Gas mixture in noninvasive ventilation

Authors: Mostafa Elshazly, Garuti Giancario, Benan Bayrakci, Jose Luis Sandoval, Hebatallah Hesham Ahmed, Antonio M. Esquinas

Abstract

Noninvasive ventilation (NIV) and high-flow nasal cannula are increasingly used to treat acute respiratory failure. Because many of these patients could also benefit from inhaled medications, combining aerosol therapy with NIV or high-flow nasal cannula is a promising approach. Effective drug delivery to the lungs is crucial for successful aerosol therapy during NIV. Prior research has identified several factors that affect aerosol delivery efficiency in NIV patients. Medical gases have a long history of use in managing various respiratory conditions. Among them, oxygen is frequently used for patients with hypoxia (e.g., hypoxemic respiratory failure and in newborns). In addition to deoxygenation, helium oxygen mixture and nitric oxide can also be administered through devices such as masks combined with NIV. This narrative review aims to provide a comprehensive overview on the application of gas mixtures (such as helium oxygen mixtures and nitric oxide) in NIV, focusing on their efficacy, safety, and optimization strategies in different clinical settings.

Introduction

Noninvasive ventilation (NIV) is gaining widespread use in managing acute and chronic respiratory failure. It offers the benefits of improved gas exchange, reduced breathing effort, and increased survival rates while minimizing the risks linked to endotracheal intubation.1 Aerosolized medications are a key treatment for patients on NIV, as many individuals with respiratory failure also require aerosol therapy. Studies have confirmed the effectiveness and practicality of administering aerosol drugs during NIV, particularly for individuals with asthma or chronic obstructive pulmonary disease (COPD). Furthermore, delivering medications during oxygen (O2) therapy helps maintain circuit integrity, enhances patient comfort, and improves overall tolerance.2 Additionally, administering medication during assisted breathing accelerates clinical effects, leading to quicker improvements in patient outcomes.3

Although there is considerable evidence supporting aerosol drug delivery during mechanical ventilation, there is limited clinical research specifically examining aerosol therapy in NIV patients. Previous in vitro researchers have identified that multiple factors can affect aerosol drug delivery in this group. These include the ventilation mode, ventilator settings, type of circuit, aerosol device placement, leak port location, type of exhalation valve, humidity levels, aerosol device type, patient interface, and the delivery technique employed. This narrative review explored the current state of knowledge regarding aerosol drug delivery and the use of heliox and nitric oxide (NO) during NIV.

Methodology

The review was conducted using a systematic search strategy across multiple electronic databases, including PubMed, Embase, Scopus, and Web of Science, from 1995 to 2023. The selection process will be conducted in two first, Screening: Titles and abstracts of retrieved articles will be independently screened by two reviewers to identify potentially relevant studies. Discrepancies will be resolved through discussion or consultation with a third reviewer. Second, Eligibility: Full texts of selected articles will be retrieved and assessed for eligibility based on pre-defined inclusion criteria.

Inclusion (1) Studies published in peer-reviewed journals; (2) Studies investigating aerosol drug delivery during NIV in adult or pediatric populations; (3) Studies examining the use of heliox or NO during NIV; (4) Clinical trials, observational studies, in vitro studies, and reviews relevant to the research question; and (5) Studies published in English. Exclusion Studies not relevant to aerosol drug delivery or gas mixtures during NIV.

The search strategy will employ a combination of keywords and terms related to the following noninvasive ventilation (“Noninvasive Ventilation,” “NIV,” “CPAP,” “BiPAP,” “Noninvasive Positive Pressure Ventilation,” and “NIPPV”), aerosol drug delivery (“Aerosol Delivery,” “Nebulizer,” “Metered-Dose Inhaler,” “pMDI,” “Drug Delivery Systems,” and “Inhalation Therapy”), gas mixtures (“Heliox,” “Nitric Oxide,” “Inhaled Nitric Oxide,” “iNO,” and “Helium-Oxygen Mixture”), and combined terms (such as “Noninvasive Ventilation AND Aerosol Delivery,” “NIV AND Heliox,” “Inhaled Nitric Oxide AND NIV,” “Aerosol Delivery AND Nitric Oxide,” “Aerosol Delivery AND Heliox,” “NIV AND Aerosol Delivery AND Heliox,” and “NIV AND Aerosol Delivery AND Nitric Oxide”).

Factors Impact Aerosol Drug Delivery

Mode of ventilation

Bi-level positive airway pressure (BiPAP) and continuous positive airway pressure (CPAP) are commonly employed in NIV.

