Maureen Chase

Thiamine deficiency in critically ill patients with sepsis.

OBJECTIVE The objective of the study was to determine the prevalence of absolute thiamine deficiency (TD) in critically ill patients with sepsis and to examine the association between thiamine levels and lactic acidosis. DESIGN This was a prospective, observational study. SETTING The setting was an urban, tertiary care center with approximately 50,000 emergency department visits per year and intensive care units numbering approximately 50 total beds. PATIENTS Thirty study patients admitted with clinical suspicion of infection and evidence of tissue hypoperfusion, as defined by a lactic acid level greater than 4 mmol/L or hypotension (systolic blood pressure <90 mm Hg) requiring vasopressor support, were enrolled. A control group of 30 patients presenting to the emergency department with minor emergencies was also enrolled. INTERVENTIONS There were no interventions. MEASUREMENTS AND MAIN RESULTS Plasma thiamine levels were measured at 0, 24, 48, 72, and 162 hours for patients in the study group. Absolute TD was defined as less than or equal to 9 nmol/L derived from established abnormal ranges per Quest laboratory. In the study group, 3 (10%) of 30 had absolute TD upon presentation; and an additional 3 patients (6/30, 20%) developed TD within 72 hours. None of the 30 controls (0/30, 0%) exhibited absolute TD. Of the vasopressor-dependent population, 7.7% (2/26) displayed TD on presentation. For the group overall, there was no correlation between thiamine and lactic acidosis. However, in patients without liver dysfunction, thiamine was statistically significantly negatively correlated with lactic acidosis (r = -.50; P = .02). The relationship between thiamine and lactic acidosis held after multivariable regression analysis controlling for age, sex, and comorbid disease (P < .02). CONCLUSIONS These preliminary findings indicate that critically ill patients may present with TD or develop this deficiency during their acute illness. We also identified a potential association between thiamine levels and lactic acidosis in patients without significant liver injury.

Statin therapy is associated with decreased mortality in patients with infection.

OBJECTIVES The objective was to investigate the association between statin therapy and mortality in emergency department (ED) patients with suspected infection. METHODS A secondary analysis of a prospective, observational cohort study was conducted at an urban, academic ED with approximately 50,000 annual visits. Data were collected between December 2003 and September 2004. Inclusion criteria consisted of age > or = 18 years, clinical suspicion of infection, and hospital admission. Patients were divided by those receiving statin therapy and those not receiving statins while hospitalized. Medication data were collected from an inpatient pharmacy database. Comparisons were conducted with Fishers exact test or Wilcoxon rank sum test. To adjust for baseline differences, multivariable logistic regression analysis controlling for gender, severity of illness (Mortality in Emergency Department Sepsis [MEDS] score), Charlson Comorbidity Index, and duration of statin therapy was performed. RESULTS Of 2,132 patients with suspected infection, 2,036 (95%) had interpretable pharmacy data and were analyzed. The cohort had a median age of 61 years (interquartile range [IQR] = 46-78 years) and a mortality of 3.9% (95% confidence interval [CI] = 3.1% to 4.8%). Patients who received statins (n = 474) had a lower unadjusted crude mortality (1.9%; 95% CI = 0.6% to 3.3%) compared to those who did not (4.5%; 95% CI = 3.4% to 5.4%; p </= 0.01). When adjusting for gender, MEDS score, Charlson Comorbidity Index, and duration of statin therapy, the odds of death for statin patients was 0.27 (95% CI = 0.1 to 0.72; p < or = 0.01). CONCLUSIONS Patients who were admitted to the hospital with infection and received statin therapy while hospitalized had a significantly lower in-hospital mortality compared to patients who did not receive a statin.

Hemorrhagic Complications in Emergency Department Patients Who Are Receiving Dabigatran Compared With Warfarin

STUDY OBJECTIVE Dabigatran is a reversible direct thrombin inhibitor recently approved for stroke prevention in patients with atrial fibrillation. An increasing number of patients receiving dabigatran present to the emergency department (ED) with bleeding complications. Unlike vitamin K antagonists, there are no accepted reversal agents for dabigatran and the data on course and management of bleeding complications are limited. The study objective is to describe the course of bleeding complications in patients admitted through the ED who are prescribed dabigatran in comparison with warfarin therapy. METHODS This was a prospective observational study of ED patients under treatment with dabigatran or warfarin who were admitted with bleeding complications during a 6-month period. Patient demographics, laboratory results, bleeding site, interventions, and outcomes are reported. RESULTS There were 15 and 123 patients admitted with dabigatran and warfarin-induced bleeding complications, respectively. Of the warfarin patients, 25 charts were randomly chosen for extraction. Patients with dabigatran-induced bleeding had a shorter length of stay (3.5 versus 6.0 days) and were older (77 versus 70 years). Patients receiving dabigatran were more likely to have gastrointestinal bleeding (80% versus 48%) and less likely to have intracranial bleeding (0% versus 32%) than those receiving warfarin. Of patients with dabigatran-induced bleeding, 53% presented with an acute kidney injury. CONCLUSION Our patients with dabigatran-induced bleeding had a more benign clinical course with a shorter length of stay compared with patients with warfarin-induced bleeding. As was the case in previous published reports, there were fewer intracranial hemorrhages in patients receiving dabigatran than warfarin. Sustaining an acute kidney injury potentially predisposes patients to bleeding while receiving dabigatran.

Randomized, Double-Blind, Placebo-Controlled Trial of Thiamine as a Metabolic Resuscitator in Septic Shock: A Pilot Study.

Objective:To determine if intravenous thiamine would reduce lactate in patients with septic shock. Design:Randomized, double-blind, placebo-controlled trial. Setting:Two US hospitals. Patients:Adult patients with septic shock and elevated (> 3 mmol/L) lactate between 2010 and 2014. Interventions:Thiamine 200 mg or matching placebo twice daily for 7 days or until hospital discharge. Measurements and Main Results:The primary outcome was lactate levels 24 hours after the first study dose. Of 715 patients meeting the inclusion criteria, 88 patients were enrolled and received study drug. There was no difference in the primary outcome of lactate levels at 24 hours after study start between the thiamine and placebo groups (median: 2.5 mmol/L [1.5, 3.4] vs. 2.6 mmol/L [1.6, 5.1], p = 0.40). There was no difference in secondary outcomes including time to shock reversal, severity of illness and mortality. 35% of the patients were thiamine deficient at baseline. In this predefined subgroup, those in the thiamine treatment group had statistically significantly lower lactate levels at 24 hours (median 2.1 mmol/L [1.4, 2.5] vs. 3.1 [1.9, 8.3], p = 0.03). There was a statistically significant decrease in mortality over time in those receiving thiamine in this subgroup (p = 0.047). Conclusion:Administration of thiamine did not improve lactate levels or other outcomes in the overall group of patients with septic shock and elevated lactate. In those with baseline thiamine deficiency, patients in the thiamine group had significantly lower lactate levels at 24 hours and a possible decrease in mortality over time.

Selective delivery of herpes virus vectors to experimental brain tumors using RMP-7

RMP-7, a bradykinin analog, has been shown to selectively open the blood-tumor barrier for the delivery of chemotherapeutic drugs to brain tumors. In contrast to bradykinin, RMP-7 has no hypotensive effects and has been approved for human use. This study was initiated to determine whether RMP-7 would open the blood-tumor barrier to virus vectors encoding tumor-killing genes in an experimental model. The herpes virus vector used, hrR3, which encodes virus thymidine kinase gene and the lacZ reporter gene, is defective in a gene encoding ribonucleotide reductase, replicates selectively in dividing tumor cells and not in postmitotic neural cells. It was determined that an optimum dose of RMP-7 (1.5–3.0 μg/kg over 10–15 minutes) enhanced viral delivery to brain tumors in rats bearing intracranial 9 L gliosarcomas when infused through the carotid artery immediately prior to virus vector application. Maximum expression of the lacZ reporter gene occurred at 3 days after intracarotid infusion. By 8 days, transgene expression was largely confined to tumor foci away from the main tumor mass. Viral delivery was essentially specific to tumor cells, with little transgene expression elsewhere in the brain. Minimal uptake and pathology was noted in the kidney, spleen, and liver. These findings indicate that intracarotid delivery of RMP-7 can augment the selective delivery of virus vectors to brain tumors in an experimental rat model, with the potential for application to human brain tumors.

ED patients with vertigo: can we identify clinical factors associated with acute stroke?

