Delayed cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage continues to be associated with high levels of morbidity and mortality. This complication had long been thought to occur secondary to severe cerebral vasospasm, but expert opinion now favors a multifactorial etiology, opening the possibility of new therapies. To date, no definitive treatment option for DCI has been recommended as standard of care, highlighting a need for further research into potential therapies. Milrinone has been identified as a promising therapeutic agent for DCI, possessing a mechanism of action for the reversal of cerebral vasospasm as well as potentially anti-inflammatory effects to treat the underlying etiology of DCI. Intra-arterial and intravenous administration of milrinone has been evaluated for the treatment of DCI in single-center case series and cohorts and appears safe and associated with improved clinical outcomes. Recent results have also brought attention to the potential outcome benefits of early, more aggressive dosing and titration of milrinone. Limitations exist within the available data, however, and questions remain about the generalizability of results across a broader spectrum of patients suffering from DCI. The development of a standardized protocol for milrinone use in DCI, specifically addressing areas requiring further clarification, is needed. Data generated from a standardized protocol may provide the impetus for a multicenter, randomized control trial. We review the current literature on milrinone for the treatment of DCI and propose a preliminary standardized protocol for further evaluation of both safety and efficacy of milrinone.

OBJECTIVE Intravenous (IV) milrinone is a promising option for the treatment of cerebral vasospasm with delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH). However, data remain limited on the efficacy of treating cases that are refractory to standard therapy with IV milrinone. The aim of this study was to determine predictors of refractory vasospasm/DCI despite treatment with IV milrinone, and to analyze the outcome of rescue therapy with intraarterial (IA) milrinone and/or mechanical angioplasty. METHODS The authors conducted a retrospective cohort study of all patients with aSAH admitted between 2010 and 2016 to the Montreal Neurological Institute and Hospital. Patients were stratified into 3 groups: no DCI, standard therapy, and rescue therapy. The primary outcome was frequency of DCI-related cerebral infarction identified on neuroimaging before hospital discharge. Secondary outcomes included functional outcome reported as modified Rankin Scale (mRS) score, and segment reversal of refractory vasospasm. RESULTS The cohort included 322 patients: 212 in the no DCI group, 89 in the standard therapy group, and 21 in the rescue therapy group. Approximately half (52%, 168/322) were admitted with poor-grade aSAH at treatment decision (World Federation of Neurosurgical Societies grade III-V). Among patients with DCI and imaging assessing severity of vasospasm, 62% (68/109) had moderate/severe radiological vasospasm on DCI presentation. Nineteen percent (21/110) of patients had refractory vasospasm/DCI and were treated with rescue therapy. Targeted rescue therapy with IA milrinone reversed 32% (29/91) of the refractory vasospastic vessels, and 76% (16/21) of those patients experienced significant improvement in their neurological status within 24 hours of initiating therapy. Moderate/severe radiological vasospasm independently predicted the need for rescue therapy (OR 27, 95% CI 8.01-112). Of patients with neuroimaging before discharge, 40% (112/277) had developed new cerebral infarcts, and only 21% (23/112) of these were vasospasm-related. Overall, 65% (204/314) of patients had a favorable functional outcome (mRS score 0-2) assessed at a median of 4 months (interquartile range 2-8 months) after aSAH, and there was no difference in functional outcome between the 3 groups (p = 0.512). CONCLUSIONS The aggressive use of milrinone was safe and effective based on this retrospective study cohort and is a promising therapy for the treatment of vasospasm/DCI after aSAH.

INTRODUCTION:Acute internal carotid artery occlusion is a devastating form of ischemic accident with significant morbidity and possible mortality. The "threatened hemisphere" is allowed limited access to collateral circulation further worsening the ischemic burden and the overall prognosis.METHODS:We present the details of a case of a 38-year-old woman who suffered from an ischemic stroke. The clinical course of which showed a hemodynamic dependence to preserve her neurological function, prompting the use of the phosphodiesterase inhibitor milrinone to maintain her neurological function.RESULT:This case represents the first case in the literature in which a medical therapy is used to salvage brain tissue in the site of acute symptomatic large vessel occlusion. This has spared the patient from a potential significant morbidity and even mortality if a revascularization procedure had been attempted.CONCLUSION:This innovative use of milrinone, if applied in more captured patients with internal carotid occlusion or those with reversible hemodynamic failure, would improve our understanding of the ischemic thresholds and cerebral vascular reserves and would improve the clinical outcome of this significant ischemic insult.

Cerebral hyperperfusion syndrome (CHS) is a complication that can occur after carotid endarterectomy (CEA), the treatment of choice to decrease the subsequent risk of fatal or disabling stroke for patients with symptomatic severe stenosis of the carotid artery. Because of its rarity and complexity, the mechanism of the condition is still unclear, making its prevention via prediction and monitoring challenging. This is especially true during surgery, when multiple factors can induce physiological changes, including blood pressure and baroreceptor functions, which are crucial factors for post-CEA hypertension and CHS. Thus, with intra-operative videos taken by surgical microscopes, we employed a new video processing technique to magnify ordinarily invisible carotid artery pulsation patterns as rhythmic color fluctuations. We applied the technique for three CEA cases, two of which developed CHS with post-CEA hypertension. For those with CHS, abnormal pulsation patterns were detected at the site of the baroreceptors. The results suggested that intra-operative baroreceptor dysfunction can potentially be linked with post-operative hypertension, as well as the occurrence of CHS. Guided by the preliminary discovery, further investigation may help establish the introduced technique as a simple and contactless technique to help predict post-CEA hypertension and CHS in order to facilitate the management and understanding of the condition and improve the care of CEA.

BACKGROUND:Vasospasm is a challenging component of the subarachnoid hemorrhage "syndrome" that is unpredictable and very difficult to monitor using noninvasive or invasive monitoring technologies in neurocritical units.METHODS:We describe the novel use of computerized tomography perfusion (CTP) imaging to choose proper targets for invasive cerebral blood flow monitors.RESULTS:A total of 3 patients are included in this report. CTP parameters were used to generate points of interest to target using invasive cerebral monitoring of the cerebral blood flow and initiate vasodilator therapy and subsequently guide its weaning.CONCLUSIONS:CTP can be useful in localizing a specific anatomical target for invasive monitoring in subarachnoid hemorrhage patients suffering from vasospasm.

OBJECTIVE: To evaluate primary causes of death after spontaneous subarachnoid hemorrhage (SAH) and externally validate the HAIR score, a prognostication tool, in a single academic institution. METHODS: We reviewed all patients with SAH admitted to our neuro-intensive care unit between 2010 and 2016. Univariate and multivariate logistic regressions were performed to identify predictors of in-hospital mortality. The HAIR score predictors were Hunt and Hess grade at treatment decision, age, intraventricular hemorrhage, and rebleeding within 24 hours. Validation of the HAIR score was characterized with the receiver operating curve, the area under the curve, and a calibration plot. RESULTS: Among 434 patients with SAH, in-hospital mortality was 14.1%. Of the 61 mortalities, 54 (88.5%) had a neurologic cause of death or withdrawal of care and 7 (11.5%) had cardiac death. Median time from SAH to death was 6 days. The main causes of death were effect of the initial hemorrhage (26.2%), rebleeding (23%) and refractory cerebral edema (193%). Factors significantly associated with in-hospital mortality in the multivariate analysis were age, Hunt and Hess grade, and intracerebral hemorrhage. Maximum lumen size was also a significant risk factor after aneurysmal SAH. The HAIR score had a satisfactory discriminative ability, with an area under the curve of 0.89. CONCLUSIONS: The in-hospital mortality is lower than in previous reports, attesting to the continuing improvement of our institutional SAH care. The major causes are the same as in previous reports. Despite a different therapeutic protocol, the HAIR score showed good discrimination and could be a useful tool for predicting mortality.

OBJECTIVE:Health care-associated infections (HAIs) after subarachnoid hemorrhage (SAH) are prevalent; however, data describing epidemiology of infection are limited. This study reports incidence rates, risk factors, and the resulting SAH patient-related outcomes.METHODS:We studied the incidence of HAIs acquired in the intensive care unit (ICU) over a 6-year period. We used Bayesian Model Averaging to identify risk factors associated with an increased risk of HAIs, particularly urinary tract infections (UTI), pneumonia, and ventriculostomy-associated infections (VAI). We also examined the impact of HAIs on risk of vasospasm, ICU and hospital length of stay, and discharge disposition and adjusted for other risk factors.RESULTS:Of 419 patients with SAH, 66 (15.8%) developed 79 HAI episodes. Mean HAI incidence rates (per 1000 ICU-days) were UTI, 7.1; pneumonia, 4.3; and VAI, 2.4. The admission characteristic associated with increased risk of overall HAI, UTI, and VAI was diabetes mellitus. Hunt and Hess grades III-V were associated with increased risk of overall HAI and VAI. Male gender, intraventricular hemorrhage, and blood glucose level (>10) were associated with increased risk of pneumonia, whereas the incidence was lower in the presence of steroids. HAI was associated with increased length of stay of 10 ICU-days and 22 hospital-days, but not vasospasm or poor discharge disposition.CONCLUSIONS:HAIs are serious complications after SAH associated with prolonged ICU and hospital length of stay. Additional rigorous infection control measures aimed at patients with identifiable risk factors should trigger prevention, and early detection of nosocomial infections is warranted to further reduce the prevalence of HAIs.

BACKGROUND:Healthcare-associated infections (HAIs) occur frequently in neurological intensive care units (neuro-ICUs); however, data differentiating associations with various diagnostic categories and resulting burdens are limited. This prospective cohort study reported incidence rates, pathogen distribution, and patient-related outcomes of HAIs in a neuro-ICU population from April 2010 to March 2016.METHODS:Laboratory results and specific clinical indicators were used to categorize infections as per National Healthcare Safety Network nosocomial infection surveillance definitions. Patient outcomes studied included length of stay and mortality.RESULTS:There were 6,033 neuro-ICU admissions resulting in 20,800 neuro-ICU days over the 6-year study period. A total of 227 HAIs were identified for a rate of 10.9/1,000 ICU days. Device-associated infections accounted for 80.6% of HAIs, with incidence rates (per 1,000 device days) being 18.4 for ventilator-associated pneumonia; 4.9 for catheter-associated urinary tract infections (CAUTIs); 4.0 for ventriculostomy-associated infections; and 0.6 for central line-associated blood stream infections (CLABSIs). Of the various diagnostic categories, subdural hematoma and intracerebral/intraventricular hemorrhage were associated with the highest pooled HAIs, with incidence rates of 21.3 and 21.1 per 1,000 neuro-ICU days, respectively. Prolonged neuro-ICU length of stay was strongly associated with all HAIs.CONCLUSIONS:This large-scale surveillance study provides estimates of the risk of common HAIs in neurocritical care patients and their effect on hospitalization. Preventive strategies kept rates of infection very low, in particular CAUTI, CLABSI, and Clostridium difficile infections, and inhibited the emergence of resistant organisms.

Background:Cerebral hypoxia is one of the most important causes of secondary brain injury during neurosurgical procedures and in neurointensive care. In patients with brain injury, cerebrovascular reactivity may be impaired and a decrease in mean arterial pressure or cerebral perfusion pressure may lead to inadequate cerebral blood flow and secondary ischemia. There are several techniques available to measure brain oxygenation. In particular, near infrared spectroscopy (NIRS) is a non-invasive neuromonitoring technique and there has been a rapid expansion of clinical evidence that NIRS reduces perioperative neurologic complications. Methods:This systematic review synthesizes prospective and retrospective cohort studies that investigate the benefit of using NIRS in prevention of perioperative neurologic complications. The methodological quality of these studies is appraised.Results:Seven studies were included in this systematic review. The methodological quality of each study was assessed. They had representative patient populations, clear selection criteria and clear descriptions of study designs. Reproducible study protocols with ethics board approval were present. Clinical results were described in sufficient detail and were applicable to patient undergoing neurosurgical procedures and in neurointensive care. Limitations included small sample sizes and lack of reference standard.Conclusions:This systematic review synthesizes the most current evidence of non-invasive, inexpensive, and continuous measurement of cerebral oxygenation by NIRS. Results gained from these studies are clinically useful and shed light on how this neuromonitoring technique is beneficial in preventing perioperative neurological complications.

Early detection of vasospasm is crucial to prevent significant delayed ischemic neurological deficit post subarachnoid hemorrhage. The standard methods of detection, including cerebral angiogram and computed tomography are invasive and not safe to be repeated, as is very often indicated clinically. Transient hyperemic response test has been previously used to predict autoregulation failure in traumatic brain injury and subarachnoid hemorrhage.

April 27, 2018April 10, 2018Free AccessRisk Factors for Mortality after Spontaneous Subarachnoid Hemorrhage and External Validation of a Prediction Model (P6.326)Yasser B. Abulhasan, Najayeb S. Alabdulraheem, Gabrielle Simoneau, Mark R. Angle, and Jeanne TeitelbaumAuthors Info & AffiliationsApril 10, 2018 issue90 (15_supplement)https://doi.org/10.1212/WNL.90.15_supplement.P6.326 Letters to the Editor

BACKGROUND:Brain-body associations are essential in influencing outcome in patients with ruptured brain aneurysms. Thus far, there is scarce literature on such important relationships.METHODS:The multicenter Tirilazad database (3551 patients) was used to create this clinical outcome prediction model in order to elucidate significant brain-body associations. Traditional binary logistic regression models were used.RESULTS:Binary logistic regression main effects model included four statistically significant single prognostic variables, namely, neurological grade, age, stroke, and time to surgery. Logistic regression models demonstrated the significance of hypertension and liver disease in development of brain swelling, as well as the negative consequences of seizures in patients with a history of myocardial infarction and post-admission fever worsening neurological outcome.CONCLUSIONS:Using the aforementioned results generated from binary logistic regression models, we can identify potential patients who are in the high risk group of neurological deterioration. Specific therapies can be tailored to prevent these detriments, including treatment of hypertension, seizures, early detection and treatment of myocardial infarction, and prevention of hepatic encephalopathy.

BACKGROUND:Classification and regression tree analysis involves the creation of a decision tree by recursive partitioning of a dataset into more homogeneous subgroups. Thus far, there is scarce literature on using this technique to create clinical prediction tools for aneurysmal subarachnoid hemorrhage (SAH).METHODS:The classification and regression tree analysis technique was applied to the multicenter Tirilazad database (3551 patients) in order to create the decision-making algorithm. In order to elucidate prognostic subgroups in aneurysmal SAH, neurologic, systemic, and demographic factors were taken into account. The dependent variable used for analysis was the dichotomized Glasgow Outcome Score at 3 months.RESULTS:Classification and regression tree analysis revealed seven prognostic subgroups. Neurological grade, occurrence of post-admission stroke, occurrence of post-admission fever, and age represented the explanatory nodes of this decision tree. Split sample validation revealed classification accuracy of 79% for the training dataset and 77% for the testing dataset. In addition, the occurrence of fever at 1-week post-aneurysmal SAH is associated with increased odds of post-admission stroke (odds ratio: 1.83, 95% confidence interval: 1.56-2.45, P < 0.01).CONCLUSIONS:A clinically useful classification tree was generated, which serves as a prediction tool to guide bedside prognostication and clinical treatment decision making. This prognostic decision-making algorithm also shed light on the complex interactions between a number of risk factors in determining outcome after aneurysmal SAH.

Introduction: Vasospasm causing delayed cerebral ischemia (DCI) remains a leading cause of morbidity and mortality in aneurysmal subarachnoid hemorrhage (aSAH). Our previously reported series detailed the safety and efficacy of cardiac doses of milrinone in DCI. Since 2007, we have been treating refractory delayed cerebral ischemia (RDCI) with very large doses of IV milrinone. We report the safety and clinical effect of high-dose milrinone in aSAH with RDCI. Methods: Retrospective single center analysis of all patients treated between October 2014 and July 2015 for vasospasm refractory to the MNH protocol (RDCI). RDCI patients received a bolus and perfusion that were increased incrementally until resolution of signs. If 2 boluses and 2 increases in perfusion were unsuccessful, patients underwent angiogram for intra-arterial (IA) milrinone and possible angioplasty. Results: 40 patients were admitted for acute aSAH. Vasospasm was diagnosed clinically in 26 (65%). Initial milrinone therapy included a loading dose of 6 mg and an infusion of 0.75 mcg/kg/min. Of these patients, 18 had RDCI and received boluses of up to 8mg IV with perfusions of up to 2.75 mcg/kg/min. The maximum cumulative daily dose of milrinone was 230mg. There were no adverse cardiovascular events due to the drug. Neurologic improvement was seen in 8/18 with large IV bolus and perfusion of milrinone. Ten patients required angiography; all received IA milrinone, and angioplasty was performed in 3. Modified rankin scale (mRS) ≤ 2 on discharge was achieved in 6 of the 8 patients who improved with high-dose IV milrinone alone, 2 of 3 patients undergoing angioplasty and 4 of the 7 patients receiving IA milrinone without angioplasty. Conclusion: High doses of IV milrinone were effective in a large proportion of our patients with vasospasm and RDCI after aSAH, and it was extremely safe. This treatment could be considered prior to angioplasty.

To assess the safety and effectiveness of lumbar drains as adjuvant therapy in severe bacterial meningitis, and compare it to standard treatment.

Introduction For the treatment of cerebral vasospasm, current therapies have focused on increasing blood flow through blood pressure augmentation, hypervolemia, the use of intra-arterial vasodilators, and angioplasty of proximal cerebral vessels. Through a large case series, we present our experience of treating cerebral vasospasm with a protocol based on maintenance of homeostasis (correction of electrolyte and glucose disturbances, prevention and treatment of hyperthermia, replacement of fluid losses), and the use of intravenous milrinone to improve microcirculation (the Montreal Neurological Hospital protocol). Our objective is to describe the use milrinone in our practice and the neurological outcomes associated with this approach. Methods Large case series based on the review of all patients diagnosed with delayed ischemic neurologic deficits after aneurysmal subarachnoid hemorrhage between April 1999 and April 2006. Results 88 patients were followed for a mean time of 44.6 months. An intravenous milrinone infusion was used for a mean of 9.8 days without any significant side effects. No medical complications associated with this protocol were observed. There were five deaths; of the surviving patients, 48.9 % were able to go back to their previous baseline and 75 % had a good functional outcome (modified Rankin scale ≤2). Conclusion A protocol using intravenous milrinone, and the maintenance of homeostasis is simple to use and requires less intensive monitoring and resources than the standard triple H therapy. Despite the obvious limitations of this study’s design, we believe that it would be now appropriate to proceed with formal prospective studies of this protocol.