OPTIMIZING SEDATION FOLLOWING MAJOR VASCULAR-SURGERY - A DOUBLE-BLIND-STUDY OF MIDAZOLAM ADMINISTERED BY CONTINUOUS-INFUSION

A randomized double-blind study was undertaken to determine the dose requirements, recovery characteristics, and pharmacokinetic variables of midazolam given by continuous infusion for sedation in patients following abdominal aortic surgery. Thirty subjects, 50-75 yr, scheduled to undergo aortic reconstructive surgery entered the study. Following a nitrous oxide-isoflurane-opioid anaesthetic technique, patients were randomly allocated to receive one of three loading doses (0.03, 0.06 or 0.1 mg . kg(-1)) and initial infusion rates (0.5, 1.0 or 1.5 mu g . kg(-1) . min(-1)) of midazolam, corresponding to groups low (L), moderate (M) and high (H). The infusion of midazolam was adjusted to maintain sedation levels of ''3, 4 or 5,'' which permitted rye opening in response to either verbal command or a light shoulder tap, using a seven-point scale ranging from ''0'' (awake, agitated) to ''6'' (asleep, non-responsive). Additionally, morphine was given in increments of 1.0 mg iv pm for analgesia. On the morning after surgery, midazolam was discontinued, and the tracheas were extubated when patients were awake. Blood samples were taken during, and at increasing intervals for 48 hr following discontinuation of the infusion, and analyzed by gas chromatography. The desired level of sedation was maintained during more than 94% of the infusion period in all three groups, with a maximum of three dose adjustments per patient, for treatment which lasted 16.3 +/- 0.6 hr. There war, however, an increase in both the infusion rates and mean plasma concentrations from Group L to Group H (P < 0.05), which corresponded to an inverse relationship of morphine requirements during the period of sedation (P < 0.05, Group H vs Group L). Optimal midazolam infusion rates and resulting plasma concentrations at the times the infusions were discontinued (in parentheses) were as follows - Group L: 0.60 +/- 0.18 mu g . kg(-1) . min(-1) (76 +/- 32 ng . mL(-1)), Group M: 0.90 +/- 0.52 mu g . kg(-1) . min(-1) (133 +/- 71 ng . mL(-1)), and Group H: 1.34 +/- 0.69 mu g . kg(-1) . min(-1) (206 +/- 106 ng . mL(-1)). Times to awakening were longer in Group H: 3.1 +/- 3.4 hr, than in Group L: 1.1 +/- 0.8 h, P < 0.05. Pharmacokinetic variables were found to be dose-independent over the range of infusion rates. Mean values were t(1/2)beta = 4.4 +/- 1.5 hr, CL = 5.94 +/- 1.69 mL . min(-1) . kg(-1), Vd = 3.13 +/- 1.07 L . kg(-1). It is concluded that midazolam, infused between 0.6-0.9 mu g . kg(-1) . min(-1) provides a stable level of sedation, when administered in conjunction with intermittent iv morphine following AAS. This sedation technique, which costs $165 +/- 0.73 hr(-1) ($Can), is associated with rapid recovery and minimal side effects.