avoid plavix plus nexium/prevacid

FDA: Avoid Coadministration of Clopidogrel and Omeprazole, Esomeprazole

SILVER SPRING, Md -- November 17, 2009 -- The US Food and Drug Administration (FDA) has new data showing that the proton pump inhibitor (PPI) omeprazole (Prilosec/Prilosec OTC) reduces the anti-blood clotting effect of clopidogrel (Plavix) by almost half when these 2 medicines are taken by the same patient. Patients at risk for heart attacks or strokes who use clopidogrel to prevent blood clots will not get the full effect of this medicine if they are also taking omeprazole; therefore, the FDA recommends that the coadministration of omeprazole and clopidogrel be avoided.

The new recommendations, updated from a January 2009 Early Communication, are based on study results from the manufacturers of clopidogrel. The studies confirm that coadministration of omeprazole with clopidogrel results in decreased levels of clopidogrel's active metabolite, reducing clopidogrel's anticlotting effect.

Omeprazole inhibits the drug-metabolising enzyme (CYP2C19), which is responsible for the conversion of clopidogrel into its active metabolite. The new studies compared the amount of clopidogrel's active metabolite in the blood and its effect on platelets in patients who took clopidogrel plus omeprazole versus those who took clopidogrel alone. A reduction in active metabolite levels of about 45% was found in those who received clopidogrel with omeprazole compared with those taking clopidogrel alone. The effect of clopidogrel on platelets was reduced by as much as 47% in patients receiving clopidogrel and omeprazole together. These reductions were seen whether the drugs were given at the same time or 12 hours apart.

Since the level of inhibition among other PPIs varies, it is unknown to what amount other PPIs may interfere with clopidogrel. However, esomeprazole (Nexium), a PPI that is a component of omeprazole, inhibits CYP2C19 and should also be avoided in combination with clopidogrel.

Other stomach acid-reducing drugs, such as ranitidine (Zantac), famotidine (Pepcid), nizatidine (Axid), or antacids, are not expected to interfere with the anticlotting activity of clopidogrel because they do not inhibit CYP2C19 activity. However, cimetidine (Tagamet/Tagamet HB) does inhibit CYP2C19 activity and should not be used.

In addition to cimetidine, other drugs that are potent inhibitors of the CYP2C19 enzyme would be expected to have a similar effect and should be avoided in combination with clopidogrel. These include fluconazole (Diflucan), ketoconazole (Nizoral), voriconazole (VFEND), etravirine (Intelence), felbamate (Felbatol), fluoxetine (Prozac, Sarafem, Symbyax), fluvoxamine (Luvox), and ticlopidine (Ticlid).

Sanofi-aventis and Bristol-Myers Squibb, the makers of Plavix (clopidogrel), are updating this drug's label with the details of the studies and are conducting follow-up studies to further explore drug interactions with clopidogrel.

Until further information is available, FDA recommends the following:
• The concomitant use of omeprazole and clopidogrel should be avoided because of the effect on clopidogrel's active metabolite levels and anticlotting activity. Patients at risk for heart attacks or strokes, who are given clopidogrel to prevent blood clots, may not get the full protective anticlotting effect if they also take prescription omeprazole or the OTC form.
• Separating the dose of clopidogrel and omeprazole in time will not reduce this drug interaction.
• Other drugs that should be avoided in combination with clopidogrel because they may have a similar interaction include esomeprazole, cimetidine, fluconazole, ketoconazole, voriconazole, etravirine, felbamate, fluoxetine, fluvoxamine, and ticlopidine.
• At this time the FDA does not have sufficient information about drug interactions between clopidogrel and PPIs other than omeprazole and esomeprazole to make specific recommendations about their coadministration. Healthcare professionals and patients should consider all treatment options carefully before beginning therapy.
• There is no evidence that other drugs that reduce stomach acid, such as most H2 blockers ranitidine (Zantac), famotidine (Pepcid), nizatidine (Axid), except cimetidine (Tagamet and Tagamet HB - a CYP2C19 inhibitor), or antacids interfere with the anticlotting activity of clopidogrel. Ranitidine and famotidine are available by prescription and OTC to relieve and prevent heartburn and antacids are available OTC to relieve heartburn.
• Talk with your patients about the OTC medicines they take. Be aware that patients may be taking nonprescription forms of omeprazole and cimetidine.

The FDA will continue to investigate other drug interactions with clopidogrel. The FDA plans on presenting this issue at the next meeting of the FDA's Drug Safety Oversight Board in November. The Agency will communicate any further recommendations or conclusions once additional information is available.

RELATED LINKS:
PPIs Thwart Clopidogrel's Anticlotting Effectiveness in Diabetics Post Stenting: Presented at ADA

Effectiveness of Clopidogrel May Be Reduced by Common Heartburn Drugs: Presented at SCAI

Certain PPIs Increase Risk of Heart Attacks for Patients on Clopidogrel

SOURCE: US Food and Drug Administration

erythropoietin and vasospasm after SAH- synergistic with statins

 J Neurosurg  

Interaction of neurovascular protection of erythropoietin with age, sepsis, and statin therapy following aneurysmal subarachnoid hemorrhage; Tseng MY, Hutchinson PJ, Kirkpatrick PJ; Journal of Neurosurgery (Nov 2009)

Object In a previous randomized controlled trial, the authors demonstrated that acute erythropoietin (EPO) therapy reduced severe vasospasm and delayed ischemic deficits (DIDs) following aneurysmal subarachnoid hemorrhage. In this study, the authors aimed to investigate the potential interaction of neurovascular protection by EPO with age, sepsis, and concurrent statin therapy. Methods The clinical events of 80 adults older than 18 years and with<72 hours of aneurysmal subarachnoid hemorrhage, who were randomized to receive 30,000 U of intravenous EPO-beta or placebo every 48 hours for a total of 3 doses, were analyzed by stratification according to age (< or≥ 60 years), sepsis, or concomitant statin therapy. End points in the trial included cerebral vasospasm and impaired autoregulation on transcranial Doppler ultrasonography, DIDs, and unfavorable outcome at discharge and at 6 months measured with the modified Rankin Scale and Glasgow Outcome Scale. Analyses were performed using the t-test and/or ANOVA for repeated measurements. Results Younger patients (<60 years old) or those without sepsis obtained benefits from EPO by a reduction in vasospasm, impaired autoregulation, and unfavorable outcome at discharge. Compared with nonseptic patients taking EPO, those with sepsis taking EPO had a lower absolute reticulocyte count (nonsepsis vs sepsis, 143.5 vs. 105.8 x 10(9)/L on Day 6; p = 0.01), suggesting sepsis impaired both hematopoiesis and neurovascular protection by EPO. In the EPO group, none of the statin users suffered DIDs (p = 0.078), implying statins may potentiate neuroprotection by EPO. Conclusions Erythropoietin-related neurovascular protection appears to be attenuated by old age and sepsis and enhanced by statins, an important finding for designing Phase III trials.

Platelets transfusions does not help mortality in mild TBI in ASA/Plavix takers

 Am Surg Does platelet administration affect mortality in elderly head-injured patients taking antiplatelet medications?; Monson B, Butler KL, Fortuna GR, Saxe JM, Dolan JP, Markert RJ, McCarthy MC, Downey DM; American Surgeon 75 (11), 1100-3 (Nov 2009)

A significant portion of patients sustaining traumatic brain injury (TBI) take antiplatelet medications (aspirin or clopidogrel), which have been associated with increased morbidity and mortality. In an attempt to alleviate the risk of increased bleeding, platelet transfusion has become standard practice in some institutions. This study was designed to determine if platelet transfusion reduces mortality in patients with TBI on antiplatelet medications. Databases from two Level I trauma centers were reviewed. Patients with TBI 50 years of age or older with documented preinjury use of clopidogrel or aspirin were included in our cohort. Patients who received platelet transfusions were compared with those who did not to assess outcome differences between them. Demographics and other patient characteristics abstracted included Injury Severity Score, Glasgow Coma Scale, hospital length of stay, and warfarin use. Three hundred twenty-eight patients comprised the study group. Of these patients, 166 received platelet transfusion and 162 patients did not. Patients who received platelets had a mortality rate of 17.5 per cent (29 of 166), whereas those who did not receive platelets had a mortality rate of 16.7 per cent (27 of 162) (P = 0.85). Transfusion of platelets in patients with TBI using antiplatelet therapy did not reduce mortality.

Neuropsych and carotid stenosis

M. Silvestrini, MD, I. Paolino, MD, F. Vernieri, MD, C. Pedone, MD, R. Baruffaldi, MD, B. Gobbi, MD, C. Cagnetti, MD, L. Provinciali, MD and M. Bartolini, MD . Cerebral hemodynamics and cognitive performance in patients with asymptomatic carotid stenosis. NEUROLOGY 2009;72:1062-1068

Objective: The aim of this study was to investigate whether the presence of severe internal carotid artery stenosis may be associated with different cognitive performance in relation to the side of the stenosis and its hemodynamic consequences.

Methods: Eighty-three patients with asymptomatic severe unilateral internal carotid stenosis were included. A neuropsychological investigation including Verbal Fluency using phonemic and category access, Coloured Progressive Matrices, and Complex Figure Test Copy was performed. Each patient underwent an assessment of cerebrovascular reactivity (CVR) to hypercapnia with transcranial Doppler ultrasonography using the breath-holding index (BHI). Thirty healthy subjects comparable for demographic characteristics and vascular risk profile served as controls. Subjects with carotid stenosis were classified into two groups: preserved CVR (BHI 0.69), 48 patients (25 with left and 23 with right stenosis); and impaired CVR (BHI <0.69), 35 patients (19 with left and 16 with right stenosis).

Results: Subjects with left stenosis and reduced CVR had significantly lower performances at phonemic verbal fluency with respect to controls and the other groups of stenosis. In subjects with right stenosis and reduced CVR, scores obtained in Coloured Progressive Matrices and in Complex Figure Test Copy were significantly lower with respect to the other groups.

Conclusions: These results suggest that an alteration of cerebrovascular reactivity may be responsible for reduction in some cognitive abilities involving the function of the hemisphere ipsilateral to carotid stenosis. Such findings may be of interest for providing a more comprehensive indication to surgical treatment in subgroups of subjects with asymptomatic carotid stenosis.

safety of CT perfusions per FDA

For more information, please see FDA's Safety Investigation of CT Brain Perfusion Scans:  Initial Notification at:

  http://www.fda.gov/MedicalDevices/Safety/AlertsandNotices/ucm185898.htm <http://www.fda.gov/MedicalDevices/Safety/AlertsandNotices/ucm185898.htm>

d-dimer predicts cardioembolic stroke

D-dimer assay may differentiate subtypes of ischemic stroke; study of 126 patients hospitalized with acute ischemic stroke;
stroke subtypes were cardioembolic in 34 (27%),
atherothrombotic in 34 (27%),
lacunar in 31 (25%),
unknown in 27 (21%);

mean D-dimer levels on day 1 were 2.96 mcg/mL with cardioembolic stroke, 1.34 mcg/mL with atherothrombotic stroke and 0.67 mcg/mL with lacunar stroke; similar results at days 6 and 12; D-dimer > 2 mcg/mL had 59% sensitivity and 93% specificity for predicting cardioembolic stroke, D-dimer < 0.54 mcg/mL had 61% sensitivity and 96% specificity for predicting lacunar stroke

(Arch Intern Med 2002 Dec 9/23;162(22):2589)

Biomarkers for stroke

Foerch C, Montaner J, Furie KL,Ning MM, Lo EH. Searching for oracles: blood biomarkers for acute stroke . Invited Article. Neurology 2009; 73: 393-399.


Article discusses batteries of biomarkers used together to diagnose acute stroke or intracranial hemorrhage. They note that CT excludes hemorrhage, but does not include stroke, so a panel of markers may play a useful role.

To diagnose acute ischemic stroke, authors suggest a need for higher sensitivity than specificity to avoide missing treatable strokes.

NMDA antibodies are typically high early in stroke (first 3 hours) but may be false positive in patients with atherosclerosis or old strokes. New research focuses on fragments of NMDA rather than antibodies.

Reynolds et al. (Clin Chemisty2003) tested 50 markers and found a panel of four or five significantly predicted ischemic stroke. They were S100b, B type neurotropic growth factor, VWF, MMP-9, and monocyte chemotactic protein 1.They had a combined sens/spec of 91/97 for IS within 12 hours of stroke onset. The same group in a 2d study found S100b, MMP-9. vascular adhesion molecule, and VWF to have a combined sens/spec of 90/90. (Lynch JR Stroke 2004). Laskowitz found a panel of BNP, CRP, d-dimer, MMP-9, and S100b has a sens/spec of 81/70. Laskowitz et al. published a prospective multicenter trial (Stroke 2009) of 1100 patients using d-dimer, BNP, MMP-9, and S100b within 24 hours of stroke onset and found a s/s of 86/37.

For intracranial hemorrhage, markers include GFAP, which is also high in gliomas. In another analysis, RAGE and S100b best differentiated group from controls. ApoC1 and especially ApoC3 differentiate ICH from controls.

Montaner et al (Circulation 2003) found that MMP-9 was a powerful predictor of hemorrhagic risk in patients given alteplase. MMP-9 is also a predictor of HT in non lysed patients. Fibronectin has a similar pattern.

S100B which tends to correlate with infarct size, was also a predictor of malignant edema in one study (Foerch et al., Stroke 2004).

Bypass, strokes and Lou Caplan's call for action

Caplan LR. Translating what is known about neurological complications of coronary artery bypass graft complications into action. Arch Neurol 2009; 66: 1062-1064.

Dr Caplan editorializes about stroke and CABG and distills knowledge into 3 pages and a number of points that can be bulleted.

1. Complications from bypass are increasing as bypass patients are sicker. In 1994, the rate of stroke and delirium after bypass were 2.9 and 7.7 % respectively, at Johns Hopkins Hospital. In 2004, the respective rates were 4.5 and 13.8 %.

2. There is virtually no relationship between carotid disease, especially asymptomatic, and cardiac risk during bypass. In the large series, 95 % had strokes not in the territory of a diseased carotid artery. Of the four patients who did have strokes in the diseased carotid territory, the carotid was occluded in 3 of 4 so the mechanism was not hemodynamic but embolic.

3, Aortic atheromatosis is the most important cause of stroke after bypass, with cardiac factors second. The use of aortic filters, the use of off pump bypass or avoidance of cross clamping and identifying patients in advance results in improved outcomes. Identifying susceptible patients can be done with TEE, chest x ray, chest CT, or intraoperative epiaortic ultrasound before clamping. Most patients have not had this done.

4. ECHO to look at ventricular contractile function and thrombi is often not done but should be done.

5. Identification of a cardiologist and in some cases, neurologist in house to see patient preop would be helpful.

6. Risk of stroke is highest in those with previous TIA or stroke.

hypercoagulation profile based on scenario-Oregon

 NEUROLOGY VENOUS THROMBOSIS PANEL:
- Protein C Activity
- Protein S Activity
- Antithrombin Activity
- Activated Protein C Resistance
- Prothrombin G20210A PCR
- Lupus Anticoagulant
- Anticardiolipin IgG and IgM
- Homocysteine

NEUROLOGY ARTERIAL THROMBOSIS PANEL
- Lupus Anticoagulant
- Anticardiolipin IgG and IgM
- Homocysteine
- Lipoprotein (a)

NEUROLOGY ARTERIAL THROMBOSIS PANEL, WOMEN>40
- Lupus Anticoagulant
- Anticardiolipin IgG and IgM
- Homocysteine
- Lipoprotein (a)
- Activated Protein C Resistance
- Prothrombin G20210A PCR

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Hypercoagulable workup (incl effects warfarin on tests)

hat tip David Gordon, MD Professor/Chairman Neurology at OKL


Hypercoagulable Profile
􀂃 Protein C
􀂃 Protein S free and total
􀂃 Antithrombin III
􀂃 Fibrinogen
􀂃 Factor VII
􀂃 Factor VIII
􀂃 Activated protein C resistance (APCR)
􀂃 Factor V Leiden mutation
􀂃 Prothrombin G20210A mutation
􀂃 Anticardiolipin antibodies
􀂃 Anti-beta-2-glycoprotein I antibodies
􀂃 Antiphosphatidylserine antibodies
􀂃 Lupus anticoagulant
􀂃 Lipoprotein (a)
􀂃 C-reactive protein
􀂃 Methyltetrahydrofolate reductase C677T and A1298C
􀂃 Sickle prep (if African heritage)
Affect of Coumadin on Hypercoagulable Profile
􀂃 Protein C (may be decreased with warfarin)
􀂃 Protein S free and total (may be decreased with warfarin)
􀂃 Antithrombin III (not affected by warfarin)
􀂃 Fibrinogen (not affected by warfarin)
􀂃 Factor VII (may be affected by warfarin)
􀂃 Factor VIII (not affected by warfarin)
􀂃 Activated protein C resistance (must alter methods to compensate for warfarin)
􀂃 Factor V Leiden mutation (not affected by warfarin)
􀂃 Prothrombin 20210 mutation (not affected by warfarin)
􀂃 Anticardiolipin antibodies (not affected by warfarin)
􀂃 Anti-beta-2-glycoprotein I antibodies (not affected by warfarin)
􀂃 Antiphosphatidylserine antibodies (not affected by warfarin)
􀂃 Lupus anticoagulant (screening tests not affected by warfarin, but “mixing studies” to
confirm are affected by warfarin)
􀂃 Lipoprotein (a) (not affected by warfarin)
􀂃 C-reactive protein (not affected by warfarin)
􀂃 Methyltetrahydrofolate reductase C677T and A1298C (not affected by warfarin)
􀂃 Sickle prep (if African heritage) (not affected by warfarin

North American moya moya is different

Hallemeier et al. Stroke 2006. Authors looked at 34 adults with the condition. 22 had bilateral and 12 unilateral moya moyal vessels. North Americans present more often with ischemic stroke whereas Asians present with hemorrhage more often. 0/12 unilateral patients subsequently developed contralateral symptoms. Symptomatic patients had high levels of recurrence both homolaterally and contralaterally, and asymptomatic patients had a low risk of ischemic events. Surgical treatment revascularization led to less recurrence, with a fairly high perioperative morbidity and mortality ( as high as 17 % for the latter). N American moya moya may be a different entity than the Japanese kind.

Statins prevent vasospasm after subarachnoid hemorrhage

McGirt Mj et al. J Neurosurg 2006; 105: 671-674. (Duke) 115 patients were retrospectively reviewed with multivariate regression analysis. Statin therapy started on admission with SAH resulted in a elevenfold decrease in vasospasm. ACA/ICA aneurysm also was associated with vasospasm. Tseng MY al (Stroke 2005; J Neurosurg 2007) also published 2 articles on the subject . The mechanism is thought to be cholesterol independent, perhaps related to nitrous oxide.

Number to harm with iv tpa

Saver JL Hemorrhage after thrombolytic therapy for stroke. The clinically relevant number needed to harm Stroke 2007; 38: 2279-2283

Author reviews original NINDS data on hemorrhages, n=20/312 patients treated, and noted that they tended to be older, have mass effect on CT, have higher serum glucose, and more severe strokes. The number needed to harm, ie an additional dead or disabled outcome (MRS>= 3) attributable to SICH is 707, based on the expected outcome of these 20 patients.

NNH for dead disabled outcome MRS (.=4) 126, for fatal outcome 36.5, and for worsening of any degree between 30 and 40.

Basic conclusion is that most patients with SICH are destined for bad outcomes from the get go.

IV alteplase plus mutlimerci is safe

Smith WS et al. Safety of mechanical thromobectomy and iv tpa in acute ischemic stroke. Results of the Multi Mechanical Embolus in Cerebral Ischemia (Merci) trial part I. AJNR 2006; 27: 1177- 1182.

Study enrolled patients who either did not receive iv tpa or received it and did not recanalize. It was an international prospective single arm trial up to 88 hours post stroke. 111 patients received the procedure with mean NIHSS of 19 +/= 6.3 30/111 received tpa prior. 60/111 recanalized with retriever alone, 77/111 with adjunctive therapy. 9 % has SICH. 5 % had procedural complications.

Clinical outcomes not given

Blogger note: Like many radiology studies, this one has important limitations. The study does show that Multi Merci is safe and efficacious using recanalization, but fails to look at clinical outcome of the patient. PROACT 2 is the single study showing clinical benefit of interventional therapy for stroke, namely intrarterial lysis.

Warfarin in elderly -- Birmingham study

Mant J et al. for BAFTA investigators. Warfarin v. aspirin in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a randomized clinical trial

patients: 973 patients 75+ age, mean 81, SD 4 from primary care were randomized to aspirin 75 mg or warfarin with INR target of 2-3, and followed a mean 2.7 years. The endpoint was fatal or disabling stroke, ICH, an arterial embolism.

results: in warfarin group there were 24 events, with 2 ICH and remainder ischemic strokes, in aspirin group there were 48 events. Yearly risk reduction was 3.8 percent in aspirin group, 1.8 percent in warfarin group, risk reduction 2 %, p=0.003. Risk of hemorrhagic events increased 0.2 % in warfarin group, 1.4 to 1.6 percent.

Warfarin is treatment of choice.

Aspirin v. anticoagulation in carotid dissection

Georgiadis D, Arnold M, et al. Neurology 2009; 72:1810-1815

A study of 298 patients with spontaneous Carotid artery dissection

Main points

ischemia is relatively rare after dissection in 3 months ischemic stroke occurred in 0.3 %, TIA 3.4 %, retinal ischemia 1 % with no significant difference between groups. Ischemic events were commoner in those with ischemic events at onset. It is important to separate these two groups. Anticoagulation had a predictable 2 % complication rate. There was 97 % followup with exam or structured telephone interview. In literature review , 2 recent meta analyses showed no difference. (see Cochrane database Syst Rev 2003, and Lyrer et al, Stroke 2004). This was not a RCT, and warfarin was prescribed up to 1997 and aspirin thereafter. The number of patients was too small to evaluate treatment differences. The primary finding was the low rate of strokes after sicd.

criteria for alteplase in community setting

from a highly placed stroke neurologist:
IA therapy has already been endorsed as reasonable in selected patients
by AHA/ASA, ACC  -  virtually all comprehensive stroke centers are doing
it. FDA approval is years away and is not required per se. IA case
selection variables have been quasi standardized: NIHSS > 10; major
vessel occlusion (M1/M2 MCA and basilar artery are favored sites for
intervention; carotid T and ICA occlusion somewhat more controversial
but doable); < 6 hours from stroke onset (some argue intervention should
be completed < 8 hours from stroke onset based on PROACT 2 . MERCI
retriever for clot removal is give
n as 8 hours); no standard thrombolytic exclusions. Many would add MR
or CT mismatch imaging as another selection factor especially as
you.approach 6 to 8 hours or in patients > 80 years of age with NIHSS >
20 (no standard criteria yet but 20% mismatch is probably too low; if
you had >50% mismatch and DW volume < 100 cc that would be favorable).
So until and unless you want to randomize into a (nonexistent) clinical
trial you.could simply not do IA (using the specious (in my view)
“unproven” argument) or you could have access to an experienced
comprehensive stroke center and do “drip and ship.”  You could
possibly develop IA at a certified primary stroke center if resources
(angio suite; interventionalist 24/7 etc) were available. Otherwise I do
not advocate IA stroke therapy at community hospitals. 

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ALL ASA guidelines re stroke in one website

http://www.americanheart.org/presenter.jhtml?identifier=3004586

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Stroke Outcome by NIHSS and type

rates of recanalization after iv tpa BA 10 % M1 25 %, M2-5 50-60 %,

Outcome based on NIHSS
3-6 90 % excellent regardless
16-22 40 % excellent
lacunar-- 30 % greater chance of improved outcome
NIH > 23, high rate hemorrhage

a radiology link site

http://www.radswiki.net/main/index.php?title=Category:Neuro&until=Nose

Critical management SAH

Pearls very quick hits new stuff last 20 y
Nimodipine is still used to prevent vasospasm, so is asa and tirilizad
fludrocortison is used to prevent /treat cerebral salt wasting
nonconvulsive seizures occur in about 18%

 

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CADASIL notes

Major criteria-- headaches, migraine, mood disorder, stroke, tia
Other neurologic --epilepsy, scord infarcts, ICH, episodic increased ICP
path-- osmiophilic granular deposits on vascular basal lamina
increased oxygen extraction rate
notch 3 protein beneficial
thalamic predominance
cerebral microbleeds
CSF may have mild increase protein, otherwise normal
prenanatal testing available with CVS or amnio
chr 19, 50 + mutations
cysteine residue mutation

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Stroke pearls valvular disease

infective endocarditis== high stroke risk, 20 % usu in first 48 hours, dramatically reduced c ABX, late stroke risk lower 5 %
 
mechanical valves-- stroke risk highest MV on anticoag rate 3-4 %, AV is 1.2 %, ASA + warfarin is superior

Mycotic aneurysms-- distal branch point serial reimaging, clip if no response to ABX

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decompressive craniectomy

Cerebral hemorrhage pearls
peaks after age 50
women more than men
anterior more than posterior
aneurysm anterior, AVM posterior
Rupture risk:  higher with BA, budding tip,
Size and risk:  < 10 mm, 0.05 % per year; 10 mm 1 %/yr;  > 25 mm 6 % per year

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U MASS protocol for patient selection for stroke

0-3 hours

*CT, CTA , CT perfusion
*BA, ICA, M-1 occlusion  OR ineligible for iv-- consider IA alteplase
*Others i-v alteplase

3-6 hours

CT, CTA, CT perfusion
(alt.) MRI, MRA, MR D/P
Mismatch and occlusion-- proceed with intrarterial

No patient eligible for alteplase intravenously is denied.

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VerifyNow Platelet function assay system (Accumetrix)

Distilled:
Plavix PF (for Plavix and Ticlid) ICD-9 code V58.63
Aspirin PF (For aspirin) ICD-9 Code V58.66
separate tests for integrilin and reopro (not interested)

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FDA recommendation re clopidogrel and PPI's

http://www.fda.gov/Cder/drug/early_comm/clopidogrel_bisulfate.htm

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Neuroflo device in acute ischemic stroke AAN abstract

[P02.087] A Novel Treatment in the Management of Acute Ischemic Stroke

Mohamed M. Ibrahim, Maher Saqqur, Arabesque Parker, Monica Saini, Dulka Manawadu, Ken Butcher, Derek Emery, Ashfaq Shuaib, Edmonton, AB, Canada

OBJECTIVE: Role of Transcranial Doppler (TCD) monitoring in acute stroke patients treated with NeuroFlo device . BACKGROUND: The NeuroFlo device has been implemented as an experimental tool for potential interventional treatment in non- IV rt-PA responder patients with acute ischemic stroke. The presumed mechanism of action is enhancement of blood flow diversion to cerebral collaterals to minimise infarct volume and improve clinical outcomes. DESIGN/METHODS: Patients presenting to our ER with acute ischemic stroke, who did not show significant improvement after thrombolysis were screened; after an informed consent, they were enrolled in the Feasibility and Safety of NeuroFlo in Stroke Patients Receiving rt-PA. An intra-aortic balloon was inflated after completion of the rtPA infusion, resulting in the partial occlusion of abdominal Aorta for 45 minutes. TCD was performed at baseline, at the end of IV rt-PA treatment, before and during balloon inflation. RESULTS: We enrolled 9 cases, 4 patients did not had TCD study, of the remaining 5 patients 3 patients had MCA occlusion and 2 Terminal ICA occlusion. Three patients had good long term outcome Modified Rankin Scale (MRS) at 90 days were 1, zero and Zero respectively. There TCD during balloon inflation revealed: 1- Enhancing flow at the occlusion site (mean flow velocity increased from 18 to 24, 8 to 22 and 14 to 46 cm/sec) 2- Two patients had anterior cross filing developed through anterior communicating artery (ACom). 3- Enhancing flow through contralateral MCA (MFV 108 to 177 cm/sec) and ips ACA flow (MFV 22 to 81 cm/sec) in one patient. Two patients had poor outcome (MRS at 90 days 3) both had no enhancing flow during balloon inflation. CONCLUSIONS/RELEVANCE: NeuroFlo device might provide a new treatment for acute stroke patients beyond the 3 hours window by enhancing the flow at the occlusion site and opening up collateral flow.
Category - Cerebrovascular Disease - Acute Stroke Therapy

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negative effect of alteplase on stroke patients with CHF AAN abstract

[P02.083] Clinical Outcomes of Patients with Congestive Heart Failure Who Receive Thrombolytic Therapy for Acute Ischemic Stroke

Kachikwu Illoh, Miriam Morales, Tamara Humphrey, Alexander Katcheves, Nneka Ifejika, Francisco Fuentes, Mc Lean, VA, Houston, TX

OBJECTIVE: To determine whether thrombolytic therapy improved outcome among patients with CHF presenting with AIS. BACKGROUND: Patients with severe congestive heart failure (CHF) often have impaired cerebral perfusion. They have poor clinical outcomes on presenting with acute ischemic stroke (AIS). In these patients, it is likely that prompt thrombolysis would stem further decline in an already compromised cerebral perfusion state. Whether thrombolytic therapy improves the outcome in these patients is unclear. DESIGN/METHODS: In a cohort study with retrospective review of records from a prospectively collected database, we included AIS patients who were consecutively admitted to the stroke service of a large tertiary care center. Poor clinical outcome was defined as a modified Rankin score (mRS) of greater than 3. We examined the characteristics of AIS patients with history of CHF by their thrombolytic therapy status and compared their clinical outcomes with non-CHF patients. RESULTS: A total of 2,180 AIS patients with a mean age of 65 (SD, 15) years and 53% females were enrolled. Of the entire cohort, 26% (576/2180) received intravenous thrombolytic therapy, and 9% (196/2180) had history of CHF. The in-hospital mortality overall was 6% (129/2081); among CHF patients mortality was 8%. Of the 196 CHF patients, 66 (34%) got thrombolytic therapy. Yet, the CHF patients who received thrombolytic therapy did not achieve better mortality outcome compared to those not receiving the treatment (9% versus 8%, P = 0.786). Likewise, there was no difference in functional outcome between CHF patients who got thrombolytic therapy and CHF patients without the treatment (mRS >3; 49% versus 50%; P = 1.000). CONCLUSIONS/RELEVANCE: In patients with history of CHF who presented with AIS, thrombolytic therapy was not associated with an improvement in their clinical outcome. This finding needs further exploration in larger studies as more aggressive management of CHF may be required to augment thro mbolytic therapy.
Category - Cerebrovascular Disease - Acute Stroke Therapy

Tuesday, April 28, 2009 11:30 AM

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alteplase and malignancy at AAN

[P02.082] Outcomes of Patients with Malignancy Treated with Thrombolytics

Ramy El Khoury, Miriam M. Morales, Oleg Chernyshev, Anitha Abraham, M. Rick Sline, Indrani Acosta, Vivek Misra, Andrew Barreto, Sean Savitz, Kachikwu Illoh, James Grotta, Nicole R. Gonzales, Bellaire, TX, Mc Lean, VA, Houston, TX

OBJECTIVE: Treating patients with a history of cancer for ischemic strokes with thrombolytics may not alter patient's outcome. BACKGROUND: Very limited literature discusses the outcome of patients with malignancy treated with thrombolytics for ischemic stroke. The purpose of our research is to describe our experience in treating patients who have malignancy with thrombolysis. DESIGN/METHODS: We conducted a retrospective case-control study comparing the outcomes of patients receiving thrombolysis with a history of or active cancer (cancer positive, CP) compared with a control group (cancer negative, CN) matched for age and baseline NIHSS. Primary outcome measure was symptomatic intracerebral hemorrhage (sICH). Secondary outcome measures included good outcome (discharge modified Rankin Scale (mRS) <3), and good discharge disposition (discharge home or in-patient rehabilitation). RESULTS: From 2003-2008, 679 patients were treated with thrombolytics (IV, IV/IA, or IA only). Of these, 60 patients were CP with a mean age 73 (SD, 13) years and 120 CN patients were matched for age and baseline NIHSS. Baseline median NIHSS was 12 in both groups with similar ranges (p=0.835). There were no significant differences among baseline characteristics between the two groups. The most common malignancies were prostate 27% and breast 22%. There was no significant difference among 24 hour post-tPA NIHSS, good outcomes, length of stay, sICH, or good disposition. CONCLUSIONS/RELEVANCE: Our data demonstrates that patients with malignancy (or a history of) who receive thrombolysis have outcomes similar to CN patients and do not appear to be at increased risk of sICH. It also suggests that the presence or history of malignancy should not preclude thrombolysis if the patient is otherwise a thrombolytic candidate.
Category - Cerebrovascular Disease - Acute Stroke Therapy

Tuesday, April 28, 2009 11:30 AM

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AAN venous anomaly and malignant MCA infarction

[P02.080] Ipsilateral Cerebral Venous Outflow Obstruction Is Associated with Life-Threatening Brain Edema of Middle Cerebral Artery Infarction

Wengui Yu, Joanna Rives, Babu Welch, Jonathan White, Duke Samson, Dallas, TX

OBJECTIVE: The aim of this study was to investigate the role of cerebral venous anomaly in the development of life-threatening brain edema after middle cerebral artery (MCA) infarction. BACKGROUND: Approximately 35% of the patients with complete MCA infarction develop life-threatening brain edema and herniation. Although infarct size was the major determinant, its predictive value was only moderate. DESIGN/METHODS: This is a retrospective study of consecutive patients with complete MCA infarction who were admitted to our Neurointensive Care Unit from January 2007 to October 2008. Patient demographics and clinical features were reviewed. Brain edema on serial CT or MRI scans and cerebral venous anatomy on CTA or digital subtraction angiography were evaluated. Functional outcome at discharge was estimated using modified Rankin scales. RESULTS: A total of 14 patients were identified to have complete MCA infarction and cerebral venography. Four patients (25.6%) were found to have ipsilateral cerebral venous anomaly, including transverse sinus atresia (1), hypoplasia (2), and previous surgical ligation of internal jugular vein (1). All of them had fatal brain edema. The severity and timing of maximal edema were correlated with the degree of cerebral venous outflow obstruction. They all refused surgery and died from transtentorial herniation. The remaining 10 patients had symmetric or ipsilateral dominant cerebral venous drainage. Only one of them developed life-threatening edema possibly due to poor collateral circulation and bilateral carotid stenosis. He underwent decompressive surgery and recovered with moderate left hemiparesis. Patient age, sex, co-morbidity, carotid artery occlusion, or infarct size was not independently associated with life-threatening edema. CONCLUSIONS/RELEVANCE: Our preliminary results suggest that ipsilateral cerebral venous outflow obstruction is independently associated with life-threatening brain edema after MCA infarction and may be an indication for early decompressive craniectomy.
Category - Cerebrovascular Disease - Acute Stroke Therapy

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HHT and stroke (aka Osler Weber Rendu s)

Felix S et al., Neurology 2008; 71: 2012-2013.

Hereditary hemorrhagic telangiectasia (HHT) is a rare aut dom disease caused by one of 2 mutations, designated HHT1 and HHT2. The mutations are in the ENG and ALK1 genes. Diagnosis required 3 of the following 4: spontaneous epistaxis, cutaneous telangiectasias. av malformations of the interior organs and positive family history. Complications are anemia, portal hypertension, hypoxemia, brain abscess and stroke.

Authors of a case report demonstrate occurrence of a stroke after embolization of the pulmonary artery venous malformation. Authors note the need to check platelet function prior to using antiplatelet drugs in patients with HHT for prevention before endovascular procedures.

MRI may show lots of tiny hemorrhages.

Recommendation is to screen relatives

notes
avm rupture can cause paradoxical pulmonary fistula
conjunctival
lung liver gi and brain

stroke is due to paradoxical emboli across the PAVM
rarely due to anemia, hypoxia or air emboli

PAVM are most concerning if larger than 2 cm

signs and symptoms
epistaxis long precedes telangiectasias
Dyspnea is second most common symptoms
Hemoptysis is third most
others  clubbing cyanosis,GI bleeds in the over 58, less often chest pain and syncope
can auscultate a murmur over the PAVM in about half

Neurologic symptoms are present in about half including confusion, syncope, paresis, headache and vertigo especially

Migraines 43 percent
TIA   37 percent
stroke  18 percent
brain abscess in 9 percent
seizure 8 percent

more with advancing age

AHA abstract of note: Relationship of BNP level to cardiac thromus in patients with CVA and AF

Presentation Number:

ASA P12

Publishing Title:

Brain Natriuretic Polypeptide is a Marker Associated with Cardiac Thrombus in Stroke Patients

with Atrial Fibrillation

Author Block:

Yoko Okada

, Ehime hospital, Toon, Japan; Kensaku Shibazaki, Kazumi Kimura, Noriko Matsumoto, Yasuyuki

Iguchi, Kawasaki Medical Sch, Kurashiki, Japan

Abstract Body:

Background and purpose

Brain natriuretic peptide (BNP) is used as a biological marker of heart diseases. 8-10% of acute stroke patients

with atrial fibrillation (AF) have cardiac thrombus (CTh), which is considered as a high risk of stroke recurrence.

We investigated whether high BNP levels could be a biological marker of CTh in acute stroke patients with AF.

=0 A

Methods

Between November 2006 and June 2008, acute ischemic stroke patients with AF within 7 days of stroke onset

who underwent transesophageal echocardiography (TEE) were enrolled. We measured BNP using rapidly assay

(SHIONOSPOT® BNP) on TEE examination. Patients were divided into two groups according to the absence and

presence of CTh (Negative and Positive groups). We compared clinical characteristics including age, gender,

previous ischemic stroke, vascular risk factors, National Institutes of Health Stroke Scale (NIHSS) score on

admission, and BNP level between the two groups. Moreover, the factors associated with CTh were investigated

by multivariate logistic regression model.

Results

67 patients (male 40; mean age, 76.5±11.1 years) were enrolled. 17 (25.4%) patients had CTh. Hypertension

(88.2% vs. 58.0%, p= 0.037) was higher in the Positive group than in the Negative group. There were no

significant differences between the Positive group and Negative group in age (76.5±9.5 vs. 76.4±11.7, p=0.730),

female (58.8% vs. 34.0%, p=0.072), previous ischemic stroke (23.5% vs. 30.0%, p=0.760), diabetes mellitus

(35.3% vs. 20.0%, p=0.201), hyperlipidemia (17.6% vs. 14.0%, p=0.706), smoking (41.2% vs. 52.0%, p=0.441),

and NIHSS score on admission (9.8±8.3 vs. 7.0±7.8, p=0.237). The mean±SD BNP level was significantly higher

in the Positive group than in the Negative group (307.3±270.6 vs. 146.5±119.0 pg/ml, p=0.024). The optimal cutoff

level, sensitivity, and specificity of BNP levels to distinguish the Positive group from the Negative group were

145.0 pg/ml, 70.6% and 64.0%, respectively. Multivariate logistic regression analysis demonstrated that plasma

BNP level of >145.0 pg/ml (odds ratio, 4.61; 95%CI, 1.29 to 16.51, p=0.019) was independent factor associated

with CTh.

Conclusions

BNP is a marker associated with CTh in stroke patients with AF.

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risk factors for arterial dissection

tobacco use,
HTN, OCPs, migraines , MTHFR genotype, alpha 1 antitripsin deficiency,
hyperhomocysteinemia, ADPKD, Ehlers-Danlos (vascular type), TRAUMA

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More on statins and stroke

Coull BM, Johnston SC Statins: not just for the faint of heart. (editorial) Neurology 2009; 72: 684-685.

Nice discussion of statins and stroke.
"Ironclad" evidence of reduction of cvd and cva in patients treated with HMGCOA.

Chaturverdi et al. compared 2000+ patients over 65 with those under 65 in posthoc analysis of SPARCL data. They found rr of stroke in elderly group was reduced by 10 %, and in the younger group by 26 %; only the second was statistically significant. However, with reduced sample sizes the two groups were not different (go figure, ask a math guy).

For atorvastatin, there was a 1.5 % reduction in second stroke at 5 years, giving a NNT of 327 for STROKE in elderly. However, for all heart disease and stroke the reduction was 4.1 % with a NNT of 120 per year, which was highly significant and probably cost effective. No one knows if simvastatin is better but it is cheaper. Authors urge use of a HIGH DOSE statin.

Inflammatory bowel disease

Strokes occur in one percent
Elevated fibrinogen, decreased protein S or increased clotting factors usually are implicated.Other causes include increased homocysteine due to B12 deficiency, or optic neuropathy, or vasculitis.

Cogan's syndrome

is caused by a vasculitis similar to PAN, causing bilateral deafness (often simultaneous), uveitis and blindness secondary to retinal ischemia. Fever, chills, weight loss, thrombocytopenia, and abnormal CSF also occur. Treatment is with immunosuppressive drugs.

interstitial keratitis- granular corneal infiltration
SN hearing loss
aortitis with aortic insufficiency
some need AVR

Pearls: Infectious stroke

1. For most infections, CSF exam is the tipoff
2. In syphilitic meningovascular disease, a branch of the MCA or aorta may be involved
3. HIV itself, coexisting syphilis or NBTE , fungal or zoster infections occur in HIV infected patients.
4. Zoster stroke in MCA distribution occurs several weeks after cutaneous zoster infection. Steroids are critical, and antiplatelet drugs also are used.
5. Cysticercosis has stroke in about ten percent, usually lacunes, CSF may be helpful, and treatment is with albendazole, praziquental, and steroids or occassionally surgery.
6. Mucormycosis has typical and dramatic presentation, but it can include cavernous sinus thrombosis with ICA occlusion and stroke. Signs of include bilateral exopthalmos, proptosis, chemosis, ocular impairments and visual loss.
7. Cat scratch disease due to bartonella can cause an arteritis and stroke

Moya moya disease pearls

Review article NEJM 2009; 360:1226-1237

1. There are many disease associations esp SCD, NF1, irradiation, and Down's syndrome, and less commonly cardiac anomaly, renal artery stenosis, giant cervicofacial hemangioma and hyperthyroidism.
2. It occurs throughout the world but especially in northeast Asia, 10x frequency as in N America
3. In Japan the responsible gene is 17q25.  Other genetic association is RNF 213 autosomal dominant AD
4. The disease is more fulminant in children ; can be triggered by exertion, crying, hyperventilation, dehydration, or anaesthesia, presumably related to decreased CO2 tension in a compensated and fragile system.
5. Ischemic stroke is more common in children and adults, but hemorrhagic stroke occurs much more frequently in adults than in children
6. Headache, often refractory, occurs in two thirds, and may resolve within a year of revascularization surgery
7. Choreiform movement disorders in children occassionally resolve with revascularization surgery
8. Morning glory disc is associated and should prompt a consideration of the diagnosis
http://images.google.com/imgres?imgurl=http://www.nature.com/eye/journal/v21/n10/images/6702851f7.jpg&imgrefurl=http://www.nature.com/eye/journal/v21/n10/fig_tab/6702851f7.html&usg=__ycWmZRS6FxhD_gWU8YhCPzJQ1v8=&h=306&w=390&sz=112&hl=en&start=2&sig2=ybxbCPAci2WQ5GHSHYrFqQ&tbnid=oCbcKU1tcEBAIM:&tbnh=97&tbnw=123&prev=/images%3Fq%3Dmorning%2Bglory%2Bdisc%26gbv%3D2%26hl%3Den&ei=OGPJSY_1M5usMvW3wdYD
9. Pathology is smooth muscle proliferation and caspace dependent apoptosis. Some walls are stressed with microaneurysms which can explain hemorrhage.
10. EC IC bypass may be indicated in some . This is because the disease is inexorably progressive without surgical treatment and standard medical treatment does not work. Metaanalysis studies suggest treatment can halt progression.
11. Suzuki.Takaku developed a grading system for arterial changes
http://content.karger.com/ProdukteDB/produkte.asp?Aktion=ShowPDF&ArtikelNr=119568&Ausgabe=235294&ProduktNr=224273&filename=119568.pdf
10. Cessation of smoking and birth control pills is indicated
11. "Ivy sign" radiographically may be seen in 70 % and resolve with bypass, consists of leptomeningeal enhancement with pial engorgement going into cortex. This is seen on FLAIR and post contrast images and resembles ivy creeping up on stone.

morning glory disc

Buerger disease

Signs and symptoms include
1. Digital ischemia leading to ulceration
2. Claudication of the upper and lower limbs
3. Superficial thrombophlebitis

History-- heavy tobacco use, three fourths are young or middle aged men

Rarely strokes occur

Treatment is smoking cessation, possibly antiplatelets

Pearls on fibromuscular dysplasia

1. Predominance of women
2. Associations: young adults, Ollier's disease, saccular aneurysms
3. String of beads, long tapered segment, and false aneurysm may be found radiographically
4. Usual location is 1.5 cm above bifurcation although other sites may be implicated
5. Complications include dissection or vasospasm due to angiography
6. Half may develop TIA or stroke
7. Other signs include asymptomatic bruit, pulsatile tinnitus
8. Overall prognosis is relatively benign with less recurrent strokes than with atheromatous disease
9.HTN
10, usually extracranial, due to abnormal Media. middle portion of artery familial or sporadic SAH
11.  Renal aa involved  

Causes of dilated or other cardiomyopathy

1. Ischemic heart disease
2. Post partum
3. Chronic alcohol use
4. Viral illness
5. Mitochondrial disease (Melas, Merrf)
6. Myotonic, limb girdle and scapuloperoneal dystrophy
7. Primary oxalosis leads to calcification and heart embolus

Atrial myxoma

Presentation is obstructive, constitutional syndromes and stroke. Obstruction presents with sudden decreased cardiac output, even death with obstruction of mitral orifice. The usual sign is a murmur with a change in posture. Constitutional signs include low grade fever, arthralgias, skin eruptions and fleeting neurological signs. Elevated sed rate and abnormal serum proteins may lead to a misdiagnosis of lupus. One third will have neurological symptoms, including stroke, that can be the presenting sign of the illness. EKG shows nonspecific signs. Tumor embolus can act as a nidus for intracranial aneurysm formation. Rarely, a fibroelastic or malignant tumor of the heart can cause a stroke. Surgical resection is indicated. Anticoagulation does not work.

Libman Saks endocarditis pearls

1. Associated with Lupus and apl
2. Changes may be detectable on cardiac imaging
3. MV disease with apl's can lead to micro brain infarction (multiple) in PAN
4. Sneddon's syndrome has livedo reticularis, apl's and digital ischemia

Pearls on NBTE

1. Uncommon condition, but one third develop strokes

2. May be multiple and hemorragic

3. Mental status changes are common

4. DIC associations include thrombocytopenia, decreased fibrinogen, elevated FDP, increased d-dimer

5. Vegetations usually affect mitral and aortic valves

6. Vegetations may be too small to see on cardiac imaging

7. Treatment includes anticoagulation for DIC and treatment of malignancy

8. Associations include adenoca (pancreas, lung, ovary,bowel); DM, pregnancy, surgery, AIDS, dehydration.

9. Due to underlying condition, prognosis is poor.

Atrial fibrillation pearls

1. AF increases the stroke risk by 5-6 times
2. In presence of heart disease AF increases stroke risk 15 times
3. 10 % of stroke patients will be found to have AF
4. Europeans found 14 % silent stroke rate in AF patients.
5. In Oxfordshire, 30 day mortality for stroke with AF is 23 %, 8 % without
6. Presence of AF increases health spending 15-29 times
7. Lone AF depends on age, risk of 0.5 % ages 50-59, 9 % ages 80-89
8. Risk is higher in patients with HTN, DM, elderly and prior stroke
9. Presence of murmur or any heart disease precludes a diagnosis of lone AF
10. TEE may not be needed if clinical neurologic symptoms prove need for anticoagulation
11. Warfarin may lower risk of stroke in susceptible patients by 80%
12. Anticoagulate for 3-4 weeks before and after cardioversion, consider a TEE before

Aortic dissection pearls

1. Presents with chest or back pain, may be stroke if proximal enough
2. Thrombolysis is dangerous in this setting
3. Syphilis is a classic etiology that is currently likely overrated,but other causes are Marfan's or atherosclerosis
4. Also consider with unstable vital signs, hypotension, unequal pulses, or widened aortic silhouette on chest x ray
5. Surgical treatment (replacement of the aorta) is performed but the results are poor overall.
6. Warfarin is used but some believe it can lead to cholesterol embolization and purple toe syndrome
7. Antiplatelet agents might be the best treatment although that is not proved.

Unusual carotid syndromes

JP Mohr chapter, Barnett book.

Opticocerebral syndrome (combined) is very rare, less than .5% in Bogousslavsky's series.

TMB-- usually does not occur with finding of cholesterol emboli (hollenhorst plaques).

CRAO has associated carotid appropriate pathology 50-70 % of time. TIA's are common

Ischemic optic neuropathy-- findings include RAPD, neovascularization. (rebeosis iridis) , secondary glaucoma, proliferative retinopathy, microaneurysms, flame shaped hemorrhages, venous stasis, optic atrophy.

Migraine variant= Raeder syndrome= pericarotid syndrome--facial pain and ipsilateral oculosympathetic effect.

Notes on Thrombolytic systems

from text of barnett et al. c 9 Keyt et al.
t-PA inhibits conversion of plasminogen to plasmin, and plasmin , and fibrin clot, which is formed by the action of thrombin on fibrinogen, is dissolved by plasmin. Plasmin also feedback activates t-PA and enhances conversion into double chain form. Activation of system leads to a cascade leading to production of thrombin.

Arterial and venous clot are morphologically different (red v. white clot) but difference is more quantitative than qualitative. t-PA works much better on fibrin rich clots than on platelet rich white clots.

SAFETY antiplatelet drugs

SUMMARY
• Antiplatelet drugs (aspirin, dipyridamole,
clopidogrel), given in single- or dualagent
regimens, are the treatment of
choice for secondary prevention in
ischemic NCS
• Choice of single- or dual-agent therapy
depends upon calculation of safety risk
relative to preventive efficacy
• Key safety concerns are hemorrhage
(aspirin + clopidogrel), GI effects (all antiplatelet
agents) and headache (dipyridamole)
• ESPS-2: Dual therapy with aspirin + ER
dipyridamole significantly improved prevention in
patients with a history of TIA or stroke, without
excess risk of bleeding, compared with aspirin
alone
• ESPRIT: In patients with a history of TIA or minor
stroke, aspirin + dipyridamole resulted in fewer
cardio- or cerebrovascular endpoint events,
including first ischemic stroke, compared with
aspirin alone, with fewer major bleeding
complications; dipyridamole-related headache
was a notable cause of study withdrawal
• MATCH: Adding aspirin to clopidogrel did not
significantly reduce risk of major vascular events
(including stroke) in patients with stroke/TIA
history, but did significantly increase risk of lifethreatening,
major, and minor bleeding
• CHARISMA: In a broader patient population than
MATCH (with multiple atherothrombotic risk
factors or symptomatic, documented vascular
disease), vascular events were not significantly
reduced, but moderate bleeding was
significantly increased, with the combination of
aspirin + clopidogrel compared with aspirin
alone
• Based on available evidence, AHA guidelines
advise the practicing physician to prescribe:
• Aspirin
• The combination of aspirin and ER
dipyridamole or clopidogrel monotherapy for
survivors of stroke or TIA
• Aspirin + ER dipyridamole over aspirin alone
to avoid routine use of dual therapy with aspirin
+ clopidogrel because of excess bleeding risk
• The complex histories of many poststroke and
post-TIA patients require an individual approach,
considering the need for anticoagulation, use of
aspirin + clopidogrel post-PCI, bleeding risks,
and the potentials for drug allergy, resistance,
and intolerance

ACTIVE and SPS3

ACTIVE
Another important study underway is ACTIVE
(Atrial fibrillation Clopidogrel Trial with Irbesartan
for Vascular Events). This multicenter trial plans
to enroll a total of 14,000 patients with AF and
at least 1 risk factor for stroke, including but not
limited to prior stroke or TIA.7
ACTIVE comprises 3 component trials—ACTIVE
W, ACTIVE A, and ACTIVE I. ACTIVE W is a
randomized, open, noninferiority trial comparing
oral anticoagulation therapy (target
international normalized ratio [INR] of 2 to 3)
with aspirin (75 to 100 mg/day) + clopidogrel
(75 mg/day).7 ACTIVE A, which included
patients ineligible for randomization to anticoagulation,
is a double-blind comparison of
clopidogrel + aspirin with aspirin alone.7
Patients participating in ACTIVE W or A could
be enrolled in ACTIVE I, a partial factorial,
double-blind trial in which irbesartan
(300 mg/day) or placebo is added to the
regimen of ACTIVE W or A.7
Planned follow-up is 3 years (mean).7 For
ACTIVE W and A, the primary outcome is the
composite of first occurrence of stroke,
non–central nervous system (non-CNS) systemic
embolism, myocardial infarction (MI), or
vascular death, with major bleeding as a
secondary outcome.7 ACTIVE I has 2-part
primary outcomes of stroke, MI, and vascular
death with and without hospitalization for
heart failure.7
Although ACTIVE A and I remain ongoing,16
ACTIVE W was recently terminated prematurely
because of “clear evidence of superiority of
anticoagulation therapy” compared with aspirin
+ clopidogrel.16 Oral anticoagulation provided
more effective prevention of the primary endpoint
events (P=.0003) and of stroke (P=.001;
Figure 2).16 Minor bleeding was more common
with aspirin + clopidogrel (P=.0009), with
major bleeding similar between the groups;
total incidence of hemorrhage was significantly
greater with aspirin + clopidogrel than with

SPS3

SPS3
Small subcortical strokes (S3), also known as
lacunar or small-vessel strokes, account for
about 25% of brain infarctions and are associated
with vascular dementia. These strokes are
especially frequent in younger and minority
populations, and patients with symptomatic S3
strokes have a recurrent stroke rate of 8%.8
Secondary Prevention of Small Subcortical
ASA = aspirin; ER-DP = extended-release dipyridamole; C = clopidogrel; T =telmisartan;
W = warfarin (or, in ACTIVE, the available vitamin K antagonist anticoagulant); I = irbesartan; S = simvastatin
TABLE 1
Brief Summary of Studies
STUDY PROJECTED N POPULATION DESIGN/COMPARISON PRIMARY OUTCOME
PRoFESS1,4,
10,11,12,13,15,17
20,333 Recent ischemic stroke
history
Randomized, double-blind, multicenter
2x2 factorial
ASA + ER-DP vs C; T in half of population
Time to second stroke
ACTIVE7,8,10,17 14,000 AF history with ³1 risk
factor for stroke (including
prior stroke/TIA)
All ACTIVE trials are multicenter
ACTIVE W (completed): randomized, open,
noninferiority trial W vs ASA + C
ACTIVE A: double-blind ASA + C vs ASA
ACTIVE I: partial factorial, double-blind
Irbesartan (I) or placebo added to regimen
of ACTIVE W or A
Composite of first
occurrence of stroke,
non-CNS systematic
embolism, MI, vascular
death (ACTIVE I
eliminates non-CNS
systemic embolism and
adds hospitalization for
heart failure
SPS324 2500 Small subcortical
stroke history
Factorial, multicenter
ASA + C vs ASA; hypertensive subset receives
usual or aggressive BP reduction therapy
Stroke prevention
CASTIA10,19-22 2400 Acute ischemic stroke/TIA
(first 24 h)
Randomized
ASA + C vs ASA
Composite of stroke,
new MRI-documented
infarction, MI,
vascular death
FASTER20,23 500 (pilot)
7500 (total)
Acute ischemic stroke/TIA
(first 24 h)
Randomized, double-blind, multicenter
2x2 factorial
4 arms of study:
ASA alone; ASA + C;
ASA + S; ASA + C + S
Recurrent stroke
ARCH9,17,25 1500 Atherosclerosis of
aortic arch
Recent (<6 months)
cerebral or peripheral
embolic event)
Open, randomized, multicenter
W vs ASA + C
Composite of recurrent
stroke, acute MI,
peripheral embolism,
vascular death

Strokes (SPS3) is a 45-center, randomized
trial that will assess stroke prevention (primary
endpoint) and cognition (secondary endpoint)
in a planned cohort of 2500 patients with a
history of S3.8,10,17 A factorial design will
compare aspirin + placebo vs aspirin +
clopidogrel; hypertensive patients in these
2 groups will also receive either usual blood
pressure control (to a target of 130-149
mmHg systolic BP) or intensive control (to a
target of <130 mmHg systolic BP).8 Mean
follow-up will be 3 years.8 SPS3 will provide
data on the stroke prevention with aspirin +
clopidogrel in a population with cerebrovascular
manifestations of atherothrombosis.18

CaSTIA, fASTER AND ARCH

CASTIA
Can acute antiplatelet treatment make a
difference in stroke recurrence? Clopidogrel
in Acute Stroke and TIA (CASTIA) will randomize
a projected 2400 patients with
acute, minor ischemic stroke or TIA within
the first 24 hours of symptom onset; all
patients will be treated with aspirin,
75 mg/day, and will also receive either
placebo or clopidogrel at an initial loading
dose of 300 mg/day followed by maintenance
at 75 mg/day.10,19,20 Primary
composite outcome will include stroke, new
infarction documented by MRI, MI, and
vascular death at 90 days of follow-up.19,20
FASTER
The preventive benefits of acute care are
also the subject of FASTER (Fast Assessment
of Stroke and Transient ischemic attack
to prevent Early Recurrence).21,22 This randomized,
double-blind trial is expected to
enroll 500 stroke/TIA patients at 19 centers
in a pilot phase, eventually enrolling
7500 patients if the pilot proves feasibility.19-23
FASTER will use a 2x2 factorial design: in the
first 24 hours after stroke/TIA, all patients will
be treated with aspirin, and randomized to
placebo or clopidogrel (300 mg/day load,
followed by 75 mg/day) and to placebo or
simvastatin 40 mg/day.19-22 This creates
4 possible treatment arms: aspirin alone,
aspirin + clopidogrel, aspirin + simvastatin,
and aspirin + clopidogrel + simvastatin.23
Eligible patients will not be candidates for
acute thrombolytic therapy.21,22 Patients will
be treated for 1 month, and follow-up will be
90 days.19-22 The primary outcome measure
is recurrent stroke.19,20 Results of FASTER’s
pilot program are anticipated soon,19,20 and
will provide some indication of the utility of
dual antiplatelet therapy, with or without a
statin for short-term stroke prevention.

ARCH
Aortic arch atheroma is a significant risk
factor for ischemic stroke.9 To date, there
has been no evidence regarding the choice
of preventive strategies for recurrent stroke
in this population.9 ARCH (Aortic Arch
Related Cerebral Hazard) is an open,
randomized trial with a projected enrollment
of 1500 patients at 15 centers, enrolling
patients with atherosclerosis of the aortic
arch and a recent (less than 6 months)
cerebral or peripheral embolic event.9,17 The
study will compare oral anticoagulation with
warfarin (target INR, 2-3) vs aspirin 75 to
325 mg/day + clopidogrel 75 mg/day.9 The
primary outcome is a composite of recurrent
stroke, acute MI, peripheral embolism, or
vascular death.9 ARCH will be the first trial to
assess prevention of secondary stroke in
this subpopulation.9

Esprit and Charisma

2006 European Stroke Conference in Brussels,
include results from the European/Australian Stroke
Prevention in Reversible Ischemia Trial (ESPRIT),
which assessed the incremental efficacy of aspirin
+ ER dipyridamole over aspirin alone. Data also
included results from a substudy of patients
enrolled in CHARISMA who experienced stroke
during study treatment with aspirin + clopidogrel
or aspirin alone.


SPIRIT—the Stroke Prevention in Reversible
Ischemia Trial.1 The objective of SPIRIT (n=1316)
was to compare the efficacy and safety of oral
anticoagulation (to an international normalized ratio
[INR] 3.0 to 4.5) vs low-dose aspirin (30 mg/d) for
secondary prevention of cardio- and cerebrovascular
events after TIA or minor stroke.8 SPIRIT
reported an excess of primary outcome events—
vascular death, nonfatal stroke, nonfatal MI, or
nonfatal major bleeding complication—in the group
treated with oral anticoagulation.8 This excess was
predominantly due to a high rate of bleeding
complications, which increased by a factor of 1.43
with each 0.5-unit increase in INR; this high
incidence of anticoagulant-related bleeding
resulted in early termination of SPIRIT at only 17%
of its expected number of observed patient-years.

BLOGGER COMMENT- Overdosed warfarin, underdoses ASA


SUMMARY
n Current secondary event–prevention guidelines
from the AHA recommend intervention
with antiplatelet agents in patients who have
suffered NCS or TIA; however, questions
remain about which regimen is optimal
n Although oral anticoagulation therapy is a
mainstay for treatment of patients with
cardiogenic cerebral embolism, it has not
shown sufficient efficacy in NCS to justify the
substantial risk of bleeding complications. In
CHARISMA, clopidogrel + aspirin tended to
increase moderate-to-severe bleeding risk
compared with aspirin alone. In ESPRIT, while
major bleeding was less frequent with aspirin
+ dipyridamole than with aspirin alone,
investigators thought this may have been a
chance effect
n New data presented at ESC 2006 provide
further evidence on optimization of antiplatelet
therapy. These data come from 2 clinical
studies (ESPRIT and the CHARISMA Stroke
Substudy)
n The objective of ESPRIT was to determine if
aspirin + ER dipyridamole provided greater
preventive benefit than aspirin alone; this
result was documented in the earlier ESPS-2
trial, but there was some uncertainty about
the result, owing to conflicting findings in
other studies
n Results from ESPRIT confirm that aspirin +
dipyridamole is more effective than aspirin
alone in the prevention of vascular events
following NCS or TIA
n ESPRIT also confirmed that there is no
significant increase in bleeding events with
aspirin + dipyridamole vs aspirin alone

Antiplatelet agents, plaque, misc for stroke

1. Mechanism of injury is plaque rupture that causes platelet activation, exposure of platelets to VWF that tethers and causes to adhere other platelets to site. Platelet granules release alpah granules and fibrinogen and ADP that causes more platelet activation. Platelet also derives thromboxane A2 and thrombin. Also get G2 protein receptor, platelet shape change (round to discoid with extending filaments) increased cAMP intracellularly, P2Y1 receptor causes an ADP mediated increased cytosolic calcium, P2Y12 receptor potentiates granule secretion, recruitment of platelets and aggregation.
2. ASA blocks thromboxane A 2 mediated path. Plavix blocks P2Y12 receptor. Dipyridamole increases ic cAMP deterring platelet activation and is vasodilatory due to secondary inhibition of phosphodiesterase (PDE). It blocks ADP nucleic acid uptake in dose dependent manner.
3. Acetylcyclic acid inhibits cyclooxygenase 1 (Cox 1) aka PGH synthase. Inhibition of Cox 1 is irreversible for 8-10 day lifetime of platelets. However, thrmobotic potential exists with 20 % Cox 1 activity so daily ASA is advised. Low doses may be effective because platelets in portal circulation are extensively exposed before degradation (hepatic metabolism, renal excretion).
4 As a vasodilator, dipyridamole should be used cautiously in patients with CAD or hypotension. It lasts half day (extended form) is conjugated to glucuronic acid and excreted via bile into feces.
5. Clopidogrel must be metabolized into an unknown active metabolite by liver.Actions affect dense granule secretion, fibrinogen activity, and coag rate, and TXA2 function. Affects thrombus size and duration but NOT platelet shape. Affects platelet irreversibly. Typically effects are seen within 2 hours, with steady state 40-60 % inhibition at 2-3 days (steady state).

Managment of asymptomatic stenosis==

Bob Brown
*Use ASA as antiplatelet choice
* selective not widespread carotid screening
* CEA in select patients, consider age, general health and life expectancy, surgeon, high grade v. progressive stenosis, CAS in high risk

Carotid Bruits-- Pearls

1. 8.2 % prevalence in age> 75; 40 % of those with ? 50 % stenosis have a bruit
2. Only characteristic of a bruit predictive of stenosis is a diastolic bruit
3. With greater than 75 % stenosis, the stroke risk at one year is 5.5 % with bruit
For 75-94 % stenosis, risk of stroke at one year is 3.7 %
4. In asymptomatic patients, keep in mind cardiac ischemia, risk is increased
5. Risk of noncardiac surgery not higher with bruit
6. Symptomatic VB stenosis confers 6 % risk of GET
7. Asymptomatic intracranial stenosis, carotid stenosis does not increase risk of general anesthesia except CABG

Acute treatment of stroke

Based on Tom Brott lecture-- many obvious guidelines are omitted and only a few of less obvious ones are listed below, based on my own discretion

*treat hypoxia
* treat fever
*cardiac monitoring for 24 hours
*Until more definitive data, cautious approach to treating BP in first 24 hours
* Alteplase guidelines for BP management also apply to other interventional procedures
* In first 24 hours, withholding meds for BP unless BP> 220-120
*Hypovolemia should be corrected
* Hypoglycemia should be corrected
* Beware of AE of angioedema with alteplase
* For arterial therapy, centers are encouraged to define criteria to credential
* ASA dose of 325 is now recommended within 24-48 hours
* Patients possibly needing neurosurgery (cerebellar infarct, major hemispheric infarct) should be transferred to a facility with that capability
* Hydrocephalus due to a cerebellar stroke can be treated with a drain

For hemorrhage:
* Use protamine/vit K to reverse anticoagulation if applicable
* Surgical removal dangerous cerebellar hemorrhage > 3 cm

Metabolic syndrome in stroke

3 or more of following:

*abdominal obesity (> 102 cm in men, 88 in women)
* Elevated TG;s (>150)
* low HDL (< 40 in men, <50 in women)
* BP (>130/85
* FBS elevated glc intolerance or DM ( >110)

WEIGHT LOSS, DIETARY CHANGE, EXERCISE

Management of stroke in diabetics: sec prevention

* independent risk factor for stroke, 2x normal risk
* secondary prevention may reduce microvascular complications more than cardiovascular
* aggressive control with diet, exercise, oral agents and insulin as needed.
* use of ACEI or ARB in HTN
* statin even if lipids are normal

Risk factors to be assessed in stroke

HTN--
Cigarette smoking
dyslipidemia
DM
Metabolic syndrome
? Elevated homocystein
Excess alcohol consumption
Obesity
Physical inactivity
Sleep apnea syndrome esp Obstructive

Hospitalize after TIA?

stratify risk (ABCD(2)) if higher risk, if a candidate for alteplase, if need rapid evaluation, carotid stenosis, AF

Notes Carotid disease accounts for about 11 % of TIA's and short term risk of stroke may be as high as 20 % in 90 days.

Stroke risk after stroke

about 4 % in 90 days based on

IST 3.3 %
Cast 1.6 %
TOAST 5.7 %
nascet 2.3 %

MAY BE HIGHER RISK WITH RAPID RECOVERY

Small vessel pathology AND cerebral blood flow

from Continuum chapter on pathophysiology

Small vessel disease- 20-30 % of total

1.lipohyalinosis is replacement of vessel wall with fibrin and collagen due to to HTN

2.microatheroma is an atheromatous plaque at the origin of a penetrating artery may cause larger subcortical strokes.

3. Fibrinoid necrosis is associated with very high BP leading to necrosis of smooth muscle cells extravasation of plasma proteins which appear as fine granular eosinophilic deposits in the connective tissue of the vessel wall.

4. Charcot-Brouchard aneurysms are areas of focal dilations in the wall that thrombose and occlude the vessel



CBF

Main factors of tissue outcome are regional CBF and duration of occlusion.

Local tissue perfusion pressure, which is main factor accounting for outcome, depends on collaterals, on arterial blood pressure, and inversely correlates with local tissue pressure, which is due partly to edema.



Thresholds:

studied in carotid clamping surgeries decades ago, reversible ischemia occurred with loss of CBF to 30-50 % of normal, and permanent with less than 30 % perfusion pressure. Higher CBF values required a longer time to infarct. EEG slows at CBF<23 flat at 15.

High and low risk cardiac conditions for stroke

from Continuum 2008 chapter on pathophys

High risk for stroke-- atrial fibrillation with structural disease, sustained atrial flutter, sick sinus syndrome, left atrial thrombus, left atrial/ appendage thrombus, left atrial myxoma, mitral stenosis, mechanical valve, infective endocarditis, non-infective endocarditis, left ventricular myxoma, recent anterior MI, dilated cardiomyopathy , left intraventricular thrombus

Low or uncertain risk for stroke
Lone AF, PFO, ASA, spontaneous atrial contrast, MVP, calcific aortic stenosis, fibroelastoma, Giant Lambel excrescence, akinetic or dyskinetic ventricular wall segment, Subaortic hypertrophic cardiomyopathy, congestive heart failure , ventricular aneurysm,






also see http://strokenotes.blogspot.com/2007/02/treatment-of-cardiac-problems-in-stroke.html

Minutiae of pathophysiology of acute stroke

from corresponding chapter in Continuum late 2008
1. Occlusive infarcts are divided into "white" and "red", the latter of which corresponds to hemorragic transformation due to leaky blood cells into dying brain and are not equivalent to parenchymal hematoma due to vessel burstage. Hemorrhagic transformation occurs in up to 80 %.
2. Pathological stages (garcia, 1998) first 24 hours-- lesion barely visible. Swelling peaks days 3-5. Between days 5-10, the infarcted tissue become sharply demarcated from unaffected brain tissue. The fourth stage , lasting weeks to months, is liquefaction necrosis.

3. Mechanism for low flow stroke may be due to decreased cardiac output, systemic hypotension, increased metabolic demands of tissue (fever, acidosis), or steal of flow from affected to unaffected areas (Alexcandrov, Stroke, 2007). Caplan wonders whether low flow may potentiate emboli due to impaired clearance of emboli with low flow states.

4.

Mechanisms of neuronal damage in stroke

necrosis
apoptosis
excitotoxicity
inflammation
periinfarct depolarization
acidosis
free radical formation

Accurate diagnosis of TIA would reduce incidence by 33 % annually (from 180,000) and commensurately increase number of strokes by 7 % (from 820,000 in US annually).

Continuum Acute Stroke

Notes on a few minutiae in the book that were not at first transparently obvious to me (not that is a criterion).
from "Diagnosis" chapter
1. The presence of early infarct changes (EIC) on CT were not independently associated with adverse outcome in the NINDS trial and should not preclude thrombolysis (Patel, 2001).
2. Another study found interobserver agreement "moderate to poor" on the presence of EIC's and increased outcome of poor results in their presence (Wardlaw and Meilke, 2005).
3. Clearly delineated hypodensity and mass effect is "incompatible" with three hour window.
4. Six percent of patients with brain tumors presenting to ER's had symptoms of less than 1 day duration (Snyder, 1993).
5. The critical glucose number bandied around for "hypoglycemia" is 45.
6. Chest pain as part of a stroke syndrome mimicking MI is reported after stroke of the thalamus, lateral medulla, and corona radiata.
7.

Lack of utility of bariatric chamber in stroke

A Cochrane review of the subject 2.5 yrs ago found no evidence to support its use (Stroke 2006;37;1953-1954)

Summary of Stroke meeting 2008 by L Caplan

again throwaway journal not cited
Dr Caplan emphasizes stroke care is not easily duplicated by nonexpert personnel. Strategies to improve recovery involve the following:
1. Manipulating transmitters -- ach, ne, ser da
2. Stimulating growth factors -- VEGF, NGF,erythropoeitin
3. Cell based treatment eg stem cells
4. Brain stimulation-- magnetic and electrical current
5. Robotic facilitation of movement
6. Brain imagery and eye movement to drive computer assisted functions
7. Novel PT such as treadmill gait training
8. Neuroprosthetics that facilitate/train limb functions

citicholine

based on an article by Jeff Saver in a throwaway therefore not cited. Citicholine is available as a supplement. Individual trials were negative or inconclusive, but a metaanalysis suggests less death and disability. Reinvestigation is underway. Citicholine is neuroprotective and neurorestorative. Saver suggests small studies show mild benefit in cognitive enhancement in vascular dementia, head trauma and possibly PD and ION

adding aspirin to coumadin

There was an analysis of the safety and efficacy of adding aspirin to warfarin
published as a
substudy of the SPORTIF trials, first author was Scott Kasner.

It showed that adding aspirin to either coumadin (or ximelagatran) in high risk
patients with hx of
stroke and atrial fibrillation (eg those with coexisting coronary disease) did
not lower the
ischemic event risk, but significantly raised the risk of major bleeding. Based
on that, I would be
very wary of adding aspirin at any dose to warfarin.

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hypertonic saline for impending herniation

The article on the beneficial effects of 3% Na on CT midline shift was based on
simple clinical findings - serum Na and Ct scan. **Qureshi AI, Suarez JI,
Bhardwaj A, Mirski M, Schnitzer MS, Hanley DF, Ulatowski JA.
Use of hypertonic (3%) saline/acetate infusion in the treatment of cerebral
edema: Effect on intracranial pressure and lateral displacement of the
brain.Crit Care Med. 1998 Mar;26(3):440-6

The first article on 23.4% and refractory - used clinical clinical exam, common
ICP monitors (bolts and ventric drain) and typical lab Na). **Suarez JI, Qureshi
AI, Bhardwaj A, Williams MA, Schnitzer MS, Mirski M, Hanley DF, Ulatowski
JA.Treatment of refractory intracranial hypertension with 23.4% saline. Crit
Care Med. 1998 Jun;26(6):1118-22

Among the report on functional outcome after reversal of transtentorial
herniation with brain resuscitation (including - use hypertonic saline) used GCS
and pupils and common clinical parameters. **Qureshi AI, Geocadin RG, Suarez JI,
Ulatowski JA.Long-term outcome after medical reversal of transtentorial
herniation in patients with supratentorial mass lesions.Crit Care Med. 2000
May;28(5):1556-64.

And recently, the use of 23.4% Na bolus to reverse transtentorial herniation -
was again based on bedside clinical finding of GCS change, pupillary size and
light reactivity, serum Na monitoring. **Koenig MA, Bryan M, Lewin JL 3rd,
Mirski MA, Geocadin RG, Stevens RD. Reversal of transtentorial herniation with
hypertonic saline. Neurology. 2008 Mar 25;70(13):1023-9. Epub 2008 Feb 13.

Hypertonic saline is readily available and seems to be very beneficial (yes I
understand that we lack level 1 RCT); it maybe even be better than mannitol and
it helped us realize that the dreadful event of transtentorial herniation is
reversible and survivable. So we must do our best to make this treatment
available in as many ICUs and appropriate patients as possible.

Certainly, we should encourage more research to understand this problem and the
use of LICOX or other similar technologies is a promising direction. It is great
that many top centers are using this as a research or adjunct tool but until
more definite data comes, I believe that these devices should not be made to
define or limit the care we provide.

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