Background
High-flow nasal cannula oxygen therapy (HFNC) consists of a totally conditioned, warmed, and humidified air/oxygen blend through a wide-bore nasal cannula at a flow rate between 20 and 60 L/min [
1]. Compared with the ‘conventional’ oxygen therapy devices, which deliver gas at 5–20 L/min (conventional O
2), during HFNC the tracheal inspiratory oxygen fraction (FiO
2) is more predictable [
2] and the mucociliary function is better preserved [
3]. In addition, HFNC generates a positive airway pressure (between 2 and 8 cmH
2O at the pharyngeal level) which resembles positive end-expiratory pressure (PEEP) and is proportional to the administered gas flow rate and varies with the patient breathing pattern (i.e., breathing with the mouth open or closed) [
4]. Furthermore, HFNC results in a significant, flow-dependent ‘CO
2 wash out effect’ of the nasopharyngeal space which decreases the anatomical dead space ventilation and therefore the CO
2 rebreathing [
5]. It seems likely that the overall impact of HFNC on the respiratory function results from the synergistic interaction of the mechanisms described above as well as other, more subtle, and as yet incompletely understood mechanisms [
6].
Since its introduction, HFNC has been applied to treat patients with hypoxemic respiratory failure [
2,
7‐
9] and to prevent reintubation in patients at risk of extubation failure [
10‐
12]. In these patients, compared with conventional O
2 therapy, HFNC improves oxygenation and decreases the work of breathing (WOB) [
10,
13]. Studies in patients with stable chronic obstructive pulmonary disease (COPD) in a home-care setting suggest favorable effects on the WOB and gas exchange [
14‐
16]. However, far less known are the physiological effects of HFNC on neuroventilatory drive and WOB in patients with COPD in the critical care setting.
The electric activity of the diaphragm (EAdi) is a ‘processed’ diaphragmatic electromyography signal recorded through an array of electrode pairs mounted on the wall of a nasogastric feeding tube [
17]. The EAdi is proportional to the intensity of the electrical stimuli directed to the diaphragm, i.e., the neuroventilatory drive [
18‐
20]. Recently, Bellani and coworkers demonstrated that EAdi can be used to estimate the instantaneous WOB [
21].
In this physiological study, we administered HFNC and conventional O2 therapy via a face mask postextubation in patients with a background of COPD who had received mechanical ventilation for hypercapnic respiratory failure from various etiologies. The hypothesis of this study was that, in these patients, HFNC decreases the neuroventilatory drive and WOB compared with conventional O2 therapy.
Discussion
This study shows that postextubation HFNC significantly decreases the neuroventilatory drive and work of breathing in patients with COPD who had received mechanical ventilation for hypercapnic respiratory failure due to various etiologies.
The EAdi reflects the rate of discharge of the phrenic nerve and therefore it is a measure of the neuroventilatory drive [
17‐
20,
31,
32]. Thus, our data clearly show that HFNC decreases the neuroventilatory drive (EAdi
PEAK and EAdi
SLOPE) compared with conventional O
2 therapy. Neuroventilatory drive and work of breathing are key factors for the weaning process and an excessive respiratory drive predicts weaning failure [
26,
32]. In fact, a high ventilatory drive may be associated either with excessive mechanical load posed on the inspiratory muscles, diaphragm weakness, or inappropriately high activation of the respiratory centers due to pain, fever, anxiety, and acidosis [
32]. In a mixed population of critically ill patients, Liu and coworkers found that an EAdi
PEAK lower than 15–20 μV during a spontaneous breathing trial (T-tube) was associated with weaning success [
26]. Similar results were recently obtained in two other studies by Dres et al. [
33] and Barwing et al. [
34]. In our study, we found that the EAdiP
EAK was below this threshold in most of the patients during both HFNC periods (Fig.
4), while it was on average 1.5-times higher than this threshold during conventional O
2. Accordingly, considering that COPD patients are intrinsically at risk of weaning failure [
35], our results are potentially clinically relevant.
Although the work of breathing is proportional to the neuroventilatory drive, its absolute value depends on the ability of the respiratory muscles to convert the electrical stimuli into mechanical contraction (electromechanical coupling) [
18,
32]. We measured the work of breathing in terms of PTP
DI per breath and per minute, a well-known index of respiratory muscle oxygen consumption (Table
3 and Fig.
4). According to physiological studies in mixed populations of critically ill patients, an ‘acceptable’ PTP
DI/min is between 50 and 150 cmH
2O/s/min [
36,
37]. The PTP
DI/min was in this range in 64.3% of our patients (i.e., 9/14) both during HFNC1 and HFNC2 periods, whereas the PTP
DI/min was above this acceptable range in 78.6% of patients during the conventional O
2 period (i.e., 11/14) (Fig.
3).
