VA, two ways

One of the recommendations in the 2017 ERS/ATS DLCO standards was that VA should be calculated using a mass balance equation. I’ve discussed this approach previously, but basically the volume of the exhaled tracer gas is accumulated over the entire exhalation and the amount of tracer gas presumed to remain in the lung is used to calculate VA. The conceptual problem with this for DLCO measurements is that VA is calculated using the entire exhalation but CO uptake is based solely on the CO concentration in the alveolar sample. Since VA calculated using mass balance tends to be larger than VA calculated traditionally in subjects with ventilation inhomogeneities this mean that DLCO calculated with a mass balance VA is also going to be proportionally larger as well.

This problem has concerned me for a while but what wasn’t clear was what difference should be expected in the VA (and DLCO) when it is calculated both ways. In order to figure this out I’ve taken a real-world example of a subject with severe COPD and calculated the difference in VA and DLCO.

Fortunately, my lab software lets me download the raw data for DLCO tests (volume, CH4, CO at 10 msec intervals) into a spreadsheet. The PFT results for the subject looked like this:

  Observed: %Predicted:
FVC (L): 2.39 97%
FEV1 (L): 0.66 36%
FEV1/FVC: 27 38%
TLC (L): 6.11 126%
FRC (L): 4.84 174%
RV (L): 4.04 171%
DLCO: 9.21 57%
VA (L): 3.19 68%
Vinsp (L): 2.32  

In order to use the mass balance approach with the spreadsheet I found that I could determine the start of exhalation after the breath-holding period but determining where the alveolar plateau started was much more difficult. For this reason I had to include the dead space but made adjustments for this when calculating VA.

To start off with, using the inspired volume and concentration of CH4 in the DLCO test gas mixture, the volume of inhaled CH4 was:

2.32 L x 0.003 = 6.96 ml.

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COHb and Pulse Oximetry

I was reviewing a report recently that included the results for walking oximetry. These showed that the individual has a resting SaO2 of 97% and desaturated significantly to 86% after walking a couple hundred yards. This was curious since a DLCO had also been performed and the results for that test were 94% of predicted. It’s unusual for somebody with a normal DLCO to have that low of an SaO2 but I have seen it before in individuals who were unable to ventilate adequately because of a paralyzed diaphragm. I’ve also seen it happen sometimes when somebody has a peripheral vascular disease like Reynaud’s that produces a poor quality oximeter signal. Buried in the technician’s notes however, was an additional piece of information that called into question both the resting and the exercise SaO2 readings. Specifically, the notes mentioned that an ABG had been performed and that the subject’s COHb was 9%.

Oxygen saturation is measured spectrophotometrically. The different forms of hemoglobin, i.e. oxyhemoglobin (O2Hb), deoxyhemoglobin, methemoglobin (MetHb) and carboxyhemoglobin (COHb) absorb the frequencies of red and infrared light differently.

from Hampson NH. Pulse oximetry in severe carbon monoxide poisoning. Chest 1998; 114: 1036-1041

Although non-invasive oximetry was first developed during the 1930’s and 1940’s (in 1935 by K. Mathes in Germany and independently in 1942 by G. Milliken in the USA), current pulse oximeter technology dates from 1972 (by Takuo Aoyagi, researcher for Nihon Koden in Japan). The original pulse oximeters were large, bulky and generally stationary pieces of equipment. Oximeters underwent progressive miniaturization during the 1980’s and 1990’s and rapidly evolved into the handheld and fingertip units we see today and the only “stationary” oximeters that remain are those used in ICU-type monitoring systems.

Modern laboratory CO-oximeters measure the absorption of light in a blood sample at up to 128 wavelengths, spread across the entire hemoglobin absorption spectrum. Using mathematical analysis they can report total hemoglobin concentration and oxygen saturation in addition to fractional deoxyhemoglobin, COHb, and MetHb.

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What’s wrong with an elevated DLCO?

Well, not necessarily anything, although as usual that depends on the circumstances. Recently I was contacted by an individual who was concerned that their DLCO had decreased from 120% of predicted to 99% of predicted. They also mentioned that their DLCO results have normally ranged from 117% to 140% of predicted over the last 9 months.

More interestingly however, they said that

“the technician told me before I even took the test that anything over 100% for DLCO is essentially a testing error.”

Wow. That statement is wrong on so many levels it’s hard to know where to start but I’ll give it a shot anyway.

