Neurological Prognostication of Cardiac Arrest in an Era of Extracorporeal Membrane Oxygenation.

A neuron-specific enolase level greater than 33 ng/mL at days 1 to 3 or status myoclonus within 1 day are traditional indicators of poor neurological prognosis in survivors of cardiac arrest. We report the case of a 70-year-old man who received extracorporeal membrane oxygenation following cardiac arrest. Despite having both an elevated neuron-specific enolase concentration of 68 ng/mL and status myoclonus, he made an excellent neurological recovery. The value of traditional markers of poor prognosis such as elevated neuron-specific enolase or status myoclonus has not been systematically validated in patients treated with extracorporeal membrane oxygenation or therapeutic hypothermia. Straightforward application of practice guidelines in these cases may result in tragic outcomes. This case underscores the need for reliable prognostic markers that account for recent advances in cardiopulmonary and neurological therapies.

A 59-year-old man with acute onset of paralysis.

Botulism is a neuroparalytic illness resulting from the action of a potent toxin produced by the organism Clostridium botulinum. It can present with a classic triad of clear mentation, bulbar palsy and symmetric descending paralysis. Treatment is symptomatic and includes a botulinum antitoxin.

Hemicraniectomy and durotomy upon deterioration from infarction-related swelling trial: randomized pilot clinical trial.

BACKGROUND AND PURPOSE: Hemicraniectomy and Durotomy Upon Deterioration From Infarction-Related Swelling Trial (HeADDFIRST) was a randomized pilot study to obtain information necessary to design a Phase III trial to evaluate the benefit of surgical decompression for brain swelling from large supratentorial cerebral hemispheric infarction. METHODS: All patients with stroke were screened for eligibility (age 18-75 years, National Institutes of Health Stroke Scale≥18 with Item 1a<2 [responsive to minor stimulation], and CT demonstrating unilateral, complete middle cerebral artery territory infarction by specific imaging criteria). All enrolled patients were treated using a standardized medical treatment protocol. Those with both≥4 mm of pineal shift and deterioration in level of arousal or ≥7.5 mm of anteroseptal shift within 96 hours of stroke onset were randomized to continued medical treatment only or medical treatment plus surgery. Death at 21 days was the primary outcome measure. RESULTS: Among 4909 screened patients, only 66 (1.3%) patients were eligible for HeADDFIRST. Forty patients were enrolled, and 26 patients developed the requisite brain swelling for randomization. All who failed to meet randomization criteria were alive at 21 days. Mortality at 21 and 180 days was 40% (4/10) in the medical treatment only and 21% (3/14) and 36% (5/14) in the medical treatment plus surgery arms, respectively. CONCLUSIONS: HeADDFIRST randomization criteria effectively distinguished low from high risk of death from large supratentorial cerebral hemispheric infarction. Lower mortality in the medical treatment only group than in other published trials suggests a possible benefit to standardizing medical management. These results can inform the interpretation of recently completed European trials concerning patient selection and medical management. CLINICAL TRIAL REGISTRATION: This trial was not registered because enrollment began before July 1, 2005.

A young man with altered mental status and new-onset seizures.

Signs and symptoms of a subacute, progressive, imaging-negative encephalopathy can be misdiagnosed as a neuropsychiatric or progressive neurodegenerative disorder. However, encephalopathies often can be reversed if the autoimmune component is recognized early through a careful history and diagnostic testing, including cerebrospinal fluid analysis for antibodies.

Depressed mood and quality of life after subarachnoid hemorrhage.

BACKGROUND: Cognitive impairment is widely considered the main cause of disability and handicap after subarachnoid hemorrhage (SAH). The impact of depression on recovery after SAH remains poorly defined. We sought to determine the frequency of post-SAH depression, identify risk factors for its development, and evaluate the impact of depression on quality of life (QOL) during the first year of recovery. METHODS: We prospectively studied 216 of 534 SAH patients treated between July 1996 and December 2001 with complete one-year follow-up data. Depression was evaluated with the Center for Epidemiological Studies Depression (CES-D) scale, cognitive status with the Telephone Interview for Cognitive Status (TICS), and QOL with the Sickness Impact Profile (SIP) 3 and 12 months after SAH. RESULTS: Depressed mood occurred in 47% of patients during the first year of recovery; 26% were depressed at both 3 and 12 months. Non-white ethnicity predicted early (3 month) and late (12 month) depressions; early depression was also predicted by previously-diagnosed depression, cigarette smoking, and cerebral infarction, whereas late depression was predicted by prior social isolation and lack of medical insurance. Depression was associated with inferior QOL in all domains of the SIP, and changes in depression status were associated with striking parallel changes in QOL, disability, and cognitive function during the first year of recovery. CES-D scores accounted for over 60% of the explained variance in SIP total scores, whereas TICS performance accounted for no more than 6%. CONCLUSION: Depression affects nearly half of SAH patients during the first year of recovery, and is associated with poor QOL. Systematic screening and early treatment for depression are promising strategies for improving outcome after SAH.

Efficacy spectrum of antishivering medications: meta-analysis of randomized controlled trials.

OBJECTIVES: Shivering after anesthesia or in the critical care setting is frequent, can be prolonged, and has the potential for serious adverse events and worsening outcomes. Furthermore, there are conflicting published data and clinical protocols on how to best treat shivering. In this study, we aimed to critically analyze the published evidence of antishivering medications. DATA SOURCES: We systematically reviewed, categorized, and analyzed all literature on antishivering medications published in English. Target key words and study types were determined and major scientific databases (PubMed, EMBASE, the Cochrane Controlled Trials Register, Ovid-Medline, and JAMA Evidence) and individual target journals were systematically searched up to August 1, 2011. STUDY SELECTION: Publications were categorized by the pharmacological intervention used, regardless of whether the subjects were ventilated, underwent surgery, received anesthesia, or received additional medications. Randomized, double-blinded, placebo-controlled trials investigating antishivering treatment were extracted and evaluated for clinical and statistical homogeneity and, if suitable, included in a subsequent meta-analysis using linear comparisons calculating shivering risk-reduction ratios. DATA EXTRACTION: A total of 41 individual and eight combination antishivering medications were tested in 124 publications containing 208 substudies and recruiting a total of 9,668 subjects. Among those, 80 publications containing 119 substudies were identified as randomized, double-blinded, placebo-controlled of which 94 substudies were subjected to linear comparison analysis. DATA SYNTHESIS: Study drug frequencies, calculated pooled risk benefits, and pooled numbers needed to treat of the five most frequently studied and efficacious medications were clonidine (22 studies; risk ratio: 1.6, numbers needed to treat: 4), meperidine (16; 2.2, 2), tramadol (8; 2.2, 2), nefopam (7; 2.1, 2), and ketamine (7; 1.8, 3). CONCLUSIONS: There is significant heterogeneity in the literature with respect to study methods and efficacy testing of antishivering treatments. Clonidine, meperidine, tramadol, nefopam, and ketamine were the most frequently reported pharmacological interventions and showed a variable degree of efficacy in randomized, double-blinded, placebo-controlled trials.

Factors contributing to ventriculostomy infection.

OBJECTIVE: Catheter-related infection remains a cause of morbidity in the use of external ventricular drains (EVDs). The aim of this retrospective single-center study was to assess the rate and factors related to ventriculostomy infections in the setting of the published literature. METHODS: Patients that underwent EVD placement in a single-center were retrospectively reviewed. Diagnosis, treatment, hospital course, and infection-related data were collected and analyzed in reference to ventriculitis rates. The protocols for EVD placement and maintenance were reviewed. RESULTS: Of 343 patients, 12 acquired an EVD infection. No significant differences existed between those with and without ventriculitis for age, sex, underlying diagnosis, or concomitant systemic infection. Although not significant, concomitant systemic infection existed in 4.7% of patients with ventriculitis versus 1.5% without. There was a significant difference in length of EVD placement in patients with ventriculitis (20.9 ± 15.3 days) versus those without (12.1 ± 18.2; P = 0.005). Coagulase-negative Staphylococcus and Staphylococcus aureus represented the most commonly associated pathogens. With an overall cumulative incidence of 3.5%, our rate compared favorably to the published literature (cumulative incidence 9.5%; range, 3.9%-23.2%). CONCLUSIONS: Catheter-related infection remains an important complication of EVD placement. Of factors evaluated, length of time of catheter placement has the most notable relationship to infection incidence, suggesting that early drain removal should be a goal whenever medically appropriate.

Locked-in syndrome from rostro-caudal herniation.

Locked-in syndrome (LIS) is often caused by ventral pontine injury involving the perforating pontine vessels of the basilar artery and recovery is rarely reported. We report a patient who developed LIS acutely after aneurysmal subarachnoid haemorrhage and rostro-caudal herniation from hydrocephalus. The patient's clinical course and diagnostic studies suggest that the likely mechanism of this patient's LIS is mechanical compression of the ventral pons anteriorly against the clivus. The patient's slow but full recovery allowed us to further differentiate this clinical entity from the more common LIS due to ischaemic mechanisms.

Simple intravenous fluid regimens to control fever in hospitalized stroke patients: a theoretical evaluation.

Fever is an independent predictor of worse outcome in stroke patients. We hypothesized that a peripheral infusion of saline in chilled or ice slurry form can be a practical adjuvant therapy to maintain euthermia. We developed a theoretical model simulating systemic body cooling in response to 0 degrees C saline and 50% ice slurry. Temperature elevations up to 39 degrees C were studied with respect to the time needed to reach a core temperature of 37 degrees C. Mathematical modeling identified a cooling rate of 0.48 degrees C/hr and 0.24 degrees C/hr using a 450 mL/hr infusion of 50% ice slurry and chilled saline. A reduction of the infusion rate to 150 mL/hr decreased euthermia time by a factor of 3; however, the total amount of coolant remained constant. Thus, based on mathematical modeling, peripheral infusions of saline in chilled or ice slurry form can be used as an adjunct therapy to achieve euthermia and control fever. Using intravenous coolants in an on-demand, temperature-guided and supervised treatment setting seems most reasonable to avoid potentially unsafe use of extended fluid volumes and infusion times.

Encapsulation and release of plasminogen activator from biodegradable magnetic microcarriers.

There are a number of therapies available to recanalize occluded arteries. However, even though proven beneficial, these approaches are not without significant shortcomings. Previous research showed that by encapsulating therapeutic thrombolytic enzymes in liposomic formulations, the reperfusion times in vivo were significantly lower than for administration of free thrombolytic. Like liposomes, biodegradable, diblock polymers of poly(lactic acid)-poly(ethylene glycol) (PLA-PEG) have been shown to have therapeutic benefit as delivery vehicles for a variety of drug delivery concepts. We report on new formulations based on tissue plasminogen activator (tPA) encapsulated in magnetic, PLA-PEG microcarriers. We studied the tPA encapsulation efficiency, loading, and release after varying the molecular weight of polymer, carrier size, tPA solution composition, and use of ultrasound to enhance release. We loaded 3.3-9.4wt% tPA and 12-17wt% magnetite into the carriers, depending on the exact formulation. The release of tPA was complete 20min after reconstitution. Ultrasound insonation failed to enhance tPA release rates in smaller carriers but significantly enhanced release in larger carriers. With these formulations, we should be able to achieve lytic concentrations if we can magnetically concentrate 5mg of carrier within about 11ml of blood volume near the clot.

Capture of magnetic carriers within large arteries using external magnetic fields.

Our overall research goal is to advance the safety and effectiveness of acute ischemic stroke therapy by improving the benefit/risk ratio of thrombolysis and hence, the long-term outcome of acute ischemic stroke victims. Our approach is the development of a novel tissue plasminogen activator (t-PA) delivery system based on t-PA-loaded magnetic nano- and microcarriers guided directly to the site of vascular occlusion by external magnetic fields. Such a t-PA delivery system would conveniently combine the advantages of both intravenous (systemic) and intraarterial (catheter-facilitated) thrombolysis: non-invasiveness - the magnetic t-PA carriers can be injected intravenously and targeted, as drug delivery is magnetically guided to and t-PA focally released at and within the vascular clot to induce lysis. The focus of our discussion are the two necessary, fundamental and interrelated bioengineering steps: the research and development of well-characterized, biocompatible, functionally active and t-PA-loaded (encapsulated) magnetic nano- and microcarriers able to induce effective thrombolysis, and the design of magnetic guidance systems for targeted tPA-delivery allowing also the triggered release of the thrombolytic agent at the clot site. In this paper, we theoretically demonstrated magnetic trapping of blood borne magnetic nano- and microcarriers from human large vessels, especially arteries. Then, some preliminary experiments using primate models (monkeys) were done to identify successful in vivo sequestration of magnetic carriers in large and smaller arterial branches after arterial upstream and systemic venous injection. Histology (hematoxylin-eosin stain) verified intraarterial carrier concentration (identified as black carrier agglomerates on H and E staining) at the arterial region above the surface magnet. The results revealed the feasibility of magnetic drug-targeting at arteries and solidified the proposed t-PA delivery system.

Brainstem ischemia in acute herniation syndrome.

Brain herniation from hemispheric mass lesions injures mainly the upper brainstem around the tentorial incisura. While mechanical tissue compression is usually the process of deterioration and injury, the primary injury mechanism in some patients is early brainstem ischemia from arterial compromise as demonstrated by this patient's magnetic resonance imaging (MRI) and pathology.

Improvement of in vitro thrombolysis employing magnetically-guided microspheres.

Significant shortcomings in clinical thrombolysis efficiencies and arterial recanalization rates still exist to date necessitating the development of additional thrombolysis-enhancing technologies. For example, to improve tPA-induced systemic clot lysis several supplementary treatment methods have been proposed, among them ultrasound-enhanced tissue plasminogen activator (tPA) thrombolysis which has already found some clinical applicability. The rationale of this study was to investigate whether biodegradable, magnetic spheres can be a useful adjuvant to currently existing tPA-induced thrombolysis and further enhance clot lysis results. Based on an envisioned, novel thrombolysis technology--magnetically-guided, tPA-loaded nanocarriers with triggered release of the shielded drug at an intravascular target site--we evaluated the lysis efficiencies of magnetically-guided, non-medicated magnetic spheres in various combinations with tPA and ultrasound. When tPA was used in conjunction with magnetic spheres and a magnetic field, the lysis efficiency under static, no-flow conditions improved by 1.7 and 2.7 fold for red and white clots, respectively. In dynamic lysis studies, the addition of ultrasound and magnetically-guided spheres to lytic tPA dosages resulted in both maximum clot lysis efficiency and shortest reperfusion time corresponding to a 2-fold increase in lysis and 7-fold reduction in recanalization time, respectively. Serial microscopic evaluations on histochemical sections reconfirmed that tPA penetration into and fragmentation of the clot increased with escalating exposure time to tPA and magnetic spheres/field. These results delineate the effectiveness of magnetic spheres as an adjuvant to tPA therapy accelerating in vitro lysis efficiencies beyond values found for tPA with and without ultrasound. We demonstrated that the supplementary use of magnetically-guided, non-medicated magnetic spheres significantly enhances in vitro static and dynamic lysis of red and white blood clots.

2D modeling and preliminary in vitro investigation of a prototype high gradient magnetic separator for biomedical applications.

High gradient magnetic separation (HGMS) of magnetic materials from fluids or waste products has many established industrial applications. However, there is currently no technology employing HGMS for ex-vivo biomedical applications, such as for the removal of magnetic drug- or toxin-loaded spheres from the human blood stream. Importantly, human HGMS applications require special design modifications as, in contrast to conventional use where magnetic elements are permanently imbedded within the separation chambers, medical separators need to avoid direct contact between the magnetic materials and blood to reduce the risk of blood clotting and to facilitate convenient and safe treatment access for many individuals. We describe and investigate the performance of a magnetic separator prototype designed for biomedical applications. First, the capture efficiency of a prototype HGMS separator unit consisting of a short tubing segment and two opposing magnetizable fine wires along the outside of the tubing was investigated using 2D mathematical modeling. Second, the first-pass effectiveness to remove commercially available, magnetic polystyrene spheres from human blood using a single separator unit was experimentally verified. The theoretical and experimental data correlated well at low flow velocities (<5.0 cm/s) and high external magnetic fields (>0.05 T). This prototype separator unit removed >90% in a single pass of the magnetic spheres from water at mean flow velocity < or =8.0 cm/s and from blood mimic fluids (ethylene glycol-water solutions) at mean flow velocity < or =2.0 cm/s. In summary, we describe and prove the feasibility of a HGMS separator for biomedical applications.

A comprehensive in vitro investigation of a portable magnetic separator device for human blood detoxification.

A portable magnetic separator device is being developed for a proposed magnetically based detoxification system. In this paper, the performance of this device was evaluated via preliminary in vitro flow experiments using simple fluids and a separator unit consisting of one tube and two metal wires, each at the top and bottom of the tube. The effects of the following factors were observed: mean flow velocity U(o) (0.14-45 cm s(-1)), magnetic field strength micro(o)H(o) (0.125-0.50 T), wire size R(w) (0.125, 0.250 and 0.500 mm), wire length L(w) (2, 5 and 10 cm), wire materials (nickel, stainless steel 304 and 430) and tube size (outer radius R(o) = 0.30 mm and inner radius R(i) = 0.25 mm; R(o) = 0.50 mm and R(i) = 0.375 mm; and R(o) = 2.0 mm and R(i) = 1.0 mm). Our observations showed that the experimental results fit well with the corresponding theoretical results from the model we previously developed at a low flow velocity area (for example, U(o) < or = 20 cm s(-1)), strong external magnetic field (for example, > or = 0.30 T) and long wire length (for example, L(w) = 10 cm). The experimental results also showed that more than 90% capture efficiency is indeed achievable under moderate systemic and operational conditions. Pressure drop measurements revealed that the device could work well under human physiological and clinical conditions, and sphere buildup would not have any considerable effect on the pressure drop of the device. The breakthrough experiments demonstrated that a lower flow rate V, higher applied magnetic field micro(o)H(o) and diluted sphere suspension, i.e. lower C(o), would delay the breakthrough. All the results indicate the promise of this portable magnetic separator device to efficiently in vivo sequestrate nano-/micro-spheres from blood flow in the future magnetically based detoxification system.

Three-dimensional modeling of a portable medical device for magnetic separation of particles from biological fluids.

A portable separator has been developed to quantitatively separate blood-borne magnetic spheres in potentially high-flow regimes for the human detoxification purpose. In the separator design, an array of biocompatible capillary tubing and magnetizable wires is immersed in an external magnetic field that is generated by two permanent magnets. The wires are magnetized and the high magnetic field gradient from the magnetized wires helps to collect blood-borne magnetic nano/micro-spheres from the blood flow. In this study, a 3D numerical model was created and the effect of tubing-wire configurations on the capture efficiency of the system was analyzed using COMSOL Multiphysics 3.3(R). The results showed that the configuration characterized by bi-directionally alternating wires and tubes was the best design with respect to the four starting configurations. Preliminary in vitro experiments verified the numerical predictions. The results helped us to optimize a prototype portable magnetic separator that is suitable for rapid sequestration of magnetic nano/micro-spheres from the human blood stream while accommodating necessary clinical boundary conditions.

Outcome in patients with subarachnoid hemorrhage treated with antiepileptic drugs.

OBJECT: Prophylactic use of antiepileptic drugs (AEDs) in patients admitted with aneurysmal subarachnoid hemorrhage (SAH) is common practice; however, the impact of this treatment strategy on in-hospital complications and outcome has not been systematically studied. The goal in this study was twofold: first, to describe the prescribing pattern for AEDs in an international study population; and second, to delineate the impact of AEDs on in-hospital complications and outcome in patients with SAH. METHODS: The authors examined data collected in 3552 patients with SAH who were entered into four prospective, randomized, double-blind, placebo-controlled trials conducted in 162 neurosurgical centers and 21 countries between 1991 and 1997. The prevalence of AED use was assessed by study country and center. The impact of AEDs on in-hospital complications and outcome was evaluated using conditional logistic regressions comparing treated and untreated patients within the same study center. RESULTS: Antiepileptic drugs were used in 65.1% of patients and the prescribing pattern was mainly dependent on the treating physicians: the prevalence of AED use varied dramatically across study country and center (intraclass correlation coefficients 0.22 and 0.66, respectively [p < 0.001]). Other predictors included younger age, worse neurological grade, and lower systolic blood pressure on admission. After adjustment, patients treated with AEDs had odds ratios of 1.56 (95% confidence interval [CI] 1.16-2.10; p = 0.003) for worse outcome based on the Glasgow Outcome Scale; 1.87 (95% CI 1.43-2.44; p < 0.001) for cerebral vasospasm; 1.61 (95% CI 1.25-2.06; p < 0.001) for neurological deterioration; 1.33 (95% CI 1.01-1.74; p = 0.04) for cerebral infarction; and 1.36 (95% CI 1.03-1.80; p = 0.03) for elevated temperature during hospitalization. CONCLUSIONS: Prophylactic AED treatment in patients with aneurysmal SAH is common, follows an arbitrary prescribing pattern, and is associated with increased in-hospital complications and worse outcome.

Intraventricular hemorrhage from ruptured aneurysm: clinical characteristics, complications, and outcomes in a large, prospective, multicenter study population.

OBJECT: In this study the authors analyzed the relationship of intraventricular hemorrhage (IVH) to in-hospital complications and clinical outcome in a large population of patients with aneurysmal subarachnoid hemorrhage (SAH). METHODS: Data from 3539 patients with aneurysmal SAH were evaluated, and these data were obtained from four prospective, randomized, double-blind, placebo-controlled trials of tirilazad that had been conducted between 1991 and 1997. Clinical characteristics, in-hospital complications, and outcome at 3 months post-SAH (Glasgow Outcome Scale score) were analyzed with regard to the presence or absence of IVH. RESULTS: Patients with SAH and IVH differ in demographic and admission characteristics from those with SAH but without IVH and are more likely to suffer in-hospital complications and a worse outcome at 3 months post-SAH. CONCLUSIONS: The presence of IVH in patients with SAH has an important predictive value with regard to these aspects.

Prognostic factors for outcome in patients with aneurysmal subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: The purpose of this study was to describe prognostic factors for outcome in a large series of patients undergoing neurosurgical clipping of aneurysms after subarachnoid hemorrhage (SAH). METHODS: Data were analyzed from 3567 patients with aneurysmal SAH enrolled in 4 randomized clinical trials between 1991 and 1997. The primary outcome measure was the Glasgow outcome scale 3 months after SAH. Multivariable logistic regression with backwards selection and Cox proportional hazards regression models were derived to define independent predictors of unfavorable outcome. RESULTS: In multivariable analysis, unfavorable outcome was associated with increasing age, worsening neurological grade, ruptured posterior circulation aneurysm, larger aneurysm size, more SAH on admission computed tomography, intracerebral hematoma or intraventricular hemorrhage, elevated systolic blood pressure on admission, and previous diagnosis of hypertension, myocardial infarction, liver disease, or SAH. Variables present during hospitalization associated with poor outcome were temperature >38 degrees C 8 days after SAH, use of anticonvulsants, symptomatic vasospasm, and cerebral infarction. Use of prophylactic or therapeutic hypervolemia or prophylactic-induced hypertension were associated with a lower risk of unfavorable outcome. Time from admission to surgery was significant in some models. Factors that contributed most to variation in outcome, in descending order of importance, were cerebral infarction, neurological grade, age, temperature on day 8, intraventricular hemorrhage, vasospasm, SAH, intracerebral hematoma, and history of hypertension. CONCLUSIONS: Although most prognostic factors for outcome after SAH are present on admission and are not modifiable, a substantial contribution to outcome is made by factors developing after admission and which may be more easily influenced by treatment.