Journal of Perinatology (2010) 30, S67S72 r 2010 Nature America, Inc. All rights reserved.

0743-8346/10
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REVIEW

Nasal respiratory support through the nares: its time has come
R Ramanathan
Division of Neonatal Medicine, Department of Pediatrics, Los Angeles County University of Southern California Medical Center and Childrens Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA Introduction Respiratory failure requiring mechanical ventilation is a very frequent presentation in preterm infants admitted to the neonatal intensive care unit (NICU). Surfactant administration followed by invasive mechanical ventilation using an endotracheal tube (ETT) in preterm infants with respiratory distress syndrome (RDS) has become the standard of care. However, invasive ventilation through the ETT is independently associated with an increased risk for the development of bronchopulmonary dysplasia (BPD) in about one-third of very low birth weight infants (birth weight <1500 g). Indeed, the incidence of clinical BPD, dened as oxygen requirement at 36 weeks of postmenstrual age in preterm infants with a birth weight <1250 g, was about 35%, with large center to center variations.1 To standardize the denition of BPD and minimize center to center variations in the reported incidence of BPD among different centers, a physiological denition for BPD, based on a timed room air challenge at 361 weeks of gestation was proposed by Walsh et al.1 Incidence of physiological BPD was about 25% and use of this denition for BPD reduced the variation among centers. Despite the increased use of antenatal corticosteroids2,3 and improved invasive ventilation techniques, the incidence of BPD has not decreased. This is important, as BPD is associated with short- as well as long-term pulmonary and nonpulmonary morbidities. Injury to the developing lung results from the interaction between a susceptible host and a number of contributing factors, such as mechanical ventilation, oxygen toxicity and specic and nonspecic inammation. Preterm infants are at greater risk because they have increased pulmonary epithelial and capillary permeability, immature antioxidant defenses and immune responses compared with term newborns. BPD is considered as an inammatory lung disease in which the injury often is initiated at birth4 or even before birth in infants born to mothers with chorioamnionitis,5 and as mentioned above, is triggered by several factors, including positive-pressure ventilation through the ETT, supplemental oxygen and postnatal inammation.6 Decreased production of anti-inammatory cytokines, such as interleukin (IL)-10, and relative adrenal insufciency have also been suggested to contribute to the prolonged proinammatory state of preterm neonates who develop BPD. In addition to lung inammation, the presence of

Respiratory distress syndrome (RDS) is the most common respiratory morbidity in preterm infants. Surfactant therapy and invasive mechanical ventilation through the endotracheal tube (ETT) have been the cornerstones in RDS management. Despite improvements in the provision of mechanical ventilation, bronchopulmonary dysplasia (BPD), a multifactorial disease in which invasive mechanical ventilation is a known contributory factor, remains an important cause of morbidity among preterm infants. Barotrauma, volutrauma or oxygen-induced lung inammation (oxy-trauma) contributes signicantly to the development of BPD in neonates ventilated through an ETT. Recently, nasal respiratory support has been increasingly used in preterm infants in an attempt to decrease post-extubation failure and, perhaps, BPD, and for the treatment of apnea of prematurity in nonventilated neonates. Observational studies using noninvasive respiratory support, such as nasal continuous positive airway pressure (NCPAP), have shown a decrease in the incidence of BPD when used to avoid intubation or minimize the duration of invasive mechanical ventilation through the ETT. Moreover, synchronized as well as nonsynchronized nasal intermittent positive-pressure ventilation (NIPPV) have been shown to signicantly decrease post-extubation failure compared with NCPAP and their use has been associated with a reduced risk of BPD in small randomized controlled clinical trials. More recently, early surfactant administration followed by extubation to NIPPV has been suggested to be synergistic in decreasing BPD. Although these ndings are promising, additional studies evaluating different nasal interfaces, ow synchronization, synchronization using neurally adjusted ventilatory assist mode, and closed loop control of oxygen during nasal ventilation to minimize lung injury are needed in an attempt to further decrease the incidence of lung injury in preterm neonates requiring respiratory support. Journal of Perinatology (2010) 30, S67S72; doi:10.1038/jp.2010.99

Keywords: mechanical ventilation; nasal ventilation; NCPAP; NIPPV; BPD

Correspondence: Professor R Ramanathan, Division of Neonatal Medicine, Department of Pediatrics, Los Angeles County University of Southern California Medical Center and Childrens Hospital Los Angeles, Keck School of Medicine, University of Southern California, 1200, North State Street, IRD-Building-Room 820, Los Angeles, CA 90033, USA. E-mail: ramanath@usc.edu This paper resulted from the Evidence vs. Experience in Neonatal Practices Conference, 19 to 20 June 2009, sponsored by Dey LP.

