The Effects of Dexmedetomidine on Myocardial Repolarization in Children
Phase: PHASE4
Conditions: Myocardial Repolarization, Healthy
Sponsor: University of British Columbia

 
STUDY PROTOCOL 
 
Title 
The effects of dexmedetomidine on myocardial repolarization in children 
 
Principal Investigator 
Dr Simon Whyte 
 
Co-Investigators 
Sonia M. Brodie, Dr Lindsay Rawling, Dr Elizabeth D Sherwin, Dr Shubhayan Sanatani, Aryannah 
Umedaly, Andrew Poznikoff 
 
Question 
What are the effects of a bolus dose of dexmedetomidine on indices of myocardial repolarization, 
and on blood glucose and potassium concentrations in healthy children undergoing total intravenous 
general anesthesia (TIVA)?  
 
Background 
Dexmedetomidine (Precedex® , Hospira Healthcare) is a potent, centrally acting α2 adrenoreceptor 
agonist with sympatholytic, sedative, amnestic, anxiolytic and analgesic effects, which properties 
make it popular for use in both pediatric anesthesia and intensive care (1,2). The reported benefits 
include reduced post-operative analgesic requirements (3), reduced emergence delirium 
(4,5),smoother extubation conditions(6), treatment of emergence delirium (7,8) and reduced post-
operative shivering (9). Its respiratory sparing effects may also be of value in children with 
obstructive sleep apnea undergoing adenotonsillectomy, who are at particular risk of opioid- and 
anesthetic-induced respiratory complications post-operatively (10). Furthermore it has promising 
future applications in neuroprotection (11,12) 
 
In 2013, dexmedetomidine was added to the “possible risk factor for torsades de pointes (TdP)” 
drug list (13). Clinicians are currently advised to be vigilant about potential QT prolongation with 
dexmedetomidine, especially in patients with congenital long QT syndrome (LQTS).  However, 
current evidence for dexmedetomidine-induced prolonged heart-rate corrected QT (QTc) is sparse 
and somewhat contradictory. One recent case report described profound QTc prolongation with use 
of dexmedetomidine in a pediatric clinical care setting, and suggested that LQTS Type 2 was 
“unmasked” by the drug (14). Another study investigating the effects of dexmedetomidine on 
cardiac electrophysiology in children indicated that the drug significantly increased the length of 
QTc intervals; however none of the patients actually developed abnormally long QT (>445ms) 
(15). In contrast, one study in adults showed that dexmedetomidine promoted a faster recovery 
from a prolonged QTc interval induced by spinal anesthesia, and may in fact be helpful in patients 
who have a prolonged QTc interval (16).  
 
Another consideration is that drug-induced QTc prolongation is not synonymous with drug 
torsadogenicity (i.e. risk of causing TdP). A more relevant measure of torsadogenicity is the interval 
between the peak and the end of the ECG T wave (Tp-e), which is a marker of transmural 
dispersion of repolarization (TDR) across the myocardial wall. Research supports the concept of 
exaggerated TDR as a more appropriate substrate for TdP (17,18) However, the effect of 
dexmedetomidine on the Tp-e interval has not been reported in detail in adults or children. 
 
Another poorly defined pharmacodynamic effect of dexmedetomidine is its effect on blood glucose 
concentration. The α2A adrenoreceptor has been identified as an important regulator of blood 
glucose homeostasis. Activation of α2 receptors on pancreatic β cells inhibits insulin secretion (19). 
Administration of dexmedetomidine would therefore be expected to cause hypoinsulinaemia and a 
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resultant increase in blood glucose levels (hyperglycaemia). Previous studies are in contrast to this 
however; Mukhtar and colleagues reported that dexmedetomidine decreased cortisol levels leading 
to reduced blood glucose levels, and suggested that dexmedetomidine may attenuate the 
neuroendocrine response to stress (20). Furthermore, a case report describing a child who was 
given a 60-fold increase in the intended dose of dexmedetomidine as a drug error during a cardiac 
catheterization procedure reported significant hypoglycemia (21). The authors postulated that a 
large decrease in circulating norepinephrine caused by an overdose of dexmedetomidine, might also 
inhibit β-adrenergic stimulation, thereby causing hypoglycemia. Considering the popularity of 
dexmedetomidine use in pediatric anesthesia, pediatric intensive care and its increasing use in the 
neonatal population, increased knowledge of the effect of dexmedetomidine on blood glucose 
would be valuable.   
 
