Healthy, Myocardial Repolarization
Conditions
Keywords
changes in myocardial repolarization in healthy children
Brief summary
Dexmedetomidine is a sedative drug that is commonly used to improve calmness and reduce pain in children waking up after surgery. Some of the side effects of dexmedetomidine, such as a potential change in how the heart muscles contract and changes in blood sugar and potassium levels, are poorly understood. The current study aims to examine these changes directly in healthy children undergoing elective surgery by measuring the heart beats (with an electrocardiogram) and blood sugar and potassium at specific times before and after dexmedetomidine is given. The investigators aim to establish a better understanding of this drug's safety profile.
Detailed description
Purpose: This study is being conducted to evaluate the effect of three different doses of dexmedetomidine (Precedex® , Hospira Healthcare) on myocardial repolarization, and blood glucose and potassium levels in children undergoing elective surgery. Hypotheses: The investigators hypothesize that administering a dexmedetomidine bolus will have some effect on myocardial repolarization, blood glucose, and potassium concentrations in a dose-dependent manner, whereas a saline bolus will not. Justification: Dexmedetomidine is a potent, centrally acting α-2 adrenoreceptor agonist with sympatholytic, sedative, amnestic, anxiolytic and analgesic effects, which properties make it popular for use in both pediatric anesthesia and intensive care. In 2013, dexmedetomidine was added to the possible risk factor for torsades de pointes (TdP) drug list on crediblemeds.org. 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 QT is sparse and somewhat contradictory, and the effect of dexmedetomidine on the Tp-e interval has yet to be reported in detail in adults or children. Another poorly defined pharmacodynamic effect of dexmedetomidine is its effect on blood glucose concentration. Theoretically, dexmedetomidine would be expected to cause hypoinsulinaemia and a resultant increase in blood glucose levels (hyperglycemia). Previous studies are in contrast to this however; with reports of hypoglycemia after large doses of the drug. Considering the use of dexmedetomidine 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. 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. In sum, 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. Objectives: The primary objective of this study is to investigate the effects of three different doses of dexmedetomidine (0.25/0.5/0.75 mcg/kg) on indices of myocardial repolarization (QTc and Tp-e intervals). As a secondary objective, this study will also sample blood glucose and potassium levels before and after dexmedetomidine administration to ascertain if there is any significant effect of a single bolus dose on blood glucose concentrations. Research Method: The investigators propose a randomized, single-blinded, 4-group comparative study to characterize the effects of different doses of dexmedetomidine on myocardial repolarization and blood glucose levels in healthy children undergoing elective surgery. The study-specific interventions will include giving a bolus of dexmedetomidine (0.25/0.5/0.75 mcg/kg; or 10mL saline) after induction of general anesthesia, recording two 12-lead ECGs (one before and one after dexmedetomidine administration), and taking three venous blood samples (one before and two after dexmedetomidine administration) to measure glucose and potassium. If the anesthetist would like to administer dexmedetomidine to a participant in the control (saline) group as part of their normal practice, they can do so after the study period is over (after the last blood sample).
Interventions
DRUGDexmedetomidine
DRUGSaline
Sponsors
University of British Columbia
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
3 Years to 10 Years
Healthy volunteers
No
Inclusion criteria
* ASA Physical Status I-II * Age 3 to 10yrs * Elective surgical procedure requiring general anesthesia * Use of dexmedetomidine acceptable to the staff anesthesiologist * Un-premedicated * Ability to read and understand English (parent/legal guardian(s) and child)
Exclusion criteria
* Long QT syndrome (LQTS) * 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 * 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Myocardial Repolarization (QTc and TP-e Intervals) 1min After Intervention | 60 seconds post-intervention | Absolute QTc and TP-e values 1min after a bolus of dexmedetomidine or saline. Measured with 12-lead ECG. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Blood Glucose Levels at 15min and 30min Post-intervention | over 30 minutes post-intervention | Blood glucose levels at 15 min and 30 min after a bolus of dexmedetomidine or saline. Measured from 1 mL venous blood sample with blood gas analyzer. |
| Blood Potassium Levels at 15min and 30min Post-intervention | over 30 minutes post-intervention | Blood potassium levels at 15 min and 30 min after a bolus of dexmedetomidine or saline. Measured from 1mL venous blood sample with blood gas analyzer |
Countries
Canada
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dexmedetomidine 0.25mcg/kg 0.25mcg/kg dexmedetomidine diluted with normal saline in a 10mL syringe, administered intravenously over 60 seconds starting 3 minutes after induction of anesthesia.
