J. Ricardo Carhuapoma

Guidelines for the Management of Aneurysmal Subarachnoid Hemorrhage: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association

Purpose— The aim of this guideline is to present current and comprehensive recommendations for the diagnosis and treatment of aneurysmal subarachnoid hemorrhage (aSAH). Methods— A formal literature search of MEDLINE (November 1, 2006, through May 1, 2010) was performed. Data were synthesized with the use of evidence tables. Writing group members met by teleconference to discuss data-derived recommendations. The American Heart Association Stroke Councils Levels of Evidence grading algorithm was used to grade each recommendation. The guideline draft was reviewed by 7 expert peer reviewers and by the members of the Stroke Council Leadership and Manuscript Oversight Committees. It is intended that this guideline be fully updated every 3 years. Results— Evidence-based guidelines are presented for the care of patients presenting with aSAH. The focus of the guideline was subdivided into incidence, risk factors, prevention, natural history and outcome, diagnosis, prevention of rebleeding, surgical and endovascular repair of ruptured aneurysms, systems of care, anesthetic management during repair, management of vasospasm and delayed cerebral ischemia, management of hydrocephalus, management of seizures, and management of medical complications. Conclusions— aSAH is a serious medical condition in which outcome can be dramatically impacted by early, aggressive, expert care. The guidelines offer a framework for goal-directed treatment of the patient with aSAH.

Minimally Invasive Surgery Plus Recombinant Tissue-type Plasminogen Activator for Intracerebral Hemorrhage Evacuation Decreases Perihematomal Edema

Background and Purpose— Perihematomal edema (PHE) can worsen outcomes after intracerebral hemorrhage (ICH). Reports suggest that blood degradation products lead to PHE. We hypothesized that hematoma evacuation will reduce PHE volume and that treatment with recombinant tissue-type plasminogen activator (rt-PA) will not exacerbate it. Methods— Minimally invasive surgery and rt-PA in ICH evacuation (MISTIE) phase II tested safety and efficacy of hematoma evacuation after ICH. We conducted a semiautomated, computerized volumetric analysis on computed tomography to assess impact of hematoma removal on PHE and effects of rt-PA on PHE. Volumetric analyses were performed on baseline stability and end of treatment scans. Results— Seventy-nine surgical and 39 medical patients from minimally invasive surgery and rt-PA in ICH evacuation phase II (MISTIE II) were analyzed. Mean hematoma volume at end of treatment was 19.6±14.5 cm3 for the surgical cohort and 40.7±13.9 cm3 for the medical cohort (P<0.001). Edema volume at end of treatment was lower for the surgical cohort: 27.7±13.3 cm3 than medical cohort: 41.7±14.6 cm3 (P<0.001). Graded effect of clot removal on PHE was observed when patients with >65%, 20% to 65%, and <20% ICH removed were analyzed (P<0.001). Positive correlation between PHE reduction and percent of ICH removed was identified (&rgr;=0.658; P<0.001). In the surgical cohort, 69 patients underwent surgical aspiration and rt-PA, whereas 10 underwent surgical aspiration only. Both cohorts achieved similar clot reduction: surgical aspiration and rt-PA, 18.9±14.5 cm3; and surgical aspiration only, 24.5±14.0 cm3 (P=0.26). Edema at end of treatment in surgical aspiration and rt-PA was 28.1±13.8 cm3 and 24.4±8.6 cm3 in surgical aspiration only (P=0.41). Conclusions— Hematoma evacuation is associated with significant reduction in PHE. Furthermore, PHE does not seem to be exacerbated by rt-PA, making such neurotoxic effects unlikely when the drug is delivered to intracranial clot.

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.

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.

Frameless stereotactic aspiration and thrombolysis of spontaneous intracerebral hemorrhage

AbstractIntroduction: To test the feasibility and safety of a minimally invasive technique, we report our experience in treating spontaneous intracerebral hemorrhage (ICH) patients by using frameless stereotactic clot aspiration-thrombolysis and its effects on their 30-day survival. We compared the observed cohort mortality with its predicted 30-day ICH mortality, by using previously validated methods. Methods: Selection criteria were diagnosis of hypertensive ICH ≥35 cc, reduced level of consciousness, and no brainstem compression. Frameless stereotactic puncture/clot aspiration followed by intraclot external catheter placement was performed. Two milligrams of recombinant tissue plasminogen activator (rtPA) was administered q12 hours until ICH volume ≤10 cc, or the catheter fenestrations were no longer in continuity with the clot. Results: Fifteen patients were treated, mean age was 60.7 years. Hemorrhage locations included basal ganglia (13), thalamic (1), and lobar (1); mean systolic blood pressure; and admission ICH volumes were 229.3 mmHg and 59.1 cc, respectively. Median time from ictus to clot aspiration/thrombolysis was 1 (range 0–3) day. Mean hematoma volume was reduced to 17% of pretreatment size. Complications were ventriculitis (6.6%) and clot enlargement (13.3%). Two patients were dead at 30 days. Median Glasgow Coma Scale (GCS) scores were 10.5 (4–15) at admission and 11.0 (3–15) at discharge. By using the most conservative estimate for analysis, probability of observing two or fewer deaths among 15 patients with an overall probability of dying calculated at 0.33 was p = 0.079. Conclusions: In this selected cohort of patients with ICH, stereotactic aspiration and thrombolytic washout seemed to be feasible and to have a trend towards improved 30-day survival, when using their predicted mortality data as “historical control.” Complications did not exceed expected incidence rates. Based on the experience presented here as well as previous similar reports, a larger, randomized study addressing dose escalation, patient selection, and best therapeutic window is needed.

Energy expenditure in patients with nontraumatic intracranial hemorrhage.

BACKGROUND Patients with intracerebral (ICH), intraventricular (IVH) and subarachnoid hemorrhage (SAH) have increased morbidity and mortality compared with other forms of stroke. We postulate that the systemic inflammatory state triggered by these forms of nontraumatic intracranial hemorrhage (IH) translates into higher nutrition requirements than traditionally assumed. In order to test this hypothesis, we performed a retrospective study comparing the resting energy expenditure (REE) of 14 mechanically ventilated IH patients with the REE of 6 severe traumatic brain injury (sTBI) patients (a disease known to induce an increased metabolic state). METHODS Using nonparametric analysis, we compared 2 contemporary cohorts of patients-IH and sTBI-who required mechanical ventilation and who underwent indirect calorimetry (IC) within 7 days after the ictus. RESULTS Fourteen patients with nontraumatic IH (IVH, 2; SAH, 9; SAH/ICH, 1; ICH/SAH/IVH, 2) who underwent IC within 7 days from injury were identified; median age: 59 (28-84) years, median admission Glasgow Coma Scale (GCS): 6 (4-9), and median APACHE II: 19.5 (15-28). A control cohort of 6 patients with sTBI was identified; median age: 57.5 (18-80) years, admission GCS: 6.5 (4-8), and APACHE II: 16 (11-31). Sedation was used in 11/14 patients with IH and in 5/6 severe TBI patients. No patient was pharmacologically paralyzed. Median REE was 1810 (1124-2806) and 2238 (1860-2780) kcal/d for the IH and for the sTBI patient cohorts, respectively. Using Wilcoxon signed ranks test, the 2 patient groups were found comparable in regard to baseline clinical variables and disease severity (APACHE II). We did not identify a statistically significant difference in the REE between these 2 cohorts of patients (p = .25). CONCLUSIONS Patients with severe TBI and patients with IH have similar increments in metabolic rate during the initial phase (1 week from onset) of their disease. This information needs to be confirmed in a larger cohort of patients. If reproduced, our results suggest that nontraumatic IH patients are at high risk of inadequate nutrition if their metabolic rate is estimated after conventional nutrition practice.

Introducing hypertonic saline for cerebral edema: an academic center experience.

AbstractIntroduction: Use of hypertonic saline (HTS) is gaining acceptance in the neurosciences critical care unit (NCCU) based on its efficacy in reducing cerebral edema and its favorable hemodynamic profile. In the NCCU, unfamiliarity with the use of HTS may result in implementation difficulties. We report our initial experience using HTS, its ability to achieve a hypernatremic state, and adverse effects. Methods: Analysis of 19 consecutive patients who were admitted to the NCCU and treated with 2 or 3% HTS infusion for cerebral edema (target serum sodium: 145–155 mEq/L) included patient diagnoses, laboratory data, length of treatment, adverse effects, and outcome at discharge. We compared the adverse effects of those patients to a contemporary cohort of patients who received mannitol as the sole form of osmotherapy. Results: The HTS cohort had a median age of 46 years (range: 18–70). Median GCS and APACHE II scores were 11 (range: 3–15) and 18 (range: 8–30), respectively. Median length of HTS treatment was 5 days (range: 1–17). Target hypernatremia was achieved in 14 patients (74%), 7 of whom achieved hypernatremia within the first 24 hours. The median number of rescue interventions received for ICP control was 3 (range: 1–30). The adverse effects between the HTS and mannitol cohorts were not found to be significantly different. Conclusion: The use of HTS for cerebral edema requires intensive efforts by the medical team to rapidly achieve and maintain a hypernatremic state. The continuous infusion of HTS was used safely.

Treatment of refractory fever in the neurosciences critical care unit using a novel, water-circulating cooling device. A single-center pilot experience.

Fever after acute brain injury affects neuronal function and recovery. Standard therapies have proven to be inadequate in treating hyperthermia in this patient population. We report on safety/efficacy pilot data collected using a noninvasive, novel, water-circulating cooling device in febrile acute brain injury patients. We enrolled patients who developed fever (rectal temperature ≥38.0°C) refractory to pharmacological therapy. The treatment device uses an ice water circulating system embedded in hydrogel-coated, energy transfer pads. Its thermoregulatory feedback control uses cold water (4.0°C–42.0°C) and was set at 36.5°C for this study. We analyzed the temperature response during 600 consecutive minutes of treatment. Six consecutive patients were enrolled and seven episodes of fever were recorded; the mean age of the patients was 59.7 years (range 46–71 years; five male, one female). Diagnoses were as follows: subarachnoid hemorrhage (two), severe traumatic brain injury (two), status epilepticus following massive cerebral infarction (one), and intracerebral/intraventricular hemorrhage (one). Hand warming was applied at treatment onset on all patients; shivering only responsive to meperidine occurred in five of them. Fever of 38.4°C (range 38.0°C–38.9°C) was reduced to 36.9°C (range 36.0°C–38.0°C) after 120 minutes (P < 0.001). Core temperature remained “locked” during the remainder of the treatment (36.6°C, P = 0.5; 36.6°C, P = 0.9; and 36.5°C, P = 0.9 at 180, 300, and 600 minutes, respectively). Skin integrity under the pads was preserved in all study subjects. Our results indicate that use of this novel technique is safe, rapidly effective, and able to maintain sustained normothermia following fever in a cohort of critically ill neurologic/neurosurgical patients.

Bleeding and infection with external ventricular drainage: a systematic review in comparison with adjudicated adverse events in the ongoing Clot Lysis Evaluating Accelerated Resolution of Intraventricular Hemorrhage Phase III (CLEAR-III IHV) trial.

BACKGROUND Retrospective series report varied rates of bleeding and infection with external ventricular drainage (EVD). There have been no prospective studies of these risks with systematic surveillance, threshold definitions, or independent adjudication. OBJECTIVE To analyze the rate of complications in the ongoing Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage Phase III (CLEAR III) trial, providing a comparison with a systematic review of complications of EVD in the literature. METHODS Patients were prospectively enrolled in the CLEAR III trial after placement of an EVD for obstructive intraventricular hemorrhage and randomized to receive recombinant tissue-type plasminogen activator or placebo. We counted any detected new hemorrhage (catheter tract hemorrhage or any other distant hemorrhage) on computed tomography scan within 30 days from the randomization. Meta-analysis of published series of EVD placement was compiled with STATA software. RESULTS Growing or unstable hemorrhage was reported as a cause of exclusion from the trial in 74 of 5707 cases (1.3%) screened for CLEAR III. The first 250 patients enrolled have completed adjudication of adverse events. Forty-two subjects (16.8%) experienced ≥1 new bleeds or expansions, and 6 of 250 subjects (2.4%) suffered symptomatic hemorrhages. Eleven cases (4.4%) had culture-proven bacterial meningitis or ventriculitis. CONCLUSION Risks of bleeding and infection in the ongoing CLEAR III trial are comparable to those previously reported in EVD case series. In the present study, rates of new bleeds and bacterial meningitis/ventriculitis are very low despite multiple daily injections, blood in the ventricles, the use of thrombolysis in half the cases, and generalization to >60 trial sites.

Hypothermia: Comparing technology

Hypothermia has recently been shown to be beneficial in certain clinical settings of acute brain injury, such as cardiac arrest. The available technology to induce and maintain this state is advancing quickly. This review will focus on the current state of available technology and devices as well as their limitations in attaining this potentially neuroprotective state. Furthermore, we will present the efficacy of the individual systems as well as potential side effects and complications that are associated with the technology chosen.