Change in Oxygen Consumption Following Inhalation of Albuterol in Comparison With Levalbuterol in Healthy Adult Volunteers
Phase: NA
Conditions: Oxygen Consumption
Sponsor: Children's Hospital Los Angeles

 
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NCT # 02802111 
Document Date September 18, 2014 
Comparing peak oxygen consumption following administration of albuterol vs Levalbuterol 
Investigators: 
Christopher Newth MD 
Patrick Ross MD 
Manpreet Virk MD 
 
Department of Anesthesiology and Critical Care Medicine, Children’s Hospital Los Angeles 
University of Southern California 
Study Contact Person: 
 
Manpreet Virk MD 
4650 Sunset Blvd Mailstop 3 
Los Angeles, CA 90027 
Email: mvirk@chla.usc.edu 
 
 
A. Abstract 
Asthma is a pulmonary disease characterized by reversible airway obstruction and inflammation 
affecting 7 million children in the United States. It is a highly prevalent condition and the most 
common medical emergency in pediatrics. β 2 agonists remain the mainstay of pharmacotherapy 
in asthma. β 2 selective agonists are desirable to avoid the non-selective α and β 1 receptor 
stimulation which may cause adverse effects. Albuterol (β 2 agonist) remains the most commonly 
used bronchodilator in asthma and patients with chronic lung disease. Albuterol is a 50:50 mixture 
of R albuterol (levalbuterol) the active moiety responsible for the bronchodilatory effect and S 
albuterol. S albuterol was earlier thought to be an inactive isomer however recent studies suggest 
otherwise. Evidence from pre-clinical studies suggests that the S enantiomer has 
brochoconstricting and pro inflammatory properties and is metabolized 12 times slower than the 
R isomer which results in higher circulating levels of the S enantiomer as compared to the active 
R enantiomer following administration of racemic albuterol.   However cardiovascular adverse 
effects remain the main dose-limiting factor for β2 selective agent usage namely tachycardia, 
diastolic hypotension, arrhythmias and other side effects include skeletal muscle tremor and 
nausea. We propose that the underlying mechanism for these effects is due to increased oxygen 
consumption caused by the racemic albuterol as shown in animal studies specifically the S 
enantiomer. Previous Rhesus monkey studies performed by our group have shown that racemic 
albuterol increases the oxygen consumption by 46.5% from baseline compared to a 10% increase 
after administration of levalbuterol. To date there are no human studies that have measured the 
change in oxygen consumption following administration of levalbuterol.  

 
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B. Background 
 
Albuterol a β2-adrenoreceptor agonist was first marketed in 1968 known for its 
brochodilatory action. Albuterol contains a racemic mixture of two enantiomers namely the R(active 
form) and the L(considered inert) form. Some of the side effects of the racemic albuterol include 
jitteriness, anxiety and palpitations. Levalbuterol contains the single enantiomer (R – form) and is 
preferred in instances where the tachycardia caused by the racemate may be detrimental to the overall 
clinical status of the patient. However there are no studies to date that have elucidated the potential 
cause of the tachycardia in patients receiving albuterol attributed mainly to its β2 receptor agonist 
function. 
 
 
Field et al1 measured the cost of breathing in 13 patients on mechanical ventilation as the 
difference between the oxygen consumption during spontaneous respiration and that during 
mechanical ventilation and found that the oxygen cost of breathing increases from less than 5 % of 
total VO2 (oxygen consumption) in a normal resting spontaneously breathing patient to a range of 
8 -24 % of total VO2 on mechanical ventilation. Patients with cardiorespiratory or lung diseases 
have been shown to have elevated oxygen consumption while mechanically ventilated. β agonists 
can increase the oxygen consumption either by increasing minute ventilation through stimulation of 
the respiratory center or by directly stimulating the respiratory muscles. Furthermore there are no 
studies that have measured the change in oxygen consumption following administration of 
levalbuterol. Oxygen consumption increases in diseases states such as fever, sepsis and trauma and 
leads to an increased metabolic demand. Increase in oxygen consumption that is disparate to the 
oxygen delivery leads to anaerobic metabolism and lactic acidosis and can further worsen the clinical 
status or delay recovery. Also there may be impaired oxygen extraction or use at the cellular level 
i.e. cytopathic hypoxia thus creating a functional arteriovenous shunt. Maintaining adequate oxygen 
delivery to meet the metabolic demands is fundamental in treating critically ill patients. 
 
