Modulation of oxidative and nitrosative stress attenuates microvascular hyperpermeability in ovine model of Pseudomonas aeruginosa sepsis

In sepsis, microvascular hyperpermeability caused by oxidative/nitrosative stress (O&NS) plays an important role in tissue edema leading to multi-organ dysfunctions and increased mortality. We hypothesized that a novel compound R-107, a modulator of O&NS, effectively ameliorates the severity of microvascular hyperpermeability and preserves multi-organ function in ovine sepsis model. Sepsis was induced in twenty-two adult female Merino sheep by intravenous infusion of Pseudomonas aeruginosa (PA) (1 × 1010 CFUs). The animals were allocated into: 1) Control (n = 13): intramuscular injection (IM) of saline; and 2) Treatment (n = 9): IM of 50 mg/kg R-107. The treatment was given after the PA injection, and monitored for 24-h. R-107 treatment significantly reduced fluid requirement (15–24 h, P < 0.05), net fluid balance (9–24 h, P < 0.05), and water content in lung/heart/kidney (P = 0.02/0.04/0.01) compared to control. R-107 treatment significantly decreased lung injury score/modified sheep SOFA score at 24-h (P = 0.01/0.04), significantly lowered arterial lactate (21–24 h, P < 0.05), shed syndecan-1 (3–6 h, P < 0.05), interleukin-6 (6–12 h, P < 0.05) levels in plasma, and significantly attenuated lung tissue 3-nitrotyrosine and vascular endothelial growth factor-A expressions (P = 0.03/0.002) compared to control. There was no adverse effect in R-107 treatment. In conclusion, modulation of O&NS by R-107 reduced hyperpermeability markers and improved multi-organ function.

Modulation of Oxidative and Nitrosative Stress Attenuates Microvascular Hyperpermeability in Ovine Model of Pseudomonas Aeruginosa Sepsis

In sepsis, microvascular hyperpermeability caused by oxidative/nitrosative stress (O&NS) plays an important role in tissue edema leading to multi-organ dysfunctions and increased mortality. We hypothesized that a novel compound R-107, a modulator of O&NS, effectively ameliorates the severity of microvascular hyperpermeability and preserves multi-organ function in ovine sepsis model. Sepsis was induced in twenty-two adult female Merino sheep by intravenous infusion of Pseudomonas aeruginosa (PA) (1x1010 CFUs). The animals were allocated into: 1) Control (n = 13): intramuscular injection (IM) of saline; and 2) Treatment (n = 9): IM of 50 mg/kg R-107. The treatment was given after the PA injection, and monitored for 24-hour. R-107 treatment significantly reduced fluid requirement (15–24 hours, p < 0.05), net fluid balance (9–24 hours, p < 0.05), and water content in lung/heart/kidney (p = 0.02/0.04/0.01) compared to control. R-107 treatment significantly decreased lung injury score/modified sheep SOFA score at 24-hour (p = 0.01/0.04), significantly lowered arterial lactate (21–24 hours, p < 0.05), shed syndecan-1 (3–6 hours, p < 0.05), interleukin-6 (6–12 hours, p < 0.05) levels in plasma, and significantly attenuated lung tissue 3-nitrotyrosine and vascular endothelial growth factor-A expressions (p = 0.03/0.002) compared to control. There was no adverse effect in R-107 treatment. In conclusion, modulation of O&NS by R-107 reduced hyperpermeability markers and improved multi-organ function.

