Noninvasive Ventilation of Preterm Infants: An Alternative to Mechanical Ventilation








  • Continuous positive airway pressure (CPAP) is an effective respiratory support for preterm infants for a range of indications, especially when delivered via binasal prongs at set pressures equal to or greater than 25 cm H 2 O.



  • Extremely preterm infants may be managed with CPAP from the delivery room onward as an alternative to routine intubation.



  • Nasal intermittent positive-pressure ventilation is a useful method for augmenting the benefits of CPAP, especially when synchronized with the infant’s breathing.



  • Noninvasive high-frequency ventilation is a promising modality that requires further study in randomized trials.



  • Nasal high-flow is an alternative to CPAP as postextubation support for preterm infants and as primary support if CPAP is available as backup.



Acknowledgments


The authors thank Professor Colin Morley for his work on the previous versions of this chapter.


BJM is supported by an Australian National Health and Medical Research Council (NHMRC) Early Career Fellowship (No. 1088279). BAY is partially supported by the NICHD (No. UG1-HD0872266-01). PGD is supported by an NHMRC Practitioner Fellowship (No. 1059111).


The primary concern of the clinician making choices about treatment is whether one therapy leads to better outcomes than the alternatives. This chapter draws heavily on evidence from randomized controlled trials (RCTs), and reviews found in the neonatal module of the Cochrane Library ( www.nichd.nih.gov.easyaccess1.lib.cuhk.edu.hk/cochrane/default.cfm ). Consistent with presentation in the library, estimates of treatment effect are expressed as relative risk (RR) or risk difference (RD) and the differences are statistically significant if the 95% confidence interval (CI) does not include 1 (for RR) or 0 (for RD). Other levels of evidence—for example, from observational studies—are presented, particularly when no RCTs exist.


We believe that before the examination of available evidence, a summary of the physiologic principles underpinning noninvasive ventilation (NIV) usefully informs clinicians and researchers. This chapter focuses on current modes of NIV in clinical use or under investigation in clinical trials: nasal continuous positive airway pressure (NCPAP), nasal intermittent positive-pressure ventilation (NIPPV), high-frequency nasal ventilation (HFNV), and nasal high-flow therapy (NHFT).




Why Do Preterm Infants Experience Respiratory Failure and How Can Noninvasive Ventilation Help?


Respiratory Distress Syndrome


Respiratory distress syndrome (RDS) is a disease of newborns, increasing in prevalence with decreasing gestational age. It is characterized by immature lung development and inadequate surfactant production. The lungs of affected infants may not expand normally immediately after birth, do not easily maintain a residual volume, and are at risk of atelectasis. Other factors also contribute to a loss of lung volume, including muscle hypotonia, a compliant chest wall, and slow clearance of fetal lung liquid. Repeated lung expansion, followed by atelectasis during expiration, leads to shearing forces and stretch injury that damage the airway and saccular alveolar epithelium, causing leakage of protein-rich fluid from the pulmonary capillaries. This leakage in turn inhibits any endogenous surfactant present. Damage to the lungs is exacerbated by mechanical ventilation (MV), high oxygen concentrations, and infection.


Apnea of Prematurity


The pharyngeal airway of the preterm newborn is very compliant. The cartilaginous components are more flexible, and the fat-laden superficial fascia of the neck that stabilizes the upper airway of term infants is not well developed. The intrathoracic airways, including trachea, bronchi, and small airways, are similarly compliant and prone to collapse during expiration. The breathing patterns of very premature infants are frequently erratic and at times inadequate. The causes of apnea of prematurity include hypoxia owing to a reduced functional residual capacity, particularly in active sleep. Upper airway obstruction, alone or in combination with a central respiratory pause, accompanies most apneic events.


The Role of CPAP


CPAP effectively supports the breathing of preterm infants through a number of mechanisms. It mechanically splints the upper airway, thereby minimizing obstruction and reducing apnea. Distention of the airways reduces resistance to air flow and so diminishes work of breathing. CPAP aids lung expansion and so reduces ventilation-perfusion mismatch and improves oxygenation. By preventing repeated alveolar collapse and reexpansion, CPAP reduces protein leak and helps conserve surfactant.


Why Might NIV Be Superior to Mechanical Ventilation via an Endotracheal Tube?


MV via an endotracheal tube (ETT) has been the mainstay of neonatal intensive care almost since its inception. Many lives have been saved by this technique but its adverse effects are well documented, as follows:




  • Cardiovascular and cerebrovascular instability during intubation



  • Complications of the ETT, including subglottic stenosis and tracheal lesions



  • Infections, both pulmonary and systemic



  • Acute and chronic lung damage, primarily related to stretch-mediated effects of nonhomogeneous tidal volume delivery at the cellular level. Studies have demonstrated a differential effect between MV and NIV on both abundance and activation of membrane-based mechanotransducer molecules.



