propofol - link.springer.com · 2/3/2003 · propofol. propofol sedation is associated with slight...

CNS Drugs 2003; 17 (4): 235-272ADIS DRUG EVALUATION 1172-7047/03/0004-0235/$30.00/0

© Adis Data Information BV 2003. All rights reserved.

PropofolA Review of its Use in Intensive Care Sedation of Adults

Kate McKeage and Caroline M. Perry

Adis International Limited, Auckland, New Zealand

Various sections of the manuscript reviewed by:L. Burry, Departments of Pharmacy and Critical Care, Mt Sinai Hospital, Toronto, ON, Canada; C. Chamorro,Intensive Care Unit, Clinica Puerta de Hierro, Madrid, Spain; D. Drover, Department of Anesthesia, StanfordUniversity Medical Center, Stanford, CA, USA; R. Hall, Department of Anaesthesia, Queen Elizabeth IIHealth Sciences Centre, Halifax, NS, Canada; S Mehta, Departments of Pharmacy and Critical Care, Mt SinaiHospital, Toronto, ON, Canada; S. K. Samra, Department of Anesthesiology, University of Michigan HealthSystem, Ann Arbor, MI, USA; N. R. Searle, Department of Anaesthesia, Montreal Heart Institute, Montreal,PQ, Canada.

Data Selection Sources: Medical literature published in any language since 1980 on propofol, identified using Medline and EMBASE, supplemented byAdisBase (a proprietary database of Adis International). Additional references were identified from the reference lists of published articles.Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.Search strategy: Medline search terms were ‘propofol,’ ‘ICU’ or ‘intensive care*’ and ‘sedation’. EMBASE search terms were ‘propofol’,‘ICU’ or ‘intensive care*’ and ‘sedation’. AdisBase search terms were ‘propofol’, ‘ICU’ or ‘intensive care*’ and ‘sedation’. Searches were lastupdated 3 February 2003.Selection: Studies in patients who received propofol for intensive care unit sedation. Inclusion of studies was based mainly on the methodssection of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevantpharmacodynamic and pharmacokinetic data are also included. Index terms: ICU sedation, pharmacodynamics, pharmacokinetics, propofol, therapeutic use.

ContentsSummary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2361. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2402. Pharmacodynamic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240

2.1 Sedative Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2402.2 Haemodynamic Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242

2.2.1 Effects on Blood Pressure and Heart Rate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2422.2.2 Effect on Oxygen Consumption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243

2.3 Respiratory Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2442.4 Neurological Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244

2.4.1 Cerebral Haemodynamics and Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2442.4.2 Effects on the EEG . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2452.4.3 Other Neurological Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245

2.5 Effects on Lipid Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2462.6 Effects on Endocrine Response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2462.7 Other Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247

2.7.1 Effect on Gastrointestinal Motility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2472.7.2 Effects on the Immune System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247

2.8 Effects of Propofol Containing Disodium Edetate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248

236 McKeage & Perry

3. Pharmacokinetic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2483.1 Blood Concentrations and Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2483.2 Metabolism and Elimination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2493.3 Special Populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250

3.3.1 Elderly Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2503.3.2 Obese Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2503.3.3 Patients with Renal or Hepatic Impairment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250

3.4 Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2504. Clinical Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251

4.1 Sedation For Medical Conditions, Trauma and Following General Surgery . . . . . . . . . . . . . . . . . 2514.1.1 Quality of Sedation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2514.1.2 Rate of Recovery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253

4.2 Sedation Following Cardiac Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2554.3 Sedation Following Head Injury or Neurosurgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2574.4 Sedation in Special Patient Populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258

5. Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2585.1 Cardiovascular Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259

5.1.1 Propofol-Infusion Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2595.2 Neurological Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2595.3 Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2605.4 Other Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260

6. Pharmacoeconomic Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2616.1 Short- and Medium-Term Sedation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2626.2 Long-Term Sedation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2636.3 Comparisons of Short-, Medium- and Long-Term Sedation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 264

7. Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2648. Place of Propofol in the Intensive Care Sedation of Adults . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265

Summary Propofol (Diprivan®1) is a phenolic derivative with sedative and hypnoticAbstractproperties but is unrelated to other sedative/hypnotic agents. Formulated as anoil-in-water emulsion for intravenous use, it is highly lipophilic and rapidlycrosses the blood-brain barrier resulting in a rapid onset of action. Emergencefrom sedation is also rapid because of a fast redistribution into peripheral tissuesand metabolic clearance. The depth of sedation increases in a dose-dependentmanner.

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

Propofol is associated with generally good haemodynamic stability but inducesa dose-dependent decrease in blood pressure and heart rate. Bolus administrationmay cause transient hypotension, and slow initial infusions are recommended in

1 Use of tradenames is for product identification purposes only and does not imply endorsement.

© Adis Data Information BV 2003. All rights reserved. CNS Drugs 2003; 17 (4)

Propofol: A Review 237

most patients. Serum triglyceride concentrations should be monitored duringprolonged infusions (>3 days) because of the risk of hypertriglyceridaemia. Theadministration of 2% propofol can reduce this risk. Strict aseptic technique mustbe used during the handling of the product to prevent accidental extrinsicmicrobial contamination.

Despite a higher acquisition cost with propofol, most studies of short-termsedation (approximately <3 days) showed that overall costs were lower withpropofol than with midazolam, because a faster time to extubation reduced totalICU costs. However, as the period of sedation increased, the cost differencedecreased.Conclusion: The efficacy of propofol in the sedation of adults in the ICU is wellestablished, and clinical trials have demonstrated a similar quality of sedation tomidazolam. Because of a rapid distribution and clearance, the duration of action ofpropofol is short and recovery is rapid. Emergence from sedation is more rapidwith propofol than with midazolam, even after long-term administration (>72hours), which enables better control of the depth of sedation in response totitration and more predictable recovery times. Thus, for the ICU sedation of adultsin a variety of clinical settings, propofol provides effective sedation with a morerapid and predictable emergence time than midazolam.

Continuous infusions of propofol (Diprivan®) increase the depth of sedation in aPharmacodynamicdose-dependent manner. A good correlation generally exists between plasmaPropertiespropofol concentrations and the depth of sedation. The target plasma propofolconcentrations identified to achieve a Ramsay sedation score of 2–5 ranged from0.25 to 2.0 mg/L.

A rapid metabolic clearance and redistribution into peripheral tissues result infaster emergence from sedation than midazolam, even after prolonged periods ofsedation (≥7 days). The emergence from propofol sedation is dependent on thedepth 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 lessmarked decrease in heart rate. Hypotension is greater with propofol than midazo-lam during administration of a bolus dose, but similar to midazolam duringcontinuous infusions. The mean heart rate associated with propofol sedation isgenerally lower than that associated with midazolam. Propofol decreases totaloxygen consumption to a similar extent to midazolam. Right ventricular ejectionfraction was improved in patients with acute respiratory failure sedated withpropofol. Propofol sedation is associated with slight respiratory depression.

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

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

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


238 McKeage & Perry

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

Propofol has a linear pharmacokinetic profile. At steady state, the clearance ofpropofol is dependent on metabolism and distribution to peripheral tissues. Thevolume of distribution is large and increases as the duration of the infusionincreases, but once peripheral compartments become saturated, the distributionalcomponent of clearance decreases. In obese patients, a greater accumulation in thefatty tissues can cause slower clearance. The total body clearance of propofolranges from approximately 96 to 204 L/h (23–50 mL/kg/min) and exceeds hepaticblood flow, indicating some form of extrahepatic metabolism. Propofol is exten-sively metabolised and excreted in the urine (≥88%), mainly as inactive metabo-lites.

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

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

In patients sedated for general medical conditions, trauma or followinggeneral surgery, propofol provided a similar quality of sedation to midazolam,lorazepam, dexmedetomidine and isoflurane. Propofol infusions administered forvarying periods at mean infusion rates of 1.62–2.8 mg/kg/h provided adequatesedation for 62–97% of the time compared with 57–93% of the time withmidazolam (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 withpropofol generally awoke more rapidly and with less variability than those treatedwith midazolam. For example, in a study of critically ill patients sedated forapproximately 80 hours, those treated with propofol had a mean time to recoveryof 23 minutes versus 137 minutes in the midazolam group (p < 0.05). Even afterreceiving sedative infusions for >7 days, propofol was associated with a fastertime to recovery than midazolam. The control of the depth of sedation was easierwith propofol than with midazolam, since patients receiving propofol respondedmore quickly to changes in the infusion rate.

After undergoing cardiac surgery, propofol provided patients with a similar orimproved quality of sedation to midazolam. Compared with midazolam, propofolwas associated with a faster mean time to spontaneous ventilation (66–197.8 vs13.6–52 minutes, respectively) and, overall, a faster mean time to extubation.



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

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

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

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

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

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

A sensitivity analysis based on a hypothetical model developed from a welldesigned study of patients sedated for periods of approximately 16 hours predicteda potential saving with propofol of between $Can244 and $Can570 (1997 dollars)for each ICU patient compared with midazolam. This saving was due to theshorter time to extubation leading to improved discharge planning. Extubationtime 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 andmidazolam 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 costadvantage over midazolam, but for longer periods of sedation (>72 hours), thehigher acquisition cost of propofol offset the savings made from the reduced timein ICU.


240 McKeage & Perry

Propofol intravenous injectable infusions should be initiated slowly at a dosage ofDosage and0.3 mg/kg/h and adjusted upwards, as clinically indicated, in increments ofAdministration0.3–0.6 mg/kg/h at intervals of at least 5 minutes. A rate of between 0.3 and 3.0mg/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 maychange over time. Titration of the propofol dosage should be made to clinicalresponse, and daily assessment of sedation levels and CNS function are importantto determine the minimum dosage required. Bolus doses of 1% propofol may begiven if clinically indicated and if hypotension is not likely to occur. A light levelof sedation is recommended during the weaning process with discontinuation ofthe infusion 10–15 minutes before extubation.

1. Introduction compound, the formulation also contains soybeanoil, glycerol, egg lecithin, sodium hydrochloride and

Propofol (Diprivan®) is an established intrave- water. To reduce the risk of infection, a formulationnous anaesthetic agent that gained US FDA approv- of propofol containing disodium edetate (ethylene-al for the sedation of mechanically ventilated adults diaminetetraacetic acid [EDTA]) [0.005% w/v], ain the intensive care unit (ICU) in 1993. Extensive bacteriostatic agent, is also available.[3] The mainclinical experience in ICU sedation in a variety of pharmacodynamic properties of the drug are sum-clinical settings now exists, and much of this was marised in table I.previously reviewed in Drugs.[1] This review focus-es solely on the use of propofol for ICU sedation and

2.1 Sedative Effectsexpands on the clinical knowledge of the formula-tion gained since that time. Pharmacological data Propofol is highly lipophilic and thus readily andtaken from studies of propofol given for indications rapidly crosses the blood-brain barrier resulting in aother than sedation have also been included. Al- rapid onset of sedation.[4] The depth of sedationthough generic formulations of propofol have re- increased in a dose-dependent manner in healthycently become available, the use of propofol volunteers[5] and in patients after cardiac surgery,[6,7]

throughout this review refers to Diprivan®. Unless and a correlation generally exists between plasmastated otherwise, the discussion of propofol refers to propofol concentrations and the level of sedation.[50]

the 1% (10 mg/mL) formulation. However, in one study of 22 patients sedated aftercoronary artery bypass graft (CABG) surgery, no

2. Pharmacodynamic Properties correlation was found between plasma concentra-tions of propofol and depth of sedation, whereas aPropofol is a phenolic derivative (figure 1) for-good correlation (r = 0.62) was found between themulated as an oil-in-water emulsion. It has sedativeinfusion rate and plasma concentration.[51]

and hypnotic properties but is unrelated to otherEmergence from sedation after the propofol infu-sedative/hypnotic agents.[2] In addition to the active

sion is stopped is rapid as a result of the fast redistri-bution of the drug into peripheral tissues (section3.1) and metabolic clearance (section 3.2). Emer-gence is faster following propofol sedation thanafter treatment with midazolam (sections 4.1.2 and4.2), even after prolonged periods of sedation (≥7days) [section 4.1.2]. A noncomparative study of 30

CH(CH3)2

OH

CH(CH3)2

Fig. 1. Structural formula of propofol.



Table I. Summary of the pharmacodynamic properties of propofol

Sedative effects Highly lipophilic and rapidly crosses the blood-brain barrier resulting in a rapid onset of action[4]

The depth of sedation increases in a dose-dependent manner[5-7]

Rapidly redistributes into peripheral tissues resulting in a rapid emergence from sedation, faster than thatobserved with midazolam[8-20]

The desired level of sedation is achieved with target plasma propofol concentrations of 0.2–2.1 mg/L[21,22]

Haemodynamic effects Causes a dose-dependent decrease in blood pressure,[6,7,17,23] and transient hypotension is associated withbolus doses[10,14,18,24,25]

Heart rate is decreased and is lower than that observed with midazolam[8,17]

Generally reduces total body oxygen consumption[26,27]

Respiratory effects Causes a slight dose-dependent respiratory depressant effect[28]

Appears to have a mild bronchodilator effect[29-31]

Neurological effects Maintains or decreases intracranial pressure[32-36]

Maintains cerebral perfusion pressure[32-34]

Some patients may develop tolerance during long-term sedation (>5 days) and require an increaseddosage[37-39]

Effects on lipid metabolism Long-term infusions (>3 days) may increase serum triglycerides as a result of the lipid vehicle of thedrug.[9,40,41] 2% propofol reduces the lipid content administered and can be considered for long-termsedation[42,43]

Effects on endocrine Serum cortisol and adrenaline (epinephrine) concentrations are lower in patients sedated with propofol thanresponse with midazolam after coronary artery bypass graft surgery[44]

Effects on immune system In vitro propofol inhibits immune function.[45-47] This effect may be related to the lipid emulsion[48,49]

adult male patients (aged 21–80 years) requiring emergence times after 24 and 72 hours and 7 and 14sedation for mechanical ventilation for >24 hours in days of light sedation (i.e. time taken for sedationa general medical and surgical ICU demonstrated score to decrease from 3 to 2) with propofol were 13,that the emergence from propofol sedation is 34, 198 and 203 minutes, respectively, and afterdependent on the depth of sedation, the duration of deep sedation (sedation score from 5 to 2), 25, 59,sedation (section 3.1) and the size of the patient 71 and 74 hours. To facilitate emergence from light(section 3.3.2).[21] Propofol was administered via a sedation, a 58% decrease in propofol plasma con-target controlled infusion (TCI) system, which is a centration was required, and for emergence fromcomputer-assisted infusion pump that controls the deep sedation, an 88% decrease was needed. Theinfusion rate to achieve and maintain a predeter- model predicted light and deep sedation with pro-mined plasma concentration of the drug. Based on pofol with 73% accuracy.[21]

the pharmacokinetic profile of the drug in the firstSimilar target propofol plasma concentrations20 study participants given propofol dosages based

(range of 0.2–2.1 mg/L) were identified to achieve aon short-term anaesthetic dosages, a pharmaco-desired level of sedation in a study using thekinetic-pharmacodynamic model for propofol seda-

tion was developed and prospectively tested on thelast ten patients.

The average steady-state infusion rate in the pro-spectively tested patients was 1.9 mg/kg/h, and allpatients received intravenous or epidural infusionsof fentanyl (≤200 μg/h) for analgesia as required.[21]

The predicted propofol plasma concentrations re-quired to induce modified Ramsay sedation scalescores of 2, 3, 4 and 5 (defined in table II) were 0.25,0.6, 1.0 and 2.0 mg/L, respectively. The predicted

Table II. Ramsay sedation scale[53]

Sedation score Level of sedation

Awake levels

1 Anxious, agitated and/or restless

2 Cooperative, oriented and tranquil

3 Responds to commands only

Asleep levels

4 Brisk response to stimulus

5 Sluggish response to stimulus

6 No response to stimulus


242 McKeage & Perry

Diprifusor™ TCI system to sedate patients (≥18 following CABG surgery, mean arterial pressureyears), requiring mechanical ventilation in the (MAP) decreased by 15% (from 79.6 to 67.5mmICU.[22] The multicentre, noncomparative study in- Hg; p < 0.05) in the propofol group compared withcluded patients admitted for general medical or sur- 7% in the midazolam group (76.8 to 71.1mm Hg;gical care (n = 47) or after brain injury (n = 18) or not significant).[17] This initial decrease in MAP incardiac surgery (n = 57). No significant differences patients receiving propofol lasted approximately 15between predicted and measured plasma concentra- minutes, and after 1 hour of infusion, valuestions were observed during sedation.[22] stabilised at approximately 11% lower than baseline

Results of a further study also demonstrate the (figure 2), which was considered clinically accept-relationship between depth of sedation and propofol able. Cardiac output remained stable and there wereplasma concentration. To maintain a Ramsay seda- no signs of myocardial ischaemia.[17]

tion score of 2–3, the mean plasma concentration of MAP and mean pulmonary arterial pressure de-propofol in critically ill patients (n = 10) was 0.58 creased during propofol infusion, because of a re-mg/L, achieved by a mean infusion rate of 0.71 mg/ duction in systemic and pulmonary vascular resis-kg/h.[52]

tance, in a study of 20 patients with acute respiratoryAlthough the mechanism has not been deter-

mined, coadministration of propofol and midazolamproduces a synergistic sedative effect.[19] Meanmaintenance dosages of both agents were reducedby 68% when they were coadministered to 25 pa-tients after CABG surgery.[19] Synergistic hypnoticeffects were observed in anaesthetic studies whenpropofol was combined with alfentanil, thiopental,midazolam or midazolam plus alfentanil, whereasan additive hypnotic effect was observed when pro-pofol was coadministered with fentanyl (reviewedby Fulton and Sorkin[1]).

