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LETTER TO THE EDITOR
Their histograms (Fig. 2) show intra- and extravascular PO2 volume fractions of 
10 and 20%, respectively, with PO2 values of 100–140 Torr. The maximum PO2 in arterial blood leaving the lungs is 100 mmHg, and the existence of a longitudinal gradient downstream is a well established feature of PO2 in the vasculature (8). Even in small animals, it is not clear how the PO2 of blood in the vasculature or the tissue of the limbs can exceed PO2 of blood in the lungs. A measurement technique that records such high PO2 values in the interstitial and the intravascular space raises questions about how the measurements relate to the distribution of PO2 in the tissue reported by previous investigators.
The review of Tsai et al. (8) on oxygen gradients in the microcirculation shows that the highest PO2 value recorded in 12 studies of arterioles up to 100 µm using either the microelectrode or the phosphorescence technique was 80 Torr. Boeghhold and Johnson (1), 1988, recorded in 55-µm-diameter arterioles of the cat sartorious muscle a periarteriolar PO2 of 52 ± 3 mmHg (SE) when tissue PO2 was 23 ± 3 mmHg (SE) using Whalen microelectrodes. Smith et al. (6), 2004, in similar- sized arterioles in rat spinotrapezius muscle, measured a PO2 of 37 ± 2 mmHg and 31 ± 3 mmHg in venules with the oxygen phosphorescence quenching technique. The review reports the highest venular PO2 found in eight studies was 40 mmHg (8). Thus the finding of Wilson et al. (9) that 30% of the intravascular volume had PO2 values over 80 Torr (their Fig. 2) is difficult to reconcile with previous reports. Regarding tissue PO2, Nolte et al. (4), 1997, used the multiwire surface electrodes to map tissue PO2 in the awake hamster window chamber model and reported tissue PO2 values of 19 ± 2 mmHg, showing no values >40 mmHg. Wilson et al. found that >60% of their tissue values were above that level. These large discrepancies with the findings of Wilson et al. call into question conclusions regarding a gradient between intravascular and tissue measurements on the basis of their technique.
The problem with the tissue PO2 measurements by Wilson et al. (9) may be due in part to their methodology, which requires direct injection of a chromophore into the tissue. They inserted a needle 1 cm into the tissue, delivering injections of 20 µl at three neighboring locations. This procedure is very likely to damage the microcirculatory vessels with leakage of blood into the tissue, elevation of local tissue pressure, and blood flow stoppage. Thus the "tissue" values will be compromised by red blood cells and plasma in the area of measurements. Assuming that the mouse tissue involved was 1 cm3 in volume, introducing 60 µl caused at least a 6% tissue volume expansion, potentially increasing tissue fluid by 50%, a major perturbation in the tissue.
The authors (9) compare the tissue PO2 histograms in the 5% volume fraction with the lowest PO2 (average 15.9 ± 6.1 Torr) to the same volume fraction tagged by the intravascular marker (average 17.4 ± 4.0 Torr), concluding that 1.5 Torr difference does not represent a capillary wall gradient "... supporting the hypothesis that the vessel walls do not provide a significant barrier to oxygen delivery." In addition to the cited technique problems, no evidence is given to justify choosing the lowest 5% of the values from each compartment to represent capillaries and adjacent tissue. They indicate that the 1.5 Torr difference contradicts the finding of Tsai et al. (7), 1998, in arterioles while apparently recognizing that arterioles cannot be compared to capillaries. Their data were from awake animals, where "... oxygen histograms were highly variable, and many had very broad histograms with peaks at PO2 values of 60 Torr and above. These broad distributions with increased high PO2 values correlated with the visual evidence of agitation ..." Their data show a gradient of 6.1 Torr for isofluorane-anesthetized animals (free of motion artifacts?) for the same histogram PO2 range. Although it is likely fortuitous, this is the gradient previously reported for hamster capillaries (3).
Assigning a histogram PO2 level to a microvascular anatomical feature is problematic since the microvascular PO2 distribution is "U" shaped, many arterioles and venules having similar PO2 values. The lowest PO2 values may be due to signals from outside the capillary, measurement of tissue PO2 near collecting venules or from PO2 signals from terminal lymphatics, the lowest PO2 in the tissue (2). Venules contain most of the blood volume in the microcirculation, whose PO2 is above tissue PO2 (5). The large intravascular venular blood volume vs. capillary and arteriolar volume should bias PO2 toward lower values; however, the results of Wilson et al. (9) show that more than half of intravascular volume has PO2 >50 Torr.
In summary, this new technique for measuring tissue and intravascular PO2 appears to be flawed since it reports tissue and intravascular PO2 measurements (100–140 Torr) not compatible with the physics of oxygen distribution in a mammal. Very high PO2 values in the distribution indicate the presence of effects that probably influence the whole data set. In the muscle microcirculation there is no evidence of PO2 values greater than 60–70 mmHg, and, as reported by previous investigators, most values are much lower. A careful reevaluation of the in vivo application of this method would appear to be in order.
GRANTS
This research was supported by National Heart, Lung, and Blood Institute Grants HL-76182, HL-62318, HL-62354, and HL-64395.
FOOTNOTES
Address for reprint requests and other correspondence: M. Intaglietta, Univ. of California, San Diego, Dept. of Bioengineering, 9500 Gilman Dr., La Jolla, CA 92093–0412 (e-mail: mintagli{at}ucsd.edu)
REFERENCES
This article has been cited by other articles:
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  D. F. Wilson, W. M. F. Lee, S. Makonnen, O. Finikova, S. Apreleva, and S. A. Vinogradov Reply to Tsai, Cabrales, Johnson, and Intaglietta J Appl Physiol, May 1, 2007; 102(5): 2083 - 2083. [Full Text] [PDF]
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