A narrative review on trans-nasal pulmonary aerosol delivery

In 2018, Bräunlich and colleagues reported that 26 patients with stable chronic obstructive pulmonary disease (COPD), who inhaled 2.5 mg albuterol and 0.5 mg ipratropium via a small volume jet nebulizer (JN) and mouthpiece or in-line with HFNC (TNI medical AG, Wuerzburg, Germany) at a gas flow of 35 L/min, had similar bronchodilator effect (p = 0.5) [9]. Likewise, Réminiac and colleagues compared delivery of 2.5 mg albuterol with a vibrating mesh nebulizer (VMN) (Aerogen Solo, Aerogen, Ireland) via HFNC (Airvo2, Fisher & Paykel, New Zealand) versus a JN with mask in a cross-over RCT in 25 stable patients with reversible airflow obstruction and reported similar improvements in forced expiratory volume in the first second (FEV₁) (p = 0.11) [10]. In a crossover RCT with 12 stable COPD patients, Madney and colleagues compared systemic bioavailability of albuterol administered by JN or VMN in line with HFNC at 5 L/min. Urinary albuterol excretion at 30 min and 24 h was 2-fold higher with the VMN than the JN (p < 0.05) [11].

The label dose of albuterol solution in the USA and Europe is 2.5 mg. Li and co-workers performed a dose-response relationship study in 42 stable asthma and COPD patients with known positive responses to 400 mcg albuterol via metered dose inhaler (MDI) and spacer. The subjects inhaled escalating doubling doses via VMN and HFNC with gas flow of 15–20 L/min. The improvement of FEV₁ at the cumulative dose of 1.5 mg with VMN and HFNC was similar to that with MDI and spacer (p = 0.878) (Fig. 1) [12].

Inhaled epoprostenol, a pulmonary vasodilator, has been used off-label for several decades to treat mechanically ventilated patients with pulmonary hypertension and/or refractory hypoxemia [20, 21]. In two small retrospective studies, adult patients with pulmonary hypertension and refractory hypoxemia improved oxygenation after inhaling epoprostenol via HFNC at an average gas flow of 40 L/min [13, 14]. Mean pulmonary arterial pressure was reduced more effectively by titrating HFNC gas flow based on individual response to inhaled epoprostenol at the bedside compared with a constant HFNC flow [15]. Future prospective studies with larger sample size are needed to validate these findings.

In 2015, Morgan and colleagues studied five infants with acute bronchiolitis and respiratory distress unresponsive to three treatments with JN via mask [16]. After inhaling albuterol via VMN and HFNC, infants appeared markedly more comfortable, suggesting that albuterol administration with HFNC was beneficial. An observed increase in heart rate probably reflected delivery of a higher albuterol dose via VMN and HFNC. Likewise, in children receiving albuterol by VMN via HFNC with flow at 2–4 L/min or via face mask, the heart rates increased by 10 beats/min after inhaling albuterol via HFNC (p < 0.001 vs mask) [18]. In a cross-over RCT in 6 infants with bronchiolitis, albuterol delivery via VMN with HFNC (~ 8 L/min) improved patients’ comfort and satisfaction with treatment compared to JN and mask [17].

In a retrospective study of 39 children with status asthmaticus (10 had severe acidosis with pH < 7.30) who failed ≥ 3 treatments with nebulized albuterol via JN, intermittent boluses of albuterol delivered via HFNC at a maximum flow of 1.0 [0.8–1.1] L/kg/min were considered as a contributor in avoiding intubation [19].

The standard bronchodilator doses delivered via HFNC at 15–35 L/min for adults and 1 L/kg/min for children generated similar clinical responses to those delivered with conventional aerosol devices. Further studies need to quantify aerosol delivery efficiency in critically ill patients.

When a JN is placed in-line with HFNC, the total gas flow in the HFNC system is greater than 6 L/min, which is the minimal flow to operate the JN. This flow requirement limits the use of JN via HFNC for infants and small children, who require HFNC flow ≤ 6 L/min. Moreover, JN integrated into a HFNC system may be contraindicated in systems that incorporate their own flow generators (e.g., Airvo 2 from Fisher & Paykel) as it alters oxygen, total flow, and pressure. In contrast, VMNs are driven by electricity with no additional gas flow required. Additionally, the residual volume of drug remaining in nebulizers is higher in JN than VMN (45% vs 3%) [41, 43]. Consequently, VMN generated 2–3 times higher inhaled dose than JN via HFNC for both pediatric and adult populations (Table 2) [11, 33, 38, 41]. For these reasons, VMNs are preferred over JNs for aerosol delivery with HFNC [8].

HFNC gas functions as the “carrier” for aerosol, so that gas flow rate, gas density, and humidity could affect aerosol delivery efficiency.

