Author: Richard Johnston

Recently a CPET report for an individual whose primary complaint was tachycardia and DOE with minimal activity came across my desk. Since the patient had had an pneumonectomy (one lung removed) about a year ago there wasn’t much doubt the results would be reduced, the question was whether they were reduced more than they should have been.

You might expect lung function to decrease by half following a pneumonectomy but because the remaining lung always expands to some extent FVC and TLC tend to be approximately 60%-65% of their pre-surgical volume. Although this increase in volume however does not increase the alveolar-capillary surface area the entire cardiac output needs to pass through the remaining lung which causes an increase in the pulmonary capillary blood volume. For this reason DLCO also tends to be about 65% of baseline.

	Observed:	%Predicted:
FVC (L):	2.08	62%
FEV1 (L):	1.62	57%
FEV1/FVC (%):	79	92%
TLC (L):	2.89	64%
DLCO (ml/min/mmHg):	11.55	54%

With the exception of the DLCO the patient’s pulmonary function results were about what would be expected following a pneumonectomy. It’s hard to be sure the DLCO is anomalously low because the surgery was performed at a different hospital and we don’t have any pre-surgical pulmonary function results to compare them to. Since this is also the first time the patient had a CPET there isn’t anything to compare the current results to either.

	Max:	%Predicted:
VO2 (LPM):	0.95	54%
VO2 (ml/kg/min):	18.2	54%
VCO2 (LPM):	1.05
RER:	1.11
Ve (LPM):	31.3	48%
Vt (L):	1.12
RR:	28
HR (BPM):	165	86%
O2 Pulse (ml/beat):	5.8	63%

In addition, the patient stopped exercising because of dizziness, not because of shortness of breath or leg fatigue, so it wasn’t really as maximal a test as it could have been. Given that the RER was 1.11 and the maximum heart rate was 86% of predicted it was at least an adequate test but it’s somewhat doubtful that the maximum VO2 from the CPET was truly the maximum VO2 the patient was capable of.

Taking the CPET results at face value it was interesting to see that the patient did not show any pulmonary limitations to speak of. The maximum minute ventilation was less than half of predicted and there had been only minor increases in tidal volume and respiratory rate so the patient wasn’t even close to a pulmonary mechanical limitation.

In terms of gas exchange there was no desaturation (SpO2 at peak exercise was 97%), the Ve-VCO2 slope was 22.1 and the Ve/VCO2 at AT was 32, both of which are well within normal limits. Other than the DLCO being a bit lower than might be expected there was no indication of pulmonary vascular disease.

What the results do indicate was that the primary limitation is probably cardiovascular. The chronotropic index (the slope of heart rate versus VO2) was elevated at 1.51 (normal range is 0.8 to 1.3) and the maximum O2 pulse was reduced at 63% of predicted. If I had not known about the pneumonectomy I would have said there there was a cardiovascular limitation secondary to a reduced stroke volume but the real question is whether this is a normal post-pneumonectomy pattern or not.

It’s been quite a while since I last saw a CPET performed on somebody with a pneumonectomy so I spent some time researching the subject. I was disappointed to find that for the first time in a long time Wasserman failed me. Wasserman has always been my go-to source for CPET interpretation and I wasn’t able to find a single thing about assessing post-pneumonectomy CPETs in his textbook. When I searched the literature I was able to find hundreds of articles on the use of PFTs and CPETs in pre-operative assessment but only a handful of articles that had actual pre- and post-surgical comparisons.

The consensus, such as it is, it that the post-pneumonectomy VO2 and Ve do not decrease quite as much as FVC or DLCO and that this decrease tends to range between 20% and 30%. It has also been noted that both cardiac output and stroke volume decrease following a pneumonectomy. This is due to an increase in pulmonary vascular resistance which in turn is due to the increased blood flow through the remaining vasculature. Not surprisingly the decreases in cardiac output and stroke volume are proportional to the decrease in VO2 (or should that be vice-versa?).

These facts makes the patient’s max VO2 of 54% and max O2 pulse of 63% of predicted look excessively low. Mitigating that to some extent is the fact that we don’t know what the patient’s pre-surgical PFT or CPET results were. There is also the fact that the max VO2 (and O2 pulse) is likely a bit less than the patient is actually capable of.

Even so the maximum VO2 as probably lower than it should be. There are three primary factors that can limit VO2. Pulmonary mechanical (the ability to get air in and out of the lung), pulmonary vascular (the ability to exchange oxygen and carbon dioxide) and cardiovascular (the ability to pump blood around the body):

• There is no apparent pulmonary mechanical limitation. Despite the decrease in TLC and VC caused by the pneumonectomy the maximum minute ventilation was still well below the predicted maximum.

• There is no apparent pulmonary vascular limitation. SpO2 and the Ve-VCO2 slope were quite normal. Because pulmonary arterial pressure usually rises following a pneumonectomy you might expect a pattern similar to pulmonary hypertension but other than the DLCO that may be reduced more than it should there was no evidence for that.
• There does appear to be a cardiovascular limitation. This is shown by the reduced maximum O2 pulse and elevated chronotropic index. These appear to be reduced out of proportion to what would be expected from a pneumonectomy.

The evidence therefore continues to be in favor of a cardiovascular limitation.

Over the last year or so our ECG system and metabolic cart finally failed, although at different times. Not surprising since they were about 14 years old. Neither was supported by their manufacturer any more and neither could be repaired. We were able to get them replaced but one unfortunate side effect was that the procurement process for each system was different and we ended up with an ECG system and metabolic cart that couldn’t be interfaced with each other.

We still get good information from each system but one graph we no longer routinely get is heart rate versus VO2. Since the patient had complained of tachycardia at low levels of exercise I thought it would be worthwhile to take a closer look at the relationship between heart rate and VO2. I manually entered the 30-second interval data from both systems into a spread sheet and when I graphed the data I found that the HR-VO2 slope seemed to increase at a HR of around 140.

For the same reasons O2 pulse also needs to be manually calculated. When I did this, I found that the patient’s O2 pulse plateaued at about the same time.

Normal, both heart rate and stoke volume increase throughout exercise. In this case however, it appears that the patient’s stroke volume plateaued around a heart rate of 140. This means that above a heart rate of 140 the only way that cardiac output and VO2 could increase was by increasing heart rate. Although a decrease in stroke volume is one consequence of a pneumonectomy, plateaus in O2 pulse have not been reported. This may be a limitation of the studies however, since I’ve found that only the peak exercise values were reported and you need the interval data to see a plateau.

In the past we’ve see this change in HR-VO2 slope only once or twice a year. When I’ve been able to follow up with this the most frequent cause appears to have been valve disease although the literature on this says that ischemia is also a possible cause. This patient will likely be sent for a more complete cardiac workup.

This problem points out a limitation in the chronotropic index calculations since they are performed with only the resting and maximum heart rate and VO2. This patient’s chronotropic index was elevated, which by itself indicates a reduced stroke volume, but that single number does not indicate there was a change in the HR-VO2 slope mid-exercise which has a quite different interpretation. Even though this is a relatively infrequent problem I will take this as a stern reminder to myself that if you don’t look for it, you won’t find it. In the future we will plot this data for every CPET we perform.

It is obvious that a pneumonectomy will reduce pulmonary function and exercise capacity but these decreases are not necessarily as great as might be expected at first glance. The ability to accurately assess post-pneumonectomy PFT and CPET results however, requires knowledge of their pre-surgical values. Although the lack of this information hampered our ability to interpret the results in this case there appears to be an abnormal stroke volume limitation and not as might be expected, a pulmonary mechanical or pulmonary vascular limitation.

References:

Bolliger CT, Jordan P, Soler M, Stulz P, Tamm M, Wyser Ch, Gonon M, Perruchoud AP. Pulmonary function and exercise capacity after lung resection. Eur Respir J 1996; 9: 415-421.

Brunelli A, Refai M, Salati M, Xiume F, Sabbatini A. Predicted versus observed FEV1 and DLCO after major lung resection: A prospective evaluation at different postoperative periods. Ann Thorac Surg 2007; 83: 1134-1139.

Hsia CC, Carlin JI, Cassidy SS, Ramanathan M, Johnson RL. Hemodynamic changes after pneumonectomy in the exercising foxhound. J Appl Physiol 1990; 69(1): 51-57.

Hsia CCW, Ramanathan M, Estrera AS. Recruitment of diffusing capacity with exercise in patients after pneumonectomy. Amer Rev Resp Dis 1992; 145(4): 811-816.

Nezu K, Kushibe K, Tojo T, Takahama M, Kitamura S. Recovery and limitation of exercise capacity after lung resection for lung cancer. Chest 1998; 113: 1511-1516.

Nugent AM, Carragher AM, McManus K, McGuigan JA, Gibbon JRP, Riley MS, Nicholls DP. Effect of thoracotomy and lung resection on exercise capacity in patients with lung cancer. Thorax 1999; 54: 334-338.

Pelletier C, Lapointe L, LeBlanc P. Effects of lung resection on pulmonary function and exercise capacity. Thorax 1990; 45: 497-502

Wasserman K, Hansen JE, Sue DY, Stringer WW, Whipp BJ. Principles of exercise testing and interpretation, Fourth Edition, Published by Lippincott, Williams and Wilkins, 2005.

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

When I review the results from a CPET I am used to considering a maximum minute ventilation (Ve) greater than 85% of predicted as an indication of a pulmonary mechanical limitation. Recently a CPET report came across my desk with a maximum minute ventilation that was 142% of predicted. How is this possible and does it indicate a pulmonary mechanical limitation or not?

It is unusual to see a Ve that is greater than 100% of predicted. We derive our predicted max Ve from baseline spirometry and calculate it using FEV1 x 40. We have tried performing pre-exercise MVV tests in the past and using the maximum observed MVV as the predicted maximum Ve but our experience with this has been poor. Patients often have difficulty performing the MVV test correctly and realistically even if it is performed well the breathing maneuver used during an MVV test is not the same as what occurs during exercise. Since both Wasserman and the ATS/ACCP statement on cardiopulmonary exercise testing recommend the use of FEV1 x 35 or FEV1 x 40 as the predicted maximum minute ventilation we no longer use the MVV.

There are usually only two situations where a patient’s exercise Ve is greater than their predicted max Ve. First, when a patient is severely obstructed their FEV1 is quite low and FEV1 x 40 may underestimate what they are capable of since they are occasionally able to reach a Ve a couple of liters per minute higher than we expected. Second, if the FEV1 is underestimated due to poor test quality then the predicted max Ve will also be underestimated. In this case however, the baseline spirometry had good quality, was repeatable and the results did not show severe obstruction but instead looked more like mild restriction.

