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1.  Efficacy and adverse events of high-frequency oscillatory ventilation in adult patients with acute respiratory distress syndrome: a meta-analysis 
Critical Care  2014;18(3):R102.
Theoretically, high-frequency oscillatory ventilation (HFOV) achieves all goals of a lung-protective ventilatory mode and seems ideal for the treatment of adult patients with acute respiratory distress syndrome (ARDS). However, its effects on mortality and adverse clinical outcomes remain uncertain given the paucity of high-quality studies in this area. This meta-analysis was performed to evaluate the efficacy and adverse events of HFOV in adults with ARDS.
We searched PubMed, EMBASE and Cochrane Central Register of Controlled Trials through February 2014 to retrieve randomized controlled trials of HFOV in adult ARDS patients. Two independent reviewers extracted data on study methods, clinical and physiological outcomes and adverse events. The primary outcome was 30-day or hospital mortality. Risk of bias was evaluated with the Cochrane Collaboration’s tool. Mortality, oxygenation and adverse effects of HFOV were compared to those of conventional mechanical ventilation. A random-effects model was applied for meta-analysis.
A total of five trials randomly assigning 1,580 patients met inclusion criteria. Pooled data showed that HFOV significantly improved oxygenation on day one of therapy (four studies; 24% higher; 95% confidence interval (CI) 11 to 40%; P <0.01). However, HFOV did not reduce mortality risk (five studies; risk ratio (RR) 1.04; 95% CI 0.83 to 1.31; P = 0.71) and two early terminated studies suggested a harmful effect of HFOV in ARDS (two studies; RR 1.33; 95% CI 1.09 to 1.62; P <0.01). Safety profiles showed that HFOV was associated with a trend toward increased risk of barotrauma (five studies; RR 1.19; 95% CI 0.83 to 1.72; P = 0.34) and unfavorable hemodynamics (five studies; RR 1.16; 95% CI 0.97 to 1.39; P = 0.12).
HFOV improved oxygenation in adult patients with ARDS; however, it did not confer a survival benefit and might cause harm in the era of lung-protective ventilation strategy. The evidence suggests that HFOV should not be a routine practice in ARDS and further studies specifically selecting patients for this ventilator mode should be pursued.
PMCID: PMC4075239  PMID: 24886674
2.  Bench-to-bedside review: High-frequency oscillatory ventilation in adults with acute respiratory distress syndrome 
Critical Care  2006;10(6):240.
Mechanical ventilation is the cornerstone of therapy for patients with acute respiratory distress syndrome (ARDS). Paradoxically, mechanical ventilation can exacerbate lung damage – a phenomenon known as ventilator-induced lung injury. While new ventilation strategies have reduced the mortality rate in patients with ARDS, this mortality rate still remains high. High-frequency oscillatory ventilation (HFOV) is an unconventional form of ventilation that may improve oxygenation in patients with ARDS, while limiting further lung injury associated with high ventilatory pressures and volumes delivered during conventional ventilation. HFOV has been used for almost two decades in the neonatal population, but there is more limited experience with HFOV in the adult population. In adults, the majority of the published literature is in the form of small observational studies in which HFOV was used as 'rescue' therapy for patients with very severe ARDS who were failing conventional ventilation. Two prospective randomized controlled trials, however, while showing no mortality benefit, have suggested that HFOV, compared with conventional ventilation, is a safe and effective ventilation strategy for adults with ARDS. Several studies suggest that HFOV may improve outcomes if used early in the course of ARDS, or if used in certain populations. This review will summarize the evidence supporting the use of HFOV in adults with ARDS.
PMCID: PMC1794464  PMID: 17184554
3.  High frequency oscillatory ventilation compared with conventional mechanical ventilation in adult respiratory distress syndrome: a randomized controlled trial [ISRCTN24242669] 
Critical Care  2005;9(4):R430-R439.
To compare the safety and efficacy of high frequency oscillatory ventilation (HFOV) with conventional mechanical ventilation (CV) for early intervention in adult respiratory distress syndrome (ARDS), a multi-centre randomized trial in four intensive care units was conducted.
Patients with ARDS were randomized to receive either HFOV or CV. In both treatment arms a priority was given to maintain lung volume while minimizing peak pressures. CV ventilation strategy was aimed at reducing tidal volumes. In the HFOV group, an open lung strategy was used. Respiratory and circulatory parameters were recorded and clinical outcome was determined at 30 days of follow up.
The study was prematurely stopped. Thirty-seven patients received HFOV and 24 patients CV (average APACHE II score 21 and 20, oxygenation index 25 and 18 and duration of mechanical ventilation prior to randomization 2.1 and 1.5 days, respectively). There were no statistically significant differences in survival without supplemental oxygen or on ventilator, mortality, therapy failure, or crossover. Adjustment by a priori defined baseline characteristics showed an odds ratio of 0.80 (95% CI 0.22–2.97) for survival without oxygen or on ventilator, and an odds ratio for mortality of 1.15 (95% CI 0.43–3.10) for HFOV compared with CV. The response of the oxygenation index (OI) to treatment did not differentiate between survival and death. In the HFOV group the OI response was significantly higher than in the CV group between the first and the second day. A post hoc analysis suggested that there was a relatively better treatment effect of HFOV compared with CV in patients with a higher baseline OI.
No significant differences were observed, but this trial only had power to detect major differences in survival without oxygen or on ventilator. In patients with ARDS and higher baseline OI, however, there might be a treatment benefit of HFOV over CV. More research is needed to establish the efficacy of HFOV in the treatment of ARDS. We suggest that future studies are designed to allow for informative analysis in patients with higher OI.
PMCID: PMC1269459  PMID: 16137357
4.  The initial Mayo Clinic experience using high-frequency oscillatory ventilation for adult patients: a retrospective study 
High-frequency oscillatory ventilation (HFOV) was introduced in our institution in June 2003. Since then, there has been no protocol to guide the use of HFOV, and all decisions regarding ventilation strategies and settings of HFOV were made by the treating intensivist. The aim of this study is to report our first year of experience using HFOV.
