Improvement in Aerosol Delivery with Helium Oxygen Mixtures during Mechanical Ventilation

Similar documents
JAMES B. FINK, RAJIV DHAND, JERRY GRYCHOWSKI, PATRICK J. FAHEY, and MARTIN J. TOBIN

Gustavo J. Rodrigo, MD; Carlos Rodrigo, MD; Charles V. Pollack, MD; and Brian Rowe, MD, MSc, CCFP (EM)

Special Problems in Aerosol Delivery: Artificial Airways

Factors affecting bronchodilator delivery in mechanically ventilated adults

Invited Review. Development of Aerosol Drug Delivery with Helium Oxygen Gas Mixtures ABSTRACT

Respiratory Care in PICU Aerosol Therapy ส พ ชชา ชา แสงโขต โรงพยาบาลสมเด จพระป นเกล า

Heliox for treatment of exacerbations of chronic obstructive pulmonary disease (Review)

Basic Techniques for Aerosol Delivery During Mechanical Ventilation. Rajiv Dhand MD

Pediatrics in mechanical ventilation

Should Heliox Be Used for Mechanically Ventilated Patients?

I. Subject: Medication Delivery by Metered Dose Inhaler (MDI)

600 RESPIRATORY CARE MAY 2016 VOL 61 NO 5

Delivering Aerosol Medication in ICU

Effects of Heat and Moisture Exchangers and Exhaled Humidity on Aerosol Deposition in a Simulated Ventilator-Dependent Adult Lung Model

Misty Max 10 nebulizer

Bronchodilator delivery by metered-dose inhaler in mechanically ventilated COPD patients: influence of flow pattern

Lack of Benefit of Heliox During Mechanical Ventilation of Subjects With Severe Air-Flow Obstruction

Bronchodilator delivery by metered-dose inhaler in mechanically ventilated COPD patients: influence of end-inspiratory pause

Overcoming the Adverse Effect of Humidity in Aerosol Delivery via Pressurized Metered-Dose Inhalers during Mechanical Ventilation

Aerosol Delivery and Modern Mechanical Ventilation In Vitro/In Vivo Evaluation

Metered Dose Inhalers with Valved Holding Chamber: A Pediatric Hospital Experience

I. Subject: Continuous Positive Airway Pressure CPAP by Continuous Flow Device

The Effects of Aerosol Drug Delivery on Airway Resistance through Heat-Moisutre Exchangers

NIV and Aerosoltherapy

8/13/11. RSPT 1410 Humidity & Aerosol Therapy Part 3. Humidification Equipment. Aerosol Therapy

I. Subject: Continuous Aerosolization of Bronchodilators

Revision 2. Improving Aerosol Drug Delivery During Invasive Mechanical Ventilation with Redesigned Components

Original Contributions

Simone Gambazza, PT Cystic Fibrosis Centre, Milan Fondazione I.R.C.C.S. Cà Granda Ospedale Maggiore Policlinico

Aerosol Delivery Through Adult High Flow Nasal Cannula With Heliox and Oxygen

Supplementary Medications during asthma attack. Prof. Dr Finn Rasmussen PhD. DrMedSc. Near East University Hospital North Cyprus

Review Clinical review: Use of helium-oxygen in critically ill patients Marc Gainnier and Jean-Marie Forel

Vibrating Mesh Nebulizer Compared With Metered-Dose Inhaler in Mechanically Ventilated Subjects

Lecture Notes. Chapter 3: Asthma

Albuterol Delivery via Intrapulmonary Percussive Ventilator and Jet Nebulizer in a Pediatric Ventilator Model

Rush University, College of Health Sciences

Latex Free. An affordable, easy to use, high density, small volume nebulizer with a breath enhanced design! Breath Enhanced High Density Jet Nebulizer

Aerosolized Antibiotics in Mechanically Ventilated Patients

Small Volume Nebulizer Treatment (Hand-Held)

A Review of the use of Heliox in the Critically Ill

Articles. The Advantages of Nebulization in the Treatment of Mechanically Ventilated Neonates. Kristin Smith, RRT-NPS

Delay Between Actuation and Shaking of a Hydrofluoroalkane Fluticasone Pressurized Metered-Dose Inhaler

Oxygenation Without Intubation

Intracheal antibiotics administration

Aerosol Delivery Devices

Oxygen and aerosolized drug delivery: Matching the device to the patient

Dolci U 1, Sidler-Moix AL 1, Di Paolo ER 1,Berger- Gryllaki 1 M, Pannatier A 1, Cotting J 2

NEBULIZERS, METERED DOSE INHALERS, AND DRY POWDER INHALERS

Effect of Interval Between Actuations of Albuterol Hydrofluoroalkane Pressurized Metered-Dose Inhalers on Their Aerosol Characteristics

10/6/2014. Tommy s Story: An Overview of Asthma Mangement. Disclosure. Objectives for this talk.