	Effort 1:	Effort 2:	Effort 3:
FVC (L):	2.51	2.52	2.60
FEV1 (L):	1.86	1.87	1.95
FEV1/FVC %:	74	74	75
PEF:	6.26	6.46	6.37

The patient’s TLC had been 70% of predicted when measured a month previously. Despite this and the somewhat restrictive looking spirometry, the diagnosis we had been given for the CPET was Asthma. One of the more common effects that exercise usually has on an individual with asthma is Exercise Induced Bronchoconstriction (EIB). This is one of the primary reasons that we routinely perform pre- and post-exercise spirometry as part of our CPETs. Most people usually have a small increase (3%-5%) in their FEV1 following exercise. When we see a significant decrease in FEV1 (greater than 12%) following exercise we usually consider EIB to be the cause. A small number of asthmatics however, do not bronchoconstrict with exercise, they bronchodilate, and that is what this patient did.

	Pre-Exercise:	%Predicted:	Predicted:	Post-Exercise:	%Predicted:	%Change:
FVC (L):	2.60	57%	4.57	3.02	66%	+16%
FEV1 (L):	1.95	54%	3.59	2.30	64%	+18%
FEV1/FVC%:	75	95%	78	76	97%	+2%

The patient was actually rather physically fit and other than their Ve had an above-average exercise test.

	AT	%Predicted:	Peak	%Predicted:
VO2 (LPM):	1.63	64%	3.01	118%
VO2 (ml/kg):	21.2	61%	39.2	112%
VCO2 (LPM):	1.44		3.27
RER:	0.88		1.09
SpO2:	98%		97%
PETCO2:	37.4		34.1
Ve/VCO2:	30		34
Ve (LPM):	43.0	55%	110.3	142%
Vt (L):	1.64		2.57
RR:	26		43
HR:	123	71%	171	99%
O2/Pulse:	13.3	90%	17.6	119%

[In addition, the Ve-VCO2 slope from rest to AT was 27.5 and from rest to peak exercise was 30.3 both of which are normal, and the chronotropic index was 0.81 which is low normal.]

One final point is that we measure Inspiratory Capacity (IC) during a CPET in order to track a patient’s End-Expiratory Lung Volume (EELV). EELV is a surrogate for FRC and we use it to see if a patient is hyperinflating during exercise. This is a common limiting factor for patients with COPD but we routinely measure it on all of our patients (if you don’t look for it you won’t find it!). In this case, not only did this patient’s EELV decrease during exercise by 0.80 L but the maximum IC that was measured during the test was 3.30 L, which is approximately 10% greater than their post-exercise FVC and 27% greater than their pre-exercise FVC.

My take on this patient’s CPET results is that there was a markedly elevated bronchodilation response during exercise. In fact, because we perform post-exercise spirometry at least 10 or 15 minutes following exercise I strongly suspect that this patient’s post-exercise spirometry is significantly underestimating the degree to which they bronchodilated.

So was there a pulmonary mechanical limitation? Since we can’t know for sure how much the patient bronchodilated that question can’t be answered with any certainty. Even using the post-exercise FEV1 x 40, the Ve was 120% of predicted. Usually when we think of an exercise limitation, whether it is pulmonary mechanical, pulmonary vascular or cardiovascular, we are thinking in terms of something that limits or prevents a patient from achieving a normal exercise capacity. When a patient reaches a threshold for one limitation or another but still has a normal maximum oxygen consumption we usually phrase it as the patient “achieved” the limit rather than saying it was an actual limitation. I know that’s just semantics, but how else should it be described?

One final note is that the patient’s main complaint and the reason they weren’t able to go any further was leg fatigue, not shortness of breath. This fact, along with all the others, leads me to suspect that a pulmonary mechanical limit did not in fact occur.

And the low TLC? Some investigators have hypothesized that airway constriction and inflammation occurs heterogeneously in some individuals with asthma. This means that gas trapping occurs patchily all across the lung. During exhalation, these parts of the lung remain inflated and can cause further airway constriction and gas trapping in nearby parts of the lung that are not otherwise involved. This may be the reason that some asthmatics (as many as 10%?) can have a symmetrically decreased FEV1 and FVC with a normal FEV1/FVC ratio during an exacerbation. This patient’s lung volume measurements were performed using helium dilution and it is possible that heterogeneous gas trapping caused their TLC to be underestimated. Having said that there is no reason a patient can’t have both restrictive and obstructive defects simultaneously but if that was the case then this patient’s maximum VO2 of 118% of predicted is even more remarkable.

Is this asthma? In many ways this patient’s clinical course has not been typical and somewhat of a puzzle to their pulmonary physician; hence the CPET. I am not a clinician and my view may be too simplistic, but reactive airways are reactive airways even if the way they react is to bronchodilate rather than bronchoconstrict. A search of the literature indicates that bronchodilation during exercise is not all that unusual, although the degree that it appears to have occurred in this case is exceptionally large. There is a lot of research being performed on the genetics and biochemical pathways of asthma and I suspect that we will eventually find out that what we call asthma is actually just the way that a wide variety of underlying syndromes present themselves. Until that time I think that this just needs to be considered an unusual asthma variant.

Using FEV1 to predict an individual’s maximum minute ventilation does not take into consideration inspiratory flow rates. This is why FEV1 x 40 can underestimate Ve in individuals with severe airway obstruction. FEV1 can also increase during and post-exercise due to bronchodilation. When significant bronchodilation occurs, I have reported CPET results with two predicted Ve’s, one based on the pre-exercise FEV1 and one based on the post-exercise FEV1. Doing this has moved some patients from having an apparent pulmonary mechanical limit to being WNL. In this case, the patient achieved a maximum minute ventilation that was well above either predicted value. Even so I think that this helps make it clear that performing pre- and post-exercise spirometry is important not only to assess EIB but also to detect bronchodilation.

Using FEV1 x 40 to estimate an individual’s maximum minute ventilation is not perfect but it is probably better than any other approach we have at this time. When a patient’s maximum minute ventilation during a CPET exceeds what is predicted for them this can be a sign of poor baseline spirometry (or MVV) test quality or the ability of a compromised patient to slightly exceed expectations. In this case it appears to be a sign of a somewhat unusual asthmatic response to exercise.

References:

ATS/ACCP Statement on Cardiopulmonary exercise testing. Am J Resp Crit Care Med 2003; 167: 211-277.

Gelb AF, Tashkin DP, Epstein JD, Gong H, Zamel N. Exercise-induced bronchodilation in asthma. Chest 1985; 87: 196-201.

Hyatt RE, Cowl CT, Bjoraker JA, Scanlon PD. Conditions associated with an abnormal nonspecific pattern of pulmonary function tests. Chest 2009; 135: 419-424.

Wasserman K, Hansen JE, Sue DY, Stringer WW, Whipp BJ. Principles of exercise testing and interpretation, Fourth Edition, Published by Lippincott, Williams and Wilkins, 2005.

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

As New Year’s Day approaches it is a tradition for people look back to see what has happened during the last year and then look forward and guess what will happen during the next year. I’ve never done a New Year’s blog before but I’ve been mulling over a number of ideas for a while and this looks like a good place to explore them.

I’ve had the opportunity over the last several years to research the history of pulmonary function testing. There are a couple of interesting lessons from the past that may be useful, particularly when we are trying to guess what direction pulmonary function testing is heading towards in the future.

The spirometer as we know it and the measurement of the Vital Capacity began with John Hutchinson in 1846. In a sense there was really nothing new in what he did. His spirometer was a modified gasometer that had been invented by James Watt in 1790 and used by other researchers (notably Humphrey Davy who was the first person to measure the Residual Volume). The Vital Capacity had also been measured previously by many individuals. The remarkable thing that Hutchinson did however, was to present the first true population study and to clearly show the relationship between age, height and the Vital Capacity.

Measuring the Vital Capacity took off like a rocket and researchers all across Europe and the United States studied it in many different diseases and locations. An incredibly wide variety of spirometer technologies were developed as well, some of which are still in use. Over and over again researchers tried to show the value of the Vital Capacity (particularly in Tuberculosis) but the reality is that the clinical value of the Vital Capacity is quite limited. This is because when you only look at the volume of the Vital Capacity there are many reason why it can be reduced and so the finding of a reduced Vital Capacity is non-specific. The clinical use of spirometers languished for decades and the biggest use of spirometers wasn’t clinical at all, they were instead mostly used in schools, gymnasiums and penny arcades to measure lung “power”.

It wasn’t until over a hundred years after Hutchinson presented his first paper on spirometry that Tiffeneau in 1948 and Gaensler in 1950 presented their papers on the FEV1 and FEV1/FVital Capacity ratio and an entire paradigm shift occurred almost overnight. Today spirometry is mostly about flow rates and only partly about volume. It is the flow rates (Peak flow, FEV1) that are so incredibly clinically relevant and in just a few years after Tiffeneau’s and Gaensler’s papers spirometry became an invaluable and critical tool in the diagnosis and monitoring of many different lung diseases.

Why did it take so long for expiratory flow rates to be appreciated? This was in part because spirometers of the time were not designed to measure flow but only to measure volume. Water seal spirometer bells were often quite massive and the breathing tube and mouthpiece were quite narrow. Lightweight spirometer bells and wide bore tubing could have been manufactured almost any time after the late 1800’s but nobody tried because spirometers were only supposed to measure volume.

The first viable flow sensor, the Fleisch pneumotach, may have been invented in 1925 but it used a mirror and photographic paper that had to be developed in order to measure flow rates and this made it suited for only minor research. What actually brought expiratory flow rates to the forefront of pulmonary medicine was the Maximum Voluntary Ventilation test which itself was an attempt to mimic ventilation during exercise. The MVV test fostered an appreciation of spirometer frequency response and flow rates. Tiffeneau himself explained the FEV1 as a substitute for the MVV test.

So my first thought and question about the future of pulmonary function testing is: What test(s) are we performing now that need to be looked at from a completely different perspective?

There were a couple dozen companies manufacturing spirometers in the late 1800’s and early 1900’s. Have you heard of the Narragansett Machine Company, National Spirometer Company, Spalding, Simplex, Shepard, Lewis, Barnes or Brown? No? These companies made tens of thousands of spirometers but none of them survived more than a short time into the 20^th century. So where did all our PFT equipment come from? It came from Basal metabolism testing, not spirometry.

The last half of the 19^th century saw numerous researchers measuring exhaled CO2 production and oxygen consumption. CO2 absorbants like caustic soda (potassium hydroxide, KOH), baryatra water (barium hydroxide, BOH) and eventually, soda lime (calcium hydroxide, CaOH) were used for both purposes. Much of this research centered on metabolism and both open-circuit and closed-circuit techniques were developed and refined. Somewhere along the way, it was realized that if you filled a closed-circuit spirometer with oxygen and included a CO2 absorbant, that you could cheaply and reproducibly measure oxygen consumption by measuring the change in circuit volume over time. The science (and industry) of Basal Metabolism measurements was born.

By the 1930’s closed circuit systems intended for basal metabolism measurements were modified to measure both CO2 production and oxygen consumption (again using chemicals) and the science of spiroergometry (exercise testing) came into existence. Researchers also found that the standard closed-circuit basal metabolism equipment could be modified quite easily to measure gas dilution lung volumes and techniques for measuring FRC, TLC and RV using nitrogen, hydrogen and helium were developed. Open circuit basal metabolism systems were modified to measure lung volumes by nitrogen washout.

Around 1920 a number of companies came were formed for the purpose of manufacturing and selling Basal Metabolism systems; Collins, Sanborn, McKesson and Jones. These companies thrived and grew selling this type of equipment and were among the first companies in the 1950’s and 1960’s to design and sell test equipment for pulmonary function labs. Not all of these companies survived to the 21^st century (at least by solely manufacturing PFT equipment) but they did determine to a large extent what tests were performed and how they were performed in the years when clinical pulmonary function labs came into existence.

My next thought and question is: What companies and products that aren’t being used in pulmonary function testing now will be the core of future PFT Labs?

We tend to think of medicine and technology as a linear process that progresses logically. This is only marginally true and new discoveries and paradigm shifts cannot be predicted. They may look obvious after the fact, but that just means that we think we have 20-20 hindsight.

So what do I think will be important or at least happening in the future?

I think that oscillometry (FOT and Impulse) holds promise but there needs to be a clearer understanding of what oscillometry is really measuring and what clinical relevance the measurements have.

I think that measurements of ventilation inhomogeneity (Phase III slope of the single-breath nitrogen washout and the Lung Clearance Index) hold promise for better monitoring of the status of many (not all) obstructive lung diseases. Again there needs to be a better correlation between changes in these values and clinical status and this will require longitudinal testing.

I think that cardio-pulmonary exercise testing is under-utilized but this is largely due to the complexity and expense of the test equipment and the need for multiple staff members to be present. Advances in measurement technologies and in expert systems to monitor the tests in real-time could reduce the cost of performing CPETs greatly while keeping them safe to perform as well.

I think that measurements of trace exhaled gases and exhaled breath condensates has great promise, not necessarily for pulmonary function, but for disease diagnosis and monitoring cellular metabolic processes. Notably, however, despite this being an exhaled air measurement, other than NO, these tests are not being performed by pulmonary function labs.

I think that computerized interpretation of PFT results (still) has potential and could be quite useful where it is needed the most; doctor’s offices and clinics, but that it needs to include the ability to assess test quality, testing errors and probabilities before it will ever be more than a toy, which it has been since PUFF was first written in the 1970’s.

I think that the trend towards personal health monitoring is going to mean that more people, both those in good health and those with lung disease, will be performing their own spirometry. This will actually mean that more testing will be performed in pulmonary function labs in the long run, not less, and that monitoring personal spirometry results and trends will become part of routine clinical care.

I think that economic and regulatory forces will continue drive the development of inter-hospital communication standards and that eventually a patient’s medical records will be completely transportable. This means that when you perform PFTs on a patient, their trend report will include all their PFTs, no matter when or where they were done.

Finally, I think that we tend to be overly focused on running our PFT Labs and on performing quality pulmonary function testing as best we can according to ATS/ERS standards (at least that’s what I hope everybody is doing). This is a good thing, but it also loses sight of our real purpose and that is to diagnose and monitor lung disease. How we go about fulfilling this purpose must change as technology changes, our understanding of lung physiology and disease processes change, and our ability to treat lung disease changes.

Along the way we need to keep our perspective and our humility. We can look back at the patent nostrums and medical procedures of the 19^th century say, “What were they thinking? That was totally wrong. How did anybody survive that?” In the far future I suspect that anybody will be able to wave a tri-corder wand over themself and their personal medi-bot will say, “Hmmm, some of the peripheral airways and acini in your left upper lobe look a bit off. Here, inhale these nanobots I’ve just programmed to repair them. Let’s check again tomorrow to see how they’re doing”. That future person will look back at the 21^st century and say “What were they thinking? That was totally wrong. How did anybody survive that?” And you know what?  They will be completely right.

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

Around 20 years ago I had to write the emergency evacuation plan for the pulmonary function lab. Like many other administrative duties I learned that I needed to do this when my new administrator asked where it was and whether I had documented that I had reviewed it with the lab staff. Since I didn’t even have a real procedure manual at the time (just reprints of pertinent articles and textbook chapters) I ended up getting a crash course in writing policies. Fortunately the manager of a nearby departments let me borrow their evacuation plan and I was able quickly to knock one out that met the requirements fairly quickly. Since then I’ve had to review it annually and update it every time the lab moved or when rooms were added or taken away.

Yesterday I was reading the recently published ERS/ATS technical standards for field walking tests (and if you perform 6-minute walk or incremental shuttle tests then you will probably need to read it and update your procedures). One important change has been that because a 6-minute walk test can evoke a VO2 and heart rate response similar to CPETs the same absolute and relative contraindications now apply. For the same reason in the table of equipment required for walking tests along with the stopwatch and pulse oximeter the ERS/ATS standard now includes “An emergency plan”.

We’ve always had a physician present when we perform exercise tests. The contraindications to exercise testing are in our procedures and are included in the letter we send patients informing them of their exercise test appointment. But because we have a physician present we’ve always relied on the physician to recognize and handle the (thankfully) infrequent problems that occur during exercise. When we perform 6-minute walks however, we’re (depending on how you look at it) a building or two away from any of the pulmonary physicians.

The hospital does have a medical emergency response team (Code Blue) and we’ve called them to the pulmonary function lab maybe once a year mostly because a patient has fainted during spirometry or had a vaso-vagal response during an ABG. This was common sense however, and there isn’t anything in our procedure manual about when this needs to be done. I’m not sure why I’ve had a blind spot about this but in retrospect it is obvious that we need a policy on medical emergencies.

We already have a policy on the contraindications to testing so what we need is something that includes signs and symptoms and most importantly, an action plan. I will put together a list of the more or less obvious signs (patient becomes unconscious or has a seizure) and an action plan (call a Code Blue) but will look to the lab’s medical director to help us to expand and refine this. Once the policy has been written and approved we will also need to go back and make sure all the existing test procedures include specific contraindications, specific signs and symptoms and a referral to the medical emergency policy.

Writing, maintaining and updating policies and procedures is always a PITA (particularly since there’s always something else that needs to be done that seems more immediately important), but they’re absolutely necessary for any number of reasons. On the plus side, I’ve found that writing them has improved my understanding of the ATS/ERS standards and has made it easier to talk to lab staff, physicians and patients about testing issues. In addition there is always a certain amount of personnel turnover and new staff needs to be oriented to all testing procedures and lab policies. Even “old” staff need to be able to review the official procedure when questions about testing performance arise.

I have to be honest and say that having policies and procedures is also a way to protect yourself and your lab. In most hospitals and clinics the basic job policies have probably already been written by Human Resources but these are usually only general policies on things like attendance, patient privacy and sexual harassment. A PFT lab needs specific job performance policies and I’ve written these not just on testing, but on patient appointments, billing and performing quality control. All lab staff have to “sign off” that they’ve read both the hospital’s and the lab’s policies and procedures, usually as part of orientation as a new hire but also when there is a new or updated policy. I’ve been fortunate to have had job performance issues with lab staff relatively rarely but when this has happened what has helped is that I’ve been able to point to the lab and hospital policies that have been acknowledged and signed-off when having to discuss problems with a staff member.

Despite all the complaints that patients make about what we do to them, the rate of medical complications in pulmonary function testing is quite low. I’ve been in the field for over 40 years and although I’ve sent a number of patients to the ER (usually for cardiac arrhythmias after a CPET), they all left vertically, not horizontally. Even so it is past time my lab had a policy about recognizing and managing medical emergencies.

By the way, you do have a lab policy and procedure manual, don’t you?

References:

Holland AE et al. An official European Respiratory Society/American Thoracic Society technical standard: field walking tests in chronic respiratory disease. Eur Respi J 2014; 44: 1428-1466.

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

The March 1, 2014 issue of the American Journal of Respiratory and Critical Care Medicine had an article on the use of the Lung Clearance Index (LCI) with bronchiectasis. The study showed that the LCI was as good as high-resolution computed tomography and more sensitive than FEV1 when assessing changes in airway status. This is one of the few articles I’ve seen on the LCI that was specifically about adults and wasn’t about cystic fibrosis.

So what is the LCI and how is it measured?

When lung tissue and airways are normal, inhaled gas is distributed evenly throughout the lung and the mixing and turnover of alveolar gas is relatively rapid. When airway obstruction is present gas distribution tends to becomes more uneven and the mixing and turnover takes longer. The Lung Clearance Index (LCI) is a way to measure these ventilation inhomogeneities and is basically a description of how much ventilation is required to completely clear the FRC. It was first described by Margaret Becklake in 1952 but has languished for many years. It has been revived in the last decade or so, particularly because it requires only tidal breathing which allows it to be measured in infants and children.

The measurement process is called an Inert Gas Multi-Breath Washout. It uses an open circuit and requires a tracer gas that is both inert and relatively insoluble and for these reasons has been primarily limited to helium, nitrogen and sulfur hexafluoride (SF6) although methane and argon could potentially be used as well.

At the start of the test, the tracer gas must be well distributed throughout the lung which means that for all gases except nitrogen there needs to be a wash-in period (although there of course needs to be a prolonged period of room air breathing between nitrogen washout tests).

