NHH promotes Sepsis-associated Encephalopathy with the expression of AQP4 in astrocytes through the gut-brain Axis.

Sepsis-associated encephalopathy (SAE) is a significant cause of mortality in patients with sepsis. Despite extensive research, its exact cause remains unclear. Our previous research indicated a relationship between non-hepatic hyperammonemia (NHH) and SAE. This study aimed to investigate the relationship between NHH and SAE and the potential mechanisms causing cognitive impairment. In the in vivo experimental results, there were no significant abnormalities in the livers of mice with moderate cecal ligation and perforation (CLP); however, ammonia levels were elevated in the hippocampal tissue and serum. The ELISA study suggest that fecal microbiota transplantation in CLP mice can reduce ammonia levels. Reduction in ammonia levels improved cognitive dysfunction and neurological impairment in CLP mice through behavioral, neuroimaging, and molecular biology studies. Further studies have shown that ammonia enters the brain to regulate the expression of aquaporins-4 (AQP4) in astrocytes, which may be the mechanism underlying brain dysfunction in CLP mice. The results of the in vitro experiments showed that ammonia up-regulated AQP4 expression in astrocytes, resulting in astrocyte damage. The results of this study suggest that ammonia up-regulates astrocyte AQP4 expression through the gut-brain axis, which may be a potential mechanism for the occurrence of SAE.

Infusion of sodium DL-3-ß-hydroxybutyrate decreases cerebral injury biomarkers after resuscitation in experimental cardiac arrest.

AIMS: Cerebral complications after cardiac arrest (CA) remain a major problem worldwide. The aim was to test the effects of sodium-ß-hydroxybutyrate (SBHB) infusion on brain injury in a clinically relevant swine model of CA. RESULTS: CA was electrically induced in 20 adult swine. After 10 min, cardiopulmonary resuscitation was performed for 5 min. After return of spontaneous circulation (ROSC), the animals were randomly assigned to receive an infusion of balanced crystalloid (controls, n = 11) or SBHB (theoretical osmolarity 1189 mOsm/l, n = 8) for 12 h. Multimodal neurological and cardiovascular monitoring were implemented in all animals. Nineteen of the 20 animals achieved ROSC. Blood sodium concentrations, osmolarity and circulating KBs were higher in the treated animals than in the controls. SBHB infusion was associated with significantly lower plasma biomarkers of brain injury at 6 (glial fibrillary acid protein, GFAP and neuron specific enolase, NSE) and 12 h (neurofilament light chain, NFL, GFAP and NSE) compared to controls. The amplitude of the stereoelectroencephalograph (sEEG) increased in treated animals after ROSC compared to controls. Cerebral glucose uptake was lower in treated animals. CONCLUSIONS: In this experimental model, SBHB infusion after resuscitated CA was associated with reduced circulating markers of cerebral injury and increased sEEG amplitude.

The impact of the new acute respiratory distress syndrome (ARDS) criteria on Berlin criteria ARDS patients: a multicenter cohort study.

OBJECTIVE: The European Society of Intensive Care Medicine (ESICM) recently recommended changes to the criteria of acute respiratory distress syndrome (ARDS), patients with high-flow oxygen were included, however, the effect of these changes remains unclear. Our objectives were to evaluate the performance of these new criteria and to compare the outcomes of patients meeting the new ARDS criteria with those meeting the Berlin ARDS criteria. METHODS: This was a retrospective cohort. The patients admitted to the intensive care unit (ICU) were diagnosed with ARDS. Patients were classified as meeting Berlin criteria ARDS (n = 4279), high-flow nasal oxygen (HFNO) criteria ARDS (n = 559), or new criteria ARDS (n = 4838). RESULTS: In comparison with HFNO criteria ARDS and new criteria ARDS, patients with Berlin criteria ARDS demonstrated lower blood oxygen levels assessed by PaO2/FiO2, SpO2/FiO2, and ROX (SpO2/FiO2/respiratory rate) (p < 0.001); and higher severity of illness assessed by the Sequential Organ Failure Assessment (SOFA) score, Acute Physiology And Chronic Health Evaluations (APACHE II), Simplified Acute Physiology Score (SAPS II) (p < 0.001), (p < 0.001), and longer ICU and hospital stays (p < 0.001). In comparison with the HFNO criteria, patients meeting Berlin criteria ARDS had higher hospital mortality (10.6% vs. 16.9%; p = 0.0082), 28-day mortality (10.6% vs. 16.5%; p = 0.0079), and 90-day mortality (10.7% vs. 17.1%; p = 0.0083). ARDS patients with HFNO did not have severe ARDS; Berlin criteria ARDS patients with severe ARDS had the highest mortality rate (approximately 33%). PaO2/FiO2, SpO2/FiO2, and ROX negatively correlated with the SOFA and APACHE II scores. The SOFA and APACHE II scores had high specificity and sensitivity for prognosis in patients with new criteria ARDS. CONCLUSION: The new criteria of ARDS reduced the severity of illness, length of stay in the ICU, length of hospital stays, and overall mortality. SOFA and APACHE II scores remain important in assessing the prognosis of patients with new criteria ARDS. TRIAL REGISTRATION: Registration number: ChiCTR2200067084.

