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A Randomized, clinical trial of oral midazolam plus placebo versus oral midazolam
plus oral ketamine for sedation during laceration repair.
Amit Assa MD, Eran Kozer MD
Pediatric Emergency Service, Assaf Harofeh Medical Center, Zerifin 70300, Israel.
Address for correspondence:
Eran Kozer MD
Pediatric Emergency
Assaf Harofeh Medical Center
Zerifin 70300, Israel
Tel: 972-8-9778131 Fax: 972-8-9779914
E mail: [email protected]
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‫תקציר‬
‫מתן פומי של מידזולם וקטאמין לעומת מידזולם ואינבו במיון לצורך סדציה בילדים העוברים‬
‫תפירת חתך‪ :‬מחקר מבוקר‪ ,‬כפול סמיות‪.‬‬
‫עמית אסא‪ ,‬ערן קוצר‬
‫רקע‪ :‬ילדים רבים הפונים למיון ילדים לצורך תפירה של חתכים נזקקים לסדציה במהלך ההליך הרפואי‪ .‬אחד‬
‫מהפרוטוקלים הנפו צים ביותר טרם סדציה לצורך תפירת חתך הוא שימוש פומי במידזולם‪ ,‬אולם מספר עבודות הראו‬
‫שלעיתים עומק ההרדמה אינו מיטבי בשיטה זו‪ .‬מספר עבודות בחנו את השימוש בקטאמין פומי לסדציה לפני הליכים‬
‫רפואיים עם תוצאות מעודדות‪ .‬שילוב של שני החומרים במתן פומי נבדק רק בחולים עם ממאירויות בזמן ביצוע פעולות‬
‫פולשניות‪ .‬נכון לעת זו טרם פורסם מחקר מבוקר הבודק שימוש של שני החומרים יחדיו במתן פומי בילדים הזקוקים‬
‫לתפירת חתך‪ .‬מטרת העבודה ‪ :‬לקבוע את היעילות של הוספת קטאמין פומי למידזולם פומי לצורך סדציה בילדים‬
‫הזקוקים לתפירת חתך במיון וזאת‪ ,‬בהשוואה לשימוש במידזולם פומי יחד עם אינבו‪ .‬מתווה‪ :‬מחקר כפול סמיות‪ ,‬מבוקר‬
‫אינבו‪ .‬סביבת המחקר ‪ :‬המחלקה לרפואה דחופה בבית החולים אסף הרופא‪ .‬משתתפים‪ :‬ילדים בגילאים שנתיים עד ‪8‬‬
‫שנים עם חתכים הדורשים תפירה‪ .‬התערבות‪ :‬חולים המתאימים להכללה יחולקו באופן אקראי לשתי קבוצות‪ :‬קבוצה בה‬
‫ילדים יטופלו במידזולם פומי ואיבו וקבוצה בה יטופלו הילדים במידזולם פומי וקטאמין פומי‪ .‬מידזולם ינתן פומית במינון‬
‫של ‪ 0.7‬מ"ג‪/‬ק"ג (מינון מירבי‪ 10 -‬מ"ג) יחד עם אינבו או במינון של ‪ 0.5‬מ"ג‪/‬ק"ג (מירבי‪ 10 -‬מ"ג) יחד עם קטאמין‬
‫פומי במינון של ‪ 5‬מ"ג‪/‬ק"ג‪ .‬המטופלים והצוות הרפואי לא ידעו באיזה פרוטוקול טופלו‪ .‬ניטור החולים יבוצע ע"פ‬
‫ההמלצות לניטור וטיפול בילדים במהלך ולאחר סדציה להליכים רפואיים של האקדמיה האמריקאית לרפואת ילדים וע"פ‬
‫הנחיות משרד הבריאות הישראלי באשר לסדציה בילדים ע"י רופא שאינו מרדים‪ .‬תוצאות‪ :‬ההבדל בין ‪ 2‬הפרוטוקולים‬
‫יוערך ע"י מדידת רמת הכאב בזמן התפירה ע"י ההורה המלווה ומדידת עומק הסדציה במהלך התפירה ע"י רופא המיון‪.‬‬
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Abstract
Background: Sedation is often needed for young children undergoing minor procedures in the
emergency department (ED). Oral midazolam is one of the most commonly used regimens for
children undergoing laceration repair but its sedative efficacy was shown to be suboptimal. In
few studies oral ketamine has been used successfully for procedural sedation as well. The
efficacy of using a combination of oral midazolam and oral ketamine for procedural sedation
has been studied only for invasive procedures in children with malignancies. No randomized
control study was performed using this sedative combination in children requiring laceration
repair. Objectives: To determine the efficacy of adding oral ketamine to oral midazolam for
procedural sedation in children requiring laceration repair compares to oral midazolam plus
placebo. Design: A randomized, double blind, placebo-controlled study. Setting: Pediatric
Emergency Department. Participants: Children 2 to 8 years with laceration requiring sedation.
Interventions: Eligible patients will be randomly assigned to one of two treatment groups: oral
midazolam plus oral placebo group and oral midazolam plus oral ketamine group. Both groups
will be given the same volume of medications. Midazolam will be given orally in a dose of 0.7
mg/kg (max.-10 mg) with placebo or 0.5 mg/kg (max.- 10 mg) with oral ketamine in a dose of
5 mg/kg. The medical staff will be blinded to the treatment given. Patient monitoring will be
conducted according to the American Academy of Pediatrics (APP) and the Israeli health
ministry guidelines for monitoring and management of pediatric patients during and after
sedation for diagnostic and therapeutic procedures. Main outcome measures: Pain score:
Visual Analog Score (VAS)- by parent and sedation activity score-by ED physician. Data
analysis: Descriptive statistics will be used to describe the study population. Data will be
