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Endotoxins carried within LDL are cleared from the circulation via hepatic LDL receptor (LDLR)-mediated endocytosis. Proprotein convertase subtilisin-kexin type 9 (PCSK9) reduces this clearance by down-regulating LDLR density on hepatocytes. In addition to hepatocytes, vascular endothelial cells also express receptor targets of PCSK9, including LDLR. Therefore, we hypothesized that PCSK9 may regulate vascular endothelial cell uptake of lipopolysaccharide (LPS) and alter the vascular endothelial cell inflammatory response.We found that LPS is internalized by human umbilical vein vascular endothelial cells (HUVECs) and LPS uptake dose-dependently increased with increasing LDL concentration. Intracellular LPS co-localized with LDL. PCSK9 and, separately, blocking antibodies against LDLR, dose-dependently decreased the vascular endothelial cell uptake of LPS and, furthermore, inhibition of endocytosis using Dynasore blocked LPS uptake. In contrast, blocking antibodies against TLR4 did not alter LPS uptake. PCSK9 decreased the LPS-induced proinflammatory response (IL-6 and IL-8 gene expression and protein secretion, and VCAM-1/ICAM-1 expression) in vascular endothelial cells. In addition, a decrease in PCSK9 and increase in LDLR, mediated by triciribine or siPCSK9, increased LPS uptake and the LPS-induced proinflammatory response. Similar results were also found in aortic vascular tissue from Pcsk9Our data suggest that, similar to PCSK9 treatment in hepatocytes, PCSK9 reduces vascular endothelial cell uptake of LPS via LDLR-mediated endocytosis. Consequently, PCSK9 decreases the LPS-induced proinflammatory response in vascular endothelial cells. These results raise the possibility that PCSK9 inhibition may have additional effects on vascular endothelial inflammation via this alternative pathway, beyond the known effects of PCSK9 inhibition on LDL lowering and hepatic endotoxin clearance.

BACKGROUNDThe COVID-19 pandemic could impact frequency and mortality of non-COVID-19 community-acquired pneumonia (CAP). Changes in frequency, patient mix, treatment, and organ dysfunction could cascade together to increase mortality of CAP during compared to pre-COVID-19.METHODSHospitalized CAP patients at St. Paul’s Hospital, Vancouver, Canada pre- (fiscal years 2018/2019 and 2019/2020) and during COVID-19 pandemic (2020/2021 and 2021/2022) were evaluated.RESULTSIn 5219 CAP patients, there was no significant difference pre-versus during pandemic in mean age, gender and Charlson co-morbidity score. However, hospital mortality increased significantly from pre-versus during COVID-19 (7.5% versus 12.1% respectively, [95% CI for difference: 3.0-6.3%], pCONCLUSIONS AND RELEVANCEThe COVID-19 pandemic was associated with increases in hospital mortality, ICU admission and invasive mechanical ventilation rates of non-COVID-19 CAP and a transient, one year frequency decrease. There was no winter seasonality of CAP during the COVID-19 pandemic era. Future pandemic planning for CAP hospital care is needed.What is already known on this topicThe COVID-19 pandemic could impact frequency and mortality of non-COVID-19 community-acquired pneumonia (CAP). No prior study has examined this hypothesis.What this study addsThe COVID-19 pandemic was associated with increases in hospital mortality, ICU admission and invasive mechanical ventilation rates of non-COVID-19 CAP and a transient, one year frequency decrease. There was no winter seasonality of CAP during the COVID-19 pandemic era.How this study might affect research, practice or policyFuture pandemic planning for CAP hospital care is needed.

BACKGROUND:Prediction of severity of Post-COVID-19 condition is not clear. We determined whether hospital course variables correlated with objective and subjective outcomes 3- and 6-months post-COVID-19 onset.METHODS:Adults admitted to hospital with acute COVID-19 were recruited (Feb 15, 2020-April 1, 2021) from two tertiary hospitals in Vancouver, Canada. We recorded baseline characteristics, COVID severity score, organ function, ICU and hospital length of stay. Survivors were evaluated at 3- and 6-months post- COVID-19 onset: subjective: University of California San Diego Shortness of Breath Score, EuroQol 5D Visual Analogue Scale, Frailty Index; Objective: functional capacity (6-minute walk test), pulmonary (pulmonary function tests), cardiac (echocardiography, BNP), renal (creatinine), hepatic (AST, ALT, bilirubin), and coagulation (aPTT, INR, D-dimers, fibrinogen).RESULTS:In 133 post-COVID-19 patients (age 62 ± 14 years, 65% male with frequent comorbidities [hypertension (42%), diabetes (29%), chronic cardiac (22%)), 42% were admitted to Intensive Care Unit: 23%, 23% and 2% required ventilation, vasopressors or renal support, respectively. One-third had restrictive lung function (CONCLUSIONS:Early organ dysfunction predicts later objective pathology especially restrictive lung disease and a pro-coagulant state. These hypothesis-generating findings require further validation in additional patients.

After fluid administration for vasodilatory shock, vasopressors are commonly infused. Causes of vasodilatory shock include septic shock, post-cardiovascular surgery, post-acute myocardial infarction, postsurgery, other causes of an intense systemic inflammatory response, and drug -associated anaphylaxis. Therapeutic vasopressors are hormones that activate receptors—adrenergic: α1, α2, β1, β2; angiotensin II: AG1, AG2; vasopressin: AVPR1a, AVPR1B, AVPR2; dopamine: DA1, DA2. Vasopressor choice and dose vary widely because of patient and physician practice heterogeneity. Vasopressor adverse effects are excessive vasoconstriction causing organ ischemia/infarction, hyperglycemia, hyperlactatemia, tachycardia, and tachyarrhythmias. To date, no randomized controlled trial (RCT) of vasopressors has shown a decreased 28-day mortality rate. There is a need for evidence regarding alternative vasopressors as first-line vasopressors. We emphasize that vasopressors should be administered simultaneously with fluid replacement to prevent and decrease duration of hypotension in shock with vasodilation. Norepinephrine is the first-choice vasopressor in septic and vasodilatory shock. Interventions that decrease norepinephrine dose (vasopressin, angiotensin II) have not decreased 28-day mortality significantly. In patients not responsive to norepinephrine, vasopressin or epinephrine may be added. Angiotensin II may be useful for rapid resuscitation of profoundly hypotensive patients. Inotropic agent(s) (e.g., dobutamine) may be needed if vasopressors decrease ventricular contractility. Dopamine has fallen to almost no-use recommendation because of adverse effects; angiotensin II is available clinically; there are potent vasopressors with scant literature (e.g., methylene blue); and the novel V1a agonist selepressin missed on its pivotal RCT primary outcome. In pediatric septic shock, vasopressors, epinephrine, and norepinephrine are recommended equally because there is no clear evidence that supports the use of one vasoactive agent. Dopamine is recommended when epinephrine or norepinephrine is not available. New strategies include perhaps patients will be started on several vasopressors with complementary mechanisms of action, patients may be selected for particular vasopressors according to predictive biomarkers, and novel vasopressors may emerge with fewer adverse effects.

