- Email: [email protected]
Can mechanical ventilation strategies reduce chronic lung disease?
Seminars in Neonatology (2003) 8, 441–448
Seminars in NEONATOLOGY www.elsevierhealth.com/journals/siny
Can mechanical ventilation strategies reduce chronic lung disease? Steven M. Donn a*, Sunil K. Sinha b a
The Division of Neonatal–Perinatal Medicine, Department of Pediatrics, C.S. Mott Children's Hospital, University of Michigan Health System, Ann Arbor, MI, USA b University of Durham and The James Cook University Hospital, Middlesbrough, UK Received 1 June 2003; accepted 1 July 2003
KEYWORDS Mechanical ventilation; Chronic lung disease; Prematurity; Respiratory distress syndrome
Summary Chronic lung disease (CLD) continues to be a significant complication in newborn infants undergoing mechanical ventilation for respiratory failure. Although the aetiology of CLD is multifactorial, specific factors related to mechanical ventilation, including barotrauma, volutrauma and atelectrauma, have been implicated as important aetiologic mechanisms. This article discusses the ways in which these factors might be manipulated by various mechanical ventilatory strategies to reduce ventilator-induced lung injury. These include continuous positive airway pressure, permissive hypercapnia, patient-triggered ventilation, volume-targeted ventilation, proportional assist ventilation, high-frequency ventilation and real-time monitoring. © 2003 Elsevier Ltd. All rights reserved.
Introduction Advances in neonatal intensive care and mechanical ventilation over the past 25 years have extended the survivability of premature infants to 24 weeks' gestation, and occasionally even earlier. Unfortunately, the developing lung is a delicate structure and is easily injured by the therapies necessary to sustain life outside the womb. Thus, an increasing number of infants are surviving with chronic lung disease (CLD). CLD, also referred to as bronchopulmonary dysplasia (BPD), was first described by Northway et al. in 1967 in 13 infants surviving hyaline membrane disease after mechanical ventilation. Their gestational ages ranged from 30 to 39 weeks and their birth weights ranged from 1474 to 3204 g.1 It has been estimated that 30–40% of preterm infants requiring mechanical ventilation will develop CLD, and that there are 7500 new cases each year in the USA.2 * Corresponding author. Tel.: +1-734-763-4109; fax: +1-734-763-7728 E-mail address: [email protected] (S.M. Donn).
The precise aetiology of CLD remains unknown. In 1975, Philip suggested that oxygen, positive pressure ventilation (PPV) and time were responsible for its causation,3 and over subsequent decades, other factors, including inflammatory mediators, have also been implicated. The terms ‘barotrauma’ (implying injury caused by pressure), ‘volutrauma’ (implying injury caused by excessive tidal volume delivery) and, most recently, ‘atelectrauma’ (implying injury caused by alveolar collapse) have been applied to an overall concept of ‘ventilator-induced lung injury’ (VILI).4 As mechanical ventilation became more sophisticated, and as clinicians encountered choices beyond the traditional time-cycled, pressurelimited (TCPL) intermittent mandatory ventilation (IMV), which characterized the first three decades of the management of neonatal respiratory failure, the concept of lung-protective strategies began to evolve. The advent of exogenous surfactant therapy removed one of the major pathophysiologic abnormalities of respiratory distress syndrome (RDS), and focused attention on ways to avoid
1084-2756/03/$ - see front matter © 2003 Elsevier Ltd. All rights reserved. doi:10.1016/S1084-2756(03)00124-6
442
VILI by applying PPV more safely to the developing lung. This review discusses ventilatory strategies aimed at protecting the premature neonatal lung and reducing the incidence of CLD. It is not meant to be exhaustive, but rather a summary of the approaches that have been used to counteract this increasing problem. There is not yet enough evidence-based data to make specific recommendations, but it is the authors' hope that this review will provide a stimulus for further clinical investigation.
Pathophysiology of respiratory distress syndrome RDS is a disorder of the premature lung, characterized by biochemical and morphological immaturity. The lack of pulmonary surfactant leads to increased alveolar surface tension and a tendency for alveolar collapse, progressive atelectasis and decreased compliance. The pulmonary histology and cytoarchitectural abnormalities include: insufficient alveolarization, decreasing the surface area available for gas exchange; an increased distance between the alveolus and its adjacent capillary, impairing the diffusion of oxygen; increased capillary permeability, leading to fibrin deposition in the air spaces and impeding gas exchange; and, in some cases, excessive muscularization of the pulmonary arterioles, resulting in pulmonary hypertension and reduced pulmonary blood flow. In addition, the premature newborn has increased chest wall compliance, which further complicates pulmonary mechanics.5
Goals of mechanical ventilation The use of either continuous distending pressure (CDP) or PPV is aimed at overcoming alveolar atelectasis and achieving sufficient lung expansion to facilitate adequate pulmonary gas exchange, while reducing the infant's work of breathing. This needs to be accomplished without excessive pressure, volume or flow, while maintaining a normal functional residual capacity and avoiding atelectasis. Complications of mechanical ventilation are well documented, and include injury to the structures of the airway from endotracheal tubes, thoracic air leaks, pneumonia and, as mentioned, CLD.6
S.M. Donn and S.K. Sinha
range of choices for managing infants with respiratory failure. These range from continuous positive airway pressure (CPAP) to extracorporeal membrane oxygenation (ECMO). Even within the genre of conventional mechanical ventilation (CMV), multiple forms and modes of ventilation now exist.
‘Conservative’ techniques Continuous positive airway pressure CPAP, a form of CDP, was first introduced by Gregory et al. in 1971,7 and is usually applied by nasal prongs. It is used in spontaneously breathing infants to maintain a degree of alveolar inflation during expiration, to prevent collapse and to decrease the work of breathing.8 This technique was frequently used in the 1970s as the initial strategy in the management of RDS, but it was gradually supplanted by the use of mechanical ventilation in the presurfactant era, when it was used primarily as an adjunctive postextubation therapy. Based largely on the observational work of Wung et al. in the late 1970s and early 1980s, there was a resurgence of interest in CPAP as a primary modality for treating RDS.9 These investigators reported a dramatically decreased incidence of CLD using a very conservative strategy, which included dependence on spontaneous breathing, avoidance of sedatives and paralytics, and acceptance of blood gas and pH values at the limits of physiological norms. The ‘Columbia experience’ has been compared historically with other approaches that rely more on mechanical ventilation and, indeed, a significant reduction in the incidence of CLD has been apparent.10 Wung et al.'s observations have led to additional experiences with CPAP, but have also raised a number of questions because their work did not include a randomized, controlled trial or long-term follow-up studies. It also appears that all CPAP devices are not equivalent, and that there may be an advantage to using CPAP generated by an underwater seal (‘bubble CPAP’).11 Questions for further investigation include the following: • Does the use of CPAP in infants who subsequently do not respond delay surfactant administration, thus increasing morbidity? • Is the work of breathing with CPAP a significant caloric expense compared with mechanical ventilation?
