Response to Letter by Gaberel et al Regarding Article, “Dose Effect of Intraventricular Fibrinolysis in Ventricular Hemorrhage”
We greatly appreciate the comments by Gaberel et al considering our recently published study dealing with the dose effect of intraventricular fibrinolysis (IVF) in severe ventricular hemorrhage (IVH).1 The authors report an interesting finding from their meta-analysis of studies on IVF in patients with intracerebral hemorrhage and ventricular involvement treated with different fibrinolytic agents (tissue plasminogen activator [tPA] or urokinase). Although IVF with urokinase seemed to be beneficial considering both mortality and functional outcome, such effects could not be shown for IVF with tPA. Based on our findings showing no differences in outcome when comparing higher and lower tPA dose IVF, Gaberel et al raised the hypotheses that either intraventricular tPA is not neurotoxic when used for IVF and does not affect outcome substantially or it exerts similar neurotoxicity at lower doses as compared with higher doses leading to a similar impact on outcome.
Indeed, the neurotoxic effects of tPA are understudied in the context of IVF and intracerebral hemorrhage. Experimental evidence suggests a dose-dependent proinflammatory and proedematous effect of intraventricular tPA in a rat IVH model2 and a recent small retrospective study describes increased perihemorrhagic edema in patients with intracerebral hemorrhage and IVH treated with intraventricular tPA, although its clinical impact remains unclear.3 On the other hand, the majority of clinical studies investigating IVF with tPA in patients with intracerebral hemorrhage and IVH report lower mortality and better functional outcomes in treated patients as compared with historical collectives or literature data4; the same applies to our recent study. The available evidence certainly does not allow the recommendation of IVF for clinical routine; however, optimism still predominates, and the results of the ongoing Phase III clinical trial Clot Lysis Evaluating Accelerated Resolution of Intraventricular Hemorrhage (CLEAR-IVH; www.cleariii.com), which uses tPA, are eagerly expected.
Many open questions regarding IVF may, however, still remain unresolved, even after CLEAR-IVH will have been completed. One of those questions certainly concerns the fibrinolytic agent with the best side effects profile. At this time, it is rather unclear if we should fear the potential neurotoxicity of tPA in the setting of IVF or if mechanisms of tPA-mediated neuronal damage, as described in ischemic injury, play an important role in intracerebral hemorrhage with ventricular involvement. Because there is evidence that the proinflammatory effects of tPA in IVF are at least partially plasmin-mediated or may be additionally augmented by blood breakdown products after fibrinolysis,2 such negative effects should be also expected when other fibrinolytics such as urokinase or desmoteplase are administered. Considering the relatively low doses of tPA used for IVF, blood breakdown products, released in higher concentrations after IVF, may be more harmful to the surrounding brain tissue than the fibrinolytic agent itself. In this context, faster and more effective drainage of IVH after lysis may be crucial to attenuate inflammatory damage. Those aspects should be considered in future research. Furthermore, dose-dependent effects may still play a role and deserve further investigation despite our findings regarding mortality and outcome. The sample size and the design of our study do not allow a definite conclusion on this issue. The same criticism can be applied to the functional outcome analysis presented by Gaberel et al in their letter. Comparisons between IVF with tPA and urokinase in terms of mortality and outcome should be interpreted with caution with regard to the data used for this analysis; however, the hypotheses uttered by the authors may certainly serve as promoters for further research.
Dimitre Staykov, MD
Department of Neurology
University of Erlangen-Nuremberg
Juergen Bardutzky, MD
Department of Neurology
University of Freiburg
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