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Background An early acute marker of long-term neurological outcome would be useful to help guide clinical decision making and therapeutic effectiveness after severe traumatic brain injury (TBI). We investigated the utility of the Disability Rating Scale (DRS) as early as 1 wk after TBI as a predictor of favorable 6-mo Glasgow Outcome Scale extended (GOS-E). Objective To determine the predictability of a favorable 6-mo GOS-E using the DRS measured during weeks 1 to 4 of injury. Methods The study is a sub analysis of patients enrolled in the Epo Severe TBI Trial (n = 200) to train and validate L1-regularized logistic regression models. DRS was collected at weeks 1 to 4 and GOS-E at 6 mo. Results The average area under the receiver operating characteristic curve was 0.82 for the model with baseline demographic and injury severity variables and week 1 DRS and increased to 0.88 when including weekly DRS until week 4. Conclusion This study suggests that week 1 to 4 DRS may be predictors of favorable 6-mo outcome in severe TBI patients and thus useful both for clinical prognostication as well as surrogate endpoints for adaptive clinical trials.

Cellular therapy is a promising investigational modality to enhance poststroke recovery. We conducted a single-arm, phase I clinical trial to determine the safety and feasibility of intravenous (IV) administration of autologous bone marrow mononuclear cells (MNCs) after acute ischemic stroke (AIS). Patients with moderate severity of AIS underwent bone marrow harvest followed by IV reinfusion of MNCs within 24–72 hours of onset. A target dose of 10 million cells per kilogram was chosen based on preclinical data. Patients were followed up daily during hospitalization and at 1, 3, 6, 12, and 24 months for incidence of adverse events using laboratory, clinical (12 months), and radiological (24 months) parameters. The trial was powered to detect severe adverse events (SAEs) with incidences of at least 10% and planned to enroll 30 patients. Primary outcomes were study-related SAEs and the proportion of patients successfully completing study intervention. A propensity score-based matched control group was used for the estimation of effect size (ES) for day-90 modified Rankin score (mRS). There were no study-related SAEs and, based on a futility analysis, enrolment was stopped after 25 patients. All patients successfully completed study intervention and most received the target dose. Secondary analysis estimated the ES to be a reduction of 1 point (95% confidence interval: 0.33–1.67) in median day-90 mRS for treated patients as compared with the matched control group. Bone marrow harvest and infusion of MNCs is safe and feasible in patients with AIS. The estimated ES is helpful in designing future randomized controlled trials. Stem Cells 2019;37:1481–1491

Background Research regarding disparities in physical restraint use in the emergency department (ED) is limited. We evaluated the role of race, ethnicity, and preferred language on the application of physical restraint among ED patients held under a Massachusetts section 12(a) order for mandatory psychiatric evaluation. Methods We identified all ED patient encounters with a section 12(a) order across a large integrated 11-hospital health system from January 2018 through December 2019. Information on age, race, ethnicity, preferred language, insurance, mental illness, substance use, history of homelessness, and in-network primary care provider was obtained from the electronic health record. We evaluated for differences in physical restraint use between subgroups via a mixed-effect logistic regression with random-intercept model. Results We identified 32,054 encounters involving a section 12(a) order. Physical restraints were used in 2,458 (7.7%) encounters. Factors associated with physical restraint included male sex (adjusted odds ratio [aOR] = 1.44, 95% confidence interval [CI] = 1.28 to 1.63), Black/African American race (aOR = 1.22, 95% CI = 1.01 to 1.48), Hispanic ethnicity (aOR = 1.45, 95% CI = 1.22 to 1.73), Medicaid insurance (aOR = 1.21, 95% CI = 1.05 to 1.39), and a diagnosis of bipolar disorder or psychotic disorder (aOR = 1.51, 95% CI = 1.31 to 1.74). Across all age groups, patients who were 25 to 34 years of age were at highest risk of restraint (aOR = 2.01, 95% CI = 1.69 to 2.39). Patients with a primary care provider within our network (aOR = 0.81, 95% CI = 0.72 to 0.92) were at lower risk of restraint. No associations were found between restraint use and language, history of alcohol or substance use, or homelessness. Conclusion Black/African American and Hispanic patients under an involuntary mandatory emergency psychiatric evaluation hold order experience higher rates of physical restraint in the ED. Factors contributing to racial disparities in the use of physical restraint, including the potential role of structural racism and other forms of bias, merits further investigation.

Severe traumatic brain injury physiologically is a heterogeneous disorder that is characterized by a cascade of events from the “second-hit” phenomenon. The management of these patients is becoming increasingly sophisticated with the introduction of multimodal monitoring systems and better understanding of the complex interactions of the brain and other vital organs. Many of the traditional therapeutic options still lack level 1 evidence, however, this chapter is focused on the key therapeutic options that significantly impact the outcome of severe TBI patients.

Background Although theophylline has been shown to have anti-inflammatory effects, the therapeutic use of theophylline before sepsis is unknown. The aim of our study was to determine the effect of theophylline on COPD patients presenting with sepsis. Methods This nationwide, population-based, propensity score-matched analysis used data from the linked administrative databases of Taiwan's National Health Insurance program. Patients with COPD who were hospitalized for sepsis between 2000 and 2011 were divided into theophylline users and non-users. The primary outcome was 30-day mortality. The secondary outcome was in-hospital death, intensive care unit admission, and need for mechanical ventilation. Cox proportional hazard model and conditional logistic regression were used to calculate the risk between groups. Results A propensity score-matched cohort of 51,801 theophylline users and 51,801 non-users was included. Compared with non-users, the 30-day (HR 0.931, 95% CI 0.910–0.953), 180-day (HR 0.930, 95% CI 0.914–0.946), 365-day (HR 0.944, 95% CI 0.929–0.960) and overall mortality (HR 0.965, 95% CI 0.952–0.979) were all significantly lower in theophylline users. Additionally, the theophylline users also had lower risk of in-hospital death (OR 0.895, 95% CI 0.873–0.918) and need for mechanical ventilation (OR 0.972, 95% CI 0.949–0.997). Conclusions Theophylline use is associated with a lower risk of sepsis-related mortality in COPD patients. Pre-hospital theophylline use may be protective to COPD patients with sepsis.

