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Editorials |
Department of Paediatrics , University Hospital, University of Groningen, 9713 GZ Groningen, The Netherlands,
aE-mail w.g.zijlstra{at}bkk.azg.nl
By 1950, oxygen transport by the blood was well understood. The oxygen-carrying properties of the blood had been shown to be determined by oxygen capacity, oxygen saturation, and oxygen affinity, the latter expressed by a graph relating oxygen saturation (SO2) to oxygen tension (PO2), the oxygen saturation curve. Although these quantities could be determined in the physiology laboratory and although various oximeters for measuring SO2 in vivo had been developed (1)(2), examination of the oxygen transport status of patients was still based largely on clinical signs, such as cyanosis. The accurate evaluation of the oxygen capacity had to await the standardization of hemoglobinometry (3) and the complete determination of the composition of human hemoglobin (HbA) (4).
Standardization of hemoglobinometry on the basis of spectrophotometric determination of methemoglobincyanide, a stable hemoglobin derivative into which all hemoglobin derivatives usually present in the blood can be easily converted, involved an understanding that the total hemoglobin concentration (ctHb) includes the inactive (non-oxygen-binding) derivatives. Consequently, even in healthy individuals, the oxygen capacity per gram of hemoglobin is slightly lower than the theoretical value of 1.39 mL/g, calculated by dividing the molar volume of oxygen (22 394 mL at standard temperature and pressure dry) by one fourth of the molar mass of human HbA (16 114.5g). Oxygen capacity may be diminished in patients by an increased fraction of inactive hemoglobin, later called dyshemoglobin (5). The Beckman DU spectrophotometer soon enabled the measurement of the common dyshemoglobins, methemoglobin (MetHb) and carboxyhemoglobin (COHb), in the clinical chemical laboratory (6). Determination of ctHb by the standard method and correction for the fractions of MetHb and COHb thus made simple determination of the oxygen capacity possible. The validity of this procedure has been confirmed experimentally (2)(5).
Meanwhile, the methodology for measuring oxygen saturation in the clinical laboratory had progressed through the development of numerous (spectro)photometric methods, using Van Slyke’s manometric procedure as the reference method. Using this method, SO2 is defined as the ratio of the volume of hemoglobin-bound oxygen to the oxygen capacity. This shows that SO2 represents the fraction of the oxygen capacity that is occupied by oxygen, which is equivalent with cO2Hb/(cO2Hb + cHHb), the definition of SO2 used in photometric methods where O2Hb and HHb are oxyhemoglobin and de-oxyhemoglobin, respectively.
Around 1980, spectrophotometric multicomponent analysis (MCA) of hemoglobin derivatives became suitable for application in the clinical laboratory (7). The first automated photometer for MCA of hemoglobin derivatives was the IL282 CO-Oximeter, a four-wavelength instrument that measured HHb, O2Hb, COHb, and MetHb (8). This instrument was a real asset to the clinical laboratory, but it also was the root of widespread confusion that still hinders the evaluation of oxygen transport disturbances in patients. Contrary to the prevailing convention and disregarding the physiologic basis of the definition of SO2, the instrument was programmed to display O2Hb as a percentage of the total hemoglobin concentration. Thus, SO2 = cO2Hb/(cO2Hb + cHHb) was replaced by FO2Hb = cO2Hb/ctHb. This quantity was called "oxygen saturation", and it was plainly stated that "defining saturation in terms of all Hb species present gives a more exact and meaningful interpretation of the data" (8). This was followed by the historically incorrect remark that formerly SO2 was defined only in terms of HHb and O2Hb because these hemoglobin species make up most of the hemoglobin and because COHb and MetHb could not be easily measured.
In a report on the performance of the instrument, Zwart et al. (9) explained why substituting FO2Hb for SO2 was wrong. They advised reprogramming of the CO-oximeter so that ctHb, SO2, and dyshemoglobin fractions would be displayed, but in vain. Because the numeric difference between SO2 and FO2Hb is usually small, FO2Hb is easily mistaken for SO2, the more so because both are called "saturation". Initially, this went unnoticed. When an appreciable amount of COHb or MetHb was present, however, SO2 as calculated by a blood gas analyzer was different from FO2Hb as displayed by a CO-oximeter. This received little attention until pulse oximeters came into general use, and the arterial SO2 measured in vivo was compared with the analysis of arterial samples by a CO-oximeter (10).