Hypertonic sodium lactate infusion reduces vasopressor requirements and biomarkers of brain and cardiac injury after experimental cardiac arrest.

INTRODUCTION: Prognosis after resuscitation from cardiac arrest (CA) remains poor, with high morbidity and mortality as a result of extensive cardiac and brain injury and lack of effective treatments. Hypertonic sodium lactate (HSL) may be beneficial after CA by buffering severe metabolic acidosis, increasing brain perfusion and cardiac performance, reducing cerebral swelling, and serving as an alternative energetic cellular substrate. The aim of this study was to test the effects of HSL infusion on brain and cardiac injury in an experimental model of CA. METHODS: After a 10-min electrically induced CA followed by 5 min of cardiopulmonary resuscitation maneuvers, adult swine (n = 35) were randomly assigned to receive either balanced crystalloid (controls, n = 11) or HSL infusion started during cardiopulmonary resuscitation (CPR, Intra-arrest, n = 12) or after return of spontaneous circulation (Post-ROSC, n = 11) for the subsequent 12 h. In all animals, extensive multimodal neurological and cardiovascular monitoring was implemented. All animals were treated with targeted temperature management at 34 °C. RESULTS: Thirty-four of the 35 (97.1%) animals achieved ROSC; one animal in the Intra-arrest group died before completing the observation period. Arterial pH, lactate and sodium concentrations, and plasma osmolarity were higher in HSL-treated animals than in controls (p < 0.001), whereas potassium concentrations were lower (p = 0.004). Intra-arrest and Post-ROSC HSL infusion improved hemodynamic status compared to controls, as shown by reduced vasopressor requirements to maintain a mean arterial pressure target > 65 mmHg (p = 0.005 for interaction; p = 0.01 for groups). Moreover, plasma troponin I and glial fibrillary acid protein (GFAP) concentrations were lower in HSL-treated groups at several time-points than in controls. CONCLUSIONS: In this experimental CA model, HSL infusion was associated with reduced vasopressor requirements and decreased plasma concentrations of measured biomarkers of cardiac and cerebral injury.

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.

Evaluation of a new magnetically suspended centrifugal neonatal pump in healthy animals using a veno-venous extracorporeal membrane oxygenation configuration.