 
A double blind placebo controlled trial studied pharmacokinetics of albuterol and its 
enantiomers and showed that, in fact the S enantiomer does not have any effects on extra pulmonary 
β 2 receptors. However the S enantiomer does not exert its effects through the β 2 receptor. 
Henderson et al2 studied the clinical effects of the two enantiomers on mouse models and showed 
that the R enantiomer of albuterol increases airway edema and bronchial responsiveness in response 
to a methacholine challenge which provokes bronchoconstriction whereas the S enantiomer had the 
opposite effects. These bronchocontrictor and proinflammatory effects of the S enantiomer may 
gradually overcome the bronchodilatory effects of the R enantiomer in the racemate and that R 
enantiomer balances the bronchospastic effects of the S enantiomer in the racemate. There are studies 
suggesting the differential effects of the two enantiomers. 
 
 
Newth et al3 in 1990 reported changes in minute ventilation and oxygen consumption in 10 
anesthetized intubated rhesus monkeys in response to multiple B agonists. The study revealed that 
of the multiple β agonists (salmeterol, formoterol, fenoterol, salbutamol) along with comparison to 
normal saline and theophylline, the most profound effects on oxygen consumption were after 
administration of inhaled racemic albuterol. Racemic albuterol increased the oxygen consumption 
(VO2) by 46.5% over control (P < 0.001). Other variables such as heart rate, respiratory rate and 
minute ventilation also showed an increase of 60.2 %, 51.9% and 82.8% respectively. As the article 
stated, in patients with cardiorespiratory disease and with low reserve, the potential for hypoxemia 
will depend on the change in oxygen extraction and pulmonary vasculature and whether the cardiac 

 
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output can be increased to match the demand and if the extent of bronchodilation can increase 
ventilation to a degree that can sufficiently offset the increase in oxygen consumption. 
 
 
In a follow up study by Newth et al4 in 1997 studied the effects of Bronchodilators on 
Spontaneous Ventilation and Oxygen Consumption in anesthetized intubated Rhesus Monkeys 
showed that racemic albuterol) caused an increase in Oxygen consumption of 45% and minute 
ventilation of 50%. These changes were suppressed in the presence of a β blocker such as 
propranolol. Therefore the increase in oxygen consumption could be secondary to β adrenoreceptor 
stimulation resulting in stimulation of the respiratory center or due to increased metabolic demands.  
 
  
β agonists are used extensively in pediatric patients with chronic lung disease, asthma or 
for its mucolytic property. Many of these children are admitted primarily for another condition for 
example septic shock, in which case their oxygen demands may already be increased. In such 
conditions administering β agonists that may further increase oxygen consumption and oxygen costs 
of the body may be have deleterious effects on the overall clinical status of the patient.  
 
 
C. Hypothesis: Levalbuterol does not increase oxygen consumption to an extent that is increased by 
salbutamol (albuterol). 
 
      D. Purpose of this Study: The purpose of our study is to study the peak oxygen consumption in subjects 
scheduled to receive albuterol and compare it with that of levalbuterol using a non-invasive method with 
the Innovision Innocor machine. To date, no known human studies that have measured the change in 
oxygen consumption after levalbuterol. 
 
1. Study Objectives 
Primary objective is to measure the peak oxygen consumption at baseline and then after the 
administration of albuterol and levalbuterol inhalation in patients admitted to or currently cared 
for in the pediatric intensive care unit (PICU) or cardiothoracic intensive care unit (CTICU) at 
Children’s Hospital Los Angeles with asthma reactive airway or chronic lung disease. 
Secondary objectives are to collect change in Cardiac output, systemic vascular resistance, 
stroke volume, minute ventilation, heart rate, blood pressure, respiratory rate, pulse oximetry 
with each intervention. 
 
 
E. Significance and preliminary studies  
                  Albuterol has been in used in the treatment of asthma to relieve bronchospasm for nearly 45 
years. However numerous reports have associated long term use of racemic albuterol with increasing 
morbidity and mortality. Mechanisms underlying these observations are not well known at this point. 