Through the introduction of the pulse principle (1)(2), oximetry in vivo became suitable for routine clinical application. A pulse oximeter is a two-wavelength photometer that determines arterial SO2 by measuring light absorption in a piece of well-perfused tissue. Through proper wavelength selection, photometric interference by other hemoglobin derivatives can be minimized. When wavelengths of 660 and 940 nm are used, COHb causes a slight underestimation of SO2 and MetHb causes moderate underestimation in the higher SO2 range and overestimation in the lower SO2 range; when SO2 = 70%, the error caused by MetHb is negligible (2)(11).
Comparing SO2 obtained by pulse oximetry with FO2Hb obtained by "CO-oximetry" in patients with high fractions of COHb or MetHb led to numerous reports erroneously stating that the oxygen saturation was greatly overestimated by the pulse oximeter in these patients. This in turn led to many unnecessary experiments and to the "discovery" that there are two kinds of oxygen saturation, subsequently called "functional saturation" (for SO2) and "fractional saturation" (for FO2Hb). These new terms and the strange quantity "pulse oximeter gap", being the difference between FO2Hb and SO2, only added to the confusion.
A case in point is the recent report presenting a patient with methemoglobinemia as "a woman with low oxygen saturation" (12). Only after working through a long differential diagnosis was the tentative conclusion reached that an abnormal hemoglobin might be present, influencing the light-absorbing properties of the blood. If the CO-oximeter had been programmed to display the dyshemoglobin fractions instead of fractional saturation, the diagnosis would have been obvious after analysis of the first arterial blood sample. The fact that this report, parading the whole array of incorrect ideas of CO-oximetry and pulse oximetry, was considered fit for publication in a peer-reviewed journal shows how widespread these misconceptions have become.
Fortunately, the report by Hammond et al. in this issue of Clinical Chemistry (13) clarifies interpretation of oxygen transport and clears up past errors. The authors comprehend that SO2 is not method-dependent, that a pulse oximeter faithfully measures SO2 in the presence of COHb, and that the underestimation of SO2 by MetHb is attributable to its color, which interferes with the measurement. They note that measuring SO2 in dyshemoglobinemia is of limited value because COHb and MetHb affect oxygen capacity and oxygen affinity, not oxygen saturation. Figs. 3 and 4 [from the papers of Barker and coworkers (Refs. (8) and (13) in the article by Haymond et al.)] are reinterpreted correctly: the upper graphs show the photometric interference by COHb and MetHb, respectively, which leads to some underestimation of SO2 by the pulse oximeter; the lower graphs are simply the expression of a mathematical relationship. Note that Barker considered these graphs to demonstrate that the pulse oximeter greatly overestimates the oxygen saturation.
An important observation is that in the presence of an abnormal hemoglobin (HbM Sasketoon), even multiwavelength spectrophotometry may give erroneous results. However, in this case it cannot be ruled out that the high COHb fraction that only slowly decreased on oxygen therapy is at least partly real, although no external source of CO was found. In normal hemoglobin, the bound O2 forms a hydrogen bond with histidine at position E7. This favors O2 binding with respect to CO (14). This relative advantage of O2 is lost through the substitution of tyrosine for histidine, and the preference of the binding site for CO becomes so strong that even part of the endogenously produced CO is bound.
Hammond et al. (13) would have provided an even better service to the clinical community if they had advised against the use of FO2Hb. FO2Hb per se has no physiologic significance. It may be convenient that a normal FO2Hb signals in a single figure that SO2 is not too low and that no significant amount of dyshemoglobin is present. However, when FO2Hb is subnormal, the cause may be a low SO2, the presence of dyshemoglobin, or both. FO2Hb cannot replace SO2 and the dyshemoglobin fractions, and there is good reason to keep the latter quantities separate: SO2 has a unique relationship with PO2, whereas the dyshemoglobin fractions affect oxygen capacity and oxygen affinity.
Thus, we have run into a paradoxical situation—the necessary quantities can now be determined in the clinical laboratory, some of them even at the bedside, but we seem to have lost the ability to use them properly in the examination of the oxygen transport status of patients. Medical technology has dissociated from pathophysiologic knowledge. It was a mistake to change the definition of oxygen saturation and to substitute FO2Hb for SO2 in the first automated photometer for MCA of hemoglobin (8). The crucial step out of this quagmire is the standardization of the readout of such instruments so that unambiguous quantities are displayed, enabling clinicians to analyze oxygen transport disturbances in terms of oxygen capacity, oxygen saturation, and oxygen affinity. In most cases, ctHb, arterial SO2, and dyshemoglobin fractions will suffice; in more complicated cases, arterial PO2 and half-saturation tension (P50) may be required (15). There is no place for FO2Hb.
References
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