Background. Patients with SCD now usually live well into adulthood. Whereas transitions into adulthood are now often studied, little is published about aging beyond the transition period. We therefore studied age-associated SCD differences in utilization, pain, and psychosocial variables.Methods. Subjects were 232 adults in the Pain in Sickle Cell Epidemiology Study (PiSCES). Data included demographics, comorbidity, and psychosocial measures. SCD-related pain and health care utilization were recorded in diaries. We compared 3 age groups: 16–25 (transition), 26–36 (younger adults), and 37–64 (older adults) years.Results. Compared to the 2 adult groups, the transition group reported fewer physical challenges via comorbidities, somatic complaints, and pain frequency, though pain intensity did not differ on crisis or noncrisis pain days. The transition group utilized opioids less often, made fewer ambulatory visits, and had better quality of life, but these differences disappeared after adjusting for pain and comorbidities. However, the transition group reported more use of behavioral coping strategies.Conclusion. We found fewer biological challenges, visits, and better quality of life, in transition-aged versus older adults with SCD, but more behavioral coping. Further study is required to determine whether age-appropriate health care, behavioral, or other interventions could improve age-specific life challenges of patients with SCD.

Background Pneumonia is the leading cause of sepsis. In 2016, the 3rd International Consensus Conference for Sepsis released the Quick Sepsis-Related Organ Failure Assessment (qSOFA) to identify risk for poor outcomes in sepsis. Objective We sought to externally validate qSOFA in emergency department (ED) patients with pneumonia and compare the accuracy of qSOFA to systemic inflammatory response syndrome score (SIRS), Confusion, Respiratory Rate and Blood Pressure (CRB), Confusion, Respiratory Rate, Blood Pressure and Age (CRB-65), and DS CRB-65, which is based on the CRB-65 score and includes two additional items-presence of underlying comorbid disease and blood oxygen saturation. Methods A subgroup analysis of U.S. Critical Illness and Injury Trials Group (USCIITG-Lung Injury Prevention Study [LIPS]; ClinicalTrials.gov ID: NCT00889772) prospective cohort. The primary outcome was in-hospital mortality. Secondary outcomes were measures of intensive care unit (ICU) utilization. Sensitivity, specificity, and area under the curve (AUC) were reported. Results From March to August 2009, 5584 patients were enrolled; 713 met inclusion criteria. Median age was 61 years (interquartile range 49-75 years). SIRS criteria had the highest sensitivity for death (89%) and lowest specificity (25%), while CRB had the highest specificity (88%) and lowest sensitivity (31%), followed by qSOFA (80% and 53%, respectively). This trend was maintained for the secondary outcomes. There was no significant difference in the AUC for death using qSOFA (AUC 0.75; 95% confidence interval [CI] 0.66-0.84), SIRS (AUC 0.70; 95% CI 0.61-0.78), CRB (AUC 0.71; 95% CI 0.62-0.80), CRB-65 (AUC 0.71; 95% CI 0.63-0.80), and DS CRB-65 (AUC 0.73; 95% CI 0.64-0.82). Conclusions In this multicenter observational study of ED patients hospitalized with pneumonia, we found no significant differences between qSOFA and SIRS for predicting in-hospital death. In addition, several popular pneumonia-specific severity scores performed nearly identically to qSOFA score in predicting death and ICU utilization. Validation is needed in a larger sample.

The original unstructured Glasgow Outcome Scale (uGOS) and the newer structured interviews GOS and the Extended GOS (GOS-E) have been used widely as outcomes in severe traumatic brain injury (TBI) trials. We compared outcome categories (ranging from dead [D] to good recovery [GR]) for each measure in a randomized trial of transfusion threshold and the implications of measure choice and analysis methods for the results of the trial. We planned to explore patient symptomology possibly driving any discrepancies between the patient's uGOS and GOS scores. Category correspondence between uGOS and GOS scores occurred in 160 (88.4%) of the 181 analyzed cases. The GOS-E and GOS instruments incorporated more behavioral/cognitive/social and other components, leading to a worse outcome in some cases than for the uGOS. Choice of outcome measure and analysis led to incongruous conclusions. Dichotomizing uGOS into favorable outcome (GR and moderate disability [MD] categories) versus unfavorable (severe disability [SD], vegetative state [VS], and D categories), we observed a significant effect of transfusion threshold (odds ratio [OR] = 0.51, p = 0.03; adjusted OR = 0.40, p = 0.02). For the same dichotomization of GOS and GOS-E, the effect was not statistically significant but the ORs were similar (ORs between 0.57 and 0.68, p > 0.15 for all). An effect was not detected using ordinal logistic regression or sliding dichotomy method for all three measures. Differences in categorizations of subjects between moderate and severe disability among the scales impacted conclusions of the trial. In future studies, particular attention should be given to implementing GOS measures and describing the methodology for how outcomes were ascertained.

