Ventilatory response to hypoxia and hyperoxia

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

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

Hypoventilation is defined as ventilation below that which is needed to maintain adequate gas exchange. It can be a feature in lung diseases as diverse as chronic bronchitis and pulmonary fibrosis but determining whether it is present of not is often complicated by defects in gas exchange. When desaturation occurs during a CPET (i.e. a significant decrease in SaO2 below 95%) this is a strong indication that the primary exercise limitation is pulmonary in nature and from that point the maximum minute ventilation and the Ve-VCO2 slope can show whether the limitation is ventilatory or instead due to a gas exchange defect. But in this circumstance what what does it mean when both the maximum minute ventilation and Ve-VCO2 slope are normal?

Recently a CPET came across my desk for an individual with chronic SOB. The individual recently had a full panel of pulmonary function tests:

Observed: %Predicted:
FVC (L): 1.73 62%
FEV1 (L): 1.39 66%
FEV1/FVC: 80 106%
TLC (L): 2.99 62%
DLCO (ml/min/mmHg): 14.66 84%
DL/VA: 5.45 124%
MIP (cm H2O): 11.5 18%
MEP(cm H2O): 21.3 24%

The reduced TLC showed a mild restrictive defect. At the same time the relatively normal DLCO indicates that the restriction is probably not due to interstitial lung disease and more likely either a chest wall or a neuromuscular disorder, both of which can prevent the thorax from expanding completely but where the lung tissue remains normal. The reduced MIP and MEP tends to suggest that a neuromuscular disorder is the more likely of the two.

I take this with a grain of salt however, and that is because this individual never had pulmonary function tests before and for this reason there is no way to know what their baseline DLCO was prior to the restriction. At the same time far too many individuals perform the MIP/MEP test poorly and low results are not definitive, and in this case in particular the results are so low the individual should have been in the ER, not the PFT Lab.

The CPET results were somewhat complicated, in that a close inspection showed both pulmonary and cardiovascular limitations.
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Asleep at the wheel

During this last week I was contacted by two different individuals who were asking for help in understanding their PFT results. In both cases they had a markedly elevated TLC and the interpretation included the notation that they had gas trapping and hyperinflation. Even though the amount of information they provided was minimal I am extremely skeptical that the TLC measurements were correct.

Gas trapping usually only occurs with severe airway obstruction. Hyperinflation, which at minimum consists of a chronically elevated FRC and RV, usually only occurs after prolonged gas trapping. An elevated TLC usually occurs only with prolonged hyperinflation and given the improvements in the care and treatment of COPD I’ve seen over the last several decades, has become relatively uncommon.

But one individual had perfectly normal spirometry:

FVC: 107%
FEV1: 112%
FEV1/FVC: 105%
TLC: 143%

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Does the FEV1/SVC ratio over-diagnose airway obstruction?

A low FEV1/VC ratio is the primary indication for airway obstruction.


From ATS/ERS Interpretive Strategies for Lung Function tests, page 956.

The ATS/ERS statement on interpretation says

The VC, FEV1, FEV1/VC ratio and TLC are the basic parameters used to properly interpret lung function (fig. 2). Although FVC is often used in place of VC, it is preferable to use the largest available VC, whether obtained on inspiration (IVC), slow expiration (SVC) or forced expiration (i.e. FVC).”

I understand and in general agree with the idea of using the largest VC regardless of where it comes from and this is because the FVC is often underestimated for any number of good (and not so good) reasons. When this happens the FEV1/FVC ratio will be overestimated and airway obstruction will be under-diagnosed. However the ATS/ERS statement is also grounded in the notion that all vital capacities (FVC, SVC, IVC) are the same and this isn’t necessarily true. The problem comes from the fact that the predicted values and lower limit of normal (LLN) for the FEV1/VC ratio always come from reference equations for FEV1/FVC ratios. Because the SVC (and IVC) are usually larger than the FVC this means there is at least the potential for airway obstruction to be over-diagnosed.

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When flow-volume loops get kinky

One of the more recognizable flow-volume loop contours is the one associated with severe airway obstruction. Specifically, this type of loop shows an abrupt decrease in flow rate following the peak flow with a more gradual decrease in flow rates during the remainder of the exhalation.