There have been multiple waves in the COVID-19 pandemic in many countries. We sought to compare mortality and respiratory, cardiovascular and renal dysfunction between waves in 3 Canadian provinces.We conducted a substudy of the ARBs CORONA I study, a multicentre Canadian pragmatic observational cohort study that examined the association of pre-existing use of angiotensin receptor blockers with outcomes in adults admitted to hospital with acute COVID-19 up to April 2021 from 9 community and teaching hospitals in 3 Canadian provinces (British Columbia, Ontario and Quebec). We excluded emergency department admissions without hospital admission, readmissions and admissions for another reason. We used logistic and 0-1-inflated β regression models to compare 28-day and in-hospital mortality, and the use of invasive mechanical ventilation, vasopressors and renal replacement therapy (RRT) between the first 3 waves of the COVID-19 pandemic in these provinces.A total of 520, 572 and 245 patients in waves 1, 2 and 3, respectively, were included. Patients in wave 3 were on average younger and had fewer comorbidities than those in waves 1 and 2. The unadjusted 28-day mortality rate was significantly lower in wave 3 (7.8%) than in wave 1 (18.3%) (odds ratio [OR] 0.43, 95% confidence interval [CI] 0.24-0.78) and wave 2 (16.3%) (OR 0.46, 95% CI 0.27-0.79). After adjustment for differences in baseline characteristics, the difference in 28-day mortality remained significant (adjusted OR wave 3 v. wave 1: 0.46, 95% CI 0.26-0.81; wave 3 v. wave 2: 0.52, 95% CI 0.29-0.91). In-hospital mortality findings were similar. Use of invasive mechanical ventilation or vasopressors was less common in waves 2 and 3 than in wave 1, and use of RRT was less common in wave 3 than in wave 1.Severity of illness decreased (lower mortality and less use of organ support) across waves among patients admitted to hospital with acute COVID-19, possibly owing to changes in patient demographic characteristics and management, such as increased use of dexamethasone. Continued application of proven therapies may further improve outcomes.ClinicalTrials.gov, no. NCT04510623.

Acute kidney injury (AKI) is a potentially fatal complication of Coronavirus Disease-2019 (COVID-19). Binding of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19, to its viral receptor, angiotensin converting enzyme 2 (ACE2), results in viral entry and may cause AKI.We performed a systematic review and meta-analysis of the frequencies of AKI and renal replacement therapy (RRT) in critically ill COVID-19 patients and compared those frequencies with patients who were infected by respiratory viruses that bind or downregulate ACE2 (ACE2-associated viruses) and viruses that do not bind nor downregulate ACE2 (non-ACE2-associated viruses).Systematic review and meta-analysis.Observational studies on COVID-19 and other respiratory viral infections reporting AKI and RRT were included. The exclusion criteria were non-English articles, non-peer-reviewed articles, review articles, studies that included patients under the age of 18, studies including fewer than 10 patients, and studies not reporting AKI and RRT rates.Adult COVID-19, Severe Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome (MERS), and influenza patients.We extracted the following data from the included studies: author, year, study location, age, sex, race, diabetes mellitus, hypertension, chronic kidney disease, shock, vasopressor use, mortality, intensive care unit (ICU) admission, ICU mortality, AKI, and RRT.We systematically searched PubMed and EMBASE for articles reporting AKI or RRT. AKI was defined by authors of included studies. Critical illness was defined by ICU admission. We performed a random effects meta-analysis to calculate pooled estimates for the AKI and RRT rate within each virus group using a random intercept logistic regression model.Of 23 655 hospitalized, critically ill COVID-19 patients, AKI frequencies were not significantly different between COVID-19 patients (51%, 95% confidence interval [CI]: 44%-57%) and critically ill patients infected with ACE2-associated (56%, 95% CI: 37%-74%,Limitations of this study include the heterogeneity of definitions of AKI that were used across different virus studies. We could not match severity of infection or do propensity matching across studies. Most of the included studies were conducted in retrospective fashion. Last, we did not include non-English publications.Our findings suggest that viral ACE2 association does not significantly alter the rates of AKI and RRT among critically ill patients admitted to the ICU. However, the rate of RRT is lower in patients with COVID-19 or ACE2-associated viruses when compared with patients infected with non-ACE2-binding viruses, which might partly be due to the lower frequencies of shock and use of vasopressors in these two virus groups. Prospective studies are necessary to demonstrate whether modulation of the ACE2 axis with Renin-Angiotensin System inhibitors impacts the rates of AKI and whether they are beneficial or harmful in COVID-19 patients.L’insuffisance rénale aiguë (IRA) est une complication potentiellement mortelle de la maladie à coronavirus-2019 (COVID-19). Obligatoire du Coronavirus 2 du Syndrome Respiratoire Aigu Sévère (SARS-CoV-2), le virus responsable du COVID-19, à son récepteur, l’enzyme de conversion de l’angiotensine 2 (ACE2), entraîne une entrée virale et peut provoquer une IRA.Nous avons effectué une revue systématique et une méta-analyse des fréquences de l’IRA et de la thérapie de remplacement renal (RRT) chez les patients COVID-19 gravement malades et a comparé ces fréquences avec les patients qui ont été infectés par des voies respiratoires virus qui lient ou régulent négativement l’ACE2 (virus associés à l’ACE2) et les virus qui ne régulent pas négativement ni ne lient l’ACE2 (virus non associés à l’ACE2).Revue systématique et méta-analyse. Des études d’observation sur le COVID-19 et d’autres infections virales respiratoires signalant une AKI et une RRT ont été incluses. Les critères d’exclusion étaient des articles non anglophones, des articles non évalués par des pairs, des articles de revue, des études incluant des patients moins de 18 ans, les études incluant moins de 10 patients et les études ne rapportant pas les taux d’IRA et de RRT.Adultes COVID-19, syndrome respiratoire aigu sévère (SRAS), syndrome respiratoire du Moyen-Orient (MERS) et malades de la grippe.Nous avons extrait les données suivantes des études incluses : auteur, année, lieu de l’étude, âge, sexe, race, diabète sucré, hypertension, maladie rénale chronique, état de choc, utilisation de vasopresseurs, mortalité, admission en unité de soins intensifs (USI), Mortalité en soins intensifs, AKI et RRT.Nous avons systématiquement recherché dans PubMed et EMBASE les articles rapportant AKI ou RRT. AKI a été défini par les auteurs des études incluses. La maladie grave a été définie par l’admission aux soins intensifs. Nous avons effectué une méta-analyse à effets aléatoires pour calculer estimations regroupées pour le taux d’IRA et de RRT au sein de chaque groupe de virus à l’aide d’un modèle de régression logistique d’interception aléatoire.Sur 23 655 patients hospitalisés et gravement malades COVID-19, les fréquences AKI n’étaient pas significativement différentes entre patients COVID-19 (51 %, intervalle de confiance à 95 % [IC] : 44 %-57 %) et patients gravement malades infectés par l’ACE2 associé (56 %, IC à 95 % : 37 % à 74 %, P = 0,610) ou des virus non associés à l’ACE2 (63 %, IC à 95 % : 43 % à 79 %,Les limites de cette étude incluent l’hétérogénéité des définitions de l’IRA qui ont été utilisées pour différents virus études. Nous n’avons pas pu faire correspondre la gravité de l’infection ou faire une correspondance de propension entre les études. La plupart des études incluses ont été menées de manière rétrospective. Enfin, nous n’avons pas inclus les publications non anglophones.Nos résultats suggèrent que l’association virale ACE2 ne modifie pas de manière significative les taux d’IRA et de RRT parmi les patients gravement malades admis aux soins intensifs. Cependant, le taux de RRT est plus faible chez les patients atteints de COVID-19 ou associés à l’ACE2 virus par rapport aux patients infectés par des virus ne se liant pas à l’ACE2, ce qui pourrait être dû en partie à la plus faible fréquences de choc et utilisation de vasopresseurs dans ces deux groupes de virus. Des études prospectives sont nécessaires pour démontrer si la modulation de l’axe ACE2 avec les inhibiteurs du système rénine-angiotensine a un impact sur les taux d’IRA et si ells sont bénéfiques ou nocifs chez les patients COVID-19.

