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YPRRV-1119; No. of Pages 8 Paediatric Respiratory Reviews xxx (2016) xxx–xxx

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Paediatric Respiratory Reviews

Mini-Symposium: Ventilation strategies in the paediatric intensive care unit

Non-invasive ventilation in paediatric critical care Sarah L. Morley * Cambridge University Hospitals, Cambridge, England

EDUCATIONAL AIMS The reader will be better appreciate how to describe the:

Physiological beneﬁts of the different NIV therapies as they apply to children Ventilation systems and patient interfaces available to deliver NIV in the critical care unit Role of NIV in speciﬁc clinical settings in childhood Contraindications and complications of NIV in the acute care setting

A R T I C L E I N F O

S U M M A R Y

Keywords: Acute respiratory failure non-invasive ventilation continuous positive airway pressure bi-level positive airway pressure high ﬂow nasal cannulae

Non-invasive ventilation (NIV) is a well recognised and increasingly prevalent intervention in the paediatric critical care setting. In the acute setting NIV is used to provide respiratory support in a ﬂexible manner that avoids a requirement for endotracheal intubation or tracheostomy, with the aim of avoiding the complications of invasive ventilation. This article will explore the physiological beneﬁts, complications and epidemiology of the different modes of NIV including continuous positive airway pressure (CPAP), non-invasive positive pressure ventilation (NIPPV) and high-ﬂow nasal cannula oxygen (HFNC). The currently available equipment and patient interfaces will be described, and the practical aspects of using NIV clinically will be explored. The current evidence for use of NIV in different clinical settings will be discussed, drawing on adult and neonatal as well as paediatric literature. ß 2016 Elsevier Ltd. All rights reserved.

INTRODUCTION Non-invasive ventilation (NIV) is the delivery of mechanical ventilation without an endotracheal tube or tracheostomy. The earliest forms of non-invasive ventilation utilised negative pressures, such as the ‘‘Iron lung’’ or the cuirass ventilator. In recent decades these devices have been largely superseded by noninvasive positive pressure ventilation (NIPPV). NIPPV includes both continuous positive airway pressure (CPAP) and various modes of bi-level ventilation and can be delivered using a variety of ventilation systems. Numerous patient interface options are now available, with masks and nasal prongs the most commonly used. Although not classically considered NIPPV, high ﬂow humidiﬁed

nasal oxygen (delivered via nasal cannulae) is another NIV modality that is gaining prominence in paediatric practice. The aim of NIV is to provide many of the beneﬁts of invasive ventilation while avoiding excessive sedation and reducing lung injury and infection. It is increasingly used as a primary therapy in the management of acute and chronic respiratory failure, but also as an adjunct for weaning following invasive ventilation (‘‘step down’’ approach) and as a strategy to prevent/treat respiratory failure. This review will consider the physiology, indications, complications and modes of delivery for NIV in the paediatric critical care setting. PHYSIOLOGY

* Consultant in Paediatric Intensive Care and Long Term Ventilation. Cambridge University Hospitals, Cambridge, CB2 0QQ UK. E-mail address: [email protected].

The primary aim of mechanical ventilation is to minimise the work of breathing and improve gas exchange. Work of breathing is made up of a number of components, speciﬁcally ‘elastic work’ against the elastic recoil of the lungs, the resistance of the chest

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Please cite this article in press as: Morley SL. Non-invasive ventilation in paediatric critical care. Paediatr. Respir. Rev. (2016), http:// dx.doi.org/10.1016/j.prrv.2016.03.001

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wall and the need for organ displacement and also ‘frictional work’ most of which is due to airﬂow resistance. In a well child or adult, lung compliance is high and airway resistance is low. Newborns have relatively poor lung compliance, although this increases signiﬁcantly in the ﬁrst year of life. Conversely, the high compliance of the infant chest wall decreases with age. Functional Residual Capacity (FRC) is the volume of gas left in the lungs at the end of normal tidal expiration. FRC is the lung volume in which gas exchange is taking place. FRC is determined by the balance between the outward recoil of the chest wall and the inward recoil of the lung. In infants, the outward recoil is low, and the inward recoil is only slightly less than that in adults. This results in a low ratio of FRC to total lung capacity (TLC) of approximately 10%–15%, which limits gas exchange. Airﬂow into the lungs is predominantly driven by a pressure gradient, as the contraction of the diaphragm leads to an increase in lung volume and generates negative pressure. The volume of air moved is dependent on airway resistance and lung compliance. The main site of airway resistance in the adult is the upper airway; but in well children under 5 years the peripheral airway resistance is four times higher than adults, with the major site of resistance being the medium- sized bronchi. Children’s small airways are readily compromised by secretions, inﬂammation, airway constriction or collapse with a 50% reduction in diameter causing 16 fold increase in resistance. This is clinically apparent in infants admitted to PICU with bronchiolitis or older children with severe asthma. Airway resistance decreases as lung volume increases because stretch of elastic ﬁbres causes distension of the small airways, widening their lumen. Conversely, a decrease in lung volume narrows airways, increasing airways resistance, this effect is maximal in the dependent parts of lung due to the weight of supported lung tissue, small airway closure and ventilationperfusion (V/Q) imbalance may follow. In healthy individuals, the energy required for normal quiet breathing is low. Loss of surfactant, increased airway resistance, decreased compliance, airﬂow obstruction (Figure 1) and lung hyperinﬂation increase the work of breathing. As lungs become

