Different HFNC devices are available on the market, each one with distinctive features but basic principles apply to all systems. Key components of any HFNC device are a set of nasal cannula, a gas delivery blender that allows control on gas flow and FiO₂, and an active humidifier.

Ideally, the system should allow titration of gas flow rates between 0 and 60 l/min in order to adapt to patient’s need. Most common HFNC systems use two rotameters connected through a Y connection or a high-flow Venturi valve. The system must include a flowmeter and a gas analyzer on the inspiratory line, in order to monitor the actual flow and FiO₂ of the gas mixture provided to the patient.

Proper humidification is required for effectiveness and tolerability of the HFNC therapy. International guidelines (American Society for Testing and Materials, http://​www.​astm.​org) recommend a minimum absolute humidity of 10 mg H₂O/l for gas flow that pass through the upper airways [4]. This value roughly corresponds to standard room air characteristics, that is, a relative humidity of 50% at 22 °C. The development of active humidifiers for HFNC systems is rather new, and these devices are analogous to those already in use for invasive mechanical ventilation. Indeed, the most efficient bubble humidifier is able to reach the required absolute humidity only for gas flow up to 15 l/min [5]. Active heated humidification systems deliver a relative humidity of nearly 100% for gas flow exceeding 40 l/min at 36.5 °C [5]. An additional useful feature is the presence of heated plastic circuits of larger diameter compared to standard low-flow nasal cannula. The larger dimension of the tubes allows for lower resistance to gas flow, while the heated wire circuit avoids condense formation at the interface between plastic and cold room air, reducing the risk of tube obstruction due to water accumulation inside the circuit.

Setting HFNC system is rather simple: First choose the nasal cannula size and circuit adequate for the patient. Nasal cannula must fit comfortably the nares, without excessive leaking or total obstruction. Active humidification must be on and working before starting the treatment, and gas flow temperature must be set between 34 and 37 °C. Gas flow must be started around 6 l/min and subsequently step-by-step increased to the target flow of 35–60 l/min during a few minutes time, in order to allow the patient to progressively adapt to the treatment.

Different physiological mechanisms have been suggested for the benefits and efficacy of HFNC oxygen therapy in pediatric and adult patients with acute respiratory failure (Table 11.2):

Oxygen supplementation delivered through low-flow nasal cannula is an open system in which oxygen mixes with room air, and the maximum FiO₂ is not greater than 30%. Moreover, the dilution effect is more extensive in case of respiratory distress – consequently, actual FiO₂ is lower in patients with dyspnea and tachypnea in which PIF is increased and varies from 30 to 120 l/min [6, 7]. HFNC systems deliver gas flow close to real patient’s effort to breathe, up to 60 l/min, with excellent comfort and without injury to the upper airway mucosa. Real high FiO₂ (close to 100%) is guarantee even in hypoxemic patients with respiratory distress [8]. HFNC systems deliver FiO₂ higher than non-rebreather masks as well, as a consequence to minor room air admixture and washout of the upper airway dead space [7].

The nasopharynx is a complex anatomical space, and mouth-nasal breathing in patients with respiratory distress makes difficult a precise description of gas distribution during respiration. Numerous authors hypothesize that high gas flow rates during HFNC therapy promote the washout of the nasopharyngeal space from the expiratory air (containing CO₂) coming from the lungs. The resulting effect is double: first anatomical dead space is reduced with advantage in alveolar ventilation; moreover, the washed-out space acts as a reservoir of highly oxygenated air in the oropharynx [9]. Intratracheal insufflation techniques use different devices to obtain similar results, showing to be effective in reducing anatomical dead space with improved alveolar-to-minute ventilation ratio and clearance of CO₂ [10]. High-flow oxygen therapy, HFNC or intratracheal insufflation, compared to conventional oxygen therapy with low-flow devices showed to improve resistance to physical exercise and to reduce dyspnea symptoms in patients with chronic obstructive pulmonary disease (COPD) [11]. In another study, COPD patients showed improved oxygenation, respiratory mechanics, and resistance to exhaustion during physical exercise with HFNC oxygen supplementation [12].