In this retrospective study, we reviewed all 14 adult patients, who were consecutively ventilated with HFOV in the intensive care units of a tertiary medical center, from June 2003 to July 2004.
The mean age of the patients was 56 years, 10 were males, and all were whites. The first day median APACHE II score and its predicted hospital mortality were 35 and 83%, respectively, and the median SOFA score was 11.5. Eleven patients had ARDS, two unilateral pneumonia with septic shock, and one pulmonary edema. Patients received conventional ventilation for a median of 1.8 days before HFOV. HFOV was used 16 times for a median of 3.2 days. Improvements in oxygenation parameters were observed after 24 hours of HFOV (mean PaO2/FIO2 increased from 82 to 107, P < 0.05; and the mean oxygenation index decreased from 42 to 29; P < 0.05). In two patients HFOV was discontinued, in one because of equipment failure and in another because of severe hypotension that was unresponsive to fluids. No change in mean arterial pressure, or vasopressor requirements was noted after the initiation of HFOV. Eight patients died (57 %, 95% CI: 33–79); life support was withdrawn in six and two suffered cardiac arrest.
During our first year of experience, HFOV was used as a rescue therapy in very sick patients with refractory hypoxemia, and improvement in oxygenation was observed after 24 hours of this technique. HFOV is a reasonable alternative when a protective lung strategy could not be achieved on conventional ventilation.
PMCID: PMC1456987  PMID: 16464246
5.  Is high-frequency oscillatory ventilation more effective and safer than conventional protective ventilation in adult acute respiratory distress syndrome patients? A meta-analysis of randomized controlled trials 
Critical Care  2014;18(3):R111.
Comprehensively evaluating the efficacy and safety of high-frequency oscillatory ventilation (HFOV) is important to allow clinicians who are using or considering this intervention to make appropriate decisions.
To find randomized controlled trials (RCTs) comparing HFOV with conventional mechanical ventilation (CMV) as an initial treatment for adult ARDS patients, we searched electronic databases (including PubMed, MedLine, Springer Link, Elsevier Science Direct, ISI web of knowledge, and EMBASE) with the following terms: “acute respiratory distress syndrome”, “acute lung injury”, and “high frequency oscillation ventilation”. Additional sources included reference lists from the identified primary studies and relevant meta-analyses. Two investigators independently screened articles and extracted data. Meta-analysis was conducted using random-effects models.
We included 6 RCTs with a total of 1,608 patients in this meta-analysis. Compared with CMV, HFOV did not significantly reduce the mortality at 30 or 28 days. The pooled relative risk (RR) was 1.051 (95% confidence interval (CI) 0.813 to 1.358). ICU mortality was also not significantly reduced in HFOV group, with a pooled RR of 1.218 (95% CI 0.925 to 1.604). The pooled effect sizes of HFOV for oxygenation failure, ventilation failure and duration of mechanical ventilation were 0.557 (95% CI 0.351 to 0.884), 0.892 (95% CI 0.435 to 1.829) and 0.079 (95% CI −0.045 to 0.203), respectively. The risk of barotrauma and hypotension were similar between the CMV group and HFOV group, with a RR of 1.205 (95% CI 0.834 to 1.742) and a RR of 1.326 (95% CI 0.271 to 6.476), respectively.
Although HFOV seems not to increase the risk of barotrauma or hypotension, and reduces the risk of oxygenation failure, it does not improve survival in adult acute respiratory distress syndrome patients.
PMCID: PMC4095578  PMID: 24887179
6.  Physiological predictors of survival during high-frequency oscillatory ventilation in adults with acute respiratory distress syndrome 
Critical Care  2013;17(2):R40.
Data that provide clinical criteria for the identification of patients likely to respond to high-frequency oscillatory ventilation (HFOV) are scarce. Our aim was to describe physiological predictors of survival during HFOV in adults with severe acute respiratory distress syndrome (ARDS) admitted to a respiratory failure center in the United Kingdom.
Electronic records of 102 adults treated with HFOV were reviewed retrospectively. We used logistic regression and receiving-operator characteristics curve to test associations with oxygenation and mortality.
Patients had severe ARDS with a mean (SD) Murray's score of 2.98 (0.7). Partial pressure of oxygen in arterial blood to fraction of inspired oxygen (PaO2/FiO2) ratio and oxygenation index improved only in survivors. The earliest time point at which the two groups differed was at three hours after commencing HFOV. An improvement of >38% in PaO2/FiO2 occurring at any time within the first 72 hours, was the best predictor of survival at 30 days (area under the curve (AUC) of 0.83, sensitivity 93%, specificity 78% and a positive likelihood ratio (LR) of 4.3). These patients also had a 3.5 fold greater reduction in partial pressure of carbon dioxide in arterial blood (PaCO2). Multivariate analysis showed that HFOV was more effective in younger patients, when instituted early, and in patients with milder respiratory acidosis.
HFOV is effective in improving oxygenation in adults with ARDS, particularly when instituted early. Changes in PaO2/FiO2 during the first three hours of HFOV can identify those patients more likely to survive.
PMCID: PMC3733430  PMID: 23497577
7.  Volumetric Xenon-CT Imaging of Conventional and High-Frequency Oscillatory Ventilation 
Academic radiology  2009;16(6):718-725.
Rationale and Objectives
For mechanical ventilation of patients with pulmonary injuries it has been proposed that high-frequency oscillatory ventilation (HFOV) offers advantages over conventional ventilation (CV), however, these advantages have been difficult to quantify. We used volumetric, dynamic imaging of Xenon (Xe) washout of the canine lung during both HFOV and CV to compare regional ventilation in the two modalities.
Materials and Methods
Three anesthetized, mechanically ventilated animals were studied, each at three different ventilator settings. Imaging was performed on an experimental Toshiba 256-slice scanner at 80 kV, 250 mAs, and 0.5 sec scans, yielding 12.8 cm of Z-axis coverage. Repeated images were acquired at increasing intervals between 1 and 10 seconds for 90 seconds during HFOV, and using retrospective respiratory gating to end-expiration for 60 seconds during CV.