OBJECTIVES: Proprotein convertase subtilisin/kexin type 9 is a central regulator of lipid metabolism and has been implicated in regulating the host response to sepsis. Proprotein convertase subtilisin/kexin type 9 loss-of-function is associated with improved sepsis outcomes in the adult host through increased hepatic bacterial clearance. Thus, there is interest in leveraging proprotein convertase subtilisin/kexin type 9 inhibitors as a therapeutic strategy in adults with sepsis. We sought to validate this association in children with septic shock and in a juvenile murine model of sepsis. DESIGN: Prospectively enrolled cohort of children with septic shock; experimental mice. SETTING: Seventeen participating institutions; research laboratory. PATIENTS AND SUBJECTS: Five-hundred twenty-two children with septic shock; juvenile (14 d old) and adult (10–14 wk) mice with constitutive proprotein convertase subtilisin/kexin type 9 null and wildtype control mice (C57BL/6). INTERVENTIONS: Proprotein convertase subtilisin/kexin type 9 single-nucleotide polymorphisms, serum proprotein convertase subtilisin/kexin type 9, and lipid profiles in patients. Cecal slurry murine model of sepsis; survival studies in juvenile and adult mice, assessment of lipoprotein fractions, bacterial burden, and inflammation in juvenile mice. MEASUREMENTS AND MAIN RESULTS: PCSK9 loss-of-function genetic variants were independently associated with increased odds of complicated course and mortality in children with septic shock. PCSK9, low-density lipoprotein, and high-density lipoprotein concentrations were lower among patients with complicated course relative to those without. PCSK9 concentrations negatively correlated with proinflammatory cytokine interleukin-8. Proprotein convertase subtilisin/kexin type 9 loss-of-function decreased survival in juvenile mice, but increased survival in adult mice with sepsis. PCSK9 loss-of-function resulted in low lipoproteins and decreased hepatic bacterial burden in juvenile mice. CONCLUSIONS: In contrast to the adult host, proprotein convertase subtilisin/kexin type 9 loss-of-function is detrimental to the juvenile host with septic shock. PCSK9 loss-of-function, in the context of low lipoproteins, may result in reduced hepatic bacterial clearance in the juvenile host with septic shock. Our data indicate that children should be excluded in sepsis clinical trials involving proprotein convertase subtilisin/kexin type 9 inhibitors.

Purpose of review Sepsis is a common syndrome of multiorgan system dysfunction caused by a dysregulated inflammatory response to an infection and is associated with high rates of mortality. Plasma lipid and lipoprotein levels and composition change profoundly during sepsis and have emerged as both biomarkers and potential therapeutic targets for this condition. The purpose of this article is to review recent progress in the understanding of the molecular regulation of lipid metabolism during sepsis. Recent findings Patients who experience greater declines in high-density lipoprotein during sepsis are at much greater risk of succumbing to organ failure and death. Although the causality of these findings remains unclear, all lipoprotein classes can sequester and prevent the excessive inflammation caused by pathogen-associated lipids during severe infections such as sepsis. This primordial innate immune function has been best characterized for high-density lipoproteins. Most importantly, results from human genetics and preclinical animal studies have suggested that several lipid treatment strategies, initially designed for atherosclerosis, may hold promise as therapies for sepsis. Summary Lipid and lipoprotein metabolism undergoes significant changes during sepsis. An improved understanding of the molecular regulation of these changes may lead to new opportunities for the treatment of sepsis.

Rationale: High-density lipoprotein (HDL) cholesterol (HDL-C) levels decline during sepsis, and lower levels are associated with worse survival. However, the genetic mechanisms underlying changes in HDL-C during sepsis, and whether the relationship with survival is causative, are largely unknown.Objectives: We hypothesized that variation in genes involved in HDL metabolism would contribute to changes in HDL-C levels and clinical outcomes during sepsis.Methods: We performed targeted resequencing of HDL-related genes in 200 patients admitted to an emergency department with sepsis (Early Infection cohort). We examined the association of genetic variants with HDL-C levels, 28-day survival, 90-day survival, organ dysfunction, and need for vasopressor or ventilatory support. Candidate variants were further assessed in the VASST (Vasopressin versus Norepinephrine Infusion in Patients with Septic Shock Trial) cohort (n = 632) and St. Paul's Hospital Intensive Care Unit 2 (SPHICU2) cohort (n = 203).Measurements and Main Results: We identified a rare missense variant in CETP (cholesteryl ester transfer protein gene; rs1800777A) that was associated with significant reductions in HDL-C levels during sepsis. Carriers of the A allele (n = 10) had decreased survival, more organ failure, and greater need for organ support compared with noncarriers. We replicated this finding in the VASST and SPHICU2 cohorts, in which carriers of rs1800777-A (n = 35 and n = 12, respectively) had significantly reduced 28-day survival. Mendelian randomization was consistent with genetically reduced HDL levels being a causal factor for decreased sepsis survival.Conclusions: Our results identify CETP as a critical regulator of HDL levels and clinical outcomes during sepsis. These data point toward a critical role for HDL in sepsis.

OBJECTIVES: Severe acute respiratory syndrome-related coronavirus-2 binds and inhibits angiotensin-converting enzyme-2. The frequency of acute cardiac injury in patients with coronavirus disease 2019 is unknown. The objective was to compare the rates of cardiac injury by angiotensin-converting enzyme-2-binding viruses from viruses that do not bind to angiotensin-converting enzyme-2. DATA SOURCES: We performed a systematic review of coronavirus disease 2019 literature on PubMed and EMBASE. STUDY SELECTION: We included studies with ten or more hospitalized adults with confirmed coronavirus disease 2019 or other viral pathogens that described the occurrence of acute cardiac injury. This was defined by the original publication authors or by: 1) myocardial ischemia, 2) new cardiac arrhythmia on echocardiogram, or 3) new or worsening heart failure on echocardiogram. DATA EXTRACTION: We compared the rates of cardiac injury among patients with respiratory infections with viruses that down-regulate angiotensin-converting enzyme-2, including H1N1, H5N1, H7N9, and severe acute respiratory syndrome-related coronavirus-1, to those with respiratory infections from other influenza viruses that do not bind angiotensin-converting enzyme-2, including Influenza H3N2 and influenza B. DATA SYNTHESIS: Of 57 studies including 34,072 patients, acute cardiac injury occurred in 50% (95% CI, 44-57%) of critically ill patients with coronavirus disease 2019. The overall risk of acute cardiac injury was 21% (95% CI, 18-26%) among hospitalized patients with coronavirus disease 2019. In comparison, 37% (95% CI, 26-49%) of critically ill patients with other respiratory viruses that bind angiotensin-converting enzyme-2 (p = 0.061) and 12% (95% CI, 7-22%) of critically ill patients with other respiratory viruses that do not bind angiotensin-converting enzyme-2 (p < 0.001) experienced a cardiac injury. CONCLUSIONS: Acute cardiac injury may be associated with whether the virus binds angiotensin-converting enzyme-2. Acute cardiac injury occurs in half of critically ill coronavirus disease 2019 patients, but only 12% of patients infected by viruses that do not bind to angiotensin-converting enzyme-2.