In patients receiving HFNC therapy, the total inhalation flow is a combination of the patient’s inspiratory flow and HFNC gas flow. The contribution of each flow influences the efficiency of aerosol delivery. When VMN was utilized to deliver aerosol via HFNC during quiet breathing, aerosol deposition was inversely related to the gas flow (Table 3) [23, 26, 27, 33, 38, 40, 42, 44]. Turbulence generated with higher gas flow leads to greater impaction losses of the aerosol particles ≥ 3 μm during their passage through the cannula, prongs, and upper airways, thereby reducing the dose of aerosol delivered to the patient’s lower airway. Consequently, one guideline recommends reducing HFNC gas flow to 4 L/min during aerosol delivery to children [45].

In contrast, during simulated adult distressed breathing, two in vitro studies reported that inhaled aerosol dose increased when gas flow decreased from 50 to 30 L/min [26, 27] and decreased when gas flow was reduced to 10 L/min [27]. Inhaled doses were higher during distressed breathing than quiet breathing with gas flows of 30 and 50 L/min [26, 27], but not at 10 L/min [27]. Subsequently, Li and colleagues utilized 5 different gas flows (5–60 L/min) and 6 different adult breathing patterns in their in vitro study and reported that the ratio of HFNC flow to patient’s inspiratory flow was more important than HFNC flow alone [29]. Inhaled drug dose was higher when gas flow was set below the patient’s inspiratory flow compared to gas flow exceeding inspiratory flow, and plateaued when HFNC flow was set at ~ 50% of the inspiratory flow [29]. These findings were consistent with a report in infants and children (Fig. 2) [30] and formed the basis for a RCT to compare albuterol delivery and effective dose at 3 different gas flow settings with a HFNC in patients with COPD or asthma [46].

Currently, no commercial device provides breath-by-breath measurement of patient’s inspiratory flow during HFNC. However, findings on the gas flow to patient’s inspiratory flow ratio [29, 30] should remind clinicians to titrate gas flow settings when employing HFNC for aerosol delivery, especially for drugs such as inhaled epoprostenol that produce immediate clinical responses. In support of this recommendation, a retrospective study in patients with pulmonary hypertension and hypoxemia found that titration of gas flow at the bedside led to a better response to inhaled epoprostenol via HFNC compared with application of a constant gas flow [15].

Both pediatric [25, 30] and adult [26, 39] in vitro studies reported that aerosol deposition with VMN placed at the inlet of humidifier was greater than with the nebulizer placed close to patient. The exception was in infants with extremely low gas flow (≤ 0.25 L/kg/min) where nebulizer placement closer to the patient was more efficient [30]. With the VMN placed farther away from the patient, “carrier” gas flow (including delivery gas flow and patient’s inspiratory flow, combined with low tidal volume) was probably insufficient to transport aerosol to the patient before aerosol sedimentation occurred.

Open mouth breathing reduced inhaled dose compared to closed mouth breathing in the adult manikin during aerosol delivery with HFNC when gas flow was set higher than the patient’s inspiratory flow [26]. This observation was consistent with a report by Li and co-workers in a pediatric model [37]. Interestingly, when gas flow was lower than the patient’s inspiratory flow, open mouth breathing resulted in a higher inhaled dose than closed mouth breathing [37]. Perhaps aerosol carried with low gas flow collected in the nasal cavity during exhalation via mouth was drawn in with the next inhalation. In contrast, higher gas flows flushed the aerosol from the nasopharynx, thereby reducing the amount of drug available for the next inhalation [37].

Continuous generation of aerosol by nebulizers JN or VMN, in-line with HFNC, results in wastage to the atmosphere during the expiratory phase. Synchronized aerosol generation with patient’s spontaneous breathing increases inhaled dose during both invasive [53] and noninvasive ventilation [54, 55]. With a prototype breath-synchronized VMN, Li and colleagues reported inhaled dose was higher with breath-synchronized versus continuous aerosol generation when placed close to the patient with HFNC gas flow ≥ 10 L/min. However, when placed at the inlet of the humidifier, breath-synchronized VMN generated a higher inhaled dose than continuous operation only when HFNC gas flow was below 50% of patient’s inspiratory flow [39]. This finding is likely explained by storage of the aerosol in the HFNC circuit during the exhalation phase. The optimal ratio of HFNC gas flow to patient’s inspiratory flow that generates the highest inhaled dose depends on the balance between aerosol storage and gravitational sedimentation in the circuit.

Alternatives to placing nebulizers in-line to administer aerosol during HFNC include placing the nebulizer with mouthpiece/mask over the nasal cannula; or discontinuing HFNC to administer aerosol by conventional methods [8].

