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Noninvasive ventilation in neonates
c u r r e n t m e d i c i n e r e s e a r c h a n d p r a c t i c e 4 ( 2 0 1 4 ) 1 3 e1 9
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.elsevier.com/locate/cmrp
Review Article
Noninvasive ventilation in neonates Avneet Kaur, Manoj Modi, Arun Soni, Anup Thakur, Satish Saluja* Department of Neonatology, Sir Ganga Ram Hospital, Rajinder Nagar, New Delhi, India
abstract Keywords:
Nasal ventilation is a relatively newer concept that is being increasingly used in preterm
Respiratory distress syndrome
infants to reduce the adverse pulmonary outcomes which are associated with invasive
Noninvasive respiratory support
ventilation. This review analyzes the evidence from various clinical trials on the use of
Non-invasive positive pressure
nasal ventilation and various types of nasal ventilation. These have been tested both as a
ventilation
primary mode of respiratory support as well as continuing respiratory support after
CPAP
extubation from mechanical ventilation. Studies are consistently showing early weaning
Surfactant
from mechanical ventilation and benefits in infants with respiratory distress syndrome and apnea. Long term improvements in respiratory outcome have also been reported but needs to be confirmed in larger trials. Copyright ª 2014, Sir Ganga Ram Hospital. Published by Reed Elsevier India Pvt. Ltd. All rights reserved.
1.
Introduction
The advances in care of a newborn with pulmonary insufficiency have greatly improved their survival. However adverse pulmonary and neurodevelopmental outcomes remain a concern in infants who need prolonged ventilator support.1e3 Researchers have toiled hard to evolve strategies to reduce the burden of chronic lung disease amongst premature infants. It is commonly believed that invasive ventilation with endotracheal intubation may be largely responsible for lung injury and evolution of bronchopulmonary dysplasia. Even though strategies to provide respiratory support without endotracheal intubation described as noninvasive ventilation have improved short term outcomes like need for surfactant, duration of mechanical ventilation, but the long term goal to reduce chronic lung disease still remains a distant dream.4 The management of extremely premature infant includes use of antenatal steroids, frequent need for resuscitation,
surfactant replacement therapy and mechanical ventilation with increased oxygen concentrations. All these are contributory factors not only for chronic lung disease but also brain injury especially if need for respiratory support is prolonged.
2. Optimizing respiratory support in preterm infants 2.1.
Antenatal period
2.1.1.
Antenatal steroids
Over the ensuing 20 years, multiple clinical investigations have documented the effectiveness of antenatal steroids on fetal lung maturation. A 2006 Cochrane review of 21 Randomized control trials ( RCT’s) involving more than 4269 infants, reported a reduced risk of neonatal death, respiratory distress syndrome (RDS), and intra-ventricular hemorrhage (IVH) with a single course of antenatal steroids, and a strong
* Corresponding author. E-mail address: [email protected] (S. Saluja). 2352-0817/$ e see front matter Copyright ª 2014, Sir Ganga Ram Hospital. Published by Reed Elsevier India Pvt. Ltd. All rights reserved. http://dx.doi.org/10.1016/j.cmrp.2014.01.008
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Table 1 e Study population and intervention of key trials on CPAP for management of RDS in extremely preterm infants. Name SUPPORT17 COIN18 VON19 CURPAP20 Neocosur21 Total
Year published
Gestational age (wks)/Bwt.
Number of subjects
Intervention
2010 2008 2011 2010 2010
240e276 250e286 260e296 250e286 800e1500 g
1316 610 432 208 256 2822
CPAP vs prophylactic surfactant CPAP vs intubation & ventilation, surfactant if required Prophylactic vs INSURE vs CPAP CPAP vs prophylactic surfactant CPAP/INSURE vs oxygen by hood/MV and surfactant
trend towards a reduced risk of abnormal neurodevelopmental outcome on long-term follow-up of these children.5 National institute of health consensus panel recommends that all fetuses at risk for delivery between 24 & 34 weeks should be considered for antenatal steroids.
breaths may allow smoother transition, taking care that the infant does not have significant bradycardia or falling heart rate. However, this practice would need to be confirmed in clinical studies.
2.1.2. Intrapartum antibiotic prophylaxis for PROM and chorioamnionitis
3. Prophylactic continuous positive airway pressure (CPAP) at birth
Complicates one third of preterm births. Various trials have evaluated the efficacy of range of antibiotic regimens for prevention of spontaneous preterm birth in women presenting with preterm labor with intact membranes or ruptured membranes. Perinatal use of erythromycin and/or co-amoxiclav for women with preterm rupture of membrane (PROM) in ORACLE 1 trial revealed significant prolongation of pregnancy among antibiotic treated groups as compared to placebo; however no significant difference was noted in neonatal morbidity (defined as neonatal death, chronic lung disease or major cerebral abnormality on ultrasound).6 Co-amoxiclav was associated with higher incidence of necrotizing enterocolitis. Royal College of Obstetricians and Gynaecologists (RCOG) guidelines suggested that erythromycin (250 mg orally 6 hourly) should be given for 10 days following the diagnosis of PROM.
2.1.3.
Delivery room management
Many preterm neonates would require some assistance for transition to extrauterine life. Either their respiratory effort may be poor or they may not be able to rapidly absorb the alveolar fluid. Overzealous use of positive pressure breaths soon after birth may result in altered pulmonary mechanics, need for ventilation and response to surfactant. Bjorklund et al demonstrated that 6 large sustained manual breaths in surfactant deficient lungs of preterm lambs resulted in worse lung mechanics and gas exchange over subsequent 4 hours along with poor response to surfactant administration.7 Animal studies have shown that use of Positive end expiratory pressure (PEEP) during initial stabilization after birth improves functional residual capacity (FRC), gas exchange, lung compliance and reduces lung injury.8,9 However, high levels of PEEP 8e10 cm H2O may reduce pulmonary blood flow and increase the risk of pneumothorax.10,11 The 2010 Neonatal resuscitation programme (NRP) guidelines recommend that PEEP during resuscitation may be beneficial and should be used in preterm neonates who require positive pressure ventilation (PPV).8,9 Being futuristic it needs to be evaluated that in spontaneously breathing preterm neonates with inadequate efforts at birth, application of only continuous positive airway pressure (CPAP) without positive pressure
In the Cochrane meta-analysis, prophylactic CPAP starting soon after birth irrespective of their respiratory status did not show any improvements in respiratory outcomes, however there was a trend towards increase in adverse outcomes like the incidence of bronchopulmonary dysplasia (BPD) at 28 days, death and IVH in the CPAP group.12
4.
