Bone Marrow Disease, Pain
Conditions
Keywords
Pain Management, Bone Marrow Aspiration
Brief summary
St. Jude Children's Research Hospital is studying the best ways to prevent pain during and after procedures such as bone marrow aspiration and lumbar puncture with intrathecal (in the spinal fluid) chemotherapy. Researchers will study the effectiveness of combining anesthetics (medicines that help people sleep) and analgesics (medicines that relieve pain). Researchers believe that a combination of fentanyl (analgesic) and propofol (anesthetic), along with applying the skin-numbing-cream EMLA or L.M.X4™ on the area where the procedure is performed, will provide better pain control. Each patient enrolled on this study will have three different anesthetic combinations for three different procedures, in order to determine which combination worked best for each child.
Detailed description
The study focusses on the following primary aims: * To compare 0.5 mg/kg versus 1.0 mg/kg of fentanyl to control pain in patients who have a BMT/LPIT procedure in the context of propofol anesthesia and topical anesthesia with EMLA or L•M•X 4™cream (or when necessary, lidocaine for injection). * To compare placebo versus fentanyl (0.5 mg/kg or 1.0 mg/kg) in these same patients. The first BMT/LPIT for which patients receive any fentanyl will be used in this comparison. The study focusses on the following secondary aims: * To determine which dose regimen ensures best conditions to perform bone marrow aspiration (lack of motion) and maintains hemodynamic and respiratory stability as indicators of adequate levels of analgesia during bone marrow aspiration. * To evaluate the safety and complications for each dose regimen.
Interventions
DRUGFentanyl
1. Fentanyl - 1 mcg/kg in 3 ml normal saline 2. Fentanyl - 0.5 mcg/kg in 3 ml normal saline
DRUGEMLA
All patients will have EMLA or LMX4 cream applied at the anticipated site of the bone marrow aspiration to ensure topical anesthesia, and will receive a total intravenous anesthetic technique (TIVA). EMLA application has to be over at least 60 minutes and not to exceed 5 hours.
DRUGL.M.X4
All patients will have EMLA or LMX4 cream applied at the anticipated site of the bone marrow aspiration to ensure topical anesthesia, and will receive a total intravenous anesthetic technique (TIVA). In order to optimize transdermal anesthesia LMX4 application has to be over at least 30 minutes.
DRUGPropofol
Propofol - 1 mg/kg increments every 30 seconds-1minute until loss of consciousness is indicated by lack of response to verbal command and loss of eyelid reflex.
Sponsors
St. Jude Children's Research Hospital
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
2 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* Patients undergoing bone marrow aspiration (unilateral), with lumbar puncture and intrathecal chemotherapy. * Age 2 to 17 years * ASA I-III * Patients with acute lymphoblastic leukemia or lymphoblastic lymphoma in remission or on the day of anticipated remission procedures occurring at the end of remission induction. * Patients must have three anticipated bone marrow aspirates and lumbar punctures with intrathecal chemotherapy remaining in their treatment
Exclusion criteria
* Newly diagnosed patients * Patients with low platelet count (less than 50000) * Patients undergoing bone marrow biopsy in addition to bone marrow aspiration * Age less than 2 years or over 17 years * ASA IV-V * Patients taking opioid medication for pre-existent pain for more than 2 weeks at the time of the procedure * Neurological impairment that would increase susceptibility to opioids (Down's syndrome) * Clinical contraindications for general anesthesia (large mediastinal mass) or specific use of propofol, Fentanyl, EMLA, L•M•X 4™ or Lidocaine for injection
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pain(Yes/No) | The participant was monitored from the end of the procedure until sedation recovery, which lasted a maximum of 65 min. Discharge from the recovery area was determined by hospital standards of care. | During the sedation recovery period, pain was measured by one of three validated pediatric scales. Scales were applied according to the developmental ability of the participant: Numerical Pain Scale, FACES pain scale, and FLACC pain scale (a score based on behaviors observed: face, legs, activity, cry, and consolability). All three scales are scored from 0 - 10 units on a scale, and are interchangeable for comparison purposes. Any score \>0 was coded pain, and score of 0 was coded no pain, yielding one score for each participant's procedure. |
| Pain (Yes/No) | The participant was monitored from the end of the procedure until sedation recovery, which lasted a maximum of 65 min. Discharge from the recovery area was determined by hospital standards of care. | During the sedation recovery period, pain was measured by one of three validated pediatric scales. Scales were applied according to the developmental ability of the participant: Numerical Pain Scale, FACES pain scale, and FLACC pain scale (a score based on behaviors observed: face, legs, activity, cry, and consolability). All three scales are scored from 0 - 10 units on a scale, and are interchangeable for comparison purposes. Any score \>0 was coded pain, and score of 0 was coded no pain, yielding one score for each participant's procedure. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 20% or Greater Change in Heart Rate | The participant was monitored from the end of the procedure until sedation recovery, which lasted a maximum of 65 min. Discharge from the recovery area was determined by hospital standards of care. | Measurements of 20% change in Heart Rate (yes/no) taken during recovery after surgery. |
| 20% or Greater Change in Respiratory Rate | The participant was monitored from the end of the procedure until sedation recovery, which lasted a maximum of 65 min. Discharge from the recovery area was determined by hospital standards of care. | Measurements of 20% change in respiratory rate(yes/no) taken during recovery after surgery. |
| 20% or Greater Change in Blood Pressure | The participant was monitored from the end of the procedure until sedation recovery, which lasted a maximum of 65 min. Discharge from the recovery area was determined by hospital standards of care. | Measurements of 20% change in blood pressure(yes/no) taken during recovery after surgery. |
| Movement | The participant was monitored from the end of the procedure until sedation recovery, which lasted a maximum of 65 min. Discharge from the recovery area was determined by hospital standards of care. | Movement (yes/no) measured during recovery after surgery. |
Countries
United States
Participant flow
Recruitment details
A total of 168 participants were enrolled between March, 2002 and August, 2007.
