Aneurysmal Subarachnoid Hemorrhage, Cerebral Vasospasm
Conditions
Keywords
Lipid, Peroxidation, N-Acetylcysteine, Acetaminophen, Vasospasm
Brief summary
The objective of this study is to determine whether acetaminophen (APAP), N-acetylcysteine (NAC), and APAP in combination with NAC will inhibit lipid peroxidation in aneurysmal subarachnoid hemorrhage (aSAH), utilizing F2-IsoPs as biomarkers for lipid peroxidation.
Detailed description
Aneurysmal subarachnoid hemorrhage (aSAH) is an often devastating form of stroke with high morbidity and mortality despite advances in surgical management. Approximately 30,000 patients annually suffer aSAH in the U.S. For patients who survive the initial subarachnoid hemorrhage, delayed cerebral vasospasm occurring from days 4-14 is the greatest cause of neurological disability and death. A growing body of evidence incriminates hemoprotein-catalyzed lipid peroxidation as the mediator of the vasospasm. Hemoglobin released from lysed red cells in the subarachnoid space becomes oxidized, in which state it acts as a pseudoperoxidase and generates the protein radicals that induce lipid peroxidation. F2-isoprostanes formed by this lipid peroxidation are highly potent constrictors of cerebral arterioles. We have demonstrated a more than 5 fold mean increase in F2-isoprostanes in the cerebrospinal fluid of patients with aSAH; this increase is maximal at the time of delayed vasospasm, and the level of increase is a function of the severity of the aSAH. We hypothesize that such vasoconstrictors are major contributors to the vasospasm produced by the hemoproteins, hemoglobin and myoglobin, in diseases in which they are released from their cellular confines. We have discovered that acetaminophen (APAP) is a potent inhibitor of hemoprotein-catalyzed lipid peroxidation with an IC50 for hemoglobin of 15 uM, which is in the range of plasma levels resulting from therapeutic doses of the drug in humans. Acetaminophen acts by reducing the ferryl-oxo radical form of the heme, and thereby prevents formation of the hemoprotein radical that initiates lipid peroxidation. To assess proof of concept in vivo, we determined the effect of acetaminophen in a rat model of rhabdomyolysis in which renal failure results from intense vasospasm. Acetaminophen blocked lipid peroxidation in this model, and prevented the renal failure with a dose that produced plasma levels in the therapeutic range for humans. We also have demonstrated that N-acetylcysteine (NAC) will inhibit hemoprotein-catalyzed lipid peroxidation. Moreover, NAC administration increases the levels of glutathione in vivo, and glutathione is a co-substrate for the glutathione peroxidases that can reduce the levels of peroxides in the environment of the aSAH . This is important as acetaminophen is most potent in inhibiting hemoprotein-catalyzed lipid peroxidation when peroxide concentrations are low. This concerted evidence is the basis for a hypothesis that NAC will augment the efficacy of acetaminophen as an inhibitor of hemoprotein-catalyzed lipid peroxidation in aSAH. These finding provide the rationale for a pilot study seeking proof of the concept that acetaminophen-based regimens can inhibit lipid peroxidation in patients with subarachnoid hemorrhage. Lipid peroxidation will be determined by analysis of F2-isoprostanes in cerebrospinal fluid. If such inhibition is seen, that then would provide a basis for a larger multi-center investigation to assess the effect on clinical endpoints. This pilot study will determine whether APAP, NAC, and APAP in combination with NAC will inhibit lipid peroxidation in aneurysmal subarachnoid hemorrhage.
Interventions
DRUGPlacebos for acetaminophen and N-acetylcysteine
Placebos for acetaminophen and N-acetylcysteine
DRUGAPAP 1 gm every 6 hours and N-acetylcysteine placebo
Acetaminophen 1 gm every 6 hours and N-acetylcysteine placebo
DRUGNAC IV infusion at 0.5 gm hourly and APAP placebo
N-acetylcysteine IV infusion at 0.5 gm hourly and acetaminophen placebo
DRUGAPAP 1 gm q6 hours, plus NAC IV infusion at 0.5 gm hourly
Acetaminophen 1 gm every 6 hours, plus N-acetylcysteine IV infusion at 0.5 gm hourly
DRUGAPAP 1.5 gm q6 hours, plus NAC IV infusion at 0.5 gm hourly
Acetaminophen 1.5 gm every 6 hours, plus N-acetylcysteine IV infusion at 0.5 gm hourly
Sponsors
National Institutes of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Vanderbilt University Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Ages ≥ 20 * Fisher Grade III or III + IV SAH based upon admitting CT scan * Aneurysm secured by either clipping or coiling within 72 hours of SAH * Intracranial aneurysm confirmed by angiography or CTA * Presence of ventriculostomy for external ventricular drainage (EVD) prior to randomization
Exclusion criteria
* Consent unobtainable * Enrollment in another interventional study * Patient is pregnant or lactating * Known co-morbidities that could affect outcome of this study * Contraindication to CTA * Serum creatinine \> 1.4 * Documented allergy to iodinated contrast that cannot be adequately treated with premedication * Documented allergy and/or intolerance to ApAP * Baseline liver disease * History of recent alcohol abuse with documented ALT or AST above normal laboratory values * Documented history of both malnutrition and decreased serum albumin below normal lab values * Documented abnormal platelet count below normal lab values * Documented abnormal PT or PTT above normal lab values * History or evidence of active asthma * Documented allergy and/or intolerance to N-acetylcysteine * Currently taking phenytoin, carbamazepine, or phenobarbital * Currently taking isoniazid (INH, Lanzid, Nydrazid) * Severe life-threatening complications resulting from standard aneurysm treatments that will likely prevent completion of the study * Patient unsuitable for the study, in the opinion of the investigator(s)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Vasospasm Based on Magnetic Resonance Angiography (MRA) | 8 Days post subarachnoid hemorrhage (SAH) event | Presence of vasospasm measured Magnetic Resonance Angiography (MRA). MRA measures the degree of arterial narrowing, with a higher score indicating more severe vasospasm. An MRA score of 84% sensitivity and 72% specificity is indicative of vasospasm. |
| Number of Patients With Vasospasm Based on Computed Tomographic Angiography (CTA) | 8 Days post subarachnoid hemorrhage (SAH) event | Presence of vasospasm measured by Computed Tomographic Angiography (CTA). CTA scores range from 0 (no vasospasm) to 34, where a score of 10 or more is indicative of vasospasm. |
| National Institutes of Health Stroke Scale (NIHSS) Score | 8 Days post subarachnoid hemorrhage (SAH) event | The scale measures the severity of symptoms associated with patient's stroke. It assesses the severity of impairments related to stroke. The impairments are graded on a 3-4 point scale with scores that range from 0-42. Patients with a higher score have a more severe impairment, and patients with a lower score have a less severe impairment. |
| Modified Rankin Scale (MRS) Score | 8 Days post subarachnoid hemorrhage (SAH) event | The modified Rankin Scale (mRS) is used for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. The 7 point ordinal scale ranges from No symptoms (0) to Death (6), with higher scores representing worse outcome. |
| Glasgow Outcome Scale (GOS) Score | 8 Days post subarachnoid hemorrhage (SAH) event | The Glasgow Outcome Scale (GOS) is a scale used to assess recovery of participants with brain damage. The scale has 5 categories: Death (1), Persistent vegetative state (2), Severe disability (3), Moderate disability (4), Good recovery (5). |
| The Barthel Index Score | 8 Days post subarachnoid hemorrhage (SAH) event | The Barthel index measures the extent to which someone can function independently during basic activities of daily living. Scores range from (from 0 to 100), 0 meaning disability and 100 meaning independence, therefore, higher score, better outcome. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| N-acetylcysteine IV Infusion at 0.5 gm Hourly N-acetylcysteine IV infusion at 0.5 gm hourly | 16 |
| Placebo for N-acetylcysteine IV Infusion at 0.5 gm Hourly Placebo for N-acetylcysteine IV infusion at 0.5 gm hourly | 17 |
| Aacetaminophen and N-acetylcysteine Infusion Acetaminophen 1.5gm every 6 hours, plus N-acetylcysteine IV infusion at 0.5 gm hourly | 11 |
| Total | 44 |
Baseline characteristics
| Characteristic | N-acetylcysteine IV Infusion at 0.5 gm Hourly | Placebo for N-acetylcysteine IV Infusion at 0.5 gm Hourly | Aacetaminophen and N-acetylcysteine Infusion | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 15 Participants | 15 Participants | 8 Participants | 38 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 2 Participants | 3 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 16 Participants | 16 Participants | 10 Participants | 42 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 3 Participants | 1 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) White | 15 Participants | 13 Participants | 9 Participants | 37 Participants |
| Region of Enrollment United States | 16 participants | 17 participants | 11 participants | 44 participants |
| Sex: Female, Male Female | 12 Participants | 13 Participants | 8 Participants | 33 Participants |
| Sex: Female, Male Male | 4 Participants | 4 Participants | 3 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 16 | 6 / 17 | 0 / 11 |
| other Total, other adverse events | 1 / 16 | 1 / 17 | 1 / 11 |
| serious Total, serious adverse events | 1 / 16 | 4 / 17 | 2 / 11 |
Outcome results
Primary
Glasgow Outcome Scale (GOS) Score
The Glasgow Outcome Scale (GOS) is a scale used to assess recovery of participants with brain damage. The scale has 5 categories: Death (1), Persistent vegetative state (2), Severe disability (3), Moderate disability (4), Good recovery (5).
Time frame: 8 Days post subarachnoid hemorrhage (SAH) event
Population: No data for the prespecified outcome was analyzed due to the NIH-approved SAP that is powered for 34 placebo subjects and 34 N-acetylcysteine subjects to be able to reject the null hypothesis that the failure rates for placebo and N-acetylcysteine subjects are equal with probability (power) 0.8. Only 44 participants were randomized. As such, no data analysis will be completed for this underpowered study.
Primary
Modified Rankin Scale (MRS) Score
The modified Rankin Scale (mRS) is used for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. The 7 point ordinal scale ranges from No symptoms (0) to Death (6), with higher scores representing worse outcome.
Time frame: 8 Days post subarachnoid hemorrhage (SAH) event
Population: No data for the prespecified outcome was analyzed due to the NIH-approved SAP that is powered for 34 placebo subjects and 34 N-acetylcysteine subjects to be able to reject the null hypothesis that the failure rates for placebo and N-acetylcysteine subjects are equal with probability (power) 0.8. Only 44 participants were randomized. As such, no data analysis will be completed for this underpowered study.
Primary
National Institutes of Health Stroke Scale (NIHSS) Score
The scale measures the severity of symptoms associated with patient's stroke. It assesses the severity of impairments related to stroke. The impairments are graded on a 3-4 point scale with scores that range from 0-42. Patients with a higher score have a more severe impairment, and patients with a lower score have a less severe impairment.
Time frame: 8 Days post subarachnoid hemorrhage (SAH) event
Population: No data for the prespecified outcome was analyzed due to the NIH-approved SAP that is powered for 34 placebo subjects and 34 N-acetylcysteine subjects to be able to reject the null hypothesis that the failure rates for placebo and N-acetylcysteine subjects are equal with probability (power) 0.8. Only 44 participants were randomized. As such, no data analysis will be completed for this underpowered study.
Primary
Number of Patients With Vasospasm Based on Computed Tomographic Angiography (CTA)
Presence of vasospasm measured by Computed Tomographic Angiography (CTA). CTA scores range from 0 (no vasospasm) to 34, where a score of 10 or more is indicative of vasospasm.
Time frame: 8 Days post subarachnoid hemorrhage (SAH) event
Population: No data for the prespecified outcome was analyzed due to the NIH-approved SAP that is powered for 34 placebo subjects and 34 N-acetylcysteine subjects to be able to reject the null hypothesis that the failure rates for placebo and N-acetylcysteine subjects are equal with probability (power) 0.8. Only 44 participants were randomized. As such, no data analysis will be completed for this underpowered study.
Primary
Number of Patients With Vasospasm Based on Magnetic Resonance Angiography (MRA)
Presence of vasospasm measured Magnetic Resonance Angiography (MRA). MRA measures the degree of arterial narrowing, with a higher score indicating more severe vasospasm. An MRA score of 84% sensitivity and 72% specificity is indicative of vasospasm.
Time frame: 8 Days post subarachnoid hemorrhage (SAH) event
Population: No data for the prespecified outcome was analyzed due to the NIH-approved SAP that is powered for 34 placebo subjects and 34 N-acetylcysteine subjects to be able to reject the null hypothesis that the failure rates for placebo and N-acetylcysteine subjects are equal with probability (power) 0.8. Only 44 participants were randomized. As such, no data analysis will be completed for this underpowered study.
Primary
The Barthel Index Score
The Barthel index measures the extent to which someone can function independently during basic activities of daily living. Scores range from (from 0 to 100), 0 meaning disability and 100 meaning independence, therefore, higher score, better outcome.
Time frame: 8 Days post subarachnoid hemorrhage (SAH) event
Population: No data for the prespecified outcome was analyzed due to the NIH-approved SAP that is powered for 34 placebo subjects and 34 N-acetylcysteine subjects to be able to reject the null hypothesis that the failure rates for placebo and N-acetylcysteine subjects are equal with probability (power) 0.8. Only 44 participants were randomized. As such, no data analysis will be completed for this underpowered study.