Noninvasive ventilation
The noninvasive strategies include forms of respiratory support without endotracheal intubation. Positive end expiratory pressure (PEEP) is the key element of this strategy. This could either be continuous positive airway pressure (CPAP), high flow nasal cannulas (HFNC) or assisted CPAP in the form of NIPPV or SNIPPV (non-synchronized or synchronized intermittent positive pressure ventilation in addition to PEEP). First successful use of CPAP in management of RDS was reported by Gregory et al in 1971.13 Subsequently for almost two decades it became a part of mechanical ventilation (PEEP) and was being used as post extubation strategy. It was only when meta-analysis and surveys revealed that CPAP alone could reduce the need for mechanical ventilation and those units which primarily used CPAP had lower incidence of chronic lung disease, the interest in this mode of noninvasive ventilation was revived.14,15 Before surfactant was used to treat RDS, many trials were done to demonstrate the use of CPAP in RDS. A Cochrane meta-analysis on use of CPAP for treatment of RDS in preterm infants in presurfactant era was published in 2002.16 Very few extremely preterm babies were enrolled in these trials and use of antenatal steroid was not wide spread at this time. The key findings of this meta-analysis were that the use of CPAP to treat RDS in preterm infants was associated with less death or use of mechanical ventilation (RR 0.65, 95% CI 0.52, 0.81) (number needed to treat, NNT 5, 95% CI 4,10) and less overall mortality (RR 0.52, 95% CI 0.32,0.81) (NNT 7, 95% CI 4,25). They also noted an increased risk of pneumothorax (RR 2.64, 95% CI 1.39, 5.04) (number needed to harm, NNH 17, 95% CI 17, 25) in the CPAP group.
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Table 2 e Surfactant usage and primary outcomes. Name
Surfactant usage in CPAP arm (%)
Primary outcome BPD or death, n/N (%)
Risk ratio (95% CI)
CPAP control SUPPORT COIN VON CURPAP Neocosur Overall
67 38 45 74 37 67
323/663 104/307 68/223 23/105 18/131 539/1429
(49) (34) (31) (22) (14) (38)
The use of CPAP as the primary mode of respiratory support in preterm neonates with respiratory distress or the INSURE strategy (Intubate, Surfactant and Rapid extubation) were evaluated over next two decades. In recent times there have been five randomized trials comparing use of early CPAP vs early surfactant administration. The details of these trials are listed in Table 1. The five trials are: Surfactant Positive Airway Pressure and Pulse Oximetry trial [SUPPORT],17 Continuous Positive Airway pressure or Intubation at Birth [COIN trial],18 Vermont Oxford Network Delivery Room Management trial [VON], Efficacy of Combining Prophylactic Curosurf with Early Nasal CPAP in Delivery Room [CURPAP study]20 and South American Neocosur Network trial [Neocosur]. The population, number of subjects, interventions and main outcomes of these five major trials are shown in Tables 1e3.
333/653 118/303 76/209 22/103 24/125 573/1393
(54) (39) (37) (21) (19) (41)
0.91 (0.83e1.01) 0.80 (0.58e1.12) 0.83 (0.64e1.09) 1.03 (0.61e1.72) 0.72 (0.41e1.25) 0.92 (0.84e1.00)
These studies indicate that early CPAP even in extremely premature infants is feasible, effective and in almost more than half of neonates can avoid the need for mechanical ventilation and surfactant administration. Despite these short term benefits this strategy does not significantly reduce the composite outcome of death or BPD in extremely preterm infants. Also, in country like ours where sepsis still remains a significant problem any reduction in invasive ventilation is likely to be associated with both short term and long term benefits. With the current evidence it is imperative that all premature infants who develop respiratory distress soon after birth should be started on early CPAP while in the delivery room, transported to neonatal intensive care unit (NICU) on CPAP and proceed with further management. Depending on the availability of expertise and manpower, each neonatal unit should draw their cut offs for CPAP failure and threshold
Table 3 e Primary and secondary outcomes. Name
Primary outcome
Secondary outcomes
SUPPORT
Death or BPD comparable in two groups
COIN
Death or BPD comparable in two groups Survivors with oxygen comparable Surfactant usage: 38% in CPAP group
No difference in Need for supplemental oxygen Need for mechanical ventilation Air leak IVH, NEC, ROP or use of postnatal steroids No difference in Need for supplemental oxygen Need for mechanical ventilation IVH, NEC, ROP or use of postnatal steroids
Air Leak Pneumothorax 9.1% vs 3.0% (p ¼ 0.001) VON Intubated in 1st hour surfactant
PS 99% 98.6
INSURE 98.6% 98.2
CPAP 17.9% 45.1
CURPAP
Need for mechanical ventilation within 5 days comparable in two groups Surfactant usage in CPAP group 48.5%
Neocosur
Significantly higher number required mechanical ventilation 29.8% vs 50.4% (p 0.001) Higher surfactant usage 27.5% vs 46.4% (p ¼ 0.002)
No difference in Mortality, BPD Air leaks, Pulm hemorrhage PDA, NEC, PVL, Sepsis, ROP No difference in: Mortality BPD Air Leaks IVH, PDA or ROP, NEC or PVL Use of postnatal Steroids Comparable Mortality BPD Air leaks PDA, IVH, NEC, ROP, Sepsis
Higher nasal damage in CPAP group 8.4% vs 0% (p ¼ 0.001) PS: prophylactic surfactant, INSURE: intubate, surfactant and rapid extubation, NEC: necrotising enterocolitis, ROP: retinopathy of prematurity, PDA: patent ductus arteriosus, PVL: periventricular leukomalacia.
