The evidence for non-invasiveventilation in the preterm infantEduardo Bancalari, Nelson Claure

Non-invasive ventilation was among theearliest forms of respiratory support usedin infants with respiratory failure in theearly seventies.1 Its use in preterm infants,however, subsided to the use of nasal con-tinuous positive airway pressure(N-CPAP). Continuous distending pres-sure provided by N-CPAP improves oxy-genation by stabilising lung volume ininfants with respiratory distress syndrome(RDS), reduces apnoea of prematurity andattenuates distortion of the chest wallduring inspiration. The use of N-CPAP asa primary mode of respiratory support toavoid invasive ventilation and facilitateweaning from the ventilator has becomestandard practice. Although successful in alarge proportion of infants, N-CPAP isnot always effective in avoiding the needfor intubation or preventing extubationfailure.2–5 This is most evident in themore immature infants who are the onesat a higher risk of developing complica-tions associated with invasive mechanicalventilation.

Nasal intermittent positive pressureventilation (N-IPPV) is being increasinglyused in preterm infants with respiratoryfailure in lieu of or to facilitate removalfrom invasive mechanical ventilation.N-IPPV consisting of positive pressurecycles delivered on top of the continuousdistending pressure delivered by N-CPAPis used as an intermediate mode ofrespiratory support between N-CPAP andinvasive mechanical ventilation.

Several investigations have explored thephysiological and clinical effects ofN-IPPV in preterm infants. This manu-script describes the evidence provided bythese studies and discusses the areaswhere further research is needed.

PHYSIOLOGICAL EFFECTSThe proposed mechanisms by whichN-IPPV may enhance the support pro-vided by N-CPAP include increased venti-lation, higher mean airway pressure,

washout of the upper airway anatomicaldead space and a possible stimulatoryeffect of intermittent cycling on therespiratory drive.Although it is difficult to determine

what portion of the positive pressure istransmitted to the distal airways duringN-IPPV, physiological data from studiesinvolving the use of N-IPPV in preterminfants shortly after extubation showedincreased ventilation and reducedPaCO2.

6 7 The improved ventilation wasaccompanied by reductions in breathingeffort and frequency.7

In more stable infants N-IPPV canunload the respiratory pump withoutinducing changes in ventilation or gasexchange. The use of N-IPPV in patienttriggered modalities such as nasal assist/control, pressure support or synchronisedintermittent mandatory ventilationdecreased the breathing effort comparedwith N-CPAP.8–10 In these infants whowere able to maintain their own ventila-tion on N-CPAP, N-IPPV did not improveventilation. However, in infants with ahigher baseline PaCO2, N-IPPV didincrease ventilation when compared withN-CPAP.9 This observation suggests agreater benefit of N-IPPV in infants withsome degree of ventilatory failure orthose struggling to maintain adequate ven-tilation on N-CPAP alone.Distortion of the preterm infant’s soft

chest wall during inspiration was attenu-ated by synchronised N-IPPV comparedwith N-CPAP.9 11 This is most likely theresult of the synchronous increase inairway pressure and a decrease in inspira-tory effort.Nasal bi-level positive airway pressure

(N-BiPAP) is a form of nasal ventilatory

support where airway pressure increasesmodestly above the basal N-CPAP levelintermittently. Depending on the durationof the cycle, frequency and pressurechange, N-BiPAP can be considered asproviding either two levels of CPAP orN-IPPV. A possible advantage offered bythe intermittent increase in airway pres-sure is better lung recruitment andvolume stability while avoiding the sideeffects of a continuously applied highN-CPAP level. In preterm infants,N-BiPAP produced a decrease in transcu-taneous PCO2 and an increase in oxygen-ation which was likely the result of lungrecruitment due to the higher distendingairway pressure.12

CLINICAL EFFECTS OF N-IPPVApnoeaIn short term studies, N-IPPVappears to bemore effective than N-CPAP in reducingthe occurrence of apnoea among prematureinfants who present with frequent apnoeaspells but less consistent among infant withinfrequent spells6 13 14 (table 1). Trials com-paring N-IPPV and N-CPAP after extuba-tion describe severe apnoea as a commoncause of extubation failure among infantsreceiving N-CPAP. The findings of thesetrials are discussed later.

Respiratory distress syndromeClinical reports indicate that N-CPAPfailure rates and the need for subsequentmechanical ventilation in small preterminfants with RDS ranges from 20 to morethan 50%.2–5 Consequently, there is con-siderable interest in the use of N-IPPV inthis population during the initial phase ofrespiratory failure to avoid the use ofinvasive ventilation.

