Initial Ventilation Strategies During Newborn Resuscitation

Clin Perinatol 33 (2006) 65 – 82

Initial Ventilation Strategies During Newborn Resuscitation Benjamin J. Stenson, MDa,T, David W. Boyle, MDb, Edgardo G. Szyldc a

Simpson Centre for Reproductive Health, Royal Infirmary of Edinburgh, Edinburgh, EH16 4SU UK b Department of Pediatrics, Neonatal-Perinatal Medicine Fellowship Program, Indiana University School of Medicine, Indianapolis, IN, USA c Department of Newborn Medicine, Neonatal Medicine Fellowship Program (University of Buenos Aires), Hospital Interzonal General de Agudos Dr. Diego Paroissien, Buenos Aires Argentina

In term and preterm infants, the transition from intrauterine to extrauterine life requires the lungs to change from being fluid-filled to air-filled and for regular spontaneous respiration to become established. Many infants do not achieve this transition promptly without assistance and are given some form of artificial ventilation. Some infants may be profoundly asphyxiated and in need of substantial resuscitation, whereas others may be only mildly depressed or immature and in need of very little assistance. Professional guidelines advocate establishment of ventilation as the primary concern of neonatal resuscitation [1]. Until now, little distinction has been made between term and preterm infants in describing the most appropriate methods and equipment for providing artificial ventilation [1]. General guidance has been that ventilation with higher inflation pressures and longer inflation times may be required for the first several breaths than for subsequent breaths, that efficacy should judged by watching adequacy of chest rise and improvement in vital signs, and that if the ventilation device has a pressure release valve, it should release at approximately 30 cm H2O pressure [1]. Considering the frequency with which these techniques and devices are used,

T Corresponding author. E-mail address: [email protected] (B.J. Stenson). 0095-5108/06/$ – see front matter D 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.clp.2005.11.015 perinatology.theclinics.com

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there have been relatively few clinical studies in newborns on which to base recommendations for practice. Much of the information comes from small case series, studies performed in asphyxiated or immature animals, and in vitro tests. The Neonatal Working Group of the International Liaison Committee on Resuscitation (ILCOR) developed an international consensus on the scientific evidence in the literature relating to resuscitation of the newborn. The quality of the evidence was reviewed and discussed at a series of meetings, and the process of evidence gathering and evaluation was published on the Internet and opened to external peer review. This article reviews the literature to present the evidence base for recommendations with regard to the optimal devices and techniques for providing artificial ventilation during neonatal resuscitation.

Devices for delivering positive-pressure ventilation The devices and approaches that have been described most frequently for providing artificial ventilation during newborn resuscitation are as follows: Flow-inflating bags (anesthesia bags). These fill only when a source of compressed gas (oxygen, air, or a mix of the two) is connected. They do not usually have a fixed safety pop/off valve and may be used with or without an attached manometer. Self-inflating bags. These inflate automatically without a compressed gas source and entrain room air if piped gas is not connected. Most include a pop/off valve regulated to limit inflation pressure to around 35 cm H2O. Self-inflating bags are presently the most commonly used manual ventilation device [2,3]. T-piece. Piped compressed gas is delivered at a user-determined pressure to one port of a T-piece. One of the remaining two openings is attached to the facemask or endotracheal tube. Occlusion of the remaining open port of the device delivers gas to the mask or endotracheal tube at the preset inflation pressure for as long as the occlusion is maintained. The pressure delivered usually is displayed on a manometer. One commercially available T-piece device also allows positive end-expiratory pressure (PEEP) to be maintained between inflations (Neopuff; Fisher & Paykel, Auckland, New Zealand). Mouth ventilation. Mouth-to-mouth and mouth-to-nose ventilation can be used if no other equipment is available. Providers must be aware that this method carries a risk of infection from blood and birth canal materials, and it cannot be recommended. In areas of high human immunodeficiency virus prevalence, this risk may be substantial. If the method is used, the provider should wipe obvious material from the infant’s mouth and avoid swallowing or inhaling material [4]. Mouth-to-mask ventilation is associated with similar concerns.