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Table 4 e Criteria for CPAP failure in major trials. Name
CPAP failure FiO2
SUPPORT
COIN
VON
CURPAP
Neocosur
FiO2 > 0.50 to maintain saturation of peripheral oxygen SpO2 at or above 88% for 1 hour Metabolic acidosis not responsive to treatment, or treatment with more than a 60% conc. of oxygen Requirement for FIO2 of >0.4 to maintain oxygen saturation of 86%e94%. Intubation was discretionary if FIO2 was 0.4e0.6 and mandatory if FIO2 > 0.6 FIO2 > 0.4 on nCPAP to maintain oxygen saturation of 85%e92% for at least 30 minutes Fio2 >0.60 at least 2 hours after surfactant administration Need for a third dose of surfactant
PaCO2 PaCO2 > 65 mmHg
An arterial pH of less than 7.25 with a partial pressure of arterial carbon dioxide (PaCO2) of more than 60 mm Hg (8.0 kPa) PCO2 > 65 mm Hg on arterial or capillary blood gas
PaCO2 >60 mm Hg with pH <7.20 on consecutive arterial blood gas analyses within 30 minutes.
More than 3 episodes of apnea and bradycardia (heart rate <80/minute)
When the first use of CPAP was described it was classical bubble CPAP delivered through the expiratory limb of ventilatory circuit dipped into a column of water. The length of tube under the water level was used to describe the amount of CPAP in cm of H2O. Since then bubble CPAP has gone many innovations and now specially designed bubble CPAP equipment’s are available. CPAP can also be delivered through a ventilator; however bubble CPAP is cheap and more useful in resource limited settings. Kahn et al described unpredictable
Table 5 e Suggested settings for NIPPV.
Rate, breaths per minute PIP, cm H20
Positive end expiratory pressure, cmH20 Time e inspiratory, s Flow rate, L/minute
>12 episodes of apnea that required stimulation or more than 1 episode that required bagging in a 6-hour period.
Apnea defined as >4 episodes of apnea per hour or > 2 episodes of apnea per hour when ventilation with bag and mask was required
5. Delivery device of continuous positive airway pressure (CPAP)
Treatment of RDS
Hemodynamic instability defined as a blood pressure that was low for gestational age, poor perfusion, or both, requiring volume or pressor support for a period of 4 hours or more. Apnea unresponsive to stimulation and methlyxanthine treatment (>6 episodes requiring stimulation in 6 hours or requiring >1 episode of positive pressure ventilation)
PCO2 >65 mm Hg pH < 7.2
to intubate and give surfactant replacement therapy. The criteria for CPAP failure in the above trials are shown in Table 4.
Ventilator variable
Others
Support after extubation
40
10e25
2 to 4 > PIP on manual PPV 4e6
2 to 4 > PIP on mechanical ventilation 5
0.4e0.45 8e10
0.3e0.5 8e10
PIP, peak inspiratory pressure; PPV, positive pressure ventilation. Adapted from Bhandari V. Noninvasive respiratory support in the preterm infant. Clin Perinatol. 2012;39(3):497e511. (23)
delivery of pressure while using bubble CPAP and its dependence on the flow of gases.22 Some claim that bubble CPAP by virtue of producing noise factor may be more effective as compared to CPAP delivered through ventilator.23 Many studies have shown no difference in these two techniques as these studies recruited small number of subjects. Gupta et al reported in an RCT that bubble CPAP was more effective in terms of extubation and need for oxygen supplementation in preterm neonates ventilated for less than 14 days, when compared to CPAP delivered through ventilator.24 The bubbles may induce some oscillatory effects to improve oxygenation. Further research is ongoing to device ways to improve this effect.
6. Assisted continuous positive airway pressure (CPAP): nasal intermittent positive pressure ventilation (NIPPV) This is a type of respiratory support where the CPAP is combined with intermittent positive pressure breaths delivered by the ventilator through the same interface. Presently most people use intermittent positive pressure ventilation (IPPV) which is not synchronized with infant’s spontaneous breathing. However, almost 1/4th of the spontaneous breaths have been shown to be synchronized with mechanical breaths by increasing tidal volume.25 The technology to synchronize NIPPV is being developed and some early experiences have shown to reduce spontaneous breathing effort.26 NIPPV has been used to treat RDS in preterm neonates. However, most studies have compared NIPPV and nCPAP and have reported reduced need for mechanical ventilation, chronic lung disease.27,28 However, more data is required to show definite benefits of this strategy.29,30 NIPPV has also been used along with INSURE strategy and after extubation with benefits of
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a.m. p.m.
Night shift
reduced extubation failures. However, a large multicentric RCT of nCPAP vs NIPPV has not shown any difference in primary outcome of death or BPD.31 Bhandari et al have suggested guidelines for the ventilator settings for the use of NIPPV (Table 5.).32
Night shift
7. Interface for delivery of continuous positive airway pressure (CPAP)
Night shift
a.m. p.m.
Many devices namely single nasal prongs, binasal short prongs or nasopharyngeal prongs have been used to deliver nasal CPAP. Meta-analysis published in 2008 showed that short binasal prongs are associated with reduced reintubation rates as compared to single nasal or nasopharyngeal prongs [RR 0.59 (CI: 0.41,0.85), NNT 5 (CI: 3,14)].33
Internal Nare Left Right External Nare Left Right Philtrum Septum Total Score
Score. 0 ¼ normal. 1 ¼ pink/red. 2 ¼ bleeding/ulcer/scab. 3 ¼ skin tear.
Night shift
a.m. p.m.
Night shift
a.m. p.m.
Night shift
a.m. p.m.
Night shift
a.m. p.m.
