Abstract Background In the setting of high-risk surgery, preventive strategies to maintain intestinal tissue integrity are of particular importance, as no bridging organ replacement therapy exists. Remote ischemic preconditioning (RIPC) has been reported to attenuate organ injury under conditions of restricted oxygen delivery. However, its effectiveness in hemorrhagic shock followed by blood transfusion is barely described. This study was designed to investigate the protective effects of RIPC, when applied 24 h prior to hemorrhagic shock, on intestinal tissue oxygenation, microcirculation, and mitochondrial function as key determinants of cell death and organ dysfunction. Methods Male rats received either RIPC, consisting of 4 cycles with 5 min of bilateral hindlimb vascular occlusion and 5 min of reperfusion each, or a sham treatment. After 24 h, animals were subjected to a fixed-pressure hemorrhage (40 ± 5 mmHg; 1 h) followed by shed blood transfusion and a 2 h observation period. Control animals were observed over time without induction of shock. Microvascular measurements and evaluation of intestinal microvascular oxygenation were assessed after median laparotomy. Intestinal microvascular oxygenation (µHbO 2 ) was assessed by white-light spectroscopy. Microvascular perfusion was evaluated using laser Doppler flowmetry and incident dark-field imaging. Mitochondrial function was analyzed by high-resolution respirometry. Results Hemorrhagic shock markedly impaired intestinal microvascular oxygenation and microvascular perfusion. RIPC applied 24 h prior to shock induction did not exert sustained protective effects on intestinal µHbO 2 , microcirculatory perfusion, or mitochondrial function. Conclusions RIPC applied 24 h before hemorrhagic shock failed to improve tissue oxygenation, microcirculation, and mitochondrial function as key determinants of cell survival and organ function. Elucidating the molecular mechanisms underlying RIPC remains essential to enable its effective translation into clinical practice.

Microcirculatory dysfunction is a key pathophysiological feature of sepsis and contributes to organ failure and mortality. In the gastrointestinal tract, impaired barrier function due to microcirculatory injury promotes translocation of inflammatory mediators and bacteria, worsening systemic inflammation and multiorgan dysfunction. Inotropic and vasoactive agents may improve microvascular perfusion through vasodilation in addition to their inotropic effects. Milrinone, a phosphodiesterase-3 inhibitor, and levosimendan, a calcium sensitizer, have shown promising but inconsistent effects in sepsis, while data on their direct microcirculatory and mitochondrial effects in abdominal organs remain limited. Sub-therapeutic vasopressin has demonstrated beneficial effects on gut microcirculation in experimental models, but its combination with inotropes has not been investigated. We hypothesized that (1) milrinone and levosimendan increase colonic and hepatic microvascular blood flow and oxygenation, (2) adjunctive low-dose vasopressin further enhances gastrointestinal microcirculation, and (3) mitochondrial respiration does not differ between treatment groups. Male Wistar rats (n = 105) underwent colon ascendens stent peritonitis (CASP) or sham surgery to induce moderate sepsis. Twenty-four hours later, animals received intravenous infusions of vehicle, milrinone, levosimendan, or the respective inotrope with low-dose vasopressin. Colonic and hepatic microvascular oxygenation and blood flow were assessed using tissue-reflectance spectrophotometry and laser Doppler flowmetry. Mitochondrial respiration in colonic and hepatic tissue homogenates from septic animals was analyzed by respirometry. Statistical analyses included mixed-effects models with Tukey or Dunnett post-hoc tests and Kruskal–Wallis tests with Dunn’s correction, using a two-sided significance level of α = 0.05. In septic animals, milrinone and levosimendan increased colonic and hepatic microvascular blood flow. With adjunctive vasopressin, colonic perfusion remained increased, whereas hepatic blood flow did not increase. Microvascular oxygenation remained unchanged in both organs. In sham-operated animals, microvascular blood flow and oxygenation did not differ between treatment groups. Mitochondrial respiration in colon and liver was unchanged across treatments, as indicated by respiratory control index and ADP/O ratio. In experimental abdominal sepsis, milrinone and levosimendan increase colonic and hepatic microvascular blood flow without affecting mitochondrial respiration. Adjunctive vasopressin alters hepatic but not colonic microvascular responses during combined inotropic therapy.

