Propofol and midazolam versus propofol alone for sedation following coronary artery bypass grafting: a randomized,placebo-controlled trial

The aim was to compare the efficacy and side-effects of propofol combined with a constant, low dose of midazolam versus propofol alone for sedation. In a prospective, randomized and double-blinded study, 60 male patients scheduled for elective coronary bypass grafting were enrolled. Postoperatively, patients were stratified to receive either a continuous intravenous infusion of midazolam 1 mg/h or placebo. Target Ramsay sedation score was 3 to 5 corresponding to conscious sedation. An intention-to-treat design for propofol was performed to reach target sedation. Efficacy of sedation was statistically significantly higher in the group midazolam + intention-to-treat with propofol compared with the group placebo + intention-to-treat with propofol (91% vs 79%; P=0.0005). Nine of 27 patients in the midazolam group (33.4%) and nine of 26 patients in the placebo group (34.6%) needed no supplementary propofol. Weaning time from mechanical ventilation was longer in the midazolam group whether or not they required supplemental propofol when compared with placebo group (all: 432 +/- 218 min vs 319 +/- 223 min; P=0.04; supplementary propofol: 424 +/- 234 min vs 265 +/- 175 min; P=0.03). The cumulative number of patients remaining intubated was significantly higher in the group midazolam + propofol compared with the group placebo + propofol (P=0.03). In conclusion, target sedation is reached slightly more often by the co-administration of propofol and a low dose of midazolam, but weaning time from mechanical ventilation is prolonged by the co-administration of propofol and a low dose of midazolam.     

Bispectral index monitoring during sedation with sevoflurane, midazolam, and propofol.

BACKGROUND: Bispectral Index (BIS) has been used to measure sedation depth. Ideally, to guide anesthetic management, range of BIS scores at different sedation levels should not overlap, and BIS should be independent of drug used. This study assessed ability of BIS to predict sedation depth between sevoflurane, propofol, and midazolam. Quality of recovery was also compared. METHODS: Patients undergoing surgery with local or regional anesthesia and sedation were randomized to sevoflurane (n = 23), midazolam (n = 21), or propofol (n = 22). Sedation was titrated to Observers's Assessment of Alertness-Sedation score of 3 (responds slowly to voice). BIS and Observers's Assessment of Alertness-Sedation were measured every 5 min. BIS prediction probability (PK) was compared between drugs. Recovery was assessed by BIS and Digit Symbol Substitution and memory tests. RESULTS: Bispectral Index of responders to voice was significantly different from nonresponders (86 +/- 10 vs. 74 +/- 14, mean +/- SD; P < 0.001) However, wide variability and overlap in BIS were observed (25th-75th percentile, responders vs. non-responders: 79-96 vs. 65-83). BIS of responders was different for sevoflurane versus propofol and midazolam. BIS was a better predictor of propofol sedation than sevoflurane or midazolam (PK = 0.87 +/- 0.11, 0.76 +/- 0.01, and 0.69 +/- 0.02, respectively; P < 0.05). At 10 min after the procedure, 76, 48, and 24% of sevoflurane, propofol, midazolam patients, respectively, returned to baseline Digit Symbol Substitution scores (P < 0.05). Excitement-disinhibition occurred in 70, 36, and 5% of sevoflurane, propofol, and midazolam patients, respectively (P < 0.05). CONCLUSION: Individual BIS scores demonstrate significant variability, making it difficult to predict sedation depth. The relation between BIS and sedation depth may not be independent of anesthetic agent. Quality of recovery was similar between drugs, but excitement occurred frequently with sevoflurane.     

Sequential use of midazolam and propofol for long-term sedation in postoperative mechanically ventilated patients

Acute withdrawal syndromes, including agitation and a long weaning time, are common adverse effects after long-term sedation with midazolam. We performed this study to determine whether the sequential use of midazolam and propofol could reduce adverse effects as compared with midazolam alone. We studied 26 patients receiving mechanical ventilation for three or more days after surgery. Patients were randomly assigned to two groups. In Group M, patients were sedated with midazolam alone. In Group M-P, midazolam was switched to propofol approximately 24 h before the expected stopping of sedation. The level of sedation was maintained at 4 or 5 on the Ramsay sedation scale. The sedation agitation scale was evaluated for 24 h after extubation. The recovery time from stopping of sedation to extubation was significantly shorter in Group M-P (1.3 +/- 0.4 h) compared with Group M (4.0 +/- 2.4 h). The incidence of agitation in Group M-P (8%) was significantly less frequent than that in Group M (54%). The results indicate that sequential use of midazolam and propofol for long-term sedation could reduce the incidence of agitation compared with midazolam alone. IMPLICATIONS: Our study indicates that sequential use of midazolam and propofol could reduce the incidence of agitation compared with midazolam alone.     

