Comparison of Intranasal Midazolam, Intranasal Ketamine, and Oral Chloral Hydrate for Conscious Sedation During Paediatric Echocardiography: Results of a Prospective Randomized Study

Alp H, Elmaci AM, Alp EK, Say B

Cardiology in the Young 2019; 29: 1189 – 95
DOI:  10.1017/S1047951119001835
PMID: 31451130

Take Home Points

  • Intranasal midazolam, intranasal ketamine, and oral chloral hydrate all provide adequate sedation for transthoracic echocardiography in acyanotic children ages 9 – 38 months with a failed sedation rate of 4.1%, 4.1% and 5.5%, respectively.
  • Midazolam had the shortest onset of action at 14 (range 7-65) minutes.
  • Ketamine had the shortest duration of sedation at 55 (range 25-75) minutes.
  • Each of the sedatives had modest side effects, including agitation (midazolam), respiratory (midazolam and chloral hydrate) and gastrointestinal (ketamine and chloral hydrate).

Commentary by Lori Q. Riegger, MD
Associate Professor, Mott Children’s Hospital, Michigan Medicine in Ann Arbor, Michigan

Young children often require sedation to obtain high quality diagnostic images during transthoracic echocardiography. Midazolam, ketamine, and chloral hydrate are used for sedation in varying doses and with various routes of administration. Onset, duration, side effects and success of the sedatives are key elements in choice of appropriate medication for sedation and were the focus of this study.

This prospective randomized study compared the efficacy of three sedatives: intranasal midazolam, intranasal ketamine and oral chloral hydrate in acyanotic children aged 9 – 38 months, undergoing a transthoracic echocardiogram to assess a cardiac murmur. The goal was to determine the ideal sedative, defined as providing adequate sedation (as evidenced by high quality images), rapid onset, optimal duration and low incidence of side effects.  Two-hundred seventeen children, with median age 22 months (range 9 – 38 months), were included. There were no statistically significant differences in age, weight or gender between the groups. All subjects were awake for at least six hours prior to sedation. They were randomized to one of the three groups; 73 received midazolam (0.2 mg/kg, max 5 mg), 72 received ketamine, (4 mg/kg, max 100 mg), 72 received chloral hydrate (50 mg/kg, max 1 gram). 

After the medication was given, depth of sedation was assessed using the Richmond Agitation Sedation Scale (RASS) at 15, 30, 45, and 60 minutes by two blinded pediatricians, using 1) calm 2) drowsy or 3) sedated to assess the level of sedation. Sedation was defined as complete unconsciousness and lack of movement. Rescue medications were not used during the study. Success was defined by RASS scores and ability to obtain high quality echocardiographic images.

Vitals, including temperature, blood pressure, heart rate, respiratory rate and oxygen saturation, showed no statistically significant differences between the groups during the sedated and non-sedated phases. Echocardiography could not be performed due to failed sedation in three children each in the midazolam and ketamine groups and four in the chloral hydrate group. Successful sedation thus occurred in 95.9% of the midazolam, 95.9% of the ketamine and 94.5% of the chloral hydrate cohorts.

Fifteen minutes after administration midazolam demonstrated the shortest onset of action with 37.1% drowsy and 35.8% sedated, while ketamine had 34.7% drowsy and none sedated, and chloral hydrate had 23.6% drowsy and none sedated. The median onset of sedation was 14 (range 7-65) minutes (p < 0.001) for midazolam, 34 (range 12-56) minutes for ketamine (p < 0.001), and 40 (range 25-57) minutes for chloral hydrate (p < 0.001). At 60 minutes all of the midazolam and ketamine patients and 92.7% of the chloral hydrate patients were sedated. Median duration of sedation was 68 (range 20-75) minutes for patients receiving midazolam (p = 0.023), 55 (range 25-75) minutes for ketamine (p = 0.712), and 61 (range of 34-78) minutes for chloral hydrate (p= 0.045).

One patient in the midazolam group and one in the chloral hydrate group required oxygen to maintain saturation > 95%, and in both patients, the oxygen was weaned off during the first 60 minutes of sedation. Other side effects included agitation in three midazolam patients, and nausea and vomiting in two ketamine and eight chloral hydrate patients.

What does this mean for us?
In this study, intranasal midazolam, intranasal ketamine and oral chloral hydrate were all demonstrated to be efficacious in providing adequate sedation with a low side effect profile in acyanotic young children undergoing transthoracic echocardiography. A limitation of this study is that it did not include children with cyanotic cardiac disease and therefore, these findings cannot be extrapolated to that population.

Although midazolam provided the shortest onset of sedation at 14 (7-65) minutes, ketamine patients spent less time sedated at 55 (25-75) minutes, which the authors concluded to be optimal. This should be enough time for all but the most difficult echocardiograms. Each of the sedatives had side effects including agitation (midazolam), respiratory (midazolam and chloral hydrate), and gastrointestinal (ketamine and chloral hydrate), all of which have been reported previously with these medications. The side effects involved few patients and were minor.

The authors do not comment on the overall length of time from administration to complete recovery, but if one assesses the median time of onset of sedation and the median duration of sedation, it appears that patients who received chloral hydrate required monitoring for longer periods of time compared with the patients who had received midazolam or ketamine. In fact, it is somewhat surprising that the study did not demonstrate any prolonged sedative effects of chloral hydrate, including lack of muscle tone and coordination, which have been previously reported. Also, chloral hydrate has become scarce in the United States, so the chloral hydrate arm of the study is likely to be more pertinent for those outside that country.

A similar study involving the more commonly used intranasal dexmedetomidine compared with midazolam and ketamine may be more relevant for those who practice in the United States.

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