Neuroprotection, Spinal Ischemia, Stroke
Conditions
Keywords
Surgical complications, Spinal ischemia, Stroke, Neuroprotection
Brief summary
Numerous neuroprotectants have been effective when given prior to ischemic stroke in animals, yet they have all have failed when given after ischemic stroke in humans. A novel approach to ischemic neuroprotection is needed. Many patients who undergo cardiac, vascular, and neurosurgical procedures develop ischemic central nervous system (CNS) complications. These high risk surgeries present a unique opportunity to administer neuroprotectant medication prior to the injury, greatly increasing the likelihood that it will have a positive impact on outcomes. Patients undergoing descending thoracic aortic (DTA) and thoracoabdominal aortic (TAA) surgery have a particularly high rate of both brain and spine ischemia. In addition, these surgeries require placement of a lumbar cerebrospinal fluid (CSF) drain, allowing access to CSF in order to monitor markers of injury and penetration of medication into the CNS. We are performing a pilot dose finding trial of prophylactic darbepoetin alfa, a long-acting erythropoiesis medication with putative neuroprotectant properties, in patients undergoing DTA and TAA surgery.
Detailed description
Numerous neuroprotectants have been effective when given prior to ischemic stroke in animals, yet they have all have failed when given after ischemic stroke in humans. A novel approach to ischemic neuroprotection is needed. Many patients who undergo cardiac, vascular, and neurosurgical procedures develop ischemic central nervous system (CNS) complications. These high risk surgeries present a unique opportunity to administer neuroprotectant medication prior to the injury, greatly increasing the likelihood that it will have a positive impact on outcomes. Patients undergoing descending thoracic aortic (DTA) and thoracoabdominal aortic (TAA) surgery have a particularly high rate of both brain and spine ischemia. In addition, these surgeries require placement of a lumbar cerebrospinal fluid (CSF) drain, allowing access to CSF in order to monitor markers of injury and penetration of medication into the CNS. We performed a pilot dose finding trial of prophylactic darbepoetin alfa, a long-acting erythropoiesis medication with putative neuroprotectant properties, in patients undergoing DTA and TAA surgery. This dose finding trial was stopped early after 9 patients were enrolled at the request of the FDA after an unrelated trial of erythropoietin in acute stroke performed in Germany was negative and showed possible harm in those patients who received intravenous tissue plasminogen activaor (tPA). We then enrolled 9 additional patients who did not receive any intervention in order to compare them to the patients who received darbepoetin.
Interventions
DRUGDarbepoetin alfa
Patients will receive one IV injection of Darbepoetin alfa at doses ranging from 1mcg/kg to 6.5 mcg/kg prior to surgery
OTHERStandard care
Sponsors
University of Pennsylvania
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
* Are men and women between the ages of 18 - 100 years old (inclusive) * Require descending thoracic or thoracoabdominal aorta surgical repair * Can provide informed consent
Exclusion criteria
* Have a traumatic aortic dissection * Have a baseline NIHSS \> 1 or modified Rankin Scale \> 1 * Have a history of stroke or myocardial infarction within the past 30 days * Have a preoperative hemoglobin \< 9 or \> 14 * Have a history of polycythemia vera or essential thrombocytosis * Have a history of hematologic malignancy * Have a history of arterial or venous thrombosis in the past three months * Have uncontrolled hypertension * Have active malignancy requiring treatment * Are receiving hemodialysis * Are currently using recombinant human erythropoietin or darbepoetin alfa, or have an expectation to require these medications within 30 days of surgery. * Have a known allergy to recombinant human erythropoietin or darbepoetin alfa * Are pregnant or breast-feeding. Women of childbearing potential must have a negative pregnancy test (urine pregnancy test or serum beta-HCG)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Death or Neurologic Disability, Defined as an National Institutes of Health Stroke Scale (NIHSS)>4 or American Spinal Injury Association (ASIA) Lower Extermity Motor Score <25 | Discharge from the hospital | The NIHSS is a validated quasi-ordinal measure of stroke severity. An NIHSS \>4 is generally considered moderate or severe. The ASIA Lower Extremity Motor Score is a cumulative total of assessments of strength in 5 muscles in each leg, using the Medical Research Council 0-5 stroke score. ASIA score \< 25 is associated with impaired ambulation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| CSF S100beta | 48 hours | Cerebrospinal fluid S100beta level |
| Hemoglobin | 24 hours post-surgery | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Darbepoetin Alfa Patients receive 1 mg/kg IV darbepoetin immediately before surgery | 9 |
| Standard Care No darbepoetin | 9 |
| Total | 18 |
Baseline characteristics
| Characteristic | Darbepoetin Alfa | Standard Care | Total |
|---|---|---|---|
| Age, Continuous | 57 years | 62 years | 59 years |
| Prior aortic surgery | 6 Participants | 7 Participants | 13 Participants |
| Prior stroke | 3 Participants | 3 Participants | 6 Participants |
| Region of Enrollment United States | 9 participants | 9 participants | 18 participants |
| Sex: Female, Male Female | 4 Participants | 3 Participants | 7 Participants |
| Sex: Female, Male Male | 5 Participants | 6 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 9 | 0 / 9 |
| serious Total, serious adverse events | 4 / 9 | 3 / 9 |
Outcome results
Primary
Death or Neurologic Disability, Defined as an National Institutes of Health Stroke Scale (NIHSS)>4 or American Spinal Injury Association (ASIA) Lower Extermity Motor Score <25
The NIHSS is a validated quasi-ordinal measure of stroke severity. An NIHSS \>4 is generally considered moderate or severe. The ASIA Lower Extremity Motor Score is a cumulative total of assessments of strength in 5 muscles in each leg, using the Medical Research Council 0-5 stroke score. ASIA score \< 25 is associated with impaired ambulation.
Time frame: Discharge from the hospital
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Darbepoetin Alfa | Death or Neurologic Disability, Defined as an National Institutes of Health Stroke Scale (NIHSS)>4 or American Spinal Injury Association (ASIA) Lower Extermity Motor Score <25 | 1 Participants |
| Standard Care | Death or Neurologic Disability, Defined as an National Institutes of Health Stroke Scale (NIHSS)>4 or American Spinal Injury Association (ASIA) Lower Extermity Motor Score <25 | 3 Participants |
Secondary
CSF S100beta
Cerebrospinal fluid S100beta level
Time frame: 48 hours
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Darbepoetin Alfa | CSF S100beta | 214 pg/mL |
| Standard Care | CSF S100beta | 260 pg/mL |
Secondary
Hemoglobin
Time frame: 24 hours post-surgery
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Darbepoetin Alfa | Hemoglobin | 10.4 gm/dL | Standard Deviation 2.1 |
| Standard Care | Hemoglobin | 9.5 gm/dL | Standard Deviation 0.7 |