1. Bozkurt P. Premedication of the pediatric patient – anesthesia for the uncooperative child.

Curr
Opin Anaesthesiol 2007; 20: 211– 215.

Premedication of the pediatric patient -

anesthesia for the uncooperative child
 PMID: 17479023
 DOI: 10.1097/ACO.0b013e328105e0dd

Abstract
Purpose of review: Inadequate handling of an uncooperative child preoperatively results in
postoperative behavior problems. Premedication enables a calm induction and helps to decrease
postoperative problems. Several premedicants will be covered in this review.

Recent findings: Questions raised about the effects of oral midazolam use in children for
premedication are now finding answers. New agents (dexmedetomidine and atypical
antipsychotic agents) can be alternatives in premedication, especially in severely uncooperative
children. The current literature highlights the missing information about the rather older
premedicants.

Summary: The benefits and disadvantages of new and older drugs should be weighed against
each other, and decisions should be made according to the requirements of surgery, ward
conditions and the severity of psychologic, developmental or mental disease. Further studies for
the evaluation of the anxiolytic, sedative and antipsychotic drugs are still required.

2. Strom S. Preoperative evaluation, premedication, and induction of anesthesia in infants and

children. Curr Opin Anesthesiol 2012; 25: 321–325.

Preoperative evaluation, premedication, and

induction of anesthesia in infants and
children
 PMID: 22488124
 DOI: 10.1097/ACO.0b013e3283530e0d

Abstract
Purpose of review: Preparation for and induction of anesthesia in children has evolved
significantly over the last decade, with particular reference to the reduction of perioperative
anxiety reduction by nonpharmacologic and pharmacologic means. Several new large population
studies and meta-analyses further scrutinize the current techniques.

Recent findings: Many nonpharmacologic methods to reduce anxiety are effective λU similar to
sedative premedications, with the exception of parent present induction of anesthesia. Healthcare
providers can be taught to increase anxiety-reducing behaviors through an educational
intervention. Clonidine and dexmedetomidine have many similar or superior qualities to
midazolam.

Summary: Larger studies still need to be conducted before wide-scale application of many
nonpharmalogical interventions such as parental acupuncture. Similarly, more investigation
should be done on outcomes such as onset, emergence, and discharge times, as well as the
postoperative response with reference to emergence delirium and postoperative nausea and
vomiting prevention to outline the differences among sedative premedications such as
midazolam, clonidine, and dexmedetomidine.

3. Chorney JM, Kain ZN. Behavioral analysis of children’s response to induction of anesthesia.
Anesth Analg 2009; 109: 1434–1440.

Behavioral analysis of children's response to

induction of anesthesia
 PMID: 19713262
 DOI: 10.1213/ane.0b013e3181b412cf

Abstract
Background: It is documented that children experience distress at anesthesia induction, but little
is known about the prevalence of specific behaviors exhibited by children.

Method: Digital audiovisual recordings of 293 children undergoing outpatient elective surgery
were coded using Observer XT software and the validated Revised Perioperative Child-Adult
Medical Procedure Interaction Scale. Multiple pass second-by-second data recording was used to
capture children's behaviors across phases of anesthesia induction.

Results: More than 40% of children aged 2-10 yr displayed some distress behavior during
induction with 17% of these children displaying significant distress and more than 30% of
children resisting anesthesiologists during induction. Children's distress and nondistress
behaviors displayed four profiles over the course of anesthesia induction: Acute Distress,
Anticipatory Distress, Early Regulating Behaviors, and Engagement with Procedure. Older
children had higher scores on early regulating and engagement profiles whereas younger children
had higher scores on Acute Distress. There were no differences across age in children's
Anticipatory Distress. Construct validity of behavior profiles was supported via correlations of
profile score (overall and on the walk to the operating room) with a validated assessment of
children's anxiety at induction.

Conclusions: Children undergoing anesthesia display a range of distress and nondistress

behaviors. A group of behaviors was identified that, when displayed on the walk to the operating
room, is associated with less distress at anesthesia induction. These data provide the first
examination of potentially regulating behaviors of children, but more detailed sequential analysis
is required to validate specific functions of these behaviors.
 4. Watson AT, Visram A. Children’s preoperative anxiety and postoperative behaviour. Pediatr
Anaesth 2003; 13: 188–204.

5. Almenrader N, Passariello M, Coccetti B et al. Premedication in children: a comparison of oral

midazolam and oral clonidine. Pediatr Anesth 2007; 17: 1143–1149.