2.2 Haemodynamic Effects

2.2.1 Effects on Blood Pressure and Heart Rate Propofol causes a decrease in blood pressure,

which is generally dose dependent[6,7,23] and thoughtto be due to a combination of decreased systemicvascular resistance and myocardial contractility.[54]

In clinical practice, haemodynamic parameters aremaintained within prescribed limits by the adminis-tration of inotropic drugs and intravenous fluids.Thus, in comparative studies, the hypotensive effectof propofol was not significantly different from thatof midazolam during periods of continuous infusion(section 5.1). However, transient hypotension wasassociated with bolus doses of propofol in clinicaltrials (section 5.1).

After an initial bolus dose of propofol (1 mg/kg)or midazolam (0.07 mg/kg) was given to 30 patients

0 15 30 60 120 180 240 300 360

Time (min)

PropofolMidazolam

60

62

64

66

68

70

72

74

76

78

80

82

Mea

n ar

teria

l pre

ssur

e (m

m H

g)H

eart

rat

e (b

eats

/min

)

0

10

20

30

40

50

60

70

80

90

100

**

*

Fig. 2. The comparative effects of propofol and midazolam onmean arterial pressure and heart rate. Patients were randomised toa propofol loading dose of 1 mg/kg followed by a mean infusion rateof 2.7 mg/kg/h (n = 15) or a midazolam loading dose of 0.07 mg/kgfollowed by a mean infusion rate of 0.092 mg/kg/h (n = 15) aftercoronary artery bypass graft surgery.[17] * p < 0.05 vs comparator.



failure requiring mechanical ventilation in the discontinuation of the infusion, mean heart rate inICU.[55] The decrease in pulmonary arterial pressure the dexmedetomidine group returned to baselineled to an improved right ventricular ejection fraction values with no further difference between groups.[57]

(p < 0.01 vs pretreatment values). Mean blood pressure appeared to be similarlyaffected by 1% or 2% propofol in one study,[58] but In comparative studies of patients requiring se-in another,[59] the effect on heart rate was different.dation following cardiac surgery, the requirementIn patients sedated for >48 hours after trauma (n =for concomitant vasodilators (sodium nitroprusside63), mean blood pressure and heart rate were similaror nitroglycerin) to treat postoperative hypertensionwith 1% or 2% propofol or midazolam.[58] However,was similar or reduced with propofol sedation com-in patients sedated after cardiac surgery, 1% (n = 19)pared with midazolam.[16-19,24,56]

or 2% (n = 20) propofol had a similar effect on bloodPropofol causes a decrease in heart rate despitepressure, but mean heart rate was higher in the 2%reducing MAP. Mean heart rate decreased signifi-propofol group during the period of 30–480 minutescantly from baseline (p < 0.05) in 53 critically ill(p = 0.006 from 1 to 4 hours). The reason for thispatients treated with propofol (mean infusion rate ofobservation is unknown.[59]

1.77 mg/kg/h), but not in those receiving midazolam(n = 47) [mean infusion rate of 0.10 mg/kg/h] for 2.2.2 Effect on Oxygen Consumption≤24 hours in a general medical and surgical ICU.[8]

After cardiac bypass surgery, patients need toIn patients sedated after CABG surgery, the de- restore their normal body temperature. Rewarmingcrease in mean heart rate from baseline was not is often associated with increased body oxygen con-significant at any timepoint up to 6 hours from the sumption (VO2) and shivering, which places addi-start of the propofol infusion, whereas in the tional stress on the newly revascularised heart.[26]

midazolam group, mean heart rate was significantly Propofol and midazolam were shown to reduce sys-higher than baseline at hours 5 and 6 (p < 0.05).[17]

temic VO2 to a similar extent in one randomisedMean heart rate values at hours 4, 5 and 6 were study of patients (n = 73) in a medical ICU.[27]

significantly lower in patients receiving propofol However, in another randomised study of patients inthan in those receiving midazolam (p < 0.05), and the first 4 hours after cardiac surgery (or untilthe difference increased over time (figure 2).[17]

rewarmed to 37°C), total body VO2 was reducedIn another study of patients sedated for approxi- more in the group administered propofol 2 mg/kg/h

mately 14 hours after cardiac surgery, mean heart (n = 12) than in the control group (n = 12) whichrate was significantly reduced from baseline in the received midazolam (dosage titrated to achieve a25 patients receiving propofol (from 110 to 93 beats satisfactory level of sedation).[26] Total VO2 wasper minute; p < 0.05), whereas patients receiving measured using a pulmonary artery catheter. Medianmidazolam (n = 25) showed a slight increase in VO2 levels during rewarming were 1.8 L/h/m2 (30mean heart rate (from 106 to 112 beats per minute; mL/min/m2) less in the propofol group than in thosenonsignificant difference).[19]

receiving control (6.3 vs 8.1 L/h/m2 [105.2 vs 135.3mL/min/m2]; p = 0.01). Shivering was also reducedRecipients of dexmedetomidine sedation (medi-in the group receiving propofol compared with thean infusion rate of 0.00086 mg/kg/h; n = 10) had acontrol group, however, this difference did not reachsignificantly lower mean heart rate than propofolstatistical significance. Patients receiving propofolrecipients (1–3 mg/kg/h; n = 10) during 8 hours ofwere more heavily sedated (median Ramsay seda-continuous infusion (p = 0.034); the study popula-tion score of 5) than those in the control grouption consisted of postoperative patients requiring(median Ramsay sedation score of 3) [p = 0.001].[26]mechanical ventilation.[57] Respective mean heart

rate values at baseline and at hour 8 were 94 and 91 In patients receiving light sedation after coronarybeats/min for propofol and 92 and 72 beats/min for artery surgery, low-dose propofol (1 mg/kg/h) plusdexmedetomidine (values taken from graph). After diazepam as required (n = 15) was associated with


244 McKeage & Perry

slight haemodynamic suppression but did not de- ly lower tidal volume (0.342 vs 0.245L; p = 0.006)crease total-body VO2 compared with placebo plus and higher RSBI (114.8 vs 155.6 breaths/min/L; p =diazepam (n = 15).[60] A dose-dependent effect on 0.004). These results indicate that although propofolcardiopulmonary response to chest physical therapy may cause rapid shallow breathing, this does notwas observed with propofol bolus infusions of 0.35 always mean that the patient is not ready to beginand 0.75 mg/kg administered 2 minutes before ther- spontaneous ventilation.[65] This is less likely to beapy.[61] Increases in VO2, oxygen delivery index and the case with benzodiazepines, particularly aftercardiac output were suppressed with both dosage prolonged sedation, because of the likelihood ofgroups, but effects were more marked with the prolonged respiratory depression after the infusionhigher dosage. is stopped.[66]

A reduction in peak inspiratory pressure has been2.3 Respiratory Effects associated with propofol infusions, which suggests a

mild bronchodilator effect.[29-31] In addition, pro-Propofol has a slight, dose-dependent respiratory pofol provided a good quality of sedation in patients

depressant effect, which has been reviewed pre- with chronic obstructive pulmonary disease and fa-viously.[28] Respiratory depression is not of concern cilitated a rapid recovery.[67]

in patients undergoing mechanical ventilation but isan important consideration during weaning from 2.4 Neurological Effectsventilation.[62] Because propofol is rapidly clearedfrom the blood (section 3.2), the respiratory depres- 2.4.1 Cerebral Haemodynamics and Metabolismsant effect resolves quickly once the drug is The dose-dependent effect of anaesthetic dosagesstopped.[63] of propofol on cerebral metabolism and decreased

Similar effects on respiratory parameters were cerebral blood flow have been reviewed previous-observed during weaning from mechanical ventila- ly.[28] In patients with head injury receiving propofoltion or after extubation in patients receiving pro- for sedation during mechanical ventilation in thepofol or midazolam in clinical trials,[14,18,24,25,56,64] ICU, intracranial pressure (ICP) was either main-with one exception.[20] In a study of 100 patients tained or decreased[32-36] and, in most cases, meansedated after cardiac surgery, patients receiving cerebral perfusion pressure (CPP = MAP – ICP) wasmidazolam (0.034 mg/kg/h; n = 50) had significant- maintained above the target value of 60mm Hg.[32-34]

ly higher mean arterial partial pressure of carbon In one study (n = 31), a further subgroup analysisdioxide (PaCO2) levels than patients receiving pro- demonstrated that the decrease in ICP was signifi-pofol (1.15 mg/kg/h; n = 50) [p < 0.001]. However, cant in patients with a high (>16mm Hg) baselinethe significantly greater amounts of morphine ad- ICP (p < 0.05) and was unchanged in patients withministered to patients receiving midazolam (p < low (≤16mm Hg) baseline ICP.[35]

0.001) may have accounted for this difference in After severe head injury, a decrease in ICP wasPaCO2.[20] not observed in 15 patients receiving a mean pro-

pofol dosage of 232 mg/h.[68] However, propofolPropofol was associated with rapid shallow spon-was associated with a transient decrease in globaltaneous breathing in a noncomparative study of tenbrain metabolism, which was reduced 4 hours aftercritically ill patients, but this effect on respirationthe start of the infusion but returned to presedationresolved within 30 minutes of stopping the infu-values at 8 hours.[68]sion.[65] The ratio of respiration rate to tidal volume

determines the rapid shallow breathing index, which Propofol improved cerebral autoregulation aftermay be used to assess whether a patient is ready to head injury in a study of eight patients admitted tobe weaned from mechanical ventilation. Compared the ICU.[69] Autoregulation was tested three times inwith 20–30 minutes after the propofol infusion was each patient: during midazolam and fentanyl seda-stopped, during treatment patients had a significant- tion, during sedation with propofol 6 mg/kg/h and



during sedation with propofol 12 mg/kg/h. The in- sedated with propofol (n = 10) required 3-fold moredex of autoregulation (IOR) was defined as the ratio alfentanil than those receiving dexmedetomidine (nof the percent change in the estimated cerebral vas- = 10) in one randomised study (p = 0.004).[57] Pro-cular resistance to the percent change in the MAP. pofol has a slight amnesic effect, but less than thatPreliminary results, presented in an abstract, demon- observed with the benzodiazepines.[54]

strate that the IOR was significantly improved with In some patients requiring sedation for >7 days,administration of propofol 12 mg/kg/h (IOR = 0.99; there have been reports of a need for an increasingp < 0.05) but was not improved in the other treat- dosage of propofol because of the development ofment groups.[69]

tolerance.[37,38] In a noncomparative study designedto evaluate the development of tolerance in patients2.4.2 Effects on the EEGsedated with propofol (approximate dosage of During conscious sedation, propofol has been0.5–4.0 mg/kg/h) for >5 days, 3 of 11 patients wereassociated with a dose-dependent increase in theconsidered to demonstrate tolerance because of aactivation of the electroencephalogram (EEG),statistically significant increase in both the infusionprimarily in the β1-frequency range (as reviewed byrate and blood concentration of propofol (p <Kishimoto et al.[70]). EEG derivatives, such as the0.05).[39] These results indicate a possible need forbispectral index, have been used to assess brainincreasing the dosage in some patients who requirewave activity to determine the depth of sedation.[71]

long-term sedation.Computer-controlled infusions of propofol toachieve target plasma concentrations of 0.3, 0.6, 0.9 Sleep deprivation can exacerbate emotionaland 1.2 mg/L for a median duration of 87 minutes stress in critically ill patients in the ICU.[74] A diur-produced a progressive increase in mean reaction nal sleep-wake cycle was achieved in most criticallytimes as well as a progressive decrease in the long ill patients (n = 29) receiving additional night seda-latency cognitive P300 auditory evoked re- tion (ANS) with 2% propofol alternating with con-sponse.[72] However, more recent evidence suggests stant light sedation (CLS) with 2% propofol duringa nonlinear relationship between electrocortical ac- the day.[75] Patients were randomised to receive 50tivity and depth of sedation during a longer period of hours of CLS day and night (n = 15) or alternatingconstant sedation (>12 hours).[71] Administration of light sedation with ANS (n = 15). The propofolpropofol 1–4 mg/kg/h for >12 hours was associated infusion rate was titrated based on the Ramsay scalewith a decrease in EEG frequency.[71] Because of (defined in table II), with a target Ramsay score ofthis time-dependent deceleration in EEG frequency, 2–3 for light sedation and a target score of 4–5 forEEG parameters should be used cautiously to moni- ANS. Morphine was also administered as required.tor the depth of ICU sedation over the longer A significantly improved rhythm of sedation levelsterm.[71] was observed in the group receiving ANS compared

with those receiving CLS (p < 0.01). The mean2.4.3 Other Neurological Effectspropofol infusion rate in the CLS group was 1.01Data regarding the analgesic properties of pro-mg/kg/h during the day and 0.97 mg/kg/h at night,pofol are equivocal (reviewed by Fulton andand in the ANS group respective propofol day andSorkin[1]), and other reviews suggest that at sedativenight infusion rates were 0.56 and 0.94 mg/kg/h.dosages, propofol has no analgesic effects.[63,73] Ad-ICU patients least likely to exhibit a diurnal sedationequate pain relief in critically ill patients is usuallypattern in response to ANS were those who wereachieved with opioid analgesics, which will de-well enough to establish normal diurnal fluctuationscrease the overall requirement for sedation.[63] Com-and those who were severely ill with obtunded con-pared with patients receiving midazolam after cardi-sciousness.[75]

ac surgery, patients treated with propofol had low-Sleep quality improved to a similar extent iner[16,20,24] or similar[17-19,56] requirements for

patients receiving propofol (n = 19) or midazolam (nanalgesia during ICU sedation. However, patients


246 McKeage & Perry

= 13) in a study evaluating overnight sedation of In a further study, the effects on plasma totalnon-intubated conscious patients admitted to ICU cholesterol and triglyceride levels observed with 1%following trauma or general surgery.[74] However, and 2% propofol were not significantly different.[77]

this did not appear to affect the level of anxiety and In this randomised, multicentre, nonblind study ofdepression, which was considered high in both treat- patients requiring mechanical ventilation in the ICU,ment groups in the first 5 days in the ICU.[74] infusion rates of propofol were similar in both the

1% and 2% treatment groups, and the mean durationAmnesia has been reported to occur in a dose-of sedation was 58 and 55 hours, respectively (n =dependent fashion with the administration of pro-28 in both groups).[77] Higher cholesterol and trig-pofol anaesthesia (reviewed by Fulton andlyceride concentrations were observed in patientsSorkin[1]). However, propofol caused less amnesiareceiving 1% propofol on days 1 and 2, but on day 3,than midazolam in critically ill patients[14] andtriglyceride concentrations were higher in patientshealthy volunteers[76] at dosages that produced simi-receiving 2% propofol. The differences between thelar sedative effects.groups did not reach statistical significance. Trig-lyceride concentrations were raised to above the

2.5 Effects on Lipid Metabolism upper normal limit (1.6–1.92 mmol/L) in three pa-tients in the 1% group and in one patient in the 2%

As a result of the lipid content of propofol, long- group.[77]

term infusions (>3 days) have been associated with Pancreatic dysfunction, resulting from raised se-progressive increases in serum triglycerides (section rum triglycerides, has been associated with pro-5.4).[9,40,41] In addition, the acute-phase response longed propofol administration.[78-81] A randomisedfollowing major stress in critically ill patients can study compared the effects of postoperative sedationhave an effect on lipid metabolism, lowering serum with propofol (n = 21) or midazolam (n = 21) oncholesterol and raising triglycerides.[42]

pancreatic function.[82] Four hours after the start ofPropofol infusions of >7 days (mean mainte- sedation in the ICU, mean serum triglyceride con-

nance dosage of 2.31 mg/kg/h) caused 3 to 4-fold centrations were within normal limits but were sig-increases in serum triglyceride concentrations, and nificantly higher in the propofol group (1.58 mmol/the return to presedation values was variable, in L) than in the midazolam group (0.92 mmol/L) [p <some instances taking several days.[40]

0.05]. However, there were no significant differ-When more prolonged sedation is indicated, the ences between treatment groups in the serum con-

administration of 2% propofol reduces the lipid concentrations of markers of pancreatic function (amy-tent of the dosage by half and, therefore, causes less lase, lipase and pancreatic-associated protein), andhypertriglyceridaemia (section 5.4). In a study of 30 all were inside the normal range. These results sug-critically ill patients sedated with 2% propofol for gest that pancreatic function may not be altered with>50 hours, serum triglyceride concentrations were sedative dosages of propofol administered postoper-not significantly increased.[42] A significant correla- atively.[82]

tion between C-reactive protein and triglycerides (p< 0.01) was observed, however, indicating that the

2.6 Effects on Endocrine Responseacute-phase response may have had some effect onthe mild increases in serum triglyceride concentra-tions.[42] Similarly, the frequency of hypertriglycer- Propofol sedation is associated with decreases inidaemia was reduced in patients sedated with 2% mean serum cortisol concentrations.[8,24] This effectpropofol (n = 51) for a mean duration of 122.4 hours is most likely attributable to the sedative effect ofcompared with historical data of patients receiving propofol mitigating sympathetic activity in response1% propofol (3.9 vs 20.4%, respectively; p = to stress in critically ill patients, thereby minimising0.016).[43] catecholamine release.[44]



The effect of propofol on the postoperative endo- receiving additional night sedation with either avariable infusion of 2% propofol or a constant infu-crine response was evaluated in patients after under-sion of morphine and 2% propofol (results presentedgoing CABG surgery in a randomised study.[44] Pa-in an abstract).[84] tients received a continuous infusion of propofol (n

= 61) or intermittent bolus doses of midazolam andmorphine (n = 60) to maintain a sedation level of 5 2.7 Other Effectson a modified Ramsay sedation scale. Comparedwith patients receiving midazolam, propofol recipi-