The tracer gas mixture is breathed until 30 or 60 seconds after the inspiratory and expiratory concentrations have equalized (ERS/ATS statement says 5 minutes for adults and 4 minutes for children). The patient is then detached from the tracer gas source at end-exhalation and the washout period begins (mechanically, this process is reversed for N2 washout since wash-in occurs while breathing room air and the patient needs to breath 100% oxygen during the washout period).

With each succeeding tidal breath, the tracer gas is leaves the lung.

Exhaled volume is accumulated and the test continues until the exhaled gas concentration is 1/40th the initial concentration for three consecutive tidal breaths. The exhaled tracer gas volume is integrated from the flow and gas analyzer signals and FRC is calculated from:

where:

Ftrace = fractional concentration of tracer gas.

and the Lung Clearance Index is then calculated from:

The Cumulative Exhaled Volume is expressed as liters, BTPS and corrected for system deadspace.

FRC tends to be lower when measured with SF6 than with N2. This is likely due to the fact that SF6 must be washed-in before it is washed-out and it may not completely equilibrate with the poorly ventilated parts of the lung. Despite this there doesn’t seem to be a particularly significant difference in LCI values based on which gas is used.

LCI testing may take a prolonged period of time and this is partly because both the wash-in and the wash-out periods require at least 5 minutes each but also because the LCI test should be performed several times in order to ensure that repeatable results have been obtained. Given the length of time that patients are on a mouthpiece leaks are a potential problem and for this reason it is recommended that results with an FRC 10% greater than the mean should be discarded.

Most studies of LCI have presented grouped results:

LCI (SD), Children:

Ref:	Gas:	Normal:	Cystic Fibrosis:	Asthma:
[A]	SF6	6.45 (0.49)	11.53 (2.86)
[C]	SF6	6.33 (0.48)	8.33 (2.48)
[E]	SF6	6.19	10.05
[E]	N2	6.81	11.29
[F]	SF6	7.2 (0.3)	8.4 (1.5)
[H]	SF6	6.24 (0.47)		6.69 (0.91)

LCI (SD), Adults:

Ref:	Gas:	Normal:	Cystic Fibrosis:	Asthma:	Bronchiectasis:
[B]	SF6	7.21 (0.26)
[D]	SF6	6.7 (0.4)	13.1 (3.8)
[I]	SF6				9.1 (2.0)
[J]	N2	7.19 (0.53)
[K]	N2	6.02 (0.31)		6.26 (0.42)

A recent study [G] however, has published a reference equation for LCI in healthy children (aged 2 weeks to 19 years):

Since LCI is referenced to an individual’s measured FRC there doesn’t seem to be a significant gender difference in results. It has been noted that among children LCI decreases with increasing age and height, and that among adults there seems to be a slight increase with age.

It’s not particularly clear to me why so much of the research on LCI has been done using SF6. I realize that there are additional measurements that can be made when you compare washouts with different gases (specifically it is possible to determine if the ventilation inhomogeneity is occurring at the level of the acinus or higher up in the peripheral airways), but for the LCI itself nitrogen washout seems to work as well as any of the other inert gases. This is important for the future of LCI testing since SF6 is a greenhouse gas that has not been approved for clinical applications in the United States and helium is becoming scarce and progressively more expensive.

For the last decade or so there has been a greater emphasis on early intervention for children with cystic fibrosis and a number of studies have shown that there can be significant changes in LCI without notable changes in FEV1. It’s not clear to me how the LCI measure differs from the phase III slope of the single-breath nitrogen washout, however, and these two tests have not been performed in the same patients. One major advantage of the LCI is that it only requires tidal breathing which makes it particularly suited for testing children.

Interestingly, it doesn’t appear that LCI results for individuals with asthma are substantially different from healthy controls. This is not necessarily surprising since the LCI is sensitive primarily to the peripheral airways and asthma resides in the larger airways. There are many patients with COPD however, that do not have significant changes in spirometry from visit to visit and yet report significant changes in how well they feel. Because the LCI is a measurement of ventilation inhomogeneity rather than expiratory flow rates it would interesting to see if it (or the phase III slope of the single-breath nitrogen washout) tracks patient status better than spirometry in these cases.

Theoretically the LCI could be measured by any test system that is able to perform N2 washout lung volumes. Despite the fact that both types of testing measure FRC the maneuvers are not the same however, and the software requirements are substantially different. At the present time there are no commercial test systems that are able to measure the LCI although this may change since the ERS/ATS released guidelines in 2013 that specifically addressed the technical and software requirements for LCI measurements (and if you read between the lines on their websites a couple of manufacturers are at least considering adding the LCI to their test systems).

The FEV1 and the FEV1/FVC ratio have been the primary focus for the detection and monitoring of airway obstruction for decades. This is in part understandable since the Forced Vital Capacity is a relatively simple and repeatable test that requires minimal equipment. Spirometry is not sensitive to all forms of airway obstruction and it has become evident in a variety of lung diseases that changes (or the lack of changes) in FEV1 does not match either disease progression or status. Ventilation inhomogeneity may be one of the missing pieces in this puzzle and as such, the LCI deserves more extensive research in a wider variety of lung diseases and age groups.

References:

[A] Aurora P, Gustafsson P, Bush A, Lindbla A, Oliver C, Wallis CE, Stocks J. Multiple breath inert gas washout as a measure of ventilation distribution in children with cystic fibrosis. Thorax 2004; 59: 1068-1073.

Becklake MR. A new index of the intrapulmonary mixture of inspired air. Thorax 1952; 7: 111-116.

[B] Fuchs SI, Buess C, Lum S, Kozlowska W, Stocks J, Gappa M. Multiple breath washout with a sidestream ultrasonic flow sensor and mass spectrometry. A comparative study. Pediatric Pulmonology 2006; 41: 1218-1225.

[C] Gustafsson PM, Aurora P, Lindblad A. Evaluation of ventilation maldistribution as an early indicator of lung disease in children with cystic fibrosis. Eur Respir J 2003; 22: 972-979.

Gustafsson PM, De Jong PA, Tiddens HAWN, Lindblad A. Multiple-breath inert gas washout and spirometry versus structural lung disease in cystic fibrosis. Thorax 2008; 63(2): 129-134.

[D] Horsley AR, Gustafsson PM, Macleod KA, Saunders C, Greening AP, Porteous DJ, Davies JC, Cunningham S, Alton EWFW, Innes JA. Lung clearance index is a sensitive, repeatable and practical measurement of airways disease in adults with cystic fibrosis. Thorax 2008; 63(2): 135-140.

[E] Jensen R, Stanojevic S, Gibney K, Slazar JG, Gustafsson P, Subbarjo P, Ratjen F. Multiple breath nitrogen washout: a feasibile alternative to mass spectrometry. PLOS One 2013; 8(2): e56868.

[F] Lum S et al. Early detection of cystic fibrosis lung disease: multiple-breath washout versus raised volume tests. Thorax 2007; 62: 341-347.

[G] Lum S et al. Age and height dependence of lung clearance index and functional residual capacity. Eur Respir J 2013; 41: 1371-1377.

[H] Maclead KA, Horsley AR, Bell NJ, Greening AP, Innes JA. Ventilation heterogeneity in children with well controlled asthma with normal spirometry indicates residual airways disease. Thorax 2009; 64: 33-37.

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: 507-522.

[I] Rowan SA et al. Lung Clearance Index is a repeatable and sensitive indicator of radiological changes in bronchiectasis. Am J Resp Crit Care Med 2014; 189: 586-592.

[J] Singer F, Houltz B, Latzin P, Robinson P, Gustafsson P. A realistic validation study of a new nitrogen multiple breath washout system. Plos One 2012; 7(4): e36083.

[K] Verbanck S, Paiva M, Schuermans D, Hanon S, Vincken W, Van Muylem A. Relationship between the lung clearance index and conductive and acinar ventilation heterogeneity. J Appl Physiol 2012; 112: 782-790.

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

Closing Volume (CV) is a measurement made from a single-breath nitrogen washout (SBNW) test. It was commonly performed decades ago and elevated values were considered to be an indication of small airways disease and an aid in the detection of the early stages of airways disease. It is hardly ever performed any more but I still occasionally see research studies that include this test and almost every test system that is capable of measuring lung volumes by nitrogen washout is also capable of performing a CV.

The CV test is performed with a test system with an analyzer tap immediately next to the mouthpiece and a way of delivering 100% oxygen either from a demand valve or a reservoir. Originally this test was performed using a real-time nitrogen analyzer but it is now almost always performed with an oxygen analyzer instead. A subject is placed on the mouthpiece and exhales to RV and then inhales 100% oxygen to TLC. The subject then exhales steadily to RV and during the exhalation the subject’s exhaled nitrogen (either real or calculated from the oxygen concentration) is plotted against their exhaled volume and produces a curve that looks like this:

The trace is divided into four portions. Phase I is the very beginning of exhalation where only oxygen is being exhaled and consists primarily of test system and airway deadspace. Phase II is where the nitrogen concentration rises rapidly and consists of mixture of airway and alveolar gas. Phase III is where the nitrogen concentration plateaus and its slope depends on the uniform distribution of gas in the lung. Phase IV is where the nitrogen concentration rises more or less abruptly from the plateau and is considered to be part of the closing volume. The inflection point between phase III and phase IV is not always easy to discern and may need to be extrapolated from the phase III and phase IV slopes.

Closing Volume is usually expressed either as the Closing Volume/Vital Capacity ratio (CV/VC), or Closing Capacity is calculated by adding CV to RV (which is measured as part of a separate lung volume test) and this is expressed as the Closing Capacity/Total Lung Capacity ratio (CC/TLC). An additional measurement that can be obtained from this maneuver includes the slope of phase III in percent N2 per liter (%N2/L).

When an individual exhales to RV and then inhales to TLC, at the beginning of the inhalation the inhaled air preferentially goes to the apices of the lung. This initial volume of air contains machine and airway deadspace gas that contains a high concentration of nitrogen. As the inhalation continues the basal portion of the lung then receives 100% oxygen. During exhalation, the basal portion of the lung empties first and the apices last. The nitrogen concentration abruptly rises when the flow rate from the basal portion decreases and the expiratory flow comes primarily from the apices. This inflection has been considered to be a sign of airway closure.

One of the first problems to be noted with the Closing Volume test is that the measured CV increases as the expiratory flow rate increases. For this reason expiratory flow is usually maintained at 0.4 to 0.5 L/sec either by visual feedback or a flow-limiting orifice. Although an orifice tends to increase airway pressure at least one research study has indicated that this alone does not change the measured Closing Volume.