Objectives:Long-term neurological response to treatment after a severe traumatic brain injury (sTBI) is a dynamic process. Failure to capture individual heterogeneity in recovery may impact findings from single endpoint sTBI randomized controlled trials (RCT). The present study re-examined the efficacy of erythropoietin (Epo) and transfusion thresholds through longitudinal modeling of sTBI recovery as measured by the Disability Rating Scale (DRS). This study complements the report of primary outcomes in the Epo sTBI RCT, which failed to detect significant effects of acute treatment at 6 months post-injury.Methods:We implemented mixed effects models to characterize the recovery time-course and to examine treatment efficacy as a function of time post-injury and injury severity.Results:The inter-quartile range (25th–75thpercentile) of DRS scores was 20–28 at week1; 8–24 at week 4; and 3–17 at 6 months. TBI severity group was found to significantly interact with Epo randomization group on mean DRS recovery curves. No significant differences in DRS recovery were found in transfusion threshold groups.Conclusions:This study demonstrated the value of taking a comprehensive view of recovery from sTBI in the Epo RCT as a temporally dynamic process that is shaped by both treatment and injury severity, and highlights the importance of the timing of primary outcome measurement. Effects of Epo treatment varied as a function of injury severity and time. Future studies are warranted to understand the possible moderating influence of injury severity on treatment effects pertaining to sTBI recovery. (JINS, 2019,25, 293–301)

Preclinical studies using bone marrow derived cells to treat traumatic brain injury have demonstrated efficacy in terms of blood–brain barrier preservation, neurogenesis, and functional outcomes. Phase 1 clinical trials using bone marrow mononuclear cells infused intravenously in children with severe traumatic brain injury demonstrated safety and potentially a central nervous system structural preservation treatment effect. This study sought to confirm the safety, logistic feasibility, and potential treatment effect size of structural preservation/inflammatory biomarker mitigation in adults to guide Phase 2 clinical trial design. Adults with severe traumatic brain injury (Glasgow Coma Scale 5–8) and without signs of irreversible brain injury were evaluated for entry into the trial. A dose escalation format was performed in 25 patients: 5 controls, followed 5 patients in each dosing cohort (6, 9, 12 ×106 cells/kg body weight), then 5 more controls. Bone marrow harvest, cell processing to isolate the mononuclear fraction, and re-infusion occurred within 48 hours after injury. Patients were monitored for harvest-related hemodynamic changes, infusional toxicity, and adverse events. Outcome measures included magnetic resonance imaging-based measurements of supratentorial and corpus callosal volumes as well as diffusion tensor imaging-based measurements of fractional anisotropy and mean diffusivity of the corpus callosum and the corticospinal tract at the level of the brainstem at 1 month and 6 months postinjury. Functional and neurocognitive outcomes were measured and correlated with imaging data. Inflammatory cytokine arrays were measured in the plasma pretreatment, posttreatment, and at 1 and 6 month follow-up. There were no serious adverse events. There was a mild pulmonary toxicity of the highest dose that was not clinically significant. Despite the treatment group having greater injury severity, there was structural preservation of critical regions of interest that correlated with functional outcomes. Key inflammatory cytokines were downregulated. Treatment of severe, adult traumatic brain injury using an intravenously delivered autologous bone marrow mononuclear cell infusion is safe and logistically feasible. There appears to be a treatment signal as evidenced by central nervous system structural preservation, consistent with previous pediatric trial data. Inflammatory biomarkers are downregulated after cell infusion. Video Highlight: https://youtu.be/UiCCPIe-IaQ Stem Cells 2017;35:1065–1079

We sought to determine the outcome of suicidal hanging and the impact of targeted temperature management (TTM) on hanging-induced cardiac arrest (CA) through an Eastern Association for the Surgery of Trauma (EAST) multicenter retrospective study.We analyzed hanging patient data and TTM variables from January 1992 to December 2015. Cerebral performance category score of 1 or 2 was considered good neurologic outcome, while cerebral performance category score of 3 or 4 was considered poor outcome. Classification and Regression Trees recursive partitioning was used to develop multivariate predictive models for survival and neurologic outcome.A total of 692 hanging patients from 17 centers were analyzed for this study. Their overall survival rate was 77%, and the CA survival rate was 28.6%. The CA patients had significantly higher severity of illness and worse outcome than the non-CA patients. Of the 175 CA patients who survived to hospital admission, 81 patients (46.3%) received post-CA TTM. The unadjusted survival of TTM CA patients (24.7% vs 39.4%, p0.05) and good neurologic outcome (19.8% vs 37.2%, p0.05) were worse than non-TTM CA patients. However, when subgroup analyses were performed between those with an admission Glasgow Coma Scale score of 3 to 8, the differences between TTM and non-TTM CA survival (23.8% vs 30.0%, p = 0.37) and good neurologic outcome (18.8% vs 28.7%, p = 0.14) were not significant. Targeted temperature management implementation and post-CA management varied between the participating centers. Classification and Regression Trees models identified variables predictive of favorable and poor outcome for hanging and TTM patients with excellent accuracy.Cardiac arrest hanging patients had worse outcome than non-CA patients. Targeted temperature management CA patients had worse unadjusted survival and neurologic outcome than non-TTM patients. These findings may be explained by their higher severity of illness, variable TTM implementation, and differences in post-CA management. Future prospective studies are necessary to ascertain the effect of TTM on hanging outcome and to validate our Classification and Regression Trees models.Therapeutic study, level IV; prognostic study, level III.

OBJECTIVETraumatic brain injury (TBI) is a major cause of morbidity and mortality. Multiple organ dysfunction syndrome (MODS) occurs frequently after TBI and independently worsens outcome. The present study aimed to identify potential admission characteristics associated with post-TBI MODS.METHODSThe authors performed a secondary analysis of a recent randomized clinical trial studying the effects of erythropoietin and blood transfusion threshold on neurological recovery after TBI. Admission clinical, demographic, laboratory, and imaging parameters were used in a multivariable Cox regression analysis to identify independent risk factors for MODS following TBI, defined as maximum total Sequential Organ Failure Assessment (SOFA) score > 7 within 10 days of TBI.RESULTSTwo hundred patients were initially recruited and 166 were included in the final analysis. Respiratory dysfunction was the most common nonneurological organ system dysfunction, occurring in 62% of the patients. International Mission for Prognosis and Analysis of Clinical Trials (IMPACT) probability of poor outcome at admission was significantly associated with MODS following TBI (odds ratio [OR] 8.88, 95% confidence interval [CI] 1.94–42.68, p < 0.05). However, more commonly used measures of TBI severity, such as the Glasgow Coma Scale, Injury Severity Scale, and Marshall classification, were not associated with post-TBI MODS. In addition, initial plasma concentrations of interleukin (IL)–6, IL-8, and IL-10 were significantly associated with the development of MODS (OR 1.47, 95% CI 1.20–1.80, p < 0.001 for IL-6; OR 1.26, 95% CI 1.01–1.58, p = 0.042 for IL-8; OR 1.77, 95% CI 1.24–2.53, p = 0.002 for IL-10) as well as individual organ dysfunction (SOFA component score ≥ 1). Finally, MODS following TBI was significantly associated with mortality (OR 5.95, 95% CI 2.18–19.14, p = 0.001), and SOFA score was significantly associated with poor outcome at 6 months (Glasgow Outcome Scale score < 4) when analyzed as a continuous variable (OR 1.21, 95% CI 1.06–1.40, p = 0.006).CONCLUSIONSAdmission IMPACT probability of poor outcome and initial plasma concentrations of IL-6, IL-8, and IL-10 were associated with MODS following TBI.