2.7.1 Effect on Gastrointestinal Motilityents had a 31% lower plasma cortisol concentrationIn vitro, clinically relevant dosages of propofol(p = 0.0004) and a 53% lower plasma adrenaline

impaired spontaneous contractile activity and ace-(epinephrine) concentration (p = 0.009) 8 hours aftertylcholine-induced contraction of human gastric andadmission to the ICU. Although the study was notcolonic smooth muscles.[85] However, there was nodesigned to correlate haemodynamic changes withdifference in gastro-caecal transit times in patientsthe endocrine response, a lower incidence of tachy-anaesthetised with propofol (119 minutes), pro-cardia (p = 0.038) and hypertension (p = 0.012) andpofol/ketamine (147 minutes) or isoflurane (122an increased incidence of hypotension (p = 0.001)minutes), indicating that in the ICU setting, propofolwere observed in the propofol group than in theis not likely to alter gut motility more than standardmidazolam group. Plasma noradrenalineisoflurane anaesthesia.[86]

(norepinephrine) concentrations were also lower inthe propofol group at 8 hours, but the difference did

2.7.2 Effects on the Immune Systemnot reach statistical significance. The effect on plas-Anaesthetic agents are known to effect thema dopamine concentrations was similar in both

immune system.[49] In vitro studies have shown thattreatment groups. In the period 6–12 hours afterpropofol, and other anaesthetic/sedative agents, ef-admission to the ICU, mean urinary concentrationsfect lymphocyte response,[48,87] neutrophil func-of cortisol, dopamine, adrenaline and noradrenalinetion[46,47,88] and cytokine production.[89] Althoughwere significantly lower in the propofol group thanthese effects are generally reversible after short-in the midazolam group (p ≤ 0.01).[44]

term anaesthetic use, they may be clinically relevantIn a further study of sedation after uncomplicated for the sedation of immunocompromised patients or

CABG surgery, patients receiving light sedation patients undergoing prolonged sedation in thewith propofol (Ramsay score of 2) [n = 24] did not ICU.[49] In the case of propofol, the lipid emulsionhave an increased endocrine stress response or risk may cause an immunosuppressive effect.[48,49]

of myocardial ischaemia compared with patients After 48 hours of continuous infusion, serumreceiving heavy sedation with propofol (Ramsay concentrations of pro-inflammatory cytokines (in-sedation score of 4) [n = 26].[83] In a subgroup of terleukin [IL]-1β, IL-6 and tumour necrosis factor-patients, mean plasma concentrations of adrenaline, α), which act to limit infection and provide a suita-noradrenaline and dopamine were not significantly ble environment for tissue healing, were increaseddifferent in light (n = 11) and heavy (n = 10) significantly in surgical patients receiving propofolsedation groups up to 24 hours after surgery. (p < 0.05), but decreased significantly in patients

Increasing the dosage of propofol for overnight receiving midazolam (p < 0.05).[90] The productionsedation did not restore hormonal diurnal of IL-8 was reduced significantly by both propofolrhythms.[84] There were no significant effects on (30%) and midazolam (48%) [p < 0.05 vs preinfu-mean serum concentrations of cortisol, growth hor- sion levels]. Production of the immunoregulatorymone, adrenocorticotrophic hormone, prolactin or cytokines was also affected; IL-2 production wasthyroid stimulating hormone in 30 critically ill pa- reduced by propofol (68%; p < 0.001), and interfer-tients maintained at a level of light sedation or those on-γ production was increased by propofol (30%; p


248 McKeage & Perry

Table III. Summary of the mean distribution and elimination pharmacokinetic parameters of propofol administered as a continuous infusionin patients requiring sedation in the intensive care unit

Continuous infusion for up to 24 hours (n = 18)[97]a

Vss (L/kg) 7.0b

CL (L/h) 60

t1/2α (min) NR

t1/2β (min) 90.5

t1/2γ (h) 9.3

Continuous infusion for 72 hours (n = 9)[98]c and for up to 86 hours (n = 12)[99]d

Vss (L/kg) 23.8b

CL (L/h 94.2,[98] 126.6[99]

t1/2α (min) 1.8

t1/2β (min) 70.9

t1/2γ (h) 23.5,[99] 31.3[98]

a Mean infusion rate of 1.0–3.5 mg/kg/h.

b Assuming 70kg patients.

c Infusion rate of 3 mg/kg/h.

d Mean infusion rate of 2.6 mg/kg/h.

CL = total body clearance; NR = not reported; t1/2α = distribution half-life; t1/2β = second-phase half-life; t1/2γ = terminal elimination half-life; Vss

= volume of distribution at steady state.

< 0.05), whereas midazolam did not cause a signifi- 3. Pharmacokinetic Propertiescant change in either parameter.[90]

The pharmacokinetic properties of propofol arecharacterised by a three-compartmental model: rap-2.8 Effects of Propofol Containingid initial distribution from blood into tissues, rapidDisodium Edetateredistribution and metabolic clearance, and slow

To inhibit microbial growth, propofol is also return from poorly perfused tissues into the blood.[4]

available in a formulation containing EDTA. As The rapid occurrence of the first two phases of thiswell as its bacteriostatic effect, EDTA is a chelator model results in a fast onset of action (usually withinof ions (e.g. calcium and magnesium) and trace 40 seconds) and a rapid rate of recovery from seda-metals (e.g. zinc and copper). Various well-designed tion (usually within 10–15 minutes).[3]

studies have compared the effects of propofol, with The pharmacokinetic properties of propofol haveand without EDTA, in critically ill patients.[91-95]

been well described previously.[96] This section in-The addition of EDTA to propofol does not alter cludes more recent studies of propofol in patients

calcium and magnesium homeostasis or renal func- and healthy volunteers. Table III summarises thetion in critically ill patients with pulmonary dys- mean distribution and elimination pharmacokineticfunction[91] or following general[92] or cardiac[92,93]

parameters observed in patients receiving short-termsurgery. Compared with propofol without EDTA, (≤24 hours) or long-term (72–86 hours) sedationpropofol containing EDTA was associated with a with propofol in the ICU.greater loss of zinc and iron in the urine and lowerserum concentrations of zinc, but the clinical rele- 3.1 Blood Concentrations and Distributionvance of this is not clear.[94]

Propofol with and without EDTA was shown to After the initial dose-dependent increase in bloodincrease concentrations of parathyroid hormone in propofol concentrations, the rate of increase slowshealthy volunteers[95] and patients with pulmonary as a result of rapid distribution and the high rate ofdysfunction.[91] The reasons for this increase and the metabolic clearance.[3] During continuous infusionsclinical relevance are unclear.[95] of propofol used as an anaesthetic or for ICU seda-



tion, blood concentrations at steady state are linearly percentage of free propofol, but the clinical signifi-cance of this is not clear.[102]related to the infusion rate.[100] Mean whole-blood

concentrations of propofol after a bolus dose of 1–33.2 Metabolism and Eliminationmg/kg (n = 9) ranged from 0.77 to 15.3 mg/L, and 6

hours after a subsequent continuous infusion of 3Following an initial bolus dose of propofol, plas-mg/kg/h, the mean blood propofol concentration

ma concentrations rapidly decrease as a result ofwas 1.3 mg/L. Thereafter, blood propofol concentra-rapid distribution and high metabolic clearance,tions gradually increased to reach a plateau of ap-each accounting for approximately half of the de-proximately 2 mg/L at about hour 30, which wascrease.[3] Over time, there is a reduction in the

maintained until the infusion was stopped (hourdistribution of the drug as the concentration in body

72).[98]

tissues equilibrates with that in plasma. At thisBecause propofol is highly lipophilic, it readily stage, there is no longer a transfer between tissues

crosses the blood-brain barrier.[101] The drug is also and plasma, and therefore concentrations fall moreextensively distributed into other well perfused tis- slowly when the infusion is stopped.[3]

sues, then to lean muscle tissue and finally into According to the manufacturer’s prescribing in-fat.[101] The manufacturer’s prescribing information formation, the total body clearance (CL) of propofolstates that the initial distribution half-life ranges ranges from 96 to 204 L/h (23–50 mL/kg/min) infrom 2 to 4 minutes, followed by a rapid redistribu- 70kg adults[3] and exceeds hepatic blood flow, indi-tion into poorly perfused tissue (elimination half-life cating some form of extrahepatic metabolism.[96]

[t1/2β] 30–60 minutes).[101] Individual pharmaco- Individual pharmacokinetic studies recorded a CLkinetic studies recorded an t1/2β of 70.9[99] and of 60 L/h for infusions of ≤24 hours[97] and 94.2[98]

90.5[97] minutes (table III). The final phase is cha- and 126.6[99] L/h for infusions of 72–86 hours (tableracterised by a slow redistribution from poorly per- III). Elimination is mainly via hepatic conjugation to

inactive metabolites, which are excreted via thefused tissue.[101]

kidney.[3] Less than 0.3% of unchanged propofolThe large volume of distribution of propofol iswas excreted in the urine after administration ofgreater during long-term sedation than during short-[14C]propofol (mean dose 0.47 mg/kg) in healthyterm infusions.[97] After major surgery or trauma, 18volunteers.[103] Most of the drug was excreted in thepatients were sedated with propofol via a TCI sys-urine (≥88%) as inactive glucuronide conjugates oftem (plus alfentanil for analgesia) for up to 24 hourspropofol with the corresponding quinol and the(mean duration 19 hours). The volume of distribu-4-sulphate conjugate of the quinol.[103]

tion at steady state (Vss), assuming a mean body-The terminal elimination half-life (t1/2γ) of pro-weight of 70kg, was 7 L/kg, and about 2-fold higher

pofol is characterised by the slow return of the drugthan that observed during studies of short-term pro-from poorly perfused tissue (mainly fat) back into

pofol infusions for anaesthesia.[97] Another study inthe bloodstream. Studies of patients receiving long-

patients receiving propofol sedation over 72 hoursterm infusions (up to several days) of propofol for

estimated a larger mean Vss of 23.8 L/kg (tablesedation in the ICU demonstrate a t1/2γ of 23.5[99] and

III),[98] and for infusions of 10 days, the value ap- 31.3 hours.[98] Nevertheless, this long eliminationproached 60 L/kg.[3] The observed increase in Vss phase appears to be of little clinical significance, asvalues over time probably reflects increased periph- rapid clearance from the plasma results in rapideral distribution compared with short-term infu- emergence from sedation once the infusion issions. stopped,[63] and recovery has been shown to be rapid

Propofol is highly protein bound (98–99%).[102] even after long periods of infusion in several clinicalA decrease in concentrations of serum albumin in trials (section 4.1.2 and 4.2). However, with highercritically ill patients can lead to an increase in the than recommended dosages and long-term infu-


250 McKeage & Perry

sions, the return of propofol from the peripheral when covariates of lean and fat body masses weretissues into the plasma will slow recovery after the added to the standard three-compartment modelinfusion is stopped.[3] Thus, to avoid excess drug (section 2.1).[21] In this study, the estimated Vss for aaccumulation during long-term infusions, the dos- mean infusion of 55 hours (n = 19) was almostage should be titrated to achieve clinical response 3-fold greater than a previous estimate using a(section 7).[3] noncompartmental model in patients sedated with

propofol for 72 hours (n = 9) [65 vs 23.8 L/kg].[21]The temporary increase in hepatic blood flowSimilarly, the t1/2γ value was also increased in thethat occurs after eating may affect the pharmaco-study using a three-compartmental model and in-kinetic behaviour of some drugs.[104] Switching fromcluding covariates of body mass compared with theparenteral to enteral feeding in eight patients receiv-study using a noncompartmental model (50.3 vsing long-term sedation with propofol in the ICU did31.3 hours).[21] Basing the propofol dosage on thenot affect hepatic blood flow or systemic clearanceideal bodyweight, rather than the actual bodyweightof the drug.[104]

of morbidly obese patients, should prevent signifi-cant drug accumulation and oversedation.[21]3.3 Special Populations

3.3.3 Patients with Renal or Hepatic Impairment3.3.1 Elderly Patients

The pharmacokinetic parameters of propofol an-In elderly patients, the volume of distribution and

aesthesia in patients with chronic hepatic or renalclearance of propofol is decreased and a lower dos-

impairment are not significantly different from pa-age is required (section 7).[3] In patients aged 65–80

tients with normal hepatic and renal function,[96] butyears (n = 12), the volume of distribution of pro-

the effects of long-term propofol sedation have notpofol for the central compartment was 0.32 L/kg

been evaluated in these patient groups. In a study ofcompared with 0.40 L/kg in patients aged 18–35

patients with established renal failure receiving se-years (n = 12).[105] The reduced volume of distribu-

dation with propofol and undergoing haemodiafil-tion is a result of a lower cardiac output in elderly

tration, the requirement for propofol was not affect-patients, leading to a reduced perfusion of tissue

ed but plasma propofol concentrations were reducedrelative to body mass.[105] Clearance was reduced by

with the initiation of the extracorporeal circuit.[107]28% in patients aged >60 years compared with those

The pharmacokinetics of propofol have not beenaged <60 years after receiving an infusion of pro-

determined in patients with acute renal or hepaticpofol.[106]

failure.[3]

Cation homeostasis and renal function were not3.3.2 Obese Patientsadversely affected by propofol containing EDTA inIn obese patients, the volume of distribution ispatients with chronic renal impairment.[108] The ef-increased but the clearance is slower than that ob-fect of propofol with EDTA on renal function wasserved in lean patients.[21] This is due to increasedsimilar to the effect of propofol without EDTA in asaturation and drug accumulation in the fatty tissuedouble-blind, multicentre study.[108] of obese patients, especially after long-term infu-

sions.[21] When the propofol infusion is discontinuedin this patient group, the rate of the decrease of the 3.4 Drug Interactionsplasma propofol concentration becomes lessdependent on redistribution and more dependent on The sedative effects of propofol may be in-metabolic clearance.[21] A slower rate of decrease of creased when coadministered with intramuscular orplasma propofol concentrations results, and poten- intravenous narcotics (e.g. morphine and fentanyl),tially increases the emergence time of obese pa- and a more profound reduction in blood pressuretients.[21] In a study of propofol dosage regimens, the and cardiac output may occur.[3] In adults, therepharmacokinetics of the drug were best described have been no significant interactions with propofol



and other commonly used neuromuscular blocking intravenously, in most cases via a central line. Ifagents, muscle relaxants and analgesic agents.[3] clinically indicated, a bolus dose of sedative was

given initially; thereafter the sedative was given asPropofol undergoes hydroxylation via the cyto-an infusion and the rate was titrated to achieve achrome P450 (CYP) 2C9 pathway, and systemicdesired level of sedation. This method of variable-clearance may have some dependence on CYP2C9rate infusion reduces the risk of oversedation (sec-activity.[109] When propofol was coadministeredtion 3.2). Dose-finding studies in patients receivingwith parecoxib, a parenteral cyclo-oxygenase-2 spe-sedation after cardiac surgery showed that, in gener-cific inhibitor and prodrug to a substrate for hepatical, lower dosages of propofol (<0.75 mg/kg/h) re-CYP2C9, there were no significant differences insulted in a greater need for supplementary sedationpharmacokinetic parameters compared with pro-or for analgesics, whereas higher dosages (≥1.5 mg/pofol administered in combination with placebo.[109]

kg/h) were associated with oversedation and hypo-tension.[6,7,112,113] Patients were excluded if they4. Clinical Efficacywere pregnant, were grossly obese or had a known

The efficacy of propofol as sedation for adult allergy to the study medications. Treatment groupspatients in the ICU has been assessed in numerous within studies were generally well matched in termsfully published studies in a range of patient popula- of age, weight and severity of condition.tions. This section focuses primarily on randomised,

4.1 Sedation For Medical Conditions, Traumacomparative trials, many of which were nonblindand Following General Surgerybecause the propofol formulation is readily distin-

guishable, and knowledge of treatment groups couldThe efficacy of propofol in the sedation of criti-be an advantage in the management of acute agita-

cally ill patients with various medical conditions ortion.[64] The number of evaluable patients in eachfollowing trauma or general surgery, has been com-study ranged from approximately 20 to 100, withpared with midazolam,[8-15,37,41,64] midazolam orsome of the larger studies recruiting patients fromlorazepam,[110] dexmedetomidine[57] and isoflur-several ICUs. In most cases, analyses were inten-ane.[111] Results are summarised in table IV.tion-to-treat. Efficacy parameters included assess-

Studies included patients who were expected toment of the time spent with adequate sedation,need mechanical ventilation for periods rangingwhich in most cases was measured by using thefrom approximately 8 hours to >7 days. In mostRamsay sedation scale (table II) or a modified ver-cases, an opioid analgesic was administered con-sion. Recovery from sedation was assessed by acomitantly with sedation, and the use of neuromus-variety of measures, including time to answer ques-cular blocking agents was generally limited to facili-tions, time to achieve level 3 on the Ramsay seda-tate tracheal intubation.tion scale and time to ventilator weaning and ex-

tubation (see table IV). The time to extubation and/ 4.1.1 Quality of Sedationor recovery varies greatly between studies, largely Overall, in randomised studies directly compar-because of the varying practices between ICUs and ing propofol (mean infusion rates of 1.62–2.8 mg/the different measures used to assess recovery times. kg/h) with midazolam (mean infusion rates ofIn addition, between studies there was variation in 0.04–0.2 mg/kg/h) for varying periods, the propor-the depth of sedation at which patients were main- tion of time that patients were adequately sedatedtained and diagnoses of patients. In studies of pa- was similar with both agents (table IV).[8,9,12,37,110]

tients with neurological conditions, the sedative ef- The quality of sedation was based on an assessmentfect on intracranial pressure and cranial perfusion made by nursing staff using the Ramsay sedationpressure was also assessed (section 4.3). scale, the Glasgow coma scale and/or a modified

Patients enrolled in all studies were aged between version of either. Sedation was generally considered16 and 80 years. Sedative agents were administered effective if the score was within a predetermined


252 McKeage & Perry

Table IV. Efficacy of propofol (PRO) for sedation of patients requiring mechanical ventilation in the intensive care unit. Summary ofrandomised, comparative, nonblind trials in patients with general medical conditions, with trauma or following general surgery. Trials weresingle-centre studies except for one[8]

Reference Patient type Drug and no. of Mean dosage Mean duration Results

patients enrolled (mg/kg/h) of infusion (h) time with adequate mean time toor ideal sedation recovery(%) (min)a

