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The Role of Heated Humidified High-flow Nasal Cannula as Noninvasive Respiratory Support in Neonates

  • Ke-Yun Chao
    Affiliations
    Department of Pediatrics, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan

    Department of Respiratory Therapy, Fu Jen Catholic University, Taipei, Taiwan

    Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University Taoyuan, Taiwan
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  • Yi-Ling Chen
    Affiliations
    Department of Pediatrics, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan

    School of Medicine, Taipei Medical University, Taipei, Taiwan
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  • Li-Yi Tsai
    Affiliations
    Department of Pediatrics, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan

    College of Public Health, Institute of Occupational Medicine and Industrial Hygiene, National Taiwan University, Taipei, Taiwan
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  • Yu-Hsuan Chien
    Affiliations
    Department of Pediatrics, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan
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  • Shu-Chi Mu
    Correspondence
    Corresponding author. Department of Pediatrics, 95 Wenchang Road, Shilin District, Taipei 111, Taiwan.
    Affiliations
    Department of Pediatrics, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan

    School of Medicine, Fu Jen Catholic University, Taipei, Taiwan
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Open AccessPublished:February 19, 2017DOI:https://doi.org/10.1016/j.pedneo.2016.08.007
      Recently, heated humidified high-flow nasal cannula (HHHFNC) has been introduced and applied as a noninvasive respiratory support in neonates. Although HHHFNC is widely used in neonates presenting with respiratory distress, the efficiency and safety when compared with nasal continuous positive airway pressure or noninvasive positive pressure ventilation are still controversial. This review aims to evaluate the performance and applications of HHHFNC in neonates.

      Key Words

      1. Introduction

      Respiratory distress syndrome (RDS) is one of the most common respiratory problems to be encountered in the neonatal intensive care unit (NICU). It is also the leading cause of mortality and morbidity in preterm infants.
      • Lampland A.L.
      • Plumm B.
      • Meyers P.A.
      • Worwa C.T.
      • Mammel M.C.
      Observational study of humidified high-flow nasal cannula compared with nasal continuous positive airway pressure.
      The oral and nasal cavity of newborns is not only relatively smaller than those of adults but the trachea and bronchi are also shorter, softer, and narrower. When epithelium edema occurs, airway collapse and the internal diameter of bronchi becomes narrower, which leads to respiratory distress in neonates. Symptoms of respiratory distress due to increased airway resistance include nasal flaring, intercostal retraction, grunting, and paradoxical movement. Moreover, neonates born at a gestational age (GA) of < 36 weeks may have RDS due to the immature lung and lack of surfactant production.
      Compared with adults, neonates have a smaller oral capacity and larger tongue, which causes difficulty with breathing through the mouth. The anatomical differences force them to breathe through the nasal cavity most of the time, except when crying.
      • Beachey W.
      Respiratory care anatomy and physiology foundations for clinical practice.
      The establishment of noninvasive respiratory support (NRS), such as nasal continuous positive airway pressure (NCPAP)
      • Kirpalani H.
      • Millar D.
      • Lemyre B.
      • Yoder B.A.
      • Chiu A.
      • Roberts R.S.
      • et al.
      A trial comparing noninvasive ventilation strategies in preterm infants.
      and noninvasive positive pressure ventilation (NIPPV), will quickly improve the respiratory distress symptoms.
      • Kugelman A.
      • Feferkorn I.
      • Riskin A.
      • Chistyakov I.
      • Kaufman B.
      • Bader D.
      Nasal intermittent mandatory ventilation versus nasal continuous positive airway pressure for respiratory distress syndrome: a randomized, controlled, prospective study.
      However, complications and irritation from NCPAP and NIPPV have been emphasized, especially iatrogenic damage effects. Recently, heated humidified high-flow nasal cannula (HHHFNC) has been introduced and applied as an alternative NRS.
      • Shoemaker M.T.
      • Pierce M.R.
      • Yoder B.A.
      • DiGeronimo R.J.
      High flow nasal cannula versus nasal CPAP for neonatal respiratory disease: a retrospective study.
      Several studies have suggested that HHHFNC may be as effective as NCPAP and NIPPV.
      • Fernandez-Alvarez J.R.
      • Gandhi R.S.
      • Amess P.
      • Mahoney L.
      • Watkins R.
      • Rabe H.
      Heated humidified high-flow nasal cannula versus low-flow nasal cannula as weaning mode from nasal CPAP in infants ≤28 weeks of gestation.
      • Yoder B.A.
      • Stoddard R.A.
      • Li M.
      • King J.
      • Dirnberger D.R.
      • Abbasi S.
      Heated, humidified high-flow nasal cannula versus nasal CPAP for respiratory support in neonates.
      • Manley B.J.
      • Owen L.S.
      • Doyle L.W.
      • Andersen C.C.
      • Cartwright D.W.
      • Pritchard M.A.
      • et al.
      High-flow nasal cannulae in very preterm infants after extubation.
      • Collins C.L.
      • Holberton J.R.
      • Barfield C.
      • Davis P.G.
      A randomized controlled trial to compare heated humidified high-flow nasal cannulae with nasal continuous positive airway pressure postextubation in premature infants.
      • Kugelman A.
      • Riskin A.
      • Said W.
      • Shoris I.
      • Mor F.
      • Bader D.
      A randomized pilot study comparing heated humidified high-flow nasal cannulae with NIPPV for RDS.
      The aim of this review article is to identify the role of HHHFNC in neonates.

