A Comparison of Intranasal Dexmedetomidine and Midazolam for Premedication in children - A Prospective randomised double blind controlled trial

1. __________________________________
* Corresponding author: Dr.Prabhu Thilaak
E-mail address: prabhuthilaak@gmail.com
Print ISSN: 2278 – 2648
Online ISSN: 2278 - 2656 IJ
A Comparison of Intranasal Dexmedetomidine and
Premedication in children
*Prabhu Thilaak, J.Ranganathan
Department of Anaesthesiology & critical care, Vinayaka Mission’s Kirupananda Variyar
Medical College & Hospital, Salem, Tamilnadu.
ABSTRACT
In children, preanesthetic medications are administered to alleviate the stress and fear of
parent separation and to promote a smoother induction of anesthesia. Midazolam is a commonly used drug for this
purpose. Clonidine, an 2 agonist, has been
drug than clonidine and has favourable pharmacokinetic properties
differs from other sedatives in that the patients are easily aroused and are cooperative.
preanaesthetic medications is relatively easy and gives a high bioavailability of the drugs than oral route. We
compared intranasal dexmedetomidine with intranasal midazolam for premedication in children. We conclude that
children premedicated with 1 µg/kg of intranasal dexmedetomidine
of sedation at parental separation and at induction of anesthesia than those patients who received 0.2mg/kg of
intranasal midazolam. The change in behaviour produced is favourable and is similar with both
in heart rate and blood pressure observed with intranasal dexmeditomidine are clinically insignificant and are
manageable.
Key words: Premedication in children
INTRODUCTION
In children, pre anesthetic medications are frequently
administered as pharmacologic adjuncts to alleviate
the stress and fear of surgery, to ease child
separation and to promote a smoother induction of
anesthesia [1,4-7]
. Midazolam is a commonly used
drug for this purpose[8,9,10]
. Clonidine, an alpha 2
agonist, has been suggested as an option for
premedication in children and previous studies have
shown it to be equally effective as midazolam
Dexmedetomidine is a newer  2-agonist with a more
International Journal of Research in
Pharmacology
____________________
Prabhu Thilaak
@gmail.com
Available online at www.ijrpp.com
IJRPP | Volume 2 | Issue 1 | 2013 Research
Intranasal Dexmedetomidine and Midazolam for
Premedication in children - A prospective randomised double
blind controlled trial
J.Ranganathan, P.Srinivasan, SreeSabari.S.
Department of Anaesthesiology & critical care, Vinayaka Mission’s Kirupananda Variyar
Medical College & Hospital, Salem, Tamilnadu. India
In children, preanesthetic medications are administered to alleviate the stress and fear of surgery, to ease child
parent separation and to promote a smoother induction of anesthesia. Midazolam is a commonly used drug for this
agonist, has been suggested as an alternative. Dexmedetomidine is a more
clonidine and has favourable pharmacokinetic properties. The sedation produced by dexmedetomidine
differs from other sedatives in that the patients are easily aroused and are cooperative. Intranasal administration of
relatively easy and gives a high bioavailability of the drugs than oral route. We
compared intranasal dexmedetomidine with intranasal midazolam for premedication in children. We conclude that
children premedicated with 1 µg/kg of intranasal dexmedetomidine attained more significant and satisfactory levels
of sedation at parental separation and at induction of anesthesia than those patients who received 0.2mg/kg of
The change in behaviour produced is favourable and is similar with both
in heart rate and blood pressure observed with intranasal dexmeditomidine are clinically insignificant and are
remedication in children , Intranasal, Dexmedetomidine, Midazolam.
anesthetic medications are frequently
administered as pharmacologic adjuncts to alleviate
the stress and fear of surgery, to ease child-parent
separation and to promote a smoother induction of
. Midazolam is a commonly used
. Clonidine, an alpha 2-
agonist, has been suggested as an option for
premedication in children and previous studies have
shown it to be equally effective as midazolam[11,12]
.
agonist with a more
selective action on the  2-adrenoceptors and a
shorter half-life[13-18]
. Previous studies have shown
that intranasal administration is an effective way to
administer premedication and sedation to
It is a relatively easy and a noninvasive route with a
high bioavailability of the administered drugs. We
designed a study to compare 1 µg/kg of
dexmeditomidine with 0.2mg/kg of
midazolam for premedication in children.