8.
a.m. p.m. Shift
Date
Score
Table 6 e Nasal trauma score.36
17
High flow nasal cannula
Traditionally small nasal cannula has been used for delivery of oxygen. Varying flow rates have been used and a flow rate of more than 1 L/minute is described as high flow oxygen delivery. It was believed that high flows through nasal cannula may not be feasible. However, for this mode to be effective the inhaled gases should be heated and humidified (HHHFNC: Heated Humidified High Flow Nasal Cannula). HHHFNC has been shown to generate distending pressure or CPAP. However, the amount of pressure generated varies with size of nasal cannula and flow rates. The average external diameter of binasal prongs to deliver CPAP is 3.7e4.6 mm. The commonly used nasal cannula to deliver oxygen has an external diameter of 1.5e2.4 mm. Some of the initial studies did not find any significant benefit of HFNC possibly because these used lower flow rates.34,35 The Cochrane review published in 2011 did not find enough evidence in favor of efficacy or safety of flow rates more than 1 L/minute to treat RDS in preterm neonates.35 Nasal CPAP with binasal prong may be difficult to manage for prolonged periods especially in active preterm infants. It is also likely to be associated with nasal injury, occasionally resulting in permanent disfigurement. Kaufman et al described a nasal trauma score which is a good bedside monitoring tool for early detection of nasal injury thus minimizing the damage (Table. 6).36 More work with HHHFNC showed that with varying degrees of nasal occlusion ranging from 33% to 80% and flow rates more than 2e3 L/minute could achieve significant distending pressures.37,38 Various studies comparing HHHFNC with nCPAP have shown no difference in extubation failure rates in the first week (Tables 7 and 8).39e42 With evidence emerging from more RCTs in progress, if they are able to show equivalence of HHHFNC with nCPAP, the nasal canula oxygen therapy is likely to be more widely used especially in situations where nCPAP is difficult to maintain or the risk of nasal trauma is high. Most of these trials used a flow rates ranging from 3 to 8 L/minute.38 Klingenberg compared patient comfort in 20 preterm infants <34 weeks treated with HHHFNC vs nasal continuous positive airway pressure and found that there was no difference in neonatal pain scale however parents
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Table 7 e Study population and intervention of key trials on HFNC. Name Lena Ignacio39 Collin CL40 Yoder41 Manley42 Total
Year published
GA (wks)
No. of subjects
2013 2013 2013 2013
<32 <32 28e42 <32
132 132 432 303 999
Intervention HFNC HFNC HFNC HFNC
or or or or
CPAP postextubation CPAP postextubation CPAP primary or postextubation CPAP post extubation
Table 8 e Primary and secondary outcomes of trials on HFNC. Study
Type of study
Primary outcome
Secondary outcome
Lena Ignacio
RCT
No difference in extubation failure within the 7 days after extubation
Colin CL
RCT
Yoder
RCT
No difference in extubation failure in 7days (22% vs 34%) No difference in need for intubation within 72 hours of noninvasive therapy (15.1% vs 11.4%; P ¼ 0.252)
Manley
RCT
No difference in treatment failure (34% vs 26%)
preferred HHHFNC.43 Mean respiratory rate over 24 hours was lower during HHHFNC than CPAP. To summarize noninvasive ventilation has been shown to be effective as the primary mode of treatment for RDS even in extremely preterm infants. A trial of early CPAP in delivery room should be offered to these neonates. Infants who fail on CPAP should be given early surfactant with INSURE strategy. HHHFNC looks like a promising strategy from the initial trials however larger studies are required.
Conflicts of interest All authors have none to declare.
references
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HHHFNC had less nasal trauma than those assigned to NCPAP (p < 0.001). 20% of infants on NCPAP were changed to HHHFNC due to nasal trauma in the first 7 days after extubation. HHHFNC reduced the nasal trauma score 3.1 (SD 7.2) vs NCPAP 11.8 (SD 10.7), p < 0.001 HHHFNC infants remained longer on support than nCPAP infants (median: 4 vs 2 days; p < 0.01), No differences in days on Oxygen (median: 10 vs 8 days), BPD (20% vs 16%), Discharge from the hospital on oxygen (19% vs 18%). The HFNC group had a trend toward lower re-intubation rates (18% vs 25%, p ¼ 0.12) Lower nasal trauma rates (40% vs 54%).
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43.