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Evidence review Search strategy A search was conducted of Medline (Pub Med), Embase, and the Cochrane Database for articles relevant to the choice of device used for providing manual ventilation during neonatal resuscitation, combining the terms resuscitation, newborn, lung rupture, device, and ventilation. The initial search (combining resuscitation and newborn) yielded 7434 articles. The same search yielded 90 articles when bag was added to the search terms. The term Neopuff yielded nine articles. The combination of lung rupture, newborn, and resuscitation yielded 30 articles. A search combining device, newborn, and resuscitation yielded 620 articles. Review articles were included. Article titles and, where available online, abstracts were reviewed to select human and in vitro studies that were directly relevant to the devices used for neonatal resuscitation. English, Spanish, and French articles were reviewed. The reference lists of the studies selected were hand searched for further suitable studies. No abstract-only studies were included. Only peer-reviewed studies were included. Twenty-one articles were selected as relevant.

Mask ventilation of manikins Manikins or test lungs have been used by different investigators to evaluate the performance of the personnel or the devices or both used in neonatal resuscitation. Kanter [5] evaluated the ability of pediatric residents, pediatric intensive care nurses, and respiratory therapists to deliver adequate ventilation to a neonatal manikin using either a self-inflating bag (870 mL) or a 1000-mL Mapleson D anesthesia bag. Self-inflating bags delivered better minute ventilation than anesthesia bags. Technical difficulties with the anesthesia bag that contributed to a reduced level of ventilation included difficulty selecting the appropriate gas flow rate and setting the relief valve. Terndrup et al [6] evaluated the ability of prehospital personnel to ventilate a manikin. They compared mouth-to-mouth, mouth-to-mask, and three different sizes of self-inflating bag. They found that the Laerdal pocket mask was ineffective for infant manikin ventilation. There was little difference in performance between study participants despite a wide range of experience levels. Milner et al [7] compared ventilation with a Laerdal bag (Laerdal, Stavanger, Norway) with two different mouth-to-mask techniques in two different simulators and reported a wide variation in the maximal and mean pressures obtained and in the respiratory rate and inspiratory times delivered. Limited information was acquired from these three studies, in part because of the heterogeneity of the designs, differences in personnel involved, and types of device used. In all, a wide variation in performance related to the level of training was observed, which became more evident when flow-inflating bags were used. The risk of delivering excess inflation pressures was recognized many years ago [8,9]. To reduce the risk, a water manometer was described by Hey and

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Lenney in 1973 [10]. Next, spring-loaded pressure blowoff valves were developed [11]. Caution is still required because these spring-loaded valves permit high inflation pressures to be delivered by bag devices when the bag is squeezed vigorously [12]. The addition of a manometer when performing hand ventilation to prevent delivery of excessive peak inspiratory pressure also may be useful [13,14]. More recently, the performance of T-piece devices has been compared with bag devices when ventilating manikins by mask or by endotracheal tube. Target inflation pressures were delivered more reliably with T-piece devices than with flow-inflating bags [14–16]. O’Donnell et al [17] studied ventilation of a modified manikin using a 240-mL Laerdal self-inflating bag attached to a manometer or a Neopuff. They tested 34 caregivers using the combination of both devices and masks and monitored delivered pressures and volumes. Although there was little variation in the delivered pressures, there was a lot of variation in the volumes delivered with the different devices. This variation was substantially attributable to large variations in the amount of leak around the mask. The target peak airway pressures were generated reliably using the self-inflating bag with a manometer or the Neopuff.

In vivo studies There are few data describing the use of different devices in the resuscitation of newborn infants. No randomized studies comparing different devices were identified. Descriptive studies imply that these devices can be used safely and effectively in newborns. In 1979, Cole et al [18] described a resuscitation device that combined a flowinflating bag with an adjustable underwater pressure limiting system. They used this device over 8 months, during which 2000 infants were delivered. The population and the outcomes were not described. No comparison with any other method was provided. No complications attributable to the apparatus were identified. In 1981, Vyas et al [19] described the use of a pressure-limited T-piece device to deliver a prolonged slow rise inflation in the delivery room resuscitation of 9 newborns. In 1984, Milner et al [20] published a study in which they compared the resuscitation of nine term or near-term infants with a Laerdal bag attached to a facemask with another group of nine term or near-term newborns resuscitated using a T-piece to deliver long inspiratory times (1–5 seconds) through an endotracheal tube. Although the expiratory volumes measured during resuscitation with the facemask were approximately one third of the volumes obtained during resuscitation with the ET tube, the less invasive method was sufficient to help the infants to start their own respiratory efforts. The authors attributed this result to the triggering of Head’s reflex [20]. Without citing the data, the authors reported that the first effective respiratory effort was achieved earlier in the group resuscitated with the facemask owing to the delay needed for the intubation procedure.

