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Placebo-controlled studies show that midazolam impairs explicit memory in children undergoing surgery (Buffett-Jerrott et al., Psychopharmacology 168:377-386, 2003; Kain et al., Anesthesiology 93:676-684, 2000). A recent within-subjects study showed that midazolam impaired explicit memory while leaving implicit memory intact in a sample of older children undergoing painful medical procedures (Pringle et al., Health Psychol 22:263-269, 2003). We attempted to replicate and extend these findings in a randomized, placebo-controlled design with younger children undergoing surgery. Children aged 3-6 years who were undergoing ear tube (myringotomy) surgery were randomly assigned to receive midazolam (n = 12) or placebo (n = 11). After surgery, they were tested on explicit (recognition) and implicit (priming) memory for pictures encoded before surgery. Relative to placebo, the midazolam-treated children showed poorer recognition memory on the explicit task but equivalent priming on the implicit task. Overall, it appears that midazolam induces a dissociation between explicit and implicit memory in young children in the pediatric surgery setting. Theoretical and clinical implications of the findings are discussed along with directions for future research.
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Psychopharmacology (2006) 188: 489497
DOI 10.1007/s00213-006-0402-7
ORIGINAL INVESTIGATION
Sherry H. Stewart .Susan E. Buffett-Jerrott .
G. Allen Finley .Kristi D. Wright .
Teresa Valois Gomez
Effects of midazolam on explicit vs implicit memory
in a pediatric surgery setting
Received: 31 January 2006 / Accepted: 27 March 2006 / Published online: 22 April 2006
#Springer-Verlag 2006
Abstract Rationale: Placebo-controlled studies show that
midazolam impairs explicit memory in children undergoing
surgery (Buffett-Jerrott et al., Psychopharmacology
168:377386, 2003;Kainetal.,Anesthesiology 93:676
684, 2000). A recent within-subjects study showed that
midazolam impaired explicit memory while leaving implicit
memory intact in a sample of older children undergoing
painful medical procedures (Pringle et al., Health Psychol
22:263269, 2003). Objectives: We attempted to replicate
and extend these findings in a randomized, placebo-
controlled design with younger children undergoing surgery.
Materials and methods: Children aged 36 years who were
undergoing ear tube (myringotomy) surgery were randomly
assigned to receive midazolam (n=12) or placebo (n=11).
After surgery, they were tested on explicit (recognition) and
implicit (priming) memory for pictures encoded before
surgery. Results: Relative to placebo, the midazolam-
treated children showed poorer recognition memory on the
explicit task but equivalent priming on the implicit task.
Conclusions: Overall, it appears that midazolam induces a
dissociation between explicit and implicit memory in young
children in the pediatric surgery setting. Theoretical and
clinical implications of the findings are discussed along with
directions for future research.
Keywords Benzodiazepine .Memory .Anesthesia .
Development .Attention
Surgery can be a frightening and stressful experience for
children (Kain et al. 1996). Pre-operative anxiety can
contribute to surgical complications and post-surgery
difficulties (Laycock and McNicol 1988). It has been
suggested that a drug with anxiolytic and sedative effects
administered before anesthesia might be helpful for
children (e.g., DeJong and Verburg 1988).
Benzodiazepines are drugs with anxiolytic, sedative, and
muscle relaxant properties (Buffett-Jerrott and Stewart
2002; Curran 1986). These drugs also produce antero-
grade amnesia’—forgetting of information learned after
drug administration. In contrast, benzodiazepines do not
induce retrograde amnesia’—forgetting of information
learned before drug administration (e.g., Twersky et al.
1993). It has been suggested that these anterograde
amnestic effects may be beneficial for children undergoing
S. H. Stewart (*)
Department of Psychiatry, Dalhousie University,
Life Sciences Center,
1355 Oxford Street,
Halifax, Nova Scotia B3H 4J1, Canada
e-mail: sstewart@dal.ca
Tel.: +1-902-4943793
Fax: +1-902-4946585
S. H. Stewart
Department of Psychology, Dalhousie University,
Life Sciences Center,
1355 Oxford Street,
Halifax, Nova Scotia B3H 4J1, Canada
S. E. Buffett-Jerrott
Child and Family Day Treatment Program, IWK Health Center,
Halifax, Nova Scotia, Canada
e-mail: susan.jerrott@iwk.nshealth.ca
G. A. Finley
Department of Anesthesia, Dalhousie University,
IWK Health Center,
5850 University Avenue,
Halifax, Nova Scotia B3K 6R8, Canada
G. A. Finley
Department of Psychology, Dalhousie University,
IWK Health Center,
5850 University Avenue,
Halifax, Nova Scotia B3K 6R8, Canada
e-mail: allen.finley@dal.ca
K. D. Wright
Department of Psychology, Dalhousie University,
1355 Oxford Street,
Halifax, Nova Scotia B3H 4J1, Canada
e-mail: kdwright@dal.ca
T. Valois Gomez
Department of Anesthesia, Montreal Childrens Hospital,
Montreal, Quebec, Canada
e-mail: teresa.valois@muhc.mcgill.ca
surgery (e.g., DeJong and Verburg 1988; Kupietzky et al.
