Wendy C. Ziai

A Pilot Randomized Trial of Induced Blood Pressure Elevation: Effects on Function and Focal Perfusion in Acute and Subacute Stroke

Background: Small, unrandomized studies have indicated that pharmacologically induced blood pressure elevation may improve function in ischemic stroke, presumably by improving blood flow to ischemic, but noninfarcted tissue (which may be indicated by diffusion-perfusion mismatch on MRI). We conducted a pilot, randomized trial to evaluate effects of pharmacologically induced blood pressure elevation on function and perfusion in acute stroke. Methods: Consecutive series of patients with large diffusion-perfusion mismatch were randomly assigned to induced blood pressure elevation (‘treated’ patients, n = 9) or conventional management (‘untreated’ patients, n = 6). Results: There were no significant differences between groups at baseline. NIH Stroke Scale (NIHSS) scores were lower (better) in treated versus untreated patients at day 3 (mean 5.6 vs. 12.3; p = 0.01) and week 6–8 (mean 2.8 vs. 9.7; p < 0.04). Treated (but not untreated) patients showed significant improvement from day 1 to day 3 in NIHSS score (from mean 10.2 to 5.6; p < 0.002), cognitive score (from mean 58.7 to 27.9% errors; p < 0.002), and volume of hypoperfused tissue (mean 132 to 58 ml; p < 0.02). High Pearson correlations between the mean arterial pressure (MAP) and accuracy on daily cognitive tests indicated that functional changes were due to changes in MAP. Conclusion: Results warrant a full-scale, double-blind clinical trial to evaluate the efficacy and risk of induced blood pressure elevation in selective patients with acute/subacute stroke.

Low-Dose Recombinant Tissue-Type Plasminogen Activator Enhances Clot Resolution in Brain Hemorrhage: The Intraventricular Hemorrhage Thrombolysis Trial

Background and Purpose— Patients with intracerebral hemorrhage and intraventricular hemorrhage have a reported mortality of 50% to 80%. We evaluated a clot lytic treatment strategy for these patients in terms of mortality, ventricular infection, and bleeding safety events, and for its effect on the rate of intraventricular clot lysis. Methods— Forty-eight patients were enrolled at 14 centers and randomized to treatment with 3 mg recombinant tissue-type plasminogen activator (rtPA) or placebo. Demographic characteristics, severity factors, safety outcomes (mortality, infection, bleeding), and clot resolution rates were compared in the 2 groups. Results— Severity factors, including admission Glasgow Coma Scale, intracerebral hemorrhage volume, intraventricular hemorrhage volume, and blood pressure were evenly distributed, as were adverse events, except for an increased frequency of respiratory system events in the placebo-treated group. Neither intracranial pressure nor cerebral perfusion pressure differed substantially between treatment groups on presentation, with external ventricular device closure, or during the active treatment phase. Frequency of death and ventriculitis was substantially lower than expected and bleeding events remained below the prespecified threshold for mortality (18% rtPA; 23% placebo), ventriculitis (8% rtPA; 9% placebo), symptomatic bleeding (23% rtPA; 5% placebo, which approached statistical significance; P=0.1). The median duration of dosing was 7.5 days for rtPA and 12 days for placebo. There was a significant beneficial effect of rtPA on rate of clot resolution. Conclusions— Low-dose rtPA for the treatment of intracerebral hemorrhage with intraventricular hemorrhage has an acceptable safety profile compared to placebo and historical controls. Data from a well-designed phase III clinical trial, such as CLEAR III, will be needed to fully evaluate this treatment. Clinical Trial Registration— Participant enrollment began before July 1, 2005.

Third-line antiepileptic therapy and outcome in status epilepticus: The impact of vasopressor use and prolonged mechanical ventilation

