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Anesth Analg 2000;91:1056-1061
© 2000 International Anesthesia Research Society

AMBULATORY ANESTHESIA

A Comparison of the Effects of Propofol and Midazolam on Memory During Two Levels of Sedation by Using Target-Controlled Infusion

Annemiek de Roode, MD, PhD*, Joop M. A. van Gerven, MD, PhD{dagger}, Rik C. Schoemaker, BSc, PhD{dagger}, Frank H. M. Engbers, MD*, Wim Olieman, BSc*, J. Ria Kroon, BSc{dagger}, Adam F. Cohen, MD, PhD, FFPM{dagger}, and James G. Bovill, MD, PhD, FFARCSI*

*Department of Anesthesiology and {dagger}Centre for Human Drug Research, Leiden University Medical Centre, Leiden, The Netherlands

Address correspondence and reprint requests to Annemiek de Roode, MD, PhD, Department of Anesthesiology, Leiden University Medical Centre, PO Box 9600, 2300 RC Leiden, The Netherlands. Address e-mail to A.de_Roode{at}lumc.nl


   Abstract
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 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
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.


   Introduction
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 Abstract
 Introduction
Methods
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 Discussion
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Sedation of patients is a standard procedure in many intensive care units during surgery and investigational procedures. The absence of recall for events that take place during an altered state of consciousness cannot guarantee that these events are not processed and stored in memory. It is even possible that information registered during anesthesia or sedation produces greater psychological effects than when a fully conscious subject receives the same information (1). It is known that subliminal presentations can be more effective in priming emotional responses than supraliminal stimuli in awake subjects (2).

The amnesic properties of propofol on explicit memory are similar to those of midazolam (3–5). Implicit memory appears to be impaired by midazolam and other benzodiazepines (6,7), but largely spared by propofol (8,9). The objective of our study was to investigate the influence of two clinically distinct levels of sedation with midazolam or propofol on explicit and implicit memory.


   Methods
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 Abstract
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 Methods
Results
 Discussion
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After approval of the Medical Ethics Committee and after receiving informed consent, 13 healthy male volunteers, aged 21–30 yr, were enrolled in the study. The study was a randomized, double-blinded crossover design. Each subject was tested on five separate occasions, all at the same time of day, with a washout period of 4 to 7 days. Urine screens for cannabis, amphetamines, opiates, cocaine, and benzodiazepines were performed on each study day.

Subjects fasted for 4 h before each experiment; fluids were allowed up to 2 h before the study (coffee, chocolate, tea, and tobacco were forbidden). Two 18 or 20 G venous cannulae were inserted, one in the right forearm for drug infusion, and another cannula in the left forearm for blood sampling.

The randomization consisted of two components: a single-blinded randomization of the desired sedation levels, and a double-blinded randomization of the study-drug infusions. For each experiment, one active treatment and a dummy treatment, consisting of either NaCl 0.9% (when the active treatment was propofol) or intralipid (when the active treatment was midazolam) were administered as two separate infusions. Both infusions were connected via a Y-piece to the IV cannula. Both active and dummy drugs were administered by target controlled infusion (TCI) systems by using a Psion 3a palmtop computer controlling the infusion pumps (B-D PILOT anesthesia, Becton Dickinson & Co., Brézins, France). The program, developed by one of the authors (FHME), was designed to produce a slow linearly increasing blood concentration of the drugs, based on pharmacokinetic datasets for propofol (10) and for midazolam (11). The rate of concentration increase for propofol was 25 ng · mL-1 · min-1, and 5 ng · mL-1 · min-1 for midazolam. When the appropriate level of sedation was reached, the computer-controlled infusion was set ("clamped") to maintain the concentration for approximately 30 min. A randomized, double-dummy, all-placebo session was also performed, because staying 4 to 6 h in a darkened room could impair vigilance. If a subject was still alert (level 5) after 1 h of infusion, the clamping phase was started, and all procedures were performed, including sham blood sampling. During the clamping phase, a tape with words for the memory test was presented. The electrocardiogram, noninvasive blood pressure, pulse oximetry, and expired CO2 volume percent were monitored during the infusion of the study drugs and for 30 min thereafter.