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Field et al [21] studied the use of five neonatal/pediatric manual resuscitation devices to ventilate using long inspiratory times (N0.8 second) a group of infants delivered by cesarean section. They found that bags of 200 mL, 240 mL, and 275 mL were incapable of delivering such sustained inflations. For these long inspiratory times, bags with a volume of 450 mL or 500 mL were required. Hoskyns et al [22] described mask resuscitation using a pressure-limited T-piece in 22 full-term infants delivered by cesarean section. The method was equally successful to historical control infants resuscitated by bag. Massawe et al [23] compared the effectiveness of mouth-to-mask ventilation with bag-and-mask ventilation in 174 infants. They found that it was difficult to sustain frequencies of more than 10 breaths/min with mouth-to-mask ventilation. Allwood et al [24] compared the outcome and rate of intubation of newborns resuscitated during two separate time periods: one using bag and mask and the other using Neopuff. The outcomes are difficult to interpret because of the use of historical controls and the possibility of other changes in practice during the study period. Fewer convulsions occurred in association with the use of the Neopuff even though the prevalence of meconium aspiration syndrome was stable during the two time periods. No complications resulting from the use of the Neopuff were identified when it was used for all resuscitations from a birth cohort of 8000 deliveries [24]. Neopuff also was used without complication during the stabilization of 104 infants in the National Institute of Child Health and Human Development (NICHD) network pilot study of using continuous positive airway pressure (CPAP) and PEEP in resuscitation of infants less than 28 weeks’ gestational age [25]. One of the concerns when resuscitating infants with mask ventilation is the potential for gastric distention to limit lung expansion. Vyas et al [26] showed that no gas flow reached the stomach when ventilating newborns with pressures of less than 3.5 kPa. Devices that provide positive end-expiratory pressure PEEP can be maintained during manual ventilation with a flow-inflating bag and can be delivered using a Neopuff. Studies comparing Neopuff with anesthesia bags indicate that PEEP is maintained more consistently with the Neopuff [15]. PEEP valves can be attached to self-inflating bags. No study has evaluated the efficacy of PEEP valves in relation to neonatal resuscitation. Masks Data comparing the performance of different masks for resuscitation of newborns are limited. In one study, the percentage of leak was calculated comparing five different types of masks in 44 healthy, spontaneously breathing infants during the first few days after birth. This investigation showed that a soft circular mask, which adapts its shape to the contours of the infant’s face, leaks less than a molded triangular mask. This study was not performed in infants needing resuscitation [27].

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Treatment recommendations After a consensus process, these data were condensed into a series of short clinical practice statements with associated levels of evidence. 





 

Ventilation of newborn infants can be performed effectively with a flowinflating bag, a self-inflating bag, or a pressure-limited T-piece device (level of evidence 4) [20,22,24]. There is insufficient evidence to recommend any one type of device over another. When bag-and-mask ventilation is performed, the use of an online manometer facilitates the delivery of more consistent pressures (level of evidence 6) [13,14]. Inflation pressures and inspiratory times are delivered more consistently in mechanical models when using T-piece devices than when using bags (level of evidence 6) [14–17]. The pressure-limiting pop/off valves on self-inflating bags are not fully effective when the bags are used vigorously (level of evidence 6) [12]. Although appropriate pressures can be achieved with self-inflating bags of various sizes, bags of more than 450 mL provide more consistent ventilation volumes (level of evidence 6) [21].

Initial ventilation strategies in term infants Evidence review Search strategy The literature was reviewed to determine whether there was sufficient evidence to justify specific recommendations with regard to the optimal initial ventilation strategy in term infants. A search was conducted through Medline for articles from 1966 onward, followed by hand-searching review articles and by examining the citations of individual articles (especially for references before 1966). An additional strategy was to search for articles that have referenced a specific article (eg, search for all articles that have referenced Vyas H, et al. J Pediatr 1981;99:635-639). The Medline search combined the terms infant, newborn, or infant, premature, with resuscitation or cardiopulmonary resuscitation or respiration, artificial. This search yielded 5458 articles. Adding positivepressure respiration resulted in 255 articles. Including asphyxia neonatorum in this search increased the yield to 531 articles. The search term delivery, obstetric, was exploded and substituted in the aforementioned strategy for asphyxia neonatorum resulting in 241 articles. The Embase and the Cochrane databases were searched using a similar strategy. No abstract-only studies were included. Only peer-reviewed studies were included. Studies from stillborn infants and isolated lung preparations were excluded. Twenty articles were selected as relevant and included for review.

