Hours Of Sepsis Research Articles

Quick Sequential Organ Failure Assessment Score, Lactate, and Neutrophil-Lymphocyte Ratio Help in Diagnosis and Mortality Prediction during Golden Hour of Sepsis in Emergency Department.

Sepsis is a life-threatening condition with a very narrow golden period in which confirmatory diagnosis may change the outcome dramatically. No confirmatory biomarker is available till date for early diagnosis of sepsis. This study aimed to evaluate the combined and independent role of quick sequential organ failure assessment (qSOFA) score, lactate, and neutrophil-lymphocyte ratio (NLR) in diagnosis and mortality prediction in early sepsis. This was a hospital-based, single-center, prospective cohort study conducted in a tertiary care institute, Karnataka, India. Three hundred adult sepsis patients were recruited during 10-month period, and demographic data, qSOFA score, lactate, NLR, and culture samples were collected in ED within 1 h of admission. Outcome groups (survivor and nonsurvivor) were statistically analyzed with relative frequencies (%), median, mean ± standard deviation with 95% confidence interval (CI), univariate, bivariate, and multivariate logistic regression analysis, and Receiver -operating characteristic curve (ROC) curve to test the predictive ability of initial levels of three biomarkers. Sepsis was more prevalent among middle-aged male patients. Male gender (odds ratio [OR], 6.9; 95% CI: 1.61-30.1), qSOFA (OR, 154; 95% CI: 15-1565), and lactate (OR, 1.36; 95% CI: 22-833) show 97% (area under the curve) predictive accuracy of the model for sepsis on bivariate and multivariate logistic regression analysis. A significant rise in NLR was a poor outcome indicator on univariate analysis (P = 0.773). All three biomarkers are good outcome predictors whereas qSOFA and lactate have diagnostic significance in early sepsis. These markers can be used for patient triaging, minimizing culture report dependence for treatment and ultimately the outcome.

Children with malignancies and septic shock - an attempt to understand the risk factors

ObjectivesTo explain the high mortality of septic shock in children with cancer. MethodsA retrospective cohort from 2016 to 2020, of children aged 0 to 18 years, and septic shock. ResultsThe authors included 139 patients. Acute lymphocytic leukemia was the most frequent diagnosis (16.5%), and Gram-negative bacteria were the most frequent blood culture isolates (22.3%). There were 57 deaths in ICU (41%), 10 in the first 24 hours of shock (early death). A LASSO model with variables: neutropenia (coefficient 0.215), respiratory (0.81), hematological (1.41), and neurological (0.72) dysfunctions, age (-0.002) and solid tumor recurrence (0.34) generated AUC = 0.79 for the early death outcome. Survivors had significant differences in the PRISM-IV score (mean ± SD 10.9 ± 6.2 in the survivors, 14.1 ± 6.5 in the deceased, p = 0.004), and in the mean number of organ dysfunctions (3.2 ± 1.1 in the survivors, 3.8 ± 6.5 in the deceased, p < 0.001). A positive fluid balance in the first 24 hours of sepsis between 2% and 6% of body weight showed a reduction effect on the probability of death in ICU (hazard ratio 0.47, 95% CI 0.24-0.92, p = 0.027). The recurrence of any cancer was a predictor of in-hospital death, regardless of severity. ConclusionsRecurrence of any cancer is an important risk of sepsis-related death. A positive fluid balance between 20 and 60 mL/kg or 2% and 6% of body weight in the first 24 hours after the onset of sepsis is related to lower mortality.

Serial Measurements of Protein Biomarkers in Sepsis-Induced Acute Respiratory Distress Syndrome.