Among these in vitro studies, the ratio of HFNC gas flow to patient’s inspiratory flow was critical; optimal inhaled dose was achieved when HFNC gas flow was set ~ 50% of inspiratory flow. VMN used with HFNC generated a higher inhaled dose than JN. VMN placed at the inlet of humidifier generated a greater inhaled dose than VMN placed closer to the patient. When using dry gas or heliox as HFNC carrier gas, compared with humidified gas or oxygen, respectively, the inhaled dose was higher only when HFNC gas flow exceeded patient’s inspiratory flow. However, patient’s inability to tolerate dry gas or the high cost of using heliox particularly for prolonged duration is a deterrent to their routine use. Removing HFNC to use a conventional aerosol device did not improve drug delivery, and placing a conventional aerosol device via mask/mouthpiece concurrent with HFNC reduced drug delivery.

During status asthmaticus, HFNC improves work of breathing and reduces carbon dioxide retention [2, 58, 59]. The comfort of aerosol delivery via HFNC makes it an ideal option, particularly for young children [8, 16, 17]. High gas flow setting has some benefits, but it impedes aerosol delivery to the lung. Reduction in HFNC flow from 2.0 to 0.5 L/kg/min resulted in a 21% increase in patient’s work of breathing [60]. However, the inhaled dose by trans-nasal aerosol delivery at the lower gas flow increased by 3- to 12-fold [30, 37, 38, 40]. Thus, reducing the HFNC flow improves aerosol delivery at the slight risk of losing breathing support for short periods, while using unit doses could shorten the duration of treatment. Delivery of 1 mL requires 2–4 min; reducing the gas flow for such a short period should not significantly interfere with work of breathing. We caution that when HFNC flow is reduced, the patient should be closely monitored and F_IO₂ increased if needed to maintain a target SpO₂ [61].

Patients with severe asthma often require larger than conventional bronchodilator doses. Multiple unit doses are delivered more frequently, requiring intensive use of staff resources. Bronchodilators could be delivered using HFNC with an infusion pump and prepared syringe of albuterol. In this scenario, a higher dose could be delivered to the lung by utilizing a relatively low gas flow and a slightly higher nominal dose compared to conventional bronchodilator aerosol delivery techniques [37].

HFNC is increasingly utilized for patients with COPD for its effects of washing out dead space and reducing work of breathing [2, 62]. Long-term use of HFNC could reduce the frequency and duration of COPD exacerbations and improve patient’s quality of life [63, 64]. In those studies with stable COPD, HFNC flow was set at 20–25 L/min [63, 64] due to the patient’s low inspiratory flow demand. HFNC gas flow of 15–20 L/min with a standard dose of 2.5 mg albuterol is sufficient to elicit bronchodilator effects [12].

During exacerbation of COPD, higher than usual patient’s inspiratory flow demand requires an increase of flow setting with HFNC. In 12 hypercapnic patients with COPD initially treated with noninvasive ventilation, Rittayamai and colleagues achieved similar work of breathing with HFNC flow set at 30 L/min [65]. Discontinuing HFNC to use a facemask significantly increased patients’ breathing efforts [66]. Therefore, HFNC should not be interrupted to use mask/mouthpiece with JN when acutely ill patients with COPD require aerosol treatments. In this setting, it is appropriate to deliver aerosol via HFNC at 20–30 L/min flow.

In patients with pulmonary hypertension, prolonged continuous inhalation of aerosolized epoprostenol with HFNC is convenient and comfortable for the patient. In the absence of concomitant hypoxemia and with low inspiratory flow demand, low gas flows with HFNC (5–10 L/min) could optimize delivery of inhaled epoprostenol to patients with pulmonary hypertension [15, 27, 29, 42].

When patients with pulmonary hypertension have concomitant hypoxemia, higher gas flow and F_IO₂ are required to improve oxygenation by avoiding air entrainment and generating some positive end-expiratory pressure [58, 66]. However, high gas flows reduce trans-nasal delivery of inhaled epoprostenol with a potential loss of efficacy because there is a linear correlation of inhaled dose with improvement in oxygenation [20]. A practical solution would be to titrate HFNC gas flow at the bedside to pulmonary arterial pressure and/or oxygenation [15]. This approach could determine optimal setting for individual patient, based on immediate responses to inhaled epoprostenol.

Patients, who did not require HFNC for administering high F_IO₂ and who could tolerate reduced gas flow for short periods, could be benefited by decreasing HFNC gas flow to relatively low settings, such as 15–20 L/min for stable adult patients, 20–30 L/min during COPD/asthma exacerbation among adults, and 0.25 L/kg/min for children with asthma. Employing unit doses with high drug concentration could shorten the duration for which flow was reduced. After administration of the unit dose, HFNC gas flow should be returned to its previous setting. For patients receiving HFNC therapy mainly for relief of hypoxemia and who simultaneously require inhaled epoprostenol to improve oxygenation, HFNC gas flow should be carefully titrated at the bedside based on patients’ response to both inhaled epoprostenol and gas flow.