Nimodipine for delayed cerebral ischemia prevention [Neurosurgery Wiki]

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====== Nimodipine for delayed cerebral ischemia prevention ======

Oral [[administration]] of a [[calcium channel blocker]], nimodipine, has been introduced in the European and American guidelines for the prevention of DCI in aSAH patients. Nimodipine was initially developed to prevent CV, however with the approved dosage the incidence of [[angiographic vasospasm]] was not decreased, probably due to insufficient levels reached at the site of CV occurrence due to the presence of the [[blood-brain barrier]]. An increase in dose is limited by the severe systemic side effect of the drug, such as unusually fast or slow heartbeats, fainting or severe [[dizziness]], easy bruising or bleeding, and unusual weakness due to [[hypotension]].

These side effects are often causing interruption of the treatment even at the prescribed dosage (60 mg every 4 hours). In a recent retrospective analysis conducted on 270 aSAH patients admitted at the Charité in Berlin between 2009 and 2014, was shown that only 43.6% of the aSAH patients successfully completed the whole treatment according to the guideline-recommended dosage. The rate of dose reduction and discontinuation, due to the side effects, occurred with a significantly higher frequency in patients in poor clinical condition, those who are at the highest risk of vasospasm
((Sandow N, Diesing D, Sarrafzadeh A, Vajkoczy P, Wolf S. Nimodipine Dose Reductions in the Treatment of Patients with Aneurysmal Subarachnoid Hemorrhage. Neurocrit Care. 2016 Aug;25(1):29-39. doi: 10.1007/s12028-015-0230-x. PMID: 26690937.)).
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Prevention of DCI primarily relies on [[nimodipine]] administration and optimization of blood volume and cardiac performance. Neurological monitoring is essential for early DCI detection and intervention. Serial clinical examination combined with intermittent transcranial Doppler ultrasonography and CT angiography (with or without perfusion) is the most commonly used monitoring paradigm and usually suffices in good-grade patients. By contrast, poor grade patients (WFNS grades 4 and 5) require more advanced monitoring because stupor and coma reduce sensitivity to the effects of ischemia. Greater reliance on CT perfusion imaging, continuous electroencephalography, and invasive brain multimodality monitoring are potential strategies to improve situational awareness as it relates to detecting DCI. Pharmacologically-induced hypertension combined with volume is the established first-line therapy for DCI; a good clinical response with reversal of the presenting deficit occurs in 70 % of patients. Medically refractory DCI, defined as failure to respond adequately to these measures, should trigger a step-wise escalation of rescue therapy. Level 1 rescue therapy consists of cardiac output optimization, hemoglobin optimization, and endovascular intervention, including angioplasty and intra-arterial vasodilator infusion. In highly refractory cases, level 2 rescue therapies are also considered, none of which have been validated
((Francoeur CL, Mayer SA. Management of [[delayed cerebral ischemia]] after subarachnoid hemorrhage. Crit Care. 2016 Oct 14;20(1):277. doi: 10.1186/s13054-016-1447-6. PMID: 27737684; PMCID: PMC5064957.)).
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The calcium channel blocker nimodipine remains the only therapeutic intervention proven to improve functional outcomes after SAH. The recent failure of the drug [[clazosentan]] to improve functional outcomes despite reducing [[vasoconstriction]] has moved the focus of research into [[DCI]] away from cerebral artery constriction towards a more multifactorial a[[etiology]]. 
((Rowland MJ, Hadjipavlou G, Kelly M, Westbrook J, Pattinson KT. Delayed cerebral ischaemia after subarachnoid haemorrhage: looking beyond vasospasm. Br J Anaesth. 2012 Sep;109(3):315-29. doi: 10.1093/bja/aes264. PMID: 22879655.)).
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[[Nimodipine]] and [[induced hypertension]] using [[vasopressor]]s are an integral part of standard therapy. Consequences of the opposite effect of nimodipine and vasopressors on blood pressure on patient outcome remain unclear
((Paľa A, Schick J, Klein M, Mayer B, Schmitz B, Wirtz CR, König R, Kapapa T.
The influence of nimodipine and vasopressors on outcome in patients with delayed 
cerebral ischemia after spontaneous subarachnoid hemorrhage. J Neurosurg. 2019
Mar 8:1-9. doi: 10.3171/2018.11.JNS182891. [Epub ahead of print] PubMed PMID:
30849754.
)).

Aggressive therapy combining hemodynamic augmentation, transluminal balloon angioplasty, and intra-arterial infusion of vasodilator drugs is, to varying degrees, usually implemented. A panoply of drugs, with different mechanisms of action, has been studied in SAH related vasospasm. Currently, the most promising are [[magnesium sulfate]], 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, nitric oxide donors and endothelin-1 antagonists
((Keyrouz SG, Diringer MN. Clinical review: Prevention and therapy of vasospasm 
in subarachnoid hemorrhage. Crit Care. 2007;11(4):220. Review. PubMed PMID:
17705883; PubMed Central PMCID: PMC2206512.
)).

[[Early goal directed fluid therapy]] (EGDT) is beneficial for reducing DCI and improving postoperative functional outcome in patients with poor clinical grade
((Mutoh T, Kazumata K, Terasaka S, Taki Y, Suzuki A, Ishikawa T. Early intensive
versus minimally invasive approach to postoperative hemodynamic management after 
subarachnoid hemorrhage. Stroke. 2014 May;45(5):1280-4. doi:
10.1161/STROKEAHA.114.004739. Epub 2014 Apr 1. PubMed PMID: 24692480.
)).

Current treatment [[guideline]]s to prevent [[delayed cerebral ischemia]] is limited to oral [[nimodipine]], maintenance of [[euvolemia]], induction of [[hypertension]] if ischemic signs occur and [[endovascular therapy]] for patients with continued ischemia after induced hypertension. Future investigations will involve agents targeting vasodilation, anticoagulation, inhibition of apoptosis pathways, free radical neutralization, suppression of [[cortical spreading depolarization]] and attenuation of inflammation
((Serrone JC, Maekawa H, Tjahjadi M, Hernesniemi J. Aneurysmal subarachnoid
hemorrhage: pathobiology, current treatment and future directions. Expert Rev
Neurother. 2015 Feb 26:1-14. [Epub ahead of print] PubMed PMID: 25719927.
)).