1996; Playfor et al. 2000). Midazolam is a benzodiazepine
with a short half-life, making it a good candidate for use in
the day surgery setting (Smith et al. 1981).
Substantial evidence supports a distinction between two
types of memoryexplicit and implicit. Explicit memory
involves conscious attempts to retrieve information from
memory. Implicit memory occurs when performance is
influenced by a previous experience without conscious
retrieval or awareness (Graf and Schacter 1985). Benzo-
diazepines may be useful pharmacological tools for
dissociating these two memory processes as most studies
show that these drugs impair explicit memory while
leaving implicit memory intact (Curran 1986).
Midazolam is known to impair the explicit memory
abilities of adult patients undergoing conscious sedation
while leaving their implicit memory abilities intact (e.g.,
Polster et al. 1993). Several studies have documented
impaired explicit memory in pediatric patients adminis-
tered midazolam. Nonetheless, the large majority of these
studies with children have suffered methodological
problems including small sample size, lack of placebo
control, lack of random assignment, unclear memory
assessment, lack of formal memory assessment, few
memory stimuli, failure to assess pre-drug memory, and/
or lack of control for midazolams sedative and attentional
effects (e.g., Chen et al. 2000; Cole 1982; Feld et al. 1990;
Friedman et al. 1991; Kain et al. 2000; Kupietzky et al.
1996; Payne et al. 1991; Saarnivaara et al. 1988; Saint-
Maurice et al. 1990; Sandler et al. 1992; Sievers et al. 1991;
Taylor et al. 1986; Twersky et al. 1993).
A recent study by our group (Buffett-Jerrott et al. 2003)
was designed to overcome some of these methodological
limitations. Forty 4- to 6-year-old children undergoing
myringotomy (ear tube surgery) were randomly assigned to
either midazolam or placebo. Relative to placebo, mid-
azolam impaired performance on a standardized cued recall
task (Greenbaum and Graf 1989) and decreased free recall
of hospital events occurring during the window of drug
influence.
The only study to date to assess the implicit memory
effects of midazolam pre-medication in children (Pringle et
al. 2003) was conducted with 6- to 18-year-old children
undergoing bone marrow aspiration or lumbar puncture.
Relative to pre-drug baseline, midazolam induced impair-
ments in performance on a visual recognition (explicit
memory) task while inducing no changes in performance
on a visual perceptual facilitation (implicit memory) task.
This suggested a midazolam-induced dissociation between
explicit and implicit memory in children. However, as no
placebo-control group was used in this within-subjects
study, alternative interpretations are possible (e.g., the
explicit memory task may simply have been more subject
to disruptions after the painful medical procedure).
The present study was designed as a replication and
extension of the study of Pringle et al. (2003) with the
major goal being a further examination of the effects of
midazolam on explicit vs implicit memory in children.
Methodological improvements to previous research in-
cluded the use of a randomized, double-blind, placebo-
controlled design, use of standardized and age-appropriate
memory tasks, control for guessing on the recognition task,
control for pre-drug memory performance, and control for
the effects of midazolam on sedation and attention. In
addition, this study was designed to extend the Pringle et al.
results to younger children (aged 36 years) and to children
undergoing surgery (i.e., myringotomy) rather than painful
medical procedures. It was predicted that midazolam would
impair explicit memory (hit rates on a visual recognition
task) relative to placebo (cf., Buffett-Jerrott et al. 2003;
Kain et al. 2000). In contrast, comparable implicit memory
performance (i.e., priming level on a visual perceptual
facilitation task) was expected among those in the
midazolam and placebo groups.
Materials and methods
Participants
The participants were 23 children aged 36 years (mean
age 5 years and 5 months, SD=11.55 months; 18 males, 5
females) who were scheduled for myringotomy but who
were otherwise healthy. Any history of neurological or
cognitive impairment or disease, as reported by parents,
excluded children from participation. Those with a
previous adverse reaction to benzodiazepines or Tylenol
®
(McNeil Consumer Products, Canada) as reported by
parents were also excluded as were children who were
taking medication other than antibiotics. The participants
were instructed to refrain from eating after midnight the
night before the study (normal hospital procedure). Parents
provided written informed consent; children provided
verbal assent. The study had ethical committee approval.
Only children undergoing purely myringotomy (i.e., not
in conjunction with other surgeries) were used in the
present study because the procedure and anesthetic are
simple and easily standardized. The 36 years age range
was chosen because preschool children are most likely to
require ear tubes (Giebink and Daly 1990) and to control
for the poor explicit memory of very young children
(Bullock-Drummey and Newcombe 1995; Greenbaum and
Graf 1989) and the improvement in explicit memory as
children mature (Naito 1990).