‘‘stiffer,’’ respiratory muscles become fatigued, resulting in ventilatory failure. Interventions that increase FRC should improve lung mechanics and enable more work to be generated for the same effort. TYPES OF NIV There are three basic types of NIV. CPAP provides a constant positive pressure throughout the entire respiratory cycle, while the patient is breathing spontaneously. The second is NIPPV (sometimes called BiPAP or Bi-level Positive Airway Pressure ventilation) where the ventilator provides a pre-set positive pressure at inspiration as well as a background positive expiratory pressure. The aim of NIPPV is to support tidal volume as well as FRC and to improve ventilation and gas exchange more effectively than CPAP alone. In general terms, CPAP is used with hypoxic respiratory failure whilst BiPAP is preferred for hypoxic, hypercarbic respiratory failure. NIPPV can be delivered using a range of modes and supported breaths can be delivered at mandatory frequencies, or be triggered by the patient’s spontaneous effort. Depending on the machine, the clinician may need to decide between volume controlled and pressure controlled modes. The main advantage of volume control is that tidal volume (VT) is more stable despite changing lung mechanics, especially if compliance is changing (e.g. in resolving pneumonia). Pressure control allows better volume delivery in systems with leak and may help patient comfort in modes where the patient can control inspiratory ﬂow. The terminology for the various available modes varies between equipment manufacturers. CPAP/PEEP may be called EPAP (expiratory positive airway pressure) in some systems. Pressure control (PC) (sometimes called BIPAP or Spontaneous/Timed) on NIV machines is usually a pressure controlled mode with set inspiratory time (Ti) and Pressure support (PS) (sometimes called Assisted Spontaneous Breathing) is pressure controlled without set Ti that will both deliver standard breaths according to the patient’s spontaneous rate (set rate is for backup only) and respiratory pattern. Various options exist with mandatory (set) rates but these tend not to be favoured for NIV where patients usually have adequate respiratory drive, and therefore need ventilator synchronisation. The third system is negative pressure ventilation, historically delivered by a large negative pressure chamber (iron lung or tank ventilator) but in more recent decades via smaller systems such as the cuirass. The cuirass is a plastic shell that encases the ribs and delivers either mono- or biphasic ventilator support through negative pressure. Further discussion of negative pressure ventilation is outside the scope of this article. A further system that will be discussed is not classically considered NIV, but has considerable overlap. High ﬂow nasal cannula oxygen (HFNC) is a system combining an oxygen blender and a humidiﬁcation system that can deliver high gas ﬂows via nasal cannulae. PHYSIOLOGICAL EFFECTS OF CPAP

Figure 1. Chest radiograph of a toddler with right pulmonary hypoplasia and marked tracheobronchomalacia (stented) supported perioperatively and in the homecare setting using CPAP.

During CPAP, constant ﬂow is applied throughout the respiratory cycle, during spontaneous ventilation. CPAP raises inspiratory pressure above atmospheric pressures and then applies positive end-expiratory pressure (PEEP) to exhalation. It does not generate ﬂow, and so is not truly ventilation, and does not directly increase TV. CPAP does increase FRC by overcoming some of the elastic forces [1]. The increase in FRC can help prevent or reverse atelectasis and reduce V/Q mismatch, reduce pulmonary blood ﬂow shunting and improve gas exchange. However, excessive FRC increase could cause hyperinﬂation and increase functional dead

Please cite this article in press as: Morley SL. Non-invasive ventilation in paediatric critical care. Paediatr. Respir. Rev. (2016), http:// dx.doi.org/10.1016/j.prrv.2016.03.001