Budesonide treatment of moderate and severe asthma in children: A doseresponse

Tissue Hypoxia and Oxygen Therapy

Comparison of patient spirometry and ventilator spirometry

Effect of particle size of bronchodilator aerosols on lung distribution and pulmonary function in patients

Test Bank Pilbeam's Mechanical Ventilation Physiological and Clinical Applications 6th Edition Cairo

A PRACTICAL GUIDE TO nebulization

COMPARISON OF THE RESPIRABLE FRACTION FROM THREE DIFERENT DPI DEVICES

Vancouver Coastal Health Guidelines for the use of Respiratory Equipment for Patients on Airborne Precautions in Acute Care Facilities

Unit 5 Humidity/Aerosol Generators

AEROSOL THERAPY: THE PRACTICALITIES

Continuous Aerosol Therapy

N ebulised β2 agonists are commonly used in mechanically

Lecture Notes. Chapter 4: Chronic Obstructive Pulmonary Disease (COPD)

Mechanical Ventilation Principles and Practices

cc032.qxd 14/05/99 07:00 Page 65 Research paper 65

It is recommended that a mask and protective eyewear be worn when providing care to a patient with a cough

1 Chapter 13 Respiratory Emergencies 2 Respiratory Distress Patients often complain about. Shortness of breath Symptom of many different Cause can be

1. When a patient fails to ventilate or oxygenate adequately, the problem is caused by pathophysiological factors such as hyperventilation.

Redefining Continuous Aerosol Drug Delivery PM223

Spirometry and Flow Volume Measurements

Redefining Continuous Aerosol Drug Delivery 2015 PM223

University of Groningen. Technology in practice Lexmond, Anne

Bronchodilator delivery with metered-dose inhalers in mechanically-ventilated patients

Asthma and COPD in the ICU

Teacher : Dorota Marczuk Krynicka, MD., PhD. Coll. Anatomicum, Święcicki Street no. 6, Dept. of Physiology

The optimal particle size for beta-adrenergic aerosols in mild asthmatics*

Function of the Respiratory System. Exchange CO2 (on expiration) for O2 (on inspiration)

. Type of solution/medication. Amount/dose to be delivered. Frequency/duration. Mode of administration.

Your Inhaler Devices & You

The Effects of Heliox on the Output and Particle-Size Distribution of Salbutamol using. Jet and Vibrating Mesh Nebulisers

High Flow Nasal Cannula Oxygen HFNC. Dr I S Kalla Department of Pulmonology University of the Witwatersrand

The Effect of Different Interfaces on Aerosol Delivery in Simulated Spontaneously Breathing Adult with Tracheostomy

Using an Inhaler and Nebulizer

NBRC Exam RPFT Registry Examination for Advanced Pulmonary Function Technologists Version: 6.0 [ Total Questions: 111 ]

Chapter 3. Pulmonary Function Study Assessments. Mosby items and derived items 2011, 2006 by Mosby, Inc., an affiliate of Elsevier Inc.

Albuterol Delivery via Facial and Tracheostomy Route in a Model of a Spontaneously Breathing Child

Asthma in Pregnancy. Asthma. Chronic Airway Inflammation. Objective Measures of Airflow. Peak exp. flow rate (PEFR)

Respiratory Anesthetic Emergencies in Oral and Maxillofacial Surgery. By: Lillian Han

In Vitro Comparison of Aerosol Delivery Using Different Face Masks and Flow Rates With a High-Flow Humidity System

Over the last several years various national and

Archives of Pulmonology and Respiratory Care

Aerosol and Airway Clearance Therapies: Challenges and Opportunities. Growth of the Medicare. Aerosol and ACT Therapies Terry L. Forrette, M.H.

Nitric Resource Manual

Aerosol therapy in ICU

An update on inhalation devices

PULMONARY FUNCTION TESTING. Purposes of Pulmonary Tests. General Categories of Lung Diseases. Types of PF Tests

CHAPTER 3. Correction factors for oxygen and flow-rate effects on neonatal Fleisch and Lilly pneumotachometers

EVect of breathing circuit resistance on the measurement of ventilatory function

COMMISSION ON ACCREDITATION FOR RESPIRATORY CARE TMC DETAILED CONTENT OUTLINE COMPARISON

Credential Maintenance Program

Transcription:

Improvement in Aerosol Delivery with Helium Oxygen Mixtures during Mechanical Ventilation MARK L. GOODE, JAMES B. FINK, RAJIV DHAND, and MARTIN J. TOBIN Division of Pulmonary and Critical Care Medicine, Edward Hines Jr. Veterans Affairs Hospital, and Loyola University of Chicago Stritch School of Medicine, Hines, Illinois In mechanically ventilated patients with airway obstruction, helium oxygen (He O 2 ) mixtures reduce airway resistance and improve ventilation, but their influence on aerosol delivery is unknown. Accordingly, we determined the effect of various He O 2 mixtures on albuterol delivery from metered-dose inhalers (MDIs) and jet nebulizers in an in vitro model of mechanical ventilation. Albuterol delivery from a MDI was increased when the ventilator circuit contained 80% helium and 20% oxygen (He O 2 80/20) versus O 2 : 46.7 3.3 versus 30.2 1.3 (SE)% of the nominal dose (p 0.001) the difference was mainly due to decreased drug deposition in the spacer chamber, mean 39.2% and 55.2%, respectively (p 0.001). Nebulizer efficiency at a flow rate of 6 L/min was five times lower with He O 2 80/20 than O 2, and the amount of nebulized drug was inversely correlated with gas density (r 0.94, p 0.0001). When the nebulizer was operated with O 2, greater albuterol delivery was achieved when the ventilator circuit contained He O 2 rather than O 2. In summary, He O 2 mixtures in the circuit increased aerosol delivery for both MDIs and nebulizers in the mechanically ventilated model by as much as 50%. In conclusion, at appropriate flow rates and concentrations, He O 2 in the ventilator circuit may improve aerosol delivery in mechanically ventilated patients with severe airway obstruction. A gas mixture of helium and oxygen has a lower density than air. By converting regions of density-dependent turbulent airflow within the large airways to laminar flow, helium oxygen (He O 2 ) mixtures can improve expiratory flow and decrease the resistive work of breathing (1 4). In ambulatory patients with asthma, some investigators reported that inhalation of He O 2 mixtures decreased dyspnea and pulsus paradoxus, and improved pulmonary gas exchange (5 8), whereas others reported no benefits (9 11). In spontaneously breathing patients with severe chronic obstructive pulmonary disease (COPD), inhalation of He O 2 reduced arterial carbon dioxide tension (12). In mechanically ventilated patients with severe asthma, inhalation of He O 2 decreased airway resistance and the alveolar arterial oxygen gradient, and improved CO 2 elimination (13, 14). In patients receiving noninvasive ventilation for acute exacerbations of COPD, He O 2 decreased dyspnea and work of breathing, and improved gas exchange (15, 16). The pulmonary deposition of particles within an aerosol is influenced by the density of the gas being administered to the patient (17). Accordingly, He O 2 is likely to influence pulmonary deposition of aerosolized bronchodilators, yet this interaction has been studied by surprisingly few investigators. Compared with air, Hess and colleagues (18) found that operating a nebulizer with He O 2 decreased both the fraction of the nominal dose collected on a filter placed at the end of the (Received in original form March 7, 2000 and in revised form July 14, 2000) Supported in part by VA Research Service. Correspondence and requests for reprints should be addressed to Rajiv Dhand, M.D., Division of Pulmonary and Critical Care Medicine - 111 N, Edwards Hines Jr. VA Hospital, 5th Ave. and Roosevelt Road, Hines, IL 60141. Am J Respir Crit Care Med Vol 163. pp 109 114, 2001 Internet address: www.atsjournals.org T connector, and the aerosol s respirable mass in an in vitro model. Conversely, patients with asthma who breathed He O 2 80/20 displayed greater pulmonary deposition of monodisperse Teflon particles ( 3.7 m aerodynamic diameter) than when breathing air (19, 20). The influence, however, of He O 2 on aerosol delivery during mechanical ventilation is not known. In-line nebulizers and metered-dose inhalers (MDIs) are used for bronchodilator therapy in mechanically ventilated patients (21). The efficiency of these devices in delivering aerosols to the lower respiratory tract is less in mechanically ventilated patients than in ambulatory patients (21). Methods for enhancing aerosol delivery in such patients could improve clinical benefit and reduce costs. In a pediatric model of mechanical ventilation, albuterol delivery from a MDI was increased when the device was operated with a He O 2 70/30 mixture versus the same balance of nitrogen and oxygen (22). It is not known, however, how differing concentrations of helium might influence the generation of aerosols from MDIs and nebulizers nor their delivery to the lower respiratory tract of mechanically ventilated patients. To avoid unexpected hazard to critically ill patients, we used a mechanically ventilated tracheobronchial model to study the influence of various concentrations of He O 2 on aerosol delivery from MDIs and nebulizers. In previous studies, we have shown that this in vitro model accurately reflects changes in in vivo delivery of aerosol in mechanically ventilated patients (23, 24). METHODS Description of the Lung Model Studies were conducted employing a tracheobronchial model that allows investigation of aerosol delivery during mechanical ventilation (Figure 1); this model is similar to that described in our previous publications (23, 24). A Siemens 900C ventilator (Elema AB, Solna, Sweden) was employed because it maintains accurate volumes and flows with He O 2 mixtures (25). The ventilator provided controlled mechanical ventilation with a tidal volume of 800 ml, a frequency of 12 breaths/min, and a peak inspiratory flow of 40 L/min delivered with a square-wave configuration. A H-cylinder containing He O 2 80/20 and a 50 pound per square inch regulator (Puritan Bennett Corp., Lenexa, KS) was attached to the air inlet of a standard oxygen air blender (Bird Corporation, Palm Springs, CA). The O 2 concentrations were continuously monitored with a fuel cell oxygen analyzer (Hudson, Temecula, CA), placed in the inspiratory limb between the ventilator and the MDI or between the nebulizer and endotracheal tube. To avoid erroneous readings of tidal volume and inspiratory air flow secondary to gas mixtures of varying density, a pneumotachometer (Ventrak, Wallingford, CT) was placed between the test lung and the filters (Figure 1). The pneumotachometer uses an algorithm that allows accurate readings of air flow and volume for specific concentrations of He O 2. The accuracy of the measured volumes and the linearity of the response of each pneumotachometer was verified with a volumetric syringe containing various concentrations of He O 2 and air O 2. Tidal volume, measured by the pneumotachometer, was also compared with the volume displacement of the test lung (Michigan Instruments, Grand Rapids, MI), with measurements varying between the two devices by less than 3%. The quantity of albuterol was collected on a filter with a pore size less than 0.3 m (Respirgard II bacterial/vi-

