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Midazolam attenuates ketamine-induced abnormal perception and thought process but not mood changes

Manzo Suzuki, MD^*, Kentaro Tsueda, MD^*, Peter S. Lansing, MD^*, Merritt M. Tolan, MD^*, Thomas M. Fuhrman, MD^*, Rachel A. Sheppard, BS^*, Harrell E. Hurst, PhD and Steven B. Lippmann, MD

^* From the Departments of Anesthesiology,
Pharmacology and Toxicology and,
Psychiatry, University of Louisville School of Medicine, Louisville, KY, USA.

Address correspondence to: Kentaro Tsueda MD, Department of Anesthesiology, University of Louisville, Louisville, KY 40292, USA. Phone: 502-852-5851; Fax: 502-852-6056; E-mail: rashep01{at}gwise.louisville.edu

	Abstract

TOP Abstract Introduction Materials and Methods Results Discussion References

 
Purpose: To determine the effects of midazolam, 30 ng·mL^–1, on altered perception, mood, and cognition induced by ketamine.

Methods: After ketamine was administered to achieve target concentrations of 50, 100, or 150 ng·mL^–1 in11 volunteers, perception, mood, and thought process were assessed by a visual analog scale. Mini-Mental State examination (MMSE) assessed cognition. Boluses of midazolam, 30, 14.5, and 12 µg·kg^–1, were injected every 30 min to maintain the plasma concentration at 30 ng·mL^–1, which was reached 30 min after each injection.

Results: Ketamine produced changes in perception about the body (P < 0.01, 0.001, and 0.0001 at 30, 60, and 90 min), surroundings (P < 0.01 and 0.0001 at 60 and 90 min), time (P < 0.002 and 0.0001 at 60 and 90 min), reality (P < 0.001 and 0.0001 at 60 and 90 min), sounds (P < 0.002 at 90 min), and meaning (P < 0.05 at 90 min). Subjects felt less energetic and clearheaded (P < 0.02 and 0.05) during ketamine, midazolam, and their co-administration. Ketamine impaired thought process (P < 0.003 and 0.0001 at 60 and 90 min). Ketamine and midazolam decreased mean total MMSE and recall scores (P < 0.001 for both). Co-administration reduced the number of subjects with perceptual (body, P < 0.01 and 0.001 at 30 and 60 min) and thought process abnormalities. Within the range of observation, co-administration did not affect the changes in mood or recall.

Conclusion: Midazolam attenuates ketamine-induced changes in perception and thought process.

	Introduction

TOP Abstract Introduction Materials and Methods Results Discussion References

 
NMETHYL-D-ASPARTATE (NMDA) receptors are located predominantly in the cortex, basal ganglia, and the structures associated with sensory systems and are important in corticofugal and corticocortical interaction.¹ It has been suggested that NMDA-receptor mediated synaptic potentiation may be an essential process involved in memory and learning¹ as well as the development of sensory systems.² Ketamine, an NMDA receptor antagonist, activates the thalamic and limbic systems with concomitant depression of thalamo-neocortical pathways,³ and increases cerebral oxygen consumption⁴ and hippocampal glucose utilization.⁵ At anesthetic doses (1 - 3 mg·kg^–1), ketamine may produce unpleasant dreams or psychotomimetic symptoms in more than one-third of patients on emergence from anesthesia.⁶ At subanesthetic doses (100 - 500 µg·kg^–1), ketamine impairs some domains of cognition (vigilance and memory),^2,7,8 alters mood states,^7–9 and produces a dose-related impairment of sensory perception or sensory integration in healthy human volunteers.^7–9 Perceptual and mood changes at higher ranges of analgesic doses (e.g., 500 µg·kg^–1) are shown to resemble some aspects of psychosis, as in schizophrenia, and are associated with dysphoria.⁷

Recently, low-dose ketamine has been used together with midazolam, a competitive agonist for the subreceptor of the -aminobutyric acid (GABA_A) receptor, and an opioid for sedation and analgesia during monitored anesthesia care. Benzodiazepines are reported to reduce psychotomimetic manifestations during the emergence from ketamine anesthesia.⁶ However, it is not clear whether benzodiazepines attenuate changes in perception, mood, and amnesia or affect the level of sedation induced by low-dose ketamine. We studied the effects of midazolam on the changes in perception, mood, and cognition, as well as on the sedation produced by low-dose ketamine.