Image series were analyzed to quantify regional specific ventilation (sV̇) from the regional density washout time constants.
High quality, high-resolution regional ventilation maps were obtained during both CV and HFOV. Overall ventilation decreased at smaller tidal volume, as expected. Regional sV̇ was more uniform during HFOV compared to CV but the underlying distribution of lung aeration was similar.
High-resolution volumetric ventilation maps of the lung may be obtained with the 256-slice multidetector CT scanner. There is a marked difference in the distribution of regional ventilation between CV and HFOV, with a significant gravitational ventilation gradient in CV that was not present during HFOV. This technique may be useful in exploring the mechanisms by which HFOV improves gas exchange.
PMCID: PMC2705624  PMID: 19268611
regional ventilation; computed tomography; mechanical ventilation; gas exchange; canine
8.  Late Outcomes of a Randomized Trial of High-Frequency Oscillation in Neonates 
The New England journal of medicine  2014;370(12):1121-1130.
Results from an observational study involving neonates suggested that high-frequency oscillatory ventilation (HFOV), as compared with conventional ventilation, was associated with superior small-airway function at follow-up. Data from randomized trials are needed to confirm this finding.
We studied 319 adolescents who had been born before 29 weeks of gestation and had been enrolled in a multicenter, randomized trial that compared HFOV with conventional ventilation immediately after birth. The trial involved 797 neonates, of whom 592 survived to hospital discharge. We compared follow-up data from adolescents who had been randomly assigned to HFOV with follow-up data from those who had been randomly assigned to conventional ventilation, with respect to lung function and respiratory health, health-related quality of life, and functional status, as assessed with the use of questionnaires completed when the participants were 11 to 14 years of age. The primary outcome was forced expiratory flow at 75% of the expired vital capacity (FEF75).
The HFOV group had superior results on a test of small-airway function (z score for FEF75, −0.97 with HFOV vs. −1.19 with conventional therapy; adjusted difference, 0.23 [95% confidence interval, 0.02 to 0.45]). There were significant differences in favor of HFOV in several other measures of respiratory function, including forced expiratory volume in 1 second, forced vital capacity, peak expiratory flow, diffusing capacity, and impulse-oscillometric findings. As compared with the conventional-therapy group, the HFOV group had significantly higher ratings from teachers in three of eight school subjects assessed, but there were no other significant differences in functional outcomes.
In a randomized trial involving children who had been born extremely prematurely, those who had undergone HFOV, as compared with those who had received conventional ventilation, had superior lung function at 11 to 14 years of age, with no evidence of poorer functional outcomes. (Funded by the National Institute for Health Research Health Technology Assessment Programme and others.)
PMCID: PMC4090580  PMID: 24645944
9.  Arteriovenous extracorporeal lung assist allows for maximization of oscillatory frequencies: a large-animal model of respiratory distress 
BMC Anesthesiology  2008;8:7.
Although the minimization of the applied tidal volume (VT) during high-frequency oscillatory ventilation (HFOV) reduces the risk of alveolar shear stress, it can also result in insufficient CO2-elimination with severe respiratory acidosis. We hypothesized that in a model of acute respiratory distress (ARDS) the application of high oscillatory frequencies requires the combination of HFOV with arteriovenous extracorporeal lung assist (av-ECLA) in order to maintain or reestablish normocapnia.
After induction of ARDS in eight female pigs (56.5 ± 4.4 kg), a recruitment manoeuvre was performed and intratracheal mean airway pressure (mPaw) was adjusted 3 cmH2O above the lower inflection point (Plow) of the pressure-volume curve. All animals were ventilated with oscillatory frequencies ranging from 3–15 Hz. The pressure amplitude was fixed at 60 cmH2O. At each frequency gas exchange and hemodynamic measurements were obtained with a clamped and de-clamped av-ECLA. Whenever the av-ECLA was de-clamped, the oxygen sweep gas flow through the membrane lung was adjusted aiming at normocapnia.
Lung recruitment and adjustment of the mPaw above Plow resulted in a significant improvement of oxygenation (p < 0.05). Compared to lung injury, oxygenation remained significantly improved with rising frequencies (p < 0.05). Normocapnia during HFOV was only maintained with the addition of av-ECLA during frequencies of 9 Hz and above.
In this animal model of ARDS, maximization of oscillatory frequencies with subsequent minimization of VT leads to hypercapnia that can only be reversed by adding av-ECLA. When combined with a recruitment strategy, these high frequencies do not impair oxygenation
PMCID: PMC2588559  PMID: 19014575
10.  Sustained inflation and incremental mean airway pressure trial during conventional and high-frequency oscillatory ventilation in a large porcine model of acute respiratory distress syndrome 
BMC Anesthesiology  2006;6:8.
To compare the effect of a sustained inflation followed by an incremental mean airway pressure trial during conventional and high-frequency oscillatory ventilation on oxygenation and hemodynamics in a large porcine model of early acute respiratory distress syndrome.
Severe lung injury (Ali) was induced in 18 healthy pigs (55.3 ± 3.9 kg, mean ± SD) by repeated saline lung lavage until PaO2 decreased to less than 60 mmHg. After a stabilisation period of 60 minutes, the animals were randomly assigned to two groups: Group 1 (Pressure controlled ventilation; PCV): FIO2 = 1.0, PEEP = 5 cmH2O, VT = 6 ml/kg, respiratory rate = 30/min, I:E = 1:1; group 2 (High-frequency oscillatory ventilation; HFOV): FIO2 = 1.0, Bias flow = 30 l/min, Amplitude = 60 cmH2O, Frequency = 6 Hz, I:E = 1:1. A sustained inflation (SI; 50 cmH2O for 60s) followed by an incremental mean airway pressure (mPaw) trial (steps of 3 cmH2O every 15 minutes) were performed in both groups until PaO2 no longer increased. This was regarded as full lung inflation. The mPaw was decreased by 3 cmH2O and the animals reached the end of the study protocol. Gas exchange and hemodynamic data were collected at each step.