By avoiding the local mechanical problems of an ETT and those of volutrauma, CPAP has been shown to have an advantage over MV, not just in theory but in chronic animal models as well as RCTs.




A Brief History of Invasive and Noninvasive Neonatal Ventilation


The first form of assisted ventilation for neonates was MV provided via an ETT, which became widespread in the late 1960s and early 1970s. Gregory and associates were the first to describe the use of CPAP in neonates in 1971, a therapy they developed because of the high mortality observed in infants weighing less than 1500 g, particularly those requiring assisted ventilation in the first 24 hours of life. The first series of 20 “severely ill” infants with RDS were treated with CPAP delivered predominantly via an ETT. In an attempt to avoid the complications of endotracheal intubation, other interfaces were developed, including a pressurized plastic bag and a tight-fitting face mask. Two infants in the initial Gregory series were managed in a pressure chamber around the infant’s head. In 1976, Ahlström and colleagues described the use of a face chamber providing pressures up to 15 cm H 2 O. Rhodes and Hall conducted a controlled trial involving alternate allocation of subjects to CPAP via a tight-fitting face mask or to conventional therapy consisting of warmed humidified oxygen. A trend toward increased survival was noted in the CPAP group, which was statistically significant in the subgroup of infants weighing more than 1500 g.


The local pressure effects of these devices, combined with the problems of accessibility, particularly for suctioning and feeding, led to the development of alternative interfaces for the delivery of CPAP. Novogroder and coworkers described a device composed of two ETTs inserted through the nose and then positioned under direct laryngoscopy in the posterior pharynx, joined by a Y -connector, and attached to a pressure source. Others described shorter binasal devices that were simpler to manufacture and insert. An even simpler single nasal prong, made by cutting down an ETT, became widely used. A later development in the field is that of a variable-flow device that uses jet nozzles to assist inspiratory flow while diverting flow away from the patient in expiration. This design is claimed to be superior to “conventional” CPAP in reducing work of breathing.


It should be noted that of all these trials, only the one conducted by Rhodes and Hall used a control group. Novogroder and coworkers had plans to subject their device to a randomized trial but abandoned them when “the dramatic effect of CPAP (was) observed after a brief period of treatment in all patients.” It is likely that other researchers were so convinced of the virtues of endotracheal intubation that trials comparing this therapy with CPAP were considered inappropriate. In an accompanying commentary to the study by Rhodes and Hall, Chernick congratulated the investigators on conducting a “daring controlled study” and suggested that although one or two such studies of CPAP would be welcome, many more “would be foolish.” With some notable exceptions, it seems researchers heeded his advice. The following sections describe these exceptions.




Nasal Continuous Positive Airway Pressure


Nasal Continuous Positive Airway Pressure Devices


Several interfaces have been developed for delivering nasal CPAP ( Fig. 11.1 ). Nasal prongs may be short, lying 1 to 2 cm inside the nose, or long, with the tip in the nasopharynx. They may be single or binasal. An important determinant of effectiveness of nasal CPAP devices is their ability to transmit the pressure to the airways. This ability depends on the resistance to flow of the device, which in turn depends on the length and diameter of the prongs. In an in vitro comparison of popular devices, short binasal prongs with the largest internal diameters had the lowest resistance.




Fig. 11.1


Examples of noninvasive nasal CPAP interfaces. A, Nasal mask; B, nasal mask; C, nasopharyngeal prongs; D, short binasal prongs; and E, Infant Flow System nasal prongs.

Used with permission from Dr. Louise Owen, The Royal Women’s Hospital, Melbourne, Australia.


Since its description by Moa and coworkers in 1988, the variable-flow nasal CPAP device (Aladdin nasal CPAP Infant Flow System [now called the Arabella [Hamilton Medical AG, Reno, NV], EME Infant Flow Nasal CPAP [CareFusion, San Diego, CA], or Infant Flow Driver (Electro Medical Equipment Ltd., Brighton, Sussex, UK] has become widely used around the world. In vitro studies using models of neonatal ventilation have demonstrated less pressure variation and work of breathing with the variable-flow device. Pandit and colleagues measured the work of breathing in preterm infants using respiratory inductance plethysmography and esophageal pressure monitoring. They demonstrated less work of breathing with variable-flow CPAP than with constant-flow CPAP. The same group showed, in a crossover study, that the variable-flow device led to better lung recruitment than either nasal cannulae or constant-flow CPAP.