Midazolam in combination with propofol for sedation during local anesthesia.

STUDY OBJECTIVE: To compare the sedative, anxiolytic, and amnestic effects, as well as the recovery characteristics, when midazolam (vs. a placebo) is administered to patients receiving a propofol infusion for sedation during local anesthesia. DESIGN: Randomized, double-blind, placebo-controlled study to evaluate the perioperative effects of intravenous (IV) midazolam. SETTING: Outpatient surgery center of a university-affiliated medical center. PATIENTS: One hundred thirty-nine consenting, ASA physical status I, II, and III outpatients undergoing elective surgical procedures under local anesthesia. INTERVENTIONS: Patients were randomly assigned to receive either midazolam 2 mg IV or saline 2 ml IV prior to injection of local anesthesia. Intraoperative sedation was maintained using a variable-rate propofol infusion. MEASUREMENTS AND MAIN RESULTS: Preoperative assessment of sedation, anxiety, and amnesia was performed before and after IV midazolam. Intraoperative evaluations included level of sedation, as well as cardiovascular and respiratory measurements, at 1- to 5-minute intervals during the operation. Postoperatively, recovery of psychomotor function and patients' subjective feelings were assessed using the visual analog scale and questionnaires. Amnesia was assessed using picture recall during the perioperative period. In the operating room, midazolam 2 mg IV, compared with the placebo, produced a significantly greater increase in patients' level of sedation (7 +/- 13 mm to 49 +/- 21 mm for midazolam vs. 8 +/- 11 mm to 19 +/- 21 mm for the placebo; p less than 0.01) and a greater decrease in anxiety level (62 +/- 25 mm to 21 +/- 21 mm for midazolam vs. 54 +/- 27 mm to 53 +/- 22 mm for the placebo; p less than 0.01). Although the propofol dosage requirements to maintain comparable levels of sedation were similar in both groups, midazolam decreased patients' recall of intraoperative events (e.g., propofol-induced pain on injection and discomfort with local anesthetic injection) without significantly altering cardiorespiratory parameters or prolonging times to ambulation and discharge from the outpatient facility. CONCLUSIONS: Premedication with midazolam 2 mg IV produced increased sedation, amnesia, and anxiolysis when administered immediately prior to the propofol infusion as part of a sedation technique for outpatient surgery. This combination did not prolong the recovery room stay when compared with propofol alone.     

Propofol sedation after open heart surgery A clinical and pharmacokinetic study

One hundred adult patients who required mechanical ventilation after open heart surgery for coronary revascularisation were studied. All received a standard premedication and a high dose opioid anaesthetic. On arrival in the intensive care unit they were allocated randomly to receive either propofol or midazolam to maintain sedation within a predetermined range. Patients who received propofol underwent extubation of the trachea, using standard criteria, after a mean time (log-transformed) of 7.6 minutes after sedation for approximately 17 hours. The corresponding time was 125 minutes in those given midazolam. There were significantly higher morphine requirements during sedation, and higher arterial carbon dioxide tensions 30 minutes after extubation of the trachea, in patients who received midazolam. Pharmacokinetic analysis in 20 patients showed that the elimination half-life of propofol was prolonged (470 minutes) and clearance was reduced (1.14 litres/minute) compared with subjects who had not undergone cardiopulmonary bypass. The rapid clinical recovery was reflected in a rapid redistribution half-life (13.4 minutes), but this was also longer than the redistribution time of 2-4 minutes in other patients.     

Bispectral Index Monitoring during Sedation with Sevoflurane, Midazolam, and Propofol

Background : Bispectral Index (BIS) has been used to measure sedation depth. Ideally, to guide anesthetic management, range of BIS scores at different sedation levels should not overlap, and BIS should be independent of drug used. This study assessed ability of BIS to predict sedation depth between sevoflurane, propofol, and midazolam. Quality of recovery was also compared.

