IMPROVING AEROSOL DELIVERY FOR NASAL CPAP IN INFANTS : AN IN VITRO MODEL

B. B.

James B. Fink, MS, RRT, FAARC, Ehud Ivri, Ayesh Perera, PhD., Aerogen, Inc., Mountain View, CA.

INTRODUCTION
Aerosol delivery to pre- and near-term infants with nebulizers has been inefficient with less than 1% deposition of the nominal dose, on or off the ventilator (Fok, Ped Pulmonology 1996). Aerosol delivery to infants using nasal continuous positive airway pressure (nCPAP) has not been reported using high efficiency aerosol delivery systems. However, similar deposition may be expected with aerosol delivery via nCPAP with standard placement of the nebulizer, due to gas dilution of the aerosol. We previously reported that aerosol delivery with a highefficiency nebulizer placed in the inspiratory limb of a CPAP system was 1.3% of nominal dose (Fink, Resp Care 2004). Aerogen has developed a small, lightweight Pulmonary Drug Delivery System (PDDS), capable of continuous and intermittent aerosol generation patterns, designed to be suitable for placement proximal to the infants airway (FIGURE 1). The PDDS incorporates Aerogens OnQ Micropump aerosol generator (FIGURE 2).

MATERIALS AND METHODS

A lung simulator (FIGURE 3), consisting of an adapter with orifices representing infant size nares connected to an absolute filter, and attached to a reciprocating pump animal ventilator (Harvard Apparatus), was set to infant ventilatory parameters (Vt 10 mL, resp rate 40 bpm). A constant oxygen flow of 10 L/min was used to generate a CPAP of 5 cm H2O. Albuterol sulfate (3.0 mL; 0.083%) was aerosolized with a PDDS nebulizer (n=3) placed between the main flow of the nCPAP circuit and the nasal prongs (Argyle). Aerosol was generated continuously (CONT), or intermittently (INT) with aerosol generation interrupted during exhalation. Drug was collected on a filter placed distal to the nasal prongs, and assayed using HPLC.
Gas Inlet Filter Nasal Prongs Reservoir Nebulizer Lung Simulator Bubble Type Threshold Resistor

DISCUSSION (CONTINUED)
Placement of the PDDS between the primary gas flow and the patient airway (FIGURE 4) reduces dilution of aerosol from 10 L/min (total flow through the circuit) to approximately 0.6 L/min (minute ventilation of the infant simulator). This reduction in aerosol dilution appears to be related to an increase in deposition. Care was taken to assure that only aerosol reached the filter, and that condensate remained the breathing circuit, nebulizer or adapter. This was accomplished by tilting the assembly so that the nebulizer was lower than the filter element. During continuous nebulization, there was a visible amount of aerosol that was driven from the nebulizer into the expiratory limb of the nCPAP circuit. Interrupting aerosol during expiration eliminated the visual losses and resulted in close to 50% improvement in inhaled mass.

Gas Source 10 lpm NEB Breath simulator 0.6 Lpm Gas Source

Nasal prongs Filter

Max percent of gas inhaled 6% Inhaled mass 1.3%

FIGURE 1: THE PROTOTYPE PULMONARY DRUG DELIVERY SYSTEM (PDDS; LEFT) FOR NASAL CONTINUOUS POSITIVE AIRWAY PRESSURE (nCPAP; RIGHT).

PDDS

Humidifier Inspiratory Limb

Controller

Expiratory Limb

10 lpm Breath simulator 0.6 Lpm

Nasal prongs Filter

Threshold resistor 10 cm H2O Max percent of gas inhaled 100 % Inhaled mass 26 - 40%

FIGURE 3: MODEL USED FOR MEASURING AEROSOL DELIVERY WITH SIMULATED INFANT BREATHING PATTERN DURING NASAL CONTINUOUS POSITIVE AIRWAY PRESSURE (nCPAP). THE PULMONARY DRUG DELIVERY SYSTEM (PDDS) PLACED PROXIMAL TO THE NASAL PRONGS.

RESULTS
Placement of the PDDS between the primary gas flow through the nCPAP circuit and the simulated patient airway resulted in deposition (mean SD) of 26 9% CONT and 40 9 % INT of the albuterol dose placed in the nebulizer.

FIGURE 4: DIAGRAM OF MODEL USED FOR MEASURING AEROSOL DELIVERY WITH SIMULATED INFANT BREATHING PATTERN DURING NASAL CONTINUOUS POSITIVE AIRWAY PRESSURE (nCPAP). TOP: THE TYPICAL CONFIGURATION WITH NEBULIZER PLACED IN THE INSPIRATORY LIMB OF nCPAP WITH AEROSOL DILUTED BY TOTAL FLOW OF GAS PASSING THROUGH NEBULIZER. BOTTOM: THE PROTOTYPE PULMONARY DRUG DELIVERY SYSTEM (PDDS) PLACED BETWEEN THE PRIMARY GAS FLOW AND SIMULATED PATIENT AIRWAY.

FIGURE 2: THE AEROGEN ONQ AEROSOL GENERATOR WITH THE GENERATOR (LEFT PANEL), A MICROSCOPIC VIEW OF TAPERED APERTURES (UPPER MIDDLE), AND CROSS SECTION OF APERTURES (UPPER RIGHT). HIGH SPEED MICROSCOPIC PHOTOGRAPH OF AEROSOL GENERATED FROM A SINGLE APERTURE (LOWER RIGHT).

DISCUSSION
The PDDS at the airway, with both CONT and INT aerosolization, delivered an order of magnitude more albuterol through the nasal prongs to the filter during nCPAP than we observed previously with the Aeroneb Professional Nebulizer System (Aeroneb Pro) placed in the inspiratory limb of the circuit (typical placement). We had used the Aeroneb Pro because it is a highly efficient nebulizer that has been shown to be more efficient than standard jet nebulizers in an animal model of infant ventilation (Dubus, AJRCCM 2003). In this nCPAP model, the low deposition with even this high efficiency nebulizer is due in large part to the dilution of the aerosol output of the Aeroneb Pro by the total flow of gas (10 L/min) passing through the nebulizer.

CONCLUSION
Placement of the aerosol generator proximal to the patient airway is a key factor in improving aerosol efficiency in this model of nCPAP, increasing inhaled mass by more than 10x. Intermittent nebulization is a secondary factor, improving inhaled mass by up to 50%. The high efficiency delivery of aerosol to this nCPAP infant model suggests future opportunities for administration of medications to the airways of infants. Additional work is anticipated to establish in vitro / in vivo correlation with this model of nCPAP with infant ventilation.

OBJECTIVE
To determine the effect of continuous and intermittent aerosol generation proximal to the patient airway on delivery of drug to the distal tip of the nasal prongs of an nCPAP system during simulated infant ventilation.