Hemorrhagic shock is characterized by decreased microvascular blood flow, leading to a critical depletion of tissue oxygenation, particularly within the gastrointestinal tract. The integrity of the intestinal barrier, however, plays a crucial role in maintaining systemic homeostasis. Remote ischemic preconditioning (RIPC), achieved through transient, repeated occlusion of blood flow to a limb, has been shown to exert beneficial effects on various tissues under hypoxic conditions. These effects are at least in part attributed to circulating humoral mediators with vasoactive properties. This study aimed to investigate the effect of RIPC - implemented via intermittent bilateral hind limb perfusion occlusion - on intestinal microvascular oxygenation, regional microcirculation, and mitochondrial function in a fixed-pressure model of hemorrhagic shock in rats with subsequent autologous blood transfusion. RIPC ameliorated the decrease of microvascular oxygenation in the ileum (shock: 34 ± 4% vs. shock + RIPC: 48 ± 4%), but not in the colon (shock: 51 ± 2% vs. shock + RIPC: 50 ± 4%). RIPC had neither an effect on regional microcirculation nor on mitochondrial respiration assessed ex vivo post hemorrhage and transfusion. These findings suggest that RIPC may improve intestinal tissue oxygenation in hemorrhagic shock independently of regional microcirculation and mitochondrial respiration and that this protective effect of RIPC might vary between different sections of the gastrointestinal tract. The mechanism by which RIPC improves ileal tissue oxygenation has to be clarified in future studies.

Improving intestinal tissue integrity appears to be crucial for maintaining global homeostasis in patients suffering from hemorrhagic shock. Since depletion of regional oxygen reserve might lead to cell death and tissue injury, the maintenance of regional tissue oxygenation appears to prevent intestinal mucosa from barrier shut down. Pyrrolidine dithiocarbamate (PDTC), an inducer of heme oxygenase-1 (HO-1), was reported to improve tissue integrity in various tissues under conditions of restricted oxygen delivery. Therefore, we investigated the effect of PDTC pretreatment on intestinal microvascular oxygenation (µHbO2) as a measure of regional tissue oxygen reserve in a rat model of hemorrhagic shock with subsequent shed blood transfusion. Furthermore, we explored whether the effect of systemic PDTC pretreatment on intestinal µHbO2 is associated with alterations in microvascular and mitochondrial function, as well as heme oxygenase-1 (HO-1) protein expression in the intestine. 40 male Wistar rats were randomized into 4 experimental groups and received standardized instrumentation under general anesthesia. Hemorrhagic shock was induced by arterial blood withdrawal (MAP: 40 ± 5 mmHg; 1 h). Subsequently, shed blood was transfused and animals were observed for 2 h. Control animals were observed for 3 h without the induction of hemorrhagic shock. PDTC (100 mg·kg− 1, i.p.) or saline was applied 24 h prior to hemorrhagic shock or control treatment. µHbO2 of the ileum and the colon was continuously evaluated by white-light spectrophotometry. Variables of microvascular blood flow, microvascular diffusion distance and mitochondrial respiration were determined by laser Doppler flowmetry as well as incident dark-field imaging and respirometry. HO-1 protein expression was assessed by western blot analysis. Hemorrhagic shock decreased intestinal µHbO2. Whereas systemic PDTC application did not increase µHbO2 under physiological conditions, pharmacological pretreatment significantly improved colonic µHbO2 after 60 min of hemorrhagic shock and accelerated early recovery of ileal and colonic µHbO2. This observation was independent of microvascular perfusion and mitochondrial respiration. PDTC pretreatment led to an increase of relative HO-1 protein expression in the ileum without a significant effect on colonic protein expression. The gastrointestinal tract is at persistent risk to develop tissue injury during hemorrhagic shock. The systemic application of PDTC is a promising pharmacological strategy to improve intestinal oxygen reserve during hemorrhagic shock and subsequent blood transfusion. This might lead to reduced intestinal tissue injury, maintain global homeostasis and reduce morbidity of patients suffering from hemorrhagic shock. However, the exact mechanism by which PDTC pretreatment improves intestinal oxygen reserve has to be elucidated in further studies since neither microvascular nor mitochondrial function was altered after PDTC application in this study. Furthermore, observed effects might include both HO-1-dependent and HO-1-independent mechanisms.

