Acetaminophen in aSAH to Inhibit Lipid Peroxidation and Cerebral Vasospasm

Phase 3

Terminated

Conditions: Cerebral Vasospasm
Aneurysmal Subarachnoid Hemorrhage

Interventions: Drug: Placebos for acetaminophen and N-acetylcysteine
Drug: NAC IV infusion at 0.5 gm hourly and APAP placebo
Drug: APAP 1 gm q6 hours, plus NAC IV infusion at 0.5 gm hourly
Drug: APAP 1 gm every 6 hours and N-acetylcysteine placebo
Drug: APAP 1.5 gm q6 hours, plus NAC IV infusion at 0.5 gm hourly

Registration Number: NCT00585559

Lead Sponsor: Vanderbilt University Medical Center

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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 44

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)

Study & Design

Study Type: INTERVENTIONAL

Study Design: FACTORIAL

Arm && Interventions

Group	Intervention	Description
Placebos for acetaminophen and N-acetylcysteine	Placebos for acetaminophen and N-acetylcysteine	Placebos for acetaminophen and N-acetylcysteine
N-acetylcysteine and acetaminophen	NAC IV infusion at 0.5 gm hourly and APAP placebo	N-acetylcysteine IV infusion at 0.5 gm hourly and acetaminophen placebo
Acetaminophen 1 Gram and N-acetylcysteine	APAP 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
Acetaminophen and N-acetylcysteine placebo	APAP 1 gm every 6 hours and N-acetylcysteine placebo	Acetaminophen 1 gm every 6 hours and N-acetylcysteine placebo
Acetaminophen 1.5 Gram and N-acetylcysteine	APAP 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

Primary Outcome Measures

Name	Time	Method
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.