Nitric Oxide-Based Treatment of Poor-Grade Patients After Severe Aneurysmal Subarachnoid Hemorrhage.
Adult
Aged
Aged, 80 and over
Aneurysm, Ruptured
/ surgery
Brain Ischemia
/ drug therapy
Feasibility Studies
Female
Humans
Infusions, Intravenous
Infusions, Intraventricular
Intracranial Aneurysm
/ surgery
Male
Middle Aged
Molsidomine
/ therapeutic use
Nitric Oxide Donors
/ therapeutic use
Nitroprusside
/ therapeutic use
Retrospective Studies
Rupture, Spontaneous
Subarachnoid Hemorrhage
/ therapy
Vasospasm, Intracranial
/ drug therapy
Coma
DCI
Intraventricular/intravenous nitric oxide donor
Molsidomine
Poor-grade aneurysmal SAH
Sodium nitroprusside
Transcranial Doppler sonography
Vasospasm
Journal
Neurocritical care
ISSN: 1556-0961
Titre abrégé: Neurocrit Care
Pays: United States
ID NLM: 101156086
Informations de publication
Date de publication:
06 2020
06 2020
Historique:
pubmed:
17
8
2019
medline:
8
6
2021
entrez:
17
8
2019
Statut:
ppublish
Résumé
Patients with aneurysmal subarachnoid hemorrhage (aSAH) require close treatment in neuro intensive care units (NICUs). The treatments available to counteract secondary deterioration and delayed ischemic events remain restricted; moreover, available neuro-monitoring of comatose patients is undependable. In comatose patients, clinical signs are hidden, and timing interventions to prevent the evolution of a perfusion disorder in response to fixed ischemic brain damage remain a challenge for NICU teams. Consequently, comatose patients often suffer secondary brain infarctions. The outcomes for long-term intubated patients w/wo pupil dilatation are the worst, with only 10% surviving. We previously added two nitroxide (NO) donors to the standard treatment: continuous intravenous administration of Molsidomine in patients with mild-to-moderate aSAH and, if required as a supplement, intraventricular boluses of sodium nitroprusside (SNP) in high-risk patients to overcome the so-called NO-sink effect, which leads to vasospasm and perfusion disorders. NO boluses were guided by clinical status and promptly reversed recurrent episodes of delayed ischemic neurological deficit. In this study, we tried to translate this concept, the initiation of intraventricular NO application on top of continuous Molsidomine infusion, from awake to comatose patients who lack neurological-clinical monitoring but are primarily monitored using frequently applied transcranial Doppler (TCD). In this observational, retrospective, nonrandomized feasibility study, 18 consecutive aSAH comatose/intubated patients (Hunt and Hess IV/V with/without pupil dilatation) whose poor clinical status precluded clinical monitoring received standard neuro-intensive care, frequent TCD monitoring, continuous intravenous Molsidomine plus intraventricular SNP boluses after TCD-confirmed macrospasm during the daytime and on a fixed nighttime schedule. Very likely associated with the application of SNP, which is a matter of further investigation, vasospasm-related TCD findings promptly and reliably reversed or substantially weakened (p < 0.0001) afterward. Delayed cerebral ischemia (DCI) occurred only during loose, low-dose or interrupted treatment (17% vs. an estimated 65% with secondary infarctions) in 17 responders. However, despite their worse initial condition, 29.4% of the responders survived (expected 10%) and four achieved Glasgow Outcome Scale Extended (GOSE) 8-6, modified Rankin Scale (mRS) 0-1 or National Institutes of Health Stroke Scale (NIHSS) 0-2. Even in comatose/intubated patients, TCD-guided dual-compartment administration of NO donors probably could reverse macrospasm and seems to be feasible. The number of DCI was much lower than expected in this specific subgroup, indicating that this treatment possibly provides a positive impact on outcomes. A randomized trial should verify or falsify our results.
Sections du résumé
BACKGROUND
Patients with aneurysmal subarachnoid hemorrhage (aSAH) require close treatment in neuro intensive care units (NICUs). The treatments available to counteract secondary deterioration and delayed ischemic events remain restricted; moreover, available neuro-monitoring of comatose patients is undependable. In comatose patients, clinical signs are hidden, and timing interventions to prevent the evolution of a perfusion disorder in response to fixed ischemic brain damage remain a challenge for NICU teams. Consequently, comatose patients often suffer secondary brain infarctions. The outcomes for long-term intubated patients w/wo pupil dilatation are the worst, with only 10% surviving. We previously added two nitroxide (NO) donors to the standard treatment: continuous intravenous administration of Molsidomine in patients with mild-to-moderate aSAH and, if required as a supplement, intraventricular boluses of sodium nitroprusside (SNP) in high-risk patients to overcome the so-called NO-sink effect, which leads to vasospasm and perfusion disorders. NO boluses were guided by clinical status and promptly reversed recurrent episodes of delayed ischemic neurological deficit. In this study, we tried to translate this concept, the initiation of intraventricular NO application on top of continuous Molsidomine infusion, from awake to comatose patients who lack neurological-clinical monitoring but are primarily monitored using frequently applied transcranial Doppler (TCD).
METHODS
In this observational, retrospective, nonrandomized feasibility study, 18 consecutive aSAH comatose/intubated patients (Hunt and Hess IV/V with/without pupil dilatation) whose poor clinical status precluded clinical monitoring received standard neuro-intensive care, frequent TCD monitoring, continuous intravenous Molsidomine plus intraventricular SNP boluses after TCD-confirmed macrospasm during the daytime and on a fixed nighttime schedule.
RESULTS
Very likely associated with the application of SNP, which is a matter of further investigation, vasospasm-related TCD findings promptly and reliably reversed or substantially weakened (p < 0.0001) afterward. Delayed cerebral ischemia (DCI) occurred only during loose, low-dose or interrupted treatment (17% vs. an estimated 65% with secondary infarctions) in 17 responders. However, despite their worse initial condition, 29.4% of the responders survived (expected 10%) and four achieved Glasgow Outcome Scale Extended (GOSE) 8-6, modified Rankin Scale (mRS) 0-1 or National Institutes of Health Stroke Scale (NIHSS) 0-2.
CONCLUSIONS
Even in comatose/intubated patients, TCD-guided dual-compartment administration of NO donors probably could reverse macrospasm and seems to be feasible. The number of DCI was much lower than expected in this specific subgroup, indicating that this treatment possibly provides a positive impact on outcomes. A randomized trial should verify or falsify our results.
Identifiants
pubmed: 31418143
doi: 10.1007/s12028-019-00809-1
pii: 10.1007/s12028-019-00809-1
pmc: PMC7272492
doi:
Substances chimiques
Nitric Oxide Donors
0
Nitroprusside
169D1260KM
Molsidomine
D46583G77X
Types de publication
Journal Article
Observational Study
Langues
eng
Sous-ensembles de citation
IM
Pagination
742-754Références
Frontera JA, Claassen J, Schmidt JM, Wartenberg KE, Temes R, Connolly ES Jr, et al. Prediction of symptomatic vasospasm after subarachnoid hemorrhage: the modified fisher scale. Neurosurgery. 2006;59:21–7 discussion 21–27.
pubmed: 16823296
doi: 10.1227/01.NEU.0000218821.34014.1B
Cahill J, Calvert JW, Zhang JH. Mechanisms of early brain injury after subarachnoid hemorrhage. J Cereb Blood Flow Metab. 2006;26:1341–53.
pubmed: 16482081
doi: 10.1038/sj.jcbfm.9600283
Frontera JA, Ahmed W, Zach V, Jovine M, Tanenbaum L, Sehba F, et al. Acute ischemia after subarachnoid hemorrhage, relationship with early brain injury and impact on outcome: a prospective quantitative MRI study. J Neurol Neurosurg Psychiatry. 2015;86:71–8.
pubmed: 24715224
doi: 10.1136/jnnp-2013-307313
Sehba FA, Bederson JB. Nitric oxide in early brain injury after subarachnoid hemorrhage. Acta Neurochir Suppl. 2011;110:99–103.
pubmed: 21116923
Bar B, MacKenzie L, Hurst RW, Grant R, Weigele J, Bhalla PK, et al. Hyperacute vasospasm after aneurysmal subarachnoid hemorrhage. Neurocrit Care. 2016;24(2):180–8.
pubmed: 26198438
doi: 10.1007/s12028-015-0177-y
Pluta RM, Hansen-Schwartz J, Dreier J, Vajkoczy P, Macdonald RL, Nishizawa S, Kasuya H, Wellman G, Keller E, Zauner A, Dorsch N, Clark J, Ono S, Kiris T, Leroux P, Zhang JH. Cerebral vasospasm following subarachnoid hemorrhage: time for a new world of thought. Neurol Res. 2009;31:151–8.
