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Acute vaso-occlusive episodes (VOEs) in sickle cell disease (SCD) are primarily managed with opioids. Tolerance and hyperalgesia to opioids develops due to N-methyl-D-aspartate (NMDA)-receptor mediated activation of the nociceptive system, and as a receptor antagonist, ketamine mitigates this. Intravenous (IV) ketamine has demonstrated efficacy in reducing post-operative, chronic, and cancer-related pain in pediatrics, as well as in reducing time to pain control in the emergency department (ED) in adults. Limited studies suggest efficacy in adult opioid-refractory SCD patients. This study is investigating the safety and tolerability of adjuvant low-dose IV ketamine bolus for pediatric SCD VOE in the ED, as well as its efficacy in improving pain control and reducing hospitalization.
In this cohort study, all consenting pediatric sickle-cell patients between 10 and 25 years old who were cared for at UCSF Benioff Children's Hospital Oakland (UCSFBCHO) presenting to the emergency department for VOC were enrolled in the study. Patients were compared to themselves in a time series, pre and post exposure to the study intervention (low-dose ketamine bolus at 0.2 mg/kg x 1 prior to second dose of IV opiate). The pediatric FACES pain scale was used to measure pain scales at pre-designated time points in the ED per standard nursing protocol (FACES for younger kids, visual analog scale in adolescents/young adults). Opiate usage was summed in the ED, converted to mg/kg/hour of morphine equivalents (since different opioids agents were given to different patients based on individual historical efficacy, and since length of stay in the emergency room could affect total morphine equivalents received), and compared between the pre and post-intervention groups. In addition, length of stay, time to 50% pain control, presentation and discharge pain scores, and likelihood of discharge from the ED were compared. Data was be collected via chart review in the UCSFBCHO system by study investigators. Pre-intervention data from the past three patient encounters (e.g., the mean of the mg/kg/hour of morphine equivalents used in the last three patient encounters prior to receipt of ketamine) was compared to the post intervention data. In addition, a survey, which is attached, was given to patients/families at the time of the drug administration to attempt to discern if patients subjectively experienced improvement in their pain and if they experienced any negative side effects due to the drug administration. Monitoring for adverse events was recorded for each patient encounter.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Intervention | Active Comparator | Prior to the second dose of IV opiates, the experiment was to give patients a single IV bolus of ketamine at the dose of 0.2 mg/kg. Pain scores were collected using the FACES scale currently in place. In consenting patients, chart review was performed with the following data collected: mg/kg/hour of morphine equivalents, pain scores on admission, during the encounter, and at discharge, the time to 50% pain reduction, and whether or not the patient was discharged. In addition, a survey, which is attached, was given to patients/families at the time of drug administration to determine if they experienced a subjective improvement in their pain and if they suffered any undue side effects due to drug administration. |
|
| Historical Control | No Intervention | Patient data from at least one but up three patient encounters within the prior year were compared to their visit in which they were given adjuvant ketamine, using the outcome measures in the "Intervention" arm. Since this a historical control study, patients acted as their own controls in the above manner. Patients were allowed to re-enroll 4 weeks after presentation, which is typically considered a separate vaso-occlusive episode in the literature. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Ketamine | Drug | The intervention is IV low-dose bolus ketamine as an adjuvant to standard therapy (IV opiates and NSAIDs). |
|
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants With Treatment-Emergent Adverse Events [Safety and Tolerability] | The number of serious and minor adverse events was measured via patient-completed survey as well as by nurse and medical providers on presentation to the emergency department (ED). Serious adverse events are defined as cardiorespiratory events requiring intervention. Minor adverse events are defined as nausea/vomiting, emergence reaction (dysphoria; hallucinations; frightening dreams), and a sense of de-realization or "dreamy" sensation. Both study providers and patients themselves, via a survey that the parent and/or patient (based on age) fills out post receipt of ketamine, reported serious and minor adverse events. | 18 months |
| Measure | Description | Time Frame |
|---|---|---|
| Effect of Low-dose Ketamine (LDK) on Opioid Usage in the ED | Opioid usage for at least one but up to three prior patient visits in the last one year for each patient enrolled in the study was summarized, expressed as morphine equivalents in mg/kg/h, to account for different types of opioids used per patient preference, and then this was compared to the intervention group that received LDK. Percent change in opioid usage (expressed as morphine equivalents in mg/kg/h) is reported). |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Jonathan B Cooper-Sood, MD | Children's Hospital and Research Center of Oakland | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| UCSF Benioff Children's Hospital and Research Center Oakland | Oakland | California | 94609 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 23565738 | Background | Neri CM, Pestieau SR, Darbari DS. Low-dose ketamine as a potential adjuvant therapy for painful vaso-occlusive crises in sickle cell disease. Paediatr Anaesth. 2013 Aug;23(8):684-9. doi: 10.1111/pan.12172. Epub 2013 Apr 9. | |