      2. Mechanism of NCPAP

      NCPAP was introduced by Gregory and colleagues in 1971,
      • Gregory G.A.
      • Kitterman J.A.
      • Phibbs R.H.
      • Tooley W.H.
      • Hamilton W.K.
      Treatment of the idiopathic respiratory-distress syndrome with continuous positive airway pressure.
      and subsequently became the standard therapy of neonatal respiratory care in the NICU. NCPAP increases functional residual capacity and inflates collapsed alveoli. It also reduces intrapulmonary shunt
      • Saunders R.A.
      • Milner A.D.
      • Hopkin I.E.
      The effects of continuous positive airway pressure on lung mechanics and lung volumes in the neonate.
      and increases lung compliance, which in turn improves gas exchange.
      • Elgellab A.
      • Riou Y.
      • Abbazine A.
      • Truffert P.
      • Matran R.
      • Lequien P.
      • et al.
      Effects of nasal continuous positive airway pressure (NCPAP) on breathing pattern in spontaneously breathing premature newborn infants.
      This helps to stabilize the breathing pattern in preterm neonates.
      • Martin R.J.
      • Nearman H.S.
      • Katona P.G.
      • Klaus M.H.
      The effect of a low continuous positive airway pressure on the reflex control of respiration in the preterm infant.
      NCPAP also reduces obstructive apnea
      • Miller M.J.
      • Carlo W.A.
      • Martin R.J.
      Continuous positive airway pressure selectively reduces obstructive apnea in preterm infants.
      and decreases airway resistance.
      • Gaon P.
      • Lee S.
      • Hannan S.
      • Ingram D.
      • Milner A.
      Assessment of effect of nasal continuous positive pressure on laryngeal opening using fibre optic laryngoscopy.
      Complications of excessive NCPAP levels may lead to adverse consequences which include air leak syndrome,
      • Ali H.
      • Esampalli S.
      • Aldridge L.
      • Lal M.
      1231 Pneumothorax and Air Leak Syndromes in the Newborn, a Cohort Study.
      intraventricular hemorrhage,
      • Graziani L.J.
      • Spitzer A.R.
      • Mitchell D.G.
      • Merton D.A.
      • Stanley C.
      • Robinson N.
      • et al.
      Mechanical ventilation in preterm infants: neurosonographic and developmental studies.
      and decreased cardiac output.
      • Sturgeon Jr, C.L.
      • Douglas M.E.
      • Downs J.B.
      • Dannemiller F.J.
      PEEP and CPAP: cardiopulmonary effects during spontaneous ventilation.
      Influences of renal function under NCPAP support have been documented, such as diminished urinary output, reduced urinary sodium excretion, and decreased glomerular filtration rate.
      • Tulassay T.
      • Machay T.
      • Kiszel J.
      • Varga J.
      Effects of continuous positive airway pressure on renal function in prematures.
      However, complications from NCPAP have become more evident as gastric distention, nasal bridge lesions, and patient discomfort due to head-securing devices have been documented. Furthermore, a well-trained nurse is needed in the intensive care setting to perform routine care.
      • Jatana K.R.
      • Oplatek A.
      • Stein M.
      • Phillips G.
      • Kang D.R.
      • Elmaraghy C.A.
      Effects of nasal continuous positive airway pressure and cannula use in the neonatal intensive care unit setting.
      Most importantly, the complexity of the ventilator circuit and audible ventilator alarms have been observed to intimidate parents when in close proximity to their child. Compared with NCPAP, HHHFNC is a relatively convenient and comfortable respiratory support.

      3. Mechanism of HHHFNC

      The HHHFNC system is composed of three parts:
      • 1.
        Fixed oxygen concentration system
      To constantly provide a prescribed fraction of inspired oxygen (FiO2), an oxygen blender or venturi system is required. The prescribed concise oxygen concentrations can reduce the complications of oxygen therapy or risk of oxygen toxicity.
      • Agarwal R.
      • Gupta D.
      What are high-flow and low-flow oxygen delivery systems?.
      • Shetty S.
      • Greenough A.
      Review finds insufficient evidence to support the routine use of heated, humidified high-flow nasal cannula use in neonates.
      • 2.
        Humidification system
      Gas flow must be warm (37°C) and humidified [absolute humidity (AH) of 44 mg/L, relative humidity (RH) of 100%]. During inspiration, the upper airway will be warmed and the unhumidified ambient gas humidified (22°C with AH of 10 mg/L and RH of 50%) to isothermic saturation boundary (ISB; 37°C, AH 44 mg/L, RH 100%).
      • Rathgeber J.
      • Züchner K.
      • Burchardi H.
      Conditioning of air in mechanically ventilated patients.
      • Al Ashry H.S.
      • Modrykamien A.M.
      Humidification during mechanical ventilation in the adult patient.
      • Navalesi P.
      On the imperfect synchrony between patient and ventilator.
      • 3.
        High-flow system
      The high-flow system allows the delivery of a flow rate that exceeds the patient's maximum inspiratory demand. The high-flow rate in infants should be at least 2 L/min and usually 2–8 L/min. A high-flow system can generate nasopharyngeal pressure that reduces airway resistance and work of breath, provides end-distending pressure (EDP), increases functional residual capacity, and improves lung compliance. Wash out of nasopharyngeal dead space contributes to improved alveolar ventilation and enhances the efficiency of gas exchange.
      • Agarwal R.
      • Gupta D.
      What are high-flow and low-flow oxygen delivery systems?.
      • Shetty S.
      • Greenough A.
      Review finds insufficient evidence to support the routine use of heated, humidified high-flow nasal cannula use in neonates.
      • Kubicka Z.J.
      • Limauro J.
      • Darnall R.A.
      Heated, humidified high-flow nasal cannula therapy: yet another way to deliver continuous positive airway pressure?.
      • Spence K.L.
      • Murphy D.
      • Kilian C.
      • McGonigle R.
      • Kilani R.A.
      High-flow nasal cannula as a device to provide continuous positive airway pressure in infants.
      • Saslow J.G.
      • Aghai Z.H.
      • Nakhla T.A.
      • Hart J.J.
      • Lawrysh R.
      • Stahl G.E.
      • et al.
      Work of breathing using high-flow nasal cannula in preterm infants.

