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- Fulton, B. & Sorkin, E.M. Drugs (1995) 50: 636. doi:10.2165/00003495-199550040-00006
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Propofol is a phenolic derivative that is structurally unrelated to other sedative hypnotic agents. It has been used extensively as an anaesthetic agent, particularly in procedures of short duration. More recently it has been investigated as a sedative in the intensive care unit (ICU) where it produces sedation and hypnosis in a dose-dependent manner. Propofol also provides control of stress responses and has anticonvulsant and amnesic properties. Importantly, its pharmacokinetic properties are characterised by a rapid onset and short duration of action.
Noncomparative and comparative trials have evaluated the use of propofol for the sedation of mechanically ventilated patients in the ICU (postsurgical, general medical, trauma). Overall, propofol provides satisfactory sedation and is associated with good haemodynamic stability. It produces results similar to or better than those seen with midazolam or other comparator agents when the quality of sedation and/or the amount of time that patients were at adequate levels of sedation are measured. Patients sedated with propofol also tend to have a faster recovery (time to spontaneous ventilation or extubation) than patients sedated with midazolam. Although most studies did not measure time to discharge from the ICU, propofol tended to be superior to midazolam in this respect. In a few small trials in patients with head trauma or following neurosurgery, propofol was associated with adequate sedation and control of cerebral haemodynamics.
The rapid recovery of patients after stopping propofol makes it an attractive option in the ICU, particularly for patients requiring only short term sedation. In short term sedation, propofol, despite its generally higher acquisition costs, has the potential to reduce overall medical costs if patients are able to be extubated and discharged from the ICU sooner. Because of the potential for hyperlipidaemia and the development of tolerance to its sedative effects, and because of the reduced need for rapid reversal of drug effects in long term sedation, the usefulness of propofol in long term situations is less well established.
While experience with propofol for the sedation of patients in the ICU is extensive, there are still areas re quiring further investigation. These include studies in children, trials examining cerebral and haemodynamic outcome s following long term administration and in patients with head trauma and, importantly, pharmacoeconomic investigations to determine those situations where propofol is cost effective. In the meantime, propofol is a well established treatment alternative to benzodiazepines and/or other hypnotics or analgesics when sedation of patients in the ICU is required. In particular, propofol possesses unique advantages over these agents in patients requiring only short term sedation.
Continuous infusions of propofol produce increasing levels of sedation in a dose-dependent fashion. There is a good correlation between plasma propofol concentrations and the level of sedation. Propofol also produces amnesia in a dose-dependent manner although to a lesser degree than midazolam.
Propofol has cardiac depressant effects including an infusion rate-dependent decrease in blood pressure. Heart rate is also generally decreased to a modest extent, and some but not all studies have reported a decrease in myocardial contractility. Reductions in systemic vascular resistance and heart rate help in the control of stress responses. In general, propofol is associated with adequate haemodynamic stability in patients requiring sedation in a variety of settings including those recovering from coronary bypass graft surgery.
Sedation with propofol following head injury is associated with either unchanged or slightly decreased intracranial pressure. While mean arterial pressure is also usually decreased, adequate cerebral perfusion pressure is usually maintained.
Both anticonvulsant and neuroexcitatory effects have been reported with propofol during anaesthesia. The neuroexcitatory effects are not thought to represent true cortical seizure activity.
Long term infusions of propofol tend to be associated with a progressive increase in lipid levels (particularly triglycerides), an effect related to the formulation of the drug. Cortisol levels are decreased when propofol is used in patients undergoing anaesthesia; however, these patients generally demonstrate an adequate response to exogenous adrenocorticotrophic hormone.
The pharmacokinetics of propofol are characterised by fast distribution from the blood into the tissues, rapid metabolic clearance from the blood and slow return of the drug from deep peripheral compartments into the blood. Because of its high lipophilicity, propofol rapidly penetrates the blood-brain barrier, followed by swift redistribution to peripheral tissues; this results in a fast onset but short duration of action.
After initial doses, the clearance of propofol is dependent on both metabolism and on distribution to peripheral compartments. However, as peripheral compartments fill, the distributional component of clearance decreases. Total body clearance values for patients given continuous infusions for intensive care unit (ICU) sedation range from 94.2 to 126.6 L/h, similar to values reported after short term infusions for anaesthesia. These values generally exceed hepatic blood flow, indicating extrahepatic elimination. Propofol is extensively metabolised and excreted in the urine (≥88% of the administered dose) primarily as sulphate and/or glucuronide conjugates of the parent compound or its hydroxylated metabolite. Distribution, second phase and terminal elimination half-lives of 1.8 minutes, 70.9 minutes and 23.5 to 31.3 hours, respectively, have been reported after long term continuous infusions for ICU sedation. The presence of cirrhosis or renal dysfunction does not significantly affect the pharmacokinetics of propofol.
Propofol has been evaluated as a sedative agent during mechanical ventilation in the ICU in numerous patient populations including postsurgical patients (e.g. cardiac, abdominal, neurosurgery), patients with head trauma and general medical patients. Of patients requiring sedation after cardiac surgery, the percentage who obtained adequate sedation was similar for propofol and midazolam in most comparative studies. However, both the time to spontaneous ventilation and time to extubation were shorter in patients receiving propofol (13.6 to 52 minutes and 11.9 to 250 minutes, respectively) than in those receiving midazolam (66 to 197.8 minutes and 127.9 to 391 minutes, respectively). In comparative studies with midazolam involving mixed patient populations (medical, postsurgical, trauma), parameters measuring quality of sedation or rate of recovery were either similar between groups or favoured propofol.
Data from a limited number of studies assessing the efficacy of propofol for the sedation of patients following head trauma indicate that propofol provides adequate sedation and control of cerebral haemodynamics. Propofol was as effective as fentanyl, morphine plus midazolam or morphine plus pentobarbital in controlling intracranial pressure in patients with head trauma. Propofol also produced adequate sedation and cerebral haemodynamic stability in a few small trials measuring sedation in patients after neurosurgery.
Propofol has cardiovascular depressant effects which most commonly manifest as hypotension and bradycardia. The elderly, patients with hypotension or severe cardiac disease (ejection fraction <50%) and debilitated patients may be at greatest risk for hypotension. There have also been case reports of asystole, heart block and other arrhythmias occurring during propofol anaesthesia.
Neuroexcitatory effects such as convulsions, opisthotonos, myoclonus and choreoathetoid movements have been reported during propofol anaesthesia, although they are not believed to represent true cortical seizure activity.
Postsurgical infection caused by a variety of organisms has been associated with the failure to use aseptic technique in the preparation and administration of propofol. Other adverse effects include respiratory acidosis during weaning of ventilation (3 to 10% of patients), pain on injection when administered into peripheral veins, anaphylaxis/anaphylactoid reactions and green discoloration of the urine.
The use of propofol in paediatric patients has been associated with myocardial failure, often in children with respiratory tract infections and often associated with lipaemia and metabolic acidosis.
Dosage and Administration
In mechanically ventilated adult patients in the ICU, propofol should be initiated at an intravenous dosage of 0.3 mg/kg/h and adjusted upward as clinically required in increments of 0.3 to 0.6 mg/kg/h at intervals of at least 5 minutes. Most patients require maintenance infusion rates of 0.3 to 3 mg/kg/h, although higher dosages may be needed. Daily evaluations of CNS function and the level of sedation should be performed. The use of propofol in children as an ICU sedative is not currently recommended.