IMPORTANCE:The role of early, serial measurements of protein biomarkers in sepsis-induced acute respiratory distress syndrome (ARDS) is not clear.OBJECTIVES:To determine the differences in soluble receptor for advanced glycation end-products (sRAGEs), angiopoietin-2, and surfactant protein-D (SP-D) levels and their changes over time between sepsis patients with and without ARDS.DESIGN, SETTING, AND PARTICIPANTS:Prospective observational cohort study of adult patients admitted to the medical ICU at Grady Memorial Hospital within 72 hours of sepsis diagnosis.MAIN OUTCOMES AND MEASURES:Plasma sRAGE, angiopoietin-2, and SP-D levels were measured for 3 consecutive days after enrollment. The primary outcome was ARDS development, and the secondary outcome of 28-day mortality. The biomarker levels and their changes over time were compared between ARDS and non-ARDS patients and between nonsurvivors and survivors.RESULTS:We enrolled 111 patients, and 21 patients (18.9%) developed ARDS. The three biomarker levels were not significantly different between ARDS and non-ARDS patients on all 3 days of measurement. Nonsurvivors had higher levels of all three biomarkers than did survivors on multiple days. The changes of the biomarker levels over time were not different between the outcome groups. Logistic regression analyses showed association between day 1 SP-D level and mortality (odds ratio, 1.52; 95% CI, 1.03–2.24; p = 0.03), and generalized estimating equation analyses showed association between angiopoietin-2 levels and mortality (estimate 0.0002; se 0.0001; p = 0.04).CONCLUSIONS AND RELEVANCE:Among critically ill patients with sepsis, sRAGE, angiopoietin-2, and SP-D levels were not significantly different between ARDS and non-ARDS patients but were higher in nonsurvivors compared with survivors. The trend toward higher levels of sRAGE and SP-D, but not of angiopoietin-2, in ARDS patients may indicate the importance of epithelial injury in sepsis-induced ARDS. Changes of the biomarker levels over time were not different between the outcome groups.

Persistent Aseptic Pyelonephritis After Acute Bacterial Pyelonephritis: Possible Role of Corticosteroids

Persistent Aseptic Pyelonephritis After Acute Bacterial Pyelonephritis: Possible Role of Corticosteroids

Relationship between aspartate aminotransferase to platelet ratio index and liver injury in pediatric sepsis

Background Sepsis-associated liver injury (SALI) is one of the main clinical manifestations of sepsis, as well as an independent risk factor for multiple organ dysfunction syndrome and mortality in pediatric sepsis. The early warning biomarkers for identifying SALI remain poorly defined.&#x0D; Objective To analyze the relationship between aspartate aminotransferase to platelet ratio index (APRi) and liver injury occurrence in pediatric sepsis, as well as determine the APRi cutoff value for early identification of SALI.&#x0D; Methods This retrospective study used secondary data derived from January 2019 to August 2020. The study population comprised admitted children aged 1 month to &lt;18 years who met the criteria for sepsis, and had aspartate aminotransferase (AST) and platelet laboratory parameters checked in the first 24 hours of sepsis and before administration of antibiotics. Pearson’s Chi-square test was used to analyze for correlations. Estimation of the APRi cutoff value in the early occurrence of SALI was performed with logistic regression analysis and receiver operating characteristic (ROC) curve.&#x0D; Results Of the 112 subjects, 94.6% were categorized as having septic shock and 48.2% had SALI. Logistic regression revealed that APRi was a significant predictor of SALI, as indicated by cut-off 4.726 [OR 1.098; 95%CI 1.002 to1.203; P=0.045]. The area under the curve (AUC) was 0.831 or 83.1%, which was classified as strong (80-90%).&#x0D; Conclusion The APRi is a reliable early predictor of SALI in pediatric sepsis, as indicated by an increase in APRi (&gt; 4.726) within the first 24 hours of sepsis.

Oral Midodrine Administration During the First 24 Hours of Sepsis to Reduce the Need of Vasoactive Agents: Placebo-Controlled Feasibility Clinical Trial.

