High Frequency Ventilation
Keyword : Conventional mechanical ventilation; High frequency ventilation; Pulmonary injury sequence; Tidal volume ventilation
The use of positive pressure mechanical ventilation in newborn intensive care has led to dramatic improvement in the outcome of infants with pulmonary disease, especially respiratory distress syndrome (RDS).1 As more premature infants have survived, more lung injury and chronic lung disease has been seen. In 1967, Northway and colleagues described an association between chronic lung disease and positive pressure ventilation which they called bronchopulmonary dysplasia (BPD).2 Although oxygen, pressure, and time all play a role in the etiology of BPD,3 much of the research efforts in this area over the past twenty years have focused on the creation of equipment which would oxygenate and ventilate at lower mean airway pressures.
High frequency ventilation (HFV) uses ventilatory devices which accomplish adequate alveolar ventilation with very small tidal volumes and rapid rates. Gas exchange with these devices relies on facilitated diffusion rather than bulk flow. HFV in neonates began with the use of conventional neonatal ventilators turned to maximum rates. This is called high frequency positive pressure ventilation (HFPPV). Currently used high frequency ventilatory devices can be divided into three categories:
Flow interrupters deliver a jet of gas which is interrupted proximal to the endotracheal tube of the patient. Jet ventilators introduce a jet of gas through a separate lumen of the endotracheal tube directly into the patient's airway. Oscillators utilize a piston which moves back and forth in a bias flow circuit in direct communication with the patient. Although we talk about HFV as a single entity, the differences between ventilators in these categories can be as remarkable as the differences between HFV and conventional mechanical ventilation (CMV).
During the past decade, our group has been actively involved in research using HFOV in newborns. This paper will review the basic concepts in our understanding of lung injury and then explore ways that HFOV, using an appropriate strategy, may interrupt or prevent the pulmonary injury sequence.
Development of High Frequency Ventilation
CMV delivers a large convective flux of mixed gas to eliminate carbon dioxide, establish an adequate gas exchanging volume and reduce pulmonary capillary shunting. This form of mechanical ventilation mimics spontaneous breathing and has been called tidal volume ventilation. In 1959, Mead and Collier showed that without periodic inflations or sighs, which provide lung volume recruitment, there was a progressive fall in compliance during prolonged mechanical ventilation.4 Since the introduction of the concept of lung volume recruitment, clinicians have been searching for better methods of maintaining lung volume during acute lung disease. To achieve adequate lung volume recruitment the lung must be inflated above the pressure at which atelectasis begins to resolve and then be maintained above the closing pressure of alveoli and airways. CMV uses end expiratory pressure and repetitive large convective flows to achieve lung volume recruitment. The pressure/volume costs of this form of ventilation in order to normalize physiology can become considerable. In contrast, HFOV extends our options for lung volume recruitment well beyond those attainable with CMV.
HFOV has been shown to be an effective method of ventilation and oxygenation in experimental animals with and without lung disease and in neonates with respiratory failure.5-13 In HFOV, continuous distending pressures (CDP) greater than those tolerated with CMV can be used without exposing the lung to high peak pressures. This can be accomplished while using tidal volumes less than dead space, delivered at supraphysiologic ventilatory frequencies.
The goals of HFOV use are:
In the 1970's HFOV was experimental and used only as a rescue device.6 It proved to be very successful in ventilating babies with airleak syndrome by allowing adequate oxygenation and ventilation at low mean airway pressures. This use was prompted by the desire to prevent ongoing airleak and chronic lung disease. This strategy was called the low lung volume strategy. Timing of intervention varied tremendously and comparison of devices and strategies was difficult.
In the 1980's, human and animal studies were undertaken to evaluate the usefulness of HFOV as an early intervention device in managing RDS.5,8,12-15 Although RDS is a diffuse atelectatic lung problem, some investigators continued to use low lung volume strategies and did not find any significant benefit from HFOV. With the publication of the HiFi Study in 198914 and its report of an increased incidence of intracranial hemorrhage with HFOV, many groups lost their enthusiasm for early use of HFV. However, Froese reported that by using an optimal lung volume strategy, significant benefits from the early use of HFOV could be seen in RDS.9,10,15
In any method of assisted mechanical ventilation, a disease specific ventilatory strategy is essential in achieving optimal pulmonary outcome. Appropriate ventilatory strategies need to consider the specific ventilator design, the underlying pulmonary pathophysiology, the therapeutic goals, and the potential side effects.
