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Ten to fifteen percent of awake patients develop neurological deficits secondary to cerebral hypoperfusion after carotid artery cross-clamping. The reversal of such deficits by increasing the inspired oxygen fraction (Fio2) has been demonstrated, and regional cerebral oxygenation (rSO2) has been shown to improve during carotid cross-clamping in awake patients by increasing Fio2. Paradoxical improvements in cerebral blood flow during carotid endarterectomy (CEA) at the time of cross-clamping and normalization of post–cross-clamp electroencephalographic abnormalities have been induced by hypocapnia. We performed this study to determine the influence of Fio2 and end-tidal carbon dioxide (Petco2) on rSO2 in patients undergoing CEA with general anesthesia during carotid cross-clamping.Twenty patients were recruited. Ten underwent elective shunting. Patients received standardized general anesthesia. rSO2 was measured using the INVOS 5100B monitor (Somanetics Corporation, Troy, MI). After carotid cross-clamping, Fio2 and minute ventilation were sequentially adjusted: 1) Fio2 30%, Petco2 30–35 mm Hg; 2) Fio2 100%, Petco2 30–35 mm Hg; and 3) Fio2 100%, Petco2 40–45 mm Hg. At each point, rSO2 was recorded from both operative and nonoperative sides, and arterial blood gas analysis was performed.Results from shunted and unshunted patients were analyzed separately. Increasing Fio2: Administration of 100% oxygen while maintaining Petco2 in the range 30–35 mm Hg in unshunted patients resulted in an 8% increase (P = 0.008) in rSO2 on the operative side and a 6% increase (P = 0.011) on the nonoperative side compared with an Fio2 of 30%. In shunted patients, administration of 100% oxygen while maintaining the Petco2 in the range 30–35 mm Hg resulted in a 4% increase in rSO2 on both the operative side (P = 0.008) and the nonoperative side (P = 0.011) compared with an Fio2 of 30%. Increasing Petco2: In unshunted patients, there was a 6% (P = 0.008) increase in rSO2 on the operative side and a 5% increase (P = 0.024) on the nonoperative side at Petco2 40–45 mm Hg compared with Petco2 30–35 mm Hg maintaining Fio2 at 100%. In shunted patients, there was a 3% increase (P = 0.018) in rSO2 on the operative side and a 4% increase (P = 0.007) on the nonoperative side at Petco2 40–45 mm Hg compared with Petco2 30–35 mm Hg maintaining Fio2 at 100%.rSO2 is reliably improved during carotid cross-clamping by increasing Fio2 in patients undergoing CEA with general anesthesia. Additional improvement in rSO2 may be gained by increasing Petco2.