Cerebral Ischemic Reperfusion Injury Following Recanalization of Large Vessel Occlusions

Cerebral Ischemic Reperfusion Injury Following Recanalization of Large Vessel Occlusions Abstract Although stroke has recently dropped to become the nation's fifth leading cause of mortality, it remains the top leading cause of morbidity and disability in the US. Recent advances in stroke treatment, including intravenous fibrinolysis and mechanical thromboembolectomy, allow treatment of a greater proportion of stroke patients than ever before. While intra-arterial fibrinolysis with recombinant tissue plasminogen is an effective for treatment of a broad range of acute ischemic strokes, endovascular mechanical thromboembolectomy procedures treat severe strokes due to large artery occlusions, often resistant to intravenous drug. Together, these procedures result in a greater proportion of revascularized stroke patients than ever before, up to 88% in 1 recent trial (EXTEND-IA). Subsequently, there is a growing need for neurointensivists to develop more effective strategies to manage stroke patients following successful reperfusion. Cerebral ischemic reperfusion injury (CIRI) is defined as deterioration of brain tissue suffered from ischemia that concomitantly reverses the benefits of re-establishing cerebral blood flow following mechanical or chemical therapies for acute ischemic stroke. Herein, we examine the pathophysiology of CIRI, imaging modalities, and potential neuroprotective strategies. Additionally, we sought to lay down a potential treatment approach for patients with CIRI following emergent endovascular recanalization for acute ischemic stroke. Acute ischemic stroke, Reperfusion Injury, Mechanical thrombectomy ABBREVIATIONS ABBREVIATIONS ADC average diffusion coefficient AIS acute ischemic stroke BBB blood–brain barrier CIRI cerebral ischemic reperfusion injury DWI diffusion-weighted imaging HT hemorrhagic transformation IV-tPA intravenous recombinant tissue plasminogen MCA middle cerebral artery MMP2 matrix-metalloproteinase 2 MRI magnetic resonance imaging mRS modified Rankin score NIHSS National Institutes of Health Stroke Scale PET positron emission tomography RI reperfusion injury ROS reactive oxygen species TICI Thrombolysis in Cerebral Infarction grading system Acute ischemic stroke (AIS) continues to be one of the leading causes of death and disability worldwide. AIS is estimated to be 680 000 per year with a mortality rate ranging between 53% and 94% and even higher morbidity rates.1 Intravenous recombinant tissue plasminogen (IV-tPA) and recent advances in endovascular therapies have dramatically changed the treatment paradigm.2-5 However, AIS management via therapeutic thrombolysis and/or mechanical recanalization also carries risks that neurointensivists must be aware of. Cerebral ischemic reperfusion injury (CIRI) has been defined as a biochemical cascade causing further worsening of ischemic brain tissue that concomitantly reverses the benefits of restoring cerebral circulation following systemic thrombolysis and/or mechanical thrombectomy for AIS.6 CIRI includes a range of manifestations. On one end, there is a subgroup of patients who fail to improve despite evident recanalization. This is hypothesized to occur due to incomplete tissue reperfusion, injury of the neurovascular unit, and/or distal microthrombosis, which has been termed the “no-reflow phenomenon.”7 At the other end, there is unregulated reperfusion with hemorrhagic transformation (HT). This process occurs due to activation of inflammatory mediators along with an impaired autoregulatory of the brain vasculature. These factors predispose to blood extravasation when the ischemic brain tissue is ultimately reperfused.8-10 In this review, we will highlight the pathophysiology of CIRI, review the imaging modalities to assess these processes, and potential neuroprotective strategies. Finally, we endeavor to articulate a potential treatment approach. PATHOPHYSIOLOGY OF CIRI Reperfusion injury (RI) is described as deterioration of salvageable brain tissue following cerebral reperfusion.11 Several animal models demonstrate that delayed reperfusion can lead to larger infarct volume than permanent occlusion of major cerebral arteries.11,12 Pathophysiological changes early in the ischemic process as well as later during the postreperfusion period (early and late), both mediate cell injury causing poor outcomes following stroke. Ischemia, Early Hyperperfusion, and “No-Reflow” Phenomenon Ischemia shifts cellular metabolism from aerobic to anaerobic metabolism, which results in the production of lactic acid, decreased pH, and activation of phospholipase-A2. Consequent production of leukotrienes, prostaglandins, and other inflammatory mediators cause cell injury independent of the initial ischemic insult and overshadowing the inflammatory-mediated cell damage prior to reperfusion.13 Once the tissue is reperfused, these products react with oxygen to produce free radicals. Although ischemia causes excessive release of glutamate (excitatory neurotransmitter), which activates excitotoxic pathways, clinical trials evaluating pharmacological suppression of this excitation using α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) and N-methyl-d-aspartate (NMDA) receptor antagonists failed to show any benefit.14 Thus, it appears that free radicals have a significant role in tissue injury following reperfusion. Cerebral hyperperfusion has been described as a sudden rapid rise in cerebral blood flow in excess of metabolic demand. The severity of hyperperfusion appears to correlate with poor outcomes in animal models, although this conclusion has been contested based on case reports and series in stroke patients.15 In contrast to hyperperfusion, many studies utilizing perfusion imaging demonstrate that recanalization by fibrinolysis can be associated with poor or absent perfusion.16 The condition of recanalization without adequate perfusion called “no-reflow” phenomenon, though originally applied to cardiac ischemia, is equally applicable to cerebral ischemic pathophysiology. Numerous mechanisms have been proposed for this observation, including narrowing of the blood vessel secondary to extraluminal compression by subsequent swelling in the astrocyte endfeet, constriction due to intraluminal erythrocytes, leukocytes, and platelets plugging, local tissue factor activation causing fibrin accumulation and microvascular microthrombosis, despite recanalization of the occluded vessel.6,17-20 Leukocytes in Reperfusion Injury The cerebral ischemic penumbra is defined as brain tissue at risk for infarction, however potentially salvageable if revascularization occurs promptly. Despite the possibility of recovery, tissue in the ischemic penumbra remains at risk for irreversible injury in part due to elaboration and amplification of inflammatory mediators. During ischemia, free radical production induces upregulation of endothelial P-selectin. Neutrophils initially become adherent to endothelium as neutrophil P-selectin glycoprotein-1 interacts with endothelial P-selectin resulting in neutrophil “rolling,” the process of in Situ microvascular occlusion, and consequent capillary plugging. Other adhesion molecules interact at the capillary–neutrophil interface, reinforcing adhesion and promoting transmigration of neutrophils (diapedesis) into the ischemic brain parenchyma. The leukocytes release free radicals, inflammatory mediators, and proteolytic enzymes, resulting in blood–brain barrier (BBB) breakdown, thrombosis, and neuronal apoptosis.21,22 Additional factors contributing to ischemia include hemorrhage, local cerebral edema, clotting cascade activation, and endothelial and subendothelial dysfunction.23 These changes reduce local blood flow even from collateral sources, resulting in secondary ischemia.17,23,24 Several animal models have shown the importance of leukocyte–endothelial interaction in tissue injury. In 1 study, leukocytes accumulated at sites of neuronal injury significantly more than in rats with permanent vessel occlusion, and this accumulation was related temporally to the expansion of infarct volume.25 Another study demonstrated histopathologic evidence of leukocyte accumulation in capillary beds in areas of secondary ischemia following reperfusion in a primate model.17 In animals rendered neutropenic by anti-neutrophilic antisera, severe combined immune deficiency, or gene knockdown models and monoclonal antibodies, cerebral blood flow is improved and infarct volume is decreased, suggesting amelioration of “no-flow” phenomena observed following ischemic reperfusion.26,27 Recently, regulatory T-cells have been identified to have a more impactful role in the development of RI than neutrophils alone.28 In the future, measures to address these processes will likely become important to improve AIS outcome. Reactive Oxygen Species in Reperfusion Injury Reactive oxygen species (ROS) are breakdown outputs of physiological aerobic metabolism that can cause cellular damage if produced in excess. Following reperfusion, neuronal mitochondria overcompensate for the ischemic insult by induction of metabolic pathways, resulting in excessive release of ROS. Subsequently, ROS induce cellular damage and promote apoptosis, which occurs preferentially in the ischemic penumbra following reperfusion.29,30 Furthermore, ROS inactivates nitric oxide release by cerebral vascular endothelial cells, resulting in vascular constriction and worsening of no-reflow.31 Several free radical scavengers, including glutathione, superoxide dismutase, and catalase, enzymatically eliminate ROS, aiming to reduce the damage caused by ROS. Platelets in Reperfusion Injury Platelets aggregate at the site of ischemic injury following reperfusion. In turn, these platelets release inflammatory mediators, worsening no-reflow injury.32,33 Reperfusion is thought to exact damage to the subendothelial extracellular matrix, which causes local platelet activation and aggregation.34 In 1 rat model of transient focal ischemia, rats that experienced cerebral reperfusion had significantly elevated platelet–leukocyte adhesion and P-selectin expression compared to controls, which were not reperfused.35 Platelets have been shown to induce vasospasm following coronary reperfusion, due to serotonin effect and release of other inflammatory mediators. The role of these agents remains to be studied in models of cerebral ischemia-reperfusion.32 Complement System Activation in Reperfusion Injury Complement activation is also known to cause local tissue injury by mediating the postreperfusion inflammatory cascade.36 The degree of complement activation correlates with neurological outcomes in stroke.37 C3 has been identified in the ischemic core following ischemia-reperfusion in an animal model of temporary middle cerebral artery (MCA) occlusion, and the C3 receptor appears to be upregulated in these areas.38,39 C5a is a mediator of tissue damage due to its action as leukocytes chemotactic agent in ischemic and reperfused tissue. In addition, it enacts release of inflammatory interleukins and Tumor Necrosis Factor- Alpha.40 Blockade of anaphylatoxins, C3a