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 Table of Contents  
ORIGINAL ARTICLE
Year : 2017  |  Volume : 7  |  Issue : 1  |  Page : 7-12

Does midazolam produce retrograde amnesia in surgical patients?


Department of Anesthesia, Ahmadu Bello University Teaching Hospital, Shika, Zaria, Nigeria

Date of Web Publication4-Apr-2018

Correspondence Address:
Dr. Saidu Yusuf Yakubu
Department of Anesthesia, Ahmadu Bello University Teaching Hospital, Shika, Zaria
Nigeria
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ais.ais_6_17

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  Abstract 


Background: Midazolam is the commonest benzodiazepine used in anesthesia for premedication, induction, and maintenance of anesthesia. The popularity of midazolam in many clinical situations is because of its rapid onset, nonpainful injection, lack of venous irritation, and production of anterograde amnesia. This study was to determine whether or not immediate retrograde amnesia can be produced with intravenous midazolam and to elicit the extent of amnesia seen in adult patients given midazolam at induction.
Patients and Methods: Eighty consenting American Society of Anesthesiology I and II patients between the ages of 18 and 60 years scheduled for nonmajor elective surgical procedures under general anesthesia were randomly allocated to one of four study groups: m2 (midazolam 2 mg), m5 (midazolam 5 mg), m7 (midazolam 7 mg), or m0 (normal saline). Visual recognition and recall was tested using 12 picture cards, each with an easily recognizable image.
Results: Recognition and recall rates did not differ between the groups up to the time of drug injection. However, there was a deterioration in visual recall (P < 0.001), orientation in time and event recollection (P < 0.001), and mean sedation score (P < 0.001) on administration of study drug when compared with control. There was a statistically significant anterograde amnesia for pictures seen after administration of midazolam (P = 0.000). There was no evidence of retrograde amnesia (P > 0.3).
Conclusion: Intravenous midazolam does not cause retrograde amnesia, however, it causes anterograde amnesia based on dose administered.

Keywords: Amnesia, anterograde, midazolam, retrograde, surgical patients


How to cite this article:
Yakubu SY. Does midazolam produce retrograde amnesia in surgical patients?. Arch Int Surg 2017;7:7-12

How to cite this URL:
Yakubu SY. Does midazolam produce retrograde amnesia in surgical patients?. Arch Int Surg [serial online] 2017 [cited 2021 May 15];7:7-12. Available from: https://www.archintsurg.org/text.asp?2017/7/1/7/229182




  Introduction Top


Midazolam is the commonest benzodiazepine used in anesthesia for premedication, induction, and maintenance of anesthesia. It is of the benzodiazepine class and acts through the gamma-amino butyric acid neurotransmitter.[1] Midazolam can be administered intravenously or intramuscularly. When given intravenously it acts within 5 min. When injected into a muscle it can take 15 min to act. Effects last between 1 and 4 hours. Side effects include respiratory depression and hypotension.[2]

Midazolam is a sedative drug with amnesic properties, and previous studies have shown that anterograde, not retrograde amnesia, can be demonstrated with midazolam.[3],[4] Amnesia is a condition in which memory is disturbed or lost. Anterograde amnesia is the impairment or loss of ability to form new memories through memorization.[5]

In retrograde amnesia, an individual's memories are lost to conscious recollection, beyond a normal degree of forgetfulness. The drug could be used in the unfortunate scenario where a patient experiences a painful or distressing event in the immediate preinduction period, such as repeated intravenous (IV) cannulation and lumbar punctures.[6] There is one report in the literature where midazolam was found to have anterograde as well as retrograde properties,[7] but this has not been substantiated because it was an accidental finding during a case of laparoscopic cholecystectomy published as a case report.

This study seeks to determine the occurrence of immediate retrograde amnesia following IV administration of midazolam before induction of general anesthesia (GA) in elective adult surgical patients.


  Patients and Methods Top


This study was a prospective, controlled, double-blind, randomized clinical research carried out with approval of the Ethics Committee of the hospital. Informed consent was obtained by the researcher from all patients selected to participate in the study. Included in the study were American Society of Anesthesiology (ASA) I or II adult patients between the ages of 18 and 60 years scheduled for elective minor-to-moderate surgery under GA. Excluded were ASA physical status class III or higher, age >60 years or <18 years, recent (<24 h) sedative or hypnotic administration, visual or hearing disorder, known or suspected memory impairment, recent head trauma, pregnancy, recent attack of epilepsy or antiepileptic medications, or objection to study.

Sample size

Cohen's [8] table was used to determine the sample size.

Randomization and blinding

To avoid bias and ensure equal chance of allocation of participants to the study group, computer-generated randomization method was used using the WinPepi statistical software, version 11.19 of 2012 by Abramson.[9]

Eligible patients were randomly assigned to one of four study groups according to the computer-generated random sequence. The principal investigator and patients were blinded to the treatment assignment.