110 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 163 2001 Figure 1. In vitro lung model of mechanical ventilation. A tank containing 80% helium and 20% oxygen (He O 2 80/20) was connected to the air inlet of a gas blender and O 2 was connected to the O 2 inlet. The concentration of He O 2 was adjusted by changing the flow rates of He O 2 80/20 or O 2 through the blender. A jet nebulizer connected in the inspiratory limb of the ventilator circuit 45 cm from the endotracheal tube was operated with He O 2 mixtures or O 2. A MDI and chamber spacer was placed in the ventilator circuit 15 cm from the endotracheal tube. The tracheobronchial model with filters placed at the distal ends of the main bronchi was used to collect albuterol. A gas analyzer in the inspiratory limb of the ventilator circuit was used to regulate He O 2 concentrations; inspiratory flow was continuously measured with a pneumotachometer. The ventilator circuit was connected to a test lung, and its volume displacement was used to confirm tidal volume. ral Filter, No. 303; Marquest Medical Products, Inc., Englewood, CO); the albuterol deposited on the filter was measured by spectrophotometry. Experiments with the ventilator were performed with inspired gas at ambient temperature (25 to 27 C) and a relative humidity (RH) of 30%, or when heated to 35 1 C and RH of 98 2% (Fast-Response Digital Hygrometer/Thermometer; Curtin Matheson, Houston, TX). Experiment 1: Influence of Gas Density on Aerosol Delivery with a MDI MDI canisters (albuterol; Schering, Kenilworth, NJ; manufacturer estimated dose of 90 g/puff) were warmed to hand temperature, well shaken, and primed, that is, each MDI was actuated 5 times before testing to ensure that the subsequent actuations provided a homogenous mixture of canister ingredients. Each subsequent actuation of the MDI was discharged into a MDI spacer (Aerovent; Monaghan Medical Inc., Plattsburgh, NY) in the inspiratory limb of the ventilator circuit at the onset of inspiration; successive doses from the MDI were actuated at 15-s intervals. Albuterol was administered from a set of four MDIs actuated in rotation. To determine the influence of gas density on the delivery of albuterol, 8 puffs (720 g) of albuterol were administered from a MDI into a chamber spacer during mechanical ventilation with the circuit containing air, O 2, or He O 2 mixtures of 80/20, 70/30, 60/40, and 50/50. The tests were performed either at ambient conditions of temperature and humidity or with heated and humidified gas mixtures, and were repeated six times with each gas mixture. Albuterol deposition was measured on filters placed at the ends of the bronchi in the lung model (Figure 1). To determine the effect of gas density on the location of aerosol deposition within the ventilator circuit, 8 puffs (720 g) of albuterol were administered by MDI and chamber spacer into a dry, unheated ventilator circuit containing He O 2 80/20 or O 2. Albuterol deposition was measured on filters placed immediately distal to the chamber spacer, between the elbow connector and the endotracheal tube, and at the ends of the bronchi in the lung model (Figure 1) (n 3 for each site). Experiment 2: Influence of He O 2 on Nebulizer Efficiency A small-volume nebulizer (AeroTech II; CIS-US Inc., Bedford, MA) was filled with 5 ml of albuterol sulfate solution (Proventil; Schering, Kenilworth, NJ) at a concentration of 0.5 mg/ml (nominal dose 2.5 mg) and placed in the inspiratory limb of the ventilator circuit 45 cm from the circuit wye. Oxygen or He O 2 80/20, each at a flow rate of 6 L/ min, was used to generate aerosol continuously throughout the breathing cycle. A pressure-compensated oxygen flow meter (Timeter, St. Louis, MO) was used to adjust gas flow through the nebulizer, and appropriate calibration factors were applied to correct for the lower density of the He O 2 mixtures (26). After 5 min of nebulization, albuterol deposition was measured on a filter placed immediately distal to the T-piece of the nebulizer. To determine the effect of gas density on nebulizer efficiency, the nebulizer was operated at a flow rate of 6 L/min using air, O 2, and He O 2 mixtures of 80/20, 60/40, 40/60, and 20/80. For each gas mixture, albuterol deposition was measured on a filter placed immediately distal to the T-piece of the nebulizer. To determine the influence of gas flow rates on nebulizer efficiency, the nebulizer was operated separately with He O 2 70/30 and O 2 at flow rates of 5, 10, and 15 L/min. At each flow rate, albuterol deposition was measured on a filter placed immediately distal to the T-piece of the nebulizer. Experiment 3: Optimizing Aerosol Delivery with a Nebulizer during Mechanical Ventilation To determine which combination of gas mixtures delivers the most aerosol, the nebulizer was operated at three sets of gas composition and flow rates: O 2 at 6 L/min as recommended by the nebulizer manufacturer, He O 2 70/30 at 6 L/min, and He O 2 70/30 at 15 L/min. Each run was performed in a humidified ventilator circuit containing either O 2 or He O 2 70/30; of gases commercially available, He O 2 70/30 has the highest level of helium while also ensuring an O 2 concentration of more than 20%. With the nebulizer operated with O 2 at 6 L/min, the final concentration of He O 2 in the ventilator circuit was reduced to 61/39 2%. Albuterol deposition was measured on filters placed at the ends of the main bronchi in the lung model. Assay Technique On completion of each experiment, the filters were labeled, capped and filled with 5 ml of 0.1 M sodium hydroxide, and the albuterol eluted by gently shaking for 24 h. The volume recovered from each filter was recorded and the albuterol concentration determined at a wavelength of 246 nm (DU 64 spectrophotometer; Beckman Instruments, Fullerton, CA) using 0.1 M sodium hydroxide as the reference. Individual experiments were repeated three times on different days with single-blind analysis. Data Analysis All results were expressed as the absolute amount of drug in micrograms or as the fraction of nominal dose delivered (mean SE). Results were analyzed with repeated measure analysis of variance (ANOVA) using multivariate analysis, with Scheffe s F-test; p 0.05 was considered significant. The regression coefficient (r) was calculated with statistical software (SuperANOVA; Abacus Concept, Berkeley, CA). RESULTS Experiment 1: Influence of Gas Density on Aerosol Delivery with a MDI Delivery of albuterol from a MDI and chamber spacer was greater when the ventilator circuit contained higher concentrations of He O 2 : 46.7 3.3% and 43.9 1.0% of the nominal dose for He O 2 80/20 and 70/30, respectively. The latter deliveries were higher than the drug deliveries observed with He O 2 mixtures of 60/40 and 50/50: 39.0 0.9% and 39.9 1.3%, respectively (p 0.04). Albuterol delivery was significantly greater with each of the He O 2 mixtures than with air (30.2 1.3%, p 0.0001) or O 2 (29.1 1.3%, p 0.0001). Albuterol