and C5a via receptor antagonism or with clearance of C5a with monoclonal antibodies, has been shown to be neuroprotective.41,42 The alternative complement pathway is activated in ischemic stroke even prior to onset of reperfusion.43 Complement activation is thought to interact closely with the coagulation cascade, potentiating RI.44,45 Mannose-binding lectin is known to promote microvascular thrombosis in cerebral ischemia-reperfusion mouse model.46 C1 inhibitor—which inhibits both classical pathway and mannose-binding lectin pathway—has been shown to diminish BBB breakdown plus cerebral edema in murine models of ischemia-RI.47-49 This remains an area of ongoing research in neurocritical care. BBB Breakdown in Reperfusion Injury Breakdown of the BBB occurs as a result of CIRI, increasing risk for cerebral edema, HT, and infarction.12 Increased BBB permeability occurs following reperfusion as early as 15 min in 1 rat model.50 Comparable studies in other animal models have reported similar findings.12 Others have demonstrated bimodal temporal onset of BBB breakdown at 3 and 48 h after reperfusion, which can last up to 5 wk postreperfusion.51,52 Furthermore, cerebral edema does not occur to the same degree in permanent occlusion subgroups compared with subgroups experiencing only temporary occlusion.53 Elevated matrix-metalloproteinase 2 (MMP2) levels are known to degrade tight junctions and basal lamina, enzymatically process type IV collagen, disrupt the BBB, and cause neuronal injury after ischemia.54-56 Pro-MMP2 is synthesized in astrocytes and cerebral endothelial cells in response to ischemia and remains elevated during reperfusion.57,58 Mouse models knocking out MMP2 and MMP9 individually have reduced risk of HT, cerebral edema, and neurological deficits following ischemia and reperfusion. MMP2 and MMP9 may act through a single cascade because their effect is not potentiated in a double knockout model.59,60 However, MMP2 knockout does not appear neuroprotective in models of severe ischemia.61 Synthetic MMP inhibitors reverse tight junction protein degradation and resultant BBB permeability in ischemic-reperfusion.54 Mice deficient in superoxide dismutase-2 had higher rates of HT and decreased neuronal apoptosis, suggesting ROS may cause BBB permeability.62 BBB breakdown, in addition to inflammatory cascade activation and neuronal cell death are risk factors for later HT.63 Further downstream effects include endothelial and neuronal autophagy.64,65 NEUROIMAGING OF CIRI Magnetic resonance imaging (MRI) supports the concept of ischemia as evidenced by characteristic changes in average diffusion coefficient (ADC) and diffusion-weighted imaging (DWI) sequences. DWI is a reliable indicator of cellular edema due to cellular injury. Within seconds to minutes of ischemia, ADC/DWI maps characteristically show reduced ADC or DWI hyperintensities in the area of ischemia. Following reperfusion, an ADC gain and/or loss of DWI hyperintensity may occur within 10 to 90 min. However, ADC loss with an increased number of DWI hyperintensities may recur hours after the initial ischemic insult.66-68 The time points for secondary injury vary considerably (anywhere from 2 to 72 h following reperfusion) with different animal models, duration of ischemia, and time to reperfusion.26,68,69 Some radiographic characteristics may help predict RI. A continuous increase of T2 value during the first 2 hours of reperfusion, in spite of initial ADC improvement, may predict secondary deterioration. This may indicate improving cytotoxic edema, in the presence of progressing vasogenic edema during early reperfusion.66 HT of ischemic infarction is predicted by proportion of very low ADC voxels in both rabbits and humans.70,71 MRI has been utilized to assess for degree of BBB breakdown, as T2 signal is indicative of cytotoxic cerebral edema.67 Latour et al72 showed that BBB disruption was higher in subjects who demonstrated reperfusion by perfusion-weighted imaging, and that these patients were more likely to have a poor clinical outcome and increased risk of HT. Another retrospective review of imaging in stroke patients similarly demonstrated an association between reperfusion and BBB breakdown, which, in turn, correlated with a higher incidence of HT in those managed with IV recombinant tissue plasminogen.8 Contrast enhancement, which suggests BBB breakdown, occurs with both permanent and later reperfusion subgroups in 1 rat model;73 thus, the significance of this finding alone remains to be determined. Perfusion-weighted imaging provides quantitative and qualitative information regarding cerebral blood flow. In humans, Kidwell et al74 demonstrated that areas of postischemic hyperperfusion develop more infarction compared to those without hyperperfusion. This may be an indication of dysautoregulation due to parenchymal infarction described as “luxury perfusion” or arteriovenous shunting on catheter arteriography even at the time of a mechanical revascularization procedure. In this situation, a reduction in systemic blood pressure may be important to reduce potential hyperperfusion and its consequences. This type of dysautoregulation stands in contradistinction to patients with persistent hypoperfusion due to stroke. In the case of hypoperfusion, efforts to elevate the blood pressure may help to perfuse areas of deficient blood flow. Applying induced hypertension in patients with large perfusion–diffusion mismatch showed a decrease in hypoperfused tissue and was associated with improved cognitive outcomes.75 Nuclear medicine tests offer qualitative means to assess cerebral blood flow. Both 99 m Technicium-HMPAO SPECT and 113-Xenon injection have been used to examine degree of hyperperfusion following ischemia.15 Positron emission tomography (PET) offers both qualitative and quantitative measures of cerebral blood flow and metabolism although not often available in the acute care environment. While some PET imaging studies show that areas of reperfusion, and hyperperfusion in particular, have decreased oxygen extraction fraction and cerebral metabolism have universally poor outcomes, other studies utilizing PET suggest that hyperperfused tissue is not an indicator of poor outcomes or development of RI.15 Arterial spin-labeled MRI has also been used to provide quantitative cerebral blood flow measurement and is suggested as a means to predict the onset of HT.76 The application of imaging techniques, particularly measures of cerebral blood flow, as a guide to AIS management is an area of active research. NEUROPROTECTION Magnesium sulfate was demonstrated as a neuroprotectant in animal models of stroke and has shown signs of potential efficacy with an acceptable safety when delivered early after stroke onset in human studies. The Field Administration of Stroke Therapy-Magnesium trial was a randomized controlled trial that examined the effects of intravenous infusion of magnesium sulfate initiated within the first 2 h of symptom onset on long-term functional outcome of stroke patients.77 The trial enrolled 1700 patients and demonstrated no significant difference between the magnesium and placebo groups on outcome measures of disability at 90 d using the universal modified Rankin scale (mRS), serious adverse events, or death. Glyburide has been postulated to limit cerebral edema formation by reducing MMP-9 activation through its action as a selective sulfonylurea receptor inhibitor.78,79 The Glyburide Advantage in Malignant Edema and Stroke trial was a multicenter, prospective, randomized, double-blinded study in patients who suffered a large hemispheric stroke assigned to receive intravenous infusion of glyburide or placebo within 10 h of stroke onset. Although the results have not yet been published, the trial did not meet its primary or secondary endpoints. The glyburide group exhibited a 50% reduction in midline shift at 72 to 96 h and a 40% reduction in MMP-9 compared with placebo. Higher MMP-9 levels correlated with malignant brain edema; however, no statistical difference was found between the glyburide and the placebo groups in terms of patients requiring decompressive surgery, developing serious adverse event, or ipsilateral hemispheric or lesional swelling. Other MMP-9 inhibitors representing potential neuroprotectants include Minocycline and Edaravone. Minocycline has been evaluated for its ability to reduce MMP-9 levels as well as safety.80,81 Although large randomized trials are currently lacking, in a meta-analysis examining the effect of Edaravone in 3 trials including a total of 496 participants, Edavarone appeared to increase the proportion of participants with neurological improvement compared with the controls.82 Unfortunately, because of the lack of data, no agents can be recommended at this time. Therapeutic hypothermia in the management of postinfarct ischemia has been evaluated as a type of thermal neuroprotection.83,84 The postulated mechanisms include decreasing metabolic demand, inhibiting excitatory neurotransmitters, production and activation free radicals, as well as optimizing cerebral perfusion pressure through reducing the intracranial pressure and decreasing cerebral blood volume and edema.85 Large-scale trials examining the effect of hypothermia in AIS are underway and will hopefully elucidate the optimal mode, duration, and depth of hypothermia.86,87 This remains an area of great interest despite recent disappointing results when applied to cardiac arrest. CIRI AND THE RECENT NEUROENDOVASCULAR TRIALS Although the recent endovascular trials did not directly examine CIRI, they demonstrated the fundamentals of successful intervention in AIS and indirectly shed light on the incidence and predictors of CIRI. Although data on no-reflow and reperfusion hemorrhage was not reported, there was no difference in terms of development of symptomatic HTs between the interventional arm (0%-7.7%) and the control arm (1.9%-6.4%). With regard to poor functional outcome (mRS ≥ 3), patients with partial recanalization (Thrombolysis in Cerebral Infarction grading system (TICI) grade 2a) did not do as well as the patients with nearly complete or complete recanalization (TICI grade 2b/3) reflected as functional outcome (Table).88 TABLE 1. Selected Clinical Outcomes for Recent Randomized, Clinical Trials of Endovascular Treatments for Acute Ischemic Stroke Trial MR CLEAN ESCAPE EXTEND-IA SWIFT PRIME REVASCAT Key inclusion criteria NIHSS ≥ 2, age ≥ 18 NIHSS > 5, ASPECTS > 5, moderate/good collateral on CTA Eligible for IV-tPA < 4.5 h from onset, ischemic core <70 cm3, mismatcha Eligible for IV-tPA < 4.5 h from onset, age 18-80, NIHSS 8-29, ASPECTS≥6 Age 18-80, NIHSS ≥ 6, ASPECTS ≥ 7 Interventional arm Intra-arterial Therapy Intra-arterial Therapy Endovascular Thrombectomy with Solitaire FR stentriever Endovascular Thrombectomy with Solitaire FR stentriever Endovascular Thrombectomy with Solitaire FR stentriever Control arm Best Medical Management (+/– IV-tPA) Best Medical Management (+/– IV-tPA) IV-tPA only IV-tPA only Best Medical Management (+/– IV-tPA) Time window for intervention <6 h from onset <12 h from onset <6 h from onset <6 h from onset <8 h from onset Number of patients 