Division of Cardiac Anaesthesia and Intensive Care, Department of Anaesthesia, The Toronto Hospital, University of Toronto, 585 University Avenue, Toronto, Ontario, Canada M5G 2C4*Corresponding author: Department of Anaesthesia, The Toronto Hospital, BW-4-663, 585 University Avenue, Toronto, Ontario, Canada M5G 2C4
Presented in part at the American Society of Anesthesiologists Annual Meeting, 1997
Accepted for publication: August 21, 2000
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Keywords: surgery, cardiovascular; age factors; anaesthetic techniques; complications, mental function
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Coronary artery bypass (CABG) surgery is becoming frequent in the elderly (6579 yr).5 6 Many institutions consider the elderly suitable for fast-tracking, but elderly patients are generally slower to recover and can develop delirium, confusion and agitation in the postoperative period, possibly caused by impaired drug distribution and metabolism. Poor mental performance after surgery reduces the ability of patients to communicate their needs and cooperate with medical staff, and may interfere with recovery.
We tested the hypothesis that anaesthesia and sedation with an agent with rapid clearance and less cumulative effects may cause less impairment of postoperative mental function and allow early extubation and recovery in elderly patients compared with a standard cardiac anaesthetic technique. We conducted a prospective randomized comparison of mental function, haemodynamic stability and extubation and discharge times in elderly patients, comparing propofol with midazolam for anaesthesia and sedation.
![]() |
Methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Patients were randomized before surgery to either propofol or lorazepam and midazolam using a computer-generated randomization code. Medical and physical details were recorded.
Propofol group
Benzodiazepines were not used. Preoperative sedation consisted of morphine 0.15 mg kg1 i.m. 1.5 h before surgery. Anaesthesia was induced with 1015 µg kg1 fentanyl with or without thiopental 5075 mg i.v. Tracheal intubation was facilitated by pancuronium 0.15 mg kg1. Anaesthesia was maintained before cardiopulmonary bypass (CPB) with a propofol infusion at 26 mg kg1 min1 with or without 0.52% isoflurane. The propofol infusion was continued during CPB at 26 mg kg1 h1 and was reduced to 2 mg kg1 h1 before transfer to the intensive care unit (ICU). It was continued for 3 h in the ICU at 0.56 mg kg1 h1. The propofol infusion rate was adjusted to give a Ramsay sedation score of between 3 (subject is drowsy but responds to commands) and 4 (subject is asleep but exhibits a brisk response to a light glabellar tap or a loud auditory stimulus)10 (Appendix 1). Persistent hypertension (systolic blood pressure >140 mm Hg) was treated with nitroglycerine with or without nitroprusside infusion to achieve systolic arterial pressure of 90130 mm Hg. Esmolol 20 mg or metoprolol 25 mg i.v. was used to control tachycardia (heart rate >110 beats min1). Hypotension (systolic arterial pressure <90 mm Hg) was treated with 500 ml of a colloid solution with or without dopamine infusion as dictated by the patients haemodynamic values. Shivering was treated with pethidine 2550 mg i.v. Indomethacin 50100 mg was given in suppository form for analgesia when patients arrived in the ICU. Supplementary analgesia was with morphine boluses 14 mg h1 i.v. after extubation.
Benzodiazepine group
Patients were given lorazepam 0.52 mg sublingually 1.5 h before surgery. Anaesthesia was induced with fentanyl 1015 µg kg1 with or without 5075 mg thiopental i.v. Tracheal intubation was facilitated with pancuronium 0.15 mg kg1. Midazolam 0.050.075 mg kg1 was given i.v. before CPB. Anaesthesia was maintained before and during CPB with 0.52% isoflurane and oxygen. After separation from CPB, a midazolam infusion at 0.010.05 mg kg1 h1 was started and maintained for 3 h in the ICU. The midazolam infusion rate in the ICU was adjusted to give a Ramsay sedation score of 34.10 Treatment for shivering, pain and haemodynamic disturbances was the same as for the propofol group.
Surgical procedure
Surgery was standardized. Patients had a median sternotomy and internal mammary arteries and saphenous veins were taken for grafts. Myocardial protection was with intermittent antegrade cold blood cardioplegia given through the aortic root. Systemic temperature was allowed to drift to 33°C during CPB. Roller pumps and membrane oxygenators (Maxima Metronic, Minneapolis, MN) were used in all cases. Haematocrit concentrations were maintained between 20 and 25% and CPB flow rate between 2.0 and 2.5 litre min m2. The mean perfusion pressure was kept at 5060 mm Hg by titrating phenylephrine or nitroprusside. Patients were actively rewarmed to a nasopharyngeal temperature of 38°C before removal of the aortic cross-clamp and weaning from CPB.
