Adjusting DLCO for hemoglobin

My hospital’s Oncology division treats a number of patients with lymphoma and leukemia. It also has an active bone-marrow transplant program and for all of these patients diffusing capacity measurements are a critical part of assessing treatment progress. Since these patients are also frequently anemic, correcting DLCO results for hemoglobin is also critical.

For a factor that has as much importance for the interpretation of DLCO results as it does the effect of hemoglobin on DLCO has actually been studied a relatively small number of times. Part of the reason for this is the problem of finding an acceptable model. A reduced or elevated hemoglobin is a consequence of many diseases and conditions. When studying patients longitudinally it is often difficult to separate the changes in DLCO that occur from the disease process and those that occur from changes in hemoglobin. For this reason changes in hemoglobin pre- and post-treatment in anemia and polycythemia have been studied most frequently.

The ATS/ERS currently recommends correcting DLCO for hemoglobin (although notably they recommend that the predicted DLCO be corrected, not the observed value) using the equations developed by Cotes et al in 1972. Cotes’ work was based on subjects with iron-defficienty anemia but just as importantly on theoretical considerations involving Roughton and Forster’s equation on the relationship between the membrane and hemoglobin components of the diffusing capacity:

1_over_DLCO_formula

Cotes

Several other approaches towards correcting DLCO for hemoglobin have been developed. Dinakara et al, studied a group of patients with chronic anemia and found a curvilinear relationship between hemoglobin and DLCO that although generally similar to Cotes, had a significantly greater amplitude.

Dinakara

Mohsenifar et al studied a diverse group of patients with anemia or polycythmia as well as normals and instead found a linear relationship between hemoglobin and DLCO.

Mohsenifar

Marrades et al studied a relatively small group of patients with anemia and also found a linear relationship between hemoglobin and DLCO that was quite similar to Mohsenifar.

Marrades

The amount by which each approach corrects DLCO depends variously on the observed DLCO, predicted DLCO, observed hemoglobin and the presumed value for normal hemoglobin. For this reason direct comparison of the correction equations is difficult and must be taken on a case by case basis.

DLCO_40

DLCO_70

DLCO_100

DLCO_130

The relatively significant difference in results between studies of what should be a fundamental property of the diffusing capacity makes it difficult to assess the different correction factors. Comparison is also complicated by the fact that DLCO was measured using different breath-holding times (Ogilvie vs Jones-Meade) and FIO2’s (0.21 vs 0.18). Admittedly there is often a fair amount of overlap between correction factors, however which specific factors overlap changes as the observed DLCO and hemoglobin change.

The selection of the Cotes equation by the ATS/ERS is to some extent understandable since it tends to be the most conservative of the correction factors. It’s reliance on the Roughton and Forster equation also makes it the most “scientific” of the correction factors but neither of these reasons necessarily make it the most correct. In particular, the Cotes equation has been criticized because a basic assumption is that the ratio between DMCO (the membrane component of diffusion) and Vc (the capillary blood volume) is a constant of 0.70 over a wide range of DLCO and hemoglobin values.

I found it interesting that the Mohsenifar and Marrades studies generated almost identical correction factors from two different subject groups but I am concerned that the linear relationship that they indicate exists between hemoglobin and DLCO may be too simplistic. Having said that, a comprehensive analysis of CO uptake by red blood cells indicates that DLCO does change linearly with hemoglobin but this observation was based primarily on mathematics and not on empirical data.

Finally, although the Dinakara equation was most often an outlier from the other equations, at least one study has indicated that it more accurately predicted the risk from bone marrow transplantation.

All studies can be criticized to one degree or another for their relatively small subject populations and the lack of a good study model which is unfortunate given how important hemoglobin is to DLCO. For relatively small differences in hemoglobin there is no significant different in the correction factors from the different studies but then same could probably be said of the uncorrected DLCO. At both moderate and extreme differences in DLCO and hemoglobin however, there are significant differences between the correction factors and this has implications for the interpretation of DLCO results.

This is an area that definitely needs more research but it’s far from clear how this should be done. There are reasonably significant physiological differences between acute and chronic anemia (and polycythemia) that make it difficult to develop a reliable human or animal model. In addition the changes in DLCO and hemoglobin that occur due to medications or disease and their treatment are difficult to disentangle. Although there is intriguing evidence that the correction factors developed by Marrades and Mohsenifar may be more accurate than the others, at the present time DLCO should probably continue to be corrected for hemoglobin using the Cotes equation but I say this mostly for the sake of standardization and not because there is any overwhelming evidence that it is the most accurate approach.