Experimental design and drugs
This study used a randomized, placebo-controlled design.
The participants were randomly assigned to the midazolam
(n=12) or placebo (n=11) drug group. An independent
party conducted this randomization. The active drug group
received oral midazolam [Versed
®
(Roche) for intravenous
administration, 5 mg/ml] at a dose of 0.50 mg/kg mixed
with acetaminophen [Tylenol
®
(McNeil Consumer Products,
Canada) grape-flavored suspension, 32 mg/ml] at a dose of
15 mg/kg. The placebo group received only Tylenol
®
,
without the midazolam. Drug administration was double-
490
blind; only the nurse administering the drug was aware of the
childs group assignment.
Pilot testing
Twenty-three children, recruited from local daycares, were
pilot tested on the explicit and implicit memory tasks used
in this study (Bullock-Drummey and Newcombe 1995)to
ensure that our computerized versions of these tasks were
adequate measures of these memory processes in young
children (McGuire 2003). Pilot participants were healthy
3- to 5-year-old children (12 boys). We observed priming
on the implicit task. The explicit, but not the implicit,
memory task showed improvements with age (cf., Bullock-
Drummey and Newcombe 1995).
Tasks and procedure
When a child was scheduled for myringtomy, a letter was
sent to the parents followed by a telephone call to explain
the study. Ninety minutes before surgery, the researcher
met with both the child and the parent(s) to obtain consent/
assent. The childs baseline level of sedation was then
experimenter-rated using a five-point rating scale (Wilton et
al. 1988) used in previous studies of midazolam as a pre-
operative medicant in children (e.g., Buffett-Jerrott et al.
2003; Wilton et al. 1988). This scale has excellent inter-rater
reliability (Buffett-Jerrott et al. 2003).
When the child entered the day surgery area, a nurse
took his/her body weight to determine drug dose. An
anesthesiologist also performed a pre-anesthetic assess-
ment to ensure medical eligibility for the study and to order
the study medications. Before the midazolam or placebo
was administered, children completed a variety of cogni-
tive tasks to ensure pre-drug equivalence between groups.
The narrative memory task from the NEPSY (Korkman et
al. 1997)a test of immediate free and cued recall of a
short story was used to assess baseline memory
performance. The picture deletion task for preschoolers
(PDTP; Corkum et al. 1995) assessed baseline attentional
performance. In this task, after a few practice items,
children are presented with a page of 60 shapes and asked
to scan the page to find all examples of a specific target (ten
diamonds or triangles). Children use a bingo marker to
mark each target. Time taken to complete the task and
omission and commission errors, were measured. The
motor deletion task (MDT; Corkum et al. 1995) objectively
assessed baseline psychomotor function. In this task,
children were presented with a page of 60 circles and
asked to put a mark in each circle on the page as quickly as
possible, with a 5-min time limit. Time to complete this
task as well as omission and commission errors were used
as measures of objective sedation. Another observer-rated
sedation measure was then taken. At 25 min before surgery,
the participants received their assigned drug.
At 10 min post-drug administration, the participants
were shown a series of animal pictures. Twenty animal
pictures were used for the memory portion of this
experiment (cf., Bullock-Drummey and Newcombe
1995). To ensure the ability of our 3- to 6-year-old
participants to name the pictures, all of the pictures chosen
were at or above the level at which 50% of 2-year-old
children can produce the depicted animal name (Fenson et
al. 1994). Half of the pictures were obtained from Van Fleet
childrens books (1992,1995,1998), and the other half
were obtained from an Internet search, in which we
attempted to closely match the artistic style of Van Fleet.
Each picture measured 18.5×24.5 cm. A 300-pixels/cm
resolution was used to ensure that the pictures presented in
the picture books at encoding were as perceptually similar
as possible to those later presented on the laptop in the
memory testing phase (Clarke and Morton 1983). The
pictures were compiled into two picture books (book A or
book B) for use in the pre-surgery encoding phase, with
each book containing ten different pictures. The pictures in
books A and B were matched for developmental produc-
tion norm difficulty levels (Fenson et al. 1994). Children
were shown only book A or B in the pre-surgery encoding
phase; picture book selection was counterbalanced across
drug group. The child was shown the pictures one at a time
and asked to identify the animal in each picture. If the child
was unsure or made an error, the tester told the child the
name of the animal and asked the child to repeat it.
After encoding, the tester again rated the childs
sedation. Children were then given the second PDTP
(using the target shape that was not presented pre-drug
administration) and the MDT. Children were then taken to
the operating room. All but two children separated from
their parents when leaving the day surgery room. A fourth
experimenter-rated sedation score was again assigned at
this time. Anesthesia was induced via mask using only
halothane/nitrous oxide (N
2
O).
After the child was awake and returned to the day
surgery room, he/she was administered the memory tests
(implicit and explicit) to assess his/her memory for the
pictures presented in the booklet before surgery, followed
by a final rating of sedation. The implicit memory test was
always performed first. A laptop was used to present the
stimuli in the testing phase. The same computer program
used in the pilot testing of daycare children (McGuire
2003) was used in the present study. The program was
designed to present the stimuli in a random order, both in a
progressively less degraded state (for the implicit task) and
in a clear, non-degraded state (for the explicit task).
Blurriness was defined by the number of pixels present in
the image. At 50% degradation, half of the pixels from the
original picture were replaced with random pixels from the
256 colors available to the computer. The pixels to be
replaced were selected arbitrarily and replaced with
random colors.
The implicit memory task presented ten pre-selected
pictures in a random order in progressively less-degraded
states. There were ten trials for each participant: five
primed(i.e., pictures that the child had seen previously in
the picture book during the pre-surgery encoding phase)
and five unprimed(i.e., pictures from the other book to
491
which the child had not been exposed during encoding).
One image was presented per trial. The child was asked to
identify the picture verbally as soon as he/she knew what it
was. Each trial began with a white screen. A small, black
cross then appeared on the screen followed by 500 ms of
white screen and then the stimulus presentation. There
were seven levels of degradation per trial (100, 92, 84, 76,
68, 60, and 52% blurriness). Each degradation level was
presented for 1,500 ms. The maximum cumulative iden-
tification time per trial was 15,000 ms. The researcher
pressed the right or left arrow keys upon the childs correct
identification of the picture. The computer program then
automatically recorded the childs cumulative identifica-
tion time (latency from trial onset to correct identification).
Upon correct identification, the picture was then displayed
for 1,500 ms in clear form (0% blurriness). If no response
occurred, the trial ended at 52% blurriness and the picture
was not presented in clear form. The children were told at
the beginning of the task that, when they correctly
identified the animal in the picture, they would be
presented with the clear form of the picture. Between
trials, 500 ms elapsed before the presentation of the small,
black cross signaling the start of the next trial.
The explicit memory task immediately followed the
implicit task. Different animal pictures were used for the
implicit and explicit memory tasks. The explicit memory
test was a recognition memory test for the animal pictures.
This test involved presentation of ten picture trials: five
old(i.e., pictures to which the child had been exposed
through the picture book presented in the pre-surgery
encoding phase) and five new(i.e., pictures from the
other book to which the child had not been previously
exposed). One picture was presented per trial in random
order. A small, black cross appeared on the screen,
followed by 500 ms of white screen and then the stimulus
presentation. The images were presented in clear (non-
degraded) form for 10,000 ms each. The participant was
asked to indicate whether or not the presented picture was
one that they had seen in the picture book just before
surgery. The researcher recorded the participants response
for each trial. Responses were later scored as hits, misses,
false alarms, and correct rejections (Green and Swets
1966). Between trials, 500 ms elapsed before the presen-
tation of the small, black cross that signaled the onset of the
next trial.
Results
Participant characteristics
A series of chi-square analyses and ANOVAs were
conducted to determine if the drug groups differed on
any of the demographic control variables. There was no
effect of drug group for the number of females (n=5), the
number of children who had previously undergone surgery
(n=11), the number with parents present in the operating
room (n=2), or the age of the child. No children had
previously taken midazolam.
Pre-drug cognitive functioning
Pre-drug measures of narrative memory (total memory
score from NEPSY), attention (time to complete PDTP and
omission and commission errors), psychomotor speed
(time to complete MDT and omission and commission
errors), and observer-rated sedation (at the two pre-drug
testing times) were analyzed with a series of one-way
ANOVAs to determine if the drug groups were equivalent
before drug administration. There were no significant
effects of drug group on any of the pre-drug measures.
1
Means (SDs) for these pre-drug cognitive measures are
displayed in Tables 1,2, and 3(for attention, psychomotor
speed, and observer-rated sedation, respectively). Means
(SDs) on the NEPSY were 10.09 (8.57) and 10.17 (3.27)
for placebo and midazolam, respectively.
Memory effects
Implicit memory
Performance on the implicit memory task was assessed by
comparing the mean cumulative identification time on
primed vs unprimed stimuli across drug groups. The child
was required to respond to the presented stimuli within
15,000 ms of trial onset. If no response was provided
within this window, the child was assigned a maximum
value reaction time of 15,000 ms for that particular trial.