Ventilatory strategies
Permissive hypercapnia
The proliferation of technology in neonatal intensive care has provided the clinician with a wide
The strategy of ventilating infants at a higher PaCO2 level, termed permissive hypercapnia, appears to
Mechanical ventilation and chronic lung disease
be based upon the report of Kraybill et al. in 1989.12 In a multicentre analysis of 235 preterm infants, these investigators demonstrated a higher incidence of CLD in infants with low PaCO2 on the second and fourth postnatal days.12 The rationale for permissive hypercapnia, using a low lung volume strategy, is that it may decrease volutrauma and lung injury, lessen the duration of mechanical ventilation, reduce alveolar ventilation and the complications of hypocapnia (especially reduced cerebral blood flow), and increase oxygen unloading at the tissue level (Bohr effect).13 Two prospective, randomized, controlled trials of permissive hypercapnia have been conducted. Although both studies demonstrated a significant reduction in the duration of ventilation and other secondary outcome measures, the incidence of CLD did not differ significantly between groups.14,15 Further investigation is necessary to address both the safety and efficacy of this intriguing strategy.
Conventional mechanical ventilation For nearly three decades, CMV consisted of TCPL IMV. This form of ventilation was easy to use and resulted in consistent delivery of PPV, although delivered tidal volumes were a function of pulmonary compliance. An early attempt to provide volume-cycled ventilation did not succeed because of technological limitations.16 During TCPL IMV, all ventilator parameters are set by the clinician, although the baby is able to breathe spontaneously from continuous bias flow in the ventilator circuit, but respiration is supported only by positive endexpiratory pressure (PEEP). One of the major problems with IMV is the development of patient-ventilator dyssynchrony. Babies may try to exhale against PPV, resulting in inefficient gas exchange, gas trapping and air leaks, and the need for higher levels of support.17 An association between dyssynchrony and intraventricular haemorrhage has also been reported.18 During the 1990s, microprocessor-based ventilators and sophisticated, sensitive transducers were developed that had the capability of detecting spontaneous respiratory activity. Patient-triggered ventilation (PTV) was introduced into neonatal respiratory care during this decade. Modes of ventilation utilizing PTV include synchronized intermittent mandatory ventilation (SIMV), assist/control (A/C) ventilation, and pressure support ventilation (PSV). Transducers detect some measure of respiratory effort, such as changes in thoracic or abdominal impedance or changes in airway pressure or flow, and respond with a mechanical breath timed to begin almost immediately after the
443
initiation of the patient's breath. Thus, the onset of inspiration between the baby and the ventilator is synchronized.19
Synchronized intermittent mandatory ventilation In SIMV, the clinician selects a mandatory rate of ventilation. Each time the baby is ‘due’ to receive a breath, the ventilator waits briefly for the infant to initiate a breath. If the baby breathes within this ‘timing window’, a mechanical breath will be matched to the onset of spontaneous breathing. If the baby fails to breathe, the ventilator will cycle ‘on schedule’. In between mechanical breaths, spontaneous breathing is supported by PEEP. Only mechanical breaths can be fully supported.19
Assist/control ventilation In A/C ventilation, all spontaneous breaths that exceed the trigger threshold result in the delivery of a mechanical breath that is synchronized to the onset of inspiration. If the baby is apnoeic or fails to exceed the trigger threshold, the ventilator will cycle at the control (back-up) rate. Management of infants ventilated by A/C is different from that with IMV. Provided that the patient is breathing above the control rate, reductions in the ventilator have no effect. Weaning is accomplished by decreasing the peak inspiratory pressure first, which should be beneficial in reducing both barotrauma and volutrauma.19
Pressure support ventilation PSV is primarily a weaning mode in which spontaneous breaths receive an inspiratory ‘boost’ to decrease the work of breathing and unload the respiratory musculature. A spontaneous breath triggers the delivery of a time- and pressure-limited breath, which is flow-cycled (see below). Breaths may be fully (provide a full tidal volume) or partially supported. PSV is usually applied in conjunction with SIMV, although it may be utilized alone if the baby has reliable respiratory drive and no difficulty exceeding the trigger threshold. Another feature of PSV is variable inspiratory flow, which is proportional to patient effort, and helpful in overcoming increased resistance.20
Flow cycling Cycling refers to the mechanism responsible for transitioning from inspiration to expiration and expiration to inspiration. In the past, this has
444
almost always been done by a fixed inspiratory time limit. The new technology has introduced flow cycling into clinical practice. In this mode, inspiration ends when inspiratory flow decreases to a certain percentage of peak inspiratory flow. This is ‘interpreted’ by the ventilator as a sign that the baby is about to end inspiratory effort and it may be thought of as an expiratory trigger. The advantages of flow cycling are that the baby is able to set the inspiratory time (a breath starts and ends at the baby's preference) and, at rapid rates, an inverse inspiratory:expiratory ratio cannot occur. The mechanical breath will be terminated before the baby can initiate another breath, rather than persisting for a fixed time.21 Systems providing flow cycling utilize an inspiratory time limit as well; the breath will be terminated based upon which condition is met first. Flow cycling is used in most PSV systems. It allows the baby to have control over the ventilator rate and inspiratory time, and it also enables synchronization of both inspiration and expiration.
Clinical studies of patient-triggered ventilation Early clinical trials have suggested a trend towards reductions in CLD but have been underpowered.17,22–24 A large, multicentre open trial did not show any differences in the incidence of CLD, but methodological flaws and significant user inexperience limit the interpretation of the findings.25 Although short-term benefits of PTV have been demonstrated, further studies are required to address the impact on CLD.
Volume-targeted ventilation Volume-targeted or volume-controlled ventilation has recently become available for the treatment of neonatal respiratory failure. In this form of ventilation, the clinician chooses a specific volume of gas, and delivery occurs irrespective of the pressure needed to do so, although the pressure may be limited for safety. True volume cycling probably does not occur because cuffed endotracheal tubes are not used in newborns, and there is almost always some air leak around the tube. The inherent advantage of this technique is that it automatically weans the peak inspiratory pressure as compliance improves, decreasing the risk of hyperinflation. This is especially important in clinical situations where a rapid improvement in compliance might be expected to occur, such as after the administration of surfactant or the evacuation of a pneumothorax.
S.M. Donn and S.K. Sinha
The first generation of the ‘new’ ventilators had limitations in minimal tidal volume and flow delivery, which precluded its use in babies weighing less than 1200–1500 g. More recently, smaller tidal volumes and lower flow rates have extended this capability to infants weighing as little as 500 g. Sinha et al., in the only randomized clinical trial to date, investigated the use of volume-targeted vs pressure-limited ventilation in infants with RDS who weighed >1200 g. They found a strong trend towards reduction of CLD in survivors (4 vs 25%), but this 50-patient study was too small to have statistical significance.26 However, the concept of ‘limiting’ volume delivery remains appealing, and further studies are now under way.
