Noninvasive Ventilation and High-Flow Nasal Cannulae Therapy for Children with Acute Respiratory Failure An overview *

Noninvasive ventilation (NIV) refers to the use of techniques to deliver artificial respiration to the lungs without the need for endotracheal intubation. As NIV has proven beneficial in comparison to invasive mechanical ventilation, it has become the optimal modality for initial respiratory support among children in respiratory distress. High-flow nasal cannulae (HFNC) therapy is a relatively new NIV modality and is used for similar indications. This review discusses the usefulness and applications of conventional NIV in comparison to HFNC.


Conventional Noninvasive Ventilation
5][6] In an adult randomised controlled trial (RCT), Antonelli et al. found that NIV resulted in a reduced risk of pneumonia and sinusitis; moreover, pulmonary gas exchange resulted in similar effects to invasive mechanical ventilation within the first hour of treatment. 2añez et al. reported similar findings among 50 children with respiratory failure, in which the NIV group demonstrated significant improvement following gas exchange within the first hour as well as a reduced need for intubation. 4In other studies, NIV use has reduced the length of intensive care unit (ICU) stay. 5,6Furthermore, NIV has economic advantages over conventional mechanical ventilation, as most children undergoing invasive mechanical ventilation require ICU admission and additional interventions, thereby increasing the overall cost of treatment. 7er time, NIV has become the first line of treatment for paediatric respiratory distress in many countries. 1,5,8oreover, in view of the advantages of this modality, its use has been adopted not only in specialised paediatric ICUs but also in general emergency departments, transport teams and general wards, although trained staff and proper equipment are still necessary. 9e c h a n i s m o f a c t i o n CPAP involves the use of continuous distending pressure applied to the airway at a constant level.10,11 On the other hand, BPAP delivers two different types of pressure during inspiration and expiration, respectively.11 Both CPAP and expiratory positive airway pressure during BPAP allow for the relief of upper airway obstruction and lung recruitment resulting in enhanced gas exchange, thereby reducing ventilation-perfusion mismatching and improving oxygenation and carbon dioxide (CO 2 ) clearance.10,11 In addition, BPAP devices have the option of a backup rate to ensure a minimum respiratory rate is maintained in cases where respiratory effort is inadequate.
Essouri et al. reported the physiological effects of NIV in children presenting with acute respiratory failure; the study showed that children receiving NIV had significantly improved work of breathing (WOB) as well as blood gas results and inspiratory muscle effort. 12Additionally, oesophageal and diaphragmatic pressure-time products dropped with NIV treatment, while measured tidal volume and minute ventilation increased. 12l i n i c a l i n d i c at i o n s a n d a p p l i c at i o n s For infants and children presenting with acute respiratory distress and secondary respiratory failure, NIV is the first line of treatment to improve gas exchange, avoid invasive ventilation and prevent extubation failure.Ganu et al. reported an annual 2.8% increase in NIV use among bronchiolitis patients over a nine-year period, with an annual 1.9% drop in the rate of invasive ventilation.5 Both Wolfler et al. and Essouri et al. have reported similar declines in the rate of invasive mechanical ventilation corresponding to an increase in NIV use.8,13 Different success rates with NIV use have been reported for various clinical diseases.Essouri et al. and Abadesso et al. reported overall success rates of 77% and 77.5%, respectively, among paediatric patients receiving NIV for different causes of respiratory distress.13,14 However, children admitted with acute respiratory distress syndrome (ARDS) has less favourable outcomes compared to those admitted with pneumonia, sickle cell disease presenting with acute chest syndrome and immunocompromised patients presenting with acute respiratory failure.13 In two other studies of infants treated for bronchiolitis, the NIV success rate was 81-83%.5,15 Children with asthma also reportedly respond well to NIV treatment, with improvements in WOB and asthma severity scores.16 In addition, NIV is also indicated in the prevention of postextubation respiratory failure, either prophylactically for children at high risk of extubation failure or to treat those with postextubation respiratory distress or failure.In a recent study, the NIV success rate was higher when utilised prophylactically in comparison to its use as a rescue treatment.17 In addition, NIV resulted in an overall success rate of 85% in the postextubation period among children receiving treatment after open heart surgery.18 Children with underlying malignancies who present with acute respiratory failure are also candidates for NIV.However, careful patient selection is required as therapy usually fails for cases with a more severe