Pollack et al.4 conducted a randomized clinical trial with asthma patients in the emergency department, comparing aerosol drug delivery via BiPAP to nebulizer treatment alone. They observed a marked increase in peak expiratory flow in both groups, increasing from 211 to 357 L/min with BiPAP and from 183 to 280 L/min with the nebulizer. Changes in O2 saturation, heart rate, and respiratory rate were similar between the two groups. Previous evidence also reported a greater improvement in forced expiratory volume in first second (FEV1), forced vital capacity, peak expiratory flow, and inspiratory capacity of patients with asthma after bronchodilator administration combined with NIV.5

In a study of 13 healthy volunteers, Maccari et al.6 examined the distribution of radio aerosol during spontaneous breathing, CPAP at 10 cm H2O, and BiPAP with inspiratory/expiratory pressures of 15/5 cm H2O. Their findings showed no significant difference in aerosol deposition within the trachea or either lung. Furthermore, neither CPAP nor BiPAP impaired aerosol drug delivery.

Boules et al.7 compared salbutamol delivery using low and high pressure BiPAP and high flow nasal cannula (HFNC). Drug delivery to the lungs, body, and in lab tests was similar across all three methods. Low-pressure BiPAP delivered the most medication, followed by HFNC, and then high-pressure BiPAP. However, the difference between HFNC and high-pressure BiPAP was not significant. Boules et al.8 also found the highest inhalable and fine particle doses with low-pressure BiPAP, followed by HFNC, and the lowest with high-pressure BiPAP.

During NIV more effective aerosol delivery is achieved with higher inspiratory positive airway pressure (IPAP) and lower expiratory positive airway pressure. Elevated expiratory positive airway pressure can increase the backward flow of air during exhalation, leading to aerosol leakage and reduced delivery. In an in vitro study, Sutherasan et al.9 demonstrated greater aerosol delivery efficiency at an IPAP/expiratory positive airway pressure setting of 15/5 cm H2O compared to 10/5 cm H2O, 15/10 cm H2O, and 20/10 cm H2O.

Higher IPAP was associated with reduced drug delivery to the lungs, systemic circulation, and an ex-vivo filter. This aligns with Velasco and Berlinski’s findings,10 which showed that increasing IPAP decreased drug delivery effectiveness regardless of whether the SOLO device (Aerogen, Galway, Ireland) was positioned before the mask, the Y-piece, or at the ventilator.

While low-pressure BiPAP delivered the most aerosol to the lungs, suggesting greater effectiveness, it also resulted in the highest systemic drug exposure, potentially increasing the risk of side effects.11

Volume and pressure control ventilation

Li et al.12 in a consensus statement regarding aerosol delivery during respiratory support, recommended against altering ventilator modes or settings solely for the purpose of improving aerosol delivery during routine nebulization in non-invasively ventilated patients.

While spontaneous ventilation is preferred for optimizing aerosol delivery and patient-ventilator synchrony (provided the patient can tolerate it), CPAP delivers approximately 30% more medication than controlled ventilation (at the same tidal volume). This advantage stems from the patient’s ability to control breath size and timing during spontaneous ventilation, a feature absent in controlled modes (pressure or volume control). However, controlled ventilation is necessary when spontaneous breathing is not feasible. Of the controlled modes, pressure control is preferred due to its more consistent respiratory support, even with air leaks in the NIV circuit. Pressure control also delivers higher nebulizer doses compared to volume control, especially in patients with high resistance and compliance. For pressurized metered-dose inhalers (pMDIs) within the circuit, both modes offer similar delivery.3

Other factors influencing gas delivery

Inspiratory flow rate significantly affects aerosol delivery during NIV. Higher flow rates create more turbulence, increasing inertial forces and leading to greater aerosol delivery on the central airways. França et al.13 observed a strong link between tidal volume and lung deposition during spontaneous breathing, but not during NIV. Despite higher inspiratory flow rates increasing tidal volume, they did not improve pulmonary deposition during NIV.

Other factors that can enhance drug deposition include a low respiratory rate, a high tidal volume, and incorporating an inspiratory pause.14

Aerosol device position

Aerosol devices used with NIV are typically connected to the ventilator circuit in one of three 1) directly to the vented mask with a leak port, 2) between the leak port and the ventilator, or 3) between the leak port and a non-vented mask. Studies suggest that the best placement for aerosol devices during NIV is between the leak port and the mask15 (Figure 1). Connecting a nebulizer to a vented mask with a leak port leads to significant aerosol loss during both inhalation and exhalation, severely limiting effective drug delivery.

