Author: Richard Johnston

After a couple years of waiting for the new methacholine standards to be released “any day now”, they were finally published in this month’s issue of the European Respiratory Journal. The standard is an open access article and can be downloaded by anyone.

The length of time taken to develop the standard was acknowledged and although active ATS participation was withdrawn because the original timeline was not met, for the most part the original ATS participants continued with the task group and the standard has been officially endorsed by the ATS.

The biggest difference between the 1999 standards and those from 2017 is the change from PC20 (provocative concentration causing a 20% decline in FEV) to PD20 (the provocative dose causing a 20% decline in FEV1) as the primary endpoint and this alone will make a difference in how methacholine challenges are performed and calculated.

The 1999 standard included both tidal volume and dosimeter protocols. The dosimeter protocol consisted of 5 breaths to TLC. The 2017 standards state that a dosimeter may be used but that this is primarily to make counting breaths and calculating the cumulative dose easier and that inhalations to TLC are specifically contraindicated due to “the bronchodilating or bronchoprotective effect of a maximal inspiratory manoeuvre with a breathhold at TLC”.

Other differences include:

• The 1999 standard had both absolute and relative contraindications. There are only contraindications in the 2017 standard.
• Absolute contraindications in the 1999 standards included an FEV1 < 50% of predicted (or < 1.0 L, age group unspecified) and for the 2017 standard it is an FEV1 < 60% of predicted (or 1.5 L, adults) which were relative contraindications in 1999.

• The section on technician safety is essentially identical in both the 1999 and 2017 standards, but when discussing exhalation filters the 1999 standards included a diagram of typical nebulizer-filter configurations (page 311, bottom) and the 2017 standard does not.
• Although the 1999 standards imply the use of a mouthpiece with a nebulizer this is never explicitly stated. The 2017 standard mentions the use of a face mask but states that a mouthpiece is preferred.
• In the 1999 standard patients were asked to withhold shorting-acting bronchodilators (albuterol, etc) for 8 hours prior to testing. This has been changed to 6 hours in the 2017 standard.
• In the 1999 standard patients were asked to withhold ipratropium (Atrovent) for 24 hours prior to testing. This has been changed to 12 hours in the 2017 standard.
• In the 1999 standard patients were asked to withhold long acting bronchodilators (salmeterol) for 48 hours prior to testing. This has been changed to 36 hours in the 2017 standard.
• The 2017 standard asks patients to withhold ultra-long acting beta agonists (indacterol, vilanterol, olodaterol) for 48 hours prior to testing. These medications did not exist in 1999.
• The 1999 standard asked patients to withhold cromones (nedocromil, cromolyn sodium) and leukotriene modifiers anywhere from 24 to 72 hours before testing. The 2017 standards state that it is not necessary to withhold these medications.
• The 1999 standard recommended that coffee, tea, cola drinks, chocolate be withheld the day of testing. The 2017 standard states “Normal dietary servings of caffeine and caffeine-related products (e.g. chocolate) have no effect of clinical significance…”.
• The 1999 standard stated that antihistamines (specifically hydroxazine and cetirizine) needed to be withheld 3 days ahead of testing. The 2017 standard states that “Antihistamines do not effect methacholine response.”
• The 1999 standard asked that patients “refrain from smoking for a few hours before
• testing.” The 2017 standards ask that subjects should refrain from drinking alcohol 4 hours before testing (not mentioned in the 1999 standard) and smoking 1 hour before testing.
• The 2017 standard states “Influenza vaccination, the menstrual cycle and oral contraceptives do not significantly affect airway responsiveness”. These topics were not discussed in the 1999 standard.
• Both the 1999 and 2017 standards included both 2-fold and 4-fold dilution protocols. In the 1999 standard the 2 fold dilutions were to be used with the 2-minute tidal breathing technique and the 4 fold dilutions with the dosimeter protocol. The 2017 standard indicates that the 2 fold dilution protocol is more useful in research and probably too time consuming for clinical testing.
• In the 1999 standard the 4-fold dilution protocol stopped at 0.0625 mg/ml (5 concentration steps). The 2017 4-fold dilution protocol stops at 0.015625 mg/ml (6 concentration steps).
• In the 1999 standard performing the first challenge inhalation with the diluent alone was “optional”. In the 2017 standard it is “recommended, particularly if this is the first challenge test for the patient, and to ensure there is no excessive AHR” (i.e. Airway Hyper Responsiveness).
• The 1999 standard primarily specified the use of the English Wright nebulizer for the 2-minute tidal breathing protocol and the Devilbiss 646 nebulizer for the dosimeter protocol but did note that any nebulizer with a particle mass median diameter (MMD) between 1μm and 3μm was acceptable. The 2017 standard notes that these nebulizers are no longer readily available and instead recommends that any nebulizer whose particle size distribution (although it’s unclear whether this is the same as the MMD) is ≤ 5μm can be used.
• In the 1999 standard nebulizer output was measured by changes in weight over time (page 315, bottom of column 2). The 2017 standard indicates that this approach is inaccurate because “most of the weight loss is from evaporation rather than the output of methacholine” and recommends that nebulizer output should be “measured by collection on a filter” and provided by the device manufacturer.
• The 1999 standard stated the particle size distribution for the Wright nebulizer (although interestingly not for the Devilbiss) but does not say how this was determined. The 2017 standard mentions that particle size can be measured either by “laser diffraction or inertial impaction techniques” but since this technology is out of the reach of most (if not all) PFT labs this also implies that it is the responsibility of the nebulizer manufacturer to provide this information.
• The 1999 standard suggested that the tidal breathing method should be performed for 2 minutes. The 2017 standard states that with high-output nebulizers this period can and should be shortened. In particular, it notes that for each concentration level of methacholine there is actually a specific dose target (table 4, top of page 7) and attaining this target will depend on both the nebulizer output and the subject’s cumulative inhalation time.
• In the 1999 standard, if the subject’s FEV1 decreased by ≤ 20% then albuterol was to be administered and after a 10 minute wait, spirometry was performed again. In the 2017 standard it is a 5-10 minute wait.
• The 1999 standard included the method for calculating PC20 using logarithmic interpolation (page 318). PD20 is mentioned only once and that is in the sentence “…PC20 was selected as the outcome variable because it is simple to calculate and avoids the complicated and controversial aspects of estimating a provocative dose PD20.” (last sentence, section J, page 318).
• Although the 2017 standard mentions PC20 frequently it does not indicate how PC20 should be calculated. The methods for calculating PD20 by logarithmic interpolation are included in Appendix E however the numerical values used will depend on the actual nebulizer output, length of testing, the use of dosimeter vs tidal breathing and assumptions about Ti/Ttot.
• The 1999 standard categorized the response to methacholine based on PC20 alone. The 2017 standard categorizes response primarily with the PD20 but in table 6 (page 14) includes both PC20 and PD20. In addition the 1999 standard had 4 response categories (Normal bronchial responsiveness, Borderline BHR, Mild BHR (positive test), Moderate to severe BHR). The 2017 standard has 5 categories (Normal, Borderline AHR, Mild AHR, Moderate AHR, Marked AHR).
• Interestingly, both the 1999 (figure 3, page 318) and 2017 (figure 2, page 14) standards used exactly the same graph to illustrate the pre- and post-test probability of asthma but labeled it using PC20 in the 1999 standard and PD20 in the 2017 standard.
• The 1999 standard included an FEV1 quality scoring system (page 317, section I, column 1) based on acceptability and repeatability. This is not present in the 2017 standard.
• The 1999 standard discusses the use of airway resistance and impulse oscillometry as alternatives to FEV1 but suggests that these “should be used primarily in patients who cannot perform acceptable spirometry maneuvers”. The 2017 standard raises this issue as well but states that there “is substantially less supporting research and standardisation; hence, these methods are beyond the scope of these guidelines.”

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Overall, the number of changes from the 1999 standard are small and for this reason it is hard to understand why the process of developing the 2017 standard took as long as it did. Even so, the update is welcome and will help clarify a number of ongoing questions and issues surrounding methacholine challenge testing.

As already noted the biggest change is the use of PD20 instead of PC20. I have some reservations about this, partly because even though the scientific evidence in favor of this is reasonably clear it has actually been studied relatively few times (interestingly the decision to use PD20 appears to be based on a single research study [Drotar DE et al] and just as much on the fact that it makes it easier to compare results from different nebulizers and inhalation protocols).

In addition, the effect that body (and lung) size has on PD20 does not appear to have ever been studied. It would seem to me that even though the calculated PD20 for a 160 cm, 55 kg female and a 185 cm 100 kg male might well be the same, the larger individual has more airway surface area and the amount of methacholine per square centimeter (or however you want to measure it) is less than it is for the smaller individual.

I was also disappointed in the appendices (D and E) concerning the calculation of PD20 and would have preferred to see a more comprehensive algorithm taking a hypothetical nebulizer’s output and showing the steps necessary to calculate the inhaled dose and PD20. It may not be rocket science but being more explicit would have been helpful particularly given that the emphasis on PD20 is new.

In addition, the need to calculate the inhaled dose means that we somehow have to measure inspiratory time and respiratory rate during methacholine challenges. There is no easy way to measure inspiratory time and for this reason most everybody will default to a Ti/Tot of 0.40, since that is what the 2017 standard mentions.

The authors note that PD20 is dominated by the last delivered dose and that in fact a PD20 calculated using only the final dose is as accurate as using the dose accumulated from all prior concentration levels. The 2017 standard approach towards calculating PD20 is actually a logarithmic interpolation using only the last two doses (ignoring all previous concentration levels) which probably doesn’t affect results overall but does call into question exactly what the PD20 is.

Finally, despite measuring nebulizer particle size and output, and estimating the total delivered dose, we have to be honest with ourselves and realize that we have no idea how much methacholine is actually deposited on the airways, nor do we know which airways it is being deposited on. This means there will always be some uncertainty about interpreting results regardless of whether we are using PC20 or PD20.

I do however I applaud the movement away from the Wright and Devilbiss nebulizers. When brand new the output characteristics of these nubulizer were reasonably well known, but they are both re-useable devices and after several cleanings who can say what their output really is?

I also applaud the demise of the 5-breath dosimeter protocol. It, and in particular the calculation of a PD20 using the nebulous dose units (i.e. cumulative concentration x breaths), always seemed like pseudo-science to me.