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No prospective, randomized controlled trials comparing different strategies of artificial ventilation for depressed term newborns were identified. Present recommendations are based on extrapolation from small case series in which physiologic measurements were made in newborns during the onset of spontaneous respiration and several case series in which measurements were made in asphyxiated newborns requiring resuscitation. These studies (some conducted N40 years ago) were elegantly reviewed by Milner in 1991 [28]. Animal studies of the pivotal role of effective ventilation in resuscitation from asphyxia The effectiveness of positive-pressure ventilation alone in the resuscitation of asphyxiated term newborns was established through a series of animal experiments [29–34]. These studies provide detailed descriptions of the cardiorespiratory and metabolic responses to severe asphyxia in newborn mammals of several species. The qualitative changes in the pattern of respiratory activity, heart rate, and blood pressure are similar in all species, including humans [32]. With the onset of asphyxia, there is a characteristic cycle of events. Primary apnea is followed by a variable period of gasping, after which the animal goes into secondary apnea. In all species studied, respiratory activity ceases before effective cardiac activity fails, which is in contrast to the adult, in which acute asphyxia results in abrupt circulatory failure before respiratory efforts cease [32]. Heart rate decreases immediately, whereas blood pressure tends to increase initially, then decreases. In all species, ventilation of the lungs causes a rapid increase in heart rate and blood pressure [32]. These studies show that positive-pressure ventilation alone is effective for resuscitation of apneic, bradycardic newborn animals, provided that mean arterial blood pressure is above a critical value. Uniformly, the first sign of successful resuscitation was a prompt increase in heart rate (Fig. 1). In these studies, chest compressions were initiated if the heart rate did not increase within 30 to 45 seconds of beginning ventilation. Animals that failed to respond to positivepressure ventilation alone were found to have significantly lower mean arterial blood pressure compared with animals that responded with a prompt increase in heart rate [29,30,33,34]. The level to which arterial blood pressure decreases before chest compressions are necessary differs among species. In newborn monkeys and lambs, mean arterial blood pressure is 45 to 60 mm Hg; the need for chest compressions was associated with a blood pressure less than 15 mm Hg [29,33]. The mean arterial pressure in newborn rabbits is approximately 30 mm Hg, and chest compressions do not seem to be necessary until the blood pressure has decreased to less than 5 to 8 mm Hg [30,34]. Recovery of the animals in response to chest compressions was heralded by an increase in heart rate and blood pressure. In an asphyxiated newborn rabbit, the heart rate and mean arterial blood pressure were measured immediately before starting positivepressure ventilation to evaluate whether a threshold level of heart rate or blood pressure might exist below which the animal would fail to respond to positive-pressure ventilation alone. Animals that survived had a significantly

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Fig. 1. Response of a fetal monkey to asphyxia and resuscitation. (From Dawes GS, Jacobsen HN, Mott JC, et al. The treatment of asphyxiated, mature foetal lambs and rhesus monkeys with intravenous glucose and sodium carbonate. J Physiol 1963;169:167–84; with permission.)

higher blood pressure at the start of positive-pressure ventilation than animals that failed to respond; no such relationship was found between survival and heart rate [34]. Studies of pressure and volume changes in healthy, term infants during the onset of spontaneous respiration Several small series have described the pressure and volume changes in healthy term newborns during the onset of spontaneous respiration [35–38]. In these studies, the peak inspiratory pressures generated were highly variable.

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Karlberg and Koch [35] reported pressure/volume changes with the first breaths and showed an initial tidal volume of 12 to 67 mL with negative intraesophageal pressures of 70 cm H2O (range 10 to 70 cm H2O). In one group of infants, it was noted that ‘‘inflation of any significant volume took place only after a negative intrathoracic pressure of 20–40 cmH2O was created’’ [35]. In a study by Vyas et al [38], mean inspiratory pressure, measured in the lower esophagus, was 52 cm H2O (range 28 to 105 cm H2O). The phenomenon of an ‘‘opening pressure’’ observed in earlier studies was rarely shown in later studies. Inspiratory volumes of approximately 35 to 45 mL were similar among studies. A functional residual capacity (FRC) could be shown by the end of the first breath and correlated with the inspiratory volume and possibly was related to inspiratory time [36,38].