First, there are a variety of DLCO reference equations. The ATS/ERS guidelines recommends that PFT Labs pick the reference values that most closely matches their patient population but how this is done is left to individual labs. There are at least a couple dozen DLCO reference equations to choose from and probably about a half dozen of these are in common use in PFT labs around the world.

Because no patient population is ever going to precisely match those of a study this means that DLCO results are going to tend to be above or below 100% of predicted depending on which reference equation the lab is actually using. This also means that if results from otherwise normal subjects are mostly above or mostly below 100% of predicted then the wrong reference equations are being used.

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A couple weeks ago I was asked whether it was safe for a patient with an abdominal aortic aneurysm (AAA) to have pulmonary function testing. My first thought was that it was probably unsafe but after a moment or two of thought I realized that I hadn’t reviewed the subject for a long time. When I checked the 2005 ATS/ERS general testing guidelines (there are no contraindications in the 2005 spirometry guidelines) I found that AAA wasn’t mentioned at all. In fact, the only absolute contraindication mentioned was that patients with a recent myocardial infarction (<1 month) should not be tested. Some relative contraindications were mentioned:

  • chest or abdominal pain
  • oral or facial pain
  • stress incontinence
  • dementia or confusional state

and activities that should be avoided prior to testing include:

  • smoking within 1 hour of testing
  • consuming alcohol within 4 hours of testing
  • performing vigorous exercise within 30 minutes of testing
  • wearing clothing that restricts the chest or abdomen
  • eating a large meal with 2 hours of testing

but these were factors where test results were likely to be suboptimal and not actually contraindications.

This got me curious since I thought that pulmonary function testing was contraindicated for more conditions than just an MI. I reviewed the 1994 and and then the 1987 ATS statements on spirometry but again found no mention of contraindications. Ditto on the 1993 ERS statement on spirometry and lung volumes. Finally, in the 1996 AARC clinical guidelines for spirometry I found a much longer list of contraindications:

  • hemoptysis of unknown origin
  • pneumothorax
  • recent mycardial infarction
  • recent pulmonary embolus
  • thoracic, abdominal or cerebral aneuysms
  • recent eye surgery
  • presence of an acute disease process that might interfere with test performance (e.g. nausea, vomiting)
  • recent surgery of thorax or abdomen

So where did the AARC’s list of contraindications come from? And why is there such a discrepancy between the ATS/ERS and the AARC guidelines?

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An unusual error in helium dilution lung volumes

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.

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Some DLCO errors the 2017 standards will probably fix

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.

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Which time is it?

The ATS/ERS standard for spirometry recommends reporting the highest FEV1 and the highest FVC even when they come from different tests. Our lab software allows us to do this, but only with some annoying limitations. One of the bigger limitations has to do with how expiratory time is reported. In particular, expiratory time is lumped in with a number of other values like Peak Flow (PEF) and FEF25-75. As importantly, the flow-volume loop and volume-time curve can only come from a single effort.

Our lab software defaults to choosing a single effort with the highest combined FVC+FEV1. The technician performing the tests will override this when other spirometry efforts have a larger FVC or a better FEV1 (which is chosen not just if it is higher but also on the basis of peak flow, back-extrapolation and other quality indicators). The usual order for this is to first choose a spirometry effort with the “best” FEV1, then if there is a different effort with a larger FVC that FVC is selected for reporting. When things are done this way what happens is that the expiratory time, flow-volume loop and volume-time curve that come from the effort selected for its FEV1 are reported. This means is that the expiratory time and volume-time curve often don’t match the reported FVC.

I always take a look at the raw test data whenever a spirometry report comes across my desk with an expiratory time less than 6 seconds or the technician noted that the spirometry effort is a composite. What I often find is that even though the reported expiratory time may be low, the FVC actually comes from an effort with an adequate expiratory time. Although I can select the right expiratory time the problem is that doing so also selects the PEF and the PEF from the effort with the highest FVC is often significantly less than the effort from the best FEV1. The same problem applies to selecting the volume-time curve since the associated flow-volume loop often doesn’t match the effort with the best FEV1 and best PEF. For these reasons I only select the correct expiratory time and volume-time curve when it doesn’t really affect the flow-volume loop and PEF.