BACKGROUND:Sepsis is characterized by systemic inflammation and microcirculatory dysfunction, contributing to multiorgan failure. In the gastrointestinal tract, impaired microcirculation and mitochondrial dysfunction promote barrier failure and bacterial translocation. While dobutamine is commonly used to augment cardiac output in septic shock, its direct effects on intestinal microcirculation and mitochondrial respiration remain unclear. The microcirculatory impact of adjunctive low-dose vasopressin is similarly uncertain. METHODS:Twenty-four hours after colon ascendens stent peritonitis or sham surgery, 88 male Wistar rats were randomized to receive vehicle, vasopressin, dobutamine, or their combination under septic or sham conditions. Colonic and hepatic microcirculatory oxygenation (µHbO 2 ) and microvascular blood flow (µFlow) were measured for 90 minutes using tissue-reflectance spectrophotometry and laser Doppler flowmetry. Mitochondrial respiration was assessed in colon and liver homogenates of septic animals by high-resolution respirometry. Microcirculatory data were analyzed using mixed-effects models with Tukey's and Dunnett's post hoc tests. Mitochondrial data were analyzed using the Kruskal-Wallis test. A two-sided P < 0.05 was considered statistically significant. RESULTS:In septic rats, dobutamine significantly improved colonic microvascular oxygenation (∆µHbO 2 10.2% ± 13.4% vs. -2.3% ± 4.4% in controls and vs. baseline, P < 0.05) and microvascular blood flow (∆µFlow 30 ± 20 arbitrary units vs. baseline, P < 0.05). Combined dobutamine and vasopressin increased microvascular blood flow (∆µFlow 28 ± 27 arbitrary units vs. baseline, P < 0.05) but did not improve tissue oxygenation. Hepatic microcirculation and mitochondrial respiration remained largely unaltered. CONCLUSIONS:Dobutamine improves colonic microcirculation in sepsis, whereas concomitant vasopressin attenuates its oxygenation effects.

IntroductionHemorrhagic shock is characterized by derangements of the gastrointestinal microcirculation. Topical therapy with nitroglycerine or iloprost improves gastric tissue oxygenation but not regional perfusion, probably due to precapillary adrenergic innervation. Therefore, this study was designed to investigate the local effect of the parasympathomimetic carbachol alone and in combination with either nitroglycerine or iloprost on gastric and oral microcirculation during hemorrhagic shock.MethodsIn a cross-over design five female foxhounds were repeatedly randomized into six experimental groups. Carbachol, or carbachol in combination with either nitroglycerine or iloprost were applied topically to the oral and gastric mucosa. Saline, nitroglycerine, or iloprost application alone served as control groups. Then, a fixed-volume hemorrhage was induced by arterial blood withdrawal followed by blood retransfusion after 1h of shock. Gastric and oral microcirculation was determined using reflectance spectrophotometry and laser Doppler flowmetry. Oral microcirculation was visualized with videomicroscopy. Statistics: 2-way-ANOVA for repeated measurements and Bonferroni post-hoc analysis (mean ± SEM; p < 0.05).ResultsThe induction of hemorrhage led to a decrease of gastric and oral tissue oxygenation, that was ameliorated by local carbachol and nitroglycerine application at the gastric mucosa. The sole use of local iloprost did not improve gastric tissue oxygenation but could be supplemented by local carbachol treatment. Adding carbachol to nitroglycerine did not further increase gastric tissue oxygenation. Gastric microvascular blood flow remained unchanged in all experimental groups. Oral microvascular blood flow, microvascular flow index and total vessel density decreased during shock. Local carbachol supply improved oral vessel density during shock and oral microvascular flow index in the late course of hemorrhage.ConclusionThe specific effect of shifting the autonomous balance by local carbachol treatment on microcirculatory variables varies between parts of the gastrointestinal tract. Contrary to our expectations, the improvement of gastric tissue oxygenation by local carbachol or nitroglycerine application was not related to increased microvascular perfusion. When carbachol is used in combination with local vasodilators, the additional effect on gastric tissue oxygenation depends on the specific drug combination. Therefore, modulation of tissue oxygen consumption, mitochondrial function or alterations in regional blood flow distribution should be investigated.

