Dual-wavelength near-infrared spectrophotometry (NIRS) provides a noninvasive method of assessing cerebral oxygen saturation (ScO2) based on the absorption spectra of oxygenated and deoxygenated hemoglobin and the translucency of biological tissue at wavelengths from 700 to 1000 nm (1). The ScO2, as determined by dual-wavelength spectrophotometry at 733 and 809 nm, reflects cerebral perfusion and oxygenation during hypoxic hypoxemia (1–3), during hypo- and hypercapnia, and during head-up tilt-induced vasovagal near-fainting (2,4). ScO2 is proportional to the ScO2 determined from the arterial (25%) and internal jugular venous blood (75%) (1), and ScO2 integrates the cerebral blood flow (CBF) and the arterial oxygen content (2). NIRS has been used for monitoring cerebral oxygenation during carotid endarterectomy (5), during acute heart failure (6), and during orthotopic liver transplantation (7).
Cerebral oximetry relies on the assumption that hemoglobin is a prominent absorber of light within the brain tissue and that natural components of the skin interfere little, if at all, with the determination of ScO2. However, bilirubin, a breakdown product of heme, also absorbs prominently in the near-infrared band, so much so that spectrophotometry is applied to determine the skin content of bilirubin in jaundiced newborns (8). To evaluate the extent to which metabolic breakdown products of heme influence NIRS of ScO2, we analyzed the relationship of ScO2 to bilirubin in patients during orthotopic liver transplantation. In these patients, breakdown products of heme are dominated by conjugated bilirubin (9). We hypothesized that bilirubin influences the NIRS of ScO2, but that directional changes in cerebral perfusion, as seen during early reperfusion of the grafted liver (7,10), would be reflected adequately.
We investigated 48 consecutive patients (27 male and 21 female patients; age 52 [13–69] yr, height 1.70 [1.50–1.87] m and weight 72 [36–100] kg; median [range]) who underwent orthotopic liver transplantation. The protocol was approved by the Ethics Committee of Copenhagen (KF 01-110/94).
Anesthesia was induced with IV midazolam (10 mg), fentanyl (0.2–0.4 mg), and thiopental (50–175 mg) and maintained with methohexital (200 mg/h) and fentanyl (0.50–0.75 mg/h). Muscle relaxation was achieved with pancuronium (0.1 mg/kg). Patients were ventilated with an oxygen-air mixture of 40%/60%, and minute ventilation was adjusted to a PETCO2 of 34 mm Hg. This ventilation was maintained throughout the operation. Thus, after the liver was removed, a decrease in the PETCO2 was allowed in order to limit the increase in CBF often experienced during early reperfusion of the grafted liver (10). Red blood cells and fresh frozen plasma were administered in volumes aimed at maximizing mixed central venous oxygen saturation (SvO2), i.e., maintaining a central blood volume that would not restrict cardiac index (CI) (11). To avoid clotting of the hepatic vessels, the hematocrit was maintained between 0.30 and 0.33. In four patients, nitroglycerin was used to ensure a mean arterial pressure (MAP) below 120 mm Hg, as many patients with hepatic failure have impaired CBF autoregulation and are at risk for complications related to cerebral hyperperfusion (12).
A femoral artery line was inserted to monitor MAP and a pulmonary artery catheter to monitor central venous, pulmonary artery mean, and wedge pressures, in addition to SvO2 and CI (7.5F; Baxter, Uden, Holland). CI was determined by using thermodilution. SvO2 was continuously monitored by reflectance spectrophotometry at 670 and 813 nm, and the signal was calibrated with the O2 saturation determined by sampling. PETCO2 was measured by using gas analysis, heart rate was derived from a three-lead electrocardiogram, and arterial O2 saturation (SaO2) was recorded by using pulse-oximetry at 667 and 865 nm. Also, blood samples were taken for discrete determinations of SvO2 and SaO2 (OSM-3; Radiometer, Copenhagen, Denmark). In five patients, a catheter (14-gauge; Baxter) was inserted retrogradely into the internal jugular vein for O2 saturation measurement (SjO2). Electrical impedance at 90 MHz (TI; Caspersen and Nielsen, Copenhagen, Denmark) was followed over the thorax as an index of the central intra- and extracellular fluid volume (13).
ScO2 was measured by using dual-wavelength NIRS (INVOS 3100 Cerebral Oximeter; Somanetics, Troy, MI) with the light source and the sensor placed on the forehead immediately below the hairline. The scatter and path length of light at the two wavelengths is assumed to be equal, and dual-wavelength NIRS determines ScO2 from the ratio of absorbencies of two wave lengths reflecting deoxygenated (733 nm) and the sum of deoxygenated and oxygenated hemoglobin (809 nm), respectively (1). The ScO2 is estimated from the equation MATH Yet, ScO2 values are not specified below 15%. A truly specific cerebral sample volume is not yet established (14), but the influence of extracranial blood flow is minimized by making a distinction between the NIRS signal obtained with a short interoptode distance (3.0 cm) and that obtained with a longer distance (4.0 cm).