Less clear to me however, is how easy it’s going to be to find the output characteristics for disposable nebulizers. As important as it may be I’ve never seen the particle size distribution of a nebulizer included in any sales literature. Hopefully this information is on file somewhere and now that it is a requirement in the 2017 standards it may be more forthcoming.

Anybody who performs methacholine challenges needs to read the new standards and to revise their procedures accordingly. At the same time though, we should take a moment and reflect on what it is we’re really trying to measure with a methacholine challenge. A number of years ago the medical director I had at that time said that internists and general practitioners ordered methacholine challenge tests to rule-in asthma and that pulmonary doctors ordered them to rule asthma out.

This difference in attitudes can be seen to some extent in the two standards. In 1999 the standard stated that “the most common clinical indication for MCT is to evaluate the likelihood of asthma in patients in whom the diagnosis is suggested by current symptoms but is not obvious.”. The last paragraph of the 2017 standard however states that “In summary, the major value of direct airway responsiveness challenge is to exclude a diagnosis of current asthma. Positive challenges are consistent with but not entirely diagnostic of asthma and must be interpreted in conjunction with the presence of other features of asthma or other respiratory diseases.”

So, update your procedures but keep in mind the limitations of the test and that knowing why you’re performing it shapes the answers it gives.

References:

Coates AL, Wanger J, Cockcroft DW et al. ERS technical standard on bronchial challenge testing: general considerations and performance of methacholine challenge tests. Eur Respir J 2017; 49: 1601526

Drotar DE, Davis BE, Cockcroft DW. Dose versus concentration of methacoline. Ann Allergy 1999; 83: 229-230.

Guidelines for methacholine and exercise challenge testing – 1999. Am J Respir Crit Care Med 2000; 161: 309-329

PFT Blog by Richard Johnston is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License

Inspiratory and expiratory flow rates are a function of driving pressure (i.e. the pressure difference between the alveoli and the atmosphere) and airway resistance. For this reason it would seem that airway resistance should be one of the most commonly performed pulmonary function tests but instead it is the outcome of airway resistance and driving pressure, i.e. the expiratory and inspiratory flow rates that are measured almost exclusively. One reason for this is that resistance measurements requires relatively expensive equipment such as a body plethysmograph or an impulse oscillometer as well as a fair amount of technical expertise.

The airflow perturbation device (APD) is a potentially inexpensive system for measuring respiratory resistance during tidal breathing. The device itself is mechanically simple, the concepts and mathematics that permit it to work are, however, a bit more complicated.

The APD consists of a mouth pressure transducer and a pneumotach whose end is attached to a rotating wheel. The wheel has open segments and segments with a mesh that partially obstructs airflow through the pneumotach. The rotation of the wheel causes a series of perturbations to the airflow through the pneumotach.

When the mesh obscures the airflow, mouth pressure rises and the flow rate decreases.

In some senses this is similar to occlusion resistance measurements (R_OCC) however, airflow is not occluded abruptly, it instead diminishes steadily (the developers suggest that airflow should be reduced no more than 30%) and then increases steadily as the section of the wheel with the resistance rotates past the pneumotach.

The system software uses linear interpolation using the pre- and post-perturbation flow and mouth pressure to determine what the developers call “virtual” data. Using the “virtual” and “real” data the changes in flow and mouth pressure (∆flow and ∆pressure) that occur during a perturbation are calculated. These measurements are averaged over approximately 100 perturbations before resistance is actually calculated.

The calculations start with a formula that describes the respiratory system:

Where:

P_muscle = respiratory muscle pressure

P_mouth = mouth pressure

C_resp = respiratory compliance

V = lung volume

R_resp = respiratory resistance

V’ = flow rate

I_resp = respiratory inertance

V’’ = volume acceleration

The developers note that the effects of inertance (inertia) during tidal breathing is very small and that volume acceleration is zero at peak perturbation. In addition both “real” and “virtual” compliances and lung volumes is identical during a perturbation. For these reasons the formula can (eventually and after a number of intermediate steps) be simplified and re-written as:

Research with Forced Oscillation has shown that respiratory resistance is frequency dependent and decreases significantly from 0 hz to 2 hz and then remains flat up to about 10 hz. The wheel rotation rate of the most recent version of the APD is set to provide approximately 10 perturbations/second. Experimentally frequencies of 2.2 hz, 4.4 hz, 6.7 hz have been tested and the measured resistance was not significantly different for any of these rotation rates.

In a study with a small number (7) of subjects APD measurements were shown to be highly repeatable with an intrasession coefficient of variability (COV) of 4.0%. Day to day results actually showed lower variability (COV 1.8%) but repeatability over a longer time period (week to week) was somewhat poorer (COV 7.2%) but given the small sample size this may also be due to actual changes in resistance over that period.

One advantage of the APD is that it is able to differentiate between inspiratory and expiratory resistance. Another is that it is able to tolerate small to moderate leaks around the mouthpiece without substantially affecting the results although subjects are usually expected to breathe on the APD using a mouthpiece and noseclips. In one study the APD was been used with a oronasal mask to determine nasal resistance. The same study showed no significant difference in respiratory resistance when mouth breathing (with nasal passages were occluded) using the mask was compared to breathing through a mouthpiece.

The APD has been tested with experimentally induced vocal cord dysfunction and showed changes in resistance that correlated well with glottal area as measured by a laryngoscope. The APD has also been used during exercise which may be useful for assessing exercise-induced bronchospasm and exercise-induced vocal cord dsyfunction although doing this precludes the simultaneous measurement of ventilation and gas exchange.

One study showed that the resistance measured by plethysmograph was lower than that measured by APD. Specifically a group of 20 subjects had a range of 0.45 to 1.39 cmH2O L/sec by plethysmography and a range of 2.17 to 3.90 cmH20/L/sec for average resistance by APD. A larger study of 272 patients routinely referred to a pulmonary function lab was different and showed an average APD resistance of 3.0 cmH2O/L/sec versus 3.3 cmH2O/L/sec for plethysmography. Although statistically there is little difference between these two values the scatter is actually quite large which calls into question the statistical relevance of the averaged values.

Plethysmographic and APD resistances are expected to be different however, and that is because there are airway, lung tissue and chest wall components to resistance. The resistance measured in a plethysmograph is considered to be primarily airway resistance. Airway and lung tissue resistance (pulmonary resistance) can be measured by techniques that use an esophageal balloon. Impulse Oscillometry (IOS) and the APD measure a combination of airway, lung tissue and chest cage resistance which is considered to be respiratory resistance.

Even though both APD and IOS both measure respiratory resistance and a study with 10 healthy subjects performing both IOS and APD showed a highly linear correlation between the two, there was also a systematic difference in the results with the APD resistance being on average 1.29 times larger than the IOS P5 (5 hz) resistance. The reason for this systematic difference is unclear. Using a physical model with calibrated resistances the researchers noted that IOS underestimated and APD overestimated the actual resistance and speculated that this may be due in part to differences in compliance.

Despite the number of years that the APD has been around in one form or another (it was originally described in 1974, originally patented in 1980 and re-patented in 2000), there is little information about its clinical utility. In the previously mentioned study of 272 patients routinely referred for pulmonary function testing the correlation between FEV1 and APD resistance was low. Moreover when FEV1 and APD resistance were graphed against each other the point scatter was quite large.

It should be noted that in the same study RAW measured by plethysmograph also had a low correlation with FEV1 (although slightly higher than the APD) and to some extent this is one of the problems with resistance regardless of how it is measured. Even though the FEV1 and RAW are interrelated the fact that they are measuring different things and are dependent on different factors has been pointed out by numerous researchers.

In addition even though the plethysmographic measurement of RAW was first described in 1956 the interpretation of RAW is far from straightforward and this is because it is dependent on both lung volume and the frequency it is measured at. This is the reason that sRAW, GAW and sGAW are often included in the reported results, but it also has made understanding their meaning and significance more difficult.

My personal experience has been that RAW measurements have a high degree of variability within any given individual and the selection of specific test results influences the reported RAW. Although there are quality indicators for RAW maneuvers these are often hard to apply (in particular my lab software does not let us select separate resistance slopes for inspiration and expiration) and I suspect that this may bias the way in which results are reported.

IOS systems have also been around for decades and although they have made some inroads into routine clinical testing a recent discussion of IOS on the AARC diagnostics forum indicates that many labs have abandoned their use, most often because their physicians don’t know how to interpret the results. In large part I think the reason for this it that technical discussions of oscillometry (and for that matter the airflow perturbation device) are often presented using the terminology of electrical circuitry (resistance, inductance, capacitance and impedance). This is because the mathematics that underlies these terms both electrically and physiologically are essentially identical. Having had some education in electronics I can follow these discussions to some extent (although I’ll be the first to admit I have to work at it in order to follow certain arguments) but at the same time I think that these descriptions and explanations are disconnected from the standard terminology of pulmonary physiology and this tends to make it difficult to understand them.

The APD is an interesting approach towards measuring respiratory resistance. It is certainly easier to use and would probably be much less expensive than plethysmography and IOS systems. There is also some reason to believe that APD results would be more reproducible and have less selection bias than RAW measurements. I have some reservation about the simplification of the mathematics that underpins the APD and about its use for anything other than quiet tidal breathing but the real problem the developers of the APD face is proving its clinical relevance. In particular unless they can show that it has some utility in diagnosing and managing pulmonary disorders in a way that cannot be performed by spirometry it is unlikely it will ever come into common use.

References:

Dubois AB, Botelho SY, Comroe JH: A new method for measuring airway resistance in man using a body plethysmograph: values in normal subjects and in patients with respiratory disease. J Clin Invest 1956; 35(3): 327-335

Johnson AR, Chapain P, Slaughter D, Gallena S, Vossoughi J. Inspiratory and expiratory resistances during exercise. Brit J Medicine & Med Res 2013; 3(4): 1222-1232.

Gallena SK, Tian W, Johnson AT, Vossoughi J, Sarles SA, Solomon NP. Validity of a new respiratory resistance measurement device to detect glottal-area change. J Voice 2013; 27(3): 299-304.

Haque T, Vossoughi J, Johnson AT, Bell-Ferrell W, Fitzgerald T, Scharf SM. Resistance measured by airflow perturbation compared with standard pulmonary function measures. Open J Respir Dis 2013; 3: 63-67.

Lausted CG, Johnston AT. Airflow perturbation device for measuring human respiratory resistance. Proceedings of the IEEE 1998; 97-99.

Lausted CG, Johnson AT. Respiratory resistance measured by an airflow perturbation device. Physiol Meas 1999; 20: 21-35.