Table 1 Attentional performance: means (SDs) for attentional
speed, attentional omissions, and attentional commissions as a
function of drug group and drug phase
Drug group
Placebo (n=11) Midazolam (n=12)
Attention speed
Time to complete the PDTP (s)
Pre-drug 79.97 (82.60) 51.97 (29.69)
a
Post-drug 53.92 (20.19) 106.21 (96.75)
a
Attentional omissions
Number of omissions on PDTP
Pre-drug 1.55 (3.39) 0.67 (1.15)
Post-drug 0.73 (1.49) 2.42 (3.50)
Attentional commissions
Number of commission errors on PDTP
Pre-drug 4.91 (15.95) 0.08 (0.29)
Post-drug 2.18 (3.46) 0.67 (1.07)
Means with similar superscripted letters are marginally different
from one another (p=0.06)
PDTP Picture deletion task for preschoolers (Corkum et al. 1995)
1Because Levenes test for equality of variances showed that the
equal variance assumption was violated in the case of commission
errors on the PDTP (see Table 1), we also compared the two drug
groups on this baseline variable using a non-parametric test
specifically, the MannWhitney Utest. This test confirmed that
there were no significant differences between groups on this variable
at baseline (Z=0.736, n.s.).
492
Such types of trials occurred relatively rarely (i.e., on only
41 of 230 trials). A 2×2 (drug group × priming level) mixed
model ANOVA was performed on the cumulative identi-
fication times. There was a significant effect of priming
level [F(1, 21)=6.97, p<0.05; power=0.711]: primed
pictures were identified significantly more quickly than
unprimed pictures (see Fig. 1). There was no main effect of
drug group [F(1, 21)=0.08, n.s.; power=0.058] and no drug
group × priming level interaction [F(1, 21)=0.02, n.s.;
power=0.052] (see Fig. 1).
Explicit memory
Hit rates and false alarm rates, the two explicit memory
dependent variables of interest, were expressed as propor-
tional scores. These scores were analyzed in a pair of one-
way (drug group) ANOVAs. The first ANOVA indicated
that the midazolam group showed a significantly lower hit
rate than the placebo controls [F(1, 21)=4.37, p<0.05;
power=0.513; see Fig. 2]. In the second ANOVA, there was
no significant drug group effect for false alarm rate [F(1,
21)=0.08, n.s; power=0.058; see Fig. 2], indicating that
there was no drug group difference in guessing.
Attention task
A set of 2×2 [drug group × drug phase (pre- vs post-drug
administration)] ANOVAs was conducted on the three
dependent measures from the PDTP. Means (SDs) are
presented in Table 1. A significant drug group × drug phase
interaction [F(1, 21)=5.66, p<0.05; power=0.621] was
observed for completion time. Simple effects tests
indicated a marginal effect of drug phase for the midazolam
[F(1, 11)=4.31, p=0.062] but not for the placebo-treated
Table 2 Psychomotor performance (objective sedation task): means
(SDs) for psychomotor speed, omission errors, and commission
errors as a function of drug group and drug phase
Drug group
Placebo (n=11) Midazolam (n=12)
Psychomotor speed
Time to complete the MDT (s)
Pre-drug 61.82 (29.59)
a
56.73 (21.53)
b
Post-drug 108.56 (84.94)
a
113.64 (92.54)
b
Omission errors
Number of omissions on MDT
Pre-drug 2.00 (5.71) 1.00 (2.13)
c
Post-drug 4.00 (12.00) 16.00 (21.88)
c
Commission errors
Number of commission errors on MDT
Pre-drug 2.18 (4.44) 1.50 (4.01)
Post-drug 7.18 (18.18) 2.58 (8.64)
Means with similar superscripted letters are significantly different
from one another (p<0.05)
MDT Motor deletion task (Corkum et al. 1995)
Table 3 Means (and SDs) on the observer-rated sedation measure
as a function of drug group and testing time
Testing time Drug group
placebo (n=11) Midazolam (n=12)
Waiting area 2.55 (0.52) 2.42 (0.51)
Pre-drug cognitive testing 2.46 (0.69) 2.58 (0.51)
Post-drug cognitive testing 2.46 (0.82)
a
3.58 (0.51)
a
Leave day surgery
for operating room
2.64 (1.12)
b
3.92 (1.16)
b
Day surgery room
post-recovery
2.73 (0.47) 2.50 (1.09)
Ratings made by trained observer using 15 Likert scale developed
by Wilton et al. (1988). Means with similar superscripted letters
are significantly different from one another (p<0.05)
6500
7000
7500
8000
8500
9000
9500
placebo
(n = 11)
midazolam
(n = 12)
primed RT
unprimed RT
Fig. 1 Mean cumulative identification time (in milliseconds) on the
implicit memory measure as a function of drug group and priming
level. Bars represent standard errors
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
hit rate false
alarm rate
placebo (n = 11)
midazolam (n = 12)
Fig. 2 Mean hit rate and mean false alarm rate on the explicit
recognition memory measure as functions of drug group. Bars
represent standard errors
493
participants [F(1, 10)=1.58, n.s.]. Only midazolam-treated
participants tended to take longer to complete the task after
drug administration compared to their pre-drug perfor-
mance speed (see Table 1). The ANOVAs on the attentional
omissions and commissions indicated no significant
effects, but power to detect a drug group × drug phase
interaction was relatively low (0.123 and 0.430, respec-
tively), and floor effects were evident on these variables.