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Development Neonatal Research Network. Synchronized nasal intermittent positive-pressure ventilation and neonatal outcomes. Pediatrics. 2009;124:517e526. Ramanathan R, Sekar KC, Rasmussen M, Bhatia J, Soll RF. Nasal intermittent positive pressure ventilation after surfactant treatment for respiratory distress syndrome in preterm infants <30 weeks’ gestation: a randomized, controlled trial. J Perinatol. 2012;32:336e343. Kirpalani H, Millar D, Lemyre B, Yoder BA, Chiu A, Roberts RS. NIPPV Study Group. A trial comparing noninvasive ventilation strategies in preterm infants. N Engl J Med. 2013 Aug 15;369(7):611e620. Bhandari V. Noninvasive respiratory support in the preterm infant. Clin Perinatol. 2012;39:497e511. De Paoli AG, Davis PG, Faber B, Morley CJ. Devices and pressure sources for administration of nasal continuous positive airway pressure (NCPAP) in preterm neonates. Cochrane Database Syst Rev. 2008:CD002977. http://dx.doi.org/ 10.1002/14651858.CD002977.pub2. Campbell DM, Shah PS, Shah V, Kelly EN. Nasal continuous positive airway pressure from high flow cannula versus infant flow for preterm infants. J Perinatol. 2006;26:546e549. Wilkinson D, Andersen C, O’Donnell CP, De Paoli AG. High flow nasal cannula for respiratory support in preterm infants. Cochrane Database Syst Rev. 2011:CD006405. Kaufman D, Zanelli S, Walsh B, Hicks T. Evaluation of a nasal breakdown scoring system for premature infants requiring CPAP [abstract]. Respir Care E-PAS2007:61390. www. abstracts2view.com. Accessed 06.11.12. Volsko TA, Fedor K, Amadei J, Chatburn RL. High flow through a nasal cannula and CPAP effect in a simulated infant model. Respir Care. 2011;56:1893e1900. Sivieri EM, Gerdes JS, Abbasi S. Effect of HFNC flow rate, cannula size, and nares diameter on generated airway pressures: an in vitro study. Pediatr Pulmonol. 2013;48:506e514. Ignacio L, Alfaleh K. A randomized controlled trial to compare heated humidified high-flow nasal cannulae with nasal continuous positive airway pressure postextubation in premature infants. J Clin Neonatol. 2013 Apr;2:75e77. Collins CL, Holberton JR, Barfield C, Davis PG. A randomized controlled trial to compare heated humidified high-flow nasal cannulae with nasal continuous positive airway pressure postextubation in premature infants. J Pediatr. 2013 May;162:949e954. Yoder BA, Stoddard RA, Li M, King J, Dirnberger DR, Abbasi S. Heated, humidified high-flow nasal cannula versus nasal CPAP for respiratory support in neonates. Pediatrics. 2013;131:e1482ee1490. Manley BJ, Owen LS, Doyle LW, et al. High-flow nasal cannulae in very preterm infants after extubation. N Engl J Med. 2013 Oct 10;369:1425e1433. Klingenberg C, Pettersen M, Hansen EA, et al. Patient comfort during treatment with heated humidified high flow nasal cannulae versus nasal continuous positive airway pressure: a randomised cross-over trial. Arch Dis Child Fetal Neonatal Ed. 2013 Nov 13. http://dx.doi.org/10.1136/archdischild-2013304525 [Epub ahead of print].
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.elsevier.com/locate/cmrp
Review Article
Noninvasive ventilation in neonates Avneet Kaur, Manoj Modi, Arun Soni, Anup Thakur, Satish Saluja* Department of Neonatology, Sir Ganga Ram Hospital, Rajinder Nagar, New Delhi, India
abstract Keywords:
Nasal ventilation is a relatively newer concept that is being increasingly used in preterm
Respiratory distress syndrome
infants to reduce the adverse pulmonary outcomes which are associated with invasive
Noninvasive respiratory support
ventilation. This review analyzes the evidence from various clinical trials on the use of
Non-invasive positive pressure
nasal ventilation and various types of nasal ventilation. These have been tested both as a
ventilation
primary mode of respiratory support as well as continuing respiratory support after
CPAP
extubation from mechanical ventilation. Studies are consistently showing early weaning
Surfactant
from mechanical ventilation and benefits in infants with respiratory distress syndrome and apnea. Long term improvements in respiratory outcome have also been reported but needs to be confirmed in larger trials. Copyright ª 2014, Sir Ganga Ram Hospital. Published by Reed Elsevier India Pvt. Ltd. All rights reserved.
1.
Introduction
The advances in care of a newborn with pulmonary insufficiency have greatly improved their survival. However adverse pulmonary and neurodevelopmental outcomes remain a concern in infants who need prolonged ventilator support.1e3 Researchers have toiled hard to evolve strategies to reduce the burden of chronic lung disease amongst premature infants. It is commonly believed that invasive ventilation with endotracheal intubation may be largely responsible for lung injury and evolution of bronchopulmonary dysplasia. Even though strategies to provide respiratory support without endotracheal intubation described as noninvasive ventilation have improved short term outcomes like need for surfactant, duration of mechanical ventilation, but the long term goal to reduce chronic lung disease still remains a distant dream.4 The management of extremely premature infant includes use of antenatal steroids, frequent need for resuscitation,
surfactant replacement therapy and mechanical ventilation with increased oxygen concentrations. All these are contributory factors not only for chronic lung disease but also brain injury especially if need for respiratory support is prolonged.
2. Optimizing respiratory support in preterm infants 2.1.
Antenatal period
2.1.1.
Antenatal steroids
Over the ensuing 20 years, multiple clinical investigations have documented the effectiveness of antenatal steroids on fetal lung maturation. A 2006 Cochrane review of 21 Randomized control trials ( RCT’s) involving more than 4269 infants, reported a reduced risk of neonatal death, respiratory distress syndrome (RDS), and intra-ventricular hemorrhage (IVH) with a single course of antenatal steroids, and a strong
* Corresponding author. E-mail address: [email protected] (S. Saluja). 2352-0817/$ e see front matter Copyright ª 2014, Sir Ganga Ram Hospital. Published by Reed Elsevier India Pvt. Ltd. All rights reserved. http://dx.doi.org/10.1016/j.cmrp.2014.01.008
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Table 1 e Study population and intervention of key trials on CPAP for management of RDS in extremely preterm infants. Name SUPPORT17 COIN18 VON19 CURPAP20 Neocosur21 Total
Year published
Gestational age (wks)/Bwt.
Number of subjects
Intervention
2010 2008 2011 2010 2010
240e276 250e286 260e296 250e286 800e1500 g
1316 610 432 208 256 2822
CPAP vs prophylactic surfactant CPAP vs intubation & ventilation, surfactant if required Prophylactic vs INSURE vs CPAP CPAP vs prophylactic surfactant CPAP/INSURE vs oxygen by hood/MV and surfactant
trend towards a reduced risk of abnormal neurodevelopmental outcome on long-term follow-up of these children.5 National institute of health consensus panel recommends that all fetuses at risk for delivery between 24 & 34 weeks should be considered for antenatal steroids.
breaths may allow smoother transition, taking care that the infant does not have significant bradycardia or falling heart rate. However, this practice would need to be confirmed in clinical studies.
