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Communications to the Editor |

Is the Arteriovenous Carboxyhemoglobin Gradient Really a Useful Marker in Systemic Inflammation? FREE TO VIEW

Martin Westphal, MD; Thomas P. Weber, MD
Author and Funding Information

Affiliations: University of Muenster, Muenster, Germany,  Tohoku University School of Medicine, Sendai, Japan

Correspondence to: Martin Westphal, MD, Klinik und Poliklinik für Anästhesiologie, und operative Intensivmedizin, Universitätsklinikum Münster, Albert-Schweitzer-Strasse 33, 48149 Münster, Germany; e-mail: Martin.Westphal@gmx.net



Chest. 2005;128(5):3771-3772. doi:10.1378/chest.128.5.3771
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To the Editor:

We read with great interest the study in CHEST by Dr. Yasuda and colleagues (June 2004)1elucidating the role of arteriovenous carboxyhemoglobin (a-vHb-CO) difference in patients with fevers of unknown origin. The authors reported that the presence of an a-vHb-CO difference may be a useful indicator to differentiate between pulmonary and extrapulmonary diseases. This hypothesis was generated from the idea that, in the setting of pulmonary inflammation, a-vHb-CO differences may be caused by increased carbon monoxide (CO) production secondary to the up-regulation of heme oxygenase-1.2

Conversely, we recently demonstrated that the a-vHb-CO gradient may just be a technical artifact that can be avoided by a special calibration (SAT100; Radiometer; Copenhagen, Denmark) eliminating the fetal COHb dependency on oxygen saturation.3In addition, we evaluated the implication of a-vHb-CO differences in healthy and endotoxemic sheep, and found (1) that the a-vHb-CO difference, per se, does not reflect critical illness and (2) that measurements made without the special calibration (SAT100 calibration for ABL 625 blood gas analyzer; Radiometer; Copenhagen, Denmark) underestimate COHb concentrations measured with the blood gas analyzer (ABL 725 blood gas analyzer; Radiometer) in which this special calibration was routinely performed.4 In another in vitro experiment,5 we exposed venous blood samples to fixed CO doses at incremental oxygen concentrations and showed that the affinity of CO (200 and 400 ppm) to hemoglobin progressively increased with an inspiratory oxygen fraction from 0 to 15%, whereas at higher oxygen tensions this effect vanished.

In summary, there is considerable evidence that the presence of an a-vHb-CO difference is influenced by the degree of tissue oxygenation. Therefore, a-vHb-CO difference is not inevitably a useful marker to define the site of inflammation. Due to current knowledge, the COHb levels measured by Yasuda et al1 are methodologically questionable, especially since a special calibration (SAT100) was not performed.

Yasuda, H, Sasaki, T, Yamaya, M, et al (2004) Increased arteriovenous carboxyhemoglobin differences in patients with inflammatory pulmonary diseases.Chest125,2160-2168. [CrossRef] [PubMed]
 
Meyer, J, Prien, T, Van Aken, H, et al Arteriovenous carboxyhemoglobin difference suggests carbon monoxide production by human lungs.Biochem Biophys Res Commun1998;244,230-232. [CrossRef] [PubMed]
 
Weber, TP, Grosse Hartlage, MA, Meyer, J, et al Arteriovenous carboxyhemoglobin gradient is a technical artifact that is eliminated by special calibration (SAT 100).Biochem Biophys Res Commun2000;278,447-448. [CrossRef] [PubMed]
 
Westphal, M, Eletr, D, Bone, HG, et al Arteriovenous carboxyhemoglobin difference in critical illness: fiction or fact?Biochem Biophys Res Commun2002;299,479-482. [CrossRef] [PubMed]
 
Westphal, M, Weber, TP, Meyer, J, et al Affinity of carbon monoxide to hemoglobin increases at low oxygen fractions.Biochem Biophys Res Commun2002;295,975-977. [CrossRef] [PubMed]
 
To the Editor:

We appreciate the thoughtful comments by Westphal et al on our article demonstrating that the measurement of the arteriovenous carboxyhemoglobin (Hb-CO) concentration difference could be a simple and valuable marker with which to define the site of inflammation, either in the lung or organs other than lung, in patients with fever of unknown origin.1

Westphal et al disagree with our measured concentrations of blood Hb-CO because we did not use the calibration (SAT 100; Radiometer; Copenhagen, Denmark) for the blood analyzer (ABL 725; Radiometer) that eliminates the fetal Hb-CO dependency on oxygen saturation.2In addition, they evaluated the arteriovenous Hb-CO difference in patients with critical illness3 and in endotoxemic sheep,2 and demonstrated that the arteriovenous Hb-CO difference, per se, does not reflect critical illness. Furthermore, they suggested that the affinity of carbon monoxide level (200 and 400 ppm) to hemoglobin concentration progressively increased with inspiratory oxygen fraction (0 to 15%), whereas at higher oxygen tensions this effect vanished.,4 Therefore, they concluded that the Hb-CO levels measured by us are methodologically questionable and that the arteriovenous Hb-CO difference is not a useful marker with which to define the site of inflammation.