Background: Angiotensin receptor blockers (ARBs) and/or angiotensin-converting enzyme (ACE) inhibitors could alter mortality from coronavirus disease 2019 (COVID-19), but existing meta-analyses that combined crude and adjusted results may be confounded by the fact that comorbidities are more common in ARB/ACE inhibitor users. Methods: We searched PubMed/MEDLINE/Embase for cohort studies and meta-analyses reporting mortality by preexisting ARB/ACE inhibitor treatment in hospitalized COVID-19 patients. Random effects meta-regression was used to compute pooled odds ratios for mortality adjusted for imbalance in age, sex, and prevalence of cardiovascular disease, hypertension, diabetes mellitus, and chronic kidney disease between users and nonusers of ARBs/ACE inhibitors at the study level during data synthesis. Results: In 30 included studies of 17,281 patients, 22%, 68%, 25%, and 11% had cardiovascular disease, hypertension, diabetes mellitus, and chronic kidney disease. ARB/ACE inhibitor use was associated with significantly lower mortality after controlling for potential confounding factors (odds ratio 0.77 [95% confidence interval: 0.62, 0.96]). In contrast, meta-analysis of ARB/ACE inhibitor use was not significantly associated with mortality when all studies were combined with no adjustment made for confounders (0.87 [95% confidence interval: 0.71, 1.08]). Conclusions: ARB/ACE inhibitor use was associated with decreased mortality in cohorts of COVID-19 patients after adjusting for age, sex, cardiovascular disease, hypertension, diabetes, and chronic kidney disease. Unadjusted meta-analyses may not be appropriate for determining whether ARBs/ACE inhibitors are associated with mortality from COVID-19 because of indication bias. Résumé: Introduction: Les antagonistes des récepteurs de l'angiotensine (ARA) et/ou les inhibiteurs de l'enzyme de conversion de l'angiotensine (IECA) feraient varier la mortalité liée à la COVID-19, mais il est possible que les méta-analyses actuelles qui combinaient les résultats bruts et ajustés soient invalidées du fait que les comorbidités sont plus fréquentes chez les utilisateurs d'ARA/IECA. Méthodes: Nous avons effectué des recherches dans les bases de données PubMed/MEDLINE/Embase pour trouver des études de cohorte et des méta-analyses qui portent sur la mortalité associée à un traitement préexistant par ARA/IECA chez les patients hospitalisés atteints de la COVID-19. Nous avons utilisé la métarégression à effets aléatoires pour calculer les rapports de cotes regroupés de mortalité ajustés en fonction du déséquilibre de l’âge, du sexe, et de la prévalence des maladies cardiovasculaires, de l'hypertension, du diabète sucré et de l'insuffisance rénale chronique entre les utilisateurs et les non-utilisateurs d'ARA/IECA dans le cadre de l’étude durant la synthèse des données. Résultats: Dans les 30 études portant sur 17 281 patients, 22 %, 68 %, 25 % et 11 % avaient respectivement une maladie cardiovasculaire, de l'hypertension, le diabète sucré et de l'insuffisance rénale chronique. L'utilisation des ARA/IECA a été associée à une mortalité significativement plus faible après avoir tenu compte des facteurs confusionnels potentiels (rapport de cotes 0,77 [intervalle de confiance à 95 % : 0,62, 0,96]). En revanche, la méta-analyse sur l'utilisation des ARA/IECA n'a pas été associée de façon significative à la mortalité lorsque toutes les études ont été combinées sans ajustement sur les facteurs confusionnels (0,87 [intervalle de confiance à 95 % : 0,71, 1,08]). Conclusions: L'utilisation des ARA/IECA a été associée à la diminution de la mortalité au sein des cohortes de patients atteints de la COVID-19 après l'ajustement en fonction de l’âge, du sexe, des maladies cardiovasculaires, de l'hypertension, du diabète et de l'insuffisance rénale chronique. Les méta-analyses non ajustées peuvent ne pas permettre de déterminer si les ARA/IECA sont associés à la mortalité liée à la COVID-19 en raison du biais d'indication.

Background: The high-density lipoprotein hypothesis of atherosclerosis has been challenged by clinical trials of cholesteryl ester transfer protein (CETP) inhibitors, which failed to show significant reductions in cardiovascular events. Plasma levels of high-density lipoprotein cholesterol (HDL-C) decline drastically during sepsis, and this phenomenon is explained, in part, by the activity of CETP, a major determinant of plasma HDL-C levels. We tested the hypothesis that genetic or pharmacological inhibition of CETP would preserve high-density lipoprotein levels and decrease mortality in clinical cohorts and animal models of sepsis. Methods: We examined the effect of a gain-of-function variant in CETP (rs1800777, p.Arg468Gln) and a genetic score for decreased CETP function on 28-day sepsis survival using Cox proportional hazard models adjusted for age and sex in the UK Biobank (n=5949), iSPAAR (Identification of SNPs Predisposing to Altered Acute Lung Injury Risk; n=882), Copenhagen General Population Study (n=2068), Copenhagen City Heart Study (n=493), Early Infection (n=200), St Paul’s Intensive Care Unit 2 (n=203), and Vasopressin Versus Norepinephrine Infusion in Patients With Septic Shock studies (n=632). We then studied the effect of the CETP inhibitor, anacetrapib, in adult female APOE*3-Leiden mice with or without human CETP expression using the cecal-ligation and puncture model of sepsis. Results: A fixed-effect meta-analysis of all 7 cohorts found that the CETP gain-of-function variant was significantly associated with increased risk of acute sepsis mortality (hazard ratio, 1.44 [95% CI, 1.22–1.70]; P P =0.03), whereas there was no effect of anacetrapib on the survival of APOE*3-Leiden mice that did not express CETP (50.0% versus 42.9%, Log-rank P =0.87). Conclusions: Clinical genetics and humanized mouse models suggest that inhibiting CETP may preserve high-density lipoprotein levels and improve outcomes for individuals with sepsis.

Background: Reduced activity of proprotein convertase subtilisin/kexin type 9 (PCSK9) has been associated with decreased short-term death in patients with septic shock. Whether PCSK9 genotype influences long-term outcomes in sepsis survivors is unknown. Methods: We evaluated the impact of PCSK9 loss-of-function (LOF) genotype on both 1-year mortality and infection-related readmission (IRR) after an index sepsis admission. The Derivation cohort included 342 patients who survived 28 days after a sepsis admission in a tertiary hospital (Vancouver/Canada, 2004–2014), while an independent Validation cohort included 1079 septic shock patients admitted at the same hospital (2000–2006). All patients were genotyped for three common missense PCSK9 LOF variants rs11591147, rs11583680, rs562556 and were classified in 3 groups: Wildtype, single PCSK9 LOF, and multiple PCSK9 LOF, according to the number of LOF alleles per patient. We also performed a meta-analysis using both cohorts to investigate the effects of PCSK9 genotype on 90-day survival. Findings: In the Derivation cohort, patients carrying multiple PCSK9 LOF alleles showed lower risk for the composite outcome 1-year death or IRR (HR: 0.40, P = 0.006), accelerated reduction on neutrophil counts (P = 0.010), and decreased levels of PCSK9 (P = 0.037) compared with WT/single LOF groups. Our meta-analysis revealed that the presence of multiple LOF alleles was associated with lower 90-day mortality risk (OR = 0.69, P = 0.020). Interpretation: The presence of multiple PCSK9 LOF alleles decreased the risk of 1-year death or IRR in sepsis survivors. Biological measures suggest this may be related to an enhanced resolution of the initial infection. Funding: Canadian Institutes of Health Research (PJT-156056). Keywords: PCSK9, Sepsis, Septic shock, Mortality, Readmission

Background Reduced activity of proprotein convertase subtilisin/kexin type 9 (PCSK9) has been associated with decreased short-term death in patients with septic shock. Whether PCSK9 genotype influences long-term outcomes in sepsis survivors is unknown. Methods We evaluated the impact of PCSK9 loss-of-function (LOF) genotype on both 1-year mortality and infection-related readmission (IRR) after an index sepsis admission. The Derivation cohort included 342 patients who survived 28 days after a sepsis admission in a tertiary hospital (Vancouver/Canada, 2004–2014), while an independent Validation cohort included 1079 septic shock patients admitted at the same hospital (2000–2006). All patients were genotyped for three common missense PCSK9 LOF variants rs11591147, rs11583680, rs562556 and were classified in 3 groups: Wildtype, single PCSK9 LOF, and multiple PCSK9 LOF, according to the number of LOF alleles per patient. We also performed a meta-analysis using both cohorts to investigate the effects of PCSK9 genotype on 90-day survival. Findings In the Derivation cohort, patients carrying multiple PCSK9 LOF alleles showed lower risk for the composite outcome 1-year death or IRR (HR: 0.40, P = 0.006), accelerated reduction on neutrophil counts (P = 0.010), and decreased levels of PCSK9 (P = 0.037) compared with WT/single LOF groups. Our meta-analysis revealed that the presence of multiple LOF alleles was associated with lower 90-day mortality risk (OR = 0.69, P = 0.020). Interpretation The presence of multiple PCSK9 LOF alleles decreased the risk of 1-year death or IRR in sepsis survivors. Biological measures suggest this may be related to an enhanced resolution of the initial infection. Funding Canadian Institutes of Health Research (PJT-156056).

