Magnetic Resonance Spectroscopy of Hypoxic-Ischemic Encephalopathy After Cardiac Arrest.

BACKGROUND AND OBJECTIVES: To correlate brain metabolites with clinical outcome using magnetic resonance spectroscopy (MRS) in patients undergoing targeted temperature management (TTM) after cardiac arrest and assess their relationships to MRI and EEG variables. METHODS: A prospective cohort of 50 patients was studied. The primary outcome was coma recovery to follow commands. Comparison of MRS measures in the posterior cingulate gyrus, parietal white matter, basal ganglia, and brainstem were also made to 25 normative controls. RESULTS: Fourteen of 50 patients achieved coma recovery before hospital discharge. There was a significant decrease in total N-acetylaspartate (NAA/Cr) and an increase in lactate/creatine (Lac/Cr) in patients who did not recover, with changes most prominent in the posterior cingulate gyrus. Patients who recovered had decrease in NAA/Cr as compared to controls. NAA/Cr had a strong monotonic relationship with MRI cortical apparent diffusion coefficient (ADC); Lac level exponentially increased with decreasing ADC. EEG suppression/burst suppression was strongly associated with Lac elevation. DISCUSSION: NAA and Lac changes are associated with clinical/MRI/EEG changes consistent with hypoxic-ischemic encephalopathy (HIE) and are most prominent in the posterior cingulate gyrus. NAA/Cr decrease observed in patients with good outcomes suggests mild HIE in patients asymptomatic at hospital discharge. The appearance of cortical Lac represents a deterioration of aerobic energy metabolism and is associated with EEG background suppression, synaptic transmission failure, and severe, potentially irreversible HIE. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that in patients undergoing TTM after cardiac arrest, brain MRS-determined decrease in total NAA/Cr and an increase in Lac/Cr are associated with an increased risk of not recovering.

Expanding controlled donation after the circulatory determination of death: statement from an international collaborative.

A decision to withdraw life-sustaining treatment (WLST) is derived by a conclusion that further treatment will not enable a patient to survive or will not produce a functional outcome with acceptable quality of life that the patient and the treating team regard as beneficial. Although many hospitalized patients die under such circumstances, controlled donation after the circulatory determination of death (cDCDD) programs have been developed only in a reduced number of countries. This International Collaborative Statement aims at expanding cDCDD in the world to help countries progress towards self-sufficiency in transplantation and offer more patients the opportunity of organ donation. The Statement addresses three fundamental aspects of the cDCDD pathway. First, it describes the process of determining a prognosis that justifies the WLST, a decision that should be prior to and independent of any consideration of organ donation and in which transplant professionals must not participate. Second, the Statement establishes the permanent cessation of circulation to the brain as the standard to determine death by circulatory criteria. Death may be declared after an elapsed observation period of 5 min without circulation to the brain, which confirms that the absence of circulation to the brain is permanent. Finally, the Statement highlights the value of perfusion repair for increasing the success of cDCDD organ transplantation. cDCDD protocols may utilize either in situ or ex situ perfusion consistent with the practice of each country. Methods to accomplish the in situ normothermic reperfusion of organs must preclude the restoration of brain perfusion to not invalidate the determination of death.

Treatment of Subarachnoid Hemorrhage-associated Delayed Cerebral Ischemia With Milrinone: A Review and Proposal.

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.

Brain Death Determination: An Interprofessional Simulation to Determine Brain Death and Communicate with Families Focused on Neurology Residents.

Introduction: Significant variation exists in determining brain death despite an expectation of competence for all neurology residents. In addition, family discussions regarding brain death are challenging and may influence organ donation. Methods: We developed two simulations of increasing complexity for PGY 2 and PGY 3 neurology residents. High-fidelity mannequins were used to simulate patients; standardized actors portrayed family members. In the first simulation, residents determined brain death and shared this information with a grieving family. In the second simulation, residents determined brain death in a more complicated scenario, requiring ancillary testing and accurate result interpretation. Following the determination, residents met with a challenging family. The residents worked with an interdisciplinary team and responded to the family's emotions, used active listening skills, and supported the family through next steps. Results: Twelve residents completed the simulations. Prior to the simulation, three (25%) residents felt comfortable discussing a brain death diagnosis; following the simulation, eight (67%) residents felt comfortable/very comfortable discussing brain death. Prior to the simulation, eight (67%) residents stated they knew prerequisites for performing a brain death examination and seven (58%) agreed they knew indications for ancillary testing; these numbers increased to 100% following the simulation. The number of residents who felt comfortable performing the brain death exam increased from five (42%) to 10 (83%). Discussion: This simulation of determining brain death and leading difficult family meetings was well-received by neurology residents. Further work should focus on the effects of simulation-based education on practice variation and organ donation consent rates.

Fibrinogen Concentrate for the Treatment of Thrombolysis-Associated Hemorrhage in Adult Ischemic Stroke Patients.

In patients with ischemic stroke who receive systemic recombinant tissue plasminogen activator (rt-PA), the risk of secondary hemorrhage is 1-7%. Fibrinogen supplementation with cryoprecipitate is recommended in patients with rt-PA-associated symptomatic hemorrhage. We examined whether fibrinogen concentrate can be used safely in this setting. A single-center retrospective case series was performed in patients who received fibrinogen concentrate for post-rt-PA hemorrhage between January-2012 and December-2017. The primary outcome was the incidence of in-hospital thromboembolic events and infusion reactions. Secondary outcomes included incidence of clinically significant ICH expansion within 24-hours and patient serum fibrinogen response to fibrinogen concentrate therapy. Thromboembolic events occurred in 3 (12.5%) of 24 patients included in the analysis. No patients experienced infusion-related reactions. Five of 22 patients with ICH experienced clinically significant hemorrhage expansion. Hypofibrinogenemia was corrected in 87.5%(7/8) of patients with baseline hypofibrinogenemia, with a median increase in serum fibrinogen 166 mg/dL. Median fibrinogen increase in patients without baseline hypofibrinogenemia was 18 mg/dL. Fibrinogen concentrate is a safe potential therapeutic option to restore fibrinogen levels in acute ischemic stroke patients with thrombolysis-associated hemorrhage.

Racial and Ethnic Disparities in Postcardiac Arrest Targeted Temperature Management Outcomes.

OBJECTIVES: To evaluate racial and ethnic disparities in postcardiac arrest outcomes in patients undergoing targeted temperature management. DESIGN: Retrospective study. SETTING: ICUs in a single tertiary care hospital. PATIENTS: Three-hundred sixty-seven patients undergoing postcardiac arrest targeted temperature management, including continuous electroencephalogram monitoring. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Clinical variables examined in our clinical cohort included race/ethnicity, age, time to return of spontaneous circulation, cardiac rhythm at time of arrest, insurance status, Charlson Comorbidity Index, and time to withdrawal of life-sustaining therapy. CT at admission and continuous electroencephalogram monitoring during the first 24 hours were used as markers of early injury. Outcome was assessed as good (Cerebral Performance Category 1-2) versus poor (Cerebral Performance Category 3-5) at hospital discharge. White non-Hispanic ("White") patients were more likely to have good outcomes than white Hispanic/nonwhite ("Non-white") patients (34.4 vs 21.7%; p = 0.015). In a multivariate model that included age, time to return of spontaneous circulation, initial rhythm, combined electroencephalogram/CT findings, Charlson Comorbidity Index, and insurance status, race/ethnicity was still independently associated with poor outcome (odds ratio, 3.32; p = 0.003). Comorbidities were lower in white patients but did not fully explain outcomes differences. Nonwhite patients were more likely to exhibit signs of early severe anoxic changes on CT or electroencephalogram, higher creatinine levels and receive dialysis, but had longer duration to withdrawal of lifesustaining therapy. There was no significant difference in catheterizations or MRI scans. Subgroup analysis performed with patients without early electroencephalogram or CT changes still revealed better outcome in white patients. CONCLUSIONS: Racial/ethnic disparity in outcome persists despite a strictly protocoled targeted temperature management. Nonwhite patients are more likely to arrive with more severe anoxic brain injury, but this does not account for all the disparity.

Combination of Clinical Exam, MRI and EEG to Predict Outcome Following Cardiac Arrest and Targeted Temperature Management.

BACKGROUND: Despite the widespread adoption of targeted temperature management (TTM), coma after cardiac arrest remains a common problem with a high proportion of patients suffering substantial disability. Prognostication after cardiac arrest, particularly the identification of patients with likely good outcome, remains difficult. METHODS: We performed a retrospective study of 78 patients who underwent TTM after cardiac arrest and were evaluated with both electroencephalography (EEG) and magnetic resonance imaging (MRI). We hypothesized that combining malignant versus non-malignant EEG classification with clinical exam and quantitative analysis of apparent diffusion coefficient (ADC) and fluid-attenuated inversion recovery imaging would improve prognostic ability. RESULTS: Consistent with prior literature, presence of a malignant EEG pattern was 100% specific for poor outcome. We found that decreased whole brain ADC signal intensity was associated with poor outcome (853 ± 14 vs. 950 ± 17.5 mm2/s, p < 0.0001). Less than 15% total brain volume with ADC signal intensity < 650 mm2/s was predictive of good outcome with 100% sensitivity, 51% specificity and an area under the curve of 0.787. A model combining this ADC marker with non-malignant EEG and flexor-or-better motor response was 100% sensitive and 91.1% specific for good outcome following cardiac arrest and targeted temperature management. CONCLUSION: We conclude that in the absence of malignant EEG findings, combination of physical exam and MRI findings can be a useful to identify those patients who have potential for recovery. Variability in timing of imaging and findings in different modalities argue for the need for future prospective studies of multimodal outcome prediction after cardiac arrest.

Measuring Critical Care Providers' Attitudes About Controlled Donation After Circulatory Death.

INTRODUCTION: Unfavorable attitudes and insufficient knowledge about donation after cardiac death among critical care providers can have important consequences for the appropriate identification of potential donors, consistent implementation of donation after cardiac death policies, and relative strength of support for this type of donation. The lack of reliable and valid assessment measures has hampered research to capture providers' attitudes. Design and Research Aims: Using stakeholder engagement and an iterative process, we developed a questionnaire to measure attitudes of donation after cardiac death in critical care providers (n = 112) and examined its psychometric properties. Exploratory factor analysis, internal consistency, and validity analyses were conducted to examine the measure. RESULTS: A 34-item questionnaire consisting of 4 factors (Personal Comfort, Process Satisfaction, Family Comfort, and System Trust) provided the most parsimonious fit. Internal consistency was acceptable for each of the subscales and the total questionnaire (Cronbach α > .70). A strong association between more favorable attitudes overall and knowledge ( r = .43, P < .001) provides evidence of convergent validity. Multivariable regression analyses showed that white race ( P = .002) and more experience with donation after cardiac death ( P < .001) were significant predictors of more favorable attitudes. CONCLUSION: Study findings support the utility, reliability, and validity of a questionnaire for measuring attitudes in critical care providers and for isolating targets for additional education on donation after cardiac death.

The Link Between Cerebrovascular Hemodynamics and Rehabilitation Outcomes After Aneurysmal Subarachnoid Hemorrhage.

OBJECTIVE: The aim of the study was to assess the relation between cerebrovascular function early after aneurysmal subarachnoid hemorrhage onset and functional and rehabilitation outcomes. DESIGN: Observational cohort study of subarachnoid hemorrhage patients (n = 133) admitted to rehabilitation (n = 49), discharged home (n = 52), or died before discharge (n = 10). We obtained hemodynamic markers of cerebral autoregulatory function from blood flow velocities in the middle cerebral artery and arterial pressure waveforms, recorded daily on days 2-4 after symptom onset, and functional independence measure (FIM) scores and FIM efficiency for those admitted to acute rehabilitation. RESULTS: Compared to those discharged home, the range of pressures within which autoregulation is effective was lower in patients admitted to rehabilitation (4.6 [0.2] vs. 3.9 [0.2] mm Hg) and those who died (2.7 [0.4], P = 0.04). For those admitted to rehabilitation, autoregulatory range and the ability of cerebrovasculature to increase flow were related to discharge FIM score (R = 0.33 and 0.43, P < 0.01) and efficiency (R = 0.33 and 0.47 P < 0.01). The latter marker, along with subarachnoid hemorrhage severity and admission FIM, explained 84% and 69% of the variability in discharge FIM score and efficiency, respectively, even after accounting for age. CONCLUSIONS: Early cerebrovascular function is a major contributor to functional outcomes after subarachnoid hemorrhage and may represent a modifiable target to develop therapeutic approaches. TO CLAIM CME CREDITS: Complete the self-assessment activity and evaluation online at http://www.physiatry.org/JournalCME CME OBJECTIVES: Upon completion of this article, the reader should be able to: (1) Define cerebral autoregulation; (2) Explain the importance of the integrity of cerebral autoregulation for longer-term functional and rehabilitation outcomes after aneurysmal subarachnoid hemorrhage; and (3) Theorize why treatment strategies that may be effective in reducing large-vessel vasospasms after an aneurysmal subarachnoid hemorrhage might not always translate into improved functional outcomes. LEVEL: Advanced ACCREDITATION: The Association of Academic Physiatrists is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.The Association of Academic Physiatrists designates this Journal-based CME activity for a maximum of 0.5 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Transfusion of Blood Products in the Neurocritical Care Unit: An Exploration of Rationing and Futility.

Rationing is the allocation of scarce resources, which in healthcare necessarily requires withholding potentially beneficial treatments from some individuals. While it often entails a negative connotation, rationing is unavoidable because need is limitless and resources are not. How rationing occurs is important, because it not only affects individual lives, but also reflects society's most important values. At the core of any rationing, decision is how much a limited resource may benefit a patient, which can be particularly difficult to determine in the practice of neurocritical care, as prognosis is often uncertain. We present a case for the consideration of futility and blood product rationing in neurocritical care.

Improving uniformity in brain death determination policies over time.

OBJECTIVE: To demonstrate that progress has been made in unifying brain death determination guidelines in the last decade by directly comparing the policies of the US News and World Report's top 50 ranked neurologic institutions from 2006 and 2015. METHODS: We solicited official hospital guidelines in 2015 from these top 50 institutions, generated summary statistics of their criteria as benchmarked against the American Academy of Neurology Practice Parameters (AANPP) and the comparison 2006 cohort in 5 key categories, and statistically compared the 2 cohorts' compliance with the AANPP. RESULTS: From 2008 to 2015, hospital policies exhibited significant improvement (p = 0.005) in compliance with official guidelines, particularly with respect to criteria related to apnea testing (p = 0.009) and appropriate ancillary testing (p = 0.0006). However, variability remains in other portions of the policies, both those with specific recommendation from the AANPP (e.g., specifics for ancillary tests) and those without firm guidance (e.g., the level of involvement of neurologists, neurosurgeons, or physicians with education/training specific to brain death in the determination process). CONCLUSIONS: While the 2010 AANPP update seems to be concordant with progress in achieving greater uniformity in guidelines at the top 50 neurologic institutions, more needs to be done. Whether further interventions come as grassroots initiatives that leverage technological advances in promoting adoption of new guidelines or as top-down regulatory rulings to mandate speedier approval processes, this study shows that solely relying on voluntary updates to professional society guidelines is not enough.

Delayed Deterioration of EEG Background Rhythm Post-cardiac Arrest.

BACKGROUND: Electroencephalogram (EEG) background continuity is associated with a favorable prognosis in cardiac arrest patients post-therapeutic hypothermia. However, the continuous EEG in a subset of patients will undergo 'delayed EEG deterioration'; they will invariably have poor outcome. The aim of this study was to characterize this phenomenon. METHODS: We studied a prospectively collected cohort of consecutive cardiac arrest patients who underwent therapeutic hypothermia between July 2012 and May 2015. We identified patients with an initially favorable EEG rhythm post-cooling and characterized a subset of patients with delayed EEG deterioration. RESULTS: A total of 133 patients were included in the analysis. Of these, 69/133 (51.9%) had an initially favorable EEG. Of those patients with initially favorable EEG, 7/69 (10.1%) had a subsequent deterioration. Delayed EEG deterioration was associated with poor outcome. The median time to deterioration was 55 h. CONCLUSIONS: Delayed EEG deterioration is associated with poor clinical outcomes. We hypothesize that this is the result of delayed neuronal degeneration, the exact mechanism requiring further exploration. Identifying patients with delayed EEG deterioration post-therapeutic hypothermia is paramount as further interventions may yet salvage their outcomes, though further study is needed.

Effect of stimulus type and temperature on EEG reactivity in cardiac arrest.

OBJECTIVE: Electroencephalogram (EEG) background reactivity is a reliable outcome predictor in cardiac arrest patients post therapeutic hypothermia. However, there is no consensus on modality testing and prior studies reveal only fair to moderate agreement rates. The aim of this study was to explore different stimulus modalities and report interrater agreements. METHODS: We studied a multicenter, prospectively collected cohort of cardiac arrest patients who underwent therapeutic hypothermia between September 2014 and December 2015. We identified patients with reactivity data and evaluated interrater agreements of different stimulus modalities tested in hypothermia and normothermia. RESULTS: Of the 60 patients studied, agreement rates were moderate to substantial during hypothermia and fair to moderate during normothermia. Bilateral nipple pressure is more sensitive (80%) when compared to other modalities in eliciting a reactive background in hypothermia. Auditory, nasal tickle, nailbed pressure and nipple pressure reactivity were associated with good outcomes in both hypothermia and normothermia. CONCLUSIONS: EEG reactivity varies depending on the stimulus testing modality as well as the temperature during which stimulation is performed, with nipple pressure emerging as the most sensitive during hypothermia for reactivity and outcome determination. SIGNIFICANCE: This highlights the importance of multiple stimulus testing modalities in EEG reactivity determination to reduce false negatives and optimize prognostication.

Hypernatremia at Hospital Discharge and Out of Hospital Mortality Following Primary Intracerebral Hemorrhage.

BACKGROUND AND PURPOSE: In patients with intracerebral hemorrhage (ICH), it is not clear if hypernatremia is merely a marker of disease severity or if elevated sodium levels are harmful. We hypothesized that hypernatremia at hospital discharge in primary ICH patients would be associated with increased mortality following discharge. METHODS: We performed a two-center observational study of critically ill ICH patients in Boston. We studied 5100 patients, age ≥18 years, who were diagnosed with ICH (ICD-9 code 431), received medical or surgical critical care between 1997 and 2011 and survived hospitalization. The exposure of interest was serum sodium within 24 h of hospital discharge, categorized as Na ≤ 145 mmol/L and Na > 145 mmol/L. The primary outcome was 30-day post-discharge mortality. Odds ratios were estimated by logistic regression models adjusted for age, race, gender, Deyo-Charlson Index, patient type (medical versus surgical) and sepsis. RESULTS: In ICH patients who received critical care and survived hospitalization, the serum sodium at discharge was a predictor of post-discharge mortality. Patients with a discharge Na > 145 mmol/L have an OR for mortality in the 30 days following hospital discharge of 1.82 (95 %CI 1.38-2.38; P < 0.001) and an adjusted OR of 1.87 (95 %CI 1.40-2.48; P < 0.001) both relative to patients with a discharge Na ≤ 145 mmol/L. The adjusted model showed good discrimination AUC 0.77 (95 %CI 0.74-0.79) and calibration (Hosmer-Lemeshow χ (2) P = 0.68). CONCLUSIONS: In critically ill ICH patients who survive hospitalization, hypernatremia at the time of discharge is a robust predictor of post-discharge mortality.