An understanding of the properties of different devices is useful, but for clinicians the primary question is which device performs best at reducing the severity of the respiratory problems and intubation. Head-to-head comparisons of different devices are few. Pooled analysis of the two trials comparing single and binasal prongs after extubation of preterm infants confirms that binasal prongs are superior at preventing extubation failure (RR 0.59, 95% CI 0.41 to 0.85) ( Fig. 11.2 ). Two trials have compared different binasal devices. Stefanescu and associates compared the EME Infant Flow nasal CPAP with INCA prongs (Ackrad Laboratories Inc., Cranford, NJ) and found no difference in rates of extubation failure, death, or bronchopulmonary dysplasia (BPD). Sun and coworkers reported a lower rate of reintubation using the EME Infant Flow system than with short binasal prongs.




Fig. 11.2


Comparison of single-prong (nasal) and double-prong (nasopharyngeal) nasal continuous positive airway pressure (NCPAP): effect on extubation failure. See text for details. CI, Confidence interval; df, degrees of freedom; RR, relative risk.


Mazzella and associates compared the Infant Flow Driver with a single long nasopharyngeal tube for the treatment of preterm infants with respiratory distress. Although infants randomly assigned to the Infant Flow Driver had lower fraction of inspired oxygen (F io 2 ) and respiratory rates, there were no significant differences in the need for ventilation or the duration of CPAP. The lower resistance offered by binasal prongs appears to translate to a clinical advantage for these devices over short or long single nasal prongs.


Gupta and colleagues compared bubble CPAP with the Infant Flow Driver for postextubation management of preterm infants with RDS. The duration of CPAP support was halved in the bubble CPAP group. In the subgroup of infants in which ventilation was used less than 14 days, extubation failed less often in the bubble CPAP group.


As noted early, there are a variety of devices and interfaces through which nasal CPAP is delivered. A recent bench study by Poli and colleagues suggests there may be differences in the functionality of different bubble CPAP delivery systems. Clinical trials have not been performed to compare the clinical effect, if any, of such functional differences. Over the past few years a number of centers have incorporated the “RAM” nasal cannula (Neotech, Valencia, CA) into their management scheme for delivering NIV in lieu of standard approaches to nasal CPAP. Although two small observational studies have been reported, no randomized trials have been performed to date comparing the RAM nasal cannula to other forms of NIV, including CPAP, NIPPV, or NHFT. It is important to note that several recent bench studies suggest significant limitations in the ability of the RAM nasal cannula to provide ventilator set peak or distending pressure during CPAP or NIPPV support. These studies show that only 60% to 70% of the set pressure is delivered to the proximal airway and that there is only minimal volume delivery as well. Clearly, RCTs are required to evaluate this nasal interface.


How Much Supporting Pressure Should Be Used?


The purpose of nasal CPAP is to deliver a pressure to the airways and lungs. If this purpose is achieved consistently, which device is used may not be important. A pressure of 5 cm H 2 O is a traditional starting point. Some neonatal intensive care units (NICUs) hardly vary this pressure and claim good results. There is some evidence from the Cochrane Review of postextubation nasal CPAP that pressures less than 5 cm H 2 O are ineffective in this setting. In their landmark publication on CPAP, Gregory and associates used pressures up to 15 mm Hg. A study of infants with mild RDS showed the highest end-expiratory lung volume and tidal volume, the lowest respiratory rate, and the least thoracoabdominal asynchrony occurred at a pressure of 8 cm H 2 O, which was compared with 0, 2, 4, and 6 cm H 2 O.


A more recent study from Buzzella and colleagues suggests that CPAP pressures of 8 cm H 2 O compared with 5 cm H 2 O may be more effective at preventing extubation failure in extremely low-birth-weight infants. Additionally, the higher pressure seems to be well tolerated from a cardiorespiratory standpoint. Comparisons of cardiac output, cerebral circulation, and venous return suggest the higher pressure does not compromise cerebral circulation or venous return, but it may reduce pulmonary shunting across the ductus arteriosus. An infant with RDS, relatively stiff lungs, a high F io 2 , and a chest radiograph showing opaque lungs may need a higher pressure to support lung volume than an infant with a low F io 2 treated for apneic episodes. If CPAP is to be effective, the pressure may need to be increased to the 8- to 10-cm H 2 O range in infants with very low lung compliance. If an infant shows evidence of lung disease with increasing oxygen requirements and a more opaque chest radiograph, we recommend increasing the distending pressure by increments of 1 cm H 2 O and observing the effect. It is important to note, however, that high distending pressures, if used in an infant with compliant lungs, can interfere with pulmonary blood flow and cause lung overdistention, leading to carbon dioxide retention.


The optimal CPAP pressure is not known and likely depends on the condition treated. Judging the distending airway pressure needed to optimize lung inflation, pulmonary, and systemic blood flow to result in the lowest needed F io 2 remains an art. Future research should evaluate strategies of titrating CPAP pressures to an infant’s requirements. In the absence of evidence-based guidelines, we typically use CPAP pressures in the 5- to 8-cm H 2 O range, adjusting them on the basis of oxygen requirements and clinical assessment of work of breathing.


