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* From the Department of Internal Medicine (Drs. Johnson and Beck), Mayo Clinic and Foundation, Rochester, MN; and the Department of Clinical Investigation (Drs. Zeballos and Weisman), William Beaumont Army Medical Center, El Paso, TX.
Correspondence to: Bruce D. Johnson, PhD, Cardiovascular Health Clinic 200 First St, SW, Mayo Clinic and Foundation, Rochester, MN 55905; e-mail: johnson.bruce{at}mayo.edu
Abstract
This review examines emerging technologies that are of potential use in the routine clinical pulmonary laboratory. These technologies include the following: the measurement of exercise tidal flow-volume (FV) loops plotted within the maximal FV envelope for assessment of ventilatory constraint during exercise; the use of negative expiratory pressures to asses expiratory flow limitation in various populations and under various conditions; the potential use of expired nitric oxide for assessing airway inflammation; and the use of forced oscillation for assessment of airway resistance. These methodologies have been used extensively in the research setting and are gaining increasing popularity and clinical application due to the availability of commercially available, simplified, and automated systems. An overview of each technique, its potential advantages and limitations will be discussed, along with suggestions for further investigation that is considered necessary prior to extensive clinical use.
Key Words: flow-volume • forced oscillation • negative expiratory pressure • nitric oxide
Many advances in the pulmonary laboratory have occurred over the last 2 decades. The majority of these advances involve automation of routine pulmonary function measurements, refinement of the diffusing capacity test, innovation of fast-response analyzers to obtain "real time" cardiopulmonary exercise data, and progression into the standard use of the body plethysmograph for assessment of lung volumes and airway resistance. Although there are many techniques that are applicable primarily in the research setting, there are several emerging methods that may offer unique clinical insight or may offer advantages over more "traditional" techniques. The following sections offer a brief review of several methods that are gaining popularity or, through advances in technology, are becoming available in the clinical setting. These include the following: (1) the use of the tidal flow-volume (FV) loop measurement during exercise (extFVL) to help distinguish the degree of ventilatory limitation; (2) the use of the negative expiratory pressure (NEP) technique to detect expiratory flow limitation; (3) the use of expired nitric oxide (NO) in the assessment of airway inflammation; and (4) the forced oscillation (FO) technique to assess airway resistance.
Assessment of Ventilatory Limitation Using the extFVL
There has been a growing trend in both research and clinical
laboratories to find alternative ways to evaluate ventilatory
limitation during exercise.1
2
3
4
5
This stems in part from
the realization that patients may discontinue exercise due to
ventilatory constraints and dyspnea prior to the achievement of classic
indexes associated with ventilatory limitation (ie, minute
ventilation [
E] that reaches the maximum voluntary
ventilation [MVV] or a rise in arterial CO2)
and that E limitation is not an "all or
none" phenomenon.6
Thus, investigators have used
techniques such as breathing helium-oxygen mixtures (to increase the
maximal FV envelope [MFVL]), inspired CO2, and
dead space loading (to stimulate ventilation) to assess whether
E is truly
constrained.1
2
7
8
Another approach that has gained
popularity includes the measurement of the extFVL and its plotting
within the MFVL.1
9
10
11
This latter technique provides a
good visual index of the degree of E
constraint, allows a more detailed approach to defining
E limitation (relative to the
E/MVV relationship), and has gained
popularity due to the ease of measurement using many of the
commercially available metabolic carts. Figure 1
shows an example of the rest and peak exercise FV responses in a
healthy, average fit adult plotted within the MFVL. Key features of the
E response in the healthy adult are shown
in Table 1
. In this particular example, at peak exercise, there is only minimal
encroachment on the MFVL, which implies that there is little constraint
to breathing.
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Information Gained From the extFVL
Varied information has been gleaned from the extFVL plotted within
the MFVL, from simple visual information to actual quantification of
various indexes of E constraint.3
10
14
To date, no consensus exists on which variables will prove to be the
most useful clinically or how best these may be quantified. The most
commonly reported variables are shown in Table 2
.1
3
7
10
11
13
14
Other investigators have used various
additional indexes, such as tidal volume (VT) relative to
IC or vital capacity in conjunction with breathing frequency to help
describe the degree of E
constraint.1
3
4
12
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E constraint, possible mechanisms of associated
dyspnea, as well as effectiveness of treatment (eg, surgery
or bronchodilator therapy).1
11
15
16
The advantages over
a traditional assessment of E reserve
(E/MVV ratio) includes more specific
information on the mechanisms of E
constraint and more formal quantification of the degree of constraint.