Proportional assist ventilation Proportional assist ventilation is a relatively new technique that holds promise for reducing support to the minimum necessary level. It is based on the individual pulmonary mechanics of the patient, and elastic and resistive loading and unloading. A short-term clinical trial in the USA examined the effects of proportional assist ventilation on 36 preterm infants with mild to moderate acute respiratory failure. Lower mean and peak transpulmonary pressures were generated during proportional assist ventilation, but further studies are necessary to determine long-term benefits.27
High-frequency ventilation First introduced into neonatal practice in the early 1980s, high-frequency ventilation (HFV) uses extremely small tidal volumes at rapid rates to affect gas exchange at lower alveolar pressures than CMV. There are two primary forms of HFV: high-frequency jet ventilation (HFJV) and highfrequency oscillatory ventilation (HFOV), as well as other hybrid forms.
High-frequency jet ventilation HFJV uses rates of 240–660 breaths/min, and inspiratory times are typically about 0.02 s. It is used in tandem with a conventional ventilator, which provides PEEP and optional ‘sigh’ breaths. High-velocity pulsations are injected at either the proximal airway using a special connector, or to the distal trachea using a special multiple lumen endotracheal tube. Ventilator adjustments are similar to those with CMV. The amplitude is set by adjusting peak pressure and PEEP.28 A number of clinical studies have reported longterm outcomes, including CLD, but this was not the
Mechanical ventilation and chronic lung disease
445
Fig. 1 A flow waveform showing gas trapping. Note that the expiratory portion of the waveform does not return to baseline before the inspiratory portion of the subsequent breath begins. There is insufficient time for emptying of the lung.
primary objective in most cases. However, Keszler et al. reported a reduced incidence of CLD and the need for home oxygen in infants treated with HFJV compared with CMV for uncomplicated RDS.29
High-frequency oscillatory ventilation HFOV differs from HFJV in that even smaller tidal volumes and active exhalation are used, and rates of 8–15 Hz are generally utilized. Mean airway pressure is used as a CDP to inflate the lung to a static volume, and oscillations around this mean are used to affect gas exchange. Adjustments for oxygenation (via mean airway pressure) and ventilation (via amplitude) are done independently of one another.28 A number of recent clinical trials have compared HFOV with CMV in preterm infants with RDS. Gerstmann et al. demonstrated increased survival without CLD in a study of 125 patients, but the trial did not include very small infants, who are the most likely to develop CLD.30 Rettwitz-Volk et al. studied 92 patients, but also failed to enroll very small patients, and found no differences in the two ventilatory techniques.31 A randomized trial of 76 patients reported by Thome et al. showed a shorter time to extubation, but the study was underpowered; however, its endpoint was an evaluation of the inflammatory response, and not CLD.32 A subsequent study by Thome et al., involving 284 infants, found no difference in mortality, intra-
ventricular haemorrhage or CLD.33 Two recently completed trials found differing results. The HIFO trial of Courtney et al. found a very slight reduction in CLD in babies receiving HFOV, although the control group was managed in SIMV, which may not be the ideal mode for acute management.34 The UKOS study found no difference in the incidence of CLD among infants receiving HFOV or conventional ventilation.35 Currently, there is insufficient evidence to recommend HFOV as an initial therapy for RDS if the primary goal is the avoidance of CLD.
Monitoring Advances in biomedical engineering have also substantially changed the monitoring of babies receiving mechanical ventilation. Intermittent chest radiographs and blood gas sampling have been replaced by continuous monitoring of pulmonary mechanics and pulse oximetry or transcutaneous oxygen/carbon dioxide tensions. Real-time pulmonary mechanics monitoring has become a valuable adjunct to CMV.36 The same sensor technology utilized for PTV enables measurement of changes in airway flow or pressure, which can be converted to a volume signal. Determination of tidal volume, minute ventilation and breath-to-breath displays of flow, pressure and volume waveforms are now standard techniques. Many devices also enable real-time displays of
446
S.M. Donn and S.K. Sinha
Fig. 2 A pressure–volume loop showing significant hyperinflation. Note the upper inflection point during inspiration, where the slope of the inspiratory limb flattens.
pressure–volume and flow–volume loops, and calculation of pulmonary resistance and compliance. Detection of potentially adverse situations, such as gas trapping (Fig. 1) or hyperinflation (Fig. 2), is now possible before these dangers become clinically apparent.37 Pulmonary graphics are critical in the appropriate application of some of the newer ventilatory techniques, such as PSV. Tidal volume monitoring allows adjustments that can provide optimal lung expansion. Spontaneous minute ventilation monitoring has been shown to be useful in assessing the readiness for extubation in mechanically ventilated infants.38 Pulmonary mechanics monitoring permits the clinician to select the best PEEP, and to objectively assess the effect of pharmacologic agents with a narrow therapeutic index, such as corticosteroids, bronchodilators and diuretics. Continuous pulse oximetry or blood gas analysis, using either indwelling intravascular sensors or transcutaneous electrodes, has changed ventilator management from an intermittent to a dynamic process. Maintaining oxygenation and ventilation within a desired range should help to minimize the deleterious effects of both oxygen toxicity and PPV.
Conclusions Advances in surfactant therapy, mechanical ventilation and monitoring have revolutionized the management of preterm infants with RDS. With
the improvement in the survival of these babies, the number of infants with CLD has increased. Various management strategies have been proposed, ranging from minimally invasive CPAP, to moderately invasive CMV and HFV to highly invasive ECMO. The goals of mechanical ventilation are not only adequate gas exchange and minimization of the patient's work of breathing, but also the avoidance of the factors that are believed to contribute to VILI, barotrauma, volutrauma and atelectrauma. Delivery of appropriate tidal volumes, avoidance of hyperinflation, and adequate alveolar recruitment are reasonable goals based on the principles of pulmonary physiology. Neonatologists now have a multiplicity of options available to achieve these goals. Unfortunately, very little evidence-based information exists to make direct comparisons of these techniques. Single-centre experiences or small clinical trials presently dominate the literature. It may be that safety and efficacy depend more on operator skill, experience and on the choice of strategy than on the specific device.
Practice points • Modern ventilators provide clinicians with a vast array of choices to manage neonatal
Mechanical ventilation and chronic lung disease
respiratory failure. Clinicians should learn a few of these and try not to master all of them. • At present, there is little evidence to support the use of high-frequency ventilation as a primary treatment strategy. • Real-time breath-to-breath monitoring is a valuable adjunct to ventilator management.
447
12.
13.
14.
15.
Research directions • Much work needs to be done to define ‘best practice’ strategies for neonatal ventilators and diseases. • Determination of cost:benefit ratios is still necessary for most devices. • Could a multifocal strategy involving mechanical and inflammatory modifiers reduce the incidence of chronic lung disease?
16.
17. 18.
19.