Systemic vasodilating agents like nitroglycerin (NG) or iloprost (Ilo) show beneficial effects on intestinal microcirculation during sepsis, which could be attenuated by activation of the sympathetic nervous system or systemic side effects of vasodilating agents. This exploratory study aimed to investigate the effects of topically administered vasodilators and the parasympathetic drug carbachol on colonic microcirculatory oxygenation (µHbO2), blood flow (µFlow) and mitochondrial respiration. A total of 120 male Wistar rats were randomly assigned to twelve groups and underwent either colon ascendens stent peritonitis (CASP) or sham surgery. After 24 h, animals received the following therapeutic regimes: (1) balanced full electrolyte solution, (2) carbachol, (3) NG, (4) Ilo, (5) NG + carbachol, and (6) Ilo + carbachol. Mitochondrial respiration was measured in colon homogenates by respirometry. In sham animals, NG (−13.1%*) and Ilo (−10.5%*) led to a decrease in µHbO2. Additional application of carbachol abolished this effect (NG + carbachol: −4.0%, non-significant; Ilo + carbachol: −1.4%, non-significant). In sepsis, carbachol reduced µHbO2 when applied alone (−10.5%*) or in combination with NG (−17.6%*). Thus, the direction and degree of this effect depend on the initial pathophysiologic condition.

Recent studies observed, despite an anti-hyperlipidaemic effect, a positive impact of fibrates on septic conditions. This study evaluates the effects of gemfibrozil on microcirculatory variables, mitochondrial function, and lipid peroxidation levels with regard to its potential role as an indicator for oxidative stress in the colon and liver under control and septic conditions and dependencies on PPARα-mediated mechanisms of action. With the approval of the local ethics committee, 120 Wistar rats were randomly divided into 12 groups. Sham and septic animals were treated with a vehicle, gemfibrozil (30 and 100 mg/kg BW), GW 6471 (1 mg/kg BW, PPARα inhibitor), or a combination of both drugs. Sepsis was induced via the colon ascendens stent peritonitis (CASP) model. Then, 24 h post sham or CASP surgery, a re-laparotomy was performed. Measures of vital parameters (heart rate (HR), mean arterial pressure (MAP), and microcirculation (µHbO2)) were recorded for 90 min. Mitochondrial respirometry and assessment of lipid peroxidation via a malondialdehyde (MDA) assay were performed on colon and liver tissues. In the untreated sham animals, microcirculation remained stable, while pre-treatment with gemfibrozil showed significant decreases in the microcirculatory oxygenation of the colon. In the CASP animals, µHbO2 levels in the colon and the liver were significantly decreased 90 min after laparotomy. Pre-treatment with gemfibrozil prevented the microcirculatory aberrations in both organs. Gemfibrozil did not affect mitochondrial function and lipid peroxidation levels in the sham or CASP animals. Gemfibrozil treatment influences microcirculation depending on the underlying condition. Gemfibrozil prevents sepsis-induced microcirculatory aberrances in the colon and liver PPARα-independently. In non-septic animals, gemfibrozil impairs the microcirculatory variables in the colon without affecting those in the liver.