Background: Although opioid prescribing in sickle cell disease (SCD) can be controversial, little is published about patterns of opioid use. Objective: To report on home opioid use among adults with SCD. Design: Cohort study. Participants: Adults with SCD (n = 219) who completed daily pain diaries for up to 6 months and had at least one home pain day. Main measures: Use of long-acting or short-acting opioids, other analgesics, or adjuvants; the proportion of home days, home pain days, and home crisis days with opioid use; these two outcomes according to patient characteristics. Key results: Patients used opioids on 12,311 (78 percent) of 15,778 home pain days. Eighty-five patients (38.8 percent) used long-acting opioids with or without short-acting opioids and 103 (47.0 percent) used only short-acting opioids. Twenty-one (9.6 percent) patients used only non-opioid analgesics and 10 (4.6 percent) used no analgesics. Both pain intensity and pain frequency were higher among opioid users (analysis of variance [ANOVA], p < 0.0001). Opioid users used hydroxyurea more often than nonusers, even when controlling for mean pain on pain days. Among all patients, significant relationships were found between any opioid use and somatic symptom burden, SCD stress, negative coping, and physical and mental quality of life (QOL); the relationship with SCD stress and physical QOL remained when controlled for mean pain. Among opioid users, similar associations were found between frequency of opioid use and some disease-related and psychosocial variables. Conclusions: In this adult SCD sample, opioids were used by the majority of patients. Pain was the overwhelming characteristic associated with use, but disease-related and psychosocial variables were also associated.

Background Pain diary assessment in sickle cell disease (SCD) may be expensive and impose a high respondent burden. Objective To report whether intermittent assessment could substitute for continuous daily pain assessment in SCD. Design Prospective cohort study. Setting Academic and community practices in Virginia. Patients. A total of 125 SCD patients age 16 years or older in the Pain in Sickle Cell Epidemiology Study. Measurements. Using pain measures that summarized all diaries as the gold standard, we tested the statistical equivalence of four alternative strategies that summarized diaries only from the week prior or the month prior to study completion; one week per month; or one day per week (random day). Summary measures included percent pain days, percent crisis days (self-defined), mean pain (0-9 Likert scale) on all days, and mean pain on pain days. Equivalence tests included comparisons of means, regression intercepts, and slopes, as well as measurement of R2. Results Compared with the gold standard, the one-day-per-week and one-week-per-month strategies yielded statistically equivalent means of six summary pain measures, and the week prior and month prior yielded equivalent means as some of the measures. Regression showed statistically equivalent slopes and intercepts to the gold standard using one-day-per-week and one-week-per-month strategies for percent pain days and percent crisis days, but almost no other equivalence. R2 values ranged from 0.64 to 0.989. Conclusions It is possible to simulate five- to six-month daily assessment of pain in SCD. Either one-day-per-week or one-week-per-month assessment yields an equivalent mean and fair regression equivalence.

Sepsis-3 has generated a significant amount of debate and controversy since its introduction. Specifically, Sepsis-3 introduced qSOFA as a new terminology for identifying at risk patients for sepsis.

Background: This retrospective study evaluated the use of a smartphone application to facilitate communication between the emergency physician (EP) and the interventional cardiologist in order to minimize the time to cardiac catheterization laboratory (CCL) activation and time to percutaneous coronary intervention (PCI). Methods: We retrospectively collected pertinent time-points in the management of patients diagnosed with STEMI in the emergency department and their outcome. The primary outcome was the reduction in the time from ECG interpretation to CCL activation after the implementation of a smartphone application. A total of 84 patients were enrolled. Patients' electrocardiography (ECG) were described by traditional verbal communication via telephone (group 1, n = 40) and by additional smartphone transmission of ECG images to an interventional cardiologist (group 2, n = 44). Relevant time-points were recorded for analysis. Results: The time from ECG interpretation to CCL activation was reduced from 28.3 ± 4.1 in group 1 to 17.6 ± 2.3 min in group 2 (p = 0.03). Similarly, the time from ECG interpretation to balloon inflation time (D2B) decreased from 93.1 to 73.4 min (p = 0.025). Comparing group 2 with group 1, the door to balloon (D2B) time improved to 90.4 ± 9.8 from 119.3 ± 16.3 min (p = 0.23), the proportion of patients with a D2B time less than 90 min increased to 70.5% from 52.5% (p = 0.09), and the mortality rate decreased to 2.2% from 12.5% (p = 0.07). Conclusion: The additional use of a smartphone application to transmit ECG information to interventional cardiologists by EPs facilitated communication and reduced the decision time to CCL activation and percutaneous intervention. Keywords: Cardiac catheterization laboratory, Electrocardiography, Percutaneous coronary intervention

Summary Background The aim of this study is to investigate the "weekend effect" and early mortality of patients with severe sepsis. Methods Using the Taiwanese National Healthcare Insurance Research Database, all patients who were hospitalized for the first time with an episode of severe sepsis between January 2000 and December 2011 were identified and the short-term mortality of patients admitted on weekdays was compared to those admitted on weekends. The primary endpoint was 7-day mortality. The secondary endpoints were 14 and 28-day mortality. Results A total of 398,043 patients were identified to have had the diagnosis of severe sepsis. Compared with patients admitted on weekends, patients admitted on weekdays had a lower 7-day mortality rate (adjusted odds ratio [OR] 0.89, 95% confidential interval [CI] 0.87–0.91), 14-day mortality rate (adjusted OR 0.92, 95% CI 0.90–0.93), and 28-day mortality rate (adjusted OR 0.97, 95% CI 0.95–0.98). This "weekend effect" was maintained every year throughout the 11-year study period. Conclusions Patients with severe sepsis are more likely to die in the hospital if they were admitted on weekends than if they were admitted on weekdays.

