Pain, Traumatic Limb Injury
Conditions
Brief summary
This study compares the analgesic effect of intranasal sub-dissociative dosing of ketamine and intranasal fentanyl in children presenting to the Emergency Department with acute extremity injuries.
Detailed description
Inadequate pain control, especially in the emergency department (ED), is a major public health concern. Despite increased awareness, pain continues to be underdiagnosed and undertreated, particularly in the pediatric population. Children often encounter long delays in medication administration, possibly due to the time required to obtain intravenous access. The intranasal administration route offers a more efficient alternative for faster and noninvasive delivery of pain medication. This route is gaining popularity secondary to its rapid onset of active, minimal discomfort and relative simplicity. Opioids are the most commonly used class of analgesic pain medication for children presenting in severe pain due to traumatic injuries. Despite their potential effectiveness, opioids have several concerning adverse effects, particularly when administered prior to procedural sedation in children. Administration of pre-procedural sedation opioids is associated with an increased risk of serious adverse events (oxygen desaturation, apnea, and hypotension) as well as the need for significant interventions, such as bag-mask ventilation, intubation, and pharmacologic blood pressure support. In addition, due to genetic variations that may lead to increased or diminished opioid sensitivity, ideal dosing to adequately control severe pain yet avoid adverse medication-related side effects is difficult to ascertain. Many children in severe pain do not receive opioids, receive doses that are below those recommended or experience long delays in receiving opioids. The reasons for this are unclear, but the investigators speculate that this may be due in part to fear of adverse effects of opioids, provider inexperience with opioid use in children or fear of contributing to opioid tolerance or abuse. For all of these reasons, providers often seek non-opioid alternatives for pediatric patients with acute, severe pain. Ketamine, in sub-dissociative doses administered by the intravenous or intranasal route, is emerging as an alternative medication for the treatment of moderate to severe pain in multiple settings. In adults, low dose ketamine is well tolerated and has been used successfully as an adjuvant and an alternative to opioids to provide rapid pain relief in the ED. As a dissociative anesthetic, ketamine is the most commonly used agent to facilitate painful procedures in the pediatric emergency department. At lower doses, it has been used in children to provide analgesia in a variety of acute and chronic pain settings, including terminal diagnoses, sickle cell disease, perioperative pain, traumatic injuries, extensive burns and conditions where opioids are contraindicated. Similar to adults, ketamine has been used via the intranasal route to provide adequate analgesia and sedation in children in the pre-hospital setting and in those undergoing procedures. The objective of this study is to compare intranasal sub-dissociative ketamine with intranasal fentanyl for treatment of acute pain associated with traumatic limb injuries in children presenting to the ED and to document an objective respiratory side effect profile utilizing noninvasive capnometry. If found to be an effective analgesic, intranasal ketamine would be particularly useful in children who experience adverse effects with opioids, have developed opioid tolerance as a result of chronic painful conditions, have poor opioid sensitivity due to their genetic predisposition or in pediatric trauma patients with the potential for hypotension. Additionally, for patients that require procedural sedation for fracture reduction, avoiding opioids early in the emergency department visit may decrease sedation recovery time and the risk of serious adverse events during sedation.