The maintenance of intestinal integrity and barrier function under conditions of restricted oxygen availability is crucial to avoid bacterial translocation and local inflammation. Both lead to secondary diseases after hemorrhagic shock and might increase morbidity and mortality after surviving the initial event. Monitoring of the intestinal integrity especially in the early course of critical illness remains challenging. Since microcirculation and mitochondrial respiration are main components of the terminal stretch of tissue oxygenation, the evaluation of microcirculatory and mitochondrial variables could identify tissues at risk during hypoxic challenges, indicate an increase of intestinal injury, and improve our understanding of regional pathophysiology during acute hemorrhage. Furthermore, improving intestinal microcirculation or mitochondrial respiration, e.g. by remote ischemic preconditioning (RIPC) that was reported to exert a sufficient tissue protection in various tissues and was linked to mediators with vasoactive properties could maintain intestinal integrity. In this study, postcapillary oxygen saturation (µHbO2), microvascular flow index (MFI) and plasmatic d-lactate concentration revealed to be early markers of intestinal injury in a rodent model of experimental hemorrhagic shock. Mitochondrial function was not impaired in this experimental model of acute hemorrhage. Remote ischemic preconditioning (RIPC) failed to improve intestinal microcirculation and intestinal damage during hemorrhagic shock.

Microcirculatory and mitochondrial dysfunction are considered the main mechanisms of septic shock. Studies suggest that statins modulate inflammatory response, microcirculation, and mitochondrial function, possibly through their action on peroxisome proliferator-activated receptor alpha (PPAR-α). The aim of this study was to examine the effects of pravastatin on microcirculation and mitochondrial function in the liver and colon and the role of PPAR-α under septic conditions. This study was performed with the approval of the local animal care and use committee. Forty Wistar rats were randomly divided into 4 groups: sepsis (colon ascendens stent peritonitis, CASP) without treatment as control, sepsis + pravastatin, sepsis + PPAR-α-blocker GW6471, and sepsis + pravastatin + GW6471. Pravastatin (200 µg/kg s.c.) and GW6471 (1 mg/kg) were applied 18 h before CASP-operation. 24 h after initial surgery, a relaparotomy was performed, followed by a 90 min observation period for assessment of microcirculatory oxygenation (μHbO2) of the liver and colon. At the end of the experiments, animals were euthanized, and the colon and liver were harvested. Mitochondrial function was measured in tissue homogenates using oximetry. The ADP/O ratio and respiratory control index (RCI) for complexes I and II were calculated. Reactive oxygen species (ROS) production was assessed using the malondialdehyde (MDA)-Assay. Statistics: two-way analysis of variance (ANOVA) + Tukey’s/Dunnett’s post hoc test for microcirculatory data, Kruskal–Wallis test + Dunn’s post hoc test for all other data. In control septic animals µHbO2 in liver and colon deteriorated over time (µHbO2: −9.8 ± 7.5%* and −7.6 ± 3.3%* vs. baseline, respectively), whereas after pravastatin and pravastatin + GW6471 treatment μHbO2 remained constant (liver: µHbO2 pravastatin: −4.21 ± 11.7%, pravastatin + GW6471: −0.08 ± 10.3%; colon: µHbO2 pravastatin: −0.13 ± 7.6%, pravastatin + GW6471: −3.00 ± 11.24%). In both organs, RCI and ADP/O were similar across all groups. The MDA concentration remained unchanged in all groups. Therefore, we conclude that under septic conditions pravastatin improves microcirculation in the colon and liver, and this seems independent of PPAR-α and without affecting mitochondrial function.

