Trial document





This trial has been registered retrospectively.
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  DRKS00005486

Trial Description

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Title

Incidence, extent and distribution pattern of delayed cerebral infarction in patients with non-traumatic subarachnoid hemorrhage

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Trial Acronym

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URL of the Trial

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Brief Summary in Lay Language

Introduction: Subarachnoid hemorrhage (SAH) presents a very serious disease of central nervous system that occurs due to rupture of intracranial aneurysm or spontaneously. A very high morbidity and mortality (up to 67%) of this disease comes from multiple complications of the acute phase. Herewith the occurrence of so-called „delayed cerebral ischemia” is being accepted as the strongest predictor of poor outcome. Currently available literature evidence is focused mostly on the incidence of cerebral infarctions after SAH. The evaluation of predictors for severity and distribution patterns of cerebral infarctions after SAH is the aim of current work.
Materials: Creation of a retrospective data bank with SAH patients who were admitted to our university hospital between 2005 and 2012. All new cerebral infarctions evidenced in follow-up computed tomography investigations during acute phase will be documented in accordance to our own “infarct scoring system”, developed by our neurovascular team (neurosurgical/neuroradiological/neurological departments). For the evaluation of the role of initial vascular status for the development of cerebral infarctions, all prominent findings of diagnostic conventional angiographies will be also documented. Finally, multiple clinical parameters that could potentially act as risk factors development of cerebral infarctions or may have a protective effect against infarct occurrence will be also retrospectively collected.

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Brief Summary in Scientific Language

Non-traumatic subarachnoid hemorrhage (SAH), despite improvements in surgical and medical treatments (1), is still a serious disease with the mortality rate of up to 67% (2) and significant morbidity among survivals (3). Delayed cerebral ischemia (DCI) is known to be an important cause of poor outcome after SAH (4-6). Rates of cerebral infarctions visible on computed tomography (CT) follow-up scans ranges between 24% and 65% (1,7) but was much higher when relying on magnetic resonance imaging (MRI) to identify ischemic lesions, reaching up to 81% (8,9). Many potential predictors of infarct incidence have been already reported: amount of intracranial hemorrhage (1,10-13), angiographic vasospasm (7,14,15), aneurysm location (7) and size (5), impaired initial clinical condition (1,5,13), increasing patient age (5), history of diabetes (5,9), hyperglycemia (5,12,16), history of hypertension (5), early hydrocephalus (9), requirement of external ventricular drainage (9), global cerebral edema (13), nocturnal occurrence of SAH (1), body mass index (1), febrile temperature (5), systemic inflammation (17).
However, it is still less investigated about the factors that influence the severity and the distribution patterns of cerebral infarctions. There are some attempts to systematize documented infarcts on CT scans. Most of authors tend to divide the patients with CT evidenced infarctions into those with single and multiple territorial pattern (9,13,18-20); but there are also other classification types: early and late infarction (12,13,21,22), cortical and deep infarctions (9,19,20). Recent studies present first quantitative analyses of CT infarcts performing the volumetric measurements (17,22,23). But there is still the lack of information about the true impact of infarct predictors on its severity and distribution, especially taking into account the multi-factorial nature of DCI (24-26). This all encourage for the further investigations aimed on the quantitative analyses of cerebral infarctions after SAH.

Patient selection
We retrospectively reviewed data from patients admitted to the University hospital of Freiburg with non-traumatic SAH between January 1st 2005 and December 31st 2012. Only patients admitted within 48 hours after hemorrhage and, in cases of aneurysmal SAH, with untreated aneurysm were included.

REFERENCES
1. Juvela S, Siironen J, Varis J, Poussa K, Porras M. Risk factors for ischemic lesions following aneurysmal subarachnoid hemorrhage. J Neurosurg 2005;102:194-201.
2. Nieuwkamp DJ, Setz LE, Algra A, Linn FH, de Rooij NK, Rinkel GJ. Changes in case fatality of aneurysmal subarachnoid haemorrhage over time, according to age, sex, and region: a meta-analysis. Lancet neurology 2009;8:635-42.
3. Connolly ES, Jr., Rabinstein AA, Carhuapoma JR, Derdeyn CP, Dion J, Higashida RT, et al. Guidelines for the management of aneurysmal subarachnoid hemorrhage: a guideline for healthcare professionals from the American Heart Association/american Stroke Association. Stroke 2012;43:1711-37.
4. Juvela S, Kuhmonen J, Siironen J. C-reactive protein as predictor for poor outcome after aneurysmal subarachnoid haemorrhage. Acta Neurochir (Wien) 2012;154:397-404.
5. Fergusen S, Macdonald RL. Predictors of cerebral infarction in patients with aneurysmal subarachnoid hemorrhage. Neurosurgery 2007;60:658-67; discussion 67.
6. Rowland MJ, Hadjipavlou G, Kelly M, Westbrook J, Pattinson KT. Delayed cerebral ischaemia after subarachnoid haemorrhage: looking beyond vasospasm. British journal of anaesthesia 2012;109:315-29.
7. Rabinstein AA, Friedman JA, Weigand SD, McClelland RL, Fulgham JR, Manno EM, et al. Predictors of cerebral infarction in aneurysmal subarachnoid hemorrhage. Stroke 2004;35:1862-6.
8. Kivisaari RP, Salonen O, Servo A, Autti T, Hernesniemi J, Ohman J. MR imaging after aneurysmal subarachnoid hemorrhage and surgery: a long-term follow-up study. AJNR Am J Neuroradiol 2001;22:1143-8.
9. Rabinstein AA, Weigand S, Atkinson JL, Wijdicks EF. Patterns of cerebral infarction in aneurysmal subarachnoid hemorrhage. Stroke 2005;36:992-7.
10. Suzuki J, Komatsu S, Sato T, Sakurai Y. Correlation between CT findings and subsequent development of cerebral infarction due to vasospasm in subarachnoid haemorrhage. Acta Neurochir (Wien) 1980;55:63-70.
11. Adams HP, Jr., Kassell NF, Torner JC, Haley EC, Jr. Predicting cerebral ischemia after aneurysmal subarachnoid hemorrhage: influences of clinical condition, CT results, and antifibrinolytic therapy. A report of the Cooperative Aneurysm Study. Neurology 1987;37:1586-91.
12. Siironen J, Porras M, Varis J, Poussa K, Hernesniemi J, Juvela S. Early ischemic lesion on computed tomography: predictor of poor outcome among survivors of aneurysmal subarachnoid hemorrhage. J Neurosurg 2007;107:1074-9.
13. Schmidt JM, Rincon F, Fernandez A, Resor C, Kowalski RG, Claassen J, et al. Cerebral infarction associated with acute subarachnoid hemorrhage. Neurocrit Care 2007;7:10-7.
14. Hwang G, Jung C, Sheen SH, Kim SH, Park SQ, Oh CW, et al. Procedural predictors of delayed cerebral infarction after intra-arterial vasodilator infusion for vasospasm following aneurysmal subarachnoid hemorrhage. Acta Neurochir (Wien) 2010;152:1503-9; discussion 9-10.
15. Crowley RW, Medel R, Dumont AS, Ilodigwe D, Kassell NF, Mayer SA, et al. Angiographic vasospasm is strongly correlated with cerebral infarction after subarachnoid hemorrhage. Stroke 2011;42:919-23.
16. Yoshimoto Y, Kwak S. Age-related multifactorial causes of neurological deterioration after early surgery for aneurysmal subarachnoid hemorrhage. J Neurosurg 1995;83:984-8.
17. Brown RJ, Kumar A, Dhar R, Sampson TR, Diringer MN. The relationship between delayed infarcts and angiographic vasospasm after aneurysmal subarachnoid hemorrhage. Neurosurgery 2013;72:702-7; discussion 7-8.
18. Hijdra A, Van Gijn J, Stefanko S, Van Dongen KJ, Vermeulen M, Van Crevel H. Delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage: clinicoanatomic correlations. Neurology 1986;36:329-33.
19. Naidech AM, Bendok BR, Bassin SL, Bernstein RA, Batjer HH, Bleck TP. Classification of cerebral infarction after subarachnoid hemorrhage impacts outcome. Neurosurgery 2009;64:1052-7; discussion 7-8.
20. Wanifuchi H, Sasahara A, Sato S. CT evaluation of late cerebral infarction after operation for ruptured cerebral aneurysm. In: Kırış T, Zhang J, eds. Cerebral Vasospasm: Springer Vienna; 2008:229-30.
21. Juvela S, Siironen J. Early cerebral infarction as a risk factor for poor outcome after aneurysmal subarachnoid haemorrhage. European journal of neurology : the official journal of the European Federation of Neurological Societies 2012;19:332-9.
22. Kumar A, Brown R, Dhar R, Sampson T, Derdeyn CP, Moran CJ, et al. Early vs Delayed Cerebral Infarction After Aneurysm Repair After Subarachnoid Hemorrhage. Neurosurgery 2013;73:617-23.
23. Nakamura T, Matsui T, Hosono A, Okano A, Fujisawa N, Tsuchiya T, et al. Beneficial effect of selective intra-arterial infusion of fasudil hydrochloride as a treatment of symptomatic vasospasm following SAH. Acta Neurochir Suppl 2013;115:81-5.
24. Etminan N, Vergouwen MD, Ilodigwe D, Macdonald RL. Effect of pharmaceutical treatment on vasospasm, delayed cerebral ischemia, and clinical outcome in patients with aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis. J Cereb Blood Flow Metab 2011;31:1443-51.
25. Muroi C, Seule M, Mishima K, Keller E. Novel treatments for vasospasm after subarachnoid hemorrhage. Curr Opin Crit Care 2012;18:119-26.
26. Vergouwen MD, Etminan N, Ilodigwe D, Macdonald RL. Lower incidence of cerebral infarction correlates with improved functional outcome after aneurysmal subarachnoid hemorrhage. J Cereb Blood Flow Metab 2011;31:1545-53.