Nasal CPAP for Infants With RDS or at Risk of Developing RDS


The focus of studies on the use of nasal CPAP in infants who have, or are at risk for, RDS has changed over the decades. Questions about the topic are dealt with here in roughly historical order. From a clinical perspective, studies conducted before the availability of surfactant are of limited relevance in the modern neonatal intensive care era. In general, presurfactant trials comparing the risk and benefit of prophylactic CPAP versus no continuous distending pressure (i.e., oxygen by hood or standard nasal cannula therapy) showed that CPAP reduced the rate of treatment failure (death or use of assisted ventilation; RR 0.70, 95% CI 0.55 to 0.88), and mortality (RR 0.52, 95% CI 0.32 to 0.87) ( Fig. 11.3 ). However, more pneumothoraces occurred in the patients receiving continuous distending pressure (RR 2.36, 95% CI 1.25 to 5.54).




Fig. 11.3


Comparison of continuous distending pressure (CDP) and standard care for respiratory distress syndrome: effect on rate of mortality. See text for details. CI, Confidence interval; df, degrees of freedom; RR, relative risk.


CPAP in the Surfactant Era


Surfactant is the most comprehensively evaluated treatment in neonatology. Initial randomized trials of surfactant were done nearly 30 years ago, when early CPAP was not commonly used for very preterm infants, antenatal corticosteroids were given to only 10% of eligible mothers, and neonatal mortality and morbidity rates were much higher than current rates. Surfactant therapy was provided via the ETT, and whether given prophylactically or as treatment, surfactant reduced mortality and the combined outcome of death or chronic lung disease. Surfactant therapy appeared more beneficial when given early in the course of RDS. It became common practice for all very preterm infants to be intubated in the delivery room for surfactant administration. In the past few years a number of randomized trials have evaluated “less invasive” approaches to surfactant administration in conjunction with CPAP support and are discussed in the following text. Although other methods of administration have been tried, surfactant is usually given via an ETT.


Is CPAP an Alternative to Routine Intubation of Very Preterm Infants at Birth?


More than a decade ago, several groups reported their experience following policy change from early intubation to early nasal CPAP, describing lower mortality and morbidity in the CPAP-treated group. Since then, several RCTs have compared intubation in the delivery room with early nasal CPAP. The Nasal CPAP or Intubation at Birth for Very Preterm Infants (COIN) trial randomly assigned 610 breathing infants born at 25 to 29 weeks’ gestation to CPAP or intubation and ventilation if they manifested signs of respiratory distress at 5 minutes after birth. Surfactant was administered to intubated infants at the discretion of the treating clinician. There were no differences in the rates of death or BPD between the groups. The benefits of CPAP included halving the intubation rate, a lower risk of the combined outcome of death or the need for oxygen therapy at 28 days, and fewer days of MV. However, the CPAP group had a higher rate of pneumothoraces (9% vs. 3% in the intubated group).


The Surfactant, Positive Pressure, and Oxygenation Randomized Trial (SUPPORT) group enrolled 1316 infants between 24 and 27 weeks’ gestation who were randomly allocated to immediate CPAP or intubation in the delivery room. Intubated infants were also treated with surfactant within 1 hour after birth. The rates of death or BPD did not differ significantly between the groups after adjustment for gestational age, center, and familial clustering. Although 83.1% of infants in the CPAP group ultimately required intubation and MV, 34.4% were intubated in the delivery room. Overall, infants randomly assigned to CPAP were less likely to be intubated, less likely to receive postnatal corticosteroids, had fewer days of MV, and were more likely to be alive without MV by day 7.


A Vermont Oxford Network trial compared three approaches to initial respiratory management in 648 very preterm infants born at 26 to 29 completed weeks’ gestation: (1) prophylactic surfactant followed by a period of MV, (2) prophylactic surfactant with rapid extubation to CPAP, or (3) initial management with CPAP and selective surfactant treatment. The primary outcome was the incidence of death or BPD at 36 weeks postmenstrual age. Both prophylactic surfactant with rapid extubation to CPAP and initial management with CPAP reduced the RR of death or BPD compared with prophylactic surfactant followed by a period of MV. About half the infants managed with initial CPAP avoided MV and surfactant. Mortality and other adverse outcomes were similar between the groups.


A meta-analysis including the previous RCTs and a fourth trial found a significant reduction in the combined outcome of death or BPD, at 36 weeks’ corrected gestation for infants treated with early CPAP: RR 0.91 (95% CI 0.84 to 0.99), number needed to treat: 25. The trials show that nasal CPAP can be used from birth in very preterm infants and that nearly half of such infants may not need ventilation or surfactant treatment. The absence of evidence for increased risk or adverse event rates supports increasing the use of early aggressive nasal CPAP as the initial respiratory mode in an effort to prevent intubation/MV and subsequent BPD for most extremely preterm infants.