Placing a nebulizer between the leak port and a non-vented mask allows the inspiratory pressure of NIV to propel the aerosol toward the patient. While some aerosols may escape through the leak port during exhalation, the remaining aerosol can build up in the tubing, ready to be inhaled with the next breath. Peng et al.15 discovered that adding a 15 cm extension tube between the leak port and the nebulizer minimizes aerosol loss, effectively using the extension tube as a reservoir. While adding a 15 cm extension tube could potentially increase carbon dioxide (CO2) rebreathing, previous studies have indicated that using a face mask increases CO2 rebreathing by about 3 mL per breath. Therefore, it concluded that the impact of the 15 cm extension tube on CO2 rebreathing is likely minimal.

The placement of the aerosol generator in a ventilation circuit depends on the circuit type. With a single-limb circuit, the nebulizer is usually placed closer to the patient, between the patient interface and the expiratory port. Dual-limb circuits typically position the nebulizer on the inspiratory limb, closer to the ventilator, a location that has been shown to optimize aerosol delivery and minimize medication loss.3

The leak port location

The leak port, crucial for gas washout during exhalation, influences aerosol delivery effectiveness with NIV, and its location matters. Integrating the leak port within the ventilator circuit, rather than the mask itself, leads to improved aerosol delivery.16

Exhalation valve

Various exhalation valve types, such as plateau, single arch, and whisper swivel, are incorporated into leak ports. Dai et al.17 investigated how these valves affect aerosol drug delivery in spontaneously breathing adults using NIV. Their research indicated that the single arch exhalation port (Figure 2) facilitated more effective aerosol delivery compared to both other types, specifically when the device was positioned between the leak port and a lung model.

Humidity

Inhaled air through the nose is normally humidified, but high inspiratory rates during NIV can exceed the nose’s humidification capacity. This can cause throat irritation and more nasal resistance, potentially diminishing the effectiveness of bronchodilator therapy. Therefore, providing additional humidification for patients undergoing NIV may be necessary to prevent the negative effects of dry inhaled gas and enhance patient comfort.18

Previous research has indicated that using heated and humidified ventilator circuits can reduce aerosol deposition by up to 50%.10 However, these studies used unheated/non-humidified circuits and did not simulate exhaled humidity in their lung models. Ari et al.19 pioneered the use of an in vitro lung model simulating exhaled heat and humidity to more accurately reflect how a patient’s body interacts with inhaled aerosol medication and evaluate the effect of exhaled, heated, and humidified gas on aerosol drug deposition to critically ill tracheostomy patients. Their findings revealed up to a 44% reduction in aerosol drug delivery due to exhaled humidity. The same research group later suggested that previous in vitro studies using lung models with unheated or non-humidified exhalation may have overestimated actual patient aerosol drug delivery.20 Furthermore, a study on NIV patients found no significant difference in urinary albuterol excretion between humidified and dry conditions.18 Therefore, turning off the humidifier during aerosol drug delivery in NIV patients is unnecessary. A study also reported that humidification does not significantly affect aerosol medication delivery (using vibrating mesh or jet nebulizers) during NIV with a single-limb circuit.18 A recent in vitro study found no difference in aerosol drug delivery during NIV when comparing dry and humidified conditions in a single-limb circuit with various nebulizer placements. In contrast, when using a dual-limb NIV circuit, one study found that humidification did reduce aerosol delivery, but only when the nebulizer was placed at the humidifier inlet; aerosol delivery was better in a dry setting.21

Despite numerous studies over the last 30 years suggesting humidification reduces aerosol delivery during NIV, more research is needed. Recent technological advances and in vitro findings indicate that humidification may have little to no impact on aerosol medication deposition.22

Type of aerosol device

Aerosolized drugs are delivered to patients receiving NIV using nebulizers and pMDIs. Alquaimi et al.23 compared the delivery efficiency of pMDIs, jet nebulizers, and mesh nebulizers in a spontaneously breathing adult lung model during NIV. They found that jet nebulizers delivered less aerosol than both pMDIs and mesh nebulizers. Mesh nebulizers achieved the highest aerosol delivery due to their higher nominal dose.

Vibrating mesh nebulizers delivered three to five times more aerosol medication than jet nebulizers, likely due to the smaller dead volume of mesh nebulizers.10

Galindo-Filho et al.24, who compared aerosol delivery during NIV in patients with moderate to severe COPD, found that mesh nebulizers delivered a significantly higher lung dose (12.05%) than jet nebulizers (3.14%). Alquaimi et al.23 evaluated the efficiency of jet and mesh nebulizers with NIV. Using an in vitro lung model without exhaled humidity, they found aerosol deposition rates of 13% for jet nebulizers and 29% for mesh nebulizers. Ari and Fink25 compared inhaled medication doses (measured beyond the trachea) delivered by jet and mesh nebulizers during mechanical ventilation, noninvasive ventilation, and spontaneous breathing, using identical adult breathing parameters. Consistent with earlier research, they found that mesh nebulizers were up to three times more efficient than jet nebulizers across all three ventilation methods.

