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 »  Management of St...
 »  Surgical Interve...
 »  Tranexamic Acid ...
 »  Prophylactic Hyp...
 »  Choice of Anesth...
 »  Extended Window ...
 »  Control of Arter...
 »  Dabigatran versu...
 »  TXA for Spontane...
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REVIEW ARTICLE
Year : 2021  |  Volume : 69  |  Issue : 3  |  Page : 573-577

Practice Changing Articles in Neuroanesthesiology and Neurocritical Care in Recent Years: A Literature Review


1 Institute of Neurosciences, AIG Hospitals, Hyderabad, Telangana, India
2 Department of Anesthesiology and Pain Medicine, Fortis Memorial Research Institute, Sector - 44, Opposite HUDA City Centre, Gurgaon, Haryana, India

Date of Submission02-Sep-2020
Date of Decision03-Mar-2021
Date of Acceptance12-Apr-2021
Date of Web Publication24-Jun-2021

Correspondence Address:
Dr. Hari Hara Dash
Department of Anesthesiology and Pain Medicine, Fortis Memorial Research Institute, Sector - 44, Opposite HUDA City Centre, Gurgaon - 122 002, Haryana
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.319203

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 » Abstract 


Background: Neuroanesthesiology and neurocritical care are constantly evolving branches of clinical neuroscience, and patient management is often influenced by literature such as randomized controlled trials, systematic reviews, and meta-analyses. Many controversies still exist in the management of neurologically injured patients, and most research in this field does not translate into significant changes in clinical practice.
Objective: This review aims to discuss studies of clinical importance published in preeminent journals over the time period 2017–2020, which may have the potential to influence our current management protocols.
Methods: In this review, key articles have been selected to represent neuroemergencies where recent evidence may prompt changes in practice. In preparing this article, contents of prominent journals between 2017 and 2020 were reviewed, and relevant articles were also identified from abstraction services. Areas chosen for consideration are high-quality trials researching the management of pathologies such as epilepsy, traumatic brain injury and acute ischemic stroke, cortical venous sinus thrombosis, as well as hemorrhagic stroke. For each subject, a brief review of the article is followed by “take home” points.
Conclusion: We have attempted to perform a review of some of the highest impact medical journals from 2017 till 2020 and have summarized articles with the potential to change clinical practices for readers so that management protocols for acute neuroemergencies to ensure good outcomes may be formulated.


Keywords: Neuroanesthesiology, neurocritical care, stroke, traumatic brain injury
Key Message: Adherence to evidence-based protocols may help optimize neurological outcomes in patients with acute neuro-emergencies.


How to cite this article:
Chavali S, Dash HH. Practice Changing Articles in Neuroanesthesiology and Neurocritical Care in Recent Years: A Literature Review. Neurol India 2021;69:573-7

How to cite this URL:
Chavali S, Dash HH. Practice Changing Articles in Neuroanesthesiology and Neurocritical Care in Recent Years: A Literature Review. Neurol India [serial online] 2021 [cited 2021 Jul 28];69:573-7. Available from: https://www.neurologyindia.com/text.asp?2021/69/3/573/319203




Management of patients with acute neuroemergencies, i.e., status epilepticus, ischemic stroke, head injury, intracranial hemorrhage, and cerebral venous thrombosis (CVT) is not only a great challenge for the neuroanesthesiologists and neurocritical care physicians but also a great concern for the neurologists, neurosurgeons, and neurointerventionists. Prompt and effective treatment is paramount for good neurologic recovery, and protocol-based management strategies are being pursued all over the world. These treatment protocols, over a period of time, remain shrouded in controversies. This is because the clinical disciplines of neurosciences are constantly evolving branches and rapid strides have been made in the management of these patients due to continuing clinical research in their respective fields. Treatment paradigms for acute neuroemergencies are ever changing due to randomized multicenter controlled trials, systemic reviews, and meta-analyses.

Have management strategies of acute neuroemergencies undergone any recent changes? We have reviewed some of the preeminent medical journals from 2017 till 2020, and relevant articles were also identified for the readers so that best management protocols could be formulated for patients with acute neuroemergencies to accrue good neurological outcomes.