Pre-assignment details
168 participants were enrolled and were expected to receive 3 Bone Marrow Aspirations/Lumbar Puncture Intrathecal Chemotherapy procedures; 6 patients withdrew (eg: medical withdrawal, withdrawal of consent and other). 162 were randomized, of which 77 completed all 3 treatments.
Participants by arm
| Arm | Count |
|---|---|
| Fentanyl 0.5/Placebo/Fentanyl 1 | 30 |
| Fentanyl 0.5/Fentanyl 1/Placebo | 28 |
| Placebo/Fentanyl 0.5/Fentanyl 1 | 25 |
| Placebo/Fentanyl 1/Fentanyl 0.5 | 26 |
| Fentanyl 1/Fentanyl 0.5/Placebo | 25 |
| Fentanyl 1/Placebo/Fentanyl 0.5 | 28 |
| Total | 162 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Visit One | Physician Decision | 3 | 1 | 0 | 0 | 0 | 1 |
| Visit One | Withdrawal by Subject | 1 | 0 | 0 | 0 | 0 | 1 |
| Visit Three | Death | 0 | 0 | 1 | 0 | 1 | 0 |
| Visit Three | Study Discontinued | 7 | 6 | 7 | 7 | 7 | 6 |
| Visit Three | Withdrawal by Subject | 0 | 1 | 1 | 2 | 0 | 0 |
| Visit Two | Death | 0 | 0 | 0 | 1 | 0 | 1 |
| Visit Two | Physician Decision | 1 | 0 | 0 | 0 | 0 | 0 |
| Visit Two | Study Discontinued | 3 | 2 | 1 | 7 | 5 | 6 |
| Visit Two | Withdrawal by Subject | 1 | 1 | 1 | 0 | 1 | 1 |
Baseline characteristics
| Characteristic | Fentanyl 0.5/Placebo/Fentanyl 1 | Fentanyl 0.5/Fentanyl 1/Placebo | Placebo/Fentanyl 0.5/Fentanyl 1 | Placebo/Fentanyl 1/Fentanyl 0.5 | Fentanyl 1/Fentanyl 0.5/Placebo | Fentanyl 1/Placebo/Fentanyl 0.5 | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 6.4 years STANDARD_DEVIATION 4.3 | 7.2 years STANDARD_DEVIATION 4.5 | 7.6 years STANDARD_DEVIATION 4.8 | 7.1 years STANDARD_DEVIATION 4.1 | 7.3 years STANDARD_DEVIATION 4.7 | 7.1 years STANDARD_DEVIATION 4.4 | 7.1 years STANDARD_DEVIATION 4.4 |
| Sex: Female, Male Female | 15 Participants | 11 Participants | 12 Participants | 10 Participants | 9 Participants | 13 Participants | 70 Participants |
| Sex: Female, Male Male | 15 Participants | 17 Participants | 13 Participants | 16 Participants | 16 Participants | 15 Participants | 92 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 107 | 0 / 104 | 0 / 105 |
| serious Total, serious adverse events | 0 / 107 | 0 / 104 | 0 / 105 |
Outcome results
Primary
Pain (Yes/No)
During the sedation recovery period, pain was measured by one of three validated pediatric scales. Scales were applied according to the developmental ability of the participant: Numerical Pain Scale, FACES pain scale, and FLACC pain scale (a score based on behaviors observed: face, legs, activity, cry, and consolability). All three scales are scored from 0 - 10 units on a scale, and are interchangeable for comparison purposes. Any score \>0 was coded pain, and score of 0 was coded no pain, yielding one score for each participant's procedure.
