- bronchopulmonary dysplasia
- continuous positive airway pressure
- less invasive surfactant administration
- laryngeal mask airway
- minimally invasive surfactant therapy
- mechanical ventilation
- respiratory distress syndrome
Preterm infants who have respiratory distress syndrome have for many years been managed with a combination of early intubation and exogenous surfactant therapy. It is now recognized that applying continuous positive airway pressure (CPAP) in an extremely preterm infant is a reasonable alternative to early intubation after birth. Meta-analysis of large controlled trials comparing these two approaches suggests a benefit of CPAP, with a small reduction in the risk of the composite outcome of death or bronchopulmonary dysplasia. In the past decade, there has been an upsurge in the use of CPAP as primary therapy for preterm infants, bringing with it the dilemma of whether and how to give exogenous surfactant. In an effort to circumvent this problem, techniques of minimally invasive surfactant therapy have recently been investigated, aiming to administer surfactant to spontaneously breathing infants, allowing them to remain on CPAP in the critical first days after birth and, hopefully, beyond. These techniques have included administration of exogenous surfactant by brief tracheal catheterization, aerosolization, and laryngeal mask. Of these, the methods involving brief tracheal catheterization have been most extensively studied, with surfactant administered by using both a flexible feeding tube and a semi-rigid vascular catheter. In recent clinical trials (AMV [Avoidance of Mechanical Ventilation by Surfactant Administration] trial, Take Care study, and NINSAPP [Surfactant Application During Spontaneous Breathing With Continuous Positive Airway Pressure in Premature Infants <27 Weeks] trial), surfactant delivery via a feeding tube was found to reduce the need for subsequent intubation and ventilation and to improve short-term respiratory outcomes. Despite the relatively small numbers of infants in these trials, this technique has found its way into clinical practice in some centers. Further randomized controlled trials of surfactant administration via tracheal catheterization are underway or planned, and they will help clarify the place of this therapeutic approach. Additional studies will be needed to identify the best means of infant selection, refine the instillation technique, resolve the uncertainties regarding sedation, and determine the optimal surfactant dosage.
Because there is a growing emphasis on reducing invasive ventilation for preterm infants who have respiratory distress, there is also a need for more knowledge on techniques to administer surfactant less invasively, without an endotracheal tube in situ.
After completing this article, readers should be able to:
Present up-to-date information on techniques of minimally-invasive surfactant therapy in preterm infants.
Review the evidence regarding their benefits and risks.
Highlight the unanswered questions in this field of research.
Prematurely born neonates experience difficulties in the first minutes after birth in establishing effective respiration. The anatomic and functional immaturity of the thoracic cage and lungs predisposes to respiratory insufficiency. Positive-pressure ventilation in the delivery room is frequently needed, especially in the most immature infants, to facilitate clearing of lung fluid, establishment of a functional residual capacity, and effective alveolar–capillary gas exchange. (1) However, to avoid lung collapse during the expiratory phase of respiration, deposition of surfactant on the alveolar surface is required. Surfactant is a complex biological macroaggregate of highly specialized proteins and lipids (mainly phospholipids) that facilitate respiration and lung protection. Surfactant has the ability to lower surface tension at the air–water interface within the alveoli, precluding alveolar collapse during expiration. As a consequence, functional residual capacity is maintained, gas exchange is enhanced, and work of breathing substantially reduced. (2)(3) Prematurely born infants often produce minimal quantities of surfactant; moreover, surfactant of immature infants contains less protein and phospholipids, thus rendering it less effective as a natural tensioactive agent. (2) As a consequence, surfactant-deficient infants develop respiratory insufficiency (respiratory distress syndrome [RDS]) in the first minutes after birth, and most usually require respiratory support and oxygen supplementation. (4) Administration of exogenous surfactant to preterm infants who develop respiratory distress is thus a logical therapeutic choice. Surfactant replacement therapy has proven effective in reducing mortality and pulmonary morbidity, including pneumothorax, (5)(6) and has been a mainstay of therapy in preterm infants intubated soon after birth.
