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Teaching of resuscitation measures is not mandatory in all schools in Germany. It is currently limited to individual, partly mandatory projects despite a low bystander resuscitation rate. For this reason, the Ministry for Schools and Education of North Rhine-Westphalia initiated the project "Bystander resuscitation at schools in NRW" in March 2017.The aim of this work was to evaluate this project.All secondary schools in North Rhine-Westphalia were invited to participate in the project. Medical partners from each administrative district took part, who carried out resuscitation training with existing concepts for teacher or student training. After a 3-year period, the evaluation was carried out using standardized questionnaires for school headmasters, teachers and students.In total, more than 40,000 pupils from 249 schools in NRW could be trained in resuscitation within the project with 6 different concepts. Of the students 85% answered the questions regarding resuscitation correctly and overall felt safe in resuscitation measures. The one-off investment requirement for all schools is roughly 4-6.5 million € and around 340,000 € in each budget year.A legal constitution and funding are necessary for a nationwide introduction of resuscitation in schools. All established concepts are effective, therefore each school can use them exactly according to their needs, optimally in a stepped form. Training for teachers should focus on resuscitation.HINTERGRUND: Wiederbelebungsunterricht ist nicht in allen Schulen Deutschlands verpflichtend, dieser beschränkt sich trotz niedriger Laienreanimationsrate aktuell auf einzelne, z. T verpflichtende Projekte in unterschiedlichen Bundesländern. Aus diesem Grunde hat das Ministerium für Schule und Bildung Nordrhein-Westfalen per Runderlass im März 2017 das Projekt „Laienreanimation an Schulen in NRW“ initiiert.Ziel dieser Arbeit ist die Evaluation dieses Projekts.Alle weiterführenden Schulen in Nordrhein-Westfalen wurden zur Teilnahme am Projekt eingeladen. Aus jedem Regierungsbezirk nahmen ärztliche Partner teil, welche Wiederbelebungstrainings mit bereits bestehenden Konzepten zum Lehrer- oder Schülertraining durchführten. Nach einer 3‑jährigen Laufzeit erfolgte die Evaluation anhand von standardisierten Fragebögen für Schuldezernenten, Lehrer und Schüler.Insgesamt konnten durch das Projekt mehr als 40.000 Schüler aus 249 Schulen in NRW mit 6 unterschiedlichen Konzepten in Wiederbelebung trainiert werden. Fragen bezüglich Wiederbelebungsmaßnahmen konnten durch 85 % der Schüler richtig beantwortet werden. Die Schüler fühlen sich insgesamt sicher in Wiederbelebungsmaßnahmen. Der Investitionsbedarf für alle Schulen liegt bei einmalig zwischen 4 und 6,5 Mio. € sowie rund 340.000 € in jedem Haushaltsjahr.Eine gesetzliche Verpflichtung und Finanzierung von Wiederbelebungstrainings sind unerlässlich für eine flächendeckende Durchführung. Alle durchgeführten Konzepte sind effektiv, dementsprechend kann jede Schule ein auf ihre Bedürfnisse abgestimmtes Konzept auswählen und dieses bestenfalls gestuft anwenden. Die Schulung von Lehrern sollte gezielt auf Wiederbelebung ausgerichtet sein.

Background Hypercapnia improves gastric microcirculatory oxygenation (μHbO2) and increases vasopressin plasma levels, whereas V1A receptor blockade abolishes the increase of μHbO2. The aim of this study was to evaluate the effect of exogenous vasopressin (AVP) in increasing doses on microcirculatory perfusion and oxygenation and systemic hemodynamic variables. Furthermore, we evaluated the role of the vasopressin V1A receptor in mediating the effects. Methods In repetitive experiments, six anesthetized dogs received a selective vasopressin V1A receptor inhibitor ([Pmp1, Tyr (Me)2]-Arg8-Vasopressin) or sodium chloride (control groups). Thereafter, a continuous infusion of AVP was started with dose escalation every 30 min (0.001 ng/kg/min–1 ng/kg/min). Microcirculatory variables of the oral and gastric mucosa were measured with reflectance spectrometry, laser Doppler flowmetry, and incident dark field imaging. Transpulmonary thermodilution was used to measure systemic hemodynamic variables. AVP plasma concentrations were measured during baseline conditions and 30 min after each dose escalation. Results During control conditions, gastric μHbO2 did not change during the course of experiments. Infusion of 0.001 ng/kg/min and 0.01 ng/kg/min AVP increased gastric μHbO2 to 87 ± 4% and 87 ± 6%, respectively, compared to baseline values (80 ± 7%), whereas application of 1 ng/kg/min AVP strongly reduced gastric μHbO2 (59 ± 16%). V1A receptor blockade prior to AVP treatment abolished these effects on μHbO2. AVP dose-dependently enhanced systemic vascular resistance (SVR) and decreased cardiac output (CO). After prior V1A receptor blockade, SVR was reduced and CO increased (0.1 ng/kg/min + 1 ng/kg/min AVP). Conclusions Exogenous AVP dose-dependently modulates gastric μHbO2, with an increased μHbO2 with ultra-low dose AVP. The effects of AVP on μHbO2 are abolished by V1A receptor inhibition. These effects are independent of a modulation of systemic hemodynamic variables.