Objectives: Our objectives were to determine first whether albumin prevents heparin-binding protein-induced increased endothelial cell permeability and renal cell inflammation and second, whether a plasma heparin-binding protein-to-albumin ratio predicts risk of acute kidney injury, fluid balance, and plasma cytokine levels in septic shock. Design: In vitro human endothelial and renal cell model and observation cohort of septic shock. Settings: Research laboratory and multicenter clinical trial (Vasopressin and Septic Shock Trial). Patients: Adult septic shock (norepinephrine dose > 5 μg/min for > 6 hr). Interventions: In vitro: heparin-binding protein (or thrombin) was added with or without albumin to 1) human endothelial cell monolayers to assess permeability and 2) to human renal tubular epithelial cells to assess inflammation. Measurements and Main Results: Transendothelial electrical resistance - a marker of permeability - of human endothelial cells was measured using a voltohmmeter. We measured plasma heparin-binding protein-to-albumin ratio and a panel of cytokines in septic shock patients (n = 330) to define an heparin-binding protein-to-albumin ratio that predicts risk of acute kidney injury. Albumin inhibited heparin-binding protein (and thrombin-induced) increased endothelial cell permeability at a threshold concentration of 20-30 g/L but increased renal tubular cell interleukin-6 release. Patients who developed or had worsened acute kidney injury had significantly higher heparin-binding protein-to-albumin ratio (1.6 vs 0.89; p 3.05), heparin-binding protein quartiles (> 69.8), and heparin-binding protein > 30 ng/mL were significantly associated with development or worsening of acute kidney injury (p < 0.001) in unadjusted and adjusted analyses and were robust to sensitivity analyses for death as a competing outcome. Heparin-binding protein and heparin-binding protein-to-albumin ratio were directly associated with positive fluid balance (p < 0.001) and with key inflammatory cytokines. Increasing quartiles of heparin-binding protein-to-albumin ratio and heparin-binding protein (but not albumin) were highly significantly associated with days alive and free of acute kidney injury and renal replacement therapy (p < 0.001), vasopressors (p < 0.001), ventilation (p < 0.001), and with 28-day mortality. Conclusions: Albumin inhibits heparin-binding protein-induced increased human endothelial cell permeability and heparin-binding protein greater than 30 ng/mL and heparin-binding protein-to-albumin ratio greater than 3.01 - but not serum albumin - identified patients at increased risk for acute kidney injury in septic shock. (Less)

The toxicity caused by different organisms in septic shock is substantially complex and characterized by an intricate pathogenicity that involves several systems and pathways. Immune cells’ pattern recognition receptors initiate the host response to pathogens after the recognition of pathogen-associated molecular patterns. In essence, the subsequent activation of downstream pathways may progress to infection resolution or to a dysregulated host response that represents the hallmark of organ injury in septic shock. Likewise, the management of organism toxicity in septic shock is complicated and comprises a multiplicity of suitable targets. In this review, the classic immune responses to pathogens are discussed as well as other factors that are relevant in the pathogenicity of septic shock, including sepsis-induced immune suppression, inflammasome activation, intestinal permeability, and the role of lipids and proprotein convertase subtilisin/kexin type 9. Current therapies aiming to eliminate the organisms causing septic shock, recent and ongoing trials in septic shock treatment, and potential new therapeutic strategies are also explored.

Fundamental features of septic shock are vasodilation, increased permeability, hypovolemia, and ventricular dysfunction. Vasodilation owing to increased nitric oxide and prostaglandins is treated with vasopressors (norepinephrine first). Increased permeability relates to several pathways (Slit/Robo4, vascular endothelial growth factor, angiopoietin 1 and 2/Tie2 pathway, sphingosine-1-phosphate, and heparin-binding protein), some of which are targets for therapies. Hypovolemia is common and crystalloid is recommended for fluid resuscitation. Cardiomyocyte-inflammatory interactions decrease contractility and dobutamine is recommended to increase cardiac output. There is benefit in decreasing heart rate in selected patients with esmolol. Ivabradine is a novel agent for heart rate reduction without decreasing contractility.

Background: The IL10 family of genes includes crucial immune regulators. We tested the hypothesis that single nucleotide polymorphisms (SNPs) in IL10, IL19, IL20, and IL24 of the IL10 family gene cluster alter the clinical outcome of septic shock. Methods: Patients with septic shock (n = 1,193) were genotyped for 13 tag SNPs of IL10, IL19, IL20, and IL24. IL20 gene expression was measured in genotyped lymphoblastoid cells in vitro. Cardiac surgical ICU patients (n = 981) were genotyped for IL20 rs2981573 A/G. The primary outcome variable was 28-day mortality. Results: Patients with the G allele of IL20 rs2981573 had a significantly increased hazard of death over the 28-day period compared to patients with the A allele in the septic shock cohort (adjusted hazard ratio 1.27; 95% confidence interval 1.10-1.47; p = 8.0 × 10-4). Patients with the GG genotype had more organ dysfunction (p < 0.05). The GG genotype was associated with increased IL20 gene expression in stimulated lymphoblastoid cells in vitro (p < 0.05). The cardiac surgical ICU patients with the GG genotype had an increased length of ICU stay (p = 0.032). Conclusions: The GG genotype of IL20 rs2981573 SNP was associated with increased IL20 gene expression and increased adverse outcomes in patients with septic shock and following cardiac surgery.

RATIONALE: Sepsis-induced acute kidney injury (AKI) is a common condition with high morbidity and mortality. Neutrophil-derived heparin-binding protein (HBP) induces vascular leakage and is a promising biomarker of sepsis-induced organ dysfunction. It remains unknown if HBP is prognostic of AKI in septic shock and if HBP could play a role in the pathophysiology of sepsis-induced AKI.OBJECTIVES: To determine the association of plasma HBP levels with development of AKI, investigate the role of HBP in the pathophysiology of sepsis-induced AKI, and test the effect of blocking HBP using heparin derivatives.METHODS: In 296 septic shock patients from the randomized multicenter Vasopressin and Septic Shock Trial (VASST) plasma HBP levels were associated with development of AKI and need for renal replacement therapy (RRT). Human renal tubular cells were exposed to recombinant HBP to evaluate inflammation and heparin derivatives were used to abrogate these effects. Finally, mice were exposed to HBP with and without heparin derivatives and the kidneys examined for signs of inflammation.FINDINGS: Plasma HBP levels were significantly higher in patients with AKI and those requiring RRT. HBP levels identified patients with moderate AKI with an area under curve (AUC) of 0.85. HBP increased IL-6 production in renal tubular epithelial cells. Different heparin derivatives abrogated the HBP-induced increased inflammatory response in vitro and in vivo.CONCLUSION: Elevated plasma HBP is associated with development of sepsis-induced AKI and HBP is involved in its pathophysiology. Our studies suggest that heparin(s) could be tested for efficacy and safety of prevention of sepsis-induced AKI. (Less)