The SI led to a significant improvement of the PaO2/FiO2-Index (HFOV: 200 ± 100 vs. PCV: 58 ± 15 and TAli: 57 ± 12; p < 0.001) and PaCO2-reduction (HFOV: 42 ± 5 vs. PCV: 62 ± 13 and TAli: 55 ± 9; p < 0.001) during HFOV compared to lung injury and PCV. Augmentation of mPaw improved gas exchange and pulmonary shunt fraction in both groups, but at a significant lower mPaw in the HFOV treated animals. Cardiac output was continuously deteriorating during the recruitment manoeuvre in both study groups (HFOV: TAli: 6.1 ± 1 vs. T75: 3.4 ± 0.4; PCV: TAli: 6.7 ± 2.4 vs. T75: 4 ± 0.5; p < 0.001).
A sustained inflation followed by an incremental mean airway pressure trial in HFOV improved oxygenation at a lower mPaw than during conventional lung protective ventilation. HFOV but not PCV resulted in normocapnia, suggesting that during HFOV there are alternatives to tidal ventilation to achieve CO2-elimination in an "open lung" approach.
PMCID: PMC1526714  PMID: 16792808
11.  Open lung approach associated with high-frequency oscillatory or low tidal volume mechanical ventilation improves respiratory function and minimizes lung injury in healthy and injured rats 
Critical Care  2010;14(5):R183.
To test the hypothesis that open lung (OL) ventilatory strategies using high-frequency oscillatory ventilation (HFOV) or controlled mechanical ventilation (CMV) compared to CMV with lower positive end-expiratory pressure (PEEP) improve respiratory function while minimizing lung injury as well as systemic inflammation, a prospective randomized study was performed at a university animal laboratory using three different lung conditions.
Seventy-eight adult male Wistar rats were randomly assigned to three groups: (1) uninjured (UI), (2) saline washout (SW), and (3) intraperitoneal/intravenous Escherichia coli lipopolysaccharide (LPS)-induced lung injury. Within each group, animals were further randomized to (1) OL with HFOV, (2) OL with CMV with "best" PEEP set according to the minimal static elastance of the respiratory system (BP-CMV), and (3) CMV with low PEEP (LP-CMV). They were then ventilated for 6 hours. HFOV was set with mean airway pressure (PmeanHFOV) at 2 cm H2O above the mean airway pressure recorded at BP-CMV (PmeanBP-CMV) following a recruitment manoeuvre. Six animals served as unventilated controls (C). Gas-exchange, respiratory system mechanics, lung histology, plasma cytokines, as well as cytokines and types I and III procollagen (PCI and PCIII) mRNA expression in lung tissue were measured.
We found that (1) in both SW and LPS, HFOV and BP-CMV improved gas exchange and mechanics with lower lung injury compared to LP-CMV, (2) in SW; HFOV yielded better oxygenation than BP-CMV; (3) in SW, interleukin (IL)-6 mRNA expression was lower during BP-CMV and HFOV compared to LP-CMV, while in LPS inflammatory response was independent of the ventilatory mode; and (4) PCIII mRNA expression decreased in all groups and ventilatory modes, with the decrease being highest in LPS.
Open lung ventilatory strategies associated with HFOV or BP-CMV improved respiratory function and minimized lung injury compared to LP-CMV. Therefore, HFOV with PmeanHFOV set 2 cm H2O above the PmeanBP-CMV following a recruitment manoeuvre is as beneficial as BP-CMV.
PMCID: PMC3219289  PMID: 20946631
12.  High-frequency oscillatory ventilation and short-term outcome in neonates and infants undergoing cardiac surgery: a propensity score analysis 
Critical Care  2011;15(5):R259.
Experience with high-frequency oscillatory ventilation (HFOV) after congenital cardiac surgery is limited despite evidence about reduction in pulmonary vascular resistance after the Fontan procedure. HFOV is recommended in adults and children with acute respiratory distress syndrome. The aim of the present study was to assess associations between commencement of HFOV on the day of surgery and length of mechanical ventilation, length of Intensive Care Unit (ICU) stay and mortality in neonates and infants with respiratory distress following cardiac surgery.
A logistic regression model was used to develop a propensity score, which accounted for the probability of being switched from conventional mechanical ventilation (CMV) to HFOV on the day of surgery. It included baseline characteristics, type of procedure and postoperative variables, and was used to match each patient with HFOV with a control patient, in whom CMV was used exclusively. Length of mechanical ventilation, ICU stay and mortality rates were compared in the matched set.
Overall, 3,549 neonates and infants underwent cardiac surgery from January 2001 through June 2010, 120 patients were switched to HFOV and matched with 120 controls. After adjustment for the delay to sternal closure, duration of renal replacement therapy, occurrence of pulmonary hypertension and year of surgery, the probability of successful weaning over time and the probability of ICU delivery over time were significantly higher in patients with HFOV, adjusted hazard ratios and 95% confidence intervals: 1.63, 1.17 to 2.26 (P = 0.004). and 1.65, 95% confidence intervals: 1.20 to 2.28 (P = 0.002) respectively. No association was found with mortality.
When commenced on the day of surgery in neonates and infants with respiratory distress following cardiac surgery, HFOV was associated with shorter lengths of mechanical ventilation and ICU stay than CMV.
PMCID: PMC3334810  PMID: 22035562
13.  An Assessment of H1N1 Influenza-Associated Acute Respiratory Distress Syndrome Severity after Adjustment for Treatment Characteristics 
PLoS ONE  2011;6(3):e18166.
Pandemic influenza caused significant increases in healthcare utilization across several continents including the use of high-intensity rescue therapies like extracorporeal membrane oxygenation (ECMO) or high-frequency oscillatory ventilation (HFOV). The severity of illness observed with pandemic influenza in 2009 strained healthcare resources. Because lung injury in ARDS can be influenced by daily management and multiple organ failure, we performed a retrospective cohort study to understand the severity of H1N1 associated ARDS after adjustment for treatment. Sixty subjects were identified in our hospital with ARDS from “direct injury” within 24 hours of ICU admission over a three month period. Twenty-three subjects (38.3%) were positive for H1N1 within 72 hours of hospitalization. These cases of H1N1-associated ARDS were compared to non-H1N1 associated ARDS patients. Subjects with H1N1-associated ARDS were younger and more likely to have a higher body mass index (BMI), present more rapidly and have worse oxygenation. Severity of illness (SOFA score) was directly related to worse oxygenation. Management was similar between the two groups on the day of admission and subsequent five days with respect to tidal volumes used, fluid balance and transfusion practices. There was, however, more frequent use of “rescue” therapy like prone ventilation, HFOV or ECMO in H1N1 patients. First morning set tidal volumes and BMI were significantly associated with increased severity of lung injury (Lung injury score, LIS) at presentation and over time while prior prescription of statins was protective. After assessment of the effect of these co-interventions LIS was significantly higher in H1N1 patients. Patients with pandemic influenza-associated ARDS had higher LIS both at presentation and over the course of the first six days of treatment when compared to non-H1N1 associated ARDS controls. The difference in LIS persisted over the duration of observation in patients with H1N1 possibly explaining the increased duration of mechanical ventilation.
PMCID: PMC3064596  PMID: 21464952
14.  Rescue Therapy in Adult and Pediatric Patients with H1N1 Influenza Infection: A Tertiary Center ICU Experience from April-October, 2009 
Critical care medicine  2010;38(11):2103-2107.
Severe respiratory failure is a well recognized complication of pandemic H1N1 influenza infection. Limited data regarding the efficacy of rescue therapies including high frequency oscillatory ventilation (HFOV) and extracorporeal membranous oxygenation (ECMO) have been previously reported in the setting of H1N1 influenza infection in the United States.
Retrospective, single center cohort study.
Pediatric, cardiac, surgical, and medical intensive care units in a single tertiary care center in the United States.
127 consecutive patients with confirmed Influenza A infection requiring hospitalization between April 1, 2009 and October 31, 2009.
Electronic medical records were reviewed for demographic and clinical data.
Measurements and main results
The number of ICU admissions appears inversely related to age with 69% of admissions less than 20 years of age. Median duration of ICU care was 10.0 days [4.0, 24.0], and median duration of mechanical ventilation was 8.0 days [0.0, 23.5]. Rescue therapy (HFOV or ECMO) was utilized in 36% (12/33) of ICU patients. The severity of respiratory impairment was determined by PaO2/FiO2 ratio (P/F) and oxygenation index (OI). HFOV at 24-hours resulted in improvements in median P/F (71 [58, 93] vs. 145 [126, 185]; P<0.001), OI (27 [20, 30] vs. 18 [12, 25]; P=0.016), and FiO2 (100 [70, 100] vs. 45 [40, 55]; P<0.001). ECMO resulted in anticipated improvement in parameters of oxygenation at both 2- hours and 24-hours after initiation of therapy. Despite the severity of oxygenation impairment, overall survival for both rescue therapies was 75% (9/12), 80% (4/5) for HFOV alone, and 71% (5/7) for HFOV + ECMO.
In critically ill adult and pediatric patients with H1N1 infection and severe lung injury, the utilization of HFOV and ECMO can result in significant improvements in P/F ratio, OI, and FiO2. However, the impact on mortality is less certain.
PMCID: PMC3739437  PMID: 20711068
influenza; acute respiratory distress syndrome; H1N1; mechanical ventilation; high frequency oscillatory ventilation; extracorporeal membrane oxygenation (ECMO); hypoxemia; respiratory failure; lung injury
15.  Ultrastructural Study of Alveolar Epithelial Type II Cells by High-Frequency Oscillatory Ventilation 
BioMed Research International  2013;2013:240659.
Alveolar epithelial type II cells (AECIIs) containing lamellar bodies (LBs) are alveolar epithelial stem cells that have important functions in the repair of lung structure and function after lung injury. The ultrastructural changes in AECIIs after high-frequency oscillatory ventilation (HFOV) with a high lung volume strategy or conventional ventilation were evaluated in a newborn piglet model with acute lung injury (ALI). After ALI with saline lavage, newborn piglets were randomly assigned into five study groups (three piglets in each group), namely, control (no mechanical ventilation), conventional ventilation for 24 h, conventional ventilation for 48 h, HFOV for 24 h, and HFOV for 48 h. The lower tissues of the right lung were obtained to observe the AECII ultrastructure. AECIIs with reduced numbers of microvilli, decreased LBs electron density, and vacuole-like LBs deformity were commonly observed in all five groups. Compared with conventional ventilation groups, the decrease in numbers of microvilli and LBs electron density, as well as LBs with vacuole-like appearance and polymorphic deformity, was less severe in HFOV with high lung volume strategy groups. AECIIs were injured during mechanical ventilation. HFOV with a high lung volume strategy resulted in less AECII damage than conventional ventilation.
PMCID: PMC3872375  PMID: 24386636
16.  Hepatic effects of lung-protective pressure-controlled ventilation and a combination of high-frequency oscillatory ventilation and extracorporeal lung assist in experimental lung injury 
Ventilation with high positive end-expiratory pressure (PEEP) can lead to hepatic dysfunction. The aim of this study was to investigate the hepatic effects of strategies using high airway pressures either in pressure-controlled ventilation (PCV) or in high-frequency oscillatory ventilation (HFOV) combined with an arteriovenous extracorporeal lung assist (ECLA).
Pietrain pigs underwent induction of lung injury by saline lavage. Ventilation was continued for 24 hours either as PCV with tidal volumes of 6 ml/kg and PEEP 3 cmH2O above the lower inflection point of the pressure-volume curve or as HFOV (≥12 Hz) with a mean tracheal airway pressure 3 cmH2O above the lower inflection point combined with arteriovenous ECLA (HFOV+ECLA). Fluids and norepinephrine stabilized the circulation. The indocyanine green plasma disappearance rate, serum bilirubin, aspartate aminotransferase, alanine aminotransferase, γ-glutamyltransferase, alkaline phosphatase, glutamate dehydrogenase, lactate dehydrogenase and creatine kinase were determined repeatedly. Finally, liver neutrophils were counted and liver cell apoptosis was assessed by terminal deoxynucleotidyl transferase nick end labeling (TUNEL).
