Hrev_master [page 61] [Emergency Care Journal 2017; 13:7036] Current application of high flow oxygen nasal cannula in acute hypoxemic respiratory failure in the emergency department Giulia Bottani, Fabio Centurioni, Giacomo Veronese, Fabrizio Vincenti, Elisa Forni, Andrea Bellone Department of Emergency Medicine, Niguarda Hospital, Milano, Italy Abstract High flow oxygen with nasal cannula (HFONC) is a relatively new mode of oxy- gen delivery. Advantages of HFONC versus conventional oxygen therapy (COT) encompass carbon dioxide washout, gener- ation of a slight positive end-expiratory pressure and maintenance of humidified gas flow through airways. These features are mostly shared with non-invasive mechani- cal ventilation (NIMV), although with lack of a clearly comparable efficacy. In the last few years, HFONC has gained interest as a third alternative to COT and NIMV in the management of acute hypoxemic respirato- ry failure in the critically ill patient, both in intensive care units and emergency depart- ments. The aim of this article is to review indications, effects and existing evidence on HFONC, COT and NIMV in the setting of acute hypoxemic respiratory failure. Introduction Humidified high-flow oxygen via nasal cannula (HFONC) is a relatively new method to improve fraction of inspired oxy- gen (FiO2) in hypoxemic patients.1,2 Initially used in neonatological setting, as an alterna- tive to continuous positive airway pressure (CPAP),3 HFONC has been later used in the critically ill adult, in post-extubation respira- tory assistance, in periprocedural assistance (e.g. during bronchoscopy) and in hypox- emic patients, as an alternative to conven- tional oxygen therapy (COT) or non-invasive mechanical ventilation (NIMV).4-6 Aim of this article is to review the physiological basis of HFONC, the actual evidence about its efficacy and the main indications and con- troversies. This review will analyze existing evidence about gas exchange, respiratory work, need for escalation to more invasive respiratory support (e.g. endotracheal intuba- tion), mortality and patients-reported effica- cy on dyspnea and device tolerance. Why humidified high-flow oxygen via nasal cannula? COT allows administration of oxygen mixed with room air delivered through sim- ple nasal cannula or face-masks, therefore significantly increasing fraction of inspired oxygen (FiO2) and aiming to increase arte- rial oxygen tension (PaO2). Traditional lim- its of COT are unpredictability for fixed inspired concentration of oxygen (due to the open circuit mixed up with room air), diffi- culty in maintaining humidity of the inspired gas, particularly in hypoxemic patients who need high FiO2 (e.g. > 0.5, 6 L/min or more), and the substantial lack of any effect on breathing dynamic and work of breathing. HFONC therapy is carried out using an air/oxygen blender, active humidi- fier, a single heated tube, and high diameter nasal prongs (Figure 1). It is able thus to deliver adequately heated and humidified oxygen at flows reaching 60-70 L/min and to maintain a fixed FiO2.1,2,7 Indications and contraindications HFONC is generally used for respirato- ry support in critically ill patients in varying clinical situations, such as: i) Neonatological setting, as initial respiratory support or as weaning from NIMV or endo- tracheal intubation;3 ii) Post-extubation, including following surgery;4 iii) Acute hypoxemic respiratory failure;5 iv) Pre-intu- bation oxygenation; v) Avoiding intubation in immunocompromised patients. HFONC has also been used in hyper- capnic respiratory failure for patients unable to tolerate non-invasive ventilation because of claustrophobia or intolerance of tight interface contact.1,2 Currently there is not sufficient, well-established evidence or criteria for the clinical application of HFONC as well as criteria for starting and stopping it, and indications for treatment escalation; similarly, absolute contraindica- tions are also lacking. However, it is reason- able to consider not suitable for HFONC those patients with respiratory muscles insufficiency requiring pressure support ventilation (PSV), those who need higher levels of PEEP (e.g. in the setting of acute pulmonary edema), or those who need both PSV and PEEP (e.g. in the setting of chronic obstructive pulmonary disease). For the above mentioned conditions, the use of NIMV is recommended with a strong level of evidence.8 Effects of humidified high-flow oxygen via nasal cannula on alveolar oxygenation As previously described, HFONC has been used initially in the neonatological set- ting to increase oxygenation, as an alterna- tive to CPAP in preterm