Background:Abdominal surgery is an efficient treatment of intra-abdominal sepsis. Surgical trauma and peritoneal infection lead to the activation of multiple pathological pathways. The liver is particularly susceptible to injury under septic conditions. Liver function is impaired when pathological conditions induce endoplasmic reticulum (ER) stress. ER stress triggers the unfolded protein response (UPR), aiming at restoring ER homeostasis, or inducing cell death. In order to translate basic knowledge on ER function into the clinical setting, we aimed at dissecting the effect of surgery and peritoneal infection on the progression of ER stress/UPR and inflammatory markers in the liver in a clinically relevant experimental animal model.Methods:Wistar rats underwent laparotomy followed by colon ascendens stent peritonitis (CASP) or surgery (sham) only. Liver damage (aspartate aminotransferase (AST), alanine aminotransferase (ALT) and De Ritis values), inflammatory and UPR markers were assessed in livers at 24, 48, 72, and 96 h postsurgery. Levels of inflammatory (IL-6, TNF-α, iNOS, and HO-1), UPR (XBP1, GRP78, CHOP), and apoptosis (BAX/Bcl-XL) mRNA were determined by qPCR. Splicing of XBP1 (XBP1s) was analyzed by gel electrophoresis, p-eIF2α and GRP78 protein levels using the western blots.Results:Aspartate aminotransferase levels were elevated 24 h after surgery and thereafter declined with different kinetics in sham and CASP groups. Compared with sham De Ritis ratios were significantly higher in the CASP group, at 48 and 96 h. CASP induced an inflammatory response after 48 h, evidenced by elevated levels of IL-6, TNF-α, iNOS, and HO-1. In contrast, UPR markers XBP1s, p-eIF2α, GRP78, XBP1, and CHOP did not increase in response to infection but paralleled the kinetics of AST and De Ritis ratios. We found that inflammatory markers were predominantly associated with CASP, while UPR markers were associated with surgery. However, in the CASP group, we found a stronger correlation between XBP1s, XBP1 and GRP78 with damage markers, suggesting a synergistic influence of inflammation on UPR in our model.Conclusion:Our results indicate that independent mechanisms induce ER stress/UPR and the inflammatory response in the liver. While peritoneal infection predominantly triggers inflammatory responses, the conditions associated with organ damage are predominant triggers of the hepatic UPR.

Impaired oxygen utilization is the underlying pathophysiological process in different shock states. Clinically most important are septic and hemorrhagic shock, which comprise more than 75% of all clinical cases of shock. Both forms lead to severe dysfunction of the microcirculation and the mitochondria that can cause or further aggravate tissue damage and inflammation. However, the detailed mechanisms of acute and long-term effects of impaired oxygen utilization are still elusive. Importantly, a defective oxygen exploitation can impact multiple organs simultaneously and organ damage can be aggravated due to intense organ cross-talk or the presence of a systemic inflammatory response. Complexity is further increased through a large heterogeneity in the human population, differences in genetics, age and gender, comorbidities or disease history. To gain a deeper understanding of the principles, mechanisms, interconnections and consequences of impaired oxygen delivery and utilization, interdisciplinary preclinical as well as clinical research is required. In this review, we provide a "tool-box" that covers widely used animal disease models for septic and hemorrhagic shock and methods to determine the structure and function of the microcirculation as well as mitochondrial function. Furthermore, we suggest magnetic resonance imaging as a multimodal imaging platform to noninvasively assess the consequences of impaired oxygen delivery on organ function, cell metabolism, alterations in tissue textures or inflammation. Combining structural and functional analyses of oxygen delivery and utilization in animal models with additional data obtained by multiparametric MRI-based techniques can help to unravel mechanisms underlying immediate effects as well as long-term consequences of impaired oxygen delivery on multiple organs and may narrow the gap between experimental preclinical research and the human patient.

