Hemodilution during Cardiopulmonary Bypass: Impact on Colloid Oncotic Pressure, Microcirculatory Perfusion and Pharmacokinetics and Pharmacodynamics

English Summary Hemodilution during cardiopulmonary bypass influences COP, microcirculatory perfusion and PK/PD profiles of drugs. In this context, this thesis tested the hypotheses that colloid-based priming fluids preserve COP in plasma (1), preserve microcirculatory perfusion (2), and reduce organ edema (3) compared to crystalloid-based priming fluids. To test these hypotheses, we studied the effects of various crystalloid and colloid priming fluids in patients undergoing cardiac surgery with CPB, as well as in rats on CPB. Furthermore, we examined the role of hemodilution caused by CPB on the PK/PD of anesthetics and analgesics during cardiac surgery. Chapter 2 presents a meta-analysis evaluating crystalloid and colloid CPB priming strategies, alone or with RAP, on COP (primary) and hematocrit, fluid balance, fluid requirements, weight gain, platelet count, blood loss, and transfusions (secondary). Of 29 studies, seven reported COP. Four compared colloid priming (albumin, gelofusine, HES) with crystalloid. Three of four studies showed that colloid priming better preserved COP during CPB. Comparisons between colloids revealed no differences. Overall, the evidence was limited and heterogeneous, preventing definitive recommendations. Chapter 3 describes an observational study in 60 patients undergoing CABG and/or valve surgery with CPB. Patients received gelofusine/lactated Ringers, albumin/Ringers, or Ringers alone. RAP was applied in the latter two groups at the decision of the perfusionist. COP decreased similarly at CPB initiation, but post-CPB and one hour later, the greatest decrease occurred in the gelofusine/lactated Ringers group. COP reductions correlated inversely with fluid balance, fluid requirements, and duration of invasive ventilation. These results indicate that CPB-induced hemodilution reduces COP, contributing to interstitial fluid accumulation. Chapter 4 reports a preclinical study in 18 male rats primed with albumin/lactated Ringers/mannitol or 6% HES. Pulmonary edema, measured by lung wet-to-dry weight ratios, was lower in the albumin group, while renal edema did not differ. Microcirculatory perfusion was impaired in both groups during CPB and did not recover immediately. Albumin priming reduced pulmonary edema but did not prevent microcirculatory disturbances. Chapters 5 and 6 describe the PRIME study, a double-blind randomized trial comparing albumin/Ringers, gelofusine/Ringers, and Ringers with RAP in 34 CABG patients. All strategies similarly impaired microcirculatory perfusion during and after CPB. COP was slightly better preserved in the gelofusine group, while albumin/Ringers patients showed higher interleukin-6 and angiopoietin-2 levels, indicating greater inflammatory and endothelial activation. In conclusion, despite the fact that COP was better preserved with gelofusine/Ringers, none of the priming strategies prevented the CPB-induced decrease in microcirculatory perfusion. Chapter 7 presents a post-hoc analysis comparing two microcirculatory assessment methods, semi-manual AVA 3.2 and automatic CCTools v3.2.1, using 358 sublingual videos. Poor reliability and systematic bias were observed. We concluded that the two analysis methods are not interchangeable to assess sublingual microcirculatory perfusion in patients. Finally, in Chapter 8 we reviewed current evidence regarding the impact of CPB on the PK/PD of anesthetics and analgesics during cardiac surgery. Of 22 included studies (covering propofol, sevoflurane, remifentanil, isoflurane, fentanyl, sufentanil, and alfentanil), we found CPB can alter drug behavior, highlighting the need for the recognition of potential drug alterations due to CPB to avoid dosing errors and associated adverse events.