BACKGROUND: The objective of this animal study was to evaluate the hemodynamic performance of a new centrifugal pump for extra-corporeal membrane oxygenation (ECMO) support in neonates. METHODS: Six healthy swines were supported with veno-venous ECMO with the New Born ECMOLife centrifugal pump (Eurosets, Medolla, Italy) at different flow rates: 0.25, 0.5, 0.6, and 0.8 L/min; three animals were evaluated at low-flows (0.25 and 0.5 L/min) and three at high-flows (0.6 and 0.8 L/min). Each flow was maintained for 4 hours. Blood samples were collected at different time-points. Hematological and biochemical parameters and ECMO parameters [flow, revolutions per minute (RPM), drainage pressure, and the oxygenator pressure drop] were evaluated. RESULTS: The increase of the pump flow from 0.25 to 0.5 L/min or from 0.6 to 0.8 L/min required significantly higher RPM and produced significantly higher pump pressures [from 0.25 to 0.5 L/min: 1470 (1253-1569) versus 2652 (2589-2750) RPM and 40 (26-57) versus 125 (113-139) mmHg, respectively; p < .0001 for both - from 0.60 to 0.8 L/min: 1950 (1901-2271) versus 2428 (2400-2518) RPM and 66 (62-86) versus 106 (101-113) mmHg, respectively; p < .0001 for both]. Median drainage pressure significantly decreased from -18 (-22; -16) mmHg to -55 (-63; -48) mmHg when the pump flow was increased from 0.25 to 0.5 L/min (p < .0001). When pump flow increased from 0.6 to 0.8 L/min, drainage pressure decreased from -32 (-39; -24) mmHg to -50 (-52; -43) mmHg, (p < .0001). Compared to pre-ECMO values, the median levels of lactate dehydrogenase, d-dimer, hematocrit, and platelet count decreased after ECMO start at all flow rates, probably due to hemodilution. Plasma-free hemoglobin, instead, showed a modest increase compared to pre-ECMO values during all experiments at different pump flow rates. However, these changes were not clinically relevant. CONCLUSIONS: In this animal study, the "New Born ECMOLife" centrifugal pump showed good hemodynamic performance. Long-term studies are needed to evaluate biocompatibility of this new ECMO pump.

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.

Automated Titration of Vasopressor Infusion Using a Closed-loop Controller: In Vivo Feasibility Study Using a Swine Model.

WHAT WE ALREADY KNOW ABOUT THIS TOPIC: Intraoperative hypotension has been associated with adverse postoperative outcomes.A randomized controlled trial of individualized blood pressure management in patients undergoing major abdominal surgery found reduced postoperative adverse events in patients in the blood pressure management intervention group versus the standard of care group. WHAT THIS ARTICLE TELLS US THAT IS NEW: In this study of pigs with normovolemic hypotension induced by administration of sodium nitroprusside, an automated closed-loop vasopressor administration device was able to maintain mean arterial pressure within 5 mmHg of 80 mmHg for 98% of the intraoperative period. This suggests that norepinephrine can be accurately titrated using an automated infusion device in order to maintain target blood pressure. BACKGROUND: Multiple studies have reported associations between intraoperative hypotension and adverse postoperative complications. One of the most common interventions in the management of hypotension is vasopressor administration. This approach requires careful and frequent vasopressor boluses and/or multiple adjustments of an infusion. The authors recently developed a closed-loop controller that titrates vasopressors to maintain mean arterial pressure (MAP) within set limits. Here, the authors assessed the feasibility and overall performance of this system in a swine model. The authors hypothesized that the closed-loop controller would be able to maintain MAP at a steady, predefined target level of 80 mmHg for greater than 85% of the time. METHODS: The authors randomized 14 healthy anesthetized pigs either to a control group or a closed-loop group. Using infusions of sodium nitroprusside at doses between 65 and 130 µg/min, we induced four normovolemic hypotensive challenges of 30 min each. In the control group, nothing was done to correct hypotension. In the closed-loop group, the system automatically titrated norepinephrine doses to achieve a predetermined MAP of 80 mmHg. The primary objective was study time spent within ±5 mmHg of the MAP target. Secondary objectives were performance error, median performance error, median absolute performance error, wobble, and divergence. RESULTS: The controller maintained MAP within ±5 mmHg of the target for 98 ± 1% (mean ± SD) of the time. In the control group, the MAP was 80 ± 5 mmHg for 14.0 ± 2.8% of the time (P< 0.0001). The MAP in the closed-loop group was above the target range for 1.2 ± 1.2% and below it for 0.5 ± 0.9% of the time. Performance error, median performance error, median absolute performance error, wobble, and divergence were all optimal. CONCLUSIONS: In this experimental model of induced normovolemic hypotensive episodes in pigs, the automated controller titrated norepinephrine infusion to correct hypotension and keep MAP within ±5 mmHg of target for 98% of management time.

Hypertonic Saline in Human Sepsis: A Systematic Review of Randomized Controlled Trials.