Methods : Patients undergoing surgery with local or regional anesthesia and sedation were randomized to sevoflurane (n = 23), midazolam (n = 21), or propofol (n = 22). Sedation was titrated to Observers's Assessment of Alertness-Sedation score of 3 (responds slowly to voice). BIS and Observers's Assessment of Alertness-Sedation were measured every 5 min. BIS prediction probability (PK) was compared between drugs. Recovery was assessed by BIS and Digit Symbol Substitution and memory tests.

Results : Bispectral Index of responders to voice was significantly different from nonresponders (86 +/- 10 vs. 74 +/- 14, mean +/- SD;P < 0.001) However, wide variability and overlap in BIS were observed (25th-75th percentile, responders vs. non-responders: 79-96 vs. 65-83). BIS of responders was different for sevoflurane versus propofol and midazolam. BIS was a better predictor of propofol sedation than sevoflurane or midazolam (PK = 0.87 +/- 0.11, 0.76 +/- 0.01, and 0.69 +/- 0.02, respectively;P < 0.05). At 10 min after the procedure, 76, 48, and 24% of sevoflurane, propofol, midazolam patients, respectively, returned to baseline Digit Symbol Substitution scores (P < 0.05). Excitement-disinhibition occurred in 70, 36, and 5% of sevoflurane, propofol, and midazolam patients, respectively (P < 0.05).     

Sedative infusions during local and regional anesthesia: a comparison of midazolam and propofol

STUDY OBJECTIVE: To compare the intraoperative effects and recovery characteristics when either midazolam or propofol was used for sedation during local or regional anesthesia. DESIGN: Open-label, randomized study with blinded observer assessing recovery data. SETTING: Outpatients undergoing elective surgical procedures under local or regional anesthesia at Stanford University Hospital, Stanford, California. PATIENTS: Sixty-eight consenting, unpremedicated ASA physical status I, II, or III patients. INTERVENTIONS: After achieving adequate analgesia with local anesthetic solutions, patients were administered a loading dose of either midazolam (4.2 +/- 1.4 mg) or propofol (69 +/- 23 mg) followed by a variable-rate maintenance infusion equal to 8.6 +/- 5.4 mg/h or 265 +/- 185 mg/h, respectively, to maintain a stable level of sedation during the operation. MEASUREMENTS AND MAIN RESULTS: Intraoperative assessments included level of sedation, as well as cardiovascular and respiratory status, at 1- to 5-minute intervals during the operation. Postoperatively, recovery of cognitive and psychomotor function was assessed using analog scales and the digit-symbol substitution test. The overall quality of intraoperative sedation was similar in the two sedative treatment groups. Although midazolam produced less pain on injection and more effective intraoperative amnesia, use of propofol was associated with less postoperative sedation, drowsiness, confusion, clumsiness, and amnesia, as well as more rapid recovery of cognitive function. However, discharge times were similar in the two sedative treatment groups. CONCLUSIONS: Propofol infusion is a clinically useful alternative to midazolam for sedation during ambulatory surgery under local or regional anesthesia.     

Propofol versus midazolam. Long-term sedation in the intensive care unit]