After surgery
The infusions of propofol (propofol group) and midazolam (benzodiazepine group) were continued for 3 h in the ICU. Patients were ventilated artificially to maintain PaCO2 between 35 and 43 mm Hg and PaO2 >85 mm Hg. The sedative infusions were discontinued after 3 h if the patient achieved the following specific criteria:
(i) Cardiovascular stability (CI >2 litre m2) with a dose of dopamine no more than 3 µg kg1 min1 or dobutamine no more than 5 µg kg1 min1, and without using a mechanical assist device.
(ii) Minimal bleeding from chest drains (<50 ml h1).
(iii) Core body temperature >36.5°C.
(iv) Oxygen saturation of haemoglobin >95% with an inspired oxygen concentration of 60%.
(v) No electrocardiographic changes indicating new ischaemia or myocardial infarction.
Patients who did not meet the above criteria were excluded from the trial. Patients who met the above criteria were assessed every 15 min after stopping sedation to determine when they met prespecified extubation criteria.1 3
Outcome measurements
Mental function
The tests used were as follows:
Hopkins Verbal Learning Test (HVLT). This test was developed specifically for the elderly, and tests various aspects of learning and memory.11 It requires accurate repetition of verbally presented word groups. The patient must recall as many words as possible from memory from a group of 12 words presented. We analysed three measures: (i) total recallthe total number of words recalled over three trials (maximum score is 36); (ii) delayed free recall (DFR)the number of words recalled from the presented list after a 10 minute delay, (maximum score is 12); (iii) discriminability index (DI)the number of words recognized from the presented list with category cues provided. The score is calculated by subtracting the number of false positives from true positives reported by the patient, and the maximum score is 12.
Trail-Making Test (Part A) (TMT-A).12 Patients performed the TMT-A with their dominant hand free of i.v. or arterial catheters. This tests attention, concentration and visual tracking. It requires the simultaneous integration of several cognitive functions combined with a motor response. The test is scored by the number of seconds required to complete the trail.
Folstein Mini-Mental Scale Examination (MMSE).13 This tests orientation, attention, calculation, instantaneous recall, short-term memory, language and visuomotor ability. The highest score is 30. It screens for cognitive impairment, with emphasis on orientation.
These tests were selected because they evaluated orientation, concentration, verbal learning and memoryfunctions that are important when assessing immediate or acute anaesthetic-related cognitive deficits. They were chosen considering the time available and the physical limitations of elderly patients after cardiac surgery.
Surgery started at 08:00 h. The psychological tests were timed to measure cognitive deficits caused by anaesthesia, as soon as possible after surgery. The MMSE was used 4 h after extubation to detect the earliest difference in cognitive recovery, particularly orientation, between the groups. All tests (total recall, DFR, DI, TMT-A, MMSE) were done 18 h after extubation (the morning after surgery) to allow comparison with baseline tests. Previous work1 showed that patients receiving fast-track cardiac anaesthesia are discharged from intensive care at 31.6 (SD 14.3) h, so 18 h after extubation was a practical time to measure cognitive function.
A single examiner tested each patient before and after surgery, in a quiet environment free from distractions and interruptions. Testing took approximately 1 h. Because preoperative intelligence (IQ) is a potentially important confounder when measuring changes in cognitive function, IQ was tested using the National Adult Reading Test.14 Anxiety can also confound measured changes in cognitive function. Anxiety was measured before surgery and 18 h after extubation using a StateTrait Anxiety Inventory Score.15 Pain levels were measured with a visual analogue scale (VAS) hourly for 6 h and then 18 h after extubation, as pain can also affect cognitive tests. A clinical neurological examination evaluating power, tone, coordination and sensation was performed the morning after surgery in all patients. All patients were followed up by phone 6 12 months later to determine their functional status.
Mental impairment
A decline in mental function was calculated by considering the change in performance from the preoperative assessment to the 4- and 18-h assessments for each patient. Impairment was defined as a 20% decline from the preoperative assessment to the postoperative assessment in one or more of the five tests (
20% of the tests performed).16 17 In addition, the percentage of patients with a
20% decline in each test from before to after operation was compared between the groups.