According to the 2017 European Respiratory Society–American Thoracic Society (ERS/ATS) guidelines [
38], COPD patients benefit from noninvasive ventilation to prevent reintubation. Therefore, it would have been of interest to compare the physiological effects of HFNC and NIV in our patients. However, at the time of the study, postextubation preventative NIV was not applied on a routine basis in our institution. Interestingly, a recent study by Hernandez et al. showed that HFNC is noninferior to NIV in preventing acute postextubation respiratory failure in patients at “high risk” of postextubation respiratory failure, including patients older than 65 years or those with heart failure, moderate to severe COPD, an Acute Physiology and Chronic Health Evaluation (APACHE) II score higher than 12 on extubation day, a body mass index of more than 30, those with airway patency problems, and, finally, patients with difficult or prolonged weaning [
11].
Further studies are needed to assess the beneficial mechanisms of HFNC in COPD patients. We speculate that two mechanisms are of particular relevance: a) the HFNC “PEEP” effect [
14], that may have counterbalanced the flow-limited intrinsic positive end-expiratory pressure (PEEPi), and b) the “CO
2 wash-out” effect of the anatomical dead space [
5] that may have decreased the diaphragmatic workload. The better preservation of the mucociliary function as compared with conventional O
2 therapy may have been an adjunctive mechanism [
3], but we believe that it was less important since the cross-over periods were relatively short.
In hypoxemic patients, Mauri et al. [
39] and Maggiore et al. [
10] found that HFNC significantly decreased RR compared with conventional O
2 therapy. Mauri estimated the VT through electrical impedance tomography (EIT) and found that it remained stable. In contrast, in our COPD patients, the RR remained unchanged (Table
2), while we have no data on VT since patients were breathing spontaneously and we wanted to avoid any modification in breathing pattern caused by the measurement apparatus. However, the VT likely increased since animal studies show that VT is proportional to the electrical activity of the diaphragm during unassisted spontaneous breathing [
40]. Based on this hypothesis, in our patients, the response to HFNC removal during the conventional O
2 period would have been similar to the physiological response to a sudden increase in respiratory workload during to CO
2 rebreathing, i.e., to maintain the RR as constant and to increase the VT [
41,
42]. The different impact of HFNC on RR between our study and those of Mauri and Maggiore could be explained by the different background of the respiratory failure of the studied patients (hypoxemic versus hypercapnic).
In our study, similar to previous studies [
13], we used a standard, nonocclusive oxygen facial mask with a fixed gas flow of 10 L/min in all the patients during the conventional O
2 study step (see the Methods section). Hence, in our patients the peak inspiratory flow was very likely greater than the mask gas flow and therefore the true fraction of inhaled oxygen was lower than the one provided by the mask. The “Venturi Mask” is a high-flow oxygen delivery system that provides 35–45 L/min of a mixture of oxygen and air with a delivered FiO
2 of 0.24–0.6 by taking advantage of the Bernoulli principle [
43]. By using a Venturi Mask instead of the standard mask, it is possible that we would have better matched the patient’s inspiratory flow during the conventional O
2 study period. One could also speculate that a higher mask flow could have other effects in terms of CO
2 washout from the mask or from the airways, but we are not aware of studies comparing Venturi mask and HFNC.
We must acknowledge some study limitations. First, we studied a population of patients with COPD that was admitted to the ICU with hypercapnic ventilatory failure due to various etiologies (Table
1). Only 8/14 (57%) of COPD patients were admitted because of a COPD exacerbation, while the other 6 (43%) received mechanical ventilation for postoperative ventilatory failure. In this regard, our population could be deemed as heterogenous. However, we point out that: 1) our study was conducted in the postextubation phase when the primary reason for the acute respiratory failure had resolved or at least improved (see Methods); and 2) all our patients had moderate to very severe COPD according to the GOLD classification. Second, we were not able to measure several respiratory parameters during spontaneous breathing (VT, PEEPi, inspiratory flow) that could have provided us with a more complete interpretation of the treatment effect. However, our study was conducted in spontaneously breathing patients and we sought to avoid any modification in breathing pattern caused by the measurement apparatus. Third, we measured the work of breathing based on a method recently validated by Bellani and coworkers [
21], but the correlation between work of breathing and EAdi may be misleading if the contraction of the accessory inspiratory muscles is dominant compared with the diaphragmatic contraction. Indeed, the estimation of work of breathing from EAdi assumes that the diaphragm contributes approximately 75% to the overall WOB (as occurs in normal conditions) [
23]. However, we assessed all patients for signs of paradoxical abdominal motion and use of accessory inspiratory muscles throughout the study. In addition, the method described by Bellani et al. assumes a linear relationship between EAdi and P
DI at different lung volumes based on a close correlation at different lung volumes between the P
DI obtained from the esophageal pressure and the P
DI obtained through the formula EAdi × NME [
21]. However, Bellani et al. studied patients ventilated with different levels of pressure support ventilation (PSV) and neurally adjusted ventilatory assist (NAVA) while we studied spontaneously breathing patients. Of note, other authors showed a nonlinearity between diaphragmatic efficiency and lung volumes, but only for intense diaphragmatic contractions [
19]. Fourth, we studied a small patient number that, while appropriate for a physiologically oriented study, weakens any speculation on the clinical outcomes (e.g., ICU and hospital length of stay and reintubation rate).