Sedative-analgesic treatment of patients on long-term artificial ventilation aims at protection from stress related to their disease or therapy. By stabilising both the patient's vital functions and psychological state this treatment may contribute to therapeutic success. The choice of drugs depends primarily on the nature and course of the underlying disease. Midazolam and propofol are available as hypnotics for short-term sedation during the post-operative period. The purpose of this study was to evaluate the effects of both agents on cardiovascular function, cortisol production, lipometabolism, and the recovery period following 24-h sedation. METHODS. Twenty female patients (mean body weight: 72 kg, mean age: 60 years) were randomly assigned to receive either midazolam or propofol over 24 h following major abdominal surgery. Balanced anaesthesia (halothane/O2/N2O/fentanyl) was administered for the surgical procedure. Assisted ventilation was used in all patients during the post-operative sedation period. Sedation depth was maintained at III-IV on the Ramsey scale. On arrival in the intensive care unit (ICU), an initial i.v. bolus of midazolam 0.1 mg/kg or propofol 1 mg/kg was followed by a continuous infusion (midazolam: 0.1 mg/kg.h; propofol: 2 mg/kg.h). Supplementary boluses of one-half the initial dose were given if required. Post-operative analgesia was achieved with 3 mg intravenous piritramide at 2-h intervals. A 7F Swan-Ganz catheter was inserted in the pulmonary artery and haemodynamic and biochemical parameters were monitored at 4-h intervals over 24 h starting 2 h after arrival in the ICU. Catecholamines were measured by high-pressure lipid chromatography (HPLC), cortisol by radioimmunoassay, midazolam by HPLC and ultraviolet detection, and propofol by HPLC and fluorescence detection. Data were calculated as means. The statistical analysis was performed according to the Mann-Whitney test, and significance was accepted for P less than 0.05. RESULTS. On administration of the propofol bolus at the onset of sedation, a decrease in blood pressure was particularly observed in patients with masked hypovolaemia, however, this decrease was easily controlled by volume administration. Independent of the type of sedation, the haemodynamic parameters remained unchanged throughout the observation period. At all times of measurement the mean heart rate was lower in the propofol group (90/min) when compared with the midazolam group (100/min), however, this difference did not reach significance. There were also no significant differences in cardiac index at all times of measurement, although it increased in both groups within the first 12 h by 0.6 l/min.min2. In both groups this increase was associated with a reduction in peripheral resistance and an increase in rectal temperature. To achieve the desired sedation depth, midazolam was administered at a mean dosage of 0.11 mg/kg.h and propofol at 1.9 mg/kg.h. Catecholamine levels decreased in both groups within the first 8 h: after 8 h of sedation the plasma levels of noradrenaline and adrenaline were 525 and 65 pg/ml, respectively, in the midazolam group and 327 and 51 pg/ml in the propofol group. (ABSTRACT TRUNCATED AT 400 WORDS)     

Continuous infusion of ketamine and midazolam for prolonged sedation in the intensive care unit]

The clinical effects and pharmacokinetics of ketamine and midazolam, administered continuously for prolonged sedation were studied in 7 critically ill patients under mechanical ventilation. Initially ketamine 1 mg.kg-1 and midazolam 0.1 mg.kg-1 were administered intravenously and these were followed by infusion at a rate of 1.0 mg.kg-1.hr-1 of ketamine and 0.05 mg.kg-1.hr-1 of midazolam. The infusion rate was changed every 30 minute with increments of 0.5 mg.kg-1.hr-1 of ketamine and 0.05 mg.kg-1.hr-1 of midazolam until the sedative score by Ramsy RAE reached rank 4 (i.e. slow response to loud verbal commands). The plasma concentrations of ketamine were analyzed using high performance liquid chromatography and those of midazolam using gas chromatography. The mean maintenance doses of ketamine and midazolam were 2.25 +/- 0.61 mg.kg-1.hr-1 and 0.11 +/- 0.05 mg.kg-1.hr-1 (mean +/- SD), respectively. There were no significant changes in blood pressure or heart rate before and after the injection of ketamine and midazolam in all the patients. The plasma concentrations of ketamine and midazolam were 2.98 +/- 0.20 micrograms.ml-1 and 494.1 +/- 66.7 ng.ml-1, respectively. The time to clear response to verbal commands after cessation of the continuous infusion was 168 +/- 109 min. The plasma concentrations of ketamine and midazolam decreased rapidly, and plasma half-life of ketamine was about 1 hour and for midazolam less than 2 hours. In conclusion, continuous infusion of ketamine and midazolam was very useful to sedate critically ill patients under mechanical ventilation, with minimal effect on the cardiovascular system and rapid recovery of consciousness.     

