Tag Archives: SAH

Heparin Drip for DCI prevention in Aneurysmal SAH?

Interesting article from Journal of Neurointerventional Surgery looking at use of heparin after endovascular treatment of cerebral aneurysms.  The study was retrospective, included ~400 patients (~200 given heparin post-coiling and ~200 matched controls), and collected data on incidence of vasospasm, DCI, and functional outcome.

Results of the study is shown in the graph below:

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Rate of severe vasospasm was shown to be significantly reduced in the heparin group (14.2 vs 25.4% p=0.005).  The study concluded that patients who received continuous heparin after endovascular coiling of cerebral aneurysms have a reduced rate of severe vasospasm.

 

Mechanism of Action

How does heparin prevent DCI? (theoretically)  The article explains that heparin prevents secondary injury in SAH through its anti-inflammatory effects.  Heparin is the highest negatively charged biological molecule existing.  Due to the negative charges, it can bind to positively charged proteins and surfaces, including growth factors, cytokines and chemokines – thereby reducing inflammation.  It can also bind oxyhemoglobin and block free radical activity.  It can also antagonize endothelin, reducing endothelin-related vasoconstriction.

 

Limitations

The study has several limitations – including the retrospective and single-center nature of the study design, and the potential for selection bias – even with case matching.  This study adds more evidence (albeit weak) to the argument that heparin infusions may help prevent secondary brain injury in patients with aneurysmal SAH who undergo endovascular coiling.

 

Heparin would be a potential “4th H,” adding to the 3 H’s historically used in the vasospasm prevention – i.e. hypervolemia, hemodilution, hypertension.  As with the previous H’s, randomized controlled studies will need to be performed to prove this theory.  The first 3 Hs have largely been debunked, and instead, the current standard of care is to keep patients with subarachnoid hemorrhage euvolemic, and induce hypertension only in the setting of vasospasm and/or delayed cerebral ischemia.  Therefore, as with the first 3 Hs, until more evidence surfaces, the use of continuous heparin cannot be recommended in this setting.

 

 

Reference:

Bruder, Markus et al. “Effect Of Heparin On Secondary Brain Injury In Patients With Subarachnoid Hemorrhage: An Additional ‘H’ Therapy In Vasospasm Treatment”. Journal of NeuroInterventional Surgery (2017): neurintsurg-2016-012925.

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Relative Alpha Variability

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Reference:

Vespa, Paul M. et al. “Early Detection Of Vasospasm After Acute Subarachnoid Hemorrhage Using Continuous EEG ICU Monitoring”. Electroencephalography and Clinical Neurophysiology 103.6 (1997): 607-615. Web.

DCI Prevention (Failed Interventions)

Here is a list of failed interventions (so far) for DCI prevention in subarachnoid hemorrhage.

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Table was taken from first reference listed below.  The other references listed are the source articles (RCTs) where the table was based from.

Reference

Francoeur, Charles L. and Stephan A. Mayer. “Management Of Delayed Cerebral Ischemia After Subarachnoid Hemorrhage”. Critical Care 20.1 (2016): n. pag. Web.

van den Bergh WM, Algra A, Dorhout Mees SM, van Kooten F, Dirven CMF, van Gijn J, Vermeulen M, Rinkel GJE. Randomized controlled trial of acetylsalicylic acid in aneurysmal subarachnoid hemorrhage: the MASH Study. Stroke. 2006;37:2326–30.

Petruck KC, West M, Mohr G, Weir BK, Benoit BG, Gentilli F, Disney LB, Khan MI, Grace M, Holness RO, Karwon MS, Ford RM, Cameron S, Tucker WS, Purves GB, Miller JDR, Hunter KM, Richard MT, Durity FA, Chan R, Cleain LJ, Maroun FB, Godon A. Nimodipine treatment in poor-grade aneurysm patients. J Neurosurg. 1988;68:505–17.

Siironen J, Juvela S, Varis J, Porras M, Poussa K, Ilveskero S, Hernesniemi J, Lassila R. No effect of enoxaparin on outcome of aneurysmal subarachnoid hemorrhage: a randomized, double-blind, placebo-controlled clinical trial. J Neurosurg. 2003;99:953–9.

Tseng M-Y, Hutchinson PJ, Richards HK, Czosnyka M, Pickard JD, Erber WN, Brown S, Kirkpatrick PJ. Acute systemic erythropoietin therapy to reduce delayed ischemic deficits following aneurysmal subarachnoid hemorrhage: a Phase II randomized, double-blind, placebo-controlled trial. Clinical article. J Neurosurg. 2009;111(1):171–80.

Hasan D, Lindsay KW, Wijdicks EF, Murray GD, Brouwers PJ, Bakker WH, van Gijn J, Vermeulen M. Effect of fludrocortisone acetate in patients with subarachnoid hemorrhage. Stroke. 1989;20(9):1156–61.

Mees SMD, Rinkel GJE, Vandertop WP, Pablo AA, Lavados M, van Kooten F, Kuijsten HAJM, Boiten J, van Oostenbrugge RJ, Salman RA-S, van den Bergh WM. Magnesium for aneurysmal subarachnoid haemorrhage (MASH-2): a randomised placebo-controlled trial. Lancet. 2012;380(9836):44–9.

Gomis P, Graftieaux JP, Sercombe R, Hettler D, Scherpereel B, Rousseaux P. Randomized, double-blind, placebo-controlled, pilot trial of high-dose methylprednisolone in aneurysmal subarachnoid hemorrhage. J Neurosurg. 2010;112(3):681–8.

Haley EC, Kassell NF, Torner JC. A randomized controlled trial of high-dose intravenous nicardipine in aneurysmal subarachnoid hemorrhage. A report of the Cooperative Aneurysm Study. J Neurosurg. 1993;78(4):537–47.

Zwienenberg-Lee M, Hartman J, Rudisill N, Madden LK, Smith K, Eskridge J, Newell D, Verweij B, Bullock MR, Baker A, Coplin W, Mericle R, Dai J, Rocke D, Muizelaar JP. Effect of prophylactic transluminal balloon angioplasty on cerebral vasospasm and outcome in patients with fisher grade IIi subarachnoid hemorrhage: Results of a phase II multicenter, randomized, clinical trial. Stroke. 2008;39:1759–65.

Lennihan L, Mayer SA, Fink ME, Beckford A, Paik MC, Zhang H, Wu YC, Klebanoff LM, Raps EC, Solomon RA. Effect of hypervolemic therapy on cerebral blood flow after subarachnoid hemorrhage: a randomized controlled trial. Stroke. 2000;31:383–91.

Kirkpatrick PJ, Turner CL, Smith C, Hutchinson PJ, Murray GD. Simvastatin in aneurysmal subarachnoid haemorrhage (STASH): a multicentre randomised phase 3 trial. Lancet Neurol. 2014;13(7):666–75.

Stepwise Treatment of DCI

Management of DCI is presented here as a three-stage algorithm.  Tier One therapy should be initiated for new DCI which can manifest as neurological deterioration, characteristic imaging findings or MMM abnormalities indicating ischemia.  Tier Two therapy hsould be started in cases of refractory DCI(inadequate reversal of ischemia after first-line therapy.)

 

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Reference:

Francoeur, Charles L. and Stephan A. Mayer. “Management Of Delayed Cerebral Ischemia After Subarachnoid Hemorrhage”. Critical Care 20.1 (2016).

 

Images of Vasospasm

This is a review of an interesting study from 1997 (published in Stroke) that illustrates how vasospastic arteries in a rat subarachnoid hemorrhage model looks like under the scanning electron microscope.

The researchers injected hemolysate (lysed autologous blood) into the cisterna magna of male Sprague-Dawley rats.  After ten minutes, a polymer resin casting medium was injected intravenously.  Once the resin has casted, the tissue and bones were corroded using NaOH solution, until only the vascular cast remains.  The casts were visualized under scanning electron microscope, and the following images were derived:

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Basilar artery of:  A.  saline-injected control rats;  B. hemolysate-injected rats;  arrowheads = PICA;  note the narrowing and corrugation seen in the basilar artery of the hemolysate-injected rats.

Capture.JPG Other major arteries were also observed to be in vasospasm.  (note corrugation in these arteries)

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Vasospasm (demonstrated as corrugation in the casted vessels) is seen in the major arteries (A) as well as the small arteries (B).

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High magnification showing “corrugation” of the basilar artery.  The arrows point to nuclear indentations which correspond the the endothelial cell nucleus.  (see below0

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The researchers also performed conventional SEM.  A and B are normal vessels while C and D are hemolysate-induced vasospastic blood vessels.   A and C are low magnification, B and D are high magnification.

The normal vessels (A) show that the inner surface is very smooth and the vessel wall is thin, and (B) the endothelial nuclei are clearly observed, projecting into the inner surface at regular intervals of 10-20 um.

The vasospastic vessels (C) shows that the smooth muscle layer is thicker, corrugation is observed and (D) many humps are sandwiched and flattened between hills formed by the endothelial cells.

Cast model shows corrugation, characteristic folds of endothelial cells at regular intervals and indentations of endothelial cell nuclei at each peak of those folds.  These indentations correspond to the humps seen in conventional SEM analysis.  The mechanical force of corrugation compressed the endothelial cells, flattened their nuclei and likely disturbed their function.  These physical alterations cause narrowing of the vessels, disturbs local blood flow, and may disturb blood coagulation and adhesion of WBC and platelets to the endothelium.  This may be a mechanism that explains thrombus inflammation and inflammatory response in these diseased vessels.

Their research also showed that arteries exposed to greater amount of hemolysate exhibit more severe vasospasm.

Reference:

Ono, S. et al. “Three-Dimensional Analysis Of Vasospastic Major Cerebral Arteries In Rats With The Corrosion Cast Technique”. Stroke 28.8 (1997): 1631-1638.

The Cell Index in Ventriculitis

Summarizing an old article on the CSF Cell Index published in 2004, study has not been validated, but information is “nice to know.”

The CSF cell index is a ratio between the blood cells in the ventricles (in intracranial hemorrhage) and the peripheral blood.  At the time of bleeding, blood in the ventricles is diluted within the CSF, and the relationship between WBC:RBC should equal that in the peripheral blood.  This ratio, called the CSF cell index, should approximate 1 in the absence of infection.

The CSF cell index is calculated using to the following formula:

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This study reported that the cell index rises 3 days before diagnosis of a catheter-related ventriculitis, and proper antimicrobial treatment led to a rapid decrease of the cell index.  The study concluded that a significant increase in the cell index is highly indicative of nosocomial EVD-related ventriculitis in patients with IVH, and that the increase of the cell index usually precedes diagnosis by conventional means by 3 days.

 

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Reference:

Pfausler, B. et al. “Cell Index ? A New Parameter For The Early Diagnosis Of Ventriculostomy (External Ventricular Drainage)-Related Ventriculitis In Patients With Intraventricular Hemorrhage?”. Acta Neurochirurgica 146.5 (2004): 477-481.

Subarachnoid Hemorrhage and Ventriculitis

Clinical signs of ventriculitis are difficult to recognize in SAH patients who are sedated, who have recently undergone neurosurgery, or have a sterile inflammatory response in the CSF due to the SAH.  Clinical symptoms of SAH (headache, nuchal rigidity, AMS) closely resemble bacterial ventriculitis.

Suspect with:
  • new fever
    • Fever occurs in 40 % after SAH +/- infection
  • new nuchal rigidity

 

What to do?

Exclude other causes of infection

  1. physical examination
  2. blood / sputum / urinary cultures
  3. CXR

Exclude other causes of AMS (HCP and ischemia)

  • Neuroimaging with plain CT scan
Work-up:
  • Serum:  CRP WBC glucose
  • CSF analysis (cell count, GS / CS, glu / protein)
    • Interpretation of CSF WBC problematic; CSF RBC causes aseptic ventriculitis
    • CSF cell count  helpful but low sensitivity and specificity
      CSF RBC higher in CSF culture-negative bacterial ventriculitis
    • cell index for EVD-related ventriculitis with IVH (formula proposed, but not yet validated)
  • Blood cultures
  • CSF lactate, cytokine levels, and serum procalcitonin
    • Also disturbed after SAH
    • procalcitonin discriminates between SIRS and systemic infection but value for aseptic vs bacterial ventriculitis is limited
  • CSF PCR for bacterial pathogens – low sensitivity in EVD related bacterial ventriculitis and aseptic ventriculitis after surgery
Case definitions:
  1. Clincally suspected bacterial ventriculitis – empirical antibiotic treatment for bacterial ventriculitis, but negative CSF cultures
  2. Confirmed Bacterial ventriculitis – (+) CSF culture for bacteria; if staph epidermidis – needs 2 consecutive positive cultures to rule out contamination
Treatment:
  • No good discriminative tests, treatment initiated on first suspicion
  • Antibiotic regimen for bacterial ventriculitis
    •  ceftriaxone 2 g BID + vancomycin 2 g BID
    •  ceftazidime 2 g TID + vancomycin 2 g BID if external CSF catheter in place
  • Duration
    • culture negative – discontinue ABx (after 72h)
    • culture positive – 2 weeks

 

ORDERS:
  1. Physical Examination
  2. Assessment:
    • clinically suspected bacterial ventriculitis
    • confirmed bacterial ventriculitis
  3. Blood work:
    • CBC (WBC)
    • BMP (glucose)
    • Blood cultures x 2
    • CRP
    • Procalcitonin
  4. sputum cultures
  5. urinalysis with reflex to urine culture if (+)
  6. CXR
  7. Plain CT scan
  8. CSF studies
    • cell count
    • Gram stain and culture
    • CSF glucose
    • CSF protein
    • calculate cell index
    • CSF lactate
    • *CSF cytokine levels
    • *CSF PCR for bacterial pathogens
  9. Treatment x 2 weeks
    • ceftriaxone 2 g BID + vancomycin 2 g BID
    • ceftazidime 2 g TID + vancomycin 2 g BID if (+) EVD
    • discontinue within 72 hours if cultures are negative

 

Reference:

Hoogmoed, J. et al. “Clinical And Laboratory Characteristics For The Diagnosis Of Bacterial Ventriculitis After Aneurysmal Subarachnoid Hemorrhage”. Neurocritical Care (2016): 1-9.