Intraventricular hemorrhage is a commonly seen neurological emergency in 40% of patients with ICH and 50% of patients with subarachnoid hemorrhage (SAH) [36, 37]. Studies have shown that IVH is a poor independent prognostic factor for both types of hemorrhagic stroke [38]. The mortality rate of IVH complicating ICH is as high as 50%, with the volume of intraventricular blood being proportional to the risk of this outcome [37, 34]. Even among survivors of IVH, only 20% of patients were observed to have good functional outcomes [37].
The detrimental effects of IVH can be broadly classified into two causes: A) primary brain insult due to intracranial hypertension, either as a result of the hematoma volume per se or obstructive hydrocephalus; and B) secondary insult due to hematoma-induced cytotoxicity, oxidative stress, and neuroinflammation.
Both immediate and delayed hydrocephalus can occur as a consequence of IVH. The commonest immediate life-threatening cause is acute obstructive hydrocephalus from the blockage of normal CSF flow within the ventricular system. Studies also demonstrated that both the initial total hematoma volume and the duration of intraventricular hematoma presence before its dissolution were independent determinants of communicating hydrocephalus after the acute obstructive phase [39]. The CLEAR III trial showed that 44% of patients required permanent CSF shunting when ICP exceeded 30 mmHg [34]. In a population-based study, shunting was indicated in 18% of IVH patients, and shunt-dependence was identified as an independent predictor for long-term morbidity [40, 41].
Secondary brain injury due to IVH can occur due to disruption of the blood-CSF barrier, neuroinflammation, or cytotoxicity arising from blood components. Swine model studies have shown that obstructive hydrocephalus resulted in hypoperfusion changes of periventricular structures that persisted beyond hematoma resolution [42]. The ependymal surface, the thin single-layer epithelioid glial membrane that lines the ventricular system, are often damaged during IVH [42]. This results in dysregulation of the normal transfer of extracellular fluid, ions, and small molecules between the brain parenchyma and CSF [43, 44]. Iron, a degradation product of hemoglobin, is cytotoxic and can exacerbate oxidative injury [45, 46]. Normally, ependymal cells prevent excess iron deposition in the brain, but with their disruption following IVH, its accumulation can cause persistent hydrocephalus [47]. Inflammation, mediated by transforming growth factors (TGF-β1 and TGF-β2), has also been observed to cause obliterative arachnoiditis or dysfunction of the arachnoid granulations resulting in post-hemorrhagic communicating hydrocephalus [48, 49]. In animal studies, intraventricular injection of lysed red blood cells and iron led to a significant increase in ventricular volume and elevated CSF inflammatory markers [50]. These findings were supported by another study where aseptic CSF inflammation was detected in post-IVH brain tissue [44]. Intraventricular blood volumes were also positively correlated with more extensive neuroinflammatory responses reflected by elevated CSF white blood cell (WBC) counts [44].
Despite greater understanding of the multiple pathophysiological sequelae of IVH-induced secondary brain injury, current clinical management remains directed at ICP control. For patients with obstructive hydrocephalus, EVD functions both as therapeutic relief of intracranial hypertension and pressure monitoring. The efficacy of EVD for selected patients with IVH is widely accepted. The CLEAR III trial observed a proportional increase in mortality and poorer functional outcomes for every milliliter of clot remaining in the ventricular system, with 80% clot clearance being the determining threshold for improved outcomes [34]. However, drainage alone does not effectively assist clot dissolution. The mechanism of intraventricular blood clot lysis, similar to elsewhere in the body, is highly dependent on circulatory fibrinolytic activity. Unlike in the systemic vasculature, normal CSF does not contain fibrinolytic enzymes. Studies revealed that plasminogen and tissue plasminogen activator enzyme systems in IVH become saturated by 24–48 hours, and after that, further clot dissolution reaches a steady constant rate [51, 52]. This could explain why clot clearance with EVD alone is often frequently slow, lasting several days to weeks. In addition, ventricular catheter blockage by blood clots or by the choroid plexus often necessitates flushing or even repeated catheter revisions. The number of drainage system manipulations and duration of EVD are risk factors for bacterial ventriculitis and catheter-associated intraparenchymal tract hematomas [53].
The intraventricular administration of fibrinolytic agents through the ventricular catheter was introduced to facilitate clot dissolution and drainage in the 1990s [22]. Not only were catheter obstruction rates significantly reduced, but the duration required for clot clearance was also considerably shortened compared to EVD alone [38]. Meta-analyses showed that intraventricular fibrinolysis reduced IVH mortality by half and improved patient functional outcomes [54, 37, 55]. A recent systemic review also demonstrated a reduction in shunt dependence in patients that received such treatment [54].
Preclinical studies have observed that intraventricular rtPA could be neuro-toxic and pro-inflammatory [56–58]. A randomized-controlled trial noted that CSF cytokine concentrations, particularly tumor necrosis factor-α, interferon-γ, interleukin (IL)-1, IL-4, IL-6, and WBC counts were significantly elevated compared to placebo-treated patients [59]. There is also the theoretical risk of inducing further IVH with fibrinolytic agent instillation, although this has not been confirmed with RCTs [34]. Therefore, the duration and dosage of such drugs should be carefully titrated to balance clot lysis effects against its potential adverse effects.
Current intraventricular fibrinolytic agent administration involves temporarily clamping the catheter to permit CSF flow stasis after their introduction. As the blood clot is a crosslinked solid with micropores, drug permeation is primarily driven by a concentration gradient in a closed system. However, the rate and effectiveness of drug diffusion are difficult to monitor and studies demonstrated that merely increasing dosages did not shorten clot dissolution times [25, 26].
To increase clot dissolution, a prototype flow- and pressure- gradient actuated system with uPA was designed to accelerate drug permeation into the micropores of the clot. In this proof-of-concept study, we observed that this recirculatory fibrinolytic drug-assisted EVD system shortened clot clearance durations and required significantly lower overall uPA dosages. No catheter occlusions were observed during the treatment process. These findings may have clinical implications including reducing in-dwelling catheter durations along with its attendant related complications, decreasing the risk of neurotoxic blood degradation product exposure, and the minimizing the need for CSF shunting. The potential benefits of this novel system could translate to shortened hospitalization durations and improved functional outcomes.
Endoscopic-assisted microsurgical evacuation is an emerging technique for intraventricular clot removal. Clinical trials revealed higher clot removal rate, fewer complications, and better postoperative outcomes [60–62]. However, the operative time is significantly longer than EVD catheter placement. There is a steeper skill learning curve to attain procedure proficiency and often an experienced assistant is required to hold the neuro-endoscope. With such direct instrumental intraventricular clot manipulation close attention must be paid to avoid foramen, thalamic and thalamostriate vein injury that could result in catastrophic neurological consequences. Clots, especially during the acute phase, may be highly adherent to the ventricular wall unamenable to simple suction. The narrow working field of vision of a rigid neuro-endoscope’s working channel also limits its capability to reach deep intraventricular locations, in particular the fourth ventricle. For these reasons, endoscopic-assisted microsurgical clot evacuations of IVH are not commonly performed and the efficacy and safety of this technique compared to EVD requires further investigation [63, 61, 64]. In view of these facts, it is believed that this novel recirculatory fibrinolytic drug assisted EVD system addresses the drawbacks of both these clot evacuation therapies.
There are several limitations to this study. First, the rate of clot dissolution is multifactorial. Apart from IVH volume, clearance is also affected by the clot's anatomical location and the relative position of the catheter. IVH within the third ventricle and the frontal horns of the lateral ventricles were subject to more pronounced hematoma thrombolysis than elsewhere [65]. The morphology of the experimental receptacle containing the clot in our experiment was not a patient-driven anatomical replica of the ventricular system. Clinical studies showed that catheter placement on the side predominantly involved by IVH resulted in more rapid clot clearance [66]. Future studies investigating an active recirculatory drainage system of this nature should adopt a stereolithographic model of the ventricular system. Inter-individual variations in baseline serum plasminogen and platelet count levels influenced IVH resolution durations [52]. These factors were not controlled in the blood samples collected from healthy individuals in our study. Our model also did not consider ICP elevations that would require emergent relieving measures. Therefore, maintaining a closed EVD system without disruption of the thrombolytic fluid flow gradient is a design challenge that needs to be overcome before it can be clinically applicable. Finally, the possibility of rebleeding, natural history complications commonly encountered in clinical practice, could not be studied in our ex-vivo experimental model.
To conclude, this novel recirculatory fibrinolytic agent assisted EVD system demonstrated rapid hematoma clearance at significantly lower doses. A window of optimal flow and uPA dosage rates was determined in this study. Further, in vivo animal studies are required to address the model's limitations and to realize the potential clinical benefits for this novel IVH therapy.