Background Sepsis is a major risk factor for acute respiratory distress syndrome (ARDS). However, there remains a paucity of literature examining risk factors for ARDS in septic patients early in their course. This study examined the role of early fluid administration and identified other risk factors within the first 6 h of hospital presentation associated with developing ARDS in septic patients. Methods This was a secondary analysis of septic adult patients presenting to the Emergency Department or being admitted for high-risk elective surgery from the multicenter observational cohort study, US Critical Injury and Illness trial Group-Lung Injury Prevention Study 1 (USCIITG-LIPS 1, NCT00889772). Multivariable logistic regression was performed to identify potential early risk factors for ARDS. Stratified analysis by shock status was performed to examine the association between early fluid administration and ARDS. Results Of the 5584 patients in the original study cohort, 2534 (45.4%) met our criteria for sepsis. One hundred and fifty-six (6.2%) of these patients developed ARDS during the hospital stay. In multivariable analyses, Acute Physiology and Chronic Health Evaluation (APACHE) II score (OR 1.10, 95% CI 1.07–1.13), age (OR 0.97, 95% CI 0.96–0.98), total fluid infused in the first 6 h (in liters) (OR 1.15, 95% CI 1.03–1.29), shock (OR 2.57, 95% CI 1.62–4.08), pneumonia as a site of infection (OR 2.31, 95% CI 1.59–3.36), pancreatitis (OR 3.86, 95% CI 1.33–11.24), and acute abdomen (OR 3.77, 95% CI 1.37–10.41) were associated with developing ARDS. In the stratified analysis, total fluid infused in the first 6 h (in liters) (OR 1.05, 95% CI 0.87–1.28) was not associated with the development of ARDS in the shock group, while there was an association in the non-shock group (OR 1.21, 95% CI 1.05–1.38). Conclusions In septic patients, the following risk factors identified within the first 6 h of hospital presentation were associated with ARDS: APACHE II score, presence of shock, pulmonary source of infection, pancreatitis, and presence of an acute abdomen. In septic patients without shock, the amount of fluid infused during the first 6 h of hospital presentation was associated with developing ARDS. Electronic supplementary material The online version of this article (doi:10.1186/s13613-017-0233-1) contains supplementary material, which is available to authorized users.

Background: Based on the current literature, it is unclear whether advanced age itself leads to higher mortality in critically ill patients or whether it is due to the greater number of comorbidities in the elderly patients. We hypothesized that increasing age would increase the odds of short-term and long-term mortality after adjusting for baseline comorbidities in intensive care unit (ICU) patients. Methods: We performed a retrospective cohort study of 57 160 adults admitted to any ICU over 5 years at 2 academic tertiary care centers. Patients were divided into age-groups, 18 to 39, 40 to 59, 60 to 79, and ≥80. The primary outcomes were 30-day and 365-day mortality. Results were analyzed with multivariate logistic regression adjusting for demographics and the Elixhauser-van Walraven Comorbidity Index. Results: The adjusted 30-day mortality odds ratios (ORs) were 1.39 (95% confidence interval [CI]: 1.21-1.60), 2.00 (95% CI: 1.75-2.28), and 3.33 (95% CI: 2.90-3.82) for age-groups 40 to 59, 60 to 79, and ≥80, respectively, using the age-group 18 to 39 as the reference. The adjusted 365-day mortality ORs were 1.46 (95% CI: 1.32-1.61), 2.10 (95% CI: 1.91-2.31), and 2.96 (95% CI: 2.67-3.27). Conclusion: In critically ill patients, increasing age is associated with higher odds of short-term and long-term death after correcting for existing comorbidities.

The incidence of adult respiratory distress syndrome (ARDS) in severe traumatic brain injury (TBI) is poorly reported. Recently, a new definition for ARDS was proposed, the Berlin definition. The percentage of patients represented by TBI in the Berlin criteria study is limited. This study describes the incidence and associated mortality of ARDS in TBI patients.The study was an analysis of the safety of erythropoietin administration and transfusion threshold on the incidence of ARDS in severe TBI patients. Three reviewers independently assessed all patients enrolled in the study for acute lung injury/ARDS using the Berlin and the American-European Consensus Conference (AECC) definitions. A Cox proportional hazards model was used to assess the relationship between ARDS and mortality and 6-month Glasgow Outcome Scale (GOS) score.Two hundred patients were enrolled in the study. Of the patients, 21% (41 of 200) and 26% (52 of 200) developed ARDS using the AECC and Berlin definitions, respectively, with a median time of 3 days (interquartile range, 3) after injury. ARDS by either definition was associated with increased mortality (p = 0.04) but not with differences in functional outcome as measured by the GOS score at 6 months. Adjusted analysis using the Berlin criteria showed an increased mortality associated with ADS (p = 0.01).Severe TBI is associated with an incidence of ARDS ranging from 20% to 25%. The incidence is comparable between the Berlin and AECC definitions. ARDS is associated with increased mortality in severe TBI patients, but further studies are needed to validate these findings.Epidemiologic study, level II.