2.1.2. Intrapartum antibiotic prophylaxis for PROM and chorioamnionitis
3. Prophylactic continuous positive airway pressure (CPAP) at birth
Complicates one third of preterm births. Various trials have evaluated the efficacy of range of antibiotic regimens for prevention of spontaneous preterm birth in women presenting with preterm labor with intact membranes or ruptured membranes. Perinatal use of erythromycin and/or co-amoxiclav for women with preterm rupture of membrane (PROM) in ORACLE 1 trial revealed significant prolongation of pregnancy among antibiotic treated groups as compared to placebo; however no significant difference was noted in neonatal morbidity (defined as neonatal death, chronic lung disease or major cerebral abnormality on ultrasound).6 Co-amoxiclav was associated with higher incidence of necrotizing enterocolitis. Royal College of Obstetricians and Gynaecologists (RCOG) guidelines suggested that erythromycin (250 mg orally 6 hourly) should be given for 10 days following the diagnosis of PROM.
2.1.3.
Delivery room management
Many preterm neonates would require some assistance for transition to extrauterine life. Either their respiratory effort may be poor or they may not be able to rapidly absorb the alveolar fluid. Overzealous use of positive pressure breaths soon after birth may result in altered pulmonary mechanics, need for ventilation and response to surfactant. Bjorklund et al demonstrated that 6 large sustained manual breaths in surfactant deficient lungs of preterm lambs resulted in worse lung mechanics and gas exchange over subsequent 4 hours along with poor response to surfactant administration.7 Animal studies have shown that use of Positive end expiratory pressure (PEEP) during initial stabilization after birth improves functional residual capacity (FRC), gas exchange, lung compliance and reduces lung injury.8,9 However, high levels of PEEP 8e10 cm H2O may reduce pulmonary blood flow and increase the risk of pneumothorax.10,11 The 2010 Neonatal resuscitation programme (NRP) guidelines recommend that PEEP during resuscitation may be beneficial and should be used in preterm neonates who require positive pressure ventilation (PPV).8,9 Being futuristic it needs to be evaluated that in spontaneously breathing preterm neonates with inadequate efforts at birth, application of only continuous positive airway pressure (CPAP) without positive pressure
In the Cochrane meta-analysis, prophylactic CPAP starting soon after birth irrespective of their respiratory status did not show any improvements in respiratory outcomes, however there was a trend towards increase in adverse outcomes like the incidence of bronchopulmonary dysplasia (BPD) at 28 days, death and IVH in the CPAP group.12
4.
Noninvasive ventilation
The noninvasive strategies include forms of respiratory support without endotracheal intubation. Positive end expiratory pressure (PEEP) is the key element of this strategy. This could either be continuous positive airway pressure (CPAP), high flow nasal cannulas (HFNC) or assisted CPAP in the form of NIPPV or SNIPPV (non-synchronized or synchronized intermittent positive pressure ventilation in addition to PEEP). First successful use of CPAP in management of RDS was reported by Gregory et al in 1971.13 Subsequently for almost two decades it became a part of mechanical ventilation (PEEP) and was being used as post extubation strategy. It was only when meta-analysis and surveys revealed that CPAP alone could reduce the need for mechanical ventilation and those units which primarily used CPAP had lower incidence of chronic lung disease, the interest in this mode of noninvasive ventilation was revived.14,15 Before surfactant was used to treat RDS, many trials were done to demonstrate the use of CPAP in RDS. A Cochrane meta-analysis on use of CPAP for treatment of RDS in preterm infants in presurfactant era was published in 2002.16 Very few extremely preterm babies were enrolled in these trials and use of antenatal steroid was not wide spread at this time. The key findings of this meta-analysis were that the use of CPAP to treat RDS in preterm infants was associated with less death or use of mechanical ventilation (RR 0.65, 95% CI 0.52, 0.81) (number needed to treat, NNT 5, 95% CI 4,10) and less overall mortality (RR 0.52, 95% CI 0.32,0.81) (NNT 7, 95% CI 4,25). They also noted an increased risk of pneumothorax (RR 2.64, 95% CI 1.39, 5.04) (number needed to harm, NNH 17, 95% CI 17, 25) in the CPAP group.
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Table 2 e Surfactant usage and primary outcomes. Name
Surfactant usage in CPAP arm (%)
Primary outcome BPD or death, n/N (%)
Risk ratio (95% CI)
CPAP control SUPPORT COIN VON CURPAP Neocosur Overall
67 38 45 74 37 67
323/663 104/307 68/223 23/105 18/131 539/1429
(49) (34) (31) (22) (14) (38)
The use of CPAP as the primary mode of respiratory support in preterm neonates with respiratory distress or the INSURE strategy (Intubate, Surfactant and Rapid extubation) were evaluated over next two decades. In recent times there have been five randomized trials comparing use of early CPAP vs early surfactant administration. The details of these trials are listed in Table 1. The five trials are: Surfactant Positive Airway Pressure and Pulse Oximetry trial [SUPPORT],17 Continuous Positive Airway pressure or Intubation at Birth [COIN trial],18 Vermont Oxford Network Delivery Room Management trial [VON], Efficacy of Combining Prophylactic Curosurf with Early Nasal CPAP in Delivery Room [CURPAP study]20 and South American Neocosur Network trial [Neocosur]. The population, number of subjects, interventions and main outcomes of these five major trials are shown in Tables 1e3.