500 (I:233, C:267) 315 (I:165, C:150) 70 (I:35, C:35) 196 (I:98, C:98) 206 (I:103 C:103) Mean/median age (yr) I:65.8, C:65.7 I:71, C:70 I:68.6, C:70.2 I:66.3, C:65.0 I:65.7, C:67.2 Median NIHSS I:17, C:18 I:16, C:17 I:17, C:13 I:17, C:17 I:17, C:17 Median ASPECTS I:9, C:9 I:9, C:9 NR I:9, C:9 I:7, C:8 Received IV-tPA I:87.1%, C:90.6% I:72.7%, C:78.7% I:100%, C:100% I:100%, C:100% I:68.0%, C:77.7% Median time from stroke onset to groin puncture (min) 260 241b 210 224 269 Intervention with stent retriever device 81.50% 86.10% 100% 100% 100% TICI 2b/3 recanalization 58.7% 72.4% 86.2% 88.0% 65.7% mRS 0-2 at 90 d; (improvement) I:32.6%, C:19.1%; (13.5%)* I:53.0%, C:29.3%; (23.7%)* I71.4%, C:40.0%; (31.4%)* I:60.2%, C:35.5%; (24.7%)* I:43.7%, C:28.2%; (15.5%)* Mortality at 30 d I:21.0%, C:22.1% I:10.4%, C:19.0% I:8.6%, C:20.0% I:9.2%, C:12.4% I:18.4%, C:15.5% Complications Failure to recanalize in interventional arm (TICI 0) 13.80% NR 3.40% 4.80% 7.80% TICI < 2b in interventional arm 41.30% NR 13.80% 12.00% 33.90% Embolization into new territory in interventional arm 8.6% 4.9% 5.7% NR 4.9% Any hemorrhagic transformationc I:6.9%, C:6.4% I:36.9%, C:17.3% I:11.4%, C:8.6% I:5.1%, C:7.1% I:5.8%, C:5.8% Symptomatic ICH I:7.7%, C:6.4% I:3.6%, C:2.7% I:0%, C:5.7% I:0%, C:3.1% I:1.9%, C:1.9% Poor outcome (mRS ≥ 3) I:67%, C:80% I:46.9%, C:69.3% I:28.6%, C:60.0% I:39.8%, C:64.5% I:56.3%, C:71.8% Trial MR CLEAN ESCAPE EXTEND-IA SWIFT PRIME REVASCAT Key inclusion criteria NIHSS ≥ 2, age ≥ 18 NIHSS > 5, ASPECTS > 5, moderate/good collateral on CTA Eligible for IV-tPA < 4.5 h from onset, ischemic core <70 cm3, mismatcha Eligible for IV-tPA < 4.5 h from onset, age 18-80, NIHSS 8-29, ASPECTS≥6 Age 18-80, NIHSS ≥ 6, ASPECTS ≥ 7 Interventional arm Intra-arterial Therapy Intra-arterial Therapy Endovascular Thrombectomy with Solitaire FR stentriever Endovascular Thrombectomy with Solitaire FR stentriever Endovascular Thrombectomy with Solitaire FR stentriever Control arm Best Medical Management (+/– IV-tPA) Best Medical Management (+/– IV-tPA) IV-tPA only IV-tPA only Best Medical Management (+/– IV-tPA) Time window for intervention <6 h from onset <12 h from onset <6 h from onset <6 h from onset <8 h from onset Number of patients 500 (I:233, C:267) 315 (I:165, C:150) 70 (I:35, C:35) 196 (I:98, C:98) 206 (I:103 C:103) Mean/median age (yr) I:65.8, C:65.7 I:71, C:70 I:68.6, C:70.2 I:66.3, C:65.0 I:65.7, C:67.2 Median NIHSS I:17, C:18 I:16, C:17 I:17, C:13 I:17, C:17 I:17, C:17 Median ASPECTS I:9, C:9 I:9, C:9 NR I:9, C:9 I:7, C:8 Received IV-tPA I:87.1%, C:90.6% I:72.7%, C:78.7% I:100%, C:100% I:100%, C:100% I:68.0%, C:77.7% Median time from stroke onset to groin puncture (min) 260 241b 210 224 269 Intervention with stent retriever device 81.50% 86.10% 100% 100% 100% TICI 2b/3 recanalization 58.7% 72.4% 86.2% 88.0% 65.7% mRS 0-2 at 90 d; (improvement) I:32.6%, C:19.1%; (13.5%)* I:53.0%, C:29.3%; (23.7%)* I71.4%, C:40.0%; (31.4%)* I:60.2%, C:35.5%; (24.7%)* I:43.7%, C:28.2%; (15.5%)* Mortality at 30 d I:21.0%, C:22.1% I:10.4%, C:19.0% I:8.6%, C:20.0% I:9.2%, C:12.4% I:18.4%, C:15.5% Complications Failure to recanalize in interventional arm (TICI 0) 13.80% NR 3.40% 4.80% 7.80% TICI < 2b in interventional arm 41.30% NR 13.80% 12.00% 33.90% Embolization into new territory in interventional arm 8.6% 4.9% 5.7% NR 4.9% Any hemorrhagic transformationc I:6.9%, C:6.4% I:36.9%, C:17.3% I:11.4%, C:8.6% I:5.1%, C:7.1% I:5.8%, C:5.8% Symptomatic ICH I:7.7%, C:6.4% I:3.6%, C:2.7% I:0%, C:5.7% I:0%, C:3.1% I:1.9%, C:1.9% Poor outcome (mRS ≥ 3) I:67%, C:80% I:46.9%, C:69.3% I:28.6%, C:60.0% I:39.8%, C:64.5% I:56.3%, C:71.8% ASPECTS = Alberta stroke program early computed tomography score; C = control; CTA = computed tomography angiography; I = interventional; ICH = intracranial hemorrhage; IV-tPA = intravenous recombinant tissue plasminogen activator; mRS = modified Rankin Scale; NIHSS = National Institutes of Health Stroke Scale; NR = not reported; TICI = thrombolysis in cerebral ischemia. *Statistically significant (P < .05). aMismatch defined, based on CT perfusion imaging, as a mismatch ratio >1.2 and an absolute mismatch volume >10 cm3. bTime from stroke onset to first reperfusion (time to groin puncture not reported). cDefined as any radiological ICH, including parenchymal hematoma (PH) or hemorrhagic infarction (HI). View Large TABLE 1. Selected Clinical Outcomes for Recent Randomized, Clinical Trials of Endovascular Treatments for Acute Ischemic Stroke Trial MR CLEAN ESCAPE EXTEND-IA SWIFT PRIME REVASCAT Key inclusion criteria NIHSS ≥ 2, age ≥ 18 NIHSS > 5, ASPECTS > 5, moderate/good collateral on CTA Eligible for IV-tPA < 4.5 h from onset, ischemic core <70 cm3, mismatcha Eligible for IV-tPA < 4.5 h from onset, age 18-80, NIHSS 8-29, ASPECTS≥6 Age 18-80, NIHSS ≥ 6, ASPECTS ≥ 7 Interventional arm Intra-arterial Therapy Intra-arterial Therapy Endovascular Thrombectomy with Solitaire FR stentriever Endovascular Thrombectomy with Solitaire FR stentriever Endovascular Thrombectomy with Solitaire FR stentriever Control arm Best Medical Management (+/– IV-tPA) Best Medical Management (+/– IV-tPA) IV-tPA only IV-tPA only Best Medical Management (+/– IV-tPA) Time window for intervention <6 h from onset <12 h from onset <6 h from onset <6 h from onset <8 h from onset Number of patients 500 (I:233, C:267) 315 (I:165, C:150) 70 (I:35, C:35) 196 (I:98, C:98) 206 (I:103 C:103) Mean/median age (yr) I:65.8, C:65.7 I:71, C:70 I:68.6, C:70.2 I:66.3, C:65.0 I:65.7, C:67.2 Median NIHSS I:17, C:18 I:16, C:17 I:17, C:13 I:17, C:17 I:17, C:17 Median ASPECTS I:9, C:9 I:9, C:9 NR I:9, C:9 I:7, C:8 Received IV-tPA I:87.1%, C:90.6% I:72.7%, C:78.7% I:100%, C:100% I:100%, C:100% I:68.0%, C:77.7% Median time from stroke onset to groin puncture (min) 260 241b 210 224 269 Intervention with stent retriever device 81.50% 86.10% 100% 100% 100% TICI 2b/3 recanalization 58.7% 72.4% 86.2% 88.0% 65.7% mRS 0-2 at 90 d; (improvement) I:32.6%, C:19.1%; (13.5%)* I:53.0%, C:29.3%; (23.7%)* I71.4%, C:40.0%; (31.4%)* I:60.2%, C:35.5%; (24.7%)* I:43.7%, C:28.2%; (15.5%)* Mortality at 30 d I:21.0%, C:22.1% I:10.4%, C:19.0% I:8.6%, C:20.0% I:9.2%, C:12.4% I:18.4%, C:15.5% Complications Failure to recanalize in interventional arm (TICI 0) 13.80% NR 3.40% 4.80% 7.80% TICI < 2b in interventional arm 41.30% NR 13.80% 12.00% 33.90% Embolization into new territory in interventional arm 8.6% 4.9% 5.7% NR 4.9% Any hemorrhagic transformationc I:6.9%, C:6.4% I:36.9%, C:17.3% I:11.4%, C:8.6% I:5.1%, C:7.1% I:5.8%, C:5.8% Symptomatic ICH I:7.7%, C:6.4% I:3.6%, C:2.7% I:0%, C:5.7% I:0%, C:3.1% I:1.9%, C:1.9% Poor outcome (mRS ≥ 3) I:67%, C:80% I:46.9%, C:69.3% I:28.6%, C:60.0% I:39.8%, C:64.5% I:56.3%, C:71.8% Trial MR CLEAN ESCAPE EXTEND-IA SWIFT PRIME REVASCAT Key inclusion criteria NIHSS ≥ 2, age ≥ 18 NIHSS > 5, ASPECTS > 5, moderate/good collateral on CTA Eligible for IV-tPA < 4.5 h from onset, ischemic core <70 cm3, mismatcha Eligible for IV-tPA < 4.5 h from onset, age 18-80, NIHSS 8-29, ASPECTS≥6 Age 18-80, NIHSS ≥ 6, ASPECTS ≥ 7 Interventional arm Intra-arterial Therapy Intra-arterial Therapy Endovascular Thrombectomy with Solitaire FR stentriever Endovascular Thrombectomy with Solitaire FR stentriever Endovascular Thrombectomy with Solitaire FR stentriever Control arm Best Medical Management (+/– IV-tPA) Best Medical Management (+/– IV-tPA) IV-tPA only IV-tPA only Best Medical Management (+/– IV-tPA) Time window for intervention <6 h from onset <12 h from onset <6 h from onset <6 h from onset <8 h from onset Number of patients 500 (I:233, C:267) 315 (I:165, C:150) 70 (I:35, C:35) 196 (I:98, C:98) 206 (I:103 C:103) Mean/median age (yr) I:65.8, C:65.7 I:71, C:70 I:68.6, C:70.2 I:66.3, C:65.0 I:65.7, C:67.2 Median NIHSS I:17, C:18 I:16, C:17 I:17, C:13 I:17, C:17 I:17, C:17 Median ASPECTS I:9, C:9 I:9, C:9 NR I:9, C:9 I:7, C:8 Received IV-tPA I:87.1%, C:90.6% I:72.7%, C:78.7% I:100%, C:100% I:100%, C:100% I:68.0%, C:77.7% Median time from stroke onset to groin puncture (min) 260 241b 210 224 269 Intervention with stent retriever device 81.50% 86.10% 100% 100% 100% TICI 2b/3 recanalization 58.7% 72.4% 86.2% 88.0% 65.7% mRS 0-2 at 90 d; (improvement) I:32.6%, C:19.1%; (13.5%)* I:53.0%, C:29.3%; (23.7%)* I71.4%, C:40.0%; (31.4%)* I:60.2%, C:35.5%; (24.7%)* I:43.7%, C:28.2%; (15.5%)* Mortality at 30 d I:21.0%, C:22.1% I:10.4%, C:19.0% I:8.6%, C:20.0% I:9.2%, C:12.4% I:18.4%, C:15.5% Complications Failure to recanalize in interventional arm (TICI 0) 13.80% NR 3.40% 4.80% 7.80% TICI < 2b in interventional arm 41.30% NR 13.80% 12.00% 33.90% Embolization into new territory in interventional arm 8.6% 4.9% 5.7% NR 4.9% Any hemorrhagic transformationc I:6.9%, C:6.4% I:36.9%, C:17.3% I:11.4%, C:8.6% I:5.1%, C:7.1% I:5.8%, C:5.8% Symptomatic ICH I:7.7%, C:6.4% I:3.6%, C:2.7% I:0%, C:5.7% I:0%, C:3.1% I:1.9%, C:1.9% Poor outcome (mRS ≥ 3) I:67%, C:80% I:46.9%, C:69.3% I:28.6%, C:60.0% I:39.8%, C:64.5% I:56.3%, C:71.8% ASPECTS = Alberta stroke program early computed tomography score; C = control; CTA = computed tomography angiography; I = interventional; ICH = intracranial hemorrhage; IV-tPA = intravenous recombinant tissue plasminogen activator; mRS = modified Rankin Scale; NIHSS = National Institutes of Health Stroke Scale; NR = not reported; TICI = thrombolysis in cerebral ischemia. *Statistically significant (P < .05). aMismatch defined, based on CT perfusion imaging, as a mismatch ratio >1.2 and an absolute mismatch volume >10 cm3. bTime from stroke onset to first reperfusion (time to groin puncture not reported). cDefined as any radiological ICH, including parenchymal hematoma (PH) or hemorrhagic infarction (HI). View Large CIRI MANAGEMENT Reperfusion hemorrhage develops secondary to hyperperfusion as a result of an interplay between several factors including a combination of abnormal vasodilation increased cerebral blood volume, diminished oxygen extraction fraction, and mildly increased rate of cerebral oxygen metabolism.15 Although data regarding the management of CIRI are lacking, a timely diagnosis and a step-wise strategy are integral. The best approach to managing CIRI involves a thorough understanding of conditions known to predispose to hemorrhagic change in patients undergoing fibrinolysis. The time from administration of thrombolytic therapy to HT occurrence varies in literature ranging from 5 to 10 d up to 10 d89 post-treatment. However, the majority of HT post-IV-tPA in ischemic stroke patients occurs in the first 36 h post-treatment.90,91 Multiple studies have sought to find predictors for hemorrhagic complications following endovascular reperfusion therapy. Patients with evidence of radiographic large hemispheric infarct (ASPECTS < 7) before mechanical reperfusion, or TIMI ≥ 2 after reperfusion with an ASPECTS < 7 were more likely to develop HT.92 Additionally multimodal endovascular therapies with IV-tPA were associated with higher risk of developing parenchymal hematomas. Furthermore, tandem occlusions, hyperglycemia on admission, and poorly controlled hypertension with a systolic BP > 220 mm Hg or diastolic BP >105 mm Hg were also risk factors for HT.93,94 Optimal Blood Pressure Management Avoidance of blood pressure variability in