Recent randomized multicenter trials have shown that the use of continuous positive airway pressure (CPAP) in the delivery room has been at least as effective as intubation and surfactant administration in the first minutes after birth, with trends toward reduction of mechanical ventilation (MV) and the incidence of bronchopulmonary dysplasia (BPD). (7)(8)(9) There has been an upsurge in use of CPAP as primary therapy for preterm infants, bringing with it the dilemma of whether and how to give surfactant, a medication of clear therapeutic benefit, to infants not intubated at the outset. Until recently, it has not been possible to deliver exogenous surfactant to infants who have evolving RDS while on CPAP. Delaying surfactant treatment when needed has been shown to reduce surfactant efficiency and increase morbidity. (5)
INSURE: An Interim Solution for Surfactant Delivery to Infants on CPAP
Resolution of the CPAP-surfactant dilemma came first in the form of the INSURE technique: intubation, surfactant administration, and extubation. In the 1990s, Verder and colleagues published two randomized controlled trials using the INSURE technique; these studies established the validity of the method, which has subsequently been widely adopted in Scandinavia. (10)(11)(12) The INSURE method has been applied to infants on CPAP exhibiting increasing RDS and oxygen requirement. After intubation and surfactant therapy, infants are maintained on MV until oxygenation stabilizes and work of breathing is improved. Infants are then extubated to CPAP. (12) In its fullest form, INSURE involves the following: (1) a loading dose of caffeine citrate (20 mg/kg) to stimulate breathing; (2) morphine (0.2 mg/kg) for analgesia; (3) thiopental (2–5 mg/kg) for sedation; (4) oral intubation; (5) surfactant administration through the endotracheal tube; (6) reversal of the morphine effect by naloxone administration (0.1 mg/kg) just before extubation; (7) MV until the infant achieves respiratory stability; and finally (8) extubation to CPAP. In recent years, the INSURE procedure has been extensively applied, and although study findings have not been entirely conclusive, a reduction in the need for further intubation and MV has been reported. (13)(14)(15) However, the need for premedication, secondary effects such as hypotension, and the difficulty in extubation for a substantial number of infants have boosted the search for noninvasive or minimally invasive techniques for surfactant delivery that avoid tracheal intubation and sedation. (16)(17) Recent European Consensus Guidelines still recommend the INSURE technique, especially in more mature infants, with immediate extubation to CPAP or nasal intermittent positive-pressure ventilation after surfactant administration. (18) However, in the more immature infants, clinical judgment is recommended on the part of the attending neonatologist as to whether an individual infant will tolerate extubation and noninvasive respiratory support.
The paradigm for early respiratory management in the delivery room has been challenged in recent years. Application of less invasive techniques to prevent structural and functional damage of the lung and respiratory airways, especially in very preterm infants, has become an unchallengeable objective for clinicians and researchers in neonatology. The combined results of the COIN (Continuous Positive Airway Pressure or Intubation), SUPPORT (Surfactant Positive Pressure and Pulse Oximetry Randomised Trial), and VON trials (7)(8)(9) and a recent updated review and meta-analysis (19) provide the impetus for further change. Implicit in this change in the mechanics of respiratory support is that the approach to surfactant therapy must also be different in infants commencing life on CPAP. New approaches to administering surfactant, conceptualized under the banner of minimally invasive surfactant therapy (MIST), are required. MIST in its different forms has been subjected to a number of recent reviews. (20)(21)(22)(23) Our aim in the present review was to provide an update of several methods of MIST that have recently been evaluated in feasibility studies and clinical trials, and to highlight outstanding questions to be addressed in this area of burgeoning interest for neonatal clinicians.
New Methods of Surfactant Delivery to Preterm Infants on CPAP
In the wake of the evidence that premature infants with RDS can be successfully managed with noninvasive respiratory support both in the delivery room (24) and beyond, (18) several forms of MIST have been developed and evaluated in recent years. These alternative approaches to surfactant replacement have as their goal the avoidance of intubation and, more importantly, MV. A series of feasibility studies and clinical trials have been published in which different techniques of MIST were evaluated and compared with continuation of CPAP (ie, no surfactant) or with INSURE (Tables 1 and 2).