However, I’ve always assumed that the expiratory time from the effort with the highest FVC was probably the most correct expiratory time. Yesterday however, this spirometry effort came across my desk:

Blue Red
FVC: 2.53 2.54
FEV1: 2.19 2.13
FEV1/FVC: 86 84
PEF: 6.94 5.07
Exp. Time: 3.05 5.09

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Calculating VA the mass balance way

One of the more significant changes that appeared in the 2017 ERS/ATS DLCO standards was the requirement that rapid-response gas analyzer (RGA) systems calculate VA using a mass balance approach. This is actually more straightforward than it sounds but it does raise several issues that weren’t fully addressed in the 2017 standards.

Up until this time VA has been calculated from the inspired volume and by the amount of dilution of the tracer gas in the exhaled alveolar sample. Specifically:


Which is described by:


VI = inspired volume

Vd = Anatomical and Machine deadspace

Fitrace = Inspired tracer gas concentration

FAtrace = Exhaled tracer gas concentration

The basic concept behind the mass balance approach to measuring VA is relatively simple and is described in the 2017 standard as:

…the tracer gas left in the lung at end exhalation is equal to all of the tracer gas inhaled minus the tracer gas exhaled.”

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N2 washout troubleshooting

I was recently contacted by the manager of a lab that was having problems with their N2 washout lung volumes. Specifically, their N2 washout lung volumes (FRC in particular) were coming out low and everyone being tested on the system looked like they had restriction. The system has been checked by the manufacturer’s service techs several times and they’d replaced the tubing, the O2 tank and a number of parts. Service first asked them to wait between tests and then not to bother. Most lately they’ve been asked to calibrate the system before each test. Despite all this, their system continues to under-estimate lung volumes.

We’ve all had seemingly intractable problems with our test systems at one time or another. Sometimes they’re problems that can only be fixed by replacing major components, such as a gas analyzer or a motherboard. Sometimes they turn out to be something simple that nobody noticed despite looking straight at it numerous times. Experience and good technical support helps, but for every test system there has to be at least a couple of problems that are either uncommon, difficult to diagnose or are happening for the first time. When this happens it’s best to go back to basics and try to see what it is that’s most likely to explain the symptoms.

N2 washout lung volume measurements measure the amount of nitrogen residing in the lung and use this to estimate the volume of the entire lung. Closed circuit lung volume measurements using nitrogen were first attempted in 1932 by Christie. Christie’s approach used a known volume of oxygen to dilute the nitrogen in the lung but accuracy was limited at least in part because the amount of oxygen in the closed circuit was constantly changing due to the subject’s oxygen uptake. In 1940 Darling et al demonstrated an open circuit technique that is the basis for current N2 washout tests. In this approach the nitrogen in a subject’s lung was washed out with 100% O2 and their exhaled air was collected in a Tissot spirometer. After a certain amount of time (nominally 7 minutes) the exhaled volume and the N2 concentration in the Tissot spirometer was measured. The amount of nitrogen that had been exhaled is then calculated using simple math and the subject’s FRC is estimated from that.

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Ventilatory response to hypoxia and hyperoxia

While reading a recently published article I found they had performed response to hypoxia and hyperoxia testing as part of the study. At one time or another in the past I’ve read about response to hypoxia testing but I’d never heard about hyperoxia testing before. I had some difficulty understanding their interpretation of the study’s results and for this reason I’ve spent some time reading up on the subject. I’m not sure this helped because there appears to be a lack of consensus not in only how to perform these tests but also in how they are interpreted, except perhaps in the most simplistic sense. Hypoxia and hyperoxia testing has been performed primarily to gain a deeper understanding of the way in which the peripheral (carotid) and central chemoreceptors function. There are a variety of sensor-feedback network models and results are often presented in terms of one model or another and this makes comparing results from different studies difficult. Interpretation and comparison is further complicated by the fact that results depend not only on the length of time that hypoxia or hyperoxia is maintained but whether the subject was exposed to hypoxia, hyperoxia or hypercapnia previously.

The ventilatory response to hypoxia tends to have three phases. First, once a subject begins breathing a hypoxic gas mixture within several seconds there is a rapid increase in minute ventilation known as the Acute Hypoxic Ventilatory Response (AHVR). Second, after several minutes there is a decrease in ventilation and this is usually called the Hypoxic Ventilatory Depression (HVD). Third, there is a progressive rise in ventilation after several hours which is related to acclimatization to altitude. It is the first phase, AHVR, that is most commonly measured during a hypoxic ventilatory response test. The actual length of time that is spent in any of these phases is widely variable between individuals and there is also a relatively large day-to-day variability within the same individual.
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