An evaluation of the amnesic effects of diazepam sedation

CLINICAL J Oral Maxillofac 42:712-716.

ARTICLES

Surg

1994

An Evaluation of the Amnesic Effects of Diazepam Sedation JEFFREY

L. LASKIN, DDS, MS,* AND KELLI G. WILLIAMSON,

BSt

Twenty subjects, 13 female and 7 male, aged 16 to 37 years, were studied to determine the effects on memory of intravenous sedation with diazepam (Valium@). Three tests were performed: 1) the Weschler Logical Memory Scale; 2) memory of three geometric shapes; and 3) memory of three objects presented in a drawing. Logical memory items were presented before and after sedation; other tests were presented after sedation. Anterograde amnesia was produced by diazepam sedation. No retrograde amnesia was observed. A significant drug effect was found between the pre-drug and post-drug retention intervals (Tf = 2; P < 0.005). Post-drug recognition scores were found to be approximately 42% of pre-drug recognition scores. The anterograde amnesia produced with diazepam was probably due to decreased arousal of the subject, and decreased attention to rehearsal of short-term memory stimuli, resulting in a lack of storage of the stimuli.

Intravenous (IV) sedation with diazepam (Valium@), a benzodiazepine, has been used in patient treatment situations, especially dentistry, for nearly two decades. It is used for ambulatory patients because it relieves the anxiety virtually all dental patients experience when undergoing oral surgical procedures, including that from local anesthestic injections, with minimal side effects or complications. Driscoll et al.’ point out that the chief argument for the use of IV sedation (i.e., diazepam) during oral surgery is that at the conclusion of even a technically difficult or traumatic procedure, the amnesic and still euphoric patient is almost always contented. Diazepam has minimal systemic effects when injected intravenously. The results of studies on human subjects have shown that the cardiovascular, respiratory, and secretory phenomena are not modiIied.‘y2 The general effects include rapid tranquilization or somnolence (30 to 90 seconds) manifested as a lack of concern for what is happening. There is also eyelid ptosis and a muscular hypotonicity. However, the patient still reacts to specific

stimuli, so that if there were any possibility of pain during treatment, a local anesthetic would be indicated, because diazepam has little analgesic action.2 The duration of the amnesic effect is 15 to 50 minutes, with a peak effect occurring within 10 minutes,1,3*4 and an average amnesic effect of 24 minutes.5 Gregg et al3 concluded that the amnesic effects of a wide range of doses are probably clinically similar, because they found no significant differences in the percentages of memory at the peak intervals for various dosages. Most investigations have shown that there is no memory deficit for events that happen immediately before injection of the drug.6,7 Thus, diazepam produces anterograde amnesia. Traditionally, anterograde amnesia has been delined as an impairment in the ability to commit ongoing events to memory in the absence of general intellectual deficiency, although memory for earlier events is preserved.8 Explanations of this phenomenon generally emphasize: 1) failure of storage; 2) inefficient acquisition; or 3) impairment in retrieval of stored material, possibly because of interference between relevant and irrelevant memory items.* Anterograde amnesia is explained in terms of an interference in the process of learning. In this model, stimuli initiate a sequence of events in the nervous system that manifest as electrical activity in the brain, a process termed acquisition. At this

Received from the Deuartment of Oral and Maxillofacial Surgery, Universit, of Florida, College of Dentistry, J. Hillis Miller Health Center, Box J-416. Gainesville. Florida 32610. Address cobespondence and reprint requests to Dr. Laskin. * Associate Professor. t Research Associate.

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LASKIN AND WILLIAMSON

point, the stimulus is considered to be in what has been called short-term storage. If a stimulus is to be learned, an interval of short-term storage (from minutes to an hour after the stimulus is received), with an appropriate level of training and the absence of interfering input following training is required. It has been shown that human subjects may forget rapidly during the seconds after a learning trial when the opportunity for rehearsal is prevented.‘O The likelihood of the stimulus being stored for an extended period, called long-term storage, increases with the duration of this shortterm storage activity. Long-term storage is considered to be a chemical and/or physical change in the tissues of the brain, possibly in the vicinity of the hippocampus. ‘,‘l Memory items may be “retrieved” or “called forth” from either short-term or long-term storage. The amnesic effects of diazepam and hypotheses about their cause, using the above model, may be examined with the use of recall and recognition (cued recall) tests for learned stimuli. The essence of a recall test is that the subject must generate the target(s) as defined in the recall instruction. The essence of the recognition test is that one or more potential targets are presented to the subject; there is thus no requirement for overt generation of the target. An example would be the multiple choice test, in which the recognition response consists of choosing the plausible target from distractor items.‘* Several studies have tested the ability of subjects to recall or recognize stimuli presented after diazepam injection. Clark et al.’ and Gregg et al4 concluded that the amnesia results from a deficit in ability to store material, while Peterson and Ghoneim13 concluded that diazepam diminishes the acquisition of novel stimuli. Several studies have concluded that no retrieval deficit is apparent with diazepam sedation.4*7.‘3 This investigation examined the effects of IV sedation with diazepam on memory by assessment of the ability of subjects to recall and/or recognize stimuli presented either in the presence or absence of diazepam sedation. Materials and Methods Subjects