References 1. Northway WH Jr, Rosan RC, Porter DY. Pulmonary disease following respirator therapy of hyaline-membrane disease. N Engl J Med 1967;276:357–68. 2. Davis JM. Bronchopulmonary dysplasia. In: Sinha SK, Donn SM, editors. Manual of neonatal respiratory care. Armonk: Futura Publishing Co., 2000;310–5. 3. Philip AGS. Oxygen plus pressure plus time. The etiology of bronchopulmonary dysplasia. Pediatrics 1975;55:44–50. 4. Clark RH, Gerstmann DR, Jobe AH et al. Lung injury in neonates: causes, strategies for prevention, and long-term consequences. J Pediatr 2001;139:478–86. 5. Nelson M, Becker MA, Donn SM. Basic neonatal respiratory disorders. In: Donn SM, editor. Neonatal and pediatric pulmonary graphics: principles and clinical applications. Armonk: Futura Publishing Co., 1998;253–77. 6. Donn SM, Sinha SK. Airway and respiratory complications of mechanical ventilation. In: Sinha SK, Donn SM, editors. Manual of neonatal respiratory care. Armonk: Futura Publishing Co., 2000;318–9. 7. Gregory GA, Kitterman JA, Phibbs RH et al. Treatment of the idiopathic respiratory distress syndrome with continuous positive airway pressure. N Engl J Med 1971;284:1333–40. 8. Morley CJ. Continuous positive airway pressure. In: Sinha SK, Donn SM, editors. Manual of neonatal respiratory care. Armonk: Futura Publishing Co., 2000;134–40. 9. Wung JT, James LS, Kilchevsky E et al. Management of infants with severe respiratory failure and persistence of the fetal circulation without hyperventilation. Pediatrics 1985;76:488–92. 10. Van Marter LJ, Allred EN, Pagano M et al. Do clinical markers of barotrauma and oxygen toxicity explain interhospital variation in rates of chronic lung disease? Pediatrics 2000; 105:1194–201. 11. Lee KS, Dunn MS, Fenwick M et al. A comparison of underwater bubble continuous positive airway pressure with ventilator-derived continuous positive airway pressure in
20.
21.
22.
23.
24.
25.
26.
27. 28. 29.
30.
premature neonates ready for extubation. Biol Neonate 1998;73:69–75. Kraybill EN, Runyan DK, Bose CL et al. Risk factors for chronic lung disease in infants with birth weights of 751 to 1000 grams. J Pediatr 1989;115:115–20. Ambalavanan N, Carlo WA. Hypocapnia and hypercapnia in respiratory management of newborn infants. Clin Perinatol 2001;28:517–31. Mariani G, Cifuentes J, Carlo WA. Randomized trial of permissive hypercapnia in preterm infants. Pediatrics 1999; 104:1082–8. Carlo WA, Stark AR, Bauer C et al. Effects of minimal ventilation in a multicenter randomized controlled trial of ventilator support and early corticosteroid therapy in extremely low birth weight infants. Pediatrics 1999; 104:S738–42. Bandy KP, Nicks JJ, Donn SM. Volume-controlled ventilation for severe neonatal respiratory failure. Neonatal Intensive Care 1992;5:70–3. Donn SM, Sinha SK. Controversies in patient-triggered ventilation. Clin Perinatol 1998;25:49–61. Perlman JM, McMenamin JB, Volpe JJ. Fluctuating cerebral blood flow velocity in respiratory distress syndrome: relationship to subsequent development of intraventricular hemorrhage. N Engl J Med 1983;309:204–9. Donn SM, Nicks JJ. Special ventilator techniques and modalities. I. Patient-triggered ventilation. In: Goldsmith JP, Karotkin EH, editors. Assisted ventilation of the neonate, 3rd ed. Orlando: W.B. Saunders Co., 1996;215–28. Sinha SK, Donn SM. Pressure support ventilation. In: Sinha SK, Donn SM, editors. Manual of neonatal respiratory care. Armonk: Futura Publishing Co., 2000;157–60. Becker MA, Donn SM. VIP BIRD® infant/pediatric ventilator. In: Sinha SK, Donn SM, editors. Manual of neonatal respiratory care. Armonk: Futura Publishing Co., 2000;164–71. Donn SM, Nicks JJ, Becker MA. Flow-synchronized ventilation of preterm infants with respiratory distress syndrome. J Perinatol 1994;14:90–4. Bernstein G, Mannino FL, Heldt GP et al. Randomized multicenter trial comparing synchronized and conventional intermittent mandatory ventilation in neonates. J Pediatr 1996;128:453–63. Visveshwara N, Freeman B, Peck M et al. Patient triggered synchronized assisted ventilation of newborns. Report of a preliminary study and three years' experience. J Perinatol 1991;11:347–54. Baumer JH. International randomised controlled trial of patient triggered ventilation in neonatal respiratory distress syndrome. Arch Dis Child Fetal Neonatal Ed 2000; 82:F5–F10. Sinha SK, Donn SM, Gavey J et al. A randomised trial of volume-controlled vs. time-cycled, pressure-limited ventilation in preterm infants with respiratory distress syndrome. Arch Dis Child Fetal Neonatal Ed 1997;77:F202–5. Schulze A, Bancalari E. Proportional assist ventilation. Clin Perinatol 2001;28:561–78. Keszler M, Durand DJ. Neonatal high-frequency ventilation: past, present, and future. Clin Perinatol 2001;28:579–607. Keszler M, Modanlou HD, Brudno DS et al. Multi-center controlled clinical trial of high-frequency jet ventilation in preterm infants with uncomplicated respiratory distress syndrome. Pediatrics 1997;100:593–9. Gerstmann DR, Minton SD, Stoddard RA et al. The Provo multicenter early high-frequency oscillatory ventilation
448
31.
32.
33.
34.
S.M. Donn and S.K. Sinha trial: improved pulmonary and clinical outcome in respiratory distress syndrome. Pediatrics 1996;98:1044–57. Rettwitz-Volk W, Veldman A, Roth B et al. A prospective, randomized multicenter trial of high-frequency oscillatory ventilation compared with conventional ventilation in preterm infants with respiratory distress syndrome receiving surfactant. J Pediatr 1998;132:249–54. Thome U, Gotze-Speer B, Speer CP et al. Comparison of pulmonary inflammatory mediators in preterm infants treated with intermittent positive pressure ventilation or high frequency oscillatory ventilation. Pediatr Res 1998; 44:330–7. Thome U, Kossel H, Lipowsky G et al. Randomized comparison of high-frequency ventilation with high-rate intermittent positive pressure ventilation in preterm infants with respiratory failure. J Pediatr 1999;135:39–46. Courtney SE, Durand DJ, Asselin JM et al. High-frequency oscillation ventilation versus conventional mechanical ven-
35.
36.
37.
38.
tilation for very-low-birth-weight infants. N Engl J Med 2002;347:643–52. Johnson AH, Peacock JL, Greenough A et al. High-frequency oscillatory ventilation for the prevention of chronic lung disease of prematurity. N Engl J Med 2002;347:633–42. Donn SM, editor. Neonatal and pediatric pulmonary graphics: principles and clinical applications. Armonk: Futura Publishing Co., 1998. Sinha SK, Nicks JJ, Donn SM. Graphic analysis of pulmonary mechanics in neonates receiving assisted ventilation. Arch Dis Child Fetal Neonatal Ed 1996;75:F213–8. Wilson BJ Jr, Becker MA, Linton ME et al. Spontaneous minute ventilation predicts readiness for intubation in mechanically ventilated preterm infants. J Perinatol 1998; 18:436–9.
