REVIEW URRENT C OPINION
Sustained inflation during neonatal resuscitation Martin Keszler
Purpose of review Sustained inflation performed shortly after birth to help clear lung fluid and establish functional residual capacity in preterm infants is gaining popularity, but definitive evidence for its effectiveness is lacking. Although there is a sound physiologic basis for this approach, and much preclinical experimental evidence of effectiveness, the results of recent animal studies and clinical trials have been inconsistent. Recent findings The most recent data from a multicenter randomized trial suggest a modest benefit of sustained inflation in reducing the need for mechanical ventilation in extremely-low-birth-weight infants. However, the impact may be more modest than earlier retrospective cohort comparisons suggested. The trend toward more airleak and a higher rate of intraventricular hemorrhage is worrisome. Sustained inflation may be ineffective unless some spontaneous respiratory effort is present. Several on-going trials should further clarify the putative benefits of sustained inflation. Summary Delivery room sustained inflation is an attractive concept that holds much promise, but widespread clinical application should await definitive evidence from on-going clinical trials, Keywords bronchopulmonary dysplasia, clearance of lung fluid, delivery room resuscitation, extremely low birth weight, prematurity, sustained inflation
INTRODUCTION To achieve a successful transition to extrauterine life, newborn infants must rapidly aerate their lungs, clear lung fluid from the air spaces and achieve an adequate functional residual capacity (FRC). Each of these facilitates the final critical component of neonatal transition: a dramatic increase in pulmonary blood flow. The full-term infant is usually able to achieve this remarkable transition quickly and effectively, but this is often not the case in the very preterm infant. Preterm infants, because of their limited muscle strength, excessively compliant chest wall, limited surfactant pool and incomplete lung development, are often unable to generate the critical opening pressure needed to achieve adequate lung aeration. Their excessively compliant chest wall fails to sustain any FRC that may have been achieved. Similarly, they may be unable to generate sufficient negative intrathoracic pressure to effectively move lung fluid from the air spaces to the interstitium, lymphatics and veins. Preterm infants are commonly born by cesarean delivery, often without adequate labor, a situation known to delay activation of the epithelial sodium channels, that switch the lung from a sodium-secreting to a sodium-absorbing state. This delay results in an
increased amount of residual lung fluid. The consequence of all these factors is that subsequent tidal volume (VT) breathing, whether spontaneous or generated by positive pressure ventilation, takes place in lungs that are still partially fluid-filled and partially atelectatic. This situation leads to maldistribution of the VT to a fraction of the preterm lung, which leads to volutrauma even when tidal volumes are in a ‘well tolerated’ physiologic range.
POSITIVE END-EXPIRATORY PRESSURE IN DELIVERY ROOM Extensive preclinical and clinical evidence supports the importance of positive end-expiratory pressure (PEEP) or continuous positive airway pressure (CPAP) during the initial stabilization of preterm Department of Pediatrics, Alpert Medical School of Brown University, Women and Infants Hospital, Providence, Rhode Island, USA Correspondence to Martin Keszler, MD, Department of Pediatrics, Women and Infants Hospital of Rhode Island, 101 Dudley Street, Providence, RI 02905, USA. Tel: +1 401 274 1122x47490; e-mail: [email protected] Curr Opin Pediatr 2015, 27:145–151 DOI:10.1097/MOP.0000000000000204
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KEY POINTS There is a sound physiologic basis for sustained inflation in very preterm infants and much preclinical experimental evidence of effectiveness, but results of recent animal studies and clinical trials have been inconsistent. The optimal inflation pressure and duration of sustained inflation have not been definitively established; additionally, they may vary substantially between infants. The risk–benefit ratio and the optimal target population have not yet been defined; potential risks of sustained inflation include increased airleak and increased intracranial hemorrhage. Several on-going studies may shed further light on these questions. Until then, the widespread adoption of sustained inflation is not recommended outside of clinical trials.
infants. Siew et al. [1] demonstrated the benefits of PEEP in an elegant study using phase-contrast radiography in preterm rabbits, showing that virtually no FRC was established after several minutes of positive pressure ventilation (PPV) when PPV was delivered without PEEP. In contrast, FRC was rapidly established when 5 cm of PEEP was applied. Based on limited experimental evidence and a sound theoretical basis, Neonatal Resuscitation Program (NRP) and International Liaison Committee on Resuscitation (ILCOR) guidelines state that ‘PEEP is likely to be beneficial during initial stabilization of apneic preterm infants and should be used if suitable equipment is available’ [2,3]. The CPAP or Intubation (COIN), Surfactant, Positive Pressure, and Oxygenation Randomized Trial (SUPPORT) and Vermont Oxford Network Delivery Room Management (VON-DRM) randomized controlled trials (RCTs) [4–6] demonstrated that provision of CPAP to spontaneous breathing very-low-birth-weight (VLBW) infants is at least as effective as intubation and surfactant. However, the failure rate of CPAP was high and bronchopulmonary dysplasia (BPD) rate was only marginally reduced in those studies [7]. Experimental data indicate that volutrauma can occur within minutes of birth in premature animals [8], suggesting that achieving an even distribution of VT from the very onset of tidal breathing by more rapid establishment of homogeneous lung aeration might be advantageous.
RATIONALE FOR SUSTAINED INFLATION As liquid has much greater viscosity than air, the resistance to moving liquid through small airways is 146
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orders of magnitude higher than that for air, making the time constants required to clear fluid from the airways much longer. Therefore, a prolonged (sustained) inflation applied soon after birth should be more effective than short inflations in clearing lung fluid and establishing homogeneous aeration. The concept of sustained inflation is not new; Kolobow et al. [9] promoted the concept of ‘lung conditioning’ in the early 1980s based on observations that lungs of very preterm lambs showed visible recruitment when inflated to a pressure of 35 cmH2O for several seconds, whereas short inflations at that pressure resulted in no appreciable aeration. Histologic and clinical evidence of hyaline membrane disease could be prevented by this intervention [9,10]. Similarly, more than 30 years ago, Vyas et al. [11] observed that when giving positive pressure inflations to intubated infants during initial resuscitation, air continued to enter the lung for more than 1 s. Prolonging the inflation time to 5 s resulted in improved lung inflation and facilitated the establishment of a FRC [11]. Despite much animal data support of the theoretical advantages of sustained inflation in extremely preterm infants, direct evidence from clinical trials remains inconclusive. Key older studies will be reviewed here, along with the most recent literature on the use of sustained inflation in the delivery room.
PRECLINICAL STUDIES OF SUSTAINED INFLATION te Pas et al. [12] demonstrated that both 20-s sustained inflation and 5 cmH2O of PEEP promote uniform lung aeration and create a larger FRC at birth than ventilation without PEEP. The effects of PEEP and sustained inflation were additive and PEEP was essential to maintain FRC both with and without sustained inflation. The authors suggested that combining these two techniques during stabilization of preterm infants would help establish effective breathing, promote uniform ventilation and reduce the need for intubation in the delivery room. These authors also investigated the effect of inflation time on lung aeration pattern, VT, and FRC immediately after birth in preterm rabbits [13]. The first inspiratory volume significantly increased with inflation duration from a median of 0.2 ml/kg for 1 s inflation to 4.5 ml/kg for 5-s inflation, 10.4 ml/kg for 10-s inflation and 23.4 mL/kg for 20-s sustained inflation. The lung was uniformly aerated, and the FRC fully recruited after a 20-s sustained inflation. Sobotka et al. [14] examined the effects of sustained inflation on pulmonary and carotid artery Volume 27 Number 2 April 2015
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blood flow to address concerns that sustained increase in intrathoracic pressure from a sustained inflation could have detrimental effects on pulmonary blood flow. They compared a single 40-cmH2O sustained inflation for up to 1 min (or until a volume of 20 ml was delivered) to conventional ventilation in preterm lambs of 127-day gestation. Pulmonary blood flow improved in the sustained inflation group compared with controls. Cerebral blood flow was higher in control animals, but cerebral oxygen delivery was not different. Lung compliance and gas exchange were dramatically improved in the sustained inflation group. The investigators concluded that sustained inflation did not impair the hemodynamic transition to extrauterine life.