Randomised controlled trials in infantswith mild to moderate RDS have shownthat N-IPPV is more effective thanN-CPAP in reducing the need for invasiveventilation during the first week afterbirth15–19 (table 2). The relative efficacyof N-IPPV over N-CPAP varied

Table 1 N-IPPV versus N-CPAP in apnoea

Population Outcome N-CPAP N-IPPV p Value

Ryan 1989 n=20GA: ≤32 w

Apnoea frequency 0.6±0.7 0.5±0.7 NS

Lin 1998 n=18GA: 25–32 w

Apnoea frequency 3.5 (2.3–6.8) 0.8 (0.0–5.0) 0.02

Bisceglia 2007 n=88GA: 28–34 w

Apnoea frequency 0.9±0.2 0.4±0.3 <0.05

Apnoea frequency in spells per hour.GA, gestational age; N-CPAP, nasal continuous positive airway pressure; N-IPPV, nasal intermittent positive pressureventilation.

Division of Neonatology, Department of Pediatrics,University of Miami Miller School of Medicine, Miami,Florida, USA

Correspondence to Dr Eduardo Bancalari, Division ofNeonatology, Department of Pediatrics, University ofMiami Miller School of Medicine, P.O. Box 016960R-131, Miami, FL 33101, USA; Ebancalari@miami.edu

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considerably between studies, which maybe explained by different entry criteriaand other respiratory interventions. Thesestudies enrolled infants of gestational ageranging from 24 to 34 weeks and useddifferent criteria to define RDS severity.Hence, the populations may differ interms of risk for N-CPAP failure. Some ofthese studies involved a brief intubationperiod and administration of surfactantwhich likely provided a significant benefitto the subjects and also reduced the riskof failure.

In spite of the reduced need for mech-anical ventilation, the effects of N-IPPVon respiratory outcome have not beenconsistent among the different trials ininfants with mild or moderate RDS15–19

(table 2). Some of these trials showedstriking reductions in the incidence ofbronchopulmonary dysplasia (BPD) withN-IPPV compared with N-CPAP whileother studies showed no or small differ-ences. The reasons for these discrepanciesare unclear, but they may be related to dif-ferences in the populations enrolled inthese studies. The impact of N-IPPV in

infants with mild RDS who are likely todo well on N-CPAP alone is expected tobe smaller than in infants who are failingN-CPAP and therefore have a greater needfor invasive ventilation.The use of N-IPPV to support early

extubation after a brief intubation andsurfactant administration was shown aseffective as continued invasive ventilationwith later extubation and better thanN-CPAP on the success of early extuba-tion.19 20 In these studies the incidence ofBPD was considerably lower.

PostextubationThe advantage of N-IPPV compared withN-CPAP in reducing the failure rates afterextubation has been consistently shown inmultiple randomised trials21–24 (table 3).In these trials, severe apnoea andincreased PaCO2 were the most commoncauses of failure in infants receivingN-CPAP and a larger reduction in extuba-tion failure with N-IPPV was observedamong the smaller premature infants andthose with worse lung mechanics.23

The reported rates of BPD in mostpostextubation trials have been lower inN-IPPV compared with N-CPAP.22–24

However, although well controlled, thesestudies were not individually powered todetect significant differences in BPD.Nonetheless, their consistency suggestsimportant advantages of N-IPPV overN-CPAP when used after extubation.24

A preliminary report from the largestrandomised controlled trial comparingN-IPPV and N-CPAP in the early phase ofrespiratory failure or after mechanicalventilation was completed recently. Theprimary outcome, death or BPD, did notdiffer between the two treatments. In theentire group of infants or between infantsenrolled during the first week and thoseenrolled after extubation.26 Further ana-lyses of these data are likely to provide abetter understanding of the effects ofN-IPPV and the factors that determine itsefficacy.

The clinical evidence provided by thestudies mentioned above indicate N-IPPVis as or more effective than N-CPAP inreducing the need for invasive ventilationor achieving successful weaning from theventilator. Contrary to what was expected,these findings however did not correlatewith clear improvements in long termrespiratory outcome.

Because most of the N-CPAP failureand the side effects of invasive mechanicalventilation occur in the more prematureinfants, there is considerable interest infurther evaluating the effects of N-IPPV inthe smaller and more immature infantswith moderate or severe respiratoryfailure who are at a higher risk of intub-ation and BPD. N-IPPV is not likely tooffer significant advantages to prematureinfants in whom the support provided byN-CPAP alone is sufficient. There is also aneed to further assess if N-IPPV can be aseffective and safer than invasive ventila-tion when used as the primary modalityearly after birth.