infants.3 The first studies involving the use of HFONC in adults analyzed its efficacy in periprocedur- al oxygenation, as well as in the post-extu- bation period in ICU patients or after car- dio-thoracic surgery.4-6 Later, HFONC has been investigated as a potential alternative to conventional oxygen therapy and NIMV in patients with acute hypoxemic respirato- ry failure, in order to evaluate if the theoret- ical advantage of its mechanism of action was associated with a significant increase in alveolar oxygenation compared to COT and/or if it was, at least, comparable with the known efficacy of NIMV. There are var- ied mechanisms through which HFONC devices affect the respiratory system and alter gas exchange. First of all, HFONC provides for washout of nasopharyngeal dead space, which facilitates pulmonary gas exchange, leading to PaO2 improvement and, to a minor extent, also to carbon diox- ide washout.1,2 Secondly, humidification of oxygen flow plays a role in preserving pul- monary conductance and compliance, avoiding bronchoconstriction reaction pro- voked by cool dry air flow and mediated by muscarinic receptors. Humidification also prevents the negative effects of breathing dry air, which is known to reduce nasal mucociliary clearance causing excessive water loss from the mucosa, acute damage and inflammation, potentially leading to atelectasis.9-12 Moreover, since in physio- logical condition inspiratory air needs to be warmed from room temperature to 37°C and humidified to 100% relative humidity Emergency Care Journal 2017; volume 13:7036 Correspondence: Andrea Bellone, Department of Emergency Medicine, ASST Grande Ospedale Metropolitano Niguarda, Piazza Ospedale Maggiore 3, 20162 Milano, Italy. Tel.: +39.02.64442447 – Fax: +39.02.64442339. E-mail: andrea.bellone@ospedaleniguarda.it Key words: hypoxemic respiratory failure; high flow oxygen nasal cannula; emergency medicine. Contributions: the authors contributed equally. Conflict of interests: the authors declare no potential conflict of interest. Received for publication: 5 September 2017. Revision received: 19 December 2017. Accepted for publication: 11 January 2018. This work is licensed under a Creative Commons Attribution 4.0 License (by-nc 4.0). ©Copyright G. Bottani et al., 2017 Licensee PAGEPress, Italy Emergency Care Journal 2017; 13:7036 doi:10.4081/ecj.2017.7036 Non -co mmerc ial us e o nly [Emergency Care Journal 2017; 13:7036] [page 62] by nasal mucosa, heat energy is required both to heat the air and to vaporize water into the air. Hence, heated and humidified high flow oxygen nasal cannulae produce a reduction in the metabolic cost of gas con- ditioning.13,14 Heat and humidification, along with the interface made by nasal prongs, are accountable for the great tolerance offered by the device.15,16 It is believed that high flow through the nasopharynx can be titrat- ed to provide positive distending pressure in the airways, with a consequent slight increase of PEEP and end-expiratory lung volume. Although HFONC is an open sys- tem, high flow from the nasal cannula offers resistance against expiratory flow and increases airway pressure. Some studies demonstrate that at flows of 30-50 L/min provided by HFONC system is able to pro- vide a PEEP of 3-5 cm H2O, leading to clin- ical improvements. Parke et al.17 showed that there is substantial variation in pressure during inspiration and expiration demon- strating that the predominant benefits of positive pressure occur during expiration, particularly in patients who are at risk of, or have already established, atelectasis. It could be assumed that the mean expiratory pressure may be responsible for preventing atelectasis and that the peak and mean expi- ratory pressures may be responsible for re- expansion of collapsed areas.17 However, HFNOC are likely to deliver a clinically rel- evant PEEP level only if the patient’s mouth is kept closed and the leak of flow around the nares is minimized. Corley et al.18 inves- tigated the effect of HFONC on alveolar recruitment by means of measuring the rela- tionship between airway pressure and end- expiratory lung volume using electrical impedance tomography. Compared with low-flow, HFONC significantly increased end-expiratory lung impedance and tidal impedance, suggesting an increase in end- expiratory lung volume and functional residual capacity (FRC). These improve- ments were translated into better oxygena- tion and decreased respiratory rate and dys- pnea, with the greatest benefit in patients with a higher BMI. Consequently, it seems that at least part of the improvement in oxy- genation observed in patients with