Objectives:Our preliminary data and observational studies suggested an increasing “off label” use of oral midodrine as a vasopressor sparing agent in various groups of critically ill patients, including those with sepsis. We designed this clinical trial to evaluate the feasibility of use of midodrine hydrochloride in early sepsis to reduce the duration for IV vasopressors and decrease ICU and hospital length of stay.Design:Pilot, two-center, placebo-controlled, double blinded randomized clinical trial.Setting:Medical ICUs at Mayo Clinic Rochester and Cleveland Clinic Abu Dhabi were the study sites.Patients and Methods:Adult patients (≥ 18 yr old) were included within 24 hours of meeting the Sepsis-3 definition if the mean arterial pressure remained less than 70 mm Hg despite receiving timely antibiotics and initial IV fluid bolus of 30 cc/kg.Intervention:Three doses of 10 mg midodrine versus placebo were administered.Measurements and Main Results:Total 32 patients were randomized into midodrine (n = 17) and placebo groups (n = 15). There were no major differences in baseline variables between the groups except for higher baseline creatinine in the midodrine group (2.0 ± 0.9 mg/dL) versus placebo group (1.4 ± 0.6 mg /dL), p = 0.03. The median duration of IV vasopressor requirement was 14.5 ± 8.1 hours in midodrine group versus 18.8 ± 7.1 hours in the placebo group, p value equals to 0.19. Patients in the midodrine group needed 729 ± 963 norepinephrine equivalent compared with 983 ± 1,569 norepinephrine equivalent in the placebo group, p value equals to 0.59. ICU length of stay was 2.29 days (interquartile range, 1.65–3.9 d) in the midodrine group, compared with 2.45 days (interquartile range, 1.6–3.2 d) in the placebo group, p value equals to 0.36. No serious adverse events were observed in either group.Conclusions:Phase II clinical trial powered for clinical outcomes (duration of vasopressor use, need for central venous catheter, and ICU and hospital length of stay) is justified.

Correlation between syndecan-1 level and PELOD-2 score and mortality in pediatric sepsis.

Objective:To analyze the correlation between glycocalyx disruption measured via the serum syndecan-1 level and organ dysfunctions assessed by the PELOD-2 score and to evaluate its association with mortality in pediatric sepsis.Methods:We performed a prospective observational study in a tertiary public hospital. Sixty-eight pediatric patients diagnosed with sepsis according to International Pediatric Sepsis Consensus Conference criteria were consecutively recruited. We performed measurements of day 1 and day 5 serum syndecan-1 levels and PELOD-2 score components. Patients were followed up to 28 days following sepsis diagnosis.Results:Overall, the syndecan-1 level was increased in all subjects, with a significantly higher level among septic shock patients (p = 0.01). The day 1 syndecan-1 level was positively correlated with the day 1 PELOD-2 score with a correlation coefficient of 0.35 (p = 0.003). Changes in syndecan-1 were positively correlated with changes in the PELOD-2 score, with a correlation coefficient of 0.499 (p < 0.001) during the first five days. Using the cutoff point of day 1 syndecan-1 ≥ 430ng/mL, organ dysfunction (PELOD-2 score of ≥ 8) could be predicted with an AUC of 74.3%, sensitivity of 78.6%, and specificity of 68.5% (p = 0.001).Conclusion:The day 1 syndecan-1 level was correlated with the day 1 PELOD-2 score but not 28-day mortality. Organ dysfunction (PELOD-2 ≥ 8) could be predicted by the syndecan-1 level in the first 24 hours of sepsis, suggesting its significant pathophysiological involvement in sepsis-associated organ dysfunction.

1216: Oral Midodrine in the First 24 Hours of Sepsis to Reduce Need for Vasoactive Agents: Clinical Trial

Lal, Amos1; Trivedi, Vrinda2; Rizvi, Mahrukh1; Amsbaugh, Amy1; Myers, Melissa3; Saleh, Khaled4; Kashyap, Rahul1; Gajic, Ognjen5 Author Information

Reversal of the Pathophysiological Responses to Gram-Negative Sepsis by Megadose Vitamin C.