the setting of spontaneous intraparenchymal hemorrhage has been shown to have a significant reduction in hematoma expansion.95 The management approach of CIRI has been extrapolated from intraparenchymal hemorrhage, hence strict blood pressure parameters in cases of HT after endovascular reperfusion is frequently employed at a goal systolic BP of 140 to 160 mm Hg.96 Reversal of Coagulopathy Several studies have explored the association between HT-post thrombolysis treatments with IV-tPA. In a meta-analysis of 55 studies, Whiteley et al97 found positive associations between post-IV-tPA HT and the following factors: older age, high NIHSS (National Institutes of Health Stroke Scale) on presentation, higher plasma glucose, antiplatelet agents, any warfarin use, statins, early CT ischemic changes, leukoarioisis, atrial fibrillation, diabetes, previous ischemic heart or cerebrovascular diseases, and congestive cardiac failure. However, when measured individually, they were unable to predict the risk of HT post-thrombolysis with t-PA. Occurrence of HT post-thrombolysis triggers clinicians to reverse all potential reversible causative agents (for example, antiplatelet, anticoagulations, and the newly administered thrombolysis [t-PA]). The American Heart Association recommends administering platelets and cryoprecipitate to reverse IV-tPA, although there is evidence that treatment of post-thrombolysis symptomatic intracerebral hemorrhage may not significantly reduce the likelihood of in-hospital mortality or hematoma expansion.88 Recombinant t-PA is best reversed with cryoprecipitate and platelet transfusion. Recombinant activated factor VII has been extensively studied and although it reduced hematoma growth, it did not improve survival or functional outcome after intracerebral hemorrhage.98 Other therapeutic strategies have been used to reverse the thrombolytic effect of tPA; aminocaproic acid has been used to reverse tPA using its antifibrinolytic property.99 Furthermore, fresh frozen plasma to replace fibrin degraded by the tPA effect has been proposed and used to reverse thrombolysis induced HT.99 Medications targeting the conversion of plasminogen to plasmin to reverse tPA effect in stroke patients have been reported, for example, French et al100 reported a case of a Jehovah's Witness stroke patient suffering HT post-tPA treated with tranexemic acid to control hematoma expansion. Patients on vitamin K-dependent anticoagulation (warfarin) reversal can be achieved by using vitamin K and FFP. Prothrombin complex concentrates have been used with reperfusion hemorrhages in patients on novel oral anticoagulants with varying success rates.101 Recently, the FDA approved Idarucizumab for the reversal of the direct thrombin inhibitor, dabigatran.102 Two other antidotes are in various stages of development for the reversal of other direct thrombin inhibitors. In cardiac surgery literature, platelet transfusions have been used to prevent excessive bleeding with use of the novel oral anticoagulants and GP IIb/IIIa inhibitors, as no reversal agents exist to date. Reversal of heparin with protamine sulfate can be used with CIRI that develops in the immediate post-recanalization period. Cerebral Edema and Intracranial Pressure Young patients with NIHSS > 15, hypodensity of >50% of the MCA territory, posterior cerebral artery and superior cerebellar artery infarcts predict the development of life-threatening edema and herniation.103 Clinical signs such as decline in Glasgow Coma Scale by 2 or more points, unilaterally dilated or poorly responsive pupils, or extensor posturing may all be heralding signs of active brainstem herniation and requires emergent management.103 Head of the bed elevation and avoiding neck pressure should be ensured to prevent any venous obstruction. Hyperventilation to target a pCO2 of 35 to 40 mm Hg should only be done transiently (<30 min). Osmolar therapy can be initiated with an osmolarity goal of ≤340 mOsm/L and osmolar gap <10 to 20 or Na > 160 mEq/L,104 with no proven efficacy of targeting a sodium >155 mEq/L.103 Induction of hypothermia to 33°C to 35°C for duration of 24 to 48 h in elevated intracranial pressure carries the theoretical neuroprotective benefit and has been shown to decrease metabolic demand, reduce cerebral blood volume as well as brain edema.84-87 Decompressive Hemicraniectomy Decompressive hemicraniectomy in the setting of intracerebral hemorrhage after endovascular reperfusion has not been evaluated in a randomized trial. Three randomized trials to date have shown decreased mortality rates and possibly improved functional outcomes in cases of large MCA infarcts treated with hemicraniectomy in the first 48 h after stroke; however, patients who were treated with thrombolytics were excluded.105-107 This evidence suggests that this procedure is uncommon in HT after endovascular reperfusion, likely due to concern for operating on patients who remain anticoagulated or received antiplatelet medications with prolonged effect. FUTURE DIRECTION Among the goals of mechanical thrombectomy is achieving prompt, enduring vessel recanalization, while accruing minimal to no risk of CIRI. Many questions remain unanswered by the existing evidence. With an anticipated increase in eligible mechanical thrombectomy cases, CIRI poses an inordinate challenge due to the lack of targeted management approach, as well as a thorough comprehension of its multifaceted pathobiology. 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Patient outcomes from symptomatic intracerebral hemorrhage after stroke thrombolysis . Neurology . 2011 ; 77 ( 4 ): 341 - 348 . Google Scholar CrossRef Search ADS PubMed 91. Wahlgren N , Ahmed N , Davalos A et al. Thrombolysis with alteplase for acute ischaemic stroke in the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST): an observational study . Lancet . 2007 ; 369 ( 9558 ): 275 - 282 . Google Scholar CrossRef Search ADS PubMed 92. Jickling GC , Liu D , Stamova B et al. Hemorrhagic transformation after ischemic stroke in animals and humans . J Cereb Blood Flow Metab . 2014 ; 34 ( 2 ): 185 - 199 . Google Scholar CrossRef Search ADS PubMed 93. Vora NA , Gupta R , Thomas AJ et al. Factors predicting hemorrhagic complications after multimodal reperfusion therapy for acute ischemic stroke . AJNR Am J Neuroradiol. 2007 ; 28 ( 7 ): 1391 - 1394 . Google Scholar CrossRef Search ADS PubMed 94. Wang X , Tsuji K , Lee SR et al. Mechanisms of hemorrhagic transformation after tissue plasminogen activator reperfusion therapy for ischemic stroke . Stroke . 2004 ; 35 ( 11 suppl 1 ): 2726 - 2730 . Google Scholar CrossRef Search ADS PubMed 95. Mokin M , Kan P , Kass-Hout T et al. Intracerebral hemorrhage secondary to intravenous and endovascular intraarterial revascularization therapies in acute ischemic stroke: an update on risk factors, predictors, and management . Neurosurg Focus . 2012 ; 32 ( 4 ): E2 . Google Scholar CrossRef Search ADS PubMed 96. Anderson CS , Heeley E , Huang Y et al. Rapid blood-pressure lowering in patients with acute intracerebral hemorrhage . N Engl J Med . 2013 ; 368 ( 25 ): 2355 - 2365 . Google Scholar CrossRef Search ADS PubMed 97. Whiteley WN , Slot KB , Fernandes P , Sandercock P , Wardlaw J . Risk factors for intracranial hemorrhage in acute ischemic stroke patients treated with recombinant tissue plasminogen activator: a systematic review and meta-analysis of 55 studies . Stroke . 2012 ; 43 ( 11 ): 2904 - 2909 . Google Scholar CrossRef Search ADS PubMed 98. Mayer SA , Brun NC , Begtrup K et al. Efficacy and safety of recombinant activated factor VII for acute intracerebral hemorrhage . N Engl J Med . 2008 ; 358 ( 20 ): 2127 - 2137 . Google Scholar CrossRef Search ADS PubMed 99. Goldstein JN , Marrero M , Masrur S et al. Management of thrombolysis-associated symptomatic intracerebral hemorrhage . Arch Neurol . 2010 ; 67 ( 8 ): 965 - 969 . Google Scholar CrossRef Search ADS PubMed 100. French KF , White J , Hoesch RE . Treatment of intracerebral hemorrhage with tranexamic acid after thrombolysis with tissue plasminogen activator . Neurocrit Care . 2012 ; 17 ( 1 ): 107 - 111 . Google Scholar CrossRef Search ADS PubMed 101. Mo Y , Yam FK . Recent advances in the development of specific antidotes for target-specific oral anticoagulants . Pharmacotherapy . 2015 ; 35 ( 2 ): 198 - 207 . Google Scholar CrossRef Search ADS PubMed 102. Eikelboom JW , Quinlan DJ , van Ryn J , Weitz JI . Idarucizumab: The Antidote for Reversal of Dabigatran . Circulation . 2015 ; 132 ( 25 ): 2412 - 2422 . Google Scholar CrossRef Search ADS PubMed 103. Huttner HB , Schwab S . Malignant middle cerebral artery infarction: clinical characteristics, treatment strategies, and future perspectives . Lancet Neurol. 2009 ; 8 ( 10 ): 949 - 958 . Google Scholar CrossRef Search ADS PubMed 104. Garcia-Morales EJ , Cariappa R , Parvin CA , Scott MG , Diringer MN . Osmole gap in neurologic-neurosurgical intensive care unit: Its normal value, calculation, and relationship with mannitol serum concentrations . Crit Care Med . 2004 ; 32 ( 4 ): 986 - 991 . Google Scholar CrossRef Search ADS PubMed 105. Vahedi K , Vicaut E , Mateo J et al. Sequential-design, multicenter, randomized, controlled trial of early decompressive craniectomy in malignant middle cerebral artery infarction (DECIMAL Trial) . Stroke . 2007 ; 38 ( 9 ): 2506 - 2517 . Google Scholar CrossRef Search ADS PubMed 106. Juttler E , Schwab S , Schmiedek P et al. Decompressive Surgery for the Treatment of Malignant Infarction of the Middle Cerebral Artery (DESTINY): a randomized, controlled trial . Stroke . 2007 ; 38 ( 9 ): 2518 - 2525 . Google Scholar CrossRef Search ADS PubMed 107. Hofmeijer J , Kappelle LJ , Algra A , Amelink GJ , van Gijn J , van der Worp HB . Surgical decompression for space-occupying cerebral infarction (the Hemicraniectomy After Middle Cerebral Artery infarction with Life-threatening Edema Trial [HAMLET]): a multicentre, open, randomised trial . Lancet Neurol. 2009 ; 8 ( 4 ): 326 - 333 . Google Scholar CrossRef Search ADS PubMed COMMENT This article is a comprehensive review of the literature on cerebral ischemic reperfusion injury (CIRI) and hemorrhagic transformation (HT) after thrombolysis of a large vessel occlusion. This is a very important concept as neurosurgeons are beginning to be the leaders in the field of emergent endovascular stroke management. The concept of neuroprotective agents is certainly an area where we need more research and one that promises to revolutionize stroke outcomes in a similar way stent-retriever technology already has. CIRI and HT are contributing factors to this and the authors are congratulated on bringing attention to the pathophysiology of these complex concepts. Ryan P. Morton Louis J. Kim Seattle, Washington Copyright © 2017 by the Congress of Neurological Surgeons This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Neurosurgery Oxford University Press

Cerebral Ischemic Reperfusion Injury Following Recanalization of Large Vessel Occlusions

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Oxford University Press
Copyright
Copyright © 2017 by the Congress of Neurological Surgeons
ISSN
0148-396X
eISSN
1524-4040
D.O.I.