The role of hypertonic saline in sepsis remains unclear because clinical data are limited and the balance between beneficial and adverse effects is not well defined. In this systematic literature review, we searched PubMed and Embase to identify all randomized controlled trials up until January 31, 2018 in which hypertonic saline solutions of any concentration were used in patients of all ages with sepsis and compared to a cohort of patients receiving an isotonic fluid. We identified 8 randomized controlled trials with 381 patients who had received hypertonic saline. Lower volumes of hypertonic saline than of isotonic solutions were needed to achieve the desired hemodynamic goals (standardized mean difference, -0.702; 95% CI, -1.066 to -0.337; P < .001; moderate-quality evidence). Hypertonic saline administration was associated with a transient increase in sodium and chloride concentrations without adverse effects on renal function (moderate-quality evidence). Some data suggested a beneficial effect of hypertonic saline solutions on some hemodynamic parameters and the immunomodulatory profile (very low-quality evidence). Mortality rates were not significantly different with hypertonic saline than with other fluids (odds ratio, 0.946; 95% CI, 0.688-1.301; P = .733; low-quality evidence). In conclusion, in our meta-analysis of studies in patients with sepsis, hypertonic saline reduced the volume of fluid needed to achieve the same hemodynamic targets but did not affect survival.

Effects of acute ethanol intoxication in an ovine peritonitis model.

BACKGROUND: Acute ethanol intoxication has been shown to have contrasting effects on outcomes in sepsis. The aim of this study was to explore the effects of acute ethanol intoxication on hemodynamics, renal function, brain perfusion and lactate/pyruvate in an ovine sepsis model. METHODS: Anesthetized, mechanically ventilated female sheep were randomized to an ethanol group (n = 7), which received 1 g/kg ethanol diluted in intravenous (i.v.) saline infusion or a control group (n = 7), which received the same volume of i.v. saline. Both groups received the treatment for a period of 2 h prior to induction of sepsis by intraperitoneal injection of feces. Other treatment included fluid resuscitation but no vasopressors or antibiotics. Global hemodynamics, renal blood flow, brain cortex laser Doppler flowmetry and microdialysis analyses were recorded hourly. RESULTS: In the ethanol group, blood ethanol concentrations were 137 ± 29 mg/dL at the time of feces injection and decreased to become undetectable by 12 h. Arterial hypotension occurred earlier in the ethanol than in the control group (8 [7-12] vs. 14 [11-20] hours, p = 0.03). Lactate levels increased to > 2 mmol/L earlier in the ethanol group. Renal dysfunction (9 [6-13] vs. 13 [12-15] hours, p = 0.05) and oliguria (urine output < 0.5 mL/kg/h; 10 [7-12] vs. 13 [12, 13] hours, p = 0.01) developed earlier in the ethanol than in the control group. Brain blood flow and lactate/pyruvate were unaffected. There was no significant difference in survival time. CONCLUSIONS: Acute ethanol intoxication in this model of peritonitis resulted in earlier development of shock and renal dysfunction but did not alter brain perfusion and metabolism or short-term survival.

Should Hyperoxia Be Avoided During Sepsis? An Experimental Study in Ovine Peritonitis.

OBJECTIVES: Optimizing oxygen delivery is an important part of the hemodynamic resuscitation of septic shock, but concerns have been raised over the potentially deleterious effects of hyperoxia. We evaluated the impact of hyperoxia on hemodynamics, the microcirculation, and cerebral and renal metabolism in an ovine model of septic shock. DESIGN: Randomized animal study. SETTING: University hospital animal research laboratory. SUBJECTS: Fourteen adult female sheep. INTERVENTIONS: After induction of fecal peritonitis, sheep were randomized to ventilation with an FIO2 of 100% (n = 7) or an FIO2 adjusted to maintain PaO2 between 90 and 120 mm Hg (n = 7, control). All animals were fluid resuscitated and observed until death. MEASUREMENTS AND MAIN RESULTS: In addition to hemodynamic measurements, we assessed the sublingual microcirculation, renal and cerebral microdialysis and microvascular perfusion, and brain tissue oxygen pressure. Hyperoxic animals initially had a higher mean arterial pressure than control animals. After onset of shock, hyperoxia blunted the decrease in stroke volume index observed in the control group. Hyperoxia was associated with a higher sublingual microcirculatory flow over time, with higher cerebral perfusion and brain tissue oxygen pressure and with a lower cerebral lactate-to-pyruvate ratio than in control animals. Hyperoxia was also associated with preserved renal microvascular perfusion, lower renal lactate-to-pyruvate ratio, and higher PaO2/FIO2 ratio. CONCLUSIONS: In this acute peritonitis model, hyperoxia induced during resuscitation provided better hemodynamics and peripheral microvascular flow and better preserved cerebral metabolism, renal function, and gas exchange. These observations are reassuring with recent concerns about excessive oxygen therapy in acute diseases.