333/653 118/303 76/209 22/103 24/125 573/1393
(54) (39) (37) (21) (19) (41)
0.91 (0.83e1.01) 0.80 (0.58e1.12) 0.83 (0.64e1.09) 1.03 (0.61e1.72) 0.72 (0.41e1.25) 0.92 (0.84e1.00)
These studies indicate that early CPAP even in extremely premature infants is feasible, effective and in almost more than half of neonates can avoid the need for mechanical ventilation and surfactant administration. Despite these short term benefits this strategy does not significantly reduce the composite outcome of death or BPD in extremely preterm infants. Also, in country like ours where sepsis still remains a significant problem any reduction in invasive ventilation is likely to be associated with both short term and long term benefits. With the current evidence it is imperative that all premature infants who develop respiratory distress soon after birth should be started on early CPAP while in the delivery room, transported to neonatal intensive care unit (NICU) on CPAP and proceed with further management. Depending on the availability of expertise and manpower, each neonatal unit should draw their cut offs for CPAP failure and threshold
Table 3 e Primary and secondary outcomes. Name
Primary outcome
Secondary outcomes
SUPPORT
Death or BPD comparable in two groups
COIN
Death or BPD comparable in two groups Survivors with oxygen comparable Surfactant usage: 38% in CPAP group
No difference in Need for supplemental oxygen Need for mechanical ventilation Air leak IVH, NEC, ROP or use of postnatal steroids No difference in Need for supplemental oxygen Need for mechanical ventilation IVH, NEC, ROP or use of postnatal steroids
Air Leak Pneumothorax 9.1% vs 3.0% (p ¼ 0.001) VON Intubated in 1st hour surfactant
PS 99% 98.6
INSURE 98.6% 98.2
CPAP 17.9% 45.1
CURPAP
Need for mechanical ventilation within 5 days comparable in two groups Surfactant usage in CPAP group 48.5%
Neocosur
Significantly higher number required mechanical ventilation 29.8% vs 50.4% (p 0.001) Higher surfactant usage 27.5% vs 46.4% (p ¼ 0.002)
No difference in Mortality, BPD Air leaks, Pulm hemorrhage PDA, NEC, PVL, Sepsis, ROP No difference in: Mortality BPD Air Leaks IVH, PDA or ROP, NEC or PVL Use of postnatal Steroids Comparable Mortality BPD Air leaks PDA, IVH, NEC, ROP, Sepsis
Higher nasal damage in CPAP group 8.4% vs 0% (p ¼ 0.001) PS: prophylactic surfactant, INSURE: intubate, surfactant and rapid extubation, NEC: necrotising enterocolitis, ROP: retinopathy of prematurity, PDA: patent ductus arteriosus, PVL: periventricular leukomalacia.
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Table 4 e Criteria for CPAP failure in major trials. Name
CPAP failure FiO2
SUPPORT
COIN
VON
CURPAP
Neocosur
FiO2 > 0.50 to maintain saturation of peripheral oxygen SpO2 at or above 88% for 1 hour Metabolic acidosis not responsive to treatment, or treatment with more than a 60% conc. of oxygen Requirement for FIO2 of >0.4 to maintain oxygen saturation of 86%e94%. Intubation was discretionary if FIO2 was 0.4e0.6 and mandatory if FIO2 > 0.6 FIO2 > 0.4 on nCPAP to maintain oxygen saturation of 85%e92% for at least 30 minutes Fio2 >0.60 at least 2 hours after surfactant administration Need for a third dose of surfactant
PaCO2 PaCO2 > 65 mmHg
An arterial pH of less than 7.25 with a partial pressure of arterial carbon dioxide (PaCO2) of more than 60 mm Hg (8.0 kPa) PCO2 > 65 mm Hg on arterial or capillary blood gas
PaCO2 >60 mm Hg with pH <7.20 on consecutive arterial blood gas analyses within 30 minutes.
More than 3 episodes of apnea and bradycardia (heart rate <80/minute)
When the first use of CPAP was described it was classical bubble CPAP delivered through the expiratory limb of ventilatory circuit dipped into a column of water. The length of tube under the water level was used to describe the amount of CPAP in cm of H2O. Since then bubble CPAP has gone many innovations and now specially designed bubble CPAP equipment’s are available. CPAP can also be delivered through a ventilator; however bubble CPAP is cheap and more useful in resource limited settings. Kahn et al described unpredictable
Table 5 e Suggested settings for NIPPV.
Rate, breaths per minute PIP, cm H20
Positive end expiratory pressure, cmH20 Time e inspiratory, s Flow rate, L/minute
>12 episodes of apnea that required stimulation or more than 1 episode that required bagging in a 6-hour period.
Apnea defined as >4 episodes of apnea per hour or > 2 episodes of apnea per hour when ventilation with bag and mask was required
5. Delivery device of continuous positive airway pressure (CPAP)
Treatment of RDS
Hemodynamic instability defined as a blood pressure that was low for gestational age, poor perfusion, or both, requiring volume or pressor support for a period of 4 hours or more. Apnea unresponsive to stimulation and methlyxanthine treatment (>6 episodes requiring stimulation in 6 hours or requiring >1 episode of positive pressure ventilation)
PCO2 >65 mm Hg pH < 7.2
to intubate and give surfactant replacement therapy. The criteria for CPAP failure in the above trials are shown in Table 4.
Ventilator variable
Others
Support after extubation
40
10e25
2 to 4 > PIP on manual PPV 4e6
2 to 4 > PIP on mechanical ventilation 5
0.4e0.45 8e10
0.3e0.5 8e10
PIP, peak inspiratory pressure; PPV, positive pressure ventilation. Adapted from Bhandari V. Noninvasive respiratory support in the preterm infant. Clin Perinatol. 2012;39(3):497e511. (23)
delivery of pressure while using bubble CPAP and its dependence on the flow of gases.22 Some claim that bubble CPAP by virtue of producing noise factor may be more effective as compared to CPAP delivered through ventilator.23 Many studies have shown no difference in these two techniques as these studies recruited small number of subjects. Gupta et al reported in an RCT that bubble CPAP was more effective in terms of extubation and need for oxygen supplementation in preterm neonates ventilated for less than 14 days, when compared to CPAP delivered through ventilator.24 The bubbles may induce some oscillatory effects to improve oxygenation. Further research is ongoing to device ways to improve this effect.
