Angiotensin II for the Treatment of Vasodilatory Shock.

BACKGROUND: Vasodilatory shock that does not respond to high-dose vasopressors is associated with high mortality. We investigated the effectiveness of angiotensin II for the treatment of patients with this condition. METHODS: We randomly assigned patients with vasodilatory shock who were receiving more than 0.2 µg of norepinephrine per kilogram of body weight per minute or the equivalent dose of another vasopressor to receive infusions of either angiotensin II or placebo. The primary end point was a response with respect to mean arterial pressure at hour 3 after the start of infusion, with response defined as an increase from baseline of at least 10 mm Hg or an increase to at least 75 mm Hg, without an increase in the dose of background vasopressors. RESULTS: A total of 344 patients were assigned to one of the two regimens; 321 received a study intervention (163 received angiotensin II, and 158 received placebo) and were included in the analysis. The primary end point was reached by more patients in the angiotensin II group (114 of 163 patients, 69.9%) than in the placebo group (37 of 158 patients, 23.4%) (odds ratio, 7.95; 95% confidence interval [CI], 4.76 to 13.3; P<0.001). At 48 hours, the mean improvement in the cardiovascular Sequential Organ Failure Assessment (SOFA) score (scores range from 0 to 4, with higher scores indicating more severe dysfunction) was greater in the angiotensin II group than in the placebo group (-1.75 vs. -1.28, P=0.01). Serious adverse events were reported in 60.7% of the patients in the angiotensin II group and in 67.1% in the placebo group. Death by day 28 occurred in 75 of 163 patients (46%) in the angiotensin II group and in 85 of 158 patients (54%) in the placebo group (hazard ratio, 0.78; 95% CI, 0.57 to 1.07; P=0.12). CONCLUSIONS: Angiotensin II effectively increased blood pressure in patients with vasodilatory shock that did not respond to high doses of conventional vasopressors. (Funded by La Jolla Pharmaceutical Company; ATHOS-3 ClinicalTrials.gov number, NCT02338843 .).

The impact of COVID-19 on acute ischemic stroke admissions: Analysis from a community-based tertiary care center.

BACKGROUND/OBJECTIVE: To evaluate the impact of the COVID-19 pandemic on hospital admissions and outcomes in patients admitted with acute ischemic stroke. METHODS: Single-center retrospective analysis of patients admitted to the hospital with acute ischemic stroke, between December 1st, 2019 and June 30th, 2020. Outcomes were classified as none-to-minimal disability, moderate-to-severe disability, and death based on discharge disposition, and compared between two time periods: pre-COVID-19 era (December 1st, 2019 to March 11th, 2020) and COVID-19 era (March 12th to June 30th, 2020). We also performed a comparative trend analysis for the equivalent period between 2019 and 2020. RESULTS: Five hundred and seventy-five patients with a mean age (years±SD) of 68±16 were admitted from December 1st, 2019 to June 30th, 2020, with a clinical diagnosis of acute ischemic stroke. Of these, 255 (44.3%) patients were admitted during the COVID-19 era. We observed a 22.1% and 39.5% decline in admission for acute ischemic stroke in April and May 2020, respectively. A significantly higher percentage of patients with acute ischemic stroke received intravenous thrombolysis during the COVID-19 era (p = 0.020). In patients with confirmed COVID-19, we found a higher percentage of older men with preexisting comorbidities such as hyperlipidemia, coronary artery disease, and diabetes mellitus but a lower rate of atrial fibrillation. In addition, we found a treatment delay in both intravenous thrombolysis (median 94.5 min versus 38 min) and mechanical thrombectomy (median 244 min versus 86 min) in patients with confirmed COVID-19 infection. There were no differences in patients' disposition including home, short-term, and long-term facility (p = 0.60). CONCLUSIONS: We observed a reduction of hospital admissions in acute ischemic strokes and some delay in reperfusion therapy during the COVID-19 pandemic. Prospective studies and a larger dataset analysis are warranted.

Intraosseous Administration of 23.4% NaCl for Treatment of Intracranial Hypertension.

BACKGROUND/OBJECTIVE: Prompt treatment of acute intracranial hypertension is vital to preserving neurological function and frequently includes administration of 23.4% NaCl. However, 23.4% NaCl administration requires central venous catheterization that can delay treatment. Intraosseous catheterization is an alternative route of venous access that may result in more rapid administration of 23.4% NaCl. METHODS: Single-center retrospective analysis of 76 consecutive patients, between January 2015 and January 2018, with clinical signs of intracranial hypertension received 23.4% NaCl through either central venous catheter or intraosseous access. RESULTS: Intraosseous cannulation was successful on the first attempt in 97% of patients. No immediate untoward effects were seen with intraosseous cannulation. Time to treatment with 23.4% NaCl was significantly shorter in patients with intraosseous access compared to central venous catheter (p < 0.0001). CONCLUSIONS: Intraosseous cannulation resulted in more rapid administration of 23.4% NaCl with no immediate serious complications. Further investigations to identify the clinical benefits and safety of hypertonic medication administration via intraosseous cannulation are warranted.

