Drug delivery during oxygen therapy can offer great help to patients who may be affected if the circuit is disconnected and improve tolerance [25, 26, 32, 33]. Also, when the drug is delivered during assisted breathing, it shows enhancement in the clinical effects in a faster way [5, 7]. The SOLO nebulizer was inserted in the Y limb, in case of using BiPAP modes, to provide the highest delivery [24, 29].
In the current study, the results of pulmonary, systemic, and ex-vivo drug delivery were all found to be consistent. Generally, low BiPAP delivered the highest amount followed by HFNC then high BiPAP with the least amount. However, no significant difference was found between HFNC and high BiPAP in drug delivery. These results of the present study match the results of our in-vitro study (in press) in which the total inhalable dose(TID) and Fine Particle Dose (FPD) were the greatest using low BiPAP followed by HFNC then high BiPAP with the least amount [34].
Increasing IPAP caused a reduction in the amount of drug delivered either to the lung, systemic circulation or deposited on an ex-vivo filter. This is supported by the results found by Velasco and Berlinski [24] who found that increasing IPAP decreased the drug delivery efficiency either if SOLO was inserted before the mask, before the Y-piece, and at the ventilator.
In contrast, Chatmongkolchart, et al. [35] revealed that increasing IPAP increased the drug delivery if a nebulizer was inserted distal from the BiPAP ventilator (proximal to the lung model). This may be due to the usage of a single limb ventilator with the nebulizer inserted between the exhalation port and the lung model in their study. Consequently, there was a retrograde return. However, in the same study of Chatmongkolchart, et al., in accordance with our study, they reported that increasing BiPAP decreased the drug delivery [36].
L'Her et al. found that oxygenation improved when positive end-expiratory pressure (PEEP) was increased from 5 to 10 cm H2O, also dyspnea showed the best enhancement by increasing pressure support (PS) from 10 to 15 cm H2O [37]. However, their study did not include quantification of the drug delivered.
Pressure support ventilation (PSV) is a positive airway pressure, detected by a clinician, assisted by a mechanical ventilator for the patient's spontaneous inspiratory efforts like IPAP [38]. L'Her et al. found that when PS increases, dyspnea is improved as mentioned formerly. In the present study, using IPAP generally improved RR, but there was no significant difference between low and high BiPAP in improving RR.
The PEEP is the positive pressure that remains in the airways at the end of exhalation [39] like EPAP. It helps in recruitment and stabilization of collapsed lung tissue [37, 40], a decrease of alveolar stress [40] and the effort required of mechanically ventilated patients [41] and enhancement of gas exchange [42] so enhances oxygenation [43, 44]. This can be due to that sufficient PEEP helps to evacuate the circuit from the expired CO2, preventing rebreathing, out to the atmosphere with the aid of enough time of expiration [45].
Consequently, there must be a careful choice whether to increase the PEEP level for enhanced oxygenation or to increase the PSV level for improved dyspnea and reduced respiratory muscle effort [37]. So, we recommend further studies comparing the effect of increasing EPAP while holding IPAP.
The HFNC system was earlier found to enhance all respiratory parameters and oxygenation and be well tolerated when used for long periods than traditional facemasks [14, 46]. The more the oxygen flow in the HFNC system, the better the oxygenation would be [14, 47].
Both Ari et al. [27] and Perry et al. [32] found that increasing the flow of the HFNC system caused a reduction in the drug delivery and the best flow that was found for adults was 5 L min−1. So, in the current study, oxygen was delivered at that low flow of 5 L min−1.
The HFNC system, compared to low BiPAP, delivered a lower amount of the drug. The heated humidified circuit used in HFNC leads to aerosol condensation within the circuit and loss which was augmented by the smaller diameter and longer length of nasal cannula over the BiPAP circuit [26, 32, 48, 49]. Also, when comparing nasal to mask delivery, aerosol particles are filtered more efficiently through the nose, than the mouth, leading to a reduction in the dose available to penetrate the lower respiratory tract [50]. In addition, the turbulent gas flow in the nose and rhino-pharynx may favor drug deposition decreasing the amount of drug that can reach the lungs [25, 49].
On the other hand, deposition of the large particles of aerosol in the HFNC circuit decreases the delivered dose, improves tolerance. In this way, it decreases the deposition of these large particles on the face (potentially including eyes) and upper airways which happens when using facemasks [51]. Also, it shows a better-tolerated technique than facemasks [52] which may cause the feeling of confining, coldness, irritation, preventing communication and oral intake, that may be needed to act as a worn for long periods that may lead to, especially in children, fussing, crying, and screaming so reduced aerosol lung deposition, unlike HFNC circuit, humidified and heated conditions which improves patient comfort, may improve lung deposition and increase tolerance to use for long periods [51, 52].
In the present study, the percentage of the amount of drug delivered to the patient by low BiPAP, high BiPAP, and HFNC after 30 min were 0.932, 0.649, and 0.742% of the nominal dose, respectively. The cumulative percent of the amount within 24 h delivered to the patient by low BiPAP, high BiPAP, and HFNC were 10.883, 6.488, and 6.947% of the nominal dose, respectively. The former data were found to be greatly lower than the percentage of the amount collected from the ex-vivo filter; 42.052, 29.906, and 32.512% of nominal dose delivered by low BiPAP, high BiPAP, and HFNC, respectively. That could be because the particles less than 1 µm cannot deposit in the lung unless the patients hold his breath for 5–10 s [32, 53, 54] and since this patient could not make a 5–10 s breath-hold to get deposited most of the aerosol less than 1 µm was exhaled [7]. Also, the aerosol particles produced by the SOLO of 5 μm and above decreases the percent that would reach the lung as particle sizes of 1–3 μm [54,55,56].
Although low BiPAP delivered the highest amount of aerosol to the lung indicating better efficacy, it also delivered the highest amount systemically, so more side effects can occur to the patients [1]. The results of the current study can help in dose adjustment when changing from one technique to another. Depending on pulmonary drug delivery results, the amount of salbutamol delivered to the lung using 2.50 mg salbutamol on low BiPAP mode was equivalent to the amount delivered using 3.59 mg salbutamol on high BiPAP mode and to the amount delivered using 3.14 mg salbutamol on HFNC mode. Depending on systemic drug delivery results, the amount of salbutamol delivered to the body using 2.50 mg salbutamol delivered on low BiPAP mode was equivalent to the amount delivered using 4.19 mg salbutamol on high BiPAP mode and to the amount delivered using 3.92 mg salbutamol on HFNC mode.
Consequently, dose adjustment guidelines must be developed to be used when changing from one technique to another. If similar doses are used, there may not be of clinical difference in the bronchodilation but patient safety may be affected due to change in systemic delivery [29].
In accordance with the present study results, the HFNC reduced respiratory rate efficiently in Corley et al. [57], Bell et al. [58], Makdee et al. [59] studies. Also, Sztrymf et al. [46] reported that breathing frequency decreased significantly when using HFNC. In addition, Vargas et al. [60] revealed breathing frequency decrease too when HFNC was used in acute hypoxemic respiratory failure, which can be attributed to the reduction of breathing work and enhancement of oxygenation.
The present study results showed that all the three techniques improved RR significantly from the baseline, but no significant difference was found between the three techniques. On the other hand, in Schwabbauer et al. studied [61], HFNC significantly improved RR than NIV. This can be attributed to the difference in the conditions from the current study. They used HFNC at gas flow 55 L/min which was much greater than the current study.