Neonatal Noninvasive Ventilation Techniques: Do …rc.rcjournal.com/content/respcare/56/9/1273.full.pdfNeonatal Noninvasive Ventilation Techniques: Do We Really Need to Intubate? Robert
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
Neonatal Noninvasive Ventilation Techniques:Do We Really Need to Intubate?
Robert M DiBlasi RRT-NPS FAARC
IntroductionProposed Benefits of Noninvasive VentilationNoninvasive Ventilation Modes in Neonates
The lungs of premature neonates lack structural devel-opment, ability to produce surfactant, and surface area for
gas exchange to occur. The problem is further complicatedby apnea and the infant’s inability to maintain the highwork of breathing (WOB) necessary to overcome the op-
Mr DiBlasi is affiliated with the Center for Developmental Therapeutics,Seattle Children’s Research Institute, and with the Department of Respi-ratory Care, Seattle Children’s Hospital and Research Institute, Seattle,Washington.
Mr DiBlasi presented a version of this paper at the 47th RESPIRATORY
CARE Journal Conference, “Neonatal and Pediatric Respiratory Care:What Does the Future Hold?” held November 5–7, 2010, in Scottsdale,Arizona.
Mr DiBlasi has disclosed relationships with Monaghan Medical and
GE Healthcare. Seattle Children’s Research Institute has submitted apatent application to the World Intellectual Property Organization (PCT/US2009/039957) concerning one of the devices mentioned in this paper,and Mr DiBlasi is listed as an inventor on the application and couldbenefit from the invention.
Correspondence: Robert M DiBlasi RRT-NPS FAARC, Seattle Chil-dren’s Research Institute - Respiratory Care, Center for DevelopmentalTherapeutics, 1900 Ninth Avenue, Seattle WA 98101. E-mail: [email protected].
DOI: 10.4187/respcare.01376
RESPIRATORY CARE • SEPTEMBER 2011 VOL 56 NO 9 1273
posing forces that resist lung inflation during spontaneousbreathing. As such, severe respiratory failure is prevalentin premature neonates with the respiratory distress syn-drome (RDS). Endotracheal intubation and mechanical ven-tilation, or invasive ventilation has been the prevailingintervention for supporting neonates with RDS over thelast 40 years. This practice has probably accounted forsome of the notable reductions in infant mortality prior tothe development of artificial surfactant and the widespreaduse of antenatal corticosteroids.1 However, even short-terminvasive ventilation in animal models of respiratory dis-tress has been associated with lung inflammation and in-jury,2 reduced efficacy of endogenous surfactant,3 and ar-rest of alveolar growth and development.4-6 Ventilator-induced lung injury (VILI) is characterized by excessivetidal volume (VT) delivery (volutrauma),7 shear injury re-lated to repetitive cycling of distal airways at suboptimallung volumes (atelectrauma),8 and the consequent releaseof biochemical substances that instigate pulmonary inflam-mation (biotrauma).9 VILI has been implicated as a majorfactor predisposing neonates to chronic lung disease orbronchopulmonary dysplasia (BPD).10,11 Interpreted in aliteral sense, the term “VILI” underscores the potentiallydeleterious effects of other confounding factors within theventilator system: specifically, the endotracheal tube (ETT).
‘‘Endotrauma is the name given to injury to the airwaysand lungs from the disruption of homoeostasis that occursduring, and sometimes after, artificial ventilation throughan ETT.”12 Although it is difficult to decouple and eval-uate the injurious effects related to the ETT from those ofthe ventilator, the ETT is probably a major factor addingto causal respiratory failure and injury during invasiveventilation. Endotracheal intubation is a traumatic and pain-ful procedure that requires sedation and can be associatedwith hemodynamic instabilities, airway emergencies, acuteairway injury, colonization of the trachea, reduced ciliarymovement, secretions, high resistance to air flow, and in-creased WOB.13 The ETT bypasses the glottis and hindersthe neonate’s adaptive mechanism (grunting14) for pre-serving the end-expiratory lung volume. The ETT alsoprovides a direct route into the lower, sterile airway, whichincreases the risk of ventilator-associated pneumonia andsepsis.15
Nasal continuous positive airway pressure (CPAP) is analternative to invasive ventilation that does not require anETT and permits spontaneous breathing during continuouspressure applied with prongs in the nares. CPAP improvesgas exchange, increases functional residual capacity, sta-bilizes the chest wall, enhances surfactant production, re-duces WOB, and reduces the need for intubation and sur-factant replacement therapy.16 A recent large multicenterrandomized controlled trial (RCT)17 found that prematureneonates supported initially with CPAP in the deliveryroom and given surfactant only for respiratory failure had
less need for invasive ventilation and greater survival with-out high-frequency oscillatory ventilation (HFOV) or con-ventional ventilation at 7 days than did neonates assignedto intubation and early surfactant treatment.
CPAP has redefined the care of premature neonates butdoes not sufficiently off-load the burden of high WOB, noris CPAP capable of providing effective alveolar ventila-tion for neonates whose condition worsens. As such, ap-proximately 50–67% of very-low-birth-weight prematureneonates supported initially with CPAP develop severerespiratory failure requiring intubation and invasive ven-tilation.17,18 Approximately 25–38% of infants fail CPAPfollowing surfactant administration, resulting in re-intuba-tion and invasive ventilation.19,20
Noninvasive ventilation (NIV) is a form of respiratoryassistance that provides a greater level of respiratory sup-port than does CPAP and may prevent intubation in alarger fraction of neonates who would otherwise fail CPAP.In addition to the CPAP effect of the ventilator, the pa-tient’s spontaneous breaths are assisted by patient-trig-gered (synchronized) or machine-triggered, time-cycled in-flations during NIV. NIV has been used successfully inadult and pediatric patients, with oronasal mask and withnasal mask. With advances in ventilator technology andnasal interfaces, clinicians have begun implementing off-label NIV in neonates, often with very little experimentalclinical data to guide therapy. The most commonly usedNIV modes are intermittent mandatory ventilation (IMV),neurally adjusted ventilatory assist, sigh positive airwaypressure, and high-frequency ventilation. This paper re-views these NIV modes, management strategies, and theavailable evidence related to these interventions.
Proposed Benefits of Noninvasive Ventilation
Short-term application of NIV in neonates is not a newconcept in the neonatal respiratory care community. Infact, manual resuscitators affixed with oronasal masks andPEEP valves are commonly used to assist neonates withinsufficient respiratory efforts and respiratory failure. Thelong-term use of automated NIV in neonates was firstreported in 1952 by Donald and Lord21 in a paper entitled,“Augmented Respiration: Studies in Atelectasis Neonato-rum,” nearly 2 decades prior to the initial description ofneonatal CPAP by Gregory et al.22 Donald and Lord “am-plified spontaneous breathing efforts” in neonates with asetup that included a rubber face mask and a spirometerwith a spring-loaded one-way valve that collected and mea-sured exhaled gas. Based on changes in the measured ex-haled minute volume (VE), different positive and negativepressures could be applied to the chest wall of the neonate,enclosed in a sealed plethysmograph. Further, the patientcould synchronize all of his or her spontaneous respiratoryefforts with the applied pressure by deflecting a light beam
NEONATAL NONINVASIVE VENTILATION TECHNIQUES: DO WE REALLY NEED TO INTUBATE?
1274 RESPIRATORY CARE • SEPTEMBER 2011 VOL 56 NO 9
from an electrical cell to an adjacent light mirror duringinhalation, which triggered the machine. Over the next fewdecades many negative-pressure ventilators incorporatedinto isolettes were tried, with less than promising out-comes.23
Following many failed attempts at providing invasiveventilation with adult-specific ventilators in neonates,Llewelyn et al24 described the often unforeseen complica-tions arising from prolonged endotracheal intubation in1970:
It has become evident that the advantages of such atechnique must be weighed against its complica-tions. Tube displacement and blockage are a con-stant hazard. Laryngeal edema and loss of ciliatedtracheal mucosa with ulceration are common nec-ropsy findings after prolonged intubation, and thesepredispose to permanent laryngeal and tracheal dam-age. Infection is readily established in these infants,doubtless due in part to the repeated introduction ofsuction catheters.
In an effort to avoid intubation but to retain the clinicalbenefits of positive-pressure ventilation, Llewelyn et al24
and Helmrath et al25 reported separately in 1970 their ini-tial experiences with ventilation applied with a firmly at-tached oronasal mask, using pressure-cycled intermittentpositive-pressure devices and pediatric volume-cycled ven-tilators. NIV via face mask resulted in better gas exchange,ability to wean oxygen, less lung infection, and less needfor invasive ventilation than did standard treatment withoxygen therapy.24 In 1976, Pape et al26 described severehead molding from the straps used to secure the face maskduring NIV, especially in preterm neonates � 1,500 g.Although the use of mask NIV reduced the neonatal mor-tality rate from 75% to 45% in their intensive care unit,this practice was associated with an alarmingly higher rateof cerebellar hemorrhage at autopsy than in neonates sup-ported with invasive ventilation via nasal ETT. Attemptswere made during this time to develop new techniques forsecuring the face mask that would decrease the risk ofhead molding and consequent neurologic complicationsduring NIV.27
Following the initial description of nasal prongs by Kat-tiwinkel et al28 and Caliumi-Pellegrini et al29 to deliverCPAP, Moretti et al30 described the first successful appli-cation of NIV with bi-nasal prongs in preterm neonateswith respiratory failure and apnea. The widespread use ofNIV was temporarily hampered following the publicationof a paper by Garland et al,31 who found that neonatesventilated with either oronasal mask or nasal prongs were30 times more likely to develop gastrointestinal perfora-tions than were neonates ventilated with ETT. Followingthe advent of neonatal-specific, patient-triggered ventila-tors, Friedlich et al32 introduced patient-triggered (or syn-
chronized) nasal IMV in neonates, and clinicians becameinterested in using NIV again.
As mentioned previously, the goals of NIV are to assistweak or ineffective spontaneous breathing, avoid endo-trauma, and noninvasively support a larger fraction of pre-mature neonates who would otherwise fail CPAP or re-main intubated and mechanically ventilated. In theory,minimizing invasive ventilation may reduce BPD and otherneonatal complications. In addition to supporting prema-ture neonates with RDS, NIV has been used successfullyin neonates with other forms of respiratory failure, includ-ing congenital pneumonia, meconium aspiration syndrome,transient tachypnea of the newborn, and neuromusculardisorders. Based on the successes of NIV in neonates,interest in using NIV in larger infants and toddlers withrespiratory distress has increased, but these approacheshave been hampered by the lack of available nasal airwayinterfaces designed for this population.
Neonatal nasal airway interfaces and fixation techniquesduring NIV are similar to those used for CPAP.16 Bi-nasalshort-prongs (Fig. 1) are the most commonly used nasalinterface because they impose lower resistance and, hence,less WOB than do ETTs.33 Obviating the ETT during me-chanical ventilation may avoid many of the complicationsassociated with endotrauma, but may not avoid all of thecomplications associated with VILI. The approach andsettings used to manage neonates during NIV are similarto invasive ventilation, so VILI is still a concern duringNIV. However, during NIV, a natural lung-protective pres-sure-relief valve exists via leaky nasal airway interfacesand the oropharynx, which may prevent excessive pressuretransmission to the distal airways.13 As such, some clini-
Fig. 1. A premature neonate with bi-nasal short prongs and animprovised chin strap secured with cloth and tape to prevent oralair leakage. (Courtesy of Rose DeKlerk, Vermont Oxford Network.)
NEONATAL NONINVASIVE VENTILATION TECHNIQUES: DO WE REALLY NEED TO INTUBATE?
RESPIRATORY CARE • SEPTEMBER 2011 VOL 56 NO 9 1275
cians still prefer nasopharyngeal ETTs, placed 2–3 cm intoa single nare during NIV, because the contralateral nareacts as an additional pressure pressure-relief valve that canfurther vent excessive pressure to the atmosphere morereadily than a tracheal tube or bi-nasal prongs. A potentiallimitation of excessive airway leak during NIV is thatsufficient pressure may not be delivered to maintain lunginflation.
Perhaps the greatest known benefit of NIV is that itmaintains a higher mean airway pressure than CPAP. Thisprovides a greater ability to recruit collapsed alveoli, main-tain end-expiratory lung volume, and improve oxygen-ation. Providing inflations above CPAP pressure augmentsVT and can provide sigh breaths, which may also improvegas exchange and recruit areas of microatelectasis or air-way collapse. Additionally, NIV preserves the neonate’snatural ability to augment lung volume, because the glottisis unimpeded by an ETT. Neonates who are apneic maynot always receive sufficient support from NIV, but NIVshould reduce the magnitude and severity of apneas.
In a recent survey, Owen et al34 found that 45% of allneonatal intensive care units (NICUs) in England usedsome form of NIV to support neonates. How many hos-pitals in the United States are currently using nasal IMV isunclear, but the results of some compelling new clinicalresearch suggest that this number is likely to be large andgrowing. The proposed physiologic benefits of NIV aswell as management strategies and clinical data, as theyrelate to the different forms of NIV being used to supportneonates with lung disease, are discussed below.
Noninvasive Ventilation Modes in Neonates
Nasal Intermittent Mandatory Ventilation
The most widely used and studied form of NIV in ne-onates is nasal IMV. Nasal IMV is a useful intermediatestrategy for neonates weaning from mechanical ventilationor who cannot be supported by CPAP alone. Nasal IMVembraces spontaneous breathing, with a conventional neo-natal ventilator equipped with bi-nasal prongs or a singlenasopharyngeal ETT. In some settings, clinicians have alsoadapted small nasal masks to be used during nasal IMV.The most commonly used mode for nasal IMV is time-cycled, pressure control ventilation, with or without a pre-set constant flow. Similar to CPAP, unassisted spontane-ous breathing occurs at a pre-set PEEP level, but mandatorypressure control breaths are either patient-triggered (syn-chronized) or machine-triggered (non-synchronized).
Although pressure support ventilation (PSV) is com-monly used during adult NIV, it is not used to supportspontaneous breaths during nasal IMV or as a singularmode during NIV, because it cannot flow-cycle breaths inthe presence of a large airway leak. I will only briefly
review the 2 studies that have evaluated the noninvasiveapplication of PSV in infants. In one study,35 a prototypenasal mask was used to apply PSV to larger infants (ap-proximately 4 kg) with respiratory failure. The infantssupported with PSV had lower respiratory rates (P � .001)and indices of WOB (P � .01) than did spontaneouslybreathing infants given no support.35
The only randomized crossover study in neonates thathas evaluated nasal PSV used the IV-200 SAVI ventilator(Sechrist Industries, Anaheim, California) and short bi-nasal prongs.36 Nasal PSV was delivered with the SAVImode, which is different from conventional PSV. Ratherthan using a flow signal to trigger and cycle the breath,SAVI triggers and cycles the inspiration based on signalsfrom respiratory inductance plethysmography bands placedon the chest. Nasal PSV did not measurably augment al-veolar ventilation, but did provide lower indices of WOBand respiratory effort. The SAVI ventilator is no longeravailable, and it is unclear whether this form of NIV willappear in future ventilators. Clinical data supportive of theefficacy of nasal PSV are lacking, and conventional flow-triggered, flow-cycled PSV is unlikely to be effective inthis population, especially if large leaks are present. Thus,it appears safer and easier to implement IMV, instead ofPSV, to assure proper breath-termination during NIV.
Triggering Options. The noninvasive application of ma-chine-triggered IMV involves time-triggered mandatorybreaths that may or may not be in phase with the neonate’sspontaneous inspiratory or expiratory efforts. Clinicianshave often speculated that positive pressure delivered dur-ing the expiratory phase may increase the airway pressurebeyond the set inspiratory pressure; elicit active expiratoryefforts; and increase WOB, the risk of air leak, and gastricinsufflation. Owen et al37 evaluated the range and vari-ability of delivered pressure in preterm neonates receivingmachine-triggered IMV via bi-nasal short prongs, fittedwith chin-strap attachment, and found that airway pressurecan vary considerably from the set pressure: approximately5 cm H2O less than the pre-set inspiratory pressure 37%and 83% of the time when inspiratory pressure was set at20 cm H2O and 25 cm H2O, respectively. With nasal IMV,only actively moving patients exceeded the set inspiratorypressure 13% and 6% of the time, when inspiratory pres-sure was set at 20 cm H2O and 25 cm H2O, respectively.And 63% of mechanical inflations were delivered duringspontaneous exhalation, but airway pressure did not varyaccording to whether ventilator inflation timing was dur-ing spontaneous inspiration or expiration. Many of thecurrent ventilators being used for nasal IMV will automat-ically limit inspiratory pressure to 2 cm H2O greater thanthe set inspiratory pressure. Nonetheless, adjusting the high-pressure limit is important, to assure lung protection andreduce the risk of gastric insufflation during nasal IMV.
NEONATAL NONINVASIVE VENTILATION TECHNIQUES: DO WE REALLY NEED TO INTUBATE?
1276 RESPIRATORY CARE • SEPTEMBER 2011 VOL 56 NO 9
Despite not being able to trigger the ventilator, severalof the clinical benefits of patient-triggered nasal IMV canstill be appreciated with machine-triggered nasal IMV.Patients supported by machine-triggered nasal IMV canusually easily adapt to the ventilator within a short period,especially if the ventilator rate is set to at least 50% oftheir total respiratory rate.38 The ability to adapt to theinflations is most likely related to stimulation of the Her-ing-Breuer reflex or mediated by a reflex activated by a jetof gas flow into the nasal passages.39 Older-generationventilators may have been better suited for this purposethan are current-generation ventilators, which incorporateflow-triggering options and numerous disconnect alarms.Clinicians have circumvented auto-triggering by disablingthe set flow and pressure trigger levels; however, manyventilators have disconnect alarms that cannot be silencedin the face of large leaks. There have been anecdotal re-ports of clinicians bleeding gas into the ventilator’s exha-lation limb from an auxiliary flow meter to quiet the dis-connect alarms, but that practice is not recommended, as itmay pose safety risks. Ventilator manufacturers are nowreleasing FDA-approved modes of neonatal noninvasiveIMV, but many of the devices offer only machine-trig-gered nasal IMV.
Although patient-triggered IMV has been implementedwith proximal hot-wire flow sensors38 and pressure sen-sors placed at the nares, appropriate triggering may bedifficult, if not impossible, because of the large positionalleaks that can develop between the patient’s airway andthe nasal interface.40 This often results in auto-triggeringand/or failed triggering. Additionally, the risks posed bythe added weight and dead space from a proximal flowsensor may outweigh the clinical benefits of patient-trig-gered breaths during nasal IMV. Newer-generation neo-natal ventilators incorporate flow-triggering and leak-compensation algorithms that can automatically adjust thetrigger level based on large airway leaks. Anecdotal re-ports suggest that these triggering options work well inpremature neonates during nasal IMV, but no data havebeen published on the trigger performance of these modesduring neonatal nasal IMV.
Traditionally, the most commonly used device for pa-tient-triggered nasal IMV has been the Infrasonics InfantStar ventilator (Mallinckrodt, St Louis, Missouri) with theStarSynch module, which incorporates an abdominal pneu-matic (Graseby) capsule, attached below the xiphoid pro-cess, that detects diaphragm descent, so triggering is in-dependent of oral or nasal leak. The Infant Star ventilatoris no longer being supported by the manufacturer, andmachine-triggered nasal IMV breath types are being usedwith apparent success. With the demise of the Infant Starventilator, clinicians have tried to modify other ventilatorsto provide patient-triggered nasal IMV with Graseby cap-sules and respiratory impedance bands.
In theory, patient-triggered nasal IMV is preferred be-cause the inflations are timed with the respiratory effort,and when the glottis is open, the inflations are more likelyto be transmitted effectively to the lungs. Patient-triggerednasal IMV may offer several other clinical advantagesover machine-triggered IMV for neonates; however, theresults of a recent Cochrane meta-analysis concluded thatinvasive patient-triggered IMV (synchronized IMV) in ne-onates resulted in shorter duration of ventilation and wean-ing than did invasive machine-triggered ventilation.41 It isinteresting to note that there were no differences in airleak, BPD, or any other chronic morbidities between ne-onates supported by these 2 forms of triggered ventilation.However, there have been no studies designed to assessdifferences in long-term outcomes related to the availablenoninvasive IMV triggering options.
Chang et al42 compared short-term (one-hour) physio-logic effects of machine-triggered nasal IMV (20 and40 breaths/min) and patient-triggered nasal IMV (20 and40 breaths/min) with CPAP in 16 clinically stable preterminfants. Overall, there were no differences in VT, VE, gasexchange, chest-wall distortion, apnea, hypoxemia spells,or abdominal girth between the different forms of nonin-vasive support. Patient-triggered nasal IMV provided lowerbreathing effort and better infant/ventilator interaction thandid machine-triggered IMV or CPAP. These findings weremore striking at 40 breaths/min than at 20 breaths/minduring nasal IMV. Nonetheless, these differences in ven-tilator interaction did not appear to affect patient comfortor any other measured variable. Further, the low inspira-tory pressure setting (10 cm H2O) was much lower than istypically used in the clinical setting, and may not haveresulted in sufficient pressure transmission the lungs, es-pecially if a leak was present. These findings in part aredifferent from those reported by investigators who sup-ported sicker neonates and with higher inspiratory pres-sures than those reported in the Chang et al study. Theresults from the latter studies will be discussed in the nextsection.
Based on the findings from nearly 2 decades of researchevaluating outcomes in patient-triggered ventilation dur-ing invasive ventilation, a large clinical trial to comparelong-term outcomes in premature neonates supported bymachine-triggered or patient-triggered nasal IMV is un-likely to be conducted. Such studies would require a largenumber of patients and a tremendous amount of time andfunding. Anecdotal reports and the limited clinical dataavailable suggest that new modes or ventilator platformsthat offer patient-triggered nasal IMV may be preferable,but may not be absolutely necessary at this time.
Physiologic Effects. The physiologic mechanisms bywhich nasal IMV works in preterm neonates are not fullyunderstood, and whether nasal IMV is more effective than
NEONATAL NONINVASIVE VENTILATION TECHNIQUES: DO WE REALLY NEED TO INTUBATE?
RESPIRATORY CARE • SEPTEMBER 2011 VOL 56 NO 9 1277
CPAP or invasive ventilation is a topic of intense clinicalresearch. In premature neonates, compared to CPAP, pa-tient-triggered nasal IMV has been associated with greaterVT and VE, and reduced thoracoabdominal asynchrony(chest-wall stabilization),43 respiratory rate, gas ex-change,44 and WOB,38,45 but nasal IMV may cause morediscomfort due to the high flow rate, local nasal irritation,and asynchrony. In premature neonates, Kugelman et al46
found that nasal IMV was associated with higher bloodpressure and discomfort score than was unassisted spon-taneous breathing. However, Kulkarni et al47 found nodifference in nutrition intake or weight gain between ne-onates supported by CPAP versus IMV.
Nasal IMV is more effective than is CPAP in reducingthe incidence of apnea in preterm neonates.48,49 However,nasal IMV is more likely to prevent apnea than to supporta patient who is apneic. Neonates with existing apnea maynot always be adequately supported by nasal IMV, be-cause the pressure is not always transmitted to the lungs(Fig. 2), due to large airway leaks, reduced compliance,and/or airway obstruction.48,50 The physiologic mecha-nisms responsible for the notable reductions in central andobstructive apnea are not fully understood. Since nasalIMV provides more support than CPAP, the higher infla-tion and mean airway pressure improve gas exchange,which can reduce the frequency and severity of centralapnea episodes. Nasal IMV also creates higher pharyngealpressure than does nasal CPAP, and by intermittent infla-
tion of the pharynx, nasal IMV can stent open the airway,activate the dilator muscles of the pharynx, and increasethe respiratory drive to abort obstructive apneas.48 Addi-tionally, higher inspiratory flow may produce a fast rise inthe airway pressure so that the soft palate can be pushedagainst the tongue and seal the oral cavity, resulting inbetter breath delivery during an obstructive apnea.30 IMVaugments a neonate’s spontaneous respiratory effort orincreases “sighing,” which may be useful for recruitingand maintaining distal air spaces and preventing apnea.
In a report by Lin et al 48 the chest wall excursions ofneonates were monitored during machine-triggered nasalIMV and CPAP, using respiratory impedance bands. Abiphasic inspiratory response was observed in infantstreated with nasal IMV, indicating that the onset of a pos-itive-pressure breath may induce sighing. A similar reflexwas described by Head et al in spontaneously breathingrabbits receiving positive-pressure ventilation, and hassince been called “the Head paradoxical maneuver” and isthought to arise from sensors in the lung.51
Greenough et al52,53 reported a similar phenomenon inspontaneously breathing neonates instrumented with anesophageal balloon and supported with invasive ventila-tion, wherein (Fig. 3) augmented spontaneous inspiratoryefforts were provoked at the onset of rapid positive-pres-sure inflation and were prevalent in preterm neonates withreduced compliance, higher inspiratory pressure, and ven-tilator rate � 15 breaths/min. They also found that neo-nates receiving theophylline and those following recoveryfrom chemical paralysis had a higher incidence of thisbeneficial reflex.52,53
As mentioned previously, the beneficial lung-protectiveeffects of nasal IMV have been attributed to the use of a“leaky” nasal airway interface. Only one animal study hastested the hypothesis that noninvasive IMV results in lesslung injury than invasive IMV. Lampland et al54 compareddifferences in pathophysiologic and pathologic conditionsin surfactant-deficient, lung-lavaged piglets supported bypatient-triggered invasive IMV or noninvasive IMV. An-imals from both groups were managed using a standard-ized ventilator protocol. Animals supported by noninva-sive IMV had higher arterial blood gas pH (P � .001),lower PaCO2
(P � .05), and lower respiratory rate (P � .001)than did piglets treated with synchronized IMV. The pig-lets in the invasive IMV group had a higher ratio of PaO2
to alveolar PO2(P � .04) and more pulmonary interstitial
inflammation than did noninvasive IMV treated piglets.The results from this short-term study (6 hours) demon-strate that noninvasive IMV may be less injurious to thelung and provide better ventilation with less need for sup-port than does invasive IMV.
Complications. Many of the same complications thatarise during CPAP and invasive ventilation can present
Fig. 2. A 2-min recording showing periodic breathing, stable de-livered pressure, and fluctuating oxygen saturation in a prematureneonate supported by nasal intermittent mandatory ventilation(IMV) with a set peak inspiratory pressure of 20 cm H2O and arespiratory rate of 20 inflations per minute. The loss of end-expi-ratory lung volume, denoted by the decrease in the respiratoryimpedance pneumography (RIP) sum trace at the onset of apneasuggests central apnea with an open glottis. Based on the ab-sence of chest-wall excursions during apnea, nasal IMV did notsufficiently augment tidal volume, despite the use of a chin strap.(Adapted from Reference 37, with permission.)
NEONATAL NONINVASIVE VENTILATION TECHNIQUES: DO WE REALLY NEED TO INTUBATE?
1278 RESPIRATORY CARE • SEPTEMBER 2011 VOL 56 NO 9
during nasal IMV, and can present with all forms of neo-natal NIV. The most frequently reported complication islocal irritation and trauma to the nasal septum, which mayoccur due to misalignment or improper fixation of nasalprongs. This can also result in nasal snubbing and circum-ferential distortion (widening) of the nares,16 especially ifnasal IMV is being used for more than just a few days.Clinicians have improved the level of nasal care and aremore wary of avoiding nasal airway trauma. Cannulaide(Beevers Manufacturing, McMinnville, Oregon) is a tai-lored hydrocolloid material with an adhesive backing thatis fitted over the nose and moustache area to protect skinand prevent nasal breakdown (Fig. 4). The holes on theCannulaide are a smaller diameter than the nare, so whenprongs are placed, the Cannulaide may reduce nasal leak.Owen et al55 evaluated the clinical effects prior to andfollowing Cannulaide placement during neonatal nasal IMVand found that the Cannulaide increased airway pressureand resulted in a nonsignificant trend toward fewer de-saturations and apneas.
Ramanathan and colleagues have reported successfuluse of high-flow nasal cannula as a means of avoiding
complicated fixation techniques and consequent nasal in-jury during nasal IMV. In an observational cohort, 70premature neonates were treated with nasal cannula IMV.56
All the neonates tolerated nasal cannula IMV, and therewere no cases of nasal injury, air leaks, or gastric or ear-drum perforation. The nasal cannula IMV failure rate (ie,required re-intubation) was 8%. Nasal cannula IMV hasalso been evaluated in a realistic neonatal nasal airway/lung model57 with infant and intermediate size high-flownasal cannula (Fisher Paykel, Auckland, New Zealand)and a new prototype nasal cannula (RAM, NeoTech, Va-lencia, California) which has larger-bore tubing than astandard oxygen or high-flow nasal cannula. The intendedpurpose of the larger-bore tubing is to reduce resistance sothat more pressure can be transmitted to the nares withoutadding imposed WOB during spontaneous breathing. De-spite a nasal airway leak, IMV provided through thesehybrid prongs resulted in acceptable pressure and volumedelivered to the lung model. Compared with bi-nasal shortprongs and nasal masks that are used during NIV, nasalcannula IMV represents a less cumbersome interface thatmay reduce complications and still provide sufficient ven-tilatory assistance during IMV.
Like CPAP, gastric insufflation of gases is a frequentlyreported risk during nasal IMV. In a recent study, anes-thetized neonates had gastric insufflation at inspiratorypressures of � 15 cm H2O during NIV with a manualresuscitator.58 However, these neonates were not breathingspontaneously, did not have orogastric or nasogastric tubesin place, and were ventilated with oronasal mask. Inspira-tory pressures � 15 cm H2O probably can be used safelyand effectively with bi-nasal prongs during IMV. An oro-gastric tube is placed to vent insufflated gas from thestomach and decompress the gastrointestinal tract. Ab-dominal girth should be monitored frequently during nasalIMV to assure that the orogastric tube is working properly.
The major risk from gastric insufflation is gastrointes-tinal perforation and necrotizing enterocolitis, which havebeen frequently observed during face-mask NIV in neo-nates. Despite the use of an orogastric tube, Garland et al31
reported gastric perforation in a small series of neonatesduring IMV via bi-nasal prongs and inspiratory pressure of
Fig. 3. Provoked augmented inspiratory response in a neonatereceiving invasive ventilation. In the tidal volume trace the integra-tor resets to zero at zero air flow, so an upward deflection repre-sents inspiration and a downward deflection represents expira-tion. In the esophageal pressure trace, downward deflections (ie,increasing negative pressure) are caused by spontaneous respi-ratory activity. The provoked augmented inspiration commencesat point A, shown by the large deflection in the esophageal trace,during ventilator inflation, which is at least twice the size of thatcaused by spontaneous (unassisted) inspiration. At point A thevolume (V) and the inflating pressure (P) provoke the reflex. T is thetime from the start of the inflation to the beginning of the aug-mented inspiration. A similar response has been observed in ne-onates receiving nasal IMV. (Adapted from Reference 53, withpermission.)
Fig. 4. Cannulaide (Beevers Manufacturing, McMinnville, Oregon)barrier device being applied to a doll (left) and in use with a pre-mature neonate. (Courtesy of Louise Owen MD.)
NEONATAL NONINVASIVE VENTILATION TECHNIQUES: DO WE REALLY NEED TO INTUBATE?
RESPIRATORY CARE • SEPTEMBER 2011 VOL 56 NO 9 1279
approximately 19 cm H2O (range 10–30 cm H2O). Basedon these findings, it was suggested that “nasal prongs shouldnot be routinely used to ventilate critically ill neonateswith respiratory failure.” However, neonates in that studyalso had chin straps in place to avoid excessive air leak,which may have increased the risk of gastric insufflationand perforation. The next section will review all of theobserved complications during clinical studies. In all ofthese clinical studies, nasal IMV does not place the neo-nate at any greater reported risk for developing any of theabove-mentioned complications than does CPAP.
Clinical Data. Historically, nasal IMV has been used asa means for weaning preterm neonates with apnea frominvasive ventilation to CPAP. Today nasal IMV is beingimplemented in premature neonates with the followingstrategies:
After Extubation, Following Long-Term InvasiveVentilation. Extubation following prolonged mechanicalventilation is frequently associated with post-extubationrespiratory failure due to apneas, atelectasis, hypoxemia,respiratory acidosis, and apnea.32 Compared to extubationto no respiratory support, extubation to CPAP has beenassociated with lower incidence of respiratory failure, needfor mechanical ventilation, and risk of developing BPD inpreterm neonates.59 However, nearly half of these neo-nates fail CPAP and require re-intubation.
Nasal IMV is being used immediately following extu-bation or when a patient is failing CPAP. Clinicians mayassess patients for IMV following administration and con-firmation of adequate serum aminophylline level, and oncethe patient has weaned to a mandatory breath rate of12 breaths/min, inspiratory pressure � 23 cm H2O,PEEP � 6 cm H2O, and FIO2
� 0.40.32 Table 1 shows thestudy designs, devices, initial settings, and outcomes instudies where nasal IMV was used in neonates followingextubation from prolonged invasive ventilation.
A Cochrane Collaboration comprehensive systematic re-view and meta-analysis of randomized trials of nasal IMVin preterm neonates60 included 3 studies.32,49,61 The objec-tive of the meta-analysis was to determine whether NIVwas associated with a lower extubation-failure rate, with-out adverse effects, in preterm infants extubated followingprolonged invasive ventilation than was nasal CPAP. All 3trials used patient-triggered nasal IMV. The meta-analy-sis60 found statistically significant and clinically importantreductions in the risk of meeting extubation failure crite-ria: typical risk ratio 0.21 (95% CI 0.10–0.45), typical riskdifference �0.32, (95% CI �0.45 to �0.20), number-needed-to-treat 3 (95% CI 2–5). No gastrointestinal per-forations were reported in any of the trials. The differencesin the rates of chronic lung disease approached but did notreach statistical significance, favoring nasal IMV: typical
risk ratio 0.73 (95% CI 0.49–1.07), typical risk difference�0.15 (95% CI �0.33 to 0.03).
A small retrospective study47 that was not included inthe Cochrane review60 compared outcomes in prematureneonates supported by CPAP and patient-triggered nasalIMV following prolonged invasive ventilation. The nasalIMV group had less supplemental oxygen requirement(P � .02) and BPD (P � .01) than did infants supportedby CPAP, and there were no differences in complicationsrelated to either form of respiratory support. Another study,by Ryan et al,50 reported no differences in apnea, brady-cardia, or transcutaneous CO2 between neonates on nasalIMV versus CPAP. However, that was a short-term studywith a small number of patients and used a ventilator thatprovided only machine-triggered IMV.
After Extubation, Following Surfactant Replacementand Short-Term Invasive Ventilation. One of the pri-mary reasons preterm neonates (� 34 weeks) develop se-vere respiratory failure with any form of noninvasive re-spiratory support is that the lungs are incapable of producingand secreting sufficient quantities of mature endogenoussurfactant. In recent years the practice of intubation, ad-ministering surfactant replacement (10–15 min), and short-term ventilation (usually � 1 h), with extubation to pro-phylactic CPAP has become a widely applied approach forpreterm neonates. A meta-analyses62 evaluated outcomesfrom 6 RCTs to compare early (prophylactic) surfactantadministration with brief ventilation versus selective sur-factant and continued mechanical ventilation in prematureinfants with or at risk for RDS. Intubation and early sur-factant administration followed by extubation to CPAPwas associated with a lower incidence of mechanical ven-tilation (typical risk ratio 0.67, 95% CI 0.57–0.79), airleak syndromes (typical risk ratio 0.52, 95% CI 0.28–0.96), and infant chronic lung disease (typical risk ratio0.51, 95% CI 0.26–0.99). Despite this novel approach,neonates still develop respiratory failure while receivingCPAP, which further highlights the need for intermediaryforms of respiratory support as an alternative to intubationand invasive ventilation.
Table 2 shows the study designs, devices, initial set-tings, and outcomes in studies in which nasal IMV wasused in neonates following surfactant replacement andshort-term ventilation. All but one of these trials usedpatient-triggered nasal IMV.
Santin et al63 conducted a prospective pilot study thatcompared outcomes of neonates supported with early na-sal IMV (immediately following surfactant and extuba-tion) and later nasal IMV (following surfactant, continuedventilator support, and extubation). The early-nasal IMVinfants had shorter duration of ventilation (P � .001), lesssupplemental oxygen requirement (P � .04), shorter stay(P � .04), and less parenteral nutrition (P � .002) than did
NEONATAL NONINVASIVE VENTILATION TECHNIQUES: DO WE REALLY NEED TO INTUBATE?
1280 RESPIRATORY CARE • SEPTEMBER 2011 VOL 56 NO 9
Tab
le1.
Clin
ical
Stud
ies
Tha
tE
valu
ated
Out
com
esin
Prem
atur
eN
eona
tes
Supp
orte
dW
ithN
asal
IMV
Follo
win
gPr
olon
ged
Inva
sive
Ven
tilat
ion
Firs
tA
utho
rY
ear
Stud
yD
esig
nV
entil
ator
Nas
alA
irw
ayIn
terf
aces
Nas
alIM
VT
rigg
erin
gM
echa
nism
Initi
alSe
tting
sFa
ilure
Cri
teri
aO
utco
mes
Sum
mar
y
Frie
dlic
h32
1999
Pros
pect
ive
RC
TC
PAP
(n�
19)
vsna
sal
IMV
(n�
22)
Infa
ntSt
arB
i-na
soph
aryn
geal
long
pron
gsPa
tient
-tri
gger
ed(G
rase
byab
dom
inal
caps
ule/
Star
Sync
hm
odul
e)
CPA
Ppe
rcl
inic
ian
Nas
alIM
V:
insp
irat
ory
pres
sure
pre-
extu
batio
nva
lue,
PEE
P4–
6cm
H2O
,re
spir
ator
yra
te10
brea
ths/
min
,F I
O2
set
toke
epS p
O2
�92
–95%
pH�
7.25
,P a
CO
2ch
ange
of�
25%
ofpr
e-ex
tuba
tion
valu
e,re
spir
ator
yra
te�
20br
eath
s/m
in,
insp
irat
ory
pres
sure
�26
cmH
2O
,PE
EP
�8
cmH
2O
,se
vere
apne
a
Les
sre
spir
ator
yfa
ilure
afte
rex
tuba
tion
inth
ena
sal
IMV
grou
p(5
%)
than
the
CPA
Pgr
oup
(37%
,P
�.0
2).
No
inte
stin
alpe
rfor
atio
nor
necr
otiz
ing
ente
roco
litis
inei
ther
grou
p
Rya
n50
1989
Pros
pect
ive
RC
TC
PAP
vsna
sal
IMV
(n�
20)
Bab
yB
ird
Bi-
naso
phar
ynge
allo
ngpr
ongs
orna
soph
aryn
geal
endo
trac
heal
tube
Mac
hine
-tri
gger
edC
PAP
4cm
H2O
Nas
alIM
V:
insp
irat
ory
pres
sure
20cm
H2O
,PE
EP
4cm
H2O
,re
spir
ator
yra
te20
brea
ths/
min
,F I
O2
set
toke
epS p
O2
�92
–95%
Not
men
tione
dN
odi
ffer
ence
sbe
twee
nth
egr
oups
inap
nea,
brad
ycar
dia,
ortr
ansc
utan
eous
CO
2
Bar
ring
ton4
920
01Pr
ospe
ctiv
eR
CT
CPA
P(n
�27
)vs
nasa
lIM
V(n
�27
)
Infa
ntSt
arB
i-na
sal
shor
tpr
ongs
,or
ogas
tric
tube
Patie
nt-t
rigg
ered
(Gra
seby
abdo
min
alca
psul
e/St
arSy
nch
mod
ule)
CPA
P6
cmH
2O
Nas
alIM
V:
insp
irat
ory
pres
sure
16cm
H2O
,PE
EP
6cm
H2O
,re
spir
ator
yra
te12
brea
ths/
min
,F I
O2
set
toke
epS p
O2
�92
%
P aC
O2
�70
mm
Hg,
F IO
2
�0.
70to
mai
ntai
nS p
O2
�92
%,
orse
vere
recu
rren
tap
nea
Nas
alIM
Vgr
oup
had
alo
wer
inci
denc
eof
faile
dex
tuba
tion
and
apne
ath
anC
PAP
grou
p(P
�.0
5).
No
inte
stin
alpe
rfor
atio
nor
necr
otiz
ing
ente
roco
litis
inei
ther
grou
pK
hala
f60
2001
Pros
pect
ive
RC
TC
PAP
(n�
30)
vsna
sal
IMV
(n�
34)
Bea
rC
ubfo
rC
PAP
Infa
ntSt
arfo
rna
sal
IMV
Bi-
nasa
lsh
ort
pron
gsPa
tient
-tri
gger
ed(G
rase
byab
dom
inal
caps
ule/
Star
Sync
hm
odul
e)
CPA
P4–
6cm
H2O
Nas
alIM
V:
insp
irat
ory
pres
sure
2–4
cmH
2O
�in
vasi
veve
ntila
tion,
PEE
P�
5cm
H2O
,re
spir
ator
yra
tesa
me
asin
vasi
veve
ntila
tion,
flow
8–10
L/m
in,
F IO
2se
tto
keep
S pO
290
–96%
pH�
7.25
,P a
CO
2
�60
mm
Hg,
seve
reap
nea
with
brad
ycar
dia,
F IO
2to
1.0,
orP a
O2
�50
mm
Hg
desp
iteF I
O2
of1.
0
Nas
alIM
Vgr
oup
had
asi
gnif
ican
tlyhi
gher
extu
batio
nsu
cces
sra
teth
anC
PAP
grou
p(9
4%vs
60%
,P
�.0
1)at
72h
afte
rex
tuba
tion
Kul
karn
i47
2006
Ret
rosp
ectiv
eC
PAP
(n�
30)
vsna
sal
IMV
(n�
30)
Bea
rC
ubfo
rC
PAP
Infa
ntSt
arfo
rna
sal
IMV
Bi-
nasa
lsh
ort
pron
gsPa
tient
-tri
gger
ed(G
rase
byab
dom
inal
caps
ule/
Star
Sync
hm
odul
e)
CPA
P4–
6cm
H2O
Nas
alIM
V:
insp
irat
ory
pres
sure
2–4
cmH
2O
�ve
ntila
tion,
PEE
P�
5cm
H2O
,re
spir
ator
yra
tesa
me
asin
vasi
veve
ntila
tion,
flow
8–10
L/
min
,F I
O2
set
toke
epS p
O2
90–9
6%
pH�
7.25
,P a
CO
2
�60
mm
Hg,
seve
reap
nea
with
brad
ycar
dia,
F IO
2to
1.0,
orP a
O2
�50
mm
Hg
desp
iteF I
O2
of1.
0
Nas
alIM
Vgr
oup
had
less
supp
lem
enta
lox
ygen
requ
irem
ent
(P�
.02)
and
bron
chop
ulm
onar
ydy
spla
sia
(P�
.01)
than
CPA
Pgr
oup.
No
com
plic
atio
ns
IMV
�in
term
itten
tm
anda
tory
vent
ilatio
nR
CT
�ra
ndom
ized
cont
rolle
dtr
ial
CPA
P�
cont
inuo
uspo
sitiv
eai
rway
pres
sure
NEONATAL NONINVASIVE VENTILATION TECHNIQUES: DO WE REALLY NEED TO INTUBATE?
RESPIRATORY CARE • SEPTEMBER 2011 VOL 56 NO 9 1281
Tab
le2.
Clin
ical
Stud
ies
Tha
tE
valu
ated
Out
com
esin
Prem
atur
eN
eona
tes
Supp
orte
dW
ithN
asal
IMV
Follo
win
gSu
rfac
tant
Rep
lace
men
tan
dSh
ort-
Ter
mV
entil
atio
n
Firs
tA
utho
rY
ear
Stud
yD
esig
nV
entil
ator
sN
asal
Air
way
Inte
rfac
es
Nas
alIM
VT
rigg
erin
gM
echa
nism
Initi
alSe
tting
sFa
ilure
Cri
teri
aO
utco
mes
Sum
mar
y
Sant
in63
2004
Pros
pect
ive
pilo
tN
asal
IMV
imm
edia
tely
afte
rsu
rfac
tant
,(n
�24
)vs
late
rna
sal
IMV
follo
win
gsu
rfac
tant
and
prol
onge
dve
ntila
tion
(n�
35)
Bea
rC
ubfo
rC
PAP
Infa
ntSt
arfo
rna
sal
IMV
Bi-
naso
phar
ynge
al(l
ong)
pron
gsPa
tient
-tri
gger
ed(G
rase
byab
dom
inal
caps
ule/
Star
Sync
hm
odul
e)
Nas
alIM
V:
insp
irat
ory
pres
sure
2–4
cmH
2O
�in
vasi
veve
ntila
tion,
PEE
P�
5cm
H2O
,re
spir
ator
yra
tesa
me
asin
vasi
veve
ntila
tion,
flow
8–10
L/m
in,
F IO
2se
tto
keep
S pO
290
–96%
pH�
7.25
,P a
CO
2
�60
mm
Hg,
seve
reap
nea
with
brad
ycar
dia,
F IO
2to
1.0,
orP a
O2
�50
mm
Hg
desp
iteF I
O2
of1.
0
Ear
lyna
sal
IMV
grou
pha
dsh
orte
rdu
ratio
nof
vent
ilatio
n(P
�.0
01),
less
supp
lem
enta
lox
ygen
requ
irem
ent
(P�
.04)
,sh
orte
rst
ay(P
�.0
4),
and
less
pare
nter
alnu
triti
on(P
�.0
02)
than
the
late
rna
sal
IMV
grou
p.N
odi
ffer
ence
sin
rate
ofne
crot
izin
gen
tero
colit
isor
inte
stin
alru
ptur
e.B
hand
ari6
420
07Pr
ospe
ctiv
eR
CT
Nas
alIM
Vim
med
iate
lyaf
ter
surf
acta
nt(n
�20
)vs
late
rna
sal
IMV
follo
win
gsu
rfac
tant
and
prol
onge
dve
ntila
tion
(n�
21)
Bea
rC
ubor
Infa
ntSt
arfo
rin
vasi
veve
ntila
tion
Infa
ntSt
arfo
rna
sal
IMV
Nas
opha
ryng
eal
(lon
g)pr
ongs
,ch
inst
raps
,pa
cifi
ers,
larg
e-bo
reor
ogas
tric
tube
Patie
nt-t
rigg
ered
,ho
t-w
ire
for
inva
sive
vent
ilatio
n.G
rase
byab
dom
inal
caps
ule
Star
Sync
hm
odul
efo
rna
sal
IMV
Inva
sive
:in
spir
ator
ypr
essu
re16
–20
cmH
2O
,PE
EP
4–6
cmH
2O
,in
spir
ator
ytim
e0.
35–0
.45
s,re
spir
ator
yra
te40
–60
brea
ths/
min
,F I
O2
set
toke
epS p
O2
90–9
6%N
asal
IMV
:in
spir
ator
ypr
essu
re2–
4cm
H2O
�in
vasi
veve
ntila
tion,
PEE
P�
5cm
H2O
,re
spir
ator
yra
tesa
me
asin
vasi
veve
ntila
tion,
flow
8–10
L/m
in,
F IO
2se
tto
keep
S pO
290
–96%
pH�
7.25
,P a
CO
2
�60
mm
Hg,
seve
reap
nea
with
brad
ycar
dia,
F IO
2to
1.0,
orP a
O2
�50
mm
Hg
desp
iteF I
O2
of1.
0.
Ear
lyna
sal
IMV
grou
pha
dle
ssB
PD/d
eath
(52%
vs20
%,
P�
.03)
and
less
BPD
(33%
vs10
%,
P�
.04)
than
late
rna
sal
IMV
.N
oco
mpl
icat
ions
(con
tinue
d)
NEONATAL NONINVASIVE VENTILATION TECHNIQUES: DO WE REALLY NEED TO INTUBATE?
1282 RESPIRATORY CARE • SEPTEMBER 2011 VOL 56 NO 9
Tab
le2.
Clin
ical
Stud
ies
Tha
tE
valu
ated
Out
com
esin
Prem
atur
eN
eona
tes
Supp
orte
dW
ithN
asal
IMV
Follo
win
gSu
rfac
tant
Rep
lace
men
tan
dSh
ort-
Ter
mV
entil
atio
n(c
ontin
ued)
Firs
tA
utho
rY
ear
Stud
yD
esig
nV
entil
ator
sN
asal
Air
way
Inte
rfac
es
Nas
alIM
VT
rigg
erin
gM
echa
nism
Initi
alSe
tting
sFa
ilure
Cri
teri
aO
utco
mes
Sum
mar
y
Bha
ndar
i44
2009
Ret
rosp
ectiv
eC
PAP
(n�
227)
vsna
sal
IMV
(n�
242)
both
asin
itial
form
ofsu
ppor
tan
dfo
llow
ing
surf
acta
nt/s
hort
-ter
mve
ntila
tion
Infa
ntSt
arB
i-na
sal
shor
t-pr
ongs
,ch
inst
rap,
paci
fier
,la
rge-
bore
orog
astr
ictu
be
Patie
nt-t
rigg
ered
(Gra
seby
abdo
min
alca
psul
e/St
arSy
nch
mod
ule)
CPA
P4–
6cm
H2O
Nas
alIM
V:
insp
irat
ory
pres
sure
2–4
cmH
2O
�in
vasi
veve
ntila
tion,
PEE
P4
cmH
2O
,re
spir
ator
yra
tesa
me
asin
vasi
veve
ntila
tion,
F IO
2se
tto
keep
S pO
285
–95%
,fl
ow8–
10L
/min
Res
usci
tatio
nan
d/or
resp
irat
ory
failu
rene
cess
itatin
gsu
rfac
tant
(FIO
2�
0.4
toke
epS p
O2
�90
%
Nas
alIM
Vgr
oup
had
low
erm
ean
birt
hw
eigh
tan
dge
stat
iona
lag
e,an
da
high
erin
cide
nce
ofB
PDor
deat
h(P
�.0
1)th
anC
PAP
grou
p.Su
bgro
upan
alys
is(i
nfan
ts50
0–70
0g)
:na
sal
IMV
grou
pha
dle
ssB
PD(P
�.0
1)B
PD/d
eath
(P�
.01)
,ne
urod
evel
opm
enta
lim
pair
men
t(P
�.0
4),
and
neur
odev
elop
men
tal
impa
irm
ent/d
eath
P�
.006
)th
anC
PAP
grou
pSa
iSu
nil
Kis
hore
65
2009
Pros
pect
ive
RC
TC
PAP
(n�
39)
vsna
sal
IMV
(n�
37),
both
asin
itial
form
ofsu
ppor
tan
dfo
llow
ing
surf
acta
nt
VIP
Bir
dor
Bab
ylog
Nas
opha
ryng
eal
endo
trac
heal
tube
,cu
stom
ized
chin
stra
p,or
ogas
tric
tube
Mac
hine
-tri
gger
edC
PAP
5cm
H2O
,fl
ow6–
7L
/min
Nas
alIM
V:
insp
irat
ory
pres
sure
15–1
6cm
H2O
,PE
EP
5cm
H2O
,in
spir
ator
ytim
e0.
3–0.
35s,
resp
irat
ory
rate
�50
brea
ths/
min
,fl
ow6–
7L
/min
.F I
O2
set
toke
epS p
O2
88–9
3%
P aC
O2
�60
mm
Hg
with
pH�
7.20
,se
vere
apne
a,br
adyc
ardi
a,or
freq
uent
desa
tura
tion
(SpO
2�
85%
)
Failu
rera
telo
wer
with
nasa
lIM
Vth
anC
PAP
(14%
vs36
%,
P�
.02)
.N
eed
for
intu
batio
nan
dm
echa
nica
lve
ntila
tion
by7
dw
asle
ssw
ithna
sal
IMV
(19%
vs41
%,
P�
.036
).Fa
ilure
rate
with
nasa
lIM
Vw
asle
ssin
the
subg
roup
sof
neon
ates
born
at28
–30
wee
ks(P
�.0
2)an
dw
hodi
dno
tre
ceiv
esu
rfac
tant
(P�
.02)
.
IMV
�in
term
itten
tm
anda
tory
vent
ilatio
nC
PAP
�co
ntin
uous
posi
tive
airw
aypr
essu
reB
PD�
bron
chop
ulm
onar
ydy
spla
sia
NEONATAL NONINVASIVE VENTILATION TECHNIQUES: DO WE REALLY NEED TO INTUBATE?
RESPIRATORY CARE • SEPTEMBER 2011 VOL 56 NO 9 1283
the later-nasal IMV infants. In a similar follow-up pro-spective randomized study by Bhandari et al,64 prematureneonates supported by early nasal IMV had less BPD ordeath (52% vs 20%, P � .03) and less BPD (33% vs 10%,P � .04) than did the later-nasal IMV neonates.
Bhandari et al44 conducted a retrospective study of out-comes in premature neonates supported with CPAP orIMV as an initial form of support immediately followingsurfactant, short-term ventilation, and extubation. A smallnumber of patients who never received any previous intu-bation were also enrolled. The nasal IMV group had lowermean birth weight and gestational age, and a higher inci-dence of BPD or death (P � .01) than did the CPAPinfants. However, subgroup analysis of the smallest neo-nates (500–700 g) revealed that the nasal IMV group hadless BPD (P � .01), combined outcome of BPD/death(P � .01), neurodevelopmental impairment (P � .04), andcombined outcome of neurodevelopmental impairment/death P � .006) than did the infants supported by CPAP.Additionally, PaCO2
was lower on days 7, 21, and 28 in thenasal IMV infants (P � .01).
More recently, Kishore et al65 conducted a small pro-spective RCT with a study design similar to that of Bhan-dari et al.44 The extubation failure rate was lower in thenasal IMV group (14% vs 36%, P � .02), and the need forintubation and mechanical ventilation by 7 days was less(19% vs 41%, P � .036). The failure rate with nasal IMVwas lower in the subgroup of neonates born at 28–30 weeks(P � .02) who did not receive surfactant (P � .02). Thesestudies suggest clinical benefit from early IMV, comparedto later nasal IMV or CPAP for the initial form of nonin-vasive respiratory support following surfactant adminis-tration. These data also indicate the need for a large RCTenrolling premature neonates and neonates with other lungdiseases.
A common concern is that chin straps may permit de-livery of excessive pressure and increase the risk of gastricinsufflation and pulmonary air leaks. All but one of thestudies,63 discussed above used chin straps or pacifiers tomaximize pressure delivery during nasal IMV, in combi-nation with an orogastric tube, and there were no gastro-intestinal complications during IMV.
As the Initial Form of Support. A number of studieshave been conducted to assess whether differences be-tween CPAP and nasal IMV would be observed in out-comes of premature neonates when initiated prior to in-tubation, surfactant administration, and mechanicalventilation. The goal of this approach is to eliminate theneed for any invasive ventilation. Table 3 shows the studydesigns, devices, initial settings, and outcomes of studiesin which IMV was used as an initial form of support forneonates with clinical signs of respiratory distress andapnea.
Moretti et al30 conducted an observational study wherein10 premature neonates with moderate apnea and one ne-onate with progressive respiratory failure were placed onnasal IMV for 5 days. Endotracheal intubation was neverperformed in any of the patients during the study period,and no evidence of BPD was observed. Lin et al48 con-ducted an RCT in a series of neonates with apnea, whowere supported with CPAP or nasal IMV over a 4-hourperiod. The infants treated with nasal IMV had fewer ap-neas per hour than the CPAP infants (P � .02).
Manzar et al66 conducted a prospective pilot studywherein premature neonates with moderate to severe re-spiratory failure (defined as a respiratory rate of� 60 breaths/min, grunting, nasal flaring, subcostal orintercostal retractions, and a positive chest radiograph)were supported with nasal IMV. Eighty-one percent of theneonates were adequately supported, without needing in-vasive ventilation. Bisceglia et al67 conducted an RCTwith neonates with mild to moderate RDS, defined as FIO2
� 0.4 for SpO2of 90–96%, and radiograph suggestive of
early hyaline membrane disease (ie, ground glass appear-ance and air bronchograms). Neonates were randomized toCPAP or IMV. Neonates supported by nasal IMV hadlower PaCO2
, less apnea, and a shorter duration of ventila-tion than the CPAP group (P � .05). Kugelman et al40
compared CPAP and IMV in a prospective RCT in pre-mature neonates with respiratory distress (tachypnea, grunt-ing, flaring of nostrils, retractions, and radiographic evi-dence of RDS). In the total cohort, the nasal IMV grouphad less noninvasive failure (P � .04) and a lower BPDrate (P � .03).
Obviating invasive ventilation, with or without surfac-tant replacement, is an attractive option for reducing manyof the complications experienced by premature neonates.Although the numbers of neonates enrolled in the studieshave been small, nasal IMV appears to be a better alter-native than CPAP in neonates with apnea and/or mild tomoderate respiratory distress. Additional studies may beuseful to evaluate the clinical effects of nasal IMV inneonates with moderate to severe respiratory distress as arescue strategy, as a primary mode of noninvasive respi-ratory support, or following CPAP.
Management and Monitoring. A standardized approachto optimize nasal IMV delivery is unknown. Institutionsconsidering nasal IMV for their patient population shouldconsider reviewing the approaches used in clinical studies(see Tables 1–3) or collaborating with individuals fromorganizations with established management protocols. Theongoing clinical management during nasal IMV dependson careful patient monitoring and clinicians’ ability to rec-ognize differences in the pathophysiologic condition withchanges in disease severity. Because of the inherently leakynature of the nasal airway interface, lung mechanics and
NEONATAL NONINVASIVE VENTILATION TECHNIQUES: DO WE REALLY NEED TO INTUBATE?
1284 RESPIRATORY CARE • SEPTEMBER 2011 VOL 56 NO 9
Tab
le3.
Clin
ical
Stud
ies
Tha
tE
valu
ated
Out
com
esin
Neo
nate
sSu
ppor
ted
With
Nas
alIM
Vas
anIn
itial
(Pre
-int
ubat
ion)
Form
ofSu
ppor
tfo
rPr
emat
ure
Neo
nate
sW
ithSi
gns
ofR
espi
rato
ryD
istr
ess
Firs
tA
utho
rY
ear
Stud
yD
esig
nV
entil
ator
sN
asal
Air
way
Inte
rfac
es
Nas
alIM
VT
rigg
erin
gM
echa
nism
Initi
alSe
tting
sFa
ilure
Cri
teri
aO
utco
mes
Sum
mar
y
Mor
etti3
019
81O
bser
vatio
nal
Nas
alIM
Vin
itiat
edfo
rap
nea
orse
vere
resp
irat
ory
dist
ress
(n�
10)
Cav
itron
PV-1
0B
i-na
soph
aryn
geal
(lon
g)pr
ongs
,or
ogas
tric
tube
Mac
hine
-tri
gger
ed.
Som
epa
tient
sgi
ven
nasa
lIM
Von
lyw
hen
apne
icon
CPA
P.N
asal
IMV
trig
gere
dfo
llow
ing
brad
ycar
dia
alar
mon
card
iac
mon
itor
Insp
irat
ory
pres
sure
12–2
0cm
H2O
,PE
EP
4–6
cmH
2O
,re
spir
ator
yra
te20
brea
ths/
min
,F I
O2
set
toke
epS p
O2
�85
–95%
Non
eE
ndot
rach
eal
intu
batio
nw
asne
ver
perf
orm
edin
any
ofth
epa
tient
sdu
ring
the
stud
ype
riod
.N
oev
iden
ceof
BPD
inth
ese
neon
ates
Lin
48
1998
Pros
pect
ive
RC
TC
PAP
(n�
16)
vsna
sal
IMV
(n�
18)
Bea
rC
ub75
0B
i-na
sal
shor
tpr
ongs
,or
ogas
tric
tube
Mac
hine
-tri
gger
edC
PAP
4–6
cmH
2O
Nas
alIM
V:
insp
irat
ory
pres
sure
12–2
0cm
H2O
,PE
EP
4–6
cmH
2O
,re
spir
ator
yra
te20
brea
ths/
min
,F I
O2
set
toke
epS p
O2
�85
–95%
Not
men
tione
dN
asal
IMV
grou
pha
da
grea
ter
redu
ctio
nin
apne
aspe
rho
urth
anna
sal
CPA
Pgr
oup
(P�
.02)
Man
zar6
620
04Pr
ospe
ctiv
epi
lot
Ear
lyna
sal
IMV
(n�
16)
Drä
ger
Bab
ylog
8000
Bi-
nasa
lsh
ort
pron
gsM
achi
ne-t
rigg
ered
Nas
alIM
V:
insp
irat
ory
pres
sure
18cm
H2O
,PE
EP
4cm
H2O
,re
spir
ator
yra
te25
brea
ths/
min
,F I
O2
0.5,
flow
8–10
L/m
in
F IO
2�
0.60
toke
epS p
O2
�90
%,
P aC
O2
�60
mm
Hg,
pers
iste
ntse
vere
apne
a
81%
ofne
onat
esw
ere
supp
orte
dad
equa
tely
with
nasa
lIM
V.
No
com
plic
atio
nsre
late
dto
nasa
lIM
V
Bis
cegl
ia67
2007
Pros
pect
ive
RC
TC
PAP
(n�
46)
vsna
sal
IMV
(n�
42)
Bea
rC
ub75
0B
i-na
sal
shor
tpr
ongs
Mac
hine
-tri
gger
edC
PAP
4–6
cmH
2O
Nas
alIM
V:
insp
irat
ory
pres
sure
14–2
0cm
H2O
,PE
EP
4–6
cmH
2O
,re
spir
ator
yra
te40
brea
ths/
min
,fl
ow10
L/m
in,
F IO
2se
tto
keep
S pO
290
–96%
pH�
7.20
,P a
CO
2
�60
mm
Hg,
P aO
2�
50m
mH
g
Nas
alIM
Vgr
oup
had
low
erP a
CO
2,le
ssap
nea,
and
shor
ter
dura
tion
ofve
ntila
tion
than
CPA
Pgr
oup
(P�
.05)
Kug
elm
an40
2007
Pros
pect
ive
RC
TC
PAP
(n�
41)
vsna
sal
IMV
(n�
43)
SLE
2000
Bi-
nasa
lsh
ort
pron
gsPa
tient
-tri
gger
ed,
airw
aypr
essu
rese
nsor
CPA
P4–
7cm
H2O
Nas
alIM
V:
insp
irat
ory
pres
sure
14–2
0cm
H2O
,PE
EP
4–7
cmH
2O
,re
spir
ator
yra
te12
–30
brea
ths/
min
,in
spir
ator
ytim
e0.
3s,
F IO
2se
tto
keep
S pO
288
–92%
pH�
7.20
and
P aC
O2
�60
mm
Hg,
orP a
O2
�50
mm
Hg,
orS p
O2
�88
%on
F IO
2�
0.50
,or
recu
rren
tsu
bsta
ntia
lap
nea
Nas
alIM
Vgr
oup
had
less
noni
nvas
ive
failu
re(P
�.0
4)an
dlo
wer
BPD
rate
(P�
.03)
than
CPA
Pgr
oup (c
ontin
ued)
NEONATAL NONINVASIVE VENTILATION TECHNIQUES: DO WE REALLY NEED TO INTUBATE?
RESPIRATORY CARE • SEPTEMBER 2011 VOL 56 NO 9 1285
Tab
le3.
Clin
ical
Stud
ies
Tha
tE
valu
ated
Out
com
esin
Neo
nate
sSu
ppor
ted
With
Nas
alIM
Vas
anIn
itial
(Pre
-int
ubat
ion)
Form
ofSu
ppor
tfo
rPr
emat
ure
Neo
nate
sW
ithSi
gns
ofR
espi
rato
ryD
istr
ess
(con
tinue
d)
Firs
tA
utho
rY
ear
Stud
yD
esig
nV
entil
ator
sN
asal
Air
way
Inte
rfac
es
Nas
alIM
VT
rigg
erin
gM
echa
nism
Initi
alSe
tting
sFa
ilure
Cri
teri
aO
utco
mes
Sum
mar
y
Bha
ndar
i44
2009
Ret
rosp
ectiv
eC
PAP
(n�
227)
vsna
sal
IMV
(n�
242)
;bo
thas
initi
alfo
rmof
supp
ort
and
follo
win
gsu
rfac
tant
/sho
rt-
term
vent
ilatio
n
Infa
ntSt
arB
i-na
sal
shor
t-pr
ongs
,ch
inst
rap,
paci
fier
,la
rge-
bore
orog
astr
ictu
be
Patie
nt-t
rigg
ered
(Gra
seby
abdo
min
alca
psul
e/St
arSy
nch
mod
ule)
CPA
P4–
6cm
H2O
Nas
alIM
V:
insp
irat
ory
pres
sure
2–4
cmH
2O
�in
vasi
veve
ntila
tion,
PEE
P4
cmH
2O
,re
spir
ator
yra
tesa
me
asin
vasi
veve
ntila
tion,
F IO
2se
tto
keep
S pO
285
–95%
,fl
ow8–
10L
/min
Res
usci
tatio
nan
d/or
resp
irat
ory
failu
rene
cess
itatin
gsu
rfac
tant
,F I
O2
�0.
4to
keep
S pO
2�
90%
Nas
alIM
Vgr
oup
had
low
erm
ean
birt
hw
eigh
tan
dge
stat
iona
lag
e,an
da
high
erin
cide
nce
ofB
PDor
deat
h(P
�.0
1)th
anC
PAP
grou
p.Su
bgro
upan
alys
isof
infa
nts
500–
700
g:na
sal
IMV
grou
pha
dle
ssB
PD(P
�.0
1),
BPD
/dea
th(P
�.0
1),
neur
odev
elop
men
tal
impa
irm
ent
(P�
.04)
,an
dne
urod
evel
opm
enta
lim
pair
men
t/dea
thP
�.0
06)
than
CPA
Pgr
oup
Sai
Suni
lK
isho
re65
2009
Pros
pect
ive
RC
TC
PAP
(n�
39)
vsna
sal
IMV
(n�
37),
both
asin
itial
form
ofsu
ppor
tan
dfo
llow
ing
surf
acta
nt
VIP
Bir
dor
Bab
ylog
Nas
opha
ryng
eal
endo
trac
heal
tube
,cu
stom
ized
chin
stra
p,or
ogas
tric
tube
Mac
hine
-tri
gger
edC
PAP
5cm
H2O
,fl
ow6–
7L
/min
Nas
alIM
V:
insp
irat
ory
pres
sure
15–1
6,PE
EP
5,in
spir
ator
ytim
e0.
3–0.
35s,
resp
irat
ory
rate
�50
brea
ths/
min
,fl
ow6–
7L
/min
.F I
O2
set
toke
epS p
O2
88–9
3%.
P aC
O2
�60
mm
Hg
with
pH�
7.20
,se
vere
apne
a,br
adyc
ardi
a,or
freq
uent
desa
tura
tion
(SpO
2�
85%
)
Failu
rera
tew
aslo
wer
with
nasa
lIM
Vth
anC
PAP
(14%
vs36
%,
P�
.02)
.N
eed
for
intu
batio
nan
dm
echa
nica
lve
ntila
tion
by7
dw
asle
ssw
ithna
sal
IMV
(19%
vs41
%,
P�
.036
).Fa
ilure
rate
with
nasa
lIM
Vw
asle
ssin
the
subg
roup
sbo
rnat
28–3
0w
eeks
(P�
.02)
who
did
not
rece
ive
surf
acta
nt(P
�.0
2).
IMV
�in
term
itten
tm
anda
tory
vent
ilatio
nC
PAP
�na
sal
cont
inuo
uspo
sitiv
eai
rway
pres
sure
RC
T�
rand
omiz
edco
ntro
lled
tria
lB
PD�
bron
chop
ulm
onar
ydy
spla
sia
NEONATAL NONINVASIVE VENTILATION TECHNIQUES: DO WE REALLY NEED TO INTUBATE?
1286 RESPIRATORY CARE • SEPTEMBER 2011 VOL 56 NO 9
end-expiratory lung volume are not easily measured at thebedside during nasal IMV, so lung recruitment is assessedmore on changes in respiratory distress, chest-wall expan-sion, WOB, and gas exchange. Some institutions use arespiratory scoring system such as the Silverman-Ander-son score to evaluate respiratory distress and manage re-spiratory support and patient comfort.65 Chest radiographmay be useful to diagnose changes in patient condition,but is a poor surrogate for determining lung inflation. Trans-cutaneous CO2 monitoring and pulse oximetry may offerreliable correlates for determining gas exchange in pa-tients supported by nasal IMV and are preferable to re-peated analysis of blood samples, as long as correlationwith blood gas values has been confirmed.
Few reports suggest a standardized weaning approach tonasal IMV, but some evidence suggests weaning, onceneonates are at ventilator settings of PIP/PEEP 14/4 cm H2O, respiratory rate of � 20 breaths/min, andFIO2
� 0.3, with acceptable blood gas values.63 The patientcan then be transitioned to CPAP or high-flow nasal can-nula.65
Not all neonates can be supported by nasal IMV alone,and intubation is indicated for severe ventilatory impair-ment (pH � 7.25, PaCO2
� 60 mm Hg), refractory hypox-emia (PaO2
� 50 mm Hg on FIO2of � 0.6), and frequent
apnea that does not respond to stimulation or intravenouscaffeine therapy during IMV.64No consensus exists on de-termining the maximal settings during nasal IMV. Owenet al55 showed that increasing the inspiratory pressure dur-ing nasal IMV may not always result in a linear increase indelivered pressure at the nasal airway interface. Wheninspiratory pressure was increased from 20 to 25 cm H2O,the pressure increase at the nasal prongs was only1.3 cm H2O. In fact, one of the most likely reasons neo-nates fail nasal IMV is related to poor pressure transmis-sion applied to the lungs, because of an inadequate sealbetween the tongue and soft palate,50 nasal airway inter-face, or as a consequence of the asynchrony that oftenoccurs. As lung compliance decreases, a larger leak candevelop. In some cases, upsizing the nasal prongs using achin-strap, Cannulaide, or pacifier, may prevent excessiveleak and improve pressure delivery in patients who aredeteriorating on nasal IMV.44
Nasal Neurally Adjusted Ventilatory Assist
Nasal neurally adjusted ventilatory assist (NAVA) is anovel form of noninvasive respiratory support that uses theelectrical activity of the diaphragm (EAdi) to determinethe timing and magnitude of inspiratory pressure deliveryduring spontaneous breathing. The EAdi signal is obtainedwith an indwelling 5.5 French feeding tube equipped with10 electrodes. The tube is placed in the esophagus so thatthe electrodes are at the level of the diaphragm.68,69 When
positioned properly, the electrodes and consequent EAdisignal can accurately and reliably trigger and cycle a pos-itive-pressure breath, independent of airway leak. Addi-tionally, the magnitude of the inspiratory pressure assist isa product of the EAdi signal and the pre-set NAVAlevel.68,69 This feature has been available as an invasivemode with the Servo-i ventilator (Maquet, Solna, Sweden)for about 2 years, but was FDA approved for noninvasiveapplication only recently. Nasal NAVA appears to workwell, even in the smallest of patients. Figure 5 showsServo-i ventilator graphics from a very-low birth-weightpremature neonate during nasal NAVA.
NAVA has many proposed advantages over nasal IMV;however, only 2 reports have been published, from short-term studies that evaluated patient-ventilator interactionduring nasal NAVA. There have been no studies evaluat-ing long-term outcomes in premature neonates on IMV,but many studies are underway.
Beck et al68 conducted a prospective controlled exper-iment in 10 lung-lavaged, spontaneously breathing juve-nile rabbits. Following lung lavages the animals sequen-tially underwent (1) NAVA level 1 during invasiveventilation, with and without PEEP, (2) extubation with nosupport, and (3) NAVA with a single nasal prong, withprogressively increasing NAVA levels and no PEEP. Bloodgases, hemodynamics, and esophageal pressures were mea-sured at each condition. Despite extremely leaky nasalairway interfaces (approximately 75% leak), no differenceswere observed in the animals’ abilities to initiate and cyclebreaths between invasive and noninvasive NAVA. In ad-dition, no differences were observed in gas exchange or
Fig. 5. Example ventilator screen during nasal neurally adjustedventilatory assist in a premature neonate (23 weeks gestationalage, 560 g) with respiratory distress syndrome. The yellow, green,blue, and gray lines represent airway pressure, flow, volume, andelectrical activity of the diaphragm (Edi) signal, respectively. Theinspiratory pressure, trigger, and cycle is proportional to the Edi,and is captured with every spontaneous effort made by the pa-tient. (Courtesy of Robert Tero RRT-NPS.)
NEONATAL NONINVASIVE VENTILATION TECHNIQUES: DO WE REALLY NEED TO INTUBATE?
RESPIRATORY CARE • SEPTEMBER 2011 VOL 56 NO 9 1287
gastric insufflation of gases during the study period. Anearly 4-fold increase in the NAVA level allowed theanimals’ spontaneous breathing efforts to be restored tothe pre-extubation values. This required inspiratory pres-sure of approximately 15 cm H2O. In these hypoxemicanimals, NAVA appears to be a reasonable NIV approachfor unloading the respiratory system, promoting gas ex-change, and improving synchrony, independent of leak.
A similar study by Beck et al69 was performed in 7human premature neonates (25–29 weeks gestational age)with resolving lung disease and who were ready to beextubated. In the first phase of the study, a NAVA catheterwas placed, and airway pressure and EAdi were measuredduring a 60-min period on a conventional ventilator. Theneonates were then placed on invasive NAVA at a levelthat provided airway pressure similar to that of conven-tional ventilation. Following a short period of NAVA, theneonates were extubated and supported with NAVA via asingle nasal prong and at similar NAVA as when theywere extubated. No PEEP was used because of excessiveleak during NAVA. NAVA resulted in lower mean airwaypressure (P � .002) and higher oxygen requirement(P � .003) than did the other testing conditions, due topoor pressure transmission from the leak. Interestingly,NAVA (without PEEP) resulted in a lower neural respi-ratory rate (P � .004), less breath-cycling delay, and bettercorrelation between EAdi and airway pressure (P � .001)than did invasive ventilation. This short-term study iden-tifies nasal NAVA as a reasonable way to support spon-taneously breathing premature neonates following and po-tentially prior to intubation.
Similar to other forms of NIV, NAVA requires that thepatient is breathing spontaneously. Premature neonates whoare apneic may not be able to be supported by nasal NAVA,even with use of a back-up ventilator mode. These pub-lished studies were performed with a prototype Servo 300ventilator (Maquet, Solna, Sweden), and NAVA is cur-rently commercially available only on the Servo-i venti-lator. Nasal NAVA is an invasive mode, requires frequentbedside attendance, and is relatively expensive. Future stud-ies with larger numbers of neonates will help to assessoutcomes to evaluate NAVA as a standard NIV approachfor supporting neonates with lung disease.
Sigh Continuous Positive Airway Pressure
The Infant Flow nasal “sigh” positive airway pressure(SiPAP) device (Carefusion, Yorba Linda, California) is asecond-generation noninvasive respiratory support device,similar to the Infant Flow Advance that is being used inEurope. This device is being implemented more frequentlyin NICUs to assist spontaneously breathing neonates withlung disease and apnea. Infant Flow SiPAP uses the samenasal prongs, mask, fixation, and fluidic-flip mechanism
used in Infant Flow nasal CPAP. SiPAP differs from otherforms of NIV in that it allows the neonate to breathecontinuously at 2 separate CPAP levels. The primary CPAPlevel is set at 4–6 cm H2O by adjusting flow through aflow meter, and airway pressure is displayed by an internalmanometer. The secondary CPAP level or “sigh” is setwith a second flow meter, to obtain a pressure 2–4 cm H2Ohigher than the baseline CPAP setting. The breath-hold isadjusted to between 0.5 second and 2 seconds, and therespiratory rate controls the frequency of intermittent “sigh”breaths (Fig. 6).
In combination with spontaneous breathing, these “sighs”are intended to recruit unstable air spaces, maintain end-expiratory lung volume, avoid apnea, and reduce the needfor invasive ventilation. Alveolar ventilation depends onboth the neonate’s spontaneous VE and the VE created bySiPAP transitioning between the 2 CPAP levels. Outsidethe United States, SiPAP allows patient-triggered SiPAPbreaths triggered with a Graseby capsule placed on theabdomen. In the United States, the Graseby capsule is usedonly to monitor respiratory rate. The rise in pressure fromthe primary CPAP level to the secondary CPAP level isgradual and differs from pressure support provided by con-ventional ventilators. Whether patient-triggering will bemade available is unclear. Nonetheless, investigators areevaluating the effectiveness and physiologic benefits re-lated to patient-triggering with this form of support.
In a small observational study, SiPAP provided bettergas exchange than did standard CPAP in preterm infants.71
Ancora et al72 retrospectively evaluated whether SiPAPfollowing surfactant administration and brief ventilationwould prevent re-intubation and mechanical ventilation in
Fig. 6. Example airway pressure and rib-cage impedance in apremature infant supported with the biphasic mode of SiPAP (“sigh”positive airway pressure) from the Infant Flow nasal continuouspositive airway pressure system. The arrows indicate patient-ini-tiated breaths. (From Reference 70, with permission.)
NEONATAL NONINVASIVE VENTILATION TECHNIQUES: DO WE REALLY NEED TO INTUBATE?
1288 RESPIRATORY CARE • SEPTEMBER 2011 VOL 56 NO 9
preterm neonates. Neonates in the historical control group(n � 22) were supported with 4–6 cm H2O CPAP, andneonates in the SiPAP group (n � 38) were managedusing primary CPAP at 4–6 cm H2O and secondary CPAPat 5–8 cm H2O; time high was 0.5–0.6 second, and therespiratory rate was 10–30 cycles/min. The need for me-chanical ventilation was greater in the historical controlgroup than in the infants supported with SiPAP (27% vs0%, P � .001). The mothers of the infants in the SiPAPgroup had received antenatal steroids more frequently thanhad the historical control infants (P � .003), which mayhelp explain why re-intubation was not needed in the Si-PAP infants. Nonetheless, SiPAP, combined with antena-tal steroids and surfactant, appears to be an attractive ini-tial clinical approach for preterm neonates.
In a prospective RCT, Lista et al73 compared outcomesin preterm neonates who received either CPAP (n � 20) orSiPAP (n � 20) as the initial form of support in the acutephase of RDS. All the infants received sustained lunginflations in the delivery room and surfactant (as needed),with immediate extubation. Neonates in the CPAP groupwere supported with CPAP 6 cm H2O, and the settings inthe SiPAP group were adjusted to provide similar meanairway pressure. Infants supported by SiPAP had shorterduration of mechanical ventilation (P � .03), less O2 de-pendence (P � .03), and were discharged sooner (P � .02)with similar serum levels of pro-inflammatory cytokines(interleukin 6, interleukin 8, tumor necrosis factor alpha),as did the infants supported initially with CPAP. The studysuggests that SiPAP is a more beneficial form of nonin-vasive support than is nasal CPAP at similar mean airwaypressure, without increasing lung injury.
Nasal High-Frequency Ventilation
Invasive high-frequency ventilation is a form of lung-protective ventilation that is commonly used in neonateswith lung disease, as an initial ventilation strategy or as arescue intervention if a neonate fails conventional venti-lation. In a premature baboon model, long-term HFOVresulted in better pulmonary mechanics, consistently moreuniform lung inflation, and less pulmonary inflammationthan did conventional ventilation with a low-VT strategy.74
In a recent meta-analysis75 of RCTs that compared out-comes in neonates supported by different forms of high-frequency ventilation or conventional ventilation, therewere no differences in infant chronic lung disease, mor-tality, or neurological insult. However, when randomiza-tion occurred earlier (1–4 h), HFOV was associated withless death or BPD than was conventional ventilation(P � .01).
Over the last 5 years, nasal high-frequency ventilation(HFV) has been used more commonly in clinical practiceas a form of NIV. Unlike nasal IMV and SiPAP, nasal
HFV uses lower pressure and smaller volume at higherfrequency, and may be more lung-protective than are otherhigher-pressure NIV modes. The most common ventilatorused to apply nasal HFV is the Infrasonics Infant Star.Nasal HFV is applied via either nasopharyngeal ETT orbi-nasal prongs with fixation.
The physiologic mechanism through which nasal HFVsupports spontaneously breathing neonates with RDS isunclear. Nasal HFV may improve gas exchange by pro-viding higher mean airway pressure and pneumatic stent-ing of the laryngeal structures. The effects of high-fre-quency, small-amplitude pressure oscillations applied vianasal mask have been observed in healthy adults and inadults with obstructive sleep apnea.76 The most importantfinding from that study was that pressure oscillations wereassociated with a partial or complete reversal of the upper-airway obstruction and VT increase. Those authors con-cluded that upper-airway receptors were responding to thelow-pressure, high-frequency oscillations, with input tothe genioglossus and other muscles of respiration. Theseresponses may be important for improving ventilation andreducing the adverse effects of obstructive apnea duringnasal HFV in neonates.
In a case study, Hoehn et al77 described the first suc-cessful application of nasal HFV in an extremely-low-birth-weight (760 g) preterm (27 weeks gestational age)neonate with severe CO2 retention, acidemia, and respira-tory distress. Re-intubation was avoided and PaCO2
and pHdramatically improved. The improvements in alveolar ven-tilation were probably related to the high-frequency pres-sure oscillations, which may enhance gas mixing in theupper airways through the process of facilitated augmenteddiffusion. Other proposed gas-exchange mechanisms havebeen described during nasal HFV that may not be presentduring conventional ventilation.78
In a recent animal study, Reyburn et al79 tested thehypothesis that nasal HFV would result in less lung injuryand better alveolar development than are observed withconventional invasive IMV. Two groups of prematurelambs were administered surfactant, randomized to nasalHFV or invasive conventional ventilation, and supportedfor a 3-day period. The invasive conventional ventilationgroup was managed with a respiratory rate of 60 cycles/min, inspiratory time of 0.3 s, VT of 7 mL/kg, and PEEPof 8 cm H2O. The nasal HFV group was managed withhigh-frequency percussive ventilation (VDR3, Percussion-aire, Bird Technologies, Sandpoint, Idaho) attached to anasopharyngeal tube placed into a single nare. The initialsettings were amplitude 20–25 cm H2O, mean airway pres-sure 8–12 cm H2O, and frequency 10 Hz. The 2 groupshad similar gas-exchange goals, which guided subsequentventilator adjustments and weaning over the study period.Nasal HFV resulted in smaller and more uniformly in-flated terminal respiratory units and distal air spaces, lon-
NEONATAL NONINVASIVE VENTILATION TECHNIQUES: DO WE REALLY NEED TO INTUBATE?
RESPIRATORY CARE • SEPTEMBER 2011 VOL 56 NO 9 1289
ger alveolar secondary septae, and thinner distal air-spacewalls than did invasive conventional ventilation (P � .005,Fig. 7). This implies that short-term nasal HFV may op-timize lung recruitment and promote normal alveolariza-tion in preterm lungs better than does a “gentle” invasiveventilation strategy. Additionally, at days 2 and 3, lowerFIO2
was required during nasal HFV than during invasiveventilation (P � .005).
Of particular interest was the fact that the investigatorsmeasured intratracheal pressure in the animals receivingnasal HFV, and the delivered pressure averaged only0.37 � 0.23 cm H2O. These data imply a large leak at thenasal airway interface with the nasopharyngeal ETT.Whether bi-nasal prongs are more effective in providingventilation is not resolved by these data. Conversely, it isunclear whether using bi-nasal prongs during HFV resultsin greater volutrauma, gas trapping, and lung injury andless favorable alveolarization than does HFV via nasopha-ryngeal ETT.
Unfortunately, nasal HFV is such a new form of NIVthat very few data are available to suggest a long-termmanagement strategy in neonatal patients. Short-term ob-servational studies have suggested initial mean airway pres-sure set to equal the previous CPAP, frequency set at10 Hz, amplitude adjusted to obtain visible chest-wall vi-bration and increased every 30 min by 4–6 units, if nec-essary, to maintain clinically appropriate chest-wall vibra-tion, transcutaneous CO2, or blood gas values.80,81
Clinical responses to HFV in preterm neonates in 2small studies have been reported. Van der Hoeven et al79
placed 21 preterm and term infants with moderate respi-ratory insufficiency on nasal HFV following CPAP. Anasopharyngeal ETT was placed 3–4 cm into a singlenare, and HFV was provided with the Infant Star ventilatorin the high-frequency flow-interrupter mode, with meanairway pressure settings similar to or higher than the pre-vious CPAP setting, frequency of 10 Hz; amplitude wasincreased until chest-wall oscillations were observed. Ini-tiation of HFV following CPAP resulted in a small reductionin PaCO2
(P � .001) but no significant change in pH. Five(23%) of the patients failed nasal HFV and required invasiveventilation related to severe RDS, sepsis, and apnea.
Colaizy et al81 performed a similar observational studyto compare the clinical effects of nasal HFV to CPAP inneonates with mild to moderate lung disease. All 14 sub-jects were very-low-birth-weight infants (� 1,500 g) whowere transitioned from CPAP to HFV via nasopharyngealETT, with the Infant Star ventilator in the high-frequency,flow-interrupter mode. The investigators used an approachsimilar to that of van der Hoeven et al,80 for 2 hours. After2 hours of nasal HFV, capillary blood gases were mea-sured and the subjects were returned to their pre-studyCPAP settings. Nasal HFV decreased mean transcutane-ous PCO2
from 50 mm Hg to 45 mm Hg (P � .01) andincreased pH from 7.40 to 7.37 (P � .04). In all the in-fants, chest radiograph obtained 1 hour after nasal HFVprovided no evidence of hyperinflation.
Dumas de la Roque et al82 performed a prospective RCTof nasal CPAP versus nasal HFV in 40 term neonates withrespiratory distress shortly after cesarean section. This wasthe first short-term prospective study to describe nasalHFV as an initial form of noninvasive respiratory support
Fig. 7. Histology of lung tissue from preterm lambs ventilated for3 days with invasive intermittent mandatory ventilation (IMV) (A andC) or noninvasively with nasal high-frequency ventilation (HFV) (B andD). Each row of panels has the same magnification (see scale bars).The gestation control fetal lambs were (1) delivered at the gestationage that the preterm lambs were delivered (FA132) or (2) delivered atthe gestation age when the preterm lamb studies were completed(FA136). The terminal respiratory unit (TRUs) in the preterm lambsthat received nasal HFV (B and D) have smaller and more uniformdistal air spaces (DASs), more and thinner alveolar secondary septa(arrowhead in A and B), and thinner distal air-space walls (arrow in Cand D) than the TRUs in the preterm lambs that received IMV (A andC). The TRUs in the preterm lambs that received nasal HFV are struc-turally similar to the TRUs in the FA136 gestation control lambs (F andH). On the other hand, the TRUs in the preterm lambs that receivedIMV (A and C) are structurally similar to the TRUs in the FA132 ges-tation control lambs (E and G). (From Reference 79, with permission.)
NEONATAL NONINVASIVE VENTILATION TECHNIQUES: DO WE REALLY NEED TO INTUBATE?
1290 RESPIRATORY CARE • SEPTEMBER 2011 VOL 56 NO 9
in neonates. Neonates randomized to CPAP were sup-ported with 5 cm of CPAP, and neonates in the nasal HFVgroup were supported with the VDR3 high-frequency per-cussion device, with an initial mean airway pressure of5 cm H2O and a frequency of 5 Hz. The groups had similaroxygenation goals, and the settings were not changedthroughout the study period. Lung disease resolved in allthe neonates within 10 hours, but the nasal HFV group hadshorter duration of respiratory distress, lower oxygen ther-apy level, and shorter oxygen therapy duration (P � .001)than did the CPAP group.
Some clinicians are concerned that pressure oscillationsdelivered out of phase with the neonate’s spontaneousbreathing efforts may impose high WOB. Although thecomplex interplay between spontaneous breathing and HFVhas not been described in the literature, van Heerde et al83
found a low imposed WOB during invasive HFOV, withthe 3100A HFOV ventilator (Carefusion, Yorba Linda,California) in a simulated spontaneously breathing neo-nate. How these data would compare to bi-nasal prongs ora nasopharyngeal ETT is unclear, but the effects are notlikely to be similar due to the inherently leaky nature andlower imposed resistances of these nasal airway interfaces.Carlo84 has suggested that a potential advantage of nasalHFV over IMV is that synchronization is not necessary,due to the relatively high frequencies. However, studies totest this hypothesis in neonates are needed.
The widespread use of nasal HFV in neonates withbroadly different lung diseases cannot be suggested at thistime, but HFV appears to be an NIV mode that will beevaluated in future clinical trials. The majority of the afore-mentioned studies were in animals and humans and usedhigh-frequency flow-interrupter or high-frequency percus-sive ventilation strategies, and the most frequently used ofthose devices, the Infant Star ventilator, is now obsolete.As such, there is interest in using nasal HFV with thewidely used 3100A HFOV ventilator. Whether this venti-lator has been used off-label to provide HFV in neonatesis unclear. The ventilator circuit is more rigid than arestandard ventilator circuits, which creates difficulties ininterfacing with nasal prongs without causing unnecessarytorque on the neonate’s airway. Further, the 3100A has apressure-relief (“dump”) valve that is activated by elec-tronic and pneumatic controls that open the patient circuitto ambient air when the measured mean airway pressurereaches � 20% of the maximum set mean airway pressure.This factor may be a limitation in spontaneously breathingneonates using mean airway pressure (approximately5 cm H2O) similar to those previously described in short-term human neonatal HFV studies.
De Luca et al85 evaluated the effect of ventilation pa-rameters during nasal HFOV in a bench study with the3100A HFOV ventilator. Nasal HFOV was applied to aneonatal test lung with a prototype adapter/circuit and bi-
nasal short prongs (Argyle CPAP nasal cannula, SherwoodMedical, St Louis, Missouri) of 2 different diameters (largeand small), without a leak. Oscillatory volume, VE, andmean airway pressure were measured at several mean air-way pressures and Hz settings. The power level was ad-justed to obtain an amplitude of 45 cm H2O for the entirestudy. Data from HFV were compared to a “control cir-cuit” invasive HFOV simulation, wherein the HFOV cir-cuit was attached directly to the neonatal lung model (with-out prongs or an ETT). The pressure drops between thenasal airway and test lung were calculated as 38.5 � 10.9%,35.3 � 10.1%, and 22.1 � 10.4%, for the small prongs,large prongs, and control circuit, respectively. VT was0.4 � 0.1, 0.9 � 0.3, and 1.5 � 0.5 for small prong, largeprong, and the control circuit, respectively. The pressuredelivered to the neonatal lung via the bi-nasal prongs inthat study are much larger than those observed by Reyburnet al,79 when tracheal pressure was measured in pretermlambs. Conversely, data from the bench study were ob-tained in the absence of a leak. These differences warrantfurther investigation, to compare the effects of gas trap-ping and lung injury between nasopharyngeal ETT andshort bi-nasal prong interfaces during HFV.
Based on these small, short-term studies, nasal HFVappears to be technically possible in preterm neonates.However, more bench and animal studies are needed, us-ing different nasal airway interfaces with the availablehigh-frequency ventilators, before long-term studies areperformed in human neonates with severe lung disease.
Bubble CPAP is a form of noninvasive respiratory sup-port that is being called “inexpensive nasal HFV,” becausethe bubbling in the water-seal creates small-amplitude,high-frequency oscillations that are transmitted to the na-sal airway interface of spontaneously breathing neonates.Animal studies86,87 and studies in human neonates88 haveshown that bubble CPAP may result in better alveolarventilation and lung recruitment than conventional (venti-lator-derived) CPAP. However, those studies were con-ducted in subjects who were endotracheally intubated, andno studies have evaluated these physiologic effects in sub-jects with a leaky nasal airway interface. In a recent benchtest, bubble CPAP, applied with leaky bi-nasal short prongs,resulted in measureable volume oscillations (approximately0.5–0.6 mL) delivered to a neonatal nasal airway/testlung.89 Clinicians often increase the bias flow to increasethe amplitude and frequency of airway pressure oscilla-tions during bubble CPAP, but this practice has not beenshown to enhance gas exchange or lung recruitment.90
In 2010, 2 reports appeared91,92 of a novel high-ampli-tude bubble-CPAP system that can provide a greater levelof NIV support than conventional bubble CPAP alone.Controlling the angle through which gas exits, the bubble-CPAP water-seal column was reported to enhance greatlythe airway-pressure oscillations at the nasal airway inter-
NEONATAL NONINVASIVE VENTILATION TECHNIQUES: DO WE REALLY NEED TO INTUBATE?
RESPIRATORY CARE • SEPTEMBER 2011 VOL 56 NO 9 1291
face, thus providing flexibility to meet the differing re-quirements of patients with differing levels of respiratorydistress. In a neonatal lung model with leaky nasal prongs,the high-amplitude bubble-CPAP device adjusted with theoutlet tubing at 135°, in relation to the water surface level,delivered VT similar to that previously measured duringHFOV in infants.93 In addition, high-amplitude bubbleCPAP provided noninvasive support, via bi-nasal prongs,to spontaneously breathing, lung-lavaged juvenile rabbitswith lower WOB (P � .001) and higher PaO2
(P � .007)than were observed in the same animals supported withbubble CPAP at identical mean airway pressures.91 Tworabbits supported by high-amplitude bubble CPAP becameapneic, with normal PaCO2
and vital signs. High-amplitudebubble CPAP may represent a relatively simple new strat-egy for supporting a greater fraction of neonates who wouldotherwise fail CPAP and require invasive ventilation. Neo-natal clinical trials are needed to test this hypothesis.
Summary
The prevailing message from this comprehensive re-view suggests that there is a large population of neonatalpatients who cannot be supported by CPAP, and the clin-ical consensus is that invasive ventilation should be avoidedat “all cost” to the patient. The advent of neonatal airwayinterfaces has ushered in a whole new generation of NIVstrategies for neonatal patients, specifically those affectedby RDS. In the not so distant future, clinicians may relymore on IMV, SiPAP, NAVA, and HFV as the establishedinitial NIV approach for supporting infants at risk for de-veloping most forms of neonatal respiratory distress. It isunlikely that these strategies will completely obviate in-vasive ventilation, but they may reduce the need for repeatedintubation and prolonged ventilation, and so may reduce thenumerous complications that affect this sensitive patient pop-ulation. While still early in its inception, clinicians will needfurther clinical research to determine the “best” form of NIVthat satisfies their patient population and embraces develop-ment of disease-specific management strategies.
REFERENCES
1. Singh GK, Yu SM. Infant mortality in the United States: trends,differentials, and projections, 1950 through 2010. Am J Public Health1995;85(7):957-964.
2. Jobe AH, Kramer BW, Moss TJ, Newnham JP, Ikegami M. Decreasedindicators of lung injury with continuous positive expiratory pressure inpreterm lambs. Pediatr Res 2002;52(3):387-392.
3. Bjorklund LJ, Ingimarsson J, Cursted T, John J, Robertson B, Werner O,et al. Manual ventilation with a few large breaths at birth compromisesthe therapeutic effect of subsequent surfactant replacement in immaturelambs. Pediatr Res 1997;42(3):348-355.
4. Thomson MA, Yoder BA, Winter VT, Giavedoni L, Chang LY, CoalsonJJ. Delayed extubation to nasal continuous positive airway pressure inthe immature baboon model of bronchopulmonary dysplasia: lung clin-ical and pathological findings. Pediatrics 2006;118(5):2038-50.
5. Thibeault DW, Mabry SM, Ekekezie II, Zhang X, Truog WE. Collagenscaffolding during development and its deformation with chronic lungdisease. Pediatrics 2003;111(4 Pt 1):766-776.
6. Jobe AJ. The new BPD: an arrest of lung development. Pediatr Res1999;46(6):641-643.
7. Dreyfuss D, Saumon G. Barotrauma is volutrauma but which volume isthe one responsible? Intensive Care Med 1992;18(3):139-141.
8. Muscedere JG, Mullen JB, Gan K, Slutsky AS. Tidal ventilation at lowairway pressures can augment lung injury. Am J Respir Crit Care Med1994;149(5):1327-1334.
9. Lista G, Castoldi F, Fontana P, Reali R, Reggiani A, Bianchi S, Com-pagnoni G. Lung inflammation in preterm infants with respiratory dis-tress syndrome: effects of ventilation with different tidal volumes. Pe-diatr Pulmonol 2006;41(4):357-363.
10. Avery ME, Tooley WH, Keller JB, Hurd SS, Bryan MH, Cotton RB, etal. Is chronic lung disease in low birth weight infants preventable? Asurvey of eight centers. Pediatrics 1987;79(1):26-30.
11. Van Marter LJ, Allred EN, Pagano M, Sanocka U, Parad R, Moore M,et al. Do clinical markers of barotrauma and oxygen toxicity explaininterhospital variation in rates of chronic lung disease? Pediatrics 2000;105(6):1194-201.
12. Hutchison AA, Bignall S. Non-invasive positive pressure ventilation inthe preterm neonate: reducing endotrauma and the incidence of bron-chopulmonary dysplasia. Arch Dis Child Fetal Neonatal Ed 2008;93(1):F64-F68.
13. Aly H. Ventilation without tracheal intubation. Pediatrics 2009;124(2):786-789.
14. te Pas AB, Wong C, Kamlin CO, Dawson JA, Morley CJ, Davis PG.Breathing patterns in preterm and term infants immediately after birth.Pediatr Res 2009;65(3):352-356.
15. Apisarnthanarak A, Holzmann-Pazgal G, Hamvas A, Olsen MA, FraserVJ. Ventilator-associated pneumonia in extremely preterm neonates in aneonatal intensive care unit: characteristics, risk factors, and outcomes.Pediatrics 2003;112(6 Pt 1):1283-1289.
16. DiBlasi RM. Nasal continuous positive airway pressure (CPAP) for therespiratory care of the newborn infant. Respir Care 2009;54(9):1209-1235.
17. SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neo-natal Research Network; Finer NN, Carlo WA, Walsh MC, Rich W,Gantz MG, Laptook AR, et al. Early CPAP versus surfactant in ex-tremely preterm infants. N Engl J Med 2010;362(21):1970-1979. Erra-tum in: N Engl J Med 2010;362(23):2235.
18. Morley CJ, Davis PG, Doyle LW, Brion LP, Hascoet JM, Carlin JB;COIN Trial Investigators. Nasal CPAP or intubation at birth for verypreterm infants. N Engl J Med 2008 Feb 14;358(7):700-708.
19. Stefanescu BM, Murphy WP, Hansell BJ, Fuloria M, Morgan TM,Aschner JL. A randomized, controlled trial comparing two differentcontinuous positive airway pressure systems for the successful extuba-tion of extremely low birth weight infants. Pediatrics 2003;112(5):1031-1038.
20. Verder H, Albertsen P, Ebbesen F, Greisen G, Robertson B, BertelsenA, et al. Nasal continuous positive airway pressure and early surfactanttherapy for respiratory distress syndrome in newborns of less than 30weeks’ gestation. Pediatrics 1999;103(2):24.
21. Donald I, Lord J. Augmented respiration; studies in atelectasis neona-torum. Lancet 1953;1(6749):9-17.
22. Gregory GA, Kitterman JA, Phibbs RH, Tooley WH, Hamilton WK.Treatment of the idiopathic respiratory-distress syndrome with contin-uous positive airway pressure. N Engl J Med 1971;284(25):1333-1340.
23. Stern L, Ramos AD, Outerbridge EW, Beaudry PH. Negative pressureartificial respiration: use in treatment of respiratory failure of the new-born. Can Med Assoc J 1970;102(6):595-601.
24. Llewellyn MA, Tilak KS, Swyer PR. A controlled trial of assisted ven-tilation using an oro-nasal mask. Arch Dis Child 1970;45(242):453-459.
NEONATAL NONINVASIVE VENTILATION TECHNIQUES: DO WE REALLY NEED TO INTUBATE?
1292 RESPIRATORY CARE • SEPTEMBER 2011 VOL 56 NO 9
25. Helmrath TA, Hodson WA, Oliver TK. Positive pressure ventilation inthe newborn infant: the use of a face mask. J Pediatr 1970;76(2):202-207.
26. Pape KE, Armstrong DL, Fitzhardinge PM. Central nervous systempatholgoy associated with mask ventilation in the very low birthweightinfant: a new etiology for intracerebellar hemorrhages. Pediatrics 1976;58(4):473-483.
27. Allen LP, Blake AM, Durbin GM, Ingram D, Reynolds EO, WimberleyPD. Continuous positive airway pressure and mechanical ventilation byfacemask in newborn infants. BMJ 1975;4(5989):137-139.
28. Kattwinkel J, Fleming D, Cha CC, Fanaroff AA, Klaus MH. A devicefor administration of continuous positive airway pressure by the nasalroute. Pediatrics 1973;52(1):131-134.
30. Moretti C, Marzetti G, Agostino A, Panero A, Picece-Bucci S, Mendi-cini M et al. Prolonged intermittent positive pressure ventilation by nasalprongs in intractable apnea of prematurity. Acta Paediatr Scand 1981;70(2):211-216.
31. Garland JS, Nelson DB, Rice T, Neu J. Increased risk of gastrointestinalperforations in neonates mechanically ventilated with either face maskor nasal prongs. Pediatrics 1985;76(3):406-410.
32. Friedlich P, Lecart C, Posen R, Ramicone E, Chan L, Ramanathan R. Arandomized trial of nasopharyngeal-synchronized intermittent manda-tory ventilation versus nasopharyngeal continuous positive airway pres-sure in very low birth weight infants after extubation. J Perinatol 1999;19(6 Pt 1):413-418.
33. De Paoli AG, Morley CJ, Davis PG, Lau R, Hingeley E. In vitro com-parison of nasal continuous positive airway pressure devices for neo-nates. Arch Dis Child Fetal Neonatal Ed 2002;87(1):42-45.
34. Owen LS, Morley CJ, Davis PG. Neonatal nasal intermittent positivepressure ventilation: a survey of practice in England. Arch Dis ChildFetal Neonatal Ed. 2008;93(2):F148-F150.
35. Stucki P, Perez MH, Scalfaro P, de Halleux Q, Vermeulen F, Cotting J.Feasibility of non-invasive pressure support ventilation in infants withrespiratory failure after extubation: a pilot study. Intensive Care Med2009;35(9):1623-1627.
36. Ali N, Claure N, Alegria X, D’Ugard C, Organero R, Bancalari E.Effects of non-invasive pressure support ventilation (NI-PSV) on ven-tilation and respiratory effort in very low birth weight infants. PediatrPulmonol 2007;42(8):704-710.
37. Owen LS, Morley CJ, Davis PG. Pressure variation during ventilatorgenerated nasal intermittent positive pressure ventilation in preterm in-fants. Arch Dis Child Fetal Neonatal Ed. 2010;95(5):F359-F364.
38. Moretti C, Gizzi C, Papoff P, Lampariello S, Capoferri M, Calcagnini G,Bucci G. Comparing the effects of nasal synchronized intermittent pos-itive pressure ventilation (nSIPPV) and nasal continuous positive airwaypressure (nCPAP) after extubation in very low birth weight infants.Early Hum Dev 1999;56(2–3):167-177.
39. Nonaka S, Katada A, Nakajima K, Ohsaki T, Unno T. The effects ofnasal flow stimulation on central respiratory pattern. Am J Rhinol 1995;9:203-208.
40. Kugelman A, Feferkorn I, Riskin A, Chistyakov I, Kaufman B, Bader D.Nasal intermittent mandatory ventilation versus nasal continuous posi-tive airway pressure for respiratory distress syndrome: a randomized,controlled, prospective study. J Pediatr. 2007;150(5):521-526.
41. Greenough A, Dimitriou G, Prendergast M, Milner AD. Synchronizedmechanical ventilation for respiratory support in newborn infants. Co-chrane Database Syst Rev 2008;(1):CD000456.
42. Chang HY, Claure N, D’ugard C, Torres J, Nwajei P, Bancalari E.Effects of synchronization during nasal ventilation in clinically stablepreterm infants. Pediatr Res 2011;69(1):84-89.
43. Kiciman NM, Andreasson B, Bernstein G, Mannino FL, Rich W, Hen-derson C, Heldt GP. Thoracoabdominal motion in newborns duringventilation delivered by endotracheal tube or nasal prongs. Pediatr Pul-monol 1998;25(3):175-181.
44. Bhandari V, Finer NN, Ehrenkranz RA, Saha S, Das A, Walsh MC, etal; Eunice Kennedy Shriver National Institute of Child Health and Hu-man Development Neonatal Research Network. Synchronized nasal in-termittent positive-pressure ventilation and neonatal outcomes. Pediat-rics 2009;124(2):517-526.
45. Aghai ZH, Saslow JG, Nakhla T, Milcarek B, Hart J, Lawrysh-PlunkettR, et al. Synchronized nasal intermittent positive pressure ventilation(SNIV) decreases work of breathing (WOB) in premature infants withrespiratory distress syndrome (RDS) compared to nasal continuous pos-itive airway pressure (NCPAP). Pediatr Pulmonol 2006;41(9):875-881.
46. Kugelman A, Bar A, Riskin A, Chistyakov I, Mor F, Bader D. Nasalrespiratory support in premature infants: short-term physiological effectsand comfort assessment. Acta Paediatr 2008;97(5):557-561.
47. Kulkarni A, Ehrenkranz RA, Bhandari V. Effect of introduction ofsynchronized nasal intermittent positive-pressure ventilation in a neona-tal intensive care unit on bronchopulmonary dysplasia and growth inpreterm infants. Am J Perinatol 2006;23(4):233-240.
48. Lin CH, Wang ST, Lin YJ, Yeh TF. Efficacy of nasal intermittentpositive pressure ventilation in treating apnea of prematurity. PediatrPulmonol 1998;26(5):349-353.
49. Barrington KJ, Bull D, Finer NN. Randomized trial of nasal synchro-nized intermittent mandatory ventilation compared with continuous pos-itive airway pressure after extubation of very low birth weight infants.Pediatrics 2001;107(4):638-641.
50. Ryan CA, Finer NN, Peters KL. Nasal intermittent positive-pressureventilation offers no advantages over nasal continuous positive airwaypressure in apnea of prematurity. Am J Dis Child 1989;143(10):1196-1198.
51. Head H. On the Regulation of Respiration: PART I. Experimental.J Physiol. 1889;10(1–2):1-152.
52. Greenough A, Morley CJ, Davis JA. Respiratory reflexes in ventilatedpremature babies. Early Hum Dev 1983;8(1):65-75.
53. Greenough A, Morley CJ, Davis JA. Provoked augmented inspirationsin ventilated premature babies. Early Hum Dev 1984;9(2):111-117.
54. Lampland AL, Meyers PA, Worwa CT, Swanson EC, Mammel MC.Gas exchange and lung inflammation using nasal intermittent positive-pressure ventilation versus synchronized intermittent mandatory venti-lation in piglets with saline lavage-induced lung injury: an observationalstudy. Crit Care Med 2008;36(1):183-187.
55. Owen LS, Morley CJ, Davis PG. [2010] [4407.298] Ventilator gener-ated nasal intermittent positive pressure ventilation (NIPPV): can deliv-ered pressure be improved? A randomized crossover study (abstract).Pediatric Academic Societies’ Abstract Archive 2010. http://www.abstracts2view.com/pasall/search.php?search�do&intMaxHits�10&where%5B%5D�&andornot%5B%5D�&query�Owen. Accessed onJuly 15, 2011.
56. Ramanathan R, Sekar K, Rasmussen M, Bhatia J, Soll R. Nasal inter-mittent positive pressure ventilation (nippv) versus synchronized inter-mittent mandatory ventilation (simv) after surfactant treatment for re-spiratorydistresssyndrome(rds) inpreterminfants�30weeks’gestation:multicenter, randomized, clinical trial. http://www.pas-meeting.org/2009baltimore/abstracts/lb%20pub%20all_full%20text%2009.pdf. Ac-cessed July 9, 2011.
57. Ramanathan R, Crotwell D, DiBlasi R. A novel means for deliveringnasal intermittent positive pressure ventilation (nippv) in infants: thenasal cannula. http://www.seattlechildrens.org/doc/56th-AARC-intl-resp-congress-detail.doc. Accessed July 7, 2011.
58. Lagarde S, Semjen F, Nouette-Gaulain K, Masson F, Bordes M, Mey-mat Y, Cros AM. Facemask pressure-controlled ventilation in children:what is the pressure limit? Anesth Analg 2010;110(6):1676-1679.
NEONATAL NONINVASIVE VENTILATION TECHNIQUES: DO WE REALLY NEED TO INTUBATE?
RESPIRATORY CARE • SEPTEMBER 2011 VOL 56 NO 9 1293
59. Davis PG, Henderson-Smart DJ. Nasal continuous positive airwayspressure immediately after extubation for preventing morbidity inpreterm infants. Cochrane Database Syst Rev 2003;(2):CD000143.
60. Khalaf MN, Brodsky N, Hurley J, Bhandari V. A prospective ran-domized, controlled trial comparing synchronized nasal intermittentpositive pressure ventilation versus nasal continuous positive airwaypressure as modes of extubation. Pediatrics 2001;108(1):13-17.
61. Davis PG, Lemyre B, De Paoli AG. Nasal intermittent positive pres-sure ventilation (NIV) versus nasal continuous positive airway pres-sure (NCPAP) for preterm neonates after extubation. CochraneDatabase Syst Rev 2001;(3):CD003212. DOI: 10.1002/14651858.CD003212.
62. Soll RF, Morley CJ. Prophylactic versus selective use of surfactant inpreventing morbidity and mortality in preterm infants. Cochrane Data-base Syst Rev 2001;(2):CD000510.
63. Santin R, Brodsky N, Bhandari V. A prospective observational pilotstudy of synchronized nasal intermittent positive pressure ventilation(SNIV) as a primary mode of ventilation in infants � or � 28 weekswith respiratory distress syndrome (RDS). J Perinatol 2004;24(8):487-493.
64. Bhandari V, Gavino RG, Nedrelow JH, Pallela P, Salvador A, Ehren-kranz RA, Brodsky NL. A randomized controlled trial of synchronizednasal intermittent positive pressure ventilation in RDS. J Perinatol 2007;27(11):697-703.
65. Sai Sunil Kishore M, Dutta S, Kumar P. Early nasal intermittent positivepressure ventilation versus continuous positive airway pressure for re-spiratory distress syndrome. Acta Paediatr 2009;98(9):1412-1415.
66. Manzar S, Nair AK, Pai MG, Paul J, Manikoth P, Georage M,Al-Khusaiby SM. Use of nasal intermittent positive pressure venti-lation to avoid intubation in neonates. Saudi Med J. 2004;25(10):1464-1467.
67. Bisceglia M, Belcastro A, Poerio V, Raimondi F, Mesuraca L, Crug-liano C, Corapi UP. A comparison of nasal intermittent versus contin-uous positive pressure delivery for the treatment of moderate respiratorysyndrome in preterm infants. Minerva Pediatr 2007;59(2):91-95.
68. Beck J, Campoccia F, Allo JC, Brander L, Brunet F, Slutsky AS,Sinderby C. Improved synchrony and respiratory unloading by neu-rally adjusted ventilatory assist (NAVA) in lung-injured rabbits. Pe-diatr Res 2007;61(3):289-294.
69. Beck J, Reilly M, Grasselli G, Mirabella L, Slutsky AS, Dunn MS,Sinderby C. Patient-ventilator interaction during neurally adjusted ven-tilatory assist in low birth weight infants. Pediatr Res 2009;65(6):663-668.
70. DiBlasi RM, Richardson CP. Continuous positive airway pressure. In:Walsh BK, Czervinske M, DiBlasi RM, editors. Perinatal and pediatricrespiratory care, 3rd edition. St Louis: Elsevier 2009:305-324.
71. Migliori C, Motta M, Angeli A, Chirico G. Nasal bilevel vs. continuouspositive airway pressure in preterm infants. Pediatr Pulmonol 2005;40(5):426-430.
72. Ancora G, Maranella E, Grandi S, Pierantoni L, Guglielmi M, FaldellaG. Role of bilevel positive airway pressure in the management of pre-term newborns who have received surfactant. Acta Paediatr 2010;99(12):1807-1811.
73. Lista G, Castoldi F, Fontana P, Daniele I, Cavigioli F, Rossi S, et al.Nasal continuous positive airway pressure (CPAP) versus bi-level nasalCPAP in preterm babies with respiratory distress syndrome: a random-ized control trial. Arch Dis Child Fetal Neonatal Ed 2010;95(2):F85-F89.
74. Yoder BA, Siler-Khodr T, Winter VT, Coalson JJ. High-frequency os-cillatory ventilation: effects on lung function, mechanics, and airwaycytokines in the immature baboon model for neonatal chronic lungdisease. Am J Respir Crit Care Med 2000;162(5):1867-1876.
75. Cools F, Askie LM, Offringa M, Asselin JM, Calvert SA, Courtney SE,et al.; PreVILIG collaboration. Elective high-frequency oscillatory ver-
sus conventional ventilation in preterm infants: a systematic review andmeta-analysis of individual patients’ data. Lancet 2010;375(9731):2082-2091.
76. Henke KG, Sullivan CE. Effects of high-frequency oscillating pressureson upper airway muscles in humans. J Appl Physiol 1993;75(2):856-862.
77. Hoehn T, Krause MF. Effective elimination of carbon dioxide by na-sopharyngeal high-frequency ventilation. Respir Med 2000;94(11):1132-1134.
78. Pillow JJ. High-frequency oscillatory ventilation: mechanisms of gasexchange and lung mechanics. Crit Care Med 2005;33(3 Suppl):S135-S141.
79. Reyburn B, Li M, Metcalfe DB, Kroll NJ, Alvord J, Wint A, et al. Nasalventilation alters mesenchymal cell turnover and improves alveolariza-tion in preterm lambs. Am J Respir Crit Care Med 2008;178(4):407-418.
80. van der Hoeven M, Brouwer E, Blanco CE. Nasal high frequency ven-tilation in neonates with moderate respiratory insufficiency. Arch DisChild Fetal Neonatal Ed 1998;79(1):F61-F63.
81. Colaizy TT, Younis UM, Bell EF, Klein JM. Nasal high-frequencyventilation for premature infants. Acta Paediatr 2008 Nov;97(11):1518-1522.
82. Dumas De La Roque E, Bertrand C, Tandonnet O, Rebola M, RoquandE, Renesme L, Elleau C. Nasal high frequency percussive ventilationversus nasal continuous positive airway pressure in transient tachypneaof the newborn: A pilot randomized controlled trial (NCT00556738).Pediatr Pulmonol 2010 [Epub ahead of print].
83. van Heerde M, van Genderingen HR, Leenhoven T, Roubik K, PlotzFB, Markhorst DG. Imposed work of breathing during high-frequencyoscillatory ventilation: a bench study. Crit Care 2006;10(1):R23.
84. Carlo WA. Should nasal high-frequency ventilation be used in preterminfants? Acta Paediatr 2008;97(11):1484-1485.
85. De Luca D, Carnielli VP, Conti G, Piastra M. Noninvasive high fre-quency oscillatory ventilation through nasal prongs: bench evaluation ofefficacy and mechanics. Intensive Care Med 2010;36(12):2094-2100.
86. Versmold HT, Brunstler I, Schlosser R. In: Huch R, Duc G, Rooth G:Klinisches Management des kleinen Fruhgeborenen (�1500g). Stutt-gart: Thieme; 1982:159-162. Book in German.
87. Pillow JJ, Hillman N, Moss TJ, Polglase G, Bold G, Beaumont C,Ikegami M, Jobe AH. Bubble continuous positive airway pressure en-hances lung volume and gas exchange in preterm lambs. Am J RespirCrit Care Med 2007;176(1):63-69.
88. Lee KY, Dunn MS, Fenwick M, Shennan AT. A comparison of under-water bubble CPAP with ventilator derived CPAP in premature neo-nates ready for extubation. Biol Neonate 1998;73(2):69-75.
89. DiBlasi R, Poli J, Zignego JC, Barutcu B, Richardson CP. What are theeffects of different bubble continuous positive airway pressure (b-cpap)systems on the magnitude of oscillations in lung volume while using arealistic airway/lung model of preterm infants? http://www.seattlechildrens.org/doc/56th-AARC-intl-resp-congress-detail.doc. AccessedJuly 7, 2011.
90. Morley CJ, Lau R, De Paoli A, Davis PG. Nasal continuous positiveairway pressure: does bubbling improve gas exchange? Arch Dis ChildFetal Neonatal Ed 2005;90(4):F343-F344.
91. DiBlasi RM, Zignego JC, Smith CV, Hansen TN, Richardson CP. Ef-fective gas exchange in paralyzed juvenile rabbits using simple, inex-pensive respiratory support devices. Pediatr Res 2010 [Epub ahead ofprint]
92. DiBlasi RM, Zignego JC, Tang DM, Hildebrandt J, Smith CV, HansenTN, Richardson CP. Noninvasive respiratory support of juvenile rabbitsby high-amplitude bubble continuous positive airway pressure. PediatrRes 2010;67(6):624-629.
93. Sturtz WJ, Touch SM, Locke RG, Greenspan JS, Shaffer TH. Assess-ment of neonatal ventilation during high-frequency oscillatory ventila-tion. Pediatr Crit Care Med 2008;9(1):101-104.
NEONATAL NONINVASIVE VENTILATION TECHNIQUES: DO WE REALLY NEED TO INTUBATE?
1294 RESPIRATORY CARE • SEPTEMBER 2011 VOL 56 NO 9
Discussion
Willson: Would you say more aboutthe nasal cannula you invented? I thinkthe interface is a big issue for NIV, notonly in newborns but in our populationas well, and we’ve not had anybody ad-dress that. It’s fascinating to me thatwith just a small design change it lookslike you’re a lot more successful.
DiBlasi: The RAM nasal cannula[NeoTech Products, Valencia, Califor-nia] was invented by Drs Heyman andRamanathan. I was involved with someof the design work and research. It willbe commercially available in October2011. It differs from standard oxygencannula and high-flow nasal cannula inhaving wider-bore tubing and soft sili-cone bi-nasal prongs that are similar insize to those used during nasal CPAP.The advantage is that more pressure canbe transmitted to the lungs with this can-nula during nasal IMV than with stan-dard high-flow nasal cannula, and with-out the cumbersome fixation techniquesthat are often required with nasal CPAPprongs.
My concern with developing larger-bore prongs for larger infants or smallchildren is that they would have to bemade quite large to transmit pressure tothe child’s airways, and therefore mightnot be light enough to interface as a“simple” nasal cannula and would prob-ably require a cap or straps. I believethat folks have already begun workingon such devices for toddlers and smallchildren. I am also concerned by theresistance that may be imposed whenhigher VT and flow are applied withthese interfaces as the patient gets larger.
Willson: Is it going to be availablefor older kids?
DiBlasi: To my knowledge these willonly be available for neonates at thistime.
Brown: I know you’re primarilyNICU, Rob, I think what Doug was get-ting at is that in the PICU [pediatric
ICU] it’s bronchiolitis patients who areon that support. So it’s not a stretch tothink that something that’s infant-sizedwould work for what they want to use itfor.
DiBlasi: My research is focused onneonates, but I also work in the PICUand understand the need for noninva-sive interfaces for larger infants andsmall pediatric patients. In the PICU Iwould use this new cannula on an 8-kginfant who was doing poorly on high-flow or nasal CPAP to avoid intubation,for sure. Some folks are desperate andwould use an adult nasal cannula, but Ido not advocate that.
Wiswell: Rob,aworrywithnasalcan-nula ventilation is the variability of in-trathoracic pressure generated. In sometrials in which they measured thoracicpressure there was an inverse relation-ship: the smaller the infant, the higherthe intrathoracic pressure. A smaller pre-mature baby—say, 750–900 g—maydevelop an intrathoracic pressure of28 cm H2O or more. This worries a lotof people, as we do not routinely mea-sure intrathoracicpressure. I’mintriguedby the RAM cannula. NeoTech’s med-ical director told me they’re developinga nasal cannula that has a pressure-re-lief systemonceapressureof10cmH2Ois generated. Are you familiar with that?High intrathoracic pressure worries me.Nasal cannula for ventilation is intrigu-ing, but are we sure it’s safe for babies?
DiBlasi: I don’t know much aboutthe high-flow nasal cannula situation,other than that its use is widespreadacross the United States. But that’s aseparate issue. In babies on nasal IMV,tracheal pressure measurements have in-dicated that 30–60% of the peak air-way pressure is transmitted to the tra-chea. I would be more willing to use anasal cannula to provide nasal IMV thanhigh-flow therapy, because there is anexhalation valve regulating the pressure.We don’t know what kind of intratho-racic pressure will be generated with ahigh-flow cannula system, because flow
is monophasic and the delivered pres-sure is dependent on the patient leak.There is no pressure-relief valve in theRAM cannula, but I believe NeoTech isworking on a separate cannula design,Adina, for high-flow therapy, which re-cords proximal flow and limits pressureto around 10 cm H2O.
Wiswell: I look at the nasal IMV storyas being similar to how people jumpedon the bandwagon with high-frequencyventilation in the NICU. Similarly, therehas been a widespreadincrease in using nasal CPAP. Unfortu-nately, we have minimal supportive dataon efficacy for all of these types of re-spiratory support. In the RCTs there hasbeen minimal to no improvement in themajor outcomes, including mortality,du-ration of ventilation, BPD, and chroniclung disease. But despite the scant sup-portive data, many in neonatology areusing these therapies in everyday prac-tice.Neonatologists are“gizmo-olgists.”We like playing around with new tech-nology. This worries me. I see you hadsome of Robertson’s pictures from thebabies’ nostrils,1 of damage we can see.New therapies may cause damage weare unaware of. Before jumping on thebandwagon we need to do goodclinical trials and make sure therapiesare safe and improve patient outcomes.
Branson: This low-cost ventilatorthat you guys in Seattle have been work-ing on is very interesting. A lot of us inacademia have developed technology,butwhathappenswhenyouneedtoman-ufacture it, and you have to get an ISO[International Organization for Stan-dardization] facility to make the device,and then you need to meet FDA require-ments for alarms and validation? For acompany I’m aware of it took 7 years to
NEONATAL NONINVASIVE VENTILATION TECHNIQUES: DO WE REALLY NEED TO INTUBATE?
RESPIRATORY CARE • SEPTEMBER 2011 VOL 56 NO 9 1295
get FDA approval for a bubble-CPAPsystem.With regard to this low-costven-tilator, essentially the engineers devel-oped a Baby Bird. It’s inexpensive, butit’s 30 years behind current devices.
DiBlasi: The IMV device is separatefrom the high-amplitude bubble-CPAPdevice I showed you. Interestingly, thesedevices can be combined to provide thecontinuum of respiratory care to criti-cally ill infants with respiratory failure.Nonetheless, the requirements and reg-ulatory approach for any of these de-vices will be determined by stakehold-ers in the country where they’ll bemanufactured and used. We have in-volved neonatologists and pediatriciansfrom all over India to provide feedbackon the design of this ventilator. We’repursuing FDA approval, but this devicemay or may not be used in the UnitedStates. We are looking to use these de-vices where they do not have access tosimple respiratory-support devices, sothousands of babies die every day. Theyhave nothing. I saw this first-hand on arecent trip to India and Vietnam. Thegood news is that we have engagedstakeholders in India and we have be-gun discussing strategies for manufac-turing these devices and conducting thenecessary research in India.
Branson: What are the rules if youmake it in the United States and ship itoverseas?
Rogers:* The FDA does impose ex-port regulations on mechanical respira-tory devices. Unless the company iswholly outside the United States, thereare a lot of export regulations to gothrough to get it out of the United States.
DiBlasi: Thanks Mark. That’s inter-esting information because it conflicts alittle bit with what we’ve been told insome of these countries. At this pointour goal is to manufacture these devices
in India, conduct the necessary clinicalresearch,and thenpursueFDAapproval.Luckily, we have some donors who wantto fund this project. Many of these typesof projects fizzle out and never go any-where.
Gentile: That’s great, because neo-natology is practiced differently in thosecountries. The device you showed mighthelp. Another consideration is the abil-ity to put other gases through the sys-tem, so it has multiple purposes. Re-garding NAVA, this is great science,but it’s interesting that you presented abunch of studies in which they used theInfant Star ventilator. We’d all bring theInfant Star back, because the worlddidn’t really know how good it was un-til it was gone. So far no studies havejustified the cost of NAVA. I’m all forpatient/ventilator synchrony and spon-taneous breathing, but there’s limitedspace in the esophagus, especially in tinypatients, for a nasogastric tube and theNAVA catheter.
DiBlasi: I think NAVA is a wonder-ful innovation and has a lot of potential,but I’m a little concerned becauseNAVA is invasive. Having placed manyesophageal balloons in my time, I knowthat catheters can change position andthe signal can be lost, so I’ve wonderedif that happens during NAVA. Folkswho use NAVA feel that, since you areplacing an orogastric or nasogastric tubeanyway, that negates the invasivenessof NAVA. But a standard nasogastrictube doesn’t cost $500 or $600, so thecost of NAVA is a concern.
Is there going to be a large RCT withthe 1,000-plus patients that would proveor disprove NAVA’s clinical benefit?Who’s going to fund that study? Andwill the benefits justify the cost of thesoftware and catheters? So far, more pa-pershavebeenpublishedonNAVAthanon pressure-regulated volume control inneonates, and that’s a great start. I think8 or 9 abstracts of NAVA studies havebeen submitted to the AARC [Ameri-can Association for Respiratory Care]OPEN FORUM this year.
Gentile: Esophageal balloon forPEEP and transpulmonary pressuremeasurement are becoming common inall patient populations, and these cath-eters are combined with a nasogastric,so one tube has multiple purposes. Ifwe can get it outside the body, similarto a Graseby capsule, I think that’swhere we should be headed. Simply putthe patient on a little PEEP and letthem determine their own respiratoryrate and VT, unless they require moreassistance.
Walsh: I struggle with the science,because I think we all know that NIVmay be beneficial because you transfermore of the work of breathing to thepatient. We tend to over-ventilate intu-bated patients, even though we thinkwe’re not. What would be the ideal clin-ical trial that would show whether bub-ble CPAP is better?
DiBlasi: For our device?
Walsh: Any noninvasive device:high-frequency, NAVA, et cetera. Tome, intubation doesn’t seem to be it.
DiBlasi: Several investigators havestarted that process, and some studieshave been submitted to peer-reviewedjournals. Trying to design the perfectstudy, especially in premature neonates,is very difficult, because the practice dif-fers so much from one institution to thenext. There are such disparities in prac-tice, we don’t know if we should begiving surfactant or supporting themwith CPAP initially. If we can figureout how we’re going to give the CPAPandsurfactant, thenwecangofromtherein designing trials with NIV.
Curley: In your bubble-CPAP de-vice, why does angling the bubble tubein the water affect the oscillations?
DiBlasi: With small modifications inthe distal tubing submerged in a simpleCPAP water column, we developed aflow-interrupter device to increase the
* Mark Rogers RRT, CareFusion San Diego,California.
NEONATAL NONINVASIVE VENTILATION TECHNIQUES: DO WE REALLY NEED TO INTUBATE?
1296 RESPIRATORY CARE • SEPTEMBER 2011 VOL 56 NO 9
magnitude of high-frequency pressureoscillations delivered to the nasal air-way of infants who would otherwise failbubble nasal CPAP. By moving the bub-bler angle from conventional bubble na-sal CPAP (0 degrees) to 135 degrees inthe water-column, we found that whena bubble breaks off, the airway pressureis at its lowest point; water rushes intothe tubing and occludes it; gas flow isdirected toward the nasal airway andpressure rises; gas then drives water outof the tubing, a bubble forms, and pres-sure decreases. These pressure oscilla-tions produce enough energy to providegas exchange similar to that from a con-ventional mechanical ventilator in par-alyzed juvenile rabbits.1
This device, which we have termedhigh-amplitude bubble CPAP, has alower bubbling frequency than conven-tional bubble nasal CPAP. The lowerfrequency provides more time for theairway pressure to equilibrate with thelung pressure, to displace a larger vol-ume of gas. The frequency of conven-tional bubble CPAP is 10–20 Hz withan amplitude of 2 cm H2O. The pres-sure change with the bubbler at 135 de-grees is around 8 cm H2O. So the anglechanges the way that the water interactswith the gas, which reduces the fre-quency.
We studied this with high-speedvideo. We are able to allow the airwaypressure to equilibrate with the lung or
getcloser toequilibrating,andthatdrivesgas in and out of the lung. If you wantme to go on about the complex inter-play of the gases and the water, we cando that over a drink later.
1. DiBlasi RM, Zignego JC, Smith CV, Han-sen TN, Richardson CP. Effective gas ex-change in paralyzed juvenile rabbits usingsimple, inexpensive respiratory support de-vices. Pediatr Res 2010;68(6):526-530.
Curley: How are you going to eval-uate the device in India? Have you askedthe Gates Foundation for support in this?If anyone would be interested in im-proving outcomes in developing coun-tries, it would be them.
DiBlasi: We are identifying manu-facturers and potential research sites inIndia. The goal is to conduct multiplestudies of the device over the next5 years. We have submitted a grant pro-posal to the Gates Foundation, and oth-ers. You are correct: the Gates Founda-tion could have a huge impact inresource-limited settings.
Eiserman:† Regarding nasal cannu-las, I would say “everything old is newagain.” We’re looking at creative newuses for nasal cannulas that have a lot
of potential. We should be looking atthe limitations and opportunities thatare posed by an occlusive cannula suchas Rob is talking about for infant na-sal CPAP, versus a non-occlusive can-nula, which is what’s typically used inhigh-flow nasal cannula therapy.
We hear concerns from physicians us-ing high-flow nasal cannula that theywant to know the pressures created inthe upper airways and the alveoli. I thinkone paper looked at oropharyngeal pres-sure in an adult at flows up to 40 L/minand found very low oropharyngeal pres-sure, but perhaps enough to support theupper airways. We should determinewhat’s really happening.
One of the disadvantages, from a re-search standpoint, of looking at some-thing old in a new way is that we’vebeen using nasal cannula therapy for solong that we think it’s safe therapy.We’re seeing evidence—mostly anec-dotal—that high-flow nasal cannula issafe in most instances. Most of themhave a pressure-relief valve, which isreally getting at system pressure, be-cause it’s a high-back-pressure system,as opposed to what’s necessarily goingon in the baby’s lungs. I think it’s ex-citing to look at the use of nasal cannu-las in the ways you’ve talked about, butit begs for additional research that takesa close and careful look at what we’redoing with them.
This article is approved for Continuing Respiratory Care Educationcredit. For information and to obtain your CRCE
(free to AARC members) visitwww.RCJournal.com
† Jeri E Eiserman MBA RRT FAARC, Tele-flex Medical, Research Triangle Park, NorthCarolina.
NEONATAL NONINVASIVE VENTILATION TECHNIQUES: DO WE REALLY NEED TO INTUBATE?
RESPIRATORY CARE • SEPTEMBER 2011 VOL 56 NO 9 1297