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space, worsening V/Q mismatch. Over-inﬂation may also put inspiratory muscles at a mechanical disadvantage, especially if the diaphragm is ﬂattened. In disease processes that cause air trapping and generate intrinsic PEEP, this can increase the elastic forces that must be overcome at the beginning of inspiration. CPAP can help overcome this additional workload and allow inspiratory muscles to be used to generate TV (indirectly increasing TV). CPAP can therefore be especially helpful in obstructive conditions such as asthma or bronchiolitis. Exhaling against resistance splints open smaller airways at the end of expiration, and small bronchi and alveoli do not collapse. In ﬂexible infant airways or older children with tracheobronchomalacia, there may also be splinting of large airways. Inspiratory muscles therefore do not need to work to keep them open to be recruited into inspiration. This reduces inspiratory work, relieves respiratory muscle fatigue and decreases work of breathing. Also, as the alveoli stay open, gas-exchange time is prolonged, which reduces hypoxia and reverses hypercarbic ventilatory failure. CPAP would be expected to be especially beneﬁcial for young children who have low FRC and a high degree of inward recoil, with poor compliance. It may also be especially protective in surfactant deﬁciency and where small airways develop further narrowing and obstruction due to secretions. In neonates, CPAP has long been shown to reduce apnoea. The mechanisms are not entirely clear, but the improvement in respiratory pattern may reﬂect the beneﬁts described above which reduce work of breathing (and fatigue) as well as a reduction in obstructive apnoeic episodes [2]. PHYSIOLOGICAL EFFECTS OF NIPPV NIPPV augments inspiration with volume/pressure support of inspiration as well as PEEP. The delivery of inspiratory support is triggered by patient inspiration and usually titrated to produce either constant volume or constant pressure. Pressure support is used most commonly because it supports inspiration, irrespective of the degree of the patient’s inspiratory effort, increasing TV and minute ventilation (MV). Volume support may be overcome by patient inspiratory effort and can occasionally be detrimental to TV and MV. Pressure support unloads fatigued inspiratory muscles by reducing work of breathing and oxygen consumption [3,4]. Some equipment will further enhance the pressure support mode by incorporating ‘volume guarantee’. NIPPV in all modes may be less effective, or even detrimental, if there is poor synchronisation between patient and ventilator breaths. Cardiovascular effects include decreased venous return due to increased intrathoracic pressure and may compromise a patient with right ventricular dysfunction. Conversely, stable pleural pressure may reduce LV afterload and help support a failing left ventricle. The reduced oxygen demand from inspiratory muscles may also protect a failing myocardium which has limited ability to increase cardiac output. Pulmonary vascular resistance may also be decreased by well-optimised NIV that reduces V/Q mismatch and improves oxygenation. Positive airway pressure may help push ﬂuid out of alveoli and improve gas exchange, which may be especially beneﬁcial in pulmonary oedema. VENTILATORS AVAILABLE TO DELIVER NIV Most specialist dual-limb intensive care ventilators now have NIV modes with a higher degree of leak compensation than their invasive modes (e.g. Servo-I, Draeger Evita). NIV is delivered using non-leak masks on the standard ventilator circuits and the manufacturers have developed speciﬁc interfaces for smaller infants. There are also a number of dedicated ventilators available for critical care NIV in adults that are suitable for older children.