Comparisons with MID

Short- (≤24h) and medium-term (24–72h) sedation

Aitkenhead et al.[8] Gen surg, med, trauma PRO 53 1.77 20.2 94b 5**c

MID 47 0.10 21.3 93b 148d

Beyer & Seyde[10] Abd surg PRO 20e 1.9 24 14*

MID 0.11 24 85

Boyd et al.[11] Abd surg PRO 10 24 8.3*

MID 9 24 92.8

Boyle et al.[37] Gen surg, med PRO 29 67 71

MID 29 41 71

Carrasco et al.[41] Gen surg, med, trauma PRO 20 2.3 11.9f 18*

MID 20 0.17 11.9f 150

Fruh[13] Gen surg, med, trauma PRO 10g 1.62 10 13.8h

MID 10g 0.2 10 35.3

Hall et al.[64] Gen surg, med, trauma PRO 21 336*

MID 26 714

Hall et al.[64] Gen surg, med, trauma PRO 21 444

MID 17 1 878

Wolfs et al.[15] Abd surg PRO 17 1.7 6 16.4

MID 17 0.11 6 85.2

Long-term sedation (>72h)

Barrientos-Vega et al.[9] Gen surg, med, trauma PRO 54 139.7 67i 2 088**j

MID 54 141.7 57i 5 874k

Carrasco et al.[41]l Gen surg, med, trauma PRO 16 2.3 116.4 24*

MID 12 0.17 113 810

Carrasco et al.[41] Gen surg, med, trauma PRO 10 2.3 312.1 48*

MID 10 0.17 342.3 2 196

Chamorro et al.[12] Gen surg, med, trauma PRO 50 2.8 81 97m 23*n

MID 48 0.14 88 92m 137d

Hall et al.[64] Gen surg, med, trauma PRO 4 504*

MID 10 2 808

Weinbroum et al.[14] Gen surg, med, trauma PRO 31 1.8 99 108*

MID 36 0.07 141 168

Comparison with MID or LOR

McCollam et al.[110] Gen surg, trauma PRO 10 2.0 86.4f 62b

MID 10 0.04 60f 79b

LOR 10 0.02 72f 68b

Comparison with DEX

Venn & Grounds[57] Gen surg PRO 10 8o 49.1 28

Continued next page



Table IV. Contd

Reference Patient type Drug and no. of Mean dosage Mean duration Results

patients enrolled (mg/kg/h) of infusion (h) time with adequate mean time toor ideal sedation recovery(%) (min)a

DEX 10 0.00086p 8o 46.3 29

Comparison with ISO

Millane et al.[111] Gen surg, med PRO 24g 1.4 24q 96

ISO 24g 0.35%p 27q 97

a Time to recovery assessed by various means including: time to spontaneous ventilation,[8,15] time to extubation,[9,41,57,64] time toanswer questions,[10] time to achieve level 3 on the Ramsay scale,[11] time to achieve a maximum score on a sedation scale basedon the Glasgow coma scale[12] and time to awake.[13,14]

b Ramsay score 2–4.

c 21 evaluable patients.

d 18 evaluable patients.

e Total number of patients; distribution not specified.

f Mean duration of sedation.

g Crossover study.

h Statistical tests not performed.

i Ramsay score 4–5.

j 25 evaluable patients.

k 27 evaluable patients.

l Subgroup classified as receiving sedation for medium-term duration.

m Sedation score of 3–4 on a sedation scale based on a modified Glasgow coma scale.

n 32 evaluable patients.

o Infusion duration of at least 8 hours.

p Median dosage.

q Median duration of infusion.

abd surg = abdominal surgery; DEX = dexmedetomidine; gen surg = general surgery; ISO = isoflurane; LOR = lorazepam; med = medical;MID = midazolam; * p < 0.05, ** p < 0.001 vs MID.

range on the sedation scale. Continuous infusions of 12–24 hours, patients receiving propofol (n = 30)achieved a significantly better level of sedation thanpropofol achieved adequate levels of sedationthose receiving midazolam (n = 30) [p < 0.05]62–97% of the time compared with 57–93% of the(results not presented in table IV).[25]time with midazolam (table IV).[8,9,12,37,110] In one

study of 88 patients who were sedated for periods of<24 hours to >7 days, the time spent with adequate 4.1.2 Rate of Recoverysedation significantly favoured propofol (93%) The pharmacokinetic profile of propofol allowscompared with midazolam (82%) [p < 0.05].[41] Pro- for a rapid rate of recovery from sedation due topofol also achieved adequate sedation levels for rapid redistribution and metabolic clearance (sectionsimilar periods to lorazepam or midazolam,[110]

3). Clinical trials have demonstrated that the rate ofdexmedetomidine[57] or isoflurane (table IV).[111]

recovery following cessation of the sedative infu-sion is faster with propofol than midazolam follow-One nonblind study evaluated the quality of seda-ing short- (≤24 hours), medium- (24–72 hours) andtion by using a nurses’s rating, which assessed thelong-term (>72 hours) sedation (table IV).[8-15,41,64] patient’s response to endotracheal tube suctioning or

manipulation, turning or repositioning, and dressing In the one study comparing sedation with pro-changes.[25] In postoperative, intubated, general sur- pofol (n = 10) or dexmedetomidine (n = 10), rates ofgical or orthopaedic patients requiring sedation for recovery were rapid in both treatment groups; re-


254 McKeage & Perry

spective mean times to extubation were 28 and 29 study (not tabulated).[27] Recovery from sedation inminutes (table IV).[57] <60 minutes was compared in the propofol and

midazolam treatment groups by the ability to per-form four tasks: open eyes on verbal command (p =Short- (≤24 Hours) and Medium-Term (24–72

Hours) Sedation 0.007); follow the observer with eyes (p = 0.01); Most studies in patients receiving sedation for up hand grasp on command (p = 0.017); and stick out

to 72 hours demonstrated a significantly shorter tongue on command (not significant).[27]

recovery time with propofol than with midazolamLong-Term (>72 hours) Sedation(table IV).[8,10,11,41,64] For example, in a subgroupIn patients sedated for >72 hours, the improve-analysis assessing the time to weaning from the

ment in time to recovery and extubation with pro-ventilator after approximately 20 hours of sedation;pofol compared with midazolam was generallythe mean time to successful independent breathingmore marked than the time differences to recoverywas 5 minutes for propofol recipients (n = 21)and extubation observed between the two agentscompared with 148 minutes for midazolam recipi-after shorter duration infusions (tableents (n = 18) [p < 0.001] (table IV).[8]

IV).[9,12,14,41,64]Short-term changes in the depth of sedation are

In all studies of patients receiving long-term se-often required in the ICU to facilitate proceduresdation (ranging from approximately 80 hours to 13such as physiotherapy or changing the patient’s po-days), recovery times and the time to extubationsition. Propofol (n = 10) provided better control ofwere significantly shorter with propofol treatmentthe depth of sedation than midazolam (n = 9) whenthan with midazolam treatment (tableinfusions were altered to facilitate short periods ofIV).[9,12,14,41,64] Furthermore, a subgroup analysis inphysiotherapy in patients requiring mechanical ven-one of these trials indicated that even in patientstilation following a surgical repair of an abdominaldeeply sedated at the time the infusion was stopped,aortic aneurysm.[11] After 24 hours of mechanicalthe time to recovery was rapid, and more rapid withventilation, the infusion rate of the sedative waspropofol (n = 19) than with midazolam (n = 9) [27 vsincreased to deepen the level of sedation from 3 on237 minutes, p < 0.01].[12] Recovery time was de-the Ramsay sedation scale to 5, and a standardfined as the time taken to achieve the maximumregimen of physiotherapy was given for 12–16 min-score on a sedation scale based on the Glasgowutes. During physiotherapy, patients treated withcoma scale.[12]

propofol achieved the desired sedation level moreNoncomparative studies further support theseoften than those treated with midazolam (53.9% vs

data, showing that after ICU sedation of periods of25.7% of the time; p < 0.01). After physiotherapy,up to 7 days, the time to recovery associated withinfusion rates were again adjusted to resume a Ram-propofol was rapid.[40,114,115]

say sedation level of 3. Patients receiving propofolreawakened to level 3 faster than those receiving Comparisons of Short-, Medium- andmidazolam (8.3 vs 92.8 minutes; p < 0.05). During Long-Term Sedation

physiotherapy, a similar number of dosage adjust- A greater predictability in recovery time withments were required with both agents to achieve the propofol than with midazolam was demonstrated bydesired sedation level, whereas after physiotherapy, the correlation of the duration of propofol adminis-fewer dosage adjustments were needed to the pro- tration with recovery times.[41] Infusions of propofolpofol infusion than to the midazolam infusion (0.4 for <24 hours (n = 20), from 24 hours to 7 days (n =vs 1.8, respectively; p < 0.05).[11] 16) and >7 days (n = 10) demonstrated correlations

Propofol (n = 37) also produced faster, more with the time to extubation (r = 0.83, 0.94 and 0.90,reliable wake-up times than midazolam (n = 36) in a respectively) and with the time to recovery (r = 0.98,further subgroup comparison of patients who were 0.88 and 0.92, respectively), whereas no correlationnot awake at time zero in a randomised, nonblind was observed in the midazolam group.[41]



Recovery times after short- (<24 hours), medi-um- (≥24 and <72 hours) or long-term (≥72 hours)sedation with propofol or midazolam were com-pared in 99 critically ill patients in four ICUs inCanada.[64] The use of propofol allowed for a signifi-cantly shorter time to tracheal extubation than didmidazolam in the short- and long-term sedation sub-groups (p < 0.05) [figure 3].[64] Of interest in thisstudy is the observation that, despite earlier extuba-tion with propofol than with midazolam, the time toICU discharge was longer with propofol in theshort- and medium-term sedation subgroups. Thereason for this finding is unclear.[64]

4.2 Sedation Following Cardiac Surgery

After surgery involving cardiopulmonary bypass,a short period of controlled mechanical ventilation isoften necessary as patients are vulnerable to myo-cardial ischaemia and may be haemodynamicallyunstable and hypothermic.[17] Intravenous sedationand analgesia can aid intubation by controlling pa-tient agitation as well as controlling any associatedhypertension and tachycardia.[24]

The efficacy of propofol has been evaluated fol-lowing CABG surgery in several comparative, ran-domised clinical trials, which are summarised intable V. Most trials compared propofol withmidazolam. Patients were aged over 16 years andwere considered to have a probable need formechanical ventilation for a short period (approxi-mately 8–16 hours) postoperatively. Exclusion cri-teria included left ventricular dysfunction (ejectionfraction <35–45%)[17,19,24,56] or perioperative hae-modynamic instability.[18] In most studies, patientswere also excluded if they had a history of hepatic,renal, CNS or metabolic dysfunction.[17-19,24]

Propofol maintained patients at the desired level

0

20

40

60

80

100

120

140

Mea

n tim

e af

ter

long

-ter

m s

edat

ion

(h)

Extubation

*

ICU discharge

PropofolMidazolam

0

10

20

30

40

50

60

Mea

n tim

e af

ter

shor

t-te

rm s

edat

ion

(h)

*

0

20

40

60

80

100

120

140

160

Mea

n tim

e af

ter

med

ium

-ter

m s

edat

ion

(h)

Fig. 3. Time from withdrawal of sedation with propofol or midazo-lam to tracheal extubation and intensive care unit (ICU) discharge.Critically ill patients requiring continuous sedation following generalor cardiac surgery or for the management of medical conditionswere randomised to receive infusions of either propofol or midazo-lam in a multicentre, nonblind trial. Following initial doses of pro-pofol 0.3–0.6 mg/kg/h or midazolam 0.012–0.024 mg/kg/h, dosageswere titrated to achieve a target Ramsay sedation score specifiedfor each patient. Analysis was intent-to-treat. Patients were alsostratified according to their predicted sedation time based on theirpredicted need for mechanical ventilation: short term <24h (n = 47);medium term ≥24h but <72h (n = 38); and long term ≥72h (n =14).[64] *p < 0.05 vs midazolam.

of sedation for a similar[16,18,19,24,56] or greater[20,116]

percentage of the sedation period to that achieved by in patients treated with propofol than in those re-midazolam (60–93% vs 48–88%) [table V]. Com- ceiving midazolam in all studies assessing this end-pared with alfentanil[117] or oxycodone plus thiopen- point (table V).[16-18] Compared with alfentanil, pro-tal,[118] propofol maintained adequate sedation for a pofol was associated with a similar time to sponta-similar period (table V). neous ventilation.[117] In most studies, propofol

The mean time to spontaneous ventilation was recipients were extubated significantly earlier thansignificantly shorter (p < 0.05 for all comparisons) midazolam recipients (p < 0.05).[16,17,19,20] In one


256 McKeage & Perry

Table V. Efficacy of propofol (PRO) for sedation of patients after coronary artery bypass graft surgery. Summary of randomised, compara-tive trials with midazolam (MID), MID plus propofol, alfentanil (ALF), or oxycodone plus thiopental (OXT). Unless stated otherwise, trialswere nonblind

Reference Drug and no. of Mean Mean Results

patients enrolled dosage duration of time with adequate mean time to mean time to(mg/kg/h) infusion sedation (%) spontaneous extubation (min)

(hours) ventilation (min)

Comparison with MID

Carrasco et al.[19]a PRO 25 1.2 14.4 93 54*

MID 25 0.08 14.1 88 138

PRO + MID 25 0.50 + 0.03 14.7 90 72

Du Gres & Flamens[116] PRO 19 2.2 17 79* 106

MID 19 0.04 17 48 133

Grounds et al.[16] PRO 30 0.79 8.3 91b 13.6** 24.9**

MID 30 0.016 10.3 81b 197.8 226.1

Higgins et al.[24] PRO 42 0.7 9.2 73cd

MID 38 0.018 9.4 79cd

McMurray et al.[20] PRO 50 1.15 16.7 86** 11.9**

MID 50 0.034 16.2 56 127.9

Roekaerts et al.[17] PRO 15 2.71 9.5 52**e 250*

MID 15 0.092 9.7 195 391

Searle et al.[56]af PRO 21 0.64 67 87.5

MID 20 0.02 65 91.5

Snellen et al.[18] PRO 20 0.91 10.5 60c 24*e 154

MID 20 0.038 10.6 53c 66 243

Comparison with ALF

Nollet & Verbeke[117] PRO 12 2.0 13.0 88g 32.1 73.8

ALF 13 0.038 14.2 83g 43.5 83.9

Comparison with OXT

Leino et al.[118] PRO 15 87h 125*

OXTi 15 78h 191

a Double-blind study.

b Ramsay score 2–5.

c Ramsay score 2–4.

d Derived from graph.

e Mean time from stopping sedation to the start of weaning from the ventilator.

f Patient population also included 15 who underwent single-valve replacement and one repair of an atrial septal defect.

g Ramsay score ≥3.

h Ramsay score 4–5.

i Administered as bolus dosages.

* p < 0.05, ** p < 0.001 vs comparator.

study, there was a trend toward a shorter time to haemodynamic response, and their action on cardio-extubation with propofol (p < 0.059)[18] and in two vascular parameters (section 2.2) are an importantstudies,[56,116] the time to extubation was similar with consideration during this postoperative period.[119]

both propofol and midazolam (table V). Compared with midazolam, propofol was associ-In the first 12 hours following a cardiopulmonary ated with a similar cardiovascular outcome during

bypass procedure, haemodynamic episodes often the first 12 hours following CABG surgery in aoccur. Sedative agents have the potential to affect randomised, double-blind study.[119] Patients who



were haemodynamically stable after surgery re-ceived propofol (n = 117) or midazolam (n = 150)for a minimum of 12 hours after aortic unclamping.Dosages of both agents were titrated to achievesedation level 5 on a modified Ramsay scale, andwere supplemented as necessary with bolus doses ofmorphine. The incidence of myocardial ischaemiawas not different between the two treatment groups(12% with propofol vs 13% with midazolam), and atleast one haemodynamic episode occurred in 93% ofpatients in both groups (specific events are illustrat-ed in figure 4 and discussed in section 5.1).[119]

Results of other studies also demonstrated similarcardiac outcomes with propofol or midazolam (sec-tion 2).[16,18,20,56,116]

The requirement for concomitant vasodilators(sodium nitroprusside or nitroglycerin) to treat post-operative hypertension was similar or reduced withpropofol sedation compared with midazo-lam.[16-19,24,56]

4.3 Sedation Following Head Injuryor Neurosurgery

In patients with severe head trauma, sedation isrequired to control raised intracranial pressure(while maintaining cerebral perfusion pressure>60–70mm Hg) and to facilitate mechanical ventila-tion.[32] Also of primary importance in this patientgroup is the need for rapid reversibility of sedationto enable frequent assessment of the neurologicalcondition.[120]

In noncomparative studies in patients with headinjury, propofol has been shown to maintain meancerebral perfusion pressure >60mm Hg and reduceor maintain mean intracranial pressure.[32,34]

In comparative studies, the effect of propofol onintracranial pressure in patients following head inju-

PropofolMidazolam

0

5

10

15

20

25

Inci

denc

e in

firs

t hou

r (%

)

0

10

20

30

40

50

60

70

Inci

denc

e in

hou

rs 1

–6 (

%)

*

*

*

0

10

20

30

40

50

60

Inci

denc

e in

hou

rs 6

–12

(%)

Tachycardia Hypertension Hypotension

*

Fig. 4. Incidence of haemodynamic events occurring during post-operative sedation after coronary artery bypass graft surgery in arandomised, double-blind trial.[119] Patients who were haemo-dynamically stable after surgery received propofol (n = 117) ormidazolam (n = 150) for a minimum of 12 hours after aortic un-clamping. Events were recorded postoperatively during the firsthour, hours 1–6 and hours 6–12. Dosages of both agents weretitrated to achieve sedation level 5 on a modified Ramsay scale andwere supplemented as necessary with bolus doses of morphine.[119]

* p < 0.01 vs midazolam.