Changes in kidney perfusion and renal cortex metabolism in septic shock: an experimental study.

BACKGROUND: The etiology of renal dysfunction in sepsis is currently attributed to altered perfusion, microcirculatory abnormalities and cellular alterations. To clarify these mechanisms, we characterized the changes in renal perfusion and cortex metabolism in a large animal model of sepsis. METHODS: We studied 12 adult female sheep randomized to peritonitis-induced sepsis (n = 8) or to sham procedure (n = 4). A flow probe was positioned around the renal artery to measure renal blood flow (RBF). Laser Doppler was used to measure regional flow in the kidney cortex and medulla. A microdialysis probe was inserted into the renal cortex to measure cortical glucose, lactate, and pyruvate. Fluid resuscitation was provided to keep pulmonary artery occlusion pressure at baseline levels. All animals were observed for 18 h. RESULTS: Hypotension occurred after 9 h in the septic animals (P = 0.02 versus baseline). RBF and cortical flow were significantly lower than at baseline from 12 h in the septic animals (P = 0.01 and P = 0.03, respectively). Cortical lactate and pyruvate levels increased in the septic animals from 3 and from 6 h, respectively (both P = 0.02 versus baseline), and the L/P ratio from 15 h (P = 0.01). There was a correlation between cortical flow and cortical L/P ratio after shock onset (r = -0.60, P = 0.002) but not before. CONCLUSIONS: In this peritonitis model, sepsis was associated with metabolic alterations that may reflect early induction of cortical glycolysis. Septic shock was associated with reduced renal perfusion and decreased cortical and medullary blood flow, followed by signs of anaerobic metabolism in the cortex when flow reductions became critical.

Administration of Tetrahydrobiopterin (BH4) Protects the Renal Microcirculation From Ischemia and Reperfusion Injury.

BACKGROUND: Abdominal aortic aneurysm surgery with suprarenal cross-clamping is often associated with renal injury. Although the mechanism underlying such injury is unclear, tissue ischemia and reperfusion, which induces endothelial dysfunction and decreases the availability of tetrahydrobiopterin (BH4), may play a role. We evaluated whether BH4 administration prevents renal ischemia/reperfusion injury in an animal model of aortic cross-clamping. METHODS: Nineteen anesthetized, mechanically ventilated, and invasively monitored adult sheep were randomized into 3 groups: sham animals (n = 5) that underwent surgical preparation but no aortic clamping; an ischemia/reperfusion group (n = 7), where the aorta was clamped above the renal arteries for 1 hour, and a BH4 group (n = 7), in which animals received 20 mg/kg of BH4 followed by aortic cross-clamp for 1 hour. Animals were followed for a maximum of 6 hours after reperfusion. The renal microcirculation was evaluated at baseline (before clamping), and 1, 4, and 6 hours after reperfusion using side-stream dark field videomicroscopy. The renal lactate-to-pyruvate ratio was evaluated using microdialysis. The primary outcome was the change in proportion of small perfused vessels before and after injury. Secondary outcomes were renal tissue redox state and renal function. RESULTS: Ischemia/reperfusion injury was associated with increases in heart rate and mean arterial pressure, which were blunted by BH4 administration. From the first to the sixth hour after reperfusion, the small vessel density (estimated mean difference [EMD], 1.03; 95% confidence interval [CI], 0.41-1.64; P = .003), perfused small vessel density (EMD, 0.84; 95% CI, 0.29-1.39; P = .005), and proportion of perfused small vessels (EMD, 8.60; 95% CI, 0.85-16.30; P = .031) were altered less in the BH4 than in the ischemia/reperfusion group. The renal lactate-to-pyruvate ratios were lower in the cortex in the BH4 than in the ischemia/reperfusion group from the first to the sixth hour after reperfusion (EMD, -19.16; 95% CI, -11.06 to 33.16; P = .002) and in the medulla from the first to the fourth hour (EMD, -26.62; 95% CI, -18.32 to 38.30; P = .020; and EMD, -8.68; 95% CI, -5.96 to 12.65; P = .019). At the sixth hour, serum creatinine was lower in the BH4 than in the ischemia/reperfusion group (EMD, -3.36; 95% CI, -0.29 to 1.39; P = .026). CONCLUSIONS: In this sheep model of renal ischemia/reperfusion, BH4 pretreatment reduced renal microvascular injury and improved renal metabolism and function. Further work is needed to clarify the potential role of BH4 in ischemia/reperfusion injury.