Finally, hypokalemia is listed as a treatment-emergent adverse event occurring in >2% of adult 
patients receiving dexmedetomidine in long-term intensive care unit sedation studies (22). The 
effect of dexmedetomidine on serum potassium levels in healthy children has yet to be elucidated. 
Given that hypokalemia increases the risk of TdP, and that there is a possibility that 
dexmedetomidine may be torsadogenic, this effect is also worthy of investigation.  
 
Rationale  
The use of dexmedetomidine is associated with many clinical benefits, but its effects on indices of 
myocardial repolarization, as well as its effects on glucose and potassium metabolism, remain 
poorly understood and need to be better defined in order to use this drug safely and effectively. 
 
Specific Aims 
The primary aim of this study is to investigate the effects of three different doses of 
dexmedetomidine (0.25/0.5/0.75 mcg/kg) on both QTc and Tp-e. This study will also sample 
venous blood to measure glucose and potassium concentrations before and after dexmedetomidine 
administration to ascertain if there is any significant effect of a single bolus dose on either of these. 
 
Method 
Research design  
We propose a randomized, single blinded, 4-group comparative study to characterize the effects of 
different doses of dexmedetomidine on myocardial repolarization and blood glucose and potassium 
levels. The study-specific interventions will include a bolus of dexmedetomidine (or saline) 
following induction, recording two 12-lead ECGs (one before and one after dexmedetomidine 
administration), and taking three 1mL venous blood samples (one before and two after 
dexmedetomidine administration; total blood sampling volume 3mL/patient). 
 
Inclusion Criteria   
 
• ASA I-II 
 
 
 
 
• Age ≥ 3 to ≤ 10 years  
 
 
• Elective surgical procedure requiring general anesthesia 
• Use of dexmedetomidine deemed clinically appropriate by the staff anesthesiologist 
• No pre-operative analgesic or anxiolytic medications given 
  
Exclusion criteria 
• Previous diagnosis of Long QT Syndrome (LQTS)  
• Previous diagnosis of cardiac disease or rhythm abnormalities 
• Family history of LQTS or abnormal cardiac conduction  
• Currently taking medications known to prolong QT 
• Currently taking medications known to predispose to hypokalemia 
• Known hypersensitivity to dexmedetomidine or other study medication 
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• Weight < 5th centile or > 95th centile for age 
• Previously diagnosed hypokalemia 
• Impaired renal or liver function 
• Pre-operative anxiety requiring sedatives or opioids 
• Refusal to participate 
 
Consent/Assent 
The parent or legal guardian(s) of participants meeting inclusion criteria will be approached by a 
staff nurse with a Letter of Initial Contact in the Surgical Day Care Unit (SDCU) of BC Children’s 
Hospital (BCCH). If the parent or legal guardian(s) wishes for more information they can request an 
introduction to a member of the Pediatric Anesthesia Research Team (PART), who will then 
provide them with details of the study and invite them to participate. Written informed consent will 
be obtained from the parents or guardians of eligible participants. In addition, assent will be 
obtained from children over 7 years of age. 
 
All participants will be aware of the study rationale, as well as any potential risks. For example, 
there is a small risk of unexpectedly discovering a baseline ECG abnormality. Families will be 
advised that all traces will be analyzed by a pediatric cardiologist, and should an abnormality be 
detected, they will be notified if further management is required.  
 
Treatments and Procedures 
 Preoperative 
All potential participants will have fasted according to the BCCH Pre-Anesthesia and Procedural 
Sedation Fasting Guidelines (minimum 2hrs for clear liquids, minimum 6hrs for light meal), as per 
standard practice. Once a participant has consented to be in the study, the attending anesthetist will 
ensure that they are not given oral pre-medication (eg. acetaminophen) in SDCU. Rather, simple 
analgesics, if indicated, will be given non-orally intraoperatively instead, after the second ECG has 
been obtained. Thus, analgesics will not be withheld.  
 