Studies of pulmonary mechanics in asphyxiated newborns requiring resuscitation Several case series have examined the physiologic responses of asphyxiated term and preterm infants to resuscitation [20,22,39–44]. These studies included a limited number of infants (range 9–42), most of whom were born by cesarean section. As with spontaneously breathing infants, initial inspiratory pressures were highly variable, ranging from 18 to 60 cm H2O (mean 30–40 cm H2O), to deliver an adequate tidal volume. In one study, two thirds of the infants studied required peak inflation pressures exceeding 50 cm H2O to achieve adequate minute ventilation [42]. With subsequent breaths, peak inspiratory pressures were found to be less (mean 20–29 cm H2O; range 14–42 cm H2O). In most studies, pressure was held constant, and changes in volume were measured. In a study by Hull in 1969 [41], however, asphyxiated term infants were resuscitated by positive-pressure ventilation using an apparatus set to deliver a ‘‘stroke volume’’ of 40 mL. This resulted in the generation of peak inflation pressures of 18 to 48 cm H2O (mean 27 cm H2O); subsequent pressures ranged from 14 to 35 cm H2O. FRC was established in the first minute of positive-pressure ventilation [41]. In these studies, inspiratory time varied from 0.5 to 2 seconds. Where noted, inflation rates were maintained at 30 to 40 breaths/min. Some experts have advocated the use of prolonged initial inflations. Guidelines have stated that ‘‘higher inflation pressures and longer inflation times may be required for the first several breaths than for subsequent breaths’’ [1]. In 1981, Vyas et al [19] published a series of nine patients in which a prolonged inflation of 5 seconds was used for the first breath only; subsequent breaths had an inflation time of 1 second. In four patients, the peak inspiratory pressure was set at 30 cm H2O and maintained for 5 seconds; in five patients, the peak inspiratory pressure was increased to 30 cm H2O slowly over 3 to 5 seconds. Both maneuvers produced a twofold increase in FRC compared with historical controls. In a subsequent study, 22 full-term infants were resuscitated successfully with positive pressure delivered via facemask with a prolonged first inflation of 2 to 5 seconds (mean inflation pressure 27.5 cm H2O) and subsequent inflations of 0.5 to 1 second (inflation pressure 12–32 cm H2O) [22].

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The adequacy of lung inflation also has proven to be difficult to determine in an objective manner. Current recommendations focus on peak inflating pressures or observations of chest wall movement. Relying on peak inflation pressures is a problem because the volume of gas delivered with any inflation is unpredictable and depends on lung compliance. In many of the above-cited studies, there is no mention of how the effectiveness of positive-pressure ventilation was assessed. Chest movement as an indicator of adequate ventilation was mentioned in one study [43], and in another study, ventilation was found to be ‘‘satisfactory’’ if the heart rate increased to greater than 130 beats/min within 5 to 15 seconds [42]. Measurement of tidal volume may provide the best assessment of lung inflation; however, current devices used for neonatal resuscitation do not provide any information regarding the volume of gas being delivered to the newborn. The best available information regarding the effectiveness of artificial ventilation is from the animal studies of the 1960s. As previously reviewed, the first sign of successful resuscitation was a prompt increase in heart rate. Perlman and Risser [45] performed an observational study and found that chest compressions or epinephrine were administered in 0.12% of delivery room resuscitations. In approximately two thirds of the infants who received chest compressions or epinephrine, ineffective or improper initial ventilatory support was the presumed mechanism for continued neonatal depression. The findings of this study confirm the primary importance of proper, effective initial ventilatory support in resuscitation of asphyxiated newborns in the delivery room. The role of CPAP/PEEP in the initial stabilization of term infants after birth has not been assessed. Treatment recommendations Based on the limited available data, the following consensus statements concerning initial ventilation of the apneic, bradycardic newborn term infant were agreed: 

When properly performed, positive-pressure ventilation alone is effective in resuscitation of most apneic or bradycardic newborns (level of evidence 5, 6) [29,30,33,34,42,44,45].  The primary measure of adequate initial ventilation is prompt improvement in heart rate (level of evidence 5, 6) [29,30,33,34,42]; chest wall movement has been described, but not adequately assessed (level of evidence 5, 6) [30,43].  In term infants, initial spontaneous or assisted inflations serve to initiate a FRC (level of evidence 5) [19,35–39,41,43]. The optimal pressure, inflation time, and flow rate required have not been determined.  In case series examining the physiologic changes with initial ventilation of human neonates, the peak pressures used to initiate ventilation varied (18–60 cm H2O); flow rates and inspiratory times were seldom reported.