We think that there are three problems with their conclusions. First, they demonstrated that the arteriovenous Hb-CO concentration difference did not correlate with hemodynamic parameters in endotoxemic sheep, which is an ARDS model that is characterized by systemic inflammation and vascular endothelial damage, and is quite different from pulmonary inflammation located in the lung, such as acute pneumonia and bronchial asthma attack.5 They could not conclude that there was a relationship between the arteriovenous Hb-CO difference and the site of inflammation because they studied blood Hb-CO concentrations only in cases of systemic inflammation, and not in inflammation located in the lung.

Second, we also showed that the arteriovenous Hb-CO differences were not significantly associated with acute inflammatory markers, including WBC count and C-reactive protein level, in cases of extrapulmonary inflammation, such as acute pyelonephritis and active rheumatoid arthritis,1 and in cases of systemic inflammation, such as an acute exacerbation of COPD.6 The data that we reported are consistent with those on arteriovenous Hb-CO difference reported by Westphal et al.6

Third, fetal Hb-CO level might be a marker for a pulmonary ventilation disorder because it is significantly associated with blood oxygenation influenced by respiration, as Weber et al7 described previously. Furthermore, we have shown that arterial blood Hb-CO concentration is a good biomarker of disease severity in patients with inflammatory pulmonary diseases through the induction of hemeoxygenase-1 by oxidative stress, and the reabsorption of carbon monoxide by airflow limitation1,6,810 and tumor size in patients with non-small cell lung cancer without calibration (SAT100; Radiometer) of the blood analyzer.11 These points may suggest that the value of arterial Hb-CO concentration measured without calibration faithfully indicates disease severity in these diseases, although the value of arterial Hb-CO concentration has been underestimated in comparison with that measured with calibration, as Westphal et al2 have pointed out. This suggests that their conclusion about our methodological failure in measuring blood Hb-CO without calibration of the blood analyzer cannot be verified on the basis of their data. Therefore, we did not emphasize the importance of calibration of the blood analyzer in measuring blood Hb-CO concentrations in patients with inflammatory pulmonary diseases.

In summary, arteriovenous Hb-CO difference may be a good inflammatory indicator with which to define the site of inflammation, as previously described.1

References
Yasuda, H, Sasaki, T, Yamaya, M, et al Increased arteriovenous carboxyhemoglobin differences in patients with inflammatory pulmonary diseases.Chest2004;125,2160-2168. [CrossRef] [PubMed]
 
Westphal, M, Eletr, D, Bone, HG, et al Arteriovenous carboxyhemoglobin difference in critical illness: fiction or fact?Biochem Biophys Res Commun2002;299,479-482. [CrossRef] [PubMed]
 
Eletr, D, Reich, A, Stubbe, HD, et al Arteriovenous carboxyhemoglobin difference is not correlated to TNF-α, IL-6, PCT, CRP and leukocytes in critically ill patients.Clin Chim Acta2004;349,75-80. [CrossRef] [PubMed]
 
Westphal, M, Weber, TP, Meyer, J, et al Affinity of carbon monoxide to hemoglobin increased at low oxygen fractions.Biochem Biophys Res Commun2002;295,975-977. [CrossRef] [PubMed]
 
Peng, X, Hassoun, PM, Sammani, S, et al Protective effects of sphingosine 1-phosphate in murine endotoxin-induced inflammatory lung injury.Am J Respir Crit Care Med2004;169,1245-1251. [CrossRef] [PubMed]
 
Yasuda, H, Yamaya, M, Nakayama, K, et al Increased arterial carboxyhemoglobin concentrations in chronic obstructive pulmonary disease.Am J Respir Crit Care Med2005;171,1246-1251. [CrossRef] [PubMed]
 
Weber, TP, Grosse Hartlage, MA, Meyer, J, et al Arteriovenous carboxyhemoglobin gradient is a technical artifact that is eliminated by special calibration (SAT 100).Biochem Biophys Res Commun2000;278,447-448. [CrossRef] [PubMed]
 
Yasuda, H, Yamaya, M, Yanai, M, et al Increased carboxyhaemoglobin concentrations in inflammatory diseases.Thorax2002;57,779-783. [CrossRef] [PubMed]
 
Yasuda, H, Ebihara, S, Yamaya, M, et al Increased arterial carboxyhemoglobin concentrations in elderly patients with silicosis.J Am Geriatr Soc2004;52,1403-1404. [CrossRef] [PubMed]
 
Yamada, N, Yamaya, M, Okinaga, S, et al Protective effects of heme oxygenase-1 against oxidant-induced injury in the cultured human tracheal epithelium.Am J Respir Cell Mol Biol1999;21,428-435. [PubMed]
 
Yasuda, H, Yamaya, M, Ebihara, S, et al Arterial carboxyhemoglobin concentrations in elderly patients with operable non-small cell lung cancer.J Am Geriatr Soc2004;52,1592-1593. [CrossRef] [PubMed]
 

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References

Yasuda, H, Sasaki, T, Yamaya, M, et al (2004) Increased arteriovenous carboxyhemoglobin differences in patients with inflammatory pulmonary diseases.Chest125,2160-2168. [CrossRef] [PubMed]
 
Meyer, J, Prien, T, Van Aken, H, et al Arteriovenous carboxyhemoglobin difference suggests carbon monoxide production by human lungs.Biochem Biophys Res Commun1998;244,230-232. [CrossRef] [PubMed]
 
Weber, TP, Grosse Hartlage, MA, Meyer, J, et al Arteriovenous carboxyhemoglobin gradient is a technical artifact that is eliminated by special calibration (SAT 100).Biochem Biophys Res Commun2000;278,447-448. [CrossRef] [PubMed]
 
Westphal, M, Eletr, D, Bone, HG, et al Arteriovenous carboxyhemoglobin difference in critical illness: fiction or fact?Biochem Biophys Res Commun2002;299,479-482. [CrossRef] [PubMed]
 
Westphal, M, Weber, TP, Meyer, J, et al Affinity of carbon monoxide to hemoglobin increases at low oxygen fractions.Biochem Biophys Res Commun2002;295,975-977. [CrossRef] [PubMed]
 
Yasuda, H, Sasaki, T, Yamaya, M, et al Increased arteriovenous carboxyhemoglobin differences in patients with inflammatory pulmonary diseases.Chest2004;125,2160-2168. [CrossRef] [PubMed]
 
Westphal, M, Eletr, D, Bone, HG, et al Arteriovenous carboxyhemoglobin difference in critical illness: fiction or fact?Biochem Biophys Res Commun2002;299,479-482. [CrossRef] [PubMed]
 
Eletr, D, Reich, A, Stubbe, HD, et al Arteriovenous carboxyhemoglobin difference is not correlated to TNF-α, IL-6, PCT, CRP and leukocytes in critically ill patients.Clin Chim Acta2004;349,75-80. [CrossRef] [PubMed]
 
Westphal, M, Weber, TP, Meyer, J, et al Affinity of carbon monoxide to hemoglobin increased at low oxygen fractions.Biochem Biophys Res Commun2002;295,975-977. [CrossRef] [PubMed]
 
Peng, X, Hassoun, PM, Sammani, S, et al Protective effects of sphingosine 1-phosphate in murine endotoxin-induced inflammatory lung injury.Am J Respir Crit Care Med2004;169,1245-1251. [CrossRef] [PubMed]
 
Yasuda, H, Yamaya, M, Nakayama, K, et al Increased arterial carboxyhemoglobin concentrations in chronic obstructive pulmonary disease.Am J Respir Crit Care Med2005;171,1246-1251. [CrossRef] [PubMed]
 
Weber, TP, Grosse Hartlage, MA, Meyer, J, et al Arteriovenous carboxyhemoglobin gradient is a technical artifact that is eliminated by special calibration (SAT 100).Biochem Biophys Res Commun2000;278,447-448. [CrossRef] [PubMed]
 
Yasuda, H, Yamaya, M, Yanai, M, et al Increased carboxyhaemoglobin concentrations in inflammatory diseases.Thorax2002;57,779-783. [CrossRef] [PubMed]
 
Yasuda, H, Ebihara, S, Yamaya, M, et al Increased arterial carboxyhemoglobin concentrations in elderly patients with silicosis.J Am Geriatr Soc2004;52,1403-1404. [CrossRef] [PubMed]
 
Yamada, N, Yamaya, M, Okinaga, S, et al Protective effects of heme oxygenase-1 against oxidant-induced injury in the cultured human tracheal epithelium.Am J Respir Cell Mol Biol1999;21,428-435. [PubMed]
 
Yasuda, H, Yamaya, M, Ebihara, S, et al Arterial carboxyhemoglobin concentrations in elderly patients with operable non-small cell lung cancer.J Am Geriatr Soc2004;52,1592-1593. [CrossRef] [PubMed]
 
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