	Materials and Methods

TOP Abstract Introduction Materials and Methods Results Discussion References

 
Eleven male volunteers were recruited for this randomized, double-blind, cross-over study. Age ranged from 27 to 45 yr. Body weight was 91 ± 14 (SD) kg and height was 180 ± 7 cm. None of the subjects had psychiatric diseases, psychological problems, systemic illness, drug dependence, or used medicines that affect the central nervous system. Institutionally approved, written informed consent was obtained from each subject. All subjects had four sessions, each at least one week apart, in which perception, mood, and cognition were evaluated: 1) while receiving normal saline; 2) at plasma ketamine target concentrations of 50, 100, and 150 ng·mL^–1; 3) at a plasma midazolam concentration of approximately 30 ng·mL^–1; and 4) during co-administration of ketamine at target concentrations and the midazolam target concentration, 30 ng·mL^–1. Each subject was randomly assigned, according to a computer generated schedule, to a different order in which drug regimens were studied. One of the investigators, who did not participate in the assessment of patients, prepared 10 mL syringes containing normal saline or normal saline with midazolam, and a 30 mL syringe containing normal saline with or without ketamine 0.25%.

To obtain target plasma concentrations, ketamine at a concentration of 2,500 µg·mL^–1 was infused using a Harvard pump 22^TM (Harvard Apparatus, Holliston, MA) controlled by the Stanpump program (Steven L. Shafer, M.D., Department of Anesthesiology, Stanford University) based on pharmacokinetic data.¹⁰ Three target concentrations were maintained for 30 min at each level. Four boluses of midazolam, 30, 14.5, and 12 µg·kg^–1, were injected every 30 min, to attain a plasma concentration of 30 ng·mL^–1, 30 min after each injection.¹¹

Perceptual change was assessed using a visual analog scale (VAS) in eight categories (i.e., body, surroundings, time, reality, colours, sound, voices [e.g., I hear voices that are unreal], and meaning [e.g., events, objects, and people have particular meaning for me]).⁹ The VAS was anchored by "not at all" at one end and "extremely" at the other. Mood was assessed using a similarly scaled VAS in 6 subsets of mood states (anxious-composed, hostile-agreeable, depressed-elated, unsure-confident, tired-energetic, and confused-clearheaded).⁹ Cognition was evaluated using the Mini-Mental State Examination (MMSE, 0 - 30),¹² which assessed five areas of cognitive function (i.e., orientation [0 - 10], registration [0 - 3], recall [0 - 3, attention [0 - 5], and language fluency [0 - 9]). Thought process and the content of thought were assessed using a similarly anchored VAS (i.e., I have difficulty in concentrating on a thought and/or have flight of ideas).⁹ Paranoia was assessed using the VAS to measure suspicion (i.e., I had suspicious ideas or beliefs that others were against me).⁹

Sedation was assessed by the Observer's Assessment of Alertness/Sedation (OAA/S) score: 5 = responds readily to name spoken in normal tone; 4 = lethargic response to name spoken in normal tone; 3 = responds after name is called loudly and/or repeatedly; 2 = responds after mild prodding or shaking; and 1 = does not respond to mild shaking.¹³ Subjective sense of drowsiness was assessed by a VAS in which the worst drowsiness was defined as when subjects could barely keep their eyes open.^2,9

Plasma ketamine and midazolam concentrations were measured using capillary gas chromatography with nitrogen-selective detection by adapting previously published methods for ketamine¹⁴ and midazolam.¹⁵ Phencyclidine and flurazepam, respectively, were used as internal standards. Limits of detection for both drugs were 1 ng·mL^–1. Limits for quantification were set at 10 ng·mL^–1; at this low concentration the assay exhibited coefficients of variation of 4 and 12% for the drugs, respectively.

In a quiet isolation room, an antecubital vein was cannulated for infusion in an arm in the first four patients. Both antecubital veins were cannulated for infusion and blood samples in the last seven subjects. After a rest for 20 to 30 min, baseline data were obtained on perception, mood states, cognition, paranoia, and sedation. According to the assignment, subjects received a 10 ml bolus injection over 20 sec of normal saline with or without 30 µg·kg^–1 midazolam, and infusion of normal saline or ketamine 0.25% to attain a plasma concentration of 50 ng·mL^–1. A bolus of normal saline or midazolam, 14.5 and 12.0 µg·kg^–1, was repeated every 30 min. Ketamine infusion rate was increased step-wise every 30 min to attain target plasma concentrations of 100 and 150 ng·mL^–1. Assessments of perception, mood, cognition, paranoia, and sedation were repeated 24 min after each injection. A blood sample was obtained after each assessment. A measure of electroencephalogram (EEG) (i.e., bispectral index [BIS]) was monitored using Aspect A-1000 EEG Brain Monitoring System^TM (Aspect Medical Systems, Natick, MA) with the system bandpass set at 1 Hz and 30 Hz and the electrode impedance kept below 5 kOhm (at 12 Hz). Electrocardiogram and arterial oxygen saturation were monitored. Non-invasive blood pressure (BP, mm Hg), heart rate (HR, bpm), and respiratory rate (RR, /min) were recorded every five minutes. Dysphoria was to be treated by 1-2 mg midazolam, i.v.