Pulmonary Injury Sequence
The many associated problems which occur with assisted mechanical ventilation have generally been referred to as separate clinical diseases. We think of respiratory distress syndrome (hyaline membrane disease), pulmonary interstitial emphysema, gross airleak, oxygen toxicity, and chronic lung disease (bronchopulmonary dysplasia) as separate clinical diagnoses. Through the use of animal models of lung injury we have come to understand that these many complications of mechanical ventilation are in fact a spectrum of lung injury. By better understanding this continuum we can develop a more rational therapeutic approach with a disease specific treatment strategy.
Tidal volume breathing refers to the bulk flow of gas through the upper and secondary airways, filling the dead space and moving gas into the air exchange areas of the lung. This is the normal method of breathing for newborn infants. The flow begins turbulently in upper airways, becomes more laminar in lower airways, and finally becomes diffusive in the alveoli. Conventional mechanical ventilators from their inception have used tidal volume breaths to deliver a bulk flow of gas from the ventilator through a bias flow circuit into the patient.
The premature newborn has surfactant deficient immature lungs. The spectrum of lung injury actually begins as the infant attempts to fill these atelectatic, surfactant deficient lungs with tidal volume breaths (Table I). Because of the severe alveolar collapse, the airway compliance is much greater than alveolar compliance. As the infant struggles to establish a functional residual capacity, airways are distended and stretching occurs. This stretching of immature airways results in the first step in lung injury through stretch and distortion of the airway tissues. This stretching continues and progresses as gaseous tidal volumes are distributed heterogeneously within the surfactant deficient lung. This continued movement of gas along the lowest flow resistant pathways tends to result in distribution of air to the more compliant areas of the lung leaving the non-expanded gas exchange units relatively atelectatic. As further airway stretch and dilatation occurs, there is membrane distortion and fracture of intercellular tight junctions. This is the beginning of airway injury at the microscopic level. This epithelial and endothelial injury results in the creation of proteinaceous edema fluid which leads to the formation of hyaline membranes. Thus the typical pathology of hyaline membrane formation with areas of atelectasis and overexpansion of the distal conducting airways gives the radiologic and pathologic appearance so commonly seen in RDS.
Edema fluid protein may further inactivate surfactant, resulting in a progression of this disease with worsening atelectasis. These changes result in the necessity of increasing mean airway pressure as well as inspired oxygen in order to achieve adequate inflation and gas exchange.
This continuum of injury progresses from the microscopic to the macroscopic level with the rupture of distal airways that are being overinflated. The gas which escapes from the airways results in pulmonary interstitial emphysema (PIE) and the appearance of macroscopic barotrauma. Unhalted, airleak continues with the eventual development of gross airleak in the form of pneumomediastinum, pneumothorax, pneumopericardium, or pneum-operitoneum. This dramatic gross airleak will result in further compromise of pulmonary function and gas exchange requiring higher oxygen needs and subsequent oxygen toxicity. The oxygen cytotoxic injury contributes and adds both to the micro and macro barotrauma injury which is already present. In addition, mediator release and activation contribute to the ongoing injury of oxygen toxicity.
The onset of the reparative process as these immature lungs attempt to heal themselves is the beginning of the development of an abnormal airway and parenchymal architecture with corresponding abnormalities in pulmonary function. These chronic changes in the pulmonary parenchyma including interstitial thickening, airway dysplasia, abnormal architecture, and abnormal pulmonaly function, are representative of BPD. The pulmonary injury which occurs, whether it be from the child's own respiratory effort or from CMV follows this specific sequence in the premature infant (Table II).
Prevention of the Pulmonary Injury Sequence
Understanding that injury to the lungs of a premature infant begins immediately after birth and progresses sequentially, brings the question: Can the injury sequence be prevented or interrupted? Prevention would be ideal since once injury is established, therapy will not be curative. Even appropriate ventilator strategies will only be supportive to the extent that injury does not continue. Two possible ways to prevent the pulmonary injury sequence in premature infants are:
Correction of surfactant deficiency
The correction of surfactant deficiency through exogenous surfactant replacement therapy has been a very thoroughly studied therapeutic advance in the field of neonatology.16-20 The use of surfactant has been shown to improve gas exchange and decrease mortality and morbidity amongst immature newbom infants. The ability of this intervention to prevent chronic lung disease and subsequent pulmonaly injury, however, is less well established. At the present time it does not appear that surfactant replacement alone will be sufficient in preventing chronic lung disease related to prematurity. The reasons for the inability of surfactant to do this are unclear but may include:
Elimination of tidal volume ventilation
The second method by which the pulmonary injury sequence may be prevented is through the use of ventilatory devices which can achieve gas exchange without tidal volume breathing. The concept of elimination of tidal volume breathing has been approached in two different ways.