ry was similar to that of fentanyl[35] or pentobarbitalplus morphine[121] and appeared more effective than ported in an abstract).[35] However, in a subgroupmidazolam plus morphine[33] or morphine analysis of this study, patients with high intracranialalone.[122] For example, in comatose patients with pressure (>16mm Hg) treated with propofol had asevere head injury, intracranial pressure was un-

greater decrease in intracranial pressure (from 20 tochanged in recipients of a 24-hour infusion of pro-8mm Hg) than those treated with fentanyl (from 20pofol (1–3 mg/kg/h) or fentanyl (0.3–0.5 mg/h),

both in combination with pancuronium (results re- to 13mm Hg) [p < 0.05]. Cranial perfusion pressure


258 McKeage & Perry

remained above 70mm Hg in both high and low experienced a similar quality of sedation, but pa-intracranial pressure (≤16mm Hg) subgroups.[35] tients receiving propofol were discharged earlier

from the ICU (6.25 vs 9.79 hours).[126] In a randomised, double-blind trial of patients

Propofol (n = 12) was associated with a morewith moderate or severe head injuries, intracranialrapid rate of recovery than methohexital (n = 12)pressure and cerebral perfusion pressure were gen-following sedation of neurosurgical patients, as ob-erally similar in groups treated with 2% propofol (nserved in a retrospective study reported in an ab-= 23) or morphine (n = 19), but on day 3 intracranialstract.[127] Within 6 hours of cessation of the infu-pressure was lower in patients treated with propofolsion, 75% of propofol recipients had completelythan with morphine (14mm Hg vs 18mm Hg; p <recovered compared with 58% of methohexital re-0.05).[122] The mean infusion rate and duration ofcipients (no levels of significance were given).therapy was 3.3 mg/kg/h and 95 hours for the pro-

pofol group, and 1.3 mg/h and 70 hours in the4.4 Sedation in Special Patient Populationsmorphine group. Prognostic indicators in the pro-

pofol group were generally worse than those in the Chronic obstructive pulmonary disease (COPD)morphine group, with a higher percentage of pa- can lead to acute respiratory failure and a require-tients receiving propofol recording a Glasgow Coma ment for mechanical ventilation in some patients. InScale score of 3–5 (p < 0.05).[122] Patients receiving a comparative trial of patients with COPD whopropofol required fewer neuromuscular blocking required artificial ventilation, propofol (n = 5) wasagents, benzodiazepines and pentobarbital than associated with a superior overall quality of seda-those receiving morphine. The 6-month outcome, as tion, as assessed by nursing staff, than midazolam (nassessed by the Glasgow Outcome Scale, was simi- = 6) [p = 0.0173].[67]

lar in both treatment groups.[122]Several case studies report that propofol has been

In a further small comparative study of patients used successfully in the ICU to sedate patients withwith severe head injury, propofol (mean infusion 3.6 status epilepticus unresponsive to conventional ther-mg/kg/h, mean duration 22.5 hours) produced ade- apy.[128-133] A retrospective study of 14 patients withquate control of intracranial pressure in all patients nonconvulsive status epilepticus (NCSE), reported(n = 10), whereas adequate control was achieved in in an abstract, found that treatment with intravenousonly three of seven patients receiving morphine plus propofol effectively controlled NCSE in many butmidazolam (mean dose 47.1mg, mean duration 20 not all patients; the underlying cause of the condi-hours) [levels of significance were not reported]. [33] tion was the most important prognostic factor.[134]

Propofol infusions have also been used success-Following neurosurgery, sedation is required tofully in patients with delirium tremens[135-137] andfacilitate mechanical ventilation and minimise phys-tetanus.[138-140] Continuous infusions of propofol iniological stress, which may compromise cerebralpatients with tetanus, some for as long as 25 days,function.[123] As in the treatment of head injury,have provided a good level of sedation and a rapidrapid reversal of sedation following neurosurgery israte of recovery, with patients becoming fully awakepreferable, thus enabling assessment of the patient’sat 30 minutes to a few hours after discontinuation ofneurological condition. Noncomparative trials inthe infusion.[138-140]such patients found that propofol provided adequate

sedation with haemodynamic stability[124] and al-5. Tolerabilitylowed rapid recovery.[125]

In comparison with midazolam (0.075 mg/kg/h), This section discusses the tolerability profile ofpropofol (2.67 mg/kg/h) produced similar effects on propofol when used for ICU sedation in patientscardiovascular and intracranial pressure measure- aged >16 years, using data from clinical trials dis-ments in patients (n = 20) following neurosur- cussed in section 4, as well as information from thegery.[126] Both treatment groups were judged to have manufacturer. Some data from studies in patients



receiving propofol anaesthesia have also been in- Because of the hypotension associated with pro-pofol, particular care should be taken with the ad-cluded. Because patients requiring sedation in anministration of the drug to the elderly and to patientsICU are generally critically ill, it is often difficult towho are hypotensive (see section 7), hypovolaemicdetermine whether an adverse event is related toor haemodynamically unstable.propofol therapy, the underlying disease or other

medications. According to the manufacturer’s pre- Although a causal relationship has not been con-scribing information, most reported adverse events firmed, arrhythmia, atrial fibrillation, bigeminy, car-associated with propofol are mild and transitory.[3] diac arrest, extrasystole, right heart failure and ven-

tricular tachycardia have been observed in <1% ofpatients receiving propofol sedation in the ICU.[3]

5.1 Cardiovascular Events5.1.1 Propofol-Infusion SyndromeIn the early 1990s, several case reports suggestedThe cardiovascular depressant effects associated

an association between sedation with high-dose pro-with propofol, described in section 2.2, most com-pofol (>4 mg/kg/h) and myocardial failure and deathmonly manifest as hypotension and to a lesser extentin children with respiratory tract infections.[141] Aas a reduced heart rate. In clinical trials discussed inpossible propofol-infusion syndrome was identifiedsection 4, hypotensive effects were observed withand defined as follows: a relatively sudden onset ofall sedative agents but rarely led to interruption ofmarked bradycardia resistant to treatment, with pro-the infusion. Haemodynamic parameters weregression to asystole; the presence of lipaemia; amaintained within prescribed limits by the adminis-clinically enlarged liver secondary to fatty infiltra-tration of inotropic drugs and intravenous fluids astion; the presence of severe metabolic acidosis; andclinically indicated. Thus, significant differences inthe presence of muscle involvement with evidencehaemodynamic parameters were generally not ob-of rhabdomyolysis or myoglobinuria.[142] A directserved between treatment groups.[8,12,116,126] Howev-causal link with propofol has not been established,er, if an initial bolus dose of sedative was given atbut the syndrome appears to be related to propofol tothe onset of sedation, transient hypotension wassome degree.[143] Although the syndrome has onlyassociated with propofol[10] and was greater thanbeen associated with high-dose infusions,[143] pro-that observed with the initial bolus dose of midazo-pofol is not recommended for sedation in children aslam.[14,18,24,25] According to the manufacturer’s pre-efficacy and tolerability have not been demonstrat-scribing information, hypotension occurs in 26% ofed.[101]patients receiving propofol sedation in the ICU.[3]

More recently, case reports have suggested aThe incidence of haemodynamic events (93%)similar propofol-infusion syndrome in critically illwas similar with both propofol (n = 117) andadults.[144,145] In a retrospective cohort analysis ofmidazolam (n = 150) in patients following CABGcritically ill adults with head injuries receiving long-surgery in a randomised, double-blind study, but theterm (>58 hours), high-dose (>5 mg/kg/h) infusionsnature of events differed.[119] Compared withfor the control of ICP, 7 of 67 patients developed anmidazolam, propofol was associated with less tachy-apparent propofol-infusion syndrome; 2% propofolcardia and hypertension but more hypotension fromwas used in five of these seven cases.[144]

1 to 12 hours from the start of sedation. Respectivelimits for tachycardia, hypertension and hypoten- 5.2 Neurological Eventssion for the postoperative period were 100 beats/min, 140mm Hg and 90mm Hg. Results are sum- Although propofol has demonstrated anticonvul-marised in figure 4. The incidence of hypotension sant properties,[1] neuroexcitatory events, manifest-between hours 1 and 6 was 49% in patients treated ing as abnormal movements, have been associatedwith propofol and 34% in those treated with midazo- with its use as an anaesthetic agent.[146-149] It is notlam (p < 0.01) [figure 4].[119] clear whether these abnormal movements are the


260 McKeage & Perry

result of true seizure activity or due to a noncortical the infusion line must be replaced at 12 hours or atevent.[146] the end of a procedure, whichever is the sooner.[101]

In the clinical trials of patients receiving propofol In the clinical trials discussed in section 4, theresedation in the ICU discussed in section 4, there were no reports of infection related to propofolwere no reports of neurological effects attributable infusions. The risk of nosocomial infection, there-to propofol. In a crossover trial comparing propofol fore, appears low during the routine use of propofoland isoflurane,[111] three patients reported visual hal- for sedation in the ICU. However, aseptic tech-lucinations during and/or after the cessation of seda- niques must be followed during handling and prepa-tion. All patients received propofol initially fol- ration (section 7), irrespective of whether the clini-lowed by isoflurane. cian is using original propofol or a formulation

Agitation has occurred in <1% of patients receiv- containing EDTA.[101]

ing propofol sedation in the ICU.[3]

5.4 Other Events5.3 Infection

One of the most commonly reported adverseBecause propofol is formulated as a lipid emul- events associated with propofol is pain on injection.

sion, it provides an excellent medium for the growth However, this is not usually a problem in the ICU asof a variety of organisms. In response to reports of the preferred route of administration is via a centralinfection associated with propofol anaesthesia, line.[153] Local pain on injection can be minimisedwhich in most cases appeared to be related to extrin- by using larger veins in the forearm or antecubitalsic microbial contamination due to a lapse in aseptic fossa.[101]

technique, in 1996 an additional formulation of pro- The lipid content of the propofol infusion in-pofol containing the bacteriostatic agent EDTA also creases serum triglyceride concentrations when giv-became available (section 2.8).[2] Since its introduc- en long term (>3 days) [section 2.5]. In some stud-tion, the incidence of fever and infections (approxi- ies, concentrations returned to normal when themately 20 per year) has been virtually eliminat- infusion was stopped,[9,41] but in another trial, returned.[2,150] to presedation levels was variable and in some in-

In an observational study of 100 patients receiv- stances took several days (section 2.5).[40] A rise ining a total of 302 propofol infusions (without triglyceride concentrations was observed in all tenEDTA) for sedation in the ICU for approximately patients sedated with propofol for >7 days,[41] and in4–6 hours, there were no episodes of infection or 11 of 54 patients sedated with propofol for an aver-colonisation of the infusion that could be attributed age of ≈140 hours (mean serum triglyceride concen-to contaminated drug.[151] tration 6.6 mmol/L).[9] In both trials, mean serum

Similarly, the results of a study assessing the triglyceride concentrations returned to within nor-extrinsic contamination of propofol infusions in the mal limits (3.7 mmol/L)[9] in all patients after stop-ICU suggest that the risk of bacterial and fungal ping the infusion[41] or within 72 hours.[9] Patientscontamination is low if standard infection control receiving sedation with propofol for >3 days shouldpractices are adhered to (section 7). Data from this have their lipid profiles closely monitored. In addi-study also indicate that longer periods of infusion tion, the calorific value of concomitant parenteral(>24 hours) may be associated with a higher risk of nutrition should be reduced to compensate for thecontamination.[152] However, the manufacturer’s lipid contained in the propofol infusion (sectionprescribing information, in accordance with guide- 7).[3] The use of 2% propofol halves the lipid loadlines for other lipid emulsions, clearly states that a administered to critically ill patients and has beensingle infusion of propofol must not exceed 12 hours associated with less hypertriglyceridaemia than 1%(section 7).[101] Both the reservoir of propofol and propofol (section 2.5).[42]



Table VI. Summary of randomised cost analyses with propofol (PRO) for sedation of patients requiring mechanical ventilation in theintensive care unit (ICU). Four studies were cost analyses[9,160-162] and two were cost-benefit analyses[41,163]

Reference Country [year of Regimens compared Main costs measured Results (total median cost percosting] patient during ICU stay)

Short- and medium-term sedation (<48 hours)

Anis et al.[160] Canada [1997] PRO vs MID Drug costs, nondrug- PRO $Can5718, MID $Can5950related ICU costs

Manley et al.[161] England [NR]a PRO/ALF vs MID/MOR Drug costs and PRO/ALF £3095**, MID/MORadministration, nondrug- £9511related ICU costs

Sherry et al.[162] England [1993] PRO/FEN vs MID/FEN Sedative costs, nursing PRO/FEN £315.52, MID/FENcosts £358.75

Long-term sedation (>48 hours)

Barrientos-Vega et al.[9] Spain [NR]a PRO vs MID Drug costs, nondrug- PRO $US9466, MID $US10 828related ICU costs

Comparisons of short-, medium- and long-term sedationb

Carrasco et al.[41] Spain [NR]c PRO vs MID Drug costs, nondrug- PRO Pta8900*, MID Pta10 900related ICU costs

Costa et al.[163] Spain [NR]d PRO vs MID vs MOR/DIA Drug costs, nondrug- PRO Pta9000, MID Pta10 900,related ICU costs MOR/DIA Pta12 400

a Published in 1997.

b Results of patients in short-term sedation subgroup are reported only. A cost advantage was not observed in the medium- and long-term sedation groups.

c Published in 1993.

d Published in 1994.

ALF = alfentanil; DIA = diazepam; FEN = fentanyl; MID = midazolam; MOR = morphine; NR = not reported; * p < 0.05, ** p < 0.005 vscomparator.

Respiratory acidosis has been reported during pared from a clinical (section 4) and economic view-weaning from the ventilator in approximately point. Propofol has a higher acquisition cost than3–10% of patients receiving propofol sedation in the midazolam, but clinical studies indicate a fasterICU.[3] The excretion of the phenolic metabolites of recovery time (sections 4.1.2 and 4.2). Whether thispropofol has led to green discolouration of the urine faster recovery and subsequent improved time toin isolated cases, particularly after long-term infu- extubation can offset the increased drug cost hassions.[154,155] This phenomenon of green discoloura- been evaluated in several pharmacoeconomic stud-tion has also been seen in the liver[156] and hair.[157] ies (table VI).[9,41,160-163]

The effect is transient and does not appear to affect Except for three cost-benefit analyses,[41,43,163] allrenal function or be of clinical significance. On rare studies were cost analyses and performed from aoccasions, anaphylactoid reactions have been asso- healthcare perspective only. Inclusion and exclusionciated with propofol administration[158,159] and, fol- criteria were similar to those of clinical studieslowing high dosages (4 mg/kg/h), there have been discussed in section 4, but patients with head inju-rare reports of rhabdomyolysis.[101] ries[9,161,163] or in a coma caused by a cerebrovascu-

lar accident or of unknown cause[160] were also6. Pharmacoeconomic Considerations excluded. Periods of sedation varied, and dosages

were titrated to achieve a target level of sedation.Cost considerations are important in evaluatingthe appropriate sedative for critically ill patients In all studies evaluated, sedation with propofolduring mechanical ventilation in the ICU. Two of led to a faster time to extubation than sedation withthe most commonly used ICU sedatives are propofol midazolam,[9,41,160-164] and in all studies exceptand midazolam, and both agents have been com- one[160] this led to a lower total ICU cost associated


262 McKeage & Perry

Early extubationLate extubation

0

1000

2000

3000

4000

5000

6000

Physicianfees

Physiotherapist Radiology Laboratoryservices

Mea

n ac

tual

cos

t per

pat

ient

durin

g IC

U s

tay

($C

an)

Nursingand supplies

**

TotalICU cost

**

RT,ventilator

*

Medications

*

Fig. 5. Mean actual cost per patient during an intensive care unit (ICU) stay after coronary artery bypass graft surgery. Patients wererandomised to early extubation (1–6 hours after the start of sedation) or late extubation (12–22 hours after the start of sedation) in anonblind study.[164] Patients in the early-extubation group (n = 41) received an infusion of propofol 2–6 mg/kg/h at the start of anaesthesia,which was continued for 1–4 hours in the ICU. Patients in the late extubation group (n = 41) received anaesthesia with fentanyl, isofluraneand midazolam, followed by routine morphine and midazolam (1–3 mg/h) in the ICU. Year of actual costing was not reported. RT =respiratory therapy; * p < 0.05, ** p ≤ 0.009 vs comparator.

with propofol, albeit only in the short term in two sedation regimens assessed costs of drug acquisitionstudies.[41,163] and administration, as well as nondrug-related costs

based on an ICU cost per patient per day. Costs wereThe relationship between early tracheal extuba-given in pounds sterling; at the time of the study £1tion and reduced ICU costs compared with latewas equivalent to $US1.59. The median time toextubation was demonstrated in 100 patients afterextubation was 3 hours for the propofol group (n =CABG surgery.[164] Early tracheal extubation re-17) and 50 hours for the midazolam group (n = 9) [pduced actual total ICU costs per patient by 18%= 0.006]. Respective times until patients were fit forcompared with late extubation ($Can4830 vstransfer from the ICU were 6 and 57 hours (p =$Can5892, respectively; p < 0.009), with most of the0.0012). The drug-related costs for propofol andsavings made in the area of nursing and suppliesalfentanil were higher than those for morphine and(actual year of costing not reported). Results aremidazolam (p = 0.0054), but the nondrug-relatedillustrated in figure 5. Compared with late extuba-costs, which included additional costs incurred fromtion, early extubation led to a reduced length of staya longer stay in the ICU, were higher for patientsin the ICU and in the hospital without increasing thereceiving midazolam and morphine (p = 0.0009).incidence or costs of complications.[164]