clinical course, significant pulmonary disease or haemodynamic instability.19 The NIV success rate among children with ARDS and substantial acute lung injuries is between 30-50%.20 Therefore, it is highly advised that children with ARDS are closely monitored when NIV is initiated so that any deterioration in their respiratory state can be immediately addressed.Furthermore, NIV is recommended early during the ARDS disease process in order to avoid muscle fatigue from the increase in WOB and to improve gas exchange.20 Table 1 provides a summary of selected studies investigating NIV use in children.4,8,14,19 i n t e r fa c e c h o i c e A wide range of interfaces are available for NIV therapy, including helmets, full-face masks, oronasal masks, nasal masks and nasal cannulae.For children, the choice of interface plays an important role in affecting their NIV tolerance.An ideal NIV interface is one that is comfortable, does not cause claustrophobia, has minimal leakage and results in the least patient-ventilator asynchrony.Nasal masks are generally better tolerated and have less dead space than other types of interfaces.In addition, children are often better able to communicate and thus more comfortable.However, the use of nasal masks is limited in children due to air leaking through the mouth.22,23 In contrast, full-face or oronasal masks result in minimal leakage and ventilator patient asynchrony, although patients can experience intolerance and discomfort.24 Differences in leakage, side-effects and asynchrony with different NIV interfaces are not well described in the literature.The British Thoracic Society recommends having different sizes and types of NIV interfaces available to ensure treatment success.25

m o n i t o r i n g a n d p r e d i c t i n g r e s p o n d e r s
Although NIV use is primarily advised for children with respiratory distress, it is also recommended to differ-entiate those who respond to treatment from non-responders so as to avoid delaying intubation, if necessary, thus worsening patient outcomes. 20Specific predictors of NIV failure include worsening vital signs (e.g.[28][29][30] The SpO 2 /FiO 2 ratio is used as a clinical indicator for hypoxaemia, with a lower ratio indicating greater severity. 26Children with more severe disease upon admission are at increased risk of NIV failure. 27Physiological parameters before treatment have also been linked to treatment failure, with responders showing improved respiratory rates, heart rates and blood gas results. 28In particular, response to NIV therapy is demonstrated by improved respiratory rates one hour after treatment, with continued improvement in subsequent hours. 29Likewise, responders' heart rates have shown improvement 2-6 hours following the intervention. 3028]30 Finally, children with underlying respiratory disease alone are less likely to fail NIV treatment compared to children with other comorbidities, such as underlying malignancies. 27,29gh-Flow Nasal Cannulae HFNC therapy delivers a humidified oxygen and gas mixture heated to approximately 34 °C, allowing higher air flow rates exceeding 2 L/minute. 3,31,32These features enable the delivery of air flow equal to or greater than the inspiratory flow of a spontaneously breathing patient. 31NC also has the ability to generate distending pressure. 3,312][33] Long et al. showed that, in a paediatric population presenting with respiratory failure, HFNC had a success rate of 61% when initiated in the emergency department. 34e c h a n i s m o f a c t i o n HFNC works via different mechanisms to improve oxygenation and ventilation and reduce WOB.Moreover, HFNC reduces nasopharyngeal dead space due to the effect of the high flow on nasopharyngeal oxygen-depleted gas, leading to CO 2 clearance.3 HFNC improves oxygenation as it provides higher FiO 2 compared to conventional oxygen therapy.Additionally, as the gas flow is humidified and warmed, this modality improves lung compliance, reduces airway resistance and aids in secretion clearance.3,31 Depending on the patient's weight, the HFNC flow and the size of the nasal cannulae compared to the nares, HFNC is associated with the generation of positive end-expiratory pressure (PEEP).35 The amount of generated PEEP is also affected by the degree of leakage via the mouth.35,36 An early study of preterm babies suggested that HFNC can generate positive distending pressure similar to that of CPAP and therefore treat apnoea of prematurity.37 In a neonate, a flow rate of 3-5 L/minute is equivalent to CPAP at 6 cm of water (H 2 O), with effective distending pressure.35,38 Moreover, during HFNC, inspiratory pressure remains positive throughout the breathing cycle.Milési et al. measured oesophageal pressures at different flow rates, with a pharyngeal pressure of 0.2 cm of H 2 O at 1 L/minute increasing to 4 cm of H 2 O at 6-7 L/minute.39 Overall,  The use of HFNC has broad indications, including different causes of respiratory distress.Frat et al. found that the use of HFNC in hypoxic respiratory failure reduced the intubation rate to 38%, leading to a greater number of ventilation-free days in an ICU.41 Roca et al.