| 24088202 | Background | Tawfic QA, Faris AS, Eipe N. Sickle cell pain management: are we missing the role of pronociception and neuropathic pain? Paediatr Anaesth. 2013 Nov;23(11):1104-5. doi: 10.1111/pan.12269. No abstract available. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Study Participants | Intervention: Prior to the second dose of IV opiates, the experiment was to give patients a single IV bolus of ketamine at the dose of 0.2 mg/kg. Ketamine: The intervention was IV low-dose bolus ketamine as an adjuvant to standard therapy (IV opiates and NSAIDs). Ultimately, 62 patient encounters were enrolled in the study. Historical Control: Patient data from at least one but up three patient encounters within the prior year were compared to their visit in which they were given adjuvant ketamine, using the outcome measures in the "Intervention" arm. Since this a historical control study, patients acted as their own controls in the above manner. Patients were allowed to re-enroll 4 weeks after presentation, which is typically considered a separate vaso-occlusive episode in the literature. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Study Participants | Intervention: Prior to the second dose of IV opiates, the experiment was to give patients a single IV bolus of ketamine at the dose of 0.2 mg/kg. Ketamine: The intervention is IV low-dose bolus ketamine as an adjuvant to standard therapy (IV opiates and NSAIDs). |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Number of Participants With Treatment-Emergent Adverse Events [Safety and Tolerability] | The number of serious and minor adverse events was measured via patient-completed survey as well as by nurse and medical providers on presentation to the emergency department (ED). Serious adverse events are defined as cardiorespiratory events requiring intervention. Minor adverse events are defined as nausea/vomiting, emergence reaction (dysphoria; hallucinations; frightening dreams), and a sense of de-realization or "dreamy" sensation. Both study providers and patients themselves, via a survey that the parent and/or patient (based on age) fills out post receipt of ketamine, reported serious and minor adverse events. | Posted | Count of Participants | Participants | 18 months |
|
18 months
Serious adverse events were defined per protocol as reaction to intervention causing cardiorespiratory compromise requiring medical intervention.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Intervention | Prior to the second dose of IV opiates, the experiment was to give patients a single IV bolus of ketamine at the dose of 0.2 mg/kg. Ketamine: The intervention was IV low-dose bolus ketamine as an adjuvant to standard therapy (IV opiates and NSAIDs). Ultimately, 62 patient encounters were enrolled in the study. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Nausea/vomiting | Gastrointestinal disorders | Systematic Assessment |
Given the study design (non-blinded, non-randomized), the effect of LDK on opioid usage and other secondary outcomes cannot be definitively associated with LDK itself given the possibility of a placebo effect.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Jonathan Bryan Cooper-Sood, MD | Valley Children's Hospital | 559-353-3000 | coopersoodj@usacs.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Feb 28, 2017 | Sep 23, 2020 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D000755 | Anemia, Sickle Cell |
| D000098644 | Vaso-Occlusive Crises |
| ID | Term |
|---|---|
| D000745 | Anemia, Hemolytic, Congenital |
| D000743 | Anemia, Hemolytic |
| D000740 | Anemia |
| D006402 | Hematologic Diseases |
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| ID | Term |
|---|---|
| D007649 | Ketamine |
| ID | Term |
|---|---|
| D003510 | Cyclohexanes |
| D003516 | Cycloparaffins |
| D006840 | Hydrocarbons, Alicyclic |
| D006844 | Hydrocarbons, Cyclic |
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| Up to one year prior and after LDK administration on day 1 of the study in the ED |
| Effect of Low-dose Ketamine on Pain Scores on Presentation to the ED | Patient pain scores at presentation for the enrolled encounters and for at least one but up to three visits prior to receipt of ketamine in the last one year, were assessed. At least one but up to three prior visits were averaged and compared to the intervention visit. Pain was assessed using the faces pain scale which consists of a series of line diagrams of faces with expressions of increasing distress. The score ranges from 0 (no pain) to 10 (the worst pain). | Up to one year prior and on presentation to the ED after LDK administration |
| Effect of Low-dose Ketamine on Discharge Rates From the ED | Percent discharge from the ED for intervention group and for at least one but up to three visits prior to receipt of ketamine in the last one year, were assessed. Participants were assigned a "0" if discharged or "1" if not discharged. | Up to one year prior to receipt of ketamine for the historical control arm/group and up to 18 months for the intervention arm/group |