Premedication in children: a comparison of

oral midazolam and oral clonidine
 PMID: 17986032
 DOI: 10.1111/j.1460-9592.2007.02332.x

Abstract
Background: Oral premedication is widely used in pediatric anesthesia to reduce preoperative
anxiety and ensure smooth induction. Midazolam is currently the most commonly used
premedicant, but good results have also been reported with clonidine. The aim of the present
study was to compare clinical effects of oral midazolam and oral clonidine.

Methods: We performed a prospective open study in 64 children who were randomly assigned
to receive either oral midazolam 0.5 mg.kg (-1) (group M) or oral clonidine 4 microg.kg (-1)
(group C) prior to mask induction. Drug acceptance, preoperative sedation and anxiolysis,
quality of mask acceptance, recovery profile and parental satisfaction were evaluated.

Results: The taste of oral clonidine was judged as significantly better; 14% of children rejected
oral midazolam. Onset of sedation was significantly faster after premedication with midazolam
(30+/-13.1 min) than with clonidine (38.5+/-14.6 min), but level of sedation was significantly
better after premedication with clonidine. Quality of mask induction was equally successful in
both groups. A steal-induction was performed in 66% of patients of group C, but none in group
M. We observed a trend towards an increased incidence of emergence agitation after
premedication with midazolam. Parental satisfaction was significantly higher in group C.

Conclusions: In this study, premedication with oral clonidine appeared to be superior to oral
midazolam. Quality of mask acceptance was comparable between groups, but oral clonidine was
better accepted by the child, produced more effective preoperative sedation, showed a trend
towards better recovery from anesthesia and had a higher degree of parental satisfaction.

6. Splinter WM, MacNeill HB, Menard EA et al. Midazolam reduces vomiting after tonsillectomy in
children. Can J Anaesth 1995; 42: 201–203.

Midazolam reduces vomiting after

tonsillectomy in children
Abstract
The purpose of this study was to assess the effect of midazolam on vomiting after tonsillectomy
in children. We compared 215 children aged 1.5–14 yr undergoing tonsillectomy or
adenotonsillectomy under general anaesthesia with nitrous oxide and halothane. In a double-
blind fashion the subjects were administered either placebo or midazolam 75 μg · kg−1 iv after
induction of anaesthesia. After the operation, the number of emetic episodes and the length of
stay in hospital were recorded. The groups were similar with respect to age, weight, sex, mode of
induction, duration of anaesthesia, surgical procedure, opioid administration and length of stay in
the PAR and the Day Care Surgical Unit. The 108 midazolam-treated children had a lower
incidence (42% vs 57%) of vomiting than the placebo group, P < 0.02. The placebo group had a
higher incidence (9% vs 2%) of unscheduled admissions to hospital due to nausea and vomiting,
P < 0.05. It is concluded that midazolam administered intravenously to children intraoperatively
reduces vomiting after tonsillectomy.

7. Kain ZN, Hofstadter MB, Mayes LC et al. Midazolam: effects on amnesia and anxiety in children.
Anesthesiology 2000; 93: 676–684.

Midazolam: effects on amnesia and anxiety in

children
 PMID: 10969300
 DOI: 10.1097/00000542-200009000-00016

Abstract
Background: The minimum time interval between administration of oral midazolam and
separation of children from their parents that ensures good anterograde amnesia has not been
previously determined. This is of particular importance in a busy operating room setting where
schedule delays secondary to midazolam administration may not be tolerated.

Methods: Children (n = 113) undergoing general anesthesia and surgery completed preoperative
baseline memory testing using a validated series of picture cards and were randomly assigned to
one of three midazolam groups or a control group. Exactly, 5, 10, or 20 min after receiving oral
midazolam (0.5 mg/kg) or 15 min after receiving placebo, children were administered a second
memory test that used pictures. Anxiety of children was assessed during induction of anesthesia
with use of a validated anxiety measurement tool. Postoperatively, recall and recognition for
picture cards seen during baseline testing and postintervention testing were assessed.

Results: Postoperatively, recall and recognition of pictures presented to patients after drug
administration (anterograde amnesia) showed significant group differences (P = 0.0001), with
recall impaired in the 10- (P = 0.004) and 20-min groups (P = 0.0001). Similarly, recognition
memory was impaired in the 5- (P = 0.0008), 10- (P = 0.0001) and 20-min (P = 0.0001) groups.
Significant anxiolytic effects of midazolam were observed as early as 15 +/- 4 min after
midazolam administration (P = 0.02).