showed that HFNC reduced the need for mechanical ventilation among patients with respiratory failure post-lung transplant. 42Kawaguchi et al. conducted a retrospective study evaluating intubation rates in a group of children presenting with respiratory distress. 43his study showed reduced intubation rates among children receiving HFNC in comparison to those who did not receive HFNC (38% versus 63%), with more ventilator-free days in the former group.However, no differences were observed in terms of mortality rate or paediatric ICU (PICU) length of stay. 43 a Cochrane review evaluating the effectiveness of HFNC among children with bronchiolitis, a single pilot study with 19 participants was identified comparing HFNC with oxygen delivery via a headbox; however, there was insufficient evidence to determine the effectiveness of HFNC for treating bronchiolitis. 44evertheless, a recent multicentre RCT comparing the outcomes of infants with bronchiolitis treated with low-flow oxygen or HFNC showed that there was a reduced need for escalation of care among the group receiving HFNC. 45In addition, Schlapbach et al. evaluated the safety of HFNC while transporting ill children between hospitals. 46The majority of these children had respiratory conditions requiring admission to a PICU, of which 77% were diagnosed with bronchiolitis.Overall, the intubation rate decreased from 49% to 35% (P <0.001), with none of the HFNC patients requiring intubation, developing pneumothorax or going into cardiac arrest. 46Two other studies similarly noted a reduction in intubation rates among infants admitted with bronchiolitis following the introduction of HFNC in PICUs (37% versus 7% and 23% versus 9%, respectively). 47,48Various studies investigating HFNC use in children and adults are presented in Table 2. 41,45,[49][50][51][52] In Spain, two RCTs involving seven adult ICUs were conducted to assess the effect of using HFNC in the postextubation period on the incidence of reintubation and respiratory failure in high-and low-risk patients, respectively. 49,50In the first trial, high-risk patients who passed spontaneous breathing trials randomly received either HFNC or conventional NIV while, in the second trial, low-risk patients randomly received either HFNC or conventional oxygen therapy. 49,50ble 2: Summary of selected studies evaluating the use of high-flow nasal cannulae in children and adults 41,45,[49][50][51][52] Author  No difference was found between the two modalities in terms of preventing reintubation or postextubation respiratory failure among high-risk patients. 49However, in low-risk patients, HFNC was superior to conventional oxygen therapy in reducing the risk of reintubation within a 72-hour period. 50d va n ta g e s a n d l i m i tat i o n s For infants, HFNC therapy is well tolerated, therefore reducing the need for sedation.Furthermore, the humidified oxygen improves secretion clearance. 3Among adults, HFNC minimises mouth dryness and is generally perceived to be more comfortable. 53Spentzas et al. assessed the comfort of 46 children with respiratory distress at 60-90 minutes and 8-12 hours following HFNC therapy and found that comfort significantly improved following HFNC use. 40Generally, HFNC use has been demonstrated to be safe with few reported complications.In 2005, there was an outbreak of Ralstonia mannitolilytica infections due to contaminated HFNC devices (Vapotherm Inc., Exeter, New Hampshire, USA), which were subsequently withdrawn from the market. 54In addition, three cases of serious air leak syndrome have been reported. 33evertheless, the over-all risk of air leak syndrome with HFNC is no higher than that of low-flow oxygen.As with NIV, certain clinical features can predict the response to HFNC therapy.For example, children with improved respiratory distress and heart rates are likely to be responders to HFNC therapy. 55Moreover, FiO 2 requirements and illness severity are predictors of response to treatment.Accordingly, children with high SpO 2 /FiO 2 ratios-indicating milder forms of lung injuries-and those with lower respiratory rates are likely to respond to therapy. 35Roca et al. conducted a four-year multicentre prospective observational cohort study to assess possible predictors of HFNC failure, in which the respiratory rate oxygenation (ROX) index (i.e. the ratio of pulse oximetry/FiO 2 to respiratory rate) was used to assess therapy success. 