Conformation and Domain Movement Analysis of Human Matrix Metalloproteinase-2: Role of Associated Zn2+ and Ca2+ Ions.

Matrix metaloproteinase-2 (MMP-2) is an extracellular Zn2+ protease specific to type I and IV collagens. Its expression is associated with several inflammatory, degenerative, and malignant diseases. Conformational properties, domain movements, and interactions between MMP-2 and its associated metal ions were characterized using a 1.0 µs molecular dynamics simulation. Dihedral principle component analysis revealed ten families of conformations with the greatest degree of variability occurring in the link region connecting the catalytic and hemopexin domains. Dynamic cross-correlation analysis indicated domain movements corresponding to the opening and closing of the hemopexin domain in relation to the fibronectin and catalytic domains facilitated by the link region. Interaction energies were calculated using the molecular mechanics Poisson Boltzman surface area-interaction entropy (MMPBSA-IE) analysis method and revealed strong binding energies for the catalytic Zn2+ ion 1, Ca2+ ion 1, and Ca2+ ion 3 with significant conformational stability at the binding sites of Zn2+ ion 1 and Ca2+ ion 1. Ca2+ ion 2 diffuses freely away from its crystallographically defined binding site. Zn2+ ion 2 plays a minor role in conformational stability of the catalytic domain while Ca2+ ion 3 is strongly attracted to the highly electronegative sidechains of the Asp residues around the central ß-sheet core of the hemopexin domain; however, the interacting residue sidechain carboxyl groups are outside of Ca2+ ion 3's coordination sphere.

Effects of Selective Substitution of Cysteine Residues on the Conformational Properties of Chlorotoxin Explored by Molecular Dynamics Simulations.

Chlorotoxin (CTX) is a 36⁻amino acid peptide with eight Cys residues that forms four disulfide bonds. It has high affinity for the glioma-specific chloride channel and matrix metalloprotease-2. Structural and binding properties of CTX analogs with various Cys residue substitutions with l-α-aminobutyric acid (Abu) have been previously reported. Using 4.2 µs molecular dynamics, we compared the conformational and essential space sampling of CTX and analogs with selective substitution of the Cys residues and associated disulfide bonds with either Abu or Ser. The native and substituted peptides maintained a high degree of α-helix propensity from residues 8 through 21, with the exception of substitution of the Cys5⁻Cys28 residues with Ser and the Cys16⁻Cys33 residues with Abu. In agreement with previous circular dichroism spectropolarimetry results, the C-terminal ß-sheet content varied less from residues 25 through 29 and 32 through 36 and was well conserved in most analogs. The Cys16⁻Cys33 and Cys20⁻Cys35 disulfide-bonded residues appear to be required to maintain the αß motif of CTX. Selective substitution with the hydrophilic Ser, may mitigate the destabilizing effect of Cys16⁻Cys33 substitution through the formation of an inter residue H-bond from Ser16:OγH to Ser33:OγH bridged by a water molecule. All peptides shared considerable sampled conformational space, which explains the retained receptor binding of the non-native analogs.

Effects of force fields on the conformational and dynamic properties of amyloid ß(1-40) dimer explored by replica exchange molecular dynamics simulations.

The conformational space and structural ensembles of amyloid beta (Aß) peptides and their oligomers in solution are inherently disordered and proven to be challenging to study. Optimum force field selection for molecular dynamics (MD) simulations and the biophysical relevance of results are still unknown. We compared the conformational space of the Aß(1-40) dimers by 300 ns replica exchange MD simulations at physiological temperature (310 K) using: the AMBER-ff99sb-ILDN, AMBER-ff99sb*-ILDN, AMBER-ff99sb-NMR, and CHARMM22* force fields. Statistical comparisons of simulation results to experimental data and previously published simulations utilizing the CHARMM22* and CHARMM36 force fields were performed. All force fields yield sampled ensembles of conformations with collision cross sectional areas for the dimer that are statistically significantly larger than experimental results. All force fields, with the exception of AMBER-ff99sb-ILDN (8.8 ± 6.4%) and CHARMM36 (2.7 ± 4.2%), tend to overestimate the α-helical content compared to experimental CD (5.3 ± 5.2%). Using the AMBER-ff99sb-NMR force field resulted in the greatest degree of variance (41.3 ± 12.9%). Except for the AMBER-ff99sb-NMR force field, the others tended to under estimate the expected amount of ß-sheet and over estimate the amount of turn/bend/random coil conformations. All force fields, with the exception AMBER-ff99sb-NMR, reproduce a theoretically expected ß-sheet-turn-ß-sheet conformational motif, however, only the CHARMM22* and CHARMM36 force fields yield results compatible with collapse of the central and C-terminal hydrophobic cores from residues 17-21 and 30-36. Although analyses of essential subspace sampling showed only minor variations between force fields, secondary structures of lowest energy conformers are different.