Propofol or midazolam for short-term alterations in sedation

It is often necessary to adjust a patient’s sedation level while they are in the intensive care unit. The purpose of this study was to compare propofol with midazolam for controlling short-term alterations in sedation. Twenty-three patients undergoing an interactive procedure, physiotherapy, during mechanical ventilation of the lungs were studied. The patients were randomly assigned to receive infusions of propofol or midazolam for sedation. Sedation was assessed using the method of Ramsay, where 3 is drowsy responding only to commands; and 5 is asleep with a slow response to light glabellar tap. Prior to physiotherapy sedation was deepened from 3 to 5 by increasing the sedative infusion rate, and level 5 was maintained during physiotherapy by adjusting the infusion rate whenever necessary. After physiotherapy, the sedative dose was reduced until level 3 was again achieved. During physiotherapy, sedation level 5 was achieved for 53.9% of the time with propofol but for only 25.7% with midazolam (P < 0.01). After physiotherapy, those patients sedated with propofol re-awakened to level 3 faster (8.3 ± 2.3 min, mean ±SE) than those receiving midazolam (92.8 ± 35.0 min, P < 0.05). After physiotherapy, a further 1.8 ± 0.5 dose adjustments were required to the midazolam infusion while only 0.4 ± 0.2 adjustments were required to the propofol infusion (P < 0.05). During physiotherapy 3.0 ± 0.5 dose adjustments to the propofol dose were required compared with 3.6 ± 0.5 adjustments to the midazolam dose (NS). It is concluded that, during a standardized stimulus, physiotherapy, propofol infusion allowed a desired sedation score to be maintained for more of the time than did infusion of midazolam. Subsequently, when the infusion rates were reduced, less time was taken to re-awaken to baseline levels after physiotherapy, with fewer adjustments to the infusion rate, in those patients receiving propofol than midazolam.     

The different effects of intravenous propofol and midazolam sedation on hemodynamic and heart rate variability

Heart rate (HR) and arterial blood pressure (BP) changes have been reported during conscious sedation with propofol and midazolam. One potential mechanism to explain these changes is that propofol and midazolam affect HR and BP via changes in the cardiac autonomic nervous system. Two specific hypotheses were tested by HR variability analysis: 1) propofol induces predominance of parasympathetic activity, leading to decreased HR and BP, and 2) midazolam induces predominance of sympathetic activity, leading to increased HR and decreased BP. Thirty dental patients were included in a prospective, randomized study. HR, BP, low frequency (LF), high frequency (HF), and entropy were monitored during the awake, sedation, and recovery periods and depth of sedation was assessed using the Observer's Assessment of Alertness/Sedation score. Propofol induced a significant decrease in total power (503 +/- 209 ms(2)/Hz versus 162 +/- 92 ms(2)/Hz) and LF/HF ratio (2.5 +/- 1.2 versus 1.0 +/- 0.4), despite the absence of any change in HR during the sedation period compared with baseline. Midazolam decreased normalized HF (34 +/- 10% versus 10 +/- 4%) but did not significantly change LF/HF ratio (2.3 +/- 1.1 versus 2.2 +/- 1.4) and increased HR in the sedation period. Compared with baseline, propofol was associated with a significant increase in normalized HF in the recovery period (34 +/- 11% versus 44 +/- 12%) and a significant decrease in HR, whereas midazolam was associated with an increase in LF/HF ratio (2.3 +/- 1.1 versus 3.7 +/- 1.8) with no change in HR. These results indicated a dominant parasympathetic effect of propofol and a dominant sympathetic effect of midazolam in both periods. These results should be considered during conscious sedation, especially in patients at risk of cardiovascular complications.     

Midazolam premedication reduces propofol requirements for sedation during regional anesthesia

PURPOSE: Propofol is often used for sedation during spinal anesthesia. We investigated the effects of midazolam premedication on the propofol requirements and incidence of complications during sedation. METHODS: In a prospective randomized, controlled, and single-blinded study, 50 patients undergoing elective gynecological surgery were randomly divided into control and midazolam groups. Patients in the midazolam group received 2 mg midazolam im 30 min before arrival at the operation room. After spinal anesthesia was instituted with intrathecal injection of hyperbaric tetracaine, we provided sedation using continuous infusion of propofol. The level of sedation was controlled at a level between "eyes closed but rousable to command" and "eyes closed but rousable to mild physical stimulation" by adjusting the infusion rate. During sedation, the propofol requirements and complications were recorded and patients were asked, two hours after the end of operation, whether they remembered intraoperative events. RESULTS: In the midazolam group, the loading dose, steady state infusion rate, and overall infusion rate of propofol were 0.74 mg x kg(-1), 2.86 mg x kg(-1) x hr(-1), and 3.32 mg x kg(-1) x hr(-1), respectively, which were about 17% lower than those in the control group (P<0.05). Moreover, midazolam premedication reduced the incidence of intraoperative memory (P < 0.05), but had no effects on other complications. CONCLUSION: Midazolam premedication reduced propofol requirements and the incidence of intraoperative memory during sedation. These effects on sedation using propofol during spinal anesthesia are considered beneficial for patients.     