Extubation and discharge times
Extubation time was the time from stopping sedation to tracheal extubation. Standard discharge criteria1 3 were used to assess when the patient was medically fit to be discharged from the ICU and hospital. The actual discharge time from the ICU was from entry to ICU to discharge from ICU and the actual discharge time from hospital was defined as the time from the day of surgery until discharge from hospital.
Level of consciousness
After extubation, the level of consciousness (LOC) and orientation were assessed at hourly intervals for 6 h using a 5-point LOC scale (Appendix 1) and a 10-point orientation scale (Appendix 2). A higher score on the LOC scale indicates a poorer LOC. After extubation, respiratory frequency was measured every 15 min for 1 h, then every 30 min for 1 h and hourly for the next 6 h. Arterial blood gases were measured before anaesthesia, 30 min before tracheal extubation and 30, 90 and 240 min after tracheal extubation.
Haemodynamic measurements
Heart rate, systemic blood pressure, pulmonary artery blood pressure, pulmonary capillary wedge pressure, central venous pressure and cardiac output were recorded at the following times: after induction, after intubation, after skin incision, after sternotomy, after CPB, after sternal closure, on arrival at the ICU, hourly in the ICU until the patient was extubated, then 10, 30 and 60 min after extubation and hourly for 4 h after extubation.
Postoperative complications
Perioperative myocardial infarction was diagnosed if either or both of the following findings were present: creatinine kinase isoenzyme MB (CK-MB) concentration greater than 50 IU litre1 and representing more than 8% of the total creatinine kinase or electrocardiographic changes from baseline in two or more leads. Changes were defined as new Q waves of at least 0.04 s in duration and 1 mm in depth, ST-segment elevation or depression of >2 mm lasting 48 h, and a symmetrical T-wave inversion lasting >48 h. Blood was analysed for cardiac enzymes 8, 16 and 24 h after the release of the aortic cross-clamp. An electrocardiogram was done daily for 3 days after operation.
Reintubation, pneumothorax, cardiac or respiratory arrest, cardiac arrhythmias that required medical treatment, postoperative bleeding, reoperation, postoperative renal dysfunction (creatinine >150 µmol litre1), seizures and cerebrovascular accidents were recorded. Cerebrovascular accident was defined as a sudden onset of focal neurological deficit persisting >24 h, as documented by a neurologist. Intraoperative awareness with recall was assessed using a standard postoperative interview 18 h after extubation.18 Mortality was defined as any death occurring during hospital stay.
Data collection and statistical analysis
Routine details were collected for each patient. All drugs (doses and infusion rates) given perioperatively were recorded. Patients who did not fulfil the necessary criteria to stop sedation were excluded from the trial and the reason for their failure was documented. These patients were excluded from the statistical analysis. Sample size calculation was done for an error of 0.05, a ß error of 0.8 and a proportion of 60% of patients with an episode of cognitive dysfunction in the benzodiazepine group reduced to 30% in the propofol group. Results are expressed as mean (SD) or median (range) as appropriate. Between-group analysis was with the unpaired t-test. Serial comparisons used either one-way analysis of variance or a two-way between-group analysis of variance with repeated measurements over time, followed by post hoc Tukeys test. Non-parametric data were analysed with the
2 test and the MannWhitney U-test. Logarithmic transformation of non-parametric data was performed where appropriate. Differences were considered significant if P<0.05. Statistical analysis was performed with SPSS for Windows version 6.1.2 on an IBM-compatible PC.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
|
|
|
Level of consciousness
The mean dose of midazolam administered in the ICU was 0.03 (range 0.010.045) mg kg1 h and the mean dose of propofol was 1.8 (0.53) mg kg1 h1. Use of postoperative opioids was similar in the two the groups. The total dose of prochlorperazine used was significantly greater in the propofol group. The propofol group had a significantly greater LOC score from the second hour after extubation (P=0.015) than the benzodiazepine group (Table 2). The propofol group also had significantly greater orientation scores for the first 4 h after extubation (P=0.005) than the benzodiazepine group (Table 3). Oxygen saturation, respiratory rate and arterial blood gases after extubation were similar in the two groups (Table 4).