Although not yet generalizable to the larger population, smaller
studies have suggested that in patients with asthma and
mild-to-moderate emphysema, and in healthy older subjects (subjects
with mild-to-moderate obstructive airway changes) EELV will dynamically
increase during exercise to varying degrees as expiratory flow
limitation develops to take advantage of the flow available at the
higher lung volumes.1
10
13
The increase in EELV in turn
causes greater encroachment on the IRV (the EILV/TLC ratio,
which increases elastic load) and potential encroachment by the
inspiratory tidal loop on the inspiratory FV curve.1
11
In
patients with more significant obstructive disease, the magnitude of
the rise in EELV, as assessed with serial IC maneuvers, correlates more
strongly with exercise endurance and dyspnea than do traditional
measurements of FEV1.11
17
Thus, in
some populations, the change in the EELV at rest or during exercise may
represent the most sensitive marker of ventilatory constraint. Patients
with interstitial lung disease do not appear to demonstrate significant
increases in EELV during exercise, while patients with chronic heart
failure and subjects with significant obesity may actually breathe with
reduced EELVs despite significant expiratory flow limitation and a
normal VE/MVV relationship.3
14
18
Limitations to the widespread use of the extFVL in the clinical setting
include difficulty in defining the true MFVL, effort dependence of the
IC maneuvers, and constancy of TLC.12
Small errors in
either of these measurements or assumptions could lead to erroneous
conclusions. Partial MFVLs or maneuvers of MFVLs at different levels
may be necessary to better define the maximal expiratory flow boundary
in some patient populations. Additional studies are necessary to
determine the following: (1) the optimal MFVL for comparison to the
extFVL; (2) the ability of patients to perform multiple IC maneuvers;
(3) which indexes are most clinically useful in describing the degree
of E constraint (eg, the percentage of
VT flow limited, increase in EELV, or increase in
EILV/TLC ratio); (4) the relationship of various indexes of constraint
to measurements of dyspnea and exercise intolerance; and (5) the degree
of constraint that begins to influence exercise tolerance
(eg, exercise capacity, perception of dyspnea, and
cardiovascular function).
The use of the extFVL would be helpful in many patient groups in which
dyspnea and exercise intolerance were noted and mechanical constraints
to breathing are a possibility. In patients with normal lung function
or with severe airway changes (eg,
FEV1 < 30 to 40%), such an assessment is
unlikely to yield significant additional insight, however, in patients
with more moderate obstructive changes or to assess the effectiveness
of treatment, further evaluation using the extFVL may be valuable.
Figure 2 shows an example of the rest and extFVLs plotted within the MFVL
in a physically active patient with moderate COPD. Interestingly, this
patient had a normal exercise capacity for his age, however, he clearly
could not increase E further due to the
degree of constraint (ie, increased EELV and significant
expiratory flow limitation.)
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E constraint is not only dependent on the area
circumscribed by the MFVL and the breathing strategy, but also on the
E demand. Thus, a highly fit healthy adult may
encroach to a similar degree on the MFVL as a significantly
deconditioned patient with some obstructive airway disease due to a
significantly higher VE.7
10 Assessment of Expiratory Flow Limitation Using Negative Expiratory Pressures
Expiratory flow limitation promotes a dynamic increase in EELV with a concomitant increase in inspiratory work, impairment of inspiratory muscle function, and adverse effects on hemodynamics.19 These changes, combined with the dynamic compression of airways, likely contribute to dyspnea in patients with obstructive airway disease.11 The NEP technique evolved out of a need for an accurate assessment of expiratory flow limitation.20 It was originally used to assess expiratory flow limitation during mechanical ventilation, however, it has more recently been applied to various patient populations during breathing at rest and during exercise.21 22 23 24 25
When assessing flow limitation using the tidal breath method relative to the expiratory boundary of the MFVL, it remains controversial how to best define the maximal expiratory flows for comparison to the tidal FV loop. This is due to several factors, which have been shown to have varying influences on the size of the MFVL, as summarized in Table 3 .9 13 26 27 28 \
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In healthy subjects, the influences of dynamic compression, lung volume, and flow history on the expiratory boundary of the MFVL are likely to be small, however, they can become more substantial in patients with obstructive airway changes.11 26 27 Although these changes can generally be accounted for by varying expiratory effort when performing the MFVL maneuvers, by performing partial MFVL maneuvers, or by repeating maneuvers if airway caliber is suspected to change (eg, during or after exercise), these technical concerns can, for the most part, be eliminated using the NEP technique to assess expiratory flow limitation.
