Skip to main content

Prevention of delayed cerebral vasospasm by continuous intrathecal infusion of glyceroltrinitrate and nimodipine in the rabbit model in vivo

Intensive Care Medicine volume 34, pages 932–938 (2008)Cite this article

Abstract

Objective

Intrathecal bolus administration of nitric oxide donors and calcium channel antagonists has been proposed to reduce cerebral vasospasm (CVS) in animal subarachnoid hemorrhage (SAH) models. Intrathecal continuous administration of these substances for CVS prevention has not been extensively evaluated. This study compared the efficacy of continuous intrathecal infusions of the NO donor glyceroltrinitrate and nimodipine in preventing delayed CVS associated with SAH in an animal model in vivo.

Methods

New Zealand White rabbits were randomly assigned to six groups: no SAH/NaCl, no SAH/NO, no SAH/nimodipine, SAH/NaCl, SAH/NO, or SAH/nimodipine. Glyceroltrinitrate (GTN) at 0.5 μg/μl (0.5 μl/h) or nimodipine at 0.2 μg/μl (10 μl/h) or NaCl was continuously infused into the cisterna magna via an Alzet osmotic pump from day 0 to day 5 after injection of 1.0 ml autologous blood. The magnitude of spasm in the basilar artery was determined by comparison of pre- and posttreatment angiography and was calculated as proportional change in intraluminal diameter based on automatic measurements.

Results

A total of 55 experiments and 110 angiograms were performed. SAH was associated with vasoconstriction of the basilar artery (SAH/NaCl group 19.85 ± 2.94%). Continuous intrathecal injection of GTN and nimodipine prevented SAH-induced CVS. There was significant prevention of CVS in animals treated with GTN (SAH/NO group 5.93 ± 5.2%, n = 11) and nimodipine (SAH/nimodipine group: 0.55 ± 2.66%, n = 9). There was no significant difference between the treatment groups and controls in prevention of CVS.

Conclusions

This study demonstrates that prophylactic continuous intrathecal administration of either GTN or nimodipine equally prevents SAH-associated CVS in an animal model.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2

References

  1. Brisman JL, Song JK, Newell DW (2006) Cerebral aneurysms. N Engl J Med 355:928–939

    PubMed  Article  CAS  Google Scholar 

  2. Al-Yamany M, Wallace MC (1999) Management of cerebral vasospasm in patients with aneurysmal subarachnoid hemorrhage. Intensive Care Med 25:1463–1466

    PubMed  Article  CAS  Google Scholar 

  3. Biller J, Godersky JC, Adams HP Jr (1988) Management of aneurysmal subarachnoid hemorrhage. Stroke 19:1300–1305

    PubMed  CAS  Google Scholar 

  4. Sen J, Belli A, Albon H, Morgan L, Petzold A, Kitchen N (2003) Triple-H therapy in the management of aneurysmal subarachnoid haemorrhage. Lancet Neurol 2:614–621

    PubMed  Article  Google Scholar 

  5. Porchet F, Chiolero R, de Tribolet N (1995) Hypotensive effect of nimodipine during treatment for aneurysmal subarachnoid haemorrhage. Acta Neurochir (Wien) 137:62–69

    Article  CAS  Google Scholar 

  6. Stiefel MF, Heuer GG, Abrahams JM, Bloom S, Smith MJ, Maloney-Wilensky E, Grady MS, LeRoux PD (2004) The effect of nimodipine on cerebral oxygenation in patients with poor-grade subarachnoid hemorrhage. J Neurosurg 101:594–599

    PubMed  CAS  Google Scholar 

  7. Subramani K, Ghrew M (2004) Severe myocardial depression following intravenous nimodipine for aneurysmal subarachnoid haemorrhage. Intensive Care Med 30:1498–1499

    PubMed  Article  Google Scholar 

  8. Thomas JE, Rosenwasser RH, Armonda RA, Harrop J, Mitchell W, Galaria I (1999) Safety of intrathecal sodium nitroprusside for the treatment and prevention of refractory cerebral vasospasm and ischemia in humans. Stroke 30:1409–1416

    PubMed  CAS  Google Scholar 

  9. Thomas JE, Rosenwasser RH (1999) Reversal of severe cerebral vasospasm in three patients after aneurysmal subarachnoid hemorrhage: initial observations regarding the use of intraventricular sodium nitroprusside in humans. Neurosurgery 44:48–57

    PubMed  Article  CAS  Google Scholar 

  10. Raabe A, Zimmermann M, Setzer M, Vatter H, Berkefeld J, Seifert V (2002) Effect of intraventricular sodium nitroprusside on cerebral hemodynamics and oxygenation in poor-grade aneurysm patients with severe, medically refractory vasospasm. Neurosurgery 50:1006–1013

    PubMed  Article  Google Scholar 

  11. Kumar R, Pathak A, Mathuriya SN, Khandelwal N (2003) Intraventricular sodium nitroprusside therapy: a future promise for refractory subarachnoid hemorrhage-induced vasospasm. Neurol India 51:197–202

    PubMed  CAS  Google Scholar 

  12. Wolf EW, Banerjee A, Soble-Smith J, Dohan FC Jr, White RP, Robertson JT (1998) Reversal of cerebral vasospasm using an intrathecally administered nitric oxide donor. J Neurosurg 89:279–288

    PubMed  CAS  Google Scholar 

  13. Gabikian P, Clatterbuck RE, Eberhart CG, Tyler BM, Tierney TS, Tamargo RJ (2002) Prevention of experimental cerebral vasospasm by intracranial delivery of a nitric oxide donor from a controlled-release polymer: toxicity and efficacy studies in rabbits and rats. Stroke 33:2681–2686

    PubMed  Article  Google Scholar 

  14. Aihara Y, Jahromi BS, Yassari R, Sayama T, Macdonald RL (2003) Effects of a nitric oxide donor on and correlation of changes in cyclic nucleotide levels with experimental vasospasm. Neurosurgery 52:661–667

    PubMed  Article  Google Scholar 

  15. Pradilla G, Thai QA, Legnani FG, Hsu W, Kretzer RM, Wang PP, Tamargo RJ (2004) Delayed intracranial delivery of a nitric oxide donor from a controlled-release polymer prevents experimental cerebral vasospasm in rabbits. Neurosurgery 55:1393–1399

    PubMed  Article  Google Scholar 

  16. Clatterbuck RE, Gailloud P, Tierney T, Clatterbuck VM, Murphy KJ, Tamargo RJ (2005) Controlled release of a nitric oxide donor for the prevention of delayed cerebral vasospasm following experimental subarachnoid hemorrhage in nonhuman primates. J Neurosurg 103:745–751

    PubMed  CAS  Article  Google Scholar 

  17. Tierney TS, Pradilla G, Wang PP, Clatterbuck RE, Tamargo RJ (2006) Intracranial delivery of the nitric oxide donor diethylenetriamine/nitric oxide from a controlled-release polymer: toxicity in cynomolgus monkeys. Neurosurgery 58:952–960

    PubMed  Article  Google Scholar 

  18. Suzuki Y, Osuka K, Noda A, Tanazawa T, Takayasu M, Shibuya M, Yoshida J (1997) Nitric oxide metabolites in the cisternal cerebral spinal fluid of patients with subarachnoid hemorrhage. Neurosurgery 41:807–811

    PubMed  Article  CAS  Google Scholar 

  19. Thomas JE, Nemirovsky A, Zelman V, Giannotta SL (1997) Rapid reversal of endothelin-1-induced cerebral vasoconstriction by intrathecal administration of nitric oxide donors. Neurosurgery 40:1245–1249

    PubMed  Article  CAS  Google Scholar 

  20. Macdonald RL, Zhang ZD, Curry D, Elas M, Aihara Y, Halpern H, Jahromi BS, Johns L (2002) Intracisternal sodium nitroprusside fails to prevent vasospasm in nonhuman primates. Neurosurgery 51:761–768

    PubMed  Article  Google Scholar 

  21. Pickard JD, Murray GD, Illingworth R, Shaw MD, Teasdale GM, Foy PM, Humphrey PR, Lang DA, Nelson R, Richards P et al. (1989) Effect of oral nimodipine on cerebral infarction and outcome after subarachnoid haemorrhage: British aneurysm nimodipine trial. BMJ 298:636–642

    PubMed  CAS  Article  Google Scholar 

  22. Tettenborn D, Dycka J, Volberg E, Dudden P (1985) Blood pressure and heart rate during treatment with nimodipine in patients with subarachnoid hemorrhage. Neurochirurgia (Stuttg) 28 [Suppl 1]:84–86

    Google Scholar 

  23. Tettenborn D, Dycka J (1990) Prevention and treatment of delayed ischemic dysfunction in patients with aneurysmal subarachnoid hemorrhage. Stroke 21:IV85–IV89

    PubMed  CAS  Google Scholar 

  24. Auer LM, Ito Z, Suzuki A, Ohta H (1982) Prevention of symptomatic vasospasm by topically applied nimodipine. Acta Neurochir (Wien) 63:297–302

    Article  CAS  Google Scholar 

  25. Auer LM (1984) Acute operation and preventive nimodipine improve outcome in patients with ruptured cerebral aneurysms. Neurosurgery 15:57–66

    PubMed  Article  CAS  Google Scholar 

  26. Voldby B, Petersen OF, Buhl M, Jakobsen P, Ostergaard R (1984) Reversal of cerebral arterial spasm by intrathecal administration of a calcium antagonist (nimodipine). Acta Neurochir (Wien) 70:243–254

    Article  CAS  Google Scholar 

  27. Gioia AE, White RP, Bakhtian B, Robertson JT (1985) Evaluation of the efficacy of intrathecal nimodipine in canine models of chronic cerebral vasospasm. J Neurosurg 62:721–728

    PubMed  CAS  Google Scholar 

  28. Auer LM, Brandt L, Ebeling U, Gilsbach J, Groeger U, Harders A, Ljunggren B, Oppel F, Reulen HJ, Saeveland H (1986) Nimodipine and early aneurysm operation in good condition SAH patients. Acta Neurochir (Wien) 82:7–13

    Article  CAS  Google Scholar 

  29. Lewis PJ, Weir BK, Nosko MG, Tanabe T, Grace MG (1988) Intrathecal nimodipine therapy in a primate model of chronic cerebral vasospasm. Neurosurgery 22:492–500

    PubMed  Article  CAS  Google Scholar 

  30. Artru AA, Momota T (2000) Rate of CSF formation and resistance to reabsorption of CSF during sevoflurane or remifentanil in rabbits. J Neurosurg Anesthesiol 12:37–43

    PubMed  Article  CAS  Google Scholar 

  31. Zoghbi HY, Okumura S, Laurent JP, Fishman MA (1985) Acute effect of glycerol on net cerebrospinal fluid production in dogs. J Neurosurg 63:759–762

    PubMed  CAS  Google Scholar 

  32. Zabramski J, Spetzler RF, Bonstelle C (1986) Chronic cerebral vasospasm: effect of calcium antagonists. Neurosurgery 18:129–135

    PubMed  CAS  Article  Google Scholar 

  33. Nathan C, Xie QW (1994) Nitric oxide synthases: roles, tolls, and controls. Cell 78:915–918

    PubMed  Article  CAS  Google Scholar 

  34. Koshland DE Jr (1992) The molecule of the year. Science 258:1861

    PubMed  Article  Google Scholar 

  35. Hanggi D, Steiger HJ (2006) Nitric oxide in subarachnoid haemorrhage and its therapeutics implications. Acta Neurochir (Wien) 148:605–613

    Article  CAS  Google Scholar 

  36. Kim P, Lorenz RR, Sundt TM Jr, Vanhoutte PM (1989) Release of endothelium-derived relaxing factor after subarachnoid hemorrhage. J Neurosurg 70:108–114

    PubMed  CAS  Google Scholar 

  37. Marin J, Sanchez-Ferrer CF (1990) Role of endothelium-formed nitric oxide on vascular responses. Gen Pharmacol 21:575–587

    PubMed  CAS  Google Scholar 

  38. Anggard E (1994) Nitric oxide: mediator, murderer, and medicine. Lancet 343:1199–1206

    PubMed  Article  CAS  Google Scholar 

  39. Berendji-Grun D, Kolb-Bachofen V, Kroncke KD (2001) Nitric oxide inhibits endothelial IL-1[beta]-induced ICAM-1 gene expression at the transcriptional level decreasing Sp1 and AP-1 activity. Mol Med 7:748–754

    PubMed  CAS  Google Scholar 

  40. Oshiro EM, Hoffman PA, Dietsch GN, Watts MC, Pardoll DM, Tamargo RJ (1997) Inhibition of experimental vasospasm with anti-intercellular adhesion molecule-1 monoclonal antibody in rats. Stroke 28:2031–2037

    PubMed  CAS  Google Scholar 

  41. Pluta RM (2005) Delayed cerebral vasospasm and nitric oxide: review, new hypothesis, and proposed treatment. Pharmacol Ther 105:23–56

    PubMed  Article  CAS  Google Scholar 

  42. Faraci FM (1990) Role of nitric oxide in regulation of basilar artery tone in vivo. Am J Physiol 259:H1216–H1221

    PubMed  CAS  Google Scholar 

  43. Zuccarello M, Boccaletti R, Tosun M, Rapoport RM (1996) Role of extracellular Ca2+ in subarachnoid hemorrhage-induced spasm of the rabbit basilar artery. Stroke 27:1896–1902

    PubMed  CAS  Google Scholar 

  44. Molyneux AJ, Kerr RS, Yu LM, Clarke M, Sneade M, Yarnold JA, Sandercock P (2005) International subarachnoid aneurysm trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomised comparison of effects on survival, dependency, seizures, rebleeding, subgroups, and aneurysm occlusion. Lancet 366:809–817

    PubMed  Article  Google Scholar 

  45. Citerio G, Gaini SM, Tomei G, Stocchetti N (2007) Management of 350 aneurysmal subarachnoid hemorrhages in 22 Italian neurosurgical centers. Intensive Care Med 33:1580–1586

    PubMed  Article  Google Scholar 

  46. Blaumanis OR, Grady PA (1982) Experimental cerebral vasospasm: resolution by chlorpromazine. Surg Neurol 17:263–268

    PubMed  Article  CAS  Google Scholar 

  47. Endo S, Suzuki J (1979) Experimental cerebral vasospasm after subarachnoid hemorrhage. Participation of adrenergic nerves in cerebral vessel wall. Stroke 10:703–711

    PubMed  CAS  Google Scholar 

  48. Zuccarello M, Boccaletti R, Romano A, Rapoport RM (1998) Endothelin B receptor antagonists attenuate subarachnoid hemorrhage-induced cerebral vasospasm. Stroke 29:1924–1929

    PubMed  CAS  Google Scholar 

  49. Gyring JA, Brondsted HE (1984) Repetitive measurements of intracranial pressure in awake rabbits. Acta Physiol Scand 122:299–305

    PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We gratefully thank Hans Rudolf Widmer, PhD, and Jürgen Schmid, RN, from the Department of Neurosurgery, University Hospital Berne, for their professional laboratory support.

Author information

Affiliations

  1. Department of Intensive Care Medicine, University Hospital, Freiburgstrasse 10, 3010, Berne, Switzerland

    Serge Marbacher, Volker Neuschmelting, Thilo Graupner, Stephan M. Jakob & Javier Fandino

  2. Department of Neurosurgery, University Hospital, Freiburgstrasse 10, 3010, Berne, Switzerland

    Serge Marbacher, Volker Neuschmelting, Thilo Graupner & Javier Fandino

  3. Department of Neurosurgery, Kantonsspital Aarau, Aarau, Switzerland

    Javier Fandino

Authors
  1. Serge Marbacher
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Volker Neuschmelting
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Thilo Graupner
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Stephan M. Jakob
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Javier Fandino
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Javier Fandino.

Additional information

This study was supported by the Cerebrovascular Research Fund from the Departments of Neurosurgery and Intensive Care Medicine (account no. 34-160), University of Berne, Switzerland.

Electronic supplementary material

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Marbacher, S., Neuschmelting, V., Graupner, T. et al. Prevention of delayed cerebral vasospasm by continuous intrathecal infusion of glyceroltrinitrate and nimodipine in the rabbit model in vivo. Intensive Care Med 34, 932–938 (2008). https://doi.org/10.1007/s00134-008-0995-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00134-008-0995-x

Keywords

  • Subarachnoid hemorrhage
  • Vasospasm
  • Animal models
  • Nitric oxide
  • Nimodipine