Angiotensin 1-7 in an experimental septic shock model.

BACKGROUND: Alterations in the renin-angiotensin system have been implicated in the pathophysiology of septic shock. In particular, angiotensin 1-7 (Ang-(1-7)), an anti-inflammatory heptapeptide, has been hypothesized to have beneficial effects. The aim of the present study was to test the effects of Ang-(1-7) infusion on the development and severity of septic shock. METHODS: This randomized, open-label, controlled study was performed in 14 anesthetized and mechanically ventilated sheep. Immediately after sepsis induction by bacterial peritonitis, animals received either Ang-(1-7) (n = 7) or placebo (n = 7) intravenously. Fluid resuscitation, antimicrobial therapy, and peritoneal lavage were initiated 4 h after sepsis induction. Norepinephrine administration was titrated to maintain mean arterial pressure (MAP) between 65 and 75 mmHg. RESULTS: There were no differences in baseline characteristics between groups. Septic shock was prevented in 6 of the 7 animals in the Ang-(1-7) group at the end of the 24-h period. Fluid balance and MAP were similar in the two groups; however, MAP was achieved with a mean norepinephrine dose of 0.4 µg/kg/min in the Ang-(1-7) group compared to 4.3 µg/kg/min in the control group. Heart rate and cardiac output index were lower in the Ang (1-7) than in the control group, as were plasma interleukin-6 levels, and creatinine levels. Platelet count and PaO2/FiO2 ratio were higher in the Ang-(1-7) group. Mean arterial lactate at the end of the experiment was 1.6 mmol/L in the Ang-(1-7) group compared to 7.4 mmol/L in the control group. CONCLUSIONS: In this experimental septic shock model, early Ang-(1-7) infusion prevented the development of septic shock, reduced norepinephrine requirements, limited interleukine-6 increase and prevented renal dysfunction.

Neutralization of extracellular histones by sodium-Β-O-methyl cellobioside sulfate in septic shock.

BACKGROUND: Extracellular histones have been associated with severity and outcome in sepsis. The aim of the present study was to assess the effects of sodium-ß-O-Methyl cellobioside sulfate (mCBS), a histone-neutralizing polyanion, on the severity and outcome of sepsis in an experimental model. METHODS: This randomized placebo-controlled experimental study was performed in 24 mechanically ventilated female sheep. Sepsis was induced by fecal peritonitis. Animals were randomized to three groups: control, early treatment, and late treatment (n = 8 each). mCBS was given as a bolus (1 mg/kg) followed by a continuous infusion (1 mg/kg/h) just after sepsis induction in the early treatment group, and 4 h later in the late treatment group. Fluid administration and antimicrobial therapy were initiated 4 h T4 after feces injection, peritoneal lavage performed, and a norepinephrine infusion titrated to maintain mean arterial pressure (MAP) between 65-75 mmHg. The experiment was blinded and lasted maximum 24 h. RESULTS: During the first 4 h, MAP remained > 65 mmHg in the early treatment group but decreased significantly in the others (p < 0.01 for interaction, median value at T4: (79 [70-90] mmHg for early treatment, 57 [70-90] mmHg for late treatment, and 55 [49-60] mmHg for the control group). mCBS-treated animals required significantly less norepinephrine to maintain MAP than controls (p < 0.01 for interaction) and had lower creatinine (p < 0.01), lactate (p < 0.01), and interleukin-6 (p < 0.01) levels, associated with reduced changes in H3.1 nucleosome levels (p = 0.02). Early treatment was associated with lower norepinephrine requirements than later treatment. Two control animals died; all the mCBS-treated animals survived. CONCLUSIONS: Neutralization of extracellular histones with mCBS was associated with reduced norepinephrine requirements, improved tissue perfusion, less renal dysfunction, and lower circulating IL-6 in experimental septic shock and may represent a new therapeutic approach to be tested in clinical trials.

Myocardial effects of angiotensin II compared to norepinephrine in an animal model of septic shock.

BACKGROUND: Angiotensin II is one of the vasopressors available for use in septic shock. However, its effects on the septic myocardium remain unclear. The aim of the study was to compare the effects of angiotensin II and norepinephrine on cardiac function and myocardial oxygen consumption, inflammation and injury in experimental septic shock. METHODS: This randomized, open-label, controlled study was performed in 20 anesthetized and mechanically ventilated pigs. Septic shock was induced by fecal peritonitis in 16 animals, and four pigs served as shams. Resuscitation with fluids, antimicrobial therapy and abdominal drainage was initiated one hour after the onset of septic shock. Septic pigs were randomly allocated to receive one of the two drugs to maintain mean arterial pressure between 65 and 75 mmHg for 8 h. RESULTS: There were no differences in MAP, cardiac output, heart rate, fluid balance or tissue perfusion indices in the two treatment groups but myocardial oxygen consumption was greater in the norepinephrine-treated animals. Myocardial mRNA expression of interleukin-6, interleukin-6 receptor, interleukin-1 alpha, and interleukin-1 beta was higher in the norepinephrine than in the angiotensin II group. CONCLUSIONS: In septic shock, angiotensin II administration is associated with a similar level of cardiovascular resuscitation and less myocardial oxygen consumption, and inflammation compared to norepinephrine.