      4. High-flow oxygen system

      Delivering high-flow gas does not equal high FiO2, just as delivering a low-flow rate does not equal low FiO2. A high-flow oxygen system will provide the prescribed FiO2 as the flow exceeds the patient's demand. Respiratory pattern will not influence the actual partial pressure of inspired for the patient. In a low-flow oxygen system, the inspired partial pressure is unstable as the delivered flow rates are lower than the patient's inspiratory demands, which leads to room air in the oxygen reservoir, in turn reducing the oxygen concentration.
      • Agarwal R.
      • Gupta D.
      What are high-flow and low-flow oxygen delivery systems?.
      Oxygen is also a kind of drug; for example, it has potential side effect such as retinopathy of prematurity and bronchopulmonary dysplasia.
      • Lucey J.F.
      • Dangman B.
      A reexamination of the role of oxygen in retrolental fibroplasia.
      Hyperoxia is associated with a potential harm and major morbidity in neonates. One possible mechanism for hemodynamic alterations of hyperoxia is vasoconstriction.
      • Cornet A.D.
      • Kooter A.J.
      • Peters M.J.
      • Smulders Y.M.
      The potential harm of oxygen therapy in medical emergencies.
      The unintended effect is believed to be the formation of reactive oxygen species.
      • Navalesi P.
      On the imperfect synchrony between patient and ventilator.
      • Cornet A.D.
      • Kooter A.J.
      • Peters M.J.
      • Smulders Y.M.
      The potential harm of oxygen therapy in medical emergencies.
      In order to avoid hyperoxia, oxygen concentration should be maintained carefully. Animal models also demonstrated that hyperoxia can induce vasoconstriction by acting on L-type calcium channels.
      • Welsh D.G.
      • Jackson W.F.
      • Segal S.S.
      Oxygen induces electromechanical coupling in arteriolar smooth muscle cells: a role for L-type Ca2+ channels.
      Varying oxygenation concentration results in vasoconstriction, subsequent proliferation, and abnormal vascular growth in the retina of preterm infants.
      • Lucey J.F.
      • Dangman B.
      A reexamination of the role of oxygen in retrolental fibroplasia.

      5. Humidification system

      Humidification systems contain active humidifiers, heat-wire in the inspiratory limb, and temperature sensors. A humidifier could heat and vaporize the water, which increases the temperature and humidity of delivered gas. The heat-wire and temperature sensor stabilize the temperature under ideal conditions, also preventing condensation inside the circuit.
      • Rathgeber J.
      • Züchner K.
      • Burchardi H.
      Conditioning of air in mechanically ventilated patients.
      • Al Ashry H.S.
      • Modrykamien A.M.
      Humidification during mechanical ventilation in the adult patient.
      The upper respiratory tract warms, humidifies, and cleanses 1000–21,000 L of respiratory gas daily, influenced by body size and physical capability. The ability protects the respiratory system against respiratory pathogens.
      • Wanner A.
      • Salathé M.
      • O'Riordan T.G.
      Mucociliary clearance in the airways.
      The mucociliary transport system is immature in neonates. Delivery of unhumidified and cold gas flow leads to nasopharyngeal dysfunction through drying and injury to the nasal mucosa, potentially predisposing neonates to staphylococcal infection.
      • Kopelman A.E.
      • Holbert D.
      Use of oxygen cannulas in extremely low birthweight infants is associated with mucosal trauma and bleeding, and possibly with coagulase-negative staphylococcal sepsis.
      ISB is the maximum possible humidity at a given temperature, which amounts to 44 mg/L AH and 100% RH at 37°C. The humidified respiratory gas warms in the upper airway and is conditioned further until the ISB is reached.
      • Rathgeber J.
      • Züchner K.
      • Burchardi H.
      Conditioning of air in mechanically ventilated patients.
      It takes only 5 minutes to cause injury when inspiring unhumidified ambient gas, which significantly reduces lung compliance in ventilated neonates.
      • Greenspan J.S.
      • Wolfson M.R.
      • Shaffer T.H.
      Airway responsiveness to low inspired gas temperature in preterm neonates.
      An optimal humidification provides protection for airway mucosa and also contributes to lower failure rate of extubation with fewer complications.
      • Woodhead D.D.
      • Lambert D.K.
      • Clark J.M.
      • Christensen R.D.
      Comparing two methods of delivering high-flow gas therapy by nasal cannula following endotracheal extubation: a prospective, randomized, masked, crossover trial.
      Compared with traditional nasal cannula or inspired room air, HHHFNC saves energy that is wasted in warming up the cold, unheated gas flow, and it reduces metabolic workload.
      • Kopelman A.E.
      • Holbert D.
      Use of oxygen cannulas in extremely low birthweight infants is associated with mucosal trauma and bleeding, and possibly with coagulase-negative staphylococcal sepsis.

