BMT are reviewed. Prospective hypotheses for the pathogenesis of DAH after BMT are presented. Evidence for the role of high-dose corticosteroids for treatment of DAH after BMT and the role of high-frequency oscillatory ventilation for treatment of acute hypoxemic respiratory failure in children with diffuse alveolar disease is also reviewed.This case supports the contention that early treatment with high-dose corticosteroids is warranted in children with DAH after BMT.

Objectives: To review the basic physiologic principles that support the role for high-frequency ventilation (HFV) in acutely lung-injured patients, to critically assess clinical trial data in this area, and discuss why a metasummary is not feasible and a large-scale clinical trial is needed. Data Sources: We searched a computerized database (MEDLINE) from 1976 to January 1997 using the text words high-frequency ventilation and acute respiratory distress syndrome to retrieve all relevant candidate articles. Study Selection: We retrieved all English language clinical studies conducted in tertiary care centers that employed HFV in adult acute respiratory distress syndrome (ARDS) patients. Data Extraction: Only prospective, randomized trials, cohortl case-control studies, and case series evaluating HFV vs. conventional mechanical ventilation in adult ARDS patients were included. Data Synthesis: We independently screened 3,166 articles on ARDS and 494 papers on HFV in our computer search. We checked reference lists and contacted experts in the field of mechanical ventilation in ARDS to ensure that no relevant studies had been missed. Only four articles met our inclusion criteria and were evaluated in detail. Conclusions: Current clinical studies are statistically underpowered and a metasummary is not feasible because of study quality, as well as lack of similar clinical end points and measures of magnitude of benefit. A large, multicenter trial should be initiated to define the role of HFV in the treatment of adult ARDS.

OBJECTIVE To determine whether pulmonary neutrophil sequestration and lung injury are affected by partial liquid ventilation with perfluorocarbon in a model of acute lung injury (ALI). DESIGN A prospective, controlled, in vivo animal laboratory study. SETTING An animal research facility of a health sciences university. SUBJECTS Forty-one New Zealand White rabbits. INTERVENTIONS Mature New Zealand White rabbits were anesthetized and instrumented with a tracheostomy and vascular catheters. Animals were assigned to receive partial liquid ventilation (PLV, n = 15) with perflubron (18 mL/kg via endotracheal tube), conventional mechanical ventilation (CMV, n = 15) or high-frequency oscillatory ventilation (HFOV, n = 5). Animals were ventilated, using an FIO2 of 1.0, and ventilatory settings were required to achieve a normal PaCO2. Animals were then given 0.9 mg/kg of Escherichia coli endotoxin intravenously over 30 mins. Partial liquid ventilation, conventional mechanical ventilation, or high-frequency oscillatory ventilation was continued for an additional 4 hrs before the animals were killed. A group of animals not challenged with endotoxin underwent conventional ventilation for 4.5 hrs, serving as the control group (control, n = 6). Lungs were removed and samples were frozen at -70 degrees C. Representative samples were stained for histology. A visual count of neutrophils per high-power field (hpf) was performed in five randomly selected fields per sample in a blinded fashion by light microscopy. Lung samples were homogenized in triplicate in phosphate buffer, ultrasonified, freeze-thawed, and clarified by centrifugation. Supernatants were analyzed for myeloperoxidase (MPO) activity by spectrophotometry with o-dianisidine dihydrochloride and hydrogen peroxide at 460 nm. MEASUREMENTS AND MAIN RESULTS Histologic analysis of lung tissue obtained from control animals showed normal lung architecture. Specimens from the PLV and HFOV groups showed a marked decrease in alveolar proteinaceous fluid, pulmonary vascular congestion, edema, necrotic cell debris, and gross inflammatory infiltration when compared with the CMV group. Light microscopy of lung samples of animals supported with PLV and HFOV had significantly lower neutrophil counts when compared with CMV (PLV, 4 +/- 0.3 neutrophils/hpf; HFOV, 4 +/- 0.5 neutrophils/hpf; CMV, 10 +/- 0.9 neutrophils/hpf; p < .01). In addition, MPO activity from lung extracts of PLV and HFOV animals was significantly lower than that of CMV animals (PLV, 61 +/- 13.3 units of MPO activity/lung/kg; HFOV, 43.3 +/- 6.8 units of MPO activity/lung/kg; CMV, 140 +/- 28.5 units of MPO activity/lung/kg; p < .01). MPO activity from lungs of uninjured control animals was significantly lower than that of animals in the PLV, HFOV, and CMV groups (control, 2.2 +/- 2 units of MPO activity/lung/kg; p < .001). CONCLUSIONS Partial liquid ventilation decreases pulmonary neutrophil accumulation, as shown by decreased neutrophil counts and MPO activity, in an experimental animal model of ALI induced by systemic endotoxemia. The attenuation in pulmonary leukostasis in animals treated with PLV is equivalent to that obtained by a ventilation strategy that targets lung recruitment, such as HFOV.