Surfactant Administration via Brief Tracheal Catheterization: The Cologne Experience
Since 2001, Kribs et al (25)(26) in Cologne, Germany, have pioneered the use of minimally invasive surfactant administration, rediscovering and refining a method of tracheal catheterization originally described by Verder et al in the 1990s. (25) The method of Kribs et al involves the introduction of a feeding tube or other thin catheter through the trachea under direct vision by using Magill forceps (Fig 1). Surfactant can then be administered to a spontaneously breathing infant, thus potentially avoiding the need for tracheal intubation and MV. (24) This approach was implemented in several centers across Germany and produced promising results, including a reduction in MV use. (27) In 2011, results of the AMV (Avoidance of Mechanical Ventilation by Surfactant Administration) trial were reported. (28) In this randomized controlled, multicenter trial, preterm infants of 26 to 28 weeks’ gestational age were recruited within 12 hours of birth, most being managed on nasal CPAP at birth. Infants allocated to the standard treatment group continued on CPAP, and if their respiratory status worsened, they received rescue surfactant after intubation. Infants allocated to the intervention group were managed initially on CPAP as noted earlier, but in the event of the fraction of inspired oxygen (Fio2) increasing to more than 0.30, exogenous surfactant (100 mg/kg, various preparations) was given while breathing spontaneously through a thin catheter. A total of 220 infants were studied, 112 in the standard treatment group and 108 in the intervention group. A significant reduction was noted in the number of patients mechanically ventilated during day 2 or 3 after birth in the intervention group compared with the standard group (28% vs 46%; P = .008). Moreover, fewer infants in the intervention group needed MV at any time compared with infants in the standard group (33% vs 73%; P < .0001). Infants in the intervention group had fewer days on MV and lower need for oxygen therapy at 28 days compared with the standard group. No differences in mortality or severe complications were in evidence.
Spurred by their experience, this research group has launched and conducted an additional randomized clinical trial testing their MIST method in more immature infants of gestational age 23 to 27 weeks (NINSAPP [Surfactant Application During Spontaneous Breathing With Continuous Positive Airway Pressure in Premature Infants <27 Weeks]), in this case compared with standard intubation, ventilation, and surfactant therapy. The full-published results of this trial are awaited.
Surfactant Administration via Brief Tracheal Catheterization: The Hobart Method
In 2011, Dargaville et al (29) reported an alternative method of administering surfactant to infants on CPAP by using a semi-rigid vascular catheter (Fig 2). The characteristics of the catheter facilitated its placement in the trachea, being easier to guide through the vocal cords by the operator without using Magill forceps. A full feasibility study of this method has now been published in a cohort of premature infants of 25 to 32 weeks’ gestational age. (30) Eligible infants were less than 24 hours of age at recruitment and needing CPAP of ≥7 cm H2O and Fio2 ≥0.3 (25–28 weeks’ gestation) or ≥0.35 (29–32 weeks’ gestation). Infants previously intubated were not studied. The MIST procedure consisted of surfactant instillation via brief tracheal catheterization according to the Hobart method, as previously described. (29) Comparison was made with historical controls of similar gestational age ranges managed initially on CPAP and achieving the same CPAP and Fio2 thresholds. Surfactant (poractant alfa [Curosurf®, Chiesi Farmaceutici S.p.A., Parma, Italy] 100–200 mg/kg, 1.25–2.5 mL/kg) was successfully administered by using the MIST technique in all cases, with a rapid, profound, and sustained reduction in oxygen requirement after the procedure (Fig 3). In addition, compared with historical controls, there was a significant reduction in the need for intubation at less than 72 hours for infants between 25 and 28 weeks’ gestation (32% vs 68%; P = .0011), with a similar trend in those at 29 to 32 weeks’ gestation (22% vs 45%; P = .057). Duration of ventilation and incidence of BPD were similar in both cohorts, although infants receiving MIST had a shorter duration of oxygen therapy. (30) The investigators concluded that MIST using the Hobart method was feasible, appeared to be safe, and potentially reduced the need for intubation.