N-IPPV TECHNIQUES AND OTHERCONSIDERATIONSThe patency of the upper airway plays animportant role in the transmission of thepositive pressure to the distal airwaysduring N-IPPV. Synchronised delivery ofthe N-IPPV cycles to the infant’s inspir-ation is believed to increase the efficacy ofN-IPPV because upper airway abductormechanisms are expected to assurepatency of the airway ahead of the onset ofinspiration. However, definitive data onthe advantages of synchronised N-IPPVarelacking. We have demonstrated that inpreterm infants receiving N-CPAP,

Table 2 N-IPPV versus N-CPAP in respiratory distress syndrome

Population Outcome N-CPAP N-IPPV p Value

Kugelman 2007 n=84GA: 24–34 w

FailureBPD

49%17%

25%2%

0.040.04

Sai Sunil Kishore 2009 n=76GA: 28–34 wBW: ≥750 g

FailureBPDDeath or BPD

41%10%31%

19%3%16%

0.036NS*NS*

Lista 2010 n=40GA: 28–34 w

FailureBPD

15%0

10%0

NSNS

Meneses 2011 n=200GA: 26–33 w

FailureBPDDeath or BPD

34%5%42%

25%11%40%

NSNS*NS†

BPD: Defined as oxygen supplementation at 36 weeks postmenstrual age; Failure: Defined as need for intubation.*Estimated from published data.†Author’s personal communication.BPD, bronchopulmonary dysplasia; BW, birth weight; GA, gestational age; N-CPAP, nasal continuous positive airwaypressure; N-IPPV, nasal intermittent positive pressure ventilation.

Table 3 N-IPPV versus N-CPAP postextubation

Population Outcome N-CPAP N-IPPV p Value

Friedlich 1999 n=41BW: 500–1500 g

Failure 37% 5% 0.016

Barrington 2001 n=54BW: ≤1250 g

FailureBPD

44%56%

15%44%

<0.05NS

Khalaf 2001 n=64 Failure 40% 6% <0.01GA: ≤34 w BPD 53% 35% NS

Moretti 2008 n=63BW: ≤1250 g

FailureBPDDeath or BPD

39%22%32%

6%6%16%

<0.01NSNS*

BPD: Defined as oxygen supplementation at 36 weeks postmenstrual age; Failure as per defined criteria or need forre-intubation.*Estimated from published data.BPD, bronchopulmonary dysplasia; BW, birth weight; GA, gestational age; N-CPAP, nasal continuous positive airwaypressure; N-IPPV, nasal intermittent positive pressure ventilation.

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ventilation did not improve with synchro-nised or non-synchronised N-IPPV, prob-ably reflecting a relatively good basal lungfunction in the study infants. SynchronisedN-IPPV reduced the spontaneous breath-ing effort whereas non-synchronisedN-IPPV did not, as illustrated in figures 1and 2. These findings suggest pressuretransmission during N-IPPV is improvedby synchronisation, but additional investi-gation is required to determine whethersynchronisation may offer advantages insicker infants who struggle to maintainadequate ventilation on N-CPAP.

Most physiological studies and clinicaltrials describing positive physiological orclinical effects of N-IPPV involved syn-chronised delivery of the positive pres-sure. However, the ventilator capable ofproviding synchronised N-IPPV used inthe majority of these trials is no longeravailable while other synchronised devicesare only available in some countries.Conversely, most studies showing lessstriking effects used non-synchronisedN-IPPV. Although this observation doesnot provide evidence of the benefits ofsynchronisation, it underlines the need tofurther explore this issue.

Detection of the onset and ending ofthe spontaneous inspiration with sufficientsensitivity to assure timely delivery of thepressure cycle and sufficient specificity toavoid auto-cycling is important in N-IPPV.The Graseby pressure capsule used inmany trials of N-IPPV is a non-invasivemethod that can provide adequate syn-chrony when placed properly. Our data

indicate more than 90% of N-IPPV cycleswere properly synchronised when usingthis method.10 In contrast, during non-synchronised N-IPPV only 25% of thecycles are synchronous with the onset ofthe infant’s inspiration while other investi-gators have shown that the preterminfant’s breathing frequency does notbecome entrained with the ventilator fre-quency during non-synchronisedN-IPPV.27

Other methods of synchronisationinvolve detection of the spontaneousinspiratory flow of the infant. This

however may be affected by the large andvariable gas leaks that are commonlypresent during N-IPPV. Increased gasleakage mimic spontaneous inspiratoryflow and can result in auto-cycling.Although this can be compensated bymanual or automatic adjustment of theflow trigger threshold in the ventilator,there are no published data on the efficacyof the compensatory adjustments. Newertechnologies are being developed andtested to improve infant-ventilator syn-chrony during N-IPPV. One of these,neurally adjusted ventilatory assist, usesthe electrical activity of the diaphragm todetermine the timing and magnitude ofthe ventilator pressure during N-IPPV.This modality has not been fully exam-ined in preterm infants receiving non-invasive ventilation.