Oxidative stress appears to initiate organ failure in sepsis, justifying treatment with antioxidants such as vitamin C at megadoses. We have therefore investigated the safety and efficacy of megadose sodium ascorbate in sepsis. Interventional study. Research Institute. Adult Merino ewes. Sheep were instrumented with pulmonary and renal artery flow-probes, and laser-Doppler and oxygen-sensing probes in the kidney. Conscious sheep received an infusion of live Escherichia coli for 31 hours. At 23.5 hours of sepsis, sheep received fluid resuscitation (30 mL/kg, Hartmann solution) and were randomized to IV sodium ascorbate (0.5 g/kg over 0.5 hr + 0.5 g/kg/hr for 6.5 hr; n = 5) or vehicle (n = 5). Norepinephrine was titrated to restore mean arterial pressure to baseline values (~80 mm Hg). Sepsis-induced fever (41.4 ± 0.2°C; mean ± se), tachycardia (141 ± 2 beats/min), and a marked deterioration in clinical condition in all cases. Mean arterial pressure (86 ± 1 to 67 ± 2 mm Hg), arterial Po2 (102.1 ± 3.3 to 80.5 ± 3.4 mm Hg), and renal medullary tissue Po2 (41 ± 5 to 24 ± 2 mm Hg) decreased, and plasma creatinine doubled (71 ± 2 to 144 ± 15 µmol/L) (all p < 0.01). Direct observation indicated that in all animals, sodium ascorbate dramatically improved the clinical state, from malaise and lethargy to a responsive, alert state within 3 hours. Body temperature (39.3 ± 0.3°C), heart rate (99.7 ± 3 beats/min), and plasma creatinine (32.6 ± 5.8 µmol/L) all decreased. Arterial (96.5 ± 2.5 mm Hg) and renal medullary Po2 (48 ± 5 mm Hg) increased. The norepinephrine dose was decreased, to zero in four of five sheep, whereas mean arterial pressure increased (to 83 ± 2 mm Hg). We confirmed these physiologic findings in a coronavirus disease 2019 patient with shock by compassionate use of 60 g of sodium ascorbate over 7 hours. IV megadose sodium ascorbate reversed the pathophysiological and behavioral responses to Gram-negative sepsis without adverse side effects. Clinical studies are required to determine if such a dose has similar benefits in septic patients.

Development and Verification of a Digital Twin Patient Model to Predict Specific Treatment Response During the First 24 Hours of Sepsis.

Directed acyclic graphs were used to define explicitly the causal relationship among organ systems and specific treatments used. A hybrid approach of agent-based modeling, discrete-event simulation, and Bayesian network was used to simulate treatment effect across multiple stages and interactions of major organ systems (cardiovascular, neurologic, renal, respiratory, gastrointestinal, inflammatory, and hematology). Organ systems were visualized using relevant clinical markers. The application was iteratively revised and debugged by clinical experts and engineers. Agreement statistics was used to test the performance of the model by comparing the observed patient response versus the expected response (primary and secondary) predicted by digital twin. Medical ICU of a large quaternary- care academic medical center in the United States. Adult (> 18 year yr old), medical ICU patients were included in the study. No additional interventions were made beyond the standard of care for this study. During the verification phase, model performance was prospectively tested on 145 observations in a convenience sample of 29 patients. Median age was 60 years (54-66 d) with a median Sequential Organ Failure Assessment score of 9.5 (interquartile range, 5.0-14.0). The most common source of sepsis was pneumonia, followed by hepatobiliary. The observations were made during the first 24 hours of the ICU admission with one-step interventions, comparing the output in the digital twin with the real patient response. The agreement between the observed versus and the expected response ranged from fair (kappa coefficient of 0.41) for primary response to good (kappa coefficient of 0.65) for secondary response to the intervention. The most common error detected was coding error in 50 observations (35%), followed by expert rule error in 29 observations (20%) and timing error in seven observations (5%). We confirmed the feasibility of development and prospective testing of causal artificial intelligence model to predict the response to treatment in early stages of critical illness. The availability of qualitative and quantitative data and a relatively short turnaround time makes the ICU an ideal environment for development and testing of digital twin patient models. An accurate digital twin model will allow the effect of an intervention to be tested in a virtual environment prior to use on real patients.

Beneficial Effects of Vasopressin Compared With Norepinephrine on Renal Perfusion, Oxygenation, and Function in Experimental Septic Acute Kidney Injury

To compare the effects of restoring mean arterial pressure with vasopressin or norepinephrine on systemic hemodynamics, renal blood flow, intrarenal perfusion and oxygenation, and renal function in ovine septic acute kidney injury. Interventional Study. Research Institute. Adult Merino ewes. Flow probes were implanted on the pulmonary and renal arteries (and the mesenteric artery in sheep that received vasopressin). Fiber-optic probes were implanted in the renal cortex and medulla to measure tissue perfusion and oxygen tension (PO2). Conscious sheep were administered Escherichia coli to induce septic acute kidney injury. Vasopressin (0.03 IU/min [0.03-0.05 IU/min]; n = 7) or norepinephrine (0.60 μg/kg/min [0.30-0.70 μg/kg/min]; n = 7) was infused IV and titrated to restore baseline mean arterial pressure during 24-30 hours of sepsis. Ovine septic acute kidney injury was characterized by reduced mean arterial pressure (-16% ± 2%) and creatinine clearance (-65% ± 9%) and increased renal blood flow (+34% ± 7%) but reduced renal medullary perfusion (-44% ± 7%) and PO2 (-47% ± 10%). Vasopressin infusion did not significantly affect renal medullary perfusion or PO2 and induced a sustained (6 hr) ~2.5-fold increase in creatinine clearance. Vasopressin reduced sepsis-induced mesenteric hyperemia (+61 ± 13 to +9% ± 6%). Norepinephrine transiently (2 hr) improved creatinine clearance (by ~3.5-fold) but worsened renal medullary ischemia (to -64% ± 7%) and hypoxia (to -71% ± 6%). In ovine septic acute kidney injury, restoration of mean arterial pressure with vasopressin induced a more sustained improvement in renal function than norepinephrine, without exacerbating renal medullary ischemia and hypoxia or reducing mesenteric blood flow below baseline values.

Triage and flow management in sepsis

BackgroundSepsis is a major public health problem, with a growing incidence and mortality rates still close to 30% in severe cases. The speed and adequacy of the treatment administered in the first hours of sepsis, particularly access to intensive care, are important to reduce mortality. This study compared the triage strategies and intensive care rationing between septic patients and patients with other indications of intensive care. This study included all patients with signs for intensive care, enrolled in the intensive care management system of a Brazilian tertiary public emergency hospital, from January 1, 2010, to December 31, 2016. The intensivist periodically evaluated the requests, prioritizing them according to a semi-quantitative scale. Demographic data, Charlson Comorbidity Index (CCI), Sequential Organ Failure Assessment (SOFA), and quick SOFA (qSOFA), as well as surgical interventions, were used as possible confounding factors in the construction of incremental logistic regression models for prioritization and admission to intensive care outcomes.ResultsThe study analyzed 9195 ICU requests; septic patients accounted for 1076 cases (11.7%), 293 (27.2%) of which were regarded as priority 1. Priority 1 septic patients were more frequently hospitalized in the ICU than nonseptic patients (52.2% vs. 34.9%, p < 0.01). Septic patients waited longer for the vacancy, with a median delay time of 43.9 h (interquartile range 18.2–108.0), whereas nonseptic patients waited 32.5 h (interquartile range 11.5–75.8)—p < 0.01. Overall mortality was significantly higher in the septic group than in the group of patients with other indications for intensive care (72.3% vs. 39.8%, p < 0.01). This trend became more evident after the multivariate analysis, and the mortality odds ratio was almost three times higher in septic patients (2.7, 2.3–3.1).ConclusionSeptic patients had a lower priority for ICU admission and longer waiting times for an ICU vacancy than patients with other critical conditions. Overall, this implied a 2.7-fold increased risk of mortality in septic patients.

Dexmedetomidine reduces norepinephrine requirements and preserves renal oxygenation and function in ovine septic acute kidney injury

Norepinephrine exacerbates renal medullary hypoxia in experimental septic acute kidney injury. Here we examined whether dexmedetomidine, an α2-adrenergic agonist, can restore vasopressor responsiveness, decrease the requirement for norepinephrine and attenuate medullary hypoxia in ovine gram-negative sepsis. Sheep were instrumented with pulmonary and renal artery flow probes, and laser Doppler and oxygen-sensing probes in the renal cortex and medulla. Conscious sheep received an infusion of live Escherichia coli for 30 hours. Eight sheep in each group were randomized to receive norepinephrine, norepinephrine with dexmedetomidine, dexmedetomidine alone or saline vehicle, from 24-30 hours of sepsis. Sepsis significantly reduced the average mean arterial pressure (84 to 67 mmHg), average renal medullary perfusion (1250 to 730 perfusion units), average medullary tissue pO2 (40 to 21 mmHg) and creatinine clearance (2.50 to 0.78 mL/Kg/min). Norepinephrine restored baseline mean arterial pressure (to 83 mmHg) but worsened medullary hypoperfusion (to 330 perfusion units) and medullary hypoxia (to 9 mmHg). Dexmedetomidine (0.5 μg/kg/h) co-administration significantly reduced the norepinephrine dose (0.8 to 0.4 μg/kg/min) required to restore baseline mean arterial pressure, attenuated medullary hypoperfusion (to 606 perfusion units), decreased medullary tissue hypoxia (to 29 mmHg), and progressively increased creatinine clearance (to 1.8 mL/Kg/min). Compared with vehicle time-control, dexmedetomidine given alone significantly prevented the temporal reduction in mean arterial pressure, but had no significant effects on medullary perfusion and oxygenation or creatinine clearance. Thus, in experimental septic acute kidney injury, dexmedetomidine reduced norepinephrine requirements, attenuated its adverse effects on the renal medulla, and maintained renal function.