Interventions
Sponsors
Study design
Eligibility
Inclusion criteria
* 8 years to 17 years (up to the 18th birthday) * Presenting to emergency department with one or more extremity injuries * Visual analog scale score 35 mm or greater * Parent or legal guardian present and willing to provide written consent
Exclusion criteria
* Received narcotic pain medication prior to arrival * Evidence of significant head, chest, abdomen, or spine injury * Glasgow coma score less than 15 or unable to self report pain score * Nasal trauma or aberrant nasal/airway anatomy * Active epistaxis * Allergy to ketamine, fentanyl or meperidine * Non-English speaking parent and/or child * History of psychosis * Postmenarchal female without a urine or serum assay documenting the absence of pregnancy * Brought in my juvenile detention center or in police custody * Pregnancy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Difference From Baseline in Visual Analog Scale Pain Score | 30 minutes after study medication | A VAS score is a self reported pain score of 0-100 millimeters (0 = no pain; 100 = worst possible pain). A decrease in a VAS score indicates a decrease in pain severity. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Highest Achieved University of Michigan Sedation Scale (UMSS) Score | 15, 30, and 60 minutes after study medication administration | The University of Michigan Sedation Scale is a valid and reliable tool that allows for rapid assessment of the depth of sedation in children. It is a simple observational tool that assesses the level of alertness on a five-point scale. It has been validated in children and has shown to have significant inter-rater reliability. Score is 0-4 (0 = awake and alert; 1= minimally sedated; 2 = moderately sedated; 3 = deeply sedated; 4 = unarousable) |
| Rescue Analgesia | Within the first 60 minutes after study medication | Documentation of additional pain medication after study medication administration |
| Heart Rate | 15 minutes after study medication | — |
| Respiratory Rate | 15 minutes after study medication | — |
| Difference From Baseline in Visual Analog Scale Pain Score | 15 minutes after study medication | A VAS score is a self reported pain score of 0-100 millimeters (0 = no pain; 100 = worst possible pain). A decrease in a VAS score indicates a decrease in pain severity. |
| Diastolic Blood Pressure | 15 minutes after study medication | — |
| Oxygen Saturation | 15 minutes after study medication | — |
| Capnometry Value | 15 minutes after study medication | — |
| Systolic Blood Pressure | 15 minutes after study medication | — |
Countries
United States
Participant flow
Recruitment details
This clinical trial took place at a tertiary care children's hospital emergency department from March 2016 to February 2017. The study sample was identified through an established triage process identifying children with an acute painful extremity injury. These patients were ages 8-17 years with a visual analog scale (VAS) score greater than 35 mm.
Participants by arm
| Arm | Count |
|---|---|
| Ketamine Ketamine 1.5 mg/kg intranasally for one dose | 44 |
| Fentanyl Fentanyl 2 mcg/kg intranasally for one dose | 42 |
| Total | 86 |
Baseline characteristics
| Characteristic | Ketamine | Fentanyl | Total |
|---|---|---|---|
| Age, Continuous | 11.8 years STANDARD_DEVIATION 2.6 | 12.2 years STANDARD_DEVIATION 2.3 | 12.0 years STANDARD_DEVIATION 2.5 |
| Analgesic Prior to Arrival Acetaminophen | 1 Participants | 2 Participants | 3 Participants |
| Analgesic Prior to Arrival Ibuprofen | 4 Participants | 4 Participants | 8 Participants |
| Analgesic Prior to Arrival Naproxen | 0 Participants | 1 Participants | 1 Participants |
| Analgesic Prior to Arrival No Analgesic | 39 Participants | 35 Participants | 74 Participants |