      6. Nasopharyngeal pressure and EDP

      The delivery of EDP and nasopharyngeal pressure varies. Calculated pressure generated during HHHFNC is still inconsistent.
      • Kubicka Z.J.
      • Limauro J.
      • Darnall R.A.
      Heated, humidified high-flow nasal cannula therapy: yet another way to deliver continuous positive airway pressure?.
      • Wilkinson D.J.
      • Andersen C.C.
      • Smith K.
      • Holberton J.
      Pharyngeal pressure with high-flow nasal cannulae in premature infants.
      • Sreenan C.
      • Lemke R.P.
      • Hudson-Mason A.
      • Osiovich H.
      High-flow nasal cannulae in the management of apnea of prematurity: a comparison with conventional nasal continuous positive airway pressure.
      To assess the actual pressure that NCPAP and HHHFNC delivered, three clinical studies placed the esophageal balloon in the distal esophagus and measured the esophageal pressure to indicate EDP.
      Sreenan et al
      • Sreenan C.
      • Lemke R.P.
      • Hudson-Mason A.
      • Osiovich H.
      High-flow nasal cannulae in the management of apnea of prematurity: a comparison with conventional nasal continuous positive airway pressure.
      studied 40 preterm infants and found no difference between the esophageal pressure during NCPAP at 6 cmH2O and HHHFNC at 6 L/min. HHHFNC generated EDP at flow rate up to 2.5 L/min in infants weighing < 2000 g. Saslow et al
      • Saslow J.G.
      • Aghai Z.H.
      • Nakhla T.A.
      • Hart J.J.
      • Lawrysh R.
      • Stahl G.E.
      • et al.
      Work of breathing using high-flow nasal cannula in preterm infants.
      compared NCPAP at 6 cmH2O and HHHFNC at 4 L/min, 5 L/min, and 6 L/min. The EDPs were similar in both systems but < 2 cmH2O. Alaiyan et al
      • Al-Alaiyan S.
      • Dawoud M.
      • Al-Hazzani F.
      Positive distending pressure produced by heated, humidified high flow nasal cannula as compared to nasal continuous positive airway pressure in premature infants.
      set the flow rate of HHHFNC at 4 L/min, 6 L/min, and 8 L/min and NCPAP pressure was set at 4 cmH2O, 6 cmH2O, and 8 cmH2O. Their study demonstrated that HHHFNC was able to deliver almost equal EDP to NCPAP: 4.5–6.7 cmH2O and 3.6–6.3 cmH2O, respectively (Table 1).
      Table 1Esophageal pressure during heated, humidified high-flow nasal cannula.
      ReferencePatientsHHHFNC

      flow rate (L/min)
      NCPAP

      level (cmH2O)
      MonitorResult
      Sreenan et al

      2001
      • Sreenan C.
      • Lemke R.P.
      • Hudson-Mason A.
      • Osiovich H.
      High-flow nasal cannulae in the management of apnea of prematurity: a comparison with conventional nasal continuous positive airway pressure.
      40 preterm infants, mean PMA 30.3 wk, mean CW 1260 g66The pressure transducer was placed in the distal esophagusNo difference between the EP during at 6 cmH2O and with HHHFNC 6 L/min (4.65 vs. 4.53 cmH2O)
      Saslow et al

      2006
      • Saslow J.G.
      • Aghai Z.H.
      • Nakhla T.A.
      • Hart J.J.
      • Lawrysh R.
      • Stahl G.E.
      • et al.
      Work of breathing using high-flow nasal cannula in preterm infants.
      18 preterm infants, mean GA 28 wk, mean BBW 1118 g3–56The esophageal balloon catheter was advanced into the esophagus to the lower third of the tracheal length.No significant increase in EDP in both NCPAP and HHHFNC (< 2 cmH2O)
      Al-Alaiyan et al

      2014
      • Al-Alaiyan S.
      • Dawoud M.
      • Al-Hazzani F.
      Positive distending pressure produced by heated, humidified high flow nasal cannula as compared to nasal continuous positive airway pressure in premature infants.
      12 premature infants, mean GA 28 wk, mean BBW 1040 g4, 6, and 84, 6, and 8The pressure transducer was placed in the distal esophagusHHHFNC almost have equally EP to NCPAP (4.5 vs. 3.6 at 4; 5.5 vs. 4.8 at 6; 6.7 vs. at 6.3 cmH2O)
      BBW = birthweight; CW = current weight; EDP = end-distending pressure; EP = esophageal pressure; GA = gestational age; HHHFNC = heated, humidified high-flow nasal cannula; NCPAP = nasal continuous positive airway pressure; PMA = postmenstrual age.
      Five clinical trials inserted the pressure transducer into infant's nasopharynx and measured the nasopharyngeal pressure. Spence et al
      • Spence K.L.
      • Murphy D.
      • Kilian C.
      • McGonigle R.
      • Kilani R.A.
      High-flow nasal cannula as a device to provide continuous positive airway pressure in infants.
      studied 14 infants and found that intrapharyngeal pressure significantly increased at flow rates ≥ 3 L/min in respiratory distress infants. Arora et al
      • Arora B.
      • Mahajan P.
      • Zidan M.A.
      • Sethuraman U.
      Nasopharyngeal airway pressures in bronchiolitis patients treated with high-flow nasal cannula oxygen therapy.
      and Wilkinson et al
      • Wilkinson D.J.
      • Andersen C.C.
      • Smith K.
      • Holberton J.
      Pharyngeal pressure with high-flow nasal cannulae in premature infants.
      inserted a pressure transducer into the nasopharynx and found an increase of 0.45 cmH2O and 0.8 cmH2O for each 1 L/min increase in the flow rate in infants, respectively. However, Kubicka et al
      • Kubicka Z.J.
      • Limauro J.
      • Darnall R.A.
      Heated, humidified high-flow nasal cannula therapy: yet another way to deliver continuous positive airway pressure?.
      placed the pressure transducer in the oral cavity, but no significant pressure was found. Collins et al
      • Collins C.L.
      • Holberton J.R.
      • König K.
      Comparison of the pharyngeal pressure provided by two heated, humidified high-flow nasal cannulae devices in premature infants.
      compared the generated pressure between two commonly used HHHFNC systems (Fisher & Paykel Healthcare and Vapotherm 2000i). Study flow rate was set at 2–8 L/min. Both HHHFNC systems generated similar pharyngeal pressure at flow rate of 2–6 L/min but higher in Vapotherm with flow rate of 7 L/min and 8 L/min (Table 2). Increasing the flow rate of HHHFNC seems to be associated with linear increase in nasopharyngeal pressures (Figure 1).
      Table 2Nasopharygneal pressure during heated, humidified high-flow nasal cannula.
      ReferencePatientsHHHFNC

      flow rate (L/min)
      Type of pressureMonitorResult
      Spence et al

      2007
      • Spence K.L.
      • Murphy D.
      • Kilian C.
      • McGonigle R.
      • Kilani R.A.
      High-flow nasal cannula as a device to provide continuous positive airway pressure in infants.
      14 infants, mean GA 30 wk, mean CW 1589 g1–5Intrapharyngeal pressureThe pressure transducer catheter was gently introduced to the posterior pharynx through the infant's nares or mouth.Mean pressure significantly increased at flow ≥ 3 L/min; linear relationship generated at flow ≥ 3 L/min.
      Wilkinson et al