Note: The ERS/ATS statement on inert gas washout testing specifies that the inhalation to TLC should also be at 0.4 to 0.5 L/sec but the reason for this is not explained and I have found no studies on Closing Volume that address this point. Interestingly, in one population study only 42% of its participants were able to correctly perform a Closing Volume test and the primary reason for this was an inability to inhale and exhale at the correct flow rate.

When the Closing Volume test was performed on different populations it was noted that CV/VC and CC/TLC were elevated in individuals with COPD and Asthma. It was also noted that it was elevated in smokers without apparent airway obstruction. For these reasons it was considered to be a way to measure small airways disease and many PFT labs began to perform this test routinely.

Unfortunately for the early advocates later research showed that a relatively high proportion of healthy, asymptomatic non-smokers had “abnormal” results and that CV was not significantly different between individuals with symptomatic and asymptomatic lung disease. In addition the CV test has relatively poor within-individual reproducibility and this may be one of the reasons that the normal range for CV has been found to be quite large (in one study a CV/VC up to 158% of predicted was WNL). Moreover, both normal and abnormal CV results were poor at predicting whether or not an individual developed airway obstruction in the future. The sparkle left the Closing Volume test relatively quickly and by the 1990’s it was only rarely performed either clinically or for research.

The original interpretation of Closing Volume test was that it was related to the closure of airways. A relatively recent research study using a sophisticated computer model has called this into questions. The computer model indicated that the same N2 curve will occur when airflow from the basal region slows or stops regardless of whether this is due to airway closure or not. The model can’t say that airway closure doesn’t occur, only that it isn’t the only possible interpretation of the N2 curve.

One of the alternate measurements from a SBNW test is the phase III slope of N2 (%N2/L) which has been used as a measure of ventilation homogeneity. This makes a certain amount of sense and is similar to the slope of the methane tracing during the exhalation phase of a DLCO test. I’ve noticed in the past that the methane tracing tends to be horizontal in patients without airway obstruction and that when airway obstruction is present the slope of the methane tracing is roughly proportional to the degree of airway obstruction.

The ERS/ATS statement on inert gas washout tests indicates that the phase III N2 slope should be measured using linear regression. It suggests defaulting to between 25% and 75% of the exhaled volume but also suggests that this should be manually adjusted to ensure that phase II and phase IV values are excluded. In addition the statement says that analyzer noise and cardiogenic oscillations should also be excluded but has no particular guidelines for recognizing these things. The phase III N2 slope has been used in a number of research studies but primarily as a way of characterizing their study populations and not as an outcome measurement. Although the degree of ventilation inhomogeneity is a somewhat relevant finding I am hard pressed to see that it is clinically useful enough to justify performing a SBNW.

A SBNW can usually be performed on almost any test system that is capable of performing N2 washout lung volumes. The CV and phase III N2 slope provide some interesting physiologic information about how ventilation proceeds in different parts of the lung, but their clinical usefulness is small. The early enthusiasm for the Closing Volume measurement turned out to be unfounded and it is now rarely, if ever, performed.

Although the clinical relevance is questionable there may still be some value in performing CV and phase III N2 slope tests in research studies and there are reference equations for these tests for those that are interested:

Adult male:

Reference:	Test Value:	Reference Equation:
[C]	CV (L):	(0.0144 x age) + (0.0027 x height) – 0.3735
[A]	CV/VC (%):	0.357 x age) + 0.562
[B]	CV/VC (%):	(0.311 x age) – (0.0946 x height) + (0.114 x weight) 10.1
[C]	CV/VC (%):	(0.2799 x age) – (0.0803 x height) + 15.8723
[C]	CC (L):	(0.0322 x age) + (0.0248 x height) – 2.91
[C]	CC/TLC (%):	(0.03518 x age) – (0.1126 x height) + 42.6671
[A]	CC/TLC (%):	(0.496 x age) + 14.878
[B]	%N2/L Slope	(0.00814 x age) – (0.00567 x weight) + 2.07

Adult female:

Reference:	Test Value:	Reference Equation:
[C]	CV (L):	(0.0101 x age) + (0.0056 x height) – 0.7853
[A]	CV/VC (%):	(0.293 x age) + 2.812
[B]	CV/VC (%):	(0.291 x age) + (0.0761 x weight) – 2.38
[C]	CV/VC (%):	(0.2734 x age) + 2.882
[C]	CC (L):	(0.0303 x age) + (0.0197 x height) – 2.1137
[A]	CC/TLC (%):	(0.536 x age) + 14.42
[C]	CC/TLC (%):	(0.4245 x age) + 23.6487
[B]	%N2/L Slope	(0.0163 x age) – (0.00742 x weight) + 0.854

References:

Al-Bazzaz FJ. Single-breath nitrogen washout. Chest 1979; 76(1): 83-88.

Buist AS, Ross BB. Closing volume as a simple, sensitive test for the detection of peripheral airway disease. Chest 1973; 63(4): 29S-30S.

[A] Buist AS, Ross BB. Predicted values for closing volumes using a modified single-breath nitrogen test. Am Rev Resp Dis 1973; 107: 744-752.

Buist AS. Current status of small airways disease. Chest 1984; 86(1): 100-105.

[B] Dosman JA, Cotton DJ, Graham BL, Hall DL, Froh F, Barnett GD. Sensitivity and specificity of early diagnostic tests of lung function in smokers. Chest 1981; 79(1): 8-11.

Kitaoka H, Kawase I. A novel interpretation of closing volume based on single-breath nitrogen washout interpretation. J Physiol Sci 2007; 57(6): 367-376.

Olin AC, Andelid K, Vikgren, Rosengren A, Larsson S, Bake B, Ekberg-Jansson A. Single breath N2-test and exhaled nitric oxide in men. Respiratory Medicine 2006; 100: 1013-1019.

Robinson PD et al. ERS/ATS Consensus Statement for inter gas washout measurement using multiple- and single-breath tests. Eur Respir J 2013; 41: 507-522.

Rodarte JR, Hyatt RE, Cortese DA. Influence of expiratory flow on closing capacity at low expiratory flow rates. J Appl Physiol 1975; 39(1): 60-65.

Rodarte JR, Hyatt RE, Rehder K, Marsh HM. New tests for the detection of obstructive pulmonary disease. Chest 1977; 72(6): 762-768.

Travis DM, Green M, Don H. Simultaneous comparison of helium and nitrogen expiratory “closing volumes”. J Appl Physiol 1973; 34(3): 304-308.

[C] Viegi G, Paoletti P, De Pede F, Prediletto R, Carrozzi L, Pistelli G, Giuntini. Single-breath nitrogen test in an epidemiologic survey in North Italy. Reliability, reference values and relationship with symptoms. Chest 1988; 93: 1213-1220.

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

In 1844 John Hutchinson published his first paper describing his spirometer and his research on the Vital Capacity. He was the first person to use the word “spirometer” to describe his instrument and the first to use the term “vital capacity” to designate the maximum amount of air an individual can exhale after a maximal inhalation. Although he is remembered as the inventor of the spirometer, he was not the first person to use a gasometer to measure lung volumes nor was he the first to measure the vital capacity. What made his research different from those that came before him was partly the prodigious number of individuals whose vital capacity he measured but far more importantly that he was able to show a clear relationship between standing height, age and vital capacity which had not been previously apparent. This finding galvanized researchers in England, Europe and the United States and in many ways helped set the course of research into lung function for many decades to come.

This clear relationship between standing height and vital capacity has been taken as scientific fact since that time despite inconsistencies not only in Hutchinson’s data but in almost all population studies since that time. The problem is that the relationship between standing height and vital capacity is not precise but only approximate. In order to explain the range of results that appeared in his data Hutchinson and other researchers of his time divided their study population into groups by their occupation. This approach may appear to be quaint to us now but at the time they were very serious both about the utility of doing this and what it told them about the different classes of society.

The first studies on vital capacity that divided the population by race were done in the United States. The reasons that this was done are both simple and complex, and overall there’s not a lot we can look back and be proud of. At that time there was an overwhelming societal concern with the races in general and not only the recently freed black slaves and the Amerindians but also about the different “races” of Europe that were emigrating to the United States. There was much public talk and private thought about the concepts of racial degeneracy, racial mongrelization and racial vitality, and unfortunately the vital capacity was taken as a way of measuring these things. Despite incredibly significant errors in both the methods and conclusions of these studies this approach spread to Europe during the second half of the 19^th century and dividing study populations by race has become standard practice ever since.

When I first started doing pulmonary function testing I was taught to decrease the predicted vital capacity by 15% for Blacks and 10% for Asians. Decades later ethnicity-based population studies replaced these fractions. I always took this as the correct way to approach predicted values (and it is embedded in the ATS/ERS standards) but at the same time I’ve always had patients where it was either difficult to assign ethnicity or where their results significantly exceeded their ethnicity-based reference values. Over the last several years I have had the opportunity to study the issues surrounding reference equations extensively and I have become somewhat disenchanted with the notion of ethnicity-based reference equations.

There are several reasons for this. First, and most importantly, what exactly, is ethnicity? Ethnicity may appear to be obvious but vital capacity is primarily related to the height, depth and width of the lungs and to the range of motion of the diaphragm and rib cage. The actual relationship between standing height and vital capacity is due to not only to developmental genes but also to an individual’s diet and environment during the developmental period. I am not going to say that locality-based populations that share a common diet, environment and a high percentage of genes don’t have a similar relationship between standing height and vital capacity (and FEV1, TLC, DLCO etc.). This may be what we think of as ethnicity but the problem is that there isn’t any particularly good way to define it. Is it based on skin color? Presence of an epicanthic fold? The place you were born? The place where your grandparents were born? Even if you can decide what ethnicity actually is the differences in diet, environment and genes that are the hallmarks of any ethnicity are decreasing rapidly worldwide.

Next, even when the vital capacity is studied in the same ethnic group, the differences within that group can equal or even exceed that which is considered to exist between races. Caucasians as an “ethnic” group have had more vital capacity population studies performed than all the other ethnicities put together.

Depending on age and using commonly available reference equations, for a 175 cm Caucasian male the differences in the maximum and minimum possible predicted vital capacities range from 0.56 to 0.99 L (which is 11% to 18% of the studies’ mean values). In the NHANESIII study, the differences between Caucasian and Black predicted vital capacities range from 0.47 to 0.87 L (12% to 19% of the predicted mean). How can we consider the difference in predicted FVC from different ethnicities to be so significant and yet it is in the same range as the differences from within a single ethnicity?