Introduction:Acute hemorrhage results in perfusion deficit and regional hypoxia. Since failure of intestinal integrity seem to be the linking element between hemorrhage, delayed multi organ failure, and mortality, it is crucial to maintain intestinal microcirculation in acute hemorrhage. During critical bleeding physicians increase FiO2 to raise total blood oxygen content. Likewise, a systemic hypercapnia was reported to maintain microvascular oxygenation (μHbO2). Both, O2 and CO2, may have adverse effects when applied systemically that might be prevented by local application. Therefore, we investigated the effects of local hyperoxia and hypercapnia on the gastric and oral microcirculation.Methods:Six female foxhounds were anaesthetized, randomized into eight groups and tested in a cross-over design. The dogs received a local CO2-, O2-, or N2-administration to their oral and gastric mucosa. Hemorrhagic shock was induced through a withdrawal of 20% of estimated blood volume followed by retransfusion 60 min later. In control groups no shock was induced. Reflectance spectrophotometry and laser Doppler were performed at the gastric and oral surface. Oral microcirculation was visualized by incident dark field imaging. Systemic hemodynamic parameters were recorded continuously. Statistics were performed using a two-way-ANOVA for repeated measurements and post hoc analysis was conducted by Bonferroni testing (p < 0.05).Results:The gastric μHbO2 decreased from 76 ± 3% to 38 ± 4% during hemorrhage in normocapnic animals. Local hypercapnia ameliorated the decrease of μHbO2 from 78 ± 4% to 51 ± 8%. Similarly, the oral μHbO2 decreased from 81 ± 1% to 36 ± 4% under hemorrhagic conditions and was diminished by local hypercapnia (54 ± 4%). The oral microvascular flow quality but not the total microvascular blood flow was significantly improved by local hypercapnia. Local O2-application failed to change microvascular oxygenation, perfusion or flow quality. Neither CO2 nor O2 changed microcirculatory parameters and macrocirculatory hemodynamics under physiological conditions.Discussion:Local hypercapnia improved microvascular oxygenation and was associated with a continuous blood flow in hypercapnic individuals undergoing hemorrhagic shock. Local O2 application did not change microvascular oxygenation, perfusion and blood flow profiles in hemorrhage. Local gas application and change of microcirculation has no side effects on macrocirculatory parameters.

Introduction Sepsis impairs gastrointestinal microcirculation and it is hypothesized that this might increase patient’s mortality. Sub-therapeutic vasopressin improves gastric microcirculation under physiologic conditions whereas a therapeutic dosing regimen seems to be rather detrimental. However, the effects of sub-therapeutic vasopressin on gastrointestinal microcirculation in sepsis are largely unknown. Therefore, we conducted this trial to investigate the effect of sub-therapeutic as well as therapeutic vasopressin on gastrointestinal microcirculation in sepsis. Methods 40 male Wistar rats were randomized into 4 groups. Colon ascendens stent peritonitis (CASP)-surgery was performed to establish mild or moderate sepsis. 24 hours after surgery, animals received either vasopressin with increasing dosages every 30 min (6.75, 13.5 (sub-therapeutic), 27 mU · kg-1 · h-1 (therapeutic)) or vehicle. Microcirculatory oxygenation (μHBO2) of the colon was recorded for 90 min using tissue reflectance spectrophotometry. Intestinal microcirculatory perfusion (total vessel density (TVD; mm/mm2) and perfused vessel density (PVD; mm/mm2)) were measured using incident dark field-Imaging at baseline and after 60 min. Results In mild as well as in moderate septic animals with vehicle-infusion intestinal μHbO2, TVD and PVD remained constant. In contrast, in moderate sepsis, sub-therapeutic vasopressin with 13.5 mU · kg-1 · h-1 elevated intestinal μHBO2 (+ 6.1 ± 5.3%; p < 0.05 vs. baseline) and TVD (+ 5.2 ± 3.0 mm/mm2; p < 0.05 vs. baseline). μHBO2, TVD and PVD were significantly increased compared to moderate sepsis alone. However, therapeutic vasopressin did not change intestinal microcirculation. In mild septic animals sub-therapeutic as well as therapeutic vasopressin had no relevant effect on gastrointestinal microcirculation. Systemic blood pressure remained constant in all groups. Conclusion Sub-therapeutic vasopressin improves gastrointestinal microcirculatory oxygenation in moderate sepsis without altering systemic blood pressure. This protective effect seems to be mediated by an enhanced microcirculatory perfusion and thereby increased oxygen supply. In contrast, therapeutic vasopressin did not show this beneficial effect.