Conclusions: Midazolam administered orally produces significant anterograde amnesia when

given as early as 10 min before a surgical procedure.

8. Levine MF, Spahr-Schopfer IA, Hartley E et al. Oral midazolam premedication in children: the
minimum time interval for separation from parents. Can J Anaesth 1993; 40: 726–729.

Oral midazolam premedication in children:

the minimum time interval for separation
from parents
 PMID: 8403157
 DOI: 10.1007/BF03009769

Abstract
To determine the minimum time interval between oral midazolam (0.5 mg.kg-1) premedication
and separation from parents that ensures a smooth separation, 30 children were assigned
randomly to one of three groups (ten children per group). The groups differed only in the time
interval between administration of midazolam and separation from their parents: 10, 20 or 30
min. Heart rate, systolic blood pressure, and sedation and anxiolysis scores were assessed before
midazolam premedication (baseline), at the time of separation from parents, and during the
application of a face mask at the induction of anaesthesia. We found that heart rate and systolic
blood pressure changes were similar for all three groups throughout the study period. Sedation
scores at the time of separation from parents and on application of the mask for all three groups
were greater than baseline values. Sedation scores at separation did not differ among the three
groups. Anxiolysis values did not differ from baseline values at any time for all three groups. We
conclude that children may be separated from their parents as early as ten minutes after receiving
oral midazolam, 0.5 mg.kg-1.

9. McGraw T, Kendrick A. Oral midazolam premedication and postoperative behaviour in children.

Pediatr Anaesth 1998; 8: 117–121.

Oral midazolam premedication and

postoperative behaviour in children
 PMID: 9549736
 DOI: 10.1046/j.1460-9592.1998.00724.x

Abstract
We examined the effect of oral midazolam premedication on postoperative behaviour. Seventy
children (ASA Physical Status 1 and 2; aged 1-10 yrs) were assigned randomly in a prospective,
blinded fashion to receive either midazolam 0.5 mg.kg-1 (maximum 10 mg) or placebo.
Behaviour assessments were made prior to medication, during induction of anaesthesia and 15
min following arrival to recovery room. The baseline behavioural evaluation scores were not
significantly different. The children receiving midazolam cried significantly less during
induction (P < or = 0.02). At one week follow-up, eight of 35 subjects receiving placebo had
experienced adverse behaviour changes (nightmares, night terrors, food rejection, anxiety,
negativism); 19 of 35 of the midazolam group experienced these changes (P < or = 0.02). At four
week follow-up, most behaviour changes had resolved. Children given preoperative oral
midazolam were less likely to cry and fight while being anaesthetized, and preoperative sedation
was associated with increased incidence of adverse postoperative behaviour changes.

10. Kanegaye JT, Favela JL, Acosta M et al. High-dose rectal midazolam for pediatric procedures: a
randomized trial of sedative efficacy and agitation. Pediatr Emerg Care 2003; 19: 329–336.

High-dose rectal midazolam for pediatric

procedures: a randomized trial of sedative
efficacy and agitation
John T Kanegaye 1 , Jorge L Favela, Mark Acosta, David E Bank
Affiliations

 PMID: 14578832
 DOI: 10.1097/01.pec.0000092578.40174.85

Abstract
Objectives: To compare 2 doses of rectal midazolam, used for pediatric emergency department
sedation, with regard to sedative efficacy and frequency of paradoxical agitation.

Methods: Children <or=48 months old undergoing cutaneous procedures received midazolam
by rectum, randomized in double-blind fashion to standard (0.5 mg/kg, SDM) or high (1 mg/kg,
HDM) doses. Behaviors were scored on a 5-point sedation scale before and during procedures.
Proportions manifesting successful sedation and postprocedure agitation were compared between
the 2 doses.

Results: Sixty-five patients (32 SDM, 33 HDM) underwent sedated procedures (repair of
lacerations, 97%). Behavior scores improved for both groups following medication
administration and at best sedation during procedure. HDM produced better sedation at time of
first suture (successful sedation: 70%, SDM vs. 91%, HDM; intergroup difference = 21%; 95%
confidence interval [CI] = 2, 41) and at best point during the procedure (72%, SDM vs. 97%,
HDM; Delta = 25%; 95% CI = 8, 43). However, sedative efficacy declined such that only 50%
and 73% of the SDM and HDM groups, respectively, had successful sedation at the worst point
during the procedures. Postprocedure agitation occurred in 17% of patients (6%, SDM vs. 27%,
HDM; Delta = 21%; 95% CI = 3, 39).