Is CPAP With Early Intubation for Surfactant and Brief Mechanical Ventilation Better Than CPAP Alone?


A systematic review has investigated whether early, brief intubation for surfactant administration followed by extubation to nasal CPAP was better than nasal CPAP and selective intubation, surfactant, and continued MV. Meta-analysis of the six studies identified showed that intubation, ventilation, and early surfactant therapy followed by extubation to nasal CPAP ventilation was associated with lower incidences of later MV (typical RR 0.67, 95% CI 0.57 to 0.79), air leak syndromes (typical RR 0.52, 95% CI 0.28 to 0.96), and BPD (typical RR 0.51, 95% CI 0.26 to 0.99). The early surfactant group received about 60% more surfactant. Stratified analysis of F io 2 at study entry suggested that a lower treatment threshold (F io 2 <0.45) reduced air leaks and BPD.


Further studies have been published since this review. The Colombian Neonatal Research Network enrolled infants of 27 to 31 weeks’ gestation, who were receiving oxygen and had increased work of breathing, at 15 to 60 minutes after birth. The infants were treated with bubble nasal CPAP 6 cm H 2 O and then were randomly allocated to either nasal CPAP plus surfactant ( n = 141) or nasal CPAP alone ( n = 137). The primary outcome was the need for MV started because either the F io 2 was higher than 0.75 or the partial pressure of carbon dioxide (Pa co 2 ) was higher than 65 mm Hg. The nasal CPAP plus surfactant group received two doses of surfactant (Survanta, Abbott Nutrition, Abbott Park, IL), 2 minutes apart, and were then extubated if possible to nasal CPAP 6 cm H 2 O. The need for MV was significantly lower in the nasal CPAP ventilation plus surfactant group (26% vs. 39%), although all infants who had received surfactant had been temporarily intubated and ventilated. Mortality, BPD, duration of MV, and oxygen therapy did not differ between the groups. There were fewer air leaks in the group receiving surfactant.


The CURPAP study group randomly assigned 208 infants born at 25 to 28 weeks’ gestation who were not intubated within 30 minutes of birth to either (1) intubation, surfactant (Curosurf; Cornerstone Therapeutics Inc., Cary, NC) and extubation within an hour (if possible) to nasal CPAP, or (2) nasal CPAP with early selective surfactant. Infants were intubated for MV when F io 2 exceeded 0.4, the infant had four episodes of apnea per hour, or for Pa co 2 higher than 65 mm Hg. There were no significant differences between the groups in the need for MV at 5 days of life, death, or BPD, or the rate of pneumothoraces.


All these trials show that outcomes in infants stabilized in the delivery room with either nasal CPAP or prophylactic surfactant and extubation to nasal CPAP appear to be similar to those in infants managed with surfactant followed by MV.


Less Invasive Surfactant Administration


Techniques of administering surfactant without using an ETT, less invasive surfactant administration (LISA), have recently been described. Kribs and associates performed an RCT in extremely premature infants receiving nasal CPAP with ongoing signs of RDS, comparing surfactant given via an intratracheal catheter during spontaneous breathing (LISA) to conventional therapy with surfactant via ETT. Although survival without BPD was not different, the LISA group had significantly fewer rates of intubation, days of MV, and pneumothoraces. The combined outcome of survival without serious adverse event was significantly improved in the LISA group. Dargaville and colleagues have also proposed a less invasive method of surfactant administration; in a feasibility study, nonsedated preterm infants undergoing nasal CPAP received surfactant via a 16-gauge vascular catheter under direct vision of the vocal cords. In all cases, surfactant was successfully administered and nasal CPAP was reestablished. A large RCT of this method is underway.


LISA techniques have been further evaluated in RCTs and subsequent meta-analyses. These trials, including nearly 900 preterm infants, vary by the overall LISA approach, the mode of NIV, and study population. Additionally, none of the trials has been effectively blinded. Meta-analysis of the trials to date demonstrate a significant reduction in several important respiratory outcomes, including early CPAP failure (RR 0.67, 95% CI 0.47 to 0.93), any need for MV (RR 0.66, 95% CI 0.47 to 0.93), and death or BPD (RR 0.74, 95% CI 0.58 to 0.94). Importantly, no increases in other common neonatal morbidities such as intraventricular hemorrhage, necrotizing enterocolitis, or retinopathy of prematurity were found with the LISA approach. Long-term neurodevelopmental follow-up studies remain to be completed.