 » Management of Status Epilepticus Top


Management of status epilepticus is usually according to an algorithm-based approach that escalates pharmacotherapy with the view of terminating seizure activity as early as possible. Benzodiazepines have conventionally been used as first-line medication for seizure management, and antiepileptic drugs (AED) and intravenous anesthetic agents form the mainstay for prolonged seizure activity.[1] However, the optimal sequence of drug administration remains a subject of debate. In studies conducted on the pediatric population, levetiracetam and phenytoin were found to be similar for the management of status epilepticus; however, data for the adult population remains limited.[2]

The ESETT randomized, blinded, adaptive trial in which the authors had compared the efficacy and safety of three intravenous anticonvulsive agents – levetiracetam, sodium valproate, and fosphenytoin in terms of seizure control at 60 min – in patients with status epilepticus who had received first-line antiepileptic therapy in the form of benzodiazepines.[3] In this trial, adults, as well as pediatric patients with generalized seizures lasting >5 min, were initially administered benzodiazepines (diazepam/lorazepam/midazolam). The patients were allocated to receive levetiracetam (60 mg/kg; n = 145), fosphenytoin (20 mg PE/kg; n = 118), or valproate (40 mg/kg; n = 121). The primary endpoint was seizure termination and improvement in mental status 60 min after starting the infusion, which revealed no significant difference between the three drugs. Administration of fosphenytoin was associated with a higher incidence of hypotension than levetiracetam and valproate. Approximately 50% of patients in all three groups showed ongoing seizure activity even after an hour of drug administration. The authors concluded that in benzodiazepine refractory status epilepticus, administration of these agents led to seizure cessation and improved alertness at 60 min in approximately half the patients, and all three agents were associated with a similar incidence of adverse events.

Take home points

  1. All conventional second-line antiepileptic agents showed only approximately 50% seizure control at 60 min, suggesting that a change in approach to status epilepticus may be warranted with earlier administration of third-tier therapy.
  2. All three agents had similar results in terms of seizure termination. This suggests that the drug with the safest side effect profile should be chosen for the treatment of status epilepticus.
  3. The dose of levetiracetam administered was 60 mg/kg, up to a maximum of 4.5 g IV. Larger dosing of levetiracetam may be warranted with the end goal of achieving early seizure termination, given the relatively few side effects.



 » Surgical Intervention for Drug Refractory Epilepsy in Children Top


Drug refractory epilepsy is defined as the failure of two AED schedules, and failure to treat this condition in a timely manner remains an important cause for impairment of intellectual and psychosocial parameters in children. In this condition, surgical management may be undertaken with the objective of reducing seizures and improving quality of life. Surgical technique as well as success depends on several factors such as the underlying pathology and presurgical evaluation and may result in improved outcomes as well as myriad neurological deficits. Previous literature analyzing surgical outcomes for drug-refractory epilepsy included adult patients.[4]

This study was a single-center randomized trial that aimed to evaluate if surgical intervention along with appropriate medical therapy was associated with an improvement in freedom from seizures at 12 months as compared to medical therapy alone in pediatric patients with drug-resistant epilepsy.[5] One hundred sixteen pediatric patients aged less than 18 years with drug-refractory epilepsy were randomized to undergo surgery along with appropriate medical therapy or to medical therapy alone. The median age of the patients in the surgery group was 9 and 10 in the medical management group. The primary outcome of freedom from seizures at 12 months was significantly different between the two groups, with 44 patients (77%) in the surgery group being seizure-free, as compared to 4 patients (7%) in the medical therapy group. Secondary outcome measures such as the Hague Seizure Severity score, Child Behavior Checklist, Pediatric Quality of Life Inventory, and the Vineland Social Maturity Scale also favored the surgical group. The authors concluded that children who underwent epilepsy surgery had a significantly higher rate of freedom from seizures and better quality of life and behavior scores than those who received medical therapy alone at 12 months.

Take home points

  1. Surgical intervention was associated with better outcomes in terms of seizure control as well as behavioral and quality of life indices as compared to medical management alone.
  2. Adverse events were seen in a third of the patients who underwent surgery; however, these were expected neurological deficits related to the area of resection. Major adverse events were calculated to be about 3.5%, making pediatric epilepsy surgery a safe proposition.
  3. Surgical intervention should be offered to children with drug-refractory epilepsy with lesions amenable to resection.