The total cost per patient for a stay in ICU was abouttwo-thirds less for patients treated with propofol6.1 Short- and Medium-Term Sedationplus alfentanil compared with patients treated withmidazolam plus morphine (£3095 vs £9511; p =The combination sedative regimen of propofol0.0013) [table VI).[161]

plus alfentanil had a better pharmacoeconomic pro-file than midazolam plus morphine because, as The combination of propofol and low-doseshown in other studies, times to extubation and ICU fentanyl had a lower, albeit nonsignificant, total costdischarge were shorter.[161] The mean period of se- per patient than midazolam and high-dose fentanyldation was not reported, but the study included in a trial in patients receiving sedation for up to 48patients requiring mechanical ventilation for at least hours after undergoing elective cardiac surgery (ta-12 hours (one patient was sedated for 7 days with ble VI).[162] The study aimed to compare drug costsmorphine and midazolam). A cost analysis of both and nursing dependency of patients and was not



powered for economic outcomes. Drug costs were statistical significance between treatment groups,further analysis of segments within each periodobtained from the British National Formulary (Sep-showed that the time from sedation to ‘ready fortember 1993). Nursing costs were calculated byextubation’ was significantly shorter in the propofolconverting patient extubation and discharge timesgroup (n = 46) than in the midazolam group (n = 53)into shifts required, based on one nurse for each[2.5 vs 7.1 hours; p = 0.001].[160] ventilated patient and one nurse to two extubated

The total median costs for the ICU stay werepatients. Patients receiving propofol and fentanyl (n$Can5718 for each patient treated with propofol and= 37) had a shorter median time to extubation from$Can5950 for each patient treated with midazolamICU entry than patients receiving midazolam and(table VI), and the total median sedative costs perfentanyl (n = 33) [4.33 vs 9.17 hours]. Median timepatient were $Can86.02 and $Can40.42, respective-to discharge from the ICU was similar (22.42 vsly.[160] Neither difference was significant. As a re-23.57 hours, respectively), but an ICU dischargesult, the total costs per patient did not differ betweenpolicy only allowed unit discharges between 0830treatment groups ($Can5765 in the propofol groupand 1900 hours. Mean nursing shifts required forvs $Can5998 in the midazolam group). A sensitivitypatients in the propofol group were 2.95 versus 3.68analysis suggested that the incremental cost per pa-in the midazolam group. The total cost per patient,tient for propofol varied from savings of $Can2709determined by adding nursing costs to total drugto an extra cost of $Can114.[160]

costs, was £315.52 in the propofol group comparedA further sensitivity analysis of this study[160]with £358.75 in the midazolam group (not signifi-

was based on a hypothetical model that evaluatedcant) [table VI]. However, a further analysis of log-potential cost savings through improved dischargetransformed data demonstrated that, on average, theplanning with propofol, because of the shorter timetotal cost in the propofol group was 13.3% lowerfrom sedation to ‘ready for extubation’ comparedthan that in the midazolam group (p = 0.043).[162]

with midazolam. Log-transformed sedation to ex-In contrast to the results above, a recent Canadi-

tubation time and sedative drug cost were modelledan, nonblind, multicentre study demonstrated simi-

as dependent variables adjusted by the duration oflar total ICU costs with propofol or midazolam

sedation. In this analysis, time to extubation with(approximate duration of infusion was 16 hours) propofol appeared to be 4.2-times faster and drug[table VI].[160] Treatment costs were recorded for costs 3.6-times higher than midazolam. Based oneach patient during his/her stay in the ICU, includ- this model, the sensitivity analysis demonstrated aing physician visits, nursing time, other health pro- potential saving with propofol of between $Can244fessional contacts, diagnostic tests and medications. and $Can570 for each patient when ICU daily costSedative costs were calculated from the recorded and reduced extubation times were varied within adrug quantity, including wastage, and the respective range of ±30%. Unlike other studies,[9,41,163] thisdrug prices: $Can43.01 for 1000mg/100mL of pro- model also suggested that as the duration of sedationpofol and $Can20.21 for 50mg/10mL of midazolam. increased, the potential savings associated with pro-Fixed ICU costs included overheads and opportuni- pofol increased.[160]

ty cost of resources, as well as 5% global deprecia-tion of capital equipment. All costs were expressed 6.2 Long-Term Sedationin 1997 Canadian dollars. For analytical conve-nience, the length of stay in the ICU was divided In a Spanish study published in 1997, a moreinto three consecutive periods: from admission to favourable economic profile was demonstrated withthe start of sedation, from the beginning of sedation propofol than with midazolam because of a fasterto termination of sedation and extubation, and from time from discontinuation of sedation to extubationextubation to discharge from the ICU. Although the (34.8 vs 97.9 hours; p < 0.0001).[9] Dosages rangeddifference in time spent at each period did not reach from 1 to 6 mg/kg/h for propofol and 0.1 to 0.5 mg/


264 McKeage & Perry

kg/h for midazolam, and the mean sedation period 6.3 Comparisons of Short-, Medium- andLong-Term Sedationwas ≈ 5.5 days. The total actual cost per patient,

including drug costs ($US0.026/mg for propofol and Two trials compared cost differences between$US0.123/mg for midazolam) and costs during se- groups of patients receiving propofol or midazolamdation and weaning periods, was $US9466 for pro- for short-, medium- or long-term sedation.[41,163] Inpofol (n = 54) and $US10 828 for midazolam (n = both trials, a cost advantage was observed for pro-54), a cost difference of $US1362 (table VI).[9] pofol compared with midazolam in patients receiv-

ing short-term sedation (<24 hours[41] or up to 72A cost predictive model was developed based onhours[163]) but not in those receiving longer-termthe results of this study.[9] Average costs forsedation (table VI).[41,163]

mechanical sedation in the ICU were set at $US54/In one of these studies (n = 88),[41] the acquisitionhour, and weaning costs took into account the cost

cost of propofol was three-times higher than that ofof therapeutic failure, which included 11 patientsmidazolam in the short-term sedation subgroup (<24with hypertriglyceridaemia in the propofol group,hours; n = 40), but the longer stay in the ICUand death. An assessment of weaning times associ-associated with midazolam lead to a postsedation

ated with each agent revealed that with propofol,cost four-times higher than that of propofol and a

weaning time increased if the duration of sedation significantly higher total sedation cost per patientwas prolonged. Based on this model, the study (Pta10 900 vs Pta8900; p < 0.05) [table VI]. In allfound that the cost difference between propofol and subgroups, the time to extubation and total recoverymidazolam reduces and eventually disappears as the (time at which the patient could be discharged to aduration of sedation becomes longer, assuming oth- conventional ward or intermediate care unit) wereer factors do not vary.[9] significantly shorter with propofol than with

midazolam (p < 0.05). However, this did not resultThis cost predictive model, together with histori-in a significant cost advantage for the propofol re-cal data from the same trial, was used in a morecipients in the medium- (24 hours to 7 days) or long-recent pharmacoeconomic study comparing 1% andterm (>7 days) sedation subgroups.[41]

2% propofol.[43] When more prolonged sedation isA further Spanish cost analysis also demonstrat-indicated, 2% propofol provides the advantage of

ed a lower total cost of sedation with propofol (n =less lipid administration and, therefore, less hyper-53) than with midazolam (n = 51) or morphine plus

triglyceridaemia (sections 2.5 and 5.4). The frequen-diazepam (n = 35) in patients requiring short-term

cy of hypertriglyceridaemia with 1% propofol (n =sedation (up to 72 hours) [Pta9000, Pta10 900 and

54) was 20.4% compared with 3.9% with 2% pro- Pta12 400, respectively; table VI].[163] Total costspofol (n = 51), and the therapeutic failure rates were were similar with both propofol or midazolam in the33.4% and 19.6%, respectively (not significant). medium- (3–5 days) or long-term (>5 days) sedationThe study aimed to determine if this improved thera- groups. Statistical analyses were not performed. Thepeutic failure rate with 2% propofol could lead to a total cost included the cost of drugs, the cost of thecost advantage over 1% propofol. The weaning time ICU stay (determined on a price-per-hour basis) andbetween patients treated with 1% or 2% propofol the cost of any additional care required before trans-was similar, and the difference in weaning time was fer to a ward.[163]

similar between midazolam and 1% or 2% propofol.7. Dosage and AdministrationHowever, an additional cost benefit over that shown

between 1% propofol and midazolam was not To provide intensive care sedation in mechani-demonstrated, as a higher dosage of 2% propofol cally ventilated patients, propofol should be admin-than 1% propofol was required in the first 48 hours istered by continuous infusion. The initial rateof sedation (p < 0.05).[43] should be slow, to minimise hypotension, and titrat-



ed to achieve the desired clinical effect.[3] The rec- Elevations in serum triglyceride concentrationsmay occur with prolonged infusions (>3 days) ofommended initial rate of infusion is 0.3 mg/kg/h,propofol (section 2.5), and concentrations should beincreasing in increments of 0.3–0.6 mg/kg/h at inter-monitored in patients at risk. The quantity of con-vals of at least 5 minutes, as clinically indicated.[3] Acomitant enteral or parenteral nutrition should berate of between 0.3 and 3.0 mg/kg/h should achievereduced to compensate for the lipid content of thesatisfactory sedation.[3] Bolus doses of 1% propofolpropofol infusion (1mL = 0.1g of fat [1.1 kcal]).[3]may be given if clinically indicated and if hypoten-

Because of the risk of cardiac arrest associatedsion is not likely to occur, but bolus injection of 2%with high doses of propofol (section 5.1), patientspropofol is not recommended.[3] Patients who haveshould be monitored for unexplained metabolic aci-received large dosages of opioid analgesics or nar-dosis or arrhythmias.[165] Caution should be used incotics should receive reduced dosages of propofol.[3]

patients receiving long-term (>48 hours), high-doseElderly patients (aged >55 years) also require a(>5 mg/kg/h) propofol infusions.[166]

reduced propofol infusion rate (1.8 mg/kg/h) [sec-During administration of the propofol formula-tion 3.3].[3]

tion containing EDTA, the need for supplemental Dosage requirements are variable between pa- zinc should be considered (section 2.8).[101] Renal

tients and may change over time. Titration to clinical function was not significantly affected in patientsresponse with daily assessment of sedation levels with renal impairment sedated with propofol con-and CNS function are important to determine the taining EDTA (section 3.3.3).minimum dosage required.[3] A higher than necessa-ry dosage will lead to high plasma concentrations of

8. Place of Propofol in the Intensivepropofol, which can result in a longer time to recov-Care Sedation of Adultsery (section 3.2). A light level of sedation is recom-

mended throughout the weaning process, with dis-continuation of the infusion 10–15 minutes before Effective sedation and analgesia are essential inextubation.[3] the care of the critically ill to provide patient com-

fort and avoid the risks associated with anxiety andThe oil-in-water propofol emulsion supports theagitation. Stress-induced response to the ICU envi-growth of micro-organisms (section 5.3). Strictronment, the presence of an endotracheal tube, sleepaseptic technique must be used during the handlingdeprivation and pain can lead to comorbid haemo-and preparation of the product, both with the origi-dynamic and metabolic consequences, such as hy-nal formulation and that containing the bacteriostat-pertension, tachycardia, increased oxygen consump-ic agent EDTA. In accordance with guidelines fortion, reduced immune function, and in some cases,other lipid emulsions, a single infusion of propofoldelirium.[167]

must not exceed 12 hours.[101] When a procedure isThe ideal level of sedation differs for each patientcompleted or at 12 hours, whichever is sooner, both

and may change throughout the course of care de-the reservoir of propofol and the infusion line mustpending on his/her condition and response to ther-be discarded and replaced.[101]

apy.[168] However, the primary aim for most patientsThe 1% formulation of propofol may be used is to maintain a sleepy but easily aroused state.

undiluted or diluted with 5% dextrose only, and Deeper levels of sedation are indicated in somedilutions should not exceed one in five.[101] 2% patients, such as those receiving neuromuscularpropofol should not be diluted. Once the drug is blockade.[168] To ensure that the changing needs ofprepared for use, administration should commence the patient are met, the depth and quality of sedationwithin 6 hours. It is recommended that the drug be should be monitored. This is most commonlyadministered via syringe pumps or volumetric achieved by the use of one or more of severalpumps to control infusion rates.[3] sedation scales (e.g. Ramsay Sedation Scale, Riker


266 McKeage & Perry

Sedation-Agitation Scale [SAS] and Motor Activity of excess drug accumulation in the long term, whichcould result in a delayed time to recovery. AlthoughAssessment Scale [MAAS]).[165]

long-term sedation has not been studied in patients Sedative agents induce anxiolysis, hypnosis andwith renal or hepatic impairment, propofol metabo-often a degree of amnesia, but most do not havelism does not appear to be affected in these patientsanalgesic activity.[168] The most frequently used(section 3.3.3).sedatives in the ICU are the benzodiazepines (e.g.

Propofol generally provides good haemodynamicmidazolam and lorazepam) or propofol, and both arestability and some beneficial cardiovascular effectsusually given in combination with opioid analgesics(section 2.2). Moreover, systemic vascular resis-(e.g. morphine), which can also have sedative ef-tance and heart rate are reduced (section 2.2.1),fects.[73] The benzodiazepines provide effective se-which can be beneficial in patients at risk for adation and also have anxiolytic, anticonvulsant andstress-induced sympathetic response. In addition,amnesic effects.[169] Prolonged administration (>24total VO2 appears to be reduced with higher dosageshours) can result in drug accumulation leading toof propofol (2 mg/kg/h) [section 2.2.2], therebydelayed recovery, and withdrawal symptoms havediminishing cardiac workload, a favourable effect inbeen observed when the infusion was stopped ab-patients after cardiac surgery. However, transientruptly.[170] The benzodiazepines have also been as-marked hypotension is associated with bolus admin-sociated with dose-related respiratory depressionistration (section 5.1), and in most cases infusionsand hypotension.[170] Compared with midazolam,should be initiated slowly (section 7). The hypoten-lorazepam has a slower onset of action but a lowersive effects of propofol are often more pronouncedcost and, therefore, is an option for long-term seda-in the elderly, in whom clearance of propofol istion.[171]

decreased compared with younger individuals (sec- Propofol provides effective sedation, and plasma tion 3.3.1); elderly recipients of the drug (aged >55

concentrations correlate with the depth of sedation years) may therefore require a reduced infusion rate(section 2.1). The drug also provides anxiolytic and (section 7). As with other sedative agents, propofolanticonvulsant effects (section 4.4) but does not reduced mean intracranial pressure and maintainedinduce the same level of amnesia as the benzo- mean cerebral perfusion pressure in clinical trials ofdiazepines (section 2.4.3). Because propofol is high- patients after head trauma (section 4.3).ly lipophilic, it rapidly crosses the blood-brain barri-

Several clinical trials have compared propofoler to produce a rapid onset of action. This fast onsetwith midazolam in patients requiring sedation forof sedation, together with a short duration of actiongeneral medical conditions, after general or cardiacleading to rapid recovery (section 3.1 and 3.2), aresurgery and following general trauma or head inju-the main advantages of propofol over other sedativeries (sections 4.1, 4.2 and 4.3). The quality of seda-agents. Even when propofol is administered for pro-tion achieved with propofol was at least as good aslonged periods (>7 days), recovery from sedation isthat achieved with midazolam, and in almost allrapid (section 4.1.2 and 4.2). However, over time thestudies the rate of recovery (time to spontaneousvolume of distribution increases and is greater withventilation or time to extubation) was significantlylong-term therapy (up to several days) than short-faster with propofol (sections 4.1.2 and 4.2).term infusions (<24 hours) [section 3.1]. This re-

flects the increased peripheral distribution that oc- The faster time to recovery with propofol enablescurs over time but is usually of little clinical rele- a greater predictability of recovery and easier dos-vance, as rapid clearance results in subtherapeutic age titration than that observed with midazolamplasma concentrations once the infusion is stopped. (sections 4.1.2 and 4.2). These qualities have severalTitration of the dosage to achieve the desired benefits for the care of the critically ill. A rapidclinical effect is recommended (section 7) to ensure emergence from sedation is particularly beneficialthat minimal dosages are given and to avoid the risk for patients requiring frequent neurological assess-



ment or undergoing short-term procedures, such as propofol (>3 days) as a result of the lipid vehicle ofphysiotherapy, where alterations in the depth of the formulation (section 2.5). Patients receiving in-sedation are required.[169] In patients after cardiac fusions of >3 days’ duration should have their lipidsurgery, rapid recovery can lead to early mobilisa- profiles closely monitored and the calorific value oftion, better pulmonary function and improved concomitant parenteral nutrition reduced according-haemodynamics compared with longer recovery ly (section 7). 2% propofol can be considered whentimes.[167] However, these effects have not yet been prolonged sedation is indicated. The lipid emulsionshown to produce an improved clinical outcome.[167] also creates a medium for microbial growth (sectionEarly extubation was shown to lead to earlier dis- 5.3), and strict aseptic technique is required whencharge from the ICU in a pooled analysis of ten trials handling the drug, including those formulations con-comparing early versus late extubation after cardiac taining bacteriostatic or antimicrobial agents. One ofsurgery.[172] Furthermore, total ICU costs were re- the generic formulations of propofol contains sodi-duced as a result of early extubation (1–6 hours after um metabisulphite (0.25 mg/mL) to retard thethe start of sedation) leading to earlier ICU dis- growth rate of microorganisms.[174] However, incharge compared with late extubation (12–22 hours some patients, allergic reactions to sodiumafter the start of sedation) [section 6].[164] metabisulphite have occurred, more particularly in

those with asthma.[174] In some patients receivingSince the previous review of propofol inhigher than recommended dosages of propofol (>5Drugs,[1] more data have become available on themg/kg/h) over extended periods (>58 hours), anuse of the drug for long-term sedation. The shorterapparent propofol-infusion syndrome has devel-times to recovery and extubation in critically illoped, which can lead to myocardial failure and deathpatients sedated for periods of >72 hours with pro-(section 5.1.1). For this reason, clinical practicepofol compared with midazolam was generallyguidelines recommend that patients receiving pro-more marked than the time differences to recoverypofol be monitored for unexplained metabolic aci-observed between the two agents after shorter-dura-dosis or arrhythmias and, if very high-dose sedationtion infusions (section 4.1.2). These studies did notis indicated, patients with escalating vasopressor orspecifically exclude patients with renal or hepaticinotrope requirements or cardiac failure should re-impairment, who are more likely to experience ac-ceive alternative sedative agents.[165]cumulation of midazolam.