Study design

The study was performed in the operating theatre with measurements commencing 12 min prior to induction of anesthesia based on a previous study by Bulach et al.[10]

The vital signs: heart rate (HR), mean arterial pressure (MAP), respiratory rate (RR), and oxygen saturation (SPO2) were taken on arrival of the patient to the operating room and at 5 min interval during the administration of anesthesia. An anesthetist not involved in the provision of anesthesia prepared the study medication.

The study drug was diluted with normal saline and administered as a 10 ml IV bolus at time T4 to each of the 20 patients in the four groups: m2 (midazolam 2 mg), m5 (midazolam 5 mg), m7 (midazolam 7 mg), and m0 (10 ml normal saline).

Induction of anesthesia commenced 8 min (time T12) after the injection of midazolam. No other sedative premedication was given.

Picture recognition and recall

Visual recognition and recall was tested using 12 picture cards each with an easily recognizable simple picture. Memory using picture cards were used to evaluate explicit recall. No test of implicit (subconscious) memory was performed.

Each patient was shown as a series of six (6) identical picture cards at 4 min (T0), 2 min (T2), 1 min (T3), 0 min (T4) before the injection of study drug and at 4 min intervals after study drug administration for 8 min. Patients were asked to identify each picture at the time of visual presentation after inspecting it for 1 minute. Specific events and their recall were incorporated into the study to determine whether IV midazolam would improve a patient's experience in the operating room by limiting recall of unpleasant events.

Anesthetic management of patients

Induction of anesthesia commenced from time T12(8 min after administration of study drug) and consisted of IV propofol titrated to loss of eye lash reflex and suxamethonium to facilitate endotracheal intubation. Maintenance of anesthesia was with oxygen, halothane 0.8–1%, pancuronium 0.1 mg/kg, and intermittent positive pressure ventilation. Intraoperatively, analgesia was achieved with pentazocine 0.5 mg/kg. The patient's HR, MAP, RR, ETCO2, and SPO2 were monitored every 5 min using a Dash 4000 (GE) multiparameter monitor and recorded on the anesthetic chart. For the purpose of this study, there was no data collection as soon as anesthesia was induced until 4 h after discharge from the recovery room according to a previous study by Bulach et al.[10]

At the end of surgery anesthesia was reversed with IV atropine 0.02 mg/kg and neostigmine 0.05 mg/kg. Patients were extubated awake after they had regained full consciousness and then transferred to the recovery room. Monitoring and recording of HR, MAP, RR, and SPO2 continued every 5 min in the recovery room until patients were discharged to the ward.

Assessment of level of sedation at time T12, 4, and 0 min, time of awakening, and 4 h after discharge from the recovery room

Sedation depth was determined by the Observer's Assessment of Alertness/Sedation (OAA/S) scale.[11] The OAA/S scale provides a higher discriminatory power of the different levels of sedation than the bispectral index.[12]

The degree of sedation of the patient was noted at times T0(4 min before administration of midazolam), T8(4 min after administration of midazolam), and T12(8 min after study drug administration), time of awakening as well as during the postoperative assessment 4 h after discharge from the recovery room. For the purpose of this study, an OAA/S score of 2–5 was used.

Test of patient recall of pictures, procedures, or events

Postoperatively, 4 h after discharge from the recovery room patients were shown 12 pictures (including the six preoperative pictures) and asked to identify and recall those seen preoperatively.

Patients were asked to recall a fictitious event such as a finger prick. This test was introduced as a control at the time of study drug administration to identify false reporting by the patients.

Data collection and analysis

The following patient and surgery characteristics were recorded: Age in years, weight in kg, height in cm, ASA physical status, type of surgery, duration of operation in minutes, level of sedation by OAA/S, propofol induction dose in mg, pentazocine in mg, and halothane in %. Time to awakening (from the administration of reversal to readily respond to name spoken in normal tone) was also recorded.

All memory data were analyzed using the analysis of variance (ANOVA). Categorical variables were compared using Chi-square (χ2). A two-sided P< 0.05 was considered statistically significant. All analysis was done with Statistical Package for the Social Sciences for Windows version 18.


  Results Top


Eighty (80) adult patients between the ages of 18 and 60 years who were classified as ASA I or II undergoing minor-to-moderate elective surgery were enrolled in this study. None of the patients recruited had reason to be excluded from the study.

Patient's demographic and clinical characteristics were similar in the four study groups [Table 1].
Table 1: Patients demographic and clinical characteristics

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ANOVA between the means of age, weight, height, and ASA status between the groups did not reveal any statistically significant difference (P value >0.05). Although there were more ASA I than ASA II patients in all groups, the difference was not statistically significant (P > 0.190).