Objective sedation
A set of 2×2 (drug group × drug phase) ANOVAs was
conducted on the three dependent measures from the MDT.
Means (SDs) are presented in Table 2. A significant main
effect of drug phase [F(1, 21)=6.41, p<0.05; power=0.675)
and a marginally significant drug group × drug phase
interaction [F(1, 21)=3.75, p=0.066; power=0.455] were
observed for omission errors. Simple effects tests indicated
a significant effect of drug phase for midazolam [F(1, 11)=
5.93, p<0.05] but not for placebo [F(1, 10)=1.04, n.s.].
Only midazolam-treated participants made more omission
errors on the task after drug administration compared to
their pre-drug performance (see Table 2). The ANOVA on
commission errors indicated no significant effects (see
Tabl e 2), although power to detect a drug group × drug phase
interaction was low (0.135), and floor effects were again
evident. A significant main effect of drug phase [F(1, 21)=
10.34, p<0.005; power=0.866] was observed on completion
time with completion time increasing from pre- to post-drug
administration. No effects involving the drug group factor
were observed for completion time, although power to detect
a drug group × drug phase interaction was low (0.060).
2
Observer-rated sedation
Scores on the observer-rated sedation scale were subjected
to a 2×5 (drug group × testing time) mixed-model
ANOVA. The five testing times were: (a) in the waiting
area, (b) at the pre-drug cognitive testing, (c) post-drug,
(d) on leaving the day surgery room for the operating
room, and (e) in the day surgery room after recovery. Main
effects of drug group [F(1, 21)=5.54, p<0.05; power=0.612]
and testing time [F(4, 84)=5.25, p<0.005; power=0.963]
were obtained that were qualified by a significant drug
group × testing time interaction [F(4, 84)=5.50, p<0.005;
power=0.970]. Simple effects tests indicated significantly
greater sedation scores in the midazolam- vs placebo-treated
participants at post-drug administration [F(1, 21)=15.92,
p<0.005] and leaving the day surgery room for the operating
room [F(1, 21)=7.19, p<0.05] testing points, but no
significant sedation rating differences exist between drug
groups in the waiting area [F(1, 21)=0.35, n.s.], at the pre-
drug cognitive testing [F(1, 21)=0.26, n.s.], or in the day
surgery room after recovery [F(1, 21)=0.41, n.s.]
(see Table 3).
Analyses of covariance (ANCOVAs)
ANCOVAs were conducted to control for the possible
influences of attention, psychomotor impairments, and
sedation on midazolam-induced explicit memory impair-
ments. This set of ANCOVAs re-examined the hit rate
scores on the recognition memory task while using one
index of each of these additional cognitive constructs at the
post-drug assessment time as a covariate (i.e., attention time
on the PDTP, omission errors on the MDT, and observer-
rated sedation at the post-drug administration cognitive
assessment time, respectively, each of which were sig-
nificantly influenced by midazolam). Drug group effects
remained significant when controlling for both psychomo-
tor impairments and observer-rated sedation. With respect
to the ANCOVA controlling for attention, although
covariate-adjusted hit rate index scores remained in the
same direction as before covariance (i.e., midazolam <
placebo), covarying attention speed reduced the drug group
effect to marginal significance [F(1, 20)=3.06, p=0.096].
Discussion
The results of our study demonstrate a dissociation
between explicit and implicit memory. Relative to placebo,
midazolam reduced post-surgery performance on an
explicit memory task testing recognition of animal pictures
presented before surgery. In contrast, midazolam- and
placebo-treated children showed equivalent levels of
implicit memory for the same set of animal pictures, as
evidenced by equivalent priming on a visual identification
task. Thus, when administered in a pediatric surgery
context, midazolam appears to exert effects much like
those observed for other benzodiazepines with adults
(Buffett-Jerrott and Stewart 2002).
The finding that midazolam exerted impairment relative
to placebo on the explicit recognition memory task is
consistent with the prior literature that therapeutic doses of
2Given concerns about possible violations of the assumption of
equal variances required for ANOVA (see Tables 1and 2), we also
analyzed the variables derived from the PDTP and MDT using non-
parametric tests. Wilcoxon signed-ranks tests for dependent samples
(Daniel 1978) were specifically used to compare pre- and post-drug
performance on each of the six dependent measures in each drug
group separately. One-tailed tests were used as directional predic-
tions had been made a priori. These non-parametric tests produced a
nearly identical pattern of findings to those reported for the
ANOVAs in the main body of the paper. As observed with the
ANOVAs, significant effects of drug phase were observed with
the Wilcoxon tests for: attention speed in the midazolam group (Z=
1.726, p<0.05), number of omissions on the MDT in the
midazolam group (Z=1.992, p< 0.05), psychomotor speed in the
midazolam group (Z=2.667, p<0.005), and psychomotor speed in
the placebo group (Z=1.784, p<0.05). The Wilcoxon tests revealed
an additional significant effect of drug phase for commission errors
on the attentional test in the midazolam group (Z=1.890, p<0.05).