To compare the cardiopulmonary effects of high-frequency oscillatory ventilation (HFO) and conventional ventilation (CV) in a piglet model of meconium aspiration syndrome.Prospective, randomized control study.Piglets 1 to 2 wks of age.Meconium aspiration was induced in 30 piglets. They were then randomized to CV, HFO at 10 Hz, or HFO at 15 Hz.Arterial blood gas, and systemic and pulmonary hemodynamics were measured serially. Airway opening pressure (P-Flex), static lung compliance (Crs), and trapped gas volume (TGV) were derived. Meconium instillation produced similar stable decreases in Crs (6.7 +/- 0.7 [SEM] to 4.7 +/- 0.4 mL/cm) and increases in pulmonary vascular resistance (68 +/- 6.4 vs. 91.9 +/- 8.5 mm Hg/mL/kg/min). A greater proportion of animals (40%, p.007) remained hypercarbic during HFO at 15 Hz. Oxygenation indices were similar for all groups. In regards to high-frequency support, both power and deltaP were higher in the HFO at 15 Hz group (p.001). When compared with both CV and HFO at 10 Hz, the TGV in the HFO at 15 Hz group was significantly higher following randomization to ventilator type. P-Flex was also greatest in the 15 Hz group, followed by the 10 Hz group and the CV group. Higher airway opening pressures, given identical compliance, suggest that HFO at 15 Hz resulted in greater large airway obstruction. With HFO's inherent low tidal volumes, progression of meconium to the distal airways may be delayed.Early institution of HFO at 15 Hz in meconium aspiration may exacerbate air trapping. HFO at lower rates may be the optimal method of respiratory support in meconium aspiration syndrome. HFO may extend the window of time available for removal of meconium.

OBJECTIVE To determine whether intratracheal pulmonary ventilation (ITPV) allows for effective oxygenation and ventilation at lower mean airway pressures and peak inspiratory pressures than conventional ventilation in a piglet model of meconium aspiration syndrome. DESIGN Prospective, interventional study. SETTING The animal research laboratory at Children's National Medical Center, Washington, DC. SUBJECTS Twenty newborn piglets, 2 to 7 days of age, weighing 1.8 to 2.8 kg. INTERVENTION Animals were anesthetized, paralyzed, intubated, and ventilated. Femoral arterial and venous catheters were inserted; 5 mL/kg of 20% meconium in normal saline was instilled into the endotracheal tube. Animals were randomized to either ITPV or conventional ventilation, and settings were adjusted to maintain ideal blood gases, i.e., pH 7.35 to 7.45, PCO2 40 to 45 torr (5.3 to 6 kPa), PO2 80 to 100 torr (10.7 to 13.3 kPa), and SaO2 > or = 90%. Ventilatory settings were adjusted as needed to a maximum of: FIO2 1.0, peak inspiratory pressure 40 cm H2O, positive end-expiratory pressure 5 cm H2O, and respiratory rate 80 breaths/min. MEASUREMENTS AND MAIN RESULTS Arterial blood gases were taken every 30 mins for 4 hrs and ventilatory settings were adjusted to maintain optimal blood gases. Heart rate, mean arterial blood pressure, and arterial saturation were monitored continuously. The animals in the ITPV group had significantly lower peak inspiratory pressure at 1, 2, 3, and 4 hrs after meconium instillation (p < .018) and significantly lower mean airway pressure at 2, 3, and 4 hrs after meconium instillation (p < .03). The mean peak inspiratory pressure in the ITPV animals ranged from 17 +/- 2.7 cm H2O at baseline to 16.6 +/- 5.7 cm H2O at 4 hrs compared with 16.5 +/- 2.7 cm H2O at baseline to 31.8 +/- 9.1 cm H2O at 4 hrs in the conventionally ventilated animals (p < .04). The mean airway pressure ranged from 6.3 +/- 1.1 mm Hg at baseline to 6.8 +/- 2.5 mm Hg at 4 hrs in the ITPV group compared with 5.5 +/- 1.2 mm Hg at baseline to 10.7 +/- 3.4 mm Hg at 4 hrs in the conventional ventilation group (p < .03). The lungs of the ITPV animals were less hemorrhagic and had less pathologic evidence of injury than the lungs of the conventionally ventilated animals. CONCLUSIONS These results indicate that ITPV can be used to effectively ventilate and oxygenate piglets with meconium aspiration syndrome at lower mean airway pressures and peak inspiratory pressures than conventional ventilation. This lower pressure causes less injury to the lungs of the animals.