Nasal CPAP for Postextubation Support


It is generally accepted that early extubation of preterm infants is desirable. The perceived benefits include reducing the risks of infection, local tissue damage, and BPD. On the other hand, failure of extubation and the need for reintubation is associated with instability and more local trauma. The Cochrane Review on the topic identified nine randomized trials of varying methodologic quality and using different CPAP pressures and devices. Pooled analysis showed that nasal CPAP was associated with a lower rate of respiratory failure (apnea, respiratory acidosis, or increased oxygen requirements) after extubation than management in an oxygen hood (RR 0.62, 95% CI 0.51 to 0.76). Four of the studies allowed rescue nasal CPAP for infants in whom the oxygen hood failed. Because rescue treatment with nasal CPAP was frequently successful, there was no significant difference in the rate of reintubation between the groups (RR 0.93, 95% CI 0.72 to 1.19). A study that directly compared elective with rescue nasal CPAP ventilation after extubation found no differences in reintubation rates.


Therefore it can reasonably be concluded that nasal CPAP should be used when a very preterm infant is extubated to prevent the instability associated with possible subsequent respiratory failure and reintubation. However, it appears that reserving the use of nasal CPAP for preterm infants in whom respiratory failure is developing after extubation does not lead to increased reintubation.


CPAP Failure: When Should Preterm Infants Be Intubated?


There is no universally accepted definition of CPAP “failure.” Polin and Sahni suggested that an infant with ventilation that is not improving or inadequate oxygenation with F io 2 >0.6 should be intubated and given surfactant. Others recommend intubation when the F io 2 exceeds 0.35 to 0.40. Studies suggest that lower gestational age (<26–27 weeks), more radiographic evidence of severe disease, and evidence of escalating F io 2 are key markers for preterm infants likely to have nasal CPAP failure. The following failure criteria were set for infants randomly allocated to nasal CPAP in the COIN trial: F io 2 greater than 0.6 or pH less than 7.25 with a Pa co 2 higher than 60 mm Hg, or more than one apneic episode per hour requiring stimulation. Regardless of which threshold is applied, it is important that remediable causes of CPAP failure are sought and treated before intubation. They include airway obstruction with secretions, inappropriate (too small) prong size, and inadequate distending pressure. Treating a large mouth leak and raising the applied pressure may be useful strategies before CPAP is deemed to have failed.


Complications of Nasal CPAP


Nasal CPAP ventilation is a comparatively simple form of respiratory support, yet it is not without complications. The major problems of the early days of CPAP, intracerebellar hemorrhages and hydrocephalus, were solved by alterations in delivery technique. However, nasal trauma may still occur when prongs are used, ranging in severity from redness and excoriation of the nares to necrosis of the columella and nasal septum requiring surgery. Observational studies suggest that all nasal CPAP devices may cause trauma. Robertson and coworkers reported a complication rate of 20% in a series of very low-birth-weight infants managed with the Infant Flow Driver. To minimize the incidence of nasal trauma, we try to select a prong with a diameter that is sufficient to snugly fit the infant’s nostril (avoiding excessive leak around the device), but which does not cause blanching of the nares. Positioning of binasal prongs so that there is no pressure on the columella is sometimes difficult to achieve but is critical. We have observed that supervision by skilled nurses experienced in the technique of securing nasal CPAP prongs has led to a low rate of nasal trauma.


Pneumothoraces occur in preterm infants treated with CPAP. In the COIN trial, there were significantly more pneumothoraces in the CPAP group than in the ventilated group (9% vs. 3%, respectively), raising concerns in some quarters about the use of early nasal CPAP. In the previously described Colombian Neonatal Research Network study, the group managed with early surfactant therapy had fewer pneumothoraces compared with the group managed with nasal CPAP alone (2% vs. 9%). Conversely, the SUPPORT trial found no difference in the rate of pneumothoraces between early CPAP and early MV. An RCT of early CPAP compared with passive oxygen therapy after birth for newborn infants with respiratory distress born in Australian nontertiary centers by Buckmaster and colleagues found an almost threefold increase in pneumothorax rates in the CPAP-treated group (9% vs. 3%).


Weaning CPAP


The optimal method of weaning an infant from nasal CPAP remains uncertain, and practices vary among units. An RCT comparing a strategy of weaning through reducing pressure with one of increasing time “off” nasal CPAP showed a significantly shorter duration of weaning with the “pressure” strategy. A more recent trial determined that weaning directly off nasal CPAP, rather than gradual titration over increasing time intervals, resulted in discontinuing nasal CPAP earlier. Recent follow-up from that study suggests that using a standardized approach to weaning from nasal CPAP in preterm infants younger than 30 weeks’ gestation is associated with improved outcomes, including decreased rates of BPD.