Prognostic role of automatic pupillometry in sepsis: a retrospective study.

BACKGROUND: Sepsis-associated brain dysfunction is a frequent disorder in septic patients and has a multifactorial pathophysiology. Cholinergic pathways and brainstem dysfunction may result in pupillary alterations. The aim of this study was to evaluate whether early assessment of the Neurological Pupil Index (NPiTM) derived from an automated pupillometry could predict mortality in critically ill septic patients. METHODS: Retrospective cohort study of adult critically ill septic patients admitted to the intensive care unit of a University Hospital; patients with acute or known brain damage were excluded. Patients' severity was assessed by the daily Sequential Organ Failure Assessment Score and the SOFAmax (i.e., highest SOFA Score during the first five days) was computed. The worst NPi (i.e., lowest value from one eye) was collected daily and then computed over the first five days of assessment. Mortality was assessed at hospital discharge. RESULTS: A total of 75 patients were included over the study period (median age 67 [53-75] years and median SOFA Score at admission 10 [8-12]); 64 (85%) presented septic shock; 48 (64%) died at hospital discharge. The worst NPi during the first five days of sepsis was significantly lower in non-survivors compared to survivors (4.4 [3.6-4.6] vs. 4.5 [4.2-4.7]; P=0.042). The worst NPi was also significantly lower in high severity group (i.e., SOFAmax≥12) when compared to others (4.4 [3.2- 4.5] vs. 4.5 [4.0-4.7] P=0.01). However, in the multivariate analyses, the NPi value was not independently associated with in-hospital mortality or high SOFAmax. CONCLUSIONS: In this study, no independent prognostic role of NPi was observed in septic patients. Further larger prospective studies are needed to better evaluate the role of automated pupillometry in this setting.

A comprehensive neuromonitoring approach in a large animal model of cardiac arrest.

BACKGROUND: Anoxic brain injuries represent the main determinant of poor outcome after cardiac arrest (CA). Large animal models have been described to investigate new treatments during CA and post-resuscitation phase, but a detailed model that includes extensive neuromonitoring is lacking. METHOD: Before an electrically-induced 10-minute CA and resuscitation, 46 adult pigs underwent neurosurgery for placement of a multifunctional probe (intracranial pressure or ICP, tissue oxygen tension or PbtO2 and cerebral temperature) and a bolt-based technique for the placement and securing of a regional blood flow probe and two sEEG electrodes; two modified cerebral microdialysis (CMD) probes were also inserted in the frontal lobes and accidental misplacement was prevented using a perforated head support. RESULT: 42 animals underwent the CA procedure and 41 achieved the return of spontaneous circulation (ROSC). In 4 cases (8.6%) an adverse event took place during preparation, but only in two cases (4.3%) this was related to the neurosurgery. In 6 animals (13.3%) the minor complications that occurred resolved after probe repositioning. CONCLUSION: Herein we provide a detailed comprehensive neuromonitoring approach in a large animal model of CA that might help future research.

A dynamic online nomogram predicting severe vitamin D deficiency at ICU admission.

INTRODUCTION: Although prevalent and associated with worsened outcomes, vitamin D severe deficiency is not systematically searched among intensive care unit (ICU) admissions and waiting time for measurement results range from hours to few days. Hence, we developed and internally validated a simple nomogram for predicting severe vitamin D deficiency at ICU admission. PATIENTS AND METHODS: Data of 3338 ICU admissions from an observational prospective cohort registered between January 2017 and December 2019 were analyzed. Demographic data as well as severity scores and season of admission were obtained. After splitting the population into training and test sets, a least absolute shrinkage (LASSO) regression model was used to select factors and construct the nomogram. Calibration and discrimination were used to assess the nomogram performance. Clinical use was evaluated by a decision curve analysis. RESULTS: Age, gender, Sequential Organ Failure Assessment (SOFA), Simplified Acute Physiology Score III (SAPS3) and season of admission were identified by the LASSO regression analysis as significant predictors of vitamin D severe deficiency at ICU admission. The nomogram model showed good discrimination with a 1000 bootstrap analysis and good calibration with a C-index of 0.64. The decision curve analysis showed that at a threshold probability between 30% and 50%, using the nomogram adds more benefit that considering that all patients are severely deficient or non-severely deficient. CONCLUSIONS: This easy-to-use dynamic nomogram can help physicians to select patients that could benefit the most from vitamin D supplementation at ICU admission. External validation is needed to verify the generalizability of this nomogram.