Recent trends in inpatient mortality and resource utilization for patients with stroke in the United States: 2005-2009.

BACKGROUND: The aim of the study is to evaluate recent trends in mortality, length of stay, costs, and charges for patients admitted to the US hospitals with the principal diagnosis of stroke. METHODS: This was a retrospective temporal trends study using data from the Nationwide Inpatient Sample from 2005 to 2009. RESULTS: During the study period, there were 2.7 million hospital admissions with the diagnosis of stroke in the United States (470,000 intracerebral hemorrhage, 130,000 subarachnoid hemorrhage, and 2.1 million ischemic strokes). In-hospital mortality decreased from 10.2% in 2005 to 9.0% in 2009 (26.0%-23.0%, 23.4%-23.1%, and 6.0%-5.1% for the stroke subtypes, respectively), the average length of stay decreased from 6.3 days to 5.9 days (5.6-5.2 days for ischemic stroke, remained the same for hemorrhagic stroke), and the average number of 1.3 ± 0.1 procedures per admission remained the same. The proportion of patients with major or extreme severity of illness increased from 39.2% to 47.0% (P < .0001). After adjustment for inflation, the average total charge per admission increased from $36,215 to $46,518 (P < .0001), whereas the average cost of treatment remained the same. Higher treatment cost is associated with lower in-hospital mortality after adjustment for demographic, hospital-related, and clinical confounders (odds ratio = .968 [.965-.970] per each extra $1000). CONCLUSIONS: Between 2005 and 2009, in-hospital mortality for patients hospitalized with stroke improved despite increasing severity of illness. At the same time, the average charge for hospitalization increased by 28% despite unchanged cost of treatment and shorter length of stay.

Acute lung injury in critical neurological illness.

OBJECTIVE: Acute lung injury and acute respiratory distress syndrome have been reported in a significant proportion of patients with critical neurologic illness. Our aim was to identify risk factors for acute lung injury/acute respiratory distress syndrome in this population. DESIGN: Prospective, observational study. SETTING: A 22-bed, adult neurosciences critical care unit at a tertiary care hospital. PATIENTS: Primary neurologic disorder, mechanical ventilation >48 hrs. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 192 patients were enrolled with a range of neurologic disorders. Among these, 68 (35%) were diagnosed with acute lung injury/acute respiratory distress syndrome. In a multivariate logistic regression analysis, independent risk factors for acute lung injury/acute respiratory distress syndrome were pneumonia (odds ratio [95% confidence interval] 3.12 [1.5-6.0], p = .002), circulatory shock (2.2 [1.07-4.57], p = .03), and absence of a gag or cough reflex (3.41 [1.34-8.68], p = .01). Neither neurologic diagnosis nor neurologic severity, assessed with the Glasgow Coma Scale, was significantly associated with the development of acute lung injury/acute respiratory distress syndrome. CONCLUSION: Acute lung injury/acute respiratory distress syndrome occurred in more than one third of mechanically ventilated neurosciences critical care unit patients. Loss of the cough or gag reflex is strongly predictive of acute lung injury/acute respiratory distress syndrome, while neurologic diagnosis and Glasgow Coma Scale are not. Lower brainstem dysfunction, a clinical marker of neurologic injury not captured by the Glasgow Coma Scale, is a risk factor for acute lung injury/acute respiratory distress syndrome and could inform decisions regarding airway protection and mechanical ventilation.

Rates of adverse events in patients with ischemic stroke treated at thrombectomy capable hospitals.

OBJECTIVE: To identify the beneficial effects of thrombectomy capable hospitals (TCHs), by comparing the incidence of in-hospital adverse events and discharge outcomes among patients with ischemic stroke treated at thrombectomy capable and non-thrombectomy capable hospitals in the United States. METHODS: We used the data from the Nationwide Inpatient Sample from January 2012 to December 2017. Thrombectomy capable hospitals were identified based on the number of thrombectomy procedures performed by a hospital each year among patients with ischemic stroke. If a hospital performed 10 or more thrombectomy procedures, it was labelled a TCH. The inclusion criteria were age ≥18 years, and ischemic stroke (International Classification of Diseases 433 .x1-434.x1 (ICD-9) or I63 (ICD-10)) as primary discharge diagnosis. A comparative analysis of propensity-matched patient groups was done to study the influence of TCH admissions on in-hospital outcomes. RESULTS: A total of 2 826 334 patients with primary ischemic stroke were identified. In a multivariate logistic regression model after adjusting for age, sex, race/ethnicity, hospital teaching status, comorbidities, and all patients refined diagnosis-related groups-based disease severity, patients admitted to a TCH were found to have low incidence of in-hospital adverse events: pneumonia (OR=0.86, 95% CI 0.78 to 0.93), urinary tract infection (OR=0.87, 95% CI 0.84 to 0.91), sepsis (OR=0.91, 95% CI 0.81 to 1.02), and pulmonary embolism (OR=0.89, 95% CI 0.77 to 1.03); in-hospital death (OR=0.82, 95% CI 0.78 to 0.88); and higher rate of home discharge (OR=1.09, 95% CI 1.06 to 1.12). CONCLUSIONS: A decrease in-hospital adverse events and improved discharge outcomes were observed among patients with ischemic stroke admitted to a TCH compared with a non-TCH.