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a persistent patent ductus arteriosus has been associated with a higher incidence of BPD.7 The concept that the interplay between inammation and patent ductus arteriosus contributes to the pathogenesis of BPD has been supported by the observation that the presence of IL-6 in tracheal aspirate at birth and persistent patent ductus arteriosus additively predict the risk of BPD.8 Invasive positive-pressure ventilation with its resultant barotrauma and volutrauma from using tidal volume ventilation has also been shown to be an important contributing factor. However, meta-analysis of studies comparing tidal ventilation versus nontidal volume ventilation showed no signicant difference in BPD when an optimal lung volume strategy was used.9 On the basis of these data, targets for decreasing the incidence of BPD include reducing oxygen exposure, minimizing lung infection and inammation, and avoiding ventilator-associated lung injury. Focus on decreasing the use of invasive mechanical ventilation through the ETT has led to a renewed interest in noninvasive, nasal ventilation in preterm infants.

Nasal ventilation Nasal respiratory support through the nares has been in use since the early 1970s. Gregory et al.10 rst reported the use of continuous positive airway pressure (CPAP) using the so-called Gregory box to treat RDS. Although CPAP gained a more widespread acceptance in the early 1980s, advances in mechanical ventilation technology, such as synchronized intermittent mandatory ventilation (SIMV), volume-limited and volume-guaranteed modes and high-frequency ventilation, invasive ventilation through the ETT, led to invasive ventilation becoming the standard of care in the management of neonates with respiratory failure during the 1980s and 1990s. At the same time, single-center observational studies suggested that treating very preterm infants with nasal CPAP (NCPAP) during resuscitation and in the NICU is feasible and reduces intubation rate and the incidence of BPD without increasing morbidity. More recently, ndings of nonrandomized studies on early surfactant administration followed by extubation to NCPAP, nasal intermittent positive-pressure ventilation (NIPPV) or NCPAP alone without surfactant therapy have suggested to decrease the incidence of BPD in preterm infants.11 CPAP generators A variety of devices are used to deliver CPAP to neonates. All CPAP systems have three basic components: supply of a heated and humidied gas mixture, patient interface and an expiratory valve. Pressure generated at the nasal interface is dependent on the ow rate used in all systems, including the bubble CPAP system.12 The heart of any CPAP device is the expiratory valve, which maintains the positive pressure throughout the respiratory cycle. Currently, expiratory valves are of two types: variable pressure-ow valves and threshold resistors. Variable pressure-ow valves provide a constant resistance to ow. The level of pressure within the system is equal
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to the product of gas ow through the orice of the valve and the resistance of the valve. The shortcoming of this conguration is that, as spontaneous breathing is not necessarily a steady process, pressures can uctuate widely during spontaneous breathing. For instance, when an infant attempts to exhale into a xed-resistance expiratory valve CPAP, internal pressure may increase signicantly, carrying the possibility of causing barotrauma and increased work of breathing. To deliver more stable pressures, new devices, such as the infant ow drivers with uidic ip mechanisms have been developed. NCPAP generators commonly used include bubble CPAP, the infant ow driver system with variable ow, constant ow using conventional mechanical ventilator, the Benveniste device, the Carden device, and recently, the high-ow nasal cannula (HFNC). Several studies have compared the different interface methods used in the available CPAP systems and found no difference in clinical outcomes when applying CPAP with the infant ow driver versus a conventional nasal CPAP device.13 HFNC have been used to deliver oxygen at ow rates between 0.5 l min 1 to as high as 6 l min 1, usually with no intention of delivering CPAP. However, using HFNC, a signicant amount of CPAP is generated, yet is not measured continuously at the bedside. Locke et al.14 previously demonstrated that ows of 2 l min 1 using a 0.3-cm nasal cannula produced a mean pressure of 9.8 cm H2O in infants of 30-week gestation. Another study by this group has demonstrated that the use of HFNC is associated with signicantly higher upstream pressures, which may represent a signicant hazard.15 Sreenan et al.16 used HFNC up to 2.5 l min 1 to produce CPAP of 6 cm H2O, as measured by equivalent esophageal pressures (4.5 to 4.6 cm H2O) and reported that 6 h of such treatment was equivalent to 6 h of traditional CPAP for the treatment of apnea in infants with birth weights of <2 kg. In summary, HFNC is not a reliable and safe way of delivering NCPAP in neonates because of the risk of delivering inconsistent and relatively unpredictably high pressures.17 Therefore, one must exercise extreme caution when delivering ow rates >2 l min 1 through nasal cannula in neonates. CPAP interface NCPAP is delivered using short binasal prongs, long nasopharyngeal prongs or nasal masks. Binasal prongs are more effective than single-nasal prongs for NCPAP in extremely low birth weight infants in decreasing extubation failures.18 However, the use of NCPAP or NIPPV interfaces can cause nasal injury, disgurement or infection,19,20 and hence prongs/mask sites need to be checked often and the skin integrity should be maintained carefully. An alternative is to alternate prongs and masks at certain intervals thereby minimizing nasal trauma. Nasal CPAP In 1985, Avery et al.21 reported less BPD in Babies and Childrens Hospital in New York when compared with eight other centers.