Time frame: The participant was monitored from the end of the procedure until sedation recovery, which lasted a maximum of 65 min. Discharge from the recovery area was determined by hospital standards of care.
Population: Participants in this analysis are a subset of the 162 participants randomized since not all completed 3 visits on study. If a participant completed at least Visit 2 and received each of the 2 treatments compared they are included. Treatment on each visit was randomized; therefore these numbers cannot be derived directly from the participant flow.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Fentanyl 1mcg/kg vs Placebo | Pain (Yes/No) | No-Pain on Fentanyl (1), Pain on Fentanyl (0.5) | 5 Participants |
| Fentanyl 1mcg/kg vs Placebo | Pain (Yes/No) | Pain on Fentanyl (1), Pain on Fentanyl (0.5) | 2 Participants |
| Fentanyl 1mcg/kg vs Placebo | Pain (Yes/No) | Pain on Fentanyl (1) No-pain on Fentanyl (0.5) | 3 Participants |
| Fentanyl 1mcg/kg vs Placebo | Pain (Yes/No) | No-Pain on Fentanyl (1), No-Pain on Fentanyl (0.5) | 64 Participants |
Comparison: The study was designed to achieve statistical power of 80% for this comparison. Due to the early termination of the study, the sample size needed to ensure adequate statistical power for this comparison was not obtained.p-value: 0.5McNemar
Primary
Pain(Yes/No)
During the sedation recovery period, pain was measured by one of three validated pediatric scales. Scales were applied according to the developmental ability of the participant: Numerical Pain Scale, FACES pain scale, and FLACC pain scale (a score based on behaviors observed: face, legs, activity, cry, and consolability). All three scales are scored from 0 - 10 units on a scale, and are interchangeable for comparison purposes. Any score \>0 was coded pain, and score of 0 was coded no pain, yielding one score for each participant's procedure.
Time frame: The participant was monitored from the end of the procedure until sedation recovery, which lasted a maximum of 65 min. Discharge from the recovery area was determined by hospital standards of care.
Population: Participants in this analysis are a subset of the 162 participants randomized since not all completed 3 visits on study. If a participant completed at least Visit 2 and received each of the 2 treatments compared they are included. Treatment on each visit was randomized; therefore these numbers cannot be derived directly from the participant flow.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Fentanyl 1mcg/kg vs Placebo | Pain(Yes/No) | Pain with Fentanyl and pain with Placebo | 0 Participants |
| Fentanyl 1mcg/kg vs Placebo | Pain(Yes/No) | Pain with Fentanyl and no-pain with Placebo | 7 Participants |
| Fentanyl 1mcg/kg vs Placebo | Pain(Yes/No) | No-pain with Fentanyl pain with Placebo | 10 Participants |
| Fentanyl 1mcg/kg vs Placebo | Pain(Yes/No) | No-pain with Fentanyl no-pain with Placebo | 54 Participants |
| Fentanyl 0.5mcg/kg vs Placebo | Pain(Yes/No) | No-pain with Fentanyl no-pain with Placebo | 60 Participants |
| Fentanyl 0.5mcg/kg vs Placebo | Pain(Yes/No) | Pain with Fentanyl and pain with Placebo | 6 Participants |
| Fentanyl 0.5mcg/kg vs Placebo | Pain(Yes/No) | No-pain with Fentanyl pain with Placebo | 5 Participants |
| Fentanyl 0.5mcg/kg vs Placebo | Pain(Yes/No) | Pain with Fentanyl and no-pain with Placebo | 8 Participants |
Comparison: The study was designed to achieve statistical power of 80% for this comparison. Due to the early termination of the study, the sample size needed to ensure adequate statistical power for this comparison was not obtained.p-value: 0.5McNemar
Comparison: The study was designed to achieve statistical power of 80% for this comparison. The sample size needed to ensure adequate statistical power for this comparison was obtained.p-value: 0.5McNemar
Secondary
20% or Greater Change in Blood Pressure
Measurements of 20% change in blood pressure(yes/no) taken during recovery after surgery.
Time frame: The participant was monitored from the end of the procedure until sedation recovery, which lasted a maximum of 65 min. Discharge from the recovery area was determined by hospital standards of care.
Population: Due to study termination, not all participants completed three planned visits. 107 of the 162 participants enrolled on study received treatment with Fentanyl 0.5 mcg/kg. 104 of the 162 participants enrolled on study received treatment with Fentanyl 1mcg/kg. 105 of the 162 participants enrolled on study received treatment with Placebo.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Fentanyl 1mcg/kg vs Placebo | 20% or Greater Change in Blood Pressure | Yes | 12 Participants |
| Fentanyl 1mcg/kg vs Placebo | 20% or Greater Change in Blood Pressure | No | 95 Participants |
| Fentanyl 0.5mcg/kg vs Placebo | 20% or Greater Change in Blood Pressure | No | 94 Participants |
| Fentanyl 0.5mcg/kg vs Placebo | 20% or Greater Change in Blood Pressure | Yes | 10 Participants |
| Placebo | 20% or Greater Change in Blood Pressure | No | 91 Participants |
| Placebo | 20% or Greater Change in Blood Pressure | Yes | 14 Participants |
Comparison: The generalized estimation equation (GEE) approach by Liang and Zeger was used to model the effects of 20% change in blood presure (BP) on pain (Y/N) while controlling for treatment.p-value: 0.52GEE Model
Secondary
20% or Greater Change in Heart Rate
Measurements of 20% change in Heart Rate (yes/no) taken during recovery after surgery.