Patients for this study were chosen randomly from patients undergoing third molar extractions. Only those patients who were in the American Society of Anesthesiologists risk category I were included. At an interview approximately a week before surgery, the IV sedation technique and other necessary aspects of the study were described to

the subject, and a signature of informed consent to the study, surgery, and anesthesia were obtained. Twenty subjects, 13 female and seven male, aged from 16 to 37 years, were selected. Procedures

Three groups were studied in this investigation: 1) The experimental group (n = 11) received IV sedation with diazepam, local anesthesia, and oral surgical treatment. 2) The first control group (n = 5) received local anesthesia and oral surgical treatment but no sedation. This group controlled for anxiety or any situational factors related to treatment that may have affected memory assessment. 3) The second control group (n = 4) did not receive IV sedation, local anesthesia, or oral surgical treatment. Three memory tests were given to each group. 1) The Weschler Logical Memory Scale14 consists of four 23-item stories, which are read to the subject two at a time. The story pairs were alternated to control for differences between the stories. Immediate recall was assessed, and the scores for the two pairs were averaged. Recall, as well as recognition from multiple choice arrays, was assessed 24 hours later. 2) Memory for three geometrical figures was assessed by presenting three figures to the subject for 10 seconds each. Twenty-four hours later, the subjects were asked to draw the figures or to recognize them in a multiple choice array. 3) Memory for three objects (i.e., elephant, tub, and flower) was tested by presenting them visually in a single drawing. The subjects were asked to recall the objects immediately. If they could not, they were shown the picture again until they could recall all three objects. Recall was then assessed 24 hours later. The experimental design is outlined in Table 1. The experimental group (Group 1) was read the first pair of logical memory stories 10 minutes prior to sedation to allow time for scoring of immediate recall tests and placement of the IV catheter. They then received diazepam over a course of two minutes until eyelid ptosis (half of the iris being occluded by the upper lid) and/or slurring of speech were apparent. The amount of diazepam did not exceed 30 mg. The subjects then received local anesthetic injections. Five minutes after injection of diazepam, during the peak effect, the subjects were read two other logical memory stories for which immediate recall was recorded. They were also presented three geometrical objects and three objects in the form of a picture. Immediate recall for the objects was recorded. Oral Surgical treatment began immediately after completion of the testing.

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AMNESIC EFFECTS OF DIAZEPAM

Table 1. Experimental Design to Evaluate the Amnesic Effects of Diazepam Sedation in 20 Subjects

Group 1 Group 2 Group 3

- 10 min

0 min

2 min

5 min

10 min

24 hr

Testing*

Diazepam Injection

LOCd Injection

Testingt

Oral Treatment

RKdl Recognition

X

X

X X

X X

x X X

X X X

* Only the first pair of logical memory stories (Weschler Logical Memory Scale) was administered at this time. t All tests were administered to Groups 2 and 3 at this time; all but the first pair of logical memory stories were administered Group 1.

In the first control group (Group 2), all tests were administered (including the first pair of logical memory stories) after the local anesthetic injection. This was immediately followed by oral surgical treatment. In the second control group (Group 3), the tests were administered but no sedation, anesthesia, or oral surgical treatment was given. Scoring for the tests was repeated at 24 hours for all groups. The subjects were asked to recall as many items as possible from all stories, then multiple choice questions were read to the subjects to obtain recognition scores. Next, the subjects were asked to draw the geometrical figures to test for recall and afterward were shown multiple choice answers from which to choose each figure. Drawings were scored as correct if the subjects could reproduce the figure in correct orientation and with appropriate detail (e.g., one dot per square, 16 squares, etc.). The subjects were then asked to recall the three objects in the picture that had been presented.

to

the pre-drug and post-drug recognition scores for Group 1. The scores were found to be significantly different (T+ = 4.5; P < 0.01); recognition of postdrug test items was approximately 42% that of predrug items. Wilcoxon rank sum tests were performed on the immediate (acquisition) scores and the 24-hour recall and recognition scores for the two control groups to determine whether there was a significant effect on the scores due to the local anesthesia injections, oral surgical procedures, or situational factors to which subjects in Group 2 were exposed. No significant differences were found for any of the scores. Wilcoxon rank sum tests were then performed on the acquisition, 24-hour recall, and recognition scores for the control groups (pooled) and the experimental pre-drug group to determine if there were any differences due to extraneous fac-