A comparison of the effects of propofol and midazolam on memory during two levels of sedation by using target-controlled infusion

We examined memory during sedation with target-controlled infusions of propofol and midazolam in a double-blinded five-way, cross-over study in 10 volunteers. Each active drug infusion was targeted to sedation level 1 (asleep) and level 4 (lethargic) as determined with the Observer Assessment of Alertness/Sedation scale. At the target level of sedation, drug concentration was clamped for 30 min, during which time neutral words were presented. After 2 h, explicit memory was assessed by recall, and implicit memory by using a wordstem completion test. Venous drug concentrations (mean +/- SD) were 1350 ng/mL (+/-332 ng/mL) for propofol and 208 ng/mL (+/-112 ng/mL) for midazolam during Observer Assessment of Alertness/Sedation scale level 4; and 1620 ng/mL (+/-357 ng/mL) and 249 ng/mL (+/-82 ng/mL) respectively during level 1. The wordstem completion test frequencies at low level sedation were significantly higher than spontaneous frequencies (8.7% + 2.4%; P: < 0.05 in all cases), and lower than during placebo (33.6% + 23%) (P: < 0.05 in all cases, except P: = 0.076 for propofol at level 4). Clinically distinct levels of sedation were accompanied by small differences in venous propofol or midazolam concentrations. This indicates steep concentration-effect relationships. Neutral information is still memorized during low-level sedation with both drugs. The memory effect of propofol and midazolam did not differ significantly. Implications: Implicit memory can occur during different states of consciousness and might lead to psychological damage. In 10 volunteers, implicit memory was investigated during sedation with propofol and midazolam in a double-blinded, placebo-controlled study. To compare the effects of both drugs, they were titrated using a computer-controlled infusion system to produce similar high and low levels of sedation.     

Experience with remifentanil in the ICU

BACKGROUND: Analgesia and sedation are indispensable in patients admitted to intensive care for the following, principal reasons: to control their state of anxiety, induce amnesia, improve their adaptation to mechanical ventilation, make invasive manoeuvres tolerable. The purpose of the present retrospective analysis is to assess the effectiveness of remifentanil in a total of 1085 patients admitted to our Resuscitation and Intensive Care Department in 1997-2001. METHODS: A sample of 60 adults was taken from these patients. The group was homogeneous in terms of age (67.3+/-10.2 kg), weight (66.7+/-10.2 kg), duration of sedation (6.8+/-1.6 days) and index of gravity (SAPS 30.1+/-4.4). The patients were suffering from chronic obstructive bronchopneumopathy, subjected to mechanical ventilation and sedated with remifentanil. The sample was then compared with another 2 groups (homogeneous with the first) of 20 patients each, treated with propofol and midazolam as the only drug. Following an initial bolus of 2 mg/kg (+/-0.04) for propofol and 0.15 mg/kg (+/-0.03) for midazolam (no bolus for remifentanil), the doses of subsequent continuous infusion (initial doses in the case of remifentanil) were: 0.05 mcg/kg/m (+/-0.01) for remifentanil; 1 mg/kg/h (+/-0.04) for propofol; 0.03 mg/kg/h (+/-0.006) for midazolam. In order to assess the level and quality of sedation, 2 subjective evaluation scales (Ramsey score and the Sedation-Agitation Score: SAS) and one system of objective evaluation (Bispectral Index; BIS) were employed. The BIS is a direct measure of the effects of anaesthetics on the brain. It is represented by a single digit (between 100, state of arousal, and zero, EEG flat), derived statistically and empirically from the EEG. RESULTS: No significant differences were encountered as regards quality of sedation among the 3 groups but there was a significant difference in negative cardiovascular activity in patients treated with propofol (12% reduction in Cl, 13.8% reduction in SVR). A significant accumulation of the drug was observed in cases treated with midazolam, whereas there was no accumulation for remifentanil and propofol in relation to the duration of the infusion. CONCLUSIONS: Of the various sedation modalities employed, we prefer the one which uses remifentanil as the sole drug because a good level of sedation is obtained, there is no accumulation, little interference with cardiovascular parameters and lower costs in comparison with the others.     