 
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Recent studies have shown that the S enantiomer has bronchoconstricting and pro-inflammatory properties 
which may be counterbalanced by the R enantiomer in the racemate. Numerous studies have been reported 
to question the clinical efficacy of racemic albuterol or in fact that the racemate may actually have 
deleterious effects on the bronchioles. Racemic albuterol consists of 50% each of the active and the 
inactive isoform. However there is accumulating body of data from animal studies questioning the inactive 
or rather the counteractive nature of the S isoform.  
Although β 2 agonists have been in use for a long time, controversies exist as to their efficacy and 
safety over long term use. Animal studies focusing on the long term use of racemic albuterol have shown 
that it increased airway hyper responsiveness, edema and susceptibility to spasmogens. These effects have 
been understood to be from the S isoform as previous clinical trials have demonstrated the individual 
bronchodilator properties of the R isoform along with suppression of pro inflammatory mediators.  
Mazzoni et al5 have reported that bronchospasm in sensitized animals was completely suppressed 
by an infusion of racemic albuterol, however a more prolonged infusion longer than 1 hour increased their 
susceptibility to the antigen and induced hyper responsiveness to histamine. This progressive loss of 
efficacy of racemic albuterol with time is speculated to be from disproportionate accumulation of the S 
enantiomer due to stereospecific metabolism of the R enantiomer. 
A randomized controlled trial was conducted by Wraight et al6 to study the adverse effects on lung 
function by short acting β agonists. The study included 36 subjects with mild to moderate asthma on 
racemic albuterol along with inhaled corticosteroids. Subjects were randomized to two groups, one 
receiving a combination of albuterol and ipratropium and the other receiving ipratropium alone. The study 
consisted of two phases. FEV1 measurements were done while on these medications during phase 1 and 
inhaled corticosteroids were then withdrawn during phase 2 and changes in FEV 1 and FEV1 % were 
recorded following the withdrawal. The results showed that there was a significant loss in lung function 
as evidenced by drop in FEV 1 in patients with mild to moderate asthma as compared to those on 
ipratropium. Furthermore when inhaled corticosteroids were discontinued there was a larger fall in FEV 
1 in the β agonist group compared with the ipratropium group. These data suggest that in poorly controlled 
asthma wherein patients are taking short acting agonists frequently the adverse effects may be more 
pronounced especially when the anti-inflammatory effects of the inhaled corticosteroids are absent.  
 
 
 
 
 
          F.   Research Design and Methods 
      Study Overview 

 
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This is a single center prospective randomized controlled open label cross over study in the 
24 bed multidisciplinary medical-surgical Pediatric Intensive Care Unit (PICU) and 22 bed 
multidisciplinary Cardio-Thoracic Intensive Care Unit (CTICU) at Children’s Hospital Los 
Angeles.  
a. Eligibility & Recruitment 
This will be a single center prospective randomized open label cross over study. There will be 
three cohorts of subjects. 
1. Intubated patients receiving Albuterol 
2. Non–intubated patients receiving albuterol who are cognitively able to obtain measurements 
with a mouthpiece 
3. Healthy adult volunteers  
 
a. Subject Eligibility – Intubated and non-intubated patients 
For intubated patients all subjects 1 month to 17 years of age admitted to the pediatric 
intensive care unit (PICU) or cardiothoracic intensive care unit (CTICU) will be 
screened throughout their stay for inclusion.  For non-intubated patients all subjects 
1 month to 21 years old admitted to the pediatric intensive care unit (PICU) or 
cardiothoracic intensive care unit (CTICU) will be screened throughout their stay for 
inclusion. Particular subject eligibility will be based on the following inclusion and 
exclusion criteria. 
b. Inclusion Criteria 
For intubated patients: any patient 1 month to 17 years old admitted to the pediatric 
intensive care unit (PICU) or cardiothoracic intensive care unit (CTICU) with asthma, 
reactive airways or chronic lung disease and is scheduled to receive albuterol or 
levalbuterol.   
For non-intubated patients:  any patient 1 month to 21 years old admitted to the 
pediatric intensive care unit (PICU) or cardiothoracic intensive care unit (CTICU) 
with asthma, reactive airways or chronic lung disease and is scheduled to receive 
albuterol or levalbuterol. 
c. Exclusion Criteria 
                        1. If intubated, patients with a large endotracheal tube leak (greater than 18%) 
2. SpO2 less than 95 % while receiving an FiO2 of > 40%, signifying 
intrapulmonary shunting in which case the use of albuterol or L-albuterol coud 
change the degree of intrapulmonary shunt during the testing. 