Objectives:To characterize associations between antiepileptic drugs with sedating or anesthetic effects (third-line antiepileptic drugs) vs. other antiepileptic agents, and short-term outcomes, in status epilepticus. Furthermore, to evaluate the role of adverse hemodynamic and respiratory effects of these agents in status epilepticus treatment. Design:Retrospective comparative analysis. Setting:Tertiary academic medical center with two emergency departments and two neurologic intensive care units. Patients:Adults admitted with a diagnosis of status epilepticus defined as seizures lasting continuously >5 mins, or for discrete periods in succession. Interventions:None. Measurements and Main Results:Of 126 patients with 144 separate status epilepticus admissions, 57 were female (45%) with mean age 54.7 ± 15.7 yrs. Status epilepticus was convulsive in 132 cases (92%). Status epilepticus etiologies included subtherapeutic antiepileptic drugs (43%), alcohol or other nonantiepileptic drug (13%), and acute central nervous system disease (12%). Third-line antiepileptic drugs were administered in 47 cases (33%). Seventy-eight status epilepticus episodes (54%) had good outcomes (Glasgow Outcome Score = 1, 2) at the time of hospital discharge. On univariate analysis, poor outcome (Glasgow Outcome Score > 2) was associated with older age (mean 59.8 ± 15.5 vs. 50.5 ± 13.8 yrs, p < .001), acute central nervous system disease (21% vs. 4%, p = .001), mechanical ventilation (76% vs. 53%, p = .004), longer duration of ventilation (median 10 days [range 1–56] vs. 2 days [range 1–10], p < .001), treatment with vasopressors (35% vs. 5%, p < .001), and treatment with third-line antiepileptic drugs (51% vs. 17%, p < .001). Death was associated with acute central nervous system disease, prolonged ventilation, treatment with vasopressors, and treatment with third-line antiepileptic drugs. Predictors of poor outcome among all status epilepticus episodes were older age (odds ratio 1.06; 95% confidence interval 1.03–1.09; p < .001), treatment with third-line antiepileptic therapy (odds ratio 5.64; 95% confidence interval 2.31–13.75; p < .001), and first episode of status epilepticus (odds ratio 3.73; 95% confidence interval 1.38–10.10; p = .010). Among status epilepticus episodes treated by third-line antiepileptic drugs, predictors of poor outcome were older age (odds ratio, 1.09; 95% confidence interval 1.01–1.18; p = .038) and longer ventilation (odds ratio, 1.47; 95% confidence interval 1.08–2.00; p = .015). Predictors of mortality among all status epilepticus episodes were treatment with third-line antiepileptic drugs (odds ratio, 12.08; 95% confidence interval 2.30–63.39; p = .003) and older age (odds ratio, 1.06; 95% confidence interval 1.00–1.12; p = .045). Conclusions:Third-line antiepileptic drug therapies with sedating or anesthetic effects predicted poor outcome and death in status epilepticus. Hypotension requiring vasopressor therapy and duration of mechanical ventilation induced by these agents may be contributing factors, especially when pentobarbital is used. These findings may inform decision making on drug therapy in status epilepticus and help develop safer and more effective treatment strategies to improve outcome.

Decompressive craniectomy for intractable cerebral edema: Experience of a single center

Several case reports and small clinical series have reported benefits of decompressive hemicraniectomy in patients with intractable cerebral edema and early clinical herniation. Specific indications and timing for this intervention remain unclear. We present our experience with this procedure in a subset of 18 patients with massive cerebral edema refractory to medical management, treated with decompressive craniectomy over a 3-year period (1997 to 2000). Computerized tomography (CT) scans were independently analyzed by a neuroradiologist blinded to clinical outcome. Eleven male and seven female patients, ages 20 to 69 years (mean ± SEM, 46 ± 14 years), underwent hemicraniectomy for the following diagnoses: 12 hemispheric infarcts, 3 traumatic intracerebral hemorrhages/contusions, 2 nontraumatic intraparenchymal hemorrhages (ICH), and 1 subdural empyema. This population included four patients with aneurysmal subarachnoid hemorrhage (SAH). Patients were followed for a mean of 10 months. Clinical factors including age, side of lesion, preoperative herniation signs, and early surgery (<12 or <24 hours) were not significantly associated with mortality or Glasgow outcome score (GOS). Preoperative CT evidence of transtentorial herniation (present in 5/17 patients) was associated with mortality (P = 0.04), while preoperative uncal herniation (8/17 patients) was associated with poor outcome (GOS > 1) (P = 0.01). Favorable outcome (GOS > 3) occurred in six patients, three with spontaneous or traumatic focal hematomas. Of four patients with SAH, one died while the others were severely disabled (GOS 3). Seven of nine patients with malignant MCA infarctions unrelated to SAH had poor outcomes. The overall mortality was 4/18 (22%). Patients with refractory cerebral swelling secondary to focal hematomas may have better outcomes following decompressive craniectomy. Patients with preexisting SAH seem to have poor outcomes, possibly related to other neurologic comorbidities. Hemicraniectomy requires definition of proper timing. Preoperative CT findings, especially transtentorial and uncal herniation may be useful in defining when decompressive surgery should not be performed.

Update in the Diagnosis and Management of Central Nervous System Infections

Central nervous system (CNS) infections presenting to the emergency room include meningitis, encephalitis, brain and spinal epidural abscess, subdural empyema, and ventriculitis. These conditions often require admission to an intensive care unit (ICU) and are complications of ICU patients with neurologic injury, contributing significantly to morbidity and mortality. Reducing morbidity and mortality is critically dependent on rapid diagnosis and, perhaps more importantly, on the timely initiation of appropriate antimicrobial therapy. New insights into the role of inflammation and the immune response in CNS infections have contributed to development of new diagnostic strategies using markers of inflammation, and to the study of agents with focused immunomodulatory activity, which may lead to further adjunctive therapy in human disease.

A Multicenter, Randomized, Double-Blinded, Placebo-Controlled Phase III Study of Clot Lysis Evaluation of Accelerated Resolution of Intraventricular Hemorrhage (CLEAR III)

Background In adults, intraventricular thrombolytic therapy with recombinant tissue plasminogen activator (rtPA) facilitates resolution of intraventricular haemorrhage (IVH), reduces intracranial pressure, decreases duration of cerebrospinal fluid diversion, and may ameliorate direct neural injury. We hypothesize that patients with small parenchymal haematoma volumes (<30 cc) and relatively large IVH causing acute obstructive hydrocephalus would have improved clinical outcomes when given injections of low-dose rtPA to accelerate lysis and evacuation of IVH compared with placebo. Methods The Clot Lysis Evaluation of Accelerated Resolution of Intraventricular Hemorrhage III trial is an investigator-initiated, phase III, randomized, multicenter, double-blind, placebo-controlled study comparing the use of external ventricular drainage (EVD) combined with intraventricular injection of rtPA to EVD plus intraventricular injection of normal saline (placebo) for the treatment of IVH. Patients with known symptom onset within 24 h of the computed tomography scan confirmed IVH and third or fourth ventricle obstruction, with or without supratentorial intracerebral haemorrhage volume <30 cc, who require EVD are screened with a computed tomography scan at least six hours after EVD placement and, if necessary, at consecutive 12-h intervals until stabilization of any intracranial bleeding has been established. Patients who meet clinical and imaging criteria (no ongoing coagulopathy and no suspicion of aneurysm, arteriovenous malformation, or any other vascular anomaly) will be randomized to either intraventricular rtPA or placebo. Results The primary outcome measure is dichotomized modified Rankin Scale 0–3 vs. 4–6 at 180 days. Clinical secondary outcomes include additional modified Rankin Scale dichotomizations at 180 days (0–4 vs. 5–6), ordinal modified Rankin Scale (0–6), mortality and safety events at 30 days, mortality at 180 days, functional status measures, type and intensity of intensive care unit management, rate and extent of ventricular blood clot removal, and quality of life measures.

Thrombolytic removal of intraventricular haemorrhage in treatment of severe stroke: results of the randomised, multicentre, multiregion, placebo-controlled CLEAR III trial