Renal Resistive Index on Intensive Care Unit Admission Correlates with Tissue Hypoperfusion Indices and Predicts Clinical Outcome

Background: Recent advancements in the context of shock pathophysiology, support ultrasound assessment of organ perfusion. Renal resistive index (RRI) has been used to evaluate renal blood flow. Our aim was to investigate the relation between RRI, and global tissue hypoperfusion indices, in mechanically ventilated critically ill patients and their association with clinical outcome.Methods: In this prospective observational study, RRI was measured within 24 hours of intensive care unit (ICU) admission. Clinical and laboratory data, routine hemodynamic variables and gas exchange at the time of RRI assessment were recorded. The ratio of central venous-to-arterial carbon dioxide partial pressure difference by arterial-to-central venous oxygen content difference (P(cv-a)CO2/C(a-cv)O2) and lactate were used as global tissue hypoperfusion indices. Results A total of 126 mechanically ventilated patients were included [median age 61 (IQR 28) years, 74% males]. Seventy-seven patients had RRI values >0.7. P(cv-a)CO2/C(a-cv)O2 ratio and arterial lactate, were significantly higher in patients with RRI > 0.7 compared to those with RRI ≤0.7 [2.4 (2.2) versus 1.2 (0.6) and 2.88 (3.39) versus 0.62 (0.57) mmol/l respectively, both p<0.001)]. RRI was significantly correlated with P(cv-a)CO2/C(a-cv)O2 ratio and arterial lactate for the whole patient population (rho=0.64, both p<0.0001) as well as for the subset of patients with shock (rho=0.47, p=0.001; and r=0.64, p<0.0001 respectively).All-cause ICU mortality was 27.8%. Compared to survivors, ICU non-survivors had a higher RRI [0.80 (0.10) versus 0.70 (0.10), p<0.001] and higher P(cv-a)CO2 / C(a-cv)O2 ratio [3.67 (3.8) versus 0.91 (1.4)] and lactate levels [2.80 (2.00) versus 1.50 (1.20)], both p <0.001). Logistic regression models showed a significant association between RRI and P(cv-a)CO2/C(a-cv)O2 ratio with clinical outcome. RRI showed good ability to predict ICU mortality (AUC 74.9% (95% CI 61% - 88.8%). The combination of RRI with P(cv-a)CO2)/(C(a-cv)O2 ratio and lactate better predicted mortality than RRI alone [AUC 84.8% (95% CI 5.1% - 94.4%)] versus 0.74.9%, respectively, p<0.001).Conclusions: In mechanically ventilated patients, renal blood flow impairment, assessed by the RRI on ICU admission, correlates with global tissue hypoperfusion indices. In addition, RRI in combination with tissue perfusion estimation is more valuable in predicting clinical outcome than RRI alone.

Gastric Pneumatosis With Portal Venous Gas Can Be Treated Non-operatively: a Retrospective Multi-institutional Study

Background: Gastric pneumatosis (GP) is a rare radiologic finding with an unpredictable prognosis. The aim of this study was to identify mortality risk factors from patients presenting with GP on computed tomography (CT), and to develop a model which would allow us to predict which patients would benefit most from operative management.Methods: Between 2010 and 2020, all CT-scan reports in 4 tertiary centers were searched for the following terms: “gastric pneumatosis”, “intramural gastric air” or “emphysematous gastritis”. The retrieved CT scans were reviewed by a senior surgeon and a senior radiologist. Relevant clinical and laboratory data for these patients were extracted from the institutions’ medical records. Results: Among 58 patients with GP portal venous gas and bowel ischemia were present on CT scan in 52 (90%) and 17 patients (29%), respectively. The 30-day mortality rate was 31%. Univariate analysis identified the following variables as predictive of mortality at the time of the diagnosis of GP: abdominal guarding, hemodynamic instability, arterial lactate level >2mmol/l, and absence of gastric dilatation. Multivariable analysis identified the following variables as independent predictors of mortality: arterial lactate level (OR: 1.39, 95% CI: 1.07 - 1.79) and absence of gastric dilatation (OR: 0.07, 95% CI: 0.01 - 0.79). None of the patients presenting with a baseline lactate rate <2 mmol/l died within 30 days following diagnosis, and no more than 17 patients out of 58 had bowel ischemia (29%).Conclusions: GP could be managed non-operatively, even in the presence of portal venous gas. However patients with arterial lactate level>2mmol/l, or absence of gastric dilation should be surgically explored due to a non-negligible risk of mortality.