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Average initial peak inflating pressures of 30 to 40 cm H2O (inflation time undefined) were used to ventilate unresponsive term infants successfully (level of evidence 5) [20,39–43,46].  In a single small series, a sustained inflation pressure at 30 cm H2O for 5 seconds for the first breath was found to be effective in establishing lung volume in term infants requiring resuscitation; the risks and benefits of this practice have not been evaluated (level of evidence 5) [46].  Artificial ventilation rates of 30 to 60 breaths/min are commonly used, but have not been investigated (level of evidence 8).

Initial ventilation strategies in preterm infants There is still uncertainty among clinicians whether the primary aim in the early hours of a preterm infant’s life should be to avoid intubation and provide support with nasal CPAP or to intubate electively to provide surfactant therapy before determining what other respiratory support is then appropriate. Whichever approach is preferred, many preterm infants require a period of artificial ventilation during their initial stabilization after birth. It is oversimplistic to consider prematurity as a single entity when it includes at one extreme infants at the margins of viability and at the other infants who are nearing term. Infants born after 30 weeks now seldom die of respiratory failure or develop chronic lung disease. A consideration of the risks and benefits of different methods of applying positive-pressure ventilation after birth is likely to be most relevant to infants less mature than this. Previous guidance about initial ventilation has been geared toward rapid restoration of oxygen delivery in apneic mature infants who may be asphyxiated and are at low risk of adverse pulmonary outcome rather than toward optimizing the respiratory outcomes of apniec preterm infants, most of whom are not asphyxiated. A large body of evidence shows that ventilation-induced lung injury occurs when ventilation strategies result in excess end-inspiratory lung volume (volutrauma) or inadequate end-expiratory lung volume (atelectrauma) [47–49]. The question is whether these injury mechanisms might operate sufficiently quickly in very preterm infants to give them relevance in the context of a brief period of manual ventilation after birth during initial stabilization. If so, should there be separate recommendations for preterm infants about methods for providing assisted ventilation during neonatal resuscitation? Evidence review Search strategy A search was conducted of Medline (Pub Med), Embase, and the Cochrane Database for articles relevant to the initial resuscitation at birth of preterm infants, combining the terms resuscitation, infant, newborn, and positive-pressure ventilation. This search yielded 6598 articles. The same search yielded 664 articles

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when animal, newborn, was substituted for infant, newborn. Substituting inflation pressure for positive-pressure ventilation yielded 47 articles on human infants and 13 on animal studies. The terms PEEP and newborn resuscitation were combined; this yielded 390 articles. The terms PEEP and premature newborn were combined; this yielded 520 articles. Article titles and, where available online, abstracts were reviewed to select human and animal studies that were directly relevant to resuscitation of a newborn preterm infant, particularly where the effects of immediate neonatal treatment strategies might be separable from subsequent strategies. The reference lists of these studies were hand-searched. Other articles already known to one of the authors (B.S.) were included, and their reference lists were hand-searched. No abstract-only studies were included. Only peer-reviewed studies were included. Twenty-six articles were selected as relevant to the question. No level of evidence 1 or level of evidence 2 was identified from clinical trials in preterm infants in which the primary hypothesis examined the effects of different initial ventilation strategies on clinical outcome. A considerable body of evidence from animal and human studies was found, however, to indicate that a more measured approach to the resuscitation of preterm infants should be considered pending the availability of higher quality evidence. Inflation pressures and volumes In newborn preterm animals, histologic lung injury becomes demonstrable within a few minutes of the onset of mechanical ventilation [50]. Several animal studies have examined the effect of variations in the characteristics of the initial inflations on the subsequent clinical course. Bjorklund et al [51] showed that preterm lambs who were given six very large sustained manual lung inflations after birth before the onset of pressure-controlled ventilation had a poorer response to surfactant, worse lung mechanics, and worse gas exchange during the next 4 hours and greater histologic lung injury than control lambs who were not given the large volume inflations. In a further preterm lamb study, the same authors investigated the effect of five sustained inflations of 8 mL/kg, 16 mL/kg, or 32 mL/kg before ventilation and surfactant treatment [52]. Compared with control animals without these inflations, these three groups of animals showed a dose-dependent histologic lung injury, impaired surfactant response, and lung mechanics over the next 4 hours. Wada et al [53] had similar findings. Prior administration of surfactant reduced, but did not eliminate, this injury [53,54]. When pressure-controlled ventilation with PEEP was started at birth, however, and the same inflations were given after 10 or 60 minutes, the injury was not seen [54]. Although it was injurious in preterm lambs when delivered as the first breath, a tidal volume of 8 mL/kg is within the normal range for spontaneously breathing infants with healthy lungs [55]. This fact suggests the possibility that attempting to achieve ‘‘normal’’ chest movement immediately with the first artificial breaths may be injurious in preterm infants; this has not been studied directly, but is supported by indirect evidence. Upton and Milner [43] increased

