Criteria abstracted from The Users' Guide to Medical Literature, from the Health Information Research Unit and Clinical Epidemiology and Biostatistics, McMaster University

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Article Reviewed:

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Does midazolam alter the clinical effects of intravenous ketamine sedation in children? A double-blind, randomized, controlled, emergency department trial.

Wathen JE, Roback MG, Mackenzie T, Bothner JP.

Ann Emerg Med. 2000;36(6):579-588. [abstract]

Reviewed by Julie Haizlip MD, Primary Children's Medical Center, University of Utah, Salt Lake City, Utah

Review posted May 22, 2001

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I. What is being studied?:

The study objective:

To investigate the frequency and severity of adverse effects, specifically emergence phenomena in pediatric patients receiving IV ketamine with or without midazolam.

The study design:

A prospective, randomized double-blind, controlled trial.

The patients included:

Inclusion criteria were: age 4 months to 18 years, to receive ketamine for procedural sedation in the emergency department, American Society of Anesthesiologist classification I or II (healthy or only minor systemic disease).

The patients excluded:

Exclusion criteria were:

• Age less than 4 months.
• Contraindication to ketamine - hypertension, glaucoma, globe injury, increased intracranial pressure, CNS mass, porphyria, or previous adverse reaction to ketamine.
• Contraindication to midazolam - glaucoma
• Procedures of pharynx, larynx, or trachea.
• Active upper or lower respiratory infection.
• Congenital or anatomic airway abnormalities.
• Major psychiatric disorder.

The interventions compared:

Ketamine (1 mg/kg) + Glycopyrrolate (5 mcg/kg) IV versus Ketamine (1 mg/kg) + Glycopyrrolate (5 mcg/kg) + Midazolam (0.1 mg/kg) IV

It was not stated if a maximum dose was used for larger children (i.e. Midazolam 2 mg).

The outcomes evaluated:

Primary outcome: Adverse Results - Specifically including apnea, laryngospasm, oxygen desaturation below 90%, vomiting, and emergence phenomena. Emergence phenomena was sub-classified as agitation, dysphoria, euphoria, active dreaming, nightmares, and hallucinations.

Secondary outcome: Adequacy of sedation as measured by the Observation Score of Behavioral Distress-Revised (OSBD-R) (1,2) - including duration of sedation, efficacy of sedation, physician satisfaction, and parent satisfaction.

II. Are the results of the study valid?

Primary questions:

1. Was the assignment of patients to treatments randomized?

Yes. Nurse 1, the only unmasked participant, used a standard randomization table to assign the patients to a treatment group.

2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?

Was followup complete?

One hundred thirty-nine (139) patients were assigned to receive ketamine + midazolam. Of these 139 patients, 2 received the study medications IM instead of IV. One hundred thirty patients were randomized to receive ketamine only. One of these 130 patients was given the study medication IM. Each of the remaining patients completed the emergency room portion of the study.

Phone follow-up was achieved in 87% of the enrolled patients at 2-4 weeks after treatment. It is not stated whether the patients who were unable to be contacted were equally distributed between the two treatment arms.

Were patients analyzed in the groups to which they were randomized?

Yes, with the exception of the three patients who were given IM medications rather than IV medications. These three patients were not included in the data analysis.

Secondary questions:

3. Were patients, health workers, and study personnel "blind" to treatment?

Patients and all observers were masked as to treatment assignment. Through the use of videotapes, additional observers were used. A separate, non-observer nurse prepared and administered the drugs.

4. Were the groups similar at the start of the trial?

Yes. The patient groups had no significant difference in age, gender, time since last oral intake, procedure performed and percentage that had received prior administration of narcotic analgesics.

5. Aside from the experimental intervention, were the groups treated equally?

Approximately 1/3 of each group required re-dosing of ketamine during the procedure. While it is not explicitly stated, it is implied that this second dose was not the study drug but ketamine alone. If this is the case, this could diminish the difference between the groups.

