2 Minute Medicine Rewind April 13, 2020

Association of a Care Bundle for Early Sepsis Management With Mortality Among Patients With Hospital-Onset or Community-Onset Sepsis

1. Sepsis bundles were not significantly associated with decreased risk of mortality or reduced vasopressor treatment time in community- or hospital-onset sepsis.

2. Components of the SEP-1 bundle, such as broad-spectrum IV antibiotic treatment and lactate levels were associated with improved outcomes in this population.

Evidence Rating Level: 2 (Good)

Sepsis bundles, or protocols involving multiple interventions for care of septic patients, generally focus on community-onset cases presenting to emergency departments. This was the first study to examine the association of the Early Management Bundle for Severe Sepsis/Septic Shock (SEP-1) with mortality in hospital-onset sepsis. This retrospective study occurring at four hospitals included 6,404 patients at least 18 years of age who were diagnosed with sepsis or disseminated infection (M [SD] age = 64.0 [18.2] years, 44.8% female). Defined by SEP-1, exclusion criteria were hospitalization for longer 120 days or less than six days, admission following transfer from another facility, and use of broad-spectrum IV antibiotics for over 24 hours prior the onset of sepsis. Inpatient mortality across the sample was 19.0%, with a median of 7.0 hours spent in the emergency department (IQR 4.9 to 12.6). Regarding mortality and vasopressor days in community-onset sepsis, receipt of SEP-1 was not associated with significant reductions (absolute mortality difference -0.07%, 95% CI -3.02 to 2.88; absolute vasopressor difference 0.31 days, 95% CI 0.11 to 0.51). Lack of significant associations were found among hospital-onset sepsis (absolute mortality difference -0.42%, 95% CI -6.77 to 5.93; absolute vasopressor difference 0.40 days, 95% CI -0.04 to 0.85) and the overall sample (absolute mortality difference 0.10%, 95% CI -2.41 to 2.61; absolute vasopressor difference 0.26, 95% CI 0.09 to 0.43). Specific SEP-1 components were associated with improved outcomes, such as a reduction in mortality risk in community-onset sepsis associated with serum lactate levels (absolute difference -7.61%, 95% CI -14.70 to -0.54). Broad-spectrum IV antibiotics were associated with reduced vasopressor days while, in the hospital-onset group, IV antibiotics reduced risk of mortality (absolute difference -5.20%, 95% CI -9.84 to -0.56). Overall, this study suggests that SEP-1 components can improve outcomes, SEP-1 itself is not associated with reduced risk of mortality or decreased need for vasopressor treatment in septic populations.

Association of Factors With Elevated Amyloid Burden in Clinically Normal Older Individuals

1. Preclinical amyloid-β was associated with significant cognitive decline in clinically normal adults across screening and comprehensive measures.

2. Amyloid-β-positive individuals were more likely to carry at least one APOE ε4 allele and have a family history of dementia.

Evidence Rating Level: 3 (Average)