BACKGROUND Vertigo is a common emergency department (ED) complaint with benign and serious etiologies with overlapping features. Misdiagnosis of acute stroke may result in significant morbidity and mortality. Magnetic resonance imaging (MRI) is superior to computer tomography (CT) for diagnosis of acute stroke but is costly with limited availability. OBJECTIVE The aim of this study was to identify clinical characteristics associated with a cerebrovascular cause for vertigo. METHODS We performed a retrospective chart review on patients with an MRI for vertigo, with or without additional historical or physical examination findings, over 18 months. Study patients were seen in the ED for vertigo within 2 weeks of MRI. Data collected included medical history, physical findings, and imaging results. Fishers exact test was used to identify factors associated with the primary outcome, an acute stroke. RESULTS There were 325 eligible patients; 131 were ED patients. Patients were 57 (± 18) years, and 53% were women. There were 12 ED patients with a new stroke (9.2%). Two variables were associated with acute stroke: a presenting complaint of gait instability (odds ratio, 9.3; 95% confidence interval, 2.6-33.9) or a subtle neurologic finding (odds ratio, 8.7; 95% confidence interval, 2.3-33.1). One patient with a new stroke had a prior stroke, 3 were age >65 years, and none had coronary artery disease or dysrhythmia. Among patients with acute stroke, 5 also had head CT, and none detected the stroke. CONCLUSIONS This study identified 2 variables associated with acute stroke that should be considered in the evaluation of ED patients with vertigo. Head CT was inadequate for diagnosing acute stroke in this patient population.

Early administration of epinephrine (adrenaline) in patients with cardiac arrest with initial shockable rhythm in hospital: propensity score matched analysis

Objectives To evaluate whether patients who experience cardiac arrest in hospital receive epinephrine (adrenaline) within the two minutes after the first defibrillation (contrary to American Heart Association guidelines) and to evaluate the association between early administration of epinephrine and outcomes in this population. Design Prospective observational cohort study. Setting Analysis of data from the Get With The Guidelines-Resuscitation registry, which includes data from more than 300 hospitals in the United States. Participants Adults in hospital who experienced cardiac arrest with an initial shockable rhythm, including patients who had a first defibrillation within two minutes of the cardiac arrest and who remained in a shockable rhythm after defibrillation. Intervention Epinephrine given within two minutes after the first defibrillation. Main outcome measures Survival to hospital discharge. Secondary outcomes included return of spontaneous circulation and survival to hospital discharge with a good functional outcome. A propensity score was calculated for the receipt of epinephrine within two minutes after the first defibrillation, based on multiple characteristics of patients, events, and hospitals. Patients who received epinephrine at either zero, one, or two minutes after the first defibrillation were then matched on the propensity score with patients who were “at risk” of receiving epinephrine within the same minute but who did not receive it. Results 2978patients were matched on the propensity score, and the groups were well balanced. 1510 (51%) patients received epinephrine within two minutes after the first defibrillation, which is contrary to current American Heart Association guidelines. Epinephrine given within the first two minutes after the first defibrillation was associated with decreased odds of survival in the propensity score matched analysis (odds ratio 0.70, 95% confidence interval 0.59 to 0.82; P<0.001). Early epinephrine administration was also associated with a decreased odds of return of spontaneous circulation (0.71, 0.60 to 0.83; P<0.001) and good functional outcome (0.69, 0.58 to 0.83; P<0.001). Conclusion Half of patients with a persistent shockable rhythm received epinephrine within two minutes after the first defibrillation, contrary to current American Heart Association guidelines. The receipt of epinephrine within two minutes after the first defibrillation was associated with decreased odds of survival to hospital discharge as well as decreased odds of return of spontaneous circulation and survival to hospital discharge with a good functional outcome.

Drug Repurposing Screen Identifies Foxo1-Dependent Angiopoietin-2 Regulation in Sepsis.

Objective:The recent withdrawal of a targeted sepsis therapy has diminished pharmaceutical enthusiasm for developing novel drugs for the treatment of sepsis. Angiopoietin-2 is an endothelial-derived protein that potentiates vascular inflammation and leakage and may be involved in sepsis pathogenesis. We screened approved compounds for putative inhibitors of angiopoietin-2 production and investigated underlying molecular mechanisms. Design:Laboratory and animal research plus prospective placebo-controlled randomized controlled trial (NCT00529139) and retrospective analysis (NCT00676897). Setting:Research laboratories of Hannover Medical School and Harvard Medical School. Patients:Septic patients/C57Bl/6 mice and human endothelial cells. Interventions:Food and Drug Administration–approved library screening. Measurements and Main Results:In a cell-based screen of more than 650 Food and Drug Administration–approved compounds, we identified multiple members of the 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitor drug class (referred to as statins) that suppressed angiopoietin-2. Simvastatin inhibited 3-hydroxy-3-methyl-glutaryl-CoA reductase, which in turn activated PI3K-kinase. Downstream of this signaling, PI3K-dependent phosphorylation of the transcription factor Foxo1 at key amino acids inhibited its ability to shuttle to the nucleus and bind cis-elements in the angiopoietin-2 promoter. In septic mice, transient inhibition of angiopoietin-2 expression by liposomal siRNA in vivo improved absolute survival by 50%. Simvastatin had a similar effect, but the combination of angiopoietin-2 siRNA and simvastatin showed no additive benefit. To verify the link between statins and angiopoietin-2 in humans, we performed a pilot matched case-control study and a small randomized placebo-controlled trial demonstrating beneficial effects on angiopoietin-2. Conclusions:3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors may operate through a novel Foxo1-angiopoietin-2 mechanism to suppress de novo production of angiopoietin-2 and thereby ameliorate manifestations of sepsis. Given angiopoietin-2’s dual role as a biomarker and candidate disease mediator, early serum angiopoietin-2 measurement may serve as a stratification tool for future trials of drugs targeting vascular leakage.

