Nasal Intermittent Positive Pressure Ventilation for Neonatal Respiratory Distress Syndrome

Nasal Intermittent Positive Pressure Ventilation for Neonatal Respiratory Distress SyndromeNeonatal Respiratory Distress Syndrome
Christoph M. Rüegger, MDa,*, Louise S. Owen, MD, FRACPb,c,d, Peter G. Davis, MD, FRACPb,c,d
KEYWORDS
KEY POINTS
Two device types have typically been used to deliver NIPPV: ventilators and flow-drivers, both devices can incorporate the option to synchronize pressure changes with sponta- neous breathing.
Ventilator-generated NIPPV is traditionally set up to deliver NIPPV with settings mimicking settings used during endotracheal ventilation.
Flow-driver-generated NIPPV may also be set up in this manner, albeit with lower peak pressures, but it is more typically used with settings reflective of bilevel CPAP.
Overall, NIPPV is superior to CPAP as primary and postextubation support for the preven- tion of respiratory failure in preterm infants, especially when ventilator-generated, syn- chronized NIPPV is used.
Ventilator-generated, synchronized NIPPV as either primary or postextubation support in preterm infants may reduce the risk of bronchopulmonary dysplasia, but is not associated with a decrease in mortality.
INTRODUCTION
In the past, preterm infants with signs of moderate or severe respiratory distress were intubated and mechanically ventilated. This invasive approach resulted in inflamma- tion of the lungs in the short-term and impaired development and scarring known as bronchopulmonary dysplasia (BPD) in the long-term.1 Efforts to decrease rates
a Newborn Research, Department of Neonatology, University Hospital Zurich, University of Zurich, Frauenklinikstrasse 10, Zurich 8091, Switzerland; b Newborn Research Centre and Neonatal Services, The Royal Women’s Hospital, Melbourne, Australia; c Department of Ob- stetrics and Gynaecology, The University of Melbourne, Melbourne, Australia; d Clinical Sci- ences, Murdoch Children’s Research Institute, Melbourne, Australia * Corresponding author. E-mail address: [email protected]
Clin Perinatol 48 (2021) 725–744 https://doi.org/10.1016/j.clp.2021.07.004 perinatology.theclinics.com 0095-5108/21/ª 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
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of BPD in the surfactant/antenatal steroid era have led to an increased use of nonin- vasive respiratory support for even the most immature infants.2
Prophylactic nasal continuous positive airway pressure (CPAP), started soon after birth, is now recommended for spontaneously breathing very preterm or very low- birth-weight infants with respiratory distress syndrome (RDS).3 Prophylactic CPAP re- duces the need for mechanical ventilation and surfactant administration, and lowers the rates of both BPD alone and the combined outcome of death or BPD when compared with immediate endotracheal ventilation.3
Despite the physiologic and clinical benefits, CPAP failure rates remain at approx- imately 50% in the first week of life in extremely preterm newborns at highest risk for developing BPD.4–7 CPAP failure is associated with a substantial increase in impor- tant adverse outcomes including air leak, BPD, intraventricular hemorrhage, and death.8
As a result, methods to augment the effectiveness of CPAP have gained interest.9
Noninvasive intermittent positive pressure ventilation (NIPPV) applied at the nose has become a well-established therapy for preterm infants.10 Despite its frequent use, uncertainty remains regarding the precise terminology, the appropriate clinical in- dications, the different devices and techniques used to generate NIPPV, and the level of benefit they provide. These differences complicate the interpretation of the available evidence.11,12 In this review, we address these uncertainties, with a particular focus on NIPPV as primary and postextubation respiratory support for preterm infants with RDS. For both indications, we summarize the current evidence from randomized controlled trials (RCTs) comparing NIPPV with CPAP.
NASAL INTERMITTENT POSITIVE PRESSURE VENTILATION Terminology
NIPPV is a form of noninvasive respiratory support that combines a continuous pos- itive end-expiratory airway pressure (PEEP) with intermittent higher pressures deliv- ered by a nasal mask or nasal prongs. The terminology surrounding NIPPV is confusing. There are many alternative pressure generating devices, interfaces, and settings available. In addition, some devices allow synchronization with the infant’s own breathing efforts. The most common abbreviations include nsNIPPV (non- synchronized NIPPV), sNIPPV (synchronized NIPPV), BiPAP (biphasic CPAP), bilevel CPAP, and bilevel NIPPV. Although all these modes are considered forms of NIPPV, 2 main NIPPV modalities
must be distinguished: traditional NIPPV, with settings designed to mimic ventilator settings, typically generated using a ventilator, or alternatively settings that are more reflective of bilevel CPAP, typically generated using flow-drivers. There are devices of both types which have the capacity to synchronize pressure changes with sponta- neous breathing (Table 1).
