Studies assessing short- and long-term respiratory outcomes of high-frequency oscillatory ventilation (HFOV) compared to conventional ventilation (CV) for acute pulmonary dysfunction in preterm infants

First author [ref.]Patients nBirthweight; GAAge at time of study#MethodsPrimary outcomeResultsCriticisms
HIFI trial
Rigatto [28]673 (346 CV + 327 HFOV)750–2000 g; 24–31 weeks (mean 28 weeks)Neonatal periodMulticentre (11 centres) RCT. Patients assigned within 12 h of life to HFOV (low-volume strategy) or CV (intermittent mandatory ventilation)Death or BPD (need for oxygen and pathological radiography at 28 days)No differences in BPD, mortality or level of ventilation support in the two groups. Increased incidence of IVH, PVL and pneumoperitoneum in HFOV groupMany centres had no experience with HFOV. No strategies to optimise lung volume on HFOV and CV, or antenatal steroids, or surfactant were used. Infants relatively mature
Rigatto [30]223 (118 CV + 105 HFOV)As above9 monthsNot detailed; only abstract availableRespiratory morbidity and functionNo differences between the two groups in growth, respiratory morbidity and mechanics (FEF, peak-to-peak oesophageal pressure, compliance and resistance)As above
Mannino [29]673 (346 CV + 327 HFOV)As above2 yearsNot detailed; only abstract availableRespiratory morbidity and neurodevelopmental outcomeNo differences between the two groups in survival, growth and respiratory morbidity. Worse neurodevelopmental outcome in the HFOV group (hydrocephalus, Bayley score)As above
Pianosi [31]32 (20 CV + 12 HFOV) + 15 term controlsAs above8–9 yearsObservational study. PFT: lung volumes, FEF rates and single-breath DLCO, in a body plethysmograph; repeated after salbutamolRespiratory functionMildly obstructive pattern in children born preterm and with asthma. No difference of pulmonary function in two groups of ventilation mode or between children with or without neonatal BPDAs above
UKOS trial
Johnson [39]797 (397 CV + 400 HFOV)Mean 705 g at 23–25 weeks; mean 930 g at 26–28 weeksNeonatal periodMulticentre (25 centres) RCT. Patients assigned within 1 h of life to CV (time-cycled, PLV) or HFOV (high-volume strategy). Administration of antenatal steroids and surfactant therapy (no specified dose)Death or BPD (dependence on supplemental oxygen at 36 weeks PMA)No significant difference in the two groups in terms of death or BPD and secondary outcomesInfants received HFOV for a median 3 days, then the majority were switched to CV for weaning. Protective strategies of CV (triggered modes and volume-targeted ventilation) were not used
Thomas [38]76 (34 CV + 42 HFOV)As above1 year (11–14 months)Single-centre, observational study. PFT: tidal breathing spirometry, whole-body plethysmography and helium dilutionRespiratory functionNo significant difference in pulmonary function in HFOV and CV groups: FRC, RR and inspiratory/expiratory airway resistanceSample size fell below the statistical target. Unequal group sizes. Tests of small airway function were not assessed
Marlow [37]428 (217 CV + 211 HFOV)As above2 years (22–28 months)Multicentre (25 centres), observational trial. Routine assessments by local paediatricians and parental questionnaireRespiratory morbidity and neurodevelopment outcomeMode of ventilation had no effect on respiratory morbidity (wheeze, cough, inhaled medication and readmission to hospital) and neurological outcomesThe low response rate (73% of survivors) could introduce bias; however, the perinatal variables between the two groups were similar
Zivanovic [36]319 (159 CV + 160 HFOV)As above11–14 yearsMulticentre (23 centres), observational trial. PFT: spirometry, impulse oscillometry, plethysmography, multiple-breath, helium-dilution, single-breath techniques, fraction of exhaled nitric oxide. Family history of asthma, skin-prick test. Questionnaires to children, parents and teachers: behavioural and academic achievement and quality of lifeRespiratory function and morbidity. Primary outcome: small airway function by measure of FEF75The two groups had similar respiratory morbidity. HFOV group had significantly superior lung function: FEF25, FEF50, FEV1, FEV1/FVC ratio, FVC, VC, PEF, diffusing capacity and impulse-oscillometric findings. The HFOV group was rated significantly higher in three school subjects: art and design, information technology and design and technologyChildren recruited were more likely to have a mother who was white and who did not smoke during pregnancy. The CV group had had a higher mean birthweight and GA and were more likely to have received surfactant. Full health assessment was possible in only 248 patients of the 319 enrolled
Provo multicentre trial