Lemert J, Goldman MD, Johnson A, Vossoughi J, Silverman N, Saadeh CK. Portable handheld airflow perturbation device reflects forced oscillation resistance in children with asthma. Chest 2008; 130(4): 241S (Meeting Abstracts).

Lewis OD, Whitesell P, Whitesell J, Granger W, Vossoughi J, Johnson A. Changes in respiratory measurements with the airflow perturbation device and integrated pulmonary index in patients enrolled in cardiac and pulmonary rehabilitation. Chest 2016; 150(4) Supplement: p1123A

Lopresti ER, Johnson AT, Koh FC, Scott WH, Jamshidi S, Silverman NK. Testing limits to airflow perturbation device (APD) measurements. BioMed Eng Online 2008; 7: n28

Pan J, Saltos A, Smith S, Johnson A, Vossoughi J. Comparison of respiratory resistance measurements made with an airflow perturbation device with those made from impulse oscillomtry. J Med Eng 2013; Article Id 165782.

US Patent 4220161.

US Patent 6066101.

Vossoughi J, Johnson AT, Silverman NK. In-home hand-held device to measure respiratory resistance. Proceedings of the 1^st Distributed Diagnosis and Home Healthcare Conference, 2006, 12-15.

Wong LS, Johnson AT. Decrease of resistance to air flow with nasal strips as measured by the airflow perturbation device. BioMed Eng Online 2004; 3: n38.

I was contacted recently by an individual with some questions about the pulmonary function testing needed for a Social Security Disability evaluation. With a small amount of research I was able to answer their questions but this brought up an interesting point and that is that despite the number of patients we see every year my lab only rarely performs any pulmonary function testing for disability evaluations. The reason I know this is because the Social Security Administration (SSA) has very specific requirements for the content and form of pulmonary function reports and we are very rarely asked for these reports.

The pulmonary function tests the SSA uses as part of a disability evaluation are:

• Spirometry
• Diffusing Capacity (DLCO)
• ABG
• Pulse Oximetry

Interestingly, lung volume measurements are not included. This is not specifically explained but it appears to be because evaluation for restriction is covered by the criteria for FVC and FEV1.

For all pulmonary function tests the SSA requires that the individual be medically stable, which they define as not:

• Within 2 weeks of a change in prescribed respiratory medication.
• Experiencing, or within 30 days of completion of treatment for, a lower respiratory tract infection.
• Experiencing, or within 30 days of completion of treatment for, an acute exacerbation of a chronic respiratory disorder.
• Hospitalized, or within 30 days of a hospital discharge, for an acute myocardial infarction (heart attack).

The performance and quality criteria for spirometry and diffusing capacity are essentially identical to the ATS/ERS standards. For spirometry, there needs to be three acceptable tests and acceptable is defined as:

“maximum effort following a full inspiration, and when the test tracing has a sharp takeoff and rapid rise to peak flow, has a smooth contour, and either lasts for at least 6 seconds or maintains a plateau for at least 1 second.“

Spirometry results are evaluated using the largest FVC and FEV1. There are no published requirements for repeatability but I strongly suspect that any reviewer presented with poorly reproducible results would consider this an indication that the person in question is not giving their best effort.

SSA requires post-bronchodilator spirometry if the FEV1 is less than 70% of predicted but does not specify which reference equations are used for this purpose nor does it specify which bronchodilator should be used.

The SSA requires the numerical results and the volume-time tracing (no flow-volume loops) from all three acceptable spirometry tests along with age, gender and height without shoes, along with the date of the tests. Arm span should be reported if the individual has kyphoscoliosis or other musculo-skeletal disorder that limits their ability to obtain an accurate height. Each of the volume-time graphs must be identified with the subject’s name and the date of the tests.

For DLCO the SSA requires at least two acceptable quality tests, which is defined as:

• Inspired volume at least 85% of FVC and that inspiration is less than 4 seconds.
• Breath-hold time of 8-12 seconds.
• Adequate washout volume (0.75 – 1.00 L when FVC ≥ 2.00 L and 0.50 L when FVC < 2.00 L)
• Adequate exhalation time (4 seconds for washout, 3 seconds for alveolar sample).
• The DLCO tests must be repeatable tests which is defined as within 3 mL CO (STPD)/min/mmHg of each other or within 10 percent of the highest value.

Somewhat surprisingly, DLCO results are to be reported without any correction for hemoglobin. This was not explained and given that anemia could be at least partly responsible for reduced DLCO results it’s unclear why this is the case.

The numerical DLCO results are reported along with

“…legible tracings of your VI, breath-hold maneuver, and volume of exhaled gas…”

As with spirometry, the subject’s age, gender and height without shoes needs to be reported. Arm span can be substituted for standing height if necessary. Each DLCO graph needs to identified with the subject’s name and date of testing.

ABGs must be performed at rest on room air without supplemental oxygen. The SSA does not have any requirements for how long somebody needs to be off their supplemental O2 but most labs ask their patients to be off their O2 for 15 to 30 minutes before an ABG and this should probably be adequate.

The SSA will accept an exercise ABG but specifies that it should be taken under steady-state conditions with no change in treadmill speed and elevation for at least 4 minutes. The treadmill speed and elevation is also supposed to be set for the equivalent of 5 mets (i.e. a VO2 of 17.5 ml/kg/min) which will likely limit which individuals can have this type of testing performed. If an individual is unable to exercise at this workload for 4 minutes then this needs to be documented along with the reason(s) they were unable to exercise long enough.

Only the PaO2 and PaCO2 (no pH), and the altitude or location (city and state) where the ABG sample was taken needs to be reported.

Pulse oximetry also needs to be performed while an individual is off any supplemental O2. The SSA requires that SpO2 measurement be stable, which they define as:

“…the range of SpO2 values (that is, lowest to highest) during any 15-second interval cannot exceed 2 percentage points.”

Depending on the apparent cause of the pulmonary disability the SSA may also require a graphical printout from a pulse Oximeter. Specifically:

“A graphical printout showing your SpO2 value and a concurrent, acceptable pulse wave. An acceptable pulse wave is one that shows the characteristic pulse wave; that is, sawtooth-shaped with a rapid systolic upstroke (nearly vertical) followed by a slower diastolic downstroke (angled downward).”

Pulse oximetry can be performed at rest, during a 6MWT or following a 6MWT and the SSA will use the lowest value. Results need to include the altitude or location (city and state).

The SSA webpage specifically discusses how asthma, cystic fibrosis, bronchiectasis, pulmonary hypertension, lung transplantation, respiratory failure, sleep related disorders are evaluated. Although COPD and Pulmonary Fibrosis are mentioned at various points they appear to be lumped together and evaluated as “chronic respiratory disorders”. The published rules are somewhat complicated (the SSA webpage should be consulted for specifics) and I suspect that there are a number of unwritten rules that could only be determined by looking at a number of case outcomes. For these reasons successful applications probably require at least some expert assistance.

How the pulmonary function results results are evaluated depends to some extent on what is causing the disability. For example the criteria for FVC and FEV1 are slightly different depending on whether the disability is due to chronic lung disease, asthma or cystic fibrosis. An adult (≥ 20 years) 5’ 9” (175 cm) male with COPD would need an FEV1 ≤ 1.75 L or an FVC ≤ 2.20 L. For the same person with asthma or cystic fibrosis an FEV1 would need to be ≤ 2.30 L (and FVC is not taken into consideration).

Pulmonary function results are in a sense the first stage of a disability evaluation, which is to prove the existence of an impairment. Simply because an individual meets one or more requirements in a disability evaluation does mean they will receive SSA disability status. As the SSA states:

“Once the existence of an impairment is established, SSA considers all evidence from all medical and nonmedical sources to assess the extent to which a claimant’s impairment(s) affects his or her ability to function in a work setting; or in the case of a child, the ability to function compared to that of children the same age who do not have impairments. Nonmedical sources include, but are not limited to: the claimant, educational personnel, public and private social welfare agency personnel, family members, caregivers, friends, neighbors, employers, and clergy. “

When we perform pulmonary function testing for a disability evaluation it is in the best interests of the patient that we meet all of the test quality and reporting guidelines. Whether we admit it or not, we have some wiggle room in routine clinical testing and by that I mean that after numerous tries we can (and will) accept the one good spirometry effort a patient was able to perform. When testing is for a disability evaluation however, if all the reported tests do not meet the quality, repeatablity and reporting requirements then this will significantly reduce the likelihood the patient will be able to receive a disability status, regardless of how badly they need it.

I’m still not sure why my lab gets so few patients for disability evaluations. This could be partly due to the referral patterns of local disability lawyers and physicians. It could also be due to the fact that most individuals with a pulmonary disability are older and already receiving Social Security benefits. But I also suspect that there are a lot of people who could qualify for SSA disability based on their pulmonary function results that don’t know they could.

The SSA has been criticized both for denying disability status for individuals that appear to have a clear need for it and for granting disability status to individuals who clearly don’t. In the first hospital I worked at my PFT lab usually got several disability evaluations every month and I have seen a full spectrum of applicants which has ranged from seriously ill individuals who were desperate to prove they were well enough to go back to work to obvious slackers who didn’t try to hide the fact that they were looking forward to sitting on a couch and watching TV for the rest of their lives. The problem we face is that the coaching we perform can significantly affect the results and this can leave us with the temptation to help – or hinder – an individual with their testing in order to get the results they “need”. But with disability testing in particular (and all testing in general) we shouldn’t perform any testing or report any results that we wouldn’t be willing to defend in a court of law. I say this not because I believe that has any particular probability of happening (it’s actually pretty unlikely) but more because it’s our responsibility to be a neutral party in this process and to do the best we can to get accurate and repeatable results.

PFT Blog by Richard Johnston is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License

About a month or so ago I was corresponding with the manager of a small PFT lab and in response to one of their questions I had mentioned that there were no CPT codes for MIP/MEP. They responded with “what’s a CPT code?” so I guess this means that CPT codes aren’t as well known as I thought they were.

CPT stands for Current Procedural Terminology and is managed by the American Medical Association. CPT codes are a relatively universal way to classify and describe all medical tests and procedures. They are also used by all insurance companies for medical billing so one downside to this is if there isn’t a CPT code for a test or a procedure, you can’t bill for it. CPT codes also include conditions that limit performing (or at least billing for) some tests in various combinations and to some extent this drives the way PFT tests are ordered and performed.

The CPT codes are reviewed, revised and updated annually. There have been a number of additions and changes to PFT CPT codes during the last five to ten years, and I’d say that with a few notable exceptions, most current PFT testing is adequately covered by the CPT codes. The current PFT CPT codes are:

CPT:	Description:	Exclusions:
94010	Spirometry, including graphic record, total and timed vital capacity, expiratory flow measurement(s), with or without maximum voluntary ventilation.	Do not report in conjunction with 94150, 94200, 94375, 94728.
94011	Measurement of spirometry forced expiratory flows in an infant or child through 2 years of age
94012	Measurement of spirometry forced expiratory flows, before and after bronchodilator, in an infant or child through 2 years of age.
94013	Measurement of lung volumes (i.e., functional residual capacity (FRC); forced vital capacity (FVC), and expiratory reserve volume (ERV) in an infant or child through 2 years of age.
94014	Patient-initiated spirometry recording per 30 day period of time; includes reinforced education, transmission of spirometry tracing, data capture, analysis of transmitted data, periodic recalibration and review and interpretation by a physician or other qualified health professional.
94015	[patient-initiated spirometry] recording (includes hook-up, reinforced education, data transmission, data capture, trend analysis, and periodic recalibration).
94016	[patient-initiated spirometry] review and interpretation only by a physician or other qualified health professional.
94060	Bronchodilator responsiveness, spirometry as in 94010, pre- and post-bronchodilator administration.	Do not report in conjunction with 94150, 94200, 94375, 94728. For prolonged exercise test for bronchospasm with pre- and post-spirometry use 94620.
94070	Bronchspasm provocation evaluation, multiple spirometric determination s as in 94010, with administered agents (eg. antigen(s), cold air, methacholine).

CPT:	Description:	Exclusions:
94150	Vital capacity, total (separate procedure).	Do not report in conjunction with 94010, 94060, 94728.
94200	Maximum breathing capacity, maximum voluntary ventilation.	Do not report in conjunction with 94010, 94060.
94250	Expired gas collection, quantitative, single procedure (separate procedure).
94375	Respiratory flow volume loop	Do not report in conjunction with 94010, 94060, 94728.
94400	Breathing response to CO2 (CO2 response curve).
94450	Breathing response to hypoxia (hypoxia response curve).	For high altitude simulation test (HAST) see 94452, 94453.
94452	High altitude simulation test (HAST) with interpretation and report by a physician or other qualified health professional.	Do not report in conjunction with 94453, 94760, 94761.
94453	[HAST] with supplemental oxygen titration.	Do not report in conjunction with 94452, 94760, 94761.
94620	Pulmonary stress test simple (eg. 6-minute walk test, [or] prolonged exercise test with pre- and post- spirometry and oximetry.
94621	Pulmonary stress test, complex (including measurement if CO2 production, O2 uptake, and electocardiographic recordings).
94680	Oxygen uptake, expired gas analysis, rest and exercise, direct, simple
94681	[Oxygen uptake] including CO2 output, percentage oxygen extracted.
94690	[Oxygen uptake] rest, indirect (separate procedure).
94726	Plethysmography for determination of lung volumes and when performed, airway resistance.	Do not report in conjunction with 94727.
94727	Gas dilution or washout for determination of lung volumes, and when performed distribution of ventilation and closing volume.	Do not report in conjunction with 94726.
94728	Airway resistance by impulse oscillometry	Do not report in conjunction with 94010, 94060, 94070, 94375, 94726.
94729	Diffusing capacity (eg. Carbon monoxide, membrane).	Must be reported in conjunction with 94010, 94060, 94070, 94375, 94726, 94727 or 94728.
94750	Pulmonary compliance study (eg. Plethysmography, volume and pressure measurements).
94760	Noninvasive or pulse oximetry for oxygen saturation, single determination.
94761	[Oximetry] multiple determinations (eg. During exercise).
94762	[Oximetry] by continuous overnight monitoring (separate procedure).
94799	Unlisted pulmonary service or procedure.
95012	Nitric oxide expired gas determination.
95070	Inhalation bronchial challenge testing (not including necessary pulmonary function tests); with histamine, methacholine or similar compounds.	For pulmonary function tests see 94060, 94070
95071	For pulmonary function tests see 94060, 94070	For pulmonary function tests see 94060, 94070

ABG associated CPT codes:

CPT:	Description:
36600	Arterial puncture, withdrawal of blood for diagnosis
36620	Arterial catheterization or cannulation for sampling, monitoring or transfusion (separate procedure), percutaneous.
82375	[Blood] Carboxyhemoglobin, quantitative
82800	[Blood] gases, pH only
82803	[Blood] gases, any combination of pH, pCO2, pO2, CO2, HCO3 (including calculated O2 saturation).
82805	[Blood] with O2 saturation, by direct measurement, except pulse oximetry.
82820	[Blood] Hemoglobin-oxygen affinity (pO2 for 50% hemoglobin saturation with oxygen).

Hgb Finger stick CPT codes:

CPT:	Description:
88738	Hemoglobin (Hgb), quantitative, transcutaneous.
88740	Hemoglobin, quantitative, transcutaneous, per day, carboxyhemoglbin
88741	[Hemoglobin, transcutaneous] methemoglobin.

There are a number of exclusions for different CPT codes and since a number of CPT codes contain combinations of other CPT codes much of this makes sense. You shouldn’t, for example, bill for spirometry (94010) when you’re also billing for pre- and post-BD spirometry (94060).

The exclusion for diffusing capacity (94729) however, is unusual in that it requires that a DLCO test be performed along with spirometry (which includes pre & post bronchodilator and challenge tests), lung volumes or impulse oscillometry. To some extent I understand this since the quality of a DLCO test depends on inspired volume (VC from spirometry) and VA (TLC from lung volumes) but I don’t quite get the connection with impulse oscillometry.

Interestingly, you can’t bill for impulse oscillometry (94728) if you perform any form of spirometry (94010, 94060, 94070, 94375) or plethysmography (94726). I can see why this might be the case for plethysmography since that CPT code includes airway resistance measurements (RAW) which could be considered a duplication, but it’s not as clear why any form of spirometry would be a duplication as well.

You can bill for an SVC (94150) or an MVV (94200) if they are performed by themselves but if you perform plain spirometry (94010) along with an SVC or an MVV you will only be reimbursed for the spirometry.

On the other hand, for a methacholine challenge test you can bill using both 94070 (spirometry testing) and 95070 (administration of methacholine). Similarly a cold air challenge (and probably a Eucapnic Voluntary Hyperventilation Challenge) could be billed using 94070 (spirometry) and 95071 (administration).

Based on some correspondence I’ve had in the past, there is a bit of confusion regarding 94620. The wording for this code could have been clearer since it used for either for a 6-minute walk test or for a simple exercise test (usually a bronchspasm evaluation for EIB) with pre- and post-exercise spirometry. Unfortunately 94620 has been read by a number of people as saying that a 6-minute walk test requires pre- and post-spirometry and for this reason I don’t know why separate CPT codes weren’t assigned to the 6-minute walk and the exercise challenge test.

There are a number of common pulmonary function tests however, that have no CPT code or cannot be billed because of exclusions. Most notoriously, as already mentioned, there is no CPT code for MIP or MEP and the best you can do is to charge it under 94799 (unlisted pulmonary service or procedure). This is hard to understand given that the ATS released standards for respiratory muscle testing in 2002 and that MIP and MEP were a significant part of that, but despite this there is still no CPT code for respiratory pressure measurements (MIP, MEP, NIF and SNIP).

There is also no CPT code for upright and supine spirometry. For that matter, if you perform a complex CPET (94621) pre- and post-exercise spirometry is not included with that CPT code (even though it is for 94620) but you can only bill for simple spirometry (94010).

There are a couple of somewhat leading edge tests for which equipment is being sold that have no CPT codes. Admittedly some of these tests could be considered to be more in the research arena than in clinical testing, but the lack of a CPT code is also an impediment towards the widespread adoption of the tests, even when they have been shown to be clinically useful.

As an example, even though the ERS/ATS has released standards for DLNO testing you can bill for it using the diffusing capacity CPT code (94729) only if you simultaneously perform a DLCO since the code explicitly mentions carbon monoxide and not nitric oxide. This also means that despite the extra cost of performing combined DLCO and DLNO testing, you really aren’t able to bill for it.

If you wanted to perform Lung Clearance Index (LCI) testing you would probably be able use 94727 (gas dilution or washout for determination of lung volumes) because it includes the phrase “… and when performed, distribution of ventilation …” and because FRC is also measured (although not TLC and RV) as part of the test. But that means that if you use this code for LCI you can’t bill for separate lung volume measurement even if you do so by plethysmograph (94726).

You couldn’t however, use 94727 if you wanted to perform a dual-tracer gas single breath washout (DTG-SBW) or a Closing Volume (for the phase III slope) since there is no lung volume measurement included in these tests and that is a required part of 94727.

Overall the CPT codes work relatively well for most common PFT testing situation but I still have a couple concerns. First, some of the descriptions are either ambiguous, poorly worded or rely on somewhat outdated terminology which makes it difficult at times to determine how the codes should be applied to certain situations.

Second, CPT codes are acting as an arbiter forwhich tests can be performed. A particular example is the lack of CPT codes for MIP/MEP as well as other tests that are in the process of advancing into routine clinical testing, such as DLNO, LCI and DTG-SBW. There are ATS/ERS standardization statements that have touched on most of these tests (MIP/MEP 2002, LCI 2013, DLNO 2017) but realistically it is the presence or absence of CPT codes that is determining what is and isn’t clinically relevant.

Third, CPT codes are also acting as an arbiter about how testing is performed. Although I understand and in general agree with many of the exclusions, they also limit what tests can be performed within a single testing session. There are likely legitimate clinical reasons why you’d want to perform impulse oscillometry (for airway resistance) and plethysmography (for lung volumes) but the exclusions for 94726 and 94728limits reimbursement if they are performed in the same day.

CPT exclusions can also be a dis-incentive towards performing more comprehensive patient testing. SVC testing should be performed as part of routine spirometry whenever there is any question that the FVC is being underestimated but if you do this you have to accept that you won’t be reimbursed for the extra time and effort. Ditto for upright and supine spirometry. Ditto for post-exercise spirometry for CPETs.

