Question 24

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.