III. What were the results?

1. How large was the treatment effect?

Primary outcome: adverse events

No significant difference was observed in the overall incidence of emergence phenomena between treatment groups (Ketamine 27.1% vs. Ketamine + Midazolam 26.3%). Subgroup analysis demonstrated an increased incidence of agitation in patients 10 years old or older who received both ketamine and midazolam. (Ketamine 5.7% vs. Ketamine + Midazolam 35.7%; risk difference -30%, 95% confidence interval -10.7, -49.3).

There was an increased incidence of vomiting in the ketamine group (19.4%) compared to the ketamine + midazolam group (9.6%).

Desaturation events occurred more frequently in patients receiving both ketamine + midazolam (7.3% vs. 1.6% in patients receiving ketamine alone). Of note, no patient was given supplemental oxygen prior to a desaturation event.

No significant difference was found in the incidence of apnea or laryngospasm. However, only two patients experienced laryngospasm and both were in the ketamine + midazolam group.

Telephone follow-up with parents of patients found no significant difference between treatment groups for delayed emergence phenomena or vomiting.

Adverse Effects	Ketamine (%)	Ketamine + Midazolam (%)	Rate Difference (95% CI)
Emergence Phenomena	27.1	26.3	0.9 (-9.8, 11.5)
Vomiting	19.4	9.6	9.8 (1.4, 18.2)
Oxygen Desaturation <90%	1.6	7.3	-5.7 (-10.6, -0.9)

Secondary Outcome: Efficacy of Sedation

No significant difference was found in the efficacy or duration of sedation. Physician and parent satisfactions were also similar. Ketamine re-dosing was required in a similar percentage of each group (Ketamine 27.6% vs. Ketamine + Midazolam 35.0%).

2. How precise was the estimate of the treatment effect?

Confidence intervals are listed in the table above. The ketamine-midazolam group had 9.8% less vomiting, however, the lower limit of the 95% CI is only 1.4. While "statistically significant" this is quite close to no difference and might not be clinically significant.

Issues impacting the estimate of the treatment effects: There was the risk of underestimation of adverse events because the tapes were not reviewed for observation of adverse events unless Nurse 2 identified an event at the bedside.

There was 81% agreement between nurse observers for the severity rating of observed emergence phenomena. The interrater reliability for the efficacy of sedation (rated by OSBD-R) was 98.5%

Delayed emergence phenomena were reported by parents 2-4 weeks following the sedation event. These estimates are subject to the variability between parents.

IV. Will the results help me in caring for my patients?

1. Can the results be applied to my patient care?

In many cases, yes. For simple sedation procedures on relatively healthy patients that are performed in the PICU, this sample should be representative. However, sedation procedures in the PICU are also performed in patients who are more ill and would not fit into the ASA I or II classification, in patients who have abnormal airways, and in patients who may be undergoing some type of airway stimulating procedure. The study patient population is not necessarily representative of these children.

It has also been recommended that the pre-administration of a benzodiazepine 5 minutes prior to the administration of ketamine is generally effective in preventing emergence (3). In the current study the medications were administered simultaneously. It is arguable whether the distinction of pre-treatment with benzodiazepines (versus concurrent administration) is important.

2. Were all clinically important outcomes considered?

Yes. All major possible adverse events were considered. Nonetheless, blood pressures were taken every 15 minutes. Since there is the risk of hemodynamic changes with both ketamine and midazolam, more frequent measurements may have been helpful.

3. Are the likely treatment benefits worth the potential harms and costs?

If post-sedation emesis is a significant concern, and if appropriate monitoring and interventions for hypoxia are available, children may be helped by the addition of midazolam to ketamine sedation. Otherwise, midazolam does not appear to add a substantial benefit.

References

1. Jay SM, Elliott C. Behavioral observation scales for measuring children's distress: the effects of increased methodologic rigor. J Consult Clin Psychol. 1984;52:1106-1107. [citation]
2. Elliott CH, Jay SM, Woody P. An observational scale for measuring children's distress during medical procedures. J Pediatr Psychol. 1987;12:543-551. [citation]
3. White PF, Way WL, Trevor AJ. Ketamine - its pharmacology and therapeutic uses. Anesthesiology. 1982;56:119-136. [citation]

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