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Summary For patients with chronic, life-limiting illnesses, admission to the intensive care unit (ICU) near the end of life might not improve patient outcomes or be consistent with patient and family values, goals, and preferences. In this context, advance care planning and palliative care interventions designed to clarify patients' values, goals, and preferences have the potential to reduce provision of high-intensity interventions that are unwanted or non-beneficial. In this Series paper, we have assessed interventions that are effective at helping patients with chronic, life-limiting illnesses to avoid an unwanted ICU admission. The evidence found was largely from observational studies, with considerable heterogeneity in populations, methods, and types of interventions. Results from randomised trials of interventions to improve communication about goals of care are scarce, of variable quality, and mixed. Although observational studies show that advance care planning and palliative care interventions are associated with a reduced number of ICU admissions at the end of life, causality has not been well established. Using the available evidence we suggest recommendations to help to avoid ICU admission when it does not align with patient and family values, goals, and preferences and conclude with future directions for research.

Intensive care unit (ICU) admission is common following hematopoietic cell transplant, and patients who develop critical illness following transplant experience high mortality. Given the significant potential for morbidity and mortality among critically ill patients who have undergone hematopoietic cell transplant, high-quality supportive care for these patients and their family members is essential. In addition to the key components of supportive care—high-quality communication, symptom control, and emotional and spiritual support—special aspects of supportive care for critically ill patients undergoing transplant warrant consideration. First, high-quality communication between providers of different disciplines must be considered as essential as communication with the patient and family. Second, early involvement of specialty supportive care providers should occur, particularly when symptom management or psychosocial concerns are prominent or the risk of death is very high. Finally, for patients facing death in the ICU, providers should consider several end-of-life care issues unique to this population, including the support of patients and family members as they cope with a major shift in the focus of care, challenges related to maintaining social support networks, and the need to foster closure of the therapeutic relationship with outpatient providers. This chapter will focus on these specific aspects of ICU care for patients who have undergone hematopoietic cell transplant.

Context Achieving adequate response rates from family members of critically ill patients can be challenging, especially when assessing psychological symptoms. Objectives To identify factors associated with completion of surveys about psychological symptoms among family members of critically ill patients. Methods Using data from a randomized trial of an intervention to improve communication between clinicians and families of critically ill patients, we examined patient-level and family-level predictors of the return of usable surveys at baseline, three months, and six months ( n = 181, 171, and 155, respectively). Family-level predictors included baseline symptoms of psychological distress, decisional independence preference, and attachment style. We hypothesized that family with fewer symptoms of psychological distress, a preference for less decisional independence, and secure attachment style would be more likely to return questionnaires. Results We identified several predictors of the return of usable questionnaires. Better self-assessed family member health status was associated with a higher likelihood and stronger agreement with a support-seeking attachment style with a lower likelihood, of obtaining usable baseline surveys. At three months, family-level predictors of return of usable surveys included having usable baseline surveys, status as the patient's legal next of kin, and stronger agreement with a secure attachment style. The only predictor of receipt of surveys at six months was the presence of usable surveys at three months. Conclusion We identified several predictors of the receipt of surveys assessing psychological symptoms in family of critically ill patients, including family member health status and attachment style. Using these characteristics to inform follow-up mailings and reminders may enhance response rates.

Objective:To provide clinicians with evidence-based strategies to optimize the support of the family of critically ill patients in the ICU.Methods:We used the Council of Medical Specialty Societies principles for the development of clinical guidelines as the framework for guideline development. We a

Context Racial and ethnic differences in end-of-life care may be attributable to both patient preferences and health-care disparities. Identifying factors that differentiate preferences from disparities may enhance end-of-life care for critically ill patients and their families. Objectives To understand the association of minority race/ethnicity and education with family ratings of the quality of dying and death, taking into consideration possible markers of patient and family preferences for end-of-life care as mediators of this association. Methods Data were obtained from 15 intensive care units participating in a cluster-randomized trial of a palliative care intervention. Family members of decedents completed self-report surveys evaluating quality of dying. We used regression analyses to identify associations between race/ethnicity, education, and quality of dying ratings. We then used path analyses to investigate whether advance directives and life-sustaining treatment acted as mediators between patient characteristics and ratings of quality of dying. Results Family members returned 1290 surveys for 2850 decedents. Patient and family minority race/ethnicity were both associated with lower ratings of quality of dying. Presence of a living will and dying in the setting of full support mediated the relationship between patient race and family ratings; patient race exerted an indirect, rather than direct, effect on quality of dying. Family minority race had a direct effect on lower ratings of quality of dying. Neither patient nor family education was associated with quality of dying. Conclusion Minority race/ethnicity was associated with lower family ratings of quality of dying. This association was mediated by factors that may be markers of patient and family preferences (living will, death in the setting of full support); family member minority race/ethnicity was directly associated with lower ratings of quality of dying. Our findings generate hypothesized pathways that require future evaluation.

Discussions about withdrawal of life-sustaining therapies often include family members of critically ill patients. These conversations should address essential components of the dying process, including expected time to death after withdrawal.The study objective was to aid physician communication about the dying process by identifying predictors of time to death after terminal withdrawal of mechanical ventilation.We conducted an observational analysis from a single-center, before-after evaluation of an intervention to improve palliative care. We studied 330 patients who died after terminal withdrawal of mechanical ventilation. Predictors included patient demographics, laboratory, respiratory, and physiologic variables, and medication use.The median time to death for the entire cohort was 0.58 hours (interquartile range (IQR) 0.22-2.25 hours) after withdrawal of mechanical ventilation. Using Cox regression, independent predictors of shorter time to death included higher positive end-expiratory pressure (per 1 cm H2O hazard ratio [HR], 1.07; 95% CI 1.04-1.11); higher static pressure (per 1 cm H2O HR, 1.03; 95% CI 1.01-1.04); extubation prior to death (HR, 1.41; 95% CI 1.06-1.86); and presence of diabetes (HR, 1.75; 95% CI 1.25-2.44). Higher noninvasive mean arterial pressure predicted longer time to death (per 1 mmHg HR, 0.98; 95% CI 0.97-0.99).Comorbid illness and key respiratory and physiologic parameters may inform physician predictions of time to death after withdrawal of mechanical ventilation. An understanding of the predictors of time to death may facilitate discussions with family members of dying patients and improve communication about end-of-life care.

Background: Obtaining central venous cannulation of the internal jugular vein is an important skill for physicians to master. To our knowledge, no studies to date have examined residents9 preferences or the safety of the oblique approach compared to other approaches. This study compared medical residents9 preferences for and performance of ultrasound-guided central venous access using the transverse, longitudinal, and oblique approaches. Methods: Emergency medicine and internal medicine residents (n = 72) at an urban community hospital participated in a central venous access course. To assess the residents9 preferences, residents were asked to rank the transverse, longitudinal, and oblique approaches as first, second, or third. In addition to preference, skin-to-vein time, carotid artery puncture, and successful completion on the first attempt during a final skills analysis were measured. Results: During the final skills analysis, the majority (87.5%) of residents preferred the transverse approach. The oblique approach had a significantly larger proportion of failures of technique than the transverse approach (P = 0.02). No significant differences in successful cannulation on the first attempt, skin-to-vein time, or carotid artery puncture among the 3 approaches were found during the final skills assessment. Conclusion: The majority of residents preferred the transverse approach to the longitudinal and oblique approaches. Although no significant differences among the 3 approaches were found in performance measures, more failures of technique occurred with the oblique approach. This study suggests that novices may require in-depth training and supervision to become proficient with the oblique approach.

OBJECTIVE We describe the effect of simulation-based education on residents' adherence to protocols for and performance of central venous access. METHODS Internal medicine and emergency medicine residents underwent a central venous access course that included a lecture, video presentation, readings, and simulation demonstrations presented by faculty. Baseline data were collected before the course was initiated. After a skills session where they rehearsed their ultrasound-guided central venous access skills, residents were evaluated using a procedural checklist and written knowledge exam. Residents also completed questionnaires regarding confidence in performing ultrasound-guided central venous access and opinions about the training course. RESULTS Residents demonstrated significant improvement on the written knowledge exam (P < 0.0001) and Standard Protocol Checklist (P < 0.0001) after the training course. Training improved a number of patient safety elements, including adherence to sterile technique, transparent dressing, discarding sharps, and ordering postprocedure x-rays. However, a number of residents failed to wash their hands, prepare with chlorhexidine, drape the patient using a sterile technique, anesthetize the site, and perform a preprocedure time-out. Significant improvement in procedural skills was also noted for reduction in skin-to-vein time (P < 0.003) as well as a reduction in number of residents who punctured the carotid artery (P < 0.02). CONCLUSIONS Simulation-based education significantly improved residents' knowledge and procedural skills along with their confidence. Adherence to the protocol also improved. This study illustrates that simulation-based education can improve patient safety through training and protocols.

Quality of life is frequently impaired among survivors of critical illness, and psychiatric morbidity is an important element contributing to poor quality of life in these patients. Among potential manifestations of psychiatric morbidity following critical illness, symptoms of posttraumatic stress are prevalent and intricately linked to the significant stressors present in the intensive care unit (ICU). As our understanding of the epidemiology of post-ICU posttraumatic stress disorder improves, so must our ability to identify those at highest risk for symptoms in the period of time following critical illness and our ability to implement strategies to prevent symptom development. In addition, a focus on strategies to address clinically apparent psychiatric morbidity will be essential. Much remains to be understood about the identification, prevention, and management of this significant public health problem. This article addresses the importance of uniformity in future epidemiologic studies, proposes framing of risk factors into those likely to be modifiable versus non-modifiable, and provides an assessment of modifiable risk factors in the context of a novel conceptual model that offers insight into potential strategies to attenuate symptoms of posttraumatic stress among survivors of critical illness.

When you have a serious illness, you may suffer from physical discomfort, such as pain, difficulty breathing, nausea (stomach upset) or fatigue. You may also have feelings of psychological distress, such as anxiety or depression, or feelings of spiritual distress. Your healthcare providers may provide medical therapies to treat or manage your illness, for example, antibiotics to treat pneumonia. In addition, you may receive care that helps you feel more comfortable, but does not treat or cure your illness. This type of care is called "comfort" or palliative (PAL-lee-uh-tiv) care.

Family-centered outcomes during and after critical illness assess issues that are most important to family members. An understanding of family-centered outcomes is necessary to support the provision of family-centered care and to foster development of interventions to improve care and communication in the ICU.Current family-centered outcomes in critical care include satisfaction with care, including end-of-life care, symptoms of psychological distress, and health-related quality of life. Novel measures include assessments of decisional conflict, decision regret, therapeutic alliance, and caregiver burden, as well as positive adaptations and resilience.Critical illness places a significant burden on family members. A wide variety of family-centered outcomes are available to guide improvements in care and communication. Future research should focus on developing sensitive and responsive measures that capture key elements of the family member experience during and after critical illness.

High-quality end-of-life care should be available to all individuals faced with a terminal illness. Essential components of quality end-of-life care include excellent communication, creation of a supportive environment for dying patients and their family members, and concerted efforts to address pain and suffering at the end of life. Each of these elements of care must be grounded in the individual patient’s values, goals, preferences, and needs. Importantly, these values, goals, preferences, and needs may vary based on patient characteristics such as gender, race/ethnicity, socioeconomic status, sexuality, or underlying illness. It is important that we identify and respect differences in informed patients’ values and preferences. However, we should strive to eradicate differences based on inequities in the way end-of-life care is discussed or delivered. In this chapter, we examine differences in end-of-life care across these important patient characteristics and identify areas in which differences may represent healthcare disparities.

Context An enhanced understanding of trainee attitudes about end-of-life care is needed to inform interventions to improve clinician communication about dying and death. Objectives To examine changes in trainee pessimism about end-of-life care over the course of one academic year and to explore predictors of pessimism among residents, fellows, and nurse practitioners. Methods We used baseline and follow-up surveys completed by trainees during a randomized controlled trial of an intervention to improve clinician communication skills. Surveys addressed trainee feelings about end-of-life care. Latent variable modeling was used to identify indicators of trainee pessimism, and this pessimism construct was used to assess temporal changes in trainee attitudes about end-of-life care. We also examined predictors of trainee pessimism at baseline and follow-up. Data were available for 383 trainees from two training programs. Results There was a significant decrease in pessimism between baseline and follow-up assessments. Age had a significant inverse effect on baseline pessimism, with older trainees being less pessimistic. There was a direct association of race/ethnicity on pessimism at follow-up, with greater pessimism among minority trainees ( P = 0.028). The model suggests that between baseline and follow-up, pessimism among younger white non-Hispanic trainees decreased, whereas pessimism among younger trainees in racial/ethnic minorities increased over the same period. Conclusion Overall, trainee pessimism about end-of-life care decreases over time. Pessimism about end-of-life care among minority trainees may reflect the influence of culture on clinician attitudes about communication with seriously ill patients. Further research is needed to understand the evolution of trainee attitudes about end-of-life care during clinical training.

In order for patients and their surrogates to be fully engaged in the process of shared decision-making, they must receive adequate information about proposed treatment plans and interventions. The absence of such knowledge may rob patients and their family members of the ability to make informed decisions or align treatment preferences with patient care. This lack of information becomes even more troubling when it involves interventions such as cardiopulmonary resuscitation (CPR), as uninformed decisions about resuscitation may lead to the provision or withholding of life-extending therapies in a way that is not consistent with a patient’s goals. Unfortunately, deficiencies in CPR education are abundant [1]. In this issue of Critical Care Medicine, Wilson and colleagues [2] evaluate the role of a video to improve patient and surrogate understanding of CPR choices in the intensive care unit (ICU). In this randomized controlled trial, critically ill patients and surrogate decision-makers for incapacitated patients in the ICU were randomized to receive either usual care, which consisted of a 16-page pamphlet describing CPR and CPR preference options as well as routine non-standardized code status discussions with ICU clinicians, or usual care plus an 8-minute video describing CPR and CPR preference options. Participant knowledge of CPR and CPR choices was assessed and those in the video group demonstrated significantly better understanding of CPR, including treatments used in CPR, the purpose of CPR, and the meaning of “code status”. The majority of participants in the video group reported feeling comfortable watching the video and also felt the video helped them understand their options. Given the importance of providing adequate information to patients and their family members about disease processes, prognosis, and potential medical interventions, it is tempting to believe that the provision of more information is the answer. The reality, however, is that more information is not necessarily better. The manner in which the information is shared is also a crucial component of successful education. Many factors influence the ability to comprehend and process medical information, including health literacy, learning styles, and the quality of communication provided. Health literacy, in particular, may represent a significant barrier to informed decision-making for some patients and their family members. Low health literacy may impair comprehension of information about diagnosis and prognosis, and thus lead to uncertainty in decision-making. It is promising, however, that patient education through video tools may attenuate uncertainty related to low health literacy [3]. The use of multimedia educational tools, including both written material and video, may address limitations of written and visual information when each is used in isolation. As in this study and in others assessing the ability of video to enhance knowledge, the combination of video and written information, when well-designed, can improve patient and surrogate understanding of medical information [2, 4–6]. If adequate information is able to promote informed decision-making, then it may also affect which decisions patients and their family members make. In prior studies, the introduction of a videos addressing advance care planning and end-of-life preferences have been associated with significant changes in patient preferences regarding end-of-life care [4, 6–8]. In the study by Wilson and colleagues, changes in CPR utilization and change in DNR code status were not identified. However, as the authors note, this study was not powered to detect such changes. More information is needed to know how the introduction of educational videos in the hospital environment might affect decision-making over time. Ideally, patients and their family members would have access to both written material and video in inpatient and outpatient environments in order to facilitate a sustained understanding of CPR options that they might later use to make healthcare decisions. In addition to understanding whether educational interventions change treatment preferences, it is also important to understand how those preferences change. Trials including video tools have noted a shift from preferences for more intensive care to less intensive care at the end of life after provision of video information [4, 6–8]. This shift in preferences may represent an improved understanding of CPR and other interventions at the end-of-life, but it is important to remain cognizant of changes that may occur with the introduction of educational tools. The goal of patient and surrogate education is to support the ability to make informed decisions and not to promote one set of treatment decisions over another. Given the potential for bias or inappropriate persuasion, video materials must be carefully made and, as noted in this study, production of a high-quality video can be quite costly. As more educational videos are generated, it will behoove the critical care community to identify videos that balance potential treatment options carefully and provide accurate information for patients and their family members. Otherwise, there is potential to introduce biased information that may be misleading for patients and their families. In the context of improving patient and family understanding to support decision-making, it is important to note that the desire for more information and the desire for involvement in decision-making are not always congruent. The vast majority of family members of critically ill patients want information, but their desired role in decision-making ranges from wanting to be the sole decision-maker, to wanting physicians to make all decisions [9, 10]. The distribution across this spectrum of decision-making preference may vary by country and region, but a distribution has been found in all studies to date, including those done in North America, South America, and Europe [9–12]. Importantly, our ability to match our approach to decision-making to family preference appears to be associated with a reduction in symptoms of post-traumatic stress disorder [13]. Therefore, it is important that we incorporate patient and family preference into our approach both to providing information and to conducting decision-making. Patient and surrogate education about the risks and benefits of potential interventions should be a primary objective of all clinicians caring for patients facing serious or life-threatening illness. Many types of educational materials may be made available to patients and their family members, but as this study and others have shown, the armamentarium used to provide information can and should be more encompassing than written materials. If the goal is to support informed patient- and family-centered decision-making, then clinicians may be better able to do so by embracing a multimedia approach to the education of patients and their family. Further research is needed to evaluate the use of video in the inpatient setting as a tool to improve CPR education and assist clinicians in identifying patient and family member preferred decision-making roles, but results such as these offer promise in the continued effort to support informed decision-making in the ICU.

Recent clinical trials indicate the efficacy of interferon (IFN)-beta 1b in reducing relapse rate in relapsing-remitting multiple sclerosis (MS), whereas a surge of IFN-gamma precedes and provokes acute relapses. Disruption of the cerebral endothelial barrier and transendothelial migration of inflammatory cell migration into the brain play a significant role in pathogenesis of MS and may be driven by this surge in IFN-gamma. However, the molecular mechanisms underlying the beneficial effects of IFN-beta 1b against the deleterious effects of IFN-gamma on the barrier formed by the junctional proteins remain to be characterized. The authors investigated the effects of IFN-beta 1b, IFN-beta 1a, and IFN-gamma on the integrity of two endothelial junctional proteins, occludin and vascular endothelial-cadherin (VE-cadherin). Human umbilical vein endothelial cell (HUVEC) layers were treated with IFN-beta 1b, IFN-beta 1a, IFN-gamma, IFN-beta 1b plus IFN-gamma, or IFN-beta 1a plus IFN-gamma. IFN-beta 1b, IFN-beta 1a, and IFN-gamma effects on occludin and VE-cadherin integrity and electrical resistance were assessed by Western blotting and immunofluorescence. IFN-gamma significantly reduced occludin expression and produced gaps in endothelial monolayers. VE-cadherin expression was decreased to a lesser extent in endothelial cells exposed to IFN-gamma. IFN-beta 1b significantly attenuated the IFN-gamma-induced decrease in occludin and VE-cadherin expression. The protective effects of IFN-beta 1a on IFN-gamma-treated endothelial cells were similar to those of IFN-beta 1b. IFN-gamma also significantly reduced endothelial monolayer electrical resistance; this effect was blocked by either IFN-beta 1a or IFN-beta 1b. IFN-beta 1a and IFN-beta 1b effectively prevent the IFN-gamma-induced disintegration of the endothelial tight junctions and sustain barrier against the effects of IFN-gamma. The protective effects of IFN-beta on occludin and VE-cadherin stability appear to represent molecular mechanisms for the therapeutic effects of the IFN-beta on blood brain barrier in MS.

Devic disease is characterized by an attack or attacks of optic neuritis and necrotizing myelitis without clinical or magnetic resonance imaging (MRI) evidence of brain involvement or presence of oligoclonal bands in the cerebrospinal fluid (CSF). More than a century after its first systematic study by the French physician, Eugene Devic, its cause as well as its pathogenesis, remains unknown. Devic disease is both a diagnostic and therapeutic challenge to clinicians. The authors present the latest review on the nature, course, possible mechanisms, and therapeutic options of Devic disease.

Although most intensive care unit (ICU) admissions originate in the emergency department (ED), a substantial number of admissions arrive from hospital wards. Patients transferred from the hospital ward often share clinical characteristics with those admitted from the ED, but family expectations may differ. An understanding of the impact of ICU admission source on family perceptions of end-of-life care may help improve patient and family outcomes by identifying those at risk for poor outcomes.This was a cohort study of patients with chronic illness and acute respiratory failure requiring mechanical ventilation who died after admission to an ICU in any of the 14 participating hospitals in the Seattle-Tacoma area between 2003 and 2008 (n = 1,500).Using regression models adjusted for hospital site and patient-, nurse- and family-level characteristics, we examined associations between ICU admission source (hospital ward vs. ED) and (1) family ratings of satisfaction with ICU care; (2) family and nurse ratings of quality of dying; (3) chart-based indicators of palliative care.Admission from the hospital ward was associated with lower family ratings of quality of dying [β -0.90, 95% confidence interval (CI) -1.54, -0.26, p = 0.006] and satisfaction (total score β -3.97, 95% CI -7.89, -0.05, p = 0.047; satisfaction with care domain score β -5.40, 95% CI -9.44, -1.36, p = 0.009). Nurses did not report differences in quality of dying. Patients from hospital wards were less likely to have family conferences [odds ratio (OR) 0.68, 95% CI 0.52, 0.88, p = 0.004] or discussion of prognosis in the first 72 h after ICU admission (OR 0.72, 95% CI 0.56, 0.91, p = 0.007) but were more likely to receive spiritual care (OR 1.48, 95% CI 1.14, 1.93, p = 0.003) or have life support withdrawn (OR 1.38, 95% CI 1.04, 1.82, p = 0.025).Admission from the hospital ward is associated with family perceptions of a lower quality of dying and less satisfaction with ICU care. Differences in receipt of palliative care suggest that family of patients from the hospital ward receive less communication. Nurse ratings of quality of dying did not significantly differ by ICU admission source, suggesting dissimilarities between family and nurse perspectives. This study identifies a patient population at risk for poor quality palliative and end-of-life care. Future studies are needed to identify interventions to improve care for patients who deteriorate on the wards following hospital admission.

Current evidence indicates that measurement of pleural fluid N-terminal pro-brain natriuretic peptide (NT-proBNP) levels can aid in distinguishing pleural effusions of cardiac origin from those of noncardiac origin. To date, only one study, to our knowledge, has described simultaneous measurement of pleural fluid brain natriuretic-32 peptide (BNP) and NT-proBNP. The purpose of the present study was to determine pleural fluid BNP and NT-proBNP levels and analyze the relationship between these two measurements. We hypothesized that there would be a positive correlation between pleural fluid NT-proBNP and BNP, whereas NT-proBNP levels would be higher than BNP levels.Levels of pleural fluid NT-proBNP and BNP were measured by enzyme immunoassay in a total of 80 patients: 20 with congestive heart failure, 20 status post-coronary artery bypass graft, 20 with carcinoma, and 20 with pneumonia.Comparison of NT-proBNP and BNP concentrations using the Spearman method of statistical analysis revealed a correlation coefficient of 0.572, P.001. Evaluation of the diagnostic accuracy of BNP and NT-proBNP in patients with pleural effusions of cardiac origin demonstrated an area under the receiver operating characteristic curve of 0.700 (95% CI, 0.569-0.831) and 0.835 (95% CI, 0.721-0.949), respectively.Although levels of pleural fluid BNP have a statistically significant correlation with those of NT-proBNP, this relationship only explains 32% of the variance in NT-proBNP levels. Furthermore, when compared with BNP, NT-proBNP is a more accurate diagnostic aid in the evaluation of pleural effusions of cardiac origin.

Disruption of the blood -brain barrier (BBB) and transendothelial migration of inflammatory cells are crucial steps in the development of demyelinating lesions in multiple sclerosis (MS). O ccludin and vascular endothelial-cadher in (VE-cadherin) are two major components of the tight junctions (TJs) in the brain microvasculature that help to create the BBB. In the present study, we investigated the effect of serum from MS patients on the expression of these two junctional markers and on the endothelial integrity. Serum from six MS patients in exacerbation, six in remission, and six normal controls (10% by volume) was incubated with cultured endothelial cells, and the expression of occludin and VE-cadherin was measured by immunoblotting. Serum from MS patients in exacerbation significantly reduced the expression of occludin and VE-cadherin compared with patients in remission and normal controls. This disintegrating effect was more pronounced for occludin than for VE-cadherin. We assume that the elevation in cytokines or other serum-soluble factors in MS patients in exacerbation likely provokes downregulation of occludin and VE-cadherin. This downregulation of TJs proteins may, therefore, contribute to the disruption of the BBB in this condition.

l-Glutamate is a major excitatory neurotransmitter that binds ionotropic and metabotropic glutamate receptors. Cerebral endothelial cells from many species have been shown to express several forms of glutamate receptors; however, human cerebral endothelial cells have not been shown to express either the N-methyl-d-aspartate (NMDA) receptor message or protein. This study provides evidence that human cerebral endothelial cells express the message and protein for NMDA receptors. Human cerebral endothelial cell monolayer electrical resistance changes in response to glutamate receptor agonists, antagonists, and second message blockers were tested. RT-PCR and Western blot analysis were used to demonstrate the presence of the NMDA receptor. Glutamate and NMDA (1 mM) caused a significant decrease in electrical resistance compared with sham control at 2 h postexposure; this response could be blocked significantly by MK-801 (an NMDA antagonist), 8-( N,N-diethylamino)- n-octyl-3,4,5-trimethyoxybenzoate (an intracellular Ca2+antagonist), and N-acetyl-l-cystein (an antioxidant). Trans(±)-1-amino-1,3-cyclopentanedicarboxylic acid, a metabotropic receptor agonist (1 mM), did not significantly decrease electrical resistance. Our results are consistent with a model where glutamate, at excitotoxic levels, may lead to a breakdown in the blood brain barrier via activation of NMDA receptors.