Finally, this spirometry report comes from a middle-aged Caucasian female with average height and weight. If you consider the percent predicted results to be acceptable, then we have a problem.

If this patient’s FVC and FEV1 had been 100% of predicted, then we would have said she was completely normal but in reality her FVC would have been 22% less and her FEV1 would have been 28% less than it “should” have been and she would rightly be feeling some distress about her breathing. We may consider an 8% or 12% or 15% difference in predicted FVC between different ethnicities to be terribly significant but the reality is that on an individual basis our ability to accurately predict FVC is actually mediocre at best.

So what can be done to improve this? Surprisingly the reasons for ethnic differences in lung capacity has been studied only a small number of times. Researchers have attempted to use a variety of alternative anthropometric measurements to improve the prediction of vital capacity, notably:

• sitting height
• leg height (standing minus sitting height)
• sitting/standing height ratio
• biacromial width (i.e., horizontal distance across the shoulders measured between the acromia (bony points))
• elbow breadth
• BMI
• chest expansion (difference in chest circumference between TLC and RV)
• arm span
• radiographic measurement of lung height, width, depth and surface area.

Unfortunately, no single study has made all of these measurements in a single group of subjects. In addition the number of subjects in each study was not terribly large and the number of “races” represented were limited and different from study to study. This makes it difficult to assess the significance of results across studies and most of these alternative measurements appear to make only a slight difference in the prediction of FVC.

Not altogether surprising however, radiographic measurements, specifically lung width and surface area, appear to explain many of the differences in FVC (and TLC). Radiographic measurements are a somewhat invasive measurement (annual radiation burden) and it’s not clear to me how standardized these measurements are. Most importantly radiographic measurements of this kind are not at all likely to be commonly available in patients receiving spirometry or other pulmonary function tests.

Sitting height on the other hand is totally non-invasive and reduces the apparent difference in FVC between some ethnicities (but not all) by about a third. Several studies have shown that sitting height has a statistical significance roughly equal to standing height.

I am disappointed to have been unable to find any study of individuals with significantly elevated lung capacity, even outside the context of alternative measurements. It would seem to me that these individuals hold a variety of clues about the anatomical and physiological reasons for lung capacity and that further study of them would improve our ability both to predict lung capacities for any given individual and for “ethnicities” in general.

At the moment however, there doesn’t appear to be an overwhelming good reason to replace standing height and ethnicity-based reference equations but this also doesn’t mean we should stop looking. To me the goal would be one or more anthropometric measurements that could be made relatively easily and that would make it unnecessary to determine ethnicity. I don’t think we’ve exhausted all of the possible alternative anthropometric measurements that could be made. I also don’t think that a large enough group of subjects has been studied with a sufficient number of alternative measurements and ethnicities.

I am concerned that because we “know” that differences in the relationship between standing height and lung capacity are due to “race” and “ethnicity” that we are not looking to see anything different. I am particularly concerned that simple alternative measurements such as sitting height and arm span are not routinely made or statistically analyzed in ongoing population studies. It may turn out that these (and other) alternative anthropometric measurements are not a statistically significant improvement over standing height, but as long as we continue to look only at standing height we will never find an alternative.

Genes, diet and environment likely have a powerful effect on the relationship between standing height and lung capacity. The degree to which each of these affects this relationship is unclear but as world populations become ever more urbanized and interconnected regional differences in all of these factors is decreasing. Our current approach towards assessing lung capacity based on ethnicity is flawed for a variety of reasons and we need to keep this in mind when we assess the results of our testing.

References:

Braun L. Breathing race into the machine: The surprising career of the spirometer from plantation to genetics. University of Minnesota Press, 2014.

Donnelly PM, Yang T-S, Peak JK, Woolcock AJ. What factors explain racial differences in lung volume? Eur Respir J 1991; 4: 829-838.

[A] Gutierrez C, et al. Reference values of pulmonary function tests for Canadian caucasians. Can Respir J 2004; 6: 414-424.

[B] Hankinson JL, Odencrantz JR, Fedan, KB. Spirometric reference values from a sample of the general U.S. Population. Amer J Resp Crit Care 1999; 159: 179-187

Harik-Khan RI, Fleg JL, Muller DC, Wise RA. The effect of anthropometric and socioeconomic factors on the racial difference in lung function. Am J Resp Crit Care Med 2001; 164: 1647-1654.

Jacobs DR, Nelson ET, Dontas AS, Keller J, Slattery ML, Higgins M. Are race and sex differences in lung function explained by frame size? Am Rev Resp Dis 1992; 146: 644-649.

[C] Knudson RJ, Lebowitz MD, Holberg CJ, Burrows B. Changes in the normal maximal expiratory flow volume curve with growth and aging. Am Rev Resp Dis 1983; 127: 725-734

Korotzer B, Ong S, Hansen JE. Ethnic differences in pulmonary function in health nonsmoking Asian-Americans and European-Americans. Am J Resp Crit Care Med 2000; 161: 1101-1108.

[D] Kuster SP, Kuster D, Schindler C, Rochat MK, Braun J, Held L, Brandli O. Reference equations for lung function screening of healthy never-smoking adults aged 18-80 years. Eur Respir J 2008; 31: 860-868.

Louw SJ, Goldin JG, Joubert G. Spirometry of healthy adult South African men. SAMJ 1996; 86(7): 814-819.

[E] Morris JF, Koski A, Johnson LC. Spirometric standards for healthy nonsmoking adults. Am Rev Resp Dis 1971; 103: 57-67.

[F] Morris JF, Koski A, Temple WP, Claremont A, Thomas DR. Fifteen-year interval spirometric evaluation of the Oregon Predictive equations. Chest 1988; 93: 123-27

[G] Johannessen A, Lehmann S, Omenaas ER, Side GE, Bakke PS, Gulsvik A. Post-bronchodilator spirometry reference values in Adults and implications for disease mangement. Amer J Resp Crit Care Med 2006; 173(12): 1316-1325

[H] Marsh S, Aldington S, Williams M, Weatherall M, Shirtcliffe P, McNaughton A, Pritchard A, Beaseley R. Complete reference ranges for pulmonary function tests from a single New Zealand population. New Zealand Med J 2006; 119: N1244.

[I Pereira CADC, Sato T, Rodrigues SC. New Reference Values for forced spirometry in white adults in Brazil. J Bras Pneumol 2007; 33: 397-406.

[J] Roberts CM, MacRae KD, Winning AJ, Adams L, Seed WA. Reference values and prediction equations for normal lung function in a non-smoking white urban population. Thorax 1991; 46: 643-650.

Schwartz J, Katz SA, Fegley RW, Tockman MS. Sex and race differences in the development of lung function. Am Rev Resp Dis 1988; 138: 1415-1421.

Withers RT, Bourdon PC, Crockett A. Lung volume standards for healthy male lifetime nonsmokers. Chest 1988; 92(1): 91-97.

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

I was reviewing a pre- and post-bronchodilator spirometry report that showed a relatively large increase in FVC but the change in FEV1 was not significant. It’s not impossible for a patient to show this kind of a pattern following a bronchodilator but it is somewhat unusual. Usually when I see this it means that the patient exhaled a lot longer post-BD than they did pre-BD. When I looked however, I saw that just the opposite was true, the expiratory time was actually shorter for the post-BD effort than it was for the pre-BD effort.

The reported expiratory time isn’t always accurate, though. When a patient stops exhaling during an FVC effort but doesn’t inhale our test system will sometimes continue to time the effort. When this happens the volume-time curve becomes flat and the expiratory time is reported with a falsely high value.

This is what I expected to see when I looked at the volume-time graphs for this report. What I saw instead was this:

Since it showed pre- and post-BD volume-time curves that were fairly similar why were the volumes so different? Our test system software allows the FVC, FEV1 and the graphs to all be selected from different efforts so my suspicions at this point were that the technician performing the tests had selected these values from the wrong tests by accident. When I pulled up the raw test data I saw that the pre-BD spirometry results were somewhat similar, but they were all more than a half a liter less than the best post-BD FVC.

If this was the case why were the pre- and post-BD volume-time curves so similar? When I looked at the raw graphs I saw what had happened.

The patient had stopped exhaling around 2-1/2 seconds into the spirometry effort, inhaled a small amount of air and then continued exhaling for another 8 seconds. The test system software had used the volume from the 2-1/2 second point in the exhalation when reporting the FVC but for some reason had continued measuring time until the patient “really” stopped exhaling. This means that there were two end-of-tests for this effort, one for the volume and one for time.

To some extent I can understand why our test system software measured the FVC where it did since a patient inhalation is usually a good signal that they have stopped exhaling. What I don’t understand is why the software continued to measure time until the “real” end of the test, and if it was able to measure time accurately, why didn’t it measure the “real” FVC volume accurately as well?

Surprisingly enough the ATS/ERS statement on spirometry says nothing about stopping the test when a patient inhales and instead only says that the end-of-test criteria is satisfied when “the volume-time curve shows no change in volume (<0.025 L) for >= 1 second”. I have seen this type of expiratory pattern before (i.e. exhalation, short inhalation, continued exhalation) but when I looked at it in the past the software had measured the FVC volume correctly or at least the expiratory time matched the point at which the FVC volume was measured. This is the first time I’ve noticed a distinct discrepancy and it is not clear why this occurred. The software may have a certain inspiration threshold for determining an end of exhalation and in this case maybe it was exceeded where it hadn’t been in the past but again, if that’s the case why didn’t it apply to both volume and time?

The ATS/ERS statement on interpretation says that the largest vital capacity regardless of where it comes from should be used to calculate the FEV1/VC ratio. This says to me that the spirometry software should measure the largest FVC volume even if the patient has stopped exhaling or even inhaled somewhat as long as they re-start their exhalation and reach a higher FVC. The ATS/ERS standard does not touch on this and I would hope that the next time it is updated that the end-of-test criteria are more comprehensive.

I used a graphics program to measure the “real” FVC and found it was about 2.49 L. This meant that the real pre- and post-BD change in FVC was only about 5% and that there really had been no significant response to the bronchodilator. I feel fortunate that I noticed the discrepancy because otherwise this patient’s report would have indicated that they had a significant response to bronchodilator. I will also pay more attention when I see this pattern in the future and not assume that either the FVC volume or the expiratory time are correct.