Seminars in NEONATOLOGY www.elsevierhealth.com/journals/siny
Can mechanical ventilation strategies reduce chronic lung disease? Steven M. Donn a*, Sunil K. Sinha b a
The Division of Neonatal–Perinatal Medicine, Department of Pediatrics, C.S. Mott Children's Hospital, University of Michigan Health System, Ann Arbor, MI, USA b University of Durham and The James Cook University Hospital, Middlesbrough, UK Received 1 June 2003; accepted 1 July 2003
KEYWORDS Mechanical ventilation; Chronic lung disease; Prematurity; Respiratory distress syndrome
Summary Chronic lung disease (CLD) continues to be a significant complication in newborn infants undergoing mechanical ventilation for respiratory failure. Although the aetiology of CLD is multifactorial, specific factors related to mechanical ventilation, including barotrauma, volutrauma and atelectrauma, have been implicated as important aetiologic mechanisms. This article discusses the ways in which these factors might be manipulated by various mechanical ventilatory strategies to reduce ventilator-induced lung injury. These include continuous positive airway pressure, permissive hypercapnia, patient-triggered ventilation, volume-targeted ventilation, proportional assist ventilation, high-frequency ventilation and real-time monitoring. © 2003 Elsevier Ltd. All rights reserved.
Introduction Advances in neonatal intensive care and mechanical ventilation over the past 25 years have extended the survivability of premature infants to 24 weeks' gestation, and occasionally even earlier. Unfortunately, the developing lung is a delicate structure and is easily injured by the therapies necessary to sustain life outside the womb. Thus, an increasing number of infants are surviving with chronic lung disease (CLD). CLD, also referred to as bronchopulmonary dysplasia (BPD), was first described by Northway et al. in 1967 in 13 infants surviving hyaline membrane disease after mechanical ventilation. Their gestational ages ranged from 30 to 39 weeks and their birth weights ranged from 1474 to 3204 g.1 It has been estimated that 30–40% of preterm infants requiring mechanical ventilation will develop CLD, and that there are 7500 new cases each year in the USA.2 * Corresponding author. Tel.: +1-734-763-4109; fax: +1-734-763-7728 E-mail address: [email protected] (S.M. Donn).
The precise aetiology of CLD remains unknown. In 1975, Philip suggested that oxygen, positive pressure ventilation (PPV) and time were responsible for its causation,3 and over subsequent decades, other factors, including inflammatory mediators, have also been implicated. The terms ‘barotrauma’ (implying injury caused by pressure), ‘volutrauma’ (implying injury caused by excessive tidal volume delivery) and, most recently, ‘atelectrauma’ (implying injury caused by alveolar collapse) have been applied to an overall concept of ‘ventilator-induced lung injury’ (VILI).4 As mechanical ventilation became more sophisticated, and as clinicians encountered choices beyond the traditional time-cycled, pressurelimited (TCPL) intermittent mandatory ventilation (IMV), which characterized the first three decades of the management of neonatal respiratory failure, the concept of lung-protective strategies began to evolve. The advent of exogenous surfactant therapy removed one of the major pathophysiologic abnormalities of respiratory distress syndrome (RDS), and focused attention on ways to avoid
1084-2756/03/$ - see front matter © 2003 Elsevier Ltd. All rights reserved. doi:10.1016/S1084-2756(03)00124-6
442
VILI by applying PPV more safely to the developing lung. This review discusses ventilatory strategies aimed at protecting the premature neonatal lung and reducing the incidence of CLD. It is not meant to be exhaustive, but rather a summary of the approaches that have been used to counteract this increasing problem. There is not yet enough evidence-based data to make specific recommendations, but it is the authors' hope that this review will provide a stimulus for further clinical investigation.
Pathophysiology of respiratory distress syndrome RDS is a disorder of the premature lung, characterized by biochemical and morphological immaturity. The lack of pulmonary surfactant leads to increased alveolar surface tension and a tendency for alveolar collapse, progressive atelectasis and decreased compliance. The pulmonary histology and cytoarchitectural abnormalities include: insufficient alveolarization, decreasing the surface area available for gas exchange; an increased distance between the alveolus and its adjacent capillary, impairing the diffusion of oxygen; increased capillary permeability, leading to fibrin deposition in the air spaces and impeding gas exchange; and, in some cases, excessive muscularization of the pulmonary arterioles, resulting in pulmonary hypertension and reduced pulmonary blood flow. In addition, the premature newborn has increased chest wall compliance, which further complicates pulmonary mechanics.5
Goals of mechanical ventilation The use of either continuous distending pressure (CDP) or PPV is aimed at overcoming alveolar atelectasis and achieving sufficient lung expansion to facilitate adequate pulmonary gas exchange, while reducing the infant's work of breathing. This needs to be accomplished without excessive pressure, volume or flow, while maintaining a normal functional residual capacity and avoiding atelectasis. Complications of mechanical ventilation are well documented, and include injury to the structures of the airway from endotracheal tubes, thoracic air leaks, pneumonia and, as mentioned, CLD.6
S.M. Donn and S.K. Sinha
range of choices for managing infants with respiratory failure. These range from continuous positive airway pressure (CPAP) to extracorporeal membrane oxygenation (ECMO). Even within the genre of conventional mechanical ventilation (CMV), multiple forms and modes of ventilation now exist.
‘Conservative’ techniques Continuous positive airway pressure CPAP, a form of CDP, was first introduced by Gregory et al. in 1971,7 and is usually applied by nasal prongs. It is used in spontaneously breathing infants to maintain a degree of alveolar inflation during expiration, to prevent collapse and to decrease the work of breathing.8 This technique was frequently used in the 1970s as the initial strategy in the management of RDS, but it was gradually supplanted by the use of mechanical ventilation in the presurfactant era, when it was used primarily as an adjunctive postextubation therapy. Based largely on the observational work of Wung et al. in the late 1970s and early 1980s, there was a resurgence of interest in CPAP as a primary modality for treating RDS.9 These investigators reported a dramatically decreased incidence of CLD using a very conservative strategy, which included dependence on spontaneous breathing, avoidance of sedatives and paralytics, and acceptance of blood gas and pH values at the limits of physiological norms. The ‘Columbia experience’ has been compared historically with other approaches that rely more on mechanical ventilation and, indeed, a significant reduction in the incidence of CLD has been apparent.10 Wung et al.'s observations have led to additional experiences with CPAP, but have also raised a number of questions because their work did not include a randomized, controlled trial or long-term follow-up studies. It also appears that all CPAP devices are not equivalent, and that there may be an advantage to using CPAP generated by an underwater seal (‘bubble CPAP’).11 Questions for further investigation include the following: • Does the use of CPAP in infants who subsequently do not respond delay surfactant administration, thus increasing morbidity? • Is the work of breathing with CPAP a significant caloric expense compared with mechanical ventilation?
