A Phase 2 interventional study of Ketamine in Sickle Cell Disease and Vaso-Occlusive Crisis, sponsored by UCSF Benioff Children's Hospital Oakland. Completed at 1 site in United States. Open to participants aged 10 Years to 25 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2021-04-20.
Sponsored by UCSF Benioff Children's Hospital Oakland · Phase 2, Interventional, and Treatment
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.
Exclusion Criteria:
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.
Drug: Ketamine
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.
The intervention is IV low-dose bolus ketamine as an adjuvant to standard therapy (IV opiates and NSAIDs).
Also known as: Ketalar
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.
Time frame: 18 months
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).
Time frame: 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).
Time frame: 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.
Time frame: 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.
Time frame: 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).
Time frame: 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.
Time frame: 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).
Time frame: Up to one year prior to and after LDK administration on day 1 of the study in the ED
| Milestone | Study Participants |
|---|---|
| Started | 62 |
| Completed | 62 |
| Not completed | 0 |
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.
| Participants | Intervention |
|---|---|
| Serious adverse events | 0 |
| Nausea/vomiting | 4 |
| Emergence of emergence-like symptoms | 4 |
| Dream-like/de-realized sensation | 26 |
| Blurry vision | 3 |
| Dizziness | 2 |
| Floating sensation | 1 |
| Heavy sensation | 1 |
| Dry mouth | 1 |
| No adverse event | 20 |
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).
| percent change | Intervention |
|---|---|
| Effect of Low-dose Ketamine (LDK) on Opioid Usage in the ED | -15 (-28 to -2.3) |
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).
| Score on a scale | Intervention | Historical Control |
|---|---|---|
| Effect of Low-dose Ketamine on Pain Scores on Presentation to the ED | 9.23 (8.98 to 9.47) | 9.08 (8.83 to 9.34) |
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.
| percentage of participants | Intervention | Historical Control |
|---|---|---|
| Effect of Low-dose Ketamine on Discharge Rates From the ED | 33 | 17 |
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.
| Participants | Intervention |
|---|---|
| Achieved faster pain relief? | 43 |
| Achieved more complete pain relief? | 30 |
| Desire to receive LDK in the future? | 49 |
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).
| Score on a scale | Intervention | Historical Control |
|---|---|---|
| Effect of Low-dose Ketamine on Patient Pain Scores on Discharge From the ED/Admission to the Hospital | 7.15 (6.61 to 7.68) | 7.26 (6.84 to 7.68) |
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.
| LOS in minutes | Intervention | Historical Control |
|---|---|---|
| Effect of Low-dose Ketamine on Percent Difference of Length of Stay (LOS) in the ED | 273.5 (241.3 to 305.6) | 217.3 (200.0 to 234.5) |
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).
| time to 50% pain reduction in minutes | Intervention | Historical Control |
|---|---|---|
| Effect of Low-dose Ketamine on Time to 50% Pain Reduction | 116.1 (111.6 to 220.6) | 167.3 (117.0 to 217.5) |
Collected over 18 months. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Intervention | 0/62 (0%) | 0/62 (0%) | 42/62 (67.7%) |
| Event | Intervention |
|---|---|
| Dream-like/de-realized sensationGeneral disorders | 26/62 |
| Nausea/vomitingGastrointestinal disorders | 4/62 |
| Emergence of emergence-like symptomsGeneral disorders | 4/62 |
| Blurry visionEye disorders | 3/62 |
| DizzinessVascular disorders | 2/62 |
| Floating sensationGeneral disorders | 1/62 |
| Heavy sensationGeneral disorders | 1/62 |
| Dry mouthGeneral disorders | 1/62 |
| Age, Continuous(years) | Study Participants |
|---|---|
| Mean | 18.1 (14 to 24) |
| Sex: Female, Male(Participants) | Study Participants |
|---|---|
| Female | 45 |
| Male | 17 |
| Race (NIH/OMB)(Participants) | Study Participants |
|---|---|
| American Indian or Alaska Native | 0 |
| Asian | 0 |
| Native Hawaiian or Other Pacific Islander | 0 |
| Black or African American | 61 |
| White | 0 |
| More than one race | 0 |
| Unknown or Not Reported | 1 |
| Site of pain on presentation(participants) | Study Participants |
|---|---|
| Back | 22 |
| Extremity | 16 |
| Chest | 12 |
| Whole body | 5 |
| Abdomen | 4 |
| Other | 3 |
| Unknown | 0 |
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UCSF Benioff Children's Hospital Oakland