Delayed treatment with W1-mAb, a chimpanzee-derived monoclonal antibody against protective antigen, reduces mortality from challenges with anthrax edema or lethal toxin in rats and with anthrax spores in mice.

OBJECTIVE: W1-mAb is a chimpanzee-derived monoclonal antibody to protective antigen that improved survival when administered before anthrax lethal toxin challenge in rats. To better define W1-mAb's efficacy for anthrax, we administered it after initiation of 24-hr infusions of edema toxin and lethal toxin either alone or together in rats or following anthrax spore challenge in mice. INTERVENTIONS: W1-mAb or placebo treatment. METHODS AND MAIN RESULTS: In toxin-challenged rats treated with placebo, survival rates were lower with edema toxin (500 µg/kg) compared to lethal toxin either alone (175 µg/kg) or with edema toxin (175 µg/kg each) (8%, 33%, and 32%, respectively), but the median time to death was longer (36, 11, and 9 hrs, respectively) (p ≤ .01 for all comparisons). W1-mAb administered up to 12 hrs after edema toxin and 6 hrs after lethal toxin increased survival and reduced hypotension (p ≤ .01). However, only administration of W1-mAb at 0 hrs improved these variables with lethal toxin and edema toxin together (p ≤ .0002). In C57BL/6J mice challenged with anthrax spores subcutaneously, compared to placebo treatment (0 of 15 animals survived), W1-mAb administered beginning 24 hrs after challenge increased survival (13 of 15 survived) (p ≤ .0001). CONCLUSION: While rapidity of lethality may influence the effectiveness of delayed W1-mAb treatment, these rat and mouse studies provide a basis for further exploring this agent's usefulness for anthrax.

Neurologic aspects of cardiac emergencies.

In this review, cardiac arrest is discussed, with a focus on neuroprognostication and the emerging data, with regard to identifying more accurate predictors of neurologic outcomes in the era of therapeutic hypothermia. Topics discussed include recent controversies with regard to targeted temperature management in comatose survivors of cardiac arrest; neurologic complications associated with surgical disease and procedures, namely aortic dissection, infective endocarditis, left ventricular assist devices, and coronary artery bypass grafting; and the cause, pathogenesis, and management of neurogenic stunned myocardium.

Bacillus anthracis cell wall produces injurious inflammation but paradoxically decreases the lethality of anthrax lethal toxin in a rat model.

OBJECTIVES: The in vivo inflammatory effects of the Bacillus anthracis cell wall are unknown. We therefore investigated these effects in rats and, for comparison, those of known inflammatory stimulants, Staphylococcus aureus cell wall or lipopolysaccharide (LPS). METHOD AND RESULTS: Sprague-Dawley rats (n = 103) were challenged with increasing B. anthracis cell wall doses (10, 20, 40, 80, or 160 mg/kg) or diluent (control) as a bolus or 24-h infusion. The three highest bolus doses were lethal (20-64% lethality rates) as were the two highest infused doses (13% with each). Comparisons among lethal or nonlethal doses on other measured parameters were not significantly different, and these were combined for analysis. Over the 24 h after challenge initiation with lethal bolus or infusion, compared to controls, ten inflammatory cytokines and NO levels were increased and circulating neutrophils and platelets decreased (P

Growing insights into the potential benefits and risks of activated protein C administration in sepsis: a review of preclinical and clinical studies.

Recombinant human activated protein C (rhAPC) was developed to reduce excessive coagulant and inflammatory activity during sepsis. Basic and clinical research has suggested these pathways contribute to the pathogenesis of this lethal syndrome and are inhibited by rhAPC. Based in large part on the results of a single multicenter randomized controlled trial, rhAPC was first approved in 2001 by the US Food and Drug Administration (FDA) as adjunctive therapy in septic patients with a high risk of death. This was followed closely by approval in Europe, Australia, and New Zealand. At the original FDA review of rhAPC, concerns were raised as to whether a confirmatory trial should be done before final regulatory approval because of concerns that rhAPCs bleeding risk might outweigh its potential benefit during clinical use. Since 2001, continuing basic and clinical research has further elucidated the complex role activated protein C may have in both adaptive and maladaptive responses during sepsis. Moreover, subsequent controlled trials in other types of septic patients and observational studies appear to support earlier concerns that the benefit-to-risk ratio of rhAPC may not support its clinical use. This experience has prompted additional trials presently underway, to define whether treatment with rhAPC as it was originally indicated in septic patients with persistent shock, is safe and effective. Until such trials are complete, physicians employing this agent must carefully consider which patients may be appropriate candidates for rhAPC administration.