 
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a.  Subject Eligibility – Healthy Volunteers 
Healthy volunteers less than 60 years of age available to participate on two 
consecutive days 
b.  Inclusion Criteria – Healthy volunteers less than 60 years of age 
c.  Exclusion Criteria – Any contraindication to use of Albuterol such as known 
allergy to albuterol or levalbuterol.  
 
Protocol for intubated and non-intubated patients receiving albuterol or levalbuterol 
After obtaining a written informed consent from patients/guardians that are scheduled to receive 
albuterol or levalbuterol, the subjects will be randomized using pre-prepared opaque sealed 
envelopes to two different groups, group A and B. The measurements will be done over 2 separate 
days. On Day 1 Group A will receive albuterol first followed by levalbuterol for when the next 
dose is due. On day 2 the order will be reversed and therefore levalbuterol will be given first 
followed by albuterol. Group B will be first given levalbuterol followed by albuterol for the next 
scheduled dose. If the patient is receiving albuterol as their clinically prescribed medication the 
levalbuterol dose will be chosen to be ½ that milligram amount.  If the patient is receiving 
levalbuterol as their clinically prescribed medication the albuterol dose will be chosen to be 2 times 
that milligram amount.  Typical dosages in the ICU would be albuterol 0.15 mg/kg with a 
minimum of 2.5 mg and maximum of 5 mg and levalbuterol 0.63 mg and  1.25 mg respectively. 
However, if a young child is clinically prescribed a dose of Albuterol of 1.25 mg(max dose of 
levalbuterol) then the dose of Levalbuterol for the study would be 0.63 mg.  Albuterol is only FDA 
approved for marketing to patients greater than 2 years of age but it has been used clinically at all 
age levels.  Likewise, Levalbuterol has been used clinically in infants and children but is only FDA 
approved for marketing to patients greater than 6 years of age.  Measurements of oxygen 
consumption will be done using the non-invasive device Innocor. This device has been validated 
for measurement of oxygen consumption against the gold standard Douglas bag. Oxygen 
consumption will be measured at baseline and then after giving albuterol and levalbuterol at times 
0, 5 min, 10, 20, 40 and 60 minutes. The two medications will be given at least 4 hours apart.  
 
The Innocor device has the ability to measure cardiac output by mixing in small amounts of Nitrous 
Oxide (N2O) and Sulfur Hexafluoride 6 (SF6).  Oxygen consumption is measured by the Innocor 
device without the addition of these gases.  For this study N2O and SF6 will not be used.  No part 
of the Innocor device will be attached to the skin for the purposes of this research.  The Innocor 
device can be used to measure pulmonary function tests requiring some degree of cooperation from 
subjects.  It is possible to obtain measurements of oxygen consumption using the Innocor device 
in intubated, sedated patients without their cooperation.  For non-intubated patients, they would 
only need to be able to follow the direction to breathe out through the sensor.  No timing of breaths 
are required. 
 
Protocol for Healthy Adult Volunteers 
After obtaining a written informed consent from the volunteer, the subject will be randomized 
using pre-prepared opaque sealed envelopes to which medication (albuterol or levalbuterol) they 
receive first.  The measurements will be obtained over 2 consecutive days.  The dosage of 

 
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Albuterol will be 5 mg mixed with 2 to 3 ml of saline and will be aerosolized over 10 minutes.  
The dosage of levalbuterol will be 1.25 mg mixed with 2 to 3 ml of saline and will be aerosolized 
over 10 minutes.  One day 1 of the study the patient will receive the medication they were 
randomized to.  At approximately the same time of day on day 2 the subject will receive the other 
medication.  Following each breathing treatment, oxygen consumption will be measured using the 
non-invasive Innocor machine.  Oxygen consumption will be measured at baseline and then 
following the medication at times 0, 5 min, 10, 20, 40 and 60 minutes.  Temperature will be 
measured prior to the aerosolized medication and heart rate, blood pressure, oxygen saturations, 
and respiratory rate will be measured at intervals over the 60 minutes of oxygen consumption 
measurement. 
 