Basic demographics including gender, height and weight will be recorded on the data collection 
form. Topical local anesthetic cream will be applied to potential cannulation sites approximately 
45mins before the procedure is scheduled to begin, as per standard SDCU procedures. A baseline 
12-lead ECG will then be obtained in SDCU.  This initial ECG will be screened by the attending 
anesthetist to ensure that the QTc interval is within normal range. If the QTc interval is greater than 
450msec in males, or 460msec in females, the patient will be excluded from the study and referred 
to a pediatric cardiologist for further investigation. Eligible participants will then be randomized 
into one of four treatment groups: 
 
- 
Group 1 will receive a dose of 0.25mcg/kg dexmedetomidine 
- 
Group 2 will receive a dose of 0.50mcg/kg dexmedetomidine 
- 
Group 3 will receive a dose of 0.75mcg/kg dexmedetomidine 
- 
Group 4 will receive a small volume (10mL) of normal saline solution 
 
The anesthetist will know the dose of dexmedetomidine being administered, but the subject and 
cardiologist will be blinded to this information.   
 
Intra-operative 
All participants will receive standard monitoring of vital signs (heart rate, blood pressure, SpO2) 
throughout the entire procedure. These data will be captured electronically from the patient monitor 
every second and recorded on a study laptop.  
Intravenous (IV) access will be established and anesthesia induced as per standard BCCH practice, 
with a bolus of lidocaine (0.5mg/kg) followed by a bolus of propofol (5mg/kg). In an attempt to 
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minimise sympathetic stimulation, laryngoscopy will not be permitted during the study period and 
the airway will be maintained by facemask. Immediately after induction, maintenance of anesthesia 
will be initiated with propofol 200mcg/kg/min and remifentanil 0.1mcg/kg/min administered via an 
automated infusion pump. This default infusion rate may be adjusted by the anesthetist at any time.  
 
A baseline venous blood sample (1mL) will be obtained from the IV 1 minute post induction 
(defined as the end time of propofol bolus administration). Three minutes post induction, the 
randomized bolus dose of dexmedetomidine or saline will be administered. All dexmedetomidine 
doses will be diluted with normal saline to a standard 10mL volume, and will be delivered over 60 
seconds using an automated infusion pump through the IV. While the product monograph suggests 
delivering dexmedetomidine as a loading dose over 10-20 minutes, administration as a rapid bolus 
has been shown to be safe in children (Dawes et al., 2014), and 60 seconds represents a typical 
timeframe over which dexmedetomidine is currently being administered in clinical practice at 
BCCH. Nevertheless, the anesthetist will vigilantly monitor the patient’s vital signs for instances of 
clinically-relevant dexmedetomidine-induced bradycardia or hypertension requiring intervention.  
 
A second 12-lead ECG will be obtained 60 seconds after the end time of dexmedetomidine bolus 
administration. This ECG will also be screened by the anesthetist. If the anesthetist observes 
significant QT prolongation on the second ECG, they will discuss their observations with 
cardiology, and the participant will be referred to a pediatric cardiologist if deemed appropriate. 
Blood pressure will be assessed every minute until the second ECG is complete. Thereafter, 
maintenance of anesthesia will continue at the anesthetist’s discretion, and simple analgesics will be 
administered to compensate for the absence of pre-medication if appropriate. Venous blood will be 
sampled again at 15 and 30 minutes post induction. Each sample will volume will be 1mL. All 
venous blood samples will be sent for analysis (using the GEM4000 blood gas analyzer located in 
the pediatric intensive care unit) immediately after acquisition. No dextrose-containing fluids will 
be given during the study period, to avoid altering blood glucose levels. Other fluids (eg. normal 
saline; Ringers Lactate) may be administered at the anesthetist’s discretion.  
 