Type of interface

Effective NIV relies on the patient’s ability to comfortably wear the interface. NIV interfaces include nasal pillows/plugs, nasal masks, oronasal masks, full face masks, and helmets. While studies have shown comparable improvements in blood gases with nasal and oronasal masks, oronasal masks (Figure 3) are often favored by clinicians.26

A separate bench study suggested helmets provide the least effective synchronization, making face masks a better option for NIV in children with high respiratory demands.27

The effectiveness of an NIV interface for aerosol delivery is heavily dependent on several factors, with proper fit being paramount. A poorly fitting interface leads to greater aerosol leakage and diminishes the therapeutic benefit.3

While there are numerous interfaces available for adults undergoing NIV, there are only a few options for pediatric patients. Since children primarily breathe through their noses, the nasal mask is frequently used for this pediatric patients undergoing NIV. However, the internal volume of each nasal mask differs, which can affect its performance in children.

Techniques of delivery

Previously, when inhaled medications were required for patients on NIV, clinicians would remove the mask and administer aerosol therapy using traditional methods. The drawback of this approach is that discontinuing NIV often leads to patient decompensation.

Aerosol drug delivery with NIV is more efficient compared to traditional administration of the aerosol between NIV sessions. While administration of aerosol medications with NIV caused no increase in radio aerosol pulmonary deposition, it resulted in clinical improvements in pulmonary function for who receiving aerosol therapy during NIV.28

Incorporating aerosol therapy into NIV can enhance lung function by relieving fatigued respiratory muscles, allowing patients to more easily achieve total lung capacity and improving FEV1.

Using a chamber-shaped spacer is a logical choice for enhancing aerosol therapy to patients on NIV. Timing is also crucial with pMDI actuation, as delivery of the aerosol markedly decreases when the pMDI is actuated during exhalation rather than at the start of inspiration.29

Synchronized nebulization that pulses with inhalation is more effective than continuous nebulization because it reduces medication loss during expiration. For this reason, using gas flow directly from the ventilator is better than using a separate air compressor or gas cylinder, as it allows for this synchronized, intermittent delivery.3

Gas Mixtures

NIV has become a standard of care for patients with COPD facing acute exacerbations that necessitate ventilatory support.30 A thorough understanding of the clinical and technical issues of NIV as detecting optimal indications, choosing suitable ventilators and interfaces, and enhancing patient-ventilator interaction has greatly improved the success rates of NIV. This advancement has allowed a wider range of patients to be treated solely with NIV, minimizing the complications linked to traditional invasive ventilation.31

Despite these advancements, there is still potential for further improving success rates, which could reduce the number of patients who require invasive ventilation. One area where progress could be made is in the type of gas used for ventilation.

Medical-grade gases have long been employed to manage various respiratory conditions. Chronic respiratory diseases continue to be a major concern, causing significant challenges for affected patients. O2 is commonly utilized in emergency situations for those with hypoxia-related medical conditions. Besides O2, additional gases are utilized for specific therapeutic applications.

Since its discovery in 1868, helium (He) has been used in the field of medicine.32 The use of heliox, a He/O2 mixture, began in the 1930s to help divers avoid decompression sickness.32 Although NO was discovered in the 1980s, its inhaled use for treating cardiorespiratory diseases only became prevalent in the 1990s.33 As research has evolved, the use of different medical gases has become more clearly defined, with growing evidence either supporting or questioning their specific applications. These gases are often administered via devices like masks, sometimes in conjunction with NIV.

Heliox

In contrast to an air-O2 mixture, a He/O2 mixture has consistently shown multiple benefits in conditions with elevated airway resistance, due to its lower density. The reduced He density aids in the change of the flow from turbulent to laminar, thus reducing the density-dependent components of airway resistance in the bronchi, which is especially helpful during COPD exacerbations.34 Heliox also improves the lungs’ ability to transfer gases, leading to better CO2 removal. This, along with improved gas exchange and enhanced expiratory flow, helps reduce shortness of breath. Furthermore, inhaled medications are delivered more effectively when administered with heliox in patients with obstructive lung disease.

As heliox reduces the pressure gradient required to maintain a specific flow, it enables the use of lower pressures to achieve target tidal volume and minute ventilation. This reduction in pressure helps decrease peak airway pressure and lowers the risk of barotrauma or volutrauma. By substituting air-O2 with heliox, NIV can be delivered with more lung protective strategy, requiring smaller pressure variations and even lower tidal volumes to achieve the desired pH/CO2 levels.35

Heliox is typically administered using a gas blender in one of three 80% O2 and 20% He, 70% O2 and 30% He, or 60% O2 and 40% He.

