Acetaminophen in aSAH to Inhibit Lipid Peroxidation and Cerebral Vasospasm

Study Overview
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Brief Summary
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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
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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.

Official Title
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Inhibition of Lipid Peroxidation and Cerebral Vasospasm by an Acetaminophen-Based Regimen in Patients With Aneurysmal Subarachnoid Hemorrhage

Conditions
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Aneurysmal Subarachnoid Hemorrhage, Cerebral Vasospasm

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


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebos for acetaminophen and N-acetylcysteine<br>Placebos for acetaminophen and N-acetylcysteine | Drug: Placebos for acetaminophen and N-acetylcysteine<br>* Placebos for acetaminophen and N-acetylcysteine<br>|
| Active Comparator: Acetaminophen and N-acetylcysteine placebo<br>Acetaminophen 1 gm every 6 hours and N-acetylcysteine placebo | Drug: APAP 1 gm every 6 hours and N-acetylcysteine placebo<br>* Acetaminophen 1 gm every 6 hours and N-acetylcysteine placebo<br>|
| Active Comparator: N-acetylcysteine and acetaminophen<br>N-acetylcysteine IV infusion at 0.5 gm hourly and acetaminophen placebo | Drug: NAC IV infusion at 0.5 gm hourly and APAP placebo<br>* N-acetylcysteine IV infusion at 0.5 gm hourly and acetaminophen placebo<br>|
| Active Comparator: Acetaminophen 1 Gram and N-acetylcysteine<br>Acetaminophen 1 gm every 6 hours, plus N-acetylcysteine IV infusion at 0.5 gm hourly | Drug: APAP 1 gm q6 hours, plus NAC IV infusion at 0.5 gm hourly<br>* Acetaminophen 1 gm every 6 hours, plus N-acetylcysteine IV infusion at 0.5 gm hourly<br>|
| Active Comparator: Acetaminophen 1.5 Gram and N-acetylcysteine<br>Acetaminophen 1.5 gm every 6 hours, plus N-acetylcysteine IV infusion at 0.5 gm hourly | Drug: APAP 1.5 gm q6 hours, plus NAC IV infusion at 0.5 gm hourly<br>* Acetaminophen 1.5 gm every 6 hours, plus N-acetylcysteine IV infusion at 0.5 gm hourly<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The study is to determine whether APAP, NAC, and APAP with NAC will inhibit lipid peroxidation in (aSAH), utilizing F2-IsoPs as biomarkers for lipid peroxidation. The effect on the F2-IsoPs will be the primary study endpoint. |  | 21 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine whether APAP and APAP with NAC will inhibit vasospasm and brain ischemia in aSAH, as assessed by CTA w/perfusion imaging or MRI and diffusion weighted images. |  | 8 +/- days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Vasospasm, Lipid, Peroxidation, N-Acetylcysteine, Acetaminophen