EDITORIAL article Front. Med., 08 March 2021Sec. Intensive Care Medicine and Anesthesiology https://doi.org/10.3389/fmed.2021.649828

Introduction In the immunology of sepsis microcirculatory and mitochondrial dysfunction in the gastrointestinal system are important contributors to mortality. Hydrogen sulfide (H2S) optimizes gastrointestinal oxygen supply and mitochondrial respiration predominantly via K(ATP)-channels. Therefore, we tested the hypothesis that sodium thiosulfate (STS), an inducer of endogenous H2S, improves intestinal and hepatic microcirculation and mitochondrial function via K(ATP)-channels in sepsis. Methods In 40 male Wistar rats colon ascendens stent peritonitis (CASP) surgery was performed to establish sepsis. Animals were randomized into 4 groups (1: STS 1 g • kg-1 i.p., 2: glibenclamide (GL) 5 mg • kg-1 i.p., 3: STS + GL, 4: vehicle (VE) i.p.). Treatment was given directly after CASP-surgery and 24 hours later. Microcirculatory oxygenation (µHBO2) and flow (µflow) of the colon and the liver were continuously recorded over 90 min using tissue reflectance spectrophotometry. Mitochondrial oxygen consumption in tissue homogenates was determined with respirometry. Statistic: two-way ANOVA + Dunnett´s and Tukey post - hoc test (microcirculation) and Kruskal-Wallis test + Dunn’s multiple comparison test (mitochondria). p < 0.05 was considered significant. Results STS increased µHbO2 (colon: 90 min: + 10.4 ± 18.3%; liver: 90 min: + 5.8 ± 9.1%; p < 0.05 vs. baseline). Furthermore, STS ameliorated µflow (colon: 60 min: + 51.9 ± 71.1 aU; liver: 90 min: + 22.5 ± 20.0 aU; p < 0.05 vs. baseline). In both organs, µHbO2 and µflow were significantly higher after STS compared to VE. The combination of STS and GL increased colonic µHbO2 and µflow (µHbO2 90 min: + 8.7 ± 11.5%; µflow: 90 min: + 41.8 ± 63.3 aU; p < 0.05 vs. baseline), with significantly higher values compared to VE. Liver µHbO2 and µflow did not change after STS and GL. GL alone did not change colonic or hepatic µHbO2 or µflow. Mitochondrial oxygen consumption and macrohemodynamic remained unaltered. Conclusion The beneficial effect of STS on intestinal and hepatic microcirculatory oxygenation in sepsis seems to be mediated by an increased microcirculatory perfusion and not by mitochondrial respiratory or macrohemodynamic changes. Furthermore, the effect of STS on hepatic but not on intestinal microcirculation seems to be K(ATP)-channel-dependent.

EinleitungEine passagere Ischämie der Leber zum Beispiel im Rahmen der Transplantationschirurgie, einer Leberresektion ("Pringle-Manöver"), bei Trauma oder bei hämorrhagischem Schock ist ein häufiges klinisches Ereignis, das zu schwerwiegenden Beeinträchtigungen der hepatozellulären Integrität führen kann.Die konsekutive Entwicklung eines akuten Leberversagens ist mit einer hohen Letalität vergesellschaftet.Neben einer direkten ischämischen Schädigung beruht diese Form des Leberversagens auf der Auslösung einer lokalen Entzündungsreaktion, einer gesteigerten Bildung freier Sauerstoffradikale und Störungen der Organdurchblutung während der Reperfusion.Tierexperimentelle Untersuchungen konnten zeigen, dass dem Hämoxygenase-Stoffwechsel (HO-Stoffwechsel) in der Leber unter einer Vielzahl von Stressbedingungen protektive Eigenschaften zukommen.Die Isoenzyme der Hämoxygenase katalysieren den Abbau von Häm zu Biliverdin, Kohlenmonoxid und freiem Eisen.Die protektiven Wirkungen der Induktion der Hämoxygenaseaktivität beruhen auf entzündungshemmenden, antioxidativen und durchblutungs