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inflation pressure during resuscitation until they observed chest wall movement. Most of the infants they studied were preterm. During the first 10 breaths after birth, a median pressure of 40 cm H2O was required, and the median tidal volume generated when ventilation was judged by chest rise was 8.6 mL/kg. Within 1 minute of ventilation, the same volumes could be delivered with much lower pressures. In a trial of different prophylactic surfactant regimens that enrolled 651 infants, chronic lung disease was found to be significantly more common among infants randomized to receive surfactant treatment immediately after birth than in infants administered surfactant at 10 minutes of age [56]. This may have been a chance finding, but aside from the difference in timing of surfactant in this trial protocol, the infants treated early were exposed to more manual ventilation from birth. Numerous surfactant trials have failed to show any important influence of variations in surfactant type or timing on the incidence of chronic lung disease. It is possible that the increased risk of chronic lung disease was attributable to the difference in initial manual ventilation, as observed in the animal studies. Trials of different tidal volumes during initial inflation have not been performed in newborn infants. Menakaya et al [57] resuscitated preterm infants using a ventilator with volume guarantee set to deliver a tidal volume of 5 mL/kg; despite this, the mean tidal volume delivered was 9.4 mL/kg. Volume-targeted resuscitation is likely to be challenging because of the presence of air leaks around the mask or endotracheal tube, the fact that a variable proportion of each of the early breaths is retained during the establishment of FRC, the possibility that an endotracheal tube might be inserted into one main bronchus, and the highly variable spontaneous respiratory activity of the infant. Inflation pressure is a poor proxy for inflation volume under circumstances of variable compliance. This is particularly likely to be the case when mask ventilation is used [17]. Most neonatal ventilation is pressure controlled, however, and limiting inflation pressure offers some protection against volutrauma. Comparative studies of different inflation pressures have not been done in preterm infants, so recommendations can be based only on what has been described in case series and on a general principle that excess inflation should be avoided. Three descriptive studies and one randomized trial in preterm newborn infants suggest that most can be effectively resuscitated with an inflation pressure of 20 to 25 cm H2O, and few need more than 30 cm H2O [58–61]. Hird et al [58] measured the inflation pressure during initial resuscitation in 70 intubated verylow-birth-weight infants. The median pressure required to generate adequate chest inflation was 22.8 cm H2O. No infant required a pressure greater than 30 cm H2O. Lindner et al [59] used a 15-second sustained inflation delivered through a nasopharyngeal tube to stabilize very-low-birth-weight infants (b1000 g) before starting nasal CPAP. If this inflation was not successful, it was repeated at 25 cm H2O, and nasopharyngeal intermittent positive-pressure ventilation was administered at the same pressure. Nonresponding infants were intubated. Of the 67 infants studied, 40 were stabilized without intubation. The mean inflation pressure for the intubated infants was 22 cm H2O. In a second study in which