10.1093/neuros/nyx341
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Abstract

Abstract Although stroke has recently dropped to become the nation's fifth leading cause of mortality, it remains the top leading cause of morbidity and disability in the US. Recent advances in stroke treatment, including intravenous fibrinolysis and mechanical thromboembolectomy, allow treatment of a greater proportion of stroke patients than ever before. While intra-arterial fibrinolysis with recombinant tissue plasminogen is an effective for treatment of a broad range of acute ischemic strokes, endovascular mechanical thromboembolectomy procedures treat severe strokes due to large artery occlusions, often resistant to intravenous drug. Together, these procedures result in a greater proportion of revascularized stroke patients than ever before, up to 88% in 1 recent trial (EXTEND-IA). Subsequently, there is a growing need for neurointensivists to develop more effective strategies to manage stroke patients following successful reperfusion. Cerebral ischemic reperfusion injury (CIRI) is defined as deterioration of brain tissue suffered from ischemia that concomitantly reverses the benefits of re-establishing cerebral blood flow following mechanical or chemical therapies for acute ischemic stroke. Herein, we examine the pathophysiology of CIRI, imaging modalities, and potential neuroprotective strategies. Additionally, we sought to lay down a potential treatment approach for patients with CIRI following emergent endovascular recanalization for acute ischemic stroke. Acute ischemic stroke, Reperfusion Injury, Mechanical thrombectomy ABBREVIATIONS ABBREVIATIONS ADC average diffusion coefficient AIS acute ischemic stroke BBB blood–brain barrier CIRI cerebral ischemic reperfusion injury DWI diffusion-weighted imaging HT hemorrhagic transformation IV-tPA intravenous recombinant tissue plasminogen MCA middle cerebral artery MMP2 matrix-metalloproteinase 2 MRI magnetic resonance imaging mRS modified Rankin score NIHSS National Institutes of Health Stroke Scale PET positron emission tomography RI reperfusion injury ROS reactive oxygen species TICI Thrombolysis in Cerebral Infarction grading system Acute ischemic stroke (AIS) continues to be one of the leading causes of death and disability worldwide. AIS is estimated to be 680 000 per year with a mortality rate ranging between 53% and 94% and even higher morbidity rates.1 Intravenous recombinant tissue plasminogen (IV-tPA) and recent advances in endovascular therapies have dramatically changed the treatment paradigm.2-5 However, AIS management via therapeutic thrombolysis and/or mechanical recanalization also carries risks that neurointensivists must be aware of. Cerebral ischemic reperfusion injury (CIRI) has been defined as a biochemical cascade causing further worsening of ischemic brain tissue that concomitantly reverses the benefits of restoring cerebral circulation following systemic thrombolysis and/or mechanical thrombectomy for AIS.6 CIRI includes a range of manifestations. On one end, there is a subgroup of patients who fail to improve despite evident recanalization. This is hypothesized to occur due to incomplete tissue reperfusion, injury of the neurovascular unit, and/or distal microthrombosis, which has been termed the “no-reflow phenomenon.”7 At the other end, there is unregulated reperfusion with hemorrhagic transformation (HT). This process occurs due to activation of inflammatory mediators along with an impaired autoregulatory of the brain vasculature. These factors predispose to blood extravasation when the ischemic brain tissue is ultimately reperfused.8-10 In this review, we will highlight the pathophysiology of CIRI, review the imaging modalities to assess these processes, and potential neuroprotective strategies. Finally, we endeavor to articulate a potential treatment approach. PATHOPHYSIOLOGY OF CIRI Reperfusion injury (RI) is described as deterioration of salvageable brain tissue following cerebral reperfusion.11 Several animal models demonstrate that delayed reperfusion can lead to larger infarct volume than permanent occlusion of major cerebral arteries.11,12 Pathophysiological changes early in the ischemic process as well as later during the postreperfusion period (early and late), both mediate cell injury causing poor outcomes following stroke. Ischemia, Early Hyperperfusion, and “No-Reflow” Phenomenon Ischemia shifts cellular metabolism from aerobic to anaerobic metabolism, which results in the production of lactic acid, decreased pH, and activation of phospholipase-A2. Consequent production of leukotrienes, prostaglandins, and other inflammatory mediators cause cell injury independent of the initial ischemic insult and overshadowing the inflammatory-mediated cell damage prior to reperfusion.13 Once the tissue is reperfused, these products react with oxygen to produce free radicals. Although ischemia causes excessive release of glutamate (excitatory neurotransmitter), which activates excitotoxic pathways, clinical trials evaluating pharmacological suppression of this excitation using α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) and N-methyl-d-aspartate (NMDA) receptor antagonists failed to show any benefit.14 Thus, it appears that free radicals have a significant role in tissue injury following reperfusion. Cerebral hyperperfusion has been described as a sudden rapid rise in cerebral blood flow in excess of metabolic demand. The severity of hyperperfusion appears to correlate with poor outcomes in animal models, although this conclusion has been contested based on case reports and series in stroke patients.15 In contrast to hyperperfusion, many studies utilizing perfusion imaging demonstrate that recanalization by fibrinolysis can be associated with poor or absent perfusion.16 The condition of recanalization without adequate perfusion called “no-reflow” phenomenon, though originally applied to cardiac ischemia, is equally applicable to cerebral ischemic pathophysiology. Numerous mechanisms have been proposed for this observation, including narrowing of the blood vessel secondary to extraluminal compression by subsequent swelling in the astrocyte endfeet, constriction due to intraluminal erythrocytes, leukocytes, and platelets plugging, local tissue factor activation causing fibrin accumulation and microvascular microthrombosis, despite recanalization of the occluded vessel.6,17-20 Leukocytes in Reperfusion Injury The cerebral ischemic penumbra is defined as brain tissue at risk for infarction, however potentially salvageable if revascularization occurs promptly. Despite the possibility of recovery, tissue in the ischemic penumbra remains at risk for irreversible injury in part due to elaboration and amplification of inflammatory mediators. During ischemia, free radical production induces upregulation of endothelial P-selectin. Neutrophils initially become adherent to endothelium as neutrophil P-selectin glycoprotein-1 interacts with endothelial P-selectin resulting in neutrophil “rolling,” the process of in Situ microvascular occlusion, and consequent capillary plugging. Other adhesion molecules interact at the capillary–neutrophil interface, reinforcing adhesion and promoting transmigration of neutrophils (diapedesis) into the ischemic brain parenchyma. The leukocytes release free radicals, inflammatory mediators, and proteolytic enzymes, resulting in blood–brain barrier (BBB) breakdown, thrombosis, and neuronal apoptosis.21,22 Additional factors contributing to ischemia include hemorrhage, local cerebral edema, clotting cascade activation, and endothelial and subendothelial dysfunction.23 These changes reduce local blood flow even from collateral sources, resulting in secondary ischemia.17,23,24 Several animal models have shown the importance of leukocyte–endothelial interaction in tissue injury. In 1 study, leukocytes accumulated at sites of neuronal injury significantly more than in rats with permanent vessel occlusion, and this accumulation was related temporally to the expansion of infarct volume.25 Another study demonstrated histopathologic evidence of leukocyte accumulation in capillary beds in areas of secondary ischemia following reperfusion in a primate model.17 In animals rendered neutropenic by anti-neutrophilic antisera, severe combined immune deficiency, or gene knockdown models and monoclonal antibodies, cerebral blood flow is improved and infarct volume is decreased, suggesting amelioration of “no-flow” phenomena observed following ischemic reperfusion.26,27 Recently, regulatory T-cells have been identified to have a more impactful role in the development of RI than neutrophils alone.28 In the future, measures to address these processes will likely become important to improve AIS outcome. Reactive Oxygen Species in Reperfusion Injury Reactive oxygen species (ROS) are breakdown outputs of physiological aerobic metabolism that can cause cellular damage if produced in excess. Following reperfusion, neuronal mitochondria overcompensate for the ischemic insult by induction of metabolic pathways, resulting in excessive release of ROS. Subsequently, ROS induce cellular damage and promote apoptosis, which occurs preferentially in the ischemic penumbra following reperfusion.29,30 Furthermore, ROS inactivates nitric oxide release by cerebral vascular endothelial cells, resulting in vascular constriction and worsening of no-reflow.31 Several free radical scavengers, including glutathione, superoxide dismutase, and catalase, enzymatically eliminate ROS, aiming to reduce the damage caused by ROS. Platelets in Reperfusion Injury Platelets aggregate at the site of ischemic injury following reperfusion. In turn, these platelets release inflammatory mediators, worsening no-reflow injury.32,33 Reperfusion is thought to exact damage to the subendothelial extracellular matrix, which causes local platelet activation and aggregation.34 In 1 rat model of transient focal ischemia, rats that experienced cerebral reperfusion had significantly elevated platelet–leukocyte adhesion and P-selectin expression compared to controls, which were not reperfused.35 Platelets have been