Tolerance to propofol's sedative effect in mechanically ventilated Rabbits

Propofol is commonly used for the sedation of critically ill patients undergoing mechanical ventilation. These patients may develop tolerance during long-term administration. Here, we describe the development of tolerance to propofol's sedative effect in rabbits during prolonged mechanical ventilation. Six healthy male New Zealand White rabbits were endotracheally intubated and received propofol by continuous IV infusion to maintain sedation for 48 h. The propofol infusion rate (IR) was adjusted to maintain the desired level of sedation. Assessments of the sedation level were made every 30 min or earlier if there were signs of awakening. Propofol concentrations were measured in arterial plasma after every other IR adjustment, provided there was an adequate level of sedation, using high performance liquid chromatography, and calculations of systemic clearance rates were made. The mortality rate was 100% with a survival period of 30.8 +/- 6.0 h (mean +/- sd). The course of IR adjustments followed a 5-phase pattern: 1) steady IR (mean +/- sd duration; 1.2 +/- 0.6 h), 2) increasing IR (9.4 +/- 5.5 h), 3) steady high-IR (2.3 +/- 1.2 h), 4) decreasing IR (13.7 +/- 1.9 h), and 5) steady low-IR (5.0 +/- 2.7 h). The course of propofol concentrations during the experiment in relation to propofol IR followed a 3-phase pattern: 1) steady concentration with increasing IRs (6.0 +/- 2.7 h), 2) increasing concentrations with increasing IR (5.8 +/- 2.5 h), and 3) increasing concentrations with decreasing IR (18.8 +/- 3.3 h). Propofol systemic clearance rates were progressively increased for 6.0 +/- 2.7 h and then gradually decreased for 24.6 +/- 4.7 h. In conclusion, all rabbits developed tolerance to propofol's sedative effect within the first hours of administration related to changes to the drug's metabolic clearance.     

Propofol for long-term sedation in the intensive care unit. A comparison with papaveretum and midazolam

Thirty-seven patients with a wide range of illnesses were studied during mechanical ventilation of the lungs in an intensive care unit. Fifteen were sedated with a continuous propofol infusion, with analgesia provided by bolus doses of papaveretum. Twelve received a continuous infusion of papaveretum, supplemented by bolus doses of midazolam. The level of sedation was assessed every four hours and measurements were made of haemodynamic and respiratory variables. Levels of sedation were generally satisfactory in both groups. Six patients who received propofol required the use of muscle relaxants, because of their strong respiratory drives, to achieve synchronisation with the ventilator. There was no significant difference in respiratory or haemodynamic variables between the groups, but several patients required inotropic support because of their disease. There was no evidence of inhibition of adrenal steroidogenesis in the propofol group. Propofol can be a useful sedative agent in the intensive care unit, but sedative regimens should be tailored to individual patient requirements.     

Recovery of psychomotor function after propofol sedation is prolonged in the elderly

PURPOSE: To assess the effects of age on recovery of psychomotor function for propofol sedation during spinal anesthesia. METHODS: Propofol was continuously infused during surgery and spinal anesthesia in 15 elderly patients (65-85 yr-old) and 15 younger patients (20-50 yr-old). Infusion rates were adjusted to maintain an appropriate level of sedation using the bispectral index (range 60-70). The sedative infusion was discontinued at the end of surgery. The early recovery times from the end of propofol infusion to opening of eyes on command, sustaining a hand grip, and recall of name were noted. Psychomotor function, as measured by the Trieger's dot test, was evaluated before anesthesia and 30, 60, 90, 120 min after the end of propofol infusion. RESULTS: The duration of anesthesia was 142 +/- 55 min and 134 +/- 61 min in the elderly and younger patients, respectively. No differences were observed in early recovery times between elderly and younger patients (opened their eyes on command, 6.3 +/- 4.0 min and 5.2 +/- 2.6 min; sustained a hand grip, 7.2 +/- 3.9 min and 6.1 +/- 3.5 min and recalled their name, 8.0 +/- 4.5 min and 6.5 +/- 3.8 min, P > 0.05 ). The recovery of psychomotor function in the elderly took longer compared with the younger patients, and psychomotor function in the elderly recovered at 120 min after the end of propofol infusion. CONCLUSION: Early recovery times following propofol sedation is similar between elderly and younger patients, but recovery of psychomotor function in the elderly is delayed compared with younger patients.     