Four RCTs have assessed the role of NHFT, discussed at length later in this chapter, in weaning from nasal CPAP. Trials by Tang et al. and Soonsawad et al. found NHFT contributed to shorter time receiving nasal CPAP, but the overall duration of NIV was not different. In the study by Abdel-Hadys et al., the use of NHFT at 2 L/min to wean from CPAP resulted in more days on oxygen and respiratory support, with no difference in success of CPAP weaning. In contrast, Badiee found that NHFT at 2 L/min significantly reduced the duration of supplemental oxygen and hospital stay, without increasing successful weaning from CPAP. The use of NHFT ventilation to facilitate weaning from nasal CPAP ventilation requires further investigation.


In the absence of good evidence, our practice is to incrementally wean infants to a CPAP of 5 cm H 2 O, discontinue the nasal CPAP ventilation when the infant is stable with F io 2 less than 0.30, and recommence it if oxygen requirements or the frequency of apneas increases. We do not recommend the use of NHFT as a routine weaning method.


Nasal Intermittent Positive-Pressure Ventilation


Although nasal CPAP is an effective method of postextubation support, researchers have added positive-pressure “inflations” to a background of nasal CPAP: NIPPV. This technique was first used in the 1980s but became unpopular when it was linked to gastrointestinal perforation. The availability of ventilators that “synchronized” with an infant’s inspirations led to additional studies of NIPPV. The most recent systematic review identified 10 trials enrolling 1431 infants comparing extubation of infants to NIPPV or nasal CPAP. Pooled analysis showed NIPPV to be associated with a significant reduction in the risk of extubation failure (typical RR 0.70, 95% CI 0.60 to 0.80), as well as the risk of needing reintubation (typical RR 0.76, 95% CI 0.65 to 0.88) ( Fig. 11.4 ). Despite these benefits, there was not a reduction in BPD with NIPPV compared with nasal CPAP (typical RR 0.94, 95% CI 0.80 to 1.10). Reassuringly, there was no significant difference between the two approaches in the rate of abdominal distention, gastrointestinal perforation, or necrotizing enterocolitis.




Fig. 11.4


Nasal intermittent positive pressure ventilation (NIPPV) versus nasal continuous positive airway pressure (NCPAP) for preterm neonates after extubation See text for details. CI, Confidence interval; df, degrees of freedom; M-H, Mantel-Haenszel (random-effects method for dichotomous data); RR, relative risk.


Synchronized NIPPV (S-NIPPV) appears more effective in preventing intubation than nasal CPAP alone. However, most modern neonatal ventilators do not enable synchronization during NIV. Neurally adjusted ventilatory assist (NAVA), which synchronizes ventilator breaths to diaphragmatic electrical activity, has recently been applied to NIV of neonates. Preliminary studies suggest improved synchrony and lower peak inspiratory pressures compared with conventional approaches to NIPPV. Large RCTs are needed to compare the safety and efficacy of NAVA-NIV to other NIV approaches for the prevention of BPD.


There is limited information to help clinicians optimize NIPPV settings. No RCTs have compared the safety or efficacy of different approaches to NIPPV settings, including the effect of rate. As many neonatal units are now using nonsynchronized NIPPV, it is important to recognize one potential adverse effect of this approach to the dynamic function of the upper airway and glottis. During normal breathing, the glottis musculature relaxes during inspiration, presumably to optimize the airway compliance and resistance to gas flow and minimize work of breathing. This neuromuscular response is unchanged when nasal CPAP is applied. However, recent studies demonstrate that nonsynchronized NIPPV (NS-NIPPV) induces a glottis constrictor response, mediated by bronchopulmonary receptors, leading to narrowing of the glottis region. On the other hand, a normal glottic relaxation response was noted when NIV was applied with either NAVA or NHFV.


NIPPV is also used in other clinical situations. A systematic review of NIPPV for treating apnea of prematurity found only two studies with a total of 54 infants. The pooled analysis showed a modest benefit for NIPPV over nasal CPAP and no evidence of harm. It therefore seems reasonable to try NIPPV in infants experiencing troublesome apnea during treatment with nasal CPAP. Following its success in these situations, some investigators have suggested that NIPPV be used as an initial form of support for preterm infants with respiratory distress. Meneses and colleagues studied NIPPV in this role: 200 preterm infants (26–34 weeks’ gestation) with RDS were randomly assigned to NIPPV or nasal CPAP, with surfactant given as a rescue therapy. The rates of reintubation within the first 72 hours of life were no different between the groups (RR 0.71, 95% CI 0.48 to 1.14). Observational studies suggest that the use of NIPPV for primary treatment of RDS is worth testing in further RCTs, either alone or in conjunction with prior intubation and surfactant therapy.