Esmolol Administration to Control Tachycardia in an Ovine Model of Peritonitis.

BACKGROUND: Excessive adrenergic signaling may be harmful in sepsis. Using ß-blockers to reduce sympathetic overactivity may modulate sepsis-induced cardiovascular, metabolic, immunologic, and coagulation alterations. Using a randomized ovine fecal peritonitis model, we investigated whether administration of a short-acting ß-blocker, esmolol, could control tachycardia without deleterious effects on hemodynamics, renal perfusion, cerebral perfusion, cerebral metabolism, or outcome. METHODS: After induction of fecal peritonitis, 14 anesthetized, mechanically ventilated, and hemodynamically monitored adult female sheep were randomly assigned to receive a continuous intravenous infusion of esmolol to control heart rate between 80 and 100 bpm (n = 7) or a saline infusion (control group, n = 7). Esmolol was discontinued when the mean arterial pressure decreased below 60 mm Hg. Fluid resuscitation was titrated to maintain pulmonary artery occlusion pressure at baseline values. Left renal blood flow and cerebral cortex perfusion and metabolism were monitored in addition to standard hemodynamic variables. RESULTS: Esmolol was infused for 11 (9-14) hours; the target heart rate (80-100 bpm) was achieved between 3 and 8 hours after feces injection. In the first 5 hours after the start of the infusion, the decrease in heart rate was compensated by an increase in stroke volume index; later, stroke volume index was not statistically significantly different in the 2 groups, so that the cardiac work index was lower in the esmolol than in the control group. Hypotension (mean arterial pressure <60 mm Hg) occurred earlier (10 [8-12] vs 14 [11-20] hours; P= .01) in the esmolol group than in the control animals. Renal blood flow decreased earlier in the esmolol group, but there were no differences in urine output, cerebral cortex perfusion, metabolism, or survival between the groups. CONCLUSIONS: In this ovine model of abdominal sepsis, early control of tachycardia by esmolol was associated with a transient increase in stroke volume, followed by earlier hypotension. There were no significant effects of esmolol on cerebral perfusion, metabolism, urine output, or survival.

The effects of acute renal denervation on kidney perfusion and metabolism in experimental septic shock.

BACKGROUND: Perfusion deficits likely play an important role in the development of renal dysfunction in sepsis. Renal denervation may improve kidney perfusion and metabolism. METHODS: We randomized 14 female sheep to undergo bilateral surgical renal denervation (n = 7) or sham procedure (n = 7) prior to induction of sepsis. Renal blood flow (RBF) was measured with a pre-calibrated flowprobe. Laser Doppler probes were implanted to measure cortical and medullary perfusion. Cortical glucose, lactate and pyruvate levels were measured using the microdialysis technique. Creatinine clearance was determined. Sepsis was induced by peritonitis and fluid resuscitation was provided to avoid hypovolemia. RESULTS: RBF and cortical perfusion were higher in the denervated group during the first 6 h after induction of sepsis (P < 0.001 and P < 0.05, respectively), while medullary perfusion decreased similarly in both groups. After hypotension developed, RBF decreased to similar levels in both groups. Cortical pyruvate and lactate levels were lower in the denervated animals (P < 0.001 and P < 0.001, respectively). There were no differences between groups in creatinine clearance, urine output or time to oliguria. CONCLUSION: Denervation thus caused an early increase in RBF that was distributed towards the kidney cortex. Although associated with an attenuation of early cortical metabolic alterations, denervation failed to prevent the deterioration in renal function.