Pressure and Volume Delivery
The lower pressure level (PEEP) during NIPPV offers the same physiologic benefits as CPAP, that is, stabilization of the upper airways and the compliant preterm chest wall and prevention of end-expiratory alveolar collapse. This maintains functional re- sidual capacity and reduces ventilation-perfusion mismatch, which improves oxygenation and work of breathing. The intermittent pressure peaks increase the mean airway pressure (MAP) above the PEEP level, potentially further recruiting the lung, which may improve functional residual capacity more efficiently than CPAP alone.13
Table 1 Characteristics of ‘traditional’ NIPPV and bilevel CPAP18,22,33
‘Traditional’ NIPPV Bilevel CPAP
Device Mostly ventilator, can be flow-driver with lower peak pressure settings
Flow-driver
Independent breathing on two PEEP levels
Interface Short binasal prongs, nasal masks, nasopharyngeal tubes Short binasal prongs, nasal masks
Maximum pressure Similar to endotracheal ventilation, usually 25 cm H2O 11–15 cm H2O, depending on operating modea
Peak and PEEP pressure difference
5 cm H2O 4 cm H2O
High pressure delivery rate Variable (10–60 per min) Low (10–30 per min)
High pressure duration Short (<0.5 s) Long (0.5–1 s)
Synchronization Possible, available with some ventilators Possible, usually not intended, available with some devices
Method of synchronization Pneumatic capsule (eg, Graseby), flow sensor, pressure sensor, neurally adjusted ventilator assist (NAVA)
Pneumatic capsule (eg, Graseby)34
Pressure curves
a Infant Flow SiPAP (Vyaire Medical, Mettawa, Il, USA): theoretic maximum at 11 cm H2O if nonsynchronized and at 15 cm H2O if synchronized, although delivered pressures are often well below these maximums.9,19
N a sa l In te rm
itte n t P o sitive
P re ssu
tio n
7 2 7
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Because of large and variable leaks around the nose and mouth, the transmission of applied NIPPV pressures to the lung is substantially attenuated.14,15 Moreover, observational studies demonstrate that the majority of nonsynchronized pressure peaks occur during spontaneous expiration and do not contribute to tidal volume.16
When the pressure rises coincided with spontaneous inspiration, only a 15% in- crease in relative tidal volume was noted. During apneic episodes, pressure peaks resulted in measurable tidal volumes only 5% of the time, and produced tidal vol- umes a quarter of those seen during spontaneous breathing. Higher peak inspiratory pressures did not increase the likelihood of a visible chest inflation, suggesting that higher set pressures may not provide additional respiratory assistance during apnoea.16
Whether nonsynchronized NIPPV confers any benefit over CPAP when the PEEP during CPAP is matched to the generatedMAP during NIPPV is still a matter of debate. A small crossover study including 10 infants on nonsynchronized NIPPV and CPAP delivered at the same MAP found minimal differences in short-term outcomes, sug- gesting that any advantage of nonsynchronized NIPPV may arise from a higher MAP rather than from the effect of the intermittent pressure peaks themselves.13
Synchronization
Observations of low pressure and volume delivery during nonsynchronized NIPPV suggest support may be more effective if inflations are synchronized with the infant’s own inspiratory efforts. Synchronization may be achieved by airway flow detection, which ensures that the glottis is open before pressure is applied.17 However, this is challenging because of air leakage around the prongs and masks and from the open mouth. Graseby capsules are unaffected by air leak, but may be affected by movement artifact; however, they are the most commonly used method for NIPPV synchronization.18 These cheap, lightweight, and disposable capsules are noninva- sively attached to the anterior abdominal wall below the xiphoid process; they consist of a small, flat balloon filled with air, which is sensitive to pressure variations. The balloon connects to a pressure transducer capable of detecting the beginning of the diaphragmatic contraction, which enables the synchronization of the pressure peak. Although the accuracy of the Graseby capsule is affected by its position, method of fixation, and movement artifacts, it produces reliable signals that rapidly trigger the set pressure peak with most spontaneous breaths.19–21 Other potential synchronization methods include neurally adjusted ventilatory assist, currently avail- able with the Servo-n ventilator (Maquet, Solna, Sweden) and respiratory inductance plethysmography.22
Safety