BACKGROUND Organ donation after circulatory death (DCD) is increasingly being used as a means of addressing the organ supply/demand mismatch in solid organ transplantation. There is reluctance to use DCD hearts, due to an inability to precisely identify hearts that have suffered irreversible injury. We investigated novel biomarkers and clinically relevant endpoints across a spectrum of warm ischemic times, before and during ex vivo heart perfusion (EVHP), to identify features associated with a nonviable cardiac phenotype. METHODS Donor rats sustained a hypoxic cardiac arrest, followed by variable acirculatory standoff periods (DCD groups). Left ventricular function, histochemical injury, and differences in left ventricular gene expression were studied before, and during, EVHP. RESULTS As warm ischemic time exposure increased in DCD groups, fewer hearts were functional during EVHP, and ventricular function was increasingly impaired. Histochemical assessment identified severely injured hearts during EVHP. A novel gene expression signature identified severely injured hearts during EVHP (upregulation of c-Jun, 3.19 (2.84-3.60); P = 0.0014; HMOX-1, 3.87 (2.72-5.50); P = 0.0037; and Hsp90, 7.66 (6.32-9.27); P < 0.0001 in DCD20), and may be useful in identifying high-risk hearts at the point of harvest (Hsp90). CONCLUSIONS We demonstrate that our preclinical model recapitulates the cardio-respiratory decompensation observed in humans, and that EVHP appears necessary to unmask distinguishing features of severely injured DCD hearts. Furthermore, we outline a clinically relevant multimodal approach to assessing candidate DCD hearts. Novel mRNA signatures correlated with elevations in cardiac Troponin-I in severely injured hearts during EVHP, and may also detect injury at the point of harvest.

The impact of chronic exposure to air pollution and outcomes in the acute respiratory distress syndrome (ARDS) is unknown. The Nationwide Inpatient Sample (NIS) from 2011 was utilized for this analysis. The NIS is a national database that captures 20% of all US in-patient hospitalizations from 47 states. Patients with ARDS who underwent mechanical ventilation from the highest 15 ozone pollution cities were compared with the rest of the country. Secondary analyses assessed outcomes of ARDS patients for ozone pollution and particulate matter pollution on a continuous scale by county of residence. A total of 8,023,590 hospital admissions from the 2011 NIS sample were analyzed. There were 93,950 patients who underwent mechanical ventilation for ARDS included in the study. Patients treated in high ozone regions had significantly higher unadjusted hospital mortality (34.9% versus 30.8%, p

Purpose We sought to determine whether an early high-density lipoprotein cholesterol (HDL-C) measurement at emergency department (ED) admission is prognostic of multiorgan dysfunction syndrome (MODS) and death in a suspected sepsis cohort. Materials and Methods Two hundred patients with clinically suspected sepsis were recruited at admission to our tertiary care hospital's ED. Lipids were measured at the time of first ED blood draw. Clinical data were collected via chart review. Primary outcomes of interest were development of MODS and 28-day mortality. Secondary outcomes included need for critical care, single-organ failures, days alive and free of vasopressor and ventilator support, and 90-day mortality. Results High-density lipoprotein cholesterol was greatly decreased in patients who developed MODS and/or died and remained stable over the first week of admission. Receiver operator characteristic analysis demonstrated that HDL-C had superior predictive ability compared with all routine clinical markers for both development of MODS and 28-day mortality, and identified an HDL-C cutoff of 25.1 mg/dL below which patients were at significantly greater risk for development of all adverse outcomes. Conclusions Plasma HDL-C level was characterized by early decrease and high stability, and was the best prognostic marker for adverse outcomes in a suspected sepsis cohort.

Background Sepsis is associated with decreased levels of high-density lipoprotein (HDL) cholesterol. HDL has anti-inflammatory properties, and the use of Apo A-I mimetic peptides is associated with renal function improvement in animal models of sepsis. However, it is not known whether decreased HDL level results in impaired renal function in human sepsis. We investigated whether low levels of HDL conferred an increased risk of sepsis-associated acute kidney injury (AKI) or long-term decreased estimated glomerular filtration rate (eGFR) after sepsis. Methods HDL concentration (mg dL−1) was measured in plasma samples from 180 patients with septic shock at admission to the Emergency Department (ED). We divided the patients using median HDL as a cut-off value and assessed the frequency of sepsis-associated AKI and long-term decreased eGFR after sepsis. Univariate and multivariate analyses were performed. Results Patients with low HDL had a significantly greater frequency of KDIGO 2 or 3 sepsis-associated AKI [39/90 (43.3%) vs. 12/90 (13.3%), P < 0.001] and decreased long-term eGFR [24/58 (41.4%) vs. 11/57 (19.3%), P = 0.018] compared to those with high HDL. The adjusted OR for sepsis-associated AKI and decreased eGFR after sepsis in the lower HDL group was 2.80 (95% CI 1.08–7.25, P = 0.033) and 5.45 (95% CI 1.57–18.93, P = 0.008), respectively. Conclusion Low HDL levels during sepsis are associated with increased risk of sepsis-associated AKI, and/or subsequent decreased eGFR. These results suggest that HDL may be involved and/or may be a marker of kidney injury during and after sepsis.

OBJECTIVE:To estimate the rate of acute respiratory distress syndrome (ARDS) in pregnant patients as well as to investigate clinical conditions associated with mortality.METHODS:We used the Nationwide Inpatient Sample from 2006 to 2012 to identify a cohort of pregnant patients who underwent mechanic

Chills and vomiting have traditionally been associated with severe bacterial infections and bacteremia. However, few modern studies have in a prospective way evaluated the association of these signs with bacteremia, which is the aim of this prospective, multicenter study. Patients presenting to the emergency department with at least one affected vital sign (increased respiratory rate, increased heart rate, altered mental status, decreased blood pressure or decreased oxygen saturation) were included. A total of 479 patients were prospectively enrolled. Blood cultures were obtained from 197 patients. Of the 32 patients with a positive blood culture 11 patients (34%) had experienced shaking chills compared with 23 (14%) of the 165 patients with a negative blood culture, P = 0.009. A logistic regression was fitted to show the estimated odds ratio (OR) for a positive blood culture according to shaking chills. In a univariate model shaking chills had an OR of 3.23 (95% CI 1.35–7.52) and in a multivariate model the OR was 5.9 (95% CI 2.05–17.17) for those without prior antibiotics adjusted for age, sex, and prior antibiotics. The presence of vomiting was also addressed, but neither a univariate nor a multivariate logistic regression showed any association between vomiting and bacteremia. In conclusion, among patients at the emergency department with at least one affected vital sign, shaking chills but not vomiting were associated with bacteremia.

BACKGROUND:To allow early identification of patients at risk of sepsis in the emergency department (ED), a variety of risk stratification scores and/or triage systems are used. The first aim of this study was to develop a risk stratification score for sepsis based upon vital signs and biomarkers using a statistical approach. Second, we aimed to validate the Rapid Emergency Triage and Treatment System (RETTS) for sepsis. RETTS combines vital signs with symptoms for risk stratification. METHODS:We retrospectively analysed data from two prospective, observational, multicentre cohorts of patients from studies of biomarkers in ED. A candidate risk stratification score called Sepsis Heparin-binding protein-based Early Warning Score (SHEWS) was constructed using the Least Absolute Shrinkage and Selector Operator (LASSO) method. SHEWS and RETTS were compared to National Early Warning Score 2 (NEWS2) for infection-related organ dysfunction, intensive care or death within the first 72h after admission (i.e. sepsis). RESULTS:506 patients with a diagnosed infection constituted cohort A, in which SHEWS was derived and RETTS was validated. 435 patients constituted cohort B of whom 184 had a diagnosed infection where both scores were validated. In both cohorts (A and B), AUC for infection-related organ dysfunction, intensive care or death was higher for NEWS2, 0.80 (95% CI 0.76-0.84) and 0.69 (95% CI 0.63-0.74), than RETTS, 0.74 (95% CI 0.70-0.79) and 0.55 (95% CI 0.49-0.60), p = 0.05 and p