In each case, performance was worse at post-drug than at pre-drug
baseline.
494
midazolam induce anterograde amnesia in both adults (e.g.,
OBoyle et al. 1987) and children (e.g., Twersky et al.
1993). Unlike some studies of midazolams effects on
recognition memory in children (e.g., Kain et al. 2000), we
controlled for guessing on the recognition memory task.
The fact that false alarm rates were unaffected by midazolam
ensures that the drug effects observed on the primary
dependent measure on our explicit memory task (i.e., hit
rate) were not secondary to a decreased willingness to guess
yeson the recognition task among midazolam-treated
children.
Priming effects were observed on the visual identifica-
tion (implicit memory) task such that pictures previously
viewed by children at the encoding phase before surgery
were identified much earlier (at greater levels of degrada-
tion) than were control pictures not viewed previously.
These findings extend to the pediatric surgery context,
previous findings that preschool children, as young as age
3, reliably show priming on such facilitation tasks (e.g.,
Bullock-Drummey and Newcombe 1995; McGuire 2003;
Pringle et al. 2003). The active drug and placebo groups
showed equivalent levels of priming on this implicit
memory task. Thus, although midazolam is commonly
considered an amnestic drug, our results show preserved
implicit memory for material to which midazolam-treated
children were exposed just before surgery.
Midazolam also exerted additional disruptions in cog-
nitive and psychomotor functions, relative to placebo. The
finding of slowed performance on a task requiring focused
attention (i.e., the PDTP; Corkum et al. 1995) is consistent
with our previous findings (Buffett-Jerrott et al. 2003).
Relative to placebo, midazolam also induced substantial
sedation. First, observer-rated sedation was increased in the
midazolam vs placebo group at the two testing points after
drug administration and before surgery (cf., Buffett-Jerrott
et al. 2003). Like in our previous research (Buffett-Jerrott et
al. 2003), we also observed differences between the
midazolam and placebo groups on a standardized test of
psychomotor functionthe MDT (Corkum et al. 1995).
However, in the present study, this drug group difference
was observed on omission errors (i.e., skipping circles that
should have been marked) whereas the drug group effect
was observed on completion time in our prior study where
errors were not scored (Buffett-Jerrott et al. 2003). In the
present study, we observed slowing on the MDT from pre-
to post-drug administration, but this effect was not specific
to the midazolam-treated children. This slowing may have
been due to fatigue effects at the post-drug testing point
and/or our inclusion of younger (3 years old) children who
may have tired of this task more easily. Regardless of the
reasons for this slight discrepancy from the results of our
prior study (Buffett-Jerrott et al.), considering the possibil-
ity of speedaccuracy trade-offs on such tasks, we
recommend that future cognitive psychopharmacology
studies with children score such tasks for both speed and
accuracy.
Our results further suggest that midazolam-induced
explicit memory impairments are not secondary to sedation
(cf., Buffett-Jerrott et al. 2003). Covariance analyses results
suggested that midazolam-induced attentional impairments
may contribute in part to the recognition memory
impairments observed in children administered with
midazolam. This result is not particularly surprising
given the important role of attention at encoding to later
explicit memory performance (e.g., Rabinowitz et al.
1982). However, attentional impairments do not appear
to completely explain midazolams effects in impairing
explicit memory, as the drug effect was still marginally
significant after attentional performance was covaried out.
The present findings have important theoretical as well as
clinical implications. Given the many methodological
improvements over prior research incorporated in the present
study design, this study adds to a growing body of research
supporting benzodiazepines, including midazolam, as a set
of pharmacological tools for dissociating explicit and
implicit memory processes. The results are consistent with
positions that explicit and implicit memory may be
subserved by distinct memory systems (e.g., Schacter
1994) as only explicit and not implicit memory performance
was disrupted by benzodiazepine administration.
The present findings also have clinical implications for
several areas of medical practice where midazolam is
administered as a pre-operative or pre-procedural medicant
in anxiety prevention/anxiety management. Midazolam is
an established anxiolytic for children in the pediatric
surgery context. For example, placebo-controlled research
has shown midazolam to dampen the increase in anxiety
that occurs at mask induction of anesthesia (e.g., Finley et
al. 2006). Nonetheless, there are anecdotal reports of
children previously administered with midazolam who
continue to display anticipatory anxiety at subsequent
surgeries/medical procedures (for a review, see Chen et al.