Although there were initial concerns regarding an increased risk of gastrointestinal side effects with NIPPV, recent evidence suggests that NIPPV is a safe therapy in pre- term infants.23 This has been confirmed by 2 systematic reviews of the Cochrane Collaboration on NIPPV for initial support of neonatal RDS and for preterm infants after extubation.11,12 Both reviews reported no significant differences between the NIPPV and CPAP groups in rates of feeding intolerance, gastrointestinal perforation, necro- tizing enterocolitis, or air leak. The incidence of nasal injury through tight-fitting binasal prongs has not been assessed systematically for infants receiving NIPPV. Since the risk of nasal injury, and the strategies to prevent it are considered the same for NIPPV and CPAP, use of nasal masks, rotating nasal interfaces, and nasal barrier dressings may be equally effective in reducing nasal injury during NIPPV.24
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CLINICAL EVIDENCE
The majority of clinical trials in preterm infants have compared NIPPV with CPAP as either the primary mode of treatment for neonatal RDS, or after extubation. Of these trials, Kirpalani’s NIPPV Trial dominates the literature.25 This large, pragmatic trial dif- fers from the smaller studies in that it recruited a heterogeneous study population and permitted a variety of devices to deliver NIPPV, including some that delivered synchro- nized pressure changes. Although pragmatic, the considerable degree of methodo- logical and clinical heterogeneity makes interpretation of pooled trial results difficult. To evaluate the impact of these variations, we begin with a review of Kirpalani’s NIPPV Trial and its substudies, and provide updated meta-analyses of trials comparing NIPPV with CPAP as primary or postextubation support for neonatal RDS.
Kirpalani’s Nasal Intermittent Positive Pressure Ventilation Trial
This large randomized, controlled, multicenter trial conducted between 2007 and 2011 hypothesized that NIPPV would reduce the risk of BPD in extremely low-birth-weight infants by minimizing the duration of endotracheal intubation.25 Infants with a birth weight of less than 1000 g and a gestational age of less than 30 weeks, eligible for noninvasive support within the first 28 days of life, were randomly assigned to 1 of 2 forms of noninvasive respiratory support, NIPPV or CPAP. Initial settings for respira- tory support were provided, but not mandated and clinicians could individualize care. No NIPPV delivery devices were specified, NIPPV synchronization was permitted but not mandated. The primary outcome was a composite of death or mod- erate/severe BPD according to National Institutes of Health criteria.26 Three pre- planned subgroup analyses were performed according to birth weight, prior intubation status (intubated or nonintubated before randomization), and the form of the intervention used in the NIPPV group (synchronized or nonsynchronized). A total of 1009 infants with a mean gestational age of 26 weeks and a mean birth
weight of 800 g were enrolled. The primary outcome, death or BPD occurred in 38.4% (191 of 497 infants) randomized to NIPPV and in 36.7% (180 of 490) random- ized to CPAP (adjusted odds ratio, 1.09; 95% confidence interval [CI], 0.83–1.43; P 5 .56). There were no significant differences between NIPPV and CPAP in the indi- vidual components of death or BPD, in other prespecified secondary outcomes including potential adverse effects of treatment, or in the subgroup analyses accord- ing to birth weight, prior intubation status, or synchronization. In the years following the publication of Kirpalani’s NIPPV Trial results, 2 secondary
analyses have been published with the following aims: (1) to examine whether important outcomes differed in infants who received ventilator-generated or flow-driver-generated NIPPV, and (2) to compare noninvasive ventilation failure rates in intubation-nave extremely low-birth-weight infants randomized to NIPPV or CPAP.27,28
Substudy 1: ventilator-generated versus flow-driver-generated nasal intermittent positive pressure ventilation This nonrandomized comparison from Kirpalani’s NIPPV Trial provides outcome data on the 497 infants in the NIPPV group.27 NIPPV could be delivered by a ventilator or a flow-driver device based on unit preference, practice, and device availability. Irrespec- tive of the device, traditional NIPPV settings or bilevel CPAP settings could be used. In the NIPPV group, 215 infants received ventilator-generated NIPPV and 241 received flow-driver-generated NIPPV. Forty-one infants, in whom both devices had been used, were excluded. The composite outcome, death or BPD at 36 weeks was 39% in the ventilator-generated NIPPV group and 37% in the flow-driver-generated NIPPV group (adjusted odds ratio, 0.88; 95% CI, 0.57–1.35; P 5 .56). Although rates of BPD
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were not significantly different between groups (adjusted odds ratio, 0.64; 95% CI, 0.41–1.02; P 5 .061), more deaths occurred before 36 weeks gestational age in the flow-driver-generated NIPPV group (2.3% vs 9.4%; adjusted odds ratio, 5.01; 95% CI, 1.74–14.4; P 5 .003).