Sedation scores were recorded every 5 min, from the start of infusion until the clamping phase was reached and after stopping drug infusion.

Venous blood samples were taken frequently, every 5–15 min until 1 h after the infusion was stopped, and every 30 min for the next 2 h. Propofol and midazolam concentrations were analyzed by high-pressure liquid chromatography. The coefficient of the variation in the concentration range found in this study was <=5% for propofol and <=7% for midazolam.

The Observer Assessment of Alertness/Sedation scale (OAA/S) (12) was used by the same investigator to determine the levels of sedation (See Table 1). Two distinct target sedation levels were set at 1 (high) and 4 (low). At high sedation levels, subjects had to be asleep according to the original OAA/S level 1, but in addition they were required not to respond to a strongly arousing nonpainful stimulus. This stimulus was provided by an electric current produced by a train-of-four neuromuscular monitor. Before the start of each experiment, subjects were asked to adjust the current of the neuromuscular monitor (TOF Innervator NS242; Fisher & Paykel Healthcare, Oakland, New Zealand) to produce a maximally tolerated nonpainful arousing stimulus. This set point was then used as the threshold current during the experiment.


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  		Table 1. Observer Assessment of Alertness/Sedation Scale
 
During the clamping phase of the study, subjects heard via headphones a tape-recording containing 16 common words spoken by one of the investigators. Each word was repeated twice at 5-s intervals, with a pause of 10 s between two different words. During each experiment, 16 different words were used. The words were selected from a normative list of completions to 168 wordstems validated for 200 students in the Leiden University by the Psychology Department (G. Wolters, personal communication). The words used had a spontaneous wordstem frequency of 8.7% (range 8.1%–9.0%) in the student population from which our volunteers were also recruited. Two hours after the infusion was stopped, a second tape containing 40 wordstems was played. This tape contained the 16 presented words from which the nonstem parts of each word were removed and 14 other wordstems (e.g., word = motel, stem = mo). Subjects were asked to complete the wordstem verbally with the first word that came to mind.

The percentage of words correctly recalled in the wordstem completion test (WCT) was analyzed using analysis of variance with treatment, subject, and occasion as factors by using SAS for Windows version 6.10 (SAS Institute Inc., Cary, NC). Observer-rated sedation scores were compared during the clamping phase for each treatment separately by comparing the value at 125 min with the value at 150 min (begin versus end) using paired Student’s t-tests. A value of P < 0.05 was taken as statistically significant. Results are shown as mean with standard deviation (±SD) unless indicated otherwise.


   Results
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 Results
Discussion
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Three subjects did not complete the study, one for family reasons, one because of problems with IV cannula placement, and a third because of gastrointestinal complaints after fasting for more than 6 h.

Sedation levels remained stable at OAA/S level 5 in all cases throughout the placebo occasions. One subject remained alert despite 1 h of infusion of what turned out to be propofol; he was assumed to have been given placebo and according to protocol only sham samples were taken during the half-hour clamping period and subsequent 2-h follow-up. The blood propofol concentration at the start of the clamping phase was 1101 ng/mL.

OAA/S scores gradually decreased during active drug infusion. The predefined low level of sedation (OAA/S level 4) was reached after 68.8 min (±12.9 min) with propofol and after 39.9 min (±18.4 min) with midazolam. High sedation levels (OAA/S level 1) were attained after 78.6 min (±21.5 min) and 41.1 min (±8.3 min) respectively.

The time profiles of sedation levels during and after the clamping phase are shown in Figure 1. The OAA/S scores at the beginning and end of the clamping phase were similar, indicating a stable level of sedation. All subjects showed a faster recovery after propofol than midazolam administration as determined by the OAA/S. Within 30 min of stopping drug infusions, all subjects receiving low or high propofol had a mean (±SD) sedation score of 1.2 (±0.42) and 1.4 (±0.7), respectively. For midazolam, the score was 2.7 (±0.47) and 4.7 (±1.16) for the low and high sedation levels.



