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Estrogen‐induced Changes in Protein Binding of Bupivacaine during in Vitro Fertilization

Background: Patients having in vitro fertilization (IVF) procedures that use gonadotropin‐releasing hormone agonist down‐regulation undergo hormonal manipulation of estrogen concentrations to induce oocyte maturation. After achieving minimal estrogen concentrations (baseline), stimulation increases estrogen concentrations to supraphysiologic levels, leading to egg retrieval. The isolated effect of estrogen on protein binding has not previously been reported. This study was conducted to measure the effect of estrogen concentrations on protein binding of two concentrations of bupivacaine, 1 micro gram/ml and 5 micro gram/ml, corresponding, respectively, to systemic concentrations expected after administration of epidural anesthesia and associated with bupivacaine toxicity. Serum proteins were measured to address the mechanism. Methods: Twenty‐nine healthy women undergoing IVF procedures were enrolled and venous samples were drawn at times of minimal and maximal estrogen concentrations. The percentage of free bupivacaine was determined at fixed concentrations of 1 and 5 micro gram/ml. Serum albumin and alpha1 ‐acid glycoprotein concentrations were measured at baseline and at retrieval in a group of 24 women. Results: The percentage of free bupivacaine increased between times of minimal and maximal serum estrogen concentrations, corresponding to decreased protein binding. Concentrations of serum albumin and alpha1 ‐acid glycoprotein decreased between baseline and retrieval times. Conclusions: Patients undergoing IVF procedures demonstrate a decrease in protein binding of bupivacaine from baseline concentrations. These changes may be explained by a decrease in albumin and alpha1 ‐acid glycoprotein. During anesthesia for egg retrieval, clinicians should consider the implications of increased free fraction of drug, especially for highly protein‐bound agents.