The mechanisms by which NIPPV improves clinical outcomes are uncertain. Owen studied 10 premature infants receiving NS-NIPPV and found that the pressure peaks resulted in only a small increase in relative tidal volumes when delivered during spontaneous inspiration, and only occasionally led to chest inflations when delivered during apneic periods. Another study of 11 infants demonstrated that during NS-NIPPV, the delivered positive inflation pressure was variable and frequently lower than that set. Chang and associates compared short-term effects of NS-NIPPV and S-NIPPV with nasal CPAP. Sixteen very preterm infants, 15 ± 14 days old and undergoing treatment with the Infrasonic Infant Star Ventilator (Monet Medical, Salt Lake City, UT) were randomly allocated to nasal CPAP, NS-NIPPV at 20 or 40 inflations/min, or S-NIPPV at 20 or 40 inflations/min for 1 hour each in random order. Tidal volume, minute ventilation, and gas exchange values did not differ significantly among the groups. S-NIPPV resulted in less inspiratory effort than nasal CPAP or NS-NIPPV, but NS-NIPPV had no advantage over nasal CPAP. Active expiratory effort and expiratory duration increased during NS-NIPPV. There were no benefits for gas exchange of either form of nasal ventilation over nasal CPAP. S-NIPPV reduced breathing effort and resulted in better infant-ventilator interaction than NS-NIPPV.


NIPPV appears to be useful for augmenting nasal CPAP. Further studies of NIPPV are required to determine the optimal pressure and rate settings, the safety of the nonsynchronized mode, and the role of NIPPV as primary therapy for RDS.


Noninvasive High-Frequency Nasal Ventilation


Over the past decade, noninvasive HFNV has been increasingly studied as an approach to NIV of the neonate. For interested readers, the clinical and pathologic effects of prolonged MV compared to early, sustained HFNV on lung injury and development in a sustainable preterm lamb model of BPD are available but are not discussed here.


Factors Affecting Gas Exchange During HFNV


During neonatal HFNV, several factors related to tidal volume delivery and effective gas exchange need to be considered. First, as with nasal CPAP and NIPPV, satisfactory oxygenation is achieved by establishing and maintaining adequate functional residual lung volume via the mean distending pressure within the trachea and distal airway. Second, during NIV, unlike invasive MV, the mean intratracheal pressure is proportional to, but less than, the pressure set at the ventilator. Additionally, the set peak pressure and/or amplitude setting at the ventilator is markedly attenuated (by as much as 70%) across the nasopharyngeal tube/prongs to the distal nasopharynx; pressure attenuation is greater with smaller internal diameter interfaces. Third, despite this pressure attenuation, measurable small tidal volumes can be delivered at very rapid rates assisting minute ventilation. Thus HFNV can maintain positive, albeit relatively low, end-expiratory pressure in the lungs to support oxygenation, while supporting ventilation by providing small tidal volumes at a high rate.


One factor influencing the effectiveness of any form of NIV is leak. Depending on the HFNV-nasal interface, leak may occur at the nares insertion site, contralateral nares, and the mouth. Shortened single nasopharyngeal tubes have been used, allowing leak from the contralateral nares, as well as short binasal CPAP prongs and masks. The least amount of leak is likely from a mask interface. The major consequence of leak is pressure reduction in the nasopharynx, trachea, and beyond. However, there may be an “optimal” leak that enhances ventilation by washing out dead space.


Laryngeal Effects of HFNV


During normal spontaneous breathing laryngeal muscles act in synchrony to open the upper airway during inspiration, decreasing resistance and improving the flow of gas through the glottis. This normal muscle activity during inspiration is markedly altered with the application of pressure-supported NIPPV, inducing an increase in inspiratory constrictor (thryoarytenoid) muscle activity while suppressing normal inspiratory dilator (cricothyroid) muscle activity. Contrary to the effect of NIPPV, the application of HFNV was shown been not to increase inspiratory constrictor muscle activity while maintaining normal dilator muscle activity.


Clinical Reports on Neonatal HFNV


Use of high-frequency ventilation as an NIV technique in neonates was first published almost 20 years ago by van der Hoeven and colleagues. Table 11.1 shows data from four retrospective studies ( n = 114) and two prospective trials ( n = 79) of HFNV in mostly preterm neonates. There is considerable variability across studies in study population as well as in the high-frequency ventilator used and the initial settings applied. A variety of nasal interfaces have been used. Each of the published studies suggest HFNV could successfully support many (but not all) infants more effectively than conventional nasal CPAP or nasal ventilation. Significant adverse events related to HFNV have not been reported, although the majority of neonates have been supported for only relatively short periods of time.


Dec 29, 2019 | Posted by in PEDIATRICS | Comments Off on Noninvasive Ventilation of Preterm Infants: An Alternative to Mechanical Ventilation
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