| Subjective Effect of Low Dose Ketamine on Pain Relief Assessed Via a Patient Survey | After receipt of LDK, patients and/or their parents, based on age, filled out a survey based on a Likert scale regarding their agreement (Strongly Disagree to Strongly Agree) with the following statements: Achieved faster pain relief with LDK, Achieved more complete pain relief with LDK, and Desire to receive LDK in a future vaso-occlusive crisis. There is also an area where patients could provide general comments regarding their experience in receiving LDK. Count of Participants who agree or strongly agree for each question are reported. | after LDK administration on day 1 of the study in the ED |
| Effect of Low-dose Ketamine on Patient Pain Scores on Discharge From the ED/Admission to the Hospital | Patient pain scores at time of discharge from the ED/admission to the hospital for at least one but up to three visits prior to receipt of ketamine in the last one year, were assessed. At least one but up to three prior visits were averaged and compared to the intervention visit. Pain scores post receipt of ketamine are presented for the intervention group. Pain was assessed using the faces pain scale which consists of a series of line diagrams of faces with expressions of increasing distress. The score ranges from 0 (no pain) to 10 (the worst pain). | At time of discharge from the ED/admission to the hospital (up to one year prior and after LDK administration) |
| Effect of Low-dose Ketamine on Percent Difference of Length of Stay (LOS) in the ED | Length of stay (LOS) in minutes in the ED for at least one but up to three visits prior to receipt of ketamine in the last one year, were assessed. | Up to one year prior to and after LDK administration on day 1 of the study in the ED |
| Effect of Low-dose Ketamine on Time to 50% Pain Reduction | Time to 50% pain reduction (pain reported 50% less than baseline) in minutes for at least one but up to three visits prior to receipt of ketamine in the last one year, were assessed as historical controls. Pain was assessed using the faces pain scale which consists of a series of line diagrams of faces with expressions of increasing distress. The score ranges from 0 (no pain) to 10 (the worst pain). | Up to one year prior to and after LDK administration on day 1 of the study in the ED |
| 23692261 | Background | Jennings CA, Bobb BT, Noreika DM, Coyne PJ. Oral ketamine for sickle cell crisis pain refractory to opioids. J Pain Palliat Care Pharmacother. 2013 Jun;27(2):150-4. doi: 10.3109/15360288.2013.788599. Epub 2013 May 21. |
| 20090444 | Background | Zempsky WT, Loiselle KA, Corsi JM, Hagstrom JN. Use of low-dose ketamine infusion for pediatric patients with sickle cell disease-related pain: a case series. Clin J Pain. 2010 Feb;26(2):163-7. doi: 10.1097/AJP.0b013e3181b511ab. |
| 25865160 | Background | Riha H, Aaronson P, Schmidt A. Evaluation of analgesic effects of ketamine through sub-dissociative dosing in the ED. Am J Emerg Med. 2015 Jun;33(6):847-9. doi: 10.1016/j.ajem.2015.03.045. Epub 2015 Mar 25. No abstract available. |
| 25377395 | Background | Beaudoin FL, Lin C, Guan W, Merchant RC. Low-dose ketamine improves pain relief in patients receiving intravenous opioids for acute pain in the emergency department: results of a randomized, double-blind, clinical trial. Acad Emerg Med. 2014 Nov;21(11):1193-202. doi: 10.1111/acem.12510. |
| 26130219 | Background | Drake AB, Milne WK, Carpenter CR. Hot Off the Press: Subdissociative-dose Ketamine for Acute Pain in the Emergency Department. Acad Emerg Med. 2015 Jul;22(7):887-9. doi: 10.1111/acem.12705. Epub 2015 Jun 30. No abstract available. |
| 25624076 | Background | Miller JP, Schauer SG, Ganem VJ, Bebarta VS. Low-dose ketamine vs morphine for acute pain in the ED: a randomized controlled trial. Am J Emerg Med. 2015 Mar;33(3):402-8. doi: 10.1016/j.ajem.2014.12.058. Epub 2015 Jan 7. |
| 24232306 | Background | Uprety D, Baber A, Foy M. Ketamine infusion for sickle cell pain crisis refractory to opioids: a case report and review of literature. Ann Hematol. 2014 May;93(5):769-71. doi: 10.1007/s00277-013-1954-3. Epub 2013 Nov 15. |
| 23856095 | Background | Tawfic QA, Faris AS, Kausalya R. The role of a low-dose ketamine-midazolam regimen in the management of severe painful crisis in patients with sickle cell disease. J Pain Symptom Manage. 2014 Feb;47(2):334-40. doi: 10.1016/j.jpainsymman.2013.03.012. Epub 2013 Jul 12. |
| 25488336 | Background | Ahern TL, Herring AA, Anderson ES, Madia VA, Fahimi J, Frazee BW. The first 500: initial experience with widespread use of low-dose ketamine for acute pain management in the ED. Am J Emerg Med. 2015 Feb;33(2):197-201. doi: 10.1016/j.ajem.2014.11.010. Epub 2014 Nov 15. |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Site of pain on presentation | Number | participants |
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| Secondary | Effect of Low-dose Ketamine (LDK) on Opioid Usage in the ED | Opioid usage for at least one but up to three prior patient visits in the last one year for each patient enrolled in the study was summarized, expressed as morphine equivalents in mg/kg/h, to account for different types of opioids used per patient preference, and then this was compared to the intervention group that received LDK. Percent change in opioid usage (expressed as morphine equivalents in mg/kg/h) is reported). | 62 enrolled patient-encounters were compared to their prior visits individually. At least one but up to three prior visits were averaged and compared to the intervention visit. | Posted | Mean | 95% Confidence Interval | percent change | Up to one year prior and after LDK administration on day 1 of the study in the ED |