      2008
      • Wilkinson D.J.
      • Andersen C.C.
      • Smith K.
      • Holberton J.
      Pharyngeal pressure with high-flow nasal cannulae in premature infants.
      18 infants, mean GA 34 wk, mean BBW 1619 kg2–8Nasopharyngeal pressureThe pressure transducer catheter was introduced into either nostril to a distance 1 cm less than the measured distance from tip if nose to tragus, in the nasopharynx.Mean pressure increased by 0.8 cmH2O for each 1 L/min
      Kubicka et al

      2008
      • Kubicka Z.J.
      • Limauro J.
      • Darnall R.A.
      Heated, humidified high-flow nasal cannula therapy: yet another way to deliver continuous positive airway pressure?.
      27 preterm infants, mean PMA 34 wk, mean CW 2034 g1–5Oral cavity pressureThe pressure transducer was inserted 3 cm into the oral cavityNo significant oropharyngeal pressure was generated.
      Arora et al

      2012
      • Arora B.
      • Mahajan P.
      • Zidan M.A.
      • Sethuraman U.
      Nasopharyngeal airway pressures in bronchiolitis patients treated with high-flow nasal cannula oxygen therapy.
      25 bronchiolitis children, mean age 78.1 d, mean weight 5.3 kg1–8Nasopharyngeal pressureThe pressure transducer was inserted into nasopharynx, 1 cm less than the distance between the tip of the nose and the tragusMean pressure increased by 0.45 cmH2O for each 1-L/min; linear fashion up to 6 L/min
      Collins et al

      2013
      • Collins C.L.
      • Holberton J.R.
      • König K.
      Comparison of the pharyngeal pressure provided by two heated, humidified high-flow nasal cannulae devices in premature infants.
      9 premature infants, mean GA 30 wk, mean BBW 1326 g2–8Pharyngeal pressureProcedure described by WilkinsonMean pressure increased by 0.4 cmH2O for each 1-L/min (2–6 L/min with F & P) and increased by 0.5 cmH2O for each 1 L/min (2–8 L/min with VT)
      BBW = birthweight; CW = current weight; F & P = Fisher & Paykel; GA = gestational age; HHHFNC = heated, humidified high-flow nasal cannula; NCPAP = nasal continuous positive airway pressure; PMA = postmenstrual age; VT = Vapotherm.
      Figure 1
      Figure 1Nasopharyngeal pressure of infants during heated humidified high-flow nasal cannula.
      In an in vitro study, two sizes of nasal cannula with different nostril models in infants were investigated; it was recommended that nasal prong-to-nares ratio (N-N ratio) should be 50–80% to generate pressure adequately. N-N ratio should never exceed 80%; once N-N ratio is > 80%, the pressure will increase, resulting in an adverse effect on infants.
      • Sivieri E.M.
      • Gerdes J.S.
      • Abbasi S.
      Effect of HFNC flow rate, cannula size, and nares diameter on generated airway pressures: an in vitro study.

      7. Nasal trauma and nasal deformities

      Since the 1980s, nasal trauma has been reported after using NCPAP.
      • Robertson N.J.
      • McCarthy L.S.
      • Hamilton P.A.
      • Moss A.L.
      Nasal deformities resulting from flow driver continuous positive airway pressure.
      • Loftus B.C.
      • Ahn J.
      • Haddad Jr, J.
      Neonatal nasal deformities secondary to nasal continuous positive airway pressure.
      In order to maintain efficiency of CPAP, interfaces such as nasal prongs and head-securing devices must be sufficiently tight, fitting the patient's head, face, and nostrils. However, irritation and possible nasal trauma may still be induced. The risk factors of nasal injuries include low body weight, lower GA, inappropriate size of nasal prongs, and incorrect application of the device.
      • Robertson N.J.
      • McCarthy L.S.
      • Hamilton P.A.
      • Moss A.L.
      Nasal deformities resulting from flow driver continuous positive airway pressure.
      • Loftus B.C.
      • Ahn J.
      • Haddad Jr, J.
      Neonatal nasal deformities secondary to nasal continuous positive airway pressure.
      • Bushell T.
      • McHugh C.
      • Meyer M.P.
      A comparison of two nasal continuous positive airway pressure interfaces—a randomized crossover study.
      • Yong S.C.
      • Chen S.J.
      • Boo N.Y.
      Incidence of nasal trauma associated with nasal prong versus nasal mask during continuous positive airway pressure treatment in very low birthweight infants: a randomised control study.
      A cross-sectional study by Jatana et al
      • Jatana K.R.
      • Oplatek A.
      • Stein M.
      • Phillips G.
      • Kang D.R.
      • Elmaraghy C.A.
      Effects of nasal continuous positive airway pressure and cannula use in the neonatal intensive care unit setting.
      investigated 100 patients younger than 1 year who received at least 7 days of NCPAP or nasal cannula in the NICU. Screening by external nasal examination and anterior nasal endoscopy with photographic documentation, nasal complications include columellar necrosis, granulation, ulceration, vestibular stenosis, and deformation were found in NCPAP group (12/31, 13.2%), while no complications were found in the nine patients with nasal cannula.
      • Jatana K.R.
      • Oplatek A.
      • Stein M.
      • Phillips G.
      • Kang D.R.
      • Elmaraghy C.A.
      Effects of nasal continuous positive airway pressure and cannula use in the neonatal intensive care unit setting.
      A prospective randomized controlled trial by Collins and colleagues
      • Collins C.L.
      • Barfield C.
      • Horne R.S.
      • Davis P.G.
      A comparison of nasal trauma in preterm infants extubated to either heated humidified high-flow nasal cannulae or nasal continuous positive airway pressure.
      studied 132 preterm infants, comparing HHHFNC and NCPAP with two different protective nasal dressings (Sticky Whiskers and Cannualaide). Nasal trauma scores were devised to evaluate the result of nasal trauma. HHHFNC resulting in significantly lower nasal trauma score than NCPAP, especially in very preterm infants (GA < 28 weeks; 2.8 vs. 11.7, p < 0.001). The use of different nasal dressing was not associated with decreased nasal trauma in NCPAP.
      • Collins C.L.
      • Barfield C.
      • Horne R.S.
      • Davis P.G.
      A comparison of nasal trauma in preterm infants extubated to either heated humidified high-flow nasal cannulae or nasal continuous positive airway pressure.