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  		Figure 1. Sedation score during and after the clamping phase. The start of the clamping phase was set at 120 min (the longest time needed for any subject to reach the target sedation level). • = Midazolam high, {circ} = midazolam low, {blacktriangleup} = propofol high, {triangleup} = propofol low. OOA/S = Observer Assessment of Alertness/Sedation scale, WCT = wordstem completion test.

 
Venous propofol concentrations were 1350 ng/mL (±332 ng/mL) for propofol at lower sedation levels (OAA/S level 4), and 1620 ng/mL (±357 ng/mL) at higher sedation (OAA/S level 1). Midazolam concentrations were 208 ng/mL (±112 ng/mL) and 249 ng/mL (±82 ng/mL), respectively. The individual drug concentrations that were associated with these sedation levels, however, differed considerably. In some subjects, similar or even smaller drug concentrations leading to a high sedation level on one occasion, only caused low sedation on another (Table 2). The fact that small differences in drug concentrations were associated with quite distinct levels of sedation is further illustrated by the steep concentration-effect relationships, shown in Figure 2. This average graph also shows the considerable variation and overlap in drug concentrations, associated with a certain sedation level. There were no systematic indications for a time lag or hysteresis in the individual concentration-effect curves.


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  		Table 2. Venous Blood Concentrations During the Clamping Period (Mean of Four Samples) and the Observer Assessment of Alertness/Sedation Scores at the Beginning and End of the Clamping Period for the Six Subjects Who Needed a Higher Concentration to Achieve the Low Sedation Level than the High Sedation Level
 


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  		Figure 2. Relationships between drug concentrations and sedation [Observer Assessment of Alertness/Sedation scale (OAA/S scores)].

 
There was no evidence for explicit memory (no spontaneous recall) during either active treatment, except for one subject who remembered hearing a voice (during the plateau phase with low-level propofol infusion) but did not recall the words spoken. No recall occurred in any other subject during any of the active drug treatments. The mean percentage of correct WCTs are shown in Figure 3. All active treatments produced significant memory impairment compared with placebo (P < 0.05), except for propofol during low sedation, which showed a trend in this direction (P = 0.076). Implicit memory was impaired during low-level sedation (OAA/S level 4) but not completely absent, because WCT frequencies were still 20.5% ± 16.2% with low-level propofol, and 17.6% ± 9.2% with midazolam. This was about twice as high as the spontaneous stem completion frequencies for these words, which were significantly lower at 8.7% (P = 0.038 versus low-level propofol, and P = 0.009 versus midazolam). Implicit memory was statistically nonsignificant during high sedation levels, when the WCT frequencies were 16.2% ± 12.7% with propofol and 11% ± 7.6% midazolam (P = 0.097 and P = 0.362 respectively compared with spontaneous frequencies).



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  		Figure 3. Percentage of correct words in the wordstem completion test for all groups. **Spontaneous versus placebo and low drug levels, P < 0.05; ##placebo versus low midazolam and high drug levels, P < 0.05; placebo versus low propofol, P = 0.076.

 

   Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Different tests have been proposed to test memory functions during states of reduced consciousness. Explicit memory tests usually rely on direct recall of information presented during an experiment, i.e., What do subjects remember? WCTs are often used to assess implicit memory (13). Implicit memory tests are more sensitive than tests of explicit memory (14) and may thus show evidence of memory when explicit tests do not.

Unconscious perception during anesthesia, resulting in implicit memory, may have important implications for postoperative recovery and well-being (15). During full consciousness, defense mechanisms, such as rationalization, are often used. These defense mechanisms are used after, and in response to, an earlier emotional evaluation of the presented information (16).

We found persistence of implicit memory function for neutral words during two different levels of sedation with propofol and midazolam. It is likely that an even stronger implicit memory effect would have been found if we had used emotionally charged statements or words that were meaningful to the individual (17). Negative stimuli, such as stressful situations during the procedure, negating sentences, and denigrating remarks appear to be stored more easily in memory than remarks that are unimportant to the subject (18). During the high sedation level with propofol or midazolam, WCT scores did not differ significantly among the two drugs, or from spontaneous frequencies, indicating that memory impairment is related to the level of sedation, and that propofol and midazolam impair implicit memory to a comparable degree.