Amyloid-β (Aβ) pathology is known as the preclinical phase of Alzheimer’s disease (AD) continuum, which can begin at least one decade prior to AD dementia. This cross-sectional analysis of the Anti-Amyloid Treatment in Asymptomatic Alzheimer disease (A4) Study sought to investigate whether or not Aβ burden is associated with genetic, demographic, and lifestyle factors as well as cognitive functioning in older, clinically-normal individuals. This study utilized positron emission tomography (PET) and standardized assessments to evaluate factors associated with amyloid deposition. Data from total of 4,486 individuals were collected from April 2014 to December 2017 and were eligible if between the ages of 65 and 85 years and cognitively normal in terms of the Mini-Mental Status Examination (MMSE; ≥25), Wechsler Memory Scale Logical Memory II (LM; 6-18) and amyloid PET. Across the entire sample (M [SD] age = 71.29 [4.67] years), 85% were enrolled in the US, 10% in Australia, 4% in Canada, and 2% in Japan. Approximately 29.5% were categorized as Aβ+ and 70.5% were Aβ-. The mean (SD) cortical standardized uptake value ratio (SUVr) for the Aβ+ group was 1.33 (0.18). Aβ+ individuals were slightly older than Aβ- individual (p<0.001) and had lower mean PET SUVr (p<0.001). Reports of family history of dementia in Aβ+ participants and 58% of the Aβ+ group carried one or more APOE ε4 alleles (25% of Aβ-), with the former group showing higher amyloid burden (mean [SD] SUVr = 1.36 [0.176]) compared to noncarriers (p<0.001). Neuropsychological measures suggested significantly lower scores in Aβ+ participants on each measure, including MMSE (p<0.01), Free and Cued Selective Reminding Test’s free and total scores (p<0.001), LM delay (p<0.001), and digit symbol (p<0.001). Marginal evidence was found to suggest that factors such as lower education, decreased physical activity, female sex, body mass index, or lifestyle were associated with elevated amyloid. The main limitation of this study is the limited diversity of the PET sample, such that participants of color were underrepresented. However, this study highlights the significant cognitive impact of preclinical AD and the associations with APOE ε4 and family history of dementia.

Neurological Manifestations of Hospitalized Patients With Coronavirus Disease 2019 in Wuhan, China

1. A total of 36.4% of the total sample of patients with SARS-CoV-2 infection demonstrated neurological manifestations of infection, with significantly greater likelihood found among those with severe infections.

Evidence Rating Level: 2 (Good)

While coronaviruses (CoVs) are known to impact the respiratory system they have systemic effects and can affect the central nervous system (CNS). This retrospective, observational case series aimed to study the neurological effects of SARS-CoV-2 through electronic medical records across three special care centers in Wuhan, China. These data were then separated into the following manifestation categories: 1) CNS (seizure, ataxia, headache, dizziness, impaired consciousness, cerebrovascular disease), 2) peripheral nervous system (anosmia, vision impairment, neuralgia), and 3) skeletal muscular injury. Of the 214 patients with COVID-19 (mean [SD] age = 52.7 [15.5] years, 59.3% female), 36.4% had neurological manifestations of the infection. Patients with more severe infection had greater neurologic manifestations compared to those with nonsevere infection (difference 15.3%, p = 0.02), including skeletal muscle injury (difference 14.5%, p<0.001), impaired consciousness (difference 12.4%, p<0.001), and acute cerebrovascular diseases (difference 4.9%, p = 0.03). No differences among the nonsevere groups with and without neurologic manifestations were discovered in laboratory findings. However, in the severe group, CNS manifestations were associated with lower lymphocyte levels and platelet counts, as well as higher blood urea nitrogen levels (median lymphocyte count 0.7 x 109/L [ range 0.1 to 1.6] vs 0.9 x 109/L [range 0.2 to 2.6], p = 0.007; median platelet count: 169.0 x 109/l [range 18.0 to 564.0] vs 220.0 x 109/L [range 109.0 to 576.0, p = 0.04; median blood urea nitrogen 5.00 mmol/L [range 2.3 to 48.1] vs 4.4 mmol/L [range 1.5 to 19.1], p = 0.04). This first empirical report of neurological manifestations in patients with COVID-19 strongly suggests that SARS-CoV-2 has the ability to impact more than the respiratory system. This will prove important in screening individuals who may not necessarily present with respiratory illness and in ongoing research related to brain health and functioning.

Long-Term Outcomes in Patients With Severely Reduced Left Ventricular Ejection Fraction Undergoing Percutaneous Coronary Intervention vs Coronary Artery Bypass Grafting

1. Patients with severely reduced left ventricular ejection fraction with left main, left anterior descending, or multivessel disease who underwent percutaneous coronary intervention demonstrated higher rates of mortality and major adverse cardiovascular events compared to those who underwent coronary artery bypass grafting.