Colon ascendens stent peritonitis (CASP) is one of the well-established models of experimental abdominal sepsis. In CASP surgery, an open link between the gut lumen and the abdominal cavity is created by placing a stent into the colon ascendens. This mimics well the insufficient intestinal anastomosis. It causes a continuous leakage of the gut contents into the peritoneum and leads therefore to peritonitis and sepsis. The abdominal cavity is opened under general anesthesia and a plastic stent is located through and sutured to the colonic wall. The septic severity in CASP models can be titrated by altering the size of the stent catheter. Therefore, CASP models with small stents sizes are suitable for long-term studies and studies with mild/moderate sepsis severity. Within 24 h, animals develop clinical signs of sepsis. Monitoring of the clinical state, sufficient analgesia, appropriate antibiotics and fluid resuscitation should be performed postoperatively.

Systemic administration of melatonin exerts tissue protective effects in the context of hemorrhagic shock. Intravenous application of melatonin prior to hemorrhage improves gastric microcirculatory perfusion and maintains intestinal barrier function in dogs. The aim of the present study was to analyze the effects of a topical mucosal melatonin application on gastric microcirculation during hemorrhagic shock in vivo and on mucosal barrier function in vitro. In a randomized cross-over study, six anesthetized female foxhounds received 3.3 mg melatonin or the vehicle as a bolus to the gastric and oral mucosa during physiological and hemorrhagic (−20% blood volume) conditions. Microcirculation was analyzed with reflectance spectrometry and laser doppler flowmetry. Systemic hemodynamic variables were measured with transpulmonary thermodilution. For analysis of intestinal mucosal barrier function in vitro Caco-2 monolayers were used. The transepithelial electrical resistance (TEER) and the passage of Lucifer Yellow (LY) from the apical to the basolateral compartment of Transwell chambers were measured. Potential barrier protective effects of melatonin against oxidative stress were investigated in the presence of the oxidant H2O2. During physiologic conditions topical application of melatonin had no effect on gastric and oral microcirculation in vivo. During hemorrhagic shock, gastric microcirculatory oxygenation (μHbO2) was decreased from 81 ± 8% to 50 ± 15%. Topical treatment with melatonin led to a significant increase in μHbO2 to 60 ± 13%. Topical melatonin treatment had no effect on gastric microcirculatory perfusion, oral microcirculation or systemic hemodynamics. Incubation of H2O2 stressed Caco-2 monolayers with melatonin did neither influence transepithelial electrical resistance nor LY translocation. Topical treatment of the gastric mucosa with melatonin attenuates the shock induced decrease in microcirculatory oxygenation. As no effects on local microcirculatory and systemic perfusion were recorded, the improved μHbO2 is most likely caused by a modulation of local oxygen consumption. In vitro melatonin treatment did not improve intestinal barrier integrity in the context of oxidative stress. These results extend the current knowledge on melatonin's protective effects during hemorrhage in vivo. Topical application of melatonin exerts differential effects on local microcirculation compared to systemic pretreatment and might be suitable as an adjunct for resuscitation of hemorrhagic shock.

