International Perspectives : Report on the International Seminar on Surfactant and CPAP in Extremely Low Gestational Age Neonates, Vienna

2009 Roland R. Wauer and Charles Christoph Roehr Neoreviews 2010;11;e343 DOI: 10.1542/neo.11-7-e343

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://neoreviews.aappublications.org/content/11/7/e343

Data Supplement (unedited) at: http://neoreviews.aappublications.org/content/suppl/2010/06/17/11.7.e343.DC1.html

Neoreviews is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since . Neoreviews is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright 2010 by the American Academy of Pediatrics. All rights reserved. Print ISSN: .

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international perspectives

Report on the International Seminar on Surfactant and CPAP in Extremely Low Gestational Age Neonates, Vienna 2009
Roland R. Wauer, MD, PhD*, Charles Christoph Roehr, MD* for the Scientic Committee

Background
This seminar originated as a sponsored research seminar, initiated by the European Respiratory Society (ERS) and the Charite Universita smedizin Berlin, Germany. At the invitation of the organizing committee (C. Roehr/R. Wauer/A. Greenough/ H. Verder), an international panel of expert neonatologists and researchers in neonatal medicine presented the latest data on managing extremely low gestational age neonates (ELGANs) with continuous positive airway pressure (CPAP) and surfactant. The presentations focused on the pathophysiology of neonatal lung disease and the prevention and treatment of respiratory distress in ELGANs. The international audience comprised respirologists, physicians, physiologists, and neonatal practitioners. Aims of the seminar were to: 1) Discuss the best available evidence regarding the use of surfactant and CPAP in ELGANs, 2) Identify and focus on areas of urgently needed research, and 3) form international collaborations for future research. There was a lively and productive discussion in between the presentations and during breaks as well as during the nal panel session. The individual contributions from the speakers are summarized in this article, and pertinent references are included at the end of the summary.

Drs Wauer and Roehr have disclosed no nancial relationships relevant to this article. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.

The following article in our International Perspectives series differs somewhat from the usual format. Most of these pieces either cover what is happening in a particular country or provide a regional viewpoint on a selected topic. The report of this seminar was suggested by one of our International Advisory Board members (Dr Mats Blennow from Stockholm, Sweden) and provides some insight into what is currently considered to be important by inuential neonatologists in Europe. It also provides direction for future research activity in several different areas, which may stimulate some of our North American readers (as well as our European colleagues). Not all references provided by the speakers are included with this report. The complete list of references may be obtained by contacting Dr Roehr at cristoph-roehr@charite.de. Publication of this report should not be seen as an open invitation to submit the proceedings of all such meetings to NeoReviews. However, there might be a place for other reports of international seminars/symposia, if they deal with topics that are considered to be of general interest and have not been covered in recent issues of the journal. Alistair G.S. Philip, MD Editor-in-Chief, NeoReviews

Presentations
Alan Jobe (Cincinnati Childrens Hospital, Cincinnati, Ohio, United States) began with a brief History of CPAP for Preterm Infants With
NeoReviews Vol.11 No.7 July 2010 e343

*Neonatology Clinic, Charite , Berlin University, Berlin, Germany.

