Intraventricular tissue plasminogen activator [Neurosurgery Wiki]

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====== Intraventricular tissue plasminogen activator ======

{{ ::intraventricular_thrombolysis.jpg?250|}}

{{rss>https://pubmed.ncbi.nlm.nih.gov/rss/search/1RGmO3jHeXUp8p4QWrHTNISJyMfkTLcwG7vA14RUAxIoo6s1Gj/?limit=15&utm_campaign=pubmed-2&fc=20230117110442}}

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[[Intraventricular tissue plasminogen activator]] may help lyse clot and maintain intra[[ventricular catheter]] (IVC) patency or reopen a clotted IVC. However, the [[CLEAR III clinical trial]]
((Hanley DF, Lane K, McBee N, et al. Thrombolytic removal of intraventricular haemorrhage in treat- ment of severe stroke: results of the randomised, multicentre, multiregion, placebo-controlled CLEAR III trial. Lancet. 2017; 389:603–611))
showed no benefit of using 1 mg tPA vs. saline for the primary endpoint of [[mRS]] score ≤3 at 6 mos for patients with <30 ml clot (lower mortality at 6 mos was offset by a larger number of survivors with mRS = 5).

✖ In cases of a suspected aneurysm, AVM, or other vascular malformation, it cannot be used until the source of bleeding has been neutralized
((Findlay JM, Grace MGA, Weir BKA. Treatment of Intraventricular Hemorrhage with Tissue Plasminogen Activator. Neurosurgery. 1993; 32: 941–947))
((Engelhard HH, Andrews CO, Slavin KV, et al. Current management of intraventricular hemor- rhage. Surg Neurol. 2003; 60:15–21; discussion 21-2)).

℞: 2–5 mg of tPA
((Findlay JM, Grace MGA, Weir BKA. Treatment of Intraventricular Hemorrhage with Tissue Plasminogen Activator. Neurosurgery. 1993; 32: 941–947))
((Grabb PA. Traumatic intraventricular hemorrhage treated with intraventricular recombinant-tissue plasminogen activator: technical case report. Neurosurgery. 1998; 43:966–969))
((Rohde V, Schaller C, Hassler WE. Intraventricular recombinant tissue plasminogen activator for lysis of intraventricular hemorrhage. J Neurol Neurosurg Psychiatry. 1995; 58:447–451))
in NS is administered through an intraventricular catheter (IVC) every 8 hours for up to 4 days. The IVC is closed for 2 hours after injection
((Rohde V, Schaller C, Hassler WE. Intraventricular recombinant tissue plasminogen activator for lysis of intraventricular hemorrhage. J Neurol Neurosurg Psychiatry. 1995; 58:447–451)).

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In the low dose CLEAR-IVH (Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage) trial (a phase II trial with 52 patients), 1 mg tPA intrathecally via a ventricular catheter every 8 hours up to a maximum of 4 days, was associated with a 30 d mortality of 15% (compared to an expected 80–85%)
((CLEAR result: low-dose tPA safe, effective in treating intraventricular hemorrhage. Nice, France 2008))
The hemorrhagic complication rate was 6%. 

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Luong et al. evaluated the impact of IVF on the risk of [[death]] and the [[functional outcome]]s in IVH patients with AOH.

This prospective [[cohort study]] included IVH patients with hypertensive [[intracranial hemorrhage]] complicated by AOH who required EVD. Luong et al. evaluated the risk of death and the functional outcomes at 1 and 3 months, with a specific focus on the impact of combined EVD with IVF by low-dose rtPA.

Between November 30, 2011 and December 30, 2014, 80 patients were included. Forty-five patients were treated with EVD alone (EVD group) and 35 received IVF (EVD+IVF group). The 30- and 90-day mortality rates were lower in the EVD+IVF group than in the EVD group (42.2 vs. 11.4%, p = 0.003, and 62.2 vs. 20%, p < 0.001, respectively). The Graeb scores were significantly lower in the EVD+IVF group than in the EVD group (p ≤ 0.001) during the first 3 days and on day 7 after assignment. The 30-day good functional outcome (modified Rankin Scale [mRS] score 0-3) was also higher in the EVD+IVF group than in the EVD group (6.7 vs. 28.6%, p = 0.008). However, the 90-day good functional outcome (mRS score 0-3) did not significantly increase in the EVD+IVF group (30.8% in the EVD group vs. 51.6% in the EVD+IVF group, p = 0.112).

In this prospective observational study, EVD+IVF was associated with a lower risk of death in IVH patients. EVD+IVF improved the chance of having a good functional outcome at 1 month; however, this result was no longer observed at 3 months
((Luong CQ, Nguyen AD, Nguyen CV, Mai TD, Nguyen TA, Do SN, Dao PV, Pham HTM,
Pham DT, Ngo HM, Nguyen QH, Nguyen DT, Tran TH, Le KV, Do NT, Ngo ND, Nguyen VD, 
Ngo HD, Hoang HB, Vu HV, Vu LT, Ngo BT, Nguyen BX, Khuong DQ, Nguyen DT, Vuong
TX, Be TH, Gaberel T, Nguyen LV. Effectiveness of Combined External Ventricular
Drainage with Intraventricular Fibrinolysis for the Treatment of Intraventricular
Haemorrhage with Acute Obstructive Hydrocephalus. Cerebrovasc Dis Extra. 2019 Aug
13;9(2):77-89. doi: 10.1159/000501530. [Epub ahead of print] PubMed PMID:
31408859.
)).
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[[Adult patient]]s with [[primary diagnosis]] of [[nontraumatic intracerebral hemorrhage]] requiring [[ventriculostomy]] from the [[Nationwide Inpatient Sample]] from 2002 to 2011, compared [[demographics]] and [[hospital]] characteristics, [[comorbidity]], [[inpatient]] [[outcome]]s, and [[resource utilization]] [[measure]]s between [[patient]]s treated with IVT and those managed with ventriculostomy, but without IVT. Population estimates were extrapolated using standard Nationwide Inpatient Sample weighting algorithms.

34044 patients in the analysis, of whom 1133 (3.3%) received IVT. The thrombolysis group had significantly lower inpatient mortality (32.4% versus 41.6%; P=0.001) and it remained lower after controlling for [[baseline characteristics]], hospital characteristics, comorbidity, case severity, and withdrawal of care status (adjusted odds ratio, 0.670; 95% confidence interval, 0.520-0.865; P=0.002). There was a trend toward favorable discharge (home or rehabilitation) among the thrombolysis cohort (adjusted odds ratio, 1.335; 95% confidence interval, 0.983-1.812; P=0.064). The adjusted rates of [[bacterial meningitis]] and ventricular [[shunt]] placement were similar between groups. The thrombolysis group had longer [[length of stay]] and higher inflation-adjusted cost of care, but cost of care per day length of stay was similar to the non-IVT group.

IVT for intracerebral hemorrhage requiring ventriculostomy resulted in lower inpatient mortality and a trend toward favorable discharge outcome with similar rates of inpatient complications compared with the non-IVT group
((Moradiya Y, Murthy SB, Newman-Toker DE, Hanley DF, Ziai WC. Intraventricular
thrombolysis in intracerebral hemorrhage requiring ventriculostomy: a decade-long
real-world experience. Stroke. 2014 Sep;45(9):2629-35. doi:
10.1161/STROKEAHA.114.006067. Epub 2014 Jul 24. PubMed PMID: 25061080.)).
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[[Urokinase]] (uPA) and [[tissue plasminogen activator]] (tPA) are used for IVF in Human. No [[clinical trial]] has evaluated the differential impact of these two fibrinolytics for IVF. 

Although both uPA and tPA led to reduced ventricular volumes, only uPA significantly improved functional recovery. These results could be explained by the fact that uPA, in contrast of tPA, fails to promote inflammatory processes and neurotoxicity
((Gaberel T, Montagne A, Lesept F, Gauberti M, Lemarchand E, Orset C, Goulay R, 
Bertrand T, Emery E, Vivien D. Urokinase versus Alteplase for intraventricular
hemorrhage fibrinolysis. Neuropharmacology. 2014 May 15;85C:158-165. doi:
10.1016/j.neuropharm.2014.05.001. [Epub ahead of print] PubMed PMID: 24846802.)).

Intraventricular fibrinolysis (IVF) in subarachnoid hemorrhage (SAH) is an emerging strategy aiming to hasten [[clot lysis]], treat hydrocephalus, and reduce permanent shunt rates. Because of clinical heterogeneity of investigated patient effects of IVF on permanent shunt incidence and functional outcome are widely debated. The present study is the first to investigate solely endovascular-treated SAH patients.

88 consecutive patients with aneurysmal SAH requiring external ventricular drain placement and endovascular aneurysm closure were included. Functional outcome and [[shunt dependency]] were assessed 90 days after event. A matched controlled sub-analysis was carried out to investigate the effects of IVF treatment (n = 14; matching criteria: age, neuro-status and imaging). Multivariate modeling was performed to identify independent predictors for permanent shunt dependency.

In IVF-patients neurological status was significantly poorer [Hunt&Hess: IVF = 4(3-5) vs. non-IVF = 3(1-5); p = 0.035] and the extent of ventricular hemorrhage was increased [Graeb Score: IVF = 7(6-8) vs. non-IVF = 3(1-4); p ≤ 0.001]. Consecutive matched controlled sub-analysis revealed no significant therapeutic effect of IVF with respect to shunt dependency rate and functional outcome. Multivariate analysis revealed Graeb score [OR = 1.34(1.02-1.76); p = 0.035] and sepsis [OR = 11.23(2.28-55.27); p = 0.003] as independent predictors for shunt dependency, whereas IVF did not exert significant effects (p = 0.820).

In endovascular-treated SAH patients IVF neither reduced permanent shunt dependency nor influenced functional outcome. Despite established effects on intraventricular clot resolution IVF appears less powerful in SAH as compared to ICH. Given the reported positive effects of lumbar drainage (LD) in SAH, a prospective analysis of a combined treatment approach of IVF and subsequent lumbar drain seems warranted aiming to reduce permanent shunting and improve functional outcome
((Gerner ST, Kuramatsu JB, Abel H, Kloska SP, Lücking H, Eyüpoglu IY, Doerfler
A, Schwab S, Huttner HB. Intraventricular fibrinolysis has no effects on shunt
dependency and functional outcome in endovascular-treated aneurysmal SAH.
Neurocrit Care. 2014 Dec;21(3):435-43. doi: 10.1007/s12028-014-9961-3. PubMed
PMID: 24566979.
)).

===== Case reports =====
A 15-year-old male patient presented after a motor vehicle accident with bilateral extensor posturing, intracerebral and IVH, and acute obstructive hydrocephalus.

A right EVD was placed and functioned only transiently. A left EVD was placed and functioned only transiently. Because of the inability to maintain ventricular drainage, rising intracranial pressure, and worsening clinical status, 5 mg of recombinant-tissue plasminogen activator was injected through each EVD. Excellent EVD function was obtained quickly, with control of intracranial pressure and improvement in clinical status and without hemorrhagic complication.

With obstructive hydrocephalus secondary to acute traumatic IVH that cannot be controlled with EVD because of recurrent obstruction from intraventricular blood, intraventricular recombinant-tissue plasminogen activator can be effective and safe, despite preexisting multiple hemorrhagic intracranial injuries
((Grabb PA. Traumatic intraventricular hemorrhage treated with intraventricular 
recombinant-tissue plasminogen activator: technical case report. Neurosurgery.
1998 Oct;43(4):966-9. PubMed PMID: 9766330.
)).

===== References =====