acute respiratory failure is secondary to alveolar recruitment. Hence, due to its characteris- tics and mechanisms of action, HFONC has gained widespread use especially in the set- ting of acute hypoxemic respiratory fail- ure.19 However, it is still debated whether the support provided by HFONC on work of breathing could be considered compara- ble to the one offered by NIMV.6 The strongest evidence is in favor of NIMV because of its proven ability to produce an ideal level of PEEP, especially in patients requiring high levels of PEEP. Therefore, numerous studies have been performed in order to evaluate the efficacy of HFONC, mostly compared with COT and/or NIMV. High flow oxygen with nasal cannu- la vs conventional oxygen therapy Oxygenation and gas exchange Most studies investigating HFONC effect and comparison to other oxygenation techniques focus on PaO2 and its deriva- tives PaO2/FiO2 (P/F) and peripheral oxy- gen saturation (SpO2).15 The vast majority of the studies, mostly prospective and observational, showed a sharp statistically significant benefit of HFONC versus COT in PaO2 after treatment.15,16,20-23 Oddly, the better designed and with higher population- enrolled study (FLORALI study,24 multi- center randomized and controlled) is the only one showing a slight but significant superiority of COT after 6 hours on gas exchanges. Current meta-analyses found in literature25,26 analyzed a mixed population (e.g. patients with AHRF, peri-procedural HFONC, post-surgery HFNC) and are therefore not completely reliable to deter- mine whether HFONC is actually better or at least equivalent to COT in ameliorating oxygenation in patients with AHRF. Work of breathing The main analyzed parameter involving respiratory work is represented by respira- tory rate (RR), mostly expressed as the absolute difference in breathes per minute between baseline and study (with the excep- tion of Bell et al.27 which accounted for a reduction of RR>20% from baseline). Among the studies commonly included in systematic reviews, seven5,15,20,21,23,24,28 show a statistically significant difference of RR between HFONC-group and COT-groups, in favor of HFONC, while no studies show a statistically significant difference in RR in favor of COT.29 The mechanical pattern of breathing was mainly expressed as thoraco- abdominal synchrony and was analyzed in only three of these studies. Sztrymf et al.5 have studied thoraco-abdominal asyn- chrony and supraclavicular retraction, determining a progressive improvement in time (minutes to hours) after HFONC initi- ation. The second study by Itagaki et al.21 investigated work of breathing with both clinical and quantitative parameters (ratio of maximum compartmental amplitude to tidal volume and related phase angle), showing a significant improvement of breathing mechanics with HFONC vs COT. The third study23 investigated respiratory effort quantitatively (analyzing esophageal pressure-time product per minute) and showed improvements of respiratory effort vs Venturi mask, but not vs CPAP (set at 5 cmH2O). In conclusion, limited available data seem to support efficacy of HFONC in ameliorating work of breathing vs COT. High flow oxygen with nasal cannu- la vs non-invasive mechanical ventilation Oxygenation and gas exchange NIMV is considered superior to HFONC in hypercapnic respiratory failure, Review Figure 1. Humidified high-flow oxygen via nasal cannulae device. Non -co mmerc ial us e o nly [page 63] [Emergency Care Journal 2017; 13:7036] due to its greater ability to eliminate carbon dioxide and to support work of breathing.30 Indeed, one of the most common exclusion criteria for studies involving HFONC was a PaCO2 higher than 45 mmHg.6 The majori- ty of literature compared HFONC and NIMV in selected clinical situations (most- ly post or peri-extubation and in the neona- tological setting).25,26 Only a few articles investigated its value in the general man- agement of AHRF (e.g.AHRF in an adult in the ED or inpatient). To our knowledge, only four studies investigated this feature. Amongst these, the FLORALI study24 again is the most important because of its design and the large enrolled population, with the other three22,23,31 being limited by the small number of subjects involved (14, 28 and 12 respectively). In the FLORALI study, PaO2 and P/F were compared between HFONC and NIMV at 1 and 6 hours from random- ization, showing significantly higher PaO2 and P/F for NIMV-group in both. Schwabbauer et al.22 and Vargas et al.23 did not reach statistical significance, while Frat et al.24 concluded for an increase in P/F only in the NIMV-group. It seems reasonable to assume that