Effect of Change in Clinical Practice: The Vienna Experience
Klebermass-Schrehof et al (17) recently published their single-center experience from the NICU at the Medical University of Vienna after modifying the premature newborn care protocol in the delivery room and beyond. In January 2009, they changed to the German comprehensive attendance protocol for preterm infants between 23 and 27 weeks’ gestation, (24), which included less invasive surfactant administration (LISA) according to the method of Kribs et al. (25) The study evaluated the new approach performed in their unit between January 2009 and June 2011 in infants at 23 to 27 weeks’ gestation, and compared outcomes with a historical cohort of infants managed initially on nasal CPAP and intubated for surfactant therapy if Fio2 was ≥0.3. The LISA method was undertaken soon after birth with the infant premedicated with caffeine (20 mg/kg of caffeine citrate) and placed in the right lateral position. High-flow CPAP (10–15 cm H2O positive end-expiratory pressure) via a facemask and Benveniste valve (Dameca, Rødovre, Denmark) continued throughout. Oxygen supplementation was titrated according to preductal pulse oxygen saturation (Spo2). At around 30 minutes after birth, via a thin gastric feeding tube (CH 04) was inserted into the trachea using Magill forceps under direct laryngoscope vision. Surfactant (poractant alfa, 200 mg/kg) was administered over 2 to 5 minutes with the infant breathing spontaneously. A total of 224 infants were managed with the modified protocol (including LISA), and 182 historical controls were identified. The LISA procedure was achieved in 94% of infants without needing intubation. MV was avoided in the first week in 65% of infants managed with LISA, and 41% never required intubation. Compared with local historical controls, survival was increased in the LISA group overall (76% vs 64%; P < .002) and also in the subgroup at 23 to 25 weeks’ gestation (68% vs 43%; P < .0001). In addition, the LISA group had a lower incidence of severe intraventricular hemorrhage and cystic periventricular leukomalacia, and a reduction in need for supplementary oxygen at 28 days after birth. In contrast, the LISA group had a significantly higher incidence of patent ductus arteriosus and retinopathy of prematurity.
The First Comparison of MIST With INSURE: The Take Care Trial
In the Take Care trial, surfactant administration via a thin catheter was compared in a randomized controlled trial versus the classical INSURE technique in preterm infants less than 32 weeks’ gestation. (31) The technique of tracheal catheterization used differed from that of Kribs et al (25) in that the 5-F flexible nasogastric tube was shortened and was passed through the vocal cords under direct laryngoscopy without Magill forceps. Surfactant (poractant alfa, 100 mg/kg) was then instilled in one bolus over 30 to 60 seconds, and the catheter immediately removed. Infants were randomized to receive surfactant via this method or alternatively to receive surfactant via INSURE, if they were on CPAP with Fio2 ≥0.4. Compared with INSURE, the Take Care group had a lower rate of intubation less than 72 hours (30% vs 45%; P < .02), a significantly shorter duration of both CPAP and MV, somewhat surprisingly, a lower rate of BPD (10% vs 20%; P = .009).
A Further Comparative Study of MIST and INSURE
SONSURE (Sonda Nasogástica Surfactante Extubación) is the Spanish acronym for surfactant administration by using a MIST-like technique following the Cologne method. (25) In the SONSURE study, an intervention group treated with this technique was compared with a historical cohort of infants treated with INSURE. (32) Infants of gestation 24 to 35 weeks were eligible for study if they were inborn, treated with nasal CPAP immediately after birth for RDS, and required supplemental oxygen in the first hour after birth to maintain arterial partial pressure of oxygen 50 to 70 mm Hg and/or Spo2 between 88% and 92%. All infants received intravenous caffeine, and those in the SONSURE group were premedicated with atropine. A thin catheter (3.5–4.0 FG) was inserted beyond the vocal cords with the aid of Magill forceps. Surfactant (poractant alfa, 100 mg/kg) was instilled over 1 to 3 minutes, and the catheter immediately removed. A total of 44 infants were studied in the SONSURE group and compared with 31 infants receiving INSURE. There were no significant differences in the need for intubation and MV in the first 72 hours (SONSURE: 34%; INSURE: 26% [P = .44]). However, an unexpected trend toward reduction in the incidence of necrotizing enterocolitis was noted in the SONSURE group (0% vs 9%; P = .067). More infants in the SONSURE group needed a second dose of surfactant (35% vs 6.5%; P < .001), bringing into question whether surfactant was successfully instilled into the trachea in some instances. The authors concluded that surfactant could be successfully administered to spontaneously breathing preterm infants by using the SONSURE approach, thus avoiding sedation, intubation, and MV. Training of personnel will be vital in ensuring successful surfactant delivery and avoiding the need for redosing.