pubmed: 19298755
pmcid: 2706525
doi: 10.1179/174313209X393564
Sehba FA, Friedrich V. Cerebral microvasculature is an early target of subarachnoid hemorrhage. Acta Neurochir Suppl. 2013;115:199–205.
pubmed: 22890669
Nolan CP, Macdonald RL. Can angiographic vasospasm be used as a surrogate marker in evaluating therapeutic interventions for cerebral vasospasm? Neurosurg Focus. 2006;21:E1.
pubmed: 17029333
doi: 10.3171/foc.2006.21.3.1
Dority JS, Oldham JS. Subarachnoid hemorrhage. An update. Anesthesiol Clin. 2016;34(3):577–600.
pubmed: 27521199
doi: 10.1016/j.anclin.2016.04.009
Dorsch NW. Therapeutic approaches to vasospasm in subarachnoid hemorrhage. Curr Opin Crit Care. 2002;8:128–33.
pubmed: 12386513
doi: 10.1097/00075198-200204000-00007
Clark JF, Loftspring M, Wurster WL, Beiler S, Beiler C, Wagner KR, Pyne-Geithman GJ. Bilirubin oxidation products, oxidative stress, and intracerebral hemorrhage. Acta Neurochir Suppl. 2008;105:7–12.
pubmed: 19066073
pmcid: 2765408
doi: 10.1007/978-3-211-09469-3_2
Pluta RM. Dysfunction of nitric oxide synthases as a cause and therapeutic target in delayed cerebral vasospasm after SAH. Acta Neurochir Suppl. 2008;104:139–47.
pubmed: 18456999
pmcid: 4762030
doi: 10.1007/978-3-211-75718-5_28
Pluta RM. Delayed cerebral vasospasm and nitric oxide: review, new hypothesis, and proposed treatment. Pharmacol Ther. 2005;105:23–56.
pubmed: 15626454
doi: 10.1016/j.pharmthera.2004.10.002
Pluta RM. New regulatory, signaling pathways, and sources of nitric oxide. Acta Neurochir Suppl. 2011;110(Pt 1):7–12.
pubmed: 21116907
Woitzik J, Dreier JP, Hecht N, Fiss I, Sandow N, Major S, Winkler M, Dahlem YA, Manville J, Diepers M, Muench E, Kasuya H, Schmiedek P, Vajkoczy P, COSBID study group. Delayed cerebral ischemia and spreading depolarization in absence of angiographic vasospasm after subarachnoid hemorrhage. J Cereb Blood Flow Metab. 2012;32(2):203–12.
pubmed: 22146193
doi: 10.1038/jcbfm.2011.169
Hartings JA, York J, Carroll CP, Hinzman JM, Mahoney E, Krueger B, Winkler MKL, Major S, Horst V, Jahnke P, Woitzik J, Kola V, Du Y, Hagen M, Jiang J, Dreier JP. Subarachnoid blood acutely induces spreading depolarizations and early cortical infarction. Brain. 2017;140(10):2673–90.
pubmed: 28969382
pmcid: 5841026
doi: 10.1093/brain/awx214
Ehlert A, Schmidt C, Wolfer J, et al. Molsidomine for the prevention of vasospasm-related delayed ischemic neurological deficits and delayed brain infarction and the improvement of clinical outcome after subarachnoid hemorrhage: a single-center clinical observational study. J Neurosurg. 2016;124(1):51–8.
pubmed: 26162034
doi: 10.3171/2014.12.JNS13846
Ehlert A, Manthei G, Hesselmann V, Heindel W, Ringelstein EB, Stummer W, Pluta RM, Hesselmann V. Case of hyperacute onset of vasospasm after aneurysmal subarachnoid hemorrhage and refractory vasospasm treated with intravenous and intraventricular nitric oxide: a mini review. World Neurosurg. 2016;91(673):e11–8.
Hunt WE, Hess RM. Surgical risk as related to the time of intervention in the repair of intracranial aneurysms. J Neurosurg. 1968;28(1):14–20.
pubmed: 5635959
doi: 10.3171/jns.1968.28.1.0014
Ogilvy CS, Carter BS. A proposed comprehensive grading system to predict the outcome for surgical management of intracranial aneurysms. Neurosurgery. 1998;42(5):959–68 discussion 968–70.
pubmed: 9588539
doi: 10.1097/00006123-199805000-00001
Mooij JJ. Editorial: grading and decision-making in (aneurysmal) subarachnoid hemorrhage. Interv Neuroradiol. 2001;7(4):283–9 Epub 2002 Jan 10.
pubmed: 20663360
doi: 10.1177/159101990100700402
TheCalculator.co, available at: https://www.thecalculator.co/health/Hunt-and-Hess-Scale-for-Subarachnoid-Hemorrhage-Calculator-865.html .
Naval NS, Kowalski RG, Chang TR, Caserta F, Carhuapoma JR, Tamargo RJ. The SAH Score: a comprehensive communication tool. J Stroke Cerebrovasc Dis. 2014;23(5):902–9.
pubmed: 24103667
doi: 10.1016/j.jstrokecerebrovasdis.2013.07.035
Sarrafzadeh AS, Vajkoczy P, Bijlenga P, Schaller K. Monitoring in neurointensive care—the challenge to detect delayed cerebral ischemia in high-grade aneurysmal SAH. Front Neurol. 2014;21(5):134.
Vora YY, Suarez-Almazor M, Steinke DE, Martin ML, Findlay JM. Role of transcranial Doppler monitoring in the diagnosis of cerebral vasospasm after subarachnoid hemorrhage. Neurosurgery. 1999;44(6):1237–47 discussion 1247–8.
pubmed: 10371622
DeWitt DL, Wechsler LR. Transcranial doppler. Stroke. 1988;19:915–21.
pubmed: 2968690
doi: 10.1161/01.STR.19.7.915
Raabe A, Zimmermann M, Setzer M, Vatter H, Berkefeld J, Seifert V. Effect of intraventricular sodium nitroprusside on cerebral hemodynamics and oxygenation in poor-grade aneurysm patients with severe, medically refractory vasospasm. Neurosurgery. 2002;50:1006–13 discussion 1013–1004.
pubmed: 11950403
Wintermark M, Dillon WP, Smith WS, Lau BC, Chaudhary S, Liu S, Yu M, Fitch M, Chien JD, Higashida RT, Ko NU. Visual grading system for vasospasm based on perfusion CT imaging: comparisons with conventional angiography and quantitative perfusion CT. Cerebrovasc Dis. 2008;26(2):163–70.
pubmed: 18560220
doi: 10.1159/000139664
Lindberg L, Sjöberg T, Ingemansson R, Steenb S. Inhalation of nitric oxide after lung transplantation. Ann Thorac Surg. 1996;61(3):956–62.
pubmed: 8619725
doi: 10.1016/0003-4975(95)01116-1
Baldwin ME, Macdonald RL, Huo D, Novakovic RL, Goldenberg FD, Frank JI, Rosengart AJ. Early vasospasm on admission angiography in patients with aneurysmal subarachnoid hemorrhage is a predictor for in-hospital complications and poor outcome. Stroke. 2004;35:2506–11.
pubmed: 15472099
doi: 10.1161/01.STR.0000144654.79393.cf
Konczalla J, Seifert V, Beck J, Güresir E, Vatter H, Raabe A, Marquardt G. Outcome after Hunt and Hess grade V subarachnoid hemorrhage: a comparison of the pre-coiling era (1980–1995) versus post-ISAT era (2005–2014). J Neurosurgery. 2018;128(1):100–10.
doi: 10.3171/2016.8.JNS161075
Alotaibi NM, Elkarim GA, Samuel N, Ayling OGS, Guha D, Fallah A, Aldakkan A, Jaja BNR, de Oliveira Manoel AL, Ibrahim GM, Macdonald RL. Effects of decompressive craniectomy on functional outcomes and death in poor-grade aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis. J Neurosurg. 2017;127:1315–25.
pubmed: 28059660
doi: 10.3171/2016.9.JNS161383
Rinkel GJ, Algra A. Long-term outcomes of patients with aneurysmal subarachnoid hemorrhage. Lancet Neurol. 2011;10(4):349–56.
pubmed: 21435599
doi: 10.1016/S1474-4422(11)70017-5
Al-Khindi T, Macdonald RL, Schweizer TA. Cognitive and functional outcome after aneurysmal subarachnoid hemorrhage. Stroke. 2010;41:e519–36.
pubmed: 20595669
doi: 10.1161/STROKEAHA.110.581975
Pluta RM, Dejam A, Grimes G, Gladwin MT, Oldfield EH. Nitrite infusions to prevent delayed cerebral vasospasm in a primate model of subarachnoid hemorrhage. JAMA. 2005;293:1477–84.
pubmed: 15784871
doi: 10.1001/jama.293.12.1477
Ulrich CT, Fung C, Vatter H, Setzer M, Gueresir E, Seifert V, Beck J, Raabe A. Occurrence of vasospasm and infarction in relation to a focal monitoring sensor in patients after SAH: placing a bet when placing a probe? PLoS ONE. 2013;8(5):e62754.
pubmed: 23658768
pmcid: 3642192
doi: 10.1371/journal.pone.0062754
Adami D, Berkefeld J, Platz J, Konczalla J, Pfeilschifter W, Weidauer S, Wagner M. Complication rate of intraarterial treatment of severe cerebral vasospasm after subarachnoid hemorrhage with nimodipine and percutaneous transluminal balloon angioplasty: Worth the risk? J Neuroradiol. 2019;46(1):15–24.
pubmed: 29733918
doi: 10.1016/j.neurad.2018.04.001
Ursino M. Regulation of the circulation of the brain. In: Bevan RD, Bevan JA, editors. The human brain circulation. Totowa: Humana Press; 1994. p. 291–318.
doi: 10.1007/978-1-4612-0303-2_23
Weidauer S, Lanfermann H, Raabe A, et al. Impairment of cerebral perfusion and infarct patterns attributable to vasospasm after aneurysmal subarachnoid hemorrhage: a prospective MRI and DSA study. Stroke. 2007;38(6):1831–6 Epub 2007 Apr 19.
pubmed: 17446425
doi: 10.1161/STROKEAHA.106.477976
Mocco J, Zacharia BE, Komotar RJ, et al. A review of current and future medical therapies for cerebral vasospasm following aneurysmal subarachnoid hemorrhage. Neurosurg Focus. 2006;21(3):E9.
pubmed: 17029348
doi: 10.3171/foc.2006.21.3.9
Kramer A, Fletcher J. Do endothelin-receptor antagonists prevent delayed neurological deficits and poor outcomes after aneurysmal subarachnoid hemorrhage?: A meta-analysis. Stroke. 2009;40(10):3403–6.
pubmed: 19679843
doi: 10.1161/STROKEAHA.109.560243
Shen J, Pan JW, Fan ZX, et al. Dissociation of vasospasm-related morbidity and outcomes in patients with aneurysmal subarachnoid hemorrhage treated with clazosentan: a meta-analysis of randomized controlled trials. J Neurosurg. 2013;119:180–9.
pubmed: 23641823
doi: 10.3171/2013.3.JNS121436
Stein SC, Browne KD, Chen X-H, et al. Thromboembolism and delayed cerebral ischemia after subarachnoid hemorrhage: an autopsy study. Neurosurgery. 2006;59:781–7.
pubmed: 16915120
doi: 10.1227/01.NEU.0000227519.27569.45
Neil-Dwyer G, Lang DA, Doshi B, et al. Delayed cerebral ischemia: the pathological substrate. Acta Neurochir. 1994;131:137–45.
pubmed: 7709776
doi: 10.1007/BF01401464
Bohme E. Pharmacology of molsidomine and its active metabolites. Med Klin. 1990;85(Suppl 1):7–10.
Reden J. Molsidomine. Blood Vessels. 1990;27(2–5):282–94.
pubmed: 2242448
Rosenkranz B, Winkelmann BR, Parnham MJ. Clinical pharmacokinetics of molsidomine. Clin Pharmacokinet. 1996;30:372–84.
pubmed: 8743336
doi: 10.2165/00003088-199630050-00004
Serruys PW, Deckers JW, Luijten HE, et al. Long-acting coronary vasodilatory action of the molsidomine metabolite Sin 1: a quantitative angiographic study. Eur Heart J. 1987;8:263–70.
pubmed: 3582385
doi: 10.1093/oxfordjournals.eurheartj.a062268
Hecker G, Denzer D, Wohlfeil S. Elevation of circulating NO: its effects on hemodynamics and vascular smooth muscle cell proliferation in rats. Agent Actions Suppl. 1995;45:169–76.