shown to induce vasospasm following coronary reperfusion, due to serotonin effect and release of other inflammatory mediators. The role of these agents remains to be studied in models of cerebral ischemia-reperfusion.32 Complement System Activation in Reperfusion Injury Complement activation is also known to cause local tissue injury by mediating the postreperfusion inflammatory cascade.36 The degree of complement activation correlates with neurological outcomes in stroke.37 C3 has been identified in the ischemic core following ischemia-reperfusion in an animal model of temporary middle cerebral artery (MCA) occlusion, and the C3 receptor appears to be upregulated in these areas.38,39 C5a is a mediator of tissue damage due to its action as leukocytes chemotactic agent in ischemic and reperfused tissue. In addition, it enacts release of inflammatory interleukins and Tumor Necrosis Factor- Alpha.40 Blockade of anaphylatoxins, C3a and C5a via receptor antagonism or with clearance of C5a with monoclonal antibodies, has been shown to be neuroprotective.41,42 The alternative complement pathway is activated in ischemic stroke even prior to onset of reperfusion.43 Complement activation is thought to interact closely with the coagulation cascade, potentiating RI.44,45 Mannose-binding lectin is known to promote microvascular thrombosis in cerebral ischemia-reperfusion mouse model.46 C1 inhibitor—which inhibits both classical pathway and mannose-binding lectin pathway—has been shown to diminish BBB breakdown plus cerebral edema in murine models of ischemia-RI.47-49 This remains an area of ongoing research in neurocritical care. BBB Breakdown in Reperfusion Injury Breakdown of the BBB occurs as a result of CIRI, increasing risk for cerebral edema, HT, and infarction.12 Increased BBB permeability occurs following reperfusion as early as 15 min in 1 rat model.50 Comparable studies in other animal models have reported similar findings.12 Others have demonstrated bimodal temporal onset of BBB breakdown at 3 and 48 h after reperfusion, which can last up to 5 wk postreperfusion.51,52 Furthermore, cerebral edema does not occur to the same degree in permanent occlusion subgroups compared with subgroups experiencing only temporary occlusion.53 Elevated matrix-metalloproteinase 2 (MMP2) levels are known to degrade tight junctions and basal lamina, enzymatically process type IV collagen, disrupt the BBB, and cause neuronal injury after ischemia.54-56 Pro-MMP2 is synthesized in astrocytes and cerebral endothelial cells in response to ischemia and remains elevated during reperfusion.57,58 Mouse models knocking out MMP2 and MMP9 individually have reduced risk of HT, cerebral edema, and neurological deficits following ischemia and reperfusion. MMP2 and MMP9 may act through a single cascade because their effect is not potentiated in a double knockout model.59,60 However, MMP2 knockout does not appear neuroprotective in models of severe ischemia.61 Synthetic MMP inhibitors reverse tight junction protein degradation and resultant BBB permeability in ischemic-reperfusion.54 Mice deficient in superoxide dismutase-2 had higher rates of HT and decreased neuronal apoptosis, suggesting ROS may cause BBB permeability.62 BBB breakdown, in addition to inflammatory cascade activation and neuronal cell death are risk factors for later HT.63 Further downstream effects include endothelial and neuronal autophagy.64,65 NEUROIMAGING OF CIRI Magnetic resonance imaging (MRI) supports the concept of ischemia as evidenced by characteristic changes in average diffusion coefficient (ADC) and diffusion-weighted imaging (DWI) sequences. DWI is a reliable indicator of cellular edema due to cellular injury. Within seconds to minutes of ischemia, ADC/DWI maps characteristically show reduced ADC or DWI hyperintensities in the area of ischemia. Following reperfusion, an ADC gain and/or loss of DWI hyperintensity may occur within 10 to 90 min. However, ADC loss with an increased number of DWI hyperintensities may recur hours after the initial ischemic insult.66-68 The time points for secondary injury vary considerably (anywhere from 2 to 72 h following reperfusion) with different animal models, duration of ischemia, and time to reperfusion.26,68,69 Some radiographic characteristics may help predict RI. A continuous increase of T2 value during the first 2 hours of reperfusion, in spite of initial ADC improvement, may predict secondary deterioration. This may indicate improving cytotoxic edema, in the presence of progressing vasogenic edema during early reperfusion.66 HT of ischemic infarction is predicted by proportion of very low ADC voxels in both rabbits and humans.70,71 MRI has been utilized to assess for degree of BBB breakdown, as T2 signal is indicative of cytotoxic cerebral edema.67 Latour et al72 showed that BBB disruption was higher in subjects who demonstrated reperfusion by perfusion-weighted imaging, and that these patients were more likely to have a poor clinical outcome and increased risk of HT. Another retrospective review of imaging in stroke patients similarly demonstrated an association between reperfusion and BBB breakdown, which, in turn, correlated with a higher incidence of HT in those managed with IV recombinant tissue plasminogen.8 Contrast enhancement, which suggests BBB breakdown, occurs with both permanent and later reperfusion subgroups in 1 rat model;73 thus, the significance of this finding alone remains to be determined. Perfusion-weighted imaging provides quantitative and qualitative information regarding cerebral blood flow. In humans, Kidwell et al74 demonstrated that areas of postischemic hyperperfusion develop more infarction compared to those without hyperperfusion. This may be an indication of dysautoregulation due to parenchymal infarction described as “luxury perfusion” or arteriovenous shunting on catheter arteriography even at the time of a mechanical revascularization procedure. In this situation, a reduction in systemic blood pressure may be important to reduce potential hyperperfusion and its consequences. This type of dysautoregulation stands in contradistinction to patients with persistent hypoperfusion due to stroke. In the case of hypoperfusion, efforts to elevate the blood pressure may help to perfuse areas of deficient blood flow. Applying induced hypertension in patients with large perfusion–diffusion mismatch showed a decrease in hypoperfused tissue and was associated with improved cognitive outcomes.75 Nuclear medicine tests offer qualitative means to assess cerebral blood flow. Both 99 m Technicium-HMPAO SPECT and 113-Xenon injection have been used to examine degree of hyperperfusion following ischemia.15 Positron emission tomography (PET) offers both qualitative and quantitative measures of cerebral blood flow and metabolism although not often available in the acute care environment. While some PET imaging studies show that areas of reperfusion, and hyperperfusion in particular, have decreased oxygen extraction fraction and cerebral metabolism have universally poor outcomes, other studies utilizing PET suggest that hyperperfused tissue is not an indicator of poor outcomes or development of RI.15 Arterial spin-labeled MRI has also been used to provide quantitative cerebral blood flow measurement and is suggested as a means to predict the onset of HT.76 The application of imaging techniques, particularly measures of cerebral blood flow, as a guide to AIS management is an area of active research. NEUROPROTECTION Magnesium sulfate was demonstrated as a neuroprotectant in animal models of stroke and has shown signs of potential efficacy with an acceptable safety when delivered early after stroke onset in human studies. The Field Administration of Stroke Therapy-Magnesium trial was a randomized controlled trial that examined the effects of intravenous infusion of magnesium sulfate initiated within the first 2 h of symptom onset on long-term functional outcome of stroke patients.77 The trial enrolled 1700 patients and demonstrated no significant difference between the magnesium and placebo groups on outcome measures of disability at 90 d using the universal modified Rankin scale (mRS), serious adverse events, or death. Glyburide has been postulated to limit cerebral edema formation by reducing MMP-9 activation through its action as a selective sulfonylurea receptor inhibitor.78,79 The Glyburide Advantage in Malignant Edema and Stroke trial was a multicenter, prospective, randomized, double-blinded study in patients who suffered a large hemispheric stroke assigned to receive intravenous infusion of glyburide or placebo within 10 h of stroke onset. Although the results have not yet been published, the trial did not meet its primary or secondary endpoints. The glyburide group exhibited a 50% reduction in midline shift at 72 to 96 h and a 40% reduction in MMP-9 compared with placebo. Higher MMP-9 levels correlated with malignant brain edema; however, no statistical difference was found between the glyburide and the placebo groups in terms of patients requiring decompressive surgery, developing serious adverse event, or ipsilateral hemispheric or lesional swelling. Other MMP-9 inhibitors representing potential neuroprotectants include Minocycline and Edaravone. Minocycline has been evaluated for its ability to reduce MMP-9 levels as well as safety.80,81 Although large randomized trials are currently lacking, in a meta-analysis examining the effect of Edaravone in 3 trials including a total of 496 participants, Edavarone appeared to increase the proportion of participants with neurological improvement compared with the controls.82 Unfortunately, because of the lack of data, no agents can be recommended at this time. Therapeutic hypothermia in the management of postinfarct ischemia has been evaluated as a type of thermal neuroprotection.83,84 The postulated mechanisms include decreasing metabolic demand, inhibiting excitatory neurotransmitters, production and activation free radicals, as well as optimizing cerebral perfusion pressure through reducing the intracranial pressure and decreasing cerebral blood volume and edema.85 Large-scale trials