Methodology
The NEP technique was introduced for detecting expiratory flow
limitation, which does not require the performance of forced expiratory
efforts on the part of the patient, use of a body plethysmograph to
correct for gas compression, or the performance of IC
maneuvers.20
It consists of applying a negative pressure
at the mouth during a tidal expiration and comparing the ensuing
expiratory flow curve with that of the previous control
expiration.21
Typically, subjects are attached to a
mouthpiece connected in series to a pneumotachograph and a T-tube. One
side of the T-tube is open to the atmosphere, while the other side is
equipped with a pneumatic valve, which allows for the subject to be
rapidly switched to a negative-pressure source (eg, a
vacuum). The negative-pressure source typically has been set at -3 to
-10 cm H2O in various
populations.19
24
29
NEP is generally applied at the
initiation of expiration and is maintained throughout most of
expiration for comparison to non-NEP control breaths. Figure 3
shows an example of the NEP technique applied in a subject who is not
flow limited (ie, who has an increase in flow during NEP
compared with a control breath) during spontaneous breathing and
in a patient who is flow limited (ie, who has no increase in
flow with NEP compared with a control breath).21
Commercial systems are becoming available for interface with existing
metabolic carts.
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Clinical Application
The NEP method has been applied to assess whether expiratory flow
limitation exists during spontaneous breathing in patients with
COPD,29
before and after single lung
transplantation,19
in patients with stable
asthma,23
and in patients with restrictive respiratory
disorders.24
It has also been successfully applied during
mechanical ventilation20
and in infants with cystic
fibrosis,22
as well as during exercise in COPD
patients.25
The degree of expiratory flow limitation
obtained with NEP also has been shown to be more highly correlated with
dyspnea than other indexes of pulmonary function (eg, FVC
and FEV1) in COPD patients.29
Although an effect similar to NEP could be obtained by asking subjects to simply augment expiration slightly during a transient breath, the NEP technique has the advantage of detecting expiratory flow limitation in patient groups that cannot easily respond to instruction. In addition, it is possible that breathing mechanics immediately preceding the expiration may be altered slightly when individuals are asked to prepare to augment a subsequent expiratory effort.
In subjects spontaneously breathing at rest, the application of NEP at
the onset of expiration has sometimes resulted in a drop in flow below
the flow rate generated during the preceding tidal
expiration,31
presumably due to reflexive partial or total
upper airway narrowing. A subsequent study, however, suggested that
reflex-mediated changes in upper airway diameter (genioglossus) tended
to occur near the end of expiration rather than at the initiation,
except in a few subjects.30
Another potential limitation
to the NEP technique is the inability to quantify the degree of
expiratory flow limitation. Early expiration cannot be easily assessed
due to the spike artifact caused from NEP. However, this artifact is
quite brief, and, typically, flow limitation occurs predominantly over
the later portion of expiration. Thus, in most subjects the percentage
of the tidal breath that is limited can be quantified, except perhaps
in subjects in whom expiratory time is significantly reduced. The NEP
technique alone does not provide insight on other markers of
E constraint, such as the change in EELV or an index
of elastic load. It also does not provide insight into inspiratory flow
constraints, which may occur in patients with muscle weakness or
fatigue or in those with significant hyperinflation. Unless the NEP
technique is performed with the assessment of the tidal FV loops, flow
limitation is defined as "all or none" rather than in terms of the
graded degrees of limitation defined with the tidal loops. An
all-or-none assessment of expiratory flow limitation tells little about
the degree of E constraint, especially since
subjects may augment E despite flow limitation by
dynamic hyperinflation or further encroachment on the IRV. Thus, for
the assessment of ventilatory constraint, further studies are necessary
to determine which indexes (eg, the presence of flow
limitation, degree of flow limitation, change in IC, or some other
index) will represent the most sensitive markers of
E limitation. A combination of the NEP
technique along with traditional estimates of breathing reserve and use
of the extFVL may provide the greatest amount of information on
E constraints imposed by the lung and
chest wall.
Although the use of NEP and the plotting of the tidal FV loops are
fairly easily applied techniques that advance our understanding of
E limitation in various populations without the need
for more invasive studies (ie, esophageal and gastric
balloons), other factors that may contribute significantly to exercise
limitation involving the pulmonary system clearly cannot be negated
(ie, the work and cost of breathing, pulmonary hemodynamics,
pulmonary influences on cardiac function, varying perceptions of
dyspnea, and gas-exchange abnormalities).