Aspartate aminotransferase increased in the PCV group about three-fold and in the HFOV+ECLA group five-fold (p<0.001). Correspondingly, creatine kinase increased about two-fold and four-fold, respectively (p<0.001). Lactate dehydrogenase was increased in the HFOV+ECLA group (p<0.028). The number of neutrophils infiltrating the liver tissue and the apoptotic index were low.
High airway pressure PCV and HFOV with ECLA in the treatment of lavage-induced lung injury in pigs did not cause liver dysfunction or damage. The detected elevation of enzymes might be of extrahepatic origin.
PMCID: PMC3539465  PMID: 21959601
acute respiratory distress syndrome; positive-pressure respiration; high-frequency oscillation ventilation; arteriovenous extracorporeal lung assist; liver dysfunction; liver function tests
17.  High Frequency Oscillation and Airway Pressure Release Ventilation in Pediatric Respiratory Failure 
Pediatric pulmonology  2013;49(7):707-715.
Airway pressure release ventilation (APRV) and high frequency oscillatory ventilation (HFOV) are frequently used in acute lung injury (ALI) refractory to conventional ventilation. Our aim was to describe our experience with APRV and HFOV in refractory pediatric ALI, and to identify factors associated with survival.
We analyzed 104 patients with hypoxemia refractory to conventional ventilation transitioned to either APRV or HFOV. Demographics, oxygenation index (OI), and PaO2/FiO2 (PF ratio) were recorded before transition to either mode of nonconventional ventilation (NCV) and for every 12 hr after transition.
Relative to APRV, patients on HFOV were younger and had more significant lung disease evidenced by higher OI (28.5 [18.6, 36.2] vs. 21.0 [15.5, 30.0], P = 0.008), lower PF ratios (73 [59,94] vs. 99 [76,131], P = 0.002), and more frequent use of inhaled nitric oxide. In univariate analysis, HFOV was associated with more frequent neuromuscular blockade. Forty-one of 104 patients died on NCV (39.4%). Survivors demonstrated improvement in OI 24 hr after transition to NCV, whereas non-survivors did not (12.9 [8.9, 20.9] vs. 28.1 [17.6, 37.1], P < 0.001). After controlling for immunocompromised status, number of vasopressors, and OI before transition, mode of NCV was not associated with mortality.
In a heterogeneous PICU population with hypoxemia refractory to conventional ventilation transitioned to NCV, improvement in oxygenation at 24 hr was associated with survival. Immunocompromised status, number of vasopressor infusions, and the OI before transition to NCV were independently associated with survival.
PMCID: PMC4092114  PMID: 23853049
mechanical ventilation; high frequency oscillatory ventilation; airway pressure release ventilation; acute respiratory distress syndrome; acute lung injury; pediatric
18.  High-frequency oscillatory ventilation in children: a single-center experience of 53 cases 
Critical Care  2005;9(3):R274-R279.
The present article reports our experience with high-frequency oscillatory ventilation (HFOV) in pediatric patients who deteriorated on conventional mechanical ventilation.
The chart records of 53 consecutively HFOV-treated patients from 1 January 1998 to 1 April 2004 were retrospectively analyzed. The parameters of demographic data, cause of respiratory insufficiency, Pediatric Index of Mortality score, oxygenation index and PaCO2 were recorded and calculated at various time points before and after the start of HFOV, along with patient outcome and cause of death.
The overall survival rate was 64%. We observed remarkable differences in outcome depending on the cause of respiratory insufficiency; survival was 56% in patients with diffuse alveolar disease (DAD) and was 88% in patients with small airway disease (SAD). The oxygenation index was significantly higher before and during HFOV in DAD patients than in SAD patients. The PaCO2 prior to HFOV was higher in SAD patients compared with DAD patients and returned to normal values after the initiation of HFOV.
HFOV rescue therapy was associated with a high survival percentage in a selected group of children. Patients with DAD primarily had oxygenation failure. Future studies are necessary to evaluate whether the outcome in this group of patients may be improved if HFOV is applied earlier in the course of disease. Patients with SAD primarily had severe hypercapnia and HFOV therapy was very effective in achieving adequate ventilation.
PMCID: PMC1175892  PMID: 15987401
19.  High-Frequency Oscillatory Ventilation Combined with Volume Guarantee in a Neonatal Animal Model of Respiratory Distress Syndrome 
Objective. To assess volume guarantee (VG) ventilation combined with high-frequency oscillatory ventilation (HFOV) strategy on PaCO2 regulation in an experimental model of neonatal distress syndrome. Methods. Six 2-day-old piglets weighing 2.57 ± 0.26 kg were used for this interventional experimental study. Animals were ventilated during physiologic lung conditions and after depletion of lung surfactant by bronchoalveolar lavage (BAL). The effect of HFOV combined with VG on PaCO2 was evaluated at different high-frequency expired tidal volume (VThf) at constant frequency (fR) and mean airway pressure (mPaw). Fluctuations of the pressure (ΔPhf) around the mPaw and PaCO2 were analyzed before and after lung surfactant depletion. Results. PaCO2 levels were inversely proportional to VThf. In the physiological lung condition, an increase in VThf caused a significant decrease in PaCO2 and an increase in ΔPhf. After BAL, PaCO2 did not change as compared with pre-BAL situation as the VThf remained constant by the ventilator. Conclusions. In this animal model, using HFOV combined with VG, changes in the VThf settings induced significant modifications in PaCO2. After changing the lung condition by depletion of surfactant, PaCO2 remained unchanged, as the VThf setting was maintained constant by modifications in the ΔPhf done by the ventilator.
