ences 261 (2007) 84–88www.elsevier.com/locate/jns

Journal of the Neurological Sci

The use of intraventricular thrombolytics in intraventricular hemorrhage

Paul Nyquist a,⁎, Daniel F. Hanley b

a Neurology and Anesthesia Critical Care Medicine, Johns Hopkins University School of Medicine,Meyer 8-138, 600 N. Wolfe Street, Baltimore Maryland, 21287-7840, United States

b Acute care Neurology Johns Hopkins School of Medicine, Baltimore Maryland, United States

Available online 5 June 2007

Abstract

Intraventricular hemorrhage (IVH) is associated with a high mortality and morbidity. Patients with this disorder may now be offered thepossibility of treatment. This treatment comes in the form of intraventricular thrombolytics. At present a large randomized trial is testing theefficacy of intraventricular rt-PA in IVH in the setting of intracranial hemorrhage (ICH) . Preliminary data suggests that it may be successfulin patients with IVH in this setting. This trial is the accumulation of animal and human trials completed over the last 20 years.© 2007 Elsevier B.V. All rights reserved.

Keywords: Intraventricular hemorrhage; Thrombolytics; Intracranial hemorrhage; Intracranial pressure

1. Introduction

Intraventricular hemorrhage is the direct hemorrhage ofblood into the ventricles of the brain. Mortality estimates forIVH range from 50%–80% [1–6]. The most common causeof IVH is spontaneous intracranial hemorrhage ICH, fol-lowed by subarachnoid hemorrhage (SAH). The incidence ofIVH in intracerebral hemorrhage is about twice that in SAH[5]. Approximately 10% of aneurysmal SAH and 40% ofprimary ICH experience IVH [5,7,9]. IVH in ICH and SAHaccount for about 10% and 5% respectively of the 500,000strokes occurring yearly in the United States [5,7–9]. Thetotal annual incidence of IVH in the USA is estimated to beabout 22,000 adults per year [7].

At present medical management of ICH and IVH revolvesaround the control of intracranial pressure (ICP). Despitevest medical management mortality remains high with only38% of patients surviving the first year [10]. Even with bestmedical management mortality is as high as 50% [11]. Thesestudies suggest that measures to control ICP through controlof such factors as hydrocephalus have little effect. Diringer etal. looked at the independent effect of hydrocephalus on

⁎ Corresponding author. Tel.: +1 410 9552611.E-mail address: pnyquis1@jhmi.edu (P. Nyquist).

0022-510X/$ - see front matter © 2007 Elsevier B.V. All rights reserved.doi:10.1016/j.jns.2007.04.039

outcome and found that hydrocephalus resulted in increasedmortality and greater rates of intubation [12]. Adams et al.found that control of hydrocephalus with an IVC had verylittle impact on survival in his cohort of 22 patient [13].

Surgical intervention appears to have very little impact onoutcome also. In the ISTICH trial the surgical arm was nomore or less effective than the best medical management atreducing mortality associated with ICH [14]. These studieshave left us with few options for improving outcomes in thesetting of ICH. Recent work in using stereotaxic guidedthrombolysis or minimally invasive thrombolysis (MIS) hasyielded some success at the reduction of clot size. Ruth et al.have shown the safe use of MIS with rt-PA as a thrombolytic[15]. Recently Vespa et al. have also reported improvementsin outcome with MIS and rt-PA [16]. others have reportedpost hoc analysis of uncontrolled data suggesting trendstoward improvements in mortality associated with MIS andICH [17]. At present reduction in the ventricular clot sizeseems to be the only method for reducing mortality after theICH has stabilized.