This abrupt decrease in flow rates was first described on a volume-time curve and the inflection point was called a “kink” but this point also corresponds with the inflection point on the flow-volume loop. This feature has also been called a “notch” or a “spike” but a number of researchers have called this the Airway Collapse pattern (AC) and it is more formally defined as a sharp decrease in flow rate from peak flow to a discontinuity point at less than 50% of the peak flow and occurring within the first 25% of the exhaled vital capacity.

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What’s a normal Flow-volume Loop?

Dozens of articles have been written about the correlation between different abnormal flow-volume loop contours and pulmonary disorders. In contrast very little has ever been written about what constitutes a normal flow-volume loop and what this looks like has been primarily anecdotal.

Interestingly, the ATS/ERS standard for spirometry includes an example of a “normal” flow-volume loop but its source and what makes it normal is not explained.


From the ATS/ERS standard on spirometry, page 327.

One feature that is commonly seen as a feature of normal flow-volume loops has been variously called a ‘shoulder’ or ‘knee’.


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Selecting the best FEV1. What role should PEF play?

Recently my lab has had some turnover with a couple of older staff leaving and new staff coming on board. While reviewing reports I’ve found a number of instances where the incorrect FVC and FEV1 were reported. Taking these as “teachable moments” I’ve been annoying the staff with emails whenever I find something notably wrong. I had thought that our rules for selecting the best FVC and FEV1 were fairly straightforward but given the number of corrections I’ve made lately it seemed like it would be a good idea to revisit our policy on this subject.

The process I’ve used for selecting the best FVC and FEV1 has evolved over the years. Initially I was told to select the single spirometry effort that had the largest combined FVC and FEV1. Later on test quality became a factor (not that is wasn’t in the beginning but there aren’t a lot of quality indicators for a pen trace on kymograph paper). How to juggle the different quality rules wasn’t altogether clear however (they seemed to change a bit with whichever physician was reviewing PFTs at the time), and I was still supposed to somehow select just a single spirometry effort.

Most recently this was simplified by only having to select the largest FVC (regardless of test quality) from any spirometry effort and then the largest FEV1 as long as it came from a spirometry effort with good quality. This is pretty much in accord with the ATS/ERS spirometry standards but with one important difference, and that is that we use use Peak Expiratory Flow (PEF) as an indicator of test quality.

Strictly speaking the ATS/ERS standards state that

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

There are, of course, a number of quality indicators for spirometry efforts that are used to indicate whether a curve is “usable”. These include things like back-extrapolation, expiratory time, terminal expiratory flow rate and repeatability but the one thing they do not include is PEF.

Despite not being within the ATS/ERS standards the reason that we use PEF in the selection process is found in the phrase “maximal forced effort” that is part of the ATS/ERS definition for FVC and FEV1. It has long been recognized (certainly since the early 1980’s and most likely earlier) that the FVC and FEV1 from a submaximal spirometry effort were often higher than the FVC and FEV1 from a maximal effort. So, is the largest FEV1 correct (as long as it meets the basic ATS/ERS criteria) or should it be the FEV1 from the effort with the highest PEF?

These two efforts from the same patient testing session highlight this dilemma. Both meet the ATS/ERS criteria for the start of the test which is what primarily applies to FEV1 (and PEF).



Blue: Red:
FVC (L): 2.72 3.06
FEV1 (L): 1.73 1.99
PEF (L/sec): 6.28 3.82

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A change that probably isn’t a change

Recently a report came across my desk from a patient being seen in the Tracheomalacia Clinic. The clinic is jointly operated by Cardio-Thoracic Surgery and Interventional Pulmonology and among other things they stent airways. The patient had been stented several months ago and this was a follow-up visit. Given this I expected to see an improvement in spirometry, which had happened (not a given, BTW, some people’s airways do not tolerate stenting), but what I didn’t expect to see was a significant improvement in lung volumes and DLCO.