      8. Postextubation application

      Three recent randomized controlled prospective studies indicated that the efficacy and safety of HHHFNC was similar in postextubation respiratory support compared with NCPAP for infants with GA between 28 weeks and 32 weeks. There was no significant difference in mortality and morbidity including bronchopulmonary dysplasia, patent ductus arteriosus, and intraventricular hemorrhage but significantly reduced nasal trauma in HHHFNC.
      • Yoder B.A.
      • Stoddard R.A.
      • Li M.
      • King J.
      • Dirnberger D.R.
      • Abbasi S.
      Heated, humidified high-flow nasal cannula versus nasal CPAP for respiratory support in neonates.
      • Manley B.J.
      • Owen L.S.
      • Doyle L.W.
      • Andersen C.C.
      • Cartwright D.W.
      • Pritchard M.A.
      • et al.
      High-flow nasal cannulae in very preterm infants after extubation.
      • Collins C.L.
      • Holberton J.R.
      • Barfield C.
      • Davis P.G.
      A randomized controlled trial to compare heated humidified high-flow nasal cannulae with nasal continuous positive airway pressure postextubation in premature infants.
      The starting flow rate may be a possible reason for the heterogeneity and variability to these studies. Compared with Yoder et al
      • Yoder B.A.
      • Stoddard R.A.
      • Li M.
      • King J.
      • Dirnberger D.R.
      • Abbasi S.
      Heated, humidified high-flow nasal cannula versus nasal CPAP for respiratory support in neonates.
      (3–5 L/min) and Manley et al
      • Manley B.J.
      • Owen L.S.
      • Doyle L.W.
      • Andersen C.C.
      • Cartwright D.W.
      • Pritchard M.A.
      • et al.
      High-flow nasal cannulae in very preterm infants after extubation.
      (5–6 L/min), Collins et al
      • Collins C.L.
      • Holberton J.R.
      • Barfield C.
      • Davis P.G.
      A randomized controlled trial to compare heated humidified high-flow nasal cannulae with nasal continuous positive airway pressure postextubation in premature infants.
      had a much higher initial flow rate (8 L/min; Table 3).
      Table 3Postextubation.
      ReferenceParticipant characteristicsStudy designPrimary outcomeResult
      Collins et al

      2013
      • Collins C.L.
      • Holberton J.R.
      • Barfield C.
      • Davis P.G.
      A randomized controlled trial to compare heated humidified high-flow nasal cannulae with nasal continuous positive airway pressure postextubation in premature infants.
      132 infants GA < 32 wk

      HHHFNC: (n = 67)

      Mean GA: 27.9 wk

      Mean BBW: 1123 g

      NCPAP: (n = 65)

      Mean GA: 27.6 wk

      Mean BBW: 1105
      Unblinded RCT

      HHHFNC:

      8 L/min

      NCPAP:

      7–8 cmH2O
      Extubation failure in 7 dThe reintubation rate was no significant difference in the first week (HHHFNC 17 % vs. NCPAP 24 %, p = 0.48)
      Yoder et al

      2013
      • Yoder B.A.
      • Stoddard R.A.
      • Li M.
      • King J.
      • Dirnberger D.R.
      • Abbasi S.
      Heated, humidified high-flow nasal cannula versus nasal CPAP for respiratory support in neonates.
      432 infants GA < 28 wk; BBW > 1000 g

      HHHFNC: (n = 212)

      Mean GA: 33.5 wk

      Mean BBW: 2201 g

      NCPAP: (n = 220)

      Mean GA: 33.2 wk

      Mean BBW: 2108
      Unblinded RCT

      (Muticenter)

      HHHFNC:

      3–8 L/min

      NCPAP:

      5–8 cmH2O
      Early failure (< 72 h) or extubation in any timeThere was no significant difference in early extubation failure (HHHFNC 10.8 % vs. NCPAP 8.2 %, p = 0.344)
      Manley et al

      2013
      • Manley B.J.
      • Owen L.S.
      • Doyle L.W.
      • Andersen C.C.
      • Cartwright D.W.
      • Pritchard M.A.
      • et al.
      High-flow nasal cannulae in very preterm infants after extubation.
      303 infants GA < 32 wk

      HHHFNC: (n = 152)

      Mean GA: 27.6 wk

      Mean BBW: 1041 g

      NCPAP: (n = 151)

      Mean GA: 31.0 wk

      Mean BBW: 1044 g
      Unblinded RCT

      HHHFNC:

      5–8 L/min

      NCPAP:

      5–8 cmH2O
      Treatment failure within 7 d (urgent need for reintubation)The reintubation rate was no significant difference in the first week (HHHFNC 17.8 % vs. NCPAP 25.2 %, p = 0.12)
      BBW = birthweight; GA = gestational age; HHHFNC = heated, humidified high-flow nasal cannula; NCPAP = nasal continuous positive airway pressure; RCT = randomized controlled trial.