Cardiovascular variables and ScO2 were noted each 10th minute, and data were analyzed with respect to four phases of the operation. First, anesthesia was induced and the diseased liver surgically mobilized (the dissection phase). Second, the caval vein was cross-clamped, the diseased liver removed, and the donor liver grafted (anhepatic phase). Third, the cross-clamps were removed from the caval and portal veins (early reperfusion phase) and data reported corresponding to the largest CI recorded. Fourth, the bile duct was anastomosed and the abdominal incision closed (late reperfusion phase). Bilirubin was measured at the dissection phase and at the late reperfusion phase. Changes over time were evaluated by the Friedman test and significant changes were located by the Wilcoxon’s rank sign test for matched pairs. The relation between ScO2 and plasma bilirubin was characterized by using linear regression and Pearson’s correlation matrix. In the case of ScO2 values < 15%, the value of 15% was used. A P value of <0.05 was considered significant, and regression lines were reported with 95% confidence and prediction intervals. The confidence interval includes the theoretical true regression line with 95% confidence (15). The prediction interval includes 95% of future measured ScO2.
All cardiorespiratory variables, other than heart rate and SaO2, changed during surgery (Table 1). During reperfusion of the grafted liver (value at reperfusion minus value during the anhepatic phase), MAP decreased (−7 [−30 to 41] mm Hg) (median with range) and had only partly recovered by the end of surgery. CI was lowered in the anhepatic phase (−1.2 [−2.8 to 0.5] · min−1 · m−2), and during early reperfusion it increased by 1.7 (−0.4 to 5.7) · min−1 · m−2 compared with the value at the dissection phase, and this value was re-established in the late reperfusion phase. SvO2 increased by 4 (−9 to 31)% during the early reperfusion phase, and recovered during the late reperfusion phase. During the early reperfusion phase, central venous, pulmonary artery mean, and pulmonary wedge pressures increased and remained elevated to the end of surgery. After removal of the diseased liver, PETCO2 decreased (−4 [−11 to 5] mm Hg), but recovered during reperfusion of the graft. TI (by −3.4 [17.1 to 14.0] Ω) and Hb (by −1.0 [−3.3 to 0.6] mmol/L) decreased during surgery. SjO2 tended to increase during reperfusion (from 67% [52%–71%] to 75% [63%–86%]) (P = 0.08) and was increased at the end of surgery (75% [66%–86%]) (Table 2).
Bilirubin remained unchanged at the value observed during the dissection phase (71 [6–619] μmol/L), and only 12 patients had a bilirubin level below the approximate detection value for jaundice (35 μmol/L). The initial ScO2 and the bilirubin were correlated (r = −0.72), and the regression line decreased 7.4% for each 100-μmol/L step increase in plasma bilirubin (Figure 1). The 95% prediction interval included ScO2 values of 15% and 0% at bilirubin values of 370 and 550 μmol/L, respectively. For SvO2 and SaO2, direct oximetry and sampling yielded equal values, and an influence from bilirubin was not apparent.
Compared with the value during the anhepatic phase, ScO2 increased by 7% (−8% to 17%) during the early reperfusion phase, and it returned to the dissection phase value by the end of surgery. During surgery, the mean standard deviation of ScO2 was 5%. ScO2 co-varied with SjO2 (Table 2): in five of seven instances in which ScO2 changed by >5%, a directionally similar change in SjO2 was seen, and in five of eight instances in which SjO2 changed by >5%, ScO2 followed.
Bilirubin tended to dampen the increase in ScO2 during early reperfusion. Although the 95% prediction interval included a change in ScO2 of 0% even at normal bilirubin values, the 95% confidence interval included the zero slope line only at bilirubin values higher than 650 μmol/L (Figure 2). In two patients with bilirubin values of 373 and 619 μmol/L, respectively, the ScO2 persistently read <15%. The latter patient had a green skin tone for days and the ScO2 remained <15% three days after surgery, despite a decrease in bilirubin to 125 μmol/L and an absence of symptoms of cerebral hypoperfusion.
This study presents two findings. First, in patients with jaundice, dual-wavelength (733 and 809 nm) NIRS-determined ScO2 co-varied negatively with plasma bilirubin, and the 95% prediction interval for ScO2 included the lowest measurable value of 15% at a bilirubin value of approximately 370 μmol/L. Determination of SaO2 and SvO2 by using spectrophotometry appeared unaffected by bilirubin. Second, directional changes in cerebral perfusion are reflected by NIRS even at high bilirubin values. As demonstrated in one patient with a green skin tone, near-infrared light can be attenuated despite a normal plasma bilirubin level.