There was no difference in OAA/S scores in the four study groups until the administration of the study drug. However, there was a decrease in OAA/S scores with increasing dose of midazolam [Figure 1].
Figure 1: The level of sedation of patients at time T12

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All patients were able to recall seeing preoperative pictures 1, 2, and 3, except for one of the patients in m5. One patient each in the control group and m2 were not able to recall seeing preoperative picture 4 (time of study drug administration). Three patients in m5 were not able to remember seeing preoperative picture 4. Two patients in m7 could not recall seeing preoperative picture 4 [Table 2]. These differences were not statistically significant (P > 0.3).
Table 2: Visual recall of preoperative pictures

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All 20 patients in the control group visually recalled seeing preoperative pictures 5 and 6 shown after the study drug administration. Two patients in m2 recalled seeing preoperative picture 5. All other patients were not able to recall seeing preoperative pictures 5 and 6. The tests for anterograde amnesia were statistically significant (P = 0.000). All patients who received midazolam except one in m5 and three in m7 were able to recall specific events up to the time of mask preoxygenation at time T4. None of the patients recalled the fictitious finger prick. All 20 patients in the control group recalled specific events. One patient in m2 was able to recall being asked to squeeze his eyes shut and then open them.

All other patients were not able to recall specific events from time T8 until induction of anesthesia. This inability to recall events after the study drug administration was statistically significant (P = 0.000).


  Discussion Top


In this study, there was no statistically significant difference in patient demographics and clinical characteristics in terms of age, weight, height, ASA status, and preinduction vital signs between the study groups. There is therefore a good basis for comparison of data obtained among the four study groups.

This study has shown that the benzodiazepine, midazolam, produces deeper level of temporary anterograde amnesia. This is in agreement with the findings of Hirshman et al.,[13] who demonstrated that administering midazolam prior to showing of pictures reduced free recall from an average of 12 items to an average of one or none with many participants recalling no items.

Given intravenously, midazolam causes a rapid onset of amnesia allowing for short intervals between drug administration and the showing of pictures (e.g., 1–2 min).[14] There is evidence that recognition can be based on either the retrieval of episodic information or the backup process of familiarity.[15] Research with amnesic patients and with normal subjects under the influence of a drug that produces temporary amnesia suggests that the recollective process, not the familiarity-based process, is specifically vulnerable to anterograde amnesia.[16]

This study could not show retrograde amnesia with IV midazolam 2–7 mg when injected just before the induction of anesthesia. Reported data showed that there was no evidence of retrograde amnesia. At time T3 only one patient in m5 could not recall picture shown (P > 0.3). There was also no significant difference in the rates of recall up to the time of study drug administration. After the administration of study drug, each midazolam group recalled fewer pictures than the control group and a significant dose–response effect were demonstrated. Only 2 patients in m2 and the control group recalled pictures shown at time T8(P = 0.000). The sedative and amnesic effects of midazolam became evident within 4 min after administration, as the patients could neither recall pictures shown nor the event of squeezing their eyes shut and opening them at time T8. This is similar to the findings of a previous study by Bulach et al.,[10] in which there was a dose-dependent deterioration in visual recall (P = 0.002) and event recollection (P< 0.001).

Twersky et al.[17] in their study on amnesia in pediatric surgical patients also found that compared to placebo, the midazolam group experienced a significant postoperative reduction in ability to both recall (P< 0.003) and recognize cards (P< 0.001) shown subsequent to midazolam or placebo administration (anterograde amnesia). In distinction, there was no difference between groups in postoperative ability to recall or recognize cards shown prior to midazolam or placebo administration (retrograde amnesia).

Retrograde events recall were not significantly different between study groups (P > 0.098). Anterograde events recall demonstrated a significant dose effect of midazolam. Only one patient in m2 and those in the control group could recall events (P = 0.000). In m5 and m7 more than 75% of patients could recall preoxygenation via facemask, which commenced at time T4 and continued until induction of anesthesia. This is similar with the results of a previous study in which >50% of patients in the midazolam 5 and 10 mg groups remembered mask preoxygenation [8] (P< 0.0005).

Various tests have been used in the literature for measuring the amnesic effect of midazolam.[17] The use of picture cards for visual recall and event recall in this study was based on its reliability in previous studies where pictures used were evenly mixed according to categories, familiarity, name agreement, and simplicity.[10],[17] No patient recalled any of the postoperative pictures or the fictitious finger prick. This indicates that there was no false reporting.

