Cover Sheet - Background
- Methods - Results - Discussion
- Characteristics of Included Studies -
References
- Tables & Graphs
Tushar Bhuta and David Henderson-Smart prepared the manuscript.
Intermittent positive pressure ventilation (IPPV) is used for severe respiratory failure in about 0.3% of term infants. Conventional ventilation (CV) is administered with a time cycled pressure limited ventilator providing rates usually in the range of 30 - 80 breaths per minute. This form of IPPV, together with exposure to toxic levels of oxygen, is thought to lead to lung injury and pulmonary morbidity (Clark 2000a). In some infants CV fails to maintain adequate gas exchange and they either die or are treated with extracorporeal membrane oxygenation (ECMO), a more invasive treatment.
Studies have suggested that high frequency oscillatory ventilation (HFOV) is an effective method of providing pulmonary gas exchange in animals with severe pulmonary disease (Truog 1984, deLemos 1987, Gerstmann 1988) and may also reduce the severity lung injury induced by mechanical ventilation. HFOV involves provision of an oscillatory wave form at about 10 Hz, where mean airway pressure determines oxygen transfer and amplitude of oscillation determines carbon dioxide exchange. The waveform is generated with special purpose piston oscillators, flow interrupters or diaphragms.
HFOV has been used for the mechanical ventilation of preterm infants born at less than 35 weeks gestation who have the respiratory distress syndrome (RDS). It has been used electively from the onset of mechanical ventilation or as rescue therapy when conventional ventilation fails (Bhuta 1997, Henderson-Smart 2000).
Uncontrolled rescue studies in term infants (Kohlet 1988, Carter 1990) indicate that HFOV might be of value in neonates with intractable respiratory failure who are candidates for ECMO. In the case series of Carter et al (Carter 1990) fifty term or near term infants were admitted for ECMO. All infants had a PAO2-PaO2 gradient greater than or equal to 600 mm Hg in spite of aggressive conventional ventilatory and pharmacological therapy. All patients were offered HFOV and, if no improvement occurred, were treated with ECMO. Forty-six of the patients were treated with a staged protocol using HFOV before ECMO. Twenty-one of these 46 (46%) responded to HFOV treatment alone and did not require ECMO therapy. There were no statistically significant differences in outcomes with respect to number of ventilator days, hospital days, or survival between patients responding to HFOV and patients who received ECMO. However, morbidity was increased in ECMO patients. Bleeding abnormalities, seizures, and renal failure occurred more frequently than in HFOV treated infants.
Prespecified subgroup analyses.
1) Trials with and without surfactant replacement therapy. Surfactant
therapy would increase alveolar recruitment, and may be beneficial when
used in conjunction with HFOV.
2) Trials with and without high lung volume ventilator strategies. These include the use of higher mean airway pressures, maneuvers to re-inflate the lung after suctioning and weaning of inspired oxygen before pressures.
3) Trials using different ventilators to deliver HFOV.
4) Infants with different lung pathology. These include meconium aspiration, pneumonia, respiratory distress syndrome (RDS), persistent pulmonary hypertension, diaphragmatic hernia.
5) Trials with and without the use of inhaled nitric oxide in conjunction with HFOV or CV.
1) Mortality at 28-30 days, at discharge and in the first year
2) Use of ECMO
3) Days on mechanical ventilation
4) Pulmonary air leak syndromes
Any pulmonary air leak
Gross pulmonary air leak (extra-pulmonary such as pneumothorax)
5) Supplemental oxygen at 28-30 days and at discharge home
6) Evidence of brain pathology on ultrasound, computerized tomography
or other imaging (intraventricular or intracerebral hemorrhage, cysts,
or cerebral atrophy)
7) Days in hospital and costs
8) Respiratory illness or failure (physician attendance or hospital
admissions) in the first year or in later childhood
9) Sensory (hearing and vision), motor and mental development in childhood
Methods used to collect data from the included trials:
Each author extracted data separately, then compared and resolved differences.
Data on the following predetermined endpoints also listed in 'Objectives' were collected: death, use of ECMO, level of respiratory support at 30 days of life, condition at discharge, number of days on ventilator.
Methods used to analyse the data:
The standard method of the Cochrane Neonatal Review Group using relative
risk (RR) and risk difference (RD) and their 95% confidence intervals.
