Intraarterial recombinant human tissue plasminogen activator for ischemic stroke treatment
Indications
Contraindications to intervention
Most contraindications are relative and have to be weighed against the risk of not intervening. These contraindications include:
● Hemorrhagic infarct or,ICH
● CT demonstrating hypodensity or mass effect consistent with evolving infarct of more than one-third of middle cerebral artery territory
● Recent major surgery
● Pregnancy
● When considering stenting, contraindication to anticoagulants and/or thrombolytics
Preprocedural management
This may be under the supervision of a stroke neurologist, or the neurosurgeon. Ensure the following:
● Rapid transfer of patient to a stroke center/facility with endovascular capabilities.
● ABC’s take precedence.
● Ensure patient has two intravenous lines, preferably 18G or larger. Start monitoring BP, pulse oximetry, ECG, O2 saturation, heart rate and rhythm, respiratory rate. Insert a Foley catheter.
● Verify laboratory values including Platelet count, BUN, CR, APTT, PT/INR. ß-HCG for females of reproductive age group.
● Maintain MAP ≥ 90mmHg.
● CT scan head: To rule out ICH.
● CTA: To assess location of the clot (hyperdense artery sign and vascular tortuosity.
● MRI head (select cases).
● If available and can be done without delay, then perfusion studies e.g., CTP or MRP. These perfusion studies will demonstrate viable brain (penumbra) vs completed stroke.
● In centers where available, CT, CTA and CTP all a reperformed during the same session on CT scanner.
● Be cognizant of renal insufficiency, diabetes, congestive heart failure etc., in which case consider diluted non-ionic contrast agent and carefully pre-plan, to maintain contrast load to minimum.
● If the patient is not responding to IV tPA or it if is contraindicated, then endovascular intervention is considered.
● The goal of intervention is to re-establish circulation, as soon as possible.
Various endovascular intraarterial approaches are available for treating patients with acute ischemic stroke who present with severe neurological deficits. Three randomized trials-Interventional Management of Stroke (IMS) III, Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy (MR RESCUE), and Synthesis Expansion: A Randomized Controlled Trial on Intra-Arterial Versus Intravenous Thrombolysis in Acute Ischemic Stroke (SYNTHESIS Expansion)-evaluated the efficacy of endovascular treatment of acute ischemic stroke and, after failing to demonstrate any significant clinical benefit of endovascular therapies, raised concerns and questions in the medical community regarding the future of endovascular treatment for acute ischemic stroke 1).
Patients who have perfusion/diffusion (P/D) mismatching and are treated with intraarterial thrombolysis have higher recanalization rates and a greater probability of a favorable outcome than patients who have P/D matching and receive intraarterial thrombolysis. For patients who do not undergo successful recanalization after IV-tPA or who are not indicated for IV-tPA, Won et al. recommend intraarterial thrombolysis after undergoing appropriate imaging evaluation 2).
145 retrieval trials performed for 37 patients (69.5±14.0 years, 20 men, large artery atherosclerosis, n = 7; cardioembolism, n = 22; undetermined etiology, n = 8) who had undergone intra-arterial thrombectomy. Rates of clot retrieval and successful recanalization (Arterial Occlusive Lesion score of 2-3) for separate retrieval trials were evaluated. The area occupied by red blood cell (RBC), fibrin/platelets, and white blood cell (WBC) was measured from digitized images of hematoxylin-eosin stained clots. Compositional differences were compared according to recanalization success, stroke subtype, and the presence of hyperdense clot sign on initial computed tomography and/or blooming artifact on magnetic resonance image. Of the 145 total retrieval trials (3.4±2.4 times per patient), clot was retrieved in 93 trials (64%), while recanalization was successful in 73 (50%). Fibrin/platelets (63%) occupied the greatest area in retrieved clots, followed by RBCs (33%) and WBCs (4%). Clots retrieved from successful recanalization exhibited higher RBC composition (37%) than those retrieved from non-recanalization trials (20%, p = 0.001). RBC composition was higher in cardioembolic stroke (38%) rather than large artery atherosclerosis (23%) and undetermined etiology (26%, p = 0.01). Clots exhibiting clot signs (40%) had higher RBC composition than those without clot signs (19%, p = 0.001). RBC-rich clots were associated with successful recanalization of intra-arterial thrombectomy, cardioembolic stroke, and the presence of clot-signs on initial brain images 3).
Intraarterial recombinant human tissue plasminogen activator is the only proven and effective acute ischemic stroke treatment; however, therapeutic hypothermia is increasingly recognized as having a tissue-protective function and positively influencing neurological outcome, especially in cases of ischemia caused by cardiac arrest or hypoxic-ischemic encephalopathy in newborns. Yet, many aspects of hypothermia as a treatment for ischemic stroke remain unknown. Large-scale studies examining the effects of hypothermia on stroke are currently underway 4).