Differences among groups in VAS scores for mood states, subjective sense of drowsiness, MMSE scores, OAA/S scores, vital signs, and EEG measures (mean values of 60 epochs) were tested by two-way within subjects, multivariate, repeated measures analysis of variance using baseline values as a covariate. Where applicable, the data were further analyzed using the Sidak multiple comparison method.¹⁶ Mood and BIS scores were further tested for trend over time using the SAS-PROC-MIXED (repeated measures) test. VAS values measuring perception, thought process, and suspicion were dichotomized into scores of zero (non-responder) and one (responder). The dichotomized values were analyzed using Cochran's Q statistics at 30, 60, and 90 min. P < 0.05 was considered to be statistically significant.

	Results

TOP Abstract Introduction Materials and Methods Results Discussion References

 
There was a small increase in systolic and diastolic BP during ketamine infusion (P < 0.0001 and P < 0.001) (Table I). There was no change in HR during ketamine infusion. Midazolam reduced HR (P < 0.05), but produced no change in BP. There were no changes in BP or HR during co-administration. There was no group difference in RR.

There were differences among the drug regimens in the number of subjects having perceptual abnormality in six out of eight categories (i.e., body, surrounding, time, reality, sound, and meaning) (Table II). More subjects experienced the abnormality at higher plasma ketamine concentrations. They felt heavy, light, moving, floating and/or undulating, and stated that the entire or a part of the body was tingling, or that a part of the body was out of proportion in size, displaced or absent. One subject thought his right hand was his left hand and vice versa. Two subjects felt their body was so heavy that they were unable to lift a hand. Perceptions of surroundings were described as spinning, in slow motion, smaller in appearance, or that the surroundings appeared as if on a scroll. Time was felt to pass faster or slower, or to have stopped. The subjects described colour as brighter, less bright, or blending. Sound was described as far away, louder, clearer, or amplified. Our subjects felt "weird," "strange," and/or "detached," and some felt that the reality was a slow-motion dream. Two subjects thought they were dreaming of riding a comet and a spaceship. Neither placebo nor midazolam produced perceptual change, except for one subject receiving midazolam who felt sounds were unusually loud. Coadministration of midazolam attenuated the ketamine-induced change in body perception (P < 0.01 and 0.001 at higher ketamine target concentrations). Although differences were not statistically significant in the other five categories, the numbers of subjects with perceptual changes were lower during the coadministration than they were during the infusion of ketamine alone (Figure 1). None had dysphoria, hallucinations, or psychotic symptoms.

View larger version (39K): [in this window] [in a new window]   FIGURE 1 the number of subjects having perceptual abnormality. = midazolam administration, = ketamine infusion, and = coadministration. aP < 0.01 and bP = 0.001 vs placebo, midazolam, and coadministration. cP = 0.0001, dP <0.01, and eP = 0.01 vs placebo and midazolam. fP < 0.05 vs placebo, midazolam, and coadministration. *ketamine, 45 ± 15 (SD) ng·mL–1; midazolam, 32 ± 6 ng·mL–1; ketamine, 59 ± 13 ng·mL–1 and midazolam, 32 ± 7 ng·mL–1 during coadministration. ketamine, 93 ± 29 ng·mL–1; midazolam, 29 ± 11 ng·mL–1; and ketamine, 103 ± 25 ng·mL–1 and midazolam, 35 ± 9 ng·mL–1 during coadministration. ketamine, 146 ± 34 ng·mL–1; midazolam, 29 ± 12 ng·mL–1; and ketamine, 158 ± 35 ng·mL–1 and midazolam, 32 ± 11 ng·mL–1 during coadministration.

