SummaryDexmedetomidine reduces the dose requirements for opioids and anaesthetic agents. We conducted a single-centre, open-label, noncomparative phase II study of the effect of intravenous dexmedetomidine on the dose requirement of propofol to induce loss of consciousness in 49 ASA I and II patients. The initial dexmedetomidine infusion scheme was reduced twice because of adverse events. Forty patients who received the final infusion scheme were randomly allocated to receive one of five stepped propofol infusions; loss of consciousness was assessed after 21 min. The ED 50 for the final infusion rate of propofol to suppress consciousness was 3.45 mg.kg 21 .h 21 (95% CL 2.7±4.2): ED 95 was 6.68 mg.kg 21 .h 21 (95% CL 5.1±19.1), EC 50 was 1.69 m g.ml 21 (95% CL 0.95±2.5) and EC 95 was 5.7 m g.ml 21 (95% CL 3.2 to . 10). Our final dose of dexmedetomidine of 0.63 m g.kg 21 caused a reduction in the overall concentration and dose of propofol required to produce loss of consciousness, but no significant shift in the dose±response curve compared with other studies. Drugs acting as agonists at a 2 -adrenoceptors may enhance anaesthesia by producing dose-related sedation, anxiolysis, decreased upper airway secretions, peri-operative haemodynamic stability and analgesia [1±3]. There is substantial evidence that the a 2 -agonists also exert an anaestheticsparing effect mediated in part through a decrease in central noradrenergic activity, but mainly through a direct effect on central a 2 -adrenoceptors in the locus coeruleus and other sites [4,5]. The a 2 -agonists also have activity at the imidazoline receptors involved in central blood pressure control [2,6,7].Dexmedetomidine, a specific, selective and potent a 2 -adrenoceptor agonist has been shown to have significant anaesthetic, sedative and analgesic-sparing effects in clinical studies [8±12]. Recently, the dose-dependent effects of dexmedetomidine on isoflurane [11] and sevoflurane [12] requirements have been assessed in humans. However, to date, no studies have explored the shift of a dose±response curve for intravenous agents in conjunction with the a 2 -agonists. We aimed to perform a descriptive dose-finding study to determine the effect of an infusion of dexmedetomidine on the dose and blood concentration of propofol required to suppress consciousness and motor activity during total intravenous anaesthesia with propofol and alfentanil.

Propofol has free radical scavenging properties similar to those of recognized phenol-based antioxidants. We have examined these properties in an in vitro model of radical-induced cellular injury, comparing its activity with that of thiopentone (which has also been shown to have radical scavenging activity). Haemolysis of human erythrocytes was induced using the azo compound 2,2'-azo-bis(2-amidinopropane) dihydrochloride (ABAP). This was achieved by incubating a 10% suspension of erythrocytes with ABAP 100 mmol litre-1 at 37 degrees C. For propofol, at concentrations of 12.5, 25 and 50 mumol litre-1, the times to achieve 50% haemolysis were mean 126 (SEM 7) min (95% confidence interval 108-144 min), 150 (8) (129-170) min and 182 (12) (160-180) min, respectively (Intralipid control 107 (7) (90-125) min, ANOVA P < 0.0001). For thiopentone, at concentrations of 62.5, 125 and 250 mumol litre-1, the values were 117 (2) (112-121) min, 126 (3) (119-133) min and 138 (2) (132-144) min, respectively (saline control 109 (2) (104-113) min, ANOVA P < 0.0001). Spectroscopic analysis in the visible and ultraviolet spectra demonstrated a steady increase in the proportion of methaemoglobin during haemolysis, with the highest concentrations in the propofol-containing flasks. The formation of methaemoglobin was preceded by the generation of ferrylhaemoglobin (a Fe4+ haemoglobin species). Further experiments examining oxidation of purified methaemoglobin to ferrylhaemoglobin by hydrogen peroxide suggested that propofol, but not Intralipid or thiopentone, reduced ferrylhaemoglobin back to the met- state, and thereby explained the higher concentrations of methaemoglobin in the propofol-containing erythrocyte suspensions. We conclude that propofol is a more potent free radical scavenger in this model of oxidant stress than thiopentone, and that reduction of high oxidation states of haemoglobin may contribute to such activity.

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in blood from six patients. There was no change when red cells alone were studied, but when the patients' The antioxidant capacity of plasma taken from 10 plasma was added to red cell suspensions (producing patients before and during propofol anaesthesia was 10% plasma and 10% red cell suspensions), mean H 50 measured. Mean total plasma antioxidant activity fell increased from 291 to 308 min (P=0.049). Despite from 1.73 to 1.64 mm L −1 trolox equivalents (P=0.047).there being no overall increase in plasma antioxidant This was caused by haemodilution since mean haemoactivity, the lipid soluble component of blood antiglobin concentration fell from 13.0 to 12.5 g dL −1 (P= oxidant activity appears to be increased by propofol. 0.016). The time to 50% haemolysis (H 50 ) of 10% red blood cell suspensions induced by 2,2'azo-bis(2-am-

The clinical formulation of the i.v. anaesthetic propofol contains both the substrate for and inhibitor of lipid peroxidation. In these in vitro experiments we have investigated the importance of this potential conflict in a system where haemoglobin was oxidized by reactive oxygen species generated by hypoxanthine and xanthine oxidase. The presence of lipid in the system accelerated the rate of haemoglobin oxidation. Propofol inhibited lipid-induced acceleration but not the underlying rate of reactive oxygen species-induced oxidation. The rate of conjugated diene production, measured semi-quantitatively by ultraviolet absorption at 234 nm, was not reduced by propofol. Propofol may act by preventing haemoglobin oxidation by lipid hydroperoxides.