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| Secondary | Effect of Low-dose Ketamine on Pain Scores on Presentation to the ED | Patient pain scores at presentation for the enrolled encounters and for at least one but up to three visits prior to receipt of ketamine in the last one year, were assessed. At least one but up to three prior visits were averaged and compared to the intervention visit. Pain was assessed using the faces pain scale which consists of a series of line diagrams of faces with expressions of increasing distress. The score ranges from 0 (no pain) to 10 (the worst pain). | Posted | Mean | 95% Confidence Interval | Score on a scale | Up to one year prior and on presentation to the ED after LDK administration |
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|
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| Secondary | Effect of Low-dose Ketamine on Discharge Rates From the ED | Percent discharge from the ED for intervention group and for at least one but up to three visits prior to receipt of ketamine in the last one year, were assessed. Participants were assigned a "0" if discharged or "1" if not discharged. | Posted | Number | percentage of participants | Up to one year prior to receipt of ketamine for the historical control arm/group and up to 18 months for the intervention arm/group |
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|
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| Secondary | Subjective Effect of Low Dose Ketamine on Pain Relief Assessed Via a Patient Survey | After receipt of LDK, patients and/or their parents, based on age, filled out a survey based on a Likert scale regarding their agreement (Strongly Disagree to Strongly Agree) with the following statements: Achieved faster pain relief with LDK, Achieved more complete pain relief with LDK, and Desire to receive LDK in a future vaso-occlusive crisis. There is also an area where patients could provide general comments regarding their experience in receiving LDK. Count of Participants who agree or strongly agree for each question are reported. | Posted | Count of Participants | Participants | after LDK administration on day 1 of the study in the ED |
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| Secondary | Effect of Low-dose Ketamine on Patient Pain Scores on Discharge From the ED/Admission to the Hospital | Patient pain scores at time of discharge from the ED/admission to the hospital for at least one but up to three visits prior to receipt of ketamine in the last one year, were assessed. At least one but up to three prior visits were averaged and compared to the intervention visit. Pain scores post receipt of ketamine are presented for the intervention group. Pain was assessed using the faces pain scale which consists of a series of line diagrams of faces with expressions of increasing distress. The score ranges from 0 (no pain) to 10 (the worst pain). | Posted | Mean | 95% Confidence Interval | Score on a scale | At time of discharge from the ED/admission to the hospital (up to one year prior and after LDK administration) |
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| Secondary | Effect of Low-dose Ketamine on Percent Difference of Length of Stay (LOS) in the ED | Length of stay (LOS) in minutes in the ED for at least one but up to three visits prior to receipt of ketamine in the last one year, were assessed. | Posted | Mean | 95% Confidence Interval | LOS in minutes | Up to one year prior to and after LDK administration on day 1 of the study in the ED |
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| Secondary | Effect of Low-dose Ketamine on Time to 50% Pain Reduction | Time to 50% pain reduction (pain reported 50% less than baseline) in minutes for at least one but up to three visits prior to receipt of ketamine in the last one year, were assessed as historical controls. Pain was assessed using the faces pain scale which consists of a series of line diagrams of faces with expressions of increasing distress. The score ranges from 0 (no pain) to 10 (the worst pain). | 16 participants reported a 50% pain reduction, and those 16 participants were included in the analysis of time to 50% pain reduction. | Posted | Mean | 95% Confidence Interval | time to 50% pain reduction in minutes | Up to one year prior to and after LDK administration on day 1 of the study in the ED |
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| 0 |
| 62 |
| 0 |
| 62 |
| 42 |
| 62 |
| Emergence of emergence-like symptoms | General disorders | Systematic Assessment |
|
| Dream-like/de-realized sensation | General disorders | Systematic Assessment |
|
| Blurry vision | Eye disorders | Systematic Assessment |
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| Dizziness | Vascular disorders | Systematic Assessment |
|
| Floating sensation | General disorders | Systematic Assessment |
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| Heavy sensation | General disorders | Systematic Assessment |
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| Dry mouth | General disorders | Systematic Assessment |
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| D006425 |
| Hemic and Lymphatic Diseases |
| D006453 | Hemoglobinopathies |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D006838 |
| Hydrocarbons |
| D009930 | Organic Chemicals |
| Title | Measurements |
|---|---|
|