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The simplest NIV options for young children are those initially aimed at the neonatal patient, including the infant ﬂow driver and bubble CPAP (a simple arrangement that generates pressure by passing inspired gases through tubing immersed to a chosen depth in water). There is also a large range of (predominantly single-limb circuit) portable ventilators that are intended for domiciliary use and can generate a full range of NIV modes. These ventilators are usually driven by an internal compressor or blower, rather than being driven by pressurised gas. They require interfaces with built in leak capacity (exhalation port) to facilitate CO2 clearance through the single limb circuit. They commonly do not include oxygen blenders, and supplemental oxygen is usually entrained into the ventilation circuit. These systems have excellent tolerance of mask leaks and often incorporate complex computer algorithms designed to improve patient comfort. Patient-ventilator synchrony can be affected by numerous factors. Ventilators may trigger via inspiratory ﬂow or pressure. Flow trigger may be superior in terms of timing and patient effort [3]. Trigger settings may need to be titrated carefully for each patient: too sensitive and additional breaths may be triggered by leak, inadequate sensitivity and missed breaths may occur. Either situation may lead to increased work of breathing. Some of the more reﬁned NIV systems can use complex ﬂow waveform algorithms to try to ensure synchrony and trigger. Most ventilators cycle into expiration using an algorithm that monitors reduction in inspiratory ﬂow at a given trigger level. This can be unintentionally overcome when there is excessive mask leak and this may prevent expiratory synchrony. Some intensive care ventilation systems provide the ability to use neurally adjusted ventilatory assist (NAVA), which may improve synchronisation of supported breaths to patient effort, using monitoring of electrical impulses from the diaphragm [5]. Higher levels of PS may lead to increased mask leak, although many machines can compensate for this. Higher PS may also compromise patient comfort, by requiring excessive tightness of the mask, and make ventilator tolerance more difﬁcult. HIGH FLOW NASAL CANNULA (HFNC) THERAPY In hypoxic children, supplemental oxygen is the usual initial therapy of choice. Low ﬂow supplemental oxygen is usually provided via nasal cannula, which is limited to around 2L/min of ﬂow due to the irritant effect of non-humidiﬁed gas. Where higher ﬂows or concentrations are needed, delivery is commonly via a loose-ﬁtting face-mask (with or without reservoir bag or mixing system) or via a head-box. The means of delivery is limited by the tolerance of the patient for the devices, and provision of oxygen in young children can be challenging. In adult patients, underhumidiﬁed oxygen has been associated with discomfort, even where humidiﬁcation systems have been used [6,7]. In the past decade, oxygen devices that can provide precise oxygen concentrations, at high ﬂow, and with sufﬁcient humidiﬁcation to improve patient comfort, have become increasingly popular in the critical care setting. This modality is commonly described as high ﬂow nasal cannula oxygen (HFNC) and devices are now available from a number of manufacturers. In essence, these devices usually comprise an oxygen / air blender (using either pressurized air or entrained room air) coupled with a heated humidiﬁcation chamber (with or without heated delivery tubing). The manufacturers claim to achieve precise oxygen ﬂow up to 100% oxygen, with 95-100% relative humidity independent of the patient’s inspiratory demand. Flow rates of up to 60L/min can be achieved, depending on the system used. HFNC has been adopted increasingly widely in paediatric practice, initially in the neonatal critical care and subsequently in

Please cite this article in press as: Morley SL. Non-invasive ventilation in paediatric critical care. Paediatr. Respir. Rev. (2016), http:// dx.doi.org/10.1016/j.prrv.2016.03.001

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4 Table 1 Proposed therapeutic beneﬁts of HFNC [8]

Increased fraction of inspired oxygen (FiO2) - Gas inlet ﬂow prevents secondary room-air entrainment; - Provides anatomic oxygen reservoirs using the nasopharynx and oropharynx; - Washing out of airway dead space; Development of a CPAP effect - Decreases atelectasis; - Improvement in pulmonary ventilation-perfusion; - Decreases work of breathing: counteracts intrinsic PEEP; Greater patient comfort - Warmed and humidiﬁed nasal oxygen can be better tolerated, especially with ﬂows >6 LPM.

the high dependency setting and in paediatric critical care. It is increasingly used in the emergency department and during patient transport. Recent advances also allow it to be provided in the home care setting, although the heated humidiﬁcation draws signiﬁcant electrical energy, and portable battery options are not currently available for anything other than very short-term transport. In a 2013 study of oxygen delivery via HFNC devices in adult and neonatal patients, Ward [8] concluded that high ﬂow oxygen had the therapeutic effects listed in Table 1. Several authors have suggested that HFNC provides low-level positive pressure [9]. Milesi demonstrated, in babies with bronchiolitis, that HFNC ﬂow 2 L/kg/min was associated with the generation of a mean pharyngeal pressure 4 cmH2O although only ﬂows 6 L/min provided positive PP throughout the respiratory cycle [10]. Some authors also suggest that HFNC allows improved mucous clearance and reduced mucous plugging [11]. In clinical use for children, the most striking beneﬁt of HFNC is improved patient tolerance of oxygen therapy; allowing better oxygen delivery for even the most agitated infants and young children. A recent meta-analysis suggests that HFNC is as effective as other forms of NIV for preterm infants and that it is associated with a lower incidence of nasal trauma [12]. HFNC was also shown to be better tolerated and more comfortable than an oxygen mask in adult patients [13]. HFNC was shown to produce improved oxygenation and reduced respiratory rate, with improvement in oxygenation, in a systematic review of adult HFNC [14]. In a randomized crossover study of 50 mechanically ventilated patients ready for extubation, HFNC provided as effective oxygenation and was better tolerated than standard oxygen delivery [15]. HFNC now appears to be being used in paediatric practice as a well-tolerated alternative to CPAP in infants, and to some degree older children. Clinicians are exploring the use of higher gas ﬂows in certain conditions. Although there is little objective evidence supporting this practice, it appears likely that CPAP will be entirely superseded by HFNC in infant respiratory distress, if current trends continue.