BACKGROUND Intraventricular haemorrhage is a subtype of intracerebral haemorrhage, with 50% mortality and serious disability for survivors. We aimed to test whether attempting to remove intraventricular haemorrhage with alteplase versus saline irrigation improved functional outcome. METHODS In this randomised, double-blinded, placebo-controlled, multiregional trial (CLEAR III), participants with a routinely placed extraventricular drain, in the intensive care unit with stable, non-traumatic intracerebral haemorrhage volume less than 30 mL, intraventricular haemorrhage obstructing the 3rd or 4th ventricles, and no underlying pathology were adaptively randomly assigned (1:1), via a web-based system to receive up to 12 doses, 8 h apart of 1 mg of alteplase or 0·9% saline via the extraventricular drain. The treating physician, clinical research staff, and participants were masked to treatment assignment. CT scans were obtained every 24 h throughout dosing. The primary efficacy outcome was good functional outcome, defined as a modified Rankin Scale score (mRS) of 3 or less at 180 days per central adjudication by blinded evaluators. This study is registered with ClinicalTrials.gov, NCT00784134. FINDINGS Between Sept 18, 2009, and Jan 13, 2015, 500 patients were randomised: 249 to the alteplase group and 251 to the saline group. 180-day follow-up data were available for analysis from 246 of 249 participants in the alteplase group and 245 of 251 participants in the placebo group. The primary efficacy outcome was similar in each group (good outcome in alteplase group 48% vs saline 45%; risk ratio [RR] 1·06 [95% CI 0·88-1·28; p=0·554]). A difference of 3·5% (RR 1·08 [95% CI 0·90-1·29], p=0·420) was found after adjustment for intraventricular haemorrhage size and thalamic intracerebral haemorrhage. At 180 days, the treatment group had lower case fatality (46 [18%] vs saline 73 [29%], hazard ratio 0·60 [95% CI 0·41-0·86], p=0·006), but a greater proportion with mRS 5 (42 [17%] vs 21 [9%]; RR 1·99 [95% CI 1·22-3·26], p=0·007). Ventriculitis (17 [7%] alteplase vs 31 [12%] saline; RR 0·55 [95% CI 0·31-0·97], p=0·048) and serious adverse events (114 [46%] alteplase vs 151 [60%] saline; RR 0·76 [95% CI 0·64-0·90], p=0·002) were less frequent with alteplase treatment. Symptomatic bleeding (six [2%] in the alteplase group vs five [2%] in the saline group; RR 1·21 [95% CI 0·37-3·91], p=0·771) was similar. INTERPRETATION In patients with intraventricular haemorrhage and a routine extraventricular drain, irrigation with alteplase did not substantially improve functional outcomes at the mRS 3 cutoff compared with irrigation with saline. Protocol-based use of alteplase with extraventricular drain seems safe. Future investigation is needed to determine whether a greater frequency of complete intraventricular haemorrhage removal via alteplase produces gains in functional status. FUNDING National Institute of Neurological Disorders and Stroke.

Hematology and Inflammatory Signaling of Intracerebral Hemorrhage

Although the dawn of targeted treatments for primary intracerebral hemorrhage (ICH) seems in sight, many biological questions remain, which will drive the next clinical trial and animal model steps. The objective of this review is to describe the role of inflammatory signaling molecules and the clot lysis cascade, and the role of edema as a surrogate marker for inflammation. The primary injury of hematoma formation and its expansion within brain parenchyma is mechanical damage to brain tissue causing disruption of white matter tracts and, at the most severe, resulting in herniation. The tissue at the epicenter of the clot is not likely to be salvaged because of dissection of blood, causing direct and rapid tissue destruction.1 The size of the epicenter remains unknown, some evidence suggests it is small when compared with ischemic stroke,2 thus secondary mechanisms of injury may be disproportionally important in ICH. The secondary injury of ICH can be considered as emanating from a time-dependent progression of 3 intertwined degenerative cascades in the regions both adjacent to the hematoma: inflammation, red cell lysis, and thrombin production (coagulation cascade; Figure). All 3 lead to disruption of the blood–brain barrier, resulting in cerebral edema directly or indirectly, and death of brain parenchymal cells. Figure. Mechanisms underlying brain edema and neuronal injury after intracerebral hemorrhage and potential therapeutic targets. H-O indicates heme-oxygenase; MAPKs, mitogen-activated protein kinases; PARs, protease-activated receptors; and PPARγ agonist, peroxisome proliferator–activated receptor γ agonist. These pathways are all feasible therapeutic targets as injury occurs over hours to weeks. Thus, perihematomal tissue is potentially salvageable by countering degenerative events at the appropriate time interval. Apoptosis and neuronal necrosis are common end points of the degenerative pathways, but without good clinical surrogates. Cerebral edema, on the contrary, may be a reasonable target. ### Inflammation ICH brings the immediate infiltration of …

Safety and efficacy of minimally invasive surgery plus alteplase in intracerebral haemorrhage evacuation (MISTIE): a randomised, controlled, open-label, phase 2 trial