Arterial Lactate Concentration At The End of Liver Transplantation is Independently Associated with One-Year Mortality

BACKGROUNDLiver transplant patients who develop hyperlactatemia are at increased risk of postoperative morbidity and mortality, but there are few data on longer-term outcomes. We therefore investigated whether arterial lactate concentration obtained immediately after surgery, at the time of admission to the intensive care unit (ICU), was associated with 1-year mortality. METHODS: In this retrospective cohort study, all patients who underwent liver transplant surgery between September 2013 and December 2019 were screened for inclusion. Patients who underwent combined transplantation surgery and those with a history of previous liver transplantation (i.e., redo surgery) were not included. Logistic regression modeling included univariate and multivariate analyses. Receiver operating characteristic (ROC) curves and areas under the curves (AUROCs) were calculated. Lactate thresholds and association with outcome were analyzed for specificity, sensitivity, and Youden’s index.RESULTS: Of 226 patients included, 18.4% died within 1-year of liver transplantation. Immediate postoperative lactate concentration was independently associated with 1-year mortality with an odds ratio (OR) of 1.35 (95% CI: 1.16 to 1.59; p<0.001) per mEq/L increase in lactate and an AUROC of 0.80 (95% CI: 0.72 to 0.87; p<0.001). A lactate concentration of 2.25 mEq/L (cut-off determined using Youden’s index) was associated with increased 1-year mortality with a sensitivity of 0.71 and a specificity of 0.72. CONCLUSION: Increased arterial lactate concentration on admission to the ICU immediately after orthotopic liver transplantation is independently associated with increased 1-year mortality.Trial Registration: Not Applicable

Ultra-Early Indicators of Acute Hypertriglyceridemic Pancreatitis May Influence Treatment Decision-Making By Chinese Doctors

Background: This study investigates whether ultra-early indicators can predict severity of acute hypertriyceridemic pancreatitis (HTGP) and affect clinical decisions. Methods: For this observational retrospective study, we analyzed data of 110 HTGP patients enrolled between January 2017 and February 2020. HTGP patients were categorized into mild acute pancreatitis (MAP) and moderately severe acute pancreatitis-severe acute pancreatitis (MSAP-SAP) groups, based on their final clinical outcomes. Demographic and clinical data were collected and ultra-early indicators (serum calcium, triglyceride (TG), interleukin-6(IL-6), D-dimer, hemoglobin A1c(HbAc1), arterial lactate) levels were measured within 6 hours of admission. A multivariate logistic regression analysis model and receiver operating characteristic curve were used to determine ultra-early indicators values of high-risk patients. The chi-square test method was applied to estimate the hospitalization time and associated complications in MSAP-SAP group post-plasma exchange within or more than 24 hours. Results: Among the 110 HTGP patients, 56 were in the MAP group whereas, 54 were in the MSAP-SAP group. TG, IL-6, D-dimer, HbAc1, and arterial lactate levels measured within 6 hours after admission were significantly higher in the MSAP-SAP group, but serum calcium was significantly lower, versus the mild AP group. IL-6, D-dimer and serum calcium were identified as the risk factors for MSAP-SAP and were potential ultra-early indicators for predicting HTGP severity within 6 hours of admission. MSAP-SAP patients that underwent blood purification therapy within 24 hours of admission had a shorter hospitalization time than those treated 24 hours post-admission. Conclusion: The present study reveals IL-6, D-dimer, and serum calcium - ultra-early indicators - as promising biomarkers in the assessment of AP severity in HTGP patients within 6 hours. Early blood purification presents a novel therapy among MSAP-SAP patients within 24 hours and is associated with fewer complications and a shorter hospitalization time. However, traditional therapy can be further integrated to manage MAP patients effectively with less medical expenses.