Full-face (oronasal) mask – where the most effective ventilation is required, full-face masks are the interface of choice, especially in the acute setting [16]. They offer the most rapid improvement in arterial oxygenation and CO2 clearance during NIV because of the high quality, leak free, seal that can be provided. Many patients ﬁnd them claustrophobic, and they also bring an increased risk of aspiration and air swallowing. They limit cough and communication and patients are not able to eat while wearing them. They are frequently not well tolerated by children, except when severely dyspnoeic. Nasal mask – nasal masks are the usual interface used in domiciliary ventilation and are also commonly used in the acute setting. There are miniaturised versions made for neonatal intensive care systems and a wide range of non-leak options designed for older children on dual limb intensive care ventilators. A major challenge is the lack of range of nasal masks optimised for infants and young children, especially those with facial dysmorphism. The most reﬁned versions have been developed for long-term use on portable ventilators, and usually incorporate a leak system or exhalation port for CO2 clearance. Nasal masks can be stably secured, offer higher levels of patient comfort, reduce claustrophobia and can deliver ventilation effectively. They allow patients to cough, eat and speak and reduce air swallowing. The signiﬁcant leak, which occurs with mouth opening, can limit ventilation effectiveness, especially for those who sleep open-mouthed, and can cause signiﬁcant discomfort to some children. This may be partially overcome with the use of chin-straps to reduce mouth opening, although this is not always well tolerated in children. Total face mask – the total face mask covers the whole face with a seal around the chin and hairline. They may be useful for patients who have developed pressure areas around the nose and mouth. They carry similar concerns regarding suctioning, aspiration and communication difﬁculty as full-face masks. Helmet – helmet devices encase the whole head, usually with a seal at the neck or shoulder. They have been advocated for babies as well as older children and adults [17]. They have a higher volume than other mask systems, but may promote comfort through even distribution of pressure. The use of a helmet may lead to poorer synchronisation than with a mask [18] due to delayed trigger and missed breaths. Mouthpiece – mouthpiece ventilation is most commonly used in the domiciliary setting, It is especially helpful in the daytime support of patients with neuromuscular disorders. Modern systems use a mouthpiece ﬁxed in a position accessible to the mouth of the patient. This is connected to a passive ventilation system that delivers positive pressure when triggered by a patient breath. Patients choose to trigger ventilation by making a seal on the mouthpiece and initiating a breath. This system requires the patient to be awake, to have some neck mobility and to be able to form a seal around the mouthpiece. The system can allow patients to eat and drink and speak independently, as they use the ventilator to support FRC and TV intermittently and as needed. CONTRAINDICATIONS AND COMPLICATIONS

PATIENT INTERFACES Nasal prong – the nasal prong was a commonly used CPAP delivery device used in NICU and PICU in previous decades. It is essentially a nasopharyngeal airway attached to a CPAP generator. Although an adequate delivery system, it is almost certainly uncomfortable and often poorly tolerated. Nasal cannula – many neonatal systems rely on a closely ﬁtted nasal cannula secured by a ﬁtted cap. These devices are thought to be more comfortable and are better tolerated than a prong. If well ﬁtted they can provide good CPAP delivery, but they may cause severe pressure effects and erosion of the nasal septum and nostrils.

NIV and HFNC are generally safe modalities, but complications are well documented. The successful use of these therapies relies upon appropriate case selection and the presence of expert staff, trained to closely monitor the child and the equipment and to modify settings and interfaces accordingly. The contraindications and complications of CPAP and NIV are listed in Table 2 and those of HFNC in Table 3. EPIDEMIOLOGY OF NIV There has been a steady increase in published research on NIV in the past two decades, followed by a recent increase in articles

Please cite this article in press as: Morley SL. Non-invasive ventilation in paediatric critical care. Paediatr. Respir. Rev. (2016), http:// dx.doi.org/10.1016/j.prrv.2016.03.001