Supplemental Digital Content is available in the text., Objective: HDL (high-density lipoprotein) cholesterol (HDL-C) and LDL (low-density lipoprotein) cholesterol (LDL-C) are inversely associated with infectious hospitalizations. Whether these represent causal relationships is unknown. Approach and Results: Adults of 40 to 69 years of age were recruited from across the United Kingdom between 2006 and 2010 and followed until March 31, 2016, as part of the UK Biobank. We determined HDL-C, LDL-C, and triglyceride polygenic scores for UK Biobank participants of British white ancestry (n=407 558). We examined the association of lipid levels and polygenic scores with infectious hospitalizations, antibiotic usage, and 28-day sepsis survival using Cox proportional hazards or logistic regression models. Measured levels of HDL-C and LDL-C were inversely associated with risk of infectious hospitalizations, while triglycerides displayed a positive association. A 1-mmol/L increase in genetically determined levels of HDL-C associated with a hazard ratio for infectious disease of 0.84 ([95% CI, 0.75–0.95]; P=0.004). Mendelian randomization using genetic variants associated with HDL-C as an instrumental variable was consistent with a causal relationship between elevated HDL-C and reduced risk of infectious hospitalizations (inverse weighted variance method, P=0.001). Furthermore, of 3222 participants who experienced an index episode of sepsis, there was a significant inverse association between continuous HDL-C polygenic score and 28-day mortality (adjusted hazard ratio, 0.37 [95% CI, 0.14–0.96] per 1 mmol/L increase; P=0.04). LDL-C and triglyceride polygenic scores were not significantly associated with hospitalization for infection, antibiotic use, or sepsis mortality. Conclusions: Our results provide causal inference for an inverse relationship between HDL-C, but not LDL-C or triglycerides, and risk of an infectious hospitalization.

Obese patients have lower sepsis mortality termed the "obesity paradox." We hypothesized that lipopolysaccharide, known to be carried within lipoproteins such as very low density lipoprotein, could be sequestered in adipose tissue during sepsis; potentially contributing a survival benefit.Retrospective analysis.University research laboratory.Vldlr knockout mice to decrease very low density lipoprotein receptors, Pcsk9 knockout mice to increase very low density lipoprotein receptor, and Ldlr knockout mice to decrease low density lipoprotein receptors. Differentiated 3T3-L1 adipocytes. Caucasian septic shock patients.We measured lipopolysaccharide uptake into adipose tissue 6 hours after injection of fluorescent lipopolysaccharide into mice. Lipopolysaccharide uptake and very low density lipoprotein receptor protein expression were measured in adipocytes. To determine relevance to humans, we genotyped the VLDLR rs7852409 G/C single-nucleotide polymorphism in 519 patients and examined the association of 28-day survival with genotype.Lipopolysaccharide injected into mice was found in adipose tissue within 6 hours and was dependent on very low density lipoprotein receptor but not low density lipoprotein receptors. In an adipocyte cell line decreased very low density lipoprotein receptor expression resulted in decreased lipopolysaccharide uptake. In septic shock patients, the minor C allele of VLDLR rs7852409 was associated with increased survival (p = 0.010). Previously published data indicate that the C allele is a gain-of-function variant of VLDLR which may increase sequestration of very low density lipoprotein (and lipopolysaccharide within very low density lipoprotein) into adipose tissue. When body mass index less than 25 this survival effect was accentuated and when body mass index greater than or equal to 25 this effect was diminished suggesting that the effect of variation in very low density lipoprotein receptor function is overwhelmed when copious adipose tissue is present.Lipopolysaccharide may be sequestered in adipose tissue via the very low density lipoprotein receptor and this sequestration may contribute to improved sepsis survival.

While clinical donation after circulatory death (DCD) cardiac transplantation is being implemented with increasing frequency to address the supply/demand mismatch of donor grafts, no research to date has examined a strategy of donor preconditioning to optimize the viability of DCD hearts for transplantation. In our rat model of the DCD protocol, we investigate the impact of pretreating donors with phosphorothioate-linked cytosine and guanine rich oligodeoxynucleotides (CpG ODN) and their effects on cardiac function, injury, and a novel left ventricular (LV) mRNA biomarker panel.DCD rats were subjected to a withdrawal protocol, followed by 20 minutes of warm acirculatory standoff, representing a group of severely injured hearts as previously demonstrated. Beating heart controls and DCD rats were pretreated with vehicle or stimulatory CpG ODN (beating heart control and DCD stimulated with CpG ODN, BST and DST). Hearts were harvested for ex situ heart perfusion (ESHP), where LV function, histochemical injury, and differences in gene expression were characterized between groups.Donor pretreatment with CpG ODN doubled the number of functional DCD hearts at ESHP. Pretreatment was associated with improved systolic and diastolic LV function, a reduction in histological injury, and markedly reduced elaboration of cardiac troponin-I in coronary effluent during ESHP. Pretreatment was also associated with a reduction in mRNA biomarkers associated with myocardial injury.A single dose of CpG ODN was associated with reduced biomarkers of cardiac injury and a 100% increase in cardiac viability in this rodent model of marginal DCD cardiac donation.

Previous studies have shown lipopolysaccharide from Gram-negative bacteria is cleared from the circulation via LDL receptors on hepatocytes, which are downregulated by PCSK9. Whether clearance of Gram positive bacterial lipoteichoic acid (LTA) shows similar dependence on PCSK9, and whether this is clinically relevant in Gram positive human sepsis, is unknown. We examined survival data from three cohorts of patients who had Gram positive septic shock (n = 170, n = 130, and n = 59) and found that patients who carried a PCSK9 loss-of-function (LOF) allele had significantly higher 28-day survival (73.8%) than those with no LOF alleles (52.8%) (p = 0.000038). Plasma clearance of LTA was also found to be increased in PCSK9 knockout mice compared to wildtype control mice (p = 0.002). In addition, hepatocytes pre-treated with recombinant wildtype PCSK9 showed a dose-dependent decrease in uptake of fluorescently-labeled LTA (p

Objectives:Visceral and subcutaneous adipose tissue may contribute differentially to the septic inflammatory response. Accordingly, we tested the hypothesis that the ratio of visceral to subcutaneous adipose tissue is associated with altered sepsis outcome.Design:A retrospective analysis from a coho

Angiopoietins modulate endothelial permeability via endothelial cell junctions. Angiopoietin-2 blocks the angiopoietin-1/Tie-2 interaction that stabilizes these junctions, and elevated plasma angiopoietin-2 levels are associated with vascular leakage. We hypothesized that plasma angiopoietin-1 and angiopoietin-2 levels are associated with indirect markers of increased vascular permeability, organ dysfunction, mortality, and plasma proinflammatory cytokine levels in human septic shock.Multicenter observational cohort study derived from a randomized controlled trial (Vasopressin and Septic Shock Trial of vasopressin versus norepinephrine in septic shock).ICUs of hospitals in Canada, Australia, and the United States.Three hundred forty-one patients in the randomized, controlled Vasopressin and Septic Shock Trial trial of vasopressin versus norepinephrine in septic shock.None.We measured plasma levels of angiopoietin-1 and angiopoietin-2 at study baseline and determined their association with percent fluid overload and acute organ dysfunction and generated a receiver operating characteristic curve for plasma angiopoietin-2 levels versus acute kidney injury. We also determined the association of angiopoietin-1 and angiopoietin-2 levels with hemodynamics, mortality, and plasma cytokine levels. Plasma angiopoietin-2 levels were directly associated with percent fluid overload at baseline (rs = 0.18; p = 0.0008) and at 6 hours (rs = 0.13; p = 0.023), but not at 24 hours (rs = 0.041; p = 0.46). Plasma angiopoietin-2 levels were associated with the development of hepatic (p0.0001) and coagulation (p0.0001) dysfunction and acute kidney injury (p0.0001). Receiver operating characteristic curve had an area under the curve of 0.73 for acute kidney injury. angiopoietin-2 levels were also inversely associated with days alive (r = -0.24; p = 0.010) and positively associated with increased 7-day (log-rank trend chi-square = 5.9; p = 0.015) and 28-day (log-rank chi square = 4.9; p = 0.027) mortality. A threshold of angiopoietin-2 levels above the first quartile (5,807 pg/mL) was observed to be associated with increased mortality risk, which aligns with prior studies. Plasma angiopoietin-2 levels were positively associated with plasma cytokine levels, including tumor necrosis factor-α and interleukin-6 at baseline (rs = 0.39; p0.0001 and rs = 0.51; p0.0001) and at 24 hours (rs = 0.29; p0.0001 and rs = 0.41; p0.0001).Increased plasma angiopoietin-2 levels are associated with increased fluid overload, hepatic and coagulation dysfunction, acute kidney injury, mortality, and plasma cytokines in human septic shock. angiopoietin-2 activation may increase vascular leakage leading to increased fluid requirements, organ dysfunction, and death from septic shock.