Goode, Fink, Dhand, et al.: Influence of Helium:Oxygen on Aerosol Delivery 111 Figure 2. Albuterol delivery from a MDI to filters, placed at the ends of bronchi, as a function of gas density. Eight puffs (720 g) of albuterol were administered into a chamber spacer during controlled ventilation in an unheated, dry ventilator circuit containing air, O 2, or several mixtures of He O 2 (80/20, 70/30, 60/40, 50/50). Values of albuterol delivered are expressed as a percent of the nominal dose. Albuterol delivery was inversely related to gas density in the ventilator circuit (r 0.98, p 0.005) the highest aerosol delivery occurring with the lowest density gas (He O 2 80/20). delivery was inversely related to gas density in the ventilator circuit (r 0.98, p 0.005) (Figure 2). For both He O 2 or air, albuterol delivery was reduced significantly when the ventilator circuit was heated and humidified versus a dry circuit (Table 1). In a humidified ventilator circuit, delivery of albuterol remained higher with He O 2 80/20 than with air (p 0.02). The density of gas within the ventilator circuit significantly altered the pattern of aerosol deposition (Figure 3). The enhancement in albuterol delivery to the lower airways with He O 2 80/20 over O 2 was mainly due to a decrease in aerosol deposition in the chamber spacer: mean 39.2% versus 55.2% (p 0.001). Deposition of aerosol in the endotracheal tube was also decreased by He O 2 80/20 mean 1.4 versus 4.2% for O 2 (p 0.01) (Figure 3). Albuterol deposition in the ventilator circuit between the chamber spacer and endotracheal tube was comparable for He O 2 80/20 and O 2 13.3% and 10.2%, respectively (p 0.86) (Figure 3). Experiment 2: Influence of He O 2 on Nebulizer Efficiency When the nebulizer was operated at a flow rate of 6 L/min, the use of He O 2 80/20 reduced drug delivery to a filter placed immediately distal to the T-piece of the nebulizer by fivefold compared with O 2 : 38.7 0.7 g versus 191.8 36.4 g (p 0.0005). Albuterol delivery from the nebulizer was related to Figure 3. Drug deposition, expressed as a percent of nominal dose of albuterol from a MDI, in the spacer chamber, the ventilator circuit, the endotracheal tube, and on filters at the bronchi under dry conditions (RH 30%, 27 C) during controlled mechanical ventilation. When the ventilator circuit contained O 2 or He O 2 80/20, aerosol deposition differed at the following sites: spacer, ventilator tubing, endotracheal tube, and bronchi. *p 0.01; **p 0.001. gas density (r 0.944, p 0.001), with the most dense gas, O 2, yielding the highest drug delivery (Figure 4). Albuterol delivery from the nebulizer was greater for O 2 and air than for He O 2 mixtures of 80 20 and 60/40 (p 0.001) (Figure 4). When the nebulizer was operated with He O 2 70/30, more albuterol was delivered to a filter placed immediately distal to the T-piece of the nebulizer when the flow rate was 10 L/min versus 5 L/min (p 0.001). Likewise, when the nebulizer was operated with O 2, albuterol delivery was greater with a flow of 10 L/min versus 5 L/min (p 0.01) (Table 2). At a gas flow of 5 L/min, nebulizer efficiency was 17-fold higher with O 2 than with He O 2 70/30 (p 0.001); at a gas flow of 10 L/min, nebulizer efficiency was twofold higher with O 2 (p 0.01) (Table 2). For He O 2 70/30, an increase in nebulizer flow from 10 to 15 L/min resulted in a 3.5-fold increase in nebulizer efficiency (p 0.01). It was not possible to operate the nebulizer using O 2 at a flow rate of 15 L/min because a build-up of back-pressure disconnected the tubing from the nebulizer inlet. Albuterol delivery to a filter placed immediately distal to the T-piece of the nebulizer was almost doubled when the nebulizer was operated with He O 2 70/30 at 15 L/min than with O 2 at 10/L min (p 0.0001) (Table 2). TABLE 1 EFFECT OF HUMIDITY IN VENTILATOR CIRCUITS CONTAINING He O 2 80/20 OR AIR ON ALBUTEROL DELIVERY FROM A MDI AND CHAMBER SPACER Gas Mixture % Albuterol Deposition* Dry Humid He O 2 80/20 42.4 3.2 26.3 2.0 Air 27.5 1.3 16.7 2.3 * Mean SE of albuterol delivered to filters placed at the distal ends of the main bronchi as a percentage of the nominal dose (n 3 for each condition). Dry (27 C, 30% relative humidity), Humid (32 to 35 C, 95% relative humidity). p 0.041 dry versus humid He O 2 80/20. p 0.003 dry versus humid air. p 0.015 dry He O 2 80/20 versus dry air. p 0.02 humid He O 2 versus humid air. Figure 4. Albuterol delivery as a function of the density of the gas used for operating a small-volume nebulizer. Air, O 2, and various mixtures of He O 2 (80/20, 60/40, 40/60,20/80) were used to operate a nebulizer at a constant flow rate of 6 L/min. Albuterol delivery (percent of the nominal dose of 2.5 mg) was measured on filters placed immediately distal to the nebulizer. Albuterol delivery from the nebulizer showed a positive correlation with gas density (r 0.94, p 0.0001), with the most dense gas (O 2 ) producing the greatest delivery.