      9. Initial therapy compared with NIPPV

      A single-center, prospective, randomized pilot study
      • Kugelman A.
      • Riskin A.
      • Said W.
      • Shoris I.
      • Mor F.
      • Bader D.
      A randomized pilot study comparing heated humidified high-flow nasal cannulae with NIPPV for RDS.
      recruited 76 preterm infants who were born at < 35 weeks of gestation with birthweight ≥ 1000 g with diagnosis of RDS requiring NRS as an initial therapy. It is the first study to investigate the performance of initial therapy of HHHFNC compared with NIPPV. Kugelman et al
      • Kugelman A.
      • Riskin A.
      • Said W.
      • Shoris I.
      • Mor F.
      • Bader D.
      A randomized pilot study comparing heated humidified high-flow nasal cannulae with NIPPV for RDS.
      suggested HHHFNC to be as effective as NIPPV in preventing endotracheal ventilation (28.9% vs. 34.2%) in the primary treatment of RDS in preterm infants. Although the participant number was not large enough to establish strong evidence, it provided the basis for further studies.
      • Kugelman A.
      • Riskin A.
      • Said W.
      • Shoris I.
      • Mor F.
      • Bader D.
      A randomized pilot study comparing heated humidified high-flow nasal cannulae with NIPPV for RDS.

      10. Weaning from NCPAP (a step-down therapy)

      A matched-pair cohort analysis of 79 infants of at least 28 weeks of gestation with birthweight < 1250 g on NRS was made. The study compared the performance of low-flow nasal cannula (< 0.3 L/min) and HHHFNC (2–8 L/min) in weaning from NCPAP. Total NCPAP days (median) in HHHFNC and low-flow nasal cannula groups were 25 and 13, respectively. Use of HHHFNC as a step-down therapy in very preterm infants did not prolong the duration of NRS but reduced the requirement of NCPAP. At the same time, the risk of nasal trauma was minimized.
      • Fernandez-Alvarez J.R.
      • Gandhi R.S.
      • Amess P.
      • Mahoney L.
      • Watkins R.
      • Rabe H.
      Heated humidified high-flow nasal cannula versus low-flow nasal cannula as weaning mode from nasal CPAP in infants ≤28 weeks of gestation.

      11. Surveys of HHHFNC

      The use of HHHFNC is spreading. A survey of all UK neonatal units obtained a 100% response rate. It examined the practices of either heated or unheated high-flow nasal cannula, where high-flow was defined as flow rates > 1 L/min. The result demonstrated that 77% of units humidified high-flow nasal cannula before delivery.
      • Nath P.
      • Ponnusamy V.
      • Willis K.
      • Bissett L.
      • Clarke P.
      Current practices of high and low flow oxygen therapy and humidification in UK neonatal units.
      Three surveys defined HHHFNC as flow rate > 2 L/min, with > 60% overall response rate in the USA,
      • Hochwald O.
      • Osiovich H.
      The use of high flow nasal cannulae in neonatal intensive care units: is clinical practice consistent with the evidence?.
      UK,
      • Ojha S.
      • Gridley E.
      • Dorling J.
      Use of heated humidified high-flow nasal cannula oxygen in neonates: a UK wide survey.
      and Australia.
      • Hough J.L.
      • Shearman A.D.
      • Jardine L.A.
      • Davies M.W.
      Humidified high flow nasal cannulae: current practice in Australasian nurseries, a survey.
      They obtained rates of HHHFNC use in neonates and pediatric patients of 69%, 77%, and 63%, respectively. However, without clear, accepted clinical guideline or protocols, and lacking a stronger evidence basis, the use of HHHNFC was mostly based on individual preferences and evaluation of efficacy was still dependent on experience
      • Hochwald O.
      • Osiovich H.
      The use of high flow nasal cannulae in neonatal intensive care units: is clinical practice consistent with the evidence?.
      • Ojha S.
      • Gridley E.
      • Dorling J.
      Use of heated humidified high-flow nasal cannula oxygen in neonates: a UK wide survey.
      • Hough J.L.
      • Shearman A.D.
      • Jardine L.A.
      • Davies M.W.
      Humidified high flow nasal cannulae: current practice in Australasian nurseries, a survey.
      (Table 4).
      Table 4Surveys of heated, humidified high-flow nasal cannula.
      ReferenceCountrySurvey subjectResponse rateHHHFNC using rate
      Nath et al

      2010
      • Nath P.
      • Ponnusamy V.
      • Willis K.
      • Bissett L.
      • Clarke P.
      Current practices of high and low flow oxygen therapy and humidification in UK neonatal units.
      UKSenior nurses from 214 UK neonatal units214/214 (100%)Used in 77% neonatal unit

      High flow defined as flow rate > 1 L/min
      Ojha et al

      2013
      • Ojha S.
      • Gridley E.
      • Dorling J.
      Use of heated humidified high-flow nasal cannula oxygen in neonates: a UK wide survey.
      UK57 level 2 and 3 neonatal units44/57 (77%)Used in 77% neonatal unit
      Hough et al

      2012
      • Hough J.L.
      • Shearman A.D.
      • Jardine L.A.
      • Davies M.W.
      Humidified high flow nasal cannulae: current practice in Australasian nurseries, a survey.
      ANZ157 neonatologists111/157 (71%)Used in 63% of NICU
      Hochwald et al

      2012
      • Hochwald O.
      • Osiovich H.
      The use of high flow nasal cannulae in neonatal intensive care units: is clinical practice consistent with the evidence?.
      USA97 PD of Neonatal–Perinatal Medicine Fellowship Program58/97 (60%)69% reported using HHHFNC
      ANZ = Australia and New Zealand; HHHFNC = heated, humidified high-flow nasal cannula; NICU = neonatal intensive-care unit; PD = program directors.