The systematic influence of bilirubin on the spectrophotometry of ScO2 is most likely through “competitive” absorbance of light, as bilirubin affects neither CBF nor O2 uptake. It cannot be that bilirubin affected cerebral perfusion in itself, because an independent measure of cerebral perfusion, SjO2, was not affected. SjO2 was only determined in five patients, but we reanalysed data from the 21 patients in the study by Skak et al. (7) and in these patients we could not find a correlation between bilirubin and SjO2. The lack of influence of bilirubin on O2 metabolism has been demonstrated in vitro by nuclear magnetic resonance in guinea pigs (16). Bilirubin affects the clinical significance of a low ScO2 value. Thus, in a normal population, the lowest normal value of ScO2 is 55% (6); in this icteric population, 30 patients (63%) had ScO2 below 55%.
Bilirubin only moderately affects determination of blood O2 saturation by sampling and multiwavelength catheters (17), and oximetry of SaO2 is negligibly affected (18). Unlike bile salts, which also become increased in cholestasis and biliary obstruction, bilirubin is not deposited in the cutis (9) but, as demonstrated in one patient a low value of ScO2 during severe jaundice, may be seen despite a normal plasma bilirubin level. We suspect that it was biliverdin situated in the cutis of the patient that interfered with cerebral oximetry. Thus, the interference of bilirubin on ScO2, but not on SvO2 or SaO2, probably resulted from more tissue chromophore (e.g., biliverdin) in the sample volume, in combination with a longer path length of the transmitted light and differences in absorbance of bilirubin at the designated wavelengths.
Cardiovascular changes during transplantation were comparable to those reported in previous studies (7,19,20). In our study, as in the study by Skak et al. (7), the ScO2 and SjO2 remained stable until the grafted liver was reperfused. ScO2 and SjO2 then increased, allowing assessment of the interference of bilirubin on the determination of rapid changes in cerebral perfusion by NIRS. SaO2 and the cerebral O2 uptake remained unchanged during liver transplantation (20), thus the ScO2 reflects cerebral perfusion only. In the study by Skak et al. (7), ScO2 and SjO2 increased by 5% and 6%, respectively, during reperfusion. In contrast to reperfusion during aortic declamping (21), the cerebral hyperperfusion is larger than anticipated from changes in CO2 and may indicate that a blood-borne substance has been liberated from the grafted liver (20). As seen during reperfusion of the grafted liver, directional changes in cerebral perfusion were reflected even at high bilirubin values. A rough co-variation was expected between ScO2 and SjO2, and the finding that ScO2 reflected changes in cerebral perfusion was substantiated by data from five patients in whom both SjO2 and ScO2 were followed.
No chromophores other than the breakdown products of heme have so far been found to significantly influence cerebral oximetry of hemoglobin O2 saturation. Melanin absorbs mainly below 650 nm, and skin color does not significantly influence the spectrophotometry of ScO2 (22). Water exhibits its lowest absorption of light between 300 and 1000 nm (allowing spectroscopy of other substances), and evidence against an influence from water has come from simultaneous determination of muscle water content by electrical impedance (23) and muscle O2 saturation by NIRS. During head-up tilt, muscle O2 saturation decreased and fluid accumulated in the upper arm, as seen by a reduction in electrical impedance of 1 Ω. During head-up, tilt-induced arterial hypotension, however, only the muscle O2 saturation increased (11). Thus, spectroscopy of O2 saturation was influenced by blood flow, but not by transudated fluid. In the near-infrared band, the copper center of cytochrome c (the final enzyme of the mitochondrial respiratory chain) changes absorption relative to the degree of oxidation, but cytochrome c is present in 10 times smaller a concentration than hemoglobin, and the influence on hemoglobin spectroscopy is negligible. During head-up, tilt-induced vasovagal presyncope, the oxygenated hemoglobin concentration decreases by 5.3 mmol/L, whereas the oxidized cytochrome c concentration decreases by only 0.2 mmol/L (4). Although other tissue chromophores, such as cerebrocuprein and erythrocuprein, alter their absorption spectra depending on the oxygenation state, they have virtually no absorbance in the near-infrared range (24,25).
Blood and tissue degradation products of heme absorb light in the near-infrared band and systematically influence the determination of ScO2 by transcranial oximetry. It seems that even in highly icteric patients, directional changes in ScO2 are still visible. The sensitivity of NIRS to reflect small changes in cerebral oxygenation in the presence of bilirubin is not fully characterized.
Erling Veje determined the wavelengths used by the cerebral oximeter, the pulse-oximeter, and the venous O2 saturation oximeter.
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