112 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 163 2001 TABLE 2 EFFECT OF FLOW RATES OF He O 2 70/30 OR O 2 ON ALBUTEROL DELIVERY FROM THE NEBULIZER Flow (L/min) Nebulizer Output ( g of albuterol)* He O 2 70/30 O 2 5 10.1 3.8 170.9 6.1 10 177.4 12.2 325.2 14.8 15 633.3 26.3 ** Figure 5. Determination of drug delivery to filters placed at the ends of the bronchi of the lung model when the nebulizer was operated with O 2 at a flow of 6 L/min, with He O 2 70/30 at a flow of 6 L/min and He O 2 70/30 at a flow of 15 L/min, and while the ventilator circuit contained He O 2 70/30 (open bars) or O 2 (hatched bars). Albuterol delivery was greatest when the nebulizer was operated with O 2 and the ventilator circuit contained He O 2 70/30. Bars represent SE. Experiment 3: Optimizing Aerosol Delivery with a Nebulizer by Using Various Gas Mixtures during Mechanical Ventilation When the nebulizer was operated with a flow of 6 L/min, albuterol delivery to the lower respiratory tract was approximately 50% higher with the use of O 2 versus He O 2 70/30 (Figure 5). To obtain aerosol delivery equivalent to that obtained with O 2 at a flow rate of 6 L/min, it was necessary to operate the nebulizer with He O 2 70/30 at flow rates of 15 L/min (Figure 5). The highest amount of albuterol was delivered to filters placed at the ends of the tracheobronchial model when the nebulizer was operated with O 2 and the ventilator circuit contained He O 2 70/30 (Figure 5). DISCUSSION He O 2 mixtures can substantially enhance or reduce the efficiency of bronchodilator delivery during mechanical ventilation, depending on specific circumstances. Delivery of albuterol from a MDI to the lower respiratory tract was enhanced when the ventilator circuit contained He O 2 mixtures as opposed to air or O 2 (Table 1). Conversely, when a nebulizer was operated with He O 2, instead of O 2, albuterol delivery was reduced (Table 2). The greatest delivery of aerosol to the lower respiratory tract was achieved by operating the nebulizer with O 2 and entraining the aerosol into a ventilator circuit containing He O 2. Further studies are needed to determine if the increased aerosol delivery with He O 2 mixtures enhances bronchodilation in mechanically ventilated patients. Effect of He O 2 on MDI Delivery Aerosol therapy is frequently administered to mechanically ventilated patients using a MDI and chamber spacer. We and other (23, 24, 27) have shown that several factors, including tidal volume, inspiratory flow rate, and circuit humidity influence the deposition of aerosol generated by a MDI during mechanical ventilation, but the influence of gas density on aerosol delivery was not known. In this study, we show that aerosol delivery was inversely related to the density of gas in the ventilator circuit delivery being greatest with the least dense * Mean SE of albuterol delivered on filters placed immediately distal to the nebulizer after 5 min of nebulization (n 3 for each condition). The nebulizer contained 5 ml (2.5 mg) of albuterol sulfate solution. p 0.001 O 2 versus He O 2 70/30. p 0.01 O 2 versus He O 2 70/30. p 0.001 He O 2 70/30 (5 L/min) versus He O 2 70/30 (10 L/min). p 0.01 O 2 (5 L/min) versus O 2 (10 L/min). p 0.01 He O 2 70/30 (10 L/min) versus He O 2 70/30 (15 L/min). ** Nebulizer could not be operated at these flow rates because build-up of back-pressure caused disconnection of the tubing supplying gas to the nebulizer. gas, i.e., He O 2 80/20 (Figure 2). With helium concentration of 70% or higher, albuterol delivery was increased by half or more over that achieved with air or O 2. When the ventilator circuit was humidified, delivery of albuterol to the main bronchi was decreased; the reduction was virtually identical for He O 2 80/20 and air slightly in excess of 60% (Table 1). In the presence of He O 2 80/20, aerosol delivery in a humidified circuit was comparable to aerosol delivery in a dry ventilator circuit being ventilated with air. Mechanisms for Improved Aerosol Delivery with a MDI in Circuits Containing He O 2 The deposition of aerosol particles in a ventilator circuit and the respiratory tract is mainly achieved through impaction and sedimentation. We previously showed that most of the aerosol emitted from a MDI impacts in the ventilator circuit before reaching the lungs (24). We now show that the amount of albuterol depositing in a chamber spacer and endotracheal tube is decreased when the ventilator circuit contains He O 2 rather than O 2 (Figure 3), leaving a greater fraction to reach the tracheobronchial region. Given the nature of our model, the influence of He O 2 on particle sedimentation cannot be determined. Turbulence in the airways is associated with greater impaction of aerosol particles, reducing aerosol delivery to the lungs (28, 29). With high airflow, Reynolds number, which governs the type of flow within a tube of fixed diameter, can exceed the threshold for nonlaminar flow, i.e., 2,000 units, in the human trachea (30). For a similar flow and airway dimensions, Reynolds number for He O 2 80/20 is decreased to approximately one-third that with O 2 (20). This factor reasonably explains the reduction in aerosol deposition in the spacer device, endotracheal tube, and major airways when the ventilator circuit contained He O 2 rather than O 2 (Figure 3). The inspiratory flow rates during mechanical ventilation exceed those during spontaneous breathing, and are likely to contribute to turbulent flows with increased aerosol deposition in the central airways. When a radiolabeled aerosol was administered to mechanically ventilated patients by a MDI and chamber spacer, most of it deposited in the central zone of the lung (31). We previously reported that aerosol delivery to filters placed at the ends of the bronchi in our tracheobronchial model was twofold higher at an inspiratory flow rate of 40 L/min than at 80 L/min (24). That is, turbulence in the air stream produced by high ventilator flows appears to increase aerosol deposition within the ventilator circuit and major air-