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YPRRV-1119; No. of Pages 8 S.L. Morley / Paediatric Respiratory Reviews xxx (2016) xxx–xxx Table 2 Contraindications and complications of CPAP / NIV [19,20]. Absolute Contraindications Apnoea Shock Cardiopulmonary arrest or Peri-arrest (except palliation) Life threatening hypoxaemia (except palliation) Decreased conscious level GCS <8 Inability to protect airway Untreated Pneumothorax Recent facial surgery / signiﬁcant facial fractures Inadequate monitoring / trained stafﬁng Relative Contraindications Excessive vomiting Confusion / agitation Signiﬁcant chest trauma Haemodynamic instability Facial / airway burns Bullae Recent upper gastrointestinal surgery Excessive secretions Bowel obstruction Nasal obstruction / atresia Epistaxis Complications Inadequate gas exchange Pneumothorax Decreased cardiac output (decreased pre-load and increased after-load) Gastric and abdominal distension Aspiration Pressure areas (nasal, facial, scalp) Mucus plugging Non-compliance / agitation / discomfort Failure to synchronise Interface leak – eye irritation and treatment failure Equipment failure Failure to wean

related to HFNC. These trends appear to mirror the rise in clinical use of both modalities. Wolﬂer and colleagues studied the use of NIV in Italian PICUs in 2011-12 and compared the numbers with a cohort from 2006-7. Overall 8.8% of admissions used NIV at some point. In patients not ventilated at admission, NIV was used in 15.3% with a signiﬁcant increment across the study years from 11.9% in 2006 to 21.6% in 2012. The NIV failure rate also increased from 10% to 16.1% in the same time period, possibly suggesting that NIV was being used in higher risk cases over time. Overall, the

Table 3 Contraindications and complications of HFNC Contraindications and complications of HFNC Absolute contraindications Apnoea Shock Cardiopulmonary arrest or Peri-arrest (except palliation) Life threatening hypoxaemia (except palliation) Nasal obstruction Base of skull fracture / CSF leak Inadequate monitoring / trained stafﬁng Relative Contraindications Recent upper gastrointestinal surgery Bowel obstruction Recent facial surgery / signiﬁcant facial fractures Complications Inadequate gas exchange Pneumothorax Gastric and abdominal distension Aspiration Failure to recognise deterioration Pressure areas (nasal, facial) Non-compliance / agitation / discomfort (less common) Equipment failure / cannula blockage Failure to wean

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greatest increase in NIV was in patients with primary respiratory diagnoses, especially bronchiolitis. Young children were more likely to receive CPAP and older children BIPAP. Similar trends were noted within a large Australian PICU between 1982 and 2006 [19]. SPECIFIC INDICATIONS Acute respiratory failure and Acute Respiratory Distress Syndrome NIV has been shown to reduce the likelihood of intubation in adults with acute respiratory failure in a number of settings [20]. A prospective randomized – controlled study in Chile showed that BIPAP could reduce intubation rate in children with acute respiratory failure (ARF) [21]. Essouri [22] conﬁrmed that NIPPV was associated with a signiﬁcant improvement in breathing pattern, gas exchange and respiratory muscle output in children with hypercapneic respiratory failure. Santschi and colleagues [23] undertook a point prevalence study in the US and Europe to determine the ventilation management of children with acute lung injury (including ARDS). Of 165 children identiﬁed, only 14 (8.5%) were receiving NIV at the point studied, and of these 6 (42.9%) were less than one year of age and 8 (57%) met the authors’ criteria for ARDS. NIV patients had a lower oxygenation index at the time of study (p < 0.001) and a lower PIM2 score (non-signiﬁcant) than the children receiving invasive ventilation or HFOV, suggesting that they represented the less severe end of the ALI/ARDS spectrum. In a retrospective study in children by Dohna Schwake [24], CPAP (escalated to pressure support if required) provided from a dual limb ventilator with full-face masks was used to treat ARF. They demonstrated a high level of patient tolerance and (17/74) 23% went on to intubation (although there was a total failure rate of 28% due to non-intubation orders in some cases). A consensus document on the use of NIV in acute respiratory distress syndrome (ARDS) in children has recommended that NIV may be an effective therapy to prevent intubation if used early in children at risk for ARDS, but that it is not a suitable therapy for moderate to severe established ARDS, where treatment failure is common [16]. They also recommended that NIPPV offers clinical beneﬁt over CPAP in this setting. The efﬁcacy of HFNC in early ARDS in children is not currently known. A randomized controlled trial in adults comparing HFNC with standard oxygen therapy and NIV failed to show signiﬁcantly different intubation rates between the groups, although the HFNC group showed a signiﬁcantly higher 90-day survival rate [25]. Bronchiolitis The lack of randomized studies in the use of CPAP in bronchiolitis identiﬁed for a recent Cochrane systematic review led to a conclusion that the effect of CPAP in bronchiolitis is uncertain. Clinical practice, however, has clearly moved towards NIV in this setting and numerous non-randomized studies support the use of CPAP in this group. One small randomized trial suggested that CPAP rapidly decreased inspiratory work in infants with acute bronchiolitis, with greatest early improvement in those with more severe presentation [26]. A retrospective review [27] of 520 infants with bronchiolitis identiﬁed that assisted ventilation was required for 399 (76.7%) patients. 114 (28.6%) patients were intubated directly and 285 (71.4%) had a trial of non-invasive ventilation (NIV). Use of NIV increased by 2.8%/year alongside a decline in intubation rates (1.9%/ year) (p = 0.002). Of NIV patients 83.2% required NIV alone and16.8% went on to require intubation. Median LOS was signiﬁcantly shorter in those who received NIV alone compared to