RECENT PRECLINICAL STUDIES &
Klingenberg et al. [15 ] compared no sustained inflation, five 3-s inflations and a single 30-s inflation both at 30 cmH2O in asphyxiated late preterm lambs and demonstrated a more rapid improvement in heart rate, gas exchange and lung compliance in the 30-s sustained inflation group, whereas the five short inflations offered no benefit compared with control animals. These findings are consistent with other studies and confirm the long time constants required to clear fluid from the airways. Polglase et al. [16 ] compared pressure-limited sustained inflation at 40 cmH2O for 20 s to volumecontrolled sustained inflation targeting a delivered volume of 15 ml/kg over 5 s (and sustained for another 15 s) in 131-day gestation intubated, preterm lambs. Both methods achieved a comparable degree of end-inflation lung volumes and regional ventilation homogeneity. Peak pressure during sustained inflation was significantly higher and more variable in the volume-sustained inflation lambs (50.2 6.7 cmH2O) versus pressure-sustained inflation lambs (40.8 1.2 cmH2O; P ¼ 0.004). Volume-sustained inflation increased heart rate and arterial pressure faster than pressure-sustained inflation in the first 30 s. Volume-sustained inflation had increased arterial-alveolar oxygen difference because of higher FiO2 at 15 min. No other differences in arterial or cerebral oxygenation, blood pressures or early markers of lung injury were observed. Although theoretically more attractive than pressure, the applicability of volumecontrolled sustained inflation in the delivery room is presently limited by the lack of a suitable delivery device. More importantly, volume-controlled sustained inflation would be difficult to achieve with an open system such as a mask or nasopharyngeal tube. &
&&
Hillman et al. [17 ] tested the hypothesis that sustained inflation would decrease lung injury from subsequent mechanical ventilation of fetal, preterm lambs. While maintaining placental circulation, fetuses were randomized to one of four 15-min interventions: PEEP of 8 cmH2O, 20 s sustained inflation to 50 cmH2O followed by PEEP of 8 cmH2O, mechanical ventilation with VT ¼ 7 ml/kg, or 20-s sustained inflation followed by mechanical ventilation with VT ¼ 7 ml/kg. Lambs were ventilated with 95% N2/5% CO2 and PEEP of 8 cmH2O while remaining on placental support. Sustained inflation achieved a mean FRC of 15 ml/kg (range 8–27). Fifty percentage of final FRC was achieved by 2 s, 65% by 5 s and 90% by 15 s, confirming that prolonged sustained inflation times are needed to recruit FRC. Sustained inflation itself without subsequent ventilation led to some release of acutephase proteins into the fetal lung fluid and increased mRNA expression of proinflammatory cytokines. Mechanical ventilation further increased all markers of lung injury. Sustained inflation before ventilation, regardless of the volume of FRC recruited, did not alter the acute-phase and proinflammatory responses to mechanical ventilation at birth. Thus, the main benefit of sustained inflation may rest in reducing the need for mechanical ventilation. It is unclear whether gentler ventilation approaches might have mitigated the degree of ventilatorassociated lung injury following sustained inflation. In a subsequent study, these same investigators tested the hypothesis that a 20-s sustained inflation at birth will decrease lung injury from mechanical ventilation in preterm fetal lambs that were pretreated with surfactant [18 ]. Using the same approach, except for replacement of a portion of lung fluid with 300 mg of surfactant in 15 ml of saline, they found that the sustained inflation recruited a mean volume of 6.8 0.8 ml/kg but did not alter respiratory physiology during mechanical ventilation, nor markers of lung injury from mechanical ventilation. &
HUMAN DATA Initial clinical studies have yielded conflicting information. In a retrospective study, Lindner et al. [19] compared outcomes of a new delivery room management strategy consisting of sustained inflation at 20 cmH2O, which could be repeated once with a pressure of 25 cm, with historical controls managed with standard elective intubation in the delivery room. Despite being smaller and more immature, the sustained inflation cohort required significantly less intubation in the delivery room (84 versus 40%) and 25% of these infants never required intubation
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and mechanical ventilation (compared with 7% of historical controls). Furthermore, the rate of moderate-to-severe BPD decreased from 32 to 12%. Though the approach showed promise, this report suffers from all the limitations of retrospective cohort comparisons. Subsequently, these investigators randomly assigned 61 infants of 25.0–28.9 weeks’ gestational age with signs of respiratory distress immediately after birth to either sustained pressure-controlled inflation of 15 s or to intermittent mandatory ventilation via a nasopharyngeal tube [20]. The inflation pressure was increased stepwise (20–25–30 cmH2O) according to the response of HR and oxygenation. Disappointingly, treatment failure (defined as the need for mechanical ventilation) was not different between groups (61% for sustained inflation and 70% for control, P ¼ 0.59). The rates of mortality, severe intraventricular hemorrhage and chronic lung disease were similar. Of note, this study was stopped prematurely because of slow enrollment and thus is underpowered. In a small randomized trial of 52 infants less than 31 weeks’ gestation, Harling et al. [21] compared a ‘standard’ 2-s inflation time with a 5-s sustained inflation for the first assisted breath of resuscitation. Proinflammatory cytokine levels in bronchoalveolar lavage fluid and survival without BPD were similar in both groups (though the study was woefully underpowered for the latter). Additionally, 5 s is probably insufficient to deliver an effective sustained inflation. te Pas et al. [22] randomized 207 infants less than 32 weeks’ gestation to sustained inflation coupled with early CPAP or to bag and mask ventilation using a self-inflating bag. The sustained inflation intervention consisted of a 10 s inflation delivered via a T-piece device through a nasopharyngeal tube, followed by CPAP with repeated manual inflations using a bag and mask. A pressure of 20 cmH2O was used for the first sustained inflation and 25 cm for the second, which was administered for continued inadequate breathing, bradycardia or cyanosis. Control infants received a single brief inflation with a pressure of 30–40 cmH2O using a self-inflating bag and mask with minimal PEEP. An initial FiO2 of 1.0 was used in both groups and weaned based on pulse oximetry values. Infants in the sustained inflation group required less intubation in the delivery room and at 72 h, had shorter duration of respiratory support and received fewer doses of surfactant. Survival was more than 95% in both groups; the incidence of BPD was 22% in the sustained inflation group and 34% in the control group (P ¼ 0.05). There was no increase in pulmonary airleak or intracranial hemorrhage. Although these results are 148
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encouraging, the apparent benefit of sustained inflation must be interpreted with caution. The control infants were managed with a face-mask, rather than nasopharyngeal tube; they received higher inflation pressures initially, and were ventilated with a self-inflating bag without adequate PEEP, thus introducing potential confounders. Additionally, the study included infants up to 32 weeks’ gestation (mean birth weight 1300 g and mean gestational age of 29.5 weeks); thus, the applicability of these findings to the most vulnerable extremely premature infants is uncertain. In fact, the most significant differences were observed in infants >28 weeks’ gestational age. Fuchs et al. [23] examined the heart rate (HR), arterial oxygen saturation and cerebral tissue oxygen saturation using near infrared spectroscopy in 24 preterm infants (median gestational age of 28 weeks) during resuscitation using up to three sustained inflations of 20, 25 and 30 cmH2O of 15-s duration each followed by CPAP. Most infants required more than 1 sustained inflation, as the initial 20-cmH2O sustained inflation did not often result in increased HR or oxygenation. An effective sustained inflation was defined as a rapid increase in HR and cerebral oxygen saturation. No adverse effects were observed with this strategy and 83% of the infants survived without BPD, periventricular leukomalacia (PVL), severe intraventricular hemorrhage (IVH) or necrotizing enterocolitis. Lista et al. [24] compared 89 infants treated with sustained inflation, with 119 historical control subjects. The two groups had similar gestational age and birth weight and had comparable indexes of illness severity at baseline. More infants in the sustained inflation cohort received only noninvasive respiratory support and fewer required surfactant or postnatal steroids. A shorter duration of supplemental oxygen and a decreased rate of BPD were also noted. The incidence of pneumothorax, patent ductus arteriosus (PDA), IVH and PVL were comparable. However, this single-center retrospective cohort comparison must be interpreted with caution, as other changes in practice may have occurred, which could have impacted the observed outcomes.