To its credit, the procedure for revising CPT codes is a consensus-based, evidence-driven process. But this also means that it is often slow and requires a significant time commitment for anybody requesting a change. Instructions for requesting an update to the CPT codes are on the AMA website (Applying for CPT codes). Notably, the application for requesting a new code or a revision of an older code is about 20 pages long and more than somewhat formidable in that it requires extensive knowledge and documentation concerning the subject in question.

CPT codes are a fact of life and if they didn’t already exist we’d probably re-invent them sooner rather than later. Since the way we are reimbursed for testing is determined by CPT codes and their exclusions we generally have to work within the framework they have created. This doesn’t mean that they are always right however, nor should they be taken as the final word about what is clinically relevant.

References:

Abraham M et al.  Current Procedural Terminology CPT 2015.  Published by the American Medical Association, 2014.

ATS/ERS statement on respiratory muscle testing. Amer J Respir Crit Care Med 2002; 166(4): 518-624.

Birnbaum, S. Pulse oximetry. Identifying its applications, coding and reimbursement. Chest 2009; 135(3): 838-841.

Flesch JD, Dine CJ. Lung volumes. Measurement, clinical use and coding. Chest 2012; 142(2): 506-510.

Lange NE, Mulholland M, Kreider ME. Spirometry. Don’t blow it! Chest 2009; 136(2): 608-614.

Robinson PD et al. ERS/ATS consensus statement. Consensus statement for inert gas washout measurement using multiple- and single-breath tests. Eur Respir J 2013; 41(3): 507-522.

Salzman, SH. The 6-min walk test. Clinical and research role, technique, coding and reimbursement. Chest 2009; 135(5): 1345-1352.

Zavorsky GS et al. Standardisation and application of the nitric oxide single-breath determination of nitric oxide uptake in the lung. Eur Respir J 2017; 49: n1600962.

PFT Blog by Richard Johnston is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License

Okay, this may be wrong but at the moment I’m can’t seem to find a reason why it should be. A report like this came across my desk a couple of days ago.

	Observed:	%Predicted:	Post-BD:	%Predicted:	%Change:
FVC:	4.59	94%	4.87	100%	+6%
FEV1:	3.38	89%	3.58	94%	+6%
FEV1/FVC:	73.6	95%	73.5	95%	0

Not particularly unusual and it would usually be interpreted as being within normal limits without a significant post-BD change. If you calculate the FEV1/VC ratio using the pre-BD FEV1 and the post-BD FVC however, it’s 89% of predicted and this indicates mild airway obstruction. But you’re not supposed to use the post-BD FVC this way, are you?

Well, why not?

The ATS/ERS standards for spirometry states:

“The largest FVC and the largest FEV1 (BTPS) should be recorded after examining the data from all of the usable curves, even if they do not come from the same curve.”

The ATS/ERS standards for interpretation further states:

“An obstructive ventilatory defect is a disproportionate reduction of maximal airflow from the lung in relation to the maximal volume (i.e. VC) than can be displaced from the lung.”

Nowhere does it say that the VC can’t come from a post-BD FVC. The vital capacity is a relatively fixed value based on rib cage dimensions and the distance the diaphram can travel and bronchodilators do not change this. Any increases that are seen in a post-BD FVC are almost always related to a reduction in airway resistance and gas trapping, and not to a change in lung volume. This being the case, a VC is a VC, regardless of when it is measured.

The ATS/ERS standards for interpretation seconds this point of view to some extent when it states:

“The VC, FEV1, FEV1/VC ratio and TLC are the basic parameters used to properly interpret lung function. Although FVC is often used in place of VC, it is preferable to use the largest available VC, whether obtained on inspiration (IVC), slow expiration (SVC) or forced expiration (i.e. FVC).”

So other than saying that’s not the way it’s supposed to be done, why can’t you use the post-BD FVC this way? If you accept the idea that the FEV1/IVC ratio and FEV1/SVC ratio are valid approaches to determining the presence of airway obstruction you are also accepting the idea that the FVC is often underestimated as a consequence of airway obstruction. If you accept this idea, then why isn’t the post-BD FVC as valid a measurement of VC as IVC and SVC?

I can’t think of a reason why not and the ATS/ERS standards for spirometry and interpretation don’t explicitly forbid it. They don’t explicitly approve it either, but once you accept the notion of using the FEV1/VC ratio instead of the FEV1/FVC ratio it becomes a relatively logical consequence of that train of thought.

The downside (or is it the upside?) of using the pre-BD FEV1/post-BD FVC ratio is that some individuals whose spirometry would otherwise be considered to be within normal limits would instead be considered to have mild airway obstruction. I’d point out however, that this is also what would probably happen if SVC was routinely measured and the FEV1/SVC ratio reported instead of the FEV1.

So, why isn’t the post-BD FVC used this way right now? I think the answer is mostly psychological. Pretty much from the beginning of modern spirometry in the 1950’s post-BD testing has been performed only to compare FVC to FVC and FEV1 to FEV1. Although the ATS/ERS standards mandated the use of the FEV1/VC ratio (with the VC coming from the SVC, IVC or FVC, whichever was largest) a dozen years ago, this is recent history and the idea still hasn’t trickled completely down to all PFT labs and all pulmonologists. Even with the mandate from the ATS/ERS SVC and IVC maneuvers are performed much less frequently than FVC maneuvers so most practitioners aren’t in the habit of making substitutions. This adds up to a sort of institutional blindness and I will admit to having been part of it because I’ve been in the field for over 40 years and this is the first time it ever occurred to me.

This issue really only applies when the baseline FEV1/FVC ratio is withn normal limits. I can’t find any logical reason not to insert a post-BD FVC into the FEV1/VC ratio and if it increases the number of individuals diagnosed with airway obstruction then I don’t think this is any different than it would be if we performed SVC maneuvers as part of routine spirometry.

References:

Brusasco V, Crapo R, Viegi G. ATS/ERS Task Force: Standardisation of lung function testing. Standardisation of spirometry. Eur Respir J 2005; 26: 319-338.

Brusasco V, Crapo R, Viegi G. ATS/ERS Task Force: Standardisation of lung function testing. Interpretive strategies for lung function tests. Eur Respir J 2005; 26: 948-969.

PFT Blog by Richard Johnston is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License

Over the last couple of weeks I’ve had an unusual number of patients with expiratory plateaus on their flow-volume loops. Expiratory plateaus are usually considered to be a sign of an intrathoracic central or upper airway obstruction and several of these patients had a diagnosis of tracheomalacia but many of them didn’t. Expiratory (and inspiratory) plateaus are mentioned in the ATS/ERS standards for interpretation but since there isn’t a specific definition (other than “plateau”), an expiratory plateau is a “know it when you see it” sort of thing.

The word plateau tends to imply that the flow-volume loop is both flat and level. Most textbook examples of an expiratory plateau tend to show a flow-volume loop that has been perfectly truncated, usually something like this:

or this:

but it usually isn’t that simple. An expiratory plateau is a consequence of a flow limitation, but during a forced exhalation the diameter of the airways decreases as the lung volume decreases from TLC towards RV. Depending on what is causing the flow limitation the plateau isn’t necessarily flat or level.

So it’s necessary to be a bit flexible when assessing a flow-volume loop for the presence of an expiratory plateau. But given the variability seen in routine spirometry, it’s possible for a subject to produce a single flow-volume loop that looks like it has an expiratory plateau and yet have this feature missing from their remaining spirometry efforts. For this reason the ATS/ERS statement on interpretation also states:

“at least three maximal and repeatable … expiratory flow curves are necessary..”

but this also leaves the definition of repeatability in the air. Repeatability is therefore also a “know it when you see it” sort of thing. These spirometry tests show good reapeatability:

So there’s probably no question that these subjects have an expiratory plateau. These spirometry tests on the other hand show only fair repeatability:

For these subjects it’s not as clear their expiratory plateau is “real”, but they’re probably repeatable enough to be acceptable. These spirometry tests however, show poor repeatability:

and the variability of these flow-volume loops is large enough that any apparent expiratory plateau is more likely due to poor effort than to an actual expiratory flow limitation.

One interesting question is how repeatable are expiratory plateaus over time? This probably depends on what the underlying cause is. Since close to half the patients we see with an expiratory plateau have a diagnosis of tracheomalacia and are seen in the Airway Clinic that’s run by the hospital’s CardioThoracic Division. The clinic’s surgeons implant airway stents and do tracheal re-constructions so the contour of these patients’ flow-volume loops often changes dramatically from one visit to another.

While searching our records for trends in expiratory plateaus however, I found an interesting progression:

These flow-volume loops come from a patient with a diagnosis of SOB and were performed at approximately roughly6-month intervals over a period of about 2 years. The FEV1, FVC and FEV1/FVC ratios were always within normal limits and did not change significantly from visit to visit but the contour progresses from one that has a very clear expiratory plateau to one that would be considered to be normal. The “shoulder” in the final series of flow-volume loops is even similar to the flow-volume loop labeled as normal in the ATS/ERS standards for spirometry:

This could of course just be the resolution of whatever was causing the expiratory flow limitation over time (which was never explicitly diagnosed), but it has been suggested that a “shoulder” on a flow-volume loop, even though it is “normal”, may actually a sign of flow limitation. What this makes me wonder is whether some individuals that have a “shoulder” on their flow-volume loop would at one time or another also show an expiratory plateau.

The presence of an expiratory plateau is to some extent in the eye of the beholder. Despite some staff education on my part when I see an expiratory plateau mentioned in the technician notes at all it’s usually that they were “blunted peak flows”. From my point of view a “blunted peak flow” is a low, rounded flow-volume loop with no sign of flattening. This is usually an indication of an inadequate patient effort and I don’t think this looks a lot like an expiratory plateau at all.

This probably means I need to improve the staff education about expiratory plateaus but despite seeing so many expiratory plateaus recently and despite the fact that we see a number of patients from the Airway Clinic that have them they usually aren’t that common. There’s also the fact that good expiratory plateau reproducibility is actually somewhat rare. Fair reproducibility (at best) is a lot more common so to some extent I can understand their confusion.

Expiratory plateaus are a sign of an intrathoracic central or upper airway obstruction. The causes of this kind of obstruction are varied and range from tracheomalacia to goiter and airway tumors. An expiratory plateau is not specific to any one of these conditions however, and does not accurately predict the site or extent of the obstruction. For this reason the ATS/ERS standards for interpretation states:

“…endoscopic and radiological techniques are the next step to confirm this dysfunction.”

