EditorCavaliere and colleagues report that hypoalbuminaemia does not affect the accuracy of Diprifusor during sedation with propofol.1 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 hypo- and 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).2 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.3 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.4
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.2 Further study of the pharmacodynamics of propofol in hypoalbuminaemic patients is required.
Maebashi, Japan
EditorWe are grateful to Dr Takizawa and colleagues for their interest in our paper on the influence of hypoalbuminaemia on Diprifusor performance during sedation with propofol.1 They studied propofol unbound and total concentration in blood and hepatic extraction rate before, during, and after CPB.2 In their letter they point out that: (i) propofol total concentration did not change (apart from an initial decrease) during CPB, while the unbound fraction increased; such increase was probably consequent to dilutional hypoalbuminaemia and indicates that unbound fraction can be affected by albumin levels (i.e. that albumin does not bind propofol linearly); (ii) propofol hepatic extraction rate and total body clearance did not change during CPB in spite of dilutional hypoalbuminaemia; this would suggest that hypoalbuminaemia does not affect propofol pharmacokinetics and, as a consequence, cannot affect Diprifusor performance.3 4
We think their data are very interesting but not applicable to the conditions of our study on sedation in ICU patients. Firstly, propofol mean concentration was very different in the two studies (1 vs 2.5 µg ml1), and albumin may bind propofol linearly at lower propofol concentrations and non-linearly at higher ones. In addition, acute haemodilution by CPB priming is a condition quite different from chronic hypoalbuminaemia; for example, unbound fraction, calculated as the ratio of unbound to total propofol concentrations in whole blood, may have been affected by haematocrit changes. Finally, unchanged hepatic extraction ratio does not rule out significant changes of propofol pharmacokinetics associated with CPB, which have been reported by other authors.5
We agree that an increase of propofol pharmacological effects should be expected in relation with an increase of unbound propofol concentration. Such effect was not pointed out in our study, but may be measurable with instruments more sensitive than clinical judgement.
Rome, Italy
References
1 Cavaliere F, Conti G, Moscato U, et al. Hypoalbuminemia does not impair Diprifusor performance during sedation with propofol. Br J Anaesth 2005; 94: 4538
2 Hiraoka H, Yamamoto K, Okano N, Morita T, Goto F, Horiuchi R. Changes in drug plasma concentrations of an extensively bound and highly extracted drug, propofol, in response to altered plasma binding. Clin Pharmacol Ther 2004; 75: 32430[CrossRef][ISI][Medline]
3 Benet LZ, Hoener BA. Changes in plasma protein binding have little clinical relevance. Clin Pharmacol Ther 2002; 71: 11521[CrossRef][ISI][Medline]
4 Wilkinson GR, Shand DG. Commentary: a physiological approach to hepatic drug clearance. Clin Pharmacol Ther 1975; 18: 37790[ISI][Medline]
5 Bailey JM, Mora CT, Shafer SL. Pharmacokinetics of propofol in adult patients undergoing coronary revascularization. The Multicenter Study of Perioperative Ischemia Research Group. Anesthesiology 1996; 84: 128897[CrossRef][ISI][Medline]