Heliox in adults

Heliox is appropriate for patients of different age groups, ranging from adults to newborns. It has been used to relieve respiratory difficulties in individuals with upper airway obstruction. The heliox lung-protective advantages are well-established, improving patient outcomes and enhancing comfort during breathing. Heliox therapy has been utilized to treat conditions like croup, epiglottitis, and laryngitis.36

Heliox is also utilized for individuals with lower respiratory tract disorders such as asthma, COPD, and cystic fibrosis.37 In asthma and COPD, inflammation and airflow limitations lead to airway obstruction, with COPD patients often producing excess mucus that worsens this obstruction. This increases airway resistance and causes breathing difficulties. To ease the work of breathing, heliox with NIV proves effective in managing these conditions, especially during acute exacerbations. Additionally, Heliox therapy can be used for patients with upper airway obstruction or those experiencing increased breathing effort, delivered via a noninvasive mechanical ventilator.

Heliox in children

Heliox is primarily used in pediatric care to treat upper airway obstructions caused by infections (such as laryngitis, epiglottitis, and tracheitis), inflammatory conditions (including post-extubation subglottic edema, angioedema, post-radiotherapy edema, edema from inhaled injury, and recurrent or spasmodic croup), as well as mechanical issues (such as foreign body obstruction, vocal cord paralysis, subglottic stenosis, and laryngotracheomalacia). It is also used for neoplastic conditions (such as laryngeal or tracheal growths and external compression of the larynx, trachea, or bronchi), lower airway obstructions (such as acute asthmatic crises, bronchiolitis, bronchial hyperreactivity) bronchopulmonary dysplasia and neonatal respiratory distress syndrome. Additionally, heliox is utilized as aerosol therapy during fiberoptic bronchoscopy and other airway procedures.

Indications of NIV with heliox

Positive pressure can improve alveolar recruitment and oxygenation, allowing a reduction in the fraction of inspired O2 (and thereby increasing fraction of inspired He). This is particularly beneficial for patients on NIV who exhibit inadequate ventilation as indicated by pH/partial pressure of CO2 (pCO2) levels, dyspnea, or clinical scoring. Heliox’s impact on alveolar ventilation, achieved through more expiratory flows and its effects on CO2, can potentially resolve these issues without the need to further adjust NIV parameters. Additionally, from a theoretical standpoint, heliox could be advantageous for patients on NIV whose underlying condition necessitates a protective ventilatory strategy, such as minimizing pressure-volume swings to maintain target pH/CO2 levels36 (Table 1).

Practical guide for heliox with NIV

At present, six ventilators are commercially available that are specifically designed for delivering Aptaer HELIOX Delivery System (GE Healthcare, Buckinghamshire, UK), Inspiration (E-Vent Medical Ltd., Galway, Ireland), Avea (Viasys Healthcare, Loma Linda, CA, USA), Helontix Vent (Linde Gas Therapeutics, Höllriegelskreuth, Germany), G5 (Hamilton, Reno, NV, USA), and Servo-I (Maquet, Rastatt, Germany).

He/O2 can be administered without risk by adjusting standard NIV ventilators in line with established recommendations. Hospital staff should possess technical expertise in both the ventilator and heliox therapy to reduce the side effects. In these situations, the following factors should be

When using heliox with NIV, average flow and volume measurements may not be reliable unless an external pneumotachograph, which is unaffected by the density of the gas, is used. As a result, ventilation should be managed according to programmed pressures (which are not impacted by heliox) and the resulting blood gas parameters (such as arterial O2 saturation and CO2 levels). Compared to air-O2 mixtures, NIV with heliox produces higher inspiratory and expiratory flows at the same pressure and improves CO2 diffusion. Consequently, achieving a specific CO2 target with heliox requires a lower pressure gradient than with air-O2 mixtures, offering improved lung protection.

Heliox can be given without a ventilator, typically through a non-rebreather mask. When using a noninvasive ventilator, the method for administering heliox may vary depending on the specific ventilator, but generally involves these First, confirm all connections are secure and configure the ventilator to deliver a He and O2 mixture. When the ventilator is connected to the heliox blending source, the ventilator’s O2 concentration should be set to 100%. This is essential because the ventilator will draw gas from the connected source (the heliox mixture) to ensure the correct proportions are delivered to the patient.