There was a difference in the mean total MMSE score (P < 0.01). The mean recall score was lower during administration of ketamine, midazolam, or co-administration than during the placebo run (P < 0.01) (Table III). There were no changes in the scores for registration, orientation, attention, and language fluency. The number of subjects having abnormal thought process increased, however, during ketamine infusion in a dose-dependent manner (P < 0.003 and P < 0.0001 at 60 min and 90 min assessment, respectively). The subjects described their thoughts as "flight of ideas," "my thoughts are faster, busy, racing, or jumping," or "scenes from movies or past events keep popping into my head." Two subjects stated their thoughts slowed down transiently. Neither placebo nor midazolam produced a thought disorder. Co-administration reduced the number of subjects having ketamine-induced changes in thought process by 50% (Figure 2). Those who continued to have abnormal thought processes described their thoughts as floating, fleeting, blending, or finding it difficult to concentrate. Neither midazolam, ketamine, nor the co-administration produced changes in the suspicion (i.e., paranoia) score.

View larger version (36K): [in this window] [in a new window]   FIGURE 2 The number of subjects having abnormal thought processes. = midazolam administration, = ketamine infusion, and = coadministration. aP < 0.01 and bP = 0.001 vs placebo and midazolam. *ketamine, 45 ± 15 (SD) ng·mL–1; midazolam, 32 ± 6 ng·mL–1; ketamine, 59 ± 13 ng·mL–1 and midazolam, 32 ± 7 ng·mL–1 during coadministration. ketamine, 93 ± 29 ng·mL–1; midazolam, 29 ± 11 ng·mL–1; and ketamine, 103 ± 25 ng·mL–1 and midazolam, 35 ± 9 ng·mL–1 during coadministration. ketamine, 146 ± 34 ng·mL–1; midazolam, 29 ± 12 ng·mL–1; and ketamine, 158 ± 35 ng·mL–1 and midazolam, 32 ± 11 ng·mL–1 during coadministration.

	Discussion

TOP Abstract Introduction Materials and Methods Results Discussion References

Dose-related perceptual alterations observed during ketamine infusion were not quantitative but were all qualitative. A sensation that a part of the body was missing, displaced, or the inability to tell the left hand from the right in our subjects is consistent with tactile agnosia, which is associated with a lesion in the posterior parietal lobe.¹⁷ These alterations indicate that ketamine affected a large area of sensory association cortices in our subjects, and that perceptual impairment induced by low-dose ketamine may involve the process of sensory integration.⁷ It has been shown that ketamine produces electroencephalographic ictal activity of the neocortex, thalamus, and hippocampus, and markedly increases the evoked potentials of the sensorimotor and visual cortex of cats.³ Ketamine increases porcine cerebral oxygen consumption⁴ and hippocampal glucose metabolism in rats,⁵ and has been reported to induce seizure activity in patients with temporal lobe epilepsy.¹⁸ Midazolam antagonizes the increase in oxygen consumption⁴ and the seizure activity produced by ketamine. These findings as well as the midazolam-induced attenuation of perceptual alterations observed in our subjects appear to be consistent with the concept that NMDA receptors may modulate functions of cortical and subcortical structures in adults.²

The striatal complexes (i.e., dorsal and ventral striatum and pallidum) have been recognized as a powerful inhibitory structure on the thalamus and the ascending reticular formation. Stimulation of the glutamatergic corticostriatal projection inhibits the thalamus and reticular nuclei, leading to reducted sensory transmission to cerebral cortices as well as a reduced state of arousal, whereas dopamine exerts an inhibitory influence on the striatal neurons, thus counteracting the inhibitory influence of the striatal complexes on the thalamus and the reticular formation.^19,20 When the sensory transmission becomes excessive (e.g., the NMDA-receptor antagonist), the integral capacity of the cortex may break down, and confusion or psychosis may ensue. Reduction in dopaminergic (D₂) function (e.g., the D₂-receptor antagonist) results in inhibition of motor and mental activity. Recent studies have also shown antagonistic interactions between the NMDA-receptor and the serotonergic, as well as noradrenergic and muscarinic activities.²⁰