International Journal of Research in
Pharmacology & Pharmacotherapeutics
300
Research article
Midazolam for
A prospective randomised double
Department of Anaesthesiology & critical care, Vinayaka Mission’s Kirupananda Variyar
surgery, to ease child-
parent separation and to promote a smoother induction of anesthesia. Midazolam is a commonly used drug for this
suggested as an alternative. Dexmedetomidine is a more 2 selective
. The sedation produced by dexmedetomidine
Intranasal administration of
relatively easy and gives a high bioavailability of the drugs than oral route. We
compared intranasal dexmedetomidine with intranasal midazolam for premedication in children. We conclude that
attained more significant and satisfactory levels
of sedation at parental separation and at induction of anesthesia than those patients who received 0.2mg/kg of
The change in behaviour produced is favourable and is similar with both drugs. The changes
in heart rate and blood pressure observed with intranasal dexmeditomidine are clinically insignificant and are
adrenoceptors and a
. Previous studies have shown
that intranasal administration is an effective way to
administer premedication and sedation to children [19]
.
It is a relatively easy and a noninvasive route with a
high bioavailability of the administered drugs. We
1 µg/kg of intranasal
0.2mg/kg of intranasal
midazolam for premedication in children.

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MATERIALS & METHODS
A randomized double blinded controlled clinical trial
was planned. Ninety children aged 2-9 years with
American society of anaesthesiologists (ASA)
physical status 1 scheduled for elective surgeries
(infraumbilical and lower limb surgeries)were
selected. Exclusion criteria included known allergy or
hypersensitive reaction to dexmedetomidine or
midazolam, cardiac, pulmonary and other vital organ
dysfunctions, and mental retardation. Approval of the
ethical committee was obtained. A written informed
consent was taken from the parents of the children
who participated in the study.
The patients were randomly allocated to one of the
two groups by drawing lots. Baseline heart rate
(HR), peripheral oxygen saturation (SpO2), and
blood pressure (BP) were measured. Group M
received 0.2 mg/kg intranasal midazolam and Group
D received intranasal dexmedetomidine 1 mcg/kg as
premedication 60 minutes prior to induction of
anaesthesia. The drugs were dissolved in 1 ml normal
saline and administered using a nasal drug applicator.
Heart rate, peripheral oxygen saturation (SpO2), and
BP were measured before and every 15 minutes after
intranasal drug administration until transfer to the
operating room. Sedation status was assessed by a
blinded observer every 5 minutes with a 6-point
sedation scale (Table – 1). Behavior status was
evaluated every 5 minutes with a 4-point behavior
score (Table – 1). Sedation and behavior status were
evaluated by the attending anesthesiologist (who was
blinded) at induction using the same scales.
Anaesthetic technique was decided by the attending
anaesthesiologist. Patients were discharged from the
post-anaesthetic care unit (PACU) to the ward when
they were awake, with reasonable control of pain and
with vital signs within 20% of baseline values.
Table 1. Evaluation Scale
A. Sedation scores
1. Does not respond to mild prodding or shaking
2. Responds only mild prodding or shaking
3. Responds only after name is called loudly or repeatedly
4. Lethargic response to name spoken in normal tone
5. Appear asleep but respond readily to name spoken in
normal tone
6. Appear alert and awake, response readily to name
B.Behaviour scores
1. Calm and cooperative
2. Anxious but reassurable
3. Anxious and not reassurable
4. Crying, or resisting
The primary observations made were behavior and
sedation status at separation from the parent and at
induction of anesthesia. Secondary observations
included systolic BP (SBP) and HR changes.
Statistical analysis
Comparisons between the study groups were
conducted using ANOVA (analysis of variance) by
using multivariate ANOVA test, one-way ANOVA
test, repeated measures ANOVA and Kruskal-Wallis

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ANOVA test as well as comparing mean and standard
deviation. In statistics, the Kruskal-Wallis one-way
analysis of variance by ranks (named after William
Kruskal and W. Allen Wallis) is a non-parametric
method for testing equality of population medians
among groups. It is identical to a one-way analysis of
variance with the data replaced by their ranks. It is an
extension of the -Mann-Whitney U test.
