With respect to the management of patients with aneursymal sub arachnoid haemorrhage (aSAH), briefly discuss the role of the following:

  • Nimodipine.
  • Hypertensive I hypervolaemic I haemodilution, (HHH) therapy.
  • Magnesium.
  • lnterventional radiology.

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College answer

Nimodipine;  
Level I evidence of improved neurological outcome.  Calcium antagonist. Likely prevents neuronal damage by preventing influx of Ca more than by antagonising Sm muscle contraction and directly reducing incidence of vasospasm. May lead to hypotension.  
Meta-analyses suggest oral efficacious  
IV expensive; needs co-infusion 
Recommended for all patients with aneurysmal SAH 
 
Triple H therapy: 
Haemodilution – no good evidence that works in isolation. Theoretically improved rheology => better perfusion 
Hypervolaemia – no evidence that hypervolaemia is beneficial and fluid overload associated with worse outcomes.  Hypovolaemia should be avoided as may exacerbate vasospasm. Volume loading often given to patients with clinical vasospasm to ensure euvolaemia 
Hypertensive therapy: Unsecured aneurysm a relative CI to HT therapy. Demonstrated to improve cerebral blood flow.  Not useful for prevention of vasospasm, but commonly used to treat cerebral ischaemia in the presence of vasospasm. May be titrated to clinical response. NA favoured agent.  Sometimes high doses of pressor agents required to augment MAP. Risk of stress cardiomyopathy.  Unless titrated to clear neurological signs the optimal MAP goals are unclear.  Balance of risks vs benefits.  
 
Interventional Radiology 
Intra-arterial vasodilators: e.g. verapamil / papaverine / nicardipine.  Clear angiographic benefit / used routinely for the treatment of vasospasm.   Lacking high-level data on outcome benefit.  Other angiographic interventions such as ballooning / stents are also utilised to good angiographic effect. Not routinely available in all centres. Caries the risks associated with angiography (transport, anaesthesia, contrast use, vascular injury, stroke) 
 
Magnesium: 
Several trials of MgSO4 – these have failed to show benefit. Not routinely indicated for the prevention of vasospasm although low magnesium may be associated with its development. 
 

Discussion

The college question - though asking about therapeutic options which are mainly used to prevent or treat vasospasm - is actually not worded in a way which limits one's answer to only vasospasm. Therefore, some additional material could be added to the interventional radiology section, which deals more with its merits as a diagnostic modality.

Nimodipine

  • The objective is to prevent symptomatic vasospasm, i.e. features of ischaemia and radiologically obvious strokes
  • The BRANT trial: patients receiving nimodipine were 34% less likely to develop stroke. One ought to continue nimodipine for 21 days to get the optimal effect.
  • Owing to the difficulty in identifying patients who will go on to develop vasospasm, nimodipine is given to all SAH patients.

"Triple H therapy"

  • Largely discredited practice of forced hypervolemia, hypertension and haemodilution.
  • A Cochrane review of this "circulatory volume expansion therapy" (2004) did not find any benefit. However, there was only one RCT and one "quasi-randomised" trial. The numbers were simply too small to make a recommendation.
  • On purely theoretical physiological grounds, as well as from the standpoint of lacking evidence, this therapy was savagely shredded by Myburgh in an excellent review article (2005)
  • Hypertension is the only component broadly supported by a consensus of neurosurgeons.

Magnesium infusion

  • Divalent cation which acts as a physiological antagonist for calcium, i.e. it is analogous to using a calcium channel blocker.
  • Should relax smooth muscle, and therefore either treat and/or prevent vasospasm.
  • MASH-2 trial from 2012:  a multi-center investigation of 64mmol of MgSO4 per day, randomised among 606 patients; no benefit:  "intravenous magnesium sulphate does not improve clinical outcome after aneurysmal subarachnoid haemorrhage".

Conventional 4 vessel DSA (Digital Subtraction Angiography):

  • DSA has several possible roles to play in the management of SAH:
    • Diagnostic:
      • It can be used to characterise the aneurysm (eg. to determine whether it can, or cannot be managed by coiling)
      • It can discriminate aneurysmal bleeds from AVMs
      • It can be used to look for an aneurysm in CT-negative SAH - in fact the AHA/ASA guidelines recommend this wherever there is no obvious aneurysm on the CT angiogram, according to https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5288992/Grasso et al (2017)
    • Definitive therapeutic:
      • On susceptible aneurysms, coiling could be attempted
  • This is the gold standard for both diagnosis and management of vasospasm. One can confirm that vasospasm is occurring by a CT angiogram- or, if one were to go straight to DSA one could progress to some sort of definitive treatment. Verapimil and papaverine are the two most commonly used intra-arterial vasodilators.
  • However, this requires a skilled interventional radiologist. It exposes the patient to contrast and it it in vasive, with a (not insignificant - around 1%) risk of atheroma embolism or vessel dissection..
  • There is a small chance that this technique will lead to over-treatment: vessel narrowing may be detected, but this decrease in diameter may not reflect a decrease in flow, and may not warrant an injection of vasodilator.

References

References

Oh's Intensive Care manual

Chapter   51   (pp. 568)  Acute  cerebrovascular  complications by Bernard  Riley  and  Thearina  de  Beer

LITFL offer this reference as a follow-on to their chapter:

Dabus, Guilherme, and Raul G. Nogueira. "Current Options for the Management of Aneurysmal Subarachnoid Hemorrhage-Induced Cerebral Vasospasm: A Comprehensive Review of the Literature." Interventional Neurology 2.1 (2013): 30-51.

Frontera, Jennifer A., et al. "Defining Vasospasm After Subarachnoid Hemorrhage What Is the Most Clinically Relevant Definition?." Stroke 40.6 (2009): 1963-1968.

Vergouwen, Mervyn DI, et al. "Definition of Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage as an Outcome Event in Clinical Trials and Observational Studies Proposal of a Multidisciplinary Research Group."Stroke 41.10 (2010): 2391-2395.

Etminan, Nima, et al. "Effect of pharmaceutical treatment on vasospasm, delayed cerebral ischemia, and clinical outcome in patients with aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis." Journal of Cerebral Blood Flow & Metabolism 31.6 (2011): 1443-1451.

Brathwaite, Shakira, and R. Loch Macdonald. "Current Management of Delayed Cerebral Ischemia: Update from Results of Recent Clinical Trials." Translational stroke research 5.2 (2014): 207-226.

Mir, D. I. A., et al. "CT Perfusion for detection of delayed cerebral ischemia in aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis." American Journal of Neuroradiology 35.5 (2014): 866-871.

Scheglov, Dmitry V., et al. "Endovascular Treatment of Vasospasm Related to Acute Subarachnoid Hemorrhage from Ruptured Aneurysms." Neurovascular Events After Subarachnoid Hemorrhage. Springer International Publishing, 2015. 223-229.

Serrone, Joseph C., et al. "Aneurysmal subarachnoid hemorrhage: pathobiology, current treatment and future directions." Expert review of neurotherapeutics 0 (2015): 1-14.

Rinkel, Gabriel JE, et al. "Circulatory volume expansion therapy for aneurysmal subarachnoid haemorrhage." The Cochrane Library (2004).

Connolly, E. Sander, et al. "Guidelines for the management of aneurysmal subarachnoid hemorrhage a guideline for healthcare professionals from the American heart association/American stroke association." Stroke 43.6 (2012): 1711-1737.

Macdonald, R. Loch, et al. "Clazosentan to overcome neurological ischemia and infarction occurring after subarachnoid hemorrhage (CONSCIOUS-1) randomized, double-blind, placebo-controlled Phase 2 dose-finding trial." Stroke39.11 (2008): 3015-3021.

Mees, Sanne M. Dorhout, et al. "Magnesium for aneurysmal subarachnoid haemorrhage (MASH-2): a randomised placebo-controlled trial." The Lancet380.9836 (2012): 44-49.

Zhang, Shihong, et al. "Tirilazad for aneurysmal subarachnoid haemorrhage."The Cochrane Library (2010).

Liu, Guang Jian, et al. "Systematic assessment and meta-analysis of the efficacy and safety of fasudil in the treatment of cerebral vasospasm in patients with subarachnoid hemorrhage." European journal of clinical pharmacology 68.2 (2012): 131-139.

Kirkpatrick, Peter J., et al. "Simvastatin in aneurysmal subarachnoid haemorrhage (STASH): a multicentre randomised phase 3 trial." The Lancet Neurology 13.7 (2014): 666-675.

Yoneda, Hiroshi, et al. "A prospective, multicenter, randomized study of the efficacy of eicosapentaenoic acid for cerebral vasospasm: the EVAS study."World neurosurgery 81.2 (2014): 309-315.

Teasdale, G. M., et al. "A universal subarachnoid hemorrhage scale: report of a committee of the World Federation of Neurosurgical Societies." Journal of neurology, neurosurgery, and psychiatry 51.11 (1988): 1457.

Connolly, E. Sander, et al. "Guidelines for the Management of Aneurysmal Subarachnoid Hemorrhage A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association." Stroke 43.6 (2012): 1711-1737.

Myburgh, J. A. "Triple h” therapy for aneurysmal subarachnoid haemorrhage: real therapy or chasing numbers." Crit Care Resusc 7.3 (2005): 206-212.

Bederson, Joshua B., et al. "Guidelines for the management of aneurysmal subarachnoid hemorrhage a statement for healthcare professionals from a special Writing Group of the Stroke Council, American Heart Association."Stroke 40.3 (2009): 994-1025.

Muizelaar, J. Paul, and Donald P. Becker. "Induced hypertension for the treatment of cerebral ischemia after subarachnoid hemorrhage. Direct effect on cerebral blood flow." Surgical neurology 25.4 (1986): 317-325.

Dhar, Rajat, et al. "Comparison of induced hypertension, fluid bolus, and blood transfusion to augment cerebral oxygen delivery after subarachnoid hemorrhage: Clinical article." Journal of neurosurgery 116.3 (2012): 648-656.

Pickard, J. D., et al. "Effect of oral nimodipine on cerebral infarction and outcome after subarachnoid haemorrhage: British aneurysm nimodipine trial."BMJ: British Medical Journal 298.6674 (1989): 636.

Origitano, Thomas C., et al. "Sustained increased cerebral blood flow with prophylactic hypertensive hypervolemic hemodilution (" triple-H" therapy) after subarachnoid hemorrhage." Neurosurgery 27.5 (1990): 729-740.

Marshall, Scott A., Paul Nyquist, and Wendy C. Ziai. "The role of transcranial Doppler ultrasonography in the diagnosis and management of vasospasm after aneurysmal subarachnoid hemorrhage." Neurosurgery Clinics of North America21.2 (2010): 291-303.

Greenberg, E. D., et al. "Diagnostic accuracy of CT angiography and CT perfusion for cerebral vasospasm: a meta-analysis." American Journal of Neuroradiology 31.10 (2010): 1853-1860.

Sloan, M. A., et al. "Sensitivity and specificity of transcranial Doppler ultrasonography in the diagnosis of vasospasm following subarachnoid hemorrhage." Neurology 39.11 (1989): 1514-1514.

Rivierez, M., et al. "Value of electroencephalogram in prediction and diagnosis of vasospasm after intracranial aneurysm rupture." Acta neurochirurgica 110.1-2 (1991): 17-23.

Kawamoto, Shunsuke, et al. "Effectiveness of the head-shaking method combined with cisternal irrigation with urokinase in preventing cerebral vasospasm after subarachnoid hemorrhage." Journal of neurosurgery 100.2 (2004): 236-243.

Vergouwen, Mervyn DI, et al. "Biologic effects of simvastatin in patients with aneurysmal subarachnoid hemorrhage: a double-blind, placebo-controlled randomized trial." Journal of Cerebral Blood Flow & Metabolism 29.8 (2009): 1444-1453.

Macdonald, R. Loch, et al. "Clazosentan to Overcome Neurological Ischemia and Infarction Occurring After Subarachnoid Hemorrhage (CONSCIOUS-1) Randomized, Double-Blind, Placebo-Controlled Phase 2 Dose-Finding Trial."Stroke 39.11 (2008): 3015-3021.

Bakker, Nicolaas A., et al. "International subarachnoid aneurysm trial 2009: endovascular coiling of ruptured intracranial aneurysms has no significant advantage over neurosurgical clipping." Neurosurgery 66.5 (2010): 961-962.

Fisher, C. M., J. P. Kistler, and J. M. Davis. "Relation of cerebral vasospasm to subarachnoid hemorrhage visualized by computerized tomographic scanning." Neurosurgery 6.1 (1980): 1-9.

Grasso, Giovanni, Concetta Alafaci, and R. Loch Macdonald. "Management of aneurysmal subarachnoid hemorrhage: State of the art and future perspectives." Surgical neurology international 8 (2017).