There was no difference in OAA/S scores between study groups at time T0(i.e., 4 min before injection of midazolam, P > 0.05). The level of sedation became deeper with higher doses of midazolam. This is not surprising since midazolam is known to have anxiolytic and sedative properties. Sun et al.,[18] in their study of the effects of IV midazolam premedication on age and gender, found that sedation index indicated that the midazolam-induced sedative effects were more pronounced among patients receiving midazolam 0.06 mg/kg as compared to midazolam 0.02 mg/kg. The extent of sedation as measured by OAA/S correlated with anterograde amnesia as measured by event recall. The increased amnesia demonstrated in the time period after study drug administration was closer to the time of induction of anesthesia with propofol. Midazolam administration during anesthesia may be influenced by the amnesic effects of propofol or other co-administered hypnotic drugs.[19]

This study did not take into consideration all types of memory. It was limited to the study of explicit memory. Study also focused on visual and event recall memory. A test of auditory memory was not included which could have been useful in awareness prevention. Again, observer error may not be entirely ruled out most, especially as it relates to OAA/S scoring.


  Conclusion Top


In conclusion, this study could not demonstrate that IV midazolam 2–7 mg produces retrograde amnesia. Though, the study found that midazolam causes anterograde amnesia based on the dose administered. The extent of sedation as measured by OAA/S score using visual and event recall correlated with anterograde amnesia.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Mohler H, Okada T. Benzodiazepine receptor: Demonstration in the central nervous system. Science 1977;198:849-51.  Back to cited text no. 1
    
2.
Forster A, Gardaz JP, Gemperle M, Suter PM. Respiratory depression by midazolam and diazepam. Anesthesiology 1980;53:494-7.  Back to cited text no. 2
    
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Ghoneim MM, Mewaldt SP. Benzodiazepines and human memory: A review. Anesthesiology 1990;72:926-38.  Back to cited text no. 3
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Hirshman E, Passannante A, Arndt J. Midazolam amnesia and conceptual processing in implicit memory. J Exp Psychol Gen 2001;130:453-65.  Back to cited text no. 5
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Kotoe K, Satoshi H, Ryu K, Makoto O. Predominant effects of midazolam for conscious sedation: Benefits beyond the early postoperative period. J Anesth 2010;24:869-76.  Back to cited text no. 6
    
7.
Koht A, Moss JI. Does midazolam cause retrograde amnesia, and can flumazenil reverse that amnesia? Anesth Analg 1997;85:211-2.  Back to cited text no. 7
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Cohen J. A power primer. Psychol Bull 1992;112:155-9.  Back to cited text no. 8
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Abramson JH. WinPepi statistical software for epidemiologists. Available from: http://www.epi-perspectives.com/content/8/1/1/. [Last accessed on 2012 Jul.4].  Back to cited text no. 9
    
10.
Bulach R, Myles PS, Russnak M. Double-blind randomized controlled trial to determine extent of amnesia with midazolam given immediately before general anaesthesia. Br J Anaesth 2005;94:300-5.  Back to cited text no. 10
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Chernik DA, Ghouri D, Laine H, Hendler J, Silver JM, Schwam EM, et al. Validity and reliability of the observers assessment of alertness/sedation scale: Study with intravenous midazolam. J Clin Psychopharmacol 1990;10:244-51.  Back to cited text no. 11
    
12.
Park KS, Hur EJ, Han KW, Kil HY, Han TH. Bispectral index does not correlate with observer assessment of alertness and sedation scores during 0.5% bupivacaine epidural anaesthesia with nitrous oxide sedation. Anesth Analg 2006;103:385-9.  Back to cited text no. 12
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Hirshman E, Passannante A, Henzler A. The effect of midazolam on implicit memory tests. Brain Cogn 1999;41:351-64.  Back to cited text no. 13
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Connor JT, Katz RL, Pagano RR, Graham CW. RO21-3981 for intravenous surgical premedication and induction of anaesthesia. Anesth Analg 1978;57:1-5.  Back to cited text no. 14
    
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Diana R, Reder LM, Arndt J, Park H. Models of recognition. A review of arguments in favour of a dual-process account. Psychon Bull Rev 2006;13:1-21.  Back to cited text no. 15
    
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Hirshman E, Fisher J, Henthorn T, Arndt J, Passannante A. Midazolam amnesia and the dual-process models of the word-frequency mirror effect. J Mem Lang 2002;47:499-516.  Back to cited text no. 16
    
17.
Twersky RS, Hartung J, Berger BJ, McClain J, Beaton C. Midazolam enhances anterograde but not retrograde amnesia in paediatric patients. Anesthesiology 1993;78:51-5.  Back to cited text no. 17
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Sun GC, Hsu YY, Chia YY, Chen PY, Shaw FZ. Effects of age and gender on intravenous midazolam premedication: A randomized double-blind study. Br J Anaesth 2008;101:632-9.  Back to cited text no. 18
    
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Veselis RA, Reinsel RA, Feschenko VA, Wronski M. The comparative amnesic effects of midazolam, propofol, thiopental and fentanyl at equisedative concentrations. Anesthesiology 1997;87:749-64.  Back to cited text no. 19
    


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    Tables

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