Arterial lactate levels and their prognostic value in patients undergoing pulmonary thromboendarterectomy

Objective. Evaluate the change of lactate levels and its prognostic role in the postoperative period of patients undergoing pulmonary thromboendarterectomy. Methods. Retrospective study between 2001 and 2019. Patients older than 18 years and who underwent pulmonary thromboendarterectomy were included. The U Mann Whitney test was performed to evaluate the change between lactate levels, and Cox regression analysis to evaluate the relationship with mortality. Areas under the curve were constructed for lactate levels. Results. Seventy-three patients were operated on during the study period. Median age was 51 years, 55% female. The median lactate on days 1 was 4.65 mml/L and on day 2 it was 1.62 mml/L with a change of 2.87 mml/L. No differences were found between the levels measured on day 1 and 2 between the people who died and those who did not on day 30. In the multivariate regression of COX, no relationship with mortality was found. The area under the curve shows regular performance on both day 1 and day 2 in predicting mortality outcomes. Conclusions. The behavior of the lactate in patients undergoing pulmonary thromboendarterectomy shows a rapid change during the first hours after the procedure. No role was found as a predictor of mortality neither in-hospital nor in follow-up.

The clinical significance of blood lactate levels in evaluation of adult patients with Veno-Arterial Extracorporeal Membrane Oxygenation

Funding Acknowledgements Type of funding sources: None. Background Veno-Arterial ECMO is a life supporting procedure that can be done to the patients with cardiogenic shock which is associated with hyperlactatemia . The objective of this study was to detect the validity of serial measurements of arterial lactate level in differentiating hospital mortality and neurological outcome after VA-ECMO support. Results : This retrospective study included 106 patients between 2015 and 2019 with a mean age of 40.2 ± 14.4 years and mostly males (69.8%) . The in-hospital mortality occurred in 56.6% and acute strokes occurred in 25.5% of the patients . The non-survivors and the patients with acute strokes had significantly higher arterial lactate levels at pre-ECMO initiation , post-ECMO peak and after 24 hours of ECMO support compared to the survivors and those without strokes respectively. The peak arterial lactate ≥ 14.65 mmol/L measured after ECMO support had 81.7 % sensitivity and 89.1 % specificity for predicting hospital mortality [AUROC: 0.889 , p &lt;0.001 ] while the arterial lactate level ≥ 3.25 mmol/L after 24 hours of ECMO support had 88.3% sensitivity and 97.8% specificity for predicting hospital mortality [AUROC: 0.93 , p &lt;0.001 ]. The peak lactate ≥ 15.15 mmol/L measured after ECMO support had 70.8 % sensitivity and 69 % specificity for predicting cerebral strokes [AUROC: 0.717 , p &lt;0.001 ] while the lactate level ≥ 3.25 mmol/L after 24 hours of ECMO support had 79.2% sensitivity and 72.4% specificity for predicting cerebral strokes [AUROC: 0.779, p &lt;0.001 ]. Progressive hyperlactatemia (OR = 1.427 , 95% CI : 1.048 – 1.944 , p = 0.024 ) and increasing SOFA score after 48 hours (OR = 1.819 , 95% CI : 1.374 – 2.409 , p &lt; 0.001) were significantly associated with in-hospital mortality after VA-ECMO support. Conclusion : Progressive hyperlactatemia after VA-ECMO initiation for adult patients with cardiogenic shock is a sensitive and specific predictor of hospital mortality and acute cerebrovascular strokes . According to our results , we could recommend early VA-ECMO initiation to achieve adequate circulatory support and better outcome. Predictors of hospital mortality.Studied variablesP valueOR95% CI for ORLactate peak0.0241.4271.048 - 1.944Hemodialysis0.3154.1260.344 - 51.669Atrial fibrillation0.073.2680.786 - 31.26Cardiac surgeries0.2173.4820.480 - 25.152Δ SOFA&lt;0.0011.8191.374 - 2.409Central VA-ECMO0.123.9310.482 - 24.16Abstract Figure. ROC of lactate differentiating mortality