| Baseline Diastolic Blood Pressure | 78.9 mmHg STANDARD_DEVIATION 13.6 | 73.5 mmHg STANDARD_DEVIATION 12.9 | 76.3 mmHg STANDARD_DEVIATION 13.5 |
| Baseline End Tidal Captometry | 36.6 mmHg STANDARD_DEVIATION 6.4 | 38.0 mmHg STANDARD_DEVIATION 4.4 | 37.3 mmHg STANDARD_DEVIATION 5.5 |
| Baseline Heart Rate | 90.8 beats per minute STANDARD_DEVIATION 15.2 | 88.6 beats per minute STANDARD_DEVIATION 14.8 | 89.7 beats per minute STANDARD_DEVIATION 15 |
| Baseline Oxygen Saturation | 99.8 percent STANDARD_DEVIATION 0.6 | 99.6 percent STANDARD_DEVIATION 0.6 | 99.7 percent STANDARD_DEVIATION 0.6 |
| Baseline Respiratory Rate | 22.1 breaths per minute STANDARD_DEVIATION 6.6 | 23.0 breaths per minute STANDARD_DEVIATION 7.4 | 22.5 breaths per minute STANDARD_DEVIATION 7 |
| Baseline Systolic Blood Pressure | 126.5 mmHg STANDARD_DEVIATION 19.1 | 128.9 mmHg STANDARD_DEVIATION 19.6 | 127.7 mmHg STANDARD_DEVIATION 19.4 |
| Diagnosis Dislocation | 4 participants | 2 participants | 6 participants |
| Diagnosis Fracture | 39 participants | 34 participants | 73 participants |
| Diagnosis Other | 2 participants | 1 participants | 3 participants |
| Diagnosis Sprain/Strain | 1 participants | 5 participants | 6 participants |
| Dose of Study Medication Administered (Fentanyl) | — | 1.9 micrograms per kilogram (mcg/kg) | 1.9 micrograms per kilogram (mcg/kg) |
| Dose of Study Medication Administered (Ketamine) | 1.5 milligrams per kilogram (mg/kg) | — | 1.5 milligrams per kilogram (mg/kg) |
| Extremity Lower Extremity | 13 participants | 15 participants | 28 participants |
| Extremity Upper Extremity | 33 participants | 28 participants | 61 participants |
| Initial VAS score | 74.7 score on a scale STANDARD_DEVIATION 15.3 | 72.0 score on a scale STANDARD_DEVIATION 18.6 | 73.4 score on a scale STANDARD_DEVIATION 17 |
| Mechanism of Injury Fall | 10 Participants | 13 Participants | 23 Participants |
| Mechanism of Injury Motor Vehicle Accident | 1 Participants | 2 Participants | 3 Participants |
| Mechanism of Injury Other | 3 Participants | 1 Participants | 4 Participants |
| Mechanism of Injury Sports Related/Recreational | 30 Participants | 26 Participants | 56 Participants |
| Race/Ethnicity, Customized Race/Ethnicity Black | 11 Participants | 10 Participants | 21 Participants |
| Race/Ethnicity, Customized Race/Ethnicity Hispanic | 0 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized Race/Ethnicity Other | 3 Participants | 1 Participants | 4 Participants |
| Race/Ethnicity, Customized Race/Ethnicity White | 30 Participants | 29 Participants | 59 Participants |
| Reduction Required | 19 Participants | 23 Participants | 42 Participants |
| Sedation Required | 19 Participants | 20 Participants | 39 Participants |
| Sex: Female, Male Female | 18 Participants | 11 Participants | 29 Participants |
| Sex: Female, Male Male | 26 Participants | 31 Participants | 57 Participants |
| Time of injury prior to arrival | 43.0 minutes | 51.5 minutes | 47.3 minutes |
| Time to Study Medication from Arrival | 26.6 minutes STANDARD_DEVIATION 9.9 | 26.1 minutes STANDARD_DEVIATION 10.3 | 26.4 minutes STANDARD_DEVIATION 10.1 |
| Volume of Study Medication Administered | 1.3 milliliters | 1.8 milliliters | 1.6 milliliters |
| Weight | 45.8 kilograms STANDARD_DEVIATION 14.4 | 50.8 kilograms STANDARD_DEVIATION 22.8 | 48.3 kilograms STANDARD_DEVIATION 18.6 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 44 | 0 / 42 |
| other Total, other adverse events | 34 / 44 | 13 / 42 |
| serious Total, serious adverse events | 0 / 44 | 0 / 42 |
Outcome results
Difference From Baseline in Visual Analog Scale Pain Score
A VAS score is a self reported pain score of 0-100 millimeters (0 = no pain; 100 = worst possible pain). A decrease in a VAS score indicates a decrease in pain severity.