Source: Gender: Units: Formula:
Cotes Male Ratio ((1.7 x Hb) / (10.22 + Hb))
Female Ratio ((1.7 x Hb) / (9.38 + Hb))
Dinakara Both Ratio 1 / (0.06965 x Hb)
Marrades Male DLCO (ml/min/mmHg) 1.4 x (14.6 – Hb)
Female DLCO (ml/min/mmHg) 1.4 x (13.4 – Hb)
Mohsenifar Both DLCO %predicted 1.35 x (44 – Hct)

References:

Brusasco V, Crapo R, Viegi G. ATS/ERS Task Force: Standardisation of lung function testing. Standardisation of the single-breath determination of carbon monoxide uptake in the lung. Eur Respir J 2005; 26: 720-735.

Burgess JH, Bishop JM. Pulmonary diffusing capacity and its subdivisions in polycythemia vera. J Clin Invest 1963; 42(7): 997-1006.

Chakraborty S, Balakotaiah V, Bidani A. Diffusing capacity reexamined: relative roles of diffusion and chemical reaction in red cell uptake of O2, CO, CO2 and NO. J Appl Physiol 2004; 97: 2284-2302.

Coffey DG, Pollyea DA, Myint H, Smith C, Gutman JA. Adjusting DLCO for Hb and its effects on the hematopoietic cell transplantation-specific comorbidity index. Bone Marrow Transplantation 2013; 48: 1253-1256.

Cotes JE, Dabbs JM, Elwood PC et al. Iron-deficiency anaemia: its effect on transfer factor for the lung (diffusing capacity) and ventilation and cardiac frequency during sub-maximal exercise.  Clin Sci 1972; 42: 325–335.

Cotes JE, Chinn DJ, Miller MR. Lung Function, Sixth Edition. Blackwell Publishing, 2006.

Dinakara P, Johnston RF, Kauffman LA, Solnick PB. Am Rev Resp Dis 1970; 102: 965-969.

Herbert SJ, Weil H, Stuckey WJ, Urner C, Gonzalez E, Ziskind MM. Pulmonary diffusing capacity in polycythemic states before and after phlebotomy. Chest 1965; 48(4): 408-415.

Marrades RM, Diaz O, Roca J, Campistol JM, Torregrosa JV, Barbera JA, Cobos A, Felez MA, Rodriguez-Roisini R. Adjustment of DLCO for hemoglobin concentration. Am J Respir Crit Care Med 1997; 155: 236-241.

Mohsenifar Z, Brown HV, Schnitzer B, Prause JA, Koerner SK. The effect of abnormal levels of hematocrit on the single breath diffusing capacity. Lung 1982; 160: 325-330.

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11 thoughts on “Adjusting DLCO for hemoglobin

  1. Hi Richard,

    Yes. A very complicated topic. Another major problem, and not commonly known, is the fact that we assume that all the Hb that we measure is available for gas exchange. It is not.

    About 25 years ago I did a study on 1,100 patients over a 5 year period and measured their sedimentation rates over a very wide range of diseases. The more serious the pathology, the greater the sedimentation rate. The sedimentation rate increases when the RBC’s aggregate in progressively larger chains called “rouleaux,” which causes the cells to fall more rapidly in the plasma. The fact that the RBC’s stick together means there is less surface area available for gas exchange, and essentially results in an “anemia effect,” much like when HbCO is present.

    Some studies have been done (Hsia and Nateshi) using medical models, as well as actual RBC’s, which showed that when the RBC’s are aggregated, it can effect diffusion significantly and reduce the availabilty of oxygen by as much as 50%!

    When we measure Hb in the lab, the cells are first lysed and then the Hb concentration is measured. Therefore, we can see a situation where someone may have a normal Hb, but if their RBC’s are aggregated, the actual amount of heme available for gas exchange is actually lower. How we would correct for that, even if we knew the level of aggregation, is a daunting task.

    The main point, however, is that since we don’t know the degree of RBC aggregation when we measure DLCO, correcting for Hb is tricky, and can be very misleading. I look at the corrected number, but the DLCO uncorrected is what I trust.

    I fully appreciate the fact that it would be nice to correct for Hb and know if a reduced DLCO is primarily due to anemia. But, as you point out, correcting for Hb is not a simple matter. Unfortunately, RBC aggregation even further complicates the problem.