HFOV was carried out with Sensormedics 3100 set at a frequency of 10 Hz, a fractional inspiratory time of 33% and a pressure amplitude sufficient to produce visible chest wall motion. The initial mean airway pressure was set at 1-2 cm higher than CV.
CV was provided with pressure limited, time-cycled ventilators. The target range for PCO2 was 25-35 mm Hg in patients with pulmonary hypertension and in all other patients it was 45 to 55 mm Hg.
Treatment Failure: Patients who failed to respond to the assigned mode of ventilation were crossed over to the alternative mode of ventilation. The criteria for treatment failure were 1) PaO2 less than 65 mm Hg on an FiO2 of 1.0 for 2 hours; 2) PaO2 below the target range for 2 hours; 3) air leak that was severe (more than two chest tubes) or persistent (more than 24 hours) or 4) cardiac impairment on the ventilator settings required to achieve adequate gas exchange.
ECMO criteria: To be considered for ECMO the neonate had to have reversible lung disease and have no evidence of intracranial haemorrhage or coagulopathy. In addition, the neonate had to have one of the following signs of respiratory failure: 1) alveolar-arterial difference greater than 610 mm Hg for eight hours; 2) alveolar-arterial oxygen difference greater than 605 mm Hg and peak pressure of at least 38 cm H2O for four hours; 3) oxygenation index greater than 40 on three of five post-ductal gases obtained at least 30 minutes apart; 4) severe, refractory respiratory failure with sudden decompensation despite maximum medical management for two hours.
Prespecified outcomes.
1) Mortality at 28 days occurred in one of 39 patients in the HFOV group and two of 40 in the CV group [RR 0.51 (0.05, 5.43)].
2) There was a trend towards an increase in the number of patients receiving ECMO in the HFOV group (12/39) compared to the CV group (6/40); however, this was not statistically significant [RR 2.05 (0.85, 4.92)].
3) Median days on ventilator (and range) for all subjects was 8 (3-36) in the HFOV group and 8 (2-28) in the control group.
4) Chronic lung disease, defined as requiring supplemental oxygen at 28 days, occurred in 11 of 39 in the HFOV group and 5 of 40 in the control group [RR 2.26 (0.86, 5.90)].
5) The rates of any intracranial hemorrhage by 28 days or discharge, whichever came first, were similar [RR 0.51 (0.05, 5.43)].
No other pre-specified outcomes were reported in this study. Importantly, there were no post discharge data on long term growth and development. None of the pre-specified subgroup analyses could be performed.
Outcomes that were not prespecified.
1) Failed therapy requiring crossover from assigned mode of ventilation occurred in 17 of 39 in the HFOV group and 24 of 40 in the control group [RR 0.73 (0.47, 1.13)].
2) There was no significant difference in the outcome of 'air leak increased during study' [RR 0.68 (0.21, 2.24)].
3) Median days in oxygen (and range) for all subjects was 12 (3-180) in the HFOV group and 13 (2-55) in the CV group.
4) Median days in hospital (and range) for all subjects was 21 (9-124) in the HFOV group and 22 (7-83) in the CV group.
HFOV is also used in preterm infants to prevent chronic lung disease and is the subject of another review (Henderson-Smart 2000). A recent report of the ECMO Life Support Organization (ELSO) Registry shows that high frequency ventilation is being commonly used before rescue treatment with ECMO (Roy, in press). Additionally, studies of inhaled nitric oxide have suggested that HFOV is important as a lung recruitment tool (Clark 2000b). There is increasing use of HFOV in rescuing infants with respiratory failure.
However, since the early observational studies and the one randomized study included in this review showing no significant effect on outcomes, there have been important changes in the practice of neonatal medicine including increasing use of surfactant, inhaled nitric oxide and other interventions such as inotropic agents. On the background of changing practices it is difficult to tease out confounders and so it is vitally important that controlled trials be done to establish the place of HFOV in these groups of patients.