Dexmedetomidine | 12 |
| Dexmedetomidine 0.5mcg/kg 0.5mcg/kg dexmedetomidine diluted with normal saline in a 10mL syringe, administered intravenously over 60 seconds starting 3 minutes after induction of anesthesia.
Dexmedetomidine | 12 |
| Dexmedetomidine 0.75mcg/kg 0.75mcg/kg dexmedetomidine diluted with normal saline in a 10mL syringe, administered intravenously over 60 seconds starting 3 minutes after induction of anesthesia.
Dexmedetomidine | 12 |
| Saline Bolus 10mL normal saline solution administered intravenously over 60 seconds starting 3 minutes after induction of anesthesia.
normal saline solution | 12 |
| Total | 48 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | ECG data error | 0 | 3 | 2 | 2 |
| Overall Study | Inhalational induction | 0 | 2 | 0 | 0 |
| Overall Study | OR team declined | 2 | 0 | 0 | 0 |
| Overall Study | Pre-op medication | 0 | 0 | 1 | 0 |
| Overall Study | QTc > 450 msec | 1 | 1 | 1 | 1 |
Baseline characteristics
| Characteristic | Dexmedetomidine 0.25mcg/kg | Dexmedetomidine 0.5mcg/kg | Dexmedetomidine 0.75mcg/kg | Saline Bolus | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 12 Participants | 12 Participants | 12 Participants | 12 Participants | 48 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 4.5 years | 4.5 years | 5 years | 4.5 years | 5 years |
| Corrected QT interval (ms) | 404.9 ms STANDARD_DEVIATION 17.1 | 408.8 ms STANDARD_DEVIATION 15.2 | 409.5 ms STANDARD_DEVIATION 17.2 | 404.0 ms STANDARD_DEVIATION 24.1 | 406.8 ms STANDARD_DEVIATION 18.2 |
| Heart Rate (beats/min) | 88.9 beats/min STANDARD_DEVIATION 17.8 | 85.7 beats/min STANDARD_DEVIATION 13.4 | 84.6 beats/min STANDARD_DEVIATION 12.2 | 80.7 beats/min STANDARD_DEVIATION 12.5 | 85.0 beats/min STANDARD_DEVIATION 14 |
| Interval between the peak and the end of the ECG T wave (Tp-e) | 66.7 ms STANDARD_DEVIATION 7.2 | 63.0 ms STANDARD_DEVIATION 9.4 | 62.8 ms STANDARD_DEVIATION 6.1 | 65.3 ms STANDARD_DEVIATION 5.2 | 64.4 ms STANDARD_DEVIATION 7.1 |
| Race and Ethnicity Not Collected | — | — | — | — | 0 Participants |
| Region of Enrollment Canada | 12 participants | 12 participants | 12 participants | 12 participants | 48 participants |
| Sex: Female, Male Female | 3 Participants | 5 Participants | 5 Participants | 6 Participants | 19 Participants |
| Sex: Female, Male Male | 9 Participants | 7 Participants | 7 Participants | 6 Participants | 29 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 15 | 0 / 18 | 0 / 16 | 0 / 15 |
| other Total, other adverse events | 0 / 15 | 0 / 18 | 0 / 16 | 0 / 15 |
| serious Total, serious adverse events | 0 / 15 | 0 / 18 | 0 / 16 | 0 / 15 |
Outcome results
Primary
Myocardial Repolarization (QTc and TP-e Intervals) 1min After Intervention
Absolute QTc and TP-e values 1min after a bolus of dexmedetomidine or saline. Measured with 12-lead ECG.
Time frame: 60 seconds post-intervention
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dexmedetomidine 0.25mcg/kg | Myocardial Repolarization (QTc and TP-e Intervals) 1min After Intervention | Tp-e Post-intervention | 67.8 ms | Standard Deviation 6 |
| Dexmedetomidine 0.25mcg/kg | Myocardial Repolarization (QTc and TP-e Intervals) 1min After Intervention | QTc Post-intervention | 395.9 ms | Standard Deviation 16.1 |
| Dexmedetomidine 0.5mcg/kg | Myocardial Repolarization (QTc and TP-e Intervals) 1min After Intervention | QTc Post-intervention | 390.2 ms | Standard Deviation 24 |
| Dexmedetomidine 0.5mcg/kg | Myocardial Repolarization (QTc and TP-e Intervals) 1min After Intervention | Tp-e Post-intervention | 64.0 ms | Standard Deviation 10 |
| Dexmedetomidine 0.75mcg/kg | Myocardial Repolarization (QTc and TP-e Intervals) 1min After Intervention | Tp-e Post-intervention | 64.3 ms | Standard Deviation 6.9 |
| Dexmedetomidine 0.75mcg/kg | Myocardial Repolarization (QTc and TP-e Intervals) 1min After Intervention | QTc Post-intervention | 395.4 ms | Standard Deviation 18.7 |
| Saline Bolus | Myocardial Repolarization (QTc and TP-e Intervals) 1min After Intervention | Tp-e Post-intervention | 66.3 ms | Standard Deviation 5.9 |
| Saline Bolus | Myocardial Repolarization (QTc and TP-e Intervals) 1min After Intervention | QTc Post-intervention | 416.4 ms | Standard Deviation 23.3 |
Secondary
Blood Glucose Levels at 15min and 30min Post-intervention
Blood glucose levels at 15 min and 30 min after a bolus of dexmedetomidine or saline. Measured from 1 mL venous blood sample with blood gas analyzer.