Subanesthetic doses of ketamine and its enantiomers have been shown to produce a feeling of "high" and to be anxiolytic at low doses, but anxiogenic at higher doses.^2,7 The similarity in the "highs" produced by ketamine and alcohol intoxication has been attributed to the NMDA receptor antagonist property of both drugs.⁷ Our subjects described mood during ketamine infusion as "high,' while midazolam did not produce a state of "high," and the co-administration did not affect ketamine-induced positive mood, suggesting that ketamine and midazolam involve different mechanisms for mood alteration. The mechanism for ketamine-induced mood alteration is not clear. It is possible that increased thalamic sensory output to cerebral cortices secondary to ketamine-induced blockade of the corticostriatal glutamatergic pathway^19,20 and a possible interaction with the serotonergic system, may have contributed to the ketamine-induced mood alteration.²⁰

It has been suggested that NMDA receptor-induced long-term synaptic potentiation in the hippocampus and subsequent protein synthesis may be the mechanism underlying the formation of short-term, intermediate-term, and long-term memory in vertebrates.²¹ Reports in humans have shown that ketamine impairs post-distraction and delayed word recall,^2,7,8,22 but may²² or may not^7,8 affect immediate recall. A 24-word task has shown impaired immediate recall but preserved recognition memory, suggesting that ketamine may impair retrieval of information.²² Although it was suggested that observed discrepancies on immediate recall may be due to the level of the challenge the tasks impose and also ketamine-induced attention deficit,⁷ a later study with a less challenging task failed to detect impaired retrieval.² Further, a recent study showed that ketamine-induced memory impairment was not related to concomitant attentional and behavioural changes.⁸ Thus, ketamine appears to impair early phases of memory formation, relatively sparing encoding and short-term memory. A benzodiazepine, on the other hand, has been considered to impair consolidation of newly acquired information through reduction in long-term potential, mediated by its action on the GABA_A receptor.²³ In our subjects, the MMSE showed impairment in post-distraction recall during ketamine or midazolam administration. Although midazolam did not increase ketamine-induced amnesia, a recent study reported that lorazepam increased the amnestic effect of ketamine.²⁴ The small number of subjects in our study may be a factor in the lack of a statistical significance.

Ketamine has been shown to induce frontal lobe dysfunction (i.e., executive cognitive function, verbal fluency, and vigilance) in volunteers.^7,8 A thought disorder observed in our subjects during ketamine infusion was consistent with flight of ideas, a form of disorganized thought, which occurs in hyperadrenergic states (e.g., stimulant overdose and sedative withdrawal), anxiety and agitation, as well as in psychotic and manic presentations,²⁵ suggesting that the thought disorder in our subjects may have been a manifestation of excitatory phenomenon. Benzodiazepines are usually effective for the treatment of hyperadrenergic states, anxiety, and agitation.²⁶ The thought disorder in our subjects was attenuated by midazolam. Of interest in this context was a recent study that showed amelioration of ketamine-induced impairments in executive cognitive functions by co-administration of haloperidol, a D₂-receptor antagonist, suggesting the possibility that ketamine-induced frontal lobe symptoms and disorganized, hyperactive thought may, at least in part, involve the striatal system.²⁷

The absence of additive effect on the level of sedation during the co-administration suggests that ketamine and midazolam induce sedation by different mechanisms. In our subjects, ketamine produced active thoughts and awake level BIS, while midazolam-induced sedation was associated with quiet thought and a decline in BIS, although the levels of sedation were similar. During the coadministration, the thought status and BIS were between those obtained during the administration of ketamine and midazolam alone. The mechanism by which ketamine induces sedation is not known. However, association of hyperactive thought process with sedation observed in our subjects and the observations that subjects were rather awake than sleepy while receiving subanesthetic doses of ketamine⁷ may be consistent with arousal and increase in the thalamocortical activity mediated by the striatal mechanism.^17,18 Presynaptic inhibition of the GABA receptor²⁸ may also be a possible contributor to the lack of increase in sedation during the coadministration.

Our results suggest that midazolam attenuates perceptual abnormalities and thought disorder induced by low-dose ketamine without changes in sedation or drowsiness. The results also suggest that midazolam may not affect ketamine-induced amnesia or changes in mood.

	Acknowledgments

 
The authors gratefully acknowledge Hoffman-La Roche for a gift of analytical grade midazolam, which was used for standardization of the gas chromatographic assay. We thank Robert L. Vogel PhD for his help in statistical analysis and Hassan Shahab MD for editorial advice.

Accepted for publication June 15, 2000.

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This Article Abstract Résumé de cet Article Full Text (PDF) Submit a scholarly reply Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Suzuki, M. Articles by Lippmann, S. B. Search for Related Content PubMed PubMed Citation Articles by Suzuki, M. Articles by Lippmann, S. B. Related Collections General Anesthesia