Calcium Channel Blocker Route of Administration Post Aneursymal Subarachnoid Haemorrhage

Authors: James Anstey (Intensivist), Robyn Ingram (ICU Pharmacist) November 2015

Evidence for this medication to prevent delayed ischaemic deficits, imperfect as it is, dates mainly from a study from the 1980s where the enteral form was used.  A summary of our literature review is below.

The agreed approach, endorsed by the neurosurgical Department (Prof A Kaye), is that:

A) Standard treatment post aneurysmal SAH should consist of enteral nimodipine 60 mg q4h for 21 days, unless it is not possible to deliver the nimodipine orally or by nasogastric tube

B) In patients in whom enteral admission is not possible, as well as those with vomiting or high nasogastric aspirates (defined as 2 successive nasogastric aspirates >250 ml), administration of IV nimodipine 2 mg/hr should occur instead

Should there be any concern expressed by about our choice of the enteral form, please refer to MH guideline (XYZ) and discuss any concerns with the treating Intensivist.

Question
What is the appropriate route of administration for nimodipine in patients with aneursymal subarachnoid haemorrhage (aSAH)?

Background
A landmark  NEJM study from 1983 demonstrating benefit from nimodipine use, showed that in 125 “neurologically normal” patients post secured aSAH, the risk of neurological deficit or death was decreased from 8/60 to 1/56 (p=0.03) with the use of nimodipine 0.35 mg/kg q4h given orally or nasogastrically for 21 days.1

Intravenous nimodipine may achieve higher serum concentrations in some patients2,3 , but costs about about 3.5 times more (oral nimodipine $89/day, IV nimodipine $308/day).  Moreover, intravenous administration has not translated into improved clinical outcomes, based on two randomized controlled trials comparing oral and intravenous administration:

a) A Swedish RCT published in 2009 compared 106 patients with aSAH, treated with either enteral or intravenous nimodipine, found no difference in 3-month MRI appearances or neurological outcomes (28% vs 30% delayed ischemic neurologic deficit in the enteric versus intravenous groups, respectively, p= 0.47)4

b) A Finnish RCT published in 2012 looked at 171 aSAH patients given either enteral (84 patients) or intravenous (87 patients) nimodipine, and showed no significant difference in 12-month delayed ischemic neurologic deficit, neither clinically nor on MRI.  (20% delayed ischemic neurologic deficit in the enteral group versus 16% in the IV group, p=0.61)5
The latest recommendation from the Cochrane Collaboration is that “while the evidence about the beneficial effect of nimodipine is not beyond all doubt… oral nimodipine is currently indicated in patients with aneurysmal SAH.  Intravenous administration of calcium antagonists is more expensive and potentially hazardous in view of hypotensive effects, and therefore not recommended for routine practice.”

References

  1. Allen GS, Ahn HS, Preziosi TJ,  et al Cerebral arterial spasm–a controlled trial of nimodipine in patients with subarachnoid hemorrhage.<http://www.ncbi.nlm.nih.gov/pubmed/6338383> N Engl J Med. 1983 Mar 17;308(11):619-24
  2. Soppi V, Kokki H, Koivisto T, et al  Early-phase pharmacokinetics of enteral and parenteral nimodipine in patients with acute subarachnoid haemorrhage– a pilot study.<http://www.ncbi.nlm.nih.gov/pubmed/17318527> Eur J Clin Pharmacol. 2007 Apr;63(4):355-61. Epub 2007 Feb 23
  3. Abboud T, Andresen H, Koeppen Jel al Serum levels of nimodipine in enteral and parenteral administration in patients with aneurysmal subarachnoidhemorrhage.<http://www.ncbi.nlm.nih.gov/pubmed/25701099> Acta Neurochir (Wien). 2015 May;157(5):763-7. doi: 10.1007/s00701-015-2369-9. Epub 2015 Feb 21
  4. Kronvall E, Undrén P, Romner B, et al. Nimodipine in aneurysmal subarachnoid hemorrhage: a randomized study of intravenous or peroral administration.<http://www.ncbi.nlm.nih.gov/pubmed/18847340> J Neurosurg. 2009 Jan;110(1):58-63.
  5. Soppi V, Karamanakos PN, Koivisto T, Kurki MI, Vanninen R, Jaaskelainen JE, Rinne J. A randomized outcome study of enteral versus intravenous nimodipine in 171 patients after acute aneurysmal subarachnoid hemorrhage.<http://www.ncbi.nlm.nih.gov/pubmed/22120252> World Neurosurg. 2012 Jul;78(1-2):101-9.
  6. Dorhout Mees SM, Rinkel GJ, Feigin VL, Algra A, van den Bergh WM, Vermeulen M, van Gijn J. Calcium antagonists for aneurysmal subarachnoidhaemorrhage.<http://www.ncbi.nlm.nih.gov/pubmed/17636626> Cochrane Database Syst Rev. 2007 Jul 18;(3):CD000277. Review. PubMed PMID: 17636626.