    Best,

    Ira

    • Ira –

      Thanks for bringing up this interesting point. We need to remember that DLCO (and spirometry and lung volumes) are far more complicated than they look at first. When results are reduced (or elevated) we need to take the equipment, physiology and disease processes all into consideration as possible causes. And even then there are always hidden variables (like sedimentation rate) that limits the accuracy of any assessment we can make.

      I’d also like to say that when we correct DLCO for hemoglobin and it normalizes an abnormal result we immediately think that the patient’s gas exchange is “normal”, but it really isn’t. Gas exchange is still abnormal, it’s just that part of the reason is (probably) a low hemoglobin.

      Regards,

      Richard

  2. Hello, Richard (and Ira!).

    I won’t delve into an aspect of DLCO as deep as Ira did; rather, my point is regarding “correction” vs. “adjustment”. Although these have been used interchangeably, seemingly forever, to use “correction” implies that the initial measurement was inaccurate. We’re not correcting DLCO for Hgb concentration, we’re adjusting for it. “Adjustment” is the more accurate (shall I say correct?) term. Indeed, the ATS/ERS statement refers to DLCO adjustment, not DLCO correction.

    Great job, as always; thank you for all that you share.

        • While thinking about this overnight I realized there is a related point. When DLCO adjusted for hemoglobin it is often reported as DLCOadj (or DLCOcorr) but it’s also possible to adjust DLCO for carboxyhemoglobin and altitude/PIO2 and there is no nomenclature for this and it’s at least possible to adjust DLCO for any combination of these elements. I’d hate to see to see it get where we have something horrendous like DLCOadjHbCOHbAlt but at the same time we also need to know what DLCO has been adjusted for and what it hasn’t.

          • Good point, Richard. Unless the final report displays the Hgb, COHgb, etc., we’re not telling the reviewer what the DLCO was adjusted for. Our reports display the Hgb used for adjustment and the date it was obtained within the DLCO section. It is extremely rare that we adjust for COHgb, and our reports are not formatted to display this in the DLCO section (it will be displayed with the other ABG data).

  3. I’ve been trying to find a reference for a timeframe for the Hgb value used for correction. Our lab performs a HemoCue measurement at the time of testing. Others use a “current” value. What would be considered “current”?

    • Anita –

      I don’t have a simple answer for you. As you may have noticed, even though the ATS/ERS statement on DLCO testing recommends correcting DLCO results for hemoglobin, they fail to give any guidelines about the hemoglobin measurement’s timeframe. A while back I talked to a hematologist/oncologist about how long a hemoglobin measurement could be trusted and her answer was “it depends”. For lack of any formal guidelines my lab arbitrarily settled on 1 month, so if the hemoglobin measurement is older than a month, we don’t use it.

      Out of curiosity, how often do you find a patient’s hemoglobin to be significantly reduced (<12) or elevated (>15), how long does it take you to perform the measurement (finger prick?) and do you bill for the measurement?

      – Richard

      • Thank you for your reply Richard. Also, thank you for the great blog. I found your site while trying to research this question.

        As for your questions, I’d have to say “Pretty often” for abnormal Hbg values. Many women tend to be in the 11’s. Chronically hypoxic patients will read high. People going through or soon to be going through cancer treatment tend to be low. Just the other week I had a lady (diagnosis: Dyspnea) who’s test was normal until we got to the DLco, which was 51%. When I checked her Hbg, it was only 5.2 (5.0 with 2nd check). That prompted a call to the doctor and immediate attention.

        We use the HemoCue: http://www.hemocue.us/en-us/hemocue-point-of-care-products/anemia-screening-and-hemoglobin
        It is a finger stick measurement. We use a lancet and collect the blood with a cuvette, pop it in the handheld device, scan myself, the cuvette barcode and the pt’s barcode. It takes about 2 minute to perform and receive the measurement. We do charge for the measurement and receive a unit of service.

        I can see why your resource said “it depends”. Just look at how much a non-surgery inpatient’s Hbg can vary daily with lab measurements. For healthy folks, one month seems reasonable. We debate between 72 hrs and 1 week. I say if there is a complaint of dyspnea or fatigue, or “recent” health status change, it’s important to have a current value and that’s why I feel it is important to perform at the time of testing. After all, we rarely test healthy people.

        Note that some patients with connective tissue disorders can be difficult to test. Their vascular bed can be compromised and it may be difficult to obtain a good sample. Squeezing the finger too much causes more plasma then regular blood sample, and this may give us a false low value. I’ve learned to try to lance a softer area of their finger (not the tip). These tend to be the folks that the pulse oximeter works poorly with the finger probe.

        Thanks again, Anita

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