Treatment options for sickle cell disease (SCD) pain could be tailored to pain locations. But few epidemiologic descriptions of SCD pain location exist; these are based on few subjects over short time periods. We examined whether SCD pain locations vary by disease genotype, gender, age, frequency of pain, depression, pain crisis or healthcare utilization. We enrolled 308 adults with SCD in 2002-2004. Subjects kept daily pain diaries for up to 6months, including a body chart. Mixed model and generalized estimating equations were employed for analyses. Two hundred and sixty subjects completed at least one body chart. An average of 3.3/16 sites (25%) were painful. The number of pain sites varied by age, depression, frequent pain days, crisis and unplanned hospital/ED utilization. Lower back, knee/shin and hip, hurt on average more than a third of pain days, while jaw and pelvis hurt on fewer than 10% of days. Odds of a crisis were increased substantially when pain was in the arm, shoulder, upper back, sternum, clavicle, chest or pelvis (OR>1.5) while the odds of unplanned utilization were substantially increased for the sternum, clavicle and chest (OR>2.0). Pain in SCD varies considerably both within and between subjects, although it occurs most commonly in the lower back and lower extremities. The number and location of pain sites vary significantly by age, frequent pain, crisis and utilization. Identification and understanding of combinations of pain location and intensity may help to understand the etiology of SCD and improve SCD management.

Study objective Patients with sickle cell disease often receive a substantial amount of their health care in the emergency department (ED) and some come to the ED frequently, seeking treatment for pain. As a result, patients with sickle cell disease are often stigmatized as opioid-seeking ED overutilizers. We describe the proportion of sickle cell disease patients who are high utilizers of the ED and compare them with other sickle cell disease patients on demographics, pain characteristics, health data, psychosocial characteristics, and quality of life. Methods Two hundred thirty-two patients completed baseline data and at least 30 days of daily diary data. Baseline data included demographics, health data, and quality of life (Medical Outcome Study 36 Item Short Form). Daily diary data included ED utilization for sickle cell pain and descriptors of pain and distress. Results Eighty-two (35.5%) patients were found to be high ED utilizers. Clinically important and statistically significant differences were found between high ED utilizers and all other sickle cell disease patients: lower hematocrit level, more transfusions, more pain days, more pain crises, higher mean pain and distress, and worse quality of life on Medical Outcome Study 36 Item Short Form physical function summary scales. After controlling for severity and frequency of pain, high ED utilizers did not use opioids more frequently than other sickle cell disease patients. Conclusion A substantial minority of sickle cell disease patients are high ED utilizers. However, high ED utilizers with sickle cell disease are more severely ill as measured by laboratory variables, have more pain, more distress, and have a lower quality of life.

OBJECTIVE Depression and anxiety are common in sickle cell disease (SCD) but relatively little is known about their impact on SCD adults. This study measured prevalence of depression and anxiety in SCD adults, and their effects on crisis and noncrisis pain, quality-of-life, opioid usage, and healthcare utilization. METHODS The Pain in Sickle Cell Epidemiology Study is a prospective cohort study in 308 SCD adults. Baseline variables included demographics, genotype, laboratory data, health-related quality-of-life, depression, and anxiety. Subjects completed daily diaries for up to 6 months, reporting sickle cell pain intensity, distress, interference, whether they were in a sickle cell crisis, as well as health care and opioid utilization. RESULTS Two hundred thirty-two subjects who completed at least 1 month of diaries were studied; 27.6% were depressed and 6.5% had any anxiety disorder. Depressed subjects had pain on significantly more days than nondepressed subjects (mean pain days 71.1% versus 49.6%, p < .001). When in pain on noncrisis days, depressed subjects had higher mean pain, distress from pain, and interference from pain. Both depressed and anxious subjects had poorer functioning on all eight SF-36 subscales, even after controlling for demographics, hemoglobin type, and pain. The anxious subjects had more pain, distress from pain, and interference from pain, both on noncrisis pain days and on crisis days, and used opioids more often. CONCLUSIONS Depression and anxiety predicted more daily pain and poorer physical and mental quality-of-life in adults with SCD, and accounted for more of the variance in all domains of quality-of-life than hemoglobin type.

Alcohol abuse is common in patients with chronic painful medical disorders, but it has not been studied in sickle cell disease (SCD). In a prospective cohort study of SCD adults, 31.4% were identified as abusing alcohol. There were no significant differences between alcohol abusers and nonabusers on demographics, biological variables, depression, anxiety, measures of crisis and noncrisis pain, or opioid use, but abusers reported more pain relief from opioids than nonabusers did. Alcohol abusers had fewer unscheduled clinic visits, emergency room visits, hospital days, and any health care utilization for SCD, but this was only significant for emergency room visits. Quality of life was similar between both groups, except that alcohol abusers unexpectedly had better overall physical summary scores. Alcohol abusers were more likely to report coping by ignoring pain, diverting attention, and using particular self-statements.

Cerebral dysfunction caused by traumatic brain injury may adversely affect cerebral hemodynamics and oxygenation leading to worse outcomes if oxygen capacity is decreased due to anemia. In a randomized clinical trial of 200 patients comparing transfusion thresholds

Many studies have found gender differences in frequency and intensity of pain. Women often report lower pain thresholds, higher pain ratings, and lower tolerance for pain. People with sickle cell disease (SCD) experience both chronic and acute pain throughout life.To compare adult men and women with SCD in terms of reported pain, crises, healthcare utilization, and opioid usage.Two hundred twenty-six adults with SCD in Virginia were enrolled in a prospective cohort study of pain and completed daily diaries for 1-6 months. Subjects reported for the previous day their maximum SCD-related pain, distress, and interference (0-9 scale), whether they were in a sickle cell crisis, had unplanned utilization (clinic, emergency room, or hospitalization), or used opioids. Episodes of pain, crisis, or utilization were defined as consecutive days of such. Men and women were compared, using analysis of covariance (ANCOVA), controlling for age, SCD genotype, depression, and education.There were no significant differences between men and women in the percentage of days subjects experienced pain (men 58.6% vs. women 56.5%) or the number of pain episodes/6 months (7.7 vs. 9.6). Mean pain scores were comparable, when subjects were in crisis (5.5 vs. 5.6) or not (2.5 vs. 2.2). Distress and interference results were similar. Men with the SS genotype reported a higher percentage of days with crisis(18.5% vs. 11.6%) and utilization (5.1% vs. 2.7%) than women with the SS genotype.Contrary to many studies of pain, particularly chronic pain, men and women with SCD reported generally similar pain experiences.