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RDS. After having been pushed aside by mechanical ventilation (used with positive end-expiratory pressure [PEEP]) in the mid-1970s and 1980s, the high incidence of bronchopulmonary dysplasia (BPD) in survivors of mechanical ventilation resulted in a rebirth of CPAP as a noninvasive technique to try to decrease lung injury. CPAP once again is used frequently as an initial therapy for respiratory distress syndrome (RDS), with and without surfactant administration, as early as in the delivery room. Many new types of CPAP applications are available, but the benets of CPAP in preventing BPD remain unproven by randomized, controlled trials. Dr Jobe concluded that CPAP is being embraced with a new enthusiasm in 2009. In his talk Breathing of Preterm Infants at Birth, Arjan te Pas (Leiden, the Netherlands) focused on gas ow patterns during the rst breaths after birth. He presented new evidence that spontaneous breaths differ completely from those seen when manual inations are given during neonatal resuscitation. At birth, preterm infants use intrinsic PEEP and expiratory breaking, predominantly characterized by a breath hold, to create and maintain lung volume. He hypothesized that the effectiveness of respiratory support in the delivery room may be improved by using a strategy of aeration similar to spontaneous breathing patterns. During manual ination, delivery of PEEP should be guaranteed and breath hold could be mimicked by giving several sustained inations. It appears possible that this approach (CPAP and sustained inations) may prove to be superior in supporting the breathing pattern of a preterm infant who is breathing insufciently, rather than simply taking over and providing manual inations (see Table 1 in
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data supplement for issues and proposed actions). Jane Pillow (University of Western Australia, Perth, Australia) stated in her topic Transitional Changes During the First Minutes in Life Outside the Womb: Understanding the Mechanisms of Lung Injury that static and cyclic volutrauma and exposure to toxins (eg, high oxygen concentrations) remain the central issues in resuscitation research, establishing the optimal transition to postnatal life. In her opinion, other modiable environmental factors also may inuence lung injury. For example, heat, humidication, and ow of the inspired air (so-called conditioning of gas or gas conditioning); body temperature; and distribution of surfactant all may be involved. These areas urgently warrant further research. Focusing on the establishment of functional residual capacity (FRC) and using examples from recent studies by te Pas and coworkers with phase contrast imaging of the rst postnatal breaths in newborn rabbit pups, she stated that establishment of FRC is primarily dependent on PEEP. In contrast, establishment of adequate and appropriately distributed tidal volumes can be achieved rapidly with sustained inations. Supporting the data from tePas, she also suggested that the combination of sustained inations with the rst breaths and the use of PEEP during resuscitation may help establish noninjurious cyclic ventilation at appropriate FRC more effectively and efciently than alternative approaches. During the nal discussion, both te Pas and Pillow stated that further research studies are in progress that should help to dene further the optimal application of sustained inations and establish whether the physiologic benets translate into reduced lung injury. They stressed that

depending on the outcome of these studies, planning of clinical trials to assess the merits of these approaches in human infants would be appropriate in the near future. Bronchopulmonary Dysplasia: One Disease or Two? asked Mario Ru diger (Neonatology, Carl Gustav Carus Universita t, Dresden, Germany). He stated that classical BPD and new BPD not only differ in their clinical pictures but also in their pathogenesis and morphology. The arrest in alveolarization seen in patients who have new BPD is believed to result from a postnatal disturbance of lung development. Alveoli develop in utero at low oxygen concentrations, but ELGANs are exposed to relative hyperoxia, even if breathing room air. Relative hyperoxia leads to a decrease in hypoxia-inducible factor and its products, such as vascular endothelial growth factor (VEGF). Ru diger proposed that future research concentrate on clinically useful markers for better discrimination between the two types of BPD. In a second step, interventions should be tailored according to the pathogenesis of each and targeted to either type of disease. Whereas steroids might be appropriate for classical BPD, the new BPD may be prevented by substituting lung growth factors, such as VEGF, or by reducing the effects of relative hyperoxia. Colm ODonnell (Neonatal Services, National Maternity Hospital, Holles Street, Dublin, Ireland) spoke about Handling of the Neonate in the First Minutes of Life: Practical Observations. He found that newborns often were handled roughly, dried vigorously, and suctioned perhaps too enthusiastically. Preterm infants most often cried and breathed spontaneously after birth, even before any respiratory support was given, and clinical assessment of in-

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fant condition at birth was highly subjective, with observers frequently disagreeing. He concluded that the standard approach to all infants at birth appears to be to suspect that they will behave like, and respond to the same treatment, as an acutely asphyxiated term animal. Such an approach may lead to term and preterm infants receiving interventions that are not helpful and potentially harmful. During the nal discussion, the panel accepted that lming is a useful tool for reviewing and improving resuscitation skills. Although seminar participants agreed that videotaping seems useful for research and educational purposes, it is not yet ready for use in day-to-day clinical practice. Kajsa Bohlin (Neonatal Department, Karolinska Institute, Stockholm, Sweden) summarized the Effect of Different Ventilation Techniques on Surfactant Stability and Metabolism. The surfactant synthesis rate is slow, and the recycling of surfactant components between the airspaces and alveolar type II cells is more important in preterm compared with term lungs. The efcacy of exogenous surfactant treatment depends on distribution of surfactant, surfactant metabolism, and lung injury, all of which can be inuenced by ventilation strategy. Careful delivery room management is crucial because even only a few large breaths may impair surfactant treatment response and distribution pattern. Surfactant metabolism during CPAP and promising new lung protective ventilation strategies require further study, as does a means to reduce the susceptibility to inhibition of exogenous surfactant. Methods to assess the need for surfactant treatment and studies on how to incorporate surfactant administration into an early CPAP protocol to ensure optimal treatment response are warranted.