BACKGROUND Craniotomy, according to the results from trials, does not improve functional outcome after intracerebral haemorrhage. Whether minimally invasive catheter evacuation followed by thrombolysis for clot removal is safe and can achieve a good functional outcome is not known. We investigated the safety and efficacy of alteplase, a recombinant tissue plasminogen activator, in combination with minimally invasive surgery (MIS) in patients with intracerebral haemorrhage. METHODS MISTIE was an open-label, phase 2 trial that was done in 26 hospitals in the USA, Canada, the UK, and Germany. We used a computer-generated allocation sequence with a block size of four to centrally randomise patients aged 18-80 years with a non-traumatic (spontaneous) intracerebral haemorrhage of 20 mL or higher to standard medical care or image-guided MIS plus alteplase (0·3 mg or 1·0 mg every 8 h for up to nine doses) to remove clots using surgical aspiration followed by alteplase clot irrigation. Primary outcomes were all safety outcomes: 30 day mortality, 7 day procedure-related mortality, 72 h symptomatic bleeding, and 30 day brain infections. This trial is registered with ClinicalTrials.gov, number NCT00224770. FINDINGS Between Feb 2, 2006, and April 8, 2013, 96 patients were randomly allocated and completed follow-up: 54 (56%) in the MIS plus alteplase group and 42 (44%) in the standard medical care group. The primary outcomes did not differ between the standard medical care and MIS plus alteplase groups: 30 day mortality (four [9·5%, 95% CI 2·7-22.6] vs eight [14·8%, 6·6-27·1], p=0·542), 7 day mortality (zero [0%, 0-8·4] vs one [1·9%, 0·1-9·9], p=0·562), symptomatic bleeding (one [2·4%, 0·1-12·6] vs five [9·3%, 3·1-20·3], p=0·226), and brain bacterial infections (one [2·4%, 0·1-12·6] vs zero [0%, 0-6·6], p=0·438). Asymptomatic haemorrhages were more common in the MIS plus alteplase group than in the standard medical care group (12 [22·2%; 95% CI 12·0-35·6] vs three [7·1%; 1·5-19·5]; p=0·051). INTERPRETATION MIS plus alteplase seems to be safe in patients with intracerebral haemorrhage, but increased asymptomatic bleeding is a major cautionary finding. These results, if replicable, could lead to the addition of surgical management as a therapeutic strategy for intracerebral haemorrhage. FUNDING National Institute of Neurological Disorders and Stroke, Genentech, and Codman.SUMMARY Background Craniotomy, when evaluated in trials, does not improve outcome after intracerebral haemorrhage (ICH). Whether minimally invasive catheter evacuation followed by thrombolysis is safe and can achieve a good functional outcome by removing clot is unknown. We investigated safety and efficacy of alteplase with minimally invasive surgery (MIS) in patients with intracerebral haemorrhage. Methods MISTIE was an international, randomized, open-label study and was done in 26 hospitals in the USA, Canada, the UK, and Germany. Patients (aged 18–80 years), with non-traumatic (spontaneous) ICH ≥20 mL were randomly allocated, centrally, to medical care or image-guided MIS plus rt-PA (0.3 mg or 1.0 mg every 8 hours for up to 9 doses) to remove clot using surgical aspiration followed with alteplase clot irrigation. The primary efficacy outcome was the adjusted dichotomized modified Rankin Scale (mRS) 0–3 vs 4–6 assessed at day 180 after symptom onset. Analysis was by intention to treat. (ClinicalTrials.gov number NCT00224770). Findings Between February 2, 2006 and April 8, 2013, 96 subjects were randomized and completed follow-up: 54 received treatment and 42 medical care. Primary safety outcomes: mortality, symptomatic bleeding, brain infections, as well as withdrawal of care, did not differ between groups. Asymptomatic hemorrhages were more common in the surgical group (3 (7%) vs. 12 (22%) p= 0.05) producing a difference of 15.1% (95% CI: 1.5% to 28.6%). The estimated absolute benefit, i.e., the unadjusted difference in observed proportions of all subjects with mRS 0–3 (33% vs 21%) at 180 days comparing MISPA vs. medical control, is 0.109 [95%CI: −0.088, 0.294; p=0.26], and is 0.162 [95%CI: 0.003, 0.323; p=0.05] after adjustment for potential imbalances in baseline severity between study arms (primary efficacy outcome). Interpretation MIS+rt-PA appears safe with an apparent advantage of better functional outcome at 180 days. Increased asymptomatic bleeding is a major cautionary finding. The MISTIE trial results, if replicable, could produce a meaningful functional benefit adding surgical management as a therapeutic strategy for ICH. Funding National Institute of Neurologic Disorders and Stroke, Genentech, and Codman.

The Role of Transcranial Doppler Ultrasonography in the Diagnosis and Management of Vasospasm After Aneurysmal Subarachnoid Hemorrhage

Transcranial Doppler ultrasonography (TCD) is a tool employed by the neurosurgeon and neurointensivist in the management of vasospasm in the intensive care unit after aneurysmal subarachnoid hemorrhage. A review of the current indications, monitoring parameters, indices, and relevance of modern TCD technology is provided, as well as algorithms for the use of TCD ultrasonography in the management of patients with subarachnoid hemorrhage. Other current uses of TCD ultrasonography are also discussed in the setting of neurocritical care.