Conclusions: Rectal midazolam improved sedation scores over preprocedure levels and was
more effective with a dose of 1 mg/kg than with 0.5 mg/kg. However, inadequate sedation in 27-
50% of patients and prolonged agitation in 27% of patients at higher doses counter the
advantages of rectal midazolam.
 11. Petroz GC, Sikich N, James M et al. A phase I, two-center study of the pharmacokinetics and
pharmacodynamics of dexmedetomidine in children. Anesthesiology 2006; 105: 1098– 1110.

A phase I, two-center study of the

pharmacokinetics and pharmacodynamics of
dexmedetomidine in children
 PMID: 17122572
 DOI: 10.1097/00000542-200612000-00009

Free article

Abstract
Background: To investigate dexmedetomidine in children, the authors performed an open-label
study of the pharmacokinetics and pharmacodynamics of dexmedetomidine.

Methods: Thirty-six children were assigned to three groups; 24 received dexmedetomidine and
12 received no drug. Three doses of dexmedetomidine, 2, 4, and 6 microg x kg x h, were infused
for 10 min. Cardiorespiratory responses and sedation were recorded for 24 h. Plasma
concentrations of dexmedetomidine were collected for 24 h and analyzed. Pharmacokinetic
variables were determined using nonlinear mixed effects modeling (NONMEM program).
Cardiorespiratory responses were analyzed.

Results: Thirty-six children completed the study. There was an apparent difference in the
pharmacokinetics between Canadian and South African children. The derived volumes and
clearances in the Canadian children were V1 = 0.81 l/kg, V2 = 1.0 l/kg, Cl1 (systemic clearance)
= 0.013 l x kg x min, Cl2 = 0.030 l x kg x min. The intersubject variabilities for V1, V2, and Cl1
were 45%, 38%, and 22%, respectively. Plasma concentrations in South African children were
29% less than in Canadian children. The volumes and clearances in the South African children
were 29% larger. The terminal half-life was 110 min (1.8 h). Median absolute prediction error
for the two-compartment mammillary model was 18%. Heart rate and systolic blood pressure
decreased with time and with increasing doses of dexmedetomidine. Respiratory rate and oxygen
saturation (in air) were maintained. Sedation was transient.

Conclusion: The pharmacokinetics of dexmedetomidine in children are predictable with a

terminal half-life of 1.8 h. Hemodynamic responses decreased with increasing doses of
dexmedetomidine. Respiratory responses were maintained, whereas sedation was transient.

12. Mason KP, Zgleszewski SE, Prescilla R et al. Hemodynamic effects of dexmedetomidine sedation
for CT imaging studies. Pediatr Anesth 2008; 18: 393–402.

Hemodynamic effects of dexmedetomidine

sedation for CT imaging studies
 PMID: 18363628
 DOI: 10.1111/j.1460-9592.2008.02451.x

Abstract
Background: Dexmedetomidine sedation for radiological imaging studies is a relatively recent
application for this drug. Previous studies have demonstrated some haemodynamic effects of
dexmedetomidine, however, the effects remain poorly described in children. The aim of this
study was to better define the effect of age on heart rate (HR) and blood pressure changes in
children sedated for CT imaging with dexmedetomidine.

Methods/materials: At our institution dexmedetomidine is given for sedation for CT imaging as

a bolus of 2 mcg.kg(-1) over 10 min followed by an infusion of 1 mcg.kg(-1).h(-1) with a second
bolus if required. Detailed quality assurance data sheets document patient demographics,
sedation outcomes, adverse events, and hemodynamic data are recorded for each patient.

Results: A total of 250 patients (range 0.1-10.6 years) received dexmedetomidine. ANOVA
revealed strong evidence for changes in HR and mean arterial blood pressure during bolus and
infusion relative to presedation values (P < 0.001). These changes were apparent in each age
group and similar between groups. During the first bolus and during infusion, 82% and 93% of
patients respectively were within the age-based normal range for HR. For mean arterial blood
pressure, 70% of patients were within the normal range during first bolus and 78% during
infusion.

Conclusion: In the pediatric population studied, intravenous dexmedetomidine sedation was

associated with modest fluctuations in HR and blood pressure. Hemodynamic changes were
independent of age, required no pharmacologic interventions and did not result in any adverse
events. By anticipating these possible hemodynamic effects and avoiding dexmedetomidine in
those patients who may not tolerate such fluctuations in HR and blood pressure,
dexmedetomidine is an appropriate sedative for children undergoing CT imaging.

13. Mason KP, Zurakowski D, Zgleszewski SE et al. High dose dexmedetomidine as the sole sedative
for pediatric MRI. Pediatr Anesth 2008; 18: 403–411.

High dose dexmedetomidine as the sole

sedative for pediatric MRI
 PMID: 18363626
 DOI: 10.1111/j.1460-9592.2008.02468.x

Abstract
Objective: This large-scale retrospective review evaluates the sedation profile of
dexmedetomidine.

Aim: To determine the hemodynamic responses, efficacy and adverse events associated with the
use of high dose dexmedetomidine as the sole sedative for magnetic resonance imaging (MRI)
studies.

Background: Dexmedetomidine has been used at our institution since 2005 to provide sedation
for pediatric radiological imaging studies. Over time, an effective protocol utilizing high dose
dexmedetomidine as the sole sedative agent has evolved.

Methods/materials: As part of the ongoing Quality Assurance process, data on all sedations are
reviewed monthly and protocols modified as needed. Data were analyzed from all 747
consecutive patients who received dexmedetomidine for MRI sedation from April 2005 to April
2007.

Results: Since 2005, the 10-min loading dose of our dexmedetomidine protocol increased from 2
to 3 microg.kg(-1), and the infusion rate increased from 1 to 1.5 to 2 microg.kg(-1).h(-1). The
current sedation protocol progressively increased the rate of successful sedation (able to
complete the imaging study) when using dexmedetomidine alone from 91.8% to 97.6% (P =
0.009), reducing the requirement for adjuvant pentobarbital in the event of sedation failure with
dexmedetomidine alone and decreased the mean recovery time by 10 min (P < 0.001). Although
dexmedetomidine sedation was associated with a 16% incidence of bradycardia, all concomitant
mean arterial blood pressures were within 20% of age-adjusted normal range and oxygen
saturations were 95% or higher.

Conclusion: Dexmedetomidine in high doses provides adequate sedation for pediatric MRI
studies. While use of high dose dexmedetomidine is associated with decreases in heart rate and
blood pressure outside the established 'awake' norms, this deviation is generally within 20% of
norms, and is not associated with adverse sequelae. Dexmedetomidine is useful as the sole
sedative for pediatric MRI.

14. Fazi L, Jantzen EC, Rose JB et al. A comparison of oral clonidine and oral midazolam as
preanesthetic medications in the pediatric tonsillectomy patient. Anesth Analg 2001; 92: 56–61.

A comparison of oral clonidine and oral

midazolam as preanesthetic medications in
the pediatric tonsillectomy patient
 PMID: 11133600
 DOI: 10.1097/00000539-200101000-00011

Abstract
We compared the effects of oral clonidine (4 microg/kg) and midazolam (0.5 mg/kg) on the
preanesthetic sedation and postoperative recovery profile in children during tonsillectomy with
or without adenoidectomy. In a double-blinded, double-dummy study design, 134 ASA physical
status I-II children aged 4-12 yr were randomized to receive a combination of either clonidine
and placebo (Group A), or placebo and midazolam (Group B) at 60-90 min and 30 min,
respectively, before the induction of anesthesia. Children in the clonidine group exhibited more
intense anxiety on separation and during induction of anesthesia via a mask as measured by the
modified Yale Preoperative Anxiety Scores. They also had significantly lower mean
intraoperative arterial blood pressures, shorter surgery, anesthesia, and emergence times, and a
decreased need for supplemental oxygen during recovery compared with the midazolam group.
However, the clonidine group had larger postoperative opioid requirements, maximum
excitement and pain scores based on the Children's Hospital of Eastern Ontario scale in the Phase
1 postanesthetic care unit. There were no differences between the two groups in the times to
discharge readiness, postoperative emesis, unanticipated hospital admission rates, postdischarge
maximum pain scores, and 24 h analgesic requirements. The percentage of parents who were
completely satisfied with the child's preoperative experience was significantly higher in the
midazolam group. There were no differences in parental satisfaction with the recovery period.
We conclude that under the conditions of this study, oral midazolam is superior to oral clonidine
as a preanesthetic medication in this patient population.

Implications: We compared preanesthetic sedation and postoperative recovery after oral

clonidine (4 microg/kg) and midazolam (0.5 mg/kg) in children during tonsillectomy. The
clonidine group had greater preoperative anxiety and shorter surgery and anesthesia times, but
required more postoperative analgesia. Delayed recovery and discharge times did not differ.
Midazolam was superior to clonidine as oral preanesthetic medication for these patients.