Septic Shock and Adequacy of Early Empiric Antibiotics in the Emergency Department

BACKGROUND Antibiotic resistance is an increasing concern for Emergency Physicians. OBJECTIVES To examine whether empiric antibiotic therapy achieved appropriate antimicrobial coverage in emergency department (ED) septic shock patients and evaluate reasons for inadequate coverage. METHODS Retrospective review was performed of all adult septic shock patients presenting to the ED of a tertiary care center from December 2007 to September 2008. Inclusion criteria were: 1) Suspected or confirmed infection; 2) ≥ 2 Systemic Inflammatory Response Syndrome criteria; 3) Treatment with one antimicrobial agent; 4) Hypotension requiring vasopressors. Patients were dichotomized by presentation from a community or health care setting. RESULTS Eighty-five patients with septic shock were identified. The average age was 68 ± 15.8 years. Forty-seven (55.3%) patients presented from a health care setting. Pneumonia was the predominant clinically suspected infection (n = 38, 45%), followed by urinary tract (n = 16, 19%), intra-abdominal (n = 13, 15%), and other infections (n = 18, 21%). Thirty-nine patients (46%) had an organism identified by positive culture, of which initial empiric antibiotic therapy administered in the ED adequately covered the infectious organism in 35 (90%). The 4 patients who received inadequate therapy all had urinary tract infections (UTI) and were from a health care setting. CONCLUSION In this population of ED patients with septic shock, empiric antibiotic coverage was inadequate in a small group of uroseptic patients with recent health care exposure. Current guidelines for UTI treatment do not consider health care setting exposure. A larger, prospective study is needed to further define this risk category and determine optimal empiric antibiotic therapy for patients.

The prevalence and significance of abnormal vital signs prior to in-hospital cardiac arrest

BACKGROUND Patients suffering in-hospital cardiac arrest often show signs of physiological deterioration before the event. The purpose of this study was to determine the prevalence of abnormal vital signs 1-4h before cardiac arrest, and to evaluate the association between these vital sign abnormalities and in-hospital mortality. METHODS We included adults from the Get With the Guidelines(®)- Resuscitation registry with an in-hospital cardiac arrest. We used two a priori definitions for vital signs: abnormal (heart rate (HR) ≤ 60 or ≥ 100 min(-1), respiratory rate (RR) ≤ 10 or >20 min(-1) and systolic blood pressure (SBP) ≤ 90 mm Hg) and severely abnormal (HR ≤ 50 or ≥ 130 min(-1), RR ≤ 8 or ≥ 30 min(-1) and SBP ≤ 80 mm Hg). We evaluated the association between the number of abnormal vital signs and in-hospital mortality using a multivariable logistic regression model. RESULTS 7851 patients were included. Individual vital signs were associated with in-hospital mortality. The majority of patients (59.4%) had at least one abnormal vital sign 1-4h before the arrest and 13.4% had at least one severely abnormal sign. We found a step-wise increase in mortality with increasing number of abnormal vital signs within the abnormal (odds ratio (OR) 1.53 (CI: 1.42-1.64) and severely abnormal groups (OR 1.62 (CI: 1.38-1.90)). This remained in multivariable analysis (abnormal: OR 1.38 (CI: 1.28-1.48), and severely abnormal: OR 1.40 (CI: 1.18-1.65)). CONCLUSION Abnormal vital signs are prevalent 1-4h before in-hospital cardiac arrest on hospital wards. In-hospital mortality increases with increasing number of pre-arrest abnormal vital signs as well as increased severity of vital sign derangements.