Nasopharyngeal space is essential to heat and humidify inspiratory room air. Optimal heating and humidification of inspiratory gas during HFNC therapy blunt the bronchoconstriction reflex caused by the administration of dry and cold gas. The consequence is the reduction in work of breathing [13]. Moreover, in predisposed patients, such as those with obstructive sleep apnea syndrome (OSAS), the soft tissue of the pharynx can collapse and obstruct during inspiration, leading to desaturation and CO₂ retention. High gas flow rates typical of HFNC may be equal or even superior to patient’s inspiratory effort, thus to prevent upper airway collapse and reduce supraglottic resistance. HFNC promotes the development of a positive pressure in the nasopharyngeal space that contrasts tissue obstruction [9].

Graves and Tobin were the first authors to prove the development of airway positive pressure associated with HFNC treatment in adults [14]. The amount of positive pressure produced depends upon the supplied flow rate, anatomy of patient’s airway, and individual respiratory system mechanical characteristics. Positive pressure linearly correlates with gas flow rate and system leakage [14]. Essential features for an effective HFNC support are good seal of nasal cannula, closure of patient’s mouth, and gas flow higher, or at least equal, to PIF. Numerous studies measured actual delivered PEEP, but the results showed a wide interindividual variability. In healthy volunteers median PEEP was 7.4 cmH₂O (95% confidence interval (CI) 5.4–8.8 cmH₂O) with a gas flow of 60 l/min and close mouth [15]. Airway pressure was positive even during the inspiration phase of breathing, indicating adequate gas flow, with a median value of 1.6 cm H₂O (95%CI 0.8–2.9 cmH₂O) [15]. Post-cardiac surgery patients showed a mean positive pressure of 2.7 ± 1.04 cmH₂O with gas flow of 35 l/min and close mouth during the postoperative period [16]. Ritchie et al. assessed a positive correlation between gas flow rates and mean nasopharyngeal positive pressure, used as surrogate of airway pressure, in healthy volunteers: 3 cmH₂O with a flow of 30 l/min, 4 cmH₂O with 40 l/min, and 5 cmH₂O with 50 l/min [17]. Similarly, another study found that airway pressure increased at 0.69 cmH₂O for every increment of 10 l/min in gas flow when the subject breathes with his mouth close; the increase associated with airflow is lower (0.35 cmH₂O) when the mouth is open during respiration [18].

Positive airway pressure causes improvement in gas exchange and respiratory system mechanics only if it is associated with alveolar recruitment of the lung parenchyma. Corley et al. used electrical impedance tomography (EIT) to study the association between PEEP and alveolar recruitment during HFNC therapy in post-cardiac surgery patients [19]. HFNC therapy significantly increased both PEEP (3.0 cmH₂O, 95%CI 2.4–3.7 cmH₂O) and end-expiratory lung volume (EELV) (25.6%, 95%CI 24.3–26.9%) compared to standard oxygen delivery systems. Moreover, the authors found an increase in minute ventilation associated with HFNC therapy (tidal volume increase 10.5%, 95%CI 6.1–18.3%). The eventual effect was an improvement in gas exchange and respiratory system mechanics, mirrored by a reduction in respiratory rate and dyspnea relief [19].

Optimal humidification and heating of the supplied gas is essential to guarantee a tolerable and effective therapy during HFNC support. Such high gas flow rates would be otherwise harmful for the respiratory system mucosa and would cause an increase in airway resistance by eliciting the bronchoconstriction reflex through activation of nasal receptors [20]. Mechanically ventilated children showed a reduction of lung compliance after only 5 min of ventilation with cold and dry air [21]. Furthermore, patients in acute respiratory failure show increased bronchial secretions. Active heated humidifiers prevent dryness and promote the clearance of respiratory secretions, especially in patients with chronic respiratory comorbidities (i.e., COPD, cystic fibrosis, bronchiectasis, etc.). Roca et al. found that patient’s comfort is superior and dyspnea relief is greater with HFNC therapy than standard oxygen mask supports [22]. If properly set and delivered, HFNC therapy can be used for prolonged periods of time without complications or patient’s refusal to treatment (Table 11.3) [23, 24].