| Study | Methods | Participants | Interventions | Outcomes | Notes | Allocation concealment |
| Clark 1994 | Multicentre randomised controlled trial. 4 centres. The subjects were stratified according to the admission diagnosis and then randomized. Randomization was blinded. The intervention for obvious reasons could not be blinded. Completeness of follow up: 2 patients were excluded after randomization. The outcomes of head ultrasound and CLD were blinded, however the air leak outcome was not blinded. | Eighty one infants greater than 34 weeks gestation, birthweight equal or greater than 2 kg, less than 14 days of age and requiring > 0.5 FiO2 and mean airway pressure > 10 cms were eligible for the trial. | HFOV. High volume strategy was used, thus oxygen was weaned before mean airway pressure. Frequency was set at 10Hz, pressure amplitude sufficient to produce visible chest motion. CV consisted of time cycled pressure limited IPPV with rates less than 120/min. The goal was to use the lowest possible peak pressures to avoid lung barotrauma. In patients with alkalosis-responsive pulmonary hypertension, the target partial pressure of arterial carbon dioxide was 25 to 35 mm Hg. In other patients it was 45 to 55 mm Hg. | Mortality at 28 days, failed treatment requiring crossover, use of ECMO, CLD at 28 days of age, numbers of days in hospital, on ventilator and on oxygen. | Trial specified use of the alternate treatment following failure of assigned mode of ventilation. Additional information regarding the blinding of randomization and of the outcome of head ultrasound were provided by Dr RH Clark. | A |
| Study | Reason for exclusion |
| Kinsella 1997 | This study was a randomised controlled trial comparing inhaled nitric oxide with high frequency oscillatory ventilation in severe pulmonary hypertension of the newborn. |
Clark RH, Yoder BA, Sell MS. Prospective, randomized comparison of high-frequency oscillation and conventional ventilation in candidates for extracorporeal membrane oxygenation. J Pediatr 1994;124:447-54.
Kinsella JP, Truog WE, Walsh WF, Goldberg RN, Bancalari E, Mayock, DE et al. Randomized, multicenter trial of inhaled nitric oxide and high frequency oscillatory ventilation in severe persistent pulmonary hypertension of the newborn. J Pediatr 1997;131:55-62.
* indicates the primary reference for the study
Bhuta T, Henderson-Smart DJ. Rescue high frequency oscillatory ventilation versus conventional ventilation for pulmonary dysfunction in preterm infants (Cochrane Review). In: The Cochrane Library, Issue 3, 2000. Oxford: Update Software.
Carter JM, Gerstmann DR, Clark RH. High frequency oscillation and extracorporeal membrane oxygenation for the treatment of acute neonatal respiratory failure. Pediatrics 1990;85:159-64.
Clark RH, Slutsky AS, Gerstmann DR. Lung protection strategies for ventilation in the neonate: What are they? Pediatrics 2000;105:112-114.
Clark RH, Keuser TJ, Walker MW, Southgate WM, Huckaby JL, Perez JA, Roy BJ, Keszler M, Kinsella JP, for the Clinical Inhaled Nitric Oxide Research Group. Low dose nitric oxide therapy for persistent pulmonary hypertension of the newborn. N Engl J Med 2000;342:469-474.
deLemos RA, Coalson JJ, Gerstmann DR et al. Ventilatory management of infant baboons with hyaline membrane disease; the use of high frequency ventilation. Pediatr Res 1987;21:594-602.
Gerstmann DR, deLemos RA, Coalson JJ et al. Influence of ventilatory technique on pulmonary baroinjury in baboons with hyaline membrane disease. Pediatr Pulmonol 1988;5:82-91.
Henderson-Smart DJ, Bhuta T, Cools F, Offringa M. Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants. In: Cochrane Library, Issue 3, 2000. Oxford: Update Software.
Kohlet D, Perlman M, Kirpalani H. High frequency oscillation in the rescue of infants with persistent pulmonary hypertension. Crit Care Med 1988;16:510-16.
Roy BJ, Rycus P, Conrad SA, Clark RH. The changing demographics of neonatal ECMO patients reported to the ELSO Registry. Pediatrics (in press).
Truog WE, Standaert TA, Murphy JH et al. Effects of prolonged high frequency oscillatory ventilation in premature primates with experimental hyaline membrane disease. Am Rev Respir Dis 1984;130:76-80.
Reese H Clark
Research Director
Pediatrix Medical Group Inc.
1455 North Park Drive
Fort Lauderdale
Florida USA
33326
Telephone 1: +1 954 384 0175
Facsimile: +1 954 838 9954
E-mail: Reese_Clark@pediatrix.com