The Innocor device has the ability to measure cardiac output by mixing in small amounts of Nitrous 
Oxide (N2O) and Sulfur Hexafluoride 6 (SF6).  Oxygen consumption is measured by the Innocor 
device without the addition of these gases.  For this study N2O and SF6 will not be used.  No part 
of the Innocor device will be attached to the skin for the purposes of this research.  The Innocor 
device can be used to measure pulmonary function tests requiring some degree of cooperation from 
subjects. For non-intubated patients, they would only need to be able to follow the direction to 
breathe out through the sensor.  No timing of breaths are required. 
 
 
 VO2 = (CO X CA) – (CO X CV) 
VO2 = Oxygen consumption 
CO = Cardiac Output  
CA = Oxygen concentration of arterial blood 
CV = Oxygen concentration of mixed venous blood 
 
Innocor is a non-invasive device that measures hemodynamic and gas exchange parameters for 
diagnostic purposes using the inert gas rebreathing technique and breath-by-breath analysis. The 
patient breaths through a mouthpiece or a facemask connected to the flow meter via a bacterial 
filter. A gas sampling tube is connected to the breathing assembly for side stream gas analysis. 
Carbon dioxide is measured continuously and simultaneously at the mouthpiece by a photoacoustic 
gas analyzer. Oxygen is measured by means of a laser diode absorption spectrometer.  
The breath-by-breath method is the fastest responding of the non-invasive gas exchange methods 
for determination of the various gas exchange parameters such as oxygen uptake and carbon 
dioxide excretion. The Breath-by-Breath (BBB) Option provides measurements of metabolic gas 
exchange parameters by simultaneous measurements of the respiratory flow and gas 
concentrations when breathing ambient air. The respiratory flow is measured by means of a 
differential pressure type flow meter (pneumotachometer) placed between the respiratory valve 
unit and the patient. The principle in the determination of the oxygen consumption and the carbon 
dioxide excretion is to estimate the difference between airway influx and efflux of oxygen and 
carbon dioxide during inspiration and expiration. This is done by integrating the product of oxygen 
or carbon dioxide concentration and flow in the respiratory gas over an interval, which covers a 
complete respiratory cycle.  

 
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The gold standard for measuring respiratory exchange is the Douglas bag technique. Sheth et al7 studied 
the correlation of VO2 obtained by Innocor with the Douglas bag technique. 31 children (ages 7 -17 
years) were recruited for the study. A strong correlation was found between the two methods (R 2 0.82) 
The average discrepancy between the Innocor and the Douglas bag methods was 5.4% (range 0.1 – 
32.2%). The Innocor provides a rapid mode of testing VO 2 as compared to the gold standard Douglas 
bag that involves collecting large volumes of expired gas as opposed to the Innocor where measurements 
could be completed in 60 seconds. 
Measurements of cardiac output, stroke volume, systemic vascular resistance will be done using the 
Ultrasound Cardiac Output Monitor. We intend to collect data for such as cardiac output, blood pressure, 
systemic vascular resistance. These will be done with a non-invasive method using the Ultrasonic Cardiac 
Output Monitor (USCOM). USCOM device is FDA approved for use in adults and pediatric patients and 
includes a screen and a probe. The Ultrasonic Cardiac Output Monitor was introduced for clinical use in 
2001 and measures the velocity of blood flow from either the aortic or pulmonary valve. It has previously 
been used in studies to measure cardiac output( CCI-09-00102) Cardiac output is the amount of blood 
pumped by the heart per minute expressed in litres. Cardiac output is a product of heart rate and stroke 
volume. Blood pressure will be entered manually by which the machine will calculate mean arterial 
pressure (MAP) and systemic vascular resistance (SVR). SVR =MAP/CO. Knowing changes in cardiac 
output with the interventions will provide vital information about the critical nature of their illness and 
this information can be used to tailor therapy for the patients. Our study entails measuring oxygen 
consumption. One of the fundamental tenets of critical care medicine include matching oxygen delivery 
to the oxygen consumption. Oxygen consumption that is disparate to the oxygen delivery leads to 
anaerobic metabolism and may explain the lactic acidosis seen in patients receiving albuterol. Oxygen 
delivery is the product of arterial oxygen content and cardiac output.  
Study participants will be given a questionnaire at the end of each intervention. Oxygen consumption is 
dependent on many variables such as body temperature, amount of physical activity, amount of caffeine 
consumed and if they experience any effects such as nausea, palpitations, tremors or jitteriness. Collecting 
additional information for these confounders will be crucial in analyzing the final outcomes on the two 
groups with regards to change in oxygen consumption from baseline. The volunteers will also be asked if 
they have used albuterol or levalbuterol  in the past. Albuterol is known to cause various effects such as 
nausea, palpitations, and tremors or jitteriness and knowledge about theses side effects will help the 
physicians choose the most appropriate treatment for the subject. 
 