Thyroid Hormone Profile in Children with Sepsis: Does Euthyroid Sick Syndrome Exist?

BACKGROUND:Alterations in peripheral thyroid hormone metabolism play an eminent role in the development of the euthyroid sick syndrome. Altered solvation may also lead to changes in peripheral thyroid hormones. Data on thyroid hormones in critically ill children remain unclear.AIM:This study was aimed to evaluate thyroid hormone profile in children with sepsis as well as to assess the association between thyroid level and sepsis outcome.METHODS:An observational cohort study was conducted in 80 children with sepsis from October 2015 to January 2016 in Haji Adam Malik General Hospital. T3 and T4 level were measured on day 1 and after > 72 hours of sepsis diagnosed.RESULTS:We recorded length of stay in PICU, patient outcome and analysed the relationship with the chi-square test. Level of T3 and T4 were decreased on day 1 in pediatric sepsis. Of 80 subjects, 57 (71.2%) with low-level T3 and 41 (51.2%) with low T4 were found. The relationship between T3 and T4 level on day 1 with the length of stay were not found (P = 0.500; P = 0.987). There were a significant relationship between level of T3 and T4 with outcome (P = 0.0001; OR 24.706; P = 0.014; OR 3.086). Subject with normal T3 and T4 level had 24 and 3 times life chances compare to lower level.CONCLUSION:The Euthyroid Sick Syndrome in children with sepsis does exist. There was a significant relationship between T3 and T4 level on day 1 with patient outcome.

Persistently Elevated Glucagon-Like Peptide-1 Levels among Critically Ill Surgical Patients after Sepsis and Development of Chronic Critical Illness and Dismal Long-Term Outcomes

Glucagon-like peptide-1 (GLP-1) is a gut-derived incretin hormone that stimulates insulin secretion, cellular glucose uptake, and has immune-regulatory functions. Glucagon-like peptide-1 is markedly altered after trauma and sepsis, but the implications remain unclear. We performed an analysis of a prospective, longitudinal cohort study of critically ill surgical patients with sepsis. Patient characteristics and clinical data were collected, as well as peripheral blood sampling for biomarker analysis, out to 28 days after sepsis onset. We prospectively adjudicated sepsis diagnosis, severity, clinical outcomes, and 6-month follow-up. The cohort included 157 septic surgical patients with significant physiologic derangement (Maximum Sequential Organ Failure Assessment [SOFA] score 8, interquartile range [IQR] 4 to 11), a high rate of multiple organ failure (50.3%), and septic shock (24.2%). Despite high disease severity, both early death (<14 days; n= 4, 2.9%) and overall inpatient mortality were low (n= 12, 7.6%). However, post-discharge 6-month mortality was nearly 3-fold higher (19.7%). Both GLP-1 and interleukin [IL]-6 levels were significantly elevated for 21 days (p ≤ 0.01) in patients who developed chronic critical illness (CCI) compared with patients with a rapid recovery. Elevated GLP-1 at 24 hours was a significant independent predictor for the development of CCI after controlling for IL-6 and glucose levels (p= 0.027), and at day 14 for death or severe functional disability at 6 months (WHO/Zubrod score 4-5, p= 0.014). Elevated GLP-1 within 24 hours of sepsis is a predictor of early death or persistent organ dysfunction. Among early survivors, persistently elevated GLP-1 levels at day 14 are strongly predictive of death or severe functional disability at 6 months. Persistently elevated GLP-1 levels may be a marker of a nonresolving catabolic state that is associated with muscle wasting and dismal outcomes after sepsis and chronic critical illness.