Although a number of advantages associatedOver the past decade, cost has become a morewith rapid recovery have been shown in the clinicalimportant factor in choosing a sedative agent.[173]

setting, further data on the clinical relevance of thePropofol demonstrated a cost advantage overshorter time to recovery with propofol comparedmidazolam in several cost analyses because of awith midazolam are awaited with interest. In addi-faster time to extubation and, in most cases, antion, a large comparative study of propofol and theearlier discharge from the ICU (section 6). Despitenew, potent α2-adrenoceptor agonist dexmede-the higher acquisition cost of propofol, the shortertomidine is needed. Dexmedetomidine has demon-time spent in the ICU reduced total costs over thestrated sedative, analgesic and anxiolytic effects inshort term (approximately <3 days) compared withpatients after surgery.[57] In the one small, compara-midazolam. However, in three of four pharmaco-tive study with propofol, time to recovery was rapideconomic studies, this cost advantage was reducedwith both propofol and dexmedetomidine (table IV),and eventually disappeared as the period of sedationbut patients receiving propofol required 3-fold moreincreased (section 6).analgesia than those receiving dexmedetomidine (pPropofol is generally well tolerated, but hypoten-= 0.004).[57]

sion may result from its cardiovascular depressanteffects (26% of patients; section 5.1). Hyper- In conclusion, the efficacy of propofol in thelipidaemia is associated with long-term infusions of sedation of adults in the ICU is well established, and


268 McKeage & Perry

prospective comparison. Intensive Care Med 1997 Dec; 23clinical trials have demonstrated a similar quality of(12): 1258-63

sedation to midazolam. Because of a rapid distribu- 15. Wolfs C, Kimbimbi P, Colin L, et al. A comparison of propofol/fentanyl and midazolam/fentanyl for ICU sedation after ab-tion and clearance, the duration of action of propofoldominal surgery. J Drug Dev 1991 Oct; 4 Suppl. 3: 69-71is short and recovery is rapid. Emergence from

16. Grounds RM, Lalor JM, Lumley J, et al. Propofol infusion forsedation is more rapid with propofol than with sedation in the intensive care unit: preliminary report. BMJ

1987 Feb 14; 294: 397-400midazolam, even after long-term administration17. Roekaerts PM, Huygen FJ, de Lange S. Infusion of propofol(>72 hours), which enables better control of the

versus midazolam for sedation in the intensive care unit fol-depth of sedation in response to titration and more lowing coronary artery surgery. J Cardiothorac Vasc Anesth

1993 Apr; 7 (2): 142-7predictable recovery times. Thus, for the ICU seda-18. Snellen F, Lauwers P, Demeyere R, et al. The use of midazolamtion of adults in a variety of clinical settings, pro-

versus propofol for short-term sedation following coronarypofol provides effective sedation with a more rapid artery bypass grafting. Intensive Care Med 1990; 16 (5): 312-6

19. Carrasco G, Cabre L, Sobrepere G, et al. Synergistic sedationand predictable emergence time than midazolam.with propofol and midazolam in intensive care patients aftercoronary artery bypass grafting. Crit Care Med 1998 May; 26(5): 844-51References

20. McMurray TJ, Collier PS, Carson IW, et al. Propofol sedation1. Fulton B, Sorkin EM. Propofol.: an overview of its pharmacolo-after open heart surgery: a clinical and pharmacokinetic study.gy and a review of its clinical efficacy in intensive careAnaesthesia 1990 Apr; 45 (4): 322-6sedation. Drugs 1995 Oct; 50 (4): 636-57

2. Thompson KA, Goodale DB. The recent development of pro- 21. Barr J, Egan TD, Sandoval NF, et al. Propofol dosing regimenspofol (DIPRIVAN). Intensive Care Med 2000; 26 (Suppl. 4): for ICU sedation based upon an integrated pharmacokinetic-S400-4 pharmacodynamic model. Anesthesiology 2001 Aug; 95 (2):

324-333. Diprivan 1% for I.V. administration: professional informationbrochure. Wilmington (DE): AstraZeneca, 2001 22. McMurray TJ, Johnston JR, Milligan KR, et al. Diprifusor TCI

4. Mirenda J, Broyles G. Propofol as used for sedation in ICU. for sedation of ventilated adult ICU patients: target bloodChest 1995 Aug; 108: 539-48 propofol concentration settings [poster]. Presented at the 22nd

5. Whitehead C, Sanders LD, Oldroyd G, et al. The subjective International Symposium of Intensive Care and Emergencyeffects of low-dose propofol: a double-blind study to evaluate Medicine; 2002 Mar 19-22; Brusselsdimensions of sedation and consciousness with low-dose pro- 23. Newman LH, McDonald JC, Wallace PGM, et al. Propofolpofol. Anaesthesia 1994; 49: 490-6 infusion for sedation in the intensive care unit [letter]. BMJ

6. Karski JM, Teasdale SJ, Boylan J, et al. Propofol for continuous 1987; 294: 970-1intravenous sedation after aortocoronary bypass graft surgery: 24. Higgins TL, Yared J-P, Estafanous FG, et al. Propofol versusdose finding study [abstract]. Can J Anaesth 1994; 41 (5 midazolam for intensive care unit sedation after coronarySuppl.): A17 artery bypass grafting. Crit Care Med 1994 Sep; 22 (9):

7. O’Connor M, Stow P, Mortimer A, et al. Propofol to provide 1415-23sedation after coronary artery bypass surgery: a comparison of 25. Ronan KP, Gallagher TJ, George B, et al. Comparison oftwo fixed rate infusion regimens. Acta Anaesthesiol Belg propofol and midazolam for sedation in intensive care unit1992; 43: 235-41 patients. Crit Care Med 1995 Feb; 23 (2): 286-93

8. Aitkenhead AR, Willatts SM, Park GR, et al. Comparison of26. Milne SE, James KS, Nimmo S, et al. Oxygen consumptionpropofol and midazolam for sedation in critically ill patients.

after hypothermic cardiopulmonary bypass: the effect of con-Lancet 1989 Sep 23; 2 (8665): 704-9tinuing a propofol infusion postoperatively. J Cardiothorac

9. Barrientos-Vega R, Mar Sanchez-Soria M, Morales-Garcia C, et Vasc Anesth 2002; 16 (1): 32-6al. Prolonged sedation of critically ill patients with midazolam

27. Kress JP, O’Connor MF, Pohlman AS, et al. Sedation ofor propofol: impact on weaning and costs. Crit Care Med 1997critically ill patients during mechanical ventilation: a compari-Jan; 25 (1): 33-40son of propofol and midazolam. Am J Respir Crit Care Med10. Beyer R, Seyde WC. Propofol versus midazolam: long-term1996 Mar; 153: 1012-8sedation in the intensive care unit [in German]. Anaesthesist

28. Langley MS, Heel RC. Propofol: a review of its pharmacody-1992 Jun; 41 (6): 335-41namic and pharmacokinetic properties and use as an intrave-11. Boyd O, Mackay CJ, Rushmer F, et al. Propofol or midazolamnous anaesthetic. Drugs 1988; 35: 334-72for short-term alterations in sedation. Can J Anaesth 1993 Dec;

29. Pedersen CM. The effect of sedation with propofol on post-40 (12): 1142-7operative bronchoconstriction in patients with hyperreactive12. Chamorro C, de Latorre FJ, Montero A, et al. Comparativeairway disease. Intensive Care Med 1992 Mar; 18: 45-6study of propofol versus midazolam in the sedation of critical-

30. Conti G, Ferretti A, Tellan G, et al. Propofol induces bronchodi-ly ill patients: results of a prospective, randomized, multicenterlation in a patient mechanically ventilated for statustrial. Crit Care Med 1996; 24 (6): 932-9asthmaticus [letter]. Intensive Care Med 1993 Jul; 19: 30513. Fruh B. A comparison of propofol and midazolam for long-term

sedation of ventilated patients: a cross-over study. J Drug Dev 31. Conti G, Dell’Utri D, Vilardi V, et al. Propofol induces1989; 2 Suppl. 2: 45-7 bronchodilation in mechanically ventilated chronic obstructive

14. Weinbroum AA, Halpern P, Rudick V, et al. Midazolam versus pulmonary disease (COPD) patients. Acta Anaesthesiol Scandpropofol for long-term sedation in the ICU: a randomized 1993; 37: 105-9



32. Farling PA, Johnston JR, Coppel DL. Propofol infusion for unit: relationship between dosage and serum concentration.sedation of patients with head injury in intensive care: a Acta Anaesthesiol Sin 1998 Jun; 36 (2): 93-8preliminary report. Anaesthesia 1989 Mar; 44 (3): 222-6 53. Ramsay MAE, Savege TM, Simpson BRJ, et al. Controlled

33. Farling PA, Johnston JR, Coppel DL. Propofol infusion com- sedation with alphaxalone-alphadolone. BMJ 1974; 2: 656-9pared with morphine and midazolam bolus doses for sedation 54. Angelini G, Ketzler JT, Coursin DB. Use of propofol and otherof patients with severe head injuries in the intensive care unit. J nonbenzodiazepine sedatives in the intensive care unit. CritDrug Dev 1989; 2 Suppl. 2: 97-8 Care Clin 2001 Oct; 17 (4): 863-80

34. Vezzani A, Barbagallo M, Furlan A, et al. Neurological assess- 55. Telci I, Denkel T, Esen F, et al. Cardiocirculatory effects ofment and ICP control in severe head injury: use of propofol as propofol in acute respiratory failure: a clinical trial. J Drug Deva short-acting sedative agent. J Drug Dev 1991; 4 Suppl. 3: 1991 Oct; 4 Suppl. 3: 93-4114-5 56. Searle NR, Cote S, Taillefer J, et al. Propofol or midazolam for

35. Mergaert C, Herregods L, Rolly G, et al. The effect of a 24-h sedation and early extubation following cardiac surgery. Can Jpropofol or fentanyl sedation on intracranial pressure [ab- Anaesth 1997 Jun; 44 (6): 629-35stract]. Eur J Anaesthesiol 1991; 8: 324-5 57. Venn RM, Grounds RM. Comparison between dexmede-

36. Weinstabl C, Mayer N, Plattner H, et al. Impact of propofol on tomidine and propofol for sedation in the intensive care unit:intracranial dynamics in head trauma ICU patients [abstract patient and clinician perceptions. Br J Anaesth 2001 Nov; 87no. A1217]. Anesthesiology 1990 Sep; 73 (Suppl. 3A) (5): 684-90

37. Boyle WA, Shear JM, White PF, et al. Long-term sedative 58. Sandiumenge Camps A, Sanchez-Izquierdo Riera JA, Toralinfusion in the intensive care unit: propofol versus midazolam. Vazquez D, et al. Midazolam and 2% propofol in long-termJ Drug Dev 1991 Oct; 4 Suppl. 3: 43-5 sedation of traumatized critically ill patients: efficacy and

38. Foster SJ, Buckley PM. A retrospective review of two years’ safety comparison. Crit Care Med 2000 Nov; 28 (11): 3612-9experience with propofol in one intensive care unit. J Drug 59. Ewart MC, Yau KW, Morgan M. 2% Propofol for sedation inDev 1989; 2 Suppl. 2: 73-4 the intensive care unit: a feasibility study. Anaesthesia 1992

39. Buckley PM. Propofol in patients needing long-term sedation in Feb; 47 (2): 146-8intensive care: an assessment of the development of tolerance. 60. Hammaren E, Scheinin M, Hynynen M. Effect of low-doseA pilot study. Intensive Care Med 1997 Sep; 23 (9): 969-74 propofol infusion on total-body oxygen consumption after

40. Cook S, Palma O. Propofol as a sole agent for prolonged coronary artery surgery. J Cardiothorac Vasc Anesth 1999infusion in intensive care. J Drug Dev 1989; 2 Suppl. 2: 65-7 Apr; 13 (2): 154-9

41. Carrasco G, Molina R, Costa J, et al. Propofol vs midazolam in 61. Cohen D, Horiuchi K, Kemper M, et al. Modulating effects ofshort-, medium-, and long-term sedation of critically ill pa- propofol on metabolic and cardiopulmonary responses totients; a cost-benefit analysis. Chest 1993; 103 (2): 557-64 stressful intensive care unit procedures. Crit Care Med 1996;

24 (4): 612-742. McLeod G, Dick J, Wallis C, et al. Propofol 2% in critically illpatients: effect on lipids. Crit Care Med 1997 Dec; 25 (12): 62. McMurray TC. Propofol for sedation following cardiac surgery.1976-81 J Drug Dev 1991; 4 Suppl. 3: 51-8

43. Barrientos-Vega R, Sanchez-Soria MM, Morales-Garcia C, et 63. Barr J. Propofol: a new drug for sedation in the intensive careal. Pharmacoeconomic assessment of propofol 2% used for unit. Int Anesthesiol Clin 1995 Winter; 33 (1): 131-54prolonged sedation. Crit Care Med 2001 Feb; 29 (2): 317-22 64. Hall RI, Sandham D, Cardinal P, et al. Propofol vs midazolam

44. Plunkett JJ, Reeves JD, Ngo L, et al. Urine and plasma for ICU sedation: a Canadian multicenter randomized trial.catecholamine and cortisol concentrations after myocardial Chest 2001 Apr; 119 (4): 1151-9revascularization: modulation by continuous sedation. Anes- 65. Khamiees M, Amoateng-Adjepong Y, Manthous CA. Propofolthesiology 1997 Apr; 86 (4): 785-96 infusion is associated with a higher rapid shallow breathing

45. Heller A, Heller S, Blecken S, et al. Effects of intravenous index in patients preparing to wean from mechanical ventila-anesthetics on bacterial elimination in human blood in vitro. tion. Respir Care 2002 Feb; 47 (2): 150-3Acta Anaesthesiol Scand 1998; 42: 518-26 66. Shafer A. Complications of sedation with midazolam in the

46. Mikawa K, Akamatsu H, Nishina K, et al. Propofol inhibits intensive care unit and a comparison with other sedative regi-human neutrophil functions. Anesth Analg 1998; 87: 695-700 mens. Crit Care Med 1998 May; 26 (5): 947-56

47. Galley HF, Dubbels AM, Webster NR. The effect of midazolam 67. Degaugue C, Dupuis A. A study to compare the use of propofoland propofol on interleukin-8 from human polymorphonuclear and midazolam for the sedation of patients with acute respira-leukocytes. Anesth Analg 1998; 86: 1289-93 tory failure. J Drug Dev 1991 Oct; 4 Suppl. 3: 95-7

48. Pirttikangas C-O, Perttila J, Salo M. Propofol emulsion reduces 68. Stewart L, Bullock R, Rafferty C, et al. Propofol sedation inproliferative responses of lymphocytes from intensive care severe head injury fails to control high ICP, but reduces brainpatients. Intensive Care Med 1993 Jul; 19: 299-302 metabolism. Acta Neurochir 1994; 60 Suppl.: 544-6

49. Kelbel I, Weiss M. Anaesthetics and immune function. Curr 69. Matta BF, Risdall J, Menon DK, et al. The effect of propofol onOpin Anaesthesiol 2001; 14 (6): 685-91 cerebral autoregulation after head injury: a preliminary report.

