Acetaminophen in aSAH to Inhibit Lipid Peroxidation and Cerebral Vasospasm

Sponsor

Vanderbilt University Medical Center (Other)

Overall Status

Recruiting

CT.gov ID

NCT00585559

Collaborator

National Institutes of Health (NIH) (NIH), National Institute of General Medical Sciences (NIGMS) (NIH)

120

Enrollment

Location

Arms

194

Duration (Months)

0.6

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Aneurysmal Subarachnoid Hemorrhage Cerebral Vasospasm	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	N/A

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

120 participants

Allocation:

Randomized

Intervention Model:

Factorial Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Apr 1, 2007

Anticipated Primary Completion Date :

Jun 1, 2022

Anticipated Study Completion Date :

Jun 1, 2023

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

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

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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

20 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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)