Substudy 2: nasal intermittent positive pressure ventilation versus continuous positive airway pressure in intubation-nave infants The second substudy compared the rate of ‘failure of noninvasive support’ in infants who were never intubated before enrollment and randomization.28 As opposed to the original trial and substudy 1, the primary outcome was defined as failure of noninva- sive respiratory support requiring endotracheal intubation at any time in the first 7 days after randomization. Of the 1009 extremely low-birth-weight infants initially enrolled in the NIPPV trial, 142 had not been intubated before randomization. Of those, 27.5% in the NIPPV group and 30.1% in the CPAP group were subsequently intubated (relative risk, 0.91; 95% CI, 0.54–1.53). The combined outcome of death or BPD at 36 weeks postmenstrual age was not different between groups (19.7% vs 16.7%; risk ratio, 1.18; 95% CI, 0.58–2.40). There was no significant difference in rates of air leak.
What do the results of Kirpalani’s nasal intermittent positive pressure ventilation trial and its substudies mean? In contrast with the results obtained from the pooled analysis of smaller trials that favored the use of NIPPV in preterm infants, Kirpalani’s NIPPV trial and its substudies found no significant benefit of NIPPV with respect to the risk of death or survival without BPD.11,12,29–31 There may be several reasons for the differences in findings. First, more immature infants were included in Kirpalani’s NIPPV trial (Tables 2 and 3); failure of noninvasive support is more prevalent in extremely preterm infants and is associated with a marked increase in the rate of adverse outcomes, including death and BPD.4,8 In such a high-risk population with RDS due to surfactant-deficient lungs, collapsing airways and poor muscle strength, a number of infants may still be inadequately supported with NIPPV despite the modest increase in MAP provided by additional positive pressure breaths. Second, the pragmatic trial design did not specify the ventilator device, settings, or use of synchronization. In the NIPPV group, approximately half of infants received flow-driver-generated NIPPV, typically set to deliver modest peak pressures, lower than pressures set during ventilator- generated NIPPV. Indeed, mortality was higher in infants who mostly received flow- driver-generated NIPPV, possibly due to a higher reintubation rate compared with infants receiving ventilator-generated NIPPV (adjusted rate ratio for number of reintu- bations, 1.23; 95% CI, 1.02–1.49).27 Moreover, a subgroup analysis by synchroniza- tion rather than by device revealed that ventilator-generated NIPPV was mostly applied in a nonsynchronized manner, and synchronization was more often used dur- ing flow-driver-generated NIPPV (suggesting that traditional NIPPV settings with short high-pressure durations were still commonly used during flow-driver-generated NIPPV, cf. Table 1). Both combinations of device and technique may be associated with a lack of effective pressure transmission to the lungs, and may contribute to the finding of no significant benefit of NIPPV.
Meta-Analyses of Trials Comparing Nasal Intermittent Positive Pressure Ventilation with Continuous Positive Airway Pressure
The updated meta-analyses were performed using RevMan, version 5.4.32 Relevant studies were identified by searching PubMed, The Cochrane Library, and the refer- ence lists of included articles. Studies were included if they were RCTs that enrolled