I checked the manual for our test system and I could find nothing about what conditions the software uses to determine the end of exhalation other than the ATS/ERS end-of-test criteria that has already been mentioned. Test software routinely needs to make sophisticated decisions about test quality and how results should be measured and selected. When the ATS/ERS standards do not speak to a specific situation (even when it occurs somewhat commonly) programmers have to take their best guess about how to handle it. My concern about these types of software decision is that they are usually not documented and probably not evident even to relatively sophisticated users.

Equipment manufacturers put significant resources into their software and they have a right to consider their software algorithms to be proprietary information. These algorithms have a direct bearing on test accuracy however, and over the years I’ve had numerous problems caused by undocumented software issues. I’ve contacted our equipment manufacturer about these problems many times but I’ve rarely gotten any kind of an answer and only infrequently even an acknowledgment that I’ve submitted the request. There needs to be a middle ground of some kind where both the rights of the manufacturers and those of the end-users are respected. Because computers have become an essential and irreplaceable part of testing I’d like to suggest something like an open source software model. An ATS/ERS (or ACCP or AARC or whoever) committee could publish recommended algorithms for spirometry and other pulmonary function tests. Researchers, users and manufacturers could submit and comment on suggested changes and at regular intervals (annually?) a revised standard could be released. It would be up to manufacturers to update their software and then show it meets the new standard. This would help ensure that our pulmonary function equipment uses testing algorithms that are as up-to-date and accurate as possible and yet still leaves plenty of room for manufacturers to differentiate themselves in other ways. Just a thought.

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

The current ATS/ERS guidelines require that an individual have a post-bronchodilator increase in FEV1 or FVC of at least 12% and 200 ml in order for it to be considered a significant response. Numerous studies have shown however, that many patients that don’t meet these criteria, particularly those with COPD, do have a clinically significant improvement with bronchodilators.

The September 2014 issue of Chest had a point-counterpoint set of editorials on this standard and on assessing the response to bronchodilator in general. Both sides had a number of interesting things to say but to a large extent one side was talking apples (physiology) and the other side oranges (statistics). I actually think that both sides feel there are significant problems with the ATS/ERS standards, they just differ in what they think is wrong and in the best way to fix it.

One statistical argument was that the ATS/ERS guideline is a one-size-fits-all solution that is designed more to detect asthmatic-type responses than the more subtle changes that can occur in individuals with COPD that although small, are clinically relevant. I am inclined to agree with this but as much as I and others think that the current ATS/ERS standard likely needs revision the difficulty with this is that spirometry is a “noisy” measurement with a lot of variability.

Spirometry variability and the limits to its accuracy comes from issues to familiar to all of us:

• the patient’s ability to understand and perform spirometry
• the technician’s ability to encourage and guide a patient through a spirometer maneuver
• the spirometer’s ability to measure exhaled flow and volume accurately

“Noise” is one of the reasons why it can be difficult to determine statistically and clinically significant changes. It’s also why the threshold for significant post-bronchodilator change is set as high as it is and may also be the reason why it shouldn’t be lowered.

Even though there may be reasons why the ATS/ERS guidelines for post-bronchodilator improvements in FEV1 and FVC shouldn’t be revised at the very least they need to become more inclusive and consider more factors. There is too much emphasis placed on the changes in FEV1 and FVC as the sole indication for a response to bronchodilator particularly since there are other ways in which a response can be measured.

Inspiratory flow:

During a forced expiration airways tend to narrow because of the increase in transpulmonary pressure. This narrowing may reduce or otherwise mask post-bronchodilator improvements in airway caliber. For this reason improvements in inspiratory flows may be a better indicator of bronchodilation.

Patients with COPD have been shown to have significant increases in Peak Inspiratory Flow (PIF), Forced Inspired Volume in one second (FIV1) and their Forced Inspiratory Vital Capacity (FIVC) following a bronchodilator. These increases are usually as large and frequently larger than FEV1, FVC and FEFmax (both as an absolute and as a relative change). Of note, inspiratory flows were often shown to increase even when FEV1 did not change significantly.

Compared to the number of studies on expiratory flows there are a miniscule number of studies on inspiratory flow. Analysis of results is not helped by the lack of standards either for the inspiratory maneuver or for what constitutes a significant change in the inspiratory flow rates. Nevertheless, improvements in inspiratory flow rates are linked to a decrease in symptoms of dyspnea. It would seem that a comprehensive evaluation of the spirometric response to bronchodilator, particularly in individuals with COPD, should include an inspiratory maneuver and inspection of the PIF and FIVC results.

TLC, FRC, RV and IC:

A number of investigators have shown that individuals with COPD that do not have a significant FEV1 response to bronchodilator can show significant decreases in FRC and RV. Measuring changes in FRC and RV is a time consuming process that requires specialized equipment, however. For this reason Inspiratory Capacity (IC) measurements are frequently used as a surrogate for FRC measurements. There is a lot of evidence that a increase in IC improves both dyspnea and exercise capacity even when there isn’t a significant change in FEV1.

It would seem that IC should be routinely be measured when assessing an individuals response to bronchodilator and an increase in IC of 200 ml and/or 10% of predicted has been proposed as marker for significant change following a bronchodilator. IC however, cannot be measured as part of a forced vital capacity and needs to be measured during a slow vital capacity maneuver instead. Performing both forced and slow vital capacity maneuvers increases the complexity and time for a spirometry session and this may act as a disincentive to performing both maneuvers. The fact that there is no additional reimbursement for performing both maneuvers is a further disincentive.

RAW, sGAW:

RAW and sGAW have been shown to improve post-bronchodilator in almost all subjects. As expected individuals with asthma tend to show the greatest improvement but individuals with COPD and with normal lungs improve as well. Because sGAW measurements have a high level of variance this means that a changes in RAW or sGAW need to be considered carefully, particularly since it is not necessarily clear what consititutes a clinically significant change.

RAW and sGAW measurements require a plethysmograph and repeatable measurements requires a fair degree of technical proficiency and patient cooperation. For these reasons it’s not clear that RAW and sGAW really have any particular advantage over spirometric measurements in routine clinical practice. A number of investigators have shown however, that the deep inhalation that precedes a forced vital capacity maneuver can cause bronchoconstriction and therefore decrease the apparent response to bronchodilator. It would seem that the best use of RAW and sGAW for assessing bronchodilator response would be in research and clinical trial when for one reason or another a forced vital capacity maneuver is contraindicated.

Oscillometry:

Forced Oscillation and Impulse oscillometry have been used to assess the response to bronchodilators. Investigators have reported that the greatest changes post-bronchodilator occur in resistance and reactance at specific frequencies, notably R5, R20, X5 and the resonant frequency (RF).

It’s less clear what the changes in oscillometric parameters means in terms of clinical significance particularly since oscillometry is sensitive primarily to the central and peripheral airways. A high level of variance has also been noted in oscillometry measurements of normal subjects. In addition some investigators have noted that oscillometry resistance measurements are less sensitive than spirometric measurements in both a statistical and a clinical sense. The primary advantage of oscillometry is that is only requires passive breathing by a patient which makes it ideal for use with children and this reason alone makes it a useful technique.

 

The most effective ways to assess the response to bronchodilator has been debated for decades and that is not likely to change any time soon. Changes in FEV1 and FVC have been the central point in these debates but the changes in lung physiology that occur after a bronchodilator are complex. For this reason changes in PIF, FIV1, FIVC, IC, RAW, sGAW and oscillometry can and have been used to detect improvements in airflow that are not reflected solely in the FEV1 and FVC. The current ATS/ERS standards are largely based on statistics and on the ability to defect changes. Clinically significant changes are not necessarily the same as statistically significant changes however, and the standards likely need to be revised and updated.

If I was asked (however unlikely that may be) my recommendation would be to revise the standards for spirometry to include separate forced inspiratory, forced expiratory and slow vital capacity maneuvers, particularly for a first assessment or when pre- and post-bronchodilator measurements are being made. This would permit routine measurement of PIF, FIVC, FIV1, SVC and IC as well as the regular expiratory parameters. This would provide a broader base of measurements when assessing an individual’s response to bronchodilator and would also help make sure the highest vital capacity is used to calculate the FEV1/VC ratio and that inspiratory obstruction is routinely evaluated.

Until the ATS/ERS standards are updated each lab must decide for itself which additional tests, if any, should be performed as part of a response to bronchodilator assessment, but for COPD patients in particular it is likely necessary for us to look beyond just FEV1 and FVC.

References:

Borrill ZL, Houghton CM, Woodcock AA, Vestbo J, Singh D. Measuring bronchodilation in COPD clinical trials. Br J Clin Pharmacology 2005; 59(4): 379-384.

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: 948-968.

Ewald FW, Tenholder MF. Analysis of the inspiratory flow-volume curve. Should it always precede the forced expiratory maneuver? Chest 1994; 106: 814-818.

Gimeno F, Postma DS, van Altena R. Plethysmographic parameters in the assessment of reversibility of airways obstructio in patients with clinical emphysema. Chest 1993; 104: 467-470.

Hanania NA, Celli BR, Donohue JF, Martin UJ. Bronchodilator reversibility in COPD. Chest 2011; 140(4): 1055-1063.

Kolsum U, Borrill Z, Roy K, Starkey C, Vestbo J, Houghton C, Singh D. Impulse oscillometry in COPD: Identification of measurements related to airway obstruction, airway conductance and lung volumes. Respiratory Medicine 2009; 103: 136-143.

Lavietes MH, Tayler DW. Determination of static pulmonary volumes after bronchodilator therapy. Chest 1979; 76: 425-428.

O’Donnell DE. Assessment of bronchodilator efficacy in symptomatic COPD. Is spirometry useful? Chest 2000; 117: 42S-47S.

O’Donnell DE, Forkert L, Webb KA. Evaluation of bronchodilator responses in patients with “irreversible” emphysema. Eur Respir J 2001; 18: 914-920.

Reddy R, Cook T, Tenholder MF. Bronchodilatation and the inspiratory flow-volume curve. Chest 1996; 110: 1226-1228.

Saunders, KB. Bronchodilator response patterns in patients with chronic airways obstruction: Use of peak inspiratory flow. Brit Med J 1967; 2: 399-402.

Shin YH, Jang SJ, Yoon JW, Jee HM, Choi SH,Yum HY, Warburton D, Han MY. Oscillometric and spirometric bronchodilator response in preschool children with and without asthma. Can Respir J 2012; 19(4): 273-277.