Structural properties of amyloid ß(1-40) dimer explored by replica exchange molecular dynamics simulations.

Replica exchange molecular dynamics simulations (300 ns) were used to study the dimerization of amyloid ß(1-40) (Aß(1-40)) polypeptide. Configurational entropy calculations revealed that at physiological temperature (310 K, 37°C) dynamic dimers are formed by randomly docked monomers. Free energy of binding of the two chains to each other was -93.56 ± 6.341 kJ mol-1 . Prevalence of random coil conformations was found for both chains with the exceptions of increased ß-sheet content from residues 16-21 and 29-32 of chain A and residues 15-21 and 30-33 of chain B with ß-turn/ß-bend conformations in both chains from residues 1-16, 21-29 of chain A, 1-16, and 21-29 of chain B. There is a mixed ß-turn/ß-sheet region from residues 33-38 of both chains. Analysis of intra- and interchain residue distances shows that, although the individual chains are highly flexible, the dimer system stays in a loosely packed antiparallel ß-sheet configuration with contacts between residues 17-21 of chain A with residues 17-21 and 31-36 of chain B as well as residues 31-36 of chain A with residues 17-21 and 31-36 of chain B. Based on dihedral principal component analysis, the antiparallel ß-sheet-loop-ß-sheet conformational motif is favored for many low energy sampled conformations. Our results show that Aß(1-40) can form dynamic dimers in aqueous solution that have significant conformational flexibility and are stabilized by collapse of the central and C-terminal hydrophobic cores with the expected ß-sheet-loop-ß-sheet conformational motif. Proteins 2017; 85:1024-1045. © 2017 Wiley Periodicals, Inc.

Cervical Total Disc Replacement and Anterior Cervical Discectomy and Fusion: Comparison of 30-Day Population Comorbidities and Perioperative Complications Using 6 Years of American College of Surgeons National Surgical Quality Improvement Program Participant Use File Data.

OBJECTIVE: American College of Surgeons National Surgical Quality Improvement Program Participant Use File data from 2014 through 2019 were used to compare 1- and 2-level anterior cervical discectomy and fusion (ACDF) and cervical total disc replacement (cTDR) with respect to: patient demographics, comorbidities, adverse events, and 30-day morbidity rates. METHODS: One- and 2-level ACDF and cTDR patients were identified by current procedural terminology codes. Demographics, comorbidities, and adverse events were summarized. Unmatched cohorts were compared using Wilcoxon Rank Sum test for continuous variables, Pearson χ2 test for categorical variables, and 30-day morbidity using inverse probability of treatment weighted log-binomial regression. RESULTS: American College of Surgeons National Surgical Quality Improvement Program 2014 through 2019 Participant Use File datasets represent 4,862,497 unique patients, identifying 13,347 1-level, 6933 2-level ACDF, 3114 1-level, and 862 2-level cTDR patient cohorts. Statistically significant differences between cohorts are extensive: age, sex, race, admission status, patient origin, discharge disposition, emergent surgery, surgical specialty, American Society of Anesthesiologists classification, wound class, operative time, hospital LOS, BMI, functional status, smoking, diabetes, dyspnea, chronic obstructive pulmonary disease, congestive heart failure, hypertension, renal failure, dialysis, cancer, steroid use, anemia, bleeding disorders, systemic sepsis, and number of concurrent comorbid conditions. Inverse probability of treatment weighted log-binomial models, demonstrated increased risk of deep venous thrombosis/thrombophlebitis, pulmonary embolism, deep incisional surgical site infection, pneumonia, and unplanned return to operating room associated with ACDF while increased risk of cerebral vascular accident/stroke with neurological deficit and myocardial infarction associated with cTDR. The composite complications outcome favors cTDR over ACDF for 30-day morbidity. No mortalities occurred within the cTDR cohort. CONCLUSIONS: Adjusting for demographics and comorbidities; ACDF has a higher average risk of adverse event. When ACDF and cTDR are equipoise, consideration for cTDR may be indicated in populations with higher rates of comorbid conditions.