A Selective V(1A) Receptor Agonist, Selepressin, Is Superior to Arginine Vasopressin and to Norepinephrine in Ovine Septic Shock.

OBJECTIVE: Selective vasopressin V(1A) receptor agonists may have advantages over arginine vasopressin in the treatment of septic shock. We compared the effects of selepressin, a selective V(1A) receptor agonist, arginine vasopressin, and norepinephrine on hemodynamics, organ function, and survival in an ovine septic shock model. DESIGN: Randomized animal study. SETTING: University hospital animal research laboratory. SUBJECTS: Forty-six adult female sheep. INTERVENTIONS: Fecal peritonitis was induced in the anesthetized, mechanically ventilated, fluid-resuscitated sheep, and they were randomized in two successive phases. Three late-intervention groups (each n = 6) received IV selepressin (1 pmol/kg/min), arginine vasopressin (0.25 pmol [0.1 mU]/kg/min), or norepinephrine (3 nmol [0.5 µg]/kg/min) when mean arterial pressure remained less than 70 mm Hg despite fluid challenge; study drugs were thereafter titrated to keep mean arterial pressure at 70-80 mm Hg. Three early-intervention groups (each n = 7) received selepressin, arginine vasopressin, or norepinephrine at the same initial infusion rates as for the late intervention, but already when mean arterial pressure had decreased by 10% from baseline; doses were then titrated as for the late intervention. A control group (n = 7) received saline. All animals were observed until death or for a maximum of 30 hours. MEASUREMENTS AND MAIN RESULTS: In addition to hemodynamic and organ function assessment, plasma interleukin-6 and nitrite/nitrate levels were measured. In the late-intervention groups, selepressin delayed the decrease in mean arterial pressure and was associated with lower lung wet/dry weight ratios than in the other two groups. In the early-intervention groups, selepressin maintained mean arterial pressure and cardiac index better than arginine vasopressin or norepinephrine, slowed the increase in blood lactate levels, and was associated with less lung edema, lower cumulative fluid balance, and lower interleukin-6 and nitrite/nitrate levels. Selepressin-treated animals survived longer than the other animals. CONCLUSIONS: In this clinically relevant model, selepressin, a selective V(1A) receptor agonist, was superior to arginine vasopressin and to norepinephrine in the treatment of septic shock, especially when administered early.

Effects of Different Crystalloid Solutions on Hemodynamics, Peripheral Perfusion, and the Microcirculation in Experimental Abdominal Sepsis.

BACKGROUND: Crystalloid solutions are used to restore intravascular volume in septic patients, but each solution has limitations. The authors compared the effects of three crystalloid solutions on hemodynamics, organ function, microcirculation, and survival in a sepsis model. METHODS: Peritonitis was induced by injection of autologous feces in 21 anesthetized, mechanically ventilated adult sheep. After baseline measurements, animals were randomized to lactated Ringer's (LR), normal saline (NS), or PlasmaLyte as resuscitation fluid. The sublingual microcirculation was assessed using sidestream dark field videomicroscopy and muscle tissue oxygen saturation with near-infrared spectroscopy. RESULTS: NS administration was associated with hyperchloremic acidosis. NS-treated animals had lower cardiac index and left ventricular stroke work index than LR-treated animals from 8 h and lower mean arterial pressure than LR-treated animals from 12 h. NS-treated animals had a lower proportion of perfused vessels than LR-treated animals after 12 h (median, 82 [71 to 83] vs. 85 [82 to 89], P = 0.04) and greater heterogeneity of proportion of perfused vessels than PlasmaLyte or LR groups at 18 h. Muscle tissue oxygen saturation was lower at 16 h in the NS group than in the other groups. The survival time of NS-treated animals was shorter than that of the LR group (17 [14 to 20] vs. 26 [23 to 29] h, P < 0.01) but similar to that of the PlasmaLyte group (20 [12 to 28] h, P = 0.74). CONCLUSIONS: In this abdominal sepsis model, resuscitation with NS was associated with hyperchloremic acidosis, greater hemodynamic instability, a more altered microcirculation, and more severe organ dysfunction than with balanced fluids. Survival time was shorter than in the LR group.