Protective roles of autophagy in sepsis‐induced skeletal muscle dysfunction, metabolic derangements and mortality

RationaleSepsis‐induced skeletal muscle dysfunction contributes to physical disability, and increased mortality in intensive care unit patients. Autophagy is a catabolic process by which cells degrade their own components. Recent studies indicate that sepsis triggers sustained induction of autophagy in skeletal muscles; however, the impact of autophagy on sepsis‐induced contractile and metabolic dysfunctions remains unclear. In this study, we evaluated the functional importance of autophagy in sepsis‐induced skeletal muscle dysfunction.MethodsSelective inhibition of autophagy in skeletal muscles was accomplished by cross breeding floxed Atg7 mice (Atg7f/f) with those expressing HSA‐Cre‐ERT2. Cre induction was achieved by feeding Tamoxifen. Control mice were Atg7f/f‐HSA‐Cre‐ERT2 without Tamoxifen feeding. Sepsis was induced by the cecal ligation and perforation (CLP) procedure and animals were examined after 48 and 144 hours of sepsis. Animals undergoing sham procedure served as control.ResultsDeletion of Atg7 in skeletal muscle had a major impact on sepsis‐induced loss of body weight and muscle mass as indicated by worsening of body weight loss, more severe sepsis‐induced skeletal muscle atrophy and further decline in muscle contractility in mice with Atg7 deletions vs. those with intact Atg7 undergoing sepsis for 48 hours. In additions, body weight loss, hypoglycaemia and mortality were more severe over a 144 hours period in mice with Atg7 deletion as compared to those with intact Atg7. These results suggest that induction of autophagy in septic skeletal muscles play a protective role against sepsis‐induced mortality. Furthermore, sepsis had no major effect on limb muscle mitochondrial respiration in animals with intact muscle Atg7 while those with deleted muscle Atg7 showed significant impairments of limb muscle mitochondrial respiration both in the sham and septic conditions. Finally, significant upregulation of ubiquitin E3 ligases (Atrogin‐1 and MuRF1) was observed in septic muscles. Deletion of muscle Atg7 had no effect on this response when measured after 48 hours of sepsis.ConclusionWe conclude that autophagy plays a protective role by preserving muscle mitochondrial quality and function and that autophagy inhibition in skeletal muscles worsens sepsis‐induced loss of body weight and muscle atrophy possibly due to exaggerated responses to catabolic stimuli triggered by sepsis. Our results also indicate that autophagy in septic skeletal muscles play a protective role against sepsis‐induced metabolic derangements and mortality.Support or Funding InformationThis study is funded by grants from the Canadian Institutes of Health Research. Gilles Gouspillou salary support is provided by a FQRS Chercheur Boursier Junior 1 Award. Jean‐Philippe Leduc‐Gaudet is supported by CIHR Vanier Doctoral Scholarship.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Effects of Fluid Bolus Therapy on Renal Perfusion, Oxygenation, and Function in Early Experimental Septic Kidney Injury.

To examine the effects of fluid bolus therapy on systemic hemodynamics, renal blood flow, intrarenal perfusion and oxygenation, PO2, renal function, and fluid balance in experimental early septic acute kidney injury. Interventional study. Research institute. Adult Merino ewes. Implantation of flow probes on the pulmonary and renal arteries and laser Doppler oxygen-sensing probes in the renal cortex, medulla, and within a bladder catheter in sheep. Infusion of Escherichia coli to induce septic acute kidney injury (n = 8). After 24, 25, and 26 hours of sepsis, fluid bolus therapy (500 mL of Hartmann's solution over 15 min) was administered. In conscious sheep, infusion of Escherichia coli decreased creatinine clearance and increased plasma creatinine, renal blood flow (+46% ± 6%) and cortical perfusion (+25% ± 4%), but medullary perfusion (-48% ± 5%), medullary PO2 (-56% ± 4%), and urinary PO2 (-54% ± 3%) decreased (p < 0.01). The first fluid bolus therapy increased blood pressure (+6% ± 1%), central venous pressure (+245% ± 65%), cardiac output (+11% ± 2%), medullary PO2 (+280% ± 90%), urinary PO2 (+164% ± 80%), and creatinine clearance (+120% ± 65%) at 30 minutes. The following two boluses had no beneficial effects on creatinine clearance. The improvement in medullary oxygenation dissipated following the third fluid bolus therapy. Study animals retained 69% of the total volume and 80% of sodium infused. Throughout the study, urinary PO2 correlated significantly with medullary PO2. In early experimental septic acute kidney injury, fluid bolus therapy transiently improved renal function and medullary PO2, as also reflected by increased urinary PO2. These initial effects of fluid bolus therapy dissipated within 4 hours, despite two additional fluid boluses, and resulted in significant volume retention.