Since the FVC and FEV1 often remain normal until the plateau and peak flow are moderately reduced, this form of airway obstruction that can usually only be diagnosed from the contour of the flow-volume loop. For this reason an expiratory plateau should never be ignored but at the same time it needs to be repeatable in order to be sure it isn’t just a fluke.

References:

Brusasco V, Crapo R, Viegi G. ATS/ERS Task Force: Standardisation of lung function testing. Standardisation of spirometry. Eur Respir J 2005; 26: 319-338.

Brusasco V, Crapo R, Viegi G. ATS/ERS Task Force: Standardisation of lung function testing. Interpretive strategies for lung function tests. Eur Respir J 2005; 26: 948-969.

PFT Blog by Richard Johnston is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License

I had finished reviewing a pre- and post-BD spirometry report yesterday and was about to toss it on my out pile when I noticed something a bit odd about the post-BD results. I pulled it back and spent some time trying to decide if the interpretation needed to be changed but after a lot of internal debate I finally let it go as it was. I’ve continued to think about it however, and although I’m not sure that was the right decision I still haven’t come up with a clear answer.

Here’s what I saw:

	Observed:	%Predicted:	Post-BD:	%Predicted:	%Change:
FVC:	3.70	97%	3.91	103%	+6%
FEV1:	2.82	94%	2.79	93%	-1%
FEV1/FVC:	76	95%	71	89%	-6%
PEF:	6.62	94%	7.19	102%	+9%
Exp. Time:	10.92		11.15

The reported pre-BD and post-BD results were from good quality tests and met the criteria for repeatability. My problem is that the baseline results were normal but if I had seen the post-BD results by themselves I would have considered them to show mild airway obstruction.

So what’s going on here? The results from baseline spirometry aren’t anywhere close to the borderline for airway obstruction, no matter which guidelines you use. There was a small post-BD increase in FVC (+6%) but since the ATS/ERS standards for a significant post-bronchodilator change in FEV1 or FVC is ≥12% and ≥200 ml it isn’t significant. The post-BD decrease in FEV1 was also small (-1%) and well within normal test-to-test variability, but when you put the small increase in FVC together with the small decrease in FEV1 suddenly the FEV1/FVC ratio below the LLN.

Does that mean these results show airway obstruction? One argument in favor of this is that the GOLD standards for spirometry only consider the post-BD results. The basic point of this as I see it is that since COPD is expected to have little or no bronchodilator response, this allows asthma to be ruled out as the cause of obstruction. But obstruction was only in the post-BD results, not the baseline results, so I’m not sure this applies.

The ATS/ERS interpretation algorithm also only looks at the baseline results when assessing results for obstruction and only assesses post-BD results for significant improvement.

Could the decrease in the FEV1/FVC ratio be a side-effect of albuterol? We usually use albuterol as our bronchodilator and some individuals are sensitive to it and bronchoconstrict instead of bronchodilating (read the product insert and you’ll find that this is one of the possible side-effects). This occurs in probably less than 1% of the population but I see it a couple times a year. In this case though, even though there was a small post-BD decrease in FEV1 there was a larger increase in FVC without any significant change in expiratory time, and this means there was probably more bronchodilation than bronchoconstriction.

One final point is that post-BD changes are only assessed using the FEV1 and FVC, not the FEV1/FVC ratio. If the pre-BD and post-BD results were reversed, even though the individual would have gone from mild airway obstruction to normal, the bronchodilator response still wouldn’t have been called a significant.

This situation doesn’t seem to be covered by any of the guidelines. On the one hand, if the pre-BD and post-BD results were reversed I’d have no hesitation about saying the results showed mild airway obstruction. On the other hand, the baseline spirometry was normal, the decrease in FEV1 was well within normal test-to-test variability and the increase in FVC was not significant. In the end I had to let it go as normal spirometry mostly because I couldn’t find any way to legitimately use the post-BD FEV1/FVC ratio. That doesn’t mean I haven’t second-guessed that decision a half dozen times since then, but since I keep second-guessing the second-guessing, I’ve let it stand.

Even though I couldn’t come up with any clarity for this situation what this does show is the effect that FVC can have on the FEV1/FVC ratio. When individuals respond to a bronchodilator it’s usually the FEV1 that increases and any increases in FVC are relatively small. Post-BD increases in FVC without any increase in FEV1 are relatively rare and when seen it’s almost always in individuals who’s baseline shows severe airway obstruction. When individuals have post-BD bronchoconstriction it’s usually fairly clear and usually both the FVC and FEV1 are affected. In this case however, the baseline spirometry was normal and the post-BD changes were just ambiguous enough that I don’t think there ever could be a clear answer.

PFT Blog by Richard Johnston is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License

 

Recently I was reviewing a report that included helium dilution lung volumes. What caught my eye was that the TLC and the FRC didn’t particularly fit in with the results from the other tests the patient had performed.

Test:	Observed:	%Predicted:
FVC:	2.83	114%
TLC:	3.03	71%
FRC:	0.88	39%
RV:	0.09	5%
SVC:	2.93	118%
VA:	3.64	88%

When compared to the FVC and the VA (from the DLCO test) the lung volumes are significantly lower. In particular the FRC and RV are markedly reduced. This is somewhat unusual for helium dilution lung volume since most errors usually cause FRC, RV and TLC to be over-estimated instead of being under-estimated. When I checked the other reports for the day I found that two other patients that had had their lung volumes measured on the same test system also had a TLC, FRC and RV that were noticeably reduced. Obviously we had some kind of equipment problem with that test system but it took a bit of sleuthing before I found out what had happened.

Like all lung volume tests, the helium dilution technique produces a lot of numbers, most of which are not included on the report. One of the first things I did was to call up the within-test data (our test systems store data every 15 seconds during the test and re-calculate FRC each time).

Time:	FRC, Liters	He conc. (%)	Ve (L./min.)	Vt, Liters
0:15	-1.00	9.71	6.16	0.21
0:30	0.06	8.87	10.1	0.59
0:45	0.43	8.61	11.76	0.78
1:00	0.69	8.44	9.05	0.72
1:15	0.76	8.39	8.18	0.74
1:30	0.79	8.37	8.32	0.59
1:45	0.82	8.36	8.15	0.62
2:00	0.83	8.35	7.79	0.65
2:15	0.86	8.33	5.51	0.62
2:30	0.87	8.32	5.34	0.63
2:45	0.88	8.32	0	0

When looking at this it was immediately evident there was a problem because the initial FRC was negative and this shouldn’t be possible. About the only way that helium dilution lung volumes can normally be underestimated is if the test is terminated way too early and the negative FRC ruled this out. It also narrows down the possible problems, but I had to think for a while and in doing so had to go back to the basics of the helium dilution test.

Helium dilution used to be the most common method for measuring lung volumes, but it requires a closed-circuit test system with a volume displacement spirometer. Most current test systems are open-circuit flow sensor-based systems and lung volumes are usually measured by nitrogen washout (or by plethysmography). Nevertheless, there are a couple of closed-circuit systems still being manufactured and there are a fair number of these systems still in service.

The basic concept behind the helium-dilution method is very simple and depends on the fact that helium is an inert and (and more importantly) insoluble gas. The dilution test could work with any highly insoluble gas but helium is relatively cheap and it’s easy to measure with a high degree of linearity (and reasonable accuracy) using an inexpensive katharometer (thermal conductivity) gas analyzer. You start with a system that has a known volume and a known concentration of helium:

You then connect the known system to another one that has an unknown volume and where the concentration of helium is zero. When the helium concentration has equilibrated between both systems, there will be a new and lower concentration of helium.

The unknown volume can then be calculated by:

Where:

Volume1 = original system volume
Volume2 = unknown volume
Helium1 = original helium fractional concentration
Helium2 = ending helium fractional concentration

When measuring lung volumes it’s a little more complicated than this, and there are a lot more steps in the process. One reason for the number of steps is that although katharometers tend to be highly linear unless they are calibrated with a known concentration of helium they aren’t necessarily all that accurate. Fortunately, linearity is far more important than accuracy and that is because the ratios of different helium concentrations can be used for the various calculations.

Stage 0: The closed-circuit is first flushed with air and the helium analyzer is zeroed.

Stage 1: The manifold valves close the circuit off from external circulation. Air and helium are then added to the closed circuit and after the helium concentration has equilibrated throughout the circuit, the first helium reading is taken.

Stage 2: A specific volume of air is added to the closed circuit and a second helium reading is taken after the helium concentration has re-equilibrated.

Stage 3: The patient goes on a mouthpiece and is switched into the closed circuit at end-exhalation. After several minutes of quiet breathing the helium concentration reaches a new equilibration and the third helium reading is taken.

FRC is then calculated from:

The volume of the closed-circuit at the end of stage 2 can also be calculated from ratios. Specifically:

So when you are done with a test you have a number of helium readings and a circuit volume. When I looked at these, and compared them to those from a patient whose helium dilution lung volumes looked okay and had been tested on a different system, there really wasn’t much difference:

	Low LV:	Normal LV:
Helium1:	12.31%	12.46%
Helium2:	9.87%	9.99%
Helium3:	8.32%	8.23%
System Volume (L):	10.24	10.22

One of the possibilities I considered was that helium was slowly leaking into the closed-circuit during the test. A leak would decrease the change in helium concentrations during equilibration and therefore decrease the calculated FRC, but the helium3 readings didn’t appear to be all that different between patients and test systems.

In order to be sure however, I asked one of the techs to do their own lung volumes on the test system in question but specifically asked them wait a couple of minutes between the time the system had finished setting itself up and the time they started the test. If there was a slow leak then waiting would cause the initial helium reading during the test to be higher than the helium2 reading. That turned out not to be the case and the tech’s FRC and TLC were pretty much the same as the last time they did their biological QC.

When calculating FRC you also need to subtract the system dead space (valve manifold + mouthpiece filter) so it was possible that somebody had inadvertently changed this (not supposed to be possible since you need administrative rights to do this, but still worth checking). If the dead space had somehow been set to somewhere between 0.5 and 1.0 liters that would explain both the initially negative and the reduced FRCs. When checked, these values had not been changed, however.