Hemodynamic variables including BP and HR were
analyzed by ANOVA. When a significant result was
obtained, the Tukey test was applied for post
hocpairwise comparisons. The changes of BP and
HR from baseline among the groups were tested by
Kruskal-Wallis t-test .A P-value below 0.05 was
considered significant. The statistical software used
was NCSS - PASS. For statistical analysis, sedation
scores were categorized as being satisfactory when
rated between 1 and 4 and unsatisfactory when rated
5 or 6. Behavior scores were categorized as
satisfactory when they were 1 or 2, and unsatisfactory
when they were 3 or 4.
RESULTS
Patients in the two groups were comparable with
respect to age, weight, gender, type of surgery,
duration of surgery etc. (Table2) Six out of 90 (6.5%)
children resisted intranasal drug administration. No
child complained of pain or discomfort with
intranasal drug administration. The children who
resisted the medication but who were subsequently
administered the drugs, were also included in the
analysis.
Table 2. Patients’ Demographic Data
Group M
(n _ 40)
Group D
(n _ 40)
P
Age (yr) 5.8 2.7 (4–14) 5.6 2.9 (3–11) 0.745
Body weight (kg) 16.1 6.8 17.3 7.4 0.215
Sex, M:F 20:20 20:20 0.757
Type of induction,
inhalational:intravenous
8:32 14:26 0.452
Type of surgery
Hydrocele/orchidopexy 3 (7.4%) 8 (20%) 0.638
Excision lymph nodes or lumps 8 (20%) 3 (7.5%)
Circumcision 24 (60.0%) 23 (57.5%)
Cystoscopy/ EUA 5 (12.5%) 6(12.5%)
Duration of surgery (min) 34.5 9.1 (12–45) 43.6 16.3 (17–68) 0.136
Time from premedication to
induction (min)
30.5 14.9 (45–90) 57.0 14.3 (50–100) 0.174
Values in mean SD (range) or no: (%).
EUA examination under anesthesia.
The median sedation scores at separation from the
parents were 4 and 2 for groups M and D
respectively. 27.5% and 85% of the children from
groups M and D achieved satisfactory sedation at
separation from parents. Statistical tests showed that
more children in Group D achieved satisfactory
sedation when compared with Group M (P< 0.05)
(Table 3). The median sedation scores at induction
were 5and 3 for groups M and D respectively. 25%
and 87.5% of the children from groups M and D
respectively achieved satisfactory levels of sedation.
Statistically, this was a significant difference. (P
<0.05) (Table 3). All children except three in Group
M and one in Group D had satisfactory behavior
scores at separation from parents. Statistically, no
difference was found between the two groups, in
behavior scores at separation from parents (P > 0.05)
(Table 3). All children except 2 (5%) children in
Group M and 4 (10%) children in Group D had
satisfactory behaviour scores at induction. There was
no statistically significant difference between the
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groups. 18.1% and 23.5% respectively from Group M
and D were awoken by the transfer from the
preoperative holding area to the OR. There was a
tendency for more children from Group D to awaken
during this transfer, although the differences were not
statistically significant (P > 0.05)
The proportion of children who had satisfactory
behavior at separation from parents, but became
distressed (i.e., showing unsatisfactory scores in
behavior scale) at induction of anesthesia, were 0%
and 10.0% from groups M and D respectively.
Statistically, more children in Group D were found to
develop this change in behavior from satisfactory
levels at separation to unsatisfactory behavior at
induction of anesthesia ( P value from test was
0.014). However when post hoc pairwise comparison
(done with the groups divided into different age
categories – as shown below) was done, it did not
reveal any significant difference among the groups.
(Table 3).
The median behavior score and sedation score were
further analyzed with the children divided into
different age groups age 2–5 and age 7–9, yr.