Time frame: 30 minutes after study medication
Population: One patient in the ketamine group did not have a baseline pain score documented and four patients withdrew from the study (1 in the ketamine group, 3 in the fentanyl group), resulting in 43 patients randomized to the ketamine group and 42 patients randomized to the fentanyl group included in the primary outcome analysis.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ketamine | Difference From Baseline in Visual Analog Scale Pain Score | -30.6 score on a scale |
| Fentanyl | Difference From Baseline in Visual Analog Scale Pain Score | -31.9 score on a scale |
Capnometry Value
Time frame: 60 minutes after study medication
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ketamine | Capnometry Value | 38.7 mmHg | Standard Deviation 4.2 |
| Fentanyl | Capnometry Value | 38.9 mmHg | Standard Deviation 5.4 |
Capnometry Value
Time frame: 15 minutes after study medication
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ketamine | Capnometry Value | 36.6 mmHg | Standard Deviation 5.2 |
| Fentanyl | Capnometry Value | 38.3 mmHg | Standard Deviation 4.2 |
Capnometry Value
Time frame: 30 minutes after study medication
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ketamine | Capnometry Value | 38.6 mmHg | Standard Deviation 5.6 |
| Fentanyl | Capnometry Value | 40.4 mmHg | Standard Deviation 6.8 |
Diastolic Blood Pressure
Time frame: 15 minutes after study medication
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ketamine | Diastolic Blood Pressure | 76.1 mmHg | Standard Deviation 10.7 |
| Fentanyl | Diastolic Blood Pressure | 73.4 mmHg | Standard Deviation 12.7 |
Diastolic Blood Pressure
Time frame: 60 minutes after study medication
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ketamine | Diastolic Blood Pressure | 70.8 mmHg | Standard Deviation 9.2 |
| Fentanyl | Diastolic Blood Pressure | 70.6 mmHg | Standard Deviation 10.4 |
Diastolic Blood Pressure
Time frame: 30 minutes after study medication
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ketamine | Diastolic Blood Pressure | 76.3 mmHg | Standard Deviation 10.3 |
| Fentanyl | Diastolic Blood Pressure | 73.6 mmHg | Standard Deviation 11.2 |
Difference From Baseline in Visual Analog Scale Pain Score
A VAS score is a self reported pain score of 0-100 millimeters (0 = no pain; 100 = worst possible pain). A decrease in a VAS score indicates a decrease in pain severity.
Time frame: 60 minutes after study medication
Population: One patient in the ketamine group did not have a baseline pain score documented and four patients withdrew from the study (1 in the ketamine group, 3 in the fentanyl group), resulting in 43 patients randomized to the ketamine group and 42 patients randomized to the fentanyl group included in this secondary outcome analysis.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ketamine | Difference From Baseline in Visual Analog Scale Pain Score | -27.7 score on a scale |
| Fentanyl | Difference From Baseline in Visual Analog Scale Pain Score | -29.0 score on a scale |
Difference From Baseline in Visual Analog Scale Pain Score
A VAS score is a self reported pain score of 0-100 millimeters (0 = no pain; 100 = worst possible pain). A decrease in a VAS score indicates a decrease in pain severity.
Time frame: 15 minutes after study medication
Population: One patient in the ketamine group did not have a baseline pain score documented and four patients withdrew from the study (1 in the ketamine group, 3 in the fentanyl group), resulting in 43 patients randomized to the ketamine group and 42 patients randomized to the fentanyl group included in this secondary outcome analysis.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ketamine | Difference From Baseline in Visual Analog Scale Pain Score | -24.4 score on a scale |
| Fentanyl | Difference From Baseline in Visual Analog Scale Pain Score | -25.3 score on a scale |
Heart Rate
Time frame: 15 minutes after study medication
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ketamine | Heart Rate | 90.1 beats per minute | Standard Deviation 12.8 |
| Fentanyl | Heart Rate | 84.4 beats per minute | Standard Deviation 14.1 |
Heart Rate
Time frame: 60 minutes after study medication
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ketamine | Heart Rate | 85.1 beats per minute | Standard Deviation 12.4 |
| Fentanyl | Heart Rate | 82.9 beats per minute | Standard Deviation 12.9 |
Heart Rate
Time frame: 30 minutes after study medication
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ketamine | Heart Rate | 90.5 beats per minute | Standard Deviation 12.8 |
| Fentanyl | Heart Rate | 85.6 beats per minute | Standard Deviation 13.5 |