When I took a close look at the results however, it wasn’t clear to me that there really had been a change. Here’s the results from several months ago:

Observed: %Predicted: Predicted:
FVC: 1.19 50% 2.38
FEV1: 0.64 35% 1.79
FEV1/FVC: 53 71% 76
TLC: 3.21 76% 4.22
FRC: 2.34 96% 2.43
RV: 2.11 113% 1.85
RV/TLC: 66 150% 44
SVC: 1.15 48% 2.37
IC: 0.87 48% 1.80
ERV: 0.25 41% 0.58
DLCO: 6.59 38% 16.18
VA: 1.78 43% 4.12
IVC: 1.04


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COPD and the FEV1/FVC ratio. GOLD or LLN?

Everyone uses the FEV1/FVC ratio as the primary factor in determining the presence or absence of airway obstruction but there are differences of opinion about what value of FEV1/FVC should be used for this purpose. Currently there are two main schools of thought; those that advocate the use the GOLD fixed 70% ratio and those that instead advocate the use the lower limit of normal (LLN) for the FEV1/FVC ratio.

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) has stated that a post-bronchodilator FEV1/FVC ratio less than 70% should be used to indicate the presence of airway obstruction and this is applied to individuals of all ages, genders, heights and ethnicities. The official GOLD protocol was first released in the early 2000’s and was initially (although not currently) seconded by both the ATS and ERS. The choice of 70% is partly happenstance since it was one of two fixed FEV1/FVC ratio thresholds in common use at the time (the other was 75%) and partly arbitrary (after all why not 69% or 71% or ??).

The limitations of using a fixed 70% ratio were recognized relatively early. In particular it has long been noted that the FEV1/FVC ratio declines normally with increasing age and is also inversely proportional to height. For these reasons the 70% threshold tends to over-diagnose COPD in the tall and elderly and under-diagnose airway obstruction in the short and young. Opponents of the GOLD protocol say that the age-adjusted (and sometimes height-adjusted) LLN for the FEV1/FVC ratio overcomes these obstacles.

Proponents of the GOLD protocol acknowledge the limitation of the 70% ratio when it is applied to individuals of different ages but state that the use of a simple ratio that is easy to remember means that more individuals are assessed for COPD than would be otherwise. They point to other physiological threshold values (such as for blood pressure or blood sugar levels) that are also understood to have limitations, yet remain in widespread use. They also state that it makes it easier to compare results and prevalence statistics from different studies. In addition at least two studies have shown that there is a higher mortality of all individuals with an FEV1/FVC ratio below 70% regardless of whether or not they were below the FEV1/FVC LLN. Another study noted that in a large study population individuals with an FEV1/FVC ratio below 70% but above the LLN had a greater degree of emphysema and more gas trapping (as measured by CT scan), and more follow-up exacerbations than those below the LLN but above the 70% threshold.

Since many of the LLN versus GOLD arguments are based on statistics it would be useful to look at the predicted FEV1/FVC ratios in order to get a sense of how much under- and over-estimation occurs with the 70% ratio. For this reason I graphed the predicted FEV1/FVC ratio from 54 different reference equations for both genders and a variety of ethnicities. Since a number of PFT textbooks have stated that the FEV1/FVC ratio is relatively well preserved across different populations what I initially expected to see was a clustering of the predicted values. What I saw instead was an exceptionally broad spread of values.


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A glitch in time

This relatively odd DLCO testing error came across my desk today. Although it’s fairly unusual it brings up some interesting points about how the Breath-Holding Time (BHT) is determined and what effect it has on DLCO.

Specifically, at the beginning of the DLCO test the patient took a partial breath in, then exhaled, then took a complete breath in. The patient performed the DLCO test three times and did exactly the same thing each time despite being coached by the technician to only take a single breath in. I’m sure this says something about human nature but I’m not exactly sure what.


Anyway, our test systems uses the Jones-Meade approach to measuring breath-holding time (the ATS/ERS recommendation). The J-M algorithm starts the measurement of BHT when the inhalation has reached 1/3 of the inspiratory time. In this case the computer detected the beginning of the first inspiration and detected when the patient had reached the end of inspiration (which is standardized at the point at which 90% of the final inhaled volume has been reached), but it ignored what happened in the middle. For this reason, the software set the beginning of the breath-holding time before the “real” inhalation.

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