Table 3. Distribution of Behaviour and Sedation Status at Parental Separation and at Induction
Group M Group D P
Sedation at separation from parent
Satisfactory 11 (27.5%) 34 (85%) <0.001
Unsatisfactory 29 (72.5%) 6 (15%)
Sedation at induction
Satisfactory
Unsatisfactory
10 (25%)
30 (75%)
35(87.5%)
5(12.5%)
<0.001
Change of sedation scores at
induction from satisfactory to
unsatisfactory
2/11(18.1%) 8/34(23.5%) >0.05
Behaviour at separation for
parents
Satisfactory
Unsatisfactory
37(92.5%)
3(7.5%)
39(97.5%)
1(2.5%)
>0.05
Behavior at induction
Satisfactory 38 (95.0%) 36(90.0%) >0.05
Unsatisfactory 2 (5.0%) 4(10.0%)
Change of behaviour scores at
induction from satisfactory to
unsatisfactory
0/40(0%) 4/39(10.3%) <0.05
The median sedation scores and behaviour scores at
baseline, at separation from parent, and at induction
were not different among the children from groups M
and D in all age groups. Seven children who
received midazolam were noted to become euphoric
or restless after premedication, but none after
dexmedetomidine. As this paradoxical behavior was
not prospectively sought in our observations as an
outcome variable, it was not statistically tested.
No child had a reduction of SpO2 to below 95%
during the observation period after premedication.
Post hoc analysis showed that SBP decreased
significantly in Group D when compared with Group
M (P < 0.004). It was also noted that, SBP decreased
with time and it was significantly different from
baseline at 30 min (P < 0.003), 45 min (P < 0.001),

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and 60 min (P < 0.001) after drug administration in
Group D (Figure 1). The SBP was reduced
maximally by 12.3% at 60 min in Group
Post hoc analysis showed that HR decreased
significantly with time in Group D (P
Figure 1. Systolic Blood Pressure during the
premedication period (Mean+ SD)
DISCUSSION
Midazolam is a commonly prescribed drug for
premedication in children. Premedication with
midazolam has shown to be more
parental presence or placebo in reducing anxiety and
improving compliance at induction of
anesthesia[8,9,10]
.
The beneficial effects of midazolam include sedation,
anxiolysis and reduction of postoperative
vomiting[21]
. Abrams R et al have shown that
intranasal midazolam 0.2 mg/kg is effective in
reducing both separation and induction anxiety in
children, with minimal effect on recovery
However, the acceptability of intra nasal midazolam
by pediatric patients may vary19
. Undesirable effects
like restlessness, paradoxical reaction, and negative
postoperative behavioral changes have made it a less
than ideal agent for premedication[22,23]
amnesia is considered an advantage by some
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< 0.001) after drug administration in
Figure 1). The SBP was reduced
maximally by 12.3% at 60 min in Group D.
analysis showed that HR decreased
P < 0.001). The
HR became significantly reduced from baseline at 45
and 60 min after drug administration. The Heart rate
reduced maximally by 12% from baseline at 60
minutes ( Figure 2).
Systolic Blood Pressure during the Figure 2. Heart Rate during the
premedication period (Mean
Midazolam is a commonly prescribed drug for
premedication in children. Premedication with
midazolam has shown to be more effective than
parental presence or placebo in reducing anxiety and
improving compliance at induction of
The beneficial effects of midazolam include sedation,
of postoperative
. Abrams R et al have shown that
intranasal midazolam 0.2 mg/kg is effective in
reducing both separation and induction anxiety in
children, with minimal effect on recovery time [19]
.
nasal midazolam
. Undesirable effects
like restlessness, paradoxical reaction, and negative
postoperative behavioral changes have made it a less
[22,23]
. Although
amnesia is considered an advantage by some
authorities, it has also been regarded as a possible
disadvantage by others [24,25]
.
Dexmedetomidine is a newer  2
selective action on the  2-adrenoceptors and a
shorter half-life[13-18]
. Its bioavailability is 81.8%
(72.6–92.1%) when administered via
mucosa.
A randomized, crossover evaluation
volunteers, demonstrated that intransal
dexmedetomidine produces sedation in 45
In our present study, we have shown that
dexmeditomidine produces significantly better level
of sedation during separation from parents and during
induction of anaesthesia, compared to midazolam.
The behaviour of the children was satisfactory during
separation from parents and during induction of
anaethesia in children who were administered
dexmeditomidine. This was comparable
midazolam though there was no statistically
significant difference.