Skinner C, Palmer KNV. Changes in specific airways conductance and forced expiratory volume in one second after a bronchodilator in normal subjects and patients with airway obstruction. Thorax 1974; 29: 574-577.

Smith HR, Irvin CG, Cherniack RM. The utility of spirometry in the diagnosis in reversible airways obstruction. Chest 1992; 101: 1577-1581.

Taube C, Lehnigk B, Paasch K, Kirsten DK, Jorres RA, Magnussen H. Factor analysis of changes in dyspnea and lung function parameters after bronchodilation in chronic obstructive pulmonary disease. Am J Resp Crit Care Med 2000; 162(1): 216-220.

Taube C, Kanniess F, Gronke L, Richter K, Mucke M, Paasch K, Eichler G, Jorres RA, Magnussen H. Reproducibility of forced inspiratory and expiratory volumes in patients with COPD or asthma. Respiratory Medicine 2002; 97: 568-577.

van Noord JA, Smeets J, Clement J, van de Woestijne, Demedts M. Assessment of reversibility of airflow obstruction. Am J Resp Crit Care Med 1994; 150: 551-554.

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

Patients with COPD often have a ventilatory limitation as their primary limitation to exercise. A ventilatory limitation to exercise has traditionally been assessed by the breathing index or the breathing reserve:

breathing index = Peak Ve / Predicted MVV

breathing reserve = 1 – (Peak Ve / Predicted MVV)

which are basically two different ways of saying the same thing. In either case a breathing index greater than 85% or breathing reserve less than 15% is an indication that a patient has reached a ventilatory limit to exercise. There is some disagreement as to whether the predicted MVV should come from a MBC test performed by the patient or from the patient’s FEV1 x 40. I have tried both approaches and my experience has been that FEV1 x 40 is the best indicator for a patient’s predicted MVV. This is also Wasserman’s (my go-to source for exercise testing) recommendation so this is what we use.

Individuals with COPD are occasionally hyperinflated at rest (i.e. elevated FRC and RV) and more commonly they dynamically hyperinflate during exercise. Research has shown that those individuals with are flow-limited during tidal breathing at rest almost always hyperinflate with exercise. Patients who are not flow-limited at rest but still have a low FEV1 and FEV1/FVC ratio may also hyperinflate. Because hyperinflation limits a patient’s tidal volume response to exercise it may cause an individual to have a limitation to exercise that occurs at a minute volume below the 85% threshold.

Since TLC probably remains constant during the course of an exercise test, the measurement of Inspiratory Capacity (IC) during exercise is a way of tracking changes in FRC (or more accurately the End-Expiratory Lung Volume, EELV). We routinely measure IC during cardiopulmonary exercise tests in order to determine whether hyperinflation is occurring and there are a variety of way to look at IC and its effect on ventilation:

• Change in IC (L)
• Percent change in IC (baseline – measured/baseline)
• Vt/IC
• IC/TLC
• EILV/TLC

Because we do not measure TLC as part of a CPET and only rarely does a patient have a TLC measurement that was performed recently, we do not use any comparisons that depend on TLC. We also feel that the percent change in IC is overly sensitive to the baseline IC and for this reason we look at just the change in IC (L) and the Vt/IC ratio.

When we perform a CPET we try to obtain at least two acceptable IC measurements at baseline and then at approximately two minute intervals during exercise. Unfortunately our test system’s software does not report the IC results immediately, only in the CPET reports, which makes it difficult to assess the quality and repeatability of these trial efforts. The best we can do is “eyeball” the graphs during the IC maneuver and correct the patient only if there are obvious problems.

At the present time there are no accepted normal values for changes in IC during exercise. Based on the results we’ve seen in several studies we’ve decided that a decrease in IC of 0.25 L or greater is a significant change and an indication that hyperinflation is probably occurring. We use the Vt/IC ratio to help determine whether hyperinflation, when it occurs, may be causing a ventilatory limitation. Specifically, a normal maximum Vt/IC ratio is usually 0.75 or less. The work of breathing rapidly increases at Vt/IC ratios greater than 0.85 so for this reason, we’ve use a Vt/IC ratio of 0.85 or above as an indication the patient has reached his maximum useable tidal volume.

When a patient hyperinflates this usually occurs more or less steadily throughout the exercise and this is the pattern we look for. For this reason, we tend to discount a significant change in a single IC measurement, particularly if it is the last measurement obtained during exercise and none of the previous IC measurements had shown any particular change.

Recently a CPET report came across my desk that showed a steady decrease in IC throughout exercise, with a final IC measurement that was 0.55 L less than baseline.

So why didn’t I believe that the patient was really hyperinflating?

First and most importantly, the patient’s baseline spirometry was normal. The FVC was 106% of predicted and the FEV1 was 107% of predicted and there was no significant change in either of these values following exercise. You can’t measure expiratory flow limitation with spirometry, but results like this make obstructive gas trapping exceedingly unlikely.

The CPET system’s software measures the IC automatically but because errors are not all that uncommon I usually re-measure and verify the IC volumes. When I reviewed this patient’s IC maneuvers I found was that the reported IC values were accurate but a look at the other ventilatory results showed why at the same time they probably weren’t “accurate” at all.

During a normal ventilatory response to exercise tidal volume usually increases first and usually by at least two to three times the baseline tidal volume. Respiratory rate usually increases second and only after tidal volume has more or less plateaued. In this case the patient’s tidal volume only increased slightly from their baseline value and most of the increase in minute ventilation was from an increase in respiratory rate. At peak exercise their respiratory rate was 56 and their tidal volume was only about 50% greater than it was at baseline. This is a markedly inefficient ventilatory response to exercise.

This pattern of a low tidal volume and high respiratory rate is a hallmark of restrictive lung disease but when this occurs the Vt/IC ratio is usually quite high (0.85 or above) and the maximum minute ventilation is usually above 85% of predicted. This patient’s Vt/IC ratio was 0.46 however, and therefore had the ability to significantly increase their tidal volume but for some reason wasn’t doing so. The patient’s maximum minute ventilation was also 63% of predicted. Despite the low tidal volume and high respiratory rate their overall minute ventilation was normal. So why was their IC decreasing?

It is possible that because of the high respiratory rate the patient was “stacking” breaths and actually breathing at a higher lung volume. In a sense this is hyperinflation, but if this was the case there was no apparent physiological reason for it to be occurring.

What I think is far more likely however, is that because of the high respiratory rate the patient was unable to perform an adequate IC maneuver. I’ve noticed that towards the end of a CPET, when patients get to very high respiratory rates, the final IC measurement is often significantly lower than all the others and is often the only IC measurement that showed any decrease. We almost always ignore the final IC measurement when this occurs. In this case however, the patient was at a high respiratory rate throughout testing and the IC measurements were taken at respiratory rates of 39, 47 and 53 breaths per minute.

We see this inefficient ventilatory response (low tidal volume, high respiratory rate) several times a year and it usually occurs for no apparent reason that we can see. It could be anxiety (but many patients are anxious and don’t breathe this way). It could be that the CPET is so “unnatural” that some patients feel they have to adopt an “unnatural” ventilatory pattern in order to cope with it. It could be that these patients have an elevated CO2 drive and can’t complete a normal exhalation before urgently needing to inhale again. It also could be a “learned response” in that they were either taught or decided on their own that this was the best way to increase their breathing during exercise. Regardless of the reason, this type of ventilatory response may well be why these patients are short of breath in the first place.

IC maneuvers cannot be repeated too frequently since they can skew a patient’s ventilatory pattern and their EELV. Because the IC manuever can only be performed a few times the quality of each IC measurement depends a lot on patient cooperation and effort. Patients should be given the opportunity to practice the maneuver at least a couple of times before starting the CPET and care should be taken when cuing the patient to perform the IC maneuver during exercise.

There should be at least some selectivity about deciding whether IC maneuvers should be performed in the first place. We get patients with COPD for pre-op exercise testing fairly often. For these patients the CPET is not really a diagnostic test per se but part of a surgical risk assessment and their max VO2 and Ve-VCO2 slope are what’s important, not dynamic hyperinflation.

It could be argued that there is no need to perform IC maneuvers in patients with normal spirometry who, for this reason, are unlikely to hyperinflate. The problem with this is that spirometry alone cannot determine whether or not expiratory flow-limitation is present. Even when flow-limitation and hyperinflation is not present IC maneuvers can provide additional information about an individual’s ventilatory response to exercise. For these reasons, unless there is an overwhelming reason not to we routinely perform IC maneuvers on all of our CPET patients.

Decreases in IC during exercise can indicate dynamic hyperinflation and this can be an important factor in a patient’s exercise limitation. Decreases in IC can also occur however, because of suboptimal IC maneuver quality or peculiar breathing patterns, so some care must be taken when assessing IC measurements. In this particular case the final report included the notation that the patient appeared to hyperinflate during exercise but that their low Vt/IC ratio showed that this was not a limitation.

References:

ATS/ACCP Statement on Cardiopulmonary Exercise Testing. Am J Resp Crit Care Med 2003; 167(1): 211-277

Calverley PMA. Dynamic hyperinflation. Is it worth measuring? Proc Am Thor Soc 2006; 3: 239-244.

Ferguson GT. Why does the lung hyperinflate? Proc Am Thor Soc 2006; 3: 176-179.

Fujimoto K, Yoshiike F, Yasua M, Kitaguchi Y, Urushihata K, Kubo K, Honda T. Effects of bronchodilators on dynamic hyperinflation in patients with COPD. Respirology 2007; 12: 93-99.

O’Donnell DE, Lam M, Webb KA. Measurement of symptoms, lung hyperinflation and endurance during exercise in chronic obstructive pulmonary disease. Am J Resp Crit Care Med 1998; 158(5): 1557-1565.

O’Donnell DE, Revill SM, Webb KA. Dynamic hyperinflation and exercise intolerance in chronic obstructive pulmonary disease. Am J Resp Crit Care Med 2001; 164(5): 770-777.

Pellegrino R, Brusasco V, Rodarte JR, Babb TG. Expiratory flow limitation and regulation of end-expiratory lung volume during exercise. J Appl Physiol 1993; 74(5): 2552-2558.

Wasserman K, et al. Principles of exercise testing and interpretation. Published by Lippincott, Williams & Wilkins, 2005.

Yan S, Kaminski D, Sliwinski P. Reliability of inspiratory capacity for estimating end-expiratory lung volume chanes during exercise in patients with chronic obstructive pulmonary disease. Am J Resp Crit Care Med 1997; 156(1): 55-59.

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