Prompting physicians to address a daily checklist and process of care and clinical outcomes: a single-site study.

RATIONALE: Checklists may reduce errors of omission for critically ill patients. OBJECTIVES: To determine whether prompting to use a checklist improves process of care and clinical outcomes. METHODS: We conducted a cohort study in the medical intensive care unit (MICU) of a tertiary care university hospital. Patients admitted to either of two independent MICU teams were included. Intervention team physicians were prompted to address six parameters from a daily rounding checklist if overlooked during morning work rounds. The second team (control) used the identical checklist without prompting. MEASUREMENTS AND MAIN RESULTS: One hundred and forty prompted group patients were compared with 125 control and 1,283 preintervention patients. Compared with control, prompting increased median ventilator-free duration, decreased empirical antibiotic and central venous catheter duration, and increased rates of deep vein thrombosis and stress ulcer prophylaxis. Prompted group patients had lower risk-adjusted ICU mortality compared with the control group (odds ratio, 0.36; 95% confidence interval, 0.13-0.96; P = 0.041) and lower hospital mortality compared with the control group (10.0 vs. 20.8%; P = 0.014), which remained significant after risk adjustment (odds ratio, 0.34; 95% confidence interval, 0.15-0.76; P = 0.008). Observed-to-predicted ICU length of stay was lower in the prompted group compared with control (0.59 vs. 0.87; P = 0.02). Checklist availability alone did not improve mortality or length of stay compared with preintervention patients. CONCLUSIONS: In this single-site, preliminary study, checklist-based prompting improved multiple processes of care, and may have improved mortality and length of stay, compared with a stand-alone checklist. The manner in which checklists are implemented is of great consequence in the care of critically ill patients.

Using a Data-Driven Improvement Methodology to Decrease Surgical Site Infections in a Community Neurosurgery Practice: Optimizing Preoperative Screening and Perioperative Antibiotics.

OBJECTIVE: We used a data-driven methodology to decrease the departmental surgical site infection rate to a goal of 1%. METHODS: A prospective interventional study with historical controls comparing preimplementation/intervention (unknown methicillin-sensitive Staphylococcus aureus [MSSA]/methicillin-resistant Staphylococcus aureus [MRSA] status and standard weight and drug allergy-based preoperative antibiotics) with postimplementation/intervention (optimized preoperative chlorhexidine showers, MSSA/MRSA screening, MSSA/MRSA decolonization, and optimized preoperative antibiotic order set implementation). The American College of Surgeons National Surgical Quality Improvement Program was used for case surveillance. The primary outcome was the presence of a surgical site infection with a secondary outcome of cost(s) of implementation. RESULTS: A total of 317 National Surgical Quality Improvement Program abstracted neurosurgical cases were analyzed, 163 cases before implementation and 154 cases after implementation. There were no significant differences between the preimplementation and postimplementation cohorts regarding patient demographics and baseline comorbidities, with the exceptions of inpatient and functional status (P < 0.001). The most common procedures were lumbar decompression (31%), lumbar discectomy (27%), and anterior cervical discectomy and fusion (10.4%). After implementation, 30 patients were MSSA positive (20%) and 4 MRSA positive (2.6%). Thirty patients received preoperative intranasal mupirocin decolonization (88%), and 4 patients received adjusted preoperative antibiotics (12%). After protocol implementation, the surgical site infection rate decreased from 6.7% (odds ratio, 2.82) to 0.96% (odds ratio, 0.91). The cost of implementation was $27,179, or $58 per patient. CONCLUSIONS: The findings highlight the importance of systematically investigating areas of gap in existing clinical practice and quality improvement projects to increase patient safety and enhance the value of care delivered to neurosurgical patients.

Critical care physician cognitive task analysis: an exploratory study.

INTRODUCTION: For better or worse, the imposition of work-hour limitations on house-staff has imperiled continuity and/or improved decision-making. Regardless, the workflow of every physician team in every academic medical centre has been irrevocably altered. We explored the use of cognitive task analysis (CTA) techniques, most commonly used in other high-stress and time-sensitive environments, to analyse key cognitive activities in critical care medicine. The study objective was to assess the usefulness of CTA as an analytical tool in order that physician cognitive tasks may be understood and redistributed within the work-hour limited medical decision-making teams. METHODS: After approval from each Institutional Review Board, two intensive care units (ICUs) within major university teaching hospitals served as data collection sites for CTA observations and interviews of critical care providers. RESULTS: Five broad categories of cognitive activities were identified: pattern recognition; uncertainty management; strategic vs. tactical thinking; team coordination and maintenance of common ground; and creation and transfer of meaning through stories. CONCLUSIONS: CTA within the framework of Naturalistic Decision Making is a useful tool to understand the critical care process of decision-making and communication. The separation of strategic and tactical thinking has implications for workflow redesign. Given the global push for work-hour limitations, such workflow redesign is occurring. Further work with CTA techniques will provide important insights toward rational, rather than random, workflow changes.

Diagnosis and Treatment of Isolated Cerebral Mucormycosis: Patient-Level Data Meta-Analysis and Mayo Clinic Experience.

BACKGROUND: Isolated cerebral mucormycosis is a rare and serious infection associated with intravenous drug abuse. METHODS: We performed a comprehensive meta-analysis of cases reported in studies and have included an unreported case from our institution. We searched PubMed/Medline, EMBASE, Scopus, Cochrane Databases, and our institution's electronic medical health records from inception through March 31, 2018. The cases were considered isolated (only affecting the cerebrum, cerebellum, or brainstem) if the absence of other primary sources of infection had been documented. Continuous variables were summarized using the median and interquartile range and categorical variables using frequencies and proportions. The relationships between variables were tested using the Wilcoxon rank sum and Pearson χ2 tests. RESULTS: A total of 130 studies (141 patients) met the eligibility requirements and were screened; 68 patients were included. The median age was 28 years (interquartile range, 24-38); 57% were men. Most patients had a history of intravenous drug abuse (82%), and 20% had positive human immunodeficiency virus findings. The lesion location was mostly supratentorial (91%), especially in the basal ganglia (71.2%). The cultures were positive in 38%, with Rhizopus the most common organism (59%). The mortality rate was 65%. The survivors were significantly more likely to have received amphotericin B (92% vs. 43%; P < 0.001) or to have undergone stereotactic aspiration (58% vs. 25%; P < 0.01). CONCLUSIONS: Isolated cerebral mucormycosis has a pooled mortality rate of 65%. The presence of lesions in the basal ganglia, rapidly progressive symptoms, and a history of intravenous drug abuse should raise suspicion for the early initiation of amphotericin B and stereotactic aspiration.

A validation study of a new prognostic index for patients with brain metastases: the Graded Prognostic Assessment.

OBJECT: The purpose of this study was to validate a new prognostic index for patients with brain metastases. This index, the Graded Prognostic Assessment (GPA), is based on an analysis of 1960 patients whose data were extracted from the Radiation Therapy Oncology Group (RTOG) database. The GPA is based on 4 criteria: age, Karnofsky Performance Scale score, number of brain metastases, and the presence/absence of extracranial metastases. Each of the 4 criteria is given a score of 0, 0.5, or 1.0, so the patient with best prognosis would have a GPA score of 4.0. METHODS: Between April 2005 and December 2006, 140 eligible patients with brain metastases were treated at the Gamma Knife Center at the University of Minnesota. The GPA score was calculated for each patient, and the score was then correlated with survival. Survival duration was calculated from the date treatment began for the brain metastases. Eligibility criteria included patients treated with whole-brain radiation therapy, stereotactic radiosurgery, or both. RESULTS: The median survival time in months observed in the RTOG and Minnesota data by GPA score was as follows: GPA 3.5-4.0, 11.0 and 21.7; GPA 3.0, 8.9 and 17.5; GPA 1.5-2.5, 3.8 and 5.9; and GPA 0-1.0, 2.6 and 3.0, respectively. CONCLUSIONS: The University of Minnesota data correlate well with the RTOG data and validate the use of the GPA as an effective prognostic index for patients with brain metastases. Clearly, not all patients with brain metastases have the same prognosis, and treatment decisions should be individualized accordingly. The GPA score does appear to be as prognostic as the RPA and is less subjective (because the RPA requires assessment of whether the primary disease is controlled), more quantitative, and easier to use and remember. A multi-institutional validation study of the GPA is ongoing.

Accepting critically ill transfer patients: adverse effect on a referral center's outcome and benchmark measures.

BACKGROUND: Common methods of benchmarking clinical performance rarely, if ever, account for admission source and, in particular, the effect of a patient being transferred from one medical center to another. Small biases in comparisons of observed versus expected deaths can substantially affect how high-quality institutions compare with peer hospitals. With the most sophisticated and validated set of case-mix measures available for patients, the intensive care unit is an ideal setting in which to study the effect of a patient's being transferred from another hospital. OBJECTIVE: To determine the extent of bias in benchmarking outcomes when performance measures do not account for transfer patients' greater severity of illness. DESIGN: Prospectively developed cohort study. SETTING: Medical intensive care unit (MICU) at a tertiary care university hospital. PATIENTS: 4579 consecutive admissions for 4208 patients from 1 January 1994 to 1 April 1998. MEASUREMENTS: MICU and hospital lengths of stay, MICU readmission, and hospital mortality rates. RESULTS: Compared with directly admitted patients, MICU patients transferred from another hospital had significantly higher Acute Physiology Scores at the time of admission and discharge (P = 0.001). Even after full adjustment for case mix and severity of illness, transfer patients had a 38% longer MICU stay (95% CI, 32% to 45%), a 41% longer hospital stay (CI, 34% to 50%), and a 2.2 times greater odds of hospital mortality (CI, 1.7 to 2.8) than directly admitted patients. With identical efficiency and quality, a referral hospital with a 25% MICU transfer rate compared with another with a 0% transfer rate would be penalized by 14 excess deaths per 1000 admissions when a benchmarking program adjusts only for case mix and severity of illness and not for the source of admission. CONCLUSIONS: In a setting with the most thorough diagnostic-based, case-mix adjustment and the most physiologically precise severity-of-illness information, accepting transfer patients can adversely affect efficiency and quality benchmarks. Benchmarking and profiling efforts beyond intensive care units must also recognize and account for this phenomenon; otherwise, referral centers may have an incentive to refuse care for patients who could benefit from being transferred to their facility.

Range and prevalence of cardiac abnormalities in patients hospitalized in a medical ICU.

BACKGROUND: Patients hospitalized in medical ICUs (MICUs) with acute noncardiac illnesses have an undefined prevalence of underlying cardiovascular abnormalities. Because of the acuteness of illness, the need for frequent concurrent mechanical ventilation, and the nature of the underlying diseases, routine cardiac examination may be suboptimal for identifying concurrent cardiac abnormalities. PURPOSE: The purpose of this study was to utilize transthoracic echocardiography and Doppler echocardiography interrogation to identify the range and prevalence of occult cardiac abnormalities that may be present in patients admitted to an MICU. METHODS: Over a 12-month period, 500 consecutive patients who had been admitted to the MICU of a large university tertiary care center underwent complete two-dimensional echocardiography and Doppler scanning within 18 h of admission. The final study population comprised 467 patients. No study subject had been admitted to the MICU for a primary cardiac diagnosis. Cardiovascular abnormalities were prospectively defined, and all echocardiograms were interpreted independently by blinded observers. Both MICU and overall mortality rates as well as length of stay were compared to the presence or absence of cardiac abnormalities. RESULTS: One or more cardiac abnormalities was noted in 169 patients (36%). The average (+/-SD) age of patients in the study was 52 +/- 17 years (age range, 17 to 100 years), and the average age was 57 +/- 18 years (age range, 18 to 93 years) in patients with underlying cardiac abnormalities. A single cardiac abnormality was noted in 103 patients (22%), two cardiac abnormalities were noted in 34 patients (7.2%), and three or more cardiac abnormalities were noted in 32 patients (6.8%). Based on subsequent requests for cardiac diagnostic studies, 67 patients (14.3%) were clinically suspected of having significant cardiovascular abnormalities, 39 of whom (58%) had one or more cardiac abnormalities on seen on echocardiography. Cardiac abnormalities were unsuspected in 130 of 169 patients (77%) and were only noted at the time they underwent surveillance echocardiography. Although there was no correlation between the presence of cardiac abnormalities and mortality, both MICU and hospital length of stay were increased in patients with cardiac abnormalities. CONCLUSION: A significant proportion of patients admitted to an MICU with noncardiac illness have underlying cardiac abnormalities, which can be detected with surveillance echocardiography at the time of admission. Cardiac abnormalities were associated with an increased length of stay but not with increased mortality.

Reducing costs and improving outcomes of percutaneous coronary interventions.

OBJECTIVE: To describe cost reduction and quality improvement efforts in our percutaneous coronary intervention (PCI) program and how risk adjustment was used to assess the effects of these changes. STUDY DESIGN: Single center registry analysis. PATIENTS AND METHODS: Data were collected on 2158 PCIs performed between July 1, 1994, and June 30, 1997. Of these, 1126 PCIs reflected care provided after implementation of competitive bidding for catheterization lab supplies, and efforts to reduce the use of postprocedure heparin and to implement early arterial sheaths removal (postbidding period). Hospital costs were estimated using a microcost accounting method. In-hospital mortality rates during the 2 time periods were compared using standardized mortality ratio estimated with a previously validated risk adjustment model for in-hospital mortality. RESULTS: Compared with the prebidding period, the postbidding period was characterized by a significantly higher utilization of new technology (coronary stents and atherectomy devices 46% vs 25%; abciximab 19.1% vs 3.7, P<.01), and an overall increase in case complexity. Despite these changes, the average and median postbidding cost per case was dollars 1223 and dollars 1444 lower, respectively, than in the prebidding period. After adjustment for comorbidities, procedure variables, complications, and length of hospital stay, multivariate regression modeling identified the postbidding period as an independent predictor of lower hospital costs (P<.001) with an estimated adjusted cost savings of dollars 460. These cost savings were associated with trends toward a lower observed mortality rate, a higher predicted mortality rate, and a significantly lower standardized mortality ratio (SMR .71; 95% CI 0.48-0.9; P<.05). CONCLUSION: Despite an increase in case complexity and utilization of new technology, cost reductions can be achieved through competitive bidding for supplies and modifications of periprocedure care. Risk adjustment appears to be a valid tool for assessing the effectiveness of these efforts independently from changes in case mix.

Gamma knife stereotactic radiosurgery for renal cell carcinoma and melanoma brain metastases-comparison of dose response.

BACKGROUND: Metastatic melanoma appears to have inferior local control (LC) than renal cell carcinoma (RCC) after stereotactic radiosurgery (SRS) to the brain. OBJECTIVE: To retrospectively examine RCC vs. melanoma LC dose response. METHODS: Follow-up data were available for 88 patients (RCC=38; melanoma=50) with 235 tumors (RCC=92; melanoma=143) treated with Gamma Knife SRS between Dec. 2005 to Aug. 2012. LC was compared among RCC vs. melanoma and then at each margin dose (≤18Gy, 20Gy, 22Gy, and 24Gy). Patient survival and toxicity were analyzed. Median follow-up was 9.8 months (RCC) and 5.4 months (melanoma). RESULTS: Patient characteristics were similar between RCC vs. melanoma with respect to gender, age, KPS, GPA, lesions per patient, and tumor volume. For all margin doses, LC at 6 months was 98.6% (RCC) vs. 79.2% (melanoma). When broken down by margin dose, at ≤18 Gy (P<0.0001) and 20 Gy (P=0.02), RCC had better LC compared to melanoma. At 22 Gy, LC were similar between the two histologies (P=0.19). At 24 Gy, melanoma had better LC than RCC (P=0.02). Tumor volumes were similar between RCC vs. melanoma at each margin dose (P>0.05). Small melanoma tumors (<4ml) exhibited LC dose dependence. Median survival was 16.1 months (RCC) and 9.6 months (melanoma). Toxicity was not significantly different between the two histologies and margin doses. CONCLUSIONS: RCC has significantly better LC than melanoma after SRS. Higher doses could be used for melanoma tumors <4ml to improve melanoma LC.

Medical complications drive length of stay after brain hemorrhage: a cohort study.

INTRODUCTION: Longer length of stay (LOS) is associated with higher complications and costs in ICU patients, while hospital protocols may decrease complications and LOS. We hypothesized that medical complications would increase LOS after spontaneous subarachnoid (SAH) and intracerebral (ICH) hemorrhage after accounting for severity of neurologic injury in a cohort of consecutively admitted patients. METHODS: We prospectively recorded admission characteristics, hospital complications, and LOS for 122 patients with SAH and 56 patients with ICH from February 2006 through March 2008. A multidisciplinary Neuro-ICU team included a dedicated pharmacist and intensivist on daily rounds. Hospital protocols set glucose control with intravenous insulin, ventilator bundles, pharmacist involvement, and hand hygiene. Associations were explored with univariate statistics (t-tests, ANOVA, or non-parametric statistics as appropriate) and linear regression (repeated after log transformation of ICU and hospital LOS). RESULTS: Factors associated with longer LOS after SAH and ICH were similar. In both SAH and ICH the strongest drivers of LOS were infection, fever, and acute lung injury. For SAH, vasospasm and Glasgow Coma Scale were also significant in some models, while in patients with ICH the volume of the initial bleed was significant in some models. CONCLUSION: LOS after spontaneous brain hemorrhage is driven by medical complications even after the adoption of dedicated intensive care medical staff, pharmacist involvement, and evidence-based protocols for ICU care. Further alterations in care will be necessary to eliminate "preventable" complications and minimize LOS after brain hemorrhage.

Cardiac troponin I and acute lung injury after subarachnoid hemorrhage.

INTRODUCTION: There are few predictors of acute lung injury (ALI) or the acute respiratory distress syndrome (ARDS) after subarachnoid hemorrhage (SAH). We hypothesized that cardiac troponin I, which is associated with cardiovascular morbidity, would also predict ALI. METHODS: We prospectively enrolled 171 consecutive patients with SAH. Troponin was routinely measured on admission and the next day and subsequently if abnormal. We prospectively recorded the maximum troponin, in-hospital events, and clinical endpoints. ALI and ARDS were defined by standard criteria. RESULTS: Acute lung injury was found in 10 patients (6%), ARDS in an additional 14 (8%), and pulmonary edema without lung injury in 9 (5%). Maximum troponin was different in patients without lung injury or pulmonary edema (0.03 [0.02-0.12] mcg/l), ALI (0.17 [0.04-1.4]), or ARDS (0.31 [0.9-1.8], P < 0.001). In ROC analysis, a cutoff of 0.04 mcg/l had 91% sensitivity and 42% specificity for ALI or ARDS (AUC = 0.75, P < 0.001). Troponin was associated with ALI or ARDS after accounting for neurologic grade in multivariate models without further contribution from pneumonia, packed red cell transfusion, gender, tobacco use, coronary artery disease, vasospasm, depressed ejection fraction on echocardiography, or CT grade. Lung injury was associated with worse functional outcome at 14 days, but not at 28 days or 3 months. CONCLUSION: Troponin I is associated with the development of ALI after SAH.

Aggressive red blood cell transfusion: no association with improved outcomes for victims of isolated traumatic brain injury.

BACKGROUND: Clinical studies have caused blood transfusion practices in critically ill patients to become more conservative in the last decade. However, few studies have focused on trauma patients, particularly those with severe isolated traumatic brain injury. METHODS: We conducted a retrospective study to test the hypothesis that patients with severe brain injury would not benefit from aggressive red blood cell transfusion (RBCT). End points of the study were in-hospital mortality and morbidity (pneumonia, urinary tract infection, deep venous thrombosis, pulmonary embolus, decubitus ulcer, bacteremia, septic shock, myocardial infarction, and seizure). Included in our retrospective study were patients at two urban, level I trauma centers who were admitted with a diagnosis of isolated head injury and with a Glasgow Coma Scale (GCS) score of 8 or less. We recorded demographic, interventional, and outcome variables. RESULTS: In 289 patients, 24 of 25 (96%) were transfused if their lowest recorded intensive care unit (ICU) hemoglobin level was 8.0 g/dl or less. In contrast, only 9/182 (5%) of these 289 patients were transfused if the hemoglobin levels were 10.0 g/dl or greater. In the remaining 82 patients with lowest ICU hemoglobin levels of 8.0-10.0 g/dl, 52% were transfused. These 82 patients (43 underwent RBCT and 39 did not) were included in our analysis. DISCUSSION: The overall in-hospital mortality rate was 32%; rates were similar between the two groups (29%, non-RBCT; 35%, RBCT) (P = 0.64). Likewise, in-hospital morbidity was similar between groups. Logistic and proportional hazard regression analyses identified RBCT as one predictor of mortality. CONCLUSIONS: Our results suggest that a restrictive transfusion practice is safe for severely head-injured patients.

Use of electronic alerts to enhance hand hygiene compliance and decrease transmission of vancomycin-resistant Enterococcus in a hematology unit.

BACKGROUND: Hand hygiene (HH) compliance among health care workers (HCWs) has been historically low and hampered by poor surveillance methods. This study evaluated the use of an electronic device to measure and impact HH compliance. METHODS: The study is a prospective, interventional study in a 30-bed academic medical center hematology unit. Phase I of the study monitored baseline HH compliance, and phase II monitored HH compliance using automatic alerts. The primary outcome measure was HH compliance, and the secondary end point was nosocomial transmission of vancomycin-resistant Enterococcus (VRE). RESULTS: Eight thousand two hundred thirty-five HH opportunities were measured during the study, with HH compliance improvement from 36.3% at baseline to 70.1% during phase II. The use of audible alerts improved HH compliance for both the day shift (odds ratio [OR], 3.6) and the night shift (OR, 5.9), as well as across rooms with higher HCW traffic (OR, 1.6) and lower HCW traffic (OR, 3.2). CONCLUSION: Electronic devices can effectively monitor HH compliance among HCWs and facilitate improved adherence to guidelines. Electronic devices improve HH compliance regardless of time of day or room location. The development of innovative devices to improve HH is required to validate the long-term implications of this methodology.

Fever burden and functional recovery after subarachnoid hemorrhage.

OBJECTIVE: Fever is associated with worse outcome after subarachnoid hemorrhage, but there are few prospective data to quantify this relationship. METHODS: We prospectively enrolled consecutive aneurysmal or cryptogenic subarachnoid hemorrhage patients and recorded the highest core temperature each calendar day for Day 0 (the day of hemorrhage) through Day 13. Fever burden was defined as the daily highest core temperature minus 100.4 degrees F, summed from admission through Day 13 (temperatures <100.4 degrees F did not contribute to or subtract from fever burden). Outcomes were assessed at 14 days or at the time of hospital discharge with the National Institutes of Health Stroke Scale and modified Rankin Scale, and at 28 days and 3 months with the modified Rankin Scale. Improvement was analyzed with repeated measures analysis of variance. RESULTS: We prospectively enrolled 94 patients. From 14 days to 28 days to 3 months, functional improvement was related to cumulative fever burden, admission neurological grade, aneurysm obliteration procedure, admission computed tomographic score, vasospasm, and external ventricular drainage. Good-grade patients had worse functional outcomes with increased fever burden, and poor-grade patients improved more over time when fever burden was higher (time by World Federation of Neurological Surgeons grade by fever burden interaction, P < 0.001). Patients with vasospasm (P = 0.04) and patients with higher computed tomographic scores (P = 0.002) had worse 14-day outcomes but improved more over time. Bacteremia and ventriculitis were uncommon (