|
|
|
|
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
More elderly patients are now undergoing CABG surgery.5 6 Older patients are extubated less quickly after cardiac surgery,19 but there was no difference in 30-day mortality or postoperative complications in elderly [mean age 75 (4) yr] compared with young [mean age 56 (14) yr] patients undergoing early extubation (48 h) after CABG surgery.20 A retrospective review of fast-track cardiac surgery in elderly patients [mean age 62.4 (9.4) yr] found decreased LOS and no greater postoperative morbidity or mortality compared with a previous conventionally treated group.21 The present study supports the contention that all patients, including the elderly, should be considered for early extubation.22
For early tracheal extubation after cardiac surgery, patients must recover from the anaesthetic and sedative drugs used perioperatively. Elderly patients have reduced renal clearance and reduced hepatic metabolism of drugs.2325 In addition, the percentage of body weight composed of adipose tissue increases with age, thereby increasing the volume of distribution and the elimination half-life of lipid-soluble drugs.23 26
Ageing increases the pharmacodynamic sensitivity to the hypnotic effects of benzodiazepines9 27 and is associated with decreased clearance of benzodiazepines.28 29 This increased sensitivity and prolonged clearance results in slower recovery after anaesthesia and sedation with benzodiazepines. These altered effects of benzodiazepines in the elderly may explain the longer time to extubation in the benzodiazepine compared to the propofol group found in this study.
A recent study by Butterworth et al. concluded that short-acting drugs (opioid and neuromuscular blockers) have no association with length of stay in the ICU after extubation, or length of stay in hospital after CABG surgery [mean age 63 (11) yr].30 However, the study did not examine the use of benzodiazepines or propofol in relation to length of stay, and was limited by a retrospective multicentre design and lack of standardized extubation or discharge criteria among centres. Barrientos-Vega et al. found that propofol resulted in a shorter extubation time than midazolam in general intensive care patients.31 The pharmacokinetic profile of propofol3235 favours earlier recovery from anaesthesia and sedation and thus earlier extubation.
Anaesthesia and surgery affect mental function in the elderly and the risk increases with age. This effect appears to be independent of hypoxaemia and hypotension in non-cardiac surgery, suggesting an effect of anaesthetic agents on central neurotransmission. The propofol group had significantly less impaired LOC scores and orientation scores from the second hour after extubation than the benzodiazepine group. We believe that it is important to have patients conscious and orientated early after surgery. A conscious and orientated patient will communicate their needs and cooperate with the medical staff providing postoperative care. The ability to concentrate and learn instructions may facilitate tracheal extubation, chest tube removal and cooperation with physiotherapists and nursing staff.
Benzodiazepines cause antegrade amnesia and impairment of cognitive and psychomotor functioning,36 which may explain the poorer early recovery in the immediate postoperative period in the benzodiazepine group seen in this study.
Extubation and discharge times
Patients in the propofol group met discharge criteria from the ICU and hospital significantly earlier than patients in the benzodiazepine group. However, there was no difference in actual discharge times from the ICU or hospital. There is a general reluctance to transfer patients out of the ICU during the night because of risks of complications and the inconvenience of shifting bed assignments. Standard discharge criteria provide an objective end-point in medical fitness for discharging patients from ICU or for reducing the intensity of nursing care.
Haemodynamic effects
There were no significant differences in intraoperative haemodynamics between the two groups. Patients in the propofol group had a significantly lower heart rate and MAP for the first 2 h after arrival in the ICU than patients receiving benzodiazepines, but these haemodynamic effects did not require intervention. Moderate slowing of heart rate has previously been associated with propofol infusion.37
Economics
This study did not analyse the cost-effectiveness of the fast-track anaesthetic regimens used. Although the effectivenesses of benzodiazepines and propofol for patient sedation are comparable, it is difficult to compare individual doses of these two agents. To overcome this problem a routine sedation score (Ramsay score) was used to guide infusion rates after surgery in this study, as recommended by other authors.38 Propofol is two to three times as expensive as midazolam. However, some authors have argued that propofol is associated with more rapid awakening and therefore may give a shorter weaning time, which affects the final cost.31 39
![]() |
Acknowledgements |
---|
![]() |
Appendix 1 |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2 = Patient cooperative, orientated and tranquil.
3 = Patient responds to commands only.
4 = Patient shows a brisk response to a light glabellar tap or loud auditory stimulus.
5 = Patient shows a sluggish response to a light glabellar tap or loud auditory stimulus.