That didn’t mean there hadn’t been a glitch of some kind so I went into the database and looked at all the helium dilution FRC test records from that day. When I did this I found out two things. First, the mouthpiece filter dead space was in the FRC database records and it hadn’t been changed. Second however, the valve manifold dead space was not in the database records and this raises an interesting question of where it is being stored and retrieved from. There are several possibilities; that it is stored and retrieved from individual test systems, which means that if the results were retrieved on a different test system that had a different valve manifold dead space, would the calculated FRC be different? Or was the valve manifold dead space being retrieved from a different test (DLCO?). Or is it possible that the programmers didn’t think valve manifold dead space was an issue in the helium dilution FRC calculations? This isn’t in the manual (of course it isn’t, why would you expect testing details like this to be there?) so it’s a question I’ll have to follow up on sometime in the future.

When looking at the FRC database records however, one value immediately stood out, and that was the switching error. There was a marked increase in the switching error for all the patient’s whose FRC and RV were low.

	Low LV:	Normal LV:
Switching Error (L):	1.15	0.05

Switching error is the difference between the patient’s tidal end-exhalation volume and the volume where they were switched into the closed-circuit. It’s a positive number if the patient is switched in above the end-exhalation baseline, and negative if below.

Subjects are supposed to be switched into the closed-circuit as close to FRC as possible so the switching error should be close to zero, but in this case it was a lot closer to a liter. It’s unlikely that this is actually what happened for a couple reasons. First, the patient’s tidal breathing was closer to 0.50 L so even if they were switched into the circuit at end-inhalation the switching error still wouldn’t have been as high as it was. Second, the technician performing the tests has more than 10 years of experience and this is not the kind of error they would make, particularly not on three patients in a row.

Unfortunately, even though the system reports the switching error, it does not store any of the baseline tidal breathing so it’s not possible to go back and check to see if the switch-in was performed correctly or not. Since this problem has not showed up again since that day I am far more inclined to believe it was a transient glitch of some kind, either in the test system software or its hardware.

When I corrected the patient’s FRC, RV and TLC for the switch-in error the results were far more believable. This was an interesting problem that I had not noticed previously. That doesn’t mean it hasn’t happened before, just that I haven’t noticed it. In the future however, every time I look at the raw data for helium dilution lung volumes I will check to make sure the initial FRC value is not negative and that the switching error is within reasonable limits.

PFT Blog by Richard Johnston is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License

The European Respiratory Society has just published the first standards for DLNO testing. This is a signal that DLNO is moving from a research setting into routine clinical testing. Although it is unlikely that most PFT labs will immediately jump into DLNO testing, the standard is still interesting because of an extensive discussion of DLNO, DLCO, DMCO and Vc measurements and physiology. The DLNO standards (and their supplementary material) are open-access and can be downloaded from the European Respiratory Journal.

DLNO is performed in the same manner as a single-breath DLCO and it is specifically recommended that DLCO and DLNO tests be performed simultaneously. There are however, specific test system requirements based both on the properties of NO and on the two types of NO analyzers:

• Nitric Oxide reacts with oxygen to form NO2 and at the levels used for DLNO testing (40-60 ppm) does so at a rate of approximately 1.2 ppm per minute. DLNO test gas is therefore usually stored as 400-1200 ppm NO in N2 and mixed into the DLCO test gas mixture (0.3% CO, 21% O2) ≤2 min before the DLCO/DLNO test. This would seem to require that the DLCO/DLNO test gas mixture to be held in a reservoir of some kind and to preclude the use of a demand valve but this was not specifically discussed. Because of uncertainties that occur when mixing the DLCO/DLNO gas mixture and in how long the mixture may be held in the reservoir the inspired NO concentration must also be measured immediately before the DLCO/DLNO test is performed.

• The type of NO gas analyzer will determine how the expiratory gas concentrations are measured. Chemiluminescent analyzers usually have a response time on the order of ≤70 msec, and for these reasons can be used to perform a real-time analysis of exhaled air. Chemiluminescent analyzers are expensive however, and can add significantly to the cost of a test system. Electrochemical cells are significantly less expensive but have a response time on the order of 10 seconds and are therefore suitable only to test systems that mechanically collect an alveolar sample.

• Breath-holding times of between 4 and 10 seconds have been used in DLNO research. The DLNO standard notes that breath-holding time affects the measurement of DLNO and DLCO, particularly when a ventilation inhomogeneity is present. In particular it was noted that shorter breath-hold times tended to overestimate DLCO and underestimate VA. However, it also has been noted that the exhaled NO concentration is approximately 5% of the inspired concentration after a 5 second breath-hold and 1% after a 10 second breath-hold. Electrochemical NO analyzers are less sensitive (a resolution of approximately 0.5 to 1.0 ppm) than chemiluminescent analyzers (which have a resolution of 0.5 ppb). For this reason the DLNO standards recommend that a 4-6 second breath-hold period be used with electrochemical NO analyzers whereas a 10 second breath-hold can be used with chemiluminescent analyzers.

• If DMCO and Vc are being calculated the expired alveolar O2 concentration must be measured so that 1/θCO can be calculated.

The standards for CO and NO analyzer linearity, accuracy and drift are essentially identical to those of the 2017 DLCO standards. The same applies for flow and volume accuracy and the need for daily volume calibrations. Recommendations that differ to one extent or another from the 2017 DLCO standards are:

• The gas analyzers should be zeroed before each test and the zero should be re-measured after the test. Results should be adjusted for any drift. The inspired NO concentration should be measured just before the test.

• A VA measurement check by performing a DLCO/DLNO test using a calibration syringe pulled back to the 1 liter mark is recommended. VA should be between 2.7 and 3.3 liters with the syringe dead space substituted for anatomical dead space. At the same time DLCO should be <0.5 ml/min/mmHg and DLNO should be <3.0 ml/min/mmHg.

• Hemoglobin correction for DLNO results is not recommended but corrections in DLCO for hemoglobin and COHb remain the same.

• Biological QC should be performed weekly. Differences from prior mean values should be ≤5.0 ml/min/mmHg for DLCO and ≤20.0 ml/min/mmHg for DLNO.

• The CO, NO and insoluble gas (He, CH4, Ne) analyzers should be tested monthly for linearity using serial dilutions of know gas concentrations.

Patient preparation and the DLNO testing maneuver is identical to that of the DLCO. Measuring the breath-holding period using the Jones-Meade approach is recommended. Washout and alveolar volumes are also the same as for DLCO testing. Intra-session and inter-session repeatability and reproducibility for DLCO appears to be slightly less stringent than for the 2017 DLCO standards but this may be partly due to the range of acceptable breath-holding times (5-10 seconds) for DLNO testing.

Roughton and Forster’s work on DLCO in the 1950’s showed that diffusing capacity was a series resistance with a membrane component and a blood component:

Where:

DMCO = alveolar-capillary membrane conductance

Vc = pulmonary capillary blood volume

θCO = rate at which CO is taken up by red blood cells

Early work showed that in normal subjects DLNO is approximately 5 times larger than DLCO. This is partly due to the fact that the difference in tissue diffusivity of NO is 1.97 times that of CO and because the reaction rate of NO with hemoglobin is approximately 1500 times faster than CO. In addition because NO does not compete for O2 binding sites on hemoglobin NO uptake is mostly independent of FiO2. In a sense DLNO is not excessively high, DLCO is low mostly because CO uptake is highly dependent on the pulmonary capillary blood volume and the alveolar oxygen concentration. NO uptake is however, more dependent than CO uptake is on alveolar surface area and lung volume.

Clinically DLNO is primarily related to membrane conductance and DLCO is primarily related to Vc. For this reason, the most common way of expressing the differences in these measurements for a given individual is the DLNO/DLCO ratio. Decreases in the DLNO/DLCO ratio tend to correlate with decreases in membrane conductance and/or increases in pulmonary capillary blood volume whereas increases in the DLNO/DLCO ratio correlate with increases in membrane conductance and/or decreases in pulmonary capillary blood volume.

In the early stages of COPD the DLNO/DLCO ratio has been shown to rise, while in established COPD the ratio appears relatively normal (although both DLNO and DLCO are reduced). In Cystic Fibrosis the DLNO/DLCO ratio is reduced. A reduced DLNO/DLCO ratio has also been shown in Sarcoidosis. Elevated DLNO/DLCO ratios have been found in hepatopulmonary sundrome and heart failure.

In many ways the clinical use of DLNO and the DLNO/DLCO ratio is still in its early stages and comparison between different studies is made more difficult because different DLNO measurement techniques have often been used. The DLNO standard itself notes:

“…disease-specific patterns of DLNO and DLCO, DLNO/DLCO and Vc will remain imprecise until more clinical studies are reported using a standardised technique.”

A set of DLCO and DLNO reference equations was developed from the data of four different studies but was not presented within the standards. They were however, included in a supplementary materials spreadsheet that was designed to calculate the percent predicted DLCO, DLNO, DMCO and Vc from test results. From this spreadsheet the DLNO reference equations are:

DLNO (Male) = (0.81 x height (cm)) – ((0.01 x (age²)) + 44.1

DLNO (Female) = (0.81 x height (cm)) – ((0.01 x (age²)) + 9.7

You can’t discuss DLNO testing without also discussing DMCO and Vc and this is because for a variety of reasons DLNO was initially considered to be DMCO * 1.97 (where 1.97 is the ratio of tissue diffusivity for NO compared to CO) or at least so close an approximation that any differences could be ignored. This however, depended on the assumption that the rate of NO uptake was close to infinite. Subsequent research has shown this to be incorrect and that θNO is approximately 4.5 ml/ml blood/min/mmHg.

As an interesting side note, a finite NO uptake rate also implies DMCO is significantly underestimated when measured by the traditional Roughton & Forster technique that consists of serial DLCO measurements at different FiO2’s and where DMCO is considered to be the intercept of a line plotted using 1/DLCO versus θCO (where θCO depends on FiO2). This may well be because hemoglobin has sites for 4 oxygen molecules and the FiO2’s chosen are almost always within the normal physiological range where there is at most one binding site available. Lower FiO2’s where multiple binding sites are available may well cause the 1/DLCO vs θCO line to become a curve. For this reason, although DLNO is not DMNO, DMNO is most probably equal to DMCO x 1.97.

Using realistic values for θNO and θCO it is possible however, to calculate DMCO and Vc from DLNO and DLCO. Specifically:

Where:

а = 1.97

1/θCO = (0.0062 x PAO2 + 1.16) x (Ideal Hgb / measured Hgb)

Ψ = θNO/θCO = 8.01

The publication of a standard for DLNO testing is welcome for any number of reasons. In particular DLNO provides another viewpoint concerning gas exchange in the lung. Regardless of whatever interest level there may or may not be in DLNO testing the 2017 DLNO standard’s discussion of gas exchange physiology was both interesting and helpful in understanding DLCO, DMCO and Vc. At present the effect that different lung disorders have on DLNO and the DLNO/DLCO ratio aren’t overwhelmingly clear but I expect that this will improve now that a standardized technique is available. In addition the standard’s consensus statement about 1/Θ for CO, although potentially controversial, is a welcome update in this area of study.