CONTEMPORARY CLINICAL TRIALS In the largest multicenter RCT to date, Lista et al. [25 ] randomized 291 infants 25.0/7 –28.6/7 weeks’ gestation to either a sustained inflation of 25 cmH2O for 15 s, followed by CPAP or CPAP alone in the delivery room, both delivered via a mask and a T-piece resuscitator. The intervention could be repeated once at the same pressure if the response was inadequate. The initial FiO2 (0.21–0.40) was &&
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guided by local practice. The primary endpoint was need for mechanical ventilation in the first 72 h of life. Secondary endpoints included the need for and duration of respiratory support and survival without BPD. Criteria for intubation in the delivery room included failure to reach a heart rate higher than 100 bpm and target SpO2 of 70% by 5 min or 85% by 10 min of life, despite NCPAP at 5 cmH2O. CPAP failure was defined as a pH below 7.20 with PaCO2 more than 65 mmHg, PaO2 less than 50 mmHg with FiO2 0.50 or above after surfactant treatment, or frequent episodes of apnea despite NCPAP of 5–7 cmH2O. No threshold for FiO2 requirement was specified by protocol [26]. Fewer infants were ventilated in the first 72 h of life in the sustained inflation group than in the control group (53 versus 65%; P ¼ 0.04). In contrast to the retrospective study, there was no difference in survival or the rate of BPD. Pneumothorax was seen in 6% in the sustained inflation group and 1% of the controls (P ¼ 0.06). Although the difference fell short of statistical significance, the trend is worrisome. Interestingly, the great majority of pneumothoraces occurred beyond the first 48 h of life, rather than soon after the intervention (Lista G, personal communication). One might speculate that the late pneumothoraces were related to reluctance to intubate and give surfactant in the intervention group of this unblinded study in which need for mechanical ventilation was the primary outcome, rather than the intervention itself. None of the other published studies have shown an increase in airleak in the sustained inflation group. The COIN trial, which used FiO2 of 0.60 as the criterion for failure of CPAP, resulted in more pneumothoraces in the CPAP group [5], whereas other similar studies, which used FiO2 of 0.40 to define failure, showed no such increase [4,6]. Additional important insights are provided by the recent work of Dutch investigators who have many years’ experience in providing sustained inflation. van Vonderen et al. [27 ] noted that when performing sustained inflation on preterm infants less than 32 weeks’ gestation, the intervention was ineffective unless the infants made some respiratory effort during the sustained inflation. They measured inspiratory and expiratory flow during a 10-s, 25-cmH2O inflation using a hot wire anemometer and noted a high incidence of large mask leak with little gas volume entering the infant’s lungs, unless active respiratory efforts were present. Whether the investigators could accurately detect the actual volume of gas entering the infant’s lungs during a 10-s inflation is open to question, but there is a good physiologic explanation for this phenomenon. The vocal cords may not be open except during active &&
inspiration; therefore, the pressure applied to the upper airway via facemask may not reach the lungs. This study suggests that it may be important to use methods that facilitate detection of an effective intervention, such as calorimetric CO2 detectors [28]. Stimulating breathing efforts during the sustained inflation maneuver to optimize transmission of pressure to the lungs of unintubated infants may be helpful. What conclusions can be drawn from these studies? The apparent greater benefit seen in the tePas et al.’s study could be because of the more advanced gestational age, the fact that the control group received what today would be considered less than optimal delivery room support or to the fact that the sustained inflation was delivered more effectively. In that regard, van Vonderen et al. used a nasopharyngeal tube cut down to 6 cm and would hold the mouth and opposite nostril closed while delivering sustained inflation. In contrast, Lista et al.’s RCT delivered the sustained inflation via a face mask, which was shown by Shmoltzer et al. [29] to be more susceptible to large leak and to obstruction and thus may fail to deliver an effective sustained inflation. Rigorous training or measures to monitor the effectiveness of the intervention were not described in the Lista study. A contemporary meta-analysis of four RCTs concluded that the only statistically significant benefit of sustained inflation was reduction in the need for mechanical ventilation with a number needed to treat of 10 [30 ]. The incidence of pneumothorax was identical, but a significantly higher incidence of PDAs requiring treatment and a trend toward more intraventricular hemorrhage was noted. Thus, when ‘level one’ evidence is considered, the risks and benefits of sustained inflation remain unclear. &&
ONGOING RESEARCH Optimal inflation time and inflation pressure required to establish an effective FRC in infants requiring respiratory support have not been definitively established. More information on optimal sustained inflation duration should come from ¨ lzer et al. [31] who just completed enrollment Schmo into a study that examines different inflation times to achieve lung aeration. Urlesberger et al. is examining changes in cerebral blood volume with sustained inflation [32]. An National Institute of Health-funded multinational RCT of sustained inflation versus conventional NRP-guided delivery room stabilization is currently underway, utilizing a graded approach with an initial sustained inflation of 20 cmH2O and escalating to 25 cm if a second sustained inflation is needed (both for 15 s) [33]. The
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incidence of BPD as well as short-term respiratory outcomes will be evaluated. Participating centers include virtually all institutions that have published on the topic of sustained inflation. Some of the sites in this study will operate under deferral of consent, potentially making it possible to evaluate the selection bias resulting from a requirement for antenatal consent imposed by Institutional Review Boards in the United States [34]. In addition, future studies should examine whether delayed cord clamping or cord milking compared with earlier cord clamping affects outcomes in the presence or absence of sustained inflation.
