Hypoalbuminaemia and propofol pharmacokinetics.

Editor—Cavaliere and colleagues report that hypoalbuminaemia does not affect the accuracy of Diprifusor during sedation with propofol. They hypothesized that hypoalbuminaemia may affect the accuracy of target-controlled infusion (TCI) by introducing major deviations in propofol pharmacokinetics. Their results, however, failed to show significant differences in the accuracy of the Diprifusor between hypoand normoalbuminaemic patients. A possible explanation for these results is that the effect of hypoalbuminaemia may be too small in relation to the overall degree of accuracy achieved by TCI devices. A second mechanism could be that propofol binds to albumin linearly in the range of concentrations tested in this study. We reported that a twofold increase in the concentration of unbound propofol occurred without alteration in the total propofol concentration in blood during cardiopulmonary bypass (CPB). This increase was caused mainly by a lower concentration of albumin. Furthermore, we showed that the mean value of the hepatic extraction ratio was greater than 0.8 and remained constant throughout the study despite the increase of unbound fraction. There was no significant difference in the total body clearance of propofol before, during and after CPB and concluded that hypoalbuminaemia does not affect the accuracy of Diprifusor. For drugs that are restrictively cleared, regardless of route of administration, an increase in the unbound fraction leads to accelerated total body clearance and reduced total concentration. The unbound concentration at steady state is unchanged since an increase in the unbound concentration gradually returns to the control value after redistribution. Thus the ultimate effect of changes in protein binding is only transient. In contrast, for drugs that are non-restrictively cleared and administered i.v., an increase in the unbound fraction could not affect total body clearance as such drugs are extracted by the eliminating organ so efficiently that protein binding dose not limit their removal. The total concentration at steady state is unchanged and an increase in the unbound fraction leads to an immediate and sustained increase in the unbound concentration. This is of clinical significance for highly protein-bound drugs with narrow therapeutic indices, such as propofol. Cavaliere and colleagues also reported that no increase in the sedative effect of propofol was apparent. Target concentrations were adjusted to achieve a Ramsay sedation score between 4 and 5 and were similar in the hypoalbuminaemic and normoalbuminaemic patients. However, the increase of unbound propofol without alteration in the total propofol concentration in blood might occur as a result of the hypoalbuminaemia as we demonstrated in our study. Further study of the pharmacodynamics of propofol in hypoalbuminaemic patients is required.