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Femoral access in extracorporeal life support (ECLS) has been associated with regional variations in arterial oxygen saturation, potentially predisposing the patient to ischemic tissue damage. Current monitoring techniques, however, are limited to intermittent bedside evaluation of capillary refill among other factors. The aim of this study was to assess whether cerebral and limb regional tissue oxygen saturation (rSO2) values reflect changes in various patient-related parameters during venoarterial ECLS (VA-ECLS). This retrospective observational study included adults assisted by femorofemoral VA-ECLS. Bifrontal cerebral and bilateral limb tissue oximetry was performed for the entire duration of support. Hemodynamic data were analyzed parallel to cerebral and limb rSO2. A total of 23 patients were included with a median ECLS duration of 5 [1-20] days. Cardiac arrhythmias were observed in 12 patients, which was associated with a decreased mean rSO2 from 61%±11% to 51%±10% during atrial fibrillation and 67%±9% to 58%±10% during ventricular fibrillation (P<0.001 for both). A presumably sudden increase in cardiac output due to myocardial recovery (n=8) resulted in a significant decrease in mean cerebral rSO2 from 73%±7% to 54%±6% and from 69%±9% to 53%±8% for the left and right cerebral hemisphere, respectively (P=0.012 for both hemispheres). Also, right radial artery partial gas pressure for oxygen decreased from 15.6±2.8 to 8.3±1.9 kPa (P=0.028). No differences were found in cerebral desaturation episodes between patients with and without neurologic complications. In six patients, limb rSO2 increased from on average 29.3±2.7 to 64.0±5.1 following insertion of a distal cannula in the femoral artery (P=0.027). Likewise, restoration of flow in a clotted distal cannula inserted in the femoral artery was necessary in four cases and resulted in increased limb rSO2 from 31.3±0.8 to 79.5±9.0; P=0.068. Non-invasive tissue oximetry adequately reflects events influencing cerebral and limb perfusion and can aid in monitoring tissue perfusion in patients assisted by ECLS.