One of the barriers towards the routine performance of clinical DLNO testing is that at the present time none of the major PFT equipment manufacturers in the USA offer DLNO testing systems. In addition there are no CPT codes for it yet which means that it’s not possible to bill a patient’s insurance for a DLNO test. However, since the DLNO standard advocates combined DLCO and DLNO testing there is no reason that at least the DLCO component can’t be billed.

One minor criticism of the DLNO standard is that I would like to have seen more discussion of the differences in how NO and CO are taken up by hemoglobin, in particular the reason for the different speeds at which this occurs. I also did not see any mention of the fact that the absorption of NO creates methemoglobin. The concentrations of NO used in DLNO testing are too low for this to be a safety issue, even with repeated testing, but I think it is an important physiological consideration.

An additional criticism is that existing electrochemical NO analyzers were approved for DLNO testing. Their low sensitivity and resolution requires a shorter breath-holding period and this biases both DLNO and DLCO results. I am not against electrochemical anlyzers per se but I do think that the specifications for DLNO testing should have been set with test quality and inter-lab reproducibility in mind. The use of somewhat different test standards for electrochemical and chemiluminescent analyzers creates the potential for DLNO and DLNO/DLCO results to be different depending on which technology is used to measure them.

Realistically though, the 2017 standards did an excellent job of addressing most of the issues surrounding DLNO testing and I commend its authors for providing a good foundation for future DLNO testing.

Note: A discussion of the physiology of DLNO testing was previously posted in DLNO isn’t the same as DMCO but sometimes it’s useful to pretend it (almost) is.

References:

Zavorsky GS, Hsia CCW, Hughes JMB, Borland CDR, Guenard H, van der Lee I, Steenbruggen I, Naeije R, Cao J, Dinh-Xuan AT. Standardisation and application of the single-breath determination of nitric oxide uptake in the lung. Eur Respir J 2017; 49: 1600962.

PFT Blog by Richard Johnston is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License

Last week I ran across a couple errors in some DLCO tests that I don’t remember seeing before, or at least not as distinctly as they appeared this time. If I hadn’t been looking carefully I could have missed them but both sets of errors will be a lot more evident when the 2017 ERS/ATS DLCO standards are implemented.

The first error has to do with gas analyzer offsets. What alerted me was a set of irreproducible DLCO results.

	Test 1:	Test 2:	Test 3:	Test 4:
DLCO (ml/min/mmHg):	24.53	17.21	12.91	6.74
Inspired Volume:	1.99	2.06	2.32	2.26
VA (L):	3.83	3.52	3.63	2.60
Exhaled CH4:	43.27	49.19	54.80	74.14
Exhaled CO:	16.09	23.15	31.39	49.46

When I first looked at the graphs for each test, there wasn’t anything particularly evident until I pulled up the graph for the fourth DLCO test:

This graph showed that the baseline CH4 and CO readings were significantly elevated, but this hadn’t been evident in the previous tests.

Our lab software does not report the baseline CO and CH4 readings except as part of the DLCO graphs. Fortunately, there is an option to download the raw DLCO test data and when I did this it was evident that the zero offset for the CH4 and CO gas analyzer was changing dramatically from one test to the next.

Prior to each DLCO test our lab software checks the CH4 and CO zero offsets and gain. This is not a calibration despite the fact that it puts the test systems through exactly the same steps as it does during a “real” calibration. It is also evident that it doesn’t compare the values it measures to those from the “real” calibration in order to check for any discrepancies. What it does do is to use them as scaling factors and this is what is throwing the calculated DLCO off.

Specifically, the system assumes that the difference between the baseline values for the room air and inspired CH4 and CO concentrations is 100% but also that that the zero determined during a “real” calibration still applies. Using the inspired concentrations as an anchor, it scales the exhaled CH4 and CO accordingly. What this means is that if the baseline CH4 and CO are below zero (negative zero offset) that the exhaled CH4 and CO will be reduced relative to what they “really” are. If the baseline CH4 and CO are above zero (positive zero offset) then the exhaled CH4 and CO will be elevated relative to what they “really” are.

Since calculation of DLCO is based on the difference between inhaled and exhaled CO, when the exhaled CO is falsely reduced the calculated DLCO will be elevated and when the exhaled CO is falsely elevated then the calculated DLCO will be reduced. This is exactly what the test results show.

Fortunately, even though I don’t review tests until the following day that patient’s tests were the last performed using that system so nobody else was affected. We have, of course, stopped using the system (at least for DLCO testing) until the DLCO gas analyzer can be serviced.

In a sense, the real problem was the decision by our equipment’s manufacturer to not re-calibrate the DLCO gas analyzer before each test or to at least check for significant discrepancies in the baseline and inspired gas concentrations. This is not the first time I’ve run across this error (although not in quite as dramatic a form as this) and I brought it to the attention of our equipment manufacturer over three years ago. We’ve gone through a major software update since then but the problem is still there so apparently it wasn’t considered to be particularly significant.

It was more difficult than it should have been to determine there was a problem however, since our lab software does not report the baseline CH4 and CO values and I had to do some digging in order to determine what they were. The 2017 DLCO standards require that the baseline CH4 and CO be reported. The purpose of this is to primarily to make sure that the patient has washed out the DLCO test gases before being re-tested but also to correct for the patient’s alveolar CO backpressure. When this has been implemented any problems with gas analyzer zero offsets and gains will hopefully be more evident than they are now.

The second error has to do with the alveolar sampling volume. While reviewing DLCO results I came across a test where the reported alveolar sampling volume met the 2005 ATS/ERS criteria but one look at the graphs from the test told me that it was an error. First, though, this is what the alveolar sample window looked like:

Most test systems display the alveolor sample as a exhaled CH4 and CO concentrations versus time, and there is nothing particularly unusual about this graph. When the exhaled volume is added however, the alveolar sample error is immediately evident:

 

After exhaling for a while the patient inhaled and for some reason the alveolar sample volume bridged across this. I’m speculating, but my guess is that the software first measures the washout volume by tracking forward through the volume signal after the final exhalation begins. But instead of continuing to track forward through the volume signal to find the end of the alveolar sample volume (because this is the only way this error can be explained) it tracks backwards from the end of the volume signal until it finds an exhaled volume that when subtracted from the end of the washout volume is equal to the alveolar sample volume. Why the alveolar sample volume is determined this way is completely unclear and my guess about how this algorithm works can of course be completely wrong but it’s hard to see how the alveolar sample volume could have been mis-measured otherwise.

Needless to say I corrected the sample volume.

Interestingly, the DLCO hardly changed at all. When I compared the unadjusted and adjusted values, there was little change in CH4, CO and breath-holding time (BHT), but that brought to light another problem.

	Unadjusted:	Adjusted:
DLCO:	20.55	21.77
CH4:	50.78	51.08
CO:	23.92	24.09
BHT:	10.91	10.22

BHT should have decreased by about 1.5 seconds.

We use the Jones-Meade algorithm (recommended by both the 2005 and 2017 DLCO standards) for determining the BHT. Specifically:

“breath-hold time equals the time starting from 30% of the inspiratory time to the middle of the sample collection time.”

The lack of change in BHT between the adjusted and unadjusted alveolar sample is wrong and points out another possible error in our test system software. My guess is that this statement was read be a programmer as “to the middle of the sample” not “middle of the sample collection time” but since the software algorithms are proprietary and since our equipment manufacturer never responds to questions about things like this, I probably won’t ever know for sure.

The 2017 DLCO standards now requires that the alveolar sample period be displayed as gas concentrations versus volume, not gas concentrations versus time. Once our test systems are updated to meet the new standards problems determining alveolar volume will be a lot more self-evident. Since the 2017 standards requires that graphs of the full DLCO maneuver (and the alveolar sample) are included on reports verifying the accuracy of the BHT shouldn’t be that difficult.

Once again though, these errors raise the issue of problems with proprietary software algorithms. How does your test system handle zero offsets for CH4 and CO? How does it scale the exhaled CH4 and CO? How does it determine washout and alveolar volume? How does your system measure BHT? We don’t know the answers to these questions because our equipment manufacturers haven’t ever revealed their algorithms. I realize that manufacturers have a lot of their resources invested in their software and no reason to make it public but this also means we have to take their word that their test systems meet the ATS/ERS standards and leaves us with little ability to verify that they actually do.

I’m not suggesting that our test systems don’t work reasonably well most of the time but I know over a dozen problems and idiosyncracies (some major, some minor) with our test systems. We’ve known about some of these for so long that a number of work-arounds have been part of our training program for new technicians for at least the last 6 years and sometimes for more than 10 years. This points out another problem and that is that most (not all because there are some exceptions) PFT equipment manufacturers have no mechanism whatsoever for users to report problems and to verify that they’ve been fixed.

Part of the reason for this is that FDA regulations makes medical equipment manufacturers jump through innumerable hoops and that their certification process is very slow and their documentation process very time- and labor-intensive. The FDA also treats pulmonary function equipment under the same rules it does for pacemakers, insulin pumps and heart-lung machines and changes that are only cosmetic (or at least certainly non-critical) are often treated the same as if they were critical changes.

But there is also little or no financial incentive for equipment manufacturers to update their software. Manufacturers make their money by selling new test systems and servicing systems they’ve already sold. Unless they are required to they have little reason to write new software or fix their old software.

The 2017 DLCO standards are a welcome improvement over the 2005 standards. Not only do they bring the standards up to date from a technological point of view but they also close a lot of loopholes (or at least areas where the standards were vague enough to leave a lot of wiggle room for interpretation). The 2017 standards are also welcome because they will require manufacturers to update their software and (hopefully) at the same time fix a lot of long-standing problems.

References:

MacIntyre N, et al. Series ATS/ERS task force: Standardisation of lung function testing. Standardisation of the single-breath determination of carbon monoxide uptake in the lung. Eur Respir J 2005; 26: 720-735.

Graham BL, et al. 2017 ERS/ATS standards fir single-breath carbon monoxide uptake in the lung. Eur Respir J 2017; 49: 1600016

PFT Blog by Richard Johnston is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License