Anne Greenough (Kings College Hospital, London, United Kingdom) gave an overview on Mechanical Ventilation Versus CPAP: What are the Pros and Cons? She summarized four primary points: 1) Results from randomized trials suggest prophylactic or early nasal CPAP may reduce BPD, but further studies are required to determine the relative contributions of an early lung recruitment policy, early surfactant administration, and nasal CPAP in reducing BPD. 2) Highvolume high-frequency oscillatory ventilation (HFOV) reduces BPD, but whether it improves long-term lung function requires follow-up of infants entered into randomized, controlled trials. 3) Weaning from the respirator is best achieved by using modes supporting every breath. 4) A trial of rescue HFOV in severe respiratory distress with long-term outcomes is needed. The topic of Angela Kribs (Neonatology, Universita tsmedizin, Ko ln, Germany) was Treating Preterm Infants With Surfactant: An Overview of Application Techniques and Results. After demonstration of published methods of surfactant application in the delivery room (intrapartum into the nasopharynx before birth of the shoulders, via a laryngeal mask, nebulization) and discussion of the pros and cons, she presented her preferred method of surfactant application via a thin endotracheal catheter during spontaneous breathing in ELGANs. After introduction of this method, the need for mechanical ventilation was reduced from 77% to 48%, mortality from 35% to 12%, and the incidence of more than second-degree intraventricular hemorrhage from 32% to 5% compared with historical controls. The new method is being tested in two prospective, randomized trials.

Colin Morley (Melbourne, Australia) spoke about Understanding CPAP: Why Does It Work and When Should We Use It? He presented data about how CPAP aids the formation and maintenance of FRC, improves oxygenation, reduces airway resistance, improves compliance, conserves surfactant, improves the respiratory pattern, and reduces the need for ventilation in preterm infants. He suggested that the indications for the use of CPAP were: all very preterm infants breathing at birth, all infants who have dyspnea, and for apnea and postextubation in preterm infants. He concluded that more research is needed to understand how CPAP works in different situations and the optimum pressure or device and interface to use. It is also necessary to investigate which infants do well with nasal CPAP early on and which ones will fail CPAP and require early intubation, ventilation, and surfactant (see Table 2 in data supplement for issues and proposed actions). In his topic How is CPAP Currently Being Used: An Overview, Charles Christoph Roehr (Berlin, Germany) reported results from two questionnaire-based surveys of 274 institutions from German-speaking countries about the clinical indications for and type of CPAP equipment used. The primary indications were treating RDS (98%) and apneabradycardia-syndrome (96%) and following extubation (98%). Commercial CPAP systems (mostly respirator-generated) were used by 71% of units, with exclusively mononasal by only 9%, exclusively binasal by 55%, and all other units using both interfaces. The reported differences (in the starting and maximum tolerated pressure) reect personal experiences and preferences rather than sound evidence from clinical trials. Several questions reNeoReviews Vol.11 No.7 July 2010 e345

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garding the clinical use of CPAP remain unanswered, such as the appropriate device and pressure for specic clinical conditions, the ideal individual level of ow, and a practical protocol for weaning from CPAP. Such questions should be answered in well-conducted clinical trials. Speaking on CPAP and PEEP Provision: Physiologic Effect of Different Pressure Levels, Mathias Nelle (Berne, Switzerland) reviewed the literature about effects of nasal CPAP on different organ systems in neonates, especially how lung compliance, cardiac output, and blood ow to various organs can be affected. He suggested that many questions remain unanswered and the topic remains somewhat controversial. Generally, nasal CPAP appears to be well tolerated in neonates, but factors inuencing circulation should be known and considered in daily treatment procedures. Gerd Schmalisch (Berlin, Germany) provided insight into the Monitoring of Ventilation and Air Leakage During CPAP. In contrast to adults, little is known about volume and air leakage monitoring during CPAP in neonates because the measuring conditions are difcult and suitable equipment currently is not available. Mostly, indirect methods (transthoracic impedance measurements, breathing belts) are used. However, these techniques do not allow reliable volume measurements and do not give any information about air leakage. In a survey, several different direct measurement techniques to assess ventilation and air leakage based on the different CPAP interfaces (facial mask, head box, mono- or binasal prongs, pharyngeal or endotracheal tubes) were described, and their suitability was tested in clinical studies. Based on modeling, the relationship between air leakage, leak ow, and volume
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error were investigated and validated by in vitro measurements. The current display of air leakage as a percentage of measured patient ventilation has several disadvantages and should be replaced by direct measurement and display of leakage ow. The measurement of the leakage ow may be helpful in assessment of CPAP treatment and the prevention of adverse effects (eg, impairment of the nasal or upper airway mucosa).