The first approach has been to place the newborn on some form of continuous positive airway pressure and lung bypass immediately after birth. Although this is done for larger critically ill newborns with severe respiratory failure not responsive to other interventions, it is much too invasive to consider in all newborn infants. It was, however, shown to be effective in the laboratory by Kolobow, et al, using the lamb model.21 In his studies he showed that the development of hyaline membrane disease (HMD) could be stopped by the use of immediate bypass in newborn preterm animals.
The second approach is to use HFOV to prevent the pulmonary injury sequence. In 1989, Meredith, et al, using premature baboons, demonstrated that surfactant deficient premature animals ventilated with HFOV from birth using an appropriate lung volume strategy, could be protected from developing HMD in the first 24 hours of life.22 This was in contrast to conventionally ventilated baboons who developed severe HMD after only 24 hours of assisted ventilation. Significant improvements were noted in the HFOV group with respect to clearing of chest radiographs, oxygenation, pulmonary mechanics, and pulmonary pathology. Not only did the CMV group have airway dilatation, saccular atelectasis, and typical hyaline membranes at necropsy, but they consistently required 80 percent oxygen by 24 hours of age. Thus it appears that immediate institution of HFOV prevented the development of early lung injury in these animals.
Prevention of Lung Injury with HFOV
In 1990, Jackson, et al, published data on ten premature monkeys also treated with immediate institution of HFOV.23 Although the study duration with these animals was only six hours, the investigators noted rapid clearing of chest x-rays and improved oxygenation in those treated early with HFOV. Evaluation at necropsy also revealed decreased alveolar proteinaceous fluid and increased numbers of air versus fluid filled saccules in the animals ventilated with HFOV.
These studies in animals demonstrate that the use of a ventilatory strategy that maintains intrapulmonary pressure above alveolar closing pressure can successfully alter the development of early pulmonary injury. The result is significant recruitment and maintenance of lung volume which markedly improves gas exchange. The use of such lung inflating strategy has been called a high lung volume strategy to distinguish it from the low lung volume strategies which are often used to minimize barotrauma. This strategy should more appropriately be termed the optimal lung volume strategy. The real intent of this strategy is not to overinflate the lungs or have them highly inflated, but to have them optimally inflated.
Human studies7,11,24,25 have been published, are in press, or are currently being done using HFOV as primary intervention in the management of RDS. These studies show remarkable evidence of decreased lung injury when HFOV is initiated early to prevent or interrupt the pulmonary injury sequence.
In 1992, Clark published an early intervention study, which looked at 83 infants divided into three groups: CMV, HFOV with early weaning to CMV, and HFOV alone.7 The purpose of these two HFOV groups was to evaluate the process of weaning from HFOV. By chance patients with more severe disease were randomized to the two HFOV groups. Patients in the early weaning groups were typically treated with HFOV for three to four days whereas for the other HFOV group treatment on this ventilator continued for approximately seven days. Mortality and non-pulmonary morbidity were the same for all groups. The most significant finding of this study was the reduction of the incidence of BPD at 30 days and 36 weeks post-conceptual age in the HFOV only group. The group of patients on HFOV who were weaned early appeared to have intermediate benefit with a reduction in the incidence of BPD. These improvements with HFOV occurred despite the fact that patients with more severe pulmonary disease were randomized to the HFOV groups.
In 1992, Minton, et al, published data on 176 patients with severe respiratory failure treated with continued CMV or intervention with HFOV.11 This study, termed the HiFo study, initially was undertaken to be an early intervention study. The mean age of entry into the study, however, was 22 hours. The authors found significant improvement in oxygenation and ventilation in the group of patients treated with HFOV compared to patients treated with CMV. Additionally in those patients without preexisting airleak, significantly fewer patients developed airleak syndrome when treatment was changed to HFOV.
In 1990, Ogawa reported on premature infants receiving HFOV and surfactant replacement therapy.24 This study consisted of 51 premature infants most of whom had received surfactant prior to the initiation of mechanical ventilation. There was a lower incidence of BPD in the group of infants given surfactant followed by HFOV. Although this was not statistically significant at their sample size, subsequent studies have continued to show beneficial effects of this concomitant use of surfactant and HFOV.