 » Tranexamic Acid (TXA) in Traumatic Brain Injury (TBI) Top


Antifibrinolytic therapy with TXA has been shown to reduce blood loss in patients undergoing surgery and in conditions such as postpartum hemorrhage. The CRASH-2 trial studied the effect of administration of TXA in trauma patients and found that early administration of the drug resulted in decreased all-cause mortality compared to placebo when administered within 8 h of injury.[6] Subsequently, subgroup analysis of TBI patients within the CRASH-2 cohort showed a statistically insignificant reduction in intracranial hemorrhage expansion and mortality in patients who received TXA.[7]

The CRASH-3 trial was a placebo-controlled randomized controlled trial that sought to evaluate if administration of TXA within 3 h of injury was associated with a reduction of TBI-associated in-hospital mortality within 4 weeks.[8] Patients were enrolled if they presented with a GCS of <13 or if they presented with intracranial bleeding on CT with no major extracranial bleeding. After recruitment, patients received 1-g TXA as a bolus, followed by an 8-h infusion of 1 g intravenously. Over 9,000 patients were recruited and the primary outcome of 28 days in-hospital TBI-associated mortality showed no statistically significant difference between the two groups. Subgroup analysis showed that in patients with GCS 9–15, 28 days in-hospital TBI associated mortality was significantly reduced in the TXA group as compared to placebo. Secondary outcome analysis showed that early drug administration (<60 min) was associated with greater efficacy in mild and moderate TBI, and increased risk of vasoocclusive events or seizures was not seen in the TXA group as compared to placebo. The authors concluded that administration of TXA is safe in TBI and that treatment within 3 h reduces head injury-associated deaths.

Take home points

  1. TXA is safe to administer in TBI, without significantly increasing the risk of seizure activity or vasoocclusive events in this patient population.
  2. Patients with mild to moderate TBI with evidence of bleeding on CT benefit from and should receive TXA.
  3. Patients should receive TXA as early as possible following TBI.



 » Prophylactic Hypothermia in Traumatic Brain Injury Top


Previous studies aiming to evaluate the utility of hypothermia as a therapeutic measure in the management of TBI have failed to show any significant utility. However, hypothermia remains a theoretically and physiologically attractive treatment option to ensure neuroprotection and reduce secondary brain injury.[9] Induction of hypothermia may be associated with other complications such as cardiac arrhythmias and coagulation abnormalities, which may outweigh the benefits it offers as neuroprotection.

The POLAR trial was a randomized controlled trial that compared the effect of rapidly induced hypothermia at the prehospital stage with standard care in terms of neurological outcomes at 6 months in patients with severe blunt TBI.[10] Randomization was done by prehospital paramedics or emergency department physicians. Five hundred and ten patients were randomized to receive cooling (n = 260) with an IV infusion of 0.9% NS at 4°C aiming for a temperature of 35°C, subsequently maintained with surface temperature control, or control group (n = 240). Temperatures were maintained in the cooling group for approximately 72 h, and rewarming was guided by ICP. The primary outcome, which measured neurological outcomes at 6 months following injury, was not significantly different between the two groups, with secondary outcomes such as mortality at hospital discharge, mortality at 6 months, adverse bleeding, etc., not being significantly different. The authors concluded that early and sustained prophylactic hypothermia did not improve neurological outcomes.

Take home points

  1. Hypothermia did not improve neurological outcomes; however, adverse effects such as pneumonia, bradycardia, and vasopressor use were more frequent.
  2. Prophylactic hypothermia does not seem to be of benefit in the management of severe TBI, but the role of hypothermia as a management option for refractory ICP cannot be ruled out.



 » Choice of Anesthetic Regimen for Endovascular Stroke Therapy Top


Endovascular mechanical thrombectomy is increasingly being seen as the standard of care for acute ischemic stroke secondary to anterior circulation large vessel occlusion. The procedure may be performed under local or general anesthesia, with various advantages as well as disadvantages for either technique. Previous literature suggested that general anesthesia was associated with increased case fatality as well as increased length of stay when compared with local anesthesia techniques.[11],[12] General anesthesia was thought to be an independent predictor of poor outcomes; however, sicker patients (with higher NIHSS) required a general anesthetic regimen, suggesting an association with poor outcomes rather than causality.