6. Assisted continuous positive airway pressure (CPAP): nasal intermittent positive pressure ventilation (NIPPV) This is a type of respiratory support where the CPAP is combined with intermittent positive pressure breaths delivered by the ventilator through the same interface. Presently most people use intermittent positive pressure ventilation (IPPV) which is not synchronized with infant’s spontaneous breathing. However, almost 1/4th of the spontaneous breaths have been shown to be synchronized with mechanical breaths by increasing tidal volume.25 The technology to synchronize NIPPV is being developed and some early experiences have shown to reduce spontaneous breathing effort.26 NIPPV has been used to treat RDS in preterm neonates. However, most studies have compared NIPPV and nCPAP and have reported reduced need for mechanical ventilation, chronic lung disease.27,28 However, more data is required to show definite benefits of this strategy.29,30 NIPPV has also been used along with INSURE strategy and after extubation with benefits of
c u r r e n t m e d i c i n e r e s e a r c h a n d p r a c t i c e 4 ( 2 0 1 4 ) 1 3 e1 9
a.m. p.m.
Night shift
reduced extubation failures. However, a large multicentric RCT of nCPAP vs NIPPV has not shown any difference in primary outcome of death or BPD.31 Bhandari et al have suggested guidelines for the ventilator settings for the use of NIPPV (Table 5.).32
Night shift
7. Interface for delivery of continuous positive airway pressure (CPAP)
Night shift
a.m. p.m.
Many devices namely single nasal prongs, binasal short prongs or nasopharyngeal prongs have been used to deliver nasal CPAP. Meta-analysis published in 2008 showed that short binasal prongs are associated with reduced reintubation rates as compared to single nasal or nasopharyngeal prongs [RR 0.59 (CI: 0.41,0.85), NNT 5 (CI: 3,14)].33
Internal Nare Left Right External Nare Left Right Philtrum Septum Total Score
Score. 0 ¼ normal. 1 ¼ pink/red. 2 ¼ bleeding/ulcer/scab. 3 ¼ skin tear.
Night shift
a.m. p.m.
Night shift
a.m. p.m.
Night shift
a.m. p.m.
Night shift
a.m. p.m.
8.
a.m. p.m. Shift
Date
Score
Table 6 e Nasal trauma score.36
17
High flow nasal cannula
Traditionally small nasal cannula has been used for delivery of oxygen. Varying flow rates have been used and a flow rate of more than 1 L/minute is described as high flow oxygen delivery. It was believed that high flows through nasal cannula may not be feasible. However, for this mode to be effective the inhaled gases should be heated and humidified (HHHFNC: Heated Humidified High Flow Nasal Cannula). HHHFNC has been shown to generate distending pressure or CPAP. However, the amount of pressure generated varies with size of nasal cannula and flow rates. The average external diameter of binasal prongs to deliver CPAP is 3.7e4.6 mm. The commonly used nasal cannula to deliver oxygen has an external diameter of 1.5e2.4 mm. Some of the initial studies did not find any significant benefit of HFNC possibly because these used lower flow rates.34,35 The Cochrane review published in 2011 did not find enough evidence in favor of efficacy or safety of flow rates more than 1 L/minute to treat RDS in preterm neonates.35 Nasal CPAP with binasal prong may be difficult to manage for prolonged periods especially in active preterm infants. It is also likely to be associated with nasal injury, occasionally resulting in permanent disfigurement. Kaufman et al described a nasal trauma score which is a good bedside monitoring tool for early detection of nasal injury thus minimizing the damage (Table. 6).36 More work with HHHFNC showed that with varying degrees of nasal occlusion ranging from 33% to 80% and flow rates more than 2e3 L/minute could achieve significant distending pressures.37,38 Various studies comparing HHHFNC with nCPAP have shown no difference in extubation failure rates in the first week (Tables 7 and 8).39e42 With evidence emerging from more RCTs in progress, if they are able to show equivalence of HHHFNC with nCPAP, the nasal canula oxygen therapy is likely to be more widely used especially in situations where nCPAP is difficult to maintain or the risk of nasal trauma is high. Most of these trials used a flow rates ranging from 3 to 8 L/minute.38 Klingenberg compared patient comfort in 20 preterm infants <34 weeks treated with HHHFNC vs nasal continuous positive airway pressure and found that there was no difference in neonatal pain scale however parents
18
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Table 7 e Study population and intervention of key trials on HFNC. Name Lena Ignacio39 Collin CL40 Yoder41 Manley42 Total
Year published
GA (wks)
No. of subjects
2013 2013 2013 2013
<32 <32 28e42 <32
132 132 432 303 999
Intervention HFNC HFNC HFNC HFNC
or or or or
CPAP postextubation CPAP postextubation CPAP primary or postextubation CPAP post extubation
Table 8 e Primary and secondary outcomes of trials on HFNC. Study
Type of study
Primary outcome
Secondary outcome
Lena Ignacio
RCT
No difference in extubation failure within the 7 days after extubation
Colin CL
RCT
Yoder
RCT
No difference in extubation failure in 7days (22% vs 34%) No difference in need for intubation within 72 hours of noninvasive therapy (15.1% vs 11.4%; P ¼ 0.252)
Manley
RCT
No difference in treatment failure (34% vs 26%)
preferred HHHFNC.43 Mean respiratory rate over 24 hours was lower during HHHFNC than CPAP. To summarize noninvasive ventilation has been shown to be effective as the primary mode of treatment for RDS even in extremely preterm infants. A trial of early CPAP in delivery room should be offered to these neonates. Infants who fail on CPAP should be given early surfactant with INSURE strategy. HHHFNC looks like a promising strategy from the initial trials however larger studies are required.
Conflicts of interest All authors have none to declare.
references
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HHHFNC had less nasal trauma than those assigned to NCPAP (p < 0.001). 20% of infants on NCPAP were changed to HHHFNC due to nasal trauma in the first 7 days after extubation. HHHFNC reduced the nasal trauma score 3.1 (SD 7.2) vs NCPAP 11.8 (SD 10.7), p < 0.001 HHHFNC infants remained longer on support than nCPAP infants (median: 4 vs 2 days; p < 0.01), No differences in days on Oxygen (median: 10 vs 8 days), BPD (20% vs 16%), Discharge from the hospital on oxygen (19% vs 18%). The HFNC group had a trend toward lower re-intubation rates (18% vs 25%, p ¼ 0.12) Lower nasal trauma rates (40% vs 54%).
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31.
32. 33.
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43.
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