Many studies have demonstrated the independent effectof IVH on mortality [19,21]. A prospective evaluation ofICH patients demonstrated a direct, dose–effect relationshipbetween IVH volume and mortality [8]. ICH occurs in manycerebral locations and has many distinct sizes, but despite

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well-known relationships between ICH location and neuro-logic deficits and disabilities, no clear relationship existsbetween ICH location and mortality. [19,21] There is anincremental, direct relationship between ICH volume andmortality for ICH volumes greater than 30 cc. A volume sizeof 30 cc appears to be the threshold, below which mortality isa low frequency event (about 20%) [19,21]. Present datasupport the idea that mortality in small ICH (b30 cc) withIVH extension is in large part related to IVH [8]. Tuhrimet al., report that the presence of intraventricular blood in thesetting of ICH will increase mortality significantly and is anindependent risk factor for death [18]. In those patients in his1991 study with GCS less than 8 with IVH, all died [18].Tuhrim et al., demonstrated that patients with IVH in additionto ICHwho were followed prospectively who had IVH, had alower initial GCS's and larger ICH volume. Factors relevantto survival in this situation included the overall number ofventricles involved with blood and the presence of blood inthe fourth ventricle [3]. Hemphill et al., as well as Mohr et al.,have confirmed many of these findings in their validationstudies of prognostic indicators in ICH [20].

The presence of blood in the ventricles leads to a numberof clinical scenarios that prolong illness and increase mor-tality. These include: hydrocephalus, cerebral edema, andprolonged coma. The end result is a period of dependency inthe ICU. During this period, patients are often on mechanicallife support for extended period of time with an uncertainprognosis. This results in a high 30 day mortality usuallycaused by deaths from pneumonia, DVT, and elevated ICP.This situation and the uncertainty of meaningful neurologicalrecovery in patients with IVH often provoke patient decisionmakers to withdraw care earlier rather than latter to avoidpossible survival in the setting of catastrophic neurologicaldevastation. [7,22–24]. Research into ways to limit theconsequences of IVH and reduce the length of stay in theICU may have significant effects on the perspective of cli-nicians and family on this disease and significantly improveoutcomes. Thrombolysis of clots in IVH may significantlyreduce the length of stay of patients in the ICU and possiblyimprove morbidity and mortality.

Intraventricular hemorrhage contributes to morbidity inmany ways. Prolonged presence of IVH clot deep within thebrain causes decreased level of consciousness. The greaterthe volume of blood in the ventricles and the longer theduration of exposure, the greater the length of time of coma[25,26]. One way to combat this is through the placement ofexternal ventricular drains (EVD). Studies looking at theplacement of EVDs suggest that EVDs do not affect the sizeor damage associated with circulating blood products nor dothey change the time required for blood clot resolution [24].Until now, reducing the size of the intraventricular clot anddecreasing the time that deep brain structures are exposed toclot have not been directly addressed by any current IVHtreatment. The administration of thrombolytics through theIVH may significantly improve outcomes through the earlyreduction of clot size and reduction of the CSF blood burden.

IVH forms ventricular blood clots, which block ventric-ular CSF conduits causing acute obstructive hydrocephalus.If untreated, intracranial pressure (ICP) will increase and asthe ICP approaches the arterial perfusion pressure it cancause death. In the setting of IVH, obstructive hydrocephalusis the greatest and most immediate threat to life. EVDs areused to lower ICP quickly and are continued until theventricular blood clots have dissolved sufficiently to allownormalized CSF circulation. In addition, the mass effect ofclots in the IVH may independently increase the risk ofcerebral edema and contribute to morbidity and mortality.

Blood degradation products embedded in the arachnoidgranulations by the CSF flow may contribute to morbidity.With prolonged exposure, blood degradation productspermanently occlude and scar the arachnoid granulationsand consequently inhibit CSF absorption [27–29]. This maycause communicating hydrocephalus, which impairs cogni-tion, gait and balance, and urinary continence. Thissyndrome of normal pressure or elevated pressure hydro-cephalus may require the placement of a permanentventricular shunt to facilitate treatment. Early clearance ofIVH blood through the use of thrombolytics may signifi-cantly improve outcomes in this setting [7,22–24].

Two animal studies have looked at the effects of injectedblood in the ventricles of dogs and porcine. Pang et al., utilizeda dog model to show that thrombolysis of intraventricular-ly injected blood improved mortality, resulted in earlier de-creased clot size and improved level of consciousness intreated animals [24,30,31].Mayfrank showed similar results ina porcine model of IVH also using rt-PA as a lytic agent [30].Ventricular dilatation with blood affected outcomes in a man-ner independent of the effects related to clot volume or masseffect supporting the hypothesis that there is an independentbiochemical effect of ventricular blood on outcomes. Therewas a significant decline in mass effect in pigs treated with rt-PA. In both porcine and dog models and no detectable signs ofinflammation in the meninges of sacrificed experimental ani-mals. The volume of injected blood was directly proportionalto mortality [24,31].

In the Pang dog model three important observations weremade. That intraventricular rt-PA significantly hastened theresolution of intraventricular blood, rt-PA promoted rapidreturn of consciousness, and improved neurological outcome.These observations support the conclusion that the existenceof blood and heme products in the ventricles affected out-come separately from the influence of the mechanical effectof the clot and its effects on hydrodynamics.

In the last 15 year the concept that lysis of intraventricularblood will improve outcome has gained acceptance. A num-ber of small case series present evidence that support intra-ventricular lysis of clot as a safe intervention, yet provide noconclusive evidence about its efficacy. However, the inves-tigation of techniques used to lyse clot in this disease havebeen plagued by a number of false starts. In the late 1990'surokinase was used in a number of preliminary trials withnotable success. Urokinase was withdrawn from use by the

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FDA for concerns about drug safety. There were issuesconcerning the safe manufacture of the drug. The unavail-ability of urokinase ended a successful line of inquiry em-phasizing urokinase as the lytic of choice in IVH. As aconsequence rt-PA became the lytic of choice for IVH. Anumber of clinical trials using rt-PA have been completedand demonstrated that it can be used safely. The delay causedby the withdrawal of urokinase has had a significant impacton the use of lytic agents for thrombolysis in intraventricularhemorrhage. At present a phase three study using intraven-tricular rt-PA is underway and will hopefully demonstrate theclinical efficacy of this drug in the setting of adults with IVH.This may pave the way for the use of this drug in the settingof aneurysmal SAH as well as neonatal IVH. A number ofissues have plagued the use of rt-PA for thrombolysis ofIVH.

The thrombolytic for which the best pilot data exists isUrokinase. There have been a number of small case seriesusing it as the lytic in IVH. Todo et al., first published a caseseries demonstrating the safe and efficacious use of urokinasefor the lysis of IVH clot in the 1990's. In this study in sixpatients with IVH there were no secondary hemorrhagessuggesting that urokinase could be used safely [32]. Coplinet al., published another case series with 20 patients treatedwith urokinase. He reported improved outcomes whencompared to historical controls. There was a reduced LOCand no complications associated with EVD placement [33].Naff et al., completed a case series with 20 patients. In thisstudy 20 pilot patients were treated with a dose of urokinaseranging from 5000 international units to 25,000 internationalunits. Urokinase was given every 12 h until resolution of theclot [32,33]. A prospective randomized trial using Urokinasewas recently completed. In this study by Naff et al., patientswere randomized into a treatment group in which 25,000 unitsof urokinase were administered every 12 h until prespecifiedclinical criteria were obtained [34]. Twelve patient wereenrolled, seven treatment and 5 placebo. This limited studydemonstrated earlier resolution of clot in the IVH treated group[24]. This study was discontinued because of the lack ofcommercially available urokinase. At this time rt-PA has be-come the predominant investigational agent for the use of thethrombolysis in the setting of IVH. Studies are on going toexamine the safety of rt-Pa in IVH.

The safety of thrombolysis for IVH is a question of greatconcern. Recently a comprehensive Cochran review com-pleted by Haines et al., reviewed the safety and efficacy ofthrombolysis in the Cochrane collaboration format [35].There are a number of case series and some prospectiverandomized trials. In seven independent studies, the use ofintraventricular thrombolytic agents has been reported in 74patients with ICH or SAH. Seventeen patients were treatedwith urokinase and 57 with rt-PA. The dose of rt-PA rangedfrom 4–20 mg daily. Good neurological outcome wasreported in 50 of the 74 patients as measured by each group'scriteria. Complications potentially attributable to treatment orEVD use associated with treatment included: 5 cases of

bacterial meningitis, 1 patient had an increase in hematomavolume, and 2 extradural hematomas were noted. Based onthe conclusions of this review, insufficient evidence exists tosupport clinical efficacy. The preliminary analysis doessuggest rt-PA can be administered safely in IVH. At presentthere is consensus in the clinical community that a largerandomized prospective study of rt-PA in IVH is needed [35].

Some safety concerns about the indirect systemic effectsof rt-PA have arisen. In a rat model Wang et al., reported anumber of findings. They observed that there was a dosedependent effect on the rate of clot resolution. They alsoobserved that the flow of CSF did not occur in concordancewith a reduction in clot size. There also appeared to be anindependent toxic effect of rt-PA administration in patients inwhom rt-PAwas administered. These included inflammatorychanges in the choroid plexus and leukocyte infiltration in theperiventricular white matter of the brains of treated rodents[36]. No human clinical data report the observation of thesetoxic effects of rt-PA in the ventricles of humans. Whether ornot these findings are clinically relevant remains to be seen.These concerns over safety often arise from a series of clinicalobservations seen in the use of rt-PA for Ischemic stroke. Inthat setting there is concern about the effect of rt-PA as anindependent risk factor for cerebral edema and ICH.

Thrombolysis is a potential therapy for the treatment ofIVH in the setting of SAH. Thrombolytics have been usedextensively in small clinical trials aimed at reducing the burdenof blood associated with SAH. The goal of such therapy is toreduce the risk of occurrence and the intensity of vasospasmobserved in the setting of aneurysmal SAH. This has lead tostudies looking at intracisternal thrombolysis in the setting ofSAH. The most recent study used a single intraoperative doseof rt-PA in comparison to a placebo. Thiswas associatedwith atrend in the reduction of angiographic vasospasm [37].

In the setting of IVH, thrombolytics could also reduce theamount of blood in the ventricular system and help to reducethe risk of vasospasm as well as treat the side effects of IVH.The possibility that thrombolytics may facilitate rebleedingin this setting is of great concern. Intraventricular rt-PA in thesetting of acute IVH has also been used and examinedretrospectively in a large number of case series and a fewsmall prospective trials. One of the first case series to becompleted was by Findlay et al, in 1993, in this series theyhad patients with IVH and SAH, IVH and ruptured AVM, aswell as a case of IVH from a surgical catheter placement.They were treated with individual doses of rt-PA in theranges of 2–12 mg. treatment was initiated within 24 h ofsurgery. No hemorrhagic strokes secondary to the rt-PAwerereported. The drug was dosed one time every 24 h with mostpatients receiving only one dose [38]. In this series with alarge number of patients with ruptured aneurysms, no casesof rebleeding were associated with the use of this drug. Thissuggests that this treatment may be safe and effective in thesetting of IVH and SAH [38]. Recently Varelas et al., re-ported their experience with rt-PA for IVH in a prospectivestudy in IVH in the setting of SAH. Ten patients received

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drug and their outcomes were compared with 10 age-match-ed controls. They found that the rt-PA group had a statis-tically shorter length of stay more rapidly improving GCSscale and a decreased need for shunt placement. The averagedose was 3.5 mg of rt-PA administered on admission to thehospital. The rt-PAwas only administered after the aneurysmhad been secured [39].

A number of case series and small trials have helped toelucidate the effects of rt-PA in this disease. Mayfrank et al.,reported a case series of 12 patients with IVHwhowere treatedwithin 24 h of onset of symptoms with 2–5 mg of rt-PA [40].The dose was given at 6–14 h until a substantial reduction inIVH volume as recognized on CT scan. The average time formarked reduction to normalization of the CTscanwas 24–48 hfrom the beginning of thrombolytic therapy. Improved ICPcontrol was observed in this study and only one complication,a case of meningitis, was observed. Goh et al., reported a caseseries of 10 patients, 7 with negative angiograms and threewith AVMs. Follow-up at three months identified norebleeding, and no cases of meningitis. Total doses of 6–12 mg of rt-Pa were used in this study with a 24 h dosinginterval [41]. These studies support the idea that rt-PA can besafely administered in the setting of AVM's.

The most recently published study on the use of rt-PA inIVH was completed at Mercer in Georgia. Fountas et al.,reported the results of a prospective trial of rt-PA in IVH in 21patients. These patients were exclusively ICH patients withoutaneurysms or AVMs. Thrombolytics were administered on a24 h schedule with a dose of 3 mg. There was an observedhemorrhage rate of 19%, and an infection rate of 14.3%. ACSF pleocytosis was observed in all 21 patients [42].

IVH is also commonly seen in premature infants. Theestimates of the incidence of IVH in this population range ashigh as 24.6% of all premature infants [43]. In this popu-lation bleeding occurs at the site of the immature germinalmatrix. Hypoxia secondary to respiratory distress results inan increase stress on the highly vascular germinal matrix.This causes hemorrhage from the germinal matrix directlyinto the ventricles. Protocols incorporating streptokinase inthe setting of neonatal hydrocephalus and IVH have shownno benefit at this time [45]. Whitelaw completed a Cochranmet-analysis suggesting that intraventricular lysis of clotwith streptokinase did not reduce the frequency of shuntdependency in infants with IVH and hydrocephalus [45].Whitelaw et al., have completed a phase one trial examiningthe use of rt-PA in IVH in infants and have reported the safeuse of low doses of rt-PA in infants. The doses used were1.0 mg or 0.5 mg with dosing intervals of 1–7 days. The 1 /2life of rt-PA in CSF in this setting was determined to be 24 h.Further study is needed to determine the efficacy of thistreatment at reducing dependency on shunts and avoidanceof hydrocephalus [44]. These studies have provided valuabledata for further study of IVH in the adult setting. They haveshown that smaller doses of rt-PA given at more frequentintervals maybe efficacious, they have also aided in theestablishment of rt-PA's half-life in the ventricular system.

Further testing of this technique in adults will undoubtedlyhelp to clarify concerns over safety and efficacy in neonates.

2. Conclusion

At this time there is evidence suggesting that thromboly-tics used for the lysis of blood in the setting of IVH in humansmay improve outcomes. The potential clinical benefitsinclude: faster reduction of IVH clot size, faster removal ofblood from the ventricular systems, reduction in the incidenceof hydrocephalus, reduced time in coma, and improved mor-tality. This may result in improved patient survival, reduc-tions in the number of patients requiring long term shuntingand reduced length of stay in the ICU. At this time thereappears to be a clinical consensus that rt-PA is the mostcommonly used thrombolytic and studies are testing rt-PA inthis setting. Future clinical trials using this drug are underway and rt-PA appears to be the drug for which the mostaccurate information about safety and efficacy will exist.There are number of issues that must be resolved about theuse of rt-PA in the setting of IVH. These include what dose issafest, what period of dosing is safest, when to stop treatment,and which ventrical to place catheters in for maximum clotreduction. Many of these questions will be answered byongoing clinical trials. With the completion of these trials it isthe hope of physicians that we will at last have a treatment forlyses of IVH that is safe and effective. The use of throm-bolysis in the setting of IVHmaybe one of many clinical toolsthat will improve outcomes associated with ICH and IVH.Hopefully this new tool may help to change the attitude ofmany physicians in the setting of IVH from therapeuticnihlism to dogmatic optimism.

At present there is an FDA sponsored randomized pro-spective trial on the efficacy and safety of rt-Pa in IVH. Thisstudy is the Clot Lysis: evaluating accelerated resolution ofintraventricular hemorrhage (CLEAR IVH). This study isdesigned to determine the optimum dose and timing of rt-Pain IVH. It will help to establish standard procedures aboutthe use of rt-PA in the setting of IVH and resolve many of theissues discussed above.

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