The GOLIATH trial of 2017 was a single-center prospective, randomized, blinded study that aimed to evaluate infarct growth seen in MRI scans performed before and after thrombectomy in patients who received general anesthesia or conscious sedation regimens.[13] One hundred and twenty-eight patients with large vessel anterior circulation occlusions and a median NIHSS score of 18 [IQR 14-21] were randomized to receive either general anesthesia (GA) (n = 65) or conscious sedation (CS) (n = 63). Baseline demographic, clinical, and treatment parameters were comparable between the two groups, with the exception of postinduction blood pressures. Blood pressures were significantly lower in the GA group as compared to the CS group at groin puncture (131 mmHg vs 156 mmHg), despite similar baseline systolic BP. The primary endpoint of infarct growth showed no statistically significant difference between the two groups. The authors concluded that in patients undergoing thrombectomy for acute ischemic stroke, GA did not result in worse clinical outcomes compared to CS.

Take home points

  1. The choice of anesthetic regimen (GA vs CS) is not associated with significant differences in neurological outcomes or infarct expansion in patients presenting with acute ischemic stroke.
  2. Maintenance of blood pressures within may influence outcomes and is of vital importance.
  3. Conscious sedation is associated with risks of excessive sedation and associated complications such as aspiration which may reduce its utility compared to general anesthesia, given the similar outcomes.



 » Extended Window for Stroke Thrombectomy Top


Patients who present to the hospital with acute ischemic stroke may benefit from endovascular interventions such as thrombectomy, provided they present early in their clinical course. Previous studies have evaluated the potential benefits of performing thrombectomy and showed that the greatest benefit was to be gained when performed within 6 h of symptom onset.[14] Ischemic neural tissue within the penumbra may still be viable and is characterized by clinical deficits that are disproportionate to the volume of infarct seen on imaging.

The DAWN investigators aimed to evaluate the effect of mechanical thrombectomy in addition to standard medical care on functional outcomes at 90 days, in patients who presented with a mismatch between clinical deficits and infarcts 6–24 h after symptoms of acute stroke.[15] This was a randomized trial, which enrolled 206 adult patients with ICA or MCA stroke, who presented with a baseline mRS of 0 or 1, and an NIHSS of > 10. Baseline characteristics were similar between the two groups. The thrombectomy group had a higher incidence of functional independence at 90 days as compared to the control group of standard medical management (49% vs 13%). Secondary outcomes such as early response to therapy, vessel recanalization at 24 h, and infarct volume at 24 h favored the thrombectomy group, with no significant differences noted in safety outcomes such as all-cause or stroke associated mortality at 90 days as compared to control. The authors concluded that in patients with ICA/MCA strokes and mismatch between clinical symptoms and infarct volumes on imaging who present within 6–24 h, thrombectomy was superior in terms of functional independence at 90 days.

Take home points

  1. Thrombectomy is now the standard of care in a subset of patients who present with deficit/infarct mismatch outside the conventional window period.
  2. This may be a viable treatment option for anatomically less severe strokes with lower infarct volumes.
  3. Patients with larger infarcts may require more individualized therapy, requiring larger studies. However, tissue-based approaches to stroke therapy seem to be the best therapeutic modality.



 » Control of Arterial Blood Pressure in Acute Ischemic Stroke Top


Extremes of blood pressure are associated with poor clinical outcomes as well as increased mortality in acute ischemic stroke. However, control of blood pressure using pharmacological agents remains a controversial topic, with consensus guidelines recommending maintenance of SBP between 140 and 220 mmHg, and intervention only when SBP exceeds 220 mmHg.[16] Optimal values for the maintenance of blood pressures in ischemic stroke remain unclear.[17]

The MAPAS study aimed to compare three prespecified systolic blood pressure ranges in terms of improved functional outcomes at 90 days in patients presenting within 12 h of acute ischemic stroke.[18] This was a single-center randomized controlled trial which enrolled 231 adult patients who were ineligible for IV thrombolysis, presented within 12 h of symptom onset, and randomized patients to three groups (SBP 140–160 mmHg, SBP 161–180 mmHg, SBP 181–200 mmHg) using vasoactive agents such as norepinephrine, esmolol, and nitroprusside to achieve target values. No significant differences were seen in the primary outcome of neurological outcomes at 90 days between the three groups. Secondary outcome analysis revealed similar rates of mortality between the three groups; however, there was a higher incidence of symptomatic ICH in the group with the highest SBP (1% vs 3% vs 9%, P < 0.05). The authors concluded that neurological functional outcome at 90 days was not different among the three groups, but chances for good outcomes were greater in patients in whom SBP was maintained between 161 and 180 mmHg.

