Dual antiplatelet therapy

Dual antiplatelet therapy

Indications

Adequate dual antiplatelet (AP) therapy is imperative when performing neurovascular stenting procedures.

After stenting, the patient remains on dual antiplatelet therapy (ASA + Plavix) for at least a month and ASA alone indefinitely.

Currently, no consensus for the ideal AP regimen exists.

The most frequent included acetylsalicylic acid (ASA) 325 mg+Plavix 75 mg daily (for 7 days prior) and ASA 325 mg+Plavix 75 mg daily (for 5 days prior) for routine placement of intracranial and cervical stents, respectively. For emergency placement, ASA 325 mg+Plavix 600 mg (at time of surgery) was the most frequently used.

Significant heterogeneity in dual antiplatelet regimens following Pipeline Embolization Device (PED) placement and associated costs, exists at major academic neurovascular centers. The most commonly used first line dual antiplatelet regimen consists of aspirin and clopidogrel. Two major alternate protocols involving ticagrelor and prasugrel, are administered to clopidogrel hypo-responders. The optimal dual antiplatelet regimen for patients with cerebrovascular conditions has not been established, given limited prospective data within the neurointerventional literature 1).

Given its importance, evidence based protocols are imperative. Minimal literature exists focusing on neurovasculature, and therefore understanding current practice patterns represents a first step toward generating these protocols. 2).


Dual antiplatelet therapy (e.g. ASA + Plavix®) are mandatory for 4 weeks (90 days is preferable 3) after placement of a bare metal cardiac stent, and for at least 1 year with drug-eluting stents (DES) (the risk declines from ≈ 6% to ≈ 3%) 4). Even short gaps in drug therapy (e.g. to perform neurosurgical procedures) is associated with significant risk of acute stent occlusion (and therefore elective surgery during this time is discouraged 5) DES is so effective in suppressing endothelialization that lifetime dual antiplatelet therapy may be required. Bridging DES patients with antithrombin, anticoagulants, or glycoprotein IIb/IIIa agents has not been proven effective 6).

Antiplatelet Therapy in Flow Diversion

Complications

Dual antiplatelet therapy is associated with high early risks of major and gastrointestinal bleeding that decline after the first month in trial cohorts 7).

Case reports

Ravina et al., presented in 2018 a literature review and an illustrative case of an 18-year-old man who presented with progressive headaches and was found to have a large, unruptured basilar apex aneurysm involving the origins of bilateral superior cerebellar artery and posterior cerebral artery. Given the small posterior communicating artery and complexity of the aneurysm, proximal basilar artery occlusion with unilateral superficial temporal artery-to-superior cerebellar artery bypass was recommended. Despite antiplatelet treatment with acetylsalicylic acid pre- and postoperatively, the patient developed acute ischemia of the brainstem and cerebellum as well as an embolic left temporal lobe infarct. The patient received dual antiplatelet therapy starting postoperative day 6 following which he experienced no new infarcts and made a significant neurologic recovery. The current evidence suggests that proximal BA occlusion in complex BA apex aneurysm cases is thrombogenic and can be especially dangerous if thrombosis occurs suddenly in aneurysms without pre-existing intraluminal thrombus. Dual antiplatelet therapy during the first postoperative week presents a possible strategy for reducing the risk of ischemia due to sudden aneurysm thrombosis 8).

References

1)

Gupta R, Moore JM, Griessenauer CJ, Adeeb N, Patel AS, Youn R, Poliskey K, Thomas AJ, Ogilvy CS. Assessment of Dual Antiplatelet Regimen for Pipeline Embolization Device Placement: A Survey of Major Academic Neurovascular Centers in the United States. World Neurosurg. 2016 Sep 15. pii: S1878-8750(16)30839-7. doi: 10.1016/j.wneu.2016.09.013. [Epub ahead of print] PubMed PMID: 27641263.
2)

Faught RW, Satti SR, Hurst RW, Pukenas BA, Smith MJ. Heterogeneous practice patterns regarding antiplatelet medications for neuroendovascular stenting in the USA: a multicenter survey. J Neurointerv Surg. 2014 Jan 3. doi: 10.1136/neurintsurg-2013-010954. [Epub ahead of print] PubMed PMID: 24391160.
3)

Nuttall GA, Brown MJ, Stombaugh JW, et al. Time and cardiac risk of surgery after bare-metal stent percutaneous coronary intervention. Anesthesiology. 2008; 109:588–595
4)

Rabbitts JA, Nuttall GA, Brown MJ, et al. Cardiac risk of noncardiac surgery after percutaneous coronary intervention with drug-eluting stents. Anesthesiology. 2008; 109:596–604
5) , 6)

Landesberg G, Beattie WS, Mosseri M, et al. Perioperative myocardial infarction. Circulation. 2009; 119:2936–2944
7)

Hilkens NA, Algra A, Kappelle LJ, Bath PM, Csiba L, Rothwell PM, Greving JP; CAT Collaboration. Early time course of major bleeding on antiplatelet therapy after TIA or ischemic stroke. Neurology. 2018 Jan 26. pii: 10.1212/WNL.0000000000004997. doi: 10.1212/WNL.0000000000004997. [Epub ahead of print] PubMed PMID: 29374102.
8)

Ravina K, Strickland BA, Buchanan IA, Rennert RC, Kim PE, Fredrickson VL, Russin JJ. Postoperative antiplatelet therapy in the treatment of complex basilar apex aneurysms implementing Hunterian ligation and extracranial-to-intracranial bypass: review of the literature with an illustrative case report. World Neurosurg. 2018 Dec 8. pii: S1878-8750(18)32798-0. doi: 10.1016/j.wneu.2018.11.237. [Epub ahead of print] Review. PubMed PMID: 30537547.

Triple H therapy

Triple H therapy

The combination of induced hypertensionhypervolemia, and hemodilution (triple-H therapy) is often utilized to prevent and treat cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH).

Although this paradigm has gained widespread acceptance since 1985, the efficacy of triple-H therapy and its precise role in the management of the acute phase of SAH remains uncertain. In addition, triple-H therapy may carry significant medical morbidity, including pulmonary edemamyocardial infarctionhyponatremia, renal medullary washout, indwelling catheter-related complications, cerebral hemorrhage, and cerebral edema 1).

This practice is based on low level evidence.


see Induced hypertension for vasospasm.


Many older treatment schemes for CVS included so-called “triple- H” therapy (for HypervolemiaHypertension, and Hemodilution2). This has given way to “hemodynamic augmentation” consisting of maintenance of euvolemia and induced arterial hypertension 3). While potentially confusing, this has now sometimes been referred to as Triple-H therapy 4).

Inducing HTN may be risky with an unclipped ruptured aneurysm. Once the aneurysm is treated, initiating therapy before CVS is apparent may minimize morbidity from CVS 5) 6).

Use fluids to maintain euvolemia.

Administer pressors to increase SBP in 15% increments until neurologically improved or SBP of 220 mm Hg is reached.

Agents include:

● dopamine

○ start at 2.5 mcg/kg/min (renal dose)

○ titrate up to 15–20 mcg/kg/min

● levophed

○ start at 1–2 mcg/min

○ titrate every 2–5 minutes: double the rate up to 64 mcg/min, then increase by 10 mcg/min

● neosynephrine (phenylephrine): does not exacerbate tachycardia

○ start at 5 mcg/min

○ titrate every 2–5 minutes: double the rate up to 64 mcg/min, then increase by 10 mcg/min up to a max of 10 mcg/kg

● dobutamine: positive inotrope

○ start at 5 mcg/kg/min

○ increase dose by 2.5 mcg/kg/min up to a maximum of 20 mcg/kg/min

Complications of hemodynamic augmentation:

● intracranial complications 7)

○ may exacerbate cerebral edema and increase ICP

○ may produce hemorrhagic infarction in an area of previous ischemia

● extracranial complications

○ pulmonary edema in 17%

○ 3 rebleeds (1 fatal)

○ MI in 2%

○ complications of PA catheter: 8)

– catheter related sepsis: 13%

– subclavian vein thrombosis: 1.3%

– pneumothorax: 1%

– hemothorax: may be promoted by coagulopathy from dextran 9).

Case series

In a study of Engquist et al. from UppsalaCBF was assessed by bedside xenon CT at days 0-3, 4-7, and 8-12, and the cerebral metabolic state by cerebral microdialysis (CMD), analyzing glucoselactatepyruvate, and glutamate hourly. At clinical suspicion of DCIHHH therapy was instituted for 5 days. Cerebral blood flow measurements and CMD data at baseline and during HHH therapy were required for study inclusion. Non-DCI patients with measurements in corresponding time windows were included as a reference group.

In DCI patients receiving HHH therapy (n = 12), global cortical CBF increased from 30.4 ml/100 g/min (IQR 25.1-33.8 ml/100 g/min) to 38.4 ml/100 g/min (IQR 34.2-46.1 ml/100 g/min; p = 0.006). The energy metabolic CMD parameters stayed statistically unchanged with a Lactate to Pyruvate Ratio of 26.9 (IQR 22.9-48.5) at baseline and 31.6 (IQR 22.4-35.7) during HHH. Categorized by energy metabolic patterns during HHH, no patient had severe ischemia, 8 showed derangement corresponding to mitochondrial dysfunction, and 4 were normal. The reference group of non-DCI patients (n = 11) had higher CBF and lower L/P ratios at baseline with no change over time, and the metabolic pattern was normal in all these patients.

Global and regional CBF improved and the cerebral energy metabolic CMD parameters stayed statistically unchanged during HHH therapy in DCI patients. None of the patients developed metabolic signs of severe ischemia, but a disturbed energy metabolic pattern was a common occurrence, possibly explained by mitochondrial dysfunction despite improved microcirculation 10).


An audit of the SAH patient charts was performed. A total of 508 fluid measurements were performed in 41 patients (6 with delayed cerebral ischaemia; DCI) during 14 days of observation.

Underestimating for intravenous drugs was the most frequent error (80.6%; 112), resulting in a false positive fluid balance in 2.4% of estimations. In 38.6% of the negative fluid balance cases, the physicians did not order additional fluids for the next 24h. In spite of that, the fluid intake was significantly increased after DCI diagnosis. The mean and median intake values were 3.5 and 3.8l/24h respectively, although 40% of the fluid balances were negative. The positive to negative fluid balance ratio was decreasing in the course of the 14 day observation.

This study revealed inconsistencies in the fluid orders as well as mistakes in the fluid monitoring, which illustrates the difficulties of fluid therapy and reinforces the need for strong evidence-based guidelines for hypervolemic therapy in SAH 11).

References

1)

Lee KH, Lukovits T, Friedman JA. “Triple-H” therapy for cerebral vasospasm following subarachnoid hemorrhage. Neurocrit Care. 2006;4(1):68-76. Review. PubMed PMID: 16498198.
2)

Origitano TC, Wascher TM, Reichman OH, et al. Sustained Increased Cerebral Blood Flow with Prophylactic Hypertensive Hypervolemic Hemodilution (“Triple-H” Therapy) After Subarachnoid Hemorrhage. Neurosurgery. 1990; 27:729–740
3)

Dankbaar JW, Slooter AJ, Rinkel GJ, et al. Effect of different components of triple-H therapy on cerebral perfusion in patients with aneurysmal subarachnoid haemorrhage: a systematic review. Crit Care. 2010; 14. DOI: 10.1186/cc8886
4)

Connolly ES,Jr, Rabinstein AA, Carhuapoma JR, et al. Guidelines for the management of aneurys- mal subarachnoid hemorrhage: a guideline for healthcare professionals from the American Heart Association/american Stroke Association. Stroke. 2012; 43:1711–1737
5)

Solomon RA, Fink ME, Lennihan L. Prophylactic Volume Expansion Therapy for the Prevention of Delayed Cerebral Ischemia After Early Aneurysm Surgery. Arch Neurol. 1988; 45:325–332
6)

Solomon RA, Fink ME, Lennihan L. Early Aneurysm Surgery and Prophylactic Hypervolemic Hypertensive Therapy for the Treatment of Aneurysmal Subarachnoid Hemorrhage. Neurosurgery. 1988; 23:699–704
7) , 9)

Shimoda M, Oda S, Tsugane R, et al. Intracranial Complications of Hypervolemic Therapy in Patients with a Delayed Ischemic Deficit Attributed to Vasospasm. J Neurosurg. 1993; 78: 423–429
8)

Rosenwasser RH, Jallo JI, Getch CC, et al. Complications of Swan-Ganz Catheterization for Hemodynamic Monitoring in Patients with Subarachnoid Hemorrhage. Neurosurgery. 1995; 37:872–876
10)

Engquist H, Lewén A, Hillered L, Ronne-Engström E, Nilsson P, Enblad P, Rostami E. CBF changes and cerebral energy metabolism during hypervolemia, hemodilution, and hypertension therapy in patients with poor-grade subarachnoid hemorrhage. J Neurosurg. 2020 Jan 10:1-10. doi: 10.3171/2019.11.JNS192759. [Epub ahead of print] PubMed PMID: 31923897.
11)

Szmuda T, Waszak PM, Rydz C, Springer J, Budynko L, Szydlo A, Sloniewski P, Dzierżanowski J. The challenges of hypervolemic therapy in patients after subarachnoid haemorrhage. Neurol Neurochir Pol. 2014;48(5):328-36. doi: 10.1016/j.pjnns.2014.09.001. Epub 2014 Oct 13. PubMed PMID: 25440011.

Interstitial photodynamic therapy with 5-aminolevulinic acid for malignant brain tumor

Interstitial photodynamic therapy with 5-aminolevulinic acid for malignant brain tumor

Photodynamic therapy (PDT) remains a promising therapeutic approach that requires further study in high grade gliomas. Use of 5-ALA PDT permits selective tumor targeting due to the intracellular metabolism of 5-ALA. The immunomodulatory effects of PDT further strengthen its use for treatment of HGGs and requires a better understanding. The combination of PDT with adjuvant therapies for HGGs will need to be studied in randomized, controlled studies 1). 2).

PDT might be feasible for eliminating brain tumor cells in malignant pediatric brain tumors 3)


Computer simulation of the photophysical process in ALA-iPDT can offer a quantitative tool for understanding treatment outcomes, which depend on various variables related to clinical treatment conditions. Izumoto et al. proposed a clinical simulation method of ALA-iPDT for malignant brain tumors using a singlet oxygen (O12) model and O12 threshold to induce cell death. In this method, the amount of O12 generated is calculated using a photosensitizer photobleaching coefficient and O12 quantum yield, which have been measured in several previous studies. Results of the simulation using clinical magnetic resonance imaging data show the need to specify the insertion positions of cylindrical light diffusers and the level of light fluence. Detailed analysis with a numerical brain tumor model demonstrates that ALA-iPDT treatment outcomes depend on combinations of photobleaching and threshold values. These results indicate that individual medical procedures, including pretreatment planning and treatment monitoring, will greatly benefit from simulation of ALA-iPDT outcomes 4).


Glioma stem cells (GSLCs) expressed higher mRNA levels of protoporphyrin IX (PpIX) biosynthesis enzymes and its transporters PEPT1/2 and ABCB6, when compared to the parental A172 glioma cells. Consistently, flow cytometry analysis revealed that upon incubation with ALA, GSLCs accumulate a higher level of PpIX. Finally, Fujishiro et al., from the Department of Neurosurgery, Osaka Medical College, Takatsuki, Japan showed that GSLCs were more sensitive to 5-aminolevulinic acid-mediated photodynamic therapy (ALA-PDT) than the original A172 cells, and confirmed that all patient-derived glioma sphere lines also showed significantly increased sensitivity to ALA-PDT if cultivated under the pro-stem cell condition. This data indicate that ALA-PDT has potential as a novel clinically useful treatment that might eliminate GBM stem cells that are highly resistant to the current chemo- and radio-therapy 5).

References

1)

Mahmoudi K, Garvey KL, Bouras A, Cramer G, Stepp H, Jesu Raj JG, Bozec D, Busch TM, Hadjipanayis CG. 5-aminolevulinic acid photodynamic therapy for the treatment of high-grade gliomas. J Neurooncol. 2019 Feb;141(3):595-607. doi: 10.1007/s11060-019-03103-4. Epub 2019 Jan 18. Review. PubMed PMID: 30659522; PubMed Central PMCID: PMC6538286.
2)

Beck TJ, Kreth FW, Beyer W, Mehrkens JH, Obermeier A, Stepp H, Stummer W, Baumgartner R. Interstitial photodynamic therapy of nonresectable malignant glioma recurrences using 5-aminolevulinic acid induced protoporphyrin IX. Lasers Surg Med. 2007 Jun;39(5):386-93. PubMed PMID: 17565715.
3)

Schwake M, Nemes A, Dondrop J, Schroeteler J, Schipmann S, Senner V, Stummer W, Ewelt C. In-Vitro Use of 5-ALA for Photodynamic Therapy in Pediatric Brain Tumors. Neurosurgery. 2018 Dec 1;83(6):1328-1337. doi: 10.1093/neuros/nyy054. PubMed PMID: 29538709.
4)

Izumoto A, Nishimura T, Hazama H, Ikeda N, Kajimoto Y, Awazu K. Singlet oxygen model evaluation of interstitial photodynamic therapy with 5-aminolevulinic acid for malignant brain tumor. J Biomed Opt. 2019 Dec;25(6):1-13. doi: 10.1117/1.JBO.25.6.063803. PubMed PMID: 31838789.
5)

Fujishiro T, Nonoguchi N, Pavliukov M, Ohmura N, Park Y, Kajimoto Y, Ishikawa T, Nakano I, Kuroiwa T. 5-aminolevulinic acid-mediated photodynamic therapy can target human glioma stem-like cells refractory to antineoplastic agents. Photodiagnosis Photodyn Ther. 2018 Jul 7. pii: S1572-1000(18)30185-6. doi: 10.1016/j.pdpdt.2018.07.004. [Epub ahead of print] PubMed PMID: 29990642.
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