Goode, Fink, Dhand, et al.: Influence of Helium:Oxygen on Aerosol Delivery 113 ways. The improvement in aerosol delivery with He O 2 in the ventilator circuit may be a consequence of its ability to promote a more laminar pattern at any given flow rate. Effect of He O 2 on Nebulizer Efficiency Nebulizers were originally employed in preference to MDIs for aerosol therapy in mechanically ventilated patients (32). We confirm the findings of Hess and coworkers who reported that both the nebulizer efficiency and the proportion of drug contained within respirable particles are decreased when nebulizers are operated with He O 2 rather than O 2 at similar flow rates (18). We further show that the amount of drug leaving a nebulizer decreases linearly as a function of gas density (Figure 4). Entrainment of a solution by a gas and the creation of an aerosol during jet nebulization is governed by the Bernoulli principle, which describes the relationship between gas density and velocity with pressures generated at the jet orifice. Reducing gas density or velocity diminishes the pressure drop across a jet orifice, reducing the amount of aerosol generated. Accordingly, we suspected that operating a nebulizer with a higher flow of He O 2 might increase the amount of aerosol being generated, compensating for the effects of reduced gas density. When the nebulizer was operated with He O 2 flow of 15 L/min, nebulizer efficiency matched that achieved by operating the nebulizer with O 2 at a flow rate of 6 L/min (Table 2). Nebulizer Operation with He O 2 in Mechanically Ventilated Patients During mechanical ventilation, the gas used in operating a nebulizer may be supplied intermittently, from the ventilator, or continuously from a secondary gas source, such as an air compressor or cylinder. Investigators have previously shown that the intermittent method of nebulizer operation is more efficient for aerosol delivery than continuous aerosol generation (21). Based on our findings, intermittent operation of a nebulizer with He O 2 mixtures from the ventilator would result in markedly reduced efficiency; accordingly, it is preferable to operate the nebulizer continuously using He O 2 mixtures. During continuous operation of the nebulizer, a He O 2 of 15 L/ min was required to match the efficiency achieved with O 2 at 6 L/min. Use of such continuous high flows of He O 2 through the circuit would waste gas, and also require readjustment of minute ventilation settings during nebulizer operation. Aerosol delivery to the lower respiratory tract of the tracheobronchial model could be optimized by operating the nebulizer continuously with O 2 at 6 L/min and entraining the aerosol in a ventilator circuit containing He O 2. Although this method of nebulizer operation is tedious to set up, it increases aerosol delivery by approximately 60% over that achieved in a ventilator circuit containing O 2 (Figure 5). While nebulizer performance can be improved by increasing He O 2 flow rates, nebulizer operation during mechanical ventilation with He O 2 is less straightforward than use of a MDI. Careful attention to the details of nebulizer operation is required to achieve maximal nebulizer efficiency when using He O 2 mixtures in the ventilator circuit. In summary, He O 2 in the ventilator circuit improved delivery of albuterol from both MDIs and nebulizers. The increase in aerosol delivery from a MDI was inversely correlated with the density of gas, that is, higher concentrations of helium in the ventilator circuit produced higher aerosol delivery. Conversely, efficiency of a nebulizer was markedly reduced when it was operated with helium. When using a He O 2 80/20 mixture to operate the nebulizer, 2.5 times higher flow of gas was needed to achieve nebulizer efficiency comparable to that achieved with O 2. Maximal efficiency was achieved when the nebulizer was operated with O 2 and the aerosol emitted was entrained into a ventilator circuit containing He O 2. In conclusion, with a carefully executed technique of administration, use of He O 2 mixtures in the ventilator circuit can increase delivery of aerosolized bronchodilators from both MDIs and nebulizers by as much as 50%; this degree of improvement could lead to significantly better outcomes in mechanically ventilated patients with severe airway obstruction. References 1. Chan-Yeung M, Aboud R, Tsao MS, Maclean L. Effect of helium on maximal expiratory flow in patients with asthma before and during induced bronchoconstriction. Am Rev Respir Dis 1976;113:433 443. 2. Wood LDH, Engel LA, Griffin P, Despas P, Macklem PT. Effect of gas physical properties and flow on lower pulmonary resistance. J Appl Physiol 1976;41:234 244. 3. Mink S, Ziesmann M, Wood LDH. Mechanisms of increased expiratory flow during He-O 2 breathing in dogs. J Appl Physiol 1979;47:490 502. 4. Mink S, Wood LDH. How does HeO 2 increase maximum expiratory flow in human lungs? J Clin Invest 1980;66:720 729. 5. Kass JE, Castriotta RJ. Heliox therapy in acute severe asthma. Chest 1995;107:757 760. 6. Manthous CA, Hall JB, Melmed A, Caputo MA, Walter J, Klocksieben JM, Schmidt GA, Wood LDH. Heliox improves pulsus paradoxus and peak expiratory flow in nonintubated patients with severe asthma. Am J Respir Crit Care Med 1995;151:310 314. 7. Kudukis TM, Manthous CA, Schmidt GA, Hall JB, Wylam ME. Inhaled helium oxygen revisited: effect of inhaled helium oxygen during the treatment of status asthmaticus in children. J Pediatr 1997;130:217 224. 8. Kass JE, Terregino CA. The effect of heliox in acute severe asthma: a randomized controlled trial. Chest 1999;116:296 300. 9. Carter ER, Webb CR, Moffitt DR. Evaluation of heliox in children hospitalized with acute severe asthma: a randomized crossover trial. Chest 1996;109:1256 1261. 10. Verbeek PR, Chopra A. Heliox does not improve FEV 1 in acute asthma patients. J Emerg Med 1998;16:545 548. 11. Henderson SO, Acharya P, Kilaghbian T, Perez J, Korn CS, Chan LS. Use of heliox-driven nebulizer therapy in the treatment of acute asthma. Ann Emerg Med 1999;33:141 146. 12. Swidwa DM, Montenegro HD, Goldman MD, Lutchen KR, Saidel GM. Helium oxygen breathing in severe chronic obstructive pulmonary disease. Chest 1985;87:790 795. 13. Gluck EH, Onorato DJ, Castriotta R. Helium oxygen mixtures in intubated patients with status asthmaticus and respiratory acidosis. Chest 1990;98:693 698. 14. Schaeffer EM, Pohlman A, Morgan S, Hall JB. Oxygenation in status asthmaticus improves during ventilation with helium oxygen. Crit Care Med 1999;27:2666 2670. 15. Jolliet P, Tassaux D, Thouret JM, Chevrolet JC. Beneficial effects of helium:oxygen versus air:oxygen noninvasive pressure support in patients with decompensated chronic obstructive pulmonary disease. Crit Care Med 1999;27:2422 2429. 16. Jaber S, Redouane F, Carlucci A, Boussarsar M, Pigeot J, Lemaire F, Harf A, Lofaso F, Isabey D, Brochard L. Noninvasive ventilation with helium oxygen in acute exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000;161:1191 1200. 17. Dolovich MB. Aerosols. In: Barnes PJ, Grunstein MM, Leff AR, Woolcock AJ, editors. Asthma. Philadelphia: Lippincott-Raven; 1997. p. 1349 1366. 18. Hess DR, Acosta FL, Ritz RH, Kacmarek RM, Camargo CA. The effect of heliox on nebulizer function using a -agonist bronchodilator. Chest 1999;115:184 189. 19. Svartengren M, Anderson M, Philipson K, Camner P. Human lung deposition of particles suspended in air or helium/oxygen mixture. Exp Lung Res 1989;15:575 585. 20. Anderson M, Svartengren M, Bylin G, Philipson K, Camner P. Deposition in asthmatics of particles inhaled in air or in helium oxygen. Am Rev Respir Dis 1993;147:524 528. 21. Dhand R, Tobin MJ. Pulmonary perspective: inhaled bronchodilator therapy in mechanically ventilated patients. Am J Respir Crit Care Med 1997;156:3 10. 22. Habib DM, Garner SS, Brandeburg S. Effect of helium oxygen on delivery of albuterol in a pediatric, volume-cycled, ventilated lung model. Pharmacotherapy 1999;19:143 149.

114 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 163 2001 23. Fink JB, Dhand R, Duarte AG, Jenne JW, Tobin MJ. Aerosol delivery from a metered-dose inhaler during mechanical ventilation. Am J Respir Crit Care Med 1996;154:382 387. 24. Fink JB, Dhand R, Grychowski J, Fahey PJ, Tobin MJ. Reconciling in vitro and in vivo measurements of aerosol delivery from a metereddose inhaler during mechanical ventilation and defining efficiencyenhancing factors. Am J Respir Crit Care Med 1999;159:63 68. 25. Tassaux D, Jolliet P, Thouret JM, Roeseler J, Dorne R, Chevrolet JC. Calibration of seven ICU ventilators for mechanical ventilation with helium oxygen mixtures. Am J Respir Crit Care Med 1999;160:22 32. 26. Branson RD. Gas delivery systems: regulators, flowmeters and therapy devices. In: Branson RD, Hess D, Chatburn RL, editors. Respiratory care equipment, 2nd ed. Philadelphia: Lippincott, Williams and Wilkins; 1999. p. 59. 27. Diot P, Morra L, Smaldone GC. Albuterol delivery in a model of mechanical ventilation: comparison of metered-dose inhaler and nebulizer efficiency. Am J Respir Crit Care Med 1995;152:1391 1394. 28. Dolovich M. Physical principles underlying aerosol therapy. J Aerosol Med 1989;2:171 186. 29. Heyder J, Gebbart J, Rudolf G, Stahlhofen W. Physical factors determining particle deposition in the human respiratory tract. J Aerosol Sci 1980;11:505 515. 30. Jaffrin MY, Kesic P. Airway resistance: a fluid mechanical approach. J Appl Physiol 1974;36:354 361. 31. Fuller HD, Dolovich MB, Posmituck G, Wong Pack W, Newhouse MT. Pressurized aerosol versus jet aerosol delivery to mechanically ventilated patients. Am Rev Respir Dis 1990;141:440 444. 32. Smaldone GC. Aerosolized bronchodilators in the intensive care unit: much ado about nothing? Am J Respir Crit Care Med 1999;159:1029 1030.