If the anesthetist would like to administer dexmedetomidine to a participant in the control group as 
part of their normal practice, they can do so after the study period is over (after the final blood 
sample has been taken). 
 
Outcome Measures 
Primary 
The primary outcome measure is placebo-adjusted change from baseline in myocardial 
repolarization (QTc and TP-e intervals) at 1 minute post dexmedetomidine. 
 
Secondary 
The secondary outcome measures are placebo-adjusted change in serum glucose and potassium 
concentrations at 15 and 30 minutes post dexmedetomidine. 
 
Rescue Medication and Risk Management 
According to the Canadian Product Monograph for dexmedetomidine, the most common treatment-
emergent adverse reactions, occurring in greater than 2% of adult patients in both Intensive Care 
Unit and conscious sedation studies include hypotension, bradycardia and dry mouth. Product 
literature suggests glycopyrrolate, atropine or ephedrine for drug-induced bradycardia or 
hypotension in adults. There are no recommendations for treatment options in children. 
 
For the purpose of the current study, our recommendation for hemodynamic rescue will be as 
follows: to treat significant bradycardia associated with hypotension, a bolus of glycopyrrolate 
10mcg/kg or atropine 20mcg/kg should be given, followed by reassessment after 1 minute. This 
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may be repeated as necessary, to a maximum dose of glycopyrrolate 400mcg and atropine 600mcg. 
Further interventions will be according to the clinician’s preference and the clinical situation, 
including altering or stopping the propofol and remifentanil infusion rate, raising the legs, further 
intravenous fluid boluses and/or a dose of ephedrine 0.1 mg/kg. If significant bradycardia 
associated with hypertension is observed, the subject should be observed for 1 minute followed by 
reassessment. This baroreceptor-mediated response is usually transient and has rarely required 
treatment in previous studies. In fact, an exaggerated hypertensive response has been observed 
when glycopyrrolate 5 mcg/kg was used to treat bradycardia without associated hypotension in a 
recent case report series. The mechanism for this remains unclear. Other interventions to treat 
bradycardia associated with dexmedetomidine have not been investigated. Ultimately, all rescue 
procedures will be at the anesthetist’s discretion.   
 
Discontinuation Criteria 
The study will be stopped at the request of the participant and/or the participant's parents/guardians, 
without prejudice to future treatment by the physician. However, due to the nature of the study, 
once the participant is in the operating room, the participant and the participant’s parents/guardians 
will no longer be able to make this request. If induction or maintenance of anesthesia becomes 
complicated by adverse events, such that the patient’s cardiorespiratory stability is compromised 
before or during the study period, the study will be terminated at the anesthesiologist’s discretion. 
Additionally, on receiving new information about a participant's health or their response to the 
anesthetic medications given, the attending anesthetist may consider it to be in the participant's best 
interests to withdraw them from the study without their consent if they judge that it would be better 
for their health. For example, if the anesthetist detects a prolonged QTc interval on the patient’s 
baseline ECG, that subject will be excluded from the study, and referred to a pediatric cardiologist. 
Should this occur, the parent or legal guardian(s) will be informed after the surgery is complete. 
 
In the instance of any serious adverse drug reaction (SADR), the study will immediately be stopped 
and the case will be reviewed in detail by the BCCH Data Safety Monitoring Board (DSMB) to 
determine whether the study may be continued.  
 
Study defined serious adverse drug reactions (SADR) include: 
• Hypo- or hypertension post-dexmedetomidine bolus requiring rescue intervention 
• Bradycardia, AV block or sinus arrest requiring cardiopulmonary resuscitation 
• Anaphylactic reaction requiring intervention 
 
Documentation, and any necessary treatment of SADRs, will occur both immediately after the 
intravenous administration of the study medication and immediately prior to discharge from PACU. 
SADRs occurring in hospital after the study period will be reported to the Department of Anesthesia 
and treated appropriately. All SADRs will be reported to the UBC Clinical Research Ethics Board, 
the DSMB within 72 hours of the event. A report of the SADR will also be submitted to Health 
Canada within 7 days, or within 15 days if the event was neither fatal nor life-threatening.  
 