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infants less than 29 weeks’ gestational age were randomized to receive a sustained nasopharyngeal inflation or nasopharyngeal intermittent positive-pressure ventilation after birth, Lindner et al [61] stabilized 44 of 61 infants without intubation. The inflation pressure used was 20 to 25 cm H2O in 29 infants and 30 cm H2O in 14 infants. Inflation pressures delivered to the intubated infants were not recorded. Hoskyns et al [60] resuscitated 21 intubated preterm infants of 25 to 36 weeks’ gestation using a T-piece with a mechanical pressure regulator and found that the mean (SD) inflation pressure used was 27.3 (4.8) cm H2O. Assessments of the adequacy of inflation made visually in preterm infants or manually in vitro are unreliable [62,63] and may result in unnecessarily large tidal volumes [43]. Excess pressures and volumes may be easier to avoid if a pressure-monitoring device is used [15,64]. Sustained inflations Previous guidance suggesting that longer inflation times may be necessary for the first several breaths than for subsequent breaths [1] was based on evidence from a small series of term infants [19]. The use of sustained inflations during resuscitation has since been studied in preterm infants and in preterm animals. In a randomized study in preterm lambs, Klopping-Ketelaars et al [65] found that applying a series of five inflations, each sustained for 5 seconds with PEEP between the inflations, before the onset of mechanical ventilation with PEEP produced no significant alteration in gas exchange or lung mechanics during the subsequent 8 hours compared with immediate commencement of mechanical ventilation alone. Lindner et al [61] used a ventilator to deliver controlled inflations via a nasopharyngeal tube to 61 preterm infants born at 25 to 28.9 weeks of gestation. The primary aim was to enable the infants to establish spontaneous breathing on CPAP and avoid intubation and ventilation. Infants were randomized to receive either a 15-second sustained first inflation followed by CPAP or a 30-second period of intermittent positive-pressure ventilation at 60 breaths per minute followed by CPAP. There was no significant difference in the need for intubation and ventilation between the two approaches. Harling et al [66] randomized 52 preterm infants to receive a first inflation lasting 2 seconds or 5 seconds before the commencement of tidal ventilation and identified no advantage to the sustained inflation in terms of gas exchange. Positive end-expiratory pressure There has been little work on the use of PEEP as part of the initial ventilation strategy in the delivery room. A meta-analysis in the Cochrane database identified no human trials [67]. Since the publication of that meta-analysis, one trial has been published [68]; however, the trial reports the outcomes of infants randomized to CPAP or no CPAP, and it is impossible from the study design to evaluate the role of PEEP during initial ventilation in the delivery room in ventilated infants. In preterm lambs, the application of PEEP during a 10-minute period of ventilation immediately after birth improved gas exchange and lung mechanics and reduced histologic injury compared with mechanical ventilation

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without PEEP [69]. In a similar study, Probyn et al [70] found that in addition to improving gas exchange during the first 15 minutes of life, the application of PEEP during initial ventilation of preterm lambs did not result in higher peak inspiratory pressures for a given tidal volume. Prophylactic surfactant and antenatal steroids were not used in either study. The data indicate that PEEP during resuscitation is worthy of further study and suggest that where ongoing ventilation is planned, PEEP should be applied as soon as is practicable. The use of CPAP as a primary treatment is the subject of another article in this issue. Treatment recommendations The following consensus statements about the resuscitation of newborn premature infants were agreed. Each statement is based on low-level evidence and may need to be refined as the knowledge base improves. 

When ventilating preterm infants after birth, large volume lung inflations, as indicated by excessive chest wall movement, should be avoided (level of evidence 6) [51–54].  Although measured peak inflation pressure does not correlate well with volume delivered when respiratory mechanics are changing, monitoring of pressure may help to provide consistent inflations and to avoid unnecessarily high pressures. (level of evidence 6) [15,17,64].  If positive-pressure ventilation is required during initial stabilization, an initial inflation pressure of 20 to 25 cm H2O is adequate for most preterm infants. If a prompt improvement in heart rate or chest movement is not obtained, higher pressures may needed (level of evidence 5) [58–61].  There is insufficient information about the value of PEEP during resuscitation. If ongoing ventilation is considered necessary, however, PEEP should be employed as soon as practicable (level of evidence 6) [69,70]. Gaps in the knowledge Evidence levels for the optimal devices and methods of providing ventilation during resuscitation in term and preterm infants are low, with few clinical trials. Several independent groups now have shown that randomized trials of resuscitation measures in preterm and term infants are feasible. Researchers are encouraged to study further the optimal volumes and pressures for initial lung inflation and the use of PEEP.

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