56At a cut-off value of ≥4.88, the ROX index 12 hours after the initiation of HFNC therapy yielded a sensitivity of 70% and specificity of 72.4% in predicting successful treatment for patients with pneumonia. 56inical indicators for HFNC therapy failure include a lack of improvement in oxygenation, thoracoabdominal asynchrony and the presence of haemodynamic and neurological impairment. 42,57,58According to Oto et al., a drop in heart or respiratory rate and improvement in the mean dyspnoea score 30 minutes and 12 hours after the initiation of HFNC are indic-ative of successful treatment. 55In a cohort of 113 infants with bronchiolitis undergoing HFNC therapy, Abboud et al. observed that a higher Paediatric Risk of Mortality Score-which indicates illness severity upon admission to the ICU-as well as an elevated CO 2 level before treatment were predictors of treatment failure. 59The study also emphasised that non-improvement in WOB was noted among the non-responders. 59

Comparison of Therapies
Early studies have shown that the effectiveness of HFNC is similar to CPAP, with comparable effects on WOB, oxygenation and gas exchange. 37,60The advantages of the HFNC system include the easy setup and increase in the child's comfort. 34,40In general, HFNC therapy is safe and associated complications, as described earlier, are uncommon.Likewise, NIV treatment is safe, with dry eyes, dry mouth, claustrophobia and pressure effects on the areas of the face covered by the mask being the most common complications. 22cently, several studies have assessed clinical outcomes among children receiving CPAP and HFNC therapy.Pedersen et al. reviewed clinical outcomes among a historical cohort of 49 infants admitted with severe bronchiolitis and treated with CPAP or HFNC. 51n both groups, respiratory rate declined with treatment; however, improvements in respiratory distress were faster with CPAP treatment.Moreover, in 55% of children, the mode of treatment was changed from HFNC to CPAP due to an increase in respiratory distress. 51Additionally, a multicentre RCT evaluated the clinical outcomes of infants presenting with moderate-to-severe bronchiolitis, comparing CPAP treatment at a PEEP level of 7 cm of H 2 O to HFNC therapy at a rate of 2 L/minute/kg. 52Only 5.7% of the infants required intubation, with the rest managed using either HFNC or CPAP.Interestingly, 31% of the CPAP group failed initial respiratory support compared to 50.7% of the HFNC group. 52The most common reason for failure in the CPAP group was discomfort, while the HFNC group failed due to an increase in respiratory distress.In both groups, there was a crossover of treatment in cases of failure or intolerance to the initial support modality. 52n observational study by Pilar et al. investigated the outcomes of children with asthma who were treated with HFNC or NIV. 61The study showed no failure in the NIV group, while respiratory support had to be changed to NIV among 40% of children in the HFNC group, thus showing that CPAP was associated with a more rapid improvement in respiratory distress. 61ollectively speaking, while CPAP and HFNC were both associated with improvement in respiratory distress, CPAP was superior in treating children with significant respiratory distress.On the other hand, HFNC was associated with improved tolerance in comparison to NIV. 52 Therefore, HFNC can be used to treat children presenting with milder or less severe forms of respiratory distress and in cases where patient discomfort is a concern.

Conclusion
Globally, NIV treatment has become the first line of respiratory support for children and is safe and effective in the treatment of various causes of respiratory distress.However, healthcare practitioners should be aware of the various indicators or predictors of NIV failure in order to avoid unwanted complications associated with delayed invasive ventilation.HFNC therapy is a promising NIV modality of respiratory support and is indicated for milder forms of respiratory distress.Greater use of NIV may reduce the number of referrals to ICUs as well as prevent complications resulting from invasive mechanical ventilation.