2000). We have also recently found that midazolam-treated
children display more anxious behavior shortly after
surgery than children administered with placebo (Stewart
2006). The present findings provide a possible explanation
for such paradoxical findings: midazolam preserves
implicit memory for potentially stressful events occurring
just before surgery (e.g., mask induction of anesthetic) but
induces poor explicit memory for these same events. Thus,
children administered with midazolam as a pre-operative
medicant would unconsciously remember these potentially
stressful events but at the same time would be unable to
pull them consciously to mind to work them through and
make sense of them. Thus, suggestions that midazolams
amnestic effects may be beneficial for children (e.g.,
DeJong and Verburg 1988) should be tempered by cautions
that midazolam may simultaneously interfere with explicit
memory while preserving implicit memory. Future research
495
should focus on exploring the consequences of the
particular pattern of memory impairments induced by this
commonly used pre-medicant (Kain et al. 1997) among
pediatric surgery patients.
Acknowledgements This research was supported by a category A
grant from the IWK Health Center Research Foundation. We wish to
acknowledge the support and cooperation of the surgeons of the
Division of Otolaryngology and of the nursing staff in the Day
Surgery Unit, Operating Room, and Recovery Room of the IWK
Health Center. We also wish to thank the many students and research
assistants who helped out in various ways with this project including
Allison Eisner, Alyson Currie, Katina Garduno, Courtney Maloney,
and Katie McGuire. The assistance of Dr. W. Joseph MacInnes in
programming our computer tasks is also gratefully acknowledged.
Dr. Stewart is supported by an investigator award from the Canadian
Institutes of Health Research and by a Killam research professorship
from the Dalhousie University Faculty of Science. Dr. Finley was a
Dalhousie University clinical research scholar, and Ms. Wright was
supported by a doctoral fellowship from the Canadian Institutes of
Health Research at the time this research was conducted.
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... There is a concern regarding midazolam's association with implicit memory in children (Stewart et al 2006). This is the preservation of unpleasant emotions or anxiety associated with an event, although it cannot be recalled consciously. ...
... This is the preservation of unpleasant emotions or anxiety associated with an event, although it cannot be recalled consciously. This association is thought to be a cause of distress at subsequent medical encounters in children who have previously been treated with midazolam (Stewart et al 2006) and could lead to paradoxical anxiety (Cole et al 2002). In addition, oral midazolam is usually administered as an intravenous preparation that has an unpleasant bitter taste that many children tend to spit out. ...
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Objective: To determine predictors and behavioral outcomes of preoperative anxiety in children undergoing surgery.Design: A prospective, longitudinal study.Setting: A university children's hospital.Participants: One hundred sixty-three children, 2 to 10 years of age (and their parents), who underwent general anesthesia and elective surgery.Main Outcome Measures: In the preoperative holding area, anxiety level of the child and parents was determined using self-reported and independent observational measures. At separation to the operating room, the anxiety level of the child and parents was rated again. Postoperative behavioral responses were evaluated 3 times (at 2 weeks, 6 months, and 1 year).Results: A multiple regression model (R2=0.58, F=6.4, P=.007) revealed that older children and children of anxious parents, who received low Emotionality, Activity, Sociability, and Impulsivity (EASI) ratings for activity, and with a history of poor-quality medical encounters demonstrated higher levels of anxiety in the preoperative holding area. A similar model (R2=0.42, F=8.6, P=.001) revealed that children who received low EASI ratings for activity, with a previous hospitalization, who were not enrolled in day care, and who did not undergo premedication were more anxious at separation to the operating room. Overall, 54% of children exhibited some negative behavioral responses at the 2-week follow-up. Twenty percent of the children continued to demonstrate negative behavior changes at 6-month follow-up, and, in 7.3% of the children, these behaviors persisted at 1-year follow-up. Nightmares, separation anxiety, eating problems, and increased fear of physicians were the most common problems at 2-week follow-up. Multivariate analysis demonstrated that child's age, number of siblings, and immediate preoperative anxiety of the child and mother predicted later behavioral problems.Conclusions: Variables such as situational anxiety of the mother, temperament of the child, age of the child, and quality of previous medical encounters predict a child's preoperative anxiety. Although immediate negative behavioral responses develop in a relatively large number of young children following surgery, the magnitude of these changes is limited, and long-term maladaptive behavioral responses develop in only a small minority.Arch Pediatr Adolesc Med. 1996;150:1238-1245
Article
In this study we developed preschool versions of two commonly used measures of sustained attention, the continuous performance task (Continuous Performance Task for Preschoolers; CPTP) and the cancellation task(Picture Deletion Task for Preschoolers; PDTP). Sixty children, 20 at each of 3,4, and5 years of age, who were healthy and free of developmental or behavioral problems, were tested. Our findings indicate that the level of difficulty of the revised tasks is age appropriate. Further, the tasks appear to be measuring sustained attention because performance decrements were demonstrated across the course of the session and developmental decreases in the frequency of errors were noted. Performances on the CPTP and PDTP were significantly related, but at a modest value, suggesting that the CPTP and the PDTP may be measuring somewhat different dimensions of attention. We conclude that both instruments may be valuable for the assessment of sustained attention in preschoolers.