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The amount of diazepam required for sedation ranged from 0.055-0.083 mg/kg, with a mean dose of 0.070 mg/kg. Altered speech occurred in all sedated patients, and eyelid ptosis occurred in all but one. The results of the memory tests using the three scales are given in Table 2. The Wilcoxon signed rank test of paired differences was performed on the logical memory recall scores for Group 1. In this analysis, the pre-drug (first pair of stories) and post-drug (second pair of stories) scores were analyzed as a function of the retention interval (immediate recall minus 24-hour recall). This corrected for any decreases due to time delay or other arbitrary factors. Scores of immediate and 24-hour recall are displayed graphically in Figure 1 to show the differences in pre-drug and post-drug scores at both times (T+ = 2; P < 0.005). A Wilcoxon signed rank test was performed on

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FIGURE 1. Retention intervals for pre-drug and post-drug logical memory test items. Scores are plotted for immediate and 24hour recall.

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LASKIN AND WILLIAMSON

Table 2. Results of Memory Tests of Oral Surgical Patients *dated Controls (n = g)

24-Hour Testing

Immediate Testing Logical Memory* tx ‘- SD) ReGlll

Group I§ First pair Second pair Group 27 First pair Second pair Group 311 First pair Second pair

3.32 t 11.27 10.73 t 3.71 9.20 t 2.66 9.80 2 2.84 8.63 t 2.10 10.75 + 3.20

with Diazepam (n = 11) and

Geometric Figures+ Three Objectst (x

t

320 320 3ao -

Logical Memory (x t

SD)

Recall/Recognize

SD)

9.46 2 14.62/78.00% 0.00 ? 0.00 132.70% 5.50 k 3.76 166.00% 7.75 k 6.35 /80.00% 2.50 Z!Z1.73 /65.00% 6.50 t 2.74 192.50%

(x

-t

Three Objects

SD)

(x

DGWReCOgIliZe

+ 1.40 t 1.49 2 1.35 + 1.23 k 1.00 2 0.50

0.00 ? 0 11.55 2.20 k 0.0013.00 1.75 -+ 1.53/3.00 -

2 1.79 + 0.00 k 0.00 -

+

SD)

oio 3+-o 320 -

* The Weschler Logical Memory Scale,t4 consisting of two pairs of stones. t Three objects were presented to the subjects as a single drawing. i Three geometric figures were presented to the subjects for 10 seconds each. 8 Group 1 were tested with the first pair of stories of the Weschler scale before sedation. They were then sedated with diazepam. given local anesthetic injection, tested for the second pair of stories and the three objects and given oral surgical treatment. Tests were repeated 24 hours later. The geometric figures test was also given at that time. 11Group 2 followed the same protocol as did Group 1 except that all tests were administered after local anesthetic administration. 11 Group 3 were tested but did not receive sedation or oral surgical treatment.

tors not accounted for. No significant differences were found for the immediate recall or the 24-hour recognition scores (W = 81.5 and 82.5, respectively), but a significant difference was found for the 24-hour recall scores (W = 55.0; P < 0.05). Discussion

Anterograde amnesia resulted from IV sedation with diazepam. This is apparently a drug-induced effect, as a significant difference was found between scores from pre-drug and post-drug testing. No significant differences were found between scores from the control group that underwent oral surgical treatment and those from the control group that did not. Thus, the differences in pre-drug and post-drug scores were not significantly affected by situational factors accompanying oral treatment (e.g., anxiety, local anesthesia, etc.). Additionally, pre-drug recognition scores were not significantly different from control recognition scores; thus, no retrograde amnesia was observed. A difference was observed between pre-drug 24-hour recall scores of the experimental group and 24-hour recall scores of controls, but this was due to the lower scores of the control subjects (the opposite would be the case for retrograde amnesia). The difference observed for 24hour recall was probably due to situational factors: The experimental subjects were tested in the private room where they were to undergo oral surgery, whereas the controls were tested in an open clinic,

and thus may have had more distractions during testing. Another explanation for the lower control group scores is that all logical memory stories were presented to this group at once. Waugh and Norman15 showed that events following the to-beremembered items can produce interference in recall of the items. Thus, the presentation of the second pair of stories may have interfered with the processing of the first pair. Several hypotheses for why diazepam results in anterograde amnesia may be considered. One explanation has been proposed by Wessells*6 from observations of amnesia in patients who have Korsakoff’s syndrome. Although recall of these patients is minimal, their recognition scores are approximately 83% of those of non-Korsakoff patients. Wessells concluded from this that a retrieval deficit produced the amnesia observed in Korsakoff’s syndrome. The findings of the present study were inconsistent with those of Wessells. Recognition of post-drug stimuli was only approximately 42% that of recognition of pre-drug stimuli, and only 52% (logical memory) and 0% (geometric figures) that of control recognition scores. It is apparent, therefore, that the mechanism by which diazepam produces anterograde amnesia must be different than that in Korsakoff’s syndrome. Our explanation for the anterograde amnesia produced by diazepam is based on the presumption that humans have a limit on the amount of stimuli they can process at one time; e.g., the total amount