The organization of timely care in septic patients

Intensive care clinicians are often exposed to patients with severe sepsis or septic shock. They know, by virtue of their experience, the need for action and the advantage that is created when they use the ‘golden hour of sepsis’. We know that septic patients can show fast deterioration and ultimately die due to progressive organ failure.

198 Adherence to Standardized Sepsis Order Set Associated With Lower 30-Day Hospital Re-Admission Rate

The Severe Sepsis 3-Hour Resuscitation Bundle calls for an initial administration of 30 mL/kg of crystalloid as a fluid challenge in sepsis, to correct possible underlying hypovolemia. We aimed to study whether the practice of administering 30cc/kg saline in the first 3 hours of sepsis improves outcome, especially with regard to 30-day hospital re-admission. This was an observational cohort study that took place in an urban academic teaching hospital and trauma center with over 75k annual ED visits. Participants included adult patients who presented to the ED with signs and symptoms consistent with severe sepsis or septic shock. The data abstraction was performed by trained coders blinded to the outcome of interest, and a standardized data collection tool was utilized. Data analysis performed using JMP 12.0. 168 patients met the inclusion criteria. 57% of the cohort received the recommended 30cc/kg fluid bolus in the first 3 hours of their ED stay. On univariate regression analysis, there were no significant differences between those who did receive or did not receive the fluids with regard to age, sex, arrival from emergency medical services or NH, or whether or not the sepsis bundle was ordered. The overall 30-day hospital re-admission rate for the cohort was 19%. For those who received the fluid challenge, it was 14%, as compared to 25% in those who did not. On multivariable logistic regression analysis that included demographics and laboratory values, those patients who did receive the 30cc/kg fluid resuscitation were significantly less likely to be re-admitted to the hospital within 30 days (25 versus 14%). Fluid resuscitation in the early hours after sepsis appears to be significantly correlated with a lower rate of hospital re-admission at 30 days.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

The golden hour of sepsis: An in-depth analysis of sepsis-related maternal mortality in middle-income country Suriname.

BackgroundSepsis was the main cause of maternal mortality in Suriname, a middle-income country. Objective of this study was to perform a qualitative analysis of the clinical and management aspects of sepsis-related maternal deaths with a focus on the ‘golden hour’ principle of antibiotic therapy.MethodsA nationwide reproductive age mortality survey was performed from 2010 to 2014 to identify and audit all maternal deaths in Suriname. All sepsis-related deaths were reviewed by a local expert committee to assess socio-demographic characteristics, clinical aspects and substandard care.ResultsOf all 65 maternal deaths in Suriname 29 (45%) were sepsis-related. These women were mostly of low socio-economic class (n = 23, 82%), of Maroon ethnicity (n = 14, 48%) and most deaths occurred postpartum (n = 21, 72%). Underlying causes were pneumonia (n = 14, 48%), wound infections (n = 3, 10%) and endometritis (n = 3, 10%). Bacterial growth was detected in 10 (50%) of the 20 available blood cultures. None of the women with sepsis as underlying cause of death received antibiotic treatment within the first hour, although most women fulfilled the diagnostic criteria of sepsis upon admission. In 27 (93%) of the 29 women from which sufficient information was available, substandard care factors were identified: delay in monitoring in 16 (59%) women, in diagnosis in 17 (63%) and in treatment in 21 (78%).ConclusionIn Suriname, a middle-income country, maternal mortality could be reduced by improving early recognition and timely diagnosis of sepsis, vital signs monitoring and immediate antibiotic infusion (within the golden hour).