Highest Achieved University of Michigan Sedation Scale (UMSS) Score
The University of Michigan Sedation Scale is a valid and reliable tool that allows for rapid assessment of the depth of sedation in children. It is a simple observational tool that assesses the level of alertness on a five-point scale. It has been validated in children and has shown to have significant inter-rater reliability. Score is 0-4 (0 = awake and alert; 1= minimally sedated; 2 = moderately sedated; 3 = deeply sedated; 4 = unarousable)
Time frame: 15, 30, and 60 minutes after study medication administration
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ketamine | Highest Achieved University of Michigan Sedation Scale (UMSS) Score | UMSS 0 | 23 Participants |
| Ketamine | Highest Achieved University of Michigan Sedation Scale (UMSS) Score | UMSS 1 | 17 Participants |
| Ketamine | Highest Achieved University of Michigan Sedation Scale (UMSS) Score | UMSS 2 | 4 Participants |
| Fentanyl | Highest Achieved University of Michigan Sedation Scale (UMSS) Score | UMSS 0 | 32 Participants |
| Fentanyl | Highest Achieved University of Michigan Sedation Scale (UMSS) Score | UMSS 1 | 9 Participants |
| Fentanyl | Highest Achieved University of Michigan Sedation Scale (UMSS) Score | UMSS 2 | 1 Participants |
Oxygen Saturation
Time frame: 60 minutes after study medication
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ketamine | Oxygen Saturation | 99.3 percent | Standard Deviation 0.9 |
| Fentanyl | Oxygen Saturation | 99.3 percent | Standard Deviation 0.9 |
Oxygen Saturation
Time frame: 30 minutes after study medication
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ketamine | Oxygen Saturation | 99.5 percent | Standard Deviation 0.7 |
| Fentanyl | Oxygen Saturation | 99.4 percent | Standard Deviation 0.9 |
Oxygen Saturation
Time frame: 15 minutes after study medication
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ketamine | Oxygen Saturation | 99.6 percent | Standard Deviation 0.7 |
| Fentanyl | Oxygen Saturation | 99.2 percent | Standard Deviation 0.9 |
Rescue Analgesia
Documentation of additional pain medication after study medication administration
Time frame: Within the first 60 minutes after study medication
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ketamine | Rescue Analgesia | Ibuprofen | 1 Participants |
| Ketamine | Rescue Analgesia | Fentanyl | 1 Participants |
| Ketamine | Rescue Analgesia | Morphine | 7 Participants |
| Ketamine | Rescue Analgesia | Ketamine | 1 Participants |
| Ketamine | Rescue Analgesia | Toradol | 1 Participants |
| Ketamine | Rescue Analgesia | No rescue analgesia | 33 Participants |
| Fentanyl | Rescue Analgesia | Toradol | 0 Participants |
| Fentanyl | Rescue Analgesia | Ibuprofen | 3 Participants |
| Fentanyl | Rescue Analgesia | Ketamine | 0 Participants |
| Fentanyl | Rescue Analgesia | Fentanyl | 3 Participants |
| Fentanyl | Rescue Analgesia | No rescue analgesia | 33 Participants |
| Fentanyl | Rescue Analgesia | Morphine | 3 Participants |
Respiratory Rate
Time frame: 15 minutes after study medication
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ketamine | Respiratory Rate | 23.1 breaths per minute | Standard Deviation 11.9 |
| Fentanyl | Respiratory Rate | 22.3 breaths per minute | Standard Deviation 5.8 |
Respiratory Rate
Time frame: 60 minutes after study medication
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ketamine | Respiratory Rate | 21.8 breaths per minute | Standard Deviation 8.1 |
| Fentanyl | Respiratory Rate | 19.7 breaths per minute | Standard Deviation 5.7 |
Respiratory Rate
Time frame: 30 minutes after study medication
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ketamine | Respiratory Rate | 23.3 breaths per minute | Standard Deviation 8.7 |
| Fentanyl | Respiratory Rate | 19.9 breaths per minute | Standard Deviation 5.7 |
Systolic Blood Pressure
Time frame: 30 minutes after study medication
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ketamine | Systolic Blood Pressure | 126.3 mmHg | Standard Deviation 15 |
| Fentanyl | Systolic Blood Pressure | 123.4 mmHg | Standard Deviation 15.6 |
Systolic Blood Pressure
Time frame: 15 minutes after study medication
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ketamine | Systolic Blood Pressure | 127.3 mmHg | Standard Deviation 18 |
| Fentanyl | Systolic Blood Pressure | 127.9 mmHg | Standard Deviation 19.3 |
Systolic Blood Pressure
Time frame: 60 minutes after study medication
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ketamine | Systolic Blood Pressure | 122.3 mmHg | Standard Deviation 14.9 |
| Fentanyl | Systolic Blood Pressure | 122.0 mmHg | Standard Deviation 15.1 |