During circulatory shock, gastrointestinal microcirculation is impaired, especially via activation of the renin-angiotensin-aldosterone system. Therefore, inhibition of the renin-angiotensin-aldosterone system might be beneficial in maintaining splanchnic microcirculation. The aim of this study was to analyze whether locally applied losartan influences gastric mucosal perfusion (µflow, µvelo) and oxygenation (µHbO2) without systemic hemodynamic changes. In repetitive experiments six anesthetized dogs received 30 mg losartan topically on the oral and gastric mucosa during normovolemia and hemorrhage (−20% blood volume). Microcirculatory variables were measured with reflectance spectrometry, laser Doppler flowmetry and incident dark field imaging. Transpulmonary thermodilution and pulse contour analysis were used to measure systemic hemodynamic variables. Gastric barrier function was assessed via differential absorption of inert sugars. During normovolemia, losartan increased gastric µflow from 99 ± 6 aU to 147 ± 17 aU and µvelo from 17 ± 1 aU to 19 ± 1 aU. During hemorrhage, losartan did not improve µflow. µvelo decreased from 17 ± 1 aU to 14 ± 1 aU in the control group. Application of losartan did not significantly alter µvelo (16 ± 1 aU) compared to the control group and to baseline levels (17 ± 1 aU). No effects of topical losartan on macrohemodynamic variables or microcirculatory oxygenation were detected. Gastric microcirculatory perfusion is at least partly regulated by local angiotensin receptors. Topical application of losartan improves local perfusion via vasodilation without significant effects on systemic hemodynamics. During mild hemorrhage losartan had minor effects on regional perfusion, probably because of a pronounced upstream vasoconstriction.

Background: Topical drug application is used to avoid systemic side effects. The aim of this study was to analyze whether locally applied iloprost or nitroglycerin influence gastric mucosal perfusion, oxygenation, and barrier function during physiological and hemorrhagic conditions. Methods: In repeated experiments, 5 anesthetized dogs received iloprost, nitroglycerin, or normal saline during physiological and hemorrhagic (-20% blood volume) conditions. Macro- and microcirculatory variables were recorded continuously. Gastric barrier function was assessed via translocation of sucrose into the blood. Results: During hemorrhage, gastric mucosal oxygenation decreased from 77 ± 4 to 37 ± 7%. This effect was attenuated by nitroglycerin (78 ± 6 to 47 ± 13%) and iloprost (82 ± 4 to 54 ± 9%). Sucrose plasma levels increased during hemorrhage from 7 ± 4 to 55 ± 15 relative amounts. This was alleviated by nitroglycerin (5 ± 8 to 29 ± 38 relative amounts). These effects were independent of systemic hemodynamic variables. Conclusions: During hemorrhage, topical nitroglycerin and iloprost improve regional gastric oxygenation without affecting perfusion. Nitroglycerin attenuated the shock-induced impairment of the mucosal barrier integrity. Thus, local drug application improves gastric microcirculation without compromising systemic hemodynamic variables, and it may also protect mucosal barrier function.

Introduction: The avian influenza virus (IAV) commonly cause acute respiratory distress syndrome (ARDS), shock and death Unlike the current coronavirus outbreak, IAV does not grab the same level of public attention, although its clinical implications remain dire As of 2019, a recorded 10,000 patients have died and 180,000 were hospitalized according to CDC ARDS leads to a surge in the use of mechanical ventilators for life support Host-derived cellular microRNAs (miRs) play a critical role in ARDS dependent lung injury, alveolar-capillary membrane integrity, and host responses to viral infections We hypothesize that increased miR193b-5p upon IAV infection, downregulates occludin expression, and is associated with increased inflammation and injury in experimental models of pneumonia Methods: Wild type mice (C57Bl/6J, 10 -14 weeks) were randomized to infection with H1N1 virus (A/PR/8/34) treated a miR193b-5p inhibitor (INH) versus placebo delivered on day 4 post-infection On day 8, lung injury was assessed using histology, bronchoalveolar lavage fluid cell counts and differential, membrane permeability, and viral load In vitro, Beas2b cells were infected with H1N1 and treated with or without miR- 193b-5p inhibitor (INH) or mimic, and occludin was knocked down Transcript expression levels were determined by qRT-PCR Beas2b cells were treated with IFNb and qRT-PCR and digital droplet PCR was used to assess targets Results: Intranasal infection of IAV increased pulmonary inflammation, lung edema, increased levels of miR193b-5p (20- fold) and decreased expression of occludin (>50%) that peak at day 5 days post-infection Reporter construct demonstrates miR-193b-5p binds specifically to the 3'UTR of occludin Inhibition of miR193b- 5p mitigates H1N1-induced lung injury, edema formation, viral load, and anti-viral Interferon b (IFNb) and Interferon Regulated Genes expression In vitro, silencing of occludin results in increased viral load and dysregulation of the host antiviral response miR193b-5p is IFNb responsive confirmed by qRT-PCR and ddPCR Conclusions: We demonstrate the role of miR193b-5p in barrier function, viral infection and host anti-viral responses in a murine model of H1N1 IFNb, a natural host antiviral response, promotes miR193b upregulation The upregulation of miR-193b-5p downregulates occludin And the inhibition of miR-193b-5p results in decreased lung injury, inflammation, and viral load