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300-306]
HR became significantly reduced from baseline at 45
and 60 min after drug administration. The Heart rate
reduced maximally by 12% from baseline at 60
Heart Rate during the
premedication period (Mean+ SD)
s also been regarded as a possible
-agonist with a more
adrenoceptors and a
. Its bioavailability is 81.8%
administered via the nasal
A randomized, crossover evaluation of healthy adult
volunteers, demonstrated that intransal
dexmedetomidine produces sedation in 45–60 min[26]
.
In our present study, we have shown that
dexmeditomidine produces significantly better levels
of sedation during separation from parents and during
induction of anaesthesia, compared to midazolam.
The behaviour of the children was satisfactory during
separation from parents and during induction of
anaethesia in children who were administered
editomidine. This was comparable to
though there was no statistically

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During our present study, we observed that some
children who had satisfactory scores of sedation and
behavior at separation from parents to move to
unsatisfactory levels at induction of anaesthesia. This
may be because, dexmedetomidine’s site of action in
the central nervous system (unlike conventional
gabaminergic sedative drugs, such as midazolam,) is
primarily in the locus coeruleus where it induces
electroencephalogram activity similar to natural
sleep[14,15]
. It is, therefore, not surprising that external
stimulation should facilitate arousal. However,
patients were less likely to become disorientated and
uncooperative.
Alpha 2-agonists produce a modest reduction in
Blood Pressure and Heart Rate. Munro et al. reported
that the reduction of blood pressure and HR were
less than 20% of baseline in children who were
sedated with an initial dose of 1 mcg/kg IV
dexmedetomidine, followed by a maintenance
infusion during cardiac catheterization[26]
. In this
study, dexmedetomidine was observed to reduce
Blood pressure (Fig.1) and Heart Rate(Fig.2).
However this was less than 20% of baseline and is
clinically insignificant and manageable.
Comparative effect of dexmeditomidine on the
recovery profile is beyond the scope of this study.
Further studies can be designed to study this effect.
CONCLUSION
We conclude that dexmeditomidine, in a dose of 1
mcg/Kg administered intransally as premedicant in
children aged 2-9 years, produces better sedation and
comparable behavioural scores, during separation
from parents and at induction of anaesthesia
compared to midazolam, in a dose of 0.2 mg/Kg intra
nasally. The haemodynamic changes produced with
dexmeditomidine are clinically insignificant (<20 %
of baseline) and modest.
REFERENCES
[1] Kain ZN.- Perioperative psychological trauma in children. In: Complications in Anesthesia. 1st Edition.
W.B. Saunders Company. Philadelphia 1999.
[2] Kain ZN, Caldwell-Andrews AA, Krivutza DM, Weinberg ME, Wang S-M, Gaal D. Trends in the practice
of parental presence during induction of anesthesia and the use of preoperative sedative premedication in
the United States, 1995–2002: results of a follow-up national survey. Anesth Analg 2004;98:1252–9
[3] Kain ZN, Mayes L, Bell C, Weisman S, Hofstadter M, Rimar S. - Premedication in the United States: a
status report. Anesth Analg 1997;84:427–32
[4] Kain ZN, Mayes LC, Wang SM, Caramico LA, Hofstadter MB.- Parental presence during induction of
anesthesia versus sedative premedication: which intervention is more effective? Anesthesiology
[5] Sedation and the peadiatric patient. In: Topics in Anesthesia and Critical care: Anesthesia and Intensive
Care in Neonates and Children. 1999: 1st Edition. Springer Co.
[6] Payne KA, Coetzee AR, Mattheyse FJ, et al. Behavioral changes in children following minor surgery-is
premedication beneficial? Acta Anesthesiol Belg 1992; 43:173.
[7] Watson AT, Visram A. Children’s preoperative anxiety and postoperative behaviour. Paediatr Anaesth
2003;13:188– 204
[8] Kain ZN, Hofstadter MB, Mayes LC, Krivutza DM, Alexander G, Wang SM, Reznick JS. Midazolam:
effects on amnesia and anxiety in children. Anesthesiology 2000;93:676–84
[9] Cote CJ, Cohen IT, Suresh S, Rabb M, Rose JB, Weldon C, Davis PJ, Bikhazi GB, Karl HW, Hummer KA,
Hannallah RS, Khoo KC, Collins P. A comparison of three doses of commercially prepared oral
midazolam syrup in children. Anesth Analg 2002;94:37–43
[10] Kogan A, Katz J, Efrat R, Eidelman LA. Premedication with midazolam in young children: a comparison
of four routes of administration. Paediatr Anaesth 2002;12:685–914. 19.
