BACKGROUND:Sepsis shifts cardiac metabolic fuel preference and this disruption may have implications for cardiovascular function. A greater understanding of the role of metabolism in the development ...and persistence of cardiovascular failure in sepsis could serve to identify novel pharmacotherapeutic approaches.
METHODS:Secondary analysis of prospective quantitative H-NMR metabolomic data from patients enrolled in a phase II randomized control trial of L-carnitine in septic shock. Participants with a SOFA score of > = 5, lactate > = 2, and requiring vasopressor support for at least 4 hours were eligible for enrollment. The independent prognostic value of metabolites to predict a) survival with shock resolution within 48 hours and b) vasopressor free days were assessed. Concentrations of predictive metabolites were compared between participants with and without shock resolution at 48 hours.
RESULTS:Serum H-NMR metabolomics data from 228 patients were analyzed. 81 (36%) patients met the primary outcome; 33 (14%) died prior to 48 hours. The branched chain amino acids (BCAA), valine, leucine, and isoleucine were univariate predictors of the primary outcome after adjusting for multiple hypothesis testing, while valine remained significant after controlling for SOFA score. Similar results were observed when analyzed based on vasopressor free days, and persisted after controlling for confounding variables and excluding non-survivors. BCAA concentrations at 48 hours significantly discriminated between those with shock resolution versus persistent shock.
CONCLUSIONS:Among patients with septic shock, BCAA concentrations independently predict time to shock resolution. This study provides hypothesis generating data into the potential contribution of BCAAs to the pathophysiology of cardiovascular failure in sepsis, opening areas for future investigations.
Objectives:
Early organ dysfunction in sepsis confers a high risk of in-hospital mortality, but the relative contribution of specific types of organ failure to overall mortality is unclear. The ...objective of this study was to assess the predictive ability of individual types of organ failure to in-hospital mortality or prolonged intensive care.
Methods:
Retrospective cohort study of adult emergency department patients with sepsis from October 1, 2013, to November 10, 2015. Multivariable regression was used to assess the odds ratios of individual organ failure types for the outcomes of in-hospital death (primary) and in-hospital death or ICU stay ≥ 3 days (secondary).
Results:
Of 2796 patients, 283 (10%) experienced in-hospital mortality, and 748 (27%) experienced in-hospital mortality or an ICU stay ≥ 3 days. The following components of Sequential Organ Failure Assessment (SOFA) score were most predictive of in-hospital mortality (descending order): coagulation (odds ratio OR: 1.60, 95% confidence interval CI: 1.32-1.93), hepatic (1.58, 95% CI: 1.32-1.90), respiratory (OR: 1.33, 95% CI: 1.21-1.47), neurologic (OR: 1.20, 95% CI: 1.07-1.35), renal (OR: 1.14, 95% CI: 1.02-1.27), and cardiovascular (OR: 1.13, 95% CI: 1.01-1.25). For mortality or ICU stay ≥3 days, the most predictive SOFA components were respiratory (OR: 1.97, 95% CI: 1.79-2.16), neurologic (OR: 1.72, 95% CI: 1.54-1.92), cardiovascular (OR: 1.38, 95% CI: 1.23-1.54), coagulation (OR: 1.31, 95% CI: 1.10-1.55), and renal (OR: 1.19, 95% CI: 1.08-1.30) while hepatic SOFA (OR: 1.16, 95% CI: 0.98-1.37) did not reach statistical significance (P = .092).
Conclusion:
In this retrospective study, SOFA score components demonstrated varying predictive abilities for mortality in sepsis. Elevated coagulation or hepatic SOFA scores were most predictive of in-hospital death, while an elevated respiratory SOFA was most predictive of death or ICU stay >3 days.
Early structured resuscitation of severe sepsis has been suggested to improve short term mortality; however, no previous study has examined the long-term effect of this therapy. We sought to ...determine one year outcomes associated with implementation of early goal directed therapy (EGDT) in the emergency department (ED) care of sepsis.