Ventilatory strategies
Permissive hypercapnia
The proliferation of technology in neonatal intensive care has provided the clinician with a wide
The strategy of ventilating infants at a higher PaCO2 level, termed permissive hypercapnia, appears to
Mechanical ventilation and chronic lung disease
be based upon the report of Kraybill et al. in 1989.12 In a multicentre analysis of 235 preterm infants, these investigators demonstrated a higher incidence of CLD in infants with low PaCO2 on the second and fourth postnatal days.12 The rationale for permissive hypercapnia, using a low lung volume strategy, is that it may decrease volutrauma and lung injury, lessen the duration of mechanical ventilation, reduce alveolar ventilation and the complications of hypocapnia (especially reduced cerebral blood flow), and increase oxygen unloading at the tissue level (Bohr effect).13 Two prospective, randomized, controlled trials of permissive hypercapnia have been conducted. Although both studies demonstrated a significant reduction in the duration of ventilation and other secondary outcome measures, the incidence of CLD did not differ significantly between groups.14,15 Further investigation is necessary to address both the safety and efficacy of this intriguing strategy.
Conventional mechanical ventilation For nearly three decades, CMV consisted of TCPL IMV. This form of ventilation was easy to use and resulted in consistent delivery of PPV, although delivered tidal volumes were a function of pulmonary compliance. An early attempt to provide volume-cycled ventilation did not succeed because of technological limitations.16 During TCPL IMV, all ventilator parameters are set by the clinician, although the baby is able to breathe spontaneously from continuous bias flow in the ventilator circuit, but respiration is supported only by positive endexpiratory pressure (PEEP). One of the major problems with IMV is the development of patient-ventilator dyssynchrony. Babies may try to exhale against PPV, resulting in inefficient gas exchange, gas trapping and air leaks, and the need for higher levels of support.17 An association between dyssynchrony and intraventricular haemorrhage has also been reported.18 During the 1990s, microprocessor-based ventilators and sophisticated, sensitive transducers were developed that had the capability of detecting spontaneous respiratory activity. Patient-triggered ventilation (PTV) was introduced into neonatal respiratory care during this decade. Modes of ventilation utilizing PTV include synchronized intermittent mandatory ventilation (SIMV), assist/control (A/C) ventilation, and pressure support ventilation (PSV). Transducers detect some measure of respiratory effort, such as changes in thoracic or abdominal impedance or changes in airway pressure or flow, and respond with a mechanical breath timed to begin almost immediately after the
443
initiation of the patient's breath. Thus, the onset of inspiration between the baby and the ventilator is synchronized.19
Synchronized intermittent mandatory ventilation In SIMV, the clinician selects a mandatory rate of ventilation. Each time the baby is ‘due’ to receive a breath, the ventilator waits briefly for the infant to initiate a breath. If the baby breathes within this ‘timing window’, a mechanical breath will be matched to the onset of spontaneous breathing. If the baby fails to breathe, the ventilator will cycle ‘on schedule’. In between mechanical breaths, spontaneous breathing is supported by PEEP. Only mechanical breaths can be fully supported.19
Assist/control ventilation In A/C ventilation, all spontaneous breaths that exceed the trigger threshold result in the delivery of a mechanical breath that is synchronized to the onset of inspiration. If the baby is apnoeic or fails to exceed the trigger threshold, the ventilator will cycle at the control (back-up) rate. Management of infants ventilated by A/C is different from that with IMV. Provided that the patient is breathing above the control rate, reductions in the ventilator have no effect. Weaning is accomplished by decreasing the peak inspiratory pressure first, which should be beneficial in reducing both barotrauma and volutrauma.19
Pressure support ventilation PSV is primarily a weaning mode in which spontaneous breaths receive an inspiratory ‘boost’ to decrease the work of breathing and unload the respiratory musculature. A spontaneous breath triggers the delivery of a time- and pressure-limited breath, which is flow-cycled (see below). Breaths may be fully (provide a full tidal volume) or partially supported. PSV is usually applied in conjunction with SIMV, although it may be utilized alone if the baby has reliable respiratory drive and no difficulty exceeding the trigger threshold. Another feature of PSV is variable inspiratory flow, which is proportional to patient effort, and helpful in overcoming increased resistance.20
Flow cycling Cycling refers to the mechanism responsible for transitioning from inspiration to expiration and expiration to inspiration. In the past, this has
444
almost always been done by a fixed inspiratory time limit. The new technology has introduced flow cycling into clinical practice. In this mode, inspiration ends when inspiratory flow decreases to a certain percentage of peak inspiratory flow. This is ‘interpreted’ by the ventilator as a sign that the baby is about to end inspiratory effort and it may be thought of as an expiratory trigger. The advantages of flow cycling are that the baby is able to set the inspiratory time (a breath starts and ends at the baby's preference) and, at rapid rates, an inverse inspiratory:expiratory ratio cannot occur. The mechanical breath will be terminated before the baby can initiate another breath, rather than persisting for a fixed time.21 Systems providing flow cycling utilize an inspiratory time limit as well; the breath will be terminated based upon which condition is met first. Flow cycling is used in most PSV systems. It allows the baby to have control over the ventilator rate and inspiratory time, and it also enables synchronization of both inspiration and expiration.
Clinical studies of patient-triggered ventilation Early clinical trials have suggested a trend towards reductions in CLD but have been underpowered.17,22–24 A large, multicentre open trial did not show any differences in the incidence of CLD, but methodological flaws and significant user inexperience limit the interpretation of the findings.25 Although short-term benefits of PTV have been demonstrated, further studies are required to address the impact on CLD.
Volume-targeted ventilation Volume-targeted or volume-controlled ventilation has recently become available for the treatment of neonatal respiratory failure. In this form of ventilation, the clinician chooses a specific volume of gas, and delivery occurs irrespective of the pressure needed to do so, although the pressure may be limited for safety. True volume cycling probably does not occur because cuffed endotracheal tubes are not used in newborns, and there is almost always some air leak around the tube. The inherent advantage of this technique is that it automatically weans the peak inspiratory pressure as compliance improves, decreasing the risk of hyperinflation. This is especially important in clinical situations where a rapid improvement in compliance might be expected to occur, such as after the administration of surfactant or the evacuation of a pneumothorax.
S.M. Donn and S.K. Sinha
The first generation of the ‘new’ ventilators had limitations in minimal tidal volume and flow delivery, which precluded its use in babies weighing less than 1200–1500 g. More recently, smaller tidal volumes and lower flow rates have extended this capability to infants weighing as little as 500 g. Sinha et al., in the only randomized clinical trial to date, investigated the use of volume-targeted vs pressure-limited ventilation in infants with RDS who weighed >1200 g. They found a strong trend towards reduction of CLD in survivors (4 vs 25%), but this 50-patient study was too small to have statistical significance.26 However, the concept of ‘limiting’ volume delivery remains appealing, and further studies are now under way.