Lung of the Extremely Low Gestational Age Neonate (ELGAN) in the Delivery Room. The seminar was generously funded by unconditional research grants by the ERS, Chiesi, Fisher & Paykel Healthcare, and Abbott Pharmaceuticals.

American Board of Pediatrics Neonatal-Perinatal Medicine Content Specications

Know the clinical strategies and therapies used to decrease the risk and severity of RDS. Know the indications for and techniques of continuous positive airway pressure (CPAP), Know the effects and risks of CPAP.

Essence, Reection, and Outlook

During the nal panel session of all experts, the following issues that might be answered by further research were emphasized: 1) Basic research on CPAP in the delivery room and evaluation of its chronic use; 2) Cross-over study to nd the optimal CPAP level, independent of FiO2 enhancement; 3) Search for parameters/methods to describe better the adaptation process of the term and preterm infant and the establishment of FRC; 4) Search for clinical evidence of the necessity for gas conditioning in the delivery room and during transport; 5) Search for the optimal CPAP interface between apparatus and infant (mask, single tube, binasal prongs, head box); and 6) Practical parameters for identication of preterm infants who only need CPAP and those who need additional surfactant (see Table 3 in data supplement for issues and proposed actions). The enthusiastic atmosphere of the seminar, its results, and the fruitful discussions delighted the participants and encouraged the organizers and speakers to continue this collaboration. Thanks to the generosity of the ERS, funding for a further research seminar at the upcoming ERS Congress in Barcelona on September 18, 2010, is planned. The seminar will concentrate on Managing the

Suggested Reading
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Kumar A, et al. Continuous positivepressure ventilation in acute respiratory failure. N Engl J Med. 1970;283: 1430 1436 Lindner W, et al. Delivery room management of extremely low birth weight infants: spontaneous breathing or intubation? Pediatrics. 1999;103:961967 Morley C, et al. Nasal CPAP or intubation at birth for very preterm infants. N Engl J Med. 2008;358:1529 Verder H, et al. Nasal continuous positive airway pressure and early surfactant therapy for respiratory distress syndrome in newborns of less than 30 weeks gestation, Pediatrics. 1999;103:E24 Arjan te Pas: Breathing of Preterm Infants at Birth te Pas A, et al. Breathing patterns in preterm and term infants immediately after birth. Pediatr Res. 2009;65:352356 te Pas A, et al. Spontaneous breathing patterns of very preterm infants treated with continuous positive airway pressure at birth. Pediatr Res. 2008;64:281285 te Pas A, et al. Ventilation and spontaneous breathing at birth of infants with congenital diaphragmatic hernia. J Pediatr. 2009;154:369 373 Jane Pillow: Transitional Changes During the First Minutes in Life Outside the Womb: Understanding the Mechanisms of Lung Injury Bjorklund LJ, et al. Manual ventilation with a few large breaths at birth compromises the therapeutic effect of subsequent surfactant replacement in immature lambs, Pediatr Res. 1997;42:348 Davis PG, et al. Resuscitation of newborn infants with 100% oxygen or air: a systematic review and meta-analysis. Lancet. 2004;364:1329 1333 Huh D, et al. Acoustically detectable cellular-level lung injury induced by uid mechanical stresses in microuidic airway systems. Proc Natl Acad Sci. 2007;104:18886 18891 Jobe A, et al. Injury and inammation from resuscitation of the preterm infant. Neonatology. 2008;94:190 196 Nucci G. Modeling airow-related shear stress during heterogeneous constriction and mechanical ventilation. J Appl Physiol. 2003;95:348 356 te Pas A, et al. Effect of sustained ination length on establishing functional residual capacity at birth in ventilated premature rabbits. Pediatr Res. 2009;66: 295300 te Pas A, et al. Establishing functional residual capacity at birth: the effect of sus-