The effect of the decreased serum concentration of propofol induced by rapid fluid infusion on the spectral edge frequency 90 and median frequency

The effect of decreased serum concentration of propofol induced by rapid infusion therapy on the EEG was assessed by spectral edge frequency 90% (SEF90) or median frequency (MF) during propofol anesthesia. The eight scheduled surgical patients were administered propofol with a constant rate, and the rapid infusion therapy with 10 ml.kg-1 of acetate Ringer's solution significantly decreased the serum concentration of propofol from 1.96 +/- 0.22 micrograms.ml-1 to 1.68 +/- 0.19 micrograms.ml-1 (approximately 17% reduction). Simultaneous monitoring of SEF90 and MF, however, demonstrated no change during investigation. These results suggest that the mild decrease of the concentration of propofol might not induce the significant change of EEG, or that the reduction of propofol concentration by infusion might be deceptive and produce no significant change in the concentrations of each pharmacological compartment.     

Differences between midazolam and propofol sedation on upper airway collapsibility using dynamic negative airway pressure

BACKGROUND: Upper airway obstruction (UAO) during sedation can often cause clinically significant adverse events. Direct comparison of different drugs' propensities for UAO may improve selection of appropriate sedating agents. The authors used the application of negative airway pressure to determine the pressure that causes UAO in healthy subjects sedated with midazolam or propofol infusions. METHODS: Twenty subjects (12 male and 8 female) completed the study. After achieving equivalent levels of sedation, the subjects' ventilation, end-tidal gases, respiratory inductance plethysmographic signals, and Bispectral Index values were monitored for 5 min. Negative airway pressure was then applied via a facemask in steps of 3 cm H(2)O from -3 to -18 cm H(2)O. UAO was assessed by cessation of inspiratory airflow and asynchrony between abdomen and chest respiratory inductance plethysmographic signals. RESULTS: Equivalent levels of sedation were achieved with both drugs with average (+/- SD) Bispectral Index levels of 75 +/- 5. Resting ventilation was mildly reduced without any changes in end-tidal pressure of carbon dioxide. There was no difference between the drugs in the negative pressure resulting in UAO. Five female subjects and one male subject with midazolam and four female subjects and one male subject with propofol did not show any UAO even at -18 cm H(2)O. Compared with males, female subjects required more negative pressures to cause UAO with midazolam (P = 0.02) but not with propofol (P = 0.1). CONCLUSIONS: At the mild to moderate level of sedation studied, midazolam and propofol sedation resulted in the same propensity for UAO. In this homogeneous group of healthy subjects, there was a considerable range of negative pressures required to cause UAO. The specific factors responsible for the maintenance of the upper airway during sedation remain to be elucidated.     

The cost-effectiveness of methohexital versus propofol for sedation during monitored anesthesia care

We designed this study to test the hypothesis that methohexital is a cost-effective alternative to propofol for sedation during local anesthesia. Sixty consenting women undergoing breast biopsy procedures under local anesthesia were randomly assigned to receive an infusion of either propofol (50 microg x kg(-1) x min(-1)) or methohexital (40 microg x kg(-1) x min(-1)). The sedative infusion rate was titrated to maintain an observer's assessment of alertness/sedation (OAA/S) score of 3 (with 1 = awake/alert to 5 = asleep). Fentanyl 25 microg i.v. was administered as a "rescue" analgesic during the operation. We assessed the level of sedation (OAA/S score), vital signs, time to achieve an OAA/S score of 3 at the onset and a score of 1 after discontinuing the infusion, discharge times, perioperative side effects, and patient satisfaction. The direct cost of methohexital was lower than that of propofol, based on the milligram dosage infused during the operation. The sedative onset (to achieve an OAA/S score of 3) and the recovery (to return to an OAA/S score of 1) times, as well as discharge times, did not differ between the two groups. Patients receiving methohexital had a significantly lower incidence of pain on initial injection compared with those receiving propofol (10% vs 23%). Because the use of methohexital (29.4 +/- 2.7 microg x kg(-1) x min(-1)) for sedation during breast biopsy procedures has a similar efficacy and recovery profile to that of propofol (36.8 +/- 15.9 microg x kg(-1) x min(-1)) and is less costly based on the amount infused, it seems to be a cost-effective alternative to propofol for sedation during local anesthesia. However, when the cost of the drug infused and drug wasted was calculated, there was no difference in the overall drug cost. Implications: When administered to maintain a stable level of sedation during local anesthesia, methohexital is an acceptable alternative to propofol. However, the overall drug costs were similar with the two drugs.