Table 2 Trials comparing NIPPV with CPAP for primary respiratory support (by device and synchroniza on)
Mean GAa
NIPPV CPAP
High Pressure Delivery Rate [per minute] PEEPb [cm H2O]
PEEPb
1.1.1 Ventilator-generated, nonsynchronized NIPPV
Bisceglia et al,35 2007 NDAc No 1 14–20 ND c 40 4–6 4–6
Sai Sunil Kishore et al,36 2009 30.8 Mixed 2, 3 15–26 0.3 0.35 50–60 5–6 5–7
Meneses et al,37 2011 29.6 No 4 15–20 0.4 0.50 20–30 4–6 5–6
Armanian et al,38 2014 30.0 No 4 16–20 0.4 40–50 5–6 5–6
Oncel et al,39 2015e 29.2 No 5 15–20 ND c 20–30 5–6 5–6
Sabzehei et al,40 2018e 30.1 Yes 4 14–20 0.3 0.35 30–50 5–6 5–6
Skariah & Lewis,41 2019e 31.8 No 2 11–18 0.3 0.40 18–30 3–5 3–5
1.1.2 Ventilator-generated, synchronized NIPPV
Kugelman et al,42 2007 30.9 No 5 14–22 0.3 12–30 6–7 6–7
Salama et al,43 2015 31.2 Mixed 6 5–12 0.3 0.50 15–18 4–6 6
Dursun et al,44 2019e 29.3 No 5 16–24 0.4 30–40 6–8 6–8
Gharehbaghi et al,45 2019e 30.1 No 7 18–20 0.3 0.40 30–40 5–6 5–6
1.1.3 Flow-driver-generated, nonsynchronized NIPPV
Kong et al,46 2012e 32.9 No 8 12–15 0.3 0.50 20–30 4–6 4–6
Aguiar et al,47 2015e 31.0 No 9 8 2 10 6 6–8
Sadeghnia et al,48 2016e 29.9 No 10 8 0.5 30 4 6
1.1.4 Flow-driver-generated, synchronized NIPPV
Lista et al,49 2010 30.3 Yes 9 8 0.5 0.70 30 4.5 6
Wood et al,50 2013 29.8 No 9 6–9 0.3 10 4–6 4–6
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itte n t P o sitive
P re ssu
tio n
NIPPV CPAP
High Pressure Duration [s]
PEEPb
1.1.5 Mixed methods
Ramanathan et al,51 2012 27.8 Yes 9, 11 15–20 0.50 30–40 5 5–8
Kirpalani et al,25 2013 26.2 No 2, 3, 9 18d 0.30–0.50d 10–40d 5–8d 5–8d
a GA, gestational age. b PEEP, positive end expiratory pressure. c NDA, no data available. d Suggested initiating and maximal settings. e Trials not yet included in the corresponding meta-analysis of the Cochrane Collaboration. f 1: Bear Infant Ventilator CUB 750 (Ackrad Laboratories, Cranford, NJ, USA). 2: Drager Babylog 8000 (Drager Medical Inc, Lubeck, Germany). 3: VIP Bird-R Sterling (Vyaire Medical, Il, USA). 4: Continuous flow ventilator, not specified. 5: SLE 2000 (Specialised Laboratory Equipment, Croydon, UK). 6. Neoport E100 M (DRE Med- ical, Louisville, KY, USA). 7: Inspiration 5i ventilator (eVentMedical Ltd, Ireland). 8: BiPAP device, not specified. 9: Infant Flow SiPAP System (VyaireMedical, Il, USA). 10: Fabian (Acutronic Medical Systems AG, Hirzel, Switzerland). 11: Avea CVS Ventilator (Vyaire Medical, Il, USA).
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Table 3 Trials comparing NIPPV with CPAP for postextubation support (by device and synchronization)
Mean GAa at Birth [wk] Deviceg
NIPPV CPAP
High Pressure Duration [s]
High Pressure Delivery Rate [per minute] PEEPb [cm H2O] PEEPb [cm H2O]
1.2.1 Ventilator-generated, nonsynchronized NIPPV
Khorana et al,52 2008 NDAc 1 Pre-extd Pre-extd Pre-extd Pre-extd Pre-extd
Kahramaner et al,53 2014 28.8 2 Pre-extd 12 NDAc 25 6 6
Jasani et al,54 2016 30.7 1 Pre-extd 14 NDAc Pre-extd 5 5–6
Komatsu et al,55 2016f 30.8 3 16 NDAc 12 6 6
Ribeiro et al,56 2017f 29.6 4 14–16 0.30–0.35 12–18 4–6 4–5
Estay et al,57 2020f 27.9 5 12–18 0.45–0.60 20 5–6 5–6
1.2.2 Ventilator-generated, synchronized NIPPV
Friedlich et al,58 1999 27.8 6 Pre-extd 0.60 10 4–6 4–6
Barrington et al,59 2001 26.1 6 16 NDAc 12 6 6
Khalaf et al,60 2001 28.0 6 Pre-extd 12 – 14 NDAc Pre-extd 5 4–6
Moretti et al,61 2008 27.0 7 10–20 NDAc Pre-extd 3–5 3–5
Gao et al,62 2010 32.5 5 20 NDAc 40 5 4–8
Ding et al,63 2020f 29.8 8 15–25 NDAc 15–50 4–6 6
1.2.3 Flow-driver-generated, nonsynchronized NIPPV
O’Brien et al,64 2012 27.4 9 8–10 1 20 5–7 5–7…