Take home points

  1. Intervention for blood pressure in acute ischemic stroke is best avoided if SBP lies within the range of 120-180mmHg.
  2. The greatest probability of good outcomes was in patients who did not receive pharmacological manipulation of their blood pressures. The increased incidence of adverse events was attributed to the infusion of norepinephrine.
  3. Augmentation of blood pressure may be limited to patients with significant perfusion/diffusion mismatch.



 » Dabigatran versus Warfarin in the Treatment of CVT Top


CVT is a subtype of stroke that is caused by thrombosis of the dural venous sinuses or the deep cerebral veins. This pathology is more prevalent in low- and middle-income countries and generally carries a good chance of full neurological recovery. These patients are at a higher risk of recurrent venous thromboembolisms in the cerebral as well as systemic venous systems and are usually anticoagulated with vitamin K antagonists such as warfarin for an extended duration of time.[19] Dabigatran etexilate is a new oral anticoagulant agent that acts by direct thrombin antagonism and has been seen to be effective in stroke prevention for patients with atrial fibrillation.[20]

The RE-SPECT CVT trial was conducted to compare the efficacy and safety of dabigatran with that of dose-adjusted warfarin in preventing recurrent thromboembolism in patients who have experienced CVT.[21] This was a prospective randomized, multicentre clinical trial that enrolled 120 adult patients with CVT to receive either warfarin or dabigatran 5 days after the start of parenteral anticoagulation, for a period of 24 weeks. The primary outcome was a composite of the number of patients with complications such as major bleeding or venous thromboembolism, which were not different between the two groups. Neither drug was associated with new intracranial hemorrhages or enlargement of baseline hemorrhagic lesions. The authors concluded that both dabigatran and dose adjusted warfarin may be safe options to prevent recurrent VTE in patients with CVT.

Take home points

  1. Dabigatran appears to similar to dose-adjusted warfarin in the treatment of CVT in terms of safety, as well as efficacy.
  2. Dabigatran may be a suitable alternative to warfarin for long-term therapy in cases of atypical site thromboses, given the reduced need for testing of parameters such as INR.



 » TXA for Spontaneous Intracerebral Hemorrhage Top


Parenchymal cerebral hemorrhage is associated with high morbidity as well as mortality. Expansion of the hematoma due to various causes may be a reason for secondary brain injury. Several early interventions to limit hematoma expansion such as surgery and pharmacological lowering of blood pressure have been studied.[22],[23] TXA has been used for other indications such as trauma and surgery and has a role as a hemostatic agent.

The TICH-2 trial was a multicentric randomized controlled trial evaluating the effect of TXA on functional status at 90 days compared to placebo in patients with spontaneous intracerebral hemorrhage.[24] The authors enrolled over 2000 adult patients presenting with ICH within 8 h of symptom onset and randomized them to receive either 1-g TXA IV followed by 1 g over the next 8 h or placebo. Baseline characteristics were comparable between the two groups. The primary outcome was functional status at 90 days as defined by mRS, which was comparable between the two groups. Secondary outcomes such as death at 90 days and length of hospital stay were also comparable between the two groups. The authors concluded that TXA did not affect functional status at 90 days but was associated with potential benefits such as limitation of hematoma expansion and early death.

Take home points

  1. The potential benefit of administration of TXA means that administration of this drug in patients with ICH is a rational choice, given the favorable safety profile.
  2. Patients with smaller to moderately sized hematomas (30–60 mL) appear to benefit from early administration of TXA, especially in the setting of good blood pressure control (SBP <170 mmHg).


Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 » References Top

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Glauser T, Shinnar S, Gloss D, Alldredge B, Arya R, Bainbridge J, et al. Evidence-based guideline: Treatment of convulsive status epilepticus in children and adults: Report of the guideline committee of the American epilepsy society. Epilepsy Curr 2016;16:48-61.  Back to cited text no. 1
    
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Lyttle MD, Rainford NEA, Gamble C, Messahel S, Humphreys A, Hickey H, et al. Levetiracetam versus phenytoin for second-line treatment of paediatric convulsive status epilepticus (EcLiPSE): A multicentre, open-label, randomised trial. Lancet 2019;393:2125-34.  Back to cited text no. 2
    
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Kapur J, Elm J, Chamberlain JM, Barsan W, Cloyd J, Lowenstein D, et al. Randomized trial of three anticonvulsant medications for status epilepticus. N Engl J Med 2019;381:2103-13.  Back to cited text no. 3
    
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Engel J, McDermott MP, Wiebe S, Langfitt JT, Stern JM, Dewar S, et al. Early surgical therapy for drug-resistant temporal lobe epilepsy: A randomized trial. JAMA 2012;307:922-30.  Back to cited text no. 4
    
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Dwivedi R, Ramanujam B, Chandra PS, Sapra S, Gulati S, Kalaivani M, et al. Surgery for drug-resistant epilepsy in children. N Engl J Med 2017;377:1639-47.  Back to cited text no. 5
    
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Cooper DJ, Nichol AD, Bailey M, Bernard S, Cameron PA, Pili-Floury S, et al. Effect of early sustained prophylactic hypothermia on neurologic outcomes among patients with severe traumatic brain injury: The POLAR randomized clinical trial. JAMA 2018;320:2211-20.  Back to cited text no. 10
    
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Brinjikji W, Murad MH, Rabinstein AA, Cloft HJ, Lanzino G, Kallmes DF. Conscious sedation versus general anesthesia during endovascular acute ischemic stroke treatment: A systematic review and meta-analysis. AJNR Am J Neuroradiol 2015;36:525-9.  Back to cited text no. 11
    
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Abou-Chebl A, Lin R, Hussain MS, Jovin TG, Levy EI, Liebeskind DS, et al. Conscious sedation versus general anesthesia during endovascular therapy for acute anterior circulation stroke: Preliminary results from a retrospective, multicenter study. Stroke 2010;41:1175-9.  Back to cited text no. 12
    
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Simonsen CZ, Yoo AJ, Sørensen LH, Juul N, Johnsen SP, Andersen G, et al. Effect of general anesthesia and conscious sedation during endovascular therapy on infarct growth and clinical outcomes in acute ischemic stroke: A randomized clinical trial. JAMA Neurol 2018;75:470-7.  Back to cited text no. 13
    
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Goyal M, Menon BK, van Zwam WH, Dippel DWJ, Mitchell PJ, Demchuk AM, et al. Endovascular thrombectomy after large-vessel ischaemic stroke: A meta-analysis of individual patient data from five randomised trials. Lancet 2016;387:1723-31.  Back to cited text no. 14
    
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Nogueira RG, Jadhav AP, Haussen DC, Bonafe A, Budzik RF, Bhuva P, et al. Thrombectomy 6 to 24 hours after stroke with a mismatch between deficit and infarct. N Engl J Med 2018;378:11-21.  Back to cited text no. 15
    
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Ferro JM, Coutinho JM, Dentali F, Kobayashi A, Alasheev A, Canhão P, et al. Safety and efficacy of dabigatran etexilate vs dose-adjusted warfarin in patients with cerebral venous thrombosis: A randomized clinical trial. JAMA Neurol 2019;76:1457-65.  Back to cited text no. 21
    
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Anderson CS, Huang Y, Wang JG, Arima H, Neal B, Peng B, et al. Intensive blood pressure reduction in acute cerebral haemorrhage trial (INTERACT): A randomised pilot trial. Lancet Neurol 2008;7:391-9.  Back to cited text no. 22
    
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Mendelow AD, Gregson BA, Fernandes HM, Murray GD, Teasdale GM, Hope DT, et al. Early surgery versus initial conservative treatment in patients with spontaneous supratentorial intracerebral haematomas in the International Surgical trial in intracerebral haemorrhage (STICH): A randomised trial. Lancet 2005;365:387-97.  Back to cited text no. 23
    
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Sprigg N, Flaherty K, Appleton JP, Al-Shahi Salman R, Bereczki D, Beridze M, et al. Tranexamic acid for hyperacute primary Intra Cerebral Haemorrhage (TICH-2): An international randomised, placebo-controlled, phase 3 superiority trial. Lancet 2018;391:2107-15.  Back to cited text no. 24
    




 

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