HFNC systems are widely applied for treatment of newborns and children with acute respiratory distress, and literature strongly supports the efficacy in these populations [25]. Recently, increasing interest is shown about the implementation of HFNC therapy in adults with ARF. Evidences about HFNC treatment in adults are reported accordingly to different clinical scenario.

Oxygen supplementation is the first-line therapy in hypoxemic patients, regardless of the cause of respiratory failure. Numerous studies compared the efficacy of HFNC therapy to other noninvasive techniques of respiratory support.

In a prospective sequential study, Roca et al. showed that 30 min of HFNC support increased oxygenation and reduced respiratory rate compared to standard oxygen mask in patients admitted to intensive care unit (ICU) for acute hypoxic respiratory failure (defined as SpO₂ ≤ 96% with a FiO₂ ≥ 50%) [22]. All patients reported better comfort and dyspnea relief with HFNC therapy. Similar results were obtained in other two observational prospective trials in patients with ARF and respiratory distress [26, 27]. Rello et al. published their experience in hypoxemic patients with ARF caused by influenza A/H1N1 infection [28]. Nine patients improved with HFNC therapy, and all survived, while 11 patients required intubation and invasive mechanical ventilation with an ICU mortality of 27%. Factors associated with HFNC failure were requirement of inotropic/vasopressor therapy, SOFA score > 4, APACHE score > 12, failure of improvement in oxygenation, and/or tachypnea after 6 h of HFNC support.

In a multicenter randomized trial, Frat et al. compared the efficacy of HFNC and NIV as first respiratory support in patients with ARF and a PaO₂/FiO₂ ratio below 300 [29]. Three hundred and ten patients were enrolled, 94 were randomized to standard oxygen mask, 106 were treated with HFNC at a minimum flow rate of 50 l/min, and a third group of 110 patients underwent NIV through face mask (ventilatory setting: PEEP between 2 and 10 cmH₂O, pressure support tailored to obtain a tidal volume of 7–10 ml/kg_IBW); FiO₂ (and PEEP in the NIV group) was modified to maintain a SpO₂ equal or above 92%. The authors did not find any difference in rate of intubation among the different treatments (38% for HFNC, 47% for standard oxygen mask, and 50% for NIV patients). Otherwise, the HFNC group showed a statistically significant benefit in survival, 90 days of mortality hazard ratio was 2.01 (95%CI 1.01–3.99, p = 0.046) for standard oxygen mask and 2.50 (95%CI 1.31–4.78, p = 0.006) for NIV compared to HFNC support [29].

The use of HFNC in acute respiratory distress syndrome (ARDS) was specifically addressed by a single-center observational study [30]. Out of the total 45 ARDS patients treated with HFNC support during the study period, 26 subjects successfully improved, 1 patient required NIV, and 18 were eventually intubated and mechanically ventilated. Risk factors for HFNC failure were severe hypoxemia, hemodynamic shock with inotropic/vasopressor therapy, and high SAPS II score at ICU admission [30].

Recently, a meta-analysis of six RCTs comparing efficacy of HFNC and conventional oxygen therapy or NIV in hypoxic patients found that intubation rate was significantly lower with HFNC therapy than with conventional oxygen support (RR 0.60, 95%CI 0.38–0.94). No significant difference was found between HFNC therapy and NIV (RR 0.86, 95%CI 0.68–1.09) [31]. No difference in oxygenation was found between HFNC therapy and conventional oxygen mask; NIV achieved higher PaO₂/FiO₂ ratio, although with similar PaCO₂ levels to HFNC therapy. Mortality was not different: there were 52 (5.9%) deaths in the HFNC group, 30 (6.7%) in the conventional oxygen therapy group, and 50 (9.5%) in the NIV group [31].

In conclusion, HFNC is a useful noninvasive option in ARF patients who do not require intubation and invasive mechanical ventilation. Nevertheless, additional studies are necessary to establish possible benefits in the most severely hypoxemic patients.

Patients often require oxygen therapy in the post-extubation period in order to correct residual hypoxemia. Reintubation is associated to increased morbidity and mortality; thus, optimal oxygenation is essential during this phase. Numerous studies focused on the use of HFNC support in this setting.