Aerosolized Surfactant: An Alternative to Tracheal Catheterization
More than 2 decades ago, both jet and ultrasonic nebulizers were used to deliver phospholipids extracted from a bovine lung lavage into the lungs of experimental animals. (33) Nebulized surfactant improved both gas exchange and lung mechanics, and was less harmful than intratracheal liquid instillation. Importantly, when compared with the abrupt improvement in oxygenation noted with bolus intratracheal instillation, aerosolization of surfactant resulted in a more gradual improvement in oxygenation over several minutes. Conversely, mean arterial blood pressure remained stable with aerosolization but rapidly decreased after bolus instillation.
The use of aerosolized surfactant has since gained the interest of the neonatal community because, if effective, it would clearly be the least invasive of all surfactant delivery methods and thus very attractive, especially in very preterm infants on CPAP. In the 1990s, several small clinical trials evaluated the efficacy of aerosolized surfactant. Three of the studies were performed by using a jet nebulizer, and one used a vibrating membrane aerosolization system. These trials suggested that nebulized surfactant is safe and well tolerated, with some evidence for clinical improvement. (23)
Recently, preliminary results of a clinical trial of aerosolized surfactant administration in preterm infants 29 to 33 weeks’ gestation on CPAP were reported. (34) A customized vibrating membrane nebulizer (eFlow Neonatal Nebulizer System, Pari Pharma GmbH, Starnberg, Germany) was used in the study. Preliminary results indicate a modest benefit in favor of the infants receiving nebulized surfactant, with a reduction in relative risk of intubation less than 72 hours (relative risk: 0.56 [95% confidence interval: 0.341–0.929]; P = .032). CPAP failure criteria were achieved earlier in infants not treated with aerosolized surfactant. No significant adverse effects were described, although the duration of aerosolization was relatively long (∼20 minutes). The authors concluded that the use of aerosolized surfactant in preterm infants who had RDS significantly reduced the need for intubation less than 72 hours and deserves further appraisal.
Surfactant Deposition Using a Laryngeal Mask Airway
One small study reported a comparison of late rescue administration of surfactant via a laryngeal mask airway (LMA) versus no surfactant. (35) This study enrolled 26 preterm infants ≥1,200 g and less than 72 hours of age who had RDS and were treated with nasal CPAP requiring Fio2 0.3 to 0.6. Infants were randomized to receive surfactant followed by LMA removal and restoration of CPAP or continuation of CPAP. After the intervention, Spo2 was maintained in both groups between 88% and 95%. The experimental group responded to surfactant administration with an improvement in oxygenation in the first 12 hours after intervention, but no other benefits were noted. This study and others (36)(37) have suggested that surfactant administration via LMA is safe, and it has been proposed to be potentially useful as a bridge to transfer in regional hospitals without tertiary neonatal facilities.
Current and Future Studies of Techniques of MIST
The OPTIMIST-A trial is a multicenter, randomized controlled trial of surfactant administration via tracheal catheterization (Hobart method) in preterm infants 25 to 28 weeks’ gestation on CPAP. Entry criteria include age less than 6 hours and need for CPAP with Fio2 ≥0.3. The intervention group receive surfactant (poractant alfa, 200 mg/kg) via MIST, and the control group continue on CPAP. The trial is currently open for recruitment, and further recruiting centers are being sought. Trial information can be found at: www.menzies.utas.edu.au/optimist-trials.
The SAINT Trial
The SAINT trial is a multicenter, randomized controlled trial of intratracheal surfactant instillation with a long (300-mm) catheter in preterm infants less than 32 weeks’ gestation on CPAP. The comparator group receives surfactant according to the INSURE approach. Narcotic analgesia is, in the first instance, to be given to both groups, allowing this trial to examine to some degree the effect of this form of sedation on spontaneously breathing infants. The primary outcome is oxygenation at 24 hours’ postprocedure. This trial is not yet underway.
The MIST Approach: Unanswered Questions
Given the limited scientific evidence available to date, and the heterogeneity of published studies, there remain a number of important unanswered questions regarding MIST.
