Propofol

Propofol (Diprivan®¹) is a phenolic derivative with sedative and hypnotic properties but is unrelated to other sedative/hypnotic agents. Formulated as an oil-in-water emulsion for intravenous use, it is highly lipophilic and rapidly crosses the blood-brain barrier resulting in a rapid onset of action. Emergence from sedation is also rapid because of a fast redistribution into peripheral tissues and metabolic clearance. The depth of sedation increases in a dose-dependent manner.

In well designed clinical trials in patients receiving sedation in the intensive care unit (ICU) for a variety of indications, propofol provided adequate sedation for a similar proportion of time to midazolam, but the rate of recovery was faster with propofol. Even after periods of prolonged sedation (>72 hours), propofol was generally associated with a faster time to recovery than midazolam. Propofol facilitated better predictability of recovery and an improved control of the depth of sedation in response to titration than midazolam. In patients sedated following head trauma, propofol reduced or maintained intracranial pressure.

Propofol is associated with generally good haemodynamic stability but induces a dose-dependent decrease in blood pressure and heart rate. Bolus administration may cause transient hypotension, and slow initial infusions are recommended in most patients. Serum triglyceride concentrations should be monitored during prolonged infusions (>3 days) because of the risk of hypertriglyceridaemia. The administration of 2% propofol can reduce this risk. Strict aseptic technique must be used during the handling of the product to prevent accidental extrinsic microbial contamination.

Despite a higher acquisition cost with propofol, most studies of short-term sedation (approximately <3 days) showed that overall costs were lower with propofol than with midazolam, because a faster time to extubation reduced total ICU costs. However, as the period of sedation increased, the cost difference decreased.

Continuous infusions of propofol (Diprivan®) increase the depth of sedation in a dose-dependent manner. A good correlation generally exists between plasma propofol concentrations and the depth of sedation. The target plasma propofol concentrations identified to achieve a Ramsay sedation score of 2–5 ranged from 0.25 to 2.0 mg/L.

A rapid metabolic clearance and redistribution into peripheral tissues result in faster emergence from sedation than midazolam, even after prolonged periods of sedation (≥7 days). The emergence from propofol sedation is dependent on the depth of sedation, the duration of sedation and the size of the patient.

Propofol causes a dose-dependent decrease in blood pressure as well as a less marked decrease in heart rate. Hypotension is greater with propofol than midazolam during administration of a bolus dose, but similar to midazolam during continuous infusions. The mean heart rate associated with propofol sedation is generally lower than that associated with midazolam. Propofol decreases total oxygen consumption to a similar extent to midazolam. Right ventricular ejection fraction was improved in patients with acute respiratory failure sedated with propofol. Propofol sedation is associated with slight respiratory depression.

Following head injury, sedation with propofol maintained or decreased intracranial pressure and, in most cases, mean cerebral perfusion pressure was maintained above the target value of 60mm Hg.

Long-term infusions of propofol (>7 days) may cause increases in serum triglyceride concentrations. When prolonged sedation is indicated, 2% propofol provides the advantage of less lipid administration and, therefore, less hypertriglyceridaemia.

Propofol containing the bacteriostatic agent disodium edetate (ethylene-diaminetetraacetic acid [EDTA]) did not alter calcium and magnesium homeostasis or renal function in critically ill patients in a variety of medical and surgical intensive care unit (ICU) settings.

Propofol is highly lipophilic facilitating rapid penetration of the blood-brain barrier and a fast onset of action (usually within 40 seconds). The pharmacokinetic properties are characterised by a three-compartmental model: rapid initial distribution from blood into tissues, rapid redistribution and metabolic clearance, and a slow return from poorly perfused tissues into the bloodstream. The rapid redistribution into peripheral tissues (muscles and fat) and the rapid metabolic clearance result in a short duration of action (approximate half-life 30–60 minutes) and a fast emergence from sedation when the infusion is stopped (usually within 10–15 minutes).

Propofol has a linear pharmacokinetic profile. At steady state, the clearance of propofol is dependent on metabolism and distribution to peripheral tissues. The volume of distribution is large and increases as the duration of the infusion increases, but once peripheral compartments become saturated, the distributional component of clearance decreases. In obese patients, a greater accumulation in the fatty tissues can cause slower clearance. The total body clearance of propofol ranges from approximately 96 to 204 L/h (23–50 mL/kg/min) and exceeds hepatic blood flow, indicating some form of extrahepatic metabolism. Propofol is extensively metabolised and excreted in the urine (≥88%), mainly as inactive metabolites.

In elderly patients, the volume of distribution and clearance of propofol is decreased and a lower dosage is required. In patients with renal and hepatic impairment, propofol anaesthesia did not significantly affect the pharmacokinetic parameters compared with patients with normal hepatic and renal function, but the effects of long-term sedation have not been evaluated in this patient group.

In well designed clinical trials in adult patients requiring ICU sedation in various clinical settings (including following cardiac surgery), propofol provided a similar quality of sedation to midazolam but was associated with a faster rate of recovery.