Gerstmann [33]125 (61 CV + 64 HFOV)Mean 1510 g; <36 weeks (mean 30.9 weeks)Neonatal periodMulticentre (three centres), prospective RCT. Patients assigned within 12 h of life to HFOV (high-volume strategy) or CV (time-cycled, PLV, not synchronised). Surfactant administration (100m g·kg−1 dose)Death or BPD (defined on clinical parameters at 30 days of life and discharge oxygen use and level)HFOV demonstrated less vasopressor support, surfactant redosing, oxygen or ventilator support, treatment failure, BPD, NEC, hearing abnormality and hospital costs. No differences between the two study groups in other secondary outcomes (PDA, air leak, ROP, IVH, length of hospitalisation and survival)Surfactant dose of 100 mg·kg-1. Only 24% received antenatal steroids. Few immature newborn, only 21 patients weighed 1000 g. No attempt was made to minimise tidal breathing before initiation of HFOV. CV not synchronised and without VT guarantee. Many infants who failed CV were changed to HFOV for rescue
Gerstmann [24]69 (33 CV + 36 HFOV)As above6.4 yearsSingle-centre study. PFT: whole-body phlethysmography, spirometry, single-breath technique, bronchodilation challenge. Mental and motor testing, social and health questionnairesRespiratory function and morbidity. Neurodevelopmental outcomesCV group had significantly poorer pulmonary function: decreased PEF, increased RV and greater maldistribution of ventilation. No differences between the two groups for pulmonary morbidity and neurodevelopment outcomesSample size. Larger percentage of infants in the HFOV group were exposed to household smoking
Hofhuis [35]36 (18 CV + 18 HFOV)<1250 g (mean 837 g); mean 26.8 weeks6 months and 12 monthsSingle-centre study. Inclusion criteria: 1) VLBW; 2) need for CV/HFOV from day 1 for ≥7 days; 3) need for supplemental oxygen at 28 days and/or at 36 weeks GA; 4) chest radiograph at 1 month. Surfactant (100 mg·kg−1 dose) and dexamethasone administered. PFT: rapid thoracoabdominal compression technique, whole-body plethysmographyRespiratory function. Primary outcomes: FRC and VmaxFRCVLBW infants with BPD have decreased VmaxFRC that worsens during the first year of life. At 12 months, the mean VmaxFRC was lower for children treated with CV, which may reflect abnormal development of airways. FRC was within the normal rangeVentilation strategy was not randomised. No description of the ventilation mode. Excluding very preterm neonates who did not develop BPD. In HFOV group, infants had lower birthweight and received fewer doses of surfactant
Lista [32]40 (19 CV + 21 HFOV)<1250 g (mean 1010 g); 25–32 weeks (mean 27 weeks)Neonatal periodSingle-centre RCT. A/C ventilation plus VG versus HFOV (high-volume strategy). Patients randomised within 1 h of life, maintained until the 96th hour (when neonates in HFOV started switching to A/C and then breathing spontaneously). Antenatal steroids and surfactant (200 mg·kg−1 dose) administeredPulmonary inflammation (IL-6, IL-8 and TNF in tracheal aspirate on days 1, 3 and 7 of life) and respiratory outcome (short term)In the HFOV group IL-6 levels were significantly higher on day 3 and duration of oxygen dependency was significantly longer. No significant differences were observed in duration of ventilation, surfactant administration, PVL, IVH, ROP, BPD or mortality between the two groupsRelatively small sample size. Early crossover from HFOV to A/C+VG ventilation
Lista [7]25 (13 CV + 12 HFOV)As above7 yearsObservational study. PFT: whole-body plethysmography, spirometry and reversibility test. Only non-BPD infants were enrolledRespiratory function and morbidityNo differences between the two groups for respiratory disorders and obstructive deficit (elevated values of airway resistance, RV and TLC)Small number of patients. Only infants without BPD were involved

GA: gestational age; HIFI: High-Frequency Ventilation in Premature Infants; UKOS: United Kingdom Oscillatory Study; RCT: randomised controlled trial; BPD: bronchopulmonary dysplasia; IVH: intraventricular haemorrhage; PVL: periventricular leukomalacia; FEFn: forced expiratory flow at n% of the forced vital capacity (FVC); DLCO: diffusing capacity of the lung for carbon monoxide; PLV: pressure-limited ventilation; PMA: postmenstrual age; PFT: pulmonary function test; FRC: functional residual capacity; RR: respiratory rate; FEV1: forced expiratory volume in 1 s; VC: vital capacity; PEF: peak expiratory flow; NEC: necrotising enterocolitis; PDA: patent ductus arteriosus; ROP: retinopathy of prematurity; VT: tidal volume; RV: residual volume; VLBW: very low birthweight; VmaxFRC: maximal flow at FRC; A/C: assist-control; VG: volume guarantee; IL: interleukin; TNF: tumour necrosis factor; TLC: total lung capacity. #: ages at the study time are given in corrected age.