Studies suggest that the risk of recurrent ischemia is lower if carotid revascularization is performed early after the index event. The safety of early carotid revascularization in this patient population is unclear. OBJECTIVE: To evaluate the safety of carotid revascularization in patients who received thrombolysis for acute ischemic stroke. METHODS: The Nationwide Inpatient Sample database was queried for patients admitted through the emergency room with a primary diagnosis of carotid stenosis and/or occlusion. Each patient was reviewed for administration of thrombolysis, carotid endarterectomy, (CEA) or carotid angioplasty and stenting (CAS). Primary endpoints were intracerebral hemorrhage (ICH), postprocedural stroke (PPS), poor outcome, and in-hospital mortality. Potential risk factors were examined using univariate and multivariate analyses. RESULTS: A total of 310 257 patients were analyzed. Patients who received tissue plasminogen activator (tPA) and underwent either CEA or CAS had a significantly higher risk of developing an ICH or PPS than patients who underwent either CEA or CAS without tPA administration. The increased risk of ICH or PPS in tPA-treated patients who underwent carotid revascularization diminished with time, and became similar to patients who underwent carotid revascularization without tPA administration by 7 d after thrombolysis. Patients who received tPA and underwent CEA or CAS also had higher odds of poor outcome and in-hospital mortality. CONCLUSION: Thrombolysis is a strong risk factor for ICH, PPS, poor outcome, and in-hospital mortality in patients with carotid stenosis/occlusion who undergo carotid revascularization. The increased risk of ICH or PPS due to tPA declines with time after thrombolysis. Delaying carotid revascularization in these patients may therefore be appropriate. This delay, however, will expose these patients to the risk of recurrent stroke. Future studies are needed to determine the relative risks of these 2 adverse events 5).
Complications
Intracerebral hemorrhage risk is increased with higher doses than the recommended 100 mg of alteplase (Activase®, recombinant tissue plasminogen activator (rt-PA)) 6) in older patients, in those with anterior MI or higher Killip class, and with bolus administration (vs. infusion) 7).
When heparin was used adjunctively, higher doses were associated with a higher risk of ICH 8) ICH is thought to occur in those patients with some preexisting underlying vascular abnormality 9). Immediate coronary angioplasty is safer than rt-PA when available 10). Intracerebral hemorrhage (ICH) remains a serious complication in ischemic stroke patients undergoing systemic thrombolysis.
see Intraventricular thrombolysis
Mechanical thrombectomy (MT) devices have led to improved reperfusion and clinical outcomes in acute ischemic stroke patients with emergent large vessel occlusions; however, less than one-third of patients achieve complete reperfusion. Use of intraarterial thrombolysis in the context of MT may provide an opportunity to enhance these results.
Zaidi et al., evaluated the use of intraarterial rtPA (recombinant tissue-type plasminogen activator) as rescue therapy (RT) after failed MT in the North American Solitaire Stent-Retriever Acute Stroke registry.
The North American Solitaire Stent-Retriever Acute Stroke registry recruited sites within North America to submit data on acute ischemic stroke patients treated with the Solitaire device. After restricting the population of 354 patients to use of RT and anterior emergent large vessel occlusions, we compared patients who were treated with and without intraarterial rtPA after failed MT.
A total of 37 and 44 patients was in the intraarterial rtPA RT and the no intraarterial rtPA RT groups, respectively. Revascularization success (modified Thrombolysis in Cerebral Infarction ≥2b) was achieved in more intraarterial rtPA RT patients (61.2% versus 46.6%; P=0.13) with faster times to recanalization (100±85 versus 164±235 minutes; P=0.36) but was not statistically significant. The rate of symptomatic intracranial hemorrhage (13.9% versus 6.8%; P=0.29) and mortality (42.9% versus 44.7%; P=0.87) were similar between the groups. Good functional outcome (modified Rankin Scale score of ≤2) was numerically higher in intraarterial rtPA patients (22.9% versus 18.4%; P=0.64). Further restriction of the RT population to M1 occlusions only and time of onset to groin puncture ≤8 hours, resulted in significantly higher successful revascularization rates in the intraarterial rtPA RT cohort (77.8% versus 38.9%; P=0.02).
Intraarterial rtPA as RT demonstrated a similar safety and clinical outcome profile, with higher reperfusion rates achieved in patients with M1 occlusions. Prospective studies are needed to delineate the role of intraarterial thrombolysis in MT 11).
Intraarterial recombinant human tissue plasminogen activator for ischemic stroke treatment may be the simplest endovascular technique to undertake, when compared to Stent retriever or Penumbra aspiration. However, on its own, while the recanalization rates may be better than IV tPA, they are inferior to o Stent retriever or Penumbra aspiration 12) 13).
Currently,i.a.tPA is used in conjunction with other techniques in ischemic stroke.
Bed rest
Case reports
Three female patients, aged 77, 89, and 92 years, with arterial emboli in their limbs that developed before and after recombinant tissue plasminogen activator (rt-PA) treatment for cerebral infarction. Arterial embolism in one limb developed in two patients before rt-PA treatment and in one during rt-PA treatment at the time of the first medical examination. Thrombectomy was performed in two patients. In all patients, the arterial emboli of the extremities were accompanied by acute cardiogenic cerebral emboli. Patients with cardiogenic cerebral emboli can also develop emboli in the extremities. Particularly, during rt-PA treatment of cerebral infarction, the presence of other possible thromboembolisms, in addition to hemorrhagic complications and changes in neurological symptoms, should be examined 14).