In patients sedated for general medical conditions, trauma or following general surgery, propofol provided a similar quality of sedation to midazolam, lorazepam, dexmedetomidine and isoflurane. Propofol infusions administered for varying periods at mean infusion rates of 1.62–2.8 mg/kg/h provided adequate sedation for 62–97% of the time compared with 57–93% of the time with midazolam (0.04–0.2 mg/kg/h). In studies of patients receiving short- (≤24 hours), medium- (24–72 hours) or long-term (>72 hours) sedation, patients treated with propofol generally awoke more rapidly and with less variability than those treated with midazolam. For example, in a study of critically ill patients sedated for approximately 80 hours, those treated with propofol had a mean time to recovery of 23 minutes versus 137 minutes in the midazolam group (p < 0.05). Even after receiving sedative infusions for >7 days, propofol was associated with a faster time to recovery than midazolam. The control of the depth of sedation was easier with propofol than with midazolam, since patients receiving propofol responded more quickly to changes in the infusion rate.

After undergoing cardiac surgery, propofol provided patients with a similar or improved quality of sedation to midazolam. Compared with midazolam, propofol was associated with a faster mean time to spontaneous ventilation (66–197.8 vs 13.6–52 minutes, respectively) and, overall, a faster mean time to extubation.

Propofol provides good control of cerebral haemodynamics in patients sedated following head trauma or neurosurgery. In patients with head injuries, propofol controlled intracranial pressure as effectively as fentanyl or pentobarbital plus morphine and appeared more effective than midazolam plus morphine.

Propofol has a cardiovascular depressant effect, which can lead to hypotension (incidence of 26%) and a reduced heart rate. In particular, bolus doses of propofol are associated with marked transient hypotension. Care should be taken in the elderly and in patients who are haemodynamically unstable or hypovolaemic.

The lipid emulsion of the propofol formulation provides an excellent medium for the growth of a variety of organisms. To prevent accidental extrinsic microbial contamination, strict aseptic technique must be used during handling of both the original formulation and that containing the bacteriostatic agent EDTA.

Pain on injection is common with propofol when administered into peripheral veins, but it can be reduced by using the larger veins in the forearm. Hypertriglyceridaemia is associated with propofol infusions of >3 days. Other adverse effects associated with propofol include respiratory acidosis during weaning from the ventilator (3–10%), green discolouration of the urine and the rare occurrence of anaphylactoid reactions. Case reports have suggested the risk of a possible propofol-infusion syndrome leading to myocardial failure and death in some patients receiving long-term (>58 hours), high-dose (>5 mg/kg/h) infusions.

Despite the higher acquisition cost of propofol, pharmacoeconomic studies have generally shown a cost advantage for propofol compared with midazolam, due to faster recovery times leading to reduced total ICU costs.

In patients requiring sedation for at least 12 hours, the total cost per patient for a stay in ICU was about two-thirds less for patients treated with propofol plus alfentanil compared with patients treated with midazolam plus morphine (£3 095 vs £9 511; p = 0.0013). In a study of patients receiving long-term sedation (≈5.5 days) with propofol (1–6 mg/kg/h) or midazolam (0.1–0.5 mg/kg/h), a total ICU cost difference of $US1 362 per patient was found in favour of propofol. Costs included drug costs ($US0.026/mg for propofol and $US0.123/mg for midazolam) and costs incurred during sedation and weaning periods.

A sensitivity analysis based on a hypothetical model developed from a well designed study of patients sedated for periods of approximately 16 hours predicted a potential saving with propofol of between $Can244 and $Can570 (1997 dollars) for each ICU patient compared with midazolam. This saving was due to the shorter time to extubation leading to improved discharge planning. Extubation time with propofol appeared to be 4.2 times faster, and drug costs 3.6 times higher, than with midazolam.

Overall, studies have shown that the cost differential between propofol and midazolam reduces as the period of sedation increases. During short-term sedation (<24 hours in one study and <72 hours in another) propofol had a significant cost advantage over midazolam, but for longer periods of sedation (>72 hours), the higher acquisition cost of propofol offset the savings made from the reduced time in ICU.

Propofol intravenous injectable infusions should be initiated slowly at a dosage of 0.3 mg/kg/h and adjusted upwards, as clinically indicated, in increments of 0.3–0.6 mg/kg/h at intervals of at least 5 minutes. A rate of between 0.3 and 3.0 mg/kg/h should achieve satisfactory sedation in most patients. Elderly patients (>55 years) require a reduced rate of infusion (1.8 mg/kg/h).

There is large interpatient variability in dosage requirements, which may change over time. Titration of the propofol dosage should be made to clinical response, and daily assessment of sedation levels and CNS function are important to determine the minimum dosage required. Bolus doses of 1% propofol may be given if clinically indicated and if hypotension is not likely to occur. A light level of sedation is recommended during the weaning process with discontinuation of the infusion 10–15 minutes before extubation.