Objective: To test the hypothesis that high-frequency ventilation (HFV), when compared with conventional techniques, enhances respiratory gas exchange during partial liquid ventilation (PLV). Design: A four-period crossover design. Setting: Animal research laboratory of Children's Health Care-St. Paul. Subjects: Thirty-two newborn piglets, weighing 1.40 ± 0.39 kg. Interventions: Animals were divided into four groups of eight animals: a) PLV with high-frequency jet ventilation; b) PLV with jet ventilation using a background intermittent mandatory ventilation (IMV) rate; c) PLV with high-frequency oscillation; or d) PLV with high-frequency flow interruption using a background IMV rate. After anesthesia, paralysis, and tracheotomy, a normal saline wash procedure produced lung injury. Perfluorocarbon was then instilled via the endotracheal tube in an amount estimated to represent functional residual capacity. Animals received randomly either PLV using conventional techniques or PLV using the selected HFV technique as initial treatment. Then, animals were crossed over to the alternative treatment at equal mean airway pressure, as measured at the endotracheal tube tip. This sequence was repeated for a total of four crossover periods, such that all animals were treated twice with PLV using conventional techniques and twice with PLV using HFV. Measurements and Main Results: We measured airway pressures at the endotracheal tube tip, aortic and central venous blood pressures, arterial blood gases, and respiratory system mechanics at baseline, after induction of lung injury, and at specified intervals throughout the experiment. Measurements were made before and 15 mins after crossovers, then ventilators were adjusted to normalize gas exchange. Measurements were again made 30 mins later, at the end of the treatment period. All types of PLV provided adequate gas exchange. Only PLV using jet ventilation with IMV produced gas exchange equal to that seen during PLV using conventional techniques at equivalent mean airway pressure. By the end of the treatment periods, only PLV using high-frequency oscillation continued to require higher airway pressure than PLV using conventional techniques for equivalent gas exchange. Conclusions: Gas exchange was not enhanced during PLV-HFV. Application of HFV with PLV provides no clear acute physiologic advantages to PLV using more conventional techniques.

To evaluate the safety and effectiveness of high-frequency oscillatory ventilation using a protocol designed to recruit and maintain optimal lung volume in patients with severe adult respiratory distress syndrome (ARDS).Surgical and medical intensive care units in a tertiary care, military teaching hospital.A prospective, clinical study.Seventeen patients, 17 yrs to 83 yrs of age, with severe ARDS (Lung Injury Score of 3.81 +/- 0.23) failing inverse ratio mechanical conventional ventilation (PaO2/FiO2 ratio of 68.6 +/- 21.6, peak inspiratory pressure of 54.3 +/- 12.7 cm H2O, positive end-expiratory pressure of 18.2 +/- 6.9 cm H2O).High-frequency oscillatory ventilation was instituted after varying periods of conventional ventilation (5.12 +/- 4.3 days). We employed lung volume recruitment strategy that consisted of incremental increases in mean airway pressure to achieve a PaO2 ofor = 60 torr (or = 8.0 kPa), with an FiO2 ofor = 0.6.High-frequency oscillator ventilator settings (FiO2, mean airway pressure, pressure amplitude of oscillation [delta P] frequency) and hemodynamic parameters (cardiac output, oxygen delivery [DO2]), mean systemic and pulmonary arterial pressures, and the oxygenation index (oxygenation index = [FiO2 x mean airway pressure x 100]/PaO2) were monitored during the transition to high-frequency oscillatory ventilation and throughout the course of the high-frequency protocol. Thirteen patients demonstrated improved gas exchange and an overall improvement in PaO2/FiO2 ratio (p.02). Reductions in the oxygenation index (p.01) and FiO2 (p.02) at 12, 24, and 48 hrs after starting high-frequency oscillatory ventilation were observed. No significant compromise in cardiac output or DO2 was observed, despite a significant increase in mean airway pressure (31.2 +/- 10.3 to 34.0 +/- 6.7 cm H2O, p.05) on high-frequency oscillatory ventilation. The overall survival rate at 30 days was 47%. A greater number of pretreatment days on conventional ventilation (p.009) and an entry oxygenation index of47 (sensitivity 100%, specificity 100%) were associated with mortality.High-frequency oscillatory ventilation is both safe and effective in adult patients with severe ARDS failing conventional ventilation. A lung volume recruitment strategy during high-frequency oscillatory ventilation produced improved gas exchange without a compromise in DO2. These results are encouraging and support the need for a prospective, randomized trial of algorithm-controlled conventional ventilation vs. high-frequency oscillatory ventilation for adults with severe ARDS.