examining the effect of hypothermia in AIS are underway and will hopefully elucidate the optimal mode, duration, and depth of hypothermia.86,87 This remains an area of great interest despite recent disappointing results when applied to cardiac arrest. CIRI AND THE RECENT NEUROENDOVASCULAR TRIALS Although the recent endovascular trials did not directly examine CIRI, they demonstrated the fundamentals of successful intervention in AIS and indirectly shed light on the incidence and predictors of CIRI. Although data on no-reflow and reperfusion hemorrhage was not reported, there was no difference in terms of development of symptomatic HTs between the interventional arm (0%-7.7%) and the control arm (1.9%-6.4%). With regard to poor functional outcome (mRS ≥ 3), patients with partial recanalization (Thrombolysis in Cerebral Infarction grading system (TICI) grade 2a) did not do as well as the patients with nearly complete or complete recanalization (TICI grade 2b/3) reflected as functional outcome (Table).88 TABLE 1. Selected Clinical Outcomes for Recent Randomized, Clinical Trials of Endovascular Treatments for Acute Ischemic Stroke Trial MR CLEAN ESCAPE EXTEND-IA SWIFT PRIME REVASCAT Key inclusion criteria NIHSS ≥ 2, age ≥ 18 NIHSS > 5, ASPECTS > 5, moderate/good collateral on CTA Eligible for IV-tPA < 4.5 h from onset, ischemic core <70 cm3, mismatcha Eligible for IV-tPA < 4.5 h from onset, age 18-80, NIHSS 8-29, ASPECTS≥6 Age 18-80, NIHSS ≥ 6, ASPECTS ≥ 7 Interventional arm Intra-arterial Therapy Intra-arterial Therapy Endovascular Thrombectomy with Solitaire FR stentriever Endovascular Thrombectomy with Solitaire FR stentriever Endovascular Thrombectomy with Solitaire FR stentriever Control arm Best Medical Management (+/– IV-tPA) Best Medical Management (+/– IV-tPA) IV-tPA only IV-tPA only Best Medical Management (+/– IV-tPA) Time window for intervention <6 h from onset <12 h from onset <6 h from onset <6 h from onset <8 h from onset Number of patients 500 (I:233, C:267) 315 (I:165, C:150) 70 (I:35, C:35) 196 (I:98, C:98) 206 (I:103 C:103) Mean/median age (yr) I:65.8, C:65.7 I:71, C:70 I:68.6, C:70.2 I:66.3, C:65.0 I:65.7, C:67.2 Median NIHSS I:17, C:18 I:16, C:17 I:17, C:13 I:17, C:17 I:17, C:17 Median ASPECTS I:9, C:9 I:9, C:9 NR I:9, C:9 I:7, C:8 Received IV-tPA I:87.1%, C:90.6% I:72.7%, C:78.7% I:100%, C:100% I:100%, C:100% I:68.0%, C:77.7% Median time from stroke onset to groin puncture (min) 260 241b 210 224 269 Intervention with stent retriever device 81.50% 86.10% 100% 100% 100% TICI 2b/3 recanalization 58.7% 72.4% 86.2% 88.0% 65.7% mRS 0-2 at 90 d; (improvement) I:32.6%, C:19.1%; (13.5%)* I:53.0%, C:29.3%; (23.7%)* I71.4%, C:40.0%; (31.4%)* I:60.2%, C:35.5%; (24.7%)* I:43.7%, C:28.2%; (15.5%)* Mortality at 30 d I:21.0%, C:22.1% I:10.4%, C:19.0% I:8.6%, C:20.0% I:9.2%, C:12.4% I:18.4%, C:15.5% Complications Failure to recanalize in interventional arm (TICI 0) 13.80% NR 3.40% 4.80% 7.80% TICI < 2b in interventional arm 41.30% NR 13.80% 12.00% 33.90% Embolization into new territory in interventional arm 8.6% 4.9% 5.7% NR 4.9% Any hemorrhagic transformationc I:6.9%, C:6.4% I:36.9%, C:17.3% I:11.4%, C:8.6% I:5.1%, C:7.1% I:5.8%, C:5.8% Symptomatic ICH I:7.7%, C:6.4% I:3.6%, C:2.7% I:0%, C:5.7% I:0%, C:3.1% I:1.9%, C:1.9% Poor outcome (mRS ≥ 3) I:67%, C:80% I:46.9%, C:69.3% I:28.6%, C:60.0% I:39.8%, C:64.5% I:56.3%, C:71.8% Trial MR CLEAN ESCAPE EXTEND-IA SWIFT PRIME REVASCAT Key inclusion criteria NIHSS ≥ 2, age ≥ 18 NIHSS > 5, ASPECTS > 5, moderate/good collateral on CTA Eligible for IV-tPA < 4.5 h from onset, ischemic core <70 cm3, mismatcha Eligible for IV-tPA < 4.5 h from onset, age 18-80, NIHSS 8-29, ASPECTS≥6 Age 18-80, NIHSS ≥ 6, ASPECTS ≥ 7 Interventional arm Intra-arterial Therapy Intra-arterial Therapy Endovascular Thrombectomy with Solitaire FR stentriever Endovascular Thrombectomy with Solitaire FR stentriever Endovascular Thrombectomy with Solitaire FR stentriever Control arm Best Medical Management (+/– IV-tPA) Best Medical Management (+/– IV-tPA) IV-tPA only IV-tPA only Best Medical Management (+/– IV-tPA) Time window for intervention <6 h from onset <12 h from onset <6 h from onset <6 h from onset <8 h from onset Number of patients 500 (I:233, C:267) 315 (I:165, C:150) 70 (I:35, C:35) 196 (I:98, C:98) 206 (I:103 C:103) Mean/median age (yr) I:65.8, C:65.7 I:71, C:70 I:68.6, C:70.2 I:66.3, C:65.0 I:65.7, C:67.2 Median NIHSS I:17, C:18 I:16, C:17 I:17, C:13 I:17, C:17 I:17, C:17 Median ASPECTS I:9, C:9 I:9, C:9 NR I:9, C:9 I:7, C:8 Received IV-tPA I:87.1%, C:90.6% I:72.7%, C:78.7% I:100%, C:100% I:100%, C:100% I:68.0%, C:77.7% Median time from stroke onset to groin puncture (min) 260 241b 210 224 269 Intervention with stent retriever device 81.50% 86.10% 100% 100% 100% TICI 2b/3 recanalization 58.7% 72.4% 86.2% 88.0% 65.7% mRS 0-2 at 90 d; (improvement) I:32.6%, C:19.1%; (13.5%)* I:53.0%, C:29.3%; (23.7%)* I71.4%, C:40.0%; (31.4%)* I:60.2%, C:35.5%; (24.7%)* I:43.7%, C:28.2%; (15.5%)* Mortality at 30 d I:21.0%, C:22.1% I:10.4%, C:19.0% I:8.6%, C:20.0% I:9.2%, C:12.4% I:18.4%, C:15.5% Complications Failure to recanalize in interventional arm (TICI 0) 13.80% NR 3.40% 4.80% 7.80% TICI < 2b in interventional arm 41.30% NR 13.80% 12.00% 33.90% Embolization into new territory in interventional arm 8.6% 4.9% 5.7% NR 4.9% Any hemorrhagic transformationc I:6.9%, C:6.4% I:36.9%, C:17.3% I:11.4%, C:8.6% I:5.1%, C:7.1% I:5.8%, C:5.8% Symptomatic ICH I:7.7%, C:6.4% I:3.6%, C:2.7% I:0%, C:5.7% I:0%, C:3.1% I:1.9%, C:1.9% Poor outcome (mRS ≥ 3) I:67%, C:80% I:46.9%, C:69.3% I:28.6%, C:60.0% I:39.8%, C:64.5% I:56.3%, C:71.8% ASPECTS = Alberta stroke program early computed tomography score; C = control; CTA = computed tomography angiography; I = interventional; ICH = intracranial hemorrhage; IV-tPA = intravenous recombinant tissue plasminogen activator; mRS = modified Rankin Scale; NIHSS = National Institutes of Health Stroke Scale; NR = not reported; TICI = thrombolysis in cerebral ischemia. *Statistically significant (P < .05). aMismatch defined, based on CT perfusion imaging, as a mismatch ratio >1.2 and an absolute mismatch volume >10 cm3. bTime from stroke onset to first reperfusion (time to groin puncture not reported). cDefined as any radiological ICH, including parenchymal hematoma (PH) or hemorrhagic infarction (HI). View Large TABLE 1. Selected Clinical Outcomes for Recent Randomized, Clinical Trials of Endovascular Treatments for Acute Ischemic Stroke Trial MR CLEAN ESCAPE EXTEND-IA SWIFT PRIME REVASCAT Key inclusion criteria NIHSS ≥ 2, age ≥ 18 NIHSS > 5, ASPECTS > 5, moderate/good collateral on CTA Eligible for IV-tPA < 4.5 h from onset, ischemic core <70 cm3, mismatcha Eligible for IV-tPA < 4.5 h from onset, age 18-80, NIHSS 8-29, ASPECTS≥6 Age 18-80, NIHSS ≥ 6, ASPECTS ≥ 7 Interventional arm Intra-arterial Therapy Intra-arterial Therapy Endovascular Thrombectomy with Solitaire FR stentriever Endovascular Thrombectomy with Solitaire FR stentriever Endovascular Thrombectomy with Solitaire FR stentriever Control arm Best Medical Management (+/– IV-tPA) Best Medical Management (+/– IV-tPA) IV-tPA only IV-tPA only Best Medical Management (+/– IV-tPA) Time window for intervention <6 h from onset <12 h from onset <6 h from onset <6 h from onset <8 h from onset Number of patients 500 (I:233, C:267) 315 (I:165, C:150) 70 (I:35, C:35) 196 (I:98, C:98) 206 (I:103 C:103) Mean/median age (yr) I:65.8, C:65.7 I:71, C:70 I:68.6, C:70.2 I:66.3, C:65.0 I:65.7, C:67.2 Median NIHSS I:17, C:18 I:16, C:17 I:17, C:13 I:17, C:17 I:17, C:17 Median ASPECTS I:9, C:9 I:9, C:9 NR I:9, C:9 I:7, C:8 Received IV-tPA I:87.1%, C:90.6% I:72.7%, C:78.7% I:100%, C:100% I:100%, C:100% I:68.0%, C:77.7% Median time from stroke onset to groin puncture (min) 260 241b 210 224 269 Intervention with stent retriever device 81.50% 86.10% 100% 100% 100% TICI 2b/3 recanalization 58.7% 72.4% 86.2% 88.0% 65.7% mRS 0-2 at 90 d; (improvement) I:32.6%, C:19.1%; (13.5%)* I:53.0%, C:29.3%; (23.7%)* I71.4%, C:40.0%; (31.4%)* I:60.2%, C:35.5%; (24.7%)* I:43.7%, C:28.2%; (15.5%)* Mortality at 30 d I:21.0%, C:22.1% I:10.4%, C:19.0% I:8.6%, C:20.0% I:9.2%, C:12.4% I:18.4%, C:15.5% Complications Failure to recanalize in interventional arm (TICI 0) 13.80% NR 3.40% 4.80% 7.80% TICI < 2b in interventional arm 41.30% NR 13.80% 12.00% 33.90% Embolization into new territory in interventional arm 8.6% 4.9% 5.7% NR 4.9% Any hemorrhagic transformationc I:6.9%, C:6.4% I:36.9%, C:17.3% I:11.4%, C:8.6% I:5.1%, C:7.1% I:5.8%, C:5.8% Symptomatic ICH I:7.7%, C:6.4% I:3.6%, C:2.7% I:0%, C:5.7% I:0%, C:3.1% I:1.9%, C:1.9% Poor outcome (mRS ≥ 3) I:67%, C:80% I:46.9%, C:69.3% I:28.6%, C:60.0% I:39.8%, C:64.5% I:56.3%, C:71.8% Trial MR CLEAN ESCAPE EXTEND-IA SWIFT PRIME REVASCAT Key inclusion criteria NIHSS ≥ 2, age ≥ 18 NIHSS > 5, ASPECTS > 5, moderate/good collateral on CTA Eligible for IV-tPA < 4.5 h from onset, ischemic core <70 cm3, mismatcha Eligible for IV-tPA < 4.5 h from onset, age 18-80, NIHSS 8-29, ASPECTS≥6 Age 18-80, NIHSS ≥ 6, ASPECTS ≥ 7 Interventional arm Intra-arterial Therapy Intra-arterial Therapy Endovascular Thrombectomy with Solitaire FR stentriever Endovascular Thrombectomy with Solitaire FR stentriever Endovascular Thrombectomy with Solitaire FR stentriever Control arm Best Medical Management (+/– IV-tPA) Best Medical Management (+/– IV-tPA) IV-tPA only IV-tPA only Best Medical Management (+/– IV-tPA) Time window for intervention <6 h from onset <12 h from onset <6 h from onset <6 h from onset <8 h from onset Number of patients 500 (I:233, C:267) 315 (I:165, C:150) 70 (I:35, C:35) 196 (I:98, C:98) 206 (I:103 C:103) Mean/median age (yr) I:65.8, C:65.7 I:71, C:70 I:68.6, C:70.2 I:66.3, C:65.0 I:65.7, C:67.2 Median NIHSS I:17, C:18 I:16, C:17 I:17, C:13 I:17, C:17 I:17, C:17 Median ASPECTS I:9, C:9 I:9, C:9 NR I:9, C:9 I:7, C:8 Received IV-tPA I:87.1%, C:90.6% I:72.7%, C:78.7% I:100%, C:100% I:100%, C:100% I:68.0%, C:77.7% Median time from stroke onset to groin puncture (min) 260 241b 210 224 269 Intervention with stent retriever device 81.50% 86.10% 100% 100% 100% TICI 2b/3 recanalization 58.7% 72.4% 86.2% 88.0% 65.7% mRS 0-2 at 90 d; (improvement) I:32.6%, C:19.1%; (13.5%)* I:53.0%, C:29.3%; (23.7%)* I71.4%, C:40.0%; (31.4%)* I:60.2%, C:35.5%; (24.7%)* I:43.7%, C:28.2%; (15.5%)* Mortality at 30 d I:21.0%, C:22.1% I:10.4%, C:19.0% I:8.6%, C:20.0% I:9.2%, C:12.4% I:18.4%, C:15.5% Complications Failure to recanalize in interventional arm (TICI 0) 13.80% NR 3.40% 4.80% 7.80% TICI < 2b in interventional arm 41.30% NR 13.80% 12.00% 33.90% Embolization into new territory in interventional arm 8.6% 4.9% 5.7% NR 4.9% Any hemorrhagic transformationc I:6.9%, C:6.4% I:36.9%, C:17.3% I:11.4%, C:8.6% I:5.1%, C:7.1% I:5.8%, C:5.8% Symptomatic ICH I:7.7%, C:6.4% I:3.6%, C:2.7% I:0%, C:5.7% I:0%, C:3.1% I:1.9%, C:1.9% Poor outcome (mRS ≥ 3) I:67%, C:80% I:46.9%, C:69.3% I:28.6%, C:60.0% I:39.8%, C:64.5% I:56.3%, C:71.8% ASPECTS = Alberta stroke program early computed tomography score; C = control; CTA = computed tomography angiography; I = interventional; ICH = intracranial hemorrhage; IV-tPA = intravenous recombinant tissue plasminogen activator; mRS = modified Rankin Scale; NIHSS = National Institutes of Health Stroke Scale; NR = not reported; TICI = thrombolysis in cerebral ischemia. *Statistically significant (P < .05). aMismatch defined, based on CT perfusion imaging, as a mismatch ratio >1.2 and an absolute mismatch volume >10 cm3. bTime from stroke onset to first reperfusion (time to groin puncture not reported). cDefined as any radiological ICH, including parenchymal hematoma (PH) or hemorrhagic infarction (HI). View Large CIRI MANAGEMENT Reperfusion hemorrhage develops secondary to hyperperfusion as a result of an interplay between several factors including a combination of abnormal vasodilation increased cerebral blood volume, diminished oxygen extraction fraction, and mildly increased rate of cerebral oxygen metabolism.15 Although data regarding the management of CIRI are lacking, a timely diagnosis and a step-wise strategy are integral. The best approach to managing CIRI involves a thorough understanding of conditions known to predispose to hemorrhagic change in patients undergoing fibrinolysis. The time from administration of thrombolytic therapy to HT occurrence varies in literature ranging from 5 to 10 d up to 10 d89 post-treatment. However, the majority of HT post-IV-tPA in ischemic stroke patients occurs in the first 36 h post-treatment.90,91 Multiple studies have sought to find predictors for hemorrhagic complications following endovascular reperfusion therapy. Patients with evidence of radiographic large hemispheric infarct (ASPECTS < 7) before mechanical reperfusion, or TIMI ≥ 2 after reperfusion with an ASPECTS < 7 were more likely to develop HT.92 Additionally multimodal endovascular therapies with IV-tPA were associated with higher risk of developing parenchymal hematomas. Furthermore, tandem occlusions, hyperglycemia on admission, and poorly controlled hypertension with a systolic BP > 220 mm Hg or diastolic BP >105 mm Hg were also risk factors for HT.93,94 Optimal Blood Pressure Management Avoidance of blood pressure variability in the setting of spontaneous intraparenchymal hemorrhage has been shown to have a significant reduction in hematoma expansion.95 The management approach of CIRI has been extrapolated from intraparenchymal hemorrhage, hence strict blood pressure parameters in cases of HT after endovascular reperfusion is frequently employed at a goal systolic BP of 140 to 160 mm Hg.96 Reversal of Coagulopathy Several studies have explored the association between HT-post thrombolysis treatments with IV-tPA. In a meta-analysis of 55 studies, Whiteley et al97 found positive associations between post-IV-tPA HT and the following factors: older age, high NIHSS (National Institutes of Health Stroke Scale) on presentation, higher plasma glucose, antiplatelet agents, any warfarin use, statins, early CT ischemic changes, leukoarioisis, atrial fibrillation, diabetes, previous ischemic heart or cerebrovascular diseases, and congestive cardiac failure. However, when measured individually, they were unable to predict the risk of HT post-thrombolysis with t-PA. Occurrence of HT post-thrombolysis triggers clinicians to reverse all potential reversible causative agents (for example, antiplatelet, anticoagulations, and the newly administered thrombolysis [t-PA]). The American Heart Association recommends administering platelets and cryoprecipitate to reverse IV-tPA, although there is evidence that treatment of post-thrombolysis symptomatic intracerebral hemorrhage may not significantly reduce the likelihood of in-hospital mortality or hematoma expansion.88 Recombinant t-PA is best reversed with cryoprecipitate and platelet transfusion. Recombinant activated factor VII has been extensively studied and although it reduced hematoma growth, it did not improve survival or functional outcome after intracerebral hemorrhage.98 Other therapeutic strategies have been used to reverse the thrombolytic effect of tPA; aminocaproic acid has been used to reverse tPA using its antifibrinolytic property.99 Furthermore, fresh frozen plasma to replace fibrin degraded by the tPA effect has been proposed and used to reverse thrombolysis induced HT.99 Medications targeting the conversion of plasminogen to plasmin to reverse tPA effect in stroke patients have been reported, for example, French et al100 reported a case of a Jehovah's Witness stroke patient suffering HT post-tPA treated with tranexemic acid to control hematoma expansion. Patients on vitamin K-dependent anticoagulation (warfarin) reversal can be achieved by using vitamin K and FFP. Prothrombin complex concentrates have been used with reperfusion hemorrhages in patients on novel oral anticoagulants with varying success rates.101 Recently, the FDA approved Idarucizumab for the reversal of the direct thrombin inhibitor, dabigatran.102 Two other antidotes are in various stages of development for the reversal of other direct thrombin inhibitors. In cardiac surgery literature, platelet transfusions have been used to prevent excessive bleeding with use of the novel oral anticoagulants and GP IIb/IIIa inhibitors, as no reversal agents exist to date. Reversal of heparin with protamine sulfate can be used with CIRI that develops in the immediate post-recanalization period. Cerebral Edema and Intracranial Pressure Young patients with NIHSS > 15, hypodensity of >50% of the MCA territory, posterior cerebral artery and superior cerebellar artery infarcts predict the development of life-threatening edema and herniation.103 Clinical signs such as decline in Glasgow Coma Scale by 2 or more points, unilaterally dilated or poorly responsive pupils, or extensor posturing may all be heralding signs of active brainstem herniation and requires emergent management.103 Head of the bed elevation and avoiding neck pressure should be ensured to prevent any venous obstruction. Hyperventilation to target a pCO2 of 35 to 40 mm Hg should only be done transiently (<30 min). Osmolar therapy can be initiated with an osmolarity goal of ≤340 mOsm/L and osmolar gap <10 to 20 or Na > 160 mEq/L,104 with no proven efficacy of targeting a sodium >155 mEq/L.103 Induction of hypothermia to 33°C to 35°C for duration of 24 to 48 h in elevated intracranial pressure carries the theoretical neuroprotective benefit and has been shown to decrease metabolic demand, reduce cerebral blood volume as well as brain edema.84-87 Decompressive Hemicraniectomy Decompressive hemicraniectomy in the setting of intracerebral hemorrhage after endovascular reperfusion has not been evaluated in a randomized trial. Three randomized trials to date have shown decreased mortality rates and possibly improved functional outcomes in cases of large MCA infarcts treated with hemicraniectomy in the first 48 h after stroke; however, patients who were treated with thrombolytics were excluded.105-107 This evidence suggests that this procedure is uncommon in HT after endovascular reperfusion, likely due to concern for operating on patients who remain anticoagulated or received antiplatelet medications with prolonged effect. FUTURE DIRECTION Among the goals of mechanical thrombectomy is achieving prompt, enduring vessel recanalization, while accruing minimal to no risk of CIRI. Many questions remain unanswered by the existing evidence. With an anticipated increase in eligible mechanical thrombectomy cases, CIRI poses an inordinate challenge due to the lack of targeted management approach, as well as a thorough comprehension of its multifaceted pathobiology. 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Google Scholar CrossRef Search ADS PubMed 106. Juttler E , Schwab S , Schmiedek P et al. Decompressive Surgery for the Treatment of Malignant Infarction of the Middle Cerebral Artery (DESTINY): a randomized, controlled trial . Stroke . 2007 ; 38 ( 9 ): 2518 - 2525 . Google Scholar CrossRef Search ADS PubMed 107. Hofmeijer J , Kappelle LJ , Algra A , Amelink GJ , van Gijn J , van der Worp HB . Surgical decompression for space-occupying cerebral infarction (the Hemicraniectomy After Middle Cerebral Artery infarction with Life-threatening Edema Trial [HAMLET]): a multicentre, open, randomised trial . Lancet Neurol. 2009 ; 8 ( 4 ): 326 - 333 . Google Scholar CrossRef Search ADS PubMed COMMENT This article is a comprehensive review of the literature on cerebral ischemic reperfusion injury (CIRI) and hemorrhagic transformation (HT) after thrombolysis of a large vessel occlusion. This is a very important concept as neurosurgeons are beginning to be the leaders in the field of emergent endovascular stroke management. The concept of neuroprotective agents is certainly an area where we need more research and one that promises to revolutionize stroke outcomes in a similar way stent-retriever technology already has. CIRI and HT are contributing factors to this and the authors are congratulated on bringing attention to the pathophysiology of these complex concepts. Ryan P. Morton Louis J. Kim Seattle, Washington Copyright © 2017 by the Congress of Neurological Surgeons This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

Journal

NeurosurgeryOxford University Press

Published: Jul 11, 2017

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