Evidence Rating Level: 2 (Good)

There is insufficient evidence in the literature on outcomes of revascularization strategies for patients with severely reduced left ventricular ejection fraction (LVEF). This retrospective cohort study of patients in Ontario, Canada sought to determine whether or not outcomes differ between with severely reduced LVEF with left main coronary artery, left anterior descending artery, or multivessel disease who undergo percutaneous coronary intervention (PCI) and those who undergo coronary artery bypass grafting (CABG), including all-cause mortality and death from major adverse cardiovascular events (MACE). Data from 12,113 patients across both the PCI (mean [SD] age = 64.8 [11.0] years, 27.5% female) and CABG (mean [SD] age = 65.6 [9.7] years, 17.1% female) groups were utilized. Patients were propensity score-matched, resulting in 2,397 patients from each group with a median follow-up time of 5.2 years (IQR 5.0 to 5.3). Compared to CABG, researchers found that patients who underwent PCI demonstrated significantly greater mortality rates (HR 1.6, 05% CI 1.3 to 1.7), cardiovascular disease-related death (HR 1.4, 95% CI 1.1 to 1.6), subsequent revascularization (HR 3.7, 95% CI 3.2 to 4.3), MACE (HR 2.0, 95% CI 1.9 to 2.2), and hospitalization for either heart failure (HR 1.5, 95% CI 1.3 to 1.6), heart failure (HR 1.5, 95% CI 1.3 to 1.6), or myocardial infarction (HR 3.2, 95% CI 2.6 to 3.8). Overall, these findings suggest a need to strongly consider interventions for patients with severely reduced LVEF due to the elevated risks of mortality and MACE associated with PCI.

First-Wave COVID-19 Transmissibility and Severity in China Outside Hubei After Control Measures, and Second-Wave Scenario Planning: A Modelling Impact Assessment

1. Following aggressive interventions across China since January 23, 2020, the confirmed case fatality risk in mainland China was 0.98%, five times smaller than that of Hubei, the epicenter of the COVID-19 spread.

2. Relaxing restrictions and allowing the instantaneous reproduction number to rise above 1, even if restrictions were subsequently tightened, would likely still result in health and economic losses. 

Evidence Rating Level: 3 (Average)

Mainland China has observed 13,415 confirmed cases of COVID-19 and 120 deaths as of March 18, 2020. This is outside the epicenter of the virus outbreak in Hubei province. Massive non-pharmacological interventions were implemented across the country to reduce the spread, including a lockdown of Wuhan since January 23, 2020 along with 16 neighboring cities. This study provided an impact assessment of the severity and transmissibility of COVID-19 during the first wave in four cities (confirmed cases): Beijing (411), Shanghai (337), Shenzhen (417), and Wenzhou (504). Further, a susceptible-infectious-recovered model was used to simulate the potential effects of relaxing the interventions following the first wave. An instantaneous reproduction number (Rt) of COVID-19 was defined as the average number of secondary cases that one primary case could generate and derived from various databases from each city. Rt substantially decreased following the implementation of aggressive measures, keeping it steadily below 1. The confirmed case-fatality risk (cCFR) outside Hubei was 0.98% (95% CI 0.82 to 1.16), though the authors noted substantial heterogeneity across provinces such as Hubei (cCFR 5.91%, 95% CI 5.73 to 6.09) due to variable economies and healthcare resources. A susceptible-infectious-recovered model was used to simulate the potential effects of relaxing the interventions following the first wave. It was determined that mainland China is capable of doing so very slowly, such that Rt will not exceed 1. As Rt is a function of time, quick relaxation of interventions or continuation of relaxation when the threshold had been breached resulted in a severe and exponential rise in COVID-19 cases. Relaxation should only be considered when the Rt is consistently <1 and can be kept at that level. Overall, the authors provide a basis upon which other countries with rising cases can learn, including not only aggressive measures to thwart the spread of the virus but very careful and slow relaxation of these interventions when the first wave subsides.

Image: PD

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