To describe severe myocardial manifestations in two infants with respiratory syncytial virus infection and to review published literature reporting cardiac involvement in patients with respiratory syncytial virus disease.Case report and literature review.Tertiary care pediatric intensive care unit (ICU).Two infants admitted to the pediatric ICU for dysrhythmias and severe myocardial dysfunction and infected with respiratory syncytial virus.Conventional cardiovascular, antidysrhythmic, and respiratory support, as well as extracorporeal membrane oxygenation and high-frequency oscillatory ventilation.Both patients had respiratory syncytial virus infections and clinical evidence of severe myocarditis, with dysrhythmias, cardiomegaly, and cardiogenic shock. Both infants survived their hospitalizations. To our knowledge, these two patients are the first reported cases of myocarditis in infants with respiratory syncytial virus infection.Severe myocardial dysfunction and dysrhythmias may accompany respiratory syncytial virus infection in some infants and may be reversible with aggressive supportive therapy.

Objective: To determine whether there is an improvement in oxygenation when partial liquid ventilation and high-frequency oscillatory ventilation are combined in the treatment of acute lung injury, compared with high-frequency oscillatory ventilation alone. Design: Controlled animal trial. Setting: Research laboratory in a university setting. Subjects: Ten 3-kg piglets. Interventions: Anesthetized piglets underwent high-frequency oscillatory ventilation, with mean airway pressure of 20 cm H 2 O, before induction of acute lung injury with repeated saline lavage. When Pao 2 values were

To determine the hemodynamic effects of four different modes of mechanical ventilation in an animal model of acute cardiac and pulmonary failure.Prospective, randomized, crossover design.University research laboratory.Twelve piglets weighing 10 to 16 kg.The experimental protocol consisted of three stable 30-min periods: when ventricular and pulmonary functions were normal (control), after the induction of acute cardiac failure by the administration of a beta-adrenergic receptor blocker, and after pulmonary failure induced by repeated lung lavage. Modes of mechanical ventilation included controlled mechanical ventilation, high-frequency oscillation, synchronized high-frequency jet ventilation, and external negative pressure oscillation combined with pressure support ventilation. Each mode of respiratory support was randomly and sequentially applied to each animal with the assessment of cardiopulmonary function at the end of each period.Continuous monitoring included electrocardiogram, right atrial, left ventricular end-diastolic, pulmonary arterial, intrathoracic aortic, arterial, esophageal, and transpulmonary pressures and arterial and mixed venous oxygen saturation measurements. In addition, cardiac output using the thermodilution technique was measured intermittently. Whereas in the control period cardiac index was significantly (p.05) higher during synchronized high-frequency jet ventilation (193 +/- 19.3 mL/kg/min) than during controlled mechanical ventilation (151 +/- 12.1 mL/kg/min) and high-frequency oscillation (151 +/- 18.1 mL/kg/min), there was no significant hemodynamic difference between the four modes of mechanical ventilation in the cardiac and pulmonary failure periods. In the pulmonary failure period, transpulmonary pressure was significantly higher during high-frequency oscillation (7.1 +/- 1.6 mm Hg) than during controlled mechanical ventilation (5.6 +/- 0.6 mm Hg), high-frequency ventilation (4.1 +/- 0.4 mm Hg), and external negative pressure oscillation combined with pressure support ventilation (5.3 +/- 0.5 mm Hg).Synchronized high-frequency ventilation improves cardiac performance in control conditions. No hemodynamic difference is present between the four modes of mechanical ventilation in the cardiac and pulmonary failure periods. External negative pressure oscillation combined with pressure support ventilation has moderate hemodynamic advantages over controlled mechanical ventilation and high-frequency oscillation in different clinical settings, but it also results in a deterioration of pulmonary gas exchange during the pulmonary failure period.

Objective To ascertain the feasibility and the safety of percutaneous dilational tracheostomy in patients with acute respiratory distress syndrome receiving high-frequency oscillatory ventilation. Design Case series. Setting Tertiary adult intensive care unit in a university teaching hospital. Patients Five patients with acute respiratory distress syndrome. Interventions Percutaneous dilational tracheostomy during high-frequency oscillatory ventilation. Measurements and main results Percutaneous dilational tracheostomy was safely performed on all five patients. Hemodynamic and respiratory variables remained stable during the procedure. No complications were attributable to either the percutaneous dilational tracheostomy or high-frequency oscillatory ventilation. Conclusions Percutaneous dilational tracheostomy can be safely performed on patients with acute respiratory distress syndrome during high-frequency oscillatory ventilation.

Heliox has been shown to be beneficial in the management of different obstructive pulmonary disorders. High-frequency percussive ventilation has recently been advocated to treat lung injury in children with reduced lung compliance. We report our experience of combining heliox with noninvasive high-frequency percussive ventilation in a 5-yr-old boy with severe acute respiratory failure resulting from advanced cystic fibrosis lung disease. The dramatic improvement allowed stabilization and withholding of endotracheal intubation. We hypothesize that this approach improved gas exchange by enhancing molecular diffusion and by favoring laminar flow throughout the upper and lower airways. Further investigations should study the mechanisms of this noninvasive bimodal therapy.