PMCID: PMC3732614  PMID: 23970963
20.  Effects of High-Frequency Oscillatory Ventilation and Partial Liquid Ventilation on Acute Lung Injury Induced by Steam Inhalation in New Zealand Rabbits 
Objective: to investigate the beneficial effects of high-frequency oscillatory ventilation (HFOV) and partial liquid ventilation (PLV) in treating acute lung injury induced by steam inhalation. Design: a prospective, randomized, controlled, multiple group study. Setting: an animal research centre laboratory in a university burns centre. Subjects: New Zealand rabbits (n = 30; 2.25 ± 0.25 kg) of either sex. Interventions: the animals were ventilated by HFOV with a mean airway pressure of 10 cm H 2O, a frequency of 10 Hz, an amplitude of 20 cm H 2O, an I:E ratio of 1:1, and an FiO 2of 1.0. After the induction of acute lung injury by steam inhalation, the animals were randomly assigned to receive either HFOV alone or a combined therapy of HFOV + PLV. The animals were grouped as HFOV, HFOV + PLV, and control group (without ventilation after recovery from muscular relaxation). Measurements and main results: arterial blood gases, cardiovascular haemodynamics, dynamic lung compliance, and total lung injury scores were measured. After steam inhalation, all three groups displayed low PaO 2and low dynamic lung compliance. In the control group all the animals died within 3 h. In the HFOV and HFOV + PLV groups, all the animals displayed significant improvements in dynamic lung compliance, oxygenation, and histological outcomes; HFOV + PLV showed the best results. Conclusion: in a New Zealand rabbit model of steam inhalation injury, HFOV improved oxygenation, increased dynamic lung compliance, and alleviated lung histological injury. Combined therapy with HFOV + PLV was clearly superior to that with HFOV alone during the observation period.
PMCID: PMC3188035  PMID: 21991031
high-frequency; oscillatory; ventilation; partial; liquid; ventilation; lung; injury; steam; inhalation; new zealand; rabbits
21.  Numerical study of high frequency oscillatory air flow and convective mixing in a CT-based human airway model 
Annals of biomedical engineering  2010;38(12):3550-3571.
High frequency oscillatory ventilation (HFOV) is considered an efficient and safe respiratory technique to ventilate neonates and patients with acute respiratory distress syndrome. HFOV has very different characteristics from normal breathing physiology, with a much smaller tidal volume and a higher breathing frequency. In this work, the high frequency oscillatory flow is studied using a computational fluid dynamics (CFD) analysis in three different geometrical models with increasing complexity: a straight tube, a single-bifurcation tube model, and a computed-tomography (CT)-based human airway model of up to seven generations. We aim to understand the counter-flow phenomenon at flow reversal and its role in convective mixing in these models using sinusoidal waveforms of different frequencies and Reynolds numbers. Mixing is quantified by the stretch rate analysis. In the straight-tube model, coaxial counter flow with opposing fluid streams is formed around flow reversal, agreeing with an analytical Womersley solution. However, counter flow yields no net convective mixing at end cycle. In the single-bifurcation model, counter flow at high Re is intervened with secondary vortices in the parent (child) branch at end expiration (inspiration), resulting in an irreversible mixing process. For the CT-based airway model three cases are considered, consisting of the normal breathing case, the high-frequency-normal-Re case, and the HFOV case. The counter-flow structure is more evident in the high-frequency-normal-Re case than the HFOV case. The instantaneous and time-averaged stretch rates at the end of two breathing cycles and in the vicinity of flow reversal are computed. It is found that counter flow contributes about 20% to mixing in HFOV.
PMCID: PMC3064990  PMID: 20614248
high frequency oscillatory ventilation; CT-based human airway; CFD; secondary flow; stretch rate; mixing
22.  Effect of a lung recruitment maneuver by high-frequency oscillatory ventilation in experimental acute lung injury on organ blood flow in pigs 
Critical Care  2006;10(4):R100.
The objective was to study the effects of a lung recruitment procedure by stepwise increases of mean airway pressure upon organ blood flow and hemodynamics during high-frequency oscillatory ventilation (HFOV) versus pressure-controlled ventilation (PCV) in experimental lung injury.
Lung damage was induced by repeated lung lavages in seven anesthetized pigs (23–26 kg). In randomized order, HFOV and PCV were performed with a fixed sequence of mean airway pressure increases (20, 25, and 30 mbar every 30 minutes). The transpulmonary pressure, systemic hemodynamics, intracranial pressure, cerebral perfusion pressure, organ blood flow (fluorescent microspheres), arterial and mixed venous blood gases, and calculated pulmonary shunt were determined at each mean airway pressure setting.
The transpulmonary pressure increased during lung recruitment (HFOV, from 15 ± 3 mbar to 22 ± 2 mbar, P < 0.05; PCV, from 15 ± 3 mbar to 23 ± 2 mbar, P < 0.05), and high airway pressures resulted in elevated left ventricular end-diastolic pressure (HFOV, from 3 ± 1 mmHg to 6 ± 3 mmHg, P < 0.05; PCV, from 2 ± 1 mmHg to 7 ± 3 mmHg, P < 0.05), pulmonary artery occlusion pressure (HFOV, from 12 ± 2 mmHg to 16 ± 2 mmHg, P < 0.05; PCV, from 13 ± 2 mmHg to 15 ± 2 mmHg, P < 0.05), and intracranial pressure (HFOV, from 14 ± 2 mmHg to 16 ± 2 mmHg, P < 0.05; PCV, from 15 ± 3 mmHg to 17 ± 2 mmHg, P < 0.05). Simultaneously, the mean arterial pressure (HFOV, from 89 ± 7 mmHg to 79 ± 9 mmHg, P < 0.05; PCV, from 91 ± 8 mmHg to 81 ± 8 mmHg, P < 0.05), cardiac output (HFOV, from 3.9 ± 0.4 l/minute to 3.5 ± 0.3 l/minute, P < 0.05; PCV, from 3.8 ± 0.6 l/minute to 3.4 ± 0.3 l/minute, P < 0.05), and stroke volume (HFOV, from 32 ± 7 ml to 28 ± 5 ml, P < 0.05; PCV, from 31 ± 2 ml to 26 ± 4 ml, P < 0.05) decreased. Blood flows to the heart, brain, kidneys and jejunum were maintained. Oxygenation improved and the pulmonary shunt fraction decreased below 10% (HFOV, P < 0.05; PCV, P < 0.05). We detected no differences between HFOV and PCV at comparable transpulmonary pressures.