Proportional assist ventilation Proportional assist ventilation is a relatively new technique that holds promise for reducing support to the minimum necessary level. It is based on the individual pulmonary mechanics of the patient, and elastic and resistive loading and unloading. A short-term clinical trial in the USA examined the effects of proportional assist ventilation on 36 preterm infants with mild to moderate acute respiratory failure. Lower mean and peak transpulmonary pressures were generated during proportional assist ventilation, but further studies are necessary to determine long-term benefits.27
High-frequency ventilation First introduced into neonatal practice in the early 1980s, high-frequency ventilation (HFV) uses extremely small tidal volumes at rapid rates to affect gas exchange at lower alveolar pressures than CMV. There are two primary forms of HFV: high-frequency jet ventilation (HFJV) and highfrequency oscillatory ventilation (HFOV), as well as other hybrid forms.
High-frequency jet ventilation HFJV uses rates of 240–660 breaths/min, and inspiratory times are typically about 0.02 s. It is used in tandem with a conventional ventilator, which provides PEEP and optional ‘sigh’ breaths. High-velocity pulsations are injected at either the proximal airway using a special connector, or to the distal trachea using a special multiple lumen endotracheal tube. Ventilator adjustments are similar to those with CMV. The amplitude is set by adjusting peak pressure and PEEP.28 A number of clinical studies have reported longterm outcomes, including CLD, but this was not the
Mechanical ventilation and chronic lung disease
445
Fig. 1 A flow waveform showing gas trapping. Note that the expiratory portion of the waveform does not return to baseline before the inspiratory portion of the subsequent breath begins. There is insufficient time for emptying of the lung.
primary objective in most cases. However, Keszler et al. reported a reduced incidence of CLD and the need for home oxygen in infants treated with HFJV compared with CMV for uncomplicated RDS.29
High-frequency oscillatory ventilation HFOV differs from HFJV in that even smaller tidal volumes and active exhalation are used, and rates of 8–15 Hz are generally utilized. Mean airway pressure is used as a CDP to inflate the lung to a static volume, and oscillations around this mean are used to affect gas exchange. Adjustments for oxygenation (via mean airway pressure) and ventilation (via amplitude) are done independently of one another.28 A number of recent clinical trials have compared HFOV with CMV in preterm infants with RDS. Gerstmann et al. demonstrated increased survival without CLD in a study of 125 patients, but the trial did not include very small infants, who are the most likely to develop CLD.30 Rettwitz-Volk et al. studied 92 patients, but also failed to enroll very small patients, and found no differences in the two ventilatory techniques.31 A randomized trial of 76 patients reported by Thome et al. showed a shorter time to extubation, but the study was underpowered; however, its endpoint was an evaluation of the inflammatory response, and not CLD.32 A subsequent study by Thome et al., involving 284 infants, found no difference in mortality, intra-
ventricular haemorrhage or CLD.33 Two recently completed trials found differing results. The HIFO trial of Courtney et al. found a very slight reduction in CLD in babies receiving HFOV, although the control group was managed in SIMV, which may not be the ideal mode for acute management.34 The UKOS study found no difference in the incidence of CLD among infants receiving HFOV or conventional ventilation.35 Currently, there is insufficient evidence to recommend HFOV as an initial therapy for RDS if the primary goal is the avoidance of CLD.
Monitoring Advances in biomedical engineering have also substantially changed the monitoring of babies receiving mechanical ventilation. Intermittent chest radiographs and blood gas sampling have been replaced by continuous monitoring of pulmonary mechanics and pulse oximetry or transcutaneous oxygen/carbon dioxide tensions. Real-time pulmonary mechanics monitoring has become a valuable adjunct to CMV.36 The same sensor technology utilized for PTV enables measurement of changes in airway flow or pressure, which can be converted to a volume signal. Determination of tidal volume, minute ventilation and breath-to-breath displays of flow, pressure and volume waveforms are now standard techniques. Many devices also enable real-time displays of
446
S.M. Donn and S.K. Sinha
Fig. 2 A pressure–volume loop showing significant hyperinflation. Note the upper inflection point during inspiration, where the slope of the inspiratory limb flattens.
pressure–volume and flow–volume loops, and calculation of pulmonary resistance and compliance. Detection of potentially adverse situations, such as gas trapping (Fig. 1) or hyperinflation (Fig. 2), is now possible before these dangers become clinically apparent.37 Pulmonary graphics are critical in the appropriate application of some of the newer ventilatory techniques, such as PSV. Tidal volume monitoring allows adjustments that can provide optimal lung expansion. Spontaneous minute ventilation monitoring has been shown to be useful in assessing the readiness for extubation in mechanically ventilated infants.38 Pulmonary mechanics monitoring permits the clinician to select the best PEEP, and to objectively assess the effect of pharmacologic agents with a narrow therapeutic index, such as corticosteroids, bronchodilators and diuretics. Continuous pulse oximetry or blood gas analysis, using either indwelling intravascular sensors or transcutaneous electrodes, has changed ventilator management from an intermittent to a dynamic process. Maintaining oxygenation and ventilation within a desired range should help to minimize the deleterious effects of both oxygen toxicity and PPV.
Conclusions Advances in surfactant therapy, mechanical ventilation and monitoring have revolutionized the management of preterm infants with RDS. With
the improvement in the survival of these babies, the number of infants with CLD has increased. Various management strategies have been proposed, ranging from minimally invasive CPAP, to moderately invasive CMV and HFV to highly invasive ECMO. The goals of mechanical ventilation are not only adequate gas exchange and minimization of the patient's work of breathing, but also the avoidance of the factors that are believed to contribute to VILI, barotrauma, volutrauma and atelectrauma. Delivery of appropriate tidal volumes, avoidance of hyperinflation, and adequate alveolar recruitment are reasonable goals based on the principles of pulmonary physiology. Neonatologists now have a multiplicity of options available to achieve these goals. Unfortunately, very little evidence-based information exists to make direct comparisons of these techniques. Single-centre experiences or small clinical trials presently dominate the literature. It may be that safety and efficacy depend more on operator skill, experience and on the choice of strategy than on the specific device.
Practice points • Modern ventilators provide clinicians with a vast array of choices to manage neonatal
Mechanical ventilation and chronic lung disease
respiratory failure. Clinicians should learn a few of these and try not to master all of them. • At present, there is little evidence to support the use of high-frequency ventilation as a primary treatment strategy. • Real-time breath-to-breath monitoring is a valuable adjunct to ventilator management.
447
12.
13.
14.
15.
Research directions • Much work needs to be done to define ‘best practice’ strategies for neonatal ventilators and diseases. • Determination of cost:benefit ratios is still necessary for most devices. • Could a multifocal strategy involving mechanical and inflammatory modifiers reduce the incidence of chronic lung disease?
16.
17. 18.
19.