CONCLUSION Several key factors must be considered when evaluating studies of sustained inflation. The interface by which inflation is delivered (mask, pharyngeal prong or endotracheal tube), the skill of the clinical team and the pressure-product applied will all affect the effectiveness of the intervention and thus the likelihood that it will have a measurable impact. Although some studies showed apparent benefit of inflations as short as 5 s, most studies suggest that a minimum of 10–15 s is needed because of the long time constant of lung fluid moving through the small airways of an extremelylow-birth-weight infant. It is interesting to note that both the United Kingdom and Dutch neonatal resuscitation guidelines recommend the use of five initial inflations of 2–3 s in both preterm and term infants, despite a lack of evidence of any benefits of inflations of this duration. Delivery room sustained inflation is an attractive concept that holds much promise, but widespread clinical application should await definitive evidence from on-going clinical trials. Acknowledgements I would like to thank Dr Gianluca Lista for sharing the accepted manuscript of his recent clinical trial and Dr Schmo¨ltzer for sharing a copy of his accepted metaanalysis article. Financial support and sponsorship None. Conflicts of interest The author is a consultant to Draeger Medical, Inc. and has been a recipient of a research grant and honoraria for lectures. Additional relationships include Medical Advisory Board of Discovery Laboratories and service on Data Safety Monitoring Committee for a study supported by Medipost America, Inc. 150
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REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Siew ML, Te Pas AB, Wallace MJ, et al. Positive end-expiratory pressure enhances development of a functional residual capacity in preterm rabbits ventilated from birth. J Appl Physiol (1985) 2009; 106:1487–1493. 2. American Academy of Pediatrics, American Heart Association. Textbook of neonatal resuscitation. 6th ed. Dallas, TX, Elk Grove Village, IL: American Academy of Pediatrics, American Heart Association; 2011. 3. Perlman JM, Wyllie J, Kattwinkel J, et al. Neonatal Resuscitation: 2010 International Consensus on Cardiopulmonary: resuscitation and emergency cardiovascular care science with treatment recommendations. Circulation 2010; 122:S516–S538. 4. SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network. Early CPAP versus surfactant in extremely preterm infants. N Engl J Med 2010; 362:1970–1979. 5. Morley CJ, Davis PG, Doyle LW, et al., COIN Trial Investigators. Nasal CPAP or intubation at birth for very preterm infants. N Engl J Med 2008; 358:700– 708. 6. Dunn MS, Kaempf J, de Klerk A, et al., Vermont Oxford Network DRM Study Group. Randomized trial comparing 3 approaches to the initial respiratory management of preterm neonates. Pediatrics 2011; 128:e1069–e1076. 7. Schmo¨lzer GM, Kumar M, Pichler G, et al. Noninvasive versus invasive respiratory support in preterm infants at birth: systematic review and metaanalysis. BMJ 2013; 347:f5980. 8. Bjorklund L J, Ingimarsson J, Curstedt T, 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– 355. 9. Kolobow T, Solca M, Presenti A, et al. The prevention of hyaline membrane disease (HMD) in the preterm fetal lamb through the static inflation of the lungs: The conditioning of the fetal lungs. Trans Am Soc Artif Intern Organs 1980; 26:567–572. 10. Solca M, Kolobow T, Huang HH, et al. Respiratory distress syndrome in immature lambs. Prevention through antenatal accelerated conditioning of the lung. Am Rev Respir Dis 1984; 129:979–984. 11. Vyas H, Milner AD, Hopkin IE, Boon AW. Physiologic responses to prolonged and slow-rise inflation in the resuscitation of the asphyxiated newborn infant. J Pediatr 1981; 99:635–639. 12. te Pas AB, Siew M, Wallace MJ, et al. Establishing functional residual capacity at birth: the effect of sustained inflation and positive end-expiratory pressure in a preterm rabbit. Pediatr Res 2009; 65:537–541. 13. te Pas AB, Siew M, Wallace MJ, et al. Effect of sustained inflation length on establishing functional residual capacity at birth in ventilated premature rabbits. Pediatr Res 2009; 66:295–300. 14. Sobotka KS, Hooper SB, Allison BJ, et al. An initial sustained inflation improves the respiratory and cardiovascular transition at birth in preterm lambs. Pediatr Res 2011; 70:56–60. 15. Klingenberg C, Sobotka KS, Ong T, et al. Effect of sustained inflation duration; & resuscitation of near-term asphyxiated lambs. Arch Dis Child Fetal Neonatal Ed 2013; 98:F222–F227. This is an elegant animal study exploring key factors in lung volume recruitment in newborn lambs. 16. Polglase GR, Tingay DG, Bhatia R, et al. Pressure- versus volume-limited & sustained inflations at resuscitation of premature newborn lambs. BMC Pediatr 2014; 14:43. This is an interesting attempt to optimize lung inflation using volume, rather than pressure as the primary control variable for sustained inflation; unfortunately, this may not be clinically feasible in unintubated infants. 17. Hillman NH, Kemp MW, Noble PB, et al. Sustained inflation at birth did not && protect preterm fetal sheep from lung injury. Am J Physiol Lung Cell Mol Physiol 2013; 305:L446–L453. This is an elegant animal study that explored the effect of mechanical ventilation after sustained inflation in fetal lambs still on placental support. This study suggests that sustained inflation may not prevent lung injury from mechanical ventilation. As clinical studies show a reduced need for mechanical ventilation after sustained inflation, the intervention may still be beneficial. 18. Hillman NH, Kemp MW, Miura Y, et al. Sustained inflation at birth did not alter & lung injury from mechanical ventilation in surfactant-treated fetal lambs. PLOS One 2014; 9:e113473. doi: 10.1371/journal.pone.0113473. Pretreatment with surfactant did not mitigate ventilator-associated lung injury that occurred despite an effective sustained inflation. 19. Lindner W, Vossbeck S, Hummler H, Pohlandt F. Delivery room management of extremely low birth weight infants: spontaneous breathing or intubation? Pediatrics 1999; 103:961–967. 20. Lindner W, Ho¨gel J, Pohlandt F. Sustained pressure-controlled inflation or intermittent mandatory ventilation in preterm infants in the delivery room? A randomized, controlled trial on initial respiratory support via nasopharyngeal tube. Acta Paediatr 2005; 94:303–309.
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Sustained inflation during neonatal resuscitation Keszler 21. Harling AE, Beresford MW, Vince GS, et al. Does sustained lung inflation at resuscitation reduce lung injury in the preterm infant? Arch Dis Child Fetal Neonatal Ed 2005; 90:F406–F410. 22. te Pas AB, Walther FJ. A randomized, controlled trial of delivery-room respiratory management in very preterm infants. Pediatrics 2007; 120:322–329. 23. Fuchs H, Lindner W, Buschko A, et al. Cerebral oxygenation in very low birth weight infants supported with sustained lung inflations after birth. Pediatr Res 2011; 70:176–180. 24. Lista G, Fontana P, Castoldi F, et al. Does sustained lung inflation at birth improve outcome of preterm infants at risk for respiratory distress syndrome? Neonatology 2011; 99:45–50. 25. Lista G, Boni L, Scopesi F, et al. for the SLI Trial Investigators. Sustained lung && inflation at birth for preterm infants: A randomized clinical trial. Pediatrics. 2015; 135:e457–e464. doi: 10.1542/peds.2014-1692. [Epub ahead of print]. This is the largest RCT examining the possible benefits of sustained inflation. The primary end point of need for mechanical ventilation showed improvement in the sustained inflation group. There was a trend to more pneumothoraces in the sustained inflation group. 26. Dani C, Lista G, Pratesi S, et al. Sustained lung inflation in the delivery room in preterm infants at high risk of respiratory distress syndrome (SLI STUDY): study protocol for a randomized controlled trial. Trials 2013; 14:67. 27. van Vonderen JJ, Hooper SB, Hummler HD, et al. The direct effect of a && sustained inflation in preterm infants at birth. J Pediatr 2014; 165:903– 908. This is an important clinical study indicating that sustained inflation is difficult to accomplish with a mask and often results in a large leak with ineffective sustained inflation. Spontaneous respiratory effort may be needed to achieve an effective sustained inflation.
28. Leone TA, Lange A, Rich W, Finer NN. Disposable colorimetric carbon dioxide detector used as an indicator of a patent airway during noninvasive mask ventilation. Pediatrics 2006; 118:e202–e204. 29. Schmo¨lzer GM, Dawson JA, Kamlin CO, et al. Airway obstruction and gas leak during mask ventilation of preterm infants in the delivery room. Arch Dis Child Fetal Neonatal Ed 2011; 96:F254–F257. 30. Schmo¨lzer GM, Kumar M, Aziz K, et al. Sustained inflation versus positive && pressure ventilation at birth – a systematic review and meta-analysis. ADC FN. Arch Dis Child Fetal Neonatal Ed 2014. doi: 10.1136/archdischild-2014306836. [Epub ahead of print]. This is a contemporary meta-analysis of published RCTs of sustained inflation, which shows a reduced need for mechanical ventilation with a number needed to treat of 10 as the only demonstrated benefit of sustained inflation. More infants in the sustained inflation group received treatment for patent ductus arteriosus. The authors conclude that sustained inflation should not be routinely used until more evidence becomes available from on-going trials. 31. Schmo¨lzer GM, Aziz K, OReilly M, Kumar M. Assessment of lung aeration at birth – a randomized control trial. URL: https://clinicaltrials.gov/ct2/show/ NCT01739114. [Accessed December 2014]. 32. Urlesberger B, Pichler G. Does sustained lung inflation improve cerebral oxygen saturation during resuscitation of preterm infants. https://drks-neu. uniklinikfreiburg.de/drks_web/navigate.do?navigationId¼trial.HTML&TRIAL_ ID¼DRKS00005161. [Accessed December 2014]. 33. Kirpalani H, Davis PG, Keszler M. Sustained Aeration of Infant Lungs Trial (SAIL). https://clinicaltrials.gov/ct2/show/NCT02139800. [Accessed December 2014]. 34. Rich W, Finer NN, Gantz MG, et al., SUPPORT and Generic Database Subcommittees of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Enrollment of extremely low birth weight infants in a clinical research study may not be representative. Pediatrics 2012; 129:480–484.