At present, the most common modalityused to provide N-IPPV is non-synchronised. However, there are no dataon the most adequate settings of ventila-tor frequency, pressure and inspiratorytime. This is largely due to the lack ofmonitoring parameters that would indi-cate the adequacy of ventilation otherthan visual assessment of chest expansionand blood gases to guide the adjustmentof the ventilator settings during N-IPPV.One limiting factor is gas leakage aroundthe nasal interface and through the mouthwhich prevents accurate estimation of theinspiratory or expiratory tidal volume.

The clinical benefits of N-IPPV andtransmission of the positive pressure inindividual patients vary considerably.Further investigation is needed to identifythe subgroups of infants that may benefit

Figure 1 Recordings of oesophageal (PES), airway pressure (PAW) and tidal volume (VT) byrespiratory inductance from an infant during synchronised nasal intermittent positive pressureventilation illustrate the reduction in inspiratory effort (arrows indicate smaller negative deflectionin PES) with every ventilator cycle while tidal volume remains largely unchanged (reproduced fromChang et al10).

Figure 2 Recordings of oesophageal (PES), airway pressure (PAW) and tidal volume (VT) byrespiratory inductance from an infant during non-synchronised nasal intermittent positive pressureventilation illustrate the increase in expiratory effort (arrows indicate positive deflection in PES)and prolongation of expiration with ventilator cycles that fall too late during the spontaneousrespiratory cycle (reproduced from Chang et al10).

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more and the conditions that prevent orfacilitate transmission of the N-IPPVpressure.

Proper application of N-IPPV can playa significant role in the success of thisstrategy in the individual infant. Atpresent time, N-IPPV is generally pro-vided by conventional neonatal ventilatorswith standard tubing and gas conditioningsystems and applied to the patient usingthe same interfaces used for N-CPAP.Conventional ventilators usually maintainthe end-expiratory and peak pressure witha user-set constant circulating flow.Increased gas leakage or opening of themouth can result in pressure loss unlessthe circuit flow is manually increased.Newer ventilators can adjust the circulat-ing flow to assure the set pressures areachieved.

Another important aspect is the properconditioning of the inspired gases.Insufficient humidity can lead to damageand obstruction of the air passages bymucus plugs which may render N-IPPV orN-CPAP ineffective. For this reason, fre-quent verification of the patency of the airpassages is critical during any type ofnasal support.

An area that needs further improvementis the patient interface. Although the carehas markedly improved, it is not uncom-mon to find nasal injuries due to excessivepressure applied to keep the interface inplace or because the interface itself pro-duces torque on the infant’s nasal septum.Development of better interfaces alongwith smart monitoring methods to detectpatient disconnection, large leaks or flowobstruction are needed.

Although there were early concerns ofincreased risk of gastrointestinal perfor-ation with the use of N-IPPV,28 recentclinical trials have not confirmed thesefindings or increased risks of pulmonaryinterstitial emphysema or pneumothorax.

IN SUMMARYThe available evidence on the advantagesor disadvantages of non-invasive ventila-tion in the premature infant indicatesimportant physiological advantages com-pared with N-CPAP. Evidence from clin-ical trials indicates non-invasiveventilation is more effective than N-CPAPin infants with apnoea, in reducing theneed for intubation in mild to moderateRDS and in improving the success ofextubation. In spite of these findings, non-invasive ventilation has not been provento confer significant advantages withregard to long term respiratory outcomebut there is no evidence that N-IPPV is

accompanied by increased risk of adverseevents.Further research is needed to determine

the advantages of N-IPPV over N-CPAP ina target population that is at a higher riskof intubation and poor respiratoryoutcome. This should be extended toinvestigate whether primary use of non-invasive ventilation soon after birth canprovide comparable or better results thaninvasive ventilation. Analysis of existingand future data from clinical trials shouldbe expanded to examine the effects onthe incidence of the more severe forms ofBPD.Development and testing of newer tech-

nologies to improve patient interfaces, tosynchronise the ventilator with the patientand to improve transmission of the posi-tive pressure are also needed. This shouldbe accompanied by further investigationof conditions that increase or limit theefficacy of non-invasive ventilatorysupport.

Acknowledgements We acknowledge thelongstanding support of the University of Miami ProjectNewBorn.

Funding University of Miami Project: NewBorn

Competing interests None.

Provenance and peer review Not commissioned;externally peer reviewed.

To cite Bancalari E, Claure N. Arch Dis Child FetalNeonatal Ed 2013;98:F98–F102.

Received 6 June 2012Revised 6 June 2012Accepted 30 July 2012Published Online First 8 September 2012

Arch Dis Child Fetal Neonatal Ed 2013;98:F98–F102.doi:10.1136/archdischild-2011-301266

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doi: 10.1136/archdischild-2011-301266published online September 8, 2012

2013 98: F98-F102 originallyArch Dis Child Fetal Neonatal Ed Eduardo Bancalari and Nelson Claure the preterm infantThe evidence for non-invasive ventilation in

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