G. Statistical considerations 
There is no published information on the increase in oxygen consumption caused by L-Albuterol in 
humans.  Animal studies show oxygen consumption increases from a baseline of 4.8 ± 0.3 ml/kg/min 
(Newth 1991) to 7.0 ± 0.3 ml/kg/min following L-Albuterol administration.  This was an increase in 
oxygen consumption of 46%.  Unpublished pilot data in rhesus monkeys suggests oxygen consumption 
increases from a baseline of 5.0 ± 0.6 ml/kg/min to 5.26 ± 0.8 ml/kg/min.  However, differences in 

 
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sedation compared to previous animal studies resulted in greater variability in the measurement of 
oxygen consumption.  We expect racemic albuterol will be associated with a smaller increase in oxygen 
consumption compared to L-Albuterol. A clinically significant difference in oxygen consumption might 
be as little as 10% in a child who is critically ill. We will use a paired t-test to compare mean difference 
in oxygen consumption between L-Albuterol and racemic albuterol in children. Using a paired 
difference to be detected of 10%, expected standard deviation of 20%, power of 0.9 and significance 
level (alpha) of 0.05 we calculated a sample size of 44 patients for this study.  Given the possibility of 
drop out or incomplete data collection we anticipate approaching 50 patients to complete the study.  
Given we cannot be certain that the degree of variability will remain the same across the three cohorts 
we will target recruitment to 50 subjects in each cohort.  We will perform an interim analysis after the 
first 20 patients are recruited. 
 
References: 
1 
Field S, Kelly SM, Macklem PT The oxygen cost of breathing in patients with 
cardiorespiratory disease. Am Rev Respir Dis. 1982 Jul; 
2 
Henderson WR Jr  Banerjee ER, Chi EY. Differential effects of (S)- and (R)-
enantiomers of albuterol in a mouse asthma model. J Allergy Clin Immunol. 2005 Aug 
 
3 
Newth CJ , Amsler B, Anderson GP, Morley J.  The ventilatory and oxygen costs in the 
anesthetized rhesus monkey of inhaling drugs used in the therapy and diagnosis of asthma 
Am Rev Respir Dis. 1991 Apr 
 
 
4 
Newth CJ , Amsler B, Richardson BP, Hammer J. The effects of bronchodilators on 
spontaneous ventilation and oxygen consumption in rhesus monkeys. Pediatr Res. 1997  
 
5 
Mazzoni L  Naef R, Chapman ID, Morley J. Hyperresponsiveness of the airways following 
exposure of guinea-pigs to racemic mixtures and distomers of beta 2-selective 
sympathomimetics Pulm Pharmacol. 1994 Dec 
 
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 Wraight JM, Smith AD, Cowan JO, Flannery EM, Herbison GP, Taylor DR. Adverse 
effects of short-acting beta-agonists: potential impact when anti-inflammatory therapy is 
inadequate Respirology. 2004 Jun 
 

 
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Sheth SS, Maxey DM, Drain AE, Feinstein JA. Validation of the Innocor device for 
noninvasive measurement of oxygen consumption in children and adults. Pediatr 
Cardiol. 2013 Apr