Mild systemic hypothermia increases gastric mucosal oxygenation (μHbO2) during hemorrhagic shock in dogs. In the context of critical blood loss hypothermia might be fatal due to adverse side effects. Selective regional hypothermia might overcome these limitations. The aim of our study was to analyze the effects of regional gastric and oral mucosal hypothermia on μHbO2 and perfusion (μflow). In a cross-over study six anesthetized dogs were subjected to local oral and gastric mucosal hypothermia (34°C), or maintenance of local normothermia during normovolemia and hemorrhage (-20% blood volume). Macro- and microcirculatory variables were recorded continuously. During normovolemia, local hypothermia increased gastric microcirculatory flow (μflow) without affecting oxygenation (μHbO2) or oral microcirculation. During mild hemorrhagic shock gastric μHbO2 decreased from 72±2% to 38±3% in the normothermic group. This was attenuated by local hypothermia, where μHbO2 was reduced from 74±3% to 52±4%. Local perfusion, oral microcirculation and macrocirculatory variables were not affected. Selective local hypothermia improves gastric μHbO2 during hemorrhagic shock without relevant side effects. In contrast to systemic hypothermia, regional mucosal hypothermia did not affect perfusion and oxygen supply during hemorrhage. Thus, the increased μHbO2 during local hypothermia rather indicates reduced mucosal oxygen demand.

Background Evidence suggests that early adaptive responses of hepatic mitochondria occur in experimentally induced sepsis. Little is known about both colonic mitochondrial function during abdominal infection and long-term changes in mitochondrial function under inflammatory conditions. We hypothesize that hepatic and colonic mitochondrial oxygen consumption changes time-dependently after sterile laparotomy and in the course of abdominal infection. The aim of the present study was to investigate the hepatic and colonic mitochondrial respiration after sterile laparotomy and abdominal infection over up to 96 h. Methods After approval of the local Animal Care and Use Committee, 95 Wistar rats were randomized into 8 groups (n = 11–12): 1–4 sham (laparotomy only) and 5–8 colon ascendens stent peritonitis (CASP). Healthy, unoperated animals served as controls (n = 9). The mitochondrial respiration in colon and liver homogenates was assessed 24, 48, 72, and 96 h after surgery. Mitochondrial oxygen consumption was determined using a Clark-type electrode. State 2 (oxygen consumption in the presence of the substrates for complexes I and II) and state 3 respiration (ADP dependent) were assessed. The respiratory control ratio (RCR state 3/state 2) and ADP/O ratio (ADP added/oxygen consumed) were calculated for both complexes. Data are presented as means ± SD, two-way ANOVA followed by Tukey’s post hoc test. Results Hepatic RCR was initially (after 24 h) elevated in both operated groups; after 48 h only, the septic group was elevated compared to controls. In CASP groups, the hepatic ADP/O ratio for complex I was elevated after 24 h (vs. controls) and after 48 h (vs. sham) but declined after 72 h (vs. controls). The ADP/O ratio for complex II stayed unchanged over the time period until 96 h. The colonic RCR and ADP/O did not change over time after sham or CASP operation. Conclusion Hepatic, but not colonic, mitochondrial respiration is increased in the initial phase (until 48 h) and normalizes in the longer course of time (until 96 h) of abdominal infection. Electronic supplementary material The online version of this article (10.1186/s40635-018-0219-9) contains supplementary material, which is available to authorized users.

Introduction Insufficient microvascular oxygenation (μHