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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Curr Cardiol Rep. Author manuscript; available in PMC 2013 December 1.
Published in final edited form as:
PMCID: PMC3491164

Thrombolytic Evacuation of Intracerebral and Intraventricular Hemorrhage

Mahua Dey, MD, Agnieszka Stadnik, MSc, and Issam A. Awad, MD, MSc, FACS


Intracranial hemorrhage (ICH) accounts for 10–15% of all strokes, however it causes 30–50% of stroke related mortality, disability and cost. The prevalence increases with age with only 2 cases/100,000/year for age less than 40 years to almost 350 cases/100,000/year for age more than 80 years. Several trials of open surgical evacuation of ICH have failed to show clear benefit over medical management. But, some small trials of minimal invasive hematoma evacuation in combination with thrombolytics have shown encouraging results. Based on these findings larger clinical trials are being undertaken to optimize and define therapeutic benefit of minimally invasive surgery in combination with thrombolytic clearance of hematoma. In this article we will review some of the background of minimally invasive surgery and the use of thrombolytics in the setting of ICH and intraventricular hemorrhage (IVH) and will highlight the early findings of MISTIE and CLEAR trials for these two entities respectively.

Keywords: Intracranial hemorrhage, intracerebral hemorrhage, Intraventricular hemorrhage, Minimally invasive surgery, thrombolytics

Introduction, Epidemiology and Scope of the Problem

Intracerebral hemorrhage (ICH), due to rupture of blood vessel in the brain parenchyma, can be divided into two broad categories: primary ICH and secondary ICH. ICH in the setting of pre-existing lesions like vascular malformation, tumor or in the setting of trauma is defined as secondary ICH. Primary ICH, the most frequent type of ICH and main focus of this article, refers to ICH in the absence of any clear underlying structural lesion. It is thought to be related to arteriosclerosis related to chronic and untreated hypertension, and amyloid angiopathy, which affects the arteries in the aged (1). Although spontaneous ICH with or without intraventricular hemorrhage (IVH) extension accounts for only 10–15% of all strokes, this devastating disease is associated with 30-day mortality rates of 35–52% and half of those deaths occur in the first 2 days (Fig. 1) (28).

Figure 1
Head CT demonstrating large left sided ICH with IVH. There is blood in both lateral ventricles, left more than right.

Over the past few decades the frequency of all strokes has decreased, however this decrease has primarily been driven by the decreasing frequency of ischemic strokes (9). In case of ICH there is conflicting trend with studies reporting a decrease, stable and increase in the frequency (1016). This conflicting trend can be explained by, on the one hand decrease in the frequency of hypertension related ICH due to improved medical management and on the other hand an increase in number of intracerebral hemorrhages related to increased use of anticoagulation (16). A meta-analysis of all the studies since 1980s by van Asch et al concluded that incidence of ICH increases with age and has not decreased between 1980 and 2006 (17).

Rationale for Volume Reduction in ICH

The poor outcome with ICH and the extent of associated brain damage can be correlated with the volume of parenchymal hemorrhage, and intraventricular hemorrhage. The blood mass produces direct destruction and compression of surrounding brain tissue. The volume of the hemorrhage elevates the intracranial pressure (ICP), affecting both cerebral perfusion and venous drainage. These vascular alterations are even more pronounced in the area of bleeding because of the direct mechanical effects, resulting in ischemia and poor perfusion to the damaged cells that need it most. The release of vasoactive and toxic substances from extravasated blood in the vicinity of the hematoma and the activation of the ischemic cascade further compound the brain damage and contribute to the morbidity and mortality associated with ICH. Volume of ICH is consistently shown to be a powerful predictor of poor outcome regardless of clot location, patient age, and neurological condition (1822). In a large population based study Broderick et al showed that volume of ICH, in combination with the initial Glasgow Coma Scale (GCS) score, is a powerful and easy-to-use predictor of 30-day mortality and morbidity in patients with spontaneous ICH. In their study patients with parenchymal hemorrhage volume of 60cc or more on their initial CT and GCS of 8 or less had a predicted 30-day mortality of 91% while patients with a volume of less than 30cc and GCS of 9 or more had a predicted 30-day mortality of 19% (23). Several investigators have demonstrated that the damage and changes caused by ICH is a dynamic process and serial imaging studies have revealed that clot volume often progresses following the initial event (2426). A study by Brott et al shows that within an hour after the initial scan, hemorrhage volume increases by one-third in 25% of patients and in about 10% of all patients, some additional increase occurs over the next 20 hours (25). There is a hypodense region surrounding the hematoma on CT scans, believed to be caused by serum extravasation from the blood collection itself and in 41% of patients, this area increases in volume over time and may contribute to the neurologic deficits. The impact of ICH volume on outcome has persisted despite modern critical care and aggressive treatment paradigms (27).

Several strategies of management of hemorrhagic stroke have aimed at limiting the volume of ICH and IVH, including rapid reversal of coagulopathy, and potentially more aggressive control of hypertension. But the burden of hemorrhagic stroke will nevertheless still reflect the volume of eventual ICH, which remains large and morbid in a significant fraction of patients, despite these proactive strategies.

The rationale for evacuation of ICH is based on the fact that larger hematomas result in more profound and longer-lasting alterations in adjacent brain parenchyma, attributed in part to mass effect and focal edema and reduction of clot volume may indeed improve neurological recovery and clinical outcome by removing focal mass effect, improving perfusion of compromised brain parenchyma and preventing intracranial hypertension. It also may enhance the clearance of blood breakdown products and thus preventing secondary brain edema and other potential neurotoxicity. Animal studies have in fact demonstrated that edema is diminished with the early evacuation of intracerebral clot (28).

Surgical Approaches to ICH Evacuation

Optimal treatment of ICH remains a complex and controversial issue with wide range of practice patterns. The spectrum of ICH ranges from large space occupying lesions that require surgery for acute neurological deterioration to small hematomas that should be managed conservatively, with equipoise about the management of lesions between these two extremes. Anecdotal reports document frequent dramatic recovery after emergent ICH evacuation in younger patients with impending brain herniation and these cases are typically excluded from clinical trials in ICH surgery, as are cases where ICH is caused by a vascular anomaly or tumor.

However, the majority of ICH cases affect mostly older patients, who decline slowly with a stable hematoma, and more likely with larger ICH volume. These cases have been shown not to fare as well with surgical intervention. Several clinical trials published between 1961 and 2004 failed to show clear benefit of surgical intervention over best medical management (2938). In late 1980s Auer et al published a controlled randomized study of endoscopic evacuation versus medical treatment in 100 patients with spontaneous ICH and showed that surgical patients with hematomas smaller than 50 cc made a significantly better functional recovery than did patients of the medically treated group, but had a comparable mortality rate. Conversely, patients with larger hematomas showed significantly lower mortality rates after operation but had no better functional recovery than the medically treated group. This effect from surgery was limited to patients in a preoperatively alert or somnolent state; stuporous or comatose patients had no better outcome after surgery (30). Approximately 10 years later in late 1990s Zuccarello et al reported results from a small randomized feasibility study of early surgical treatment versus current non-operative management and found a trend toward a lower 3-month morbidity with surgical intervention (34). A meta analysis of all twelve trials published prior to 2006 gave an odds ratio of 0.85(CI 0.71, 1.02) in favor of surgical treatment when the unfavorable outcome was death, and an odds ratio of 0.86 (CI 0.72, 1.03) for the 11 trials with published data when the unfavorable outcome was severe disability or death (39).

The largest clinical trial for surgical treatment of ICH, STICH trial, failed to demonstrated superiority of surgical treatment of ICH over medical management, however subgroup analysis showed that in the subset of 223 patient with lobar hematoma and no IVH, with initial conservative treatment 37% achieved a favorable outcome using the prognosis based outcome methodology where as 49% of patients achieved a favorable outcome with early surgery (p = 0.080). Furthermore using prognosis based Rankin as the outcome variable a significant benefit was observed for surgical patients in this subgroup (p = 0.013) (38). Since STICH lacked sufficient power to address this subgroup finding, STICH II trial was designed which compares craniotomy versus best medical therapy for lobar ICH and has completed enrollment, but results of follow-up have not been presented to date (40).

Application of stereotactic surgery and minimally invasive therapies to cerebrovascular surgery has led investigators to utilize such techniques toward the goal of reducing hematoma volume in the treatment of ICH. Minimally invasive surgical techniques may substantially decrease hematoma volume while avoiding the morbidity of major craniotomy procedure, especially in elderly and debilitated patients. In the randomized controlled trial performed by Auer et al ultrasound-guided endoscopic clot evacuation resulted in significantly lower mortality rates and improved clinical outcomes than medical treatment alone (30). Early attempts aimed at simple clot aspiration as well as more ingenious means of mechanical evacuation have failed to accomplish satisfactory volume reduction of ICH (41, 42). This has led to the adjunct use of fibrinolytic agents as a means of enhancing clot lysis and catheter drainage. Experimental studies have shown that infusion of urokinase promotes clot lysis and resorption without producing neurotoxicity, histopathological alterations, or recurrent bleeding (43, 44).

Since the first report by Doi et al in which direct instillation of urokinase was used after stereotactic aspiration to liquefy the hematoma (45), several reports have favorably reported usefulness of urokinase in ICH volume reduction (4650).

Thrombolytic Evacuation of the ICH

With the resurgence of modern stereotactic and image guided neurosurgical techniques, several case series of thrombolysis and catheter aspiration of ICH were published in the 1980’s and 1990’s suggesting that minimally invasive interventions are feasible, likely quite safe, and may avoid major surgical morbidity and offer improved outcome for selected patients with ICH (47, 48, 51, 52). In 2000 Montes et al reported preliminary experience with 12 consecutive cases of ICH treated by stereotactic CT-guided aspiration and thrombolysis with urokinase or recombinant tissue plasminogen activator (rtPA) (46). In this pilot series authors demonstrated that CT-guided thrombolysis and aspiration appears safe and effective in the reduction of ICH volume and this experience helped motivate the subsequent Phase II MISTIE trial. The Minimally Invasive Surgery and Thrombolysis in Intracerebral Hemorrhage (MISTIE) trial explored an aggressive avenue of treating ICH by combining minimally invasive surgery and local delivery of rtPA. MISTIE II was a phase II trial conducted from 2006 though 2011 evaluating safety, efficacy and dose escalation of rtPA in combination with minimally invasive surgery. In this trial patients with ICH volume of ≥20cc and stable for 6 hours were treated with either 0.3mg or 1mg of rTPA every 8 hour to either final volume of <10 cc or 72 hrs. Preliminary results of this trial were recently presented at the International Stroke Conference in New Orleans in February 2012 ( These demonstrated reliable safety and feasibility of ICH clot removal. The trial also showed that the amount of clot removal was directly related to the catheter placement and positioning. Poor catheter placement score was associated with higher residual clot volume and suboptimal clot resolution. Careful planning of surgical trajectory for catheter placement, deployed in the final tier of the trial, resulted in improved performance by all participating surgeons. A trend toward therapeutic advantage was also demonstrated, with greater proportion of treated cases in better outcome strata, especially among cases with greater hematoma evacuation. In essence MISTIE II validated the proof of concept, feasibility of ICH volume reduction and confirmed safety of the technique in comparison to randomized controls with third party adjudication. Based on these findings, a Phase III trial is being planned, with sufficient power to delineate the treatment effect, which was seen in MISTIE II.

Enhancing the confidence in the MISTIE approach, a recently completed trial from China reported better outcome with minimally invasive thrombolytic evacuation of ICH with urokinase thrombolysis, as compared to open craniotomy (53), but this study was limited by the absence of a cohort treated without any surgical intervention.

The Problem of Intraventricular Hemorrhage

IVH is a frequent complication of ICH, and is often associated with another type of hemorrhagic stroke, aneurysmal subarachnoid hemorrhage (SAH). IVH can range anywhere from mild layering of the blood in the horns of the lateral ventricle to complete casting of all the ventricles and presence of IVH in the setting of either ICH or SAH is independently associated with a worse outcome (5459). Even though it has been postulated that rupture of ICH into the ventricles would be beneficial in order to lessen the mass effect from the large ICH on surrounding structures, but in reality the extension of ICH into the ventricles has been consistently demonstrated as an independent predictor of poor outcome in patients with ICH (6064). In the setting of supratentorial ICH and IVH, a strong predictor exist between ventricular blood volume and poor outcome, and patients with more than 20cc of interventricular blood in general had poor outcome (65). A prospective study to determine the prognostic significance and pathophysiologic implication of intraventricular extension of ICH showed that 30-day mortality was much higher in patients with IVH and there was a direct correlation noticed between IVH volume and poor outcome. This correlation persisted when controlling for the presence or absence of hydrocephalus and size of associated ICH, thus establishing IVH volume as an independent prognostic factor of poor outcome, independent of the volume of ICH (60). In the setting of STICH trial it was noted that 42% of patients included in STICH with assessable scans also had an associated IVH. The prognosis for patients with IVH with or without hydrocephalus is much worse than that for ICH alone and removing these patients from the analysis and focusing on superficial hematomas presented a more encouraging picture for surgery (40). Similarly in the setting of aneurysmal SAH, impact of IVH has been noted to be an independently poor prognostic factor (59, 66, 67).

Several recent studies have attempted to grade the extent of IVH in relation to patient outcome (60, 64, 65, 68). The “Graeb score” takes into account the extent of involvement of the respective ventricles and associated ventriculomegaly, and has been extensively validated in outcomes studies (54, 64, 69).

Acute obstructive hydrocephalus from IVH causes elevated ICP, can lead to significant morbidity and mortality and is often treated with placement of external ventricular drain (EVD). However, the placement of EVD does not eliminate the morbidity and mortality of IVH, which is most likely due to underlying damage from the associated stroke, and the toxic effects of ventricular blood on adjacent periventricular brain tissue, including hippocampus, diencephalon and brainstem. It is generally agreed that the presence of hydrocephalus and deteriorating neurologic condition are an indication for placing an EVD, however the precise thresholds for insertion of EVD after IVH have not been clarified (70). An analysis of IVH cohort in a large prospective randomized study of surgery for ICH (71), demonstrated that continuous drainage of CSF contributes to the normalization of ICP. Catheter occlusions occur frequently in the setting of large IVH volume, with casting and clotting on ventricular blood, and these can result in poor ICP control. Catheter occlusions also require repeated catheter removals and insertions, thus increasing the risks of hemorrhage and infection (72).

Thrombolytic Clearance of IVH

The placement of EVD does not immediately clear the IVH, as the catheter may be obstructed by blood, or effect slow clearance of recalcitrant intraventricular blood cast. Blood clot resolution in CSF follows first-order kinetics, and the injection of thrombolytic agents into the ventricular space could increase the rate of clot resolution (73). Thrombolytic therapy for IVH has evolved in response to the problems of catheter obstruction and slow IVH clearance, and has been shown to be safe and effective in animal studies (7476), and in small clinical case series (7781). A systematic review of published retrospective case series comparing the outcome of conservative treatment, EVD and EVD combined with fibrinolysis in the setting of severe IVH due to SAH or ICH showed that the fatality rate for conservative treatment was 78%, for extraventricular drainage 58% and for EVD with fibrinolytic agents 6%; and the poor outcome rate for conservative treatment was 90%, EVD 89% and EVD with fibrinolytic agents 34% (82). In the setting of SAH, a prospective observational study by Nieuwkamp et al showed that massive IVH occurs in 10% of patients with SAH and approximately half of these patients may benefit from intraventricular fibrinolysis (83).

With very large IVH (>40cc) with casting and mass effect the use of bilateral simultaneous EVD catheters may increase clot resolution with or without adjunctive thrombolytic therapy (84). On the other hand Staykov et al. found no difference in clot resolution between the groups treated with one vs. two EVDs in the setting of severe IVH; however they did find a trend towards a longer EVD duration and higher infection rate in the bilateral EVD group (85). The Staykov study did not include a comparison with single catheter cases, controlling for IVH volume.

Based on these smaller case series and animal models the safety and feasibility of intraventricular thrombolysis was tested in Phase II clinical trial (73), which showed that intraventricular thrombolysis with urokinase speeds the resolution of intraventricular blood clots when compared with treatment with ventricular drainage alone. In 2011 results of CLEAR II trial was published where 48 patients were treated with 3 mg rtPA or placebo and showed that patients in the treatment arm achieved more rapid clearance of IVH and improved outcome when treated with rtPA (86). Dose optimization, safety profile, and estimates of outcome have motivated an ongoing Phase III trial for more definitive assessment of the potential benefits of thrombolysis.


Hemorrhagic stroke remains one of the deadliest and most disabling diseases with high cost burden to the society. The treatment of ICH and associated IVH remains controversial with wide range of practice patterns, a lack of standardized therapeutic approach, and persistent poor management outcomes. Therapeutic nihilism has been compounded by the failure of early clinical trials of surgical treatment in comparison to medical management. However emerging results of minimally invasive thrombolytic evacuation of ICH and IVH in MISTIE and CLEAR, respectively, have been encouraging. Ongoing clinical trials promise to change clinical practice by integrating these novel strategies in the therapeutic armamentarium.


I.A. Awad: has received grant support from NIH/NINDS.



Conflicts of interest: M. Dey: none; A. Stadnik: none;


1. Ritter MA, Droste DW, Hegedus K, Szepesi R, Nabavi DG, Csiba L, et al. Role of cerebral amyloid angiopathy in intracerebral hemorrhage in hypertensive patients. Neurology. 2005 Apr;64(7):1233–1237. [PubMed]
2. Dey M, Jaffe J, Stadnik A, Awad IA. External ventricular drainage for intraventricular hemorrhage. Curr Neurol Neurosci Rep. 2012 Feb;12(1):24–33. [PubMed]
3. Chiewvit P, Danchaivijitr N, Nilanont Y, Poungvarin N. Computed tomographic findings in non-traumatic hemorrhagic stroke. J Med Assoc Thai. 2009 Jan;92(1):73–86. [PubMed]
4. Badjatia N, Rosand J. Intracerebral hemorrhage. Neurologist. 2005 Nov;11(6):311–324. [PubMed]
5. Binz DD, Toussaint LG, 3rd, Friedman JA. Hemorrhagic complications of ventriculostomy placement: a meta-analysis. Neurocrit Care. 2009 Feb;10(2):253–256. [PubMed]
6. Ehtisham A, Taylor S, Bayless L, Klein MW, Janzen JM. Placement of external ventricular drains and intracranial pressure monitors by neurointensivists. Neurocrit Care. 2009 Apr;10(2):241–247. [PubMed]
7. Murry KR, Rhoney DH, Coplin WM. Urokinase in the treatment of intraventricular hemorrhage. Ann Pharmacother. 1998 Feb;32(2):256–258. [PubMed]
8. Sudlow CL, Warlow CP. Comparable studies of the incidence of stroke and its pathological types: results from an international collaboration. International Stroke Incidence Collaboration. Stroke. 1997 Mar;28(3):491–499. [PubMed]
9. Feigin VL, Lawes CM, Bennett DA, Barker-Collo SL, Parag V. Worldwide stroke incidence and early case fatality reported in 56 population-based studies: a systematic review. Lancet Neurol. 2009 Apr;8(4):355–369. [PubMed]
10. Islam MS, Anderson CS, Hankey GJ, Hardie K, Carter K, Broadhurst R, et al. Trends in incidence and outcome of stroke in Perth, Western Australia during 1989 to 2001: the Perth Community Stroke Study. Stroke. 2008 Mar;39(3):776–782. [PubMed]
11. Huhtakangas J, Tetri S, Juvela S, Saloheimo P, Bode MK, Hillbom M. Effect of increased warfarin use on warfarin-related cerebral hemorrhage: a longitudinal population-based study. Stroke. 2011 Sep;42(9):2431–2435. [PubMed]
12. Benatru I, Rouaud O, Durier J, Contegal F, Couvreur G, Bejot Y, et al. Stable stroke incidence rates but improved case-fatality in Dijon, France, from 1985 to 2004. Stroke. 2006 Jul;37(7):1674–1679. [PubMed]
13. Sivenius J, Tuomilehto J, Immonen-Raiha P, Kaarisalo M, Sarti C, Torppa J, et al. Continuous 15-year decrease in incidence and mortality of stroke in Finland: the FINSTROKE study. Stroke. 2004 Feb;35(2):420–425. [PubMed]
14. Flaherty ML, Kissela B, Woo D, Kleindorfer D, Alwell K, Sekar P, et al. The increasing incidence of anticoagulant-associated intracerebral hemorrhage. Neurology. 2007 Jan;68(2):116–121. [PubMed]
15. Khellaf M, Quantin C, d'Athis P, Fassa M, Jooste V, Hervieu M, et al. Age-period-cohort analysis of stroke incidence in Dijon from 1985 to 2005. Stroke. 2010 Dec;41(12):2762–2767. [PubMed]
16. Lovelock CE, Molyneux AJ, Rothwell PM. Change in incidence and aetiology of intracerebral haemorrhage in Oxfordshire, UK, between 1981 and 2006: a population-based study. Lancet Neurol. 2007 Jun;6(6):487–493. [PubMed]
17. van Asch CJ, Luitse MJ, Rinkel GJ, van der Tweel I, Algra A, Klijn CJ. Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin: a systematic review and meta-analysis. Lancet Neurol. 2010 Feb;9(2):167–176. [PubMed] Meta-analysis of all the studies till 1980 looking at incidence of ICH with age.
18. Fayad PB, Awad IA. Surgery for intracerebral hemorrhage. Neurology. 1998 Sep;51(3) Suppl 3:S69–S73. [PubMed]
19. Hankey GJ, Hon C. Surgery for primary intracerebral hemorrhage: is it safe and effective? A systematic review of case series and randomized trials. Stroke. 1997 Nov;28(11):2126–2132. [PubMed]
20. Prasad K, Browman G, Srivastava A, Menon G. Surgery in primary supratentorial intracerebral hematoma: a meta-analysis of randomized trials. Acta Neurol Scand. 1997 Feb;95(2):103–110. [PubMed]
21. Kothari RU, Brott T, Broderick JP, Barsan WG, Sauerbeck LR, Zuccarello M, et al. The ABCs of measuring intracerebral hemorrhage volumes. Stroke. 1996 Aug;27(8):1304–1305. [PubMed]
22. Lisk DR, Pasteur W, Rhoades H, Putnam RD, Grotta JC. Early presentation of hemispheric intracerebral hemorrhage: prediction of outcome and guidelines for treatment allocation. Neurology. 1994 Jan;44(1):133–139. [PubMed]
23. Broderick JP, Brott TG, Duldner JE, Tomsick T, Huster G. Volume of intracerebral hemorrhage. A powerful and easy-to-use predictor of 30-day mortality. Stroke. 1993 Jul;24(7):987–993. [PubMed]
24. Kazui S, Naritomi H, Yamamoto H, Sawada T, Yamaguchi T. Enlargement of spontaneous intracerebral hemorrhage. Incidence and time course. Stroke. 1996 Oct;27(10):1783–1787. [PubMed]
25. Brott T, Broderick J, Kothari R, Barsan W, Tomsick T, Sauerbeck L, et al. Early hemorrhage growth in patients with intracerebral hemorrhage. Stroke. 1997 Jan;28(1):1–5. [PubMed]
26. Kazui S, Minematsu K, Yamamoto H, Sawada T, Yamaguchi T. Predisposing factors to enlargement of spontaneous intracerebral hematoma. Stroke. 1997 Dec;28(12):2370–2375. [PubMed]
27. Jaffe J, AlKhawam L, Du H, Tobin K, O'Leary J, Pollock G, et al. Outcome predictors and spectrum of treatment eligibility with prospective protocolized management of intracerebral hemorrhage. Neurosurgery. 2009 Mar;64(3):436–445. discussion 45–6. [PubMed] Shows impact of ICH volume on outcome despite best medical management
28. Wagner KR, Xi G, Hua Y, Zuccarello M, de Courten-Myers GM, Broderick JP, et al. Ultra-early clot aspiration after lysis with tissue plasminogen activator in a porcine model of intracerebral hemorrhage: edema reduction and blood-brain barrier protection. J Neurosurg. 1999 Mar;90(3):491–498. [PubMed]
29. McKissock WRA, Taylor J. Primary intracerebral haemorrhage: a controlled trial of surgical and conservative treatment in 180 unselected cases. Lancet. 1961;(278):221–226.
30. Auer LM, Deinsberger W, Niederkorn K, Gell G, Kleinert R, Schneider G, et al. Endoscopic surgery versus medical treatment for spontaneous intracerebral hematoma: a randomized study. J Neurosurg. 1989 Apr;70(4):530–535. [PubMed]
31. Juvela S, Heiskanen O, Poranen A, Valtonen S, Kuurne T, Kaste M, et al. The treatment of spontaneous intracerebral hemorrhage. A prospective randomized trial of surgical and conservative treatment. J Neurosurg. 1989 May;70(5):755–758. [PubMed]
32. Batjer HH, Reisch JS, Allen BC, Plaizier LJ, Su CJ. Failure of surgery to improve outcome in hypertensive putaminal hemorrhage. A prospective randomized trial. Arch Neurol. 1990 Oct;47(10):1103–1106. [PubMed]
33. Morgenstern LB, Frankowski RF, Shedden P, Pasteur W, Grotta JC. Surgical treatment for intracerebral hemorrhage (STICH): a single-center, randomized clinical trial. Neurology. 1998 Nov;51(5):1359–1363. [PubMed]
34. Zuccarello M, Brott T, Derex L, Kothari R, Sauerbeck L, Tew J, et al. Early surgical treatment for supratentorial intracerebral hemorrhage: a randomized feasibility study. Stroke. 1999 Sep;30(9):1833–1839. [PubMed]
35. Teernstra OP, Evers SM, Lodder J, Leffers P, Franke CL, Blaauw G. Stereotactic treatment of intracerebral hematoma by means of a plasminogen activator: a multicenter randomized controlled trial (SICHPA) Stroke. 2003 Apr;34(4):968–974. [PubMed]
36. Nguyen JP, Decq P, Brugieres P, Yepes C, Melon E, Gaston A, et al. A technique for stereotactic aspiration of deep intracerebral hematomas under computed tomographic control using a new device. Neurosurgery. 1992 Aug;31(2):330–334. discussion 4–5. [PubMed]
37. Hattori N, Katayama Y, Maya Y, Gatherer A. Impact of stereotactic hematoma evacuation on activities of daily living during the chronic period following spontaneous putaminal hemorrhage: a randomized study. J Neurosurg. 2004 Sep;101(3):417–420. [PubMed]
38. Mendelow AD, Gregson BA, Fernandes HM, Murray GD, Teasdale GM, Hope DT, et al. Early surgery versus initial conservative treatment in patients with spontaneous supratentorial intracerebral haematomas in the International Surgical Trial in Intracerebral Haemorrhage (STICH): a randomised trial. Lancet. 2005 Jan-Feb;365(9457):387–397. [PubMed]
39. Prasad K, Mendelow AD, Gregson B. Surgery for primary supratentorial intracerebral haemorrhage. Cochrane Database Syst Rev. 2008 Oct;(4) CD000200. [PubMed]
40. Mendelow AD, Gregson BA, Mitchell PM, Murray GD, Rowan EN, Gholkar AR. Surgical trial in lobar intracerebral haemorrhage (STICH II) protocol. Trials. 2011 May;12:124. [PubMed] Trial for comparing craniotomy for evacuation of lobar ICH vurses best medical management.
41. Backlund EO, von Holst H. Controlled subtotal evacuation of intracerebral haematomas by stereotactic technique. Surg Neurol. 1978 Feb;9(2):99–101. [PubMed]
42. Kandel EI, Peresedov VV. Stereotaxic evacuation of spontaneous intracerebral hematomas. J Neurosurg. 1985 Feb;62(2):206–213. [PubMed]
43. Findlay JM, Weir BK, Steinke D, Tanabe T, Gordon P, Grace M. Effect of intrathecal thrombolytic therapy on subarachnoid clot and chronic vasospasm in a primate model of SAH. J Neurosurg. 1988 Nov;69(5):723–735. [PubMed]
44. Narayan RK, Narayan TM, Katz DA, Kornblith PL, Murano G. Lysis of intracranial hematomas with urokinase in a rabbit model. J Neurosurg. 1985 Apr;62(4):580–586. [PubMed]
45. Doi E, Moriwaki H, Komai N, Iwamoto M. [Stereotactic evacuation of intracerebral hematomas] Neurol Med Chir (Tokyo) 1982 Jun;22(6):461–467. [PubMed]
46. Montes JM, Wong JH, Fayad PB, Awad IA. Stereotactic computed tomographic-guided aspiration and thrombolysis of intracerebral hematoma : protocol and preliminary experience. Stroke. 2000 Apr;31(4):834–840. [PubMed]
47. Matsumoto K, Hondo H. CT-guided stereotaxic evacuation of hypertensive intracerebral hematomas. J Neurosurg. 1984 Sep;61(3):440–448. [PubMed]
48. Miller DW, Barnett GH, Kormos DW, Steiner CP. Stereotactically guided thrombolysis of deep cerebral hemorrhage: preliminary results. Cleve Clin J Med. 1993 Jul-Aug;60(4):321–324. [PubMed]
49. Hondo H, Uno M, Sasaki K, Ebisudani D, Shichijo F, Toth Z, et al. Computed tomography controlled aspiration surgery for hypertensive intracerebral hemorrhage. Experience of more than 400 cases. Stereotact Funct Neurosurg. 1990;54–55:432–437. [PubMed]
50. Mohadjer M, Braus DF, Myers A, Scheremet R, Krauss JK. CT-stereotactic fibrinolysis of spontaneous intracerebral hematomas. Neurosurg Rev. 1992;15(2):105–110. [PubMed]
51. Schaller C, Rohde V, Meyer B, Hassler W. Stereotactic puncture and lysis of spontaneous intracerebral hemorrhage using recombinant tissue-plasminogen activator. Neurosurgery. 1995 Feb;36(2):328–333. discussion 33–5. [PubMed]
52. Tzaan WC, Lee ST, Lui TN. Combined use of stereotactic aspiration and intracerebral streptokinase infusion in the surgical treatment of hypertensive intracerebral hemorrhage. J Formos Med Assoc. 1997 Dec;96(12):962–967. [PubMed]
53. Zhou H, Zhang Y, Liu L, Han X, Tao Y, Tang Y, et al. A prospective controlled study: minimally invasive stereotactic puncture therapy versus conventional craniotomy in the treatment of acute intracerebral hemorrhage. BMC Neurol. 2011 Jun;11:76. [PubMed] Clinical trial showing better outcome with minimally invasive evacuation of ICH in combination with thrombolysis compared to open craniotomy.
54. Graeb DA, Robertson WD, Lapointe JS, Nugent RA, Harrison PB. Computed tomographic diagnosis of intraventricular hemorrhage. Etiology and prognosis. Radiology. 1982 Apr;143(1):91–96. [PubMed]
55. Little JR, Blomquist GA, Jr, Ethier R. Intraventricular hemorrhage in adults. Surg Neurol. 1977 Sep;8(3):143–149. [PubMed]
56. Deshpande V, Burd E, Aardema KL, Ma CK, Moonka DK, Brown KA, et al. High levels of hepatitis C virus RNA in native livers correlate with the development of cholestatic hepatitis in liver allografts and a poor outcome. Liver Transpl. 2001 Feb;7(2):118–124. [PubMed]
57. Ruscalleda J, Peiro A. Prognostic factors in intraparenchymatous hematoma with ventricular hemorrhage. Neuroradiology. 1986;28(1):34–37. [PubMed]
58. Todo T, Usui M, Takakura K. Treatment of severe intraventricular hemorrhage by intraventricular infusion of urokinase. J Neurosurg. 1991 Jan;74(1):81–86. [PubMed]
59. Mayfrank L, Hutter BO, Kohorst Y, Kreitschmann-Andermahr I, Rohde V, Thron A, et al. Influence of intraventricular hemorrhage on outcome after rupture of intracranial aneurysm. Neurosurg Rev. 2001 Dec;24(4):185–191. [PubMed]
60. Tuhrim S, Horowitz DR, Sacher M, Godbold JH. Volume of ventricular blood is an important determinant of outcome in supratentorial intracerebral hemorrhage. Crit Care Med. 1999 Mar;27(3):617–621. [PubMed]
61. St Louis EK, Wijdicks EF, Li H, Atkinson JD. Predictors of poor outcome in patients with a spontaneous cerebellar hematoma. Can J Neurol Sci. 2000 Feb;27(1):32–36. [PubMed]
62. Bhattathiri PS, Gregson B, Prasad KS, Mendelow AD. Intraventricular hemorrhage and hydrocephalus after spontaneous intracerebral hemorrhage: results from the STICH trial. Acta Neurochir Suppl. 2006;96:65–68. [PubMed]
63. Ozdemir O, Calisaneller T, Hasturk A, Aydemir F, Caner H, Altinors N. Prognostic significance of third ventricle dilation in spontaneous intracerebral hemorrhage: a preliminary clinical study. Neurol Res. 2008 May;30(4):406–410. [PubMed]
64. Hanley DF. Intraventricular hemorrhage: severity factor and treatment target in spontaneous intracerebral hemorrhage. Stroke. 2009 Apr;40(4):1533–1538. [PMC free article] [PubMed]
65. Young WB, Lee KP, Pessin MS, Kwan ES, Rand WM, Caplan LR. Prognostic significance of ventricular blood in supratentorial hemorrhage: a volumetric study. Neurology. 1990 Apr;40(4):616–619. [PubMed]
66. Rosen DS, Macdonald RL, Huo D, Goldenberg FD, Novakovic RL, Frank JI, et al. Intraventricular hemorrhage from ruptured aneurysm: clinical characteristics, complications, and outcomes in a large, prospective, multicenter study population. J Neurosurg. 2007 Aug;107(2):261–265. [PubMed]
67. Mohr G, Ferguson G, Khan M, Malloy D, Watts R, Benoit B, et al. Intraventricular hemorrhage from ruptured aneurysm. Retrospective analysis of 91 cases. J Neurosurg. 1983 Apr;58(4):482–487. [PubMed]
68. Roos YB, Hasan D, Vermeulen M. Outcome in patients with large intraventricular haemorrhages: a volumetric study. J Neurol Neurosurg Psychiatry. 1995 May;58(5):622–624. [PMC free article] [PubMed]
69. Hallevi H, Dar NS, Barreto AD, Morales MM, Martin-Schild S, Abraham AT, et al. The IVH score: a novel tool for estimating intraventricular hemorrhage volume: clinical and research implications. Crit Care Med. 2009 Mar;37(3):969–974. e1. [PMC free article] [PubMed]
70. Naff NJ. Intraventricular Hemorrhage in Adults. Curr Treat Options Neurol. 1999 Jul;1(3):173–178. [PubMed]
71. Ziai WC, Torbey MT, Naff NJ, Williams MA, Bullock R, Marmarou A, et al. Frequency of sustained intracranial pressure elevation during treatment of severe intraventricular hemorrhage. Cerebrovasc Dis. 2009 Mar;27(4):403–410. [PMC free article] [PubMed]
72. Carhuapoma JR. Thrombolytic therapy after intraventricular hemorrhage: do we know enough? J Neurol Sci. 2002 Oct;202(1–2):1–3. [PubMed]
73. Naff NJ, Hanley DF, Keyl PM, Tuhrim S, Kraut M, Bederson J, et al. Intraventricular thrombolysis speeds blood clot resolution: results of a pilot, prospective, randomized, double-blind, controlled trial. Neurosurgery. 2004 Mar;54(3):577–583. discussion 83–4. [PubMed]
74. Pang D, Sclabassi RJ, Horton JA. Lysis of intraventricular blood clot with urokinase in a canine model: Part 3. Effects of intraventricular urokinase on clot lysis and posthemorrhagic hydrocephalus. Neurosurgery. 1986 Oct;19(4):553–572. [PubMed]
75. Pang D, Sclabassi RJ, Horton JA. Lysis of intraventricular blood clot with urokinase in a canine model: Part 2. In vivo safety study of intraventricular urokinase. Neurosurgery. 1986 Oct;19(4):547–552. [PubMed]
76. Pang D, Sclabassi RJ, Horton JA. Lysis of intraventricular blood clot with urokinase in a canine model: Part 1. Canine intraventricular blood cast model. Neurosurgery. 1986 Oct;19(4):540–546. [PubMed]
77. Shen PH, Matsuoka Y, Kawajiri K, Kanai M, Hoda K, Yamamoto S, et al. Treatment of intraventricular hemorrhage using urokinase. Neurol Med Chir (Tokyo) 1990 May;30(5):329–333. [PubMed]
78. Huttner HB, Tognoni E, Bardutzky J, Hartmann M, Kohrmann M, Kanter IC, et al. Influence of intraventricular fibrinolytic therapy with rt-PA on the long-term outcome of treated patients with spontaneous basal ganglia hemorrhage: a case-control study. Eur J Neurol. 2008 Apr;15(4):342–349. [PubMed]
79. Vereecken KK, Van Havenbergh T, De Beuckelaar W, Parizel PM, Jorens PG. Treatment of intraventricular hemorrhage with intraventricular administration of recombinant tissue plasminogen activator A clinical study of 18 cases. Clin Neurol Neurosurg. 2006 Jul;108(5):451–455. [PubMed]
80. Kumar K, Demeria DD, Verma A. Recombinant tissue plasminogen activator in the treatment of intraventricular hemorrhage secondary to periventricular arteriovenous malformation before surgery: case report. Neurosurgery. 2003 Apr;52(4):964–968. discussion 8–9. [PubMed]
81. Findlay JM, Weir BK, Stollery DE. Lysis of intraventricular hematoma with tissue plasminogen activator. Case report. J Neurosurg. 1991 May;74(5):803–807. [PubMed]
82. Nieuwkamp DJ, de Gans K, Rinkel GJ, Algra A. Treatment and outcome of severe intraventricular extension in patients with subarachnoid or intracerebral hemorrhage: a systematic review of the literature. J Neurol. 2000 Feb;247(2):117–121. [PubMed]
83. Nieuwkamp DJ, Verweij BH, Rinkel GJ. Massive intraventricular haemorrhage from aneurysmal rupture: patient proportions and eligibility for intraventricular fibrinolysis. J Neurol. 2010 Mar;257(3):354–358. [PMC free article] [PubMed]
84. Hinson HE, Melnychuk E, Muschelli J, Hanley DF, Awad IA, Ziai WC. Drainage Efficiency with Dual Versus Single Catheters in Severe Intraventricular Hemorrhage. Neurocrit Care. 2012 Jun;16(3):399–405. [PubMed]
85. Staykov D, Huttner HB, Lunkenheimer J, Volbers B, Struffert T, Doerfler A, et al. Single versus bilateral external ventricular drainage for intraventricular fibrinolysis in severe ventricular haemorrhage. J Neurol Neurosurg Psychiatry. 2010 Jan;81(1):105–108. [PubMed]
86. Naff N, Williams MA, Keyl PM, Tuhrim S, Bullock MR, Mayer SA, et al. Low-dose recombinant tissue-type plasminogen activator enhances clot resolution in brain hemorrhage: the intraventricular hemorrhage thrombolysis trial. Stroke. 2011 Nov;42(11):3009–3016. [PubMed] Clinical trial demontrating rapid clearance of IVH with intra-ventricular thrombolytics.