We performed a longitudinal analysis of a prospective before and after study conducted at a large urban ED. Adult patients were enrolled if they had suspected infection, 2 or more systemic inflammatory response criteria, and either systolic blood pressure (SBP) <90 mmHg after a fluid bolus or lactate >4 mM. Exclusion criteria were: age <18 years, no aggressive care desired, or need for immediate surgery. Clinical and outcomes data were prospectively collected on consecutive eligible patients for 1 year before and 2 years after implementing EGDT. Patients in the pre-implementation phase received non-protocolized care at attending physician discretion. The primary outcome was mortality at one year.
285 subjects, 79 in the pre- and 206 in the post-implementation phases, were enrolled. Compared to pre-implementation, post-implementation subjects had a significantly lower ED SBP (72 vs. 85 mm Hg, P < 0.001) and higher sequential organ failure assessment score (7 vs. 5, P = 0.0004). The primary outcome of 1 year mortality was observed in 39/79 (49%) pre-implementation subjects and 77/206 (37%) post-implementation subjects (difference 12%; P = 0.04).
Implementation of EGDT for the treatment of ED patients with severe sepsis and septic shock was associated with significantly lower mortality at one year.
The SARS-CoV-2 virus enters cells via Angiotensin-converting enzyme 2 (ACE2), disrupting the renin-angiotensin-aldosterone axis, potentially contributing to lung injury. Treatment with angiotensin ...receptor blockers (ARBs), such as losartan, may mitigate these effects, though induction of ACE2 could increase viral entry, replication, and worsen disease.
This study represents a placebo-controlled blinded randomized clinical trial (RCT) to test the efficacy of losartan on outpatients with COVID-19 across three hospital systems with numerous community sites in Minnesota, U.S. Participants included symptomatic outpatients with COVID-19 not already taking ACE-inhibitors or ARBs, enrolled within 7 days of symptom onset. Patients were randomized to 1:1 losartan (25 mg orally twice daily unless estimated glomerular filtration rate, eGFR, was reduced, when dosing was reduced to once daily) versus placebo for 10 days, and all patients and outcome assesors were blinded. The primary outcome was all-cause hospitalization within 15 days. Secondary outcomes included functional status, dyspnea, temperature, and viral load. (clinicatrials.gov, NCT04311177, closed to new participants)
From April to November 2020, 117 participants were randomized 58 to losartan and 59 to placebo, and all were analyzed under intent to treat principles. The primary outcome did not differ significantly between the two arms based on Barnard's test losartan arm: 3 events (5.2% 95% CI 1.1, 14.4%) versus placebo arm: 1 event (1.7%; 95% CI 0.0, 9.1%); proportion difference -3.5% (95% CI -13.2, 4.8%); p = 0.32. Viral loads were not statistically different between treatment groups at any time point. Adverse events per 10 patient days did not differ signifcantly 0.33 (95% CI 0.22–0.49) for losartan vs. 0.37 (95% CI 0.25–0.55) for placebo. Due to a lower than expected hospitalization rate and low likelihood of a clinically important treatment effect, the trial was terminated early.
In this multicenter blinded RCT for outpatients with mild symptomatic COVID-19 disease, losartan did not reduce hospitalizations, though assessment was limited by low event rate. Importantly, viral load was not statistically affected by treatment. This study does not support initiation of losartan for low-risk outpatients.
This study was supported by Minnesota Partnership for Biotechnology and Medical Genomics (CON000000076883).