Time frame: The participant was monitored from the end of the procedure until sedation recovery, which lasted a maximum of 65 min. Discharge from the recovery area was determined by hospital standards of care.
Population: Due to study termination, not all Participants completed three planned visits. 107 of the 162 participants enrolled on study received treatment with Fentanyl 0.5 mcg/kg. 104 of the 162 participants enrolled on study received treatment with Fentanyl 1mcg/kg. 105 of the 162 participants enrolled on study received treatment with Placebo.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Fentanyl 1mcg/kg vs Placebo | 20% or Greater Change in Heart Rate | Yes | 7 Participants |
| Fentanyl 1mcg/kg vs Placebo | 20% or Greater Change in Heart Rate | No | 100 Participants |
| Fentanyl 0.5mcg/kg vs Placebo | 20% or Greater Change in Heart Rate | Yes | 6 Participants |
| Fentanyl 0.5mcg/kg vs Placebo | 20% or Greater Change in Heart Rate | No | 98 Participants |
| Placebo | 20% or Greater Change in Heart Rate | Yes | 8 Participants |
| Placebo | 20% or Greater Change in Heart Rate | No | 97 Participants |
Comparison: The generalized estimation equation (GEE) approach by Liang and Zeger was used to model the effects of 20% change in heart rate (HR) on pain (Y/N) while controlling for treatment.p-value: 0.87GEE Model
Secondary
20% or Greater Change in Respiratory Rate
Measurements of 20% change in respiratory rate(yes/no) taken during recovery after surgery.
Time frame: The participant was monitored from the end of the procedure until sedation recovery, which lasted a maximum of 65 min. Discharge from the recovery area was determined by hospital standards of care.
Population: Due to study termination, not all Participants completed three planned visits. 107 of the 162 participants enrolled on study received treatment with Fentanyl 0.5 mcg/kg. 104 of the 162 participants enrolled on study received treatment with Fentanyl 1mcg/kg. 105 of the 162 participants enrolled on study received treatment with Placebo.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Fentanyl 1mcg/kg vs Placebo | 20% or Greater Change in Respiratory Rate | Yes | 21 Participants |
| Fentanyl 1mcg/kg vs Placebo | 20% or Greater Change in Respiratory Rate | No | 86 Participants |
| Fentanyl 0.5mcg/kg vs Placebo | 20% or Greater Change in Respiratory Rate | Yes | 20 Participants |
| Fentanyl 0.5mcg/kg vs Placebo | 20% or Greater Change in Respiratory Rate | No | 84 Participants |
| Placebo | 20% or Greater Change in Respiratory Rate | Yes | 24 Participants |
| Placebo | 20% or Greater Change in Respiratory Rate | No | 81 Participants |
Comparison: The generalized estimation equation (GEE) approach by Liang and Zeger was used to model the effects of 20% change in respiratory rate (RR) on pain (Y/N) while controlling for treatment.p-value: 0.67GEE Model
Secondary
Movement
Movement (yes/no) measured during recovery after surgery.
Time frame: The participant was monitored from the end of the procedure until sedation recovery, which lasted a maximum of 65 min. Discharge from the recovery area was determined by hospital standards of care.
Population: Due to study termination, not all participants completed three planned visits. 107 of the 162 participants enrolled on study received treatment with Fentanyl 0.5 mcg/kg. 104 of the 162 participants enrolled on study received treatment with Fentanyl 1mcg/kg. 105 of the 162 participants enrolled on study received treatment with Placebo.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Fentanyl 1mcg/kg vs Placebo | Movement | Yes | 57 Participants |
| Fentanyl 1mcg/kg vs Placebo | Movement | No | 50 Participants |
| Fentanyl 0.5mcg/kg vs Placebo | Movement | Yes | 45 Participants |
| Fentanyl 0.5mcg/kg vs Placebo | Movement | No | 59 Participants |
| Placebo | Movement | Yes | 58 Participants |
| Placebo | Movement | No | 47 Participants |
Comparison: The generalized estimation equation (GEE) approach by Liang and Zeger was used to model the effects of motion (Y/N)on pain (Y/N) while controlling for treatment.p-value: 0.99GEE Model