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those with invasive ventilation (either alone or following failed NIV). Lazner [28] reviewed the use of NIV in 67 ventilation episodes identiﬁed from 65 patients with bronchiolitis. 55 episodes (34 with apnoea) were treated with NIV alone and 6 were invasively ventilated at presentation. Among those on NIV 6 failed to respond and were invasively ventilated. Six patients were invasively ventilated at presentation. The authors therefore concluded that NIV was 80% successful for respiratory support in severe bronchiolitis. For those responding to NIV respiratory parameters had improved by 2 hours and this was sustained at 4 hours. Responders had a shorter hospital stay and shorter duration of ventilation and oxygen use. Borckink [29] retrospectively reviewed 133 infants requiring ventilation support (NCPAP n = 89, IMV n = 46). NCPAP was independently associated with shorter overall ventilation duration (hazard ratio 2.3, 95% CI 1.1-4.7, p = 0.022) after adjusting for PRISM II score, PCO2, SpO2 /Fi O2 ratio, chronic lung disease and occurrence of clinically suspected bacterial infection. Essouri [30] retrospectively demonstrated that institution of NCPAP was responsible for a signiﬁcant reduction in intensive care costs for children requiring ventilator support for severe bronchiolitis through shorter duration of ventilation, PICU stay and hospital length of stay. A small study by Cambonie [31] demonstrated reduced respiratory distress score (especially use of accessory muscles and wheeze) as well as shorter inspiratory and longer expiratory time after initiation of NCPAP. Oesophageal pressure monitoring showed reduced inspiratory effort and abolished expiratory muscle activity suggesting effective unloading of respiratory muscles by nCPAP in acute bronchiolitis. Infants with bronchiolitis are now commonly treated with HFNC although a recent Cochrane review [32] could identify only a single small randomized study. No studies have compared the effects of CPAP with HFNC in this group. A small physiologic study has shown that respiratory rate and respiratory effort can be reduced by HFNC in bronchiolitis [10]. Post-operative and post- extubation respiratory support NIV is an appealing option for reducing reintubation rates following surgery or invasive ventilation episodes. NIV has been

widely adopted in adults with respiratory insufﬁciency, but has been less commonly used in the paediatric population. A small randomized study of NIV versus oxygen therapy in young children post-extubation failed to show any statistically signiﬁcant reduction in reintubation rate with NIV [33]. In preterm infants a randomized study showed equivalent levels of treatment failure (34.2% vs. 25.8%) for re-intubation prevention post-extubation using HFNC or CPAP [34]. NIV is used in many centres to support children with neuromuscular or chronic respiratory disease pre- and post- major surgery (e.g. scoliosis repair, see Figure 2), but evidence relating to this practice is currently limited [35]. In adults following cardio thoracic surgery, HFNC has been shown by Stephan and colleagues to be not inferior to BIPAP [36]. Treatment failed in 87 subjects: 21.0% using HFNC and 21.9% BiPAP. No signiﬁcant mortality differences were found (6.8% vs. 5.5% respectively). Skin breakdown was signiﬁcantly more common with BiPAP after 24 hours (10%vs. 3%). Asthma A pilot study [37] which randomized children to NIPPV versus standard care has shown that NIV can be safe and well tolerated in children with status asthmaticus, when used with short acting beta-2 agonists. They demonstrated greater improvements in asthma score and respiratory rate in the NIPPV group. 9 out of 10 children tolerated the therapy and there were no major complications. In a crossover study using 2-hour sessions of NIPPV versus oxygen therapy, the researchers demonstrated lower respiratory rates, asthma scores, and reduced oxygen concentrations during the NIPPV phases [38]. Airway obstruction HFNC and NIV are used to support children with large airway obstruction in the NICU and PICU, but very little published data supports this practice. One small observational study has shown improvements in work of breathing in infants with tracheobronchomalacia using CPAP and BIPAP [39]. NIV is a well established long term therapy for obstructive sleep apnoea in childhood; a topic which has been thoroughly reviewed elsewhere [40].