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This center is known for its strategy of early and meticulous use of NCPAP. These ndings were conrmed in a subsequent comparison between two NICUs in Boston and the NICU at Babies and Childrens Hospital in New York.22 In this casecohort study, after adjusting for baseline risks, most of the increased risk of BPD in very low birth weight infants hospitalized in the two NICUs in Boston, compared with those at Babies and Childrens Hospital, was explained simply by the initiation of mechanical ventilation. Interestingly, the use of prophylactic NCPAP for the management of RDS in preterm infants in the presurfactant era reported no differences in BPD.23 Finally, NCPAP has been successfully used in neonates during air- or road-based transports, and following surfactant therapy. Nasal CPAPsurfactant NCPAP as a primary mode or a mode of respiratory support following surfactant therapy for RDS has been frequently used in preterm neonates. Meta-analysis of six randomized controlled trials (RCTs) comparing early surfactant replacement therapy with immediate extubation to NCPAP with selective surfactant replacement and continued mechanical ventilation with extubation from low ventilator support showed that early surfactant replacement therapy with immediate extubation to NCPAP was associated with less need for mechanical ventilation, lower incidence of BPD and fewer air-leak syndromes.24 A lower treatment threshold (FIO2 <0.45) conferred greater advantage in reducing the incidences of air-leak syndromes and BPD, whereas a higher treatment threshold (FIO2 >0.45) was associated with increased risk of patent ductus arteriosus. These data suggest that treatment with surfactant by transient intubation using a low treatment threshold (FIO2 p0.45) is preferable to the latter selective surfactant therapy using a higher threshold (FIO2 >0.45), or to giving surfactant at the time of respiratory failure only followed by continued mechanical ventilation.24 However, in a recent large, multinational study in infants born at 25- to 28-week gestation, the use of early NCPAP did not signicantly reduce the rate of death or BPD, as compared with intubation.25 As for the type of the ow generator, studies have shown no signicant difference in outcomes using the different types of ow generators to deliver NCPAP.26 Extubation failures requiring reintubation ranged from 20 to 80% in infants managed on NCPAP with higher failure rates in extremely low birth weight infants. Most common reasons for failures of the use of NCPAP included repeated episodes of apnea, desaturation, bradycardia or respiratory acidosis. On the other hand, the use of NIPPV has been shown to reduce extubation failures signicantly. NIPPV is a natural extension of NCPAP, which may decrease extubation failures and reduce the incidence of ventilator-associated lung injury.