Exhaled NO Measurement
NO is a highly reactive molecule formed by the enzyme NO synthase (NOS) from the precursor amino acid L-arginine. It was first described as an endogenous endothelium-derived nitrovasodilator that acts by directly activating guanylate cyclase, leading to increased cytosolic guanylate monophosphate by forming a reversible adduct with the heme moiety of the enzyme. Similarly, it may be readily inactivated by hemoglobin or cytochromes; thus, NO released into the blood stream is rapidly scavenged. It is a colorless gas that also can be carried in solution in plasma or in lipid membranes. In gaseous form, NO reacts directly with oxygen to form N2O, but in the absence of oxygen it can be quite stable. Its half-life in biological media is also quite short.
The roles of NO in physiologic processes are still being elucidated. It acts as a neurotransmitter in many tissues, including the nonadrenergic noncholinergic nervous system that innervates the pulmonary airway. There are at least four isoforms of the enzyme NOS: three constitutive forms and one inducible form. The constitutive forms require calcium for activation and produce a steady background low level of NO, whereas the inducible form of NOS is not calcium dependent and plays a role in adaptive processes such as inflammation. In the lung, the constitutive enzymes are found in endothelial cells, epithelial cells, smooth muscle cells, and inflammatory cells.
Given the presence of NOS in many of the cell types of the lung, it should be no surprise that NO can be measured in exhaled air.32 Since the first description of NO in exhaled air, much work has been done to characterize the source of NO and to correlate exhaled NO with various disease states. It is important to distinguish exhaled concentration of NO (usually expressed in parts per billion) from NO output (usually expressed in nanograms per minute). Moreover, mixed expired NO must be distinguished from instantaneous NO measurements. Exhaled NO can thus be documented in at least four ways: the NO output, the mixed expired NO, and either peak NO or end-expiratory NO. NO output from the lungs reflects a balance of pulmonary production less the diffusion of NO across the capillaries into the blood. The European Respiratory Society has issued guidelines for measurement of expired NO33 in an effort to standardize the technique and to optimize detection of pulmonary rather than nasal NO.
Where is the exhaled NO coming from? Exhaled NO was documented in isolated lung perfused with blood-free medium, indicating that the NO was not derived from the circulation. The nose is a significant source of NO that can be admixed in gas sampled at the mouth.34 The specific cell that produces the measured NO has not been clearly defined, though most investigators assume the source of NO is either the epithelial cell, the endothelial cell, or nonadre-nergic, noncholinergic neurons, although mast cells, macrophages, and eosinophils could also be significant sources.
There have been numerous studies correlating exhaled NO to various disease states (Table 4 ). Because the technical details of isolating lower from upper airway contributions have progressed simultaneously with correlations against disease states, much of this work bears repeating with standard methods.33
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Laboratory Requirements
The cost of NO analyzers is currently quite high, in the
range of $20,000 to $40,000. Most analyzers were designed for
monitoring the delivery of NO, so they are not designed for
documentation of exhaled NO. The ideal instrument for measuring exhaled
NO would be easy to calibrate and maintain, and it would be integrated
into a system with a mouth pressure transducer and a flowmeter to
monitor exhaled volume, and possibly a flow restrictor to reduce nasal
contamination and to control for the effects of exhaled flow on the
level of NO. Computer software would allow the display of concentration
vs time graphs and the calculation of various parameters from the
tests. Such instruments are just starting to become available. Thus, to
set up exhaled NO measurement for clinical or research applications,
one may need a high level of expertise in setting up instrumentation,
and in acquiring and analyzing data.
In conclusion, the measurement of exhaled NO is a potentially useful test that could be performed in the setting of routine pulmonary function testing to document the state of airway inflammation in patients with asthma. The test appears to be relatively specific for inflammation related to airway eosinophilia and could prove to be a useful indicator of the effectiveness of antiinflammatory therapy in asthma. However, standard methods must be used to avoid contamination by the nose and to standardize the effects of expiratory flow on the measurement. Furthermore, large population studies using standard methods would be useful to determine precise population 95% confidence intervals for the measurement.
FO Resistance Measurement
Resistance to the movement of gas is calculated from the ratio of pressure change to flow. Resistance is of interest from both a basic science and a clinical perspective because it is an important determinant of the work of breathing (WOB). Total resistance of the respiratory system is a lumped sum of resistance to movement of lung tissue (Rti) and airway resistance (Raw) to the flow of gas. The sum of Rti and Raw for the lung is often called lung or pulmonary resistance. The measurement of Raw would seem to be the most clinically useful parameter as it reflects the state of the airways, though Rti is increasingly recognized as contributing significantly to the WOB at normal breathing frequencies. However, separating these two components of resistance requires very technically demanding or highly invasive techniques that are available only in animal laboratories.