Patients presenting to the emergency department with heart failure are evaluated based on the subjective sensation of dyspnea. In this study, the authors sought to determine the change in dyspnea, measured by a visual analog scale (VAS), which is associated with a meaningful change in the patient's perception and the effect of dyspnea severity on the VAS. In this prospective, observational study the authors defined a meaningful change in VAS dyspnea as the difference between VAS scores when patients reported "a little less difficulty breathing" or "a little more difficulty breathing." Seventy-four patients were evaluated, and the mean for a meaningful change in VAS was 21.1 mm (95% confidence interval, 12.3-29.9 mm). Patients that recorded higher index VAS scores had a significantly greater change in VAS. VAS scores and the changes with treatment provide the treating physician with another means to assess the effects of their interventions.

Seizures are a common presentation in the prehospital and emergency department setting and status epilepticus represents an emergency neurologic condition. The classification and various types of seizures are numerous. The objectives of this narrative literature review focuses on adult patients with a presentation of status epilepticus in the prehospital and emergency department setting. In summary, benzodiazepines remain the primary first line therapeutic agent in the management of status epilepticus, however, there are new agents that may be appropriate for the management of status epilepticus as second- and third-line pharmacological agents.

BACKGROUND: Sickle cell disease (SCD) patients can receive their ambulatory care from either SCD specialists (caregivers with sickle cell-only clinics) or nonspecialized care centers. Patient satisfaction, an important factor that may influence compliance and outcome, can differ between the two groups because of the perceived quality of care, outcomes or practice style. METHODS: We administered a patient satisfaction survey to 308 participants in an SCD prospective cohort study. Of the 308 patients, 133 (43.2%) received the majority of their SCD care at specialized centers, 152 (49.3%) received their care from nonspecialized centers and 26 (7.5) did not provide information. The satisfaction surveys measured general satisfaction (GS), technical quality (TQ), interpersonal manner (IM), communication (CM), financial aspects (FA), time spent with doctor (TA), and accessibility and convenience (AC). Patients reported their levels of satisfaction using a five-point Likert scale. We compared unadjusted group means, as well as means adjusted for potential confounders such as marital status, on patient satisfaction between specialized and nonspecialized centers. RESULTS: SCD patients who received their care from specialized centers had significantly higher mean satisfaction scores, compared to those who received their care from nonspecialized centers: GS 4.00(+/-0.93) vs. 3.66 (+/- 01.16, p=0.0326), TQ 3.98 (+/- 0.77) vs. 3.65 (+/- 0.91, p=0.0058), AC 3.83 (+/-0.79) vs. 3.51 (+/- 1.02, p=0.0142) , FA 3.88 (+/-0.96) vs. 3.49 (+/-1.25, p=0.0120). There were no statistically significant group differences in IM, TA and CM. CONCLUSION: SCD patients who received most of their SCD care from specialized centers had somewhat higher satisfaction scores in some areas when compared with patients who received their care from nonspecialized centers.

In several types of chronic pain, catastrophizing has been related to higher pain intensity, and health care utilization but it has not been explored extensively in sickle cell disease (SCD). The objective of the study was to identify the role of catastrophizing in SCD, specifically in relation to painful crises, non-crisis pain, and responses to pain. Two hundred and twenty SCD adults were enrolled in a prospective cohort study of pain and completed between 30 and 188 daily diaries in 6 months. The Catastrophizing subscale (CAT) of the Coping Strategy Questionnaire (CSQ) was administered at baseline and at study exit. Depression and quality of life were measured by the Patient Health Questionnaire and SF-36, respectively, at baseline. The CAT mean was 13.6 (SD=8.4) and higher CAT was correlated with greater depression severity (r=0.48; p0.001) and poorer quality of life in all domains (r=-0.24 to -0.47; p0.001). There was no significance difference between CAT mean baseline and exit scores, and the measures were strongly correlated within patients (r=0.69; p0.001). No difference was found between higher and lower catastrophizers in intensity of pain, distress, interference, and health service utilization, both on crisis or non-crisis SCD-related pain days, after controlling for depression. Adults with SCD had a higher mean catastrophizing score than found in studies of other chronic pain conditions that are not lifelong and life-threatening. CAT scores were not correlated with pain parameters or utilization. The role of catastrophizing in other conditions cannot be generalized to SCD.

Background Sickle cell disease (SCD) is a chronic disease associated with high degrees of morbidity and increased mortality. Health-related quality of life (HRQOL) among adults with sickle cell disease has not been widely reported. Methods We administered the Medical Outcomes Study 36-item Short-Form to 308 patients in the Pain in Sickle Cell Epidemiology Study (PiSCES) to assess HRQOL. Scales included physical function, physical and emotional role function, bodily pain, vitality, social function, mental health, and general health. We compared scores with national norms using t-tests, and with three chronic disease cohorts: asthma, cystic fibrosis and hemodialysis patients using analysis of variance and Dunnett's test for comparison with a control. We also assessed whether SCD specific variables (genotype, pain, crisis and utilization) were independently predictive of SF-36 subscales, controlling for socio-demographic variables using regression. Results Patients with SCD scored significantly worse than national norms on all subscales except mental health. Patients with SCD had lower HRQOL than cystic fibrosis patients except for mental health. Scores were similar for physical function, role function and mental health as compared to asthma patients, but worse for bodily pain, vitality, social function and general health subscales. Compared to dialysis patients, sickle cell disease patients scored similarly on physical role and emotional role function, social functioning and mental health, worse on bodily pain, general health and vitality and better on physical functioning. Surprisingly, genotype did not influence HRQOL except for vitality. However, scores significantly decreased as pain levels increased. Conclusion SCD patients experience health related quality of life worse than the general population, and in general, their scores were most similar to patients undergoing hemodialysis. Practitioners should regard their HRQOL as severely compromised. Interventions in SCD should consider improvements in health related quality of life as important outcomes.