NIPPVsurfactant NIPPV is a method of augmenting NCPAP by delivering ventilator breaths through nasal or nasopharyngeal prongs. Older children and adults with respiratory failure have been shown to benet from NIPPV. NIPPV is provided using similar nasal interfaces that are commonly used during NCPAP. Synchronized NIPPV (SNIPPV), as well as nonsynchronized NIPPV have been used in preterm infants for the treatment of apnea of prematurity or following extubation. The exact mechanisms by which NIPPV works are not known. NIPPV has been shown to augment the infants spontaneous respiratory effort and may therefore decrease apneic episodes. NIPPV has also been shown to reduce asynchronous thoracoabdominal motion, perhaps as a result of reducing tube resistance and/or better stabilization of the chest wall.27 Its use improves tidal volume and minute ventilation and decreases the inspiratory effort required by neonates compared with NCPAP.28 Indeed, a decreased work of breathing has been reported with SNIPPV.29 However, the technique has not been without problems in neonates. Earlier, Garland et al.30 reported an association between the use of ventilation through nasal prongs and increased risk of gastrointestinal perforation. However, none of the studies published since 1999 have reported gastrointestinal perforation or necrotizing enterocolitis with NIPPV use. Most of the studies used the Infant Star Ventilator (Infrasonics, Nellcor Puritan Bennett, Carlsbad, CA, USA) with star-synch abdominal capsule to trigger the breaths. This device is no longer available for clinical use in the United States. NCPAP versus NIPPV To date, six RCTs have compared NCPAP versus NIPPV at the time of extubation (Figure 1).3136 Extubation failure rates were signicantly lower in infants randomized to NIPPV when compared with NCPAP in all these studies. Friedlich et al.31 published the rst study comparing NCPAP with SNIPPV and demonstrated that SNIPPV reduced extubation failure signicantly. Two subsequent

60 50 40 Percent 30 20 10 0 Ref 31 Ref 32 Ref 33

NCPAP/EF NCPAP/BPD

NIPPV/EF NIPPV/BPD

Ref 34

Ref 35

Ref 37

Ref 34

Ref 36

Ref 37

Figure 1 Nasal continuous positive airway pressure (NCPAP) versus nasal intermittent positive-pressure ventilation (NIPPV): extubation failures (EFs) and bronchopulmonary dysplasia (BPD).
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Nasal ventilation in preterm infants R Ramanathan

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NIPPV settings Initial Rate (b.p.m.) PIP cm H2Oa PEEP (cm H2O) Inspiratory time (s) Adjust FIO2b 40 1015 above PEEP 5 0.5 SpO2 8589% Maximum 40 30/20/10a 78 1 SpO2 8589% Weaning to NCPAP/low ow nasal cannula Initial F F 5 F SpO2 8589% Maximum F F 78 F SpO2 8589%

Abbreviations: FIO2, fraction of inspired oxygen; NCPAP, nasal continuous positive airway pressure; NIPPV, nasal intermittent positive-pressure ventilation; PEEP, positive end expiratory pressure; PIP, peak inspiratory pressure; Si-PAP, synchronized intermittent positive airway pressure; SpO2, arterial oxygen saturation by pulse oximetry. a 30 if nasopharyngeal prongs or nasal cannula-IMV is used, 20 for short binasal prongs, 10 for Si-PAP nasal interface. b After 3334 weeks of postmenstrual age, 9094% may be used. Weaning: wean every 612 h; wean PIP rst; when PIP is at 10, then wean rate; when rate is at 10, wean to NCPAP. When patient is stable on NCPAP of 5 cm H2O for 612 h, wean to heated nasal cannula with ow rates of <2 LPM.

