Familial multiple sclerosis in patients with Von Hippel-Lindau disease.

BACKGROUND: Multiple sclerosis (MS) is a progressive autoimmune demyelinating disorder. Recent studies suggest that a combination of genetic susceptibility and environmental insult contributes to its pathogenesis. Many candidate genes have been discovered to modulate susceptibility for developing MS by genome wide association studies (GWAS); these include major histocompatibility complex (MHC) genes and non-MHC genes. MS cases in the context of genetic diseases may provide different approaches and clues towards identifying novel genes and pathways involved in MS pathogenesis. Here, we present a case series of two related patients with concomitant Von Hippel-Lindau disease (VHLD) and MS. CASE PRESENTATION: We present two patients, a mother (case 1) and daughter (case 2), who developed superimposed relapsing-remitting multiple sclerosis in the background of the autosomal dominant genetic disorder VHLD. Several tumors characteristic of VHLD developed in both cases with pancreatic and renal neoplasms and cerebellar hemangioblastomas. In addition, both patients developed clinical symptoms consistent with multiple sclerosis, supported by radiologic lesions disseminating in time and space. CONCLUSION: Though non-MHC susceptibility genes remain elusive in MS, we present the striking finding of superimposed multiple sclerosis in a mother and daughter with VHLD. The VHL gene is known to be the primary regulator of Nrf2, the well-established target of the FDA-approved therapeutic dimethyl fumarate. These cases provide support for further studies to determine whether VHLD pathway related genes represent a novel genetic link in multiple sclerosis.

Biochemical and structural characterization of a novel cooperative binding mode by Pit-1 with CATT repeats in the macrophage migration inhibitory factor promoter.

Overexpression of the proinflammatory cytokine macrophage migration inhibitory factor (MIF) is linked to a number of autoimmune diseases and cancer. MIF production has been correlated to the number of CATT repeats in a microsatellite region upstream of the MIF gene. We have characterized the interaction of pituitary-specific positive transcription factor 1 (Pit-1) with a portion of the MIF promoter region flanking a microsatellite polymorphism (-794 CATT5-8). Using fluorescence anisotropy, we quantified tight complex formation between Pit-1 and an oligonucleotide consisting of eight consecutive CATT repeats (8xCATT) with an apparent Kd of 35 nM. Using competition experiments we found a 23 base pair oligonucleotide with 4xCATT repeats to be the minimum DNA sequence necessary for high affinity interaction with Pit-1. The stoichiometry of the Pit-1 DNA interaction was determined to be 2:1 and binding is cooperative in nature. We subsequently structurally characterized the complex and discovered a completely novel binding mode for Pit-1 in contrast to previously described Pit-1 complex structures. The affinity of Pit-1 for the CATT target sequence was found to be highly dependent on cooperativity. This work lays the groundwork for understanding transcriptional regulation of MIF and pursuing Pit-1 as a therapeutic target to treat MIF-mediated inflammatory disorders.

Chronic centrosome amplification without tumorigenesis.

Centrosomes are microtubule-organizing centers that facilitate bipolar mitotic spindle assembly and chromosome segregation. Recognizing that centrosome amplification is a common feature of aneuploid cancer cells, we tested whether supernumerary centrosomes are sufficient to drive tumor development. To do this, we constructed and analyzed mice in which centrosome amplification can be induced by a Cre-recombinase-mediated increase in expression of Polo-like kinase 4 (Plk4). Elevated Plk4 in mouse fibroblasts produced supernumerary centrosomes and enhanced the expected mitotic errors, but proliferation continued only after inactivation of the p53 tumor suppressor. Increasing Plk4 levels in mice with functional p53 produced centrosome amplification in liver and skin, but this did not promote spontaneous tumor development in these tissues or enhance the growth of chemically induced skin tumors. In the absence of p53, Plk4 overexpression generated widespread centrosome amplification, but did not drive additional tumors or affect development of the fatal thymic lymphomas that arise in animals lacking p53. We conclude that, independent of p53 status, supernumerary centrosomes are not sufficient to drive tumor formation.

Structural basis for decreased induction of class IB PI3-kinases expression by MIF inhibitors.

Macrophage migration inhibitory factor (MIF) is a master regulator of proinflammatory cytokines and plays pathological roles when not properly regulated in rheumatoid arthritis, lupus, atherosclerosis, asthma and cancer. Unlike canonical cytokines, MIF has vestigial keto-enol tautomerase activity. Most of the current MIF inhibitors were screened for the inhibition of this enzymatic activity. However, only some of the enzymatic inhibitors inhibit receptor-mediated biological functions of MIF, such as cell recruitment, through an unknown molecular mechanism. The goal of this study was to understand the molecular basis underlying the pharmacological inhibition of biological functions of MIF. Here, we demonstrate how the structural changes caused upon inhibitor binding translate into the alteration of MIF-induced downstream signalling. Macrophage migration inhibitory factor activates phosphoinositide 3-kinases (PI3Ks) that play a pivotal role in immune cell recruitment in health and disease. There are several different PI3K isoforms, but little is known about how they respond to MIF. We demonstrate that MIF up-regulates the expression of Class IB PI3Ks in leucocytes. We also demonstrate that MIF tautomerase active site inhibitors down-regulate the expression of Class IB PI3Ks as well as leucocyte recruitment in vitro and in vivo. Finally, based on our MIF:inhibitor complex crystal structures, we hypothesize that the reduction in Class IB PI3K expression occurs because of the displacement of Pro1 towards the second loop of MIF upon inhibitor binding, which results in increased flexibility of the loop 2 and sub-optimal MIF binding to its receptors. These results will provide molecular insights for fine-tuning the biological functions of MIF.

Optogenetic control of chemokine receptor signal and T-cell migration.

Adoptive cell transfer of ex vivo-generated immune-promoting or tolerogenic T cells to either enhance immunity or promote tolerance in patients has been used with some success. However, effective trafficking of the transferred cells to the target tissue sites is the main barrier to achieving successful clinical outcomes. Here we developed a strategy for optically controlling T-cell trafficking using a photoactivatable (PA) chemokine receptor. Photoactivatable-chemokine C-X-C motif receptor 4 (PA-CXCR4) transmitted intracellular CXCR4 signals in response to 505-nm light. Localized activation of PA-CXCR4 induced T-cell polarization and directional migration (phototaxis) both in vitro and in vivo. Directing light onto the melanoma was sufficient to recruit PA-CXCR4-expressing tumor-targeting cytotoxic T cells and improved the efficacy of adoptive T-cell transfer immunotherapy, with a significant reduction in tumor growth in mice. These findings suggest that the use of photoactivatable chemokine receptors allows remotely controlled leukocyte trafficking with outstanding spatial resolution in tissues and may be feasible in other cell transfer therapies.

New Insights into Mechanisms and Functions of Chemokine (C-X-C Motif) Receptor 4 Heteromerization in Vascular Smooth Muscle.

Recent evidence suggests that C-X-C chemokine receptor type 4 (CXCR4) heteromerizes with α1A/B-adrenoceptors (AR) and atypical chemokine receptor 3 (ACKR3) and that CXCR4:α1A/B-AR heteromers are important for α1-AR function in vascular smooth muscle cells (VSMC). Structural determinants for CXCR4 heteromerization and functional consequences of CXCR4:α1A/B-AR heteromerization in intact arteries, however, remain unknown. Utilizing proximity ligation assays (PLA) to visualize receptor interactions in VSMC, we show that peptide analogs of transmembrane-domain (TM) 2 and TM4 of CXCR4 selectively reduce PLA signals for CXCR4:α1A-AR and CXCR4:ACKR3 interactions, respectively. While both peptides inhibit CXCL12-induced chemotaxis, only the TM2 peptide inhibits phenylephrine-induced Ca(2+)-fluxes, contraction of VSMC and reduces efficacy of phenylephrine to constrict isolated arteries. In a Cre-loxP mouse model to delete CXCR4 in VSMC, we observed 60% knockdown of CXCR4. PLA signals for CXCR4:α1A/B-AR and CXCR4:ACKR3 interactions in VSMC, however, remained constant. Our observations point towards TM2/4 of CXCR4 as possible contact sites for heteromerization and suggest that TM-derived peptide analogs permit selective targeting of CXCR4 heteromers. A molecular dynamics simulation of a receptor complex in which the CXCR4 homodimer interacts with α1A-AR via TM2 and with ACKR3 via TM4 is presented. Our findings further imply that CXCR4:α1A-AR heteromers are important for intrinsic α1-AR function in intact arteries and provide initial and unexpected insights into the regulation of CXCR4 heteromerization in VSMC.

Acute Ankle Diastasis Injuries Treated with Dynamic, Static Fixation or Anatomic Repair: A Meta-Analysis and Systematic Review of Comparison Studies.

BACKGROUND: Acute ankle diastasis injuries are complex and debilitating. These injuries occur when the syndesmotic complex becomes compromised. Treatments of acute syndesmotic injuries include static fixation with screws, dynamic fixation with an elastic device, or anatomic repair of the damaged ligament. However, there is disagreement over which method is most effective. The primary purpose of this study was to compare the 3 treatment methods for acute syndesmotic injuries. METHODS: A systematic literature search was conducted on Embase and PubMed. Studies that compared at least 2 groups with relevant American Orthopaedic Foot & Ankle Society (AOFAS), Visual Analog Scale (VAS), reoperation rate, and complication (implant failure, implant irritation, and infection) data were analyzed. Statistical analysis for this study was performed using Review Manager 5.4, with a standard p-value of ≤0.05 for statistical significance. RESULTS: Twenty-one studies including a total of 1,059 patients (452 dynamic, 529 static, and 78 anatomic) were included for analysis. Dynamic fixation had significantly higher mean AOFAS scores at 3 months postoperation by 5.12 points (95% confidence interval [CI], 0.29-9.96, p = 0.04) as well as at 1 year postoperation by 4.64 points (95% CI, 1.74-7.55, p = 0.002) than static fixation. Anatomic repair had significantly higher AOFAS scores at 6 months postoperation by 3.20 points (95% CI, 1.06-5.34, p = 0.003) and 1 year postoperation by 1.86 points (95% CI, 0.59-3.14, p = 0.004) than static fixation. Dynamic fixation had significantly higher AOFAS scores at 6 months postoperation by 2.81 points (95% CI, 0.76-4.86, p = 0.007), 12 months postoperation by 3.17 points (95% CI, 0.76-5.58, p = 0.01), and at 2 years postoperation by 5.56 points (95% CI, 3.80-7.32, p < 0.001) than anatomic repair. Dynamic fixation also had a lower VAS score average (favorable), only significant at 12 months postoperation, than static fixation by 0.7 points (95% CI -0.99 to -0.40, p < 0.001). Anatomic repair did not have significant difference in VAS scores compared with static fixation. Anatomic repair had significantly lower VAS scores at 12 months postoperation by 0.32 points (95% CI -0.59 to -0.05, p = 0.02) than dynamic fixation. Dynamic fixation had significantly less implant failures (odds ratio [OR], 0.13, 95% CI, 0.05-0.32, p < 0.001) than static fixation. Anatomic repair was not significantly different from static fixation in the complication metrics. Dynamic fixation and anatomic repair were not significantly different in the complication metrics either. Dynamic fixation had a significantly lower reoperation rate than static fixation (OR, 0.23, 95% CI, 0.09-0.54, p < 0.001). Anatomic repair did not have a significantly different reoperation rate compared with static fixation. However, dynamic fixation had a significantly lower reoperation rate than anatomic repair (OR, 4.65, 95% CI, 1.10-19.76, p = 0.04). CONCLUSION: Dynamic fixation seems to demonstrate superior early clinical outcomes. However, these advantages become negligible in the long term when compared with alternative options. Dynamic fixation is associated with a lower risk for complications, specifically seen with the decrease in implant failures. This method also presents a significantly lower reoperation rate compared with the other treatment approaches. Apart from showing improved early clinical outcomes in comparison with static fixation, anatomic repair did not have significant distinctions in other metrics, including complications or reoperation rate. LEVEL OF EVIDENCE: Level III. See Instructions for Authors for a complete description of levels of evidence.

Immunosenescence and multiple sclerosis: inflammaging for prognosis and therapeutic consideration.

Aging is associated with a progressive decline of innate and adaptive immune responses, called immunosenescence. This phenomenon links to different multiple sclerosis (MS) disease courses among different age groups. While clinical relapse and active demyelination are mainly related to the altered adaptive immunity, including invasion of T- and B-lymphocytes, impairment of innate immune cell (e.g., microglia, astrocyte) function is the main contributor to disability progression and neurodegeneration. Most patients with MS manifest the relapsing-remitting phenotype at a younger age, while progressive phenotypes are mainly seen in older patients. Current disease-modifying therapies (DMTs) primarily targeting adaptive immunity are less efficacious in older patients, suggesting that immunosenescence plays a role in treatment response. This review summarizes the recent immune mechanistic studies regarding immunosenescence in patients with MS and discusses the clinical implications of these findings.

Development and Validation of Patient Education Tools for Deprescribing in Patients on Hemodialysis.

Background: Deprescribing is a patient-centered solution to reducing polypharmacy in patients on hemodialysis (HD). In a deprescribing pilot study, patients were hesitant to participate due to limited understanding of their own medications and their unfamiliarity with the concept of deprescribing. Therefore, patient education materials designed to address these knowledge gaps can overcome barriers to shared decision-making and reduce hesitancy regarding deprescribing. Objective: To develop and validate a medication-specific, patient education toolkit (bulletin and video) that will supplement an upcoming nationwide deprescribing program for patients on HD. Methods: Patient education tools were developed based on the content of previously validated deprescribing algorithms and literature searches for patients' preferences in education. A preliminary round of validation was completed by 5 clinicians to provide feedback on the accuracy and clarity of the education tools. Then, 3 validation rounds were completed by patients on HD across 3 sites in Vancouver, Winnipeg, and Toronto. Content and face validity were evaluated on a 4-point and 5-point Likert scale, respectively. The content validity index (CVI) score was calculated after each round, and revisions were made based on patient feedback. Results: A total of 105 patients participated in the validation. All 10 education tools achieved content and face validity after 3 rounds. The CVI score was 1.0 for most of the tools, with 0.95 being the lowest value. Face validity ranged from 72% to 100%, with majority scoring above 90%. Conclusion: Ten patient education tools on deprescribing were developed and validated by patients on HD. These validated, medication-specific education tools are the first of its kind for patients on HD and will be used in a nationwide implementation study alongside the validated deprescribing algorithms developed by our research group.

Contexte: La déprescription est une solution axée sur le patient pour réduire la polypharmacie chez les patients sous hémodialyse (HD). Dans une étude pilote sur la déprescription, les patients ont hésité à participer en raison de leur compréhension limitée de leurs propres médicaments et de leur manque de connaissance du concept de déprescription. Par conséquent, du matériel éducatif conçu pour combler ces lacunes dans les connaissances des patients pourrait surmonter les obstacles à la prise de décision partagée et réduire les hésitations à l'égard de la déprescription. Objectifs: Développer et valider une trousse d'information (bulletin et vidéo) pour les patients portant sur les médicaments. Cette trousse viendra compléter un futur programme national de déprescription pour les patients sous HD. Méthodologie: Des outils d'éducation pour les patients ont été développés à partir du contenu d'algorithmes de déprescription validés précédemment et de recherches documentaires sur les préférences des patients en matière d'éducation. Une ronde préliminaire de validation a été complétée par cinq cliniciens afin d'obtenir des commentaires sur l'exactitude et la clarté des outils d'éducation. Trois cycles de validation ont ensuite été réalisés par des patients sous HD dans trois sites: Vancouver, Winnipeg et Toronto. La validité du contenu et la validité apparente ont été évaluées à l'aide d'échelles de Likert à 4 et 5 points, respectivement. L'indice de validité du contenu (IVC) a été calculé après chaque ronde et des révisions ont été effectuées en fonction des commentaires des patients. Résultats: En tout, 105 patients ont participé à la validation. La validité du contenu et la validité apparente ont été atteintes pour les dix outils d'éducation après trois rondes auprès des patients. L'IVC s'établissait à 1,0 pour la plupart des outils évalués; 0,95 était la valeur d'indice la plus faible. La validité apparente variait entre 72% et 100%, la majorité des outils ayant obtenu un score supérieur à 90%. Conclusion: Dix outils d'éducation pour les patients portant sur la déprescription ont été développés et validés par des patients sous HD. Ces outils d'éducation validés portant spécifiquement sur les médicaments sont les premiers du genre conçus pour les patients sous HD. Ils seront utilisés dans le cadre d'une étude nationale de mise en œuvre, parallèlement aux algorithmes validés de déprescription qui ont été développés par notre groupe de recherche.

A review of the BCG vaccine and other approaches toward tuberculosis eradication.

Despite aggressive eradication efforts, Tuberculosis (TB) remains a global health burden, one that disproportionally affects poorer, less developed nations. The only vaccine approved for TB, the Bacillus of Calmette and Guérin (BCG) vaccine remains controversial because it's stated efficacy has been cited as anywhere from 0 to 80%. Nevertheless, there have been exciting discoveries about the mechanism of action of the BCG vaccine that suggests it has a role in immunization schedules today. We review recent data suggesting the vaccine imparts protection against both tuberculosis and non-tuberculosis pathogens via a newly discovered immune system called trained immunity. BCG's efficacy also appears to be tied to its affect on granulocytes at the epigenetic and hematopoietic stem cell levels, which we discuss in this article at length. We also write about how the different strains of the BCG vaccine elicit different immune responses, suggesting that certain BCG strains are more immunogenic than others. Finally, our review delves into how the current vaccine is being reformulated to be more efficacious, and track the development of the next generation vaccines against TB.

Elucidating the Efficacy of the Bacille Calmette-Guérin Vaccination in Conjunction with First Line Antibiotics and Liposomal Glutathione.

Mycobacterium tuberculosis (M. tb) is the etiological agent that is responsible for causing tuberculosis (TB). Although every year M. tb infection affects millions of people worldwide, the only vaccine that is currently available is the Bacille Calmette-Guérin (BCG) vaccine. However, the BCG vaccine has varying efficacy. Additionally, the first line antibiotics administered to patients with active TB often cause severe complications and side effects. To improve upon the host response mechanism in containing M. tb infection, our lab has previously shown that the addition of the biological antioxidant glutathione (GSH) has profound antimycobacterial effects. The aim of this study is to understand the additive effects of BCG vaccination and ex-vivo GSH enhancement in improving the immune responses against M. tb in both groups; specifically, their ability to mount an effective immune response against M. tb infection, maintain CD4+ and CD8+ T cells in the granulomas, their response to liposomal glutathione (L-GSH), with varying suboptimal levels of the first line antibiotics isoniazid (INH) and pyrazinamide (PZA), the expressions of programmed death receptor 1 (PD-1), and their ability to induce autophagy. Our results revealed that BCG vaccination, along with GSH enhancement, can prevent the loss of CD4+ and CD8+ T cells in the granulomas and improve the control of M. tb infection by decreasing the expressions of PD-1 and increasing autophagy and production of the cytokines interferon gamma IFN-γ and tumor necrosis factor-α (TNF-α).

Mortality predictions using current physiologic scoring systems in patients meeting criteria for early goal-directed therapy and the severe sepsis resuscitation bundle.

Physiologic scoring systems are often used to prognosticate mortality in critically ill patients. This study examined the performance of Acute Physiology and Chronic Health Evaluation (APACHE) II, Simplified Acute Physiology Score (SAPS) II, Mortality in Emergency Department Sepsis (MEDS), and Mortality Probability Models (MPM) II0 in predicting in-hospital mortality of patients in the emergency department meeting criteria for early goal-directed therapy and the severe sepsis resuscitation bundle. The discrimination and calibration characteristics of APACHE II, SAPS II, MEDS, and MPM II0 were evaluated. Data are presented as median and quartiles (25th, 75th). Two-hundred forty-six patients aged 68 (52, 81) years were analyzed from a prospectively maintained sepsis registry, with 76.0% of patients in septic shock, 45.5% blood culture positive, and 35.0% in-hospital mortality. Acute Physiology and Chronic Health Evaluation II, SAPS II, and MEDS scores were 29 (21, 37), 54 (40, 70), and 13 (11, 16), with predicted mortalities of 64% (40%, 85%), 58% (25%, 84%), and 16% (9%, 39%), respectively. Mortality Probability Models II0 showed a predicted mortality of 60% (27%, 80%). The area under the receiver operating characteristic curves was 0.73 for APACHE II, 0.71 for SAPS II, 0.60 for MEDS, and 0.72 for MPM II0. The standardized mortality ratios were 0.59, 0.63, 1.68, and 0.64, respectively. Thus, APACHE II, SAPS II, MEDS, and MPM II0 have variable abilities to discriminate early and estimate in-hospital mortality of patients presenting to the emergency department requiring the severe sepsis resuscitation bundle. Adoption of these prognostication tools in this setting may influence therapy and resource use for these patients.

A wearable fingernail chemical sensing platform: pH sensing at your fingertips.

This article demonstrates an example of a wearable chemical sensor based on a fingernail platform. Fingernails represent an attractive wearable platform, merging beauty products with chemical sensing, to enable monitoring of our surrounding environment. The new colorimetric pH fingernail sensor relies on coating artificial nails with a recognition layer consisted of pH indicators entrapped in a polyvinyl chloride (PVC) matrix. Such color changing fingernails offer fast and reversible response to pH changes, repeated use, and intense color change detected easily with naked eye. The PVC matrix prevents leaching out of the indicator molecules from the fingernail sensor toward such repeated use. The limited narrow working pH range of a single pH indicator has been addressed by multiplexing three different pH indicators: bromothymol blue (pH 6.0-7.6), bromocresol green (pH 3.8-5.4), and cresol red (pH 7.2-8.8), as demonstrated for analyses of real-life samples of acidic, neutral, and basic character. The new concept of an optical wearable chemical sensor on fingernail platforms can be expanded towards diverse analytes for various applications in connection to the judicious design of the recognition layer.

An Analysis of MIF Structural Features that Control Functional Activation of CD74.

For more than 15 years, the tautomerase active site of macrophage migration inhibitory factor (MIF) and its catalytic residue Pro1 have been being targeted for the development of therapeutics that block activation of its cell surface receptor, CD74. Neither the biological role of the MIF catalytic site nor the mechanistic details of CD74 activation are well understood. The inherently unstable structure of CD74 remains the biggest obstacle in structural studies with MIF for understanding the basis of CD74 activation. Using a novel approach, we elucidate the mechanistic details that control activation of CD74 by MIF surface residues and identify structural parameters of inhibitors that reduce CD74 biological activation. We also find that N-terminal mutants located deep in the catalytic site affect surface residues immediately outside the catalytic site, which are responsible for reduction of CD74 activation.

Implementation of a bundle of quality indicators for the early management of severe sepsis and septic shock is associated with decreased mortality.

OBJECTIVE: The purpose of this study was to examine the outcome implications of implementing a severe sepsis bundle in an emergency department as a quality indicator set with feedback to modify physician behavior related to the early management of severe sepsis and septic shock. DESIGN: Two-year prospective observational cohort. SETTING: Academic tertiary care facility. PATIENTS: Patients were 330 patients presenting to the emergency department who met criteria for severe sepsis or septic shock. INTERVENTIONS: Five quality indicators comprised the bundle for severe sepsis management in the emergency department: a) initiate central venous pressure (CVP)/central venous oxygen saturation (Scvo2) monitoring within 2 hrs; b) give broad-spectrum antibiotics within 4 hrs; c) complete early goal-directed therapy at 6 hrs; d) give corticosteroid if the patient is on vasopressor or if adrenal insufficiency is suspected; and e) monitor for lactate clearance. MEASUREMENTS AND MAIN RESULTS: Patients had a mean age of 63.8 +/- 18.5 yrs, Acute Physiology and Chronic Health Evaluation II score 29.6 +/- 10.6, emergency department length of stay 8.5 +/- 4.4 hrs, hospital length of stay 11.3 +/- 12.9 days, and in-hospital mortality 35.2%. Bundle compliance increased from zero to 51.2% at the end of the study period. During the emergency department stay, patients with the bundle completed received more CVP/Scvo2 monitoring (100.0 vs. 64.8%, p < .01), more antibiotics (100.0 vs. 89.7%, p = .04), and more corticosteroid (29.9 vs. 16.2%, p = .01) compared with patients with the bundle not completed. In a multivariate regression analysis including the five quality indicators, completion of early goal-directed therapy was significantly associated with decreased mortality (odds ratio, 0.36; 95% confidence interval, 0.17-0.79; p = .01). In-hospital mortality was less in patients with the bundle completed compared with patients with the bundle not completed (20.8 vs. 39.5%, p < .01). CONCLUSIONS: Implementation of a severe sepsis bundle using a quality improvement feedback to modify physician behavior in the emergency department setting was feasible and was associated with decreased in-hospital mortality.

Early goal-directed therapy, corticosteroid, and recombinant human activated protein C for the treatment of severe sepsis and septic shock in the emergency department.

OBJECTIVES: To describe our experience with early goal-directed therapy (EGDT), corticosteroid administration, and recombinant human activated protein C (rhAPC) administration in patients with severe sepsis or septic shock and an Acute Physiology and Chronic Health Evaluation (APACHE) II score > or =25 in the emergency department (ED). METHODS: This was a retrospective case series of a prospectively maintained ED sepsis registry. Data are presented as median (25th, 75th percentile). The setting was an academic tertiary ED with approximately 60,000 annual patient visits. Patients with severe sepsis or septic shock and an APACHE II score > or =25 entered in an ED sepsis registry over a four-month period were included. Patients who received rhAPC in the intensive care unit were excluded. Central venous catheterization for central venous pressure and central venous oxygen saturation monitoring, antibiotics, fluid resuscitation, mechanical ventilation, vasopressors, inotropes, corticosteroids, and rhAPC were initiated by the emergency physicians and continued in the intensive care unit by intensivists. RESULTS: Twenty-four patients were enrolled. Patient characteristics were as follows: age, 79.5 (68.0, 83.5) years; APACHE II score, 31.5 (29.8, 36.0); ED length of stay, 6.5 (4.0, 10.5) hours; predicted mortality, 76.7% (71.9, 86.4); and in-hospital mortality, 45.8%. All patients received broad-spectrum antibiotics, 54.2% completed EGDT, 33.3% received corticosteroids, and 33.3% received rhAPC. Time of antibiotic administration was 1.5 (1.0, 2.0) hours, time of central venous pressure/central venous oxygen saturation monitoring was 1.0 (0.5, 2.5) hour, and time of rhAPC administration was 9.5 (6.8, 10.5) hours after patients met criteria for severe sepsis or septic shock. In-hospital mortality of patients who received rhAPC in addition to other therapies was 25.0%. CONCLUSIONS: EGDT, corticosteroid administration, and rhAPC administration are feasible in the ED setting. While these evidence-based therapies individually have been shown to improve outcomes for patients with severe sepsis or septic shock, further studies are needed to examine their combined effectiveness during the early stages of this disease.