References 1. Northway WH Jr, Rosan RC, Porter DY. Pulmonary disease following respirator therapy of hyaline-membrane disease. N Engl J Med 1967;276:357–68. 2. Davis JM. Bronchopulmonary dysplasia. In: Sinha SK, Donn SM, editors. Manual of neonatal respiratory care. Armonk: Futura Publishing Co., 2000;310–5. 3. Philip AGS. Oxygen plus pressure plus time. The etiology of bronchopulmonary dysplasia. Pediatrics 1975;55:44–50. 4. Clark RH, Gerstmann DR, Jobe AH et al. Lung injury in neonates: causes, strategies for prevention, and long-term consequences. J Pediatr 2001;139:478–86. 5. Nelson M, Becker MA, Donn SM. Basic neonatal respiratory disorders. In: Donn SM, editor. Neonatal and pediatric pulmonary graphics: principles and clinical applications. Armonk: Futura Publishing Co., 1998;253–77. 6. Donn SM, Sinha SK. Airway and respiratory complications of mechanical ventilation. In: Sinha SK, Donn SM, editors. Manual of neonatal respiratory care. Armonk: Futura Publishing Co., 2000;318–9. 7. Gregory GA, Kitterman JA, Phibbs RH et al. Treatment of the idiopathic respiratory distress syndrome with continuous positive airway pressure. N Engl J Med 1971;284:1333–40. 8. Morley CJ. Continuous positive airway pressure. In: Sinha SK, Donn SM, editors. Manual of neonatal respiratory care. Armonk: Futura Publishing Co., 2000;134–40. 9. Wung JT, James LS, Kilchevsky E et al. Management of infants with severe respiratory failure and persistence of the fetal circulation without hyperventilation. Pediatrics 1985;76:488–92. 10. Van Marter LJ, Allred EN, Pagano M et al. Do clinical markers of barotrauma and oxygen toxicity explain interhospital variation in rates of chronic lung disease? Pediatrics 2000; 105:1194–201. 11. Lee KS, Dunn MS, Fenwick M et al. A comparison of underwater bubble continuous positive airway pressure with ventilator-derived continuous positive airway pressure in
20.
21.
22.
23.
24.
25.
26.
27. 28. 29.
30.
premature neonates ready for extubation. Biol Neonate 1998;73:69–75. Kraybill EN, Runyan DK, Bose CL et al. Risk factors for chronic lung disease in infants with birth weights of 751 to 1000 grams. J Pediatr 1989;115:115–20. Ambalavanan N, Carlo WA. Hypocapnia and hypercapnia in respiratory management of newborn infants. Clin Perinatol 2001;28:517–31. Mariani G, Cifuentes J, Carlo WA. Randomized trial of permissive hypercapnia in preterm infants. Pediatrics 1999; 104:1082–8. Carlo WA, Stark AR, Bauer C et al. Effects of minimal ventilation in a multicenter randomized controlled trial of ventilator support and early corticosteroid therapy in extremely low birth weight infants. Pediatrics 1999; 104:S738–42. Bandy KP, Nicks JJ, Donn SM. Volume-controlled ventilation for severe neonatal respiratory failure. Neonatal Intensive Care 1992;5:70–3. Donn SM, Sinha SK. Controversies in patient-triggered ventilation. Clin Perinatol 1998;25:49–61. Perlman JM, McMenamin JB, Volpe JJ. Fluctuating cerebral blood flow velocity in respiratory distress syndrome: relationship to subsequent development of intraventricular hemorrhage. N Engl J Med 1983;309:204–9. Donn SM, Nicks JJ. Special ventilator techniques and modalities. I. Patient-triggered ventilation. In: Goldsmith JP, Karotkin EH, editors. Assisted ventilation of the neonate, 3rd ed. Orlando: W.B. Saunders Co., 1996;215–28. Sinha SK, Donn SM. Pressure support ventilation. In: Sinha SK, Donn SM, editors. Manual of neonatal respiratory care. Armonk: Futura Publishing Co., 2000;157–60. Becker MA, Donn SM. VIP BIRD® infant/pediatric ventilator. In: Sinha SK, Donn SM, editors. Manual of neonatal respiratory care. Armonk: Futura Publishing Co., 2000;164–71. Donn SM, Nicks JJ, Becker MA. Flow-synchronized ventilation of preterm infants with respiratory distress syndrome. J Perinatol 1994;14:90–4. Bernstein G, Mannino FL, Heldt GP et al. Randomized multicenter trial comparing synchronized and conventional intermittent mandatory ventilation in neonates. J Pediatr 1996;128:453–63. Visveshwara N, Freeman B, Peck M et al. Patient triggered synchronized assisted ventilation of newborns. Report of a preliminary study and three years' experience. J Perinatol 1991;11:347–54. Baumer JH. International randomised controlled trial of patient triggered ventilation in neonatal respiratory distress syndrome. Arch Dis Child Fetal Neonatal Ed 2000; 82:F5–F10. Sinha SK, Donn SM, Gavey J et al. A randomised trial of volume-controlled vs. time-cycled, pressure-limited ventilation in preterm infants with respiratory distress syndrome. Arch Dis Child Fetal Neonatal Ed 1997;77:F202–5. Schulze A, Bancalari E. Proportional assist ventilation. Clin Perinatol 2001;28:561–78. Keszler M, Durand DJ. Neonatal high-frequency ventilation: past, present, and future. Clin Perinatol 2001;28:579–607. Keszler M, Modanlou HD, Brudno DS et al. Multi-center controlled clinical trial of high-frequency jet ventilation in preterm infants with uncomplicated respiratory distress syndrome. Pediatrics 1997;100:593–9. Gerstmann DR, Minton SD, Stoddard RA et al. The Provo multicenter early high-frequency oscillatory ventilation
448
31.
32.
33.
34.
S.M. Donn and S.K. Sinha trial: improved pulmonary and clinical outcome in respiratory distress syndrome. Pediatrics 1996;98:1044–57. Rettwitz-Volk W, Veldman A, Roth B et al. A prospective, randomized multicenter trial of high-frequency oscillatory ventilation compared with conventional ventilation in preterm infants with respiratory distress syndrome receiving surfactant. J Pediatr 1998;132:249–54. Thome U, Gotze-Speer B, Speer CP et al. Comparison of pulmonary inflammatory mediators in preterm infants treated with intermittent positive pressure ventilation or high frequency oscillatory ventilation. Pediatr Res 1998; 44:330–7. Thome U, Kossel H, Lipowsky G et al. Randomized comparison of high-frequency ventilation with high-rate intermittent positive pressure ventilation in preterm infants with respiratory failure. J Pediatr 1999;135:39–46. Courtney SE, Durand DJ, Asselin JM et al. High-frequency oscillation ventilation versus conventional mechanical ven-
35.
36.
37.
38.
tilation for very-low-birth-weight infants. N Engl J Med 2002;347:643–52. Johnson AH, Peacock JL, Greenough A et al. High-frequency oscillatory ventilation for the prevention of chronic lung disease of prematurity. N Engl J Med 2002;347:633–42. Donn SM, editor. Neonatal and pediatric pulmonary graphics: principles and clinical applications. Armonk: Futura Publishing Co., 1998. Sinha SK, Nicks JJ, Donn SM. Graphic analysis of pulmonary mechanics in neonates receiving assisted ventilation. Arch Dis Child Fetal Neonatal Ed 1996;75:F213–8. Wilson BJ Jr, Becker MA, Linton ME et al. Spontaneous minute ventilation predicts readiness for intubation in mechanically ventilated preterm infants. J Perinatol 1998; 18:436–9.