Figure 2. Chest radiograph of a child with severe neuromuscular scoliosis (due to Ullrich’s congenital muscular dystrophy) supported pre- and post scoliosis repair using acute and domiciliary BIPAP.

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7

Sickle cell crisis

FUTURE DIRECTIONS FOR RESEARCH

In sickle cell crisis (in adults) Fartoukh et al [41] showed that respiratory rate and gas exchange improved faster with NIV than with oxygen alone. NIV did not signiﬁcantly reduce the number of patients remaining hypoxemic at day 3, and reported patient discomfort was greater.

The assess the role of NIV in preventing the need for reintubation following surgery in the ICU patient with respiratory compromise. To determine whether NIV can reduce the need for invasive ventilation in the immunocompromised patient with a respiratory deterioration.

Immunocompromised patients The potential beneﬁts of NIV appear to be especially great in the immunocompromised patient, speciﬁcally with the aim of reducing the likelihood of invasive ventilation. Invasive ventilation brings with it the risks of iatrogenic complications such as ventilator acquired pneumonia, increased requirement for central or multiple venous access and increased length of stay. The role of NIV in children is currently informed only by retrospective analyses. The largest study compared 239 children who received at least 24 hours of NIV with 119 who were primarily invasively ventilated. 74% of the NIV group were never ventilated. 77% of the NIV group survived to PICU discharge as compared to 39% of the invasive group [42]. Two other small studies showed similar ﬁndings [43,44]. Although these studies all suggest a positive role for NIV in promoting survival, none of these studies can conclusively prove a causative association. A large randomized controlled study of NIV versus oxygen therapy in hypoxemic adults with immunocompromise did not show any difference in 28-day mortality, oxygenation failure, duration of mechanical ventilation or length of stay [45]. Many of the patients in each group received oxygen as HFNC and this may have made the outcomes less clear. Two older and smaller randomized studies did show improved oxygenation and reduced intubation rates in patients receiving NIV [46,47]. TREATMENT FAILURE In Dohna Schwake’s [24] heterogeneous PICU patient group receiving CPAP and/or BIPAP the only factor identiﬁed as an association with treatment failure was a pH <7.25. In other studies different reasons for NIV failure have been suggested including ventilation–perfusion impairment, higher Pediatric Risk of Mortality score (PRISM), lower respiratory rate decrease in early therapy [48] and the presence of ARDS, higher Pediatric Logistic Organ Dysfunction score [49] and FiO2 >80% [50], higher mean airway pressure (MAP) and inspired oxygen [51]. Regular assessment of patients during the early phase of NIV or HFNC is likely to be key in identifying treatment failure and preventing further decline [52]. CONCLUSIONS NIV and HFNC are now well-established therapies in the PICU, although much of the relevant research has been drawn from neonatal and adult intensive care populations. In paediatric use these modalities have been adopted far more rapidly than evidence has been generated to support them, and in bronchiolitis and early ARF, most clinicians would consider that equipoise no longer applies and further randomized research is unlikely. In general, NIV is commenced with a speciﬁc aim of making intubation less likely and thus reducing the complications associated with invasive ventilation. NIV and HFNC are, however, not free of complications, and further analysis of costs and beneﬁts would be helpful.

FUTURE RESEARCH DIRECTIONS Speciﬁc beneﬁts of CPAP / NIPPV and HFNC in immunocompromise and post-extubation Physiologic studies to optimise ventilator synchrony and reduce work of breathing Improved patient interfaces for children

PRACTICE POINTS Successful NIV delivery depends upon selection of the most appropriate equipment and interface for the individual child Patients receiving NIV in the acute setting require a high level of support and monitoring, especially in the early phase of therapy, to optimse efﬁcacy and detect treatment failure NIV is recommended in early acute lung injury, but is likely to fail in moderate to severe ALI/ARDS and is not recommended.

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Please cite this article in press as: Morley SL. Non-invasive ventilation in paediatric critical care. Paediatr. Respir. Rev. (2016), http:// dx.doi.org/10.1016/j.prrv.2016.03.001