NIMV is actually superior to HFONC in increasing PaO2 and P/F in adults with AHRF. Work of breathing Three studies22-24 compared RR between HFONC and NIMV: among these, the only significant difference found was an initial and temporary improvement of RR in HFONC-group at 1 hour from beginning of administration, which was lost at the six- hours control, in the FLORALI study. Dyspnea and device tolerance Assessment of dyspnea has been carried out in most RCTs using a combination of visual analog scale, visual numerical scale, five point Likert Scale, and Borg scale. Although rarely reaching significance, the majority of the studies showed improved dyspnea, comfort and tolerability scores in favor of HFONC compared with NIMV and COT.5,15,20,32-35 HFONC has been reported to lead to rapid alleviation of respiratory dis- tress in more severe patients.28 Its remark- able tolerance during acute hypoxemic res- piratory failure allows a much longer dura- tion of use, being attributable partly to the heat and humidity supplied by the device and partly to the comfort given by its inter- face.15,16 Endotracheal intubation and mortality The two main questions that still remain without a definite answer are whether or not HFONC reduces mortality and need for intubation in patients with hypoxemic acute respiratory failure. Overall, no significant difference in mortality or intubation rate was detected in adult patients with acute respiratory failure treated with HFONC, when compared with usual care defined as COT or NIMV, so that HFONC can be con- sidered at least non-inferior to NIMV with regard to these outcomes.6,26,36-41 As for the intubation rate, there is only one RCT showing a significant difference in favor of HFONC:24 in the post hoc analyses, the authors showed HFONC to be significantly superior in reducing endotracheal intuba- tion when compared with COT alone, and also superior when compared to both COT and NIMV in the subgroup with severe hypoxemic respiratory failure (P/F ratio<200 mm Hg). The study also showed a significant reduction in duration of mechanical ventilation and 90-day mortali- ty in the HFONC group as secondary out- comes. The other studies did not find any significant difference with respect either to mortality and endotracheal intubation rate. Some studies have suggested that time to intubation may be longer in patients treated with HFONC compared with COT.39 In patients treated with NIMV, the time to intubation resulted to be similar in compar- ison with HFONC patients.24,36 This could reflect the existing major controversy regarding the use of NIMV in AHRF stating that prosecution of NIMV, aimed to avoid intubation, paradoxically results in delayed intubation which in turn leads to increased mortality. Discussion Available evidence is insufficient to determine whether HFONC is actually superior to COT in the treatment of AHRF.6,24-26 This is due to multiple factors encompassing strong differences in design, primary outcomes and demography of the population enrolled in studies, as stated in almost all available reviews. As an exam- ple, it is useful to consider two studies of the same author.24,31 Frat’s first observation- al sequential pilot study enrolled 28 patients, mostly with a diagnosis of ARDS, and showed a substantial benefit of HFONC vs COT in PaO2 after the first hours of treatment. The FLORALI study,24 as already described, was designed as a RCT enrolling 310 patients mostly with a diagno- sis of pneumonia and showed the opposite results. It is clear that a different pathophys- iology may, at least partially, explain the differences in these findings. Of note, it is worth to mention that the primary outcome was not oxygenation but rate of intubation. More recent studies are trying to avoid this bias by recruiting patients based on the operative diagnosis, rather than recruiting patients with AHRF from various etiolo- gies: Mackdee et al.28 for instance found that in AHRF due to congestive heart failure in the ED, HFONC may decrease the sever- ity of dyspnea during the first hour of treat- ment, when compared to COT. Conclusions In conclusion, due to its safety, efficacy and tolerability, we suggest that HFONC is a very promising technique, currently repre- senting a valuable alternative to NIMV in selected patients with AHRF. However, HFONC non-inferiority to NIMV has not yet been clearly demonstrated and may be thus considered a half way treatment between COT and NIMV. Key elements for its right application are a correct etiological diagnosis of respiratory failure and a careful selection of patients. 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