[11] Bergendahl H, Lonnqvist P-A, Eksborg S. Clonidine in paediatric anaesthesia: a review of the literature
and comparison with benzodiazepines for premedication. Acta Anaesthesiol Scand 2006;50:135–43
[12] Almenrader N, Passariello M, Coccetti B, Haiberger R, Pietropaoli P. Steal-induction after clonidine
premedication: a comparison of the oral and nasal route. Paediatr Anaesth 2007;17:230–4

7. 306
Prabhu thilaak et al / Int. J. of Res. in Pharmacology and Pharmacotherapeutics Vol-2(1) 2013 [300-306]
www.ijrpp.com
[13] Schmidt AP, Valinetti EA, Banderira D, Bertacchi MF, Simoes CM, Jose Otavio C Auler, JR. Effects of
preanesthetic administration of midazolam, clonidine, or dexmedetomidine on postoperative pain and
anxiety in children. Paediatr Anaesth 2007;17:667–74
[14] Yuen VM, Hui TW, Yuen MK, Irwin MG. A double blind crossover assessment of the sedative and
analgesic effects of intranasal dexmedetomidine. Anesth Analg 2007;105:374–80
[15] Khan ZP, Ferguson CN, Jones RM. Alpha-2 and imidazoline receptor agonists. Their pharmacology and
therapeutic role. Anaesthesia 1999;54:146–65
[16] Bloor B, Ward D, Belleville J, Maze M. Effects of intravenous dexmedetomidine in humans. II.
Hemodynamic changes. Anesthesiology1992;77:1134–42
[17] Petroz GC, Sikich N, James M, van Dyk H, Shafer SL, Schily M, Lerman J. A phase I, two-center study of
the pharmacokinetics and pharmacodynamics of dexmedetomidine in children. Anesthesiology
2006;105:1098–110
[18] Munro HM, Tirotta CF, Felix DE, Lagueruela RG, Madril DR, Zahn EM, Nykanen DG. Initial experience
with dexmedetomidine for diagnostic and interventional cardiac catheterization in children. Paediatr
Anaesth 2007;17:109–12
[19] Abrams R, Morrison JE, Villassenor A, et al. Safety and effectiveness of intranasal administration of
sedative medications for urgent brief pediatric dental procedures. Anesth Prog 1993; 4:63-6.
[20] Kain ZN, Mayes LC, Cicchetti DV, Bagnall AL, Finley JD, Hofstadter MB. The Yale Preoperative
sedation and behaviour Scales: how does it compare with a “gold standard”? Anesth Analg 1997;85:783–8
[21] Splinter WM, MacNeill HB, Menard EA, Rhine EJ, Roberts DJ,Gould MH. Midazolam reduces vomiting
after tonsillectomy in children. Can J Anaesth 1995;42:201–3
[22] Buffett-Jerrott SE, Stewart SH, Finley GA, Loughlan HL. Effects of benzodiazepines on explicit memory
in a paediatric surgery setting. Psychopharmacology (Berl) 2003;168:377–86
[23] Cox RG, Nemish U, Ewen A, Crowe M-J. Evidence-based clinical update: does premedication with oral
midazolam lead to improved behavioural outcomes in children? Can J Anaesth 2006;53:1213–19
[24] Lonnqvist PA, Habre W. Midazolam as premedication: is the emperor naked or just half-dressed?
Paediatr Anaesth 2005;15: 263–5
[25] Rosenberg H, Goldberg M. Postoperative emotional responses. In: Complications in Anesthesiology. 2nd
Edition. Lippincott-Raven Publishers. Philadelphia 1996.
[26] Anttila M, Penttila J, Helminen A, Vuorilehto L, Scheinin H. Bioavailability of dexmedetomidine after
extravascular doses in healthy subjects. Br J Clin Pharmacol 2003;56:691–3
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