Br J Anaesth 1997 May; 78 Suppl. 1: 7250. Barr J, Egan T, Feeley T, et al. Depth of sedation vs. propofolconcentration in mechanically ventilated ICU patients [ab- 70. Kishimoto T, Kadoya C, Sneyd R, et al. Topographic electroen-stract no. A313]. Anesthesiology 1992 Sep; 77 Suppl. 3A cephalogram of propofol-induced conscious sedation. Clin

Pharmacol Ther 1995; 58: 666-7451. Sorbara C, Armellin G, Bonato A, et al. Postoperative sedationwith propofol infusion: haemodynamics and pharmacokine- 71. Theilen HJ, Adam S, Kuhlisch E, et al. Progressive electroen-tics. Clin Drug Invest 1998; 16 (6): 431-9 cephalogram frequency deceleration despite constant depth of

52. Wang S-H, Hsu K-Y, Uang Y-S. Long-term continuous infusion propofol-induced sedation. Crit Care Med 2002 Aug; 30 (8):of propofol as a means of sedation for patients in intensive care 1787-93


270 McKeage & Perry

72. Sneyd JR, Samra SK, Davidson B, et al. Electrophysiologic 92. Herr DL, Kelly K, Hall JB, et al. Safety and efficacy of propofoleffects of propofol sedation. Anesth Analg 1994; 79: 1151-8 with EDTA when used for sedation of surgical intensive care

unit patients. Intensive Care Med 2000; 26 Suppl. 4: S452-6273. Magarey JM. Propofol or midazolam - which is best for the93. Wahr J, Vender J, Gilbert HC, et al. Effect of propofol with andsedation of adult ventilated patients in intensive care units? A

without EDTA on haemodynamics and calcium and magnesi-systematic review. Aust Crit Care 2001 Nov; 14 (4): 147-54um homeostasis during and after cardiac surgery. Intensive74. Treggiari-Venzi M, Borgeat A, Fuchs-Buder T, et al. OvernightCare Med 2000; 26 Suppl.: 443-51sedation with midazolam or propofol in the ICU: effects on

94. Higgins TL, Murray M, Kett DH, et al. Trace element homeo-sleep quality, anxiety and depression. Intensive Care Medstasis during continuous sedation with propofol containing1996 Nov; 22 (11): 1186-90EDTA versus other sedatives in critically ill patients. Intensive75. McLeod G, Wallis C, Dick J, et al. Use of 2% propofol toCare Med 2000; 26 Suppl. 4: S413-21produce diurnal sedation in critically ill patients. Intensive

95. Zaloga GP, Youngs E, Teres D. Propofol-containing sedativesCare Med 1997 Apr; 23 (4): 428-34increase levels of parathyroid hormone. Intensive Care Med76. Polster MR, Gray PA, O’Sullivan G, et al. Comparison of the2000; 26 Suppl.: 405-12sedative and amnesic effects of midazolam and propofol. Br J

96. Kanto J, Gepts E. Pharmacokinetic implications for the clinicalAnaesth 1993; 70: 612-6use of propofol. Clin Pharmacokinet 1989; 17 (5): 308-2677. Montanini S, Pratico C, Tufano R, et al. Propofol for sedation in

97. Frenkel C, Schuttler J, Ihmsen H, et al. Pharmacokinetics andthe intensive care unit: comparative evaluation of 1% and 2%pharmacodynamics of propofol/alfentanil infusions for seda-formulations. Br J Intensive Care 1999; 9 (4): 110-4tion in ICU patients. Intensive Care Med 1995 Dec; 21 (12):78. Leisure GS, O’Flaherty J, Green L, et al. Propofol and post-981-8operative pancreatitis. Anesthesiology 1996; 84 (1): 224-7

98. Albanese J, Martin C, Lacarelle B, et al. Pharmacokinetics of79. Kumar AN, Schwartz DE, Lim KG. Propofol-induced pancrea-long-term propofol infusion used for sedation in ICU patients.titis: recurrence of pancreatitis after rechallenge. Chest 1999;Anesthesiology 1990; 73 (2): 214-7115: 1198-9

99. Bailie GR, Cockshott ID, Douglas EJ, et al. Pharmacokinetics80. Possidente CJ, Rogers FB, Osler TM, et al. Elevated pancreaticof propofol during and after long-term continuous infusion forenzymes after extended propofol therapy. Pharmacotherapymaintenance of sedation in ICU patients. Br J Anaesth 19921998; 18 (3): 653-5May; 68 (5): 486-91

81. Wingfield TW. Pancreatitis after propofol administration: is 100. Cockshott ID. The pharmacokinetics of propofol in the ICUthere a relationship? Anesthesiology 1996; 84 (1): 236 patient. J Drug Dev 1991 Oct; 4 Suppl. 3: 29-36

82. Piper SN, Kumle B, Maleck WH, et al. Effects of postoperative 101. AstraZeneca. Diprivan global prescribing information [online].sedation with propofol and midazolam on pancreatic function Available from URL: http://anaesthesia-az.com [Accessedassessed by pancreatitis-associated protein. Anaesthesia 2001 2002 Nov 1]Sep; 56 (9): 836-40

102. Zamacona MK, Suarez E, Aguilera L, et al. Serum protein83. Hall RI, MacLaren C, Smith MS, et al. Light versus heavy binding of propofol in critically ill patients. Acta Anaesthesiol

sedation after cardiac surgery: myocardial ischemia and the Scand 1997 Nov; 41: 1267-72stress response. Anesth Analg 1997 Nov; 85: 971-8 103. Simons PJ, Cockshott ID, Douglas EJ, et al. Disposition in male

84. Cox C, McLeod G, Wallis C, et al. Use of 2% propofol to volunteers of a subanaesthetic intravenous dose of an oil inproduce night sedation in critically ill patients: effect on hor- water emulsion of 14C-propofol. Xenobiotica 1988; 4: 429-40mones. Br J Anaesth 1995 May; 74 Suppl. 1: 114 104. Van Brandt N, Hantson P, Horsmans Y, et al. Effect of enteral

85. Lee T-L, Ang SBL, Dambisya YM, et al. The effect of propofol versus parenteral feeding on hepatic blood flow and steadyon human gastric and colonic muscle contractions. Anesth state propofol pharmacokinetics in ICU patients. IntensiveAnalg 1999 Nov; 89 (5): 1246-9 Care Med 1998 Aug; 24 (8): 795-800

86. Freye E, Sundermann S, Wilder-Smith OHG. No inhibition of 105. Kirkpatrick T, Cockshott ID, Douglas EJ, et al. Pharmacokine-gastro-intestinal propulsion after propofol- or propofol/ tics of propofol (Diprivan) in elderly patients. Br J Anaesthketamine-N2O/O2 anaesthesia: a comparison of gastro-caecal 1988; 60: 146-50transit after isoflurane anaesthesia. Acta Anaesthesiol Scand 106. Shafer A, Doze VA, Shafer SL, et al. Pharmacokinetics and1998 Jul; 42 (6): 664-9 pharmacodynamics of propofol infusions during general anes-

87. Devlin EG, Clarke RSJ, Mirakhur RK, et al. Effect of four i.v. thesia. Anesthesiology 1988; 69: 348-56induction agents on T-lymphocyte proliferations to PHA in 107. Eddleston JM, Pollard BJ, Blades JF, et al. The use of propofolvitro. Br J Anaesth 1994; 73: 315-7 for sedation of critically ill patients undergoing haemodiafil-

88. O’Donnell CA, O’Donnell NG, McSharry CP, et al. Compari- tration. Intensive Care Med 1995 Apr; 21: 342-7son of the effects of propofol and thiopentone on white blood 108. Barr J, Zaloga GP, Haupt MT, et al. Cation metabolism duringcell function. Hum Exp Toxicol 1991; 10 (6): 483 propofol sedation with and without EDTA in patients with

89. Helmy SAK, Wahby MAM, El-Nawaway M. The effect of impaired renal function. Intensive Care Med 2000; 26 Suppl.anaesthesia and surgery on plasma cytokine production. An- 4: S433-42aesthesia 1999; 54 (8): 733-8 109. Ibrahim AE, Park S, Feldman J, et al. No effect of parecoxib, a

90. Helmy SAK, Al-Attiyah RJ. The immunomodulatory effects of parenteral COX-2 specific inhibitor, on the disposition ofprolonged intravenous infusion of propofol versus midazolam propofol. Anaesth Intensive Care 2002 Apr; 30: 247in critically ill surgical patients. Anaesthesia 2001; 56: 4-8 110. McCollam JS, O’Neil MG, Norcross ED, et al. Continuous

91. Abraham E, Papadakos PJ, Tharratt RS, et al. Effects of infusions of lorazepam, midazolam, and propofol for sedationpropofol containing EDTA on mineral metabolism in medical of the critically ill surgery trauma patient: a prospective, ran-ICU patients with pulmonary dysfunction. Intensive Care Med domized comparison. Crit Care Med 1999 Nov; 27 (11):2000; 26 Suppl. 4: S422-32 2454-8



111. Millane TA, Bennett ED, Grounds RM. Isoflurane and propofol 129. McBurney JW, Teiken PJ, Moon MR. Propofol for treatingfor long-term sedation in the intensive care unit: a crossover status epilepticus. J Epilepsy 1994; 7 (1): 21-2study. Anaesthesia 1992 Sep; 47 (9): 768-74 130. Natale E, Mattaliano A, Alia G, et al. Propofol in treatment of

112. O’Connor M, Stow P, Mortimer A, et al. Propofol to provide status epilepticus: report of four cases successfully treatedsedation after coronary artery by-pass surgery: a comparison of [abstract]. Epilepsia 1993; 34 Suppl. 2: 124-5three fixed-rate infusion regimens. J Drug Dev 1989; 2 Suppl. 131. Rousseff R, Bojinov St, Platikanov W. Propofol in intractable2: 135-7 status epilepticus. Epilepsia 1996; 37 Suppl. 4: 74-5

113. Vandenberghe J, Rucquoi M, Camu F. Propofol sedation for 132. Wood PR, Browne GPR, Pugh S. Propofol infusion for thecontrolled ventilation of post-operative aortic surgery patients: treatment of status epilepticus [letter]. Lancet 1988 Feb; 1an evaluation of haemodynamics and sedation. J Drug Dev (8583): 480-11991; 4 Suppl. 3: 65-6 133. Yanny HF, Christmas D. Propofol infusions for status epilep-

114. Beller JP, Pottecher T, Lugnier A, et al. Prolonged sedation ticus [letter]. Anaesthesia 1988; 43 (6): 514with propofol in ICU patients: recovery and blood concentra- 134. Saeed AB, Javidan M. Propofol for treatment of non convulsivetion changes during periodic interruptions in infusion. Br J status epilepticus in intensive care unit [abstract]. Crit CareAnaesth 1988; 61: 583-8 Med 2000 Dec; 28 Suppl.: 98

115. d’Athis F, Chardon P, Mathieu-Daude JC, et al. Propofol for 135. Fox FL, Bostwick JM. Propofol sedation of refractory delirioussedation in the intensive care unit. J Drug Dev 1989; 2 Suppl. mania. Psychosomatics 1997; 38 (3): 288-902: 61-4

136. Ermakov S, Hoyt J, Crippen D. Conscious sedation with pro-116. Du Gres B, Flamens C. A comparison of propofol and midazo- pofol in patients with delirium tremens [abstract]. Crit Care

lam infusion for post operative sedation after cardiac surgery Med 1995; 23 (1): A68[abstract]. J Cardiothorac Anesth 1990; 4 (6 Suppl. 3): 101

137. Stiebel VG, Crippen D, Ermakov S. Treatment of delirium117. Nollet G, Verbeke J. Comparison of propofol and alfentanil as tremens with continuous propofol infusion [abstract]. Psycho-

sedative agents after coronary artery by-pass graft. J Drug Dev somatics 1994; 35 (2): 1931991; 4 Suppl. 3: 62-4

138. Borgeat A, Popovis V, Schwander D. Efficiency in a continuous118. Leino K, Nunes S, Valta P, et al. The effect of sedation on infusion of propofol in a patient with tetanus. Crit Care Med

weaning following coronary artery bypass grafting: propofol 1991; 19 (2): 295-7versus oxycodone-thiopental. Acta Anaesthesiol Scand 2000

139. Borgeat A, Dessibourg C, Rochani M, et al. Sedation byApr; 44 (4): 369-77propofol in tetanus - is it a muscular relaxant? Intensive Care

119. Wahr JA, Plunkett JJ, Ramsay JG, et al. Cardiovascular re- Med 1991; 17: 427-9sponses during sedation after coronary revascularization. Inci-

140. Orko R, Rosenberg PH, Himberg J-J. Intravenous infusion ofdence of myocardial ischemia and hemodynamic episodesmidazolam, propofol and vecuronium in a patient with severewith propofol versus midazolam. Anesthesiology 1996; 84 (6):tetanus. Acta Anaesthesiol Scand 1988 Oct; 32 (7): 590-21350-60

141. Parke TJ, Stevens JE, Rice ASC, et al. Metabolic acidosis and120. Mirski MA, Muffelman B, Ulatowski JA, et al. Sedation for thefatal myocardial failure after propofol infusion in children: fivecritically ill neurologic patient. Crit Care Med 1995; 23 (12):case reports. BMJ 1992; 305 (6854): 613-62038-53

142. Bray RJ. Propofol infusion syndrome in children. Paediatr121. Pearson K, Kruse G, Demetrion E. Sedation of patients withAnaesth 1998; 8: 491-9severe head injury. a randomized, prospective comparison of

143. Kelly DF. Propofol-infusion syndrome. J Neurosurg 2001; 95:propofol versus morphine and barbiturates [abstract no. A248].925-6Anesthesiology 1991; 75 (3A)

144. Cremer OL, Moons KGM, Bouman EAC, et al. Long-term122. Kelly DF, Goodale DB, Williams J, et al. Propofol in thepropofol infusion and cardiac failure in adult head-injuredtreatment of moderate and severe head injury: a randomized,patients [letter]. Lancet 2001 Jan 13; 357 (9250): 117-8prospective double-blinded pilot trial. J Neurosurg 1999; 90:

145. Perrier ND, Baerga-Varela Y, Murray MJ. Death related to1042-52propofol use in an adult patient. Crit Care Med 2000 Aug; 28123. Smith M. Postoperative neurosurgical care. Curr Anaesth Crit(8): 3071-4Care 1994; 5 (1): 29-35

146. Sutherland MJ, Burt P. Propofol and seizures. Anaesth Intensive124. Dewandre J, Van Bos RJ, Van Hemelrijck J, et al. ComparisonCare 1994 Dec; 22: 733-7of the 2% and 1% formulations of propofol during anaesthesia

147. Collier C, Kelly K. Propofol and convulsions: the evidencefor craniotomy. Anaesthesia 1994; 49: 8-12mounts. Anaesth Intensive Care 1991 Nov; 19: 573-5125. Escarment J, Donne X, Palmier B, et al. Quality of sedation and

148. McManus KF. Convulsion after propofol enflurane [letter].neurologic evaluation following surgery of the posterior crani-Anaesth Intensive Care 1992 May; 20: 245al fossa: the importance of propofol [in French]. Cah Anes-

thesiol 1992; 40 (1): 29-35 149. Harrigan PWJ, Browne SM, Quail AW. Multiple seizures fol-lowing re-exposure to propofol. Anaesth Intensive Care 1996126. Clarke TNS. Propofol compared with midazolam for sedationApr; 24: 261-4following prolonged neurosurgery. J Drug Dev 1991; 4 Suppl.

3: 108-9 150. Bennett SN, McNeil MM, Bland LA, et al. Postoperativeinfections traced to contamination of an intravenous anesthet-127. Loffler WH, Wallner F, Fischer J, et al. Comparison of elec-ic, propofol. N Engl J Med 1995; 333 (3): 147-54troencephalography, cerebral perfusion pressure, and recovery

times following propofol of methohexital sedation in 151. Webb SAR, Roberts B, Breheny FX, et al. Contamination ofneurosurgical patients. J Clin Monit 1993; 9 (2): 146-7 propofol infusions in the intensive care unit: incidence and

128. MacKenzie SJ, Kapadia F, Grant IS. Propofol infusion for clinical significance. Anaesth Intensive Care 1998 Apr; 26 (2):control of status epilepticus. Anaesthesia 1990; 45: 1043-5 162-4


272 McKeage & Perry

152. Bach A, Motsch J, Schmidt H, et al. In-use contamination of 165. Jacobi J, Fraser GL, Coursin DB, et al. Clinical practicepropofol. A clinical study. Eur J Anaesthesiol 1997 Mar; 14: guidelines for the sustained use of sedatives and analgesics in178-83

the critically ill adult. Crit Care Med 2002; 30 (1): 119-40153. Marinella MA. Propofol for sedation in the intensive care unit: 166. Kang TM. Propofol infusion syndrome in critically ill patients.

essentials for the clinician. Respir Med 1997 Oct; 91 (9):Ann Pharmacother 2002; 36: 1453-6505-10

167. Abraham E. Managing sedative agents in common ICU settings.154. Bodenham A, Culank LS, Park GR. Propofol infusion and greenCrit Care Med 2002; 30 (1 Suppl. A): S110-3urine [letter]. Lancet 1987; 11: 740

168. Young C, Knudsen N, Hilton A, et al. Sedation in the intensive155. Ananthanarayan C, Fisher JA. Why was the urine green? [let-ter]. Can J Anaesth 1995; 42 (1): 87-8 care unit. Crit Care Med 2000 Mar; 28 (3): 854-66

169. Hill L, Bertaccini E, Barr J, et al. ICU sedation: a review of its156. Motsch J, Schmidt H, Bach A, et al. Long-term sedation withpropofol and green discolouration of the liver. Eur J Anaes- pharmacology and assessment. J Intensive Care Med 1998; 13thesiol 1994 Nov; 11 (6): 499-502 (4): 174-83

157. Callander CC, Thomas JS, Evans CJ. Propofol and the colour 170. Radu O, Groth M. Propofol or midazolam for sedation in thegreen [letter]. Anaesthesia 1989; 44: 82

ICU: which one is better? Clin Pulmonary Med 2001; 8 (5):158. McHale SP, Konieczko K. Anaphylactoid reaction to propofol. 303-4

Anaesthesia 1992; 47: 864-5171. Shapiro BA, Warren J, Egol AB, et al. Practice parameters for

159. Laxenaire M-C, Mata-Bermejo E, Moneret-Vautrin DA, et al. intravenous analgesia and sedation for adult patients in theLife-threatening anaphylactoid reactions to propofol

intensive care unit: an executive summary. Crit Care Med(Diprivan). Anesthesiology 1992; 77: 275-801995 Sep; 23 (9): 1596-600

160. Anis AH, Wang X, Leon H, et al. Economic evaluation of172. Meade MO, Guyatt G, Butler R, et al. Trials comparing early vspropofol for sedation of patients admitted to intensive care

units. Anesthesiology 2002 Jan; 96 (1): 196-201 late extubation following cardiovascular surgery. Chest 2001

Dec; 120 (6 Suppl.): 445S-53S161. Manley NM, Fitzpatrick RW, Long T, et al. A cost analysis ofalfentanil+propofol vs morphine+midazolam for the sedation 173. Crippen D. High-tech assessment of patient comfort in theof critically ill patients. Pharmacoeconomics 1997 Aug; 12 (2

intensive care unit: time for a new look. Crit Care Med 2002Pt 2): 247-55Aug; 30 (8): 1919-20

162. Sherry KM, McNamara J, Brown JS, et al. An economic174. Baxter Healthcare Corporation. Propofol: injectable emulsionevaluation of propofol/fentanyl compared with midazolam/

1% 10 mg/ml propofol. Prescribing information. Irvine (CA):fentanyl on recovery in the ICU following cardiac surgery.Anaesthesia 1996 Apr; 51: 312-7 Baxter Healthcare Corporation, 2002 Jul

163. Costa J, Cabre L, Molina R, et al. Cost of ICU sedation:comparison of empirical and controlled sedation methods. ClinIntensive Care 1994; 5 (5 Suppl.): 17-21 Correspondence: Kate McKeage, Adis International Limited,

164. Cheng DCH, Karski J, Peniston C, et al. Early tracheal extuba- 41 Centorian Drive, Private Bag 65901, Mairangi Bay,tion after coronary artery bypass graft surgery reduces costs Auckland 10, New Zealand.and improves resource use: a prospective randomized con-trolled trial. Anesthesiology 1996; 85: 1300-10 E-mail: [email protected]


propofol - link.springer.com · 2/3/2003 · propofol. propofol sedation is associated with slight...

Documents