tained ination and positive endexpiratory pressure in a preterm rabbit model. Pediatr Res. 2009;65:537541 Mario Ru diger: Bronchopulmonary Dysplasia: One Disease or Two? Jobe A, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med. 2001;163:17231729 Lassus P, et al. Pulmonary vascular endothelial growth factor and Flt-1 in fetuses, in acute and chronic lung diseases, and in persistent pulmonary hypertension of the newborn. Am J Respir Crit Care Med. 2001;164:19811987 Lassus P, et al. Vascular endothelial growth factor in human preterm lung. Am J Respir Crit Care Med. 1999;159: 1429 1433 Northway WH Jr, et al. Pulmonary disease following respirator therapy of hyalinemembrane disease. N Engl J Med. 1967; 276:357368 Walsh MC, et al. Safety, reliability and validity of a physiologic denition of bronchopulmonary dysplasia. J Perinatol. 2003;23:451 456 Colm ODonnell: Handling of the Neonate in the First Minutes of Life: Practical Observations Niermeyer S. International guidelines for neonatal resuscitation: an excerpt from the Guidelines 2000 for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care: International Consensus on Science. Pediatrics. 2000;106: E29 ODonnell CPF. Resuscitation of extremely preterm and/or low-birth-weightinfants time to call it. Neonatology. 2008;92:295301 ODonnell CPF, et al. Interobserver variability of the 5-minute Apgar score. J Pediatr. 2006;149:486 489 ODonnell CPF, et al. Spontaneous respiratory effort of newly born extremely preterm and/or extremely low birth weight infants [abstract]. PAS. 2006;5560:331 ODonnell CPF, et al. Clinical assessment of infant colour at delivery. Arch Dis Child Fetal Neonatal Ed. 2007;92: F465F467 Omar C, et al. Accuracy of clinical assessment of infant heart rate in the delivery room. Resuscitation. 2006;71:319 321 Kajsa Bohlin: Effect of Different Ventilation Techniques on Surfactant Stability and Metabolism Bjo rklund LJ, et al. Lung recruitment at birth does not improve lung function in immature lambs receiving surfactant.

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Roehr CC, et al. Use of continuous positive airway pressure (CPAP) in neonatal unitsa survey of current preferences and practices in Germany. Eur J Med Res. 2007;12:139 144 Mathias Nelle: CPAP and PEEP Provision: Physiologic Effect of Different Pressure Levels Aly H, et al. Does the experience with the use of nasal continuous positive airway pressure improve over time in extremely low birth weight infants? Pediatrics,. 2004;114:697702 Dani C, et al. Brain haemodynamic effects of nasal continuous airway pressure in preterm infants of less than 30 weeks gestation. Acta Paediatr. 2007;96: 14211425 De Paoli AG, et al. Pharyngeal pressure in preterm infants receiving nasal continuous positive airway pressure. Arch Dis Child Fetal Neonatal Ed. 2005;90: F79 F81 de Waal KA, et al. Cardiorespiratory effects of changes in end expiratory pressure in ventilated newborns. Arch Dis Child Fetal Neonatal Ed. 2007;92:F444 F448 Moritz B, et al. Nasal continuous positive airway pressure (n-CPAP) does not change cardiac output in preterm infants. Am J Perinatol. 2008;25:105109 Nowadzky T, et al. Bubble continuous positive airway pressure, a potentially better practice, reduces the use of mechanical ventilation among very low birth weight infants with respiratory distress syndrome. Pediatrics. 2009;123:1534 1540 Owen LS, et al. Neonatal nasal intermittent positive pressure ventilation: what do we know in 2007? Arch Dis Child Fetal Neonatal Ed. 2007;92:414 418 Zaramella P, et al. Does helmet CPAP reduce cerebral blood ow and volume by comparison with infant ow driver CPAP in preterm neonates? Intensive Care Med. 2006;32:16131619 Gerd Schmalisch: Monitoring of Ventilation and Air Leakage During CPAP Fischer HS, et al. Is volume and leak monitoring feasible during nasopharyngeal CPAP in neonates? Intensive Care Med. 2009;35:1934 1941 Mahmoud R, et al. Relationship between endotracheal tube leakage and underreading of tidal volume in neonatal ventilators. Acta Paediatr. 2009;98: 1116 1122 Schmalisch G, et al. Comparison of different techniques to measure air leaks during CPAP treatment in neonates. Med Eng Phys. 2009;31:124 130

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International Perspectives : Report on the International Seminar on Surfactant and CPAP in Extremely Low Gestational Age Neonates, Vienna 2009 Roland R. Wauer and Charles Christoph Roehr Neoreviews 2010;11;e343 DOI: 10.1542/neo.11-7-e343

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