Sepsis is associated with altered cerebral microcirculation and tissue hypoxia in experimental peritonitis.

OBJECTIVE: Alterations in cerebral microvascular blood flow may develop during sepsis, but the consequences of these abnormalities on tissue oxygenation and metabolism are not well defined. We studied the evolution of microvascular blood flow, brain oxygen tension (PbO2), and metabolism in a clinically relevant animal model of septic shock. DESIGN: Prospective randomized animal study. SETTING: University hospital research laboratory. SUBJECTS: Fifteen invasively monitored and mechanically ventilated female sheep. INTERVENTIONS: The sheep were randomized to fecal peritonitis (n = 10) or a sham procedure (n = 5), and craniectomies were performed to enable evaluation of cerebral microvascular blood flow, PbO2, and metabolism. The microvascular network of the left frontal cortex was evaluated (at baseline, 6, 12, and 18 hr) using sidestream dark-field videomicroscopy. Using an off-line semiquantitative method, functional capillary density and the proportion of small perfused vessels were calculated. PbO2 was measured hourly by a parenchymal Clark electrode, and cerebral metabolism was assessed by the lactate/pyruvate ratio using brain microdialysis; both these systems were placed in the right frontal cortex. MEASUREMENT AND MAIN RESULTS: In septic animals, cerebral functional capillary density (from 3.1 ± 0.5 to 1.9 ± 0.4 n/mm, p < 0.001) and proportion of small perfused vessels (from 98% ± 2% to 84% ± 7%, p = 0.004) decreased over the 18-hour study period. Concomitantly, PbO2 decreased (61 ± 5 to 41 ± 7 mm Hg, p < 0.001) and lactate/pyruvate ratio increased (23 ± 5 to 36 ± 19, p < 0.001). At 18 hours, when shock was present, animals with a mean arterial pressure less than 65 mm Hg (n = 6) had similar functional capillary density, proportion of small perfused vessels, and PbO2 values but significantly higher lactate/pyruvate ratio (46 ± 18 vs 20 ± 4, p = 0.009) compared with animals with an mean arterial pressure of 65-70 mm Hg (n = 4). CONCLUSIONS: Impaired cerebral microcirculation during sepsis is associated with progressive impairment in PbO2 and brain metabolism. Development of severe hypotension was responsible for a further increase in anaerobic metabolism. These alterations may play an important role in the pathogenesis of brain dysfunction during sepsis.

Clinical neurophysiological assessment of sepsis-associated brain dysfunction: a systematic review.

INTRODUCTION: Several studies have reported the presence of electroencephalography (EEG) abnormalities or altered evoked potentials (EPs) during sepsis. However, the role of these tests in the diagnosis and prognostic assessment of sepsis-associated encephalopathy remains unclear. METHODS: We performed a systematic search for studies evaluating EEG and/or EPs in adult (≥ 18 years) patients with sepsis-associated encephalopathy. The following outcomes were extracted: a) incidence of EEG/EP abnormalities; b) diagnosis of sepsis-associated delirium or encephalopathy with EEG/EP; c) outcome. RESULTS: Among 1976 citations, 17 articles met the inclusion criteria. The incidence of EEG abnormalities during sepsis ranged from 12% to 100% for background abnormality and 6% to 12% for presence of triphasic waves. Two studies found that epileptiform discharges and electrographic seizures were more common in critically ill patients with than without sepsis. In one study, EEG background abnormalities were related to the presence and the severity of encephalopathy. Background slowing or suppression and the presence of triphasic waves were also associated with higher mortality. A few studies demonstrated that quantitative EEG analysis and EP could show significant differences in patients with sepsis compared to controls but their association with encephalopathy and outcome was not evaluated. CONCLUSIONS: Abnormalities in EEG and EPs are present in the majority of septic patients. There is some evidence to support EEG use in the detection and prognostication of sepsis-associated encephalopathy, but further clinical investigation is needed to confirm this suggestion.