Objectives: As mortality of septic shock decreases, new therapies focus on improving short-term organ dysfunction. However, it is not known whether short-term organ dysfunction is associated with long-term mortality of septic shock. Design: Retrospective single-center. Setting: Mixed medical-surgical ICU. Patients: One thousand three hundred and thirty-one patients with septic shock were included from 2000-2004. To remove the bias of 28-day nonsurvivors' obvious association with long-term mortality, we determined the associations of days alive and free of ventilation, vasopressors and renal replacement therapy in 28-day and 1-year survivors with 1-, 5- and 10-year mortality in unadjusted analyses and analyses adjusted for age, gender, Acute Physiology and Chronic Health Evaluation II and presence of chronic comorbidities. Interventions: None. Measurements and Main Results: Days alive and free of ventilation, vasopressors, and renal replacement therapy were highly significantly associated with 1-, 5-, and 10-year mortality (p

While the policy of too-big-to-fail has received wide attention in the literature, there is little agreement regarding economies of scale for financial firms. We take the stand that systemic risk increases when the larger players in the financial sector have a larger share of output. Calculations indicate that the cost to the macro-economy due to increased systemic risk is always much larger than the potential benefit due to scale economies. When distributional and intergenerational issues are considered, the potential benefits to economies of scale are unlikely to ever exceed the potential costs due to increased risk of a banking crisis.

OBJECTIVE Rapid and early detection of patients at risk to develop sepsis remains demanding. Heparin-binding protein (HBP) has previously demonstrated good prognostic properties in detecting organ dysfunction among patients with suspected infections. This study aimed to evaluate the plasma-levels of HBP as a prognostic biomarker for infection-induced organ dysfunction among patients seeking medical attention at the emergency department. DESIGN Prospective, international multicenter, convenience sample study SETTING:: Four general emergency departments at academic centers in Sweden, Switzerland and Canada. PATIENTS All emergency encounters among adults where one of the following criteria were fulfilled: a) respiratory rate >25 breaths per minute; b) heart rate >120 beats per minute; c) altered mental status; d) systolic blood pressure

Early administration of antibiotics is associated with better survival in sepsis, thus screening and early detection for sepsis is of clinical importance. Current risk stratification scores used for bedside detection of sepsis, for example Quick Sequential Organ Failure Assessment (qSOFA) and National Early Warning Score 2 (NEWS2), are primarily validated for death and intensive care. The primary aim of this study was to compare the diagnostic accuracy of qSOFA and NEWS2 for a composite outcome of sepsis with organ dysfunction, infection-related mortality within &lt, 72 h, or intensive care due to an infection. Retrospective analysis of data from two prospective, observational, multicentre, convenience trials of sepsis biomarkers at emergency departments were performed. Cohort A consisted of 526 patients with a diagnosed infection, 288 with the composite outcome. Cohort B consisted of 645 patients, of whom 269 had a diagnosed infection and 191 experienced the composite outcome. In Cohort A and B, NEWS2 had significantly higher area under receiver operating characteristic curve (AUC), 0.80 (95% CI 0.75&ndash, 0.83) and 0.70 (95% CI 0.65&ndash, 0.74), than qSOFA, AUC 0.70 (95% CI 0.66&ndash, 0.75) and 0.62 (95% CI 0.57&ndash, 0.67) p &lt, 0.01 and, p = 0.02, respectively for the composite outcome. NEWS2 was superior to qSOFA for screening for sepsis with organ dysfunction, infection-related mortality or intensive care due to an infection both among infected patients and among undifferentiated patients at emergency departments.

Background: Diabetes may increase sepsis risk, but it is unknown whether and how diabetes alters sepsis mortality. Our hypotheses were: (1) diabetes increases risk of sepsis and mortality; during sepsis (2) diabetes alters the inflammatory response; (3) hyperglycemia is associated with altered lipid levels. Methods: We studied four cohorts (Population-based, multi-center, and single center cohorts; 2000-2016) with minimum 28-day follow-up: UK Biobank Cohort 1 (n =484,857; diabetics n = 25,430; non-diabetics n = 459,407), Single Centre Cohort 2 (n = 727; diabetics = 37; non-diabetics n = 690), Inflammation Mechanism Cohort 3 (n = 779; diabetics n = 165; non-diabetics n = 614), Lipid Mechanism Cohort 4 (n = 200; diabetics n = 49; non-diabetics n = 151). Twenty eight-day mortality and days-alive-and-free (DAF) of vasopressors, ventilation and renal replacement therapy (RRT) of diabetics and non-diabetics were compared. Hierarchical clustering was done on 39 cytokines and glucose association with HDL and triglyceride levels was evaluated early in sepsis. Findings: Diabetics increased sepsis admission risk (n = 478/25,430 [1.89%] vs. n = 3,179/459,407 [0.70%], odds ratio (OR)[95% CI]: 2.75 [2.50 to 3.03], p

Background The indication, composition and timing of administration of non-resuscitation fluid in septic shock have so far received little attention and accordingly the potential to reduce this source of fluid is unknown. The objective of the study was to quantify and characterize non-resuscitation fluid administered to patients with septic shock. Methods This prospective observational study was performed in eight intensive care units in Sweden and Canada during 4 months in 2018. Adult patients with septic shock within 24 h of admission to the intensive care unit were eligible for inclusion. Non-resuscitation fluids were defined as fluids other than colloids, blood products and crystalloids at a rate ≥ 5 ml/kg/h. Indication, volume and type of fluid were recorded during the first 5 days after admission. A maximum of 30 patients could be included per centre. To estimate the potential to reduce administration of non-resuscitation fluid, a pragmatic “restrictive” protocol for administration of non-resuscitation fluids was devised based on the most restrictive practice already in place for non-resuscitation fluids at any of the participating centres. Data are presented as median (interquartile range [IQR]). Results A total of 200 patients were included in the study and the 30-day mortality was 35%. Patients received a total of 7870 (4060–12,340) ml of non-resuscitation fluids and 2820 (1430–4580) of resuscitation fluids during the observation period. Median volumes of non-resuscitation and resuscitation fluids were similar at day 1 (1620 [710–2320] and 1590 [520–3000]) ml, respectively) and non-resuscitation fluids represented the largest source of fluid from day 2 and onwards after admission to the ICU. Vehicles for drugs such as vasoactive drugs and antibiotics constituted the largest fraction of non-resuscitation fluids (2400 [1270–4030] ml) during the 5-day observation period. Modelling suggested that volume of non-resuscitation fluids could be reduced by 2840 (1270–4900) ml during the first 5 days of admission to the ICU, mainly through reducing maintenance fluids. Conclusions Non-resuscitation fluids constitute the major fraction of fluids administered in the ICU to patients suffering from septic shock and may represent the largest modifiable target to reduce fluid overload.