After configuring the ventilator settings for heliox delivery, it is crucial to adjust the alarms appropriately. Because He is less dense than air, the ventilator will register lower pressures, which could activate a low-pressure alarm if not adjusted. Heliox typically reduces pressures by about half compared to air, so tidal volume, minute ventilation, and pressure alarms must be set accurately. Since heliox is often supplied from tanks or cylinders, monitoring the gas supply is also important.

Ventilator-compatible circuits can differ. In the case of a single-limb circuit with an exhalation port, the cylinder may deplete more quickly due to the leak. Therefore, having backup heliox cylinders readily available is essential. Connecting heliox requires specific configurations depending on the ventilator being used, so selecting the correct settings is vital. Furthermore, all sensors must be configured according to the ventilator’s specifications.

Because standard flowmeters are not calibrated for heliox, the displayed flow rate will be inaccurate and does not represent the actual flow the patient receives. Due to the lower density of heliox, the patient actually receives a higher flow rate than indicated. To determine the true flow rate, you need to apply a conversion factor. For heliox mixtures, the conversion factors are 1.8 for 20, 1.6 for 30, and 1.4 for 40. An appropriate gas blender should also be used for accurate delivery.38

Abroug et al.37 conducted a systematic review including 15 studies dealing with the use of He/O2 for NIV in acute exacerbation COPD. Among these, three randomized controlled trials assessing the effectiveness of NIV with He/O2 during acute exacerbations of COPD were incorporated into the final analysis.3940 The research focused primarily on men (65%) with an average age of 69 ± 14 years. All participants had COPD (average baseline FEV1 = 808 ± 110 mL) and were experiencing severe exacerbations requiring ventilation. COPD diagnosis was confirmed or suspected based on smoking history, clinical and radiological findings, and lung function tests. The decision to provide ventilatory support and admit patients to the intensive care unit (ICU) was based on the presence of respiratory acidosis (pH ≤ 7.35 and partial pressure of CO2 ≥ 45 mmHg) combined with a respiratory rate of 25 breaths per minute or higher. He/O2 gas mixture used in the studies varied slightly. Jolliet et al.39 used a 78%/22% He/O2 mix, while Maggiore et al.40 employed a 65%/35% formulation.

Unlike previous research where patients received air/O2 between NIV sessions, Jolliet et al.39 administered He/O2 continuously for the first 72 hours, both during and between NIV treatments.

Two studies3940 defined NIV failure as requiring tracheal intubation. However, in the ECHO ICU trial, NIV failure was defined more broadly, encompassing either intubation or death within the ICU without intubation.

Abroug’s meta-analysis37 on controlled trials examining the use of He/O2 with NIV for hypercapnic COPD exacerbations showed no statistically significant impact on NIV failure or ICU mortality. However, the use of He/O2 was associated with a significant reduction in both ICU length of stay and complications related to NIV. The three randomized controlled trials investigating He/O2 for hypercapnic COPD exacerbations consistently overestimated the NIV failure rate in the control group. This led to underpowered studies due to underestimation of the necessary sample size. Despite this limitation, the first two randomized controlled clinical trials, conducted by Jolliet et al.39 and Maggiore et al.40, showed a reduction in intubation with He/O2 that surpassed the threshold for minimal clinical significance. It is important to note that these trials took place during a time of rapid advancement in the clinical application and understanding of NIV.41

Nitric oxide

In addition to O2 and He/O2, NO, a powerful vasodilator, is another medical gas used therapeutically.

NO is a colorless, nonflammable, tasteless, and odorless gas that is very short-lived. It functions as a potent dilator of pulmonary blood vessels and dissolves poorly in water.33

Pulmonary effects of inhaled NO

When inhaled at low concentrations (5–80 ppm), NO rapidly diffuses across the alveolar-capillary membrane and binds with hemoglobin, resulting in minimal systemic effects. Inhaled NO (iNO) therapy primarily aims to improve blood O2 levels, increase pulmonary blood flow, and lower pulmonary vascular resistance. Research has shown iNO to be highly effective in treating pulmonary hypertension in both children and adults.42 iNO has been found effective in treating various conditions, including persistent pulmonary hypertension of the newborn, meconium aspiration, bronchopulmonary dysplasia, severe hypoxemia that does not respond to other treatments, and congenital heart diseases associated with high blood pressure in in infants. It is also employed to alleviate pulmonary hypertension in both adults and children.43

Dosing

The appropriate dose of iNO to enhance the oxygenation and reduce pulmonary vascular resistance in both newborns and adults is typically low, ranging from 2 to 20 parts per million (ppm). Treatment often begins at 20 ppm and is then adjusted based on the patient’s response and tolerance.

iNO delivery through NIV

Hypoxemia is a significant contributor to respiratory failure, often necessitating mechanical ventilation. This can be partially mitigated by addressing hypoxemia with the addition of iNO to HFNC O2 therapy. Combining iNO with HFNC offers additional patients can remain awake, maintain airway patency, and clear secretions more effectively. Additionally, it decreases the reliance on inotropes since mechanical ventilation can destabilize a patient’s hemodynamics.44 iNO can be administered noninvasively via nasal continuous positive airway pressure, typically set at a pressure of 5–8 cm H2O with the fraction of inspired O2 adjusted based on the patient’s O2 saturation. Administering iNO during NIV can be complicated by leaks.45 Choosing the appropriate interface is therefore crucial for optimizing the effectiveness of the treatment.