A typical recruitment procedure at the initiation of HFOV improved oxygenation but also decreased systemic hemodynamics at high transpulmonary pressures when no changes of vasoactive drugs and fluid management were performed. Blood flow to the organs was not affected during lung recruitment. These effects were independent of the ventilator mode applied.
PMCID: PMC1751024  PMID: 16836767
23.  High‐frequency oscillatory ventilation versus conventional ventilation: hemodynamic effects on lung and heart 
Physiological Reports  2014;2(3):e00259.
High‐frequency oscillatory ventilation (HFOV) may improve gas exchange in patients who are inadequately ventilated by conventional mechanical ventilation (CV); however, the hemodynamic consequences of switching to HFOV remain unclear. We compared the effects of CV and HFOV on pulmonary vascular conductance and left ventricular (LV) preload and performance at different airway and filling pressures. In anesthetized dogs, we measured LV dimensions, aortic and pulmonary artery (PA) flow, and mean airway (AW) and pericardial pressures. Catheter‐tip pressure manometers measured aortic, LV, left atrial, and PA pressures. The pericardium and chest were closed. At LV end‐diastolic pressure (PLVED) = 5 mmHg and 12 mmHg, PEEP was varied (6 cm H2O, 12 cm H2O, and 18 cm H2O) during CV. Then, at airway pressures equal to those during CV, HFOV was applied at 4 Hz, 10 Hz, and 15 Hz. Increased AW decreased pulmonary vascular conductance. As cardiac output increased, conductance increased. At PLVED = 12 mmHg, conductance was greatest during HFOV at 4 Hz. LV preload (i.e., ALV, our index of end‐diastolic volume) was similar during HFOV and CV for all conditions. At PLVED = 12 mmHg, SWLV was similar during CV and HFOV, but, at PLVED = 5 mmHg and AW 10 cm H2O, SWLV was lower during HFOV than CV. Compared to pulmonary vascular conductance at higher frequencies, at PLVED = 12 mmHg, conductance was greater at HFOV of 4 Hz. Effects of CV and HFOV on LV preload and performance were similar except for decreased SWLV at PLVED = 5 mmHg. These observations suggest the need for further studies to assess their potential clinical relevance.
We found that conventional and high‐frequency oscillatory ventilation (HFOV) have similar effects on LV preload and performance except for worse LV performance at a low filling pressure. We also found that pulmonary vascular conductance was greater during high‐frequency oscillatory at 4 Hz at LV end‐diastolic pressure of 12 mmHg compared to at higher frequencies.
PMCID: PMC4002239  PMID: 24760513
Pulmonary vascular conductance; LV preload; performance
24.  High-frequency oscillatory ventilation and pediatric cardiac surgery: Yes, we can! 
Critical Care  2011;15(6):1011.
In the previous issue of Critical Care, Bojan and colleagues reported their experiences with high-frequency oscillatory ventilation (HFOV) after pediatric cardiac surgery. A total of 120 patients were treated with HFOV on the day of surgery, thus excluding rescue HFOV use. The main finding of the authors was that the duration of mechanical ventilation was significantly shorter in patients in whom HFOV was initiated on the day of surgery. Especially interesting about this work is that the authors used HFOV when there was evidence of pulmonary hypertension or right ventricular (RV) failure in their patients. This is an interesting approach as it is often assumed that high intra-thoracic pressures increase RV afterload and thus may enhance RV dysfunction. The findings of Bojan and colleagues may be explained by the fact that they were able to decrease the pulmonary vascular resistance by finding a proper balance between atelectasis and overdistension of the lung. It can be argued that it is possible to do so by applying positive end-expiratory pressure. But, at the same time, this may coincide with the delivery of high inspiratory pressures (>30 cm H2O). As HFOV is, in fact, a continuous positive airway pressure system, its advantage is that it is possible to maintain sufficient lung volume without large injurious pressure swings. Although the observations by Bojan and colleagues need to be confirmed in a prospective randomized trial, they have provided arguments not to rule out the early use of HFOV in pediatric cardiac surgery patients.
PMCID: PMC3388685  PMID: 22126408
25.  Comparison of respiratory indices in predicting response to high frequency oscillatory ventilation in very low birth weight infants with respiratory distress syndrome. 
Journal of Korean Medical Science  2000;15(2):153-158.
To evaluate the predictive values of oxygenation index (OI), arterial-alveolar oxygen tension ratio (a/APO)2, and alveolar-arterial oxygen gradient ((A-a)DO2) for early recognition of responsiveness to high frequency oscillatory ventilation (HFOV) in very low birth weight infants with respiratory distress syndrome (RDS), 23 infants who received HFOV treatment for severe RDS after failing to be improved with conventional mechanical ventilation from July 1995 to February 1998 were included. Twelve infants survived with HFOV (Responder group), while 11 infants could not maintain oxygenation with HFOV and died (Non-responder group). Clinical record (of each patient) were retrospectively reviewed and compared with the respiratory indices. Mean (A-a)DO2 was significantly lower in the responder group than in the non-responder group at 2 hr after HFOV (p=0.024), and the difference was more remarkable at 6 hr (p=0.005). Death in the patient with (A-a)DO2 over 350 at 2 hr after HFOV therapy was 100% in sensitivity and 80% in specificity. The earliest significant difference of mean a/APO2 between two groups was noted at 6 hr after HFOV treatment (p=0.019). OI showed no significant differences between two groups. In summary, (A-a)DO2 was the most effective and sensitive respiratory index for predicting the responsiveness to HFOV in infants with severe RDS providing due as early as 2 hr.
PMCID: PMC3054615  PMID: 10803690

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