To determine Raw, one needs to know instantaneous values for flow and the pressure that drives flow through the airways at multiple points in the breathing cycle. Body plethysmographs report the average Raw of the entire airway tree from mouth to the "average" alveolus. Plethysmographs are large and expensive, and some patients find it difficult to perform the panting maneuver required for procedure. Thus, a technique to measure resistance that would involve smaller, cheaper equipment and that would be easy to use for both patients and technical personnel potentially would be useful in a clinical setting.
The FO technique has the potential to fill this need. With FO, resistance of the pulmonary system (ie, airways, lung, and chest wall) is determined by imposing known variations in flow at the mouth and by measuring the resultant pressure changes. Early studies used pure sine waves at fixed frequency, though later studies probed with multiple frequencies to find the resonant frequency (the point at which compliance effects and inertial effects cancel, giving pure flow resistance). In the early 1970s, techniques were developed to probe a frequency range of interest with a more complex forcing function, using either "white noise" (a sound wave with a uniform representation of frequencies,37 ) or a series of brief impulses in flow at the mouth.38 With both innovations, the patient was required only to breathe quietly while the imposed forcing function was applied and measurements were made over a period of about 1 min. Because the frequency of the imposed oscillations was much higher than that of the patients’ breathing, the effects of the normal breathing cycle could be subtracted out. White noise and flow impulses both contain a range of frequencies, and mathematical techniques were used to separate out the individual frequency components to determine frequency dependence of the resistance and compliance. The equipment, mathematical analysis, and data-handling techniques have been technically very demanding for both these techniques. Recently, several manufacturers have made impressive efforts to miniaturize the equipment and to automate the data analysis and data handling to improve the user-friendliness of the FO technique. The equipment involved is considerably smaller than the body plethysmograph, and equipment setup and calibration have been automated so that technical personnel with little training can use the equipment. However, the investigator must be aware of what resistance value these devices are reporting and of both the physiologic and technical limitations of the technique (Table 5 ).
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There are several potential advantages of the FO technique over both spirometry and plethysmography (Table 6 ). The technique has potential advantages for challenge testing, as multiple tests at many dose levels will be easier to tolerate for the patient.40 41 However, the investigator must realize that the test does not require a deep inspiration. There is increasing evidence that a major defect in asthma is the reduced or paradoxical response to deep inspirations or sighs. Challenge testing without deep inspiration reduces the difference between patients with asthma and healthy subjects.42 A thorough comparison study must include dose-response determination in both healthy subjects and patients with asthma using FO and spirometry on separate days (with and without deep inspirations).
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Will these devices replace spirometry or plethysmography in the routine testing laboratory? Probably not, in the near future. Several studies have shown results of FO testing to be no more sensitive than spirometry in detecting disease or in correlating with symptoms.43 44 Because standard reporting procedures are not firmly established, and because there are only a few large population studies showing the range of normal and the patterns of abnormality with disease, the interpretation of the data should be performed very conservatively.
In conclusion, the determination of pulmonary resistance parameters using FO is a technique that has been in development for nearly 30 years, but recent efforts at automating the technique may make it available for wider clinical application. The potential advantages of FO include the ability to measure lung function with minimal patient effort, making testing available in the very young or in patients unable to perform spirometry or plethysmographic resistance tests, and the ability to separate resistance components of the system (upper airway vs lower airway). At their current state of development and validation, these tests do not replace existing pulmonary function tests.
Acknowledgements
The authors would like to thank Dr. Mark Wylam for reviewing the section on exhaled NO and Audrey Schroeder for preparation of the manuscript.
Footnotes
Abbreviations: EELV = end-expiratory lung volume;
EILV = end-inspiratory lung volume; extFVL = tidal flow-volume loop
measurement during exercise; FO = forced oscillation;
FV = flow-volume; IC = inspiratory capacity; IRV = inspiratory
reserve volume; MFVL = maximal flow-volume envelope; MVV = maximum
voluntary ventilation; NEP = negative expiratory pressure;
NO = nitric oxide; NOS = nitric oxide synthase; Raw = airway
resistance; Rti = resistance to movement of lung tissue;
TLC = total lung capacity; E = minute
ventilation; VT = tidal volume; WOB = work of breathing
This research was supported by National Heart Lung and Blood Institute Grant No. HL-52230 and Department of Health and Human Services grant No. M01RR00585.
References
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