NO in neonates

Persistent pulmonary hypertension of the newborn

It can arise from various factors, including premature closure of the ductus arteriosus, idiopathic pneumonia, meconium aspiration, prematurity, or underdeveloped lungs.46 It occurs when pulmonary vascular resistance remains elevated following birth. This leads to shunting of blood from the right side of the heart to the left through the still-open ductus arteriosus and foramen ovale, resulting in severe O2 deficiency. iNO effectively improves blood flow in these infants without causing low blood pressure. It significantly enhances oxygenation in both preterm and full-term newborns with persistent pulmonary hypertension.47

Hypoxemic respiratory failure

iNO is highly effective when used with endotracheal intubation and mechanical ventilation to treat pulmonary artery hypertension and hypoxemic respiratory failure in newborns. However, delivering NO via noninvasive nasal CPAP can help avoid the need for mechanical ventilation and its associated complications. In infants with hypoxemic respiratory failure, delivering iNO through bubble nasal CPAP has been shown to enhance O2 levels and decrease the requirement for supplemental O2.48

High O2 levels can have detrimental effects on premature newborns. The transition from the uterine to the extrauterine world involves significant cardiovascular adjustments, including a decrease in pulmonary vascular resistance and an increase in peripheral vascular resistance. These changes are regulated by various factors, including NO, a potent vasodilator. NO plays a crucial role in regulating pulmonary blood vessel tone and facilitating fluid clearance from the lungs. During the resuscitation of preterm infants, iNO can be used alongside ventilation and supplemental O2 to promote pulmonary vasodilation. This approach reduces pulmonary vascular resistance, improves the matching of ventilation and perfusion, increases blood flow to the lungs, and decreases the need for high levels of supplemental O2, thereby minimizing its potential harm.49 Sahni et al.48 studied the use of noninvasive iNO for hypoxemic respiratory failure in term and preterm infants. They analyzed the electronic medical records of 10,895 infants admitted to their neonatal ICU between 2005 and 2014 who received iNO for this condition. For those treated with noninvasive iNO via bubble nasal CPAP, they collected detailed data on infant characteristics, cardiorespiratory parameters, iNO administration, and respiratory support. Using repeated measures analysis of variance, they compared key measurements at baseline (before iNO) with those at 3, 6, 12, and 24 hours after iNO therapy began.

Within a day of starting noninvasive iNO therapy, infants required less supplemental O2 (fractional O2 decreased from 0.38 to 0.32, P < 0.0005) and their blood O2 saturation improved (from 90.7% to 91.6%, P < 0.01). Importantly, the therapy did not affect heart rate, breathing rate, blood pressure, blood pH, or CO2 levels. Noninvasive iNO typically began around day 9 of life, with a maximum dose of 20 ppm. The average iNO treatment lasted 134 hours, followed by a 51-hour weaning period. During iNO therapy, ambient air analysis showed median nitrogen dioxide levels of 0.30 ppm and median NO levels of 0.01 ppm. The study concluded that initiating or continuing iNO therapy in infants receiving bubble nasal CPAP improves oxygenation during hypoxemic respiratory failure, regardless of whether they are born at term or preterm. Noninvasive iNO may enhance the effectiveness of airway recruitment strategies such as nasal CPAP.