6 = Patient shows no response to a light glabellar tap or loud auditory stimulus.
![]() |
Appendix 2 |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2 = Lethargic. Tends to drift off to sleep when not stimulated. Spontaneous movements are decreased and awareness is limited.
3 = Obtunded. Difficult to arouse; when aroused is confused. Constant stimulation is required to elicit even marginal cooperation from the patient.
4 = Stuporous. Does not rouse spontaneously; when aroused only groans, mumbles and moves restlessly in bed.
5 = Comatose. Completely unarousable; no evidence of behavioural response to stimulation.
![]() |
Appendix 3 |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
What month is it now?
What is the date of this month?
What day of the week is this?
What season is this?
What country are we in?
What province are we in?
What city are we in?
What hospital are we in?
What floor of the hospital are we currently on?
Orientation is calculated by giving 1 point for each correct response
Total score: _/10.
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2 Westaby S, Pillai R, Parry A, OReagan D, Giannopoulos N, Grebenik K, et al. Does modern cardiac surgery require conventional intensive care? Eur J Cardio-thorac Surg 1993; 7: 3138[Abstract]
3 Cheng DCH, Karski J, Peniston C, Raveendran G, Asokumar B, Carroll J, et al. Early tracheal extubation after coronary artery bypass graft surgery reduces costs and improves resource use. Anesthesiology 1996; 85: 130010[ISI][Medline]
4 Engelman RM, Rousou JA, Flack III JE, Deaton DW, Humphrey CB, Ellison LH, et al. Fast-track recovery of the coronary bypass patient. Ann Thorac Surg 1994; 58: 17426[Abstract]
5 Naunheim KS, Fiore AC, Wadley JJ, McBride LR, Kanter KR, Pennington DG, et al. The changing profile of the patient undergoing coronary artery bypass surgery. J Am Coll Cardiol 1988; 11: 4948[ISI][Medline]
6 Naylor CD, Phil D, Ugnat AM, Weinkauf D, Anderson, GM, Wielgosz A. Coronary artery bypass grafting in Canada: What is its rate of use? Which rate is right? Can Med Assoc J 1992; 146: 8518[Abstract]
7 Thompson TL II, Moran MG, Neiss AS. Psychotropic drug use in the elderly. N Engl J Med 1983; 308: 1348[ISI][Medline]
8 Manner R, Kanto J, Salonen M. Use of simple tests to determine the residual effects of the analgesic component of balanced anaesthesia. Br J Anaesth 1987; 59: 97882[Abstract]
9 Jacobs JR, Reves JG, Marty J, White WD, Bai SA, Smith LR. Aging increases pharmacodynamic sensitivity to the hypnotic effects of midazolam. Anesth Analg 1995; 80: 1438[Abstract]
10 Ramsay MAE, Savege TM, Simpson BRJ, Goodwin R. Controlled sedation with alphaxalonealphadolone. Br Med J 1974; 2: 6569.[ISI][Medline]
11 Brandt J. The Hopkins Verbal Learning Test: development of a new memory test with six equivalent forms. Clin Neuropsychol 1991; 5: 12542
12 Reitan RM. Validity of the trail making test as an indicator of organic brain damage. Percept Mot Skills 1958; 8: 2716
13 Folstein MF, Folstein SE, McHugh PR. Mini-Mental State: a practical method for grading the cognitive states of patients for the clinician. J Psychiatr Res 1975; 12: 18998[ISI][Medline]
14 Nelson HE, OConnell A. Dementia: the estimation of premorbid intelligence levels using the new adult reading test. Cortex 1978; 14: 23444.[ISI][Medline]
15 Spielberger CD, Gorsuch RL, Lushene R, Vagg PR, Jacobs GA. Manual for StateTrait Anxiety Inventory. Palo Alto: Consulting Psychologists Press Publishers, 1983
16 Mahanna EP, Blumenthal JA, White WD, Croughwell ND, Clancy CP, Smith R, et al. Defining neuropsychological dysfunction after coronary artery bypass grafting. Ann Thorac Surg 1996; 61: 13427