716 of attention that can be deployed at any time is limited.i7 This is apparent when a person attempts to carry out multiple activities simultaneously. Decreased arousal is also known to decrease memory in humans” so that if, in the drugged state, the patient’s arousal is decreased, attention capacity might also be reduced. This is supported by the findings of this study that acquisition was reduced for post-drug immediate recall items, and also by the findings of Peterson and Ghoneim.13 An additional explanation for the amnesia produced by diazepam concerns processing of stimuli. A person can direct processing in many different ways, concentrating on input through the sense organs or on the processing of internally generated conceptualizations. l7 Perhaps in the drugged state the patient is more easily distracted by irrelevant sensory and internally generated input. This irrelevant input reduces the capacity for processing of, and thus the rehearsal of, relevant stimuli, so that because of this interference, the stimuli are never stored long-term. This explanation is supported by the significant decrease in retention that occurs in the drugged state, and is consistent with the findings of Gregg et al.4 and Clark et al.’ Another possible factor in anterograde amnesia is that learning in the presence of a drug is state-dependent. State-dependent learning or retrieval refers to the concept whereby successful recall of information depends on the reinstatement of the (drugged) condition that existed at the time of acquisition.13 Therefore, if stimuli were presented in the presence of a drug, they would be recalled more readily if the subject were under the influence of the drug at the time of recall.13 This phenomenon has been demonstrated in animals,” and two studies that addressed this effect in humans concluded that diazepam may produce state-dependent learning. However, further work must be done to confirm that such an effect does indeed occur. In summary, sedation with diazepam produced anterograde amnesia, with no apparent effect on

AMNESIC EFFECTS OF DIAZEPAM

retrograde memory. This effect was probably due to a combination of decreased arousal of the subject, resulting in lowered acquisition of stimuli and decreased attention to rehearsal of stimuli in shortterm memory. Consequently, the stimuli are never stored for long-term memory. References 1. Driscoll EG, Smilack ZH, Lightbody PM, et al: Sedation with intravenous diazepam. J Oral Surg 30:332, 1972 2. Bradley BE: The historic use of diazepam in dentistry. Anesthesia Prog March-April: 38, 1981 3. Gregg JM, Ryan DE, Levin KH: The amnesic action of diazepam. J Oral Surgery 32:651, 1974 4. Clarke PRF, Eccersley PS, Fribsy JP, et al: The amnesic effect of diazepam (Valium). Br J Anesth 42:690, 1970 5. Flinn FJ. Wineland P, Peterson LJ: Duration of amnesia during sedation with diazepam and pentazocine: preliminary report. J Oral Surg 33:23, 1975 6. Gelfman SS, Gracely RH, Driscoll EJ, et al: Conscious sedation with intravenous drugs: a study of amnesia. J Oral Surg 26: 191, 1978 7. Clark GE, Glanzer M, Tttrndort H: The pattern of memory loss resulting from intravenously administered diazepam. Arch Neurol 36:296, 1979 8. Seamon JG: Human Memory. New York, Oxford University Press, 1980 9. Deutsch D, Deutsch JA: Short-term Memory. New York, Academic Press, 1975 10. Peterson LR, Peterson MJ: Short-term retention of individual verbal items. Exp Psych 58193, 1959 11. Campbell JL, Sherman AD, Pett F: Diazepam anxiolytic activity in hippocampus. Psychopharmacol Comm 4:387, 1980 12. Brown J: Recall and Recognition. New York, John Wiley and Sons, 1976 13. Peterson RC. Ghoneim MH: Diazepam and human memory: influence on acquisition, retrieval, and state-dependent learning. Prog Neuropsychopharmacol4:81, 1980 14. Weschler D, Stone CP: Weschler memory scale. J Psych 19:87, 1945 15. Waugh NC, Norman DA: Primary memory. Psycological Review 72189, 1965 16. Wessells MG: Cognitive Psychology. Philadelphia, Harper and Row, 1982 17. Norman DA: Memory and Attention. New York, John Wiley and Sons, 1976 18. Overton DA: Discriminable effects of benzodiazepines. Psychonharmacol Comm 2:339, 1976 19. Liljequist R, Linnoila M, Mattila MJ: Effect of diazepam and chloropromazine on memory functions in man. Europ J Clin Pharmacol 13:339, 1978