Clinical applications in adults

Tremblay et al.50 performed a retrospective study in two ICUs from 2013 to 2017 to assess the hemodynamic effects and practicality of iNO in hemodynamically unstable patients with acute right ventricular dysfunction who did not require immediate invasive mechanical ventilation. Eighteen patients received iNO, with hemodynamic monitoring via pulmonary artery catheter or pulse contour analysis. The median iNO dose was 20 ppm, and the median treatment duration was 24 hours. Most patients were treated with iNO via nasal prongs (66.7%) or a high-flow nasal cannula (27.8%). Within 1 hour, iNO decreased pulmonary vascular resistance from 219.1 to 165.4 dyn·s/cm^5^ (n = 7; P < 0.001), mean pulmonary artery pressure from 28.4 to 25.3 mmHg (n = 8; P = 0.01), and central venous pressure from 17.5 to 13.1 mmHg (n = 16; P = 0.001). In the study, indexed cardiac output improved from 2.0 to 2.6 L/min/m² (n = 9, P = 0.004). The ICU mortality rate was 27.78%, and the median ICU length of stay was 7 days. While two significant bleeding events and one instance of acute kidney injury occurred during iNO therapy, no headaches were reported. The researchers concluded that noninvasive iNO demonstrated positive hemodynamic effects in ICU patients with acute right ventricular failure, suggesting it is safe and feasible, although they recommend further prospective studies to confirm these findings. Kinsella et al.51 studied late-onset pulmonary hypertension in infants with congenital diaphragmatic hernia (CDH) and investigated whether extended noninvasive iNO therapy via nasal cannula could help maintain open pulmonary blood vessels as infants transitioned from mechanical ventilation to spontaneous breathing. Their study involved analyzing data from all infants diagnosed with CDH admitted to the Children’s Hospital, Denver, between January 1996 and December 2001. Infants with elevated pulmonary blood pressure when iNO was discontinued prior to extubation were treated with iNO delivered through a nasal cannula. The key findings were 47 newborns with CDH, 30 (64%) received iNO therapy. Short-term (less than 3 months) and long-term (more than 1 year) survival rates were 85% and 75%, respectively. Ten infants (21%) required iNO through a nasal cannula after extubation due to pulmonary hypertension and significant low blood O2 levels. Nasopharyngeal NO concentrations measured during treatment were consistent with the target doses. The study concluded that late pulmonary hypertension is a common occurrence in newborns with CDH. Noninvasive iNO treatment may be beneficial in reducing the length of mechanical ventilation while effectively managing late pulmonary hypertension in these infants. Massa et al.52 used a bench model of NIV with a single-limb circuit and leak to determine if iNO delivery was feasible for pediatric patients. Their results showed that iNO delivery was consistent and reliable. They recommended further research to investigate the duration of iNO D-cylinder tanks, patient responses, and potential caregiver exposure.

Limitations

This narrative review is subject to the inherent limitations of this type of review, including potential publication bias and subjective selection and interpretation of studies. The lack of a formal quality assessment of included studies is another limitation.

Conclusion

This review has explored the multifaceted aspects of aerosol drug delivery and the use of specialized gas mixtures during NIV. Aerosol delivery during NIV is influenced by a complex interplay of factors, including ventilation mode (BiPAP, CPAP, volume/pressure control), inspiratory flow rate, breathing pattern, aerosol device type and placement, leak port characteristics, humidity levels, and the type of interface used. Mesh nebulizers have consistently demonstrated superior aerosol delivery compared to jet nebulizers, and the positioning of the aerosol device between the leak port and the mask is generally recommended. While concerns about humidity’s impact on aerosol delivery have been raised, recent evidence suggests minimal or no effect, particularly with newer technologies. The choice of NIV interface is crucial, with nasal pillows showing lower delivery efficiency compared to nasal or oronasal masks. Furthermore, synchronized intermittent nebulization offers advantages over continuous nebulization.

The review also examined the role of medical gases in NIV, specifically focusing on heliox and NO. Heliox, with its lower density, offers benefits in reducing airway resistance and improving gas exchange, particularly in patients with obstructive lung diseases. It can facilitate lower pressures for ventilation, potentially reducing the risk of barotrauma. While specific ventilators are designed for heliox delivery, standard NIV ventilators can be adapted with careful monitoring and adjustments. Studies on heliox use during NIV for COPD exacerbations have shown promising results, particularly in reducing ICU length of stay and NIV-related complications, although further research is needed to confirm its impact on intubation rates and mortality. NO, a potent pulmonary vasodilator, has demonstrated efficacy in treating pulmonary hypertension, including in the context of NIV. However, managing leaks during iNO delivery with NIV remains a challenge.

Future Recommendations

Further randomized controlled trials are needed to definitively establish the clinical benefits of heliox during NIV for COPD exacerbations, particularly regarding its impact on intubation rates and mortality.

Research is needed to optimize iNO delivery protocols during NIV, focusing on leak management and interface selection.

Studies should investigate the long-term effects of aerosol drug delivery during NIV on patient outcomes.

More research is needed to understand the optimal settings for aerosol delivery during different NIV modes and in various patient populations.

Studies should explore the potential benefits of combining heliox and iNO during NIV in specific patient populations.

This review highlights the continued evolution of aerosol drug delivery and the use of specialized gas mixtures during NIV. By incorporating the current evidence and addressing the identified research gaps, clinicians can further optimize these therapies to improve patient outcomes.