In 1996, Gerstmann, et al, published the Provo Multicenter Study which looked at the use of HFOV with the SensorMedics 3100 high frequency oscillator along with surfactant replacement therapy and compared it to CMV with surfactant replacement therapy.25 This study looked at multiple comparisons between the two groups and found no benefit from CMV in any category. In addition there were many statistically significant improvements seen in the group placed on HFOV. Among those were a decreased incidence of BPD and a significant cost/benefit from the early use of surfactant replacement and HFOV. This study further verified the safety and efficacy of this intervention and the need for the use of an optimal lung volume strategy when treating premature infants with RDS.
Potential complications with HFOV include necrotizing tracheobronchitis, focal obstruction: mucous impaction, over-inflation of the lung, impaired cardiac output, and intracranial hemorrhage. These are the same complications seen in CMV.
The transition to using HFOV as a primary mode of treatment for premature lung disease has required a major change in management strategy. Meredith and co-workers determined that a higher mean airway pressure (optimal or high lung volume strategy) was needed with HFOV versus CMV to achieve acceptable blood gases in baboons.22 However, earlier human trials including the multicenter HiFi Study, simply used existing conventional ventilator strategies with a high frequency device.14 The general presumption was that high pressure (regardless of lung inflation) was bad for the lungs. In addition it was assumed that any benefit from HFOV must come from its unorthodox method of gas exchange.
More recent research in HFOV has focused on an optimal lung volume strategy for primary use in newborns.7,10,11,24,25 By increasing mean airway pressure, attaining optimal lung volume rapidly and then preventing both atelectasis and overdistention from happening, many institutions are now using HFQV as their primary early intervention ventilator. When an appropriate strategy is used, no study has shown any benefit from CMV over HFOV and some studies have demonstrated multiple benefits from HFOV.7,11,25 Randomized controlled human clinical trials would support the early use of HFQV and surfactant replacement therapy as a primary intervention in the treatment of premature infants with RDS.
Treatment of Lung Injury with HFOV
If the pulmonary injury sequence cannot be prevented it may in fact be interrupted at various stages along its progression. A series of premature baboon experiments by deLemos, et al, examined the effectiveness of the institution of HFOV following development of significant pulmonary injury after eight (8) hours of CMV.26 Significant time related improvements in oxygenation accompanied the institution of HFQV. All animals had morphologic evidence of HMD at 24 hours of age, although there was more uniform saccular aeration and less small airway dilatation in the HFOV intervention group. The authors conclude that HFOV did not reverse the pulmonary injury that had occurred during the initial eight (8) hours of tidal volume ventilation, but that the progression of injury appeared to have been interrupted.
In 1986 Clark, et al, published work describing the use of HFOV in the rescue of 27 premature infants who had developed PIE and ventilatory failure on CMV.6 The average age at intervention with HFOV was 96 hours. Although no control group was included, surviving patients had immediate improvement in blood gas parameters with the ability to decrease inspired oxygen concentrations and mean way pressure. PIE resolved, but non-survivors developed chronic pulmonary insufficiency from which recovery was not possible.
Tidal volume breathing is the normal method of breathing for all human beings. It is also the type of breathing used in assisted CMV and appears to play an important role in the pulmonary injury sequence which presents in the premature surfactant deficient lung. The length of time necessary for injury to occur is uncertain but may be as little as minutes or hours. It appears that the continued use of tidal volume ventilation results in progressive pulmonary injury that could be prevented. Currently, it appears that pulmonary injury may be preventable, but would require the early use of surfactant replacement and HFQV.
Appropriately used, HFOV is safe and effective in the management of many newborn lung diseases. Rescue use in existing lung injury has prevented the need for ECMQ in almost 50% of patients who otherwise qualify. Its use in persistent airleak has shown remarkable results. Outcome with HFOV in congenital diaphragmatic hernia and pulmonary hypoplasia has been more treatment center dependant. In some situations patients can be weaned to CPAP and extubated directly from HFOV, however, the ideal time to transition to CMV remains to be determined.
If pulmonary injury already exists, intervention with HFOV appears to prevent further injury but does not reverse the existing injury. It is therefore worthwhile to intervene early to interrupt the progression of injury perpetuated by tidal volume breathing. Early institution of HFOV with an optimum lung volume strategy along with the concomitant use of exogenous surfactant replacement therapy appears to be the best method to prevent the pulmonary injury sequence. This approach has become standard in many institutions throughout the world.
The authors would like to thank Ms Cynthia Exdsell for her clerical assistance in the preparation of the manuscript.
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