studies conrmed these ndings.32,33 Kugelman et al.34 used nasal IMV as a primary mode of ventilatory support in preterm infants <35-week gestation, and also showed signicantly less extubation failure rates and a decreased incidence of BPD as compared with NCPAP. Nasal ow-synchronized intermittent positive-pressure ventilation (NFSIPPV) is a new noninvasive nasal ventilatory mode that delivers ow-synchronized mechanical breaths through the nasal prongs. Using NFSIPPV in 63 patients, Moretti et al.35 showed a signicant reduction in extubation failures as compared with NCPAP (6 versus 39%, P<0.01). There was also a trend toward less BPD in the NFSIPPV group (6 versus 22%, P 0.08). It is possible that gastrointestinal side effects might be reduced if ventilator breaths were delivered in synchrony with laryngeal opening, and that more consistent tidal volumes can be delivered with SNIPPV. Bhandari et al.36 in an RCT in preterm infants <30 weeks of gestational age requiring intubation and surfactant treatment soon after delivery found that extubation to SNIPPV reduced the need for invasive mechanical ventilation through the ETT, and its use was associated with a decreased incidence of BPD compared with IMV. Recently, Ramanathan et al.37 performed the largest, multicenter RCT to date comparing SIMV with NIPPV and demonstrated a signicant decrease in the number of infants on SIMV by 7 days of age, and a reduction in BPD, using either physiological or clinical denitions for BPD in the NIPPV group. Interestingly, the total duration of mechanical ventilation was similar between the groups in both these studies,36,37 suggesting that early extubation during the rst week of postnatal life to either SNIPPV or NIPPV may be important in decreasing BPD. Nonsynchronized nasal ventilation may be better than even short periods of invasive SIMV, in terms of decreasing ventilator-associated lung injury. Recently, in a large retrospective study,38 SNIPPV when compared to NCPAP in preterm neonates with birth weight of 500 to 750 g, is associated with signicantly less BPD, BPD/death, neurodevelopmental impairment or neurodevelopmental impairment/death.
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In summary, use of noninvasive ventilation as a primary mode or following brief period of invasive ventilation through the ETT is associated with improved outcomes in preterm infants with respiratory distress compared with invasive ventilation through the ETT. Short binasal prongs are more effective than single-nasal prongs to deliver NCPAP. Addition of backup rate through the nasal prongs (NIPPV) decreases post-extubation failure rates and may improve pulmonary outcomes. Future directions Nasal interfaces Currently available nasal interfaces are cumbersome and may increase the risk for nasal injury. Development of simpler nasal interfaces is needed to safely increase the use of NIPPV without decreasing the efcacy of NIPPV. We have developed a novel means of delivering time-cycled, pressure and ow-limited IMV using the nasal cannula as the nasal interface (NC-IMV) for neonates receiving nasal respiratory support. Our results with NC-IMV suggest that it is feasible, efcacious and well tolerated.39 Further studies are needed using NC-IMV to evaluate its clinical relevance, such as its impact on the incidence of BPD. Typical settings used for NIPPV are shown in Table 1. SNIPPV versus NIPPV Although physiological considerations suggest that NIPPV should be applied in the synchronized mode, no studies have compared NIPPV and SNIPPV in neonates. Studies comparing SNIPPV versus nonsynchronized NIPPV have not yet been performed in neonates and are urgently needed. NAVA NAVA is a new mode of ventilation that is controlled by electrical activity of the diaphragm (Edi). Edi-peak displays the amount of impulse sent to generate tidal volume breath-by-breath and is

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directly proportional to workload. Edi-minimum measures the tonic activity of the diaphragm at rest, which serves as a measure of physiological reection of derecruitment. In NAVA mode, the ventilator is directly triggered by the patients Edi and the degree of assist is proportional to the duration and strength of the Edi signal. There is therefore patientventilator synchrony both with respect to the timing and the size of the assisted breath. Theoretically, asynchrony is not possible with NAVA if the device is working correctly. It remains to be demonstrated whether eliminating patientventilator asynchrony with NAVA will improve pulmonary outcomes in preterm neonates. The clinical relevance of the Edi signal in weaning neonates from mechanical ventilation and whether NAVA is a practical ventilation mode in preterm neonates need to be studied. Whether the Edi signal can be used to set NAVA support level as well as guide weaning from NAVA mode are also unknown in neonates. We are currently gathering information to establish normative data on Edi signals at different gestational ages using the NAVA.

Automatic adjustment of supplemental oxygen Automatic adjustment of supplemental oxygen during nasal ventilation using a closed loop system to decrease exposure to high levels of inspired oxygen and oxy-trauma are currently in progress.

Conict of interest Rangasamy Ramanathan was a consultant for Dey, LP.

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