A comparison of effects of propofol and midazolam on memory is only valid for similar levels of sedation. Liu et al. (19) found the OAA/S score correlates with bispectral index values during sedation induced with midazolam and with bispectral index values as well as explicit memory during onset and recovery of propofol sedation (20). To avoid an overshoot in drug concentration (too deep sedation), we used a TCI system to produce linearly increasing blood concentrations to reach the desired levels of sedation slowly. In our study, a midazolam target concentration of 600 ng/mL and a propofol target concentration of 3000 ng/mL were set, with the objective of reaching these target concentrations within two hours. By using this method, we ensured that all volunteers would reach the desired sedation level within the given infusion time.

The drug concentrations that were associated with the levels of sedation reached in this study differed considerably among individuals and treatment occasions. A first reason for the poor agreement between drug concentrations and sedative effects is clearly their large variability. There is a considerable interindividual pharmacodynamic variability for both propofol (21) and midazolam (22). Many known factors contribute to this intersubject variability, such as age, comorbidity and comedication. This is clearly illustrated by one subject who showed no signs of sedation at a venous propofol concentration of 1101 ng/mL, whereas another subject was deeply asleep (OAA/S level 1) at 990 ng/mL. Our results stress that intraindividual variability for both drugs is also significant, as illustrated by the subjects shown in Table 2, where higher sedation levels were related to smaller drug concentrations on one occasion and vice versa on another. Although subjects were instructed to maintain a stable life pattern throughout the study, there may still have been considerable day-to-day fluctuations in anxiety, tiredness, motivation, tediousness, and other factors that could particularly affect the relatively low levels of sedation that were studied.

A second reason for these results is illustrated in Figure 2, demonstrating the steep concentration-effect relationships for both propofol and midazolam. Thus, a small increase in (venous) drug concentration can lead to a large decrease in the OAA/S (alertness) score.

The combination of steep concentration-effect relationships with considerable intra- and interindividual variability clearly show that concentration-controlled sedation is unfeasible without concomitant clinical monitoring of consciousness levels. This may be true in particular when infusion algorithms are based on venous, instead of arterial, blood concentrations. Propofol (10), and to a lesser extent midazolam (23), show arteriovenous concentration differences because of rapid distribution of the drugs into the central nervous system and other lipophilic extravascular compartments after IV administration. Consequently, venous blood concentrations are a suboptimal representation of the drug concentrations at the site of action. However, this is particularly relevant after rapid drug infusion, whereas in our study, drugs were infused over one to three hours. Concentration-effect relationships showed no systematic time lag (hysteresis), indicating that the venous blood levels and the central effect compartment reached an equilibrium during slow drug infusion. Thus, it seems unlikely that TCI based on arterial blood concentrations would have been associated with much less pharmacodynamic variability in this study.

In conclusion, we found that there is no significant difference in implicit memory impairment between sedation with propofol or midazolam. However, the effects of midazolam last longer (and may thus appear to be more prominent, clinically), related to its longer elimination half-life. During low sedation levels, implicit memory is largely retained; during high sedation levels, there is little evidence for implicit memory function—at least for neutral words. Both propofol and midazolam showed a wide variability in blood concentrations needed to achieve a certain desired sedation level, because of steep concentration-effect curves combined with considerable inter- and intrasubject variability. Therefore, the use of a standard dosing scheme based on milligrams/kilograms will not always sedate patients to the same extent, and may even under- or overdose the same patient on different occasions. To reduce the chance for inadvertent implicit memory activation, depth of sedation must be assessed frequently by using an appropriate clinical sedation scale. It is also prudent to avoid potentially damaging conversation in the presence of sedated patients.


   Acknowledgments
 
The authors acknowledge the help of Sammy de la Fuenta and Bobby Florea, students at the University of Leiden, during neurophysiological testing. Blood sampling and general care of our volunteers was done by Lizeth Vendrig, research nurse. We also thank Dr. G. Wolters, Psychology Department, Leiden University, for providing validated wordstem lists.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication July 18, 2000.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2000 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press