analyzed using t- tests for continuous data and Fisher exact test for categorical data.
Key words: sedation, children, ketamine, midazolam, emergency department.
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Statement of problem:
Sedation is often needed for young children undergoing minor procedures in the emergency
department (ED). Oral midazolam is one of the most commonly used regimens for children
undergoing laceration repair but its sedative efficacy was shown to be suboptimal. In few studies
oral ketamine has been used successfully for procedural sedation as well. Side effects of both
drugs are well described and are shown to be dose dependent. The efficacy of using a combination
of oral midazolam and oral ketamine for procedural sedation has been studied only for invasive
procedures in children with malignancies. To the best of our knowledge there is no published
randomized control study, up-to-date, using this regimen in children requiring laceration repair.
This prospective randomized controlled study is aimed to determine whether a protocol of oral
midazolam and oral ketamine is more efficacious by means of sedation and pain scales than oral
midazolam alone for children undergoing laceration repair.
Identification of an improved sedation regimen for children requiring laceration repair is of interest
of any ED physician in order to achieve better pain and anxiety control with as minimal side
effects as possible.
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Introduction:
Sedation is often needed for young children undergoing minor procedures in the emergency
department (ED). Oral midazolam is a commonly used sedative for children undergoing
procedures such as laceration repair. The reported efficacy of oral midazolam for procedural
sedation is 60% to 76% (1,2). Common side effects include agitation and respiratory depression
resulting in oxygen desatoration (3-7). These reactions have been shown to be dose dependent. In
few studies oral ketamine sedation has also been used successfully for wound care procedures in
children with burns (8) for invasive procedures in pediatric oncology patients (9) and for children
requiring laceration repair (10). Younge et al (11) have compared high oral doses of ketamine
versus midazolam in order to sedate children before wound repair. This study has showed better
tolerance to local anaesthetic injection with oral ketamine describing only minor, non-significant
side effects. Common known side effects of ketamine include vomiting, transient ataxia and
drowsiness (10,11,12,13). Oxygen desaturation is a rare complication described only with
intravenous or intramuscular delivery (12).
The efficacy of using oral midazolam and oral ketamine together for procedural sedation has been
studied only for invasive procedures in children with malignancies (14). It was concluded that this
combination is as effective as similar combination using rectal or intravenous route. We
hypothesize that a combination of oral midazolam and oral ketamine can provide superior sedation
to either drug alone. Furthermore, given the relationship between dose and the development of side
effects related to both drugs separately, we hypothesize that using a combination of lower doses
than that used in other studies will lead to a decrease in side effects related to both medications. To
the best of our knowledge there is no published, randomized control study which compares oral
midazolam to oral midazolam plus oral ketamine for sedation during laceration repair.
Identification of an improved sedation regimen for children requiring laceration repair is of interest
of any ED physician in order to achieve better pain and anxiety control with as minimal side
effects as possible.
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Hypothesis:
A combination of oral midazolam and oral ketamine can provide superior sedation to oral
midazolam alone in children requiring sedation for laceration repair. Adding oral ketamine to the
commonly used oral midazolam can help to achieve better sedation at lower doses of midazolam
with fewer side effects.
Objectives:
To determine the efficacy of adding oral ketamine to oral midazolam for procedural sedation in
children requiring laceration repair compares to oral midazolam.
Methods:

Design: A prospective, randomized, double blind, placebo-controlled study.

Patients: All children at age 2 to 8 years requiring sedation for laceration repair admitted
to assaf Harofeh medical center pediatric ED.
Inclusion criteria:

Age: 2 years – 8 years

Any child with laceration requiring sedation
Exclusion criteria:

Major injuries in addition to the laceration

Closed head injury associated with loss of consciousness

Abnormal neurologic examination in a previously normal child

Significant developmental delay or baseline neurologic deficit

Severe trauma with suspected internal injuries

Elevated intra-cranial pressure

Suspected hypersensitivity to midazolam or ketamine

Hypertension

alcohol intoxication or a history of alcohol abuse
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
Acute or chronic respiratory, cardiac, renal or hepatic abnormalities

Glaucoma

Known psychiatric disease
Intervention:
The study will be conducted at assaf harofeh medical center- pediatric emergency department
(PED). Eligible patients will be recruited during admission to the PED. All enrolled patients will
received either oral midazolam in a dose of 0.7 mg/kg (maximum 10 mg), a standard sedation
protocol for laceration repair in the ED, plus placebo or a combination of oral midazolam- 0.5
mg/kg and ketamine- 5 mg/kg. Patients will be randomized by the hospital pharmacist in blocks of
4 to receive either regimen. The pharmacist will be the only person aware of the randomization
status of the patient. ED nursing staff will administer all medications. Study personnel will note
compliance with the medications.
Oral midazolam (0.5 mg/kg; maximum 10 mg) will be administered first. The patient will be then
given oral ketamine or placebo, and ED nursing staff will apply lidocaine, epinephrine, and
tetracaine to the wound (if appropriate). Intradermal buffered lidocaine (1%) will be administered
if additional analgesia was necessary for either irrigation or suturing.
Laceration repair will be performed by an ED physician not involved in data collection and will be
expected to take place within 20 to 30 minutes after administration of midazolam and study
medication.
All patients will have cardiorespiratory and oxygen saturation monitoring from the time of drug
administration. A study nurse will remain with the patient from the time of sedative medication
administration until the patient will be discharged. Study personnel will document vital signs,
oxygen saturation, activity score for sedation (appendix 1), and visual analog scale (VAS) for pain
(appendix 2). A VAS chart will be given to the attending parent to fill. The activity score is
commonly used as a measure of sedation in studies of children whereas the VAS method is
commonly used as a measure of pain. Documentation of study measures will be done before
sedative administration, at the time of sedative administration, and every 5 minutes thereafter until
the patient will regain full consciousness. The study nurse also will document the presence of
complications (oxygen desaturation, vomiting ect.). Procedure time will be documented and will be
defined as the time from the draping of the patient for suturing until the time when the drape was
removed.
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Main outcome measures:

Pain score: Visual analog score (VAS)- by parent

Sedation activity score-by ED physician
Secondary outcome measures:

VAS by nurse

Time to reach activity score of less then 4

Procedure time

Time from procedure to discharge

The occurrence of side effects during the ED stay
Data analysis:
Descriptive statistics will be used to describe the study population. Data will be analyzed using ttests for continuous data and Fisher exact test for categorical data.
Sample size:
Convenient sample would be around 100 patients.
Safety:
There is satisfactory data regarding safety of oral midazolam and ketamin. None of the studies
performed on both medications- separately or in combination, has shown any life- threatening side
effect. According to the current literature we are not expecting any major complications during the
study. Patient monitoring will be conducted according to the American Academy of Pediatrics
(APP) and the Israeli health ministry guidelines for monitoring and management of pediatric
patients during and after sedation for diagnostic and therapeutic procedures.
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Ethics:
Informed consent will be obtained from every patient’s legal guardian. The study will be
conducted according to the ethical principles of the Declaration of Helsinki (Medical Association.
Declaration of Helsinki: ethical principles for medical research involving human subjects. FerneyVoltaire: WMA, 2002. www.wma.net/e/policy/b3.htm.
Significance:
Procedural sedation is still being studied intensively in order to achieve the most efficacious
sedation regimen for each specific procedure. Identification of an improved sedation regimen for
children requiring laceration repair is of interest of any ED physician in order to achieve better
pain and anxiety control with as minimal side effects as possible.
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Time table
Date
November 1st - November 30th
2006
December 1st 2006 – April 30th
2007
May 1st – June 30th 2007
Study phase
Pilot
Study period
Staff recruiting & training
Data base formation
Patients recruiting
Data analysis
Data analysis
Investigators responsibility
Responsibilities
Name
Eran Kozer
Amit Assa
Principle

Staff recruiting & training
Investigator

Data Analysis
Principle

Staff recruiting & training
Investigator

Data Analysis
Investigators resources

Dr Kozer is the head of the pediatric emergency services at Assaf Harofeh Medical
Center. Dr Kozer is an experienced investigator and conducted numerous clinical
trials.

Dr Assa is a resident in pediatrics at Assaf Harofeh Medical Center.
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Appendix 1: Activity scale
1. Asleep, not readily arousable
2. Asleep, slowly responds to verbal instructions
3. Drowsy, readily responds to verbal instructions
4. Awake, calm
5. Awake, active
Appendix 2: Visual Analog Scale (VAS)
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References
1. Davies FC, Waters M. Oral midazolam for conscious sedation of children during minor
procedures. J Accid Emerg Med 1998;15:244-8.
2. Silver T, Wilson C, Webb M. Evaluation of two dosages of oral midazolam as a conscious
sedation for physically and neurologically compromised pediatric dental patients. Pediatr Dent
1994;16:350-9.
3. Hennes HM, Wagner V, Bonadio W, et al. The effect of oral midazolam on anxiety of preschool
children during laceration repair. Ann Emerg Med 1990;19:1006–9.
4. Taiwo B, Flowers M, Zoltie N. Reducing children's' fear when undergoing painful procedures.
Arch Emerg Med 1992;9:306–9.
5. Davies FC, Waters M. Oral midazolam for conscious sedation of children during minor
procedures. J Accid Emerg Med 1998;15:244–8.
6. McMillian CO, Sparth-Schopfer IA, et al. Premedication of children with oral midazolam. Can J
Anaesth 1992;39:545–50.
7. Weldon CB, Watcha MF, White PF. Oral midazolam in children: effect of time and adjunctive
therapy. Anesth Analg 1992;75:51–5.
8. Humphries Y, Melson M, Gore D. Superiority of oral ketamine as an analgetic and sedative for
wound care procedures in the pediatric patients with burns. J Burn Care Rehabil 1997;18:34-6.
9. Tobias JD, Phipps S, Smith B, Mulhern RK. Oral ketamine premedication to alleviate the distress
of invasive procedures in pediatric oncology patients. Pediatrics 1992;90(4):537-41.
10. Qureshi FA, Mellis PT, McFadden MA. Efficacy of oral ketamine for providing sedation and
analgesia to children requiring laceration repair. Pediatr Emerg Care 1995;11:93–7.
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11. Younge PA, Kendall JM. Sedation for children requiring wound repair: a randomized controlled
double blind comparison of oral midazolam and oral ketamine. Emer Med J 2001;18:30-3.
12. Green SM, Rothrock SG, Lynch EL, et al. Intramuscular ketamine for pediatric sedation in the
emergency department: safety profile in 1,022 cases. Ann Emerg Med 1998;31:688–97.
13. McGlone RG, Ranasinghe S, Durham S. An alternative to `'brutacaine'': a comparison of low dose
intramuscular ketamine with intranasal midazolam before suturing. J Accid Emerg Med
1998;15:231–6.
14. Ozdemir D, Kayserili E, Arslanoglu S, Gulez P, Vergin C. Ketamine and midazolam for invasive
procedures in children with malignancy: a comparison of routes of intravenous, oral and rectal
administration. J Trop Pediatr 2004;50(4):224-8.