Until recent decades, sickle cell disease (SCD) was associated with recurrent, disabling pain, organ failure and death in childhood or early adulthood. SCD treatment advances have now decreased pain and prolonged survival, but episodic or chronic pain may still require substantial analgesic use and frequent hospitalization for pain episodes. This pain is poorly characterized and often poorly treated. Adult patients may face barriers to comprehensive SCD care, stigmatization of their care-seeking behavior by providers and lack of family support, forcing them into maladaptive coping strategies. The Pain in Sickle Cell Epidemiology Study (PiSCES) attempts to develop and validate a biopsychosocial model of SCD pain, pain response and healthcare utilization in a large, multisite adult cohort. PiSCES participants complete a baseline survey and six months of daily pain diaries in which they record levels of SCD-related pain and related disability and distress as well as responses to pain (e.g., medication use, hospital visits). PiSCES will advance methods of measuring pain and pain response in SCD by better describing home-managed as well as provider-managed pain. PiSCES will assess the relative contributions of biological (disease-related), psychosocial and environmental (readiness to utilize) factors to overall pain and pain response in SCD, suggesting targets for biobehavioral interventions over time. Importantly, PiSCES will also identify "triggers" of SCD pain episodes and healthcare utilization in the moment of pain, suggesting targets for timely care that mutes pain episodes.

Importance There is limited information about the effect of erythropoietin or a high hemoglobin transfusion threshold after a traumatic brain injury. Objective To compare the effects of erythropoietin and 2 hemoglobin transfusion thresholds (7 and 10 g/dL) on neurological recovery after traumatic brain injury. Design, Setting, and Participants Randomized clinical trial of 200 patients (erythropoietin, n = 102; placebo, n = 98) with closed head injury who were unable to follow commands and were enrolled within 6 hours of injury at neurosurgical intensive care units in 2 US level I trauma centers between May 2006 and August 2012. The study used a factorial design to test whether erythropoietin would fail to improve favorable outcomes by 20% and whether a hemoglobin transfusion threshold of greater than 10 g/dL would increase favorable outcomes without increasing complications. Erythropoietin or placebo was initially dosed daily for 3 days and then weekly for 2 more weeks (n = 74) and then the 24- and 48-hour doses were stopped for the remainder of the patients (n = 126). There were 99 patients assigned to a hemoglobin transfusion threshold of 7 g/dL and 101 patients assigned to 10 g/dL. Interventions Intravenous erythropoietin (500 IU/kg per dose) or saline. Transfusion threshold maintained with packed red blood cells. Main Outcomes and Measures Glasgow Outcome Scale score dichotomized as favorable (good recovery and moderate disability) or unfavorable (severe disability, vegetative, or dead) at 6 months postinjury. Results There was no interaction between erythropoietin and hemoglobin transfusion threshold. Compared with placebo (favorable outcome rate: 34/89 [38.2%; 95% CI, 28.1% to 49.1%]), both erythropoietin groups were futile (first dosing regimen: 17/35 [48.6%; 95% CI, 31.4% to 66.0%], P = .13; second dosing regimen: 17/57 [29.8%; 95% CI, 18.4% to 43.4%], P P = .28). There was a higher incidence of thromboembolic events for the transfusion threshold of 10 g/dL (22/101 [21.8%] vs 8/99 [8.1%] for the threshold of 7 g/dL, odds ratio, 0.32 [95% CI, 0.12 to 0.79], P = .009). Conclusions and Relevance In patients with closed head injury, neither the administration of erythropoietin nor maintaining hemoglobin concentration of greater than 10 g/dL resulted in improved neurological outcome at 6 months. The transfusion threshold of 10 g/dL was associated with a higher incidence of adverse events. These findings do not support either approach in this setting. Trial Registration clinicaltrials.gov Identifier:NCT00313716

Researchers of sickle cell disease have traditionally used health care utilization as a proxy for pain and underlying vaso-occlusion. However, utilization may not completely reflect the amount of self-reported pain or acute, painful episodes (crises).To examine the prevalence of self-reported pain and the relationship among pain, crises, and utilization in adults with sickle cell disease.Prospective cohort study.Academic and community practices in Virginia.232 patients age 16 years or older with sickle cell disease.Patients completed a daily diary for up to 6 months, recording their maximum pain (on a scale of 0 to 9); whether they were in a crisis (crisis day); and whether they used hospital, emergency, or unscheduled ambulatory care for pain on the previous day (utilization day). Summary measures included both simple proportions and adjusted probabilities (for repeated measures within patients) of pain days, crisis days, and utilization days, as well as mean pain intensity.Pain (with or without crisis or utilization of care) was reported on 54.5% of 31 017 analyzed patient-days (adjusted probability, 56%). Crises without utilization were reported on 12.7% of days and utilization on only 3.5% (unadjusted). In total, 29.3% of patients reported pain in greater than 95% of diary days, whereas only 14.2% reported pain in 5% or fewer diary days (adjusted). The frequency of home opiate use varied and independently predicted pain, crises, and utilization. Mean pain intensity on crisis days, noncrisis pain days, and total pain days increased as the percentage of pain days increased (P0.001). Intensity was significantly higher on utilization days (P0.001). However, utilization was not an independent predictor of crisis, after controlling for pain intensity.The study was done in a single state. Patients did not always send in their diaries.Pain in adults with sickle cell disease is the rule rather than the exception and is far more prevalent and severe than previous large-scale studies have portrayed. It is mostly managed at home; therefore, its prevalence is probably underestimated by health care providers, resulting in misclassification, distorted communication, and undertreatment.