17 Blumenthal JA, Mahanna EP, Madden DJ, White WD, Croughwell ND, Newman MF. Methodological issues in the assessment of neuropsychologic function after cardiac surgery. Ann Thorac Surg 1995; 59: 134550
18 Brice DD, Hetherington RR, Utting JE. A simple study of awareness and dreaming during anaesthesia. Br J Anaesth 1970; 42: 53542[ISI][Medline]
19 London MJ, Shroyer ALW, Coll JR, MaWhinney S, Fullerton DA, Hammermeister KE, et al. Early extubation following cardiac surgery in a veterans population. Anesthesiology 1998; 88: 144758[ISI][Medline]
20 Ott RA, Gutfinger DE, Miller MP, Selvan A, Alimadadian H, Tanner TM. Rapid recovery after coronary artery bypass grafting: is the elderly patient eligible? Ann Thorac Surg 1997; 63: 6349
21 London MJ, Shroyer ALW, Jernigan V, Fullerton DA, Wilcox D, Baltz J, et al. Fast-track cardiac surgery in a department of veterans affairs patient population. Ann Thorac Surg 1997; 64: 13441
22 Cheng DCH. Fast track cardiac surgery pathway: early extubation, process of care, and cost containment. Anesthesiology 1998; 88: 142933[ISI][Medline]
23 Greenblatt DJ, Sellers EM, Shader RI. Drug disposition in old age. N Engl J Med 1982; 306: 10818[ISI][Medline]
24 Wilkinson GR, Shand DG. A physiological approach to hepatic drug clearance. Clin Pharmacol Ther 1975; 18: 37790[ISI][Medline]
25 Lamy PP. Physiological changes due to age. Drugs Aging 1991; 1: 385404[Medline]
26 Greenblatt DJ. Reduced serum albumin concentrations in the elderly: a report from the Boston Collaborative Drug Surveillance Program. J Am Geriatr Soc 1979; 27: 202[ISI][Medline]
27 Reves JG, Fragen RJ, Vinik HR, Greenblatt DJ. Midazolam: pharmacology and uses. Anesthesiology 1985; 62: 31024[ISI][Medline]
28 Greenblatt DJ, Abernethy DR, Locniskar A, Harmatz JS, Limjuco RA, Shader RI. Effect of age, gender and obesity on midazolam kinetics. Anesthesiology 1984; 61: 2735[ISI][Medline]
29 Smith MT, Heazlewood V, Eadie MJ, Brophy TO, Tyrer JH. Pharmacokinetics of midazolam in the aged. Eur J Clin Pharmacol 1984; 26: 3818[ISI][Medline]
30 Butterworth J, James R, Prielipp RC, Cerese J, Livingston J, Burnett DA. Do shorter-acting neuromuscular blocking drugs or opioids associate with reduced intensive care unit or hospital lengths of stay after coronary artery bypass grafting? Anesthesiology 1998; 88: 143746[ISI][Medline]
31 Barrientos-Vega R, Mar Sanchez-Soria M, Morales-Garcia C, et al. Prolonged sedation of critically ill patients with midazolam or propofol: impact on weaning and costs. Crit Care Med 1997; 25: 3340[ISI][Medline]
32 White PF. Propofol: pharmacokinetics and pharmacodynamics. Semin Anesth 1988; 79 (S): 420
33 Albanese J, Martin C, Lacarelle B, Saux P, Durand A, Gouin F. Pharmacokinetics of long-term propofol infusion used for sedation in ICU patients. Anesthesiology 1990; 73: 2147[ISI][Medline]
34 Jain U. Perioperative use of propofol for cardiac surgery. J Clin Anesth 1996; 8: 61S66S[Medline]
35 Hemmeke TA, Hastings JE. Neuropsychologic alterations after cardiac operation. J Thorac Cardiovasc Surg 1988; 96: 32631.[Abstract]
36 Juergens SM. Problems with benzodiazepines in elderly patients [editorial]. Mayo Clin Proc 1993; 68: 81820[ISI][Medline]
37 Roekaerts PM, Huygen FJ, de Lange S. Infusion of propofol versus midazolam for sedation in the intensive care unit following coronary artery surgery. J Cardiothorac Vasc Anesth 1993; 7: 1427[Medline]
38 Shafer A. Complications of sedation with midazolam in the intensive care unit and a comparison with other sedative regimens. Crit Care Med 1998; 26: 94756[ISI][Medline]
39 Carrasco G, Molina R, Costa J, et al. Propofol vs midazolam in short-medium and long-term sedation of critically ill patients. A cost benefit analysis. Chest 1993; 103: 55764[Abstract]