Acetazolamide Challenge With Perfusion in the Prediction of Cerebral Vasospasm

C-arm Cone Beam CTA and CTP With Acetazolamide Challenge in Aneurysmal Subarachnoid Hemorrhage: Evaluating Predictability for Early Ischemia in Cerebral Vasospasm

The investigators propose a technique using cone beam CT perfusion (CBCTP) imaging with an acetazolamide challenge as a potential diagnostic tool to detect a defect in cerebral autoregulation at a time when it has not yet caused clinically apparent signs or symptoms. 30 participants will be enrolled at the University of Wisconsin - Madison and can expect to be on study for about 2 weeks.

Acetazolamide or vasodilatory challenge should identify subjects having a abnormal cerebrovascular reactivity capacity. More specifically, after receiving the drug there will not be the expected increase in cerebral blood flow (CBF) in some of the subjects because they are already suffering from a disturbance in the vasculature's ability to respond to the signal for vasodilation. The investigators believe the presence of this deficit will be helpful in identifying patients who are at risk for potential brain ischemia due to this decreased capacity to autoregulate if/when clinically significant vasospasm occurs. The investigators predict that acetazolamide-activated regional cerebral blood flow studies will be more sensitive in the detection of mild cerebral vasospasm and will not just detect changes in cerebral blood flow as does standard perfusion imaging, but will provide information regarding changes in cerebrovascular reactivity. Under these circumstances, a better predictor of those patients at risk of cerebral infarction due to delayed vasospasm would be delineated. Identifying this "high-risk cohort" prior to the onset of clinically apparent symptoms would result in the institution of preventative measures such as triple H therapy. The objective of this proposal is to conduct a feasibility study of acetazolamide activated C-arm cone beam CT perfusion (CBCTP) to determine its application in the prediction of symptomatic cerebral vasospasm (i.e. ischemia or stroke) in patients with aneurysmal subarachnoid hemorrhage. The initial plan is to obtain C-arm CBCTP pre- and post-intravenous infusion of 1g acetazolamide within 24 hours of symptom onset in aneurysmal subarachnoid hemorrhage patients. The hypothesis is that some of these patients that will later develop clinical vasospasm of a degree sufficient to cause cerebral ischemia. The investigators believe this cohort of patients will demonstrate altered cerebrovascular reactivity during the acetazolamide challenge at a time before there is either angiographic evidence of vasospasm or clinical evidence of abnormal perfusion.

Participants entered into the study as a cohort, will because of their participation, undergo only two additional digital subtraction angiogram (DSA) imaging acquisitions. These will be done in conjunction with their standard diagnostic DSA evaluation and consist of two CBCTPs, one before and one after administration of 1 g acetazolamide through a peripheral IV line. Each CBCTP will require administration of 75-100 mL iodinated contrast medium also through an intravenous line. Neither of these imaging studies will be used for clinical decision making, but would be processed and evaluated at later date for a formal analysis of the results. Following completion of diagnostic imaging subjects will receive the usual standard of care for treatment of their ruptured aneurysm i.e. endovascular embolization or open surgical clipping.

Clinical neurological deterioration not attributable to other causes, mores specifically not due to re-bleeding, hydrocephalus, or metabolic changes.

The data that will be statistically compared is the pre-diamox perfusion in comparison to the post-diamox perfusion. A statistically significant change increase in CBF represents an appropriate response to Diamox. Lack of change in CBF or decrease in CBF could be suggestive of potential for developing vasospasm.

Inclusion Criteria: Patients with aneurysmal subarachnoid hemorrhage presenting to our institution within 24 hours of symptom onset Adults, 18 years of age or older Women of childbearing potential must not be pregnant (negative urine pregnancy test) Exclusion Criteria: Contraindication to acetazolamide (i.e. sulfonamide allergy, renal or liver failure) Contraindication to contrast media (Allergy or abnormal serum Cr and/or GFR based on current UW guidelines for IV contrast) Renal insufficiency, history of renal failure or renal transplant Hunt and Hess grade 1 and 5 (Attached protocol provides details on the grading scale. Grade 1 have lowest yield for vasospasm and Grade 5 are by definition critically ill and unstable patients) Critically ill patients who are unstable and who cannot undergo scans within the proposed timeline i.e. within 24 hours of the onset of their symptoms.

Shinoda J, Kimura T, Funakoshi T, Araki Y, Imao Y. Acetazolamide reactivity on cerebral blood flow in patients with subarachnoid haemorrhage. Acta Neurochir (Wien). 1991;109(3-4):102-8. doi: 10.1007/BF01403003.

Tanaka A, Yoshinaga S, Nakayama Y, Tomonaga M. Cerebral blood flow and the response to acetazolamide during the acute, subacute, and chronic stages of aneurysmal subarachnoid hemorrhage. Neurol Med Chir (Tokyo). 1998 Oct;38(10):623-30; discussion 630-2. doi: 10.2176/nmc.38.623.

Lee KH, Lukovits T, Friedman JA. "Triple-H" therapy for cerebral vasospasm following subarachnoid hemorrhage. Neurocrit Care. 2006;4(1):68-76. doi: 10.1385/NCC:4:1:068.

Roger VL, Go AS, Lloyd-Jones DM, Benjamin EJ, Berry JD, Borden WB, Bravata DM, Dai S, Ford ES, Fox CS, Fullerton HJ, Gillespie C, Hailpern SM, Heit JA, Howard VJ, Kissela BM, Kittner SJ, Lackland DT, Lichtman JH, Lisabeth LD, Makuc DM, Marcus GM, Marelli A, Matchar DB, Moy CS, Mozaffarian D, Mussolino ME, Nichol G, Paynter NP, Soliman EZ, Sorlie PD, Sotoodehnia N, Turan TN, Virani SS, Wong ND, Woo D, Turner MB; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics--2012 update: a report from the American Heart Association. Circulation. 2012 Jan 3;125(1):e2-e220. doi: 10.1161/CIR.0b013e31823ac046. Epub 2011 Dec 15. No abstract available. Erratum In: Circulation. 2012 Jun 5;125(22):e1002.

Sullivan HG, Kingsbury TB 4th, Morgan ME, Jeffcoat RD, Allison JD, Goode JJ, McDonnell DE. The rCBF response to Diamox in normal subjects and cerebrovascular disease patients. J Neurosurg. 1987 Oct;67(4):525-34. doi: 10.3171/jns.1987.67.4.0525.

Hinson JS, Ehmann MR, Fine DM, Fishman EK, Toerper MF, Rothman RE, Klein EY. Risk of Acute Kidney Injury After Intravenous Contrast Media Administration. Ann Emerg Med. 2017 May;69(5):577-586.e4. doi: 10.1016/j.annemergmed.2016.11.021. Epub 2017 Jan 25.

Hauge A, Nicolaysen G, Thoresen M. Acute effects of acetazolamide on cerebral blood flow in man. Acta Physiol Scand. 1983 Feb;117(2):233-9. doi: 10.1111/j.1748-1716.1983.tb07202.x.

Kimura T, Shinoda J, Funakoshi T. Prediction of cerebral infarction due to vasospasm following aneurysmal subarachnoid haemorrhage using acetazolamide-activated 123I-IMP SPECT. Acta Neurochir (Wien). 1993;123(3-4):125-8. doi: 10.1007/BF01401867.

Bruce RJ, Djamali A, Shinki K, Michel SJ, Fine JP, Pozniak MA. Background fluctuation of kidney function versus contrast-induced nephrotoxicity. AJR Am J Roentgenol. 2009 Mar;192(3):711-8. doi: 10.2214/AJR.08.1413.