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Sustained inflation during neonatal resuscitation Martin Keszler
Purpose of review Sustained inflation performed shortly after birth to help clear lung fluid and establish functional residual capacity in preterm infants is gaining popularity, but definitive evidence for its effectiveness is lacking. Although there is a sound physiologic basis for this approach, and much preclinical experimental evidence of effectiveness, the results of recent animal studies and clinical trials have been inconsistent. Recent findings The most recent data from a multicenter randomized trial suggest a modest benefit of sustained inflation in reducing the need for mechanical ventilation in extremely-low-birth-weight infants. However, the impact may be more modest than earlier retrospective cohort comparisons suggested. The trend toward more airleak and a higher rate of intraventricular hemorrhage is worrisome. Sustained inflation may be ineffective unless some spontaneous respiratory effort is present. Several on-going trials should further clarify the putative benefits of sustained inflation. Summary Delivery room sustained inflation is an attractive concept that holds much promise, but widespread clinical application should await definitive evidence from on-going clinical trials, Keywords bronchopulmonary dysplasia, clearance of lung fluid, delivery room resuscitation, extremely low birth weight, prematurity, sustained inflation
INTRODUCTION To achieve a successful transition to extrauterine life, newborn infants must rapidly aerate their lungs, clear lung fluid from the air spaces and achieve an adequate functional residual capacity (FRC). Each of these facilitates the final critical component of neonatal transition: a dramatic increase in pulmonary blood flow. The full-term infant is usually able to achieve this remarkable transition quickly and effectively, but this is often not the case in the very preterm infant. Preterm infants, because of their limited muscle strength, excessively compliant chest wall, limited surfactant pool and incomplete lung development, are often unable to generate the critical opening pressure needed to achieve adequate lung aeration. Their excessively compliant chest wall fails to sustain any FRC that may have been achieved. Similarly, they may be unable to generate sufficient negative intrathoracic pressure to effectively move lung fluid from the air spaces to the interstitium, lymphatics and veins. Preterm infants are commonly born by cesarean delivery, often without adequate labor, a situation known to delay activation of the epithelial sodium channels, that switch the lung from a sodium-secreting to a sodium-absorbing state. This delay results in an
increased amount of residual lung fluid. The consequence of all these factors is that subsequent tidal volume (VT) breathing, whether spontaneous or generated by positive pressure ventilation, takes place in lungs that are still partially fluid-filled and partially atelectatic. This situation leads to maldistribution of the VT to a fraction of the preterm lung, which leads to volutrauma even when tidal volumes are in a ‘well tolerated’ physiologic range.
POSITIVE END-EXPIRATORY PRESSURE IN DELIVERY ROOM Extensive preclinical and clinical evidence supports the importance of positive end-expiratory pressure (PEEP) or continuous positive airway pressure (CPAP) during the initial stabilization of preterm Department of Pediatrics, Alpert Medical School of Brown University, Women and Infants Hospital, Providence, Rhode Island, USA Correspondence to Martin Keszler, MD, Department of Pediatrics, Women and Infants Hospital of Rhode Island, 101 Dudley Street, Providence, RI 02905, USA. Tel: +1 401 274 1122x47490; e-mail: [email protected] Curr Opin Pediatr 2015, 27:145–151 DOI:10.1097/MOP.0000000000000204
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KEY POINTS There is a sound physiologic basis for sustained inflation in very preterm infants and much preclinical experimental evidence of effectiveness, but results of recent animal studies and clinical trials have been inconsistent. The optimal inflation pressure and duration of sustained inflation have not been definitively established; additionally, they may vary substantially between infants. The risk–benefit ratio and the optimal target population have not yet been defined; potential risks of sustained inflation include increased airleak and increased intracranial hemorrhage. Several on-going studies may shed further light on these questions. Until then, the widespread adoption of sustained inflation is not recommended outside of clinical trials.
infants. Siew et al. [1] demonstrated the benefits of PEEP in an elegant study using phase-contrast radiography in preterm rabbits, showing that virtually no FRC was established after several minutes of positive pressure ventilation (PPV) when PPV was delivered without PEEP. In contrast, FRC was rapidly established when 5 cm of PEEP was applied. Based on limited experimental evidence and a sound theoretical basis, Neonatal Resuscitation Program (NRP) and International Liaison Committee on Resuscitation (ILCOR) guidelines state that ‘PEEP is likely to be beneficial during initial stabilization of apneic preterm infants and should be used if suitable equipment is available’ [2,3]. The CPAP or Intubation (COIN), Surfactant, Positive Pressure, and Oxygenation Randomized Trial (SUPPORT) and Vermont Oxford Network Delivery Room Management (VON-DRM) randomized controlled trials (RCTs) [4–6] demonstrated that provision of CPAP to spontaneous breathing very-low-birth-weight (VLBW) infants is at least as effective as intubation and surfactant. However, the failure rate of CPAP was high and bronchopulmonary dysplasia (BPD) rate was only marginally reduced in those studies [7]. Experimental data indicate that volutrauma can occur within minutes of birth in premature animals [8], suggesting that achieving an even distribution of VT from the very onset of tidal breathing by more rapid establishment of homogeneous lung aeration might be advantageous.
RATIONALE FOR SUSTAINED INFLATION As liquid has much greater viscosity than air, the resistance to moving liquid through small airways is 146
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orders of magnitude higher than that for air, making the time constants required to clear fluid from the airways much longer. Therefore, a prolonged (sustained) inflation applied soon after birth should be more effective than short inflations in clearing lung fluid and establishing homogeneous aeration. The concept of sustained inflation is not new; Kolobow et al. [9] promoted the concept of ‘lung conditioning’ in the early 1980s based on observations that lungs of very preterm lambs showed visible recruitment when inflated to a pressure of 35 cmH2O for several seconds, whereas short inflations at that pressure resulted in no appreciable aeration. Histologic and clinical evidence of hyaline membrane disease could be prevented by this intervention [9,10]. Similarly, more than 30 years ago, Vyas et al. [11] observed that when giving positive pressure inflations to intubated infants during initial resuscitation, air continued to enter the lung for more than 1 s. Prolonging the inflation time to 5 s resulted in improved lung inflation and facilitated the establishment of a FRC [11]. Despite much animal data support of the theoretical advantages of sustained inflation in extremely preterm infants, direct evidence from clinical trials remains inconclusive. Key older studies will be reviewed here, along with the most recent literature on the use of sustained inflation in the delivery room.
PRECLINICAL STUDIES OF SUSTAINED INFLATION te Pas et al. [12] demonstrated that both 20-s sustained inflation and 5 cmH2O of PEEP promote uniform lung aeration and create a larger FRC at birth than ventilation without PEEP. The effects of PEEP and sustained inflation were additive and PEEP was essential to maintain FRC both with and without sustained inflation. The authors suggested that combining these two techniques during stabilization of preterm infants would help establish effective breathing, promote uniform ventilation and reduce the need for intubation in the delivery room. These authors also investigated the effect of inflation time on lung aeration pattern, VT, and FRC immediately after birth in preterm rabbits [13]. The first inspiratory volume significantly increased with inflation duration from a median of 0.2 ml/kg for 1 s inflation to 4.5 ml/kg for 5-s inflation, 10.4 ml/kg for 10-s inflation and 23.4 mL/kg for 20-s sustained inflation. The lung was uniformly aerated, and the FRC fully recruited after a 20-s sustained inflation. Sobotka et al. [14] examined the effects of sustained inflation on pulmonary and carotid artery Volume 27 Number 2 April 2015
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Sustained inflation during neonatal resuscitation Keszler
blood flow to address concerns that sustained increase in intrathoracic pressure from a sustained inflation could have detrimental effects on pulmonary blood flow. They compared a single 40-cmH2O sustained inflation for up to 1 min (or until a volume of 20 ml was delivered) to conventional ventilation in preterm lambs of 127-day gestation. Pulmonary blood flow improved in the sustained inflation group compared with controls. Cerebral blood flow was higher in control animals, but cerebral oxygen delivery was not different. Lung compliance and gas exchange were dramatically improved in the sustained inflation group. The investigators concluded that sustained inflation did not impair the hemodynamic transition to extrauterine life.
RECENT PRECLINICAL STUDIES &
Klingenberg et al. [15 ] compared no sustained inflation, five 3-s inflations and a single 30-s inflation both at 30 cmH2O in asphyxiated late preterm lambs and demonstrated a more rapid improvement in heart rate, gas exchange and lung compliance in the 30-s sustained inflation group, whereas the five short inflations offered no benefit compared with control animals. These findings are consistent with other studies and confirm the long time constants required to clear fluid from the airways. Polglase et al. [16 ] compared pressure-limited sustained inflation at 40 cmH2O for 20 s to volumecontrolled sustained inflation targeting a delivered volume of 15 ml/kg over 5 s (and sustained for another 15 s) in 131-day gestation intubated, preterm lambs. Both methods achieved a comparable degree of end-inflation lung volumes and regional ventilation homogeneity. Peak pressure during sustained inflation was significantly higher and more variable in the volume-sustained inflation lambs (50.2 6.7 cmH2O) versus pressure-sustained inflation lambs (40.8 1.2 cmH2O; P ¼ 0.004). Volume-sustained inflation increased heart rate and arterial pressure faster than pressure-sustained inflation in the first 30 s. Volume-sustained inflation had increased arterial-alveolar oxygen difference because of higher FiO2 at 15 min. No other differences in arterial or cerebral oxygenation, blood pressures or early markers of lung injury were observed. Although theoretically more attractive than pressure, the applicability of volumecontrolled sustained inflation in the delivery room is presently limited by the lack of a suitable delivery device. More importantly, volume-controlled sustained inflation would be difficult to achieve with an open system such as a mask or nasopharyngeal tube. &
&&
Hillman et al. [17 ] tested the hypothesis that sustained inflation would decrease lung injury from subsequent mechanical ventilation of fetal, preterm lambs. While maintaining placental circulation, fetuses were randomized to one of four 15-min interventions: PEEP of 8 cmH2O, 20 s sustained inflation to 50 cmH2O followed by PEEP of 8 cmH2O, mechanical ventilation with VT ¼ 7 ml/kg, or 20-s sustained inflation followed by mechanical ventilation with VT ¼ 7 ml/kg. Lambs were ventilated with 95% N2/5% CO2 and PEEP of 8 cmH2O while remaining on placental support. Sustained inflation achieved a mean FRC of 15 ml/kg (range 8–27). Fifty percentage of final FRC was achieved by 2 s, 65% by 5 s and 90% by 15 s, confirming that prolonged sustained inflation times are needed to recruit FRC. Sustained inflation itself without subsequent ventilation led to some release of acutephase proteins into the fetal lung fluid and increased mRNA expression of proinflammatory cytokines. Mechanical ventilation further increased all markers of lung injury. Sustained inflation before ventilation, regardless of the volume of FRC recruited, did not alter the acute-phase and proinflammatory responses to mechanical ventilation at birth. Thus, the main benefit of sustained inflation may rest in reducing the need for mechanical ventilation. It is unclear whether gentler ventilation approaches might have mitigated the degree of ventilatorassociated lung injury following sustained inflation. In a subsequent study, these same investigators tested the hypothesis that a 20-s sustained inflation at birth will decrease lung injury from mechanical ventilation in preterm fetal lambs that were pretreated with surfactant [18 ]. Using the same approach, except for replacement of a portion of lung fluid with 300 mg of surfactant in 15 ml of saline, they found that the sustained inflation recruited a mean volume of 6.8 0.8 ml/kg but did not alter respiratory physiology during mechanical ventilation, nor markers of lung injury from mechanical ventilation. &
HUMAN DATA Initial clinical studies have yielded conflicting information. In a retrospective study, Lindner et al. [19] compared outcomes of a new delivery room management strategy consisting of sustained inflation at 20 cmH2O, which could be repeated once with a pressure of 25 cm, with historical controls managed with standard elective intubation in the delivery room. Despite being smaller and more immature, the sustained inflation cohort required significantly less intubation in the delivery room (84 versus 40%) and 25% of these infants never required intubation
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and mechanical ventilation (compared with 7% of historical controls). Furthermore, the rate of moderate-to-severe BPD decreased from 32 to 12%. Though the approach showed promise, this report suffers from all the limitations of retrospective cohort comparisons. Subsequently, these investigators randomly assigned 61 infants of 25.0–28.9 weeks’ gestational age with signs of respiratory distress immediately after birth to either sustained pressure-controlled inflation of 15 s or to intermittent mandatory ventilation via a nasopharyngeal tube [20]. The inflation pressure was increased stepwise (20–25–30 cmH2O) according to the response of HR and oxygenation. Disappointingly, treatment failure (defined as the need for mechanical ventilation) was not different between groups (61% for sustained inflation and 70% for control, P ¼ 0.59). The rates of mortality, severe intraventricular hemorrhage and chronic lung disease were similar. Of note, this study was stopped prematurely because of slow enrollment and thus is underpowered. In a small randomized trial of 52 infants less than 31 weeks’ gestation, Harling et al. [21] compared a ‘standard’ 2-s inflation time with a 5-s sustained inflation for the first assisted breath of resuscitation. Proinflammatory cytokine levels in bronchoalveolar lavage fluid and survival without BPD were similar in both groups (though the study was woefully underpowered for the latter). Additionally, 5 s is probably insufficient to deliver an effective sustained inflation. te Pas et al. [22] randomized 207 infants less than 32 weeks’ gestation to sustained inflation coupled with early CPAP or to bag and mask ventilation using a self-inflating bag. The sustained inflation intervention consisted of a 10 s inflation delivered via a T-piece device through a nasopharyngeal tube, followed by CPAP with repeated manual inflations using a bag and mask. A pressure of 20 cmH2O was used for the first sustained inflation and 25 cm for the second, which was administered for continued inadequate breathing, bradycardia or cyanosis. Control infants received a single brief inflation with a pressure of 30–40 cmH2O using a self-inflating bag and mask with minimal PEEP. An initial FiO2 of 1.0 was used in both groups and weaned based on pulse oximetry values. Infants in the sustained inflation group required less intubation in the delivery room and at 72 h, had shorter duration of respiratory support and received fewer doses of surfactant. Survival was more than 95% in both groups; the incidence of BPD was 22% in the sustained inflation group and 34% in the control group (P ¼ 0.05). There was no increase in pulmonary airleak or intracranial hemorrhage. Although these results are 148
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encouraging, the apparent benefit of sustained inflation must be interpreted with caution. The control infants were managed with a face-mask, rather than nasopharyngeal tube; they received higher inflation pressures initially, and were ventilated with a self-inflating bag without adequate PEEP, thus introducing potential confounders. Additionally, the study included infants up to 32 weeks’ gestation (mean birth weight 1300 g and mean gestational age of 29.5 weeks); thus, the applicability of these findings to the most vulnerable extremely premature infants is uncertain. In fact, the most significant differences were observed in infants >28 weeks’ gestational age. Fuchs et al. [23] examined the heart rate (HR), arterial oxygen saturation and cerebral tissue oxygen saturation using near infrared spectroscopy in 24 preterm infants (median gestational age of 28 weeks) during resuscitation using up to three sustained inflations of 20, 25 and 30 cmH2O of 15-s duration each followed by CPAP. Most infants required more than 1 sustained inflation, as the initial 20-cmH2O sustained inflation did not often result in increased HR or oxygenation. An effective sustained inflation was defined as a rapid increase in HR and cerebral oxygen saturation. No adverse effects were observed with this strategy and 83% of the infants survived without BPD, periventricular leukomalacia (PVL), severe intraventricular hemorrhage (IVH) or necrotizing enterocolitis. Lista et al. [24] compared 89 infants treated with sustained inflation, with 119 historical control subjects. The two groups had similar gestational age and birth weight and had comparable indexes of illness severity at baseline. More infants in the sustained inflation cohort received only noninvasive respiratory support and fewer required surfactant or postnatal steroids. A shorter duration of supplemental oxygen and a decreased rate of BPD were also noted. The incidence of pneumothorax, patent ductus arteriosus (PDA), IVH and PVL were comparable. However, this single-center retrospective cohort comparison must be interpreted with caution, as other changes in practice may have occurred, which could have impacted the observed outcomes.
CONTEMPORARY CLINICAL TRIALS In the largest multicenter RCT to date, Lista et al. [25 ] randomized 291 infants 25.0/7 –28.6/7 weeks’ gestation to either a sustained inflation of 25 cmH2O for 15 s, followed by CPAP or CPAP alone in the delivery room, both delivered via a mask and a T-piece resuscitator. The intervention could be repeated once at the same pressure if the response was inadequate. The initial FiO2 (0.21–0.40) was &&
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guided by local practice. The primary endpoint was need for mechanical ventilation in the first 72 h of life. Secondary endpoints included the need for and duration of respiratory support and survival without BPD. Criteria for intubation in the delivery room included failure to reach a heart rate higher than 100 bpm and target SpO2 of 70% by 5 min or 85% by 10 min of life, despite NCPAP at 5 cmH2O. CPAP failure was defined as a pH below 7.20 with PaCO2 more than 65 mmHg, PaO2 less than 50 mmHg with FiO2 0.50 or above after surfactant treatment, or frequent episodes of apnea despite NCPAP of 5–7 cmH2O. No threshold for FiO2 requirement was specified by protocol [26]. Fewer infants were ventilated in the first 72 h of life in the sustained inflation group than in the control group (53 versus 65%; P ¼ 0.04). In contrast to the retrospective study, there was no difference in survival or the rate of BPD. Pneumothorax was seen in 6% in the sustained inflation group and 1% of the controls (P ¼ 0.06). Although the difference fell short of statistical significance, the trend is worrisome. Interestingly, the great majority of pneumothoraces occurred beyond the first 48 h of life, rather than soon after the intervention (Lista G, personal communication). One might speculate that the late pneumothoraces were related to reluctance to intubate and give surfactant in the intervention group of this unblinded study in which need for mechanical ventilation was the primary outcome, rather than the intervention itself. None of the other published studies have shown an increase in airleak in the sustained inflation group. The COIN trial, which used FiO2 of 0.60 as the criterion for failure of CPAP, resulted in more pneumothoraces in the CPAP group [5], whereas other similar studies, which used FiO2 of 0.40 to define failure, showed no such increase [4,6]. Additional important insights are provided by the recent work of Dutch investigators who have many years’ experience in providing sustained inflation. van Vonderen et al. [27 ] noted that when performing sustained inflation on preterm infants less than 32 weeks’ gestation, the intervention was ineffective unless the infants made some respiratory effort during the sustained inflation. They measured inspiratory and expiratory flow during a 10-s, 25-cmH2O inflation using a hot wire anemometer and noted a high incidence of large mask leak with little gas volume entering the infant’s lungs, unless active respiratory efforts were present. Whether the investigators could accurately detect the actual volume of gas entering the infant’s lungs during a 10-s inflation is open to question, but there is a good physiologic explanation for this phenomenon. The vocal cords may not be open except during active &&
inspiration; therefore, the pressure applied to the upper airway via facemask may not reach the lungs. This study suggests that it may be important to use methods that facilitate detection of an effective intervention, such as calorimetric CO2 detectors [28]. Stimulating breathing efforts during the sustained inflation maneuver to optimize transmission of pressure to the lungs of unintubated infants may be helpful. What conclusions can be drawn from these studies? The apparent greater benefit seen in the tePas et al.’s study could be because of the more advanced gestational age, the fact that the control group received what today would be considered less than optimal delivery room support or to the fact that the sustained inflation was delivered more effectively. In that regard, van Vonderen et al. used a nasopharyngeal tube cut down to 6 cm and would hold the mouth and opposite nostril closed while delivering sustained inflation. In contrast, Lista et al.’s RCT delivered the sustained inflation via a face mask, which was shown by Shmoltzer et al. [29] to be more susceptible to large leak and to obstruction and thus may fail to deliver an effective sustained inflation. Rigorous training or measures to monitor the effectiveness of the intervention were not described in the Lista study. A contemporary meta-analysis of four RCTs concluded that the only statistically significant benefit of sustained inflation was reduction in the need for mechanical ventilation with a number needed to treat of 10 [30 ]. The incidence of pneumothorax was identical, but a significantly higher incidence of PDAs requiring treatment and a trend toward more intraventricular hemorrhage was noted. Thus, when ‘level one’ evidence is considered, the risks and benefits of sustained inflation remain unclear. &&
ONGOING RESEARCH Optimal inflation time and inflation pressure required to establish an effective FRC in infants requiring respiratory support have not been definitively established. More information on optimal sustained inflation duration should come from ¨ lzer et al. [31] who just completed enrollment Schmo into a study that examines different inflation times to achieve lung aeration. Urlesberger et al. is examining changes in cerebral blood volume with sustained inflation [32]. An National Institute of Health-funded multinational RCT of sustained inflation versus conventional NRP-guided delivery room stabilization is currently underway, utilizing a graded approach with an initial sustained inflation of 20 cmH2O and escalating to 25 cm if a second sustained inflation is needed (both for 15 s) [33]. The
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incidence of BPD as well as short-term respiratory outcomes will be evaluated. Participating centers include virtually all institutions that have published on the topic of sustained inflation. Some of the sites in this study will operate under deferral of consent, potentially making it possible to evaluate the selection bias resulting from a requirement for antenatal consent imposed by Institutional Review Boards in the United States [34]. In addition, future studies should examine whether delayed cord clamping or cord milking compared with earlier cord clamping affects outcomes in the presence or absence of sustained inflation.
CONCLUSION Several key factors must be considered when evaluating studies of sustained inflation. The interface by which inflation is delivered (mask, pharyngeal prong or endotracheal tube), the skill of the clinical team and the pressure-product applied will all affect the effectiveness of the intervention and thus the likelihood that it will have a measurable impact. Although some studies showed apparent benefit of inflations as short as 5 s, most studies suggest that a minimum of 10–15 s is needed because of the long time constant of lung fluid moving through the small airways of an extremelylow-birth-weight infant. It is interesting to note that both the United Kingdom and Dutch neonatal resuscitation guidelines recommend the use of five initial inflations of 2–3 s in both preterm and term infants, despite a lack of evidence of any benefits of inflations of this duration. Delivery room sustained inflation is an attractive concept that holds much promise, but widespread clinical application should await definitive evidence from on-going clinical trials. Acknowledgements I would like to thank Dr Gianluca Lista for sharing the accepted manuscript of his recent clinical trial and Dr Schmo¨ltzer for sharing a copy of his accepted metaanalysis article. Financial support and sponsorship None. Conflicts of interest The author is a consultant to Draeger Medical, Inc. and has been a recipient of a research grant and honoraria for lectures. Additional relationships include Medical Advisory Board of Discovery Laboratories and service on Data Safety Monitoring Committee for a study supported by Medipost America, Inc. 150
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REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Siew ML, Te Pas AB, Wallace MJ, et al. Positive end-expiratory pressure enhances development of a functional residual capacity in preterm rabbits ventilated from birth. J Appl Physiol (1985) 2009; 106:1487–1493. 2. American Academy of Pediatrics, American Heart Association. Textbook of neonatal resuscitation. 6th ed. Dallas, TX, Elk Grove Village, IL: American Academy of Pediatrics, American Heart Association; 2011. 3. Perlman JM, Wyllie J, Kattwinkel J, et al. Neonatal Resuscitation: 2010 International Consensus on Cardiopulmonary: resuscitation and emergency cardiovascular care science with treatment recommendations. Circulation 2010; 122:S516–S538. 4. SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network. Early CPAP versus surfactant in extremely preterm infants. N Engl J Med 2010; 362:1970–1979. 5. Morley CJ, Davis PG, Doyle LW, et al., COIN Trial Investigators. Nasal CPAP or intubation at birth for very preterm infants. N Engl J Med 2008; 358:700– 708. 6. Dunn MS, Kaempf J, de Klerk A, et al., Vermont Oxford Network DRM Study Group. Randomized trial comparing 3 approaches to the initial respiratory management of preterm neonates. Pediatrics 2011; 128:e1069–e1076. 7. Schmo¨lzer GM, Kumar M, Pichler G, et al. Noninvasive versus invasive respiratory support in preterm infants at birth: systematic review and metaanalysis. BMJ 2013; 347:f5980. 8. Bjorklund L J, Ingimarsson J, Curstedt T, 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– 355. 9. Kolobow T, Solca M, Presenti A, et al. The prevention of hyaline membrane disease (HMD) in the preterm fetal lamb through the static inflation of the lungs: The conditioning of the fetal lungs. Trans Am Soc Artif Intern Organs 1980; 26:567–572. 10. Solca M, Kolobow T, Huang HH, et al. Respiratory distress syndrome in immature lambs. Prevention through antenatal accelerated conditioning of the lung. Am Rev Respir Dis 1984; 129:979–984. 11. Vyas H, Milner AD, Hopkin IE, Boon AW. Physiologic responses to prolonged and slow-rise inflation in the resuscitation of the asphyxiated newborn infant. J Pediatr 1981; 99:635–639. 12. te Pas AB, Siew M, Wallace MJ, et al. Establishing functional residual capacity at birth: the effect of sustained inflation and positive end-expiratory pressure in a preterm rabbit. Pediatr Res 2009; 65:537–541. 13. te Pas AB, Siew M, Wallace MJ, et al. Effect of sustained inflation length on establishing functional residual capacity at birth in ventilated premature rabbits. Pediatr Res 2009; 66:295–300. 14. Sobotka KS, Hooper SB, Allison BJ, et al. An initial sustained inflation improves the respiratory and cardiovascular transition at birth in preterm lambs. Pediatr Res 2011; 70:56–60. 15. Klingenberg C, Sobotka KS, Ong T, et al. Effect of sustained inflation duration; & resuscitation of near-term asphyxiated lambs. Arch Dis Child Fetal Neonatal Ed 2013; 98:F222–F227. This is an elegant animal study exploring key factors in lung volume recruitment in newborn lambs. 16. Polglase GR, Tingay DG, Bhatia R, et al. Pressure- versus volume-limited & sustained inflations at resuscitation of premature newborn lambs. BMC Pediatr 2014; 14:43. This is an interesting attempt to optimize lung inflation using volume, rather than pressure as the primary control variable for sustained inflation; unfortunately, this may not be clinically feasible in unintubated infants. 17. Hillman NH, Kemp MW, Noble PB, et al. Sustained inflation at birth did not && protect preterm fetal sheep from lung injury. Am J Physiol Lung Cell Mol Physiol 2013; 305:L446–L453. This is an elegant animal study that explored the effect of mechanical ventilation after sustained inflation in fetal lambs still on placental support. This study suggests that sustained inflation may not prevent lung injury from mechanical ventilation. As clinical studies show a reduced need for mechanical ventilation after sustained inflation, the intervention may still be beneficial. 18. Hillman NH, Kemp MW, Miura Y, et al. Sustained inflation at birth did not alter & lung injury from mechanical ventilation in surfactant-treated fetal lambs. PLOS One 2014; 9:e113473. doi: 10.1371/journal.pone.0113473. Pretreatment with surfactant did not mitigate ventilator-associated lung injury that occurred despite an effective sustained inflation. 19. Lindner W, Vossbeck S, Hummler H, Pohlandt F. Delivery room management of extremely low birth weight infants: spontaneous breathing or intubation? Pediatrics 1999; 103:961–967. 20. Lindner W, Ho¨gel J, Pohlandt F. Sustained pressure-controlled inflation or intermittent mandatory ventilation in preterm infants in the delivery room? A randomized, controlled trial on initial respiratory support via nasopharyngeal tube. Acta Paediatr 2005; 94:303–309.
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Sustained inflation during neonatal resuscitation Keszler 21. Harling AE, Beresford MW, Vince GS, et al. Does sustained lung inflation at resuscitation reduce lung injury in the preterm infant? Arch Dis Child Fetal Neonatal Ed 2005; 90:F406–F410. 22. te Pas AB, Walther FJ. A randomized, controlled trial of delivery-room respiratory management in very preterm infants. Pediatrics 2007; 120:322–329. 23. Fuchs H, Lindner W, Buschko A, et al. Cerebral oxygenation in very low birth weight infants supported with sustained lung inflations after birth. Pediatr Res 2011; 70:176–180. 24. Lista G, Fontana P, Castoldi F, et al. Does sustained lung inflation at birth improve outcome of preterm infants at risk for respiratory distress syndrome? Neonatology 2011; 99:45–50. 25. Lista G, Boni L, Scopesi F, et al. for the SLI Trial Investigators. Sustained lung && inflation at birth for preterm infants: A randomized clinical trial. Pediatrics. 2015; 135:e457–e464. doi: 10.1542/peds.2014-1692. [Epub ahead of print]. This is the largest RCT examining the possible benefits of sustained inflation. The primary end point of need for mechanical ventilation showed improvement in the sustained inflation group. There was a trend to more pneumothoraces in the sustained inflation group. 26. Dani C, Lista G, Pratesi S, et al. Sustained lung inflation in the delivery room in preterm infants at high risk of respiratory distress syndrome (SLI STUDY): study protocol for a randomized controlled trial. Trials 2013; 14:67. 27. van Vonderen JJ, Hooper SB, Hummler HD, et al. The direct effect of a && sustained inflation in preterm infants at birth. J Pediatr 2014; 165:903– 908. This is an important clinical study indicating that sustained inflation is difficult to accomplish with a mask and often results in a large leak with ineffective sustained inflation. Spontaneous respiratory effort may be needed to achieve an effective sustained inflation.
28. Leone TA, Lange A, Rich W, Finer NN. Disposable colorimetric carbon dioxide detector used as an indicator of a patent airway during noninvasive mask ventilation. Pediatrics 2006; 118:e202–e204. 29. Schmo¨lzer GM, Dawson JA, Kamlin CO, et al. Airway obstruction and gas leak during mask ventilation of preterm infants in the delivery room. Arch Dis Child Fetal Neonatal Ed 2011; 96:F254–F257. 30. Schmo¨lzer GM, Kumar M, Aziz K, et al. Sustained inflation versus positive && pressure ventilation at birth – a systematic review and meta-analysis. ADC FN. Arch Dis Child Fetal Neonatal Ed 2014. doi: 10.1136/archdischild-2014306836. [Epub ahead of print]. This is a contemporary meta-analysis of published RCTs of sustained inflation, which shows a reduced need for mechanical ventilation with a number needed to treat of 10 as the only demonstrated benefit of sustained inflation. More infants in the sustained inflation group received treatment for patent ductus arteriosus. The authors conclude that sustained inflation should not be routinely used until more evidence becomes available from on-going trials. 31. Schmo¨lzer GM, Aziz K, OReilly M, Kumar M. Assessment of lung aeration at birth – a randomized control trial. URL: https://clinicaltrials.gov/ct2/show/ NCT01739114. [Accessed December 2014]. 32. Urlesberger B, Pichler G. Does sustained lung inflation improve cerebral oxygen saturation during resuscitation of preterm infants. https://drks-neu. uniklinikfreiburg.de/drks_web/navigate.do?navigationId¼trial.HTML&TRIAL_ ID¼DRKS00005161. [Accessed December 2014]. 33. Kirpalani H, Davis PG, Keszler M. Sustained Aeration of Infant Lungs Trial (SAIL). https://clinicaltrials.gov/ct2/show/NCT02139800. [Accessed December 2014]. 34. Rich W, Finer NN, Gantz MG, et al., SUPPORT and Generic Database Subcommittees of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Enrollment of extremely low birth weight infants in a clinical research study may not be representative. Pediatrics 2012; 129:480–484.
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