Time frame: over 30 minutes post-intervention
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dexmedetomidine 0.25mcg/kg | Blood Glucose Levels at 15min and 30min Post-intervention | Glucose 15 minutes after intervention | 5.3 mmol/L | Standard Deviation 0.7 |
| Dexmedetomidine 0.25mcg/kg | Blood Glucose Levels at 15min and 30min Post-intervention | Glucose 30 minutes after intervention | 5.0 mmol/L | Standard Deviation 0.7 |
| Dexmedetomidine 0.5mcg/kg | Blood Glucose Levels at 15min and 30min Post-intervention | Glucose 30 minutes after intervention | 5.0 mmol/L | Standard Deviation 0.7 |
| Dexmedetomidine 0.5mcg/kg | Blood Glucose Levels at 15min and 30min Post-intervention | Glucose 15 minutes after intervention | 5.6 mmol/L | Standard Deviation 0.7 |
| Dexmedetomidine 0.75mcg/kg | Blood Glucose Levels at 15min and 30min Post-intervention | Glucose 15 minutes after intervention | 5.9 mmol/L | Standard Deviation 0.7 |
| Dexmedetomidine 0.75mcg/kg | Blood Glucose Levels at 15min and 30min Post-intervention | Glucose 30 minutes after intervention | 5.5 mmol/L | Standard Deviation 0.6 |
| Saline Bolus | Blood Glucose Levels at 15min and 30min Post-intervention | Glucose 15 minutes after intervention | 4.9 mmol/L | Standard Deviation 0.7 |
| Saline Bolus | Blood Glucose Levels at 15min and 30min Post-intervention | Glucose 30 minutes after intervention | 5.1 mmol/L | Standard Deviation 0.7 |
Secondary
Blood Potassium Levels at 15min and 30min Post-intervention
Blood potassium levels at 15 min and 30 min after a bolus of dexmedetomidine or saline. Measured from 1mL venous blood sample with blood gas analyzer
Time frame: over 30 minutes post-intervention
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dexmedetomidine 0.25mcg/kg | Blood Potassium Levels at 15min and 30min Post-intervention | Potassium 15 minutes after intervention | 3.8 mEq/L | Standard Deviation 0.7 |
| Dexmedetomidine 0.25mcg/kg | Blood Potassium Levels at 15min and 30min Post-intervention | Potassium 30 minutes after intervention | 3.6 mEq/L | Standard Deviation 0.3 |
| Dexmedetomidine 0.5mcg/kg | Blood Potassium Levels at 15min and 30min Post-intervention | Potassium 30 minutes after intervention | 3.6 mEq/L | Standard Deviation 0.4 |
| Dexmedetomidine 0.5mcg/kg | Blood Potassium Levels at 15min and 30min Post-intervention | Potassium 15 minutes after intervention | 3.7 mEq/L | Standard Deviation 0.2 |
| Dexmedetomidine 0.75mcg/kg | Blood Potassium Levels at 15min and 30min Post-intervention | Potassium 15 minutes after intervention | 3.8 mEq/L | Standard Deviation 0.2 |
| Dexmedetomidine 0.75mcg/kg | Blood Potassium Levels at 15min and 30min Post-intervention | Potassium 30 minutes after intervention | 3.8 mEq/L | Standard Deviation 0.2 |
| Saline Bolus | Blood Potassium Levels at 15min and 30min Post-intervention | Potassium 15 minutes after intervention | 3.9 mEq/L | Standard Deviation 0.4 |
| Saline Bolus | Blood Potassium Levels at 15min and 30min Post-intervention | Potassium 30 minutes after intervention | 3.8 mEq/L | Standard Deviation 0.2 |