Data Collection  
All demographic data and measured variables are shown on the data collection form. 
 
Interim Analysis 
Meetings with the study team and the DSMB will be scheduled: 
• After 5 participants have been recruited, or 6 months after study initiation 
(whichever comes first), to discuss safety outcomes and study progress 
• After 30 participants have been recruited, to investigate preliminary results of 
outcome measures 
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• After the occurence any SADR, to discuss safety outcomes and decide whether the 
study may continue 
 
Data Analysis 
ECG Analysis Methods 
All ECG traces will be analyzed independently at a later date by a pediatric cardiology co-
investigator (Dr. Sherwin) who will be blinded to the participant, group assignment, and the timing 
of the ECG recording (pre or intra-operative), and who will not be involved in the recruitment or 
randomization of participants, or in the conduct of anesthesia or acquisition of ECG recordings. If 
an abnormality is noted in any ECG by the pediatric cardiologist, the principal investigator will be 
contacted, and will be responsible for re-identifying the participant and contacting their family in 
order to refer them to a cardiologist. 
 
The QT interval, RR interval and Tp-e interval will be measured in leads II and V5 at each time 
point. The QT interval will be measured for 3 complete P-QRS-T cycles from the start of the QRS 
complex to the end of the T-wave, defined as the point of return to the T-P baseline. If U waves are 
present, the end of the T wave will be taken as the nadir of the curve between the T and U waves. 
QT intervals will be corrected according to the formula of Bazett where QTc= QT/√RR.  
 
The Tp-e interval will be measured for 3 complete P-QRS-T cycles from the peak of the T-wave to 
the end of the T-wave. Monophasic T wave peaks can be identified visually and for more complex 
T-wave morphologies, the peak will be identified according to the criteria of Emori and 
Antzelevitch (23). 
 
Statistical Analysis 
Within-group and between-group comparisons of pre- and intra-operative ECG indices of 
myocardial repolarization and blood glucose and potassium concentrations will be performed using 
two-way factorial analysis of variance. Any identified differences will be further examined using 
Bonferroni-corrected paired t-tests within groups, and unpaired t -tests between groups. 
 
Sample size calculations are based on ECG results from previously published studies in healthy 
children. These data showed a mean/SD Tp-e of 66/12 msec in 135 pre-operative ECG traces from 
healthy children (24). Thus, we have determined that 12 patients are required per group in order to 
detect a clinically relevant difference of 25msec in Tp-e between the intra-operative means of the 4 
groups with a power of 99% and the criterion for significance set at 0.01. In order to provide a 
buffer for unplanned exclusions, 60 patients will be recruited, 15 patients in each of the 4 groups. 
An additional 9 patients will be recruited to offset unanticipated technical problems arising from the 
electronic capture and transmission of ECG data.  
 
Strengths  
This is the first study to formally investigate the effects of dexmedetomidine on myocardial 
repolarization and blood glucose and potassium levels in healthy children undergoing TIVA. 
 
Overall, the benefits of this work will be a better understanding of the safety profile of 
dexmedetomidine. Regarding the influence of dexmedetomidine on myocardial repolarization, if we 
do find that it is torsadogenic at any of the doses tested, we will conclude that it should be used with 
caution in susceptible patients and possibly in procedures more risky of arrhythmias such as cardiac 
ablation/catheterization, as well as in patients with known prolonged QT. Similarly, if we find that 
dexmedetomidine has a significant impact on blood glucose or potassium homeostasis at any of the 
doses tested, this will inform future clinical use in all patients, especially in neonates who are more 
susceptible to blood glucose dysregulation and/or in patients with liver/kidney dysfunction who are 
more prone to hypokalemia. 
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Limitations 
Our study will recruit healthy children and will specifically exclude those with or who are at risk of 
long QT syndromes. Therefore, the current results will not be directly applicable to these 
susceptible populations. They will, however, potentially help anesthetists to decide whether 
dexmedetomidine may add to pre-existing risk in such patients. 
 
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