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Organizational Data

  •   DRKS00005486
  •   2013/12/18
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  •   yes
  •   Approved
  •   446/13, Ethik-Kommission der Albert-Ludwigs-Universität Freiburg
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Secondary IDs

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Health Condition or Problem studied

  •   I60 -  Subarachnoid haemorrhage
  •   I63 -  Cerebral infarction
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Interventions/Observational Groups

  •   Arm 1 - We retrospectively review data from patients admitted to the University hospital of Freiburg with non-traumatic SAH between January 1st 2005 and December 31st 2012. Only patients admitted within 48 hours after hemorrhage and, in cases of aneurysmal SAH, with untreated aneurysm were included.
    All clinical and radiological relevant data from retrospective surveys will be collected in a separate unique database (Microsoft Access 2010, Microsoft Corporation, Redmond, WA, USA).
    The main end point of the study will be the documentation of cerebral infarctions on follow-up CT scans. The severity of SAH will be radiologically classified from the initial CT appearance according to Fisher et al.
    Following clinical data as potential predictor of cerebral infarction will be recorded:
    - Age, gender and initial clinical condition of patients (will be graded according to Hunt and Hess);
    - Presence of cardio-vascular risk factors (CVRF) at SAH patients: arterial hypertension, cigarette smoking, diabetes mellitus, obesity and previous cardiovascular diseases (coronary artery disease, atrial fibrillation, peripheral artery occlusive disease etc.);
    - Clinical grade at discharge, as well as at 3-6 months and 6-12 months after SAH according to modified Rankin scale (mRS);
    - Use of antiplatelet agents and other anti-thrombotic drugs (Aspirine, Clopidogrel, Heparin, Abciximab etc.) before onset of SAH, during aneurysm treatment and in the post-treatment phase;
    - Presence of clinical vasospasm on TCD: according to the guidelines, absolute mean flow velocities (MFV) > 160 cm/s for anterior circulation were deemed as suspicious for clinical vasospasm;
    - Occurrence of DIND, dichotomized into “reversible deficit” (RIND) and “fixed deficit” (FIND);
    - Common laboratory values: hemoglobin, hematocrit, glucose level, platelet count, base-excess, lactate, sodium and potassium in blood; cell count and protein level in cerebrospinal fluid (CSF);
    - Patient’ inflammatory state: the presence of systemic inflammatory response syndrome (SIRS), sepsis and multi-organ dysfunction syndrome (MODS); the levels of white blood cells, C- reactive protein and procalcitonin;
    - Development and severity of raised intracranial pressure (ICP): need for external ventricular drainage, additional conservative (sedation, relaxation, hypothermia, osmotic agents) and surgical treatment (implantation of intracranial sensors for permanent ICP-monitoring, decompressive craniectomy);
    - Other clinical relevant events: development of diabetes insipidus, infections of central nervous system, seizures, persistence of post-hemorrhagic hydrocephalus requiring shunting operation (primary or secondary) etc.
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Characteristics

  •   Non-interventional
  •   Observational study
  •   Single arm study
  •   Open (masking not used)
  •   [---]*
  •   Uncontrolled/Single arm
  •   Prognosis
  •   Single (group)
  •   N/A
  •   N/A
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Primary Outcome

Incidence, severity and distribution pattern of cerebral infarctions in correlation with:
- demographic (age, gender), clinical (Hunt&Hess Grade) and radiological (blood amount according to Fisher-Score, presence of intracerebral/intraventricular hemorrhage) data;
- anatomical features of vascular status, evaluated from initial/diagnostic angiography (stenosis, vascular hypo-/aplasia, anatomical variations, arteriosclerosis, macroangiopathy, fibro-muscular dysplasia, early vasospasm etc.), localisation and size of aneurysms;
- treatment modality;
- anti-coagulation therapy (aspirine, clopidogrel, heparine, ReoPro etc.);
- presence of TCD vasospasms;
- occurence of delayed neurological deficits: RIND ("reversible deficit") and FIND ("fixed deficit")
- labaratory parameters like hemoglobin, hematocrit, glucose, thrombocytes, base excess, lactate, pH, electrolytes, inflammation mediators etc.;
- invasive treatment of vasospasm with means of intra-arterial spasmolysis and angioplasty;
- treatment complications;
- cardio-vascular risk factors (CVRF) like hypertension, smoking history, diabetes
history, obesity and cardial pre-morbidity;
- early- ("at discharging") and late- ("3, 6, 12 Mo. after Stroke") Outcome.

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Secondary Outcome

- Value of infarct scoring system for prediction of early and late outcome of SAH patients;
- management of raised intracranial pressure among SAH patients: need for external liquor drain / additional conservative and surgical treatment;
- impact of complications on outcome;
- Diabetes insipidus and SAH;
- Meningitis and SAH;
- Epilepsy and SAH;
- Shunt-dependency and SAH.

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Countries of Recruitment

  •   Germany
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Locations of Recruitment

  • University Medical Center 
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Recruitment

  •   Actual
  •   2013/10/30
  •   850
  •   Monocenter trial
  •   National
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Inclusion Criteria

  •   Both, male and female
  •   no minimum age
  •   no maximum age
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Additional Inclusion Criteria

Non-traumatic subarachnoid hemorrhage

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Exclusion Criteria

- Beginn of desease earlier than 48 hours before admittion;
- treatment in other hospital

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Addresses

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    • Universitätsklinikum Freiburg
    • Hugstetter Strasse 49
    • 79095  Freiburg
    • Germany
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    • Neurochirurgie, UKL Freiburg
    • Mr.  Dr.  Ramazan  Jabbarli 
    • Dunantstr. 16a
    • 79110  Freiburg
    • Germany
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    • Neurochirurgie, UKL Freiburg
    • Mr.  Dr.  Ramazan  Jabbarli 
    • Dunantstr. 16a
    • 79110  Freiburg
    • Germany
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Sources of Monetary or Material Support

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    • Universitätsklinikum Freiburg
    • Hugstetter Strasse 49
    • 79095  Freiburg
    • Germany
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Status

  •   Recruiting complete, follow-up complete
  •   2013/11/30
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Trial Publications, Results and other Documents

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* This entry means the parameter is not applicable or has not been set.