      12. Irritation of HHHFNC and NCPAP

      A randomized controlled trial in a single tertiary neonatal unit enrolled infants with postmenstrual age < 34 weeks and with the treatment of NCPAP. It assessed the comfort and pain by Échelle Douleur Inconfort Nouveau-Né (EDIN; neonatal pain and discomfort) scale. There was no difference in EDIN scores between HHHFNC and NCPAP. However, the EDIN scores were designed to assess pain, which may not be an ideal tool to assess comfort.
      • Klingenberg C.
      • Pettersen M.
      • Hansen E.A.
      • Gustavsen L.J.
      • Dahl I.A.
      • Leknessund A.
      • et al.
      Patient comfort during treatment with heated humidified high flow nasal cannulae versus nasal continuous positive airway pressure: a randomised cross-over trial.
      Observation of comfort and pain comparing NAPCP and HHHFNC is still controversial and subjective. In the future, an applicable monitor or biomarker for pain and comfort of infants should be developed.
      Noise exposure in the NICU is a potential risk factor for hearing loss in vulnerable neonates and an irritation for all infants. Animal models have demonstrated that during the newborn period, cochlear damage occurs secondary to noise exposure.
      • Saunders J.C.
      • Chen C.S.
      Sensitive periods of susceptibility to auditory trauma in mammals.
      The American Academy of Pediatrics recommended that environmental noise levels > 45 dB should be avoided, and it warned that prolonged exposure to sound levels > 90 dB led to hearing loss.
      Noise: a hazard for the fetus and newborn. American Academy of Pediatrics. Committee on Environmental Health.
      Comparing the ambient noise levels between HHHFNC devices using flows rate at 4–8 L/min and NCPAP at pressures of 4–8 cmH2O and flow rate 8 L/min, noise levels were measured in the oral cavity of a newborn in an incubator in a quiet setting. All three devices generated noise levels > 70 dB A-weighted (dBA).
      • König K.
      • Stock E.L.
      • Jarvis M.
      Noise levels of neonatal high-flow nasal cannula devices—an in-vitro study.
      Kligenberg et al
      • Klingenberg C.
      • Pettersen M.
      • Hansen E.A.
      • Gustavsen L.J.
      • Dahl I.A.
      • Leknessund A.
      • et al.
      Patient comfort during treatment with heated humidified high flow nasal cannulae versus nasal continuous positive airway pressure: a randomised cross-over trial.
      measured the ambient noise of HHHFNC and NCPAP from 15 cm above the infant's face, and the mean noise levels were 70 dBA and 74 dBA, respectively.
      In a recently reported observational study, the ambient noise levels of bubble CPAP (BCPAP) and HHHFNC were compared. The study indicated that although both devices produced noise levels > 45 dBA, there was no difference in average noise levels (BCPAP 50.6 dBA vs. HHHFNC 49.1 dBA). There was a trend showing an increased noise level with higher gas flow in HHHFNC but not in BCPAP.
      • Roberts C.T.
      • Dawson J.A.
      • Alquoka E.
      • Carew P.J.
      • Donath S.M.
      • Davis P.G.
      • et al.
      Are high flow nasal cannulae noisier than bubble CPAP for preterm infants?.
      Kangaroo Mother Care (KMC) is an evidence-based strategy that reduces mortality and morbidity in preterm infants.
      • World Health Organization
      Kangaroo mother care: a practical guide.
      Studies suggest that KMC is a cost-effective method for treating preterm infants
      • Broughton E.I.
      • Gomez I.
      • Sanchez N.
      • Vindell C.
      The cost-savings of implementing kangaroo mother care in Nicaragua.
      and also benefits their neurodevelopment.
      • Nyqvist K.H.
      • Anderson G.C.
      • Bergman N.
      • Cattaneo A.
      • Charpak N.
      • Davanzo R.
      • et al.
      State of the art and recommendations. Kangaroo mother care: application in a high-tech environment.
      According to the World Health Organization definition, KMC consists of prolonged skin-to-skin contact between mother and infant.
      • World Health Organization
      Kangaroo mother care: a practical guide.
      Compared with HHHFNC, NCPAP could be a barrier to KMC, which may lead to difficulty in KMC practice.
      • Seidman G.
      • Unnikrishnan S.
      • Kenny E.
      • Myslinski S.
      • Cairns-Smith S.
      • Mulligan B.
      • et al.
      Barriers and enablers of kangaroo mother care practice: a systematic review.
      Disconnection of the ventilator circuit and tube leakage under NCPAP is common during KMC. The ventilator sirens may cause anxiety in the mother during KMC.

      13. Conclusion

      Studies indicate that HHHFNC may have similar efficiency and safety in neonates and preterm infants, but that reduces the risk of nasal trauma. HHHFNC is less invasive than NCPAP because the N-N ratio never exceeds 80%. Due to its user-friendly applicability for parents and clinical staff, mothers could practice KMC easily. The introduction of HHHFNC provides an option to treat neonates. Until more larger prospective randomized control trials have been done, HHHFNC should not yet be a routine or first choice of NRS for respiratory distress.

      Conflicts of interest

      The authors declare that they have no conflicts of interest, financial or otherwise.

      Acknowledgments

      This article was supported by grants from Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan (No SKH 8302-100-DR-11 ).

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