Clinical trial NCT00585559: Acetaminophen in aSAH to Inhibit Lipid Peroxidation and Cerebral Vasospasm
Official title: Inhibition of Lipid Peroxidation and Cerebral Vasospasm by an Acetaminophen-Based Regimen in Patients With Aneurysmal Subarachnoid Hemorrhage
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Aneurysmal Subarachnoid Hemorrhage
Cerebral Vasospasm
Keywords: Lipid
Peroxidation
N-Acetylcysteine
Acetaminophen
Vasospasm
Lead sponsor: Vanderbilt University Medical Center
Sponsor class: OTHER
Collaborators: name: National Institutes of Health (NIH)
name: National Institute of General Medical Sciences (NIGMS)
First posted: 2008-01-03
Enrollment: 44
Sex: ALL
Minimum age (years): 20
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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)

Primary outcomes:
measure: Number of Patients With Vasospasm Based on Magnetic Resonance Angiography (MRA)
timeFrame: 8 Days post subarachnoid hemorrhage (SAH) event
measure: Number of Patients With Vasospasm Based on Computed Tomographic Angiography (CTA)
timeFrame: 8 Days post subarachnoid hemorrhage (SAH) event
measure: National Institutes of Health Stroke Scale (NIHSS) Score
timeFrame: 8 Days post subarachnoid hemorrhage (SAH) event
measure: Modified Rankin Scale (MRS) Score
timeFrame: 8 Days post subarachnoid hemorrhage (SAH) event
measure: Glasgow Outcome Scale (GOS) Score
timeFrame: 8 Days post subarachnoid hemorrhage (SAH) event
measure: The Barthel Index Score
timeFrame: 8 Days post subarachnoid hemorrhage (SAH) event
Secondary outcomes:
Other outcomes:
Locations:
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
Study officials:
affiliation: Vanderbilt University Medical Center
name: Matthew Fusco, MD
role: PRINCIPAL_INVESTIGATOR
References: