Acta Neurochirurgica

, Volume 153, Issue 8, pp 1669–1675 | Cite as

Continuous intrathecal glyceryl trinitrate prevents delayed cerebral vasospasm in the single-SAH rabbit model in vivo

  • Ali Reza Fathi
  • Serge Marbacher
  • Thilo Graupner
  • Felix Wehrli
  • Stephan M. Jakob
  • Gerhard Schroth
  • Javier Fandino
Experimental research

Abstract

Background

Delayed cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH) is a major cause of high morbidity and mortality. The reduced availability of nitric oxide (NO) in blood and cerebrospinal fluid (CSF) is well established as a key mechanism of vasospasm. Systemic administration of glyceryl trinitrate (GTN), an NO donor also known as nitroglycerin, has failed to be established in clinical settings to prevent vasospasm because of its adverse effects, particularly hypotension. The purpose of this study was to analyze the effect of intrathecally administered GTN on vasospasm after experimental SAH in the rabbit basilar artery.

Methods

A single-hemorrhage model of SAH in rabbits was used to induce vasospasm. GTN (0.5 mg/ml) or saline was infused via a subcutaneous implanted osmotic pump with continuous drug release into the cerebellomedullary cistern over 5 days. The degree of vasospasm in the basilar artery was recorded with angiography on day 5 after SAH and was compared to baseline angiography on day 0.

Findings

Significant reduction of basilar artery diameter was observed in the SAH group with saline infusion compared to sham-operated animals. Intrathecally administered GTN had no effect on the vessel diameter in sham-operated animals, whereas it significantly prevented vasospasm in the SAH group. Intrathecal GTN infusion did not affect arterial blood pressure.

Conclusions

Prophylactic, continuous intrathecal administration of GTN prevents vasospasm of the basilar artery in the rabbit SAH model. No toxic effects could be demonstrated in this study. The clinical safety and feasibility of this strategy need to be further investigated.

Keywords

Subarachnoid hemorrhage Cerebral vasospasm Delayed ischemic neurological deficits Nitroglycerin Nitric oxide donors 

Notes

Conflicts of interest

None.

References

  1. 1.
    Agrawal A, Patir R, Kato Y, Chopra S, Sano H, Kanno T (2009) Role of intraventricular sodium nitroprusside in vasospasm secondary to aneurysmal subarachnoid haemorrhage: a 5-year prospective study with review of the literature. Minim Invasive Neurosurg 52:5–8PubMedCrossRefGoogle Scholar
  2. 2.
    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, discussion 666–667PubMedCrossRefGoogle Scholar
  3. 3.
    Fandino J, Sherman JD, Zuccarello M, Rapoport RM (2003) Cocaine-induced endothelin-1-dependent spasm in rabbit basilar artery in vivo. J Cardiovasc Pharmacol 41:158–161PubMedCrossRefGoogle Scholar
  4. 4.
    Faraci FM, Breese KR, Heistad DD (1994) Cerebral vasodilation during hypercapnia. Role of glibenclamide-sensitive potassium channels and nitric oxide. Stroke 25:1679–1683PubMedCrossRefGoogle Scholar
  5. 5.
    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 33:2681–2686PubMedCrossRefGoogle Scholar
  6. 6.
    Gow AJ, Stamler JS (1998) Reactions between nitric oxide and haemoglobin under physiological conditions. Nature 391:169–173PubMedCrossRefGoogle Scholar
  7. 7.
    Hansen-Schwartz J, Vajkoczy P, Macdonald RL, Pluta RM, Zhang JH (2007) Cerebral vasospasm: looking beyond vasoconstriction. Trends Pharmacol Sci 28:252–256PubMedCrossRefGoogle Scholar
  8. 8.
    Hop JW, Rinkel GJ, Algra A, van Gijn J (1997) Case-fatality rates and functional outcome after subarachnoid hemorrhage: a systematic review. Stroke 28:660–664PubMedCrossRefGoogle Scholar
  9. 9.
    Kassell NF, Torner JC (1984) The International Cooperative Study on Timing of Aneurysm Surgery–an update. Stroke 15:566–570PubMedCrossRefGoogle Scholar
  10. 10.
    Klemenska E, Beresewicz A (2009) Bioactivation of organic nitrates and the mechanism of nitrate tolerance. Cardiol J 16:11–19PubMedGoogle Scholar
  11. 11.
    Klimo P Jr, Kestle JR, MacDonald JD, Schmidt RH (2004) Marked reduction of cerebral vasospasm with lumbar drainage of cerebrospinal fluid after subarachnoid hemorrhage. J Neurosurg 100:215–224PubMedCrossRefGoogle Scholar
  12. 12.
    Kumar R, Pathak A, Mathuriya SN, Khandelwal N (2003) Intraventricular sodium nitroprusside therapy: a future promise for refractory subarachnoid hemorrhage-induced vasospasm. Neurol India 51:197–202PubMedGoogle Scholar
  13. 13.
    Lesley WS, Lazo A, Chaloupka JC, Weigele JB (2003) Successful treatment of cerebral vasospasm by use of transdermal nitroglycerin ointment (Nitropaste). AJNR Am J Neuroradiol 24:1234–1236PubMedGoogle Scholar
  14. 14.
    Marbacher S, Neuschmelting V, Graupner T, Jakob SM, Fandino J (2008) Prevention of delayed cerebral vasospasm by continuous intrathecal infusion of glyceroltrinitrate and nimodipine in the rabbit model in vivo. Intensive Care Med 34:932–938PubMedCrossRefGoogle Scholar
  15. 15.
    Neuschmelting V, Fathi AR, Hidalgo Staub ET, Marbacher S, Schroth G, Takala J, Jakob SM, Fandino J (2009) Norepinephrine-induced hypertension dilates vasospastic basilar artery after subarachnoid haemorrhage in rabbits. Acta Neurochir (Wien) 151:487–493CrossRefGoogle Scholar
  16. 16.
    Neuschmelting V, Marbacher S, Fathi AR, Jakob SM, Fandino J (2009) Elevated level of endothelin-1 in cerebrospinal fluid and lack of nitric oxide in basilar arterial plasma associated with cerebral vasospasm after subarachnoid haemorrhage in rabbits. Acta Neurochir (Wien) 151:795–801, discussion 801–792CrossRefGoogle Scholar
  17. 17.
    Pachl J, Haninec P, Tencer T, Mizner P, Houst'ava L, Tomas R, Waldauf P (2005) The effect of subarachnoid sodium nitroprusside on the prevention of vasospasm in subarachnoid haemorrhage. Acta Neurochir Suppl 95:141–145PubMedCrossRefGoogle Scholar
  18. 18.
    Pathak A, Mathuriya SN, Khandelwal N, Verma K (2003) Intermittent low dose intrathecal sodium nitroprusside therapy for treatment of symptomatic aneurysmal SAH-induced vasospasm. Br J Neurosurg 17:306–310PubMedCrossRefGoogle Scholar
  19. 19.
    Pluta RM, Butman JA, Schatlo B, Johnson DL, Oldfield EH (2009) Subarachnoid hemorrhage and the distribution of drugs delivered into the cerebrospinal fluid. J NeurosurgGoogle Scholar
  20. 20.
    Pluta RM, Dejam A, Grimes G, Gladwin MT, Oldfield EH (2005) Nitrite infusions to prevent delayed cerebral vasospasm in a primate model of subarachnoid hemorrhage. JAMA 293:1477–1484PubMedCrossRefGoogle Scholar
  21. 21.
    Poletti CE, Wepsic JG, Sweet WH (1972) Middle cerebral arterial spasm from subarachnoid blood: spasmolysis with topical use of nitroglycerin. Surg Forum 23:449–450PubMedGoogle Scholar
  22. 22.
    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, discussion 1399–1400PubMedCrossRefGoogle Scholar
  23. 23.
    Raabe A, Vatter H, Zimmermann M, Seifert V (2002) Reversal of tissue hypoxia by a single intraventricular dose of sodium nitroprusside in a patient with severe medically refractory cerebral vasospasm after subarachnoid haemorrhage. J Neurol Neurosurg Psychiatry 72:123–124PubMedCrossRefGoogle Scholar
  24. 24.
    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, discussion 1013–1004PubMedGoogle Scholar
  25. 25.
    Ram Z, Spiegelman R, Findler G, Hadani M (1989) Delayed postoperative neurological deterioration from prolonged sodium nitroprusside administration. Case report. J Neurosurg 71:605–607PubMedCrossRefGoogle Scholar
  26. 26.
    Reinert M, Wiest R, Barth L, Andres R, Ozdoba C, Seiler R (2004) Transdermal nitroglycerin in patients with subarachnoid hemorrhage. Neurol Res 26:435–439PubMedCrossRefGoogle Scholar
  27. 27.
    Sehba FA, Ding WH, Chereshnev I, Bederson JB (1999) Effects of S-nitrosoglutathione on acute vasoconstriction and glutamate release after subarachnoid hemorrhage. Stroke 30:1955–1961PubMedCrossRefGoogle Scholar
  28. 28.
    Sloffer CA, Augspurger L, Wagenbach A, Lanzino G (2005) Antimicrobial-impregnated external ventricular catheters: does the very low infection rate observed in clinical trials apply to daily clinical practice? Neurosurgery 56:1041–1044, discussion 1041–1044PubMedGoogle Scholar
  29. 29.
    Tanaka Y, Masuzawa T, Saito M, Yamada T, Ebihara A, Iwasa H, Mori S (2001) Combined administration of Fasudil hydrochloride and nitroglycerin for treatment of cerebral vasospasm. Acta Neurochir Suppl 77:205–207PubMedGoogle Scholar
  30. 30.
    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, discussion 57–48PubMedCrossRefGoogle Scholar
  31. 31.
    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 30:1409–1416PubMedCrossRefGoogle Scholar
  32. 32.
    Tierney TS, Clatterbuck RE, Lawson C, Thai QA, Rhines LD, Tamargo RJ (2001) Prevention and reversal of experimental posthemorrhagic vasospasm by the periadventitial administration of nitric oxide from a controlled-release polymer. Neurosurgery 49:945–951, discussion 951–943PubMedGoogle Scholar
  33. 33.
    Vajkoczy P, Hubner U, Horn P, Bauhuf C, Thome C, Schilling L, Schmiedek P, Quintel M, Thomas JE (2000) Intrathecal sodium nitroprusside improves cerebral blood flow and oxygenation in refractory cerebral vasospasm and ischemia in humans. Stroke 31:1195–1197PubMedCrossRefGoogle Scholar
  34. 34.
    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 89:279–288PubMedCrossRefGoogle Scholar
  35. 35.
    Woszczyk A, Deinsberger W, Boker DK (2003) Nitric oxide metabolites in cisternal CSF correlate with cerebral vasospasm in patients with a subarachnoid haemorrhage. Acta Neurochir (Wien) 145:257–263, discussion 263–254CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Ali Reza Fathi
    • 1
    • 2
  • Serge Marbacher
    • 1
    • 2
  • Thilo Graupner
    • 1
    • 4
  • Felix Wehrli
    • 1
    • 4
  • Stephan M. Jakob
    • 1
  • Gerhard Schroth
    • 3
  • Javier Fandino
    • 1
    • 2
  1. 1.Cerebrovascular Research Group, Department of Intensive Care MedicineUniversity of BerneBerneSwitzerland
  2. 2.Department of NeurosurgeryKantonsspital AarauAarauSwitzerland
  3. 3.Institute of Diagnostic and Interventional NeuroradiologyUniversity Hospital Inselspital BernBernSwitzerland
  4. 4.Department of NeurosurgeryUniversity Hospital Inselspital BernBernSwitzerland

Personalised recommendations