Infant Selection and Timing
Not all preterm infants managed on CPAP stand to benefit from MIST. Many have minimal or mild RDS and are well supported by CPAP alone. Conversely, some infants starting on CPAP have moderate to severe RDS, and they should ideally receive surfactant early in life to gain the most advantage. (38) Thus, for MIST to be of greatest value, it must be coupled with early selection of infants who have significant RDS. Although functional surfactant assays may ultimately be incorporated into MIST protocols, up until now clinical prediction tools (in particular, measures of oxygenation) have been used to identify infants suitable for MIST. In cohort studies, the highest appropriate Fio2 in the first hours after birth has been found to identify infants who have RDS who are at greatest likelihood of early CPAP failure related to RDS. (39)(40) In these studies, an Fio2 threshold of 0.30 seemed to offer the optimal balance between sensitivity and false-positive rate. Fio2 thresholds of 0.30 and 0.40 were used for infant selection in the AMV trial and Take Care study, respectively. (28)(31) The issue of how best to identify infants to be considered for MIST, including an investigation of the possible role of a functional surfactant assay (eg, stable microbubble test on gastric aspirate), is an important area for further research.
The MIST Procedure Itself
Although this field of enquiry is in its infancy, as presented earlier, there are already a considerable number of different techniques described under the banner of MIST, none of which have been directly compared. Undoubtedly, with training and experience, any of the described techniques of tracheal catheterization could be successfully applied by neonatal clinicians skilled in direct laryngoscopy and intubation. Most likely, there will be little difference between them in the ultimate effect of the instilled surfactant. Nevertheless, some comparison studies are warranted, focusing on ease and success rate of tracheal catheterization, and the frequency of catheter malposition as evidenced by absence of a surfactant effect (improvement in oxygenation) after the procedure. A purpose-built surfactant instillation catheter should be developed and tested to avoid off-label use of medical devices designed and licensed for a different purpose. Additional means of confirming catheter placement (other than visual inspection) need to be investigated. Finally, assessment of different techniques of laryngoscopy, including the use of a video laryngoscope, should be undertaken.
Published studies of MIST with the use of direct laryngoscopy and tracheal catheterization have used different approaches to premedication, but they have in common the avoidance of narcotic analgesia. For many clinicians, this method represents a significant departure from their usual protocol for nonemergent intubation. Thus far, the avoidance of narcotic agents does not seem to have been associated with any major deleterious effects in the short term, and the initial outcome studies of preterm infants receiving MIST do not suggest any lasting consequences. (41) Furthermore, there is preliminary evidence that spontaneous breathing during the MIST procedure may play an important role in the distribution of surfactant, (31) and thus ablation of respiratory effort by narcotics may be disadvantageous. The need for, and use of, sedation and analgesia for MIST requires a comprehensive assessment, particularly if this management approach becomes widely adopted.
Dose and Preparation
The surfactant dosage is relevant because the administration of surfactant in spontaneously breathing infants has to be performed relatively rapidly, and reflux of surfactant into the pharynx around the thin catheter is seen frequently. Surfactant dosage in the published studies has been either 100 or 200 mg/kg; there has been some suggestion of a more prolonged effect with 200 mg/kg, (22) as with studies in intubated infants. (42)(43)(44) Further studies will be needed to define the optimal surfactant dosage, as well as to establish whether surfactant preparations with a low phospholipid concentration and thus a relatively large administration volume (4–5 mL/kg) are safe and effective when used with MIST.
There is burgeoning interest in the MIST techniques for preterm infants who have RDS treated initially with CPAP. Several small clinical trials suggest an advantage of MIST over either continuation of CPAP or surfactant administration via INSURE. Additional trials of surfactant administration via tracheal catheterization are underway or planned, and they will help to clarify the place of this therapeutic approach. Further studies will be needed to identify the best means of infant selection, refine the instillation technique, resolve the uncertainties regarding sedation, and determine the optimal surfactant dosage.
American Board of Pediatrics Neonatal–Perinatal Content Specifications
Know the clinical strategies and therapies used to decrease the risk and severity of respiratory distress syndrome.
Know the management of respiratory distress syndrome, including surfactant replacement.
Dr Dargaville is the chief investigator of the OPTIMIST-A trial, funded by the Royal Hobart Hospital Research Foundation and the Australian National Health and Medical Research Council (project grant 1049114), with in-kind support from Chiesi Farmaceutici, Parma, Italy. Dr Vento, national coordinator of the Spanish Maternal, Infant and Developmental Network (Retic Red SAMID RD12/0022), acknowledges funding from the Health Research Institute Carlos III (Ministry of Economy and Competitiveness; Spain) to complete this review article. Dr Aguar has disclosed no financial relationships relevant to this article. This commentary discusses unapproved methods of delivering surfactant into the trachea in preterm infants.
- Copyright © 2014 by the American Academy of Pediatrics
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