The volume of blood in both the intraparenchymal and intraventricular spaces is a potent factor in determining mortality.2, 19
This relationship has been consistent in multiple cohorts of patients.6, 12, 20
The safety data presented here represent the first prospective effort to define the safety of a minimally invasive approach to removing clot using intraventricular low dose thrombolytics. This trial provides additional data regarding the amount and timing of blood clot removal produced by low dose rt-PA or EVD alone.
The mortality rate in both treatment groups was substantially lower than prior reports,1, 21, 22
despite the selection of a severely-impaired group of patients with a high likelihood of mortality based on their presenting GCS, ICH size, IVH size, and blood pressure.2
These severity factors were equally distributed across treatment groups and a mortality difference between the groups was not demonstrated. Case series data have suggested that extraventricular drainage controls ICP elevation, but does not alter mortality.21
This study confirms prospectively Adams’ finding that extraventricular drainage can produce controlled ICP.
Several factors could account for the substantial difference between our mortality and earlier reports.1, 21
Possible factors include good ICU care and regular patient monitoring (the Hawthorne effect). Furthermore, all patients selected for the study had an EVD in place and one goal of the study was to maintain catheter patency and to continue extraventricular drainage until acute obstructive hydrocephalus was relieved and normal CSF circulation reestablished. Possibly this practice alone is associated with improved mortality. Specifically, these clinical goals were achieved in all study survivors. Both groups also achieved marked reduction of clot size over the initial treatment phase and initial 30 days, with rt-PA treated group achieving a radiologic reduction of approximately 60% over 4 days and the placebo group the same reduction over 8 days as demonstrated by the clot reduction model. An association of improved mortality with clot reduction is consistent with animal models23–25
as well as prior observations in which attempts at blood clot removal were either not made21
Differences in patient severity between the Adams and Coplin series and ours do not appear to explain the enhanced survival we demonstrated. However, withdrawal of life sustaining therapies was more frequent in the those cohorts.26
Other cohorts have larger ICHs and smaller IVHs, thus they represent different subgroups of the overall ICH population.12, 27
Lower absolute mortality and the absence of any unfavorable comparison to either the concurrent placebo group or historical controls suggest that low dose thrombolytic therapy can be performed safely in a severely impaired group of deep ICH patients with massive intraventricular hemorrhage. Careful attention to ICP control and IVC catheter antisepsis was associated with a low frequency of ICP elevation and catheter related infections. However, a consistent trend toward increased frequency of bleeding events was noted in the rt-PA treated group. Secondary bleeding events over the 30-day study period included rebleeding at the primary site, rebleeding at secondary sites (predominantly in the catheter tract), and several instances of IVH extension. Because clinical clot stability was required prior to administration of the thrombolytic, these findings could represent evidence of ongoing drug-related susceptibility to bleeding.
Given the finding of significantly enhanced clot lysis and a strong trend towards increased secondary bleeding events, caution with respect to the overall safety of low dose rt-PA in the treatment of ICH needs to be expressed. Multiple factors, including blood pressure, coagulation state, ethnicity, diabetes mellitus, and concurrent medications such as aspirin, BP-elevating drugs and/or illicit drugs, have all been implicated as risk factors for bleeding. Data on the management of these factors and their interactions with low dose rt-PA is absent; our study is not informative as the bleeding event rate is too low to draw conclusions about these factors. Additionally, data demonstrating a dose response relationship between rt-PA and bleeding events or clot lysis rate is absent. A dose finding study is necessary to investigate whether lower doses of rt-PA may be associated with a high degree of clot lysis but provide a substantially better safety margin with respect to rebleeding.
Two methodologically robust studies of clot removal have demonstrated baseline clot lysis rates from 6 to 12% per day.6, 16
The 8 ± 2% per day intraventricular clot lysis rate in our placebo group is consistent with these prior observations and the latest estimate from this study is strengthened by the greater frequency of clot volume measurements used. Thus, we conclude that the enhanced clot lysis rate observed for the rt-PA treated patients is a robust effect, however, it is not as great or as effective as the effects demonstrated in animal models where clot removal produced decreased edema and prevented subependymal inflammation.4, 5, 28
Despite this, several other findings from the animal models were demonstrated in this human study: decreased mortality from herniation and ICP events24
and an enhanced or more rapid recovery of impaired consciousness.3
More rapid removal of clot could be translated into a shorter ICU stay, if the EVDs are removed earlier.
This study was neither designed nor powered to assess functional outcome. Others have suggested that ICH patient functional outcome is best assessed at longer time intervals after the initial event.29, 30
This suggestion is consistent with our data which demonstrated high degrees of impaired consciousness at presentation and initial therapeutic periods, with recovery of consciousness occurring slowly over the 30 day study period. The ability of patients to return to prior independent lifestyles could not be properly assessed over this time frame. However, the study demonstrates that some individuals (3 subjects) were capable of returning to their premorbid functional status within 30 days after severe IVH. Therefore, it seems likely that future studies, including the current CLEAR III (Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage Phase III) Trial, will need to assess functional performance in the 90 to 180-day time frame or as far out as 365 days. The location of ICH as well as extent of ICH should significantly influence functional outcome. The selection criteria for this study controlled for lesion location and ICH volume. Therefore, these factors will require further study and evaluation, if patient selection is to be optimized. The presence of increased brain tissue injury with prolonged blood clot exposure in animal models and humans31, 32
suggests a strong logical rationale for improving the timing and efficiency of blood clot removal in these patient groups. To date, a treatment modality to do this does not exist in the clinical arena. Multiple daily doses of rt-PA could provide the desired intervention capable of rapidly removing blood from tissue contact.
This study demonstrates that low dose rt-PA has an acceptable safety profile compared to placebo and prior historical controls of the natural history of ICH with IVH. While 3 mg of rt-PA irrigation every 12 hours clearly accelerates clot removal from the ventricular system neither dose safety nor dose efficacy was fully explored for this approach. Data from a well-designed Phase III clinical trial, such as CLEAR III, will be needed if this treatment is to be fully evaluated.