l-Carnitine is a candidate therapeutic for the treatment of septic shock, a condition that carries a ≥40% mortality. Responsiveness to l-carnitine may hinge on unique metabolic profiles that are not ...evident from the clinical phenotype. To define these profiles, we performed an untargeted metabolomic analysis of serum from 21 male sepsis patients enrolled in a placebo-controlled l-carnitine clinical trial. Although treatment with l-carnitine is known to induce changes in the sepsis metabolome, we found a distinct set of metabolites that differentiated 1-year survivors from nonsurvivors. Following feature alignment, we employed a new and innovative data reduction strategy followed by false discovery correction, and identified 63 metabolites that differentiated carnitine-treated 1-year survivors versus nonsurvivors. Following identification by MS/MS and database search, several metabolite markers of vascular inflammation were determined to be prominently elevated in the carnitine-treated nonsurvivor cohort, including fibrinopeptide A, allysine, and histamine. While preliminary, these results corroborate that metabolic profiles may be useful to differentiate l-carnitine treatment responsiveness. Furthermore, these data show that the metabolic signature of l-carnitine-treated nonsurvivors is associated with a severity of illness (e.g., vascular inflammation) that is not routinely clinically detected.
The burden of senescent cells (SnCs), which do not divide but are metabolically active and resistant to death by apoptosis, is increased in older adults and those with chronic diseases. These ...individuals are also at the greatest risk for morbidity and mortality from SARS‐CoV‐2 infection. SARS‐CoV‐2 complications include cytokine storm and multiorgan failure mediated by the same factors as often produced by SnCs through their senescence‐associated secretory phenotype (SASP). The SASP can be amplified by infection‐related pathogen‐associated molecular profile factors. Senolytic agents, such as Fisetin, selectively eliminate SnCs and delay, prevent, or alleviate multiple disorders in aged experimental animals and animal models of human chronic diseases, including obesity, diabetes, and respiratory diseases. Senolytics are now in clinical trials for multiple conditions linked to SnCs, including frailty; obesity/diabetes; osteoporosis; and cardiovascular, kidney, and lung diseases, which are also risk factors for SARS‐CoV‐2 morbidity and mortality. A clinical trial is underway to test if senolytics decrease SARS‐CoV‐2 progression and morbidity in hospitalized older adults. We describe here a National Institutes of Health‐funded, multicenter, placebo‐controlled clinical trial of Fisetin for older adult skilled nursing facility (SNF) residents who have been, or become, SARS‐CoV‐2 rtPCR‐positive, including the rationale for targeting fundamental aging mechanisms in such patients. We consider logistic challenges of conducting trials in long‐term care settings in the SARS‐CoV‐2 era, including restricted access, consent procedures, methods for obtaining biospecimens and clinical data, staffing, investigational product administration issues, and potential solutions for these challenges. We propose developing a national network of SNFs engaged in interventional clinical trials.
To describe the effect of liver disease (LD) on lactate clearance during early sepsis resuscitation.
This is a multicenter randomized clinical trial. An initial lactate >2 mmol/L and subsequent serum ...lactate measurement within 6 hours were required for inclusion. LD was categorized by two methods: 1) past medical history (PMH) categorized as no LD, mild LD (no Child's score criteria, but PMH of hepatitis B/C), cirrhosis; and 2) measurable liver dysfunction determined by the liver component of the sequential organ failure assessment (L-SOFA) score as no dysfunction (L-SOFA score 0), mild dysfunction (score 1), moderate-severe dysfunction (score 2 to 4). Primary outcome was the rate of lactate normalization.
One hundred eighty-seven patients were included. When categorized by PMH, 169 patients had no LD, 6 mild LD, and 12 cirrhosis. 63/169 (37%) of patients with no LD achieved lactate normalization, compared to 4/6 (67%) with mild LD, and 1/12 (8%) with cirrhosis (P<0.03). Categorized by L-SOFA score, 59/124 (47%) patients with L-SOFA 0 achieved lactate normalization, compared to 6/31 (19%) with L-SOFA 1, and 3/32 (9%) with L-SOFA 2-4 (P<0.01). Relative lactate clearance (initial lactate-subsequent lactate)/initial lactate was lower in patients with more advanced LD by PMH (37.7 vs. 40.4 vs. 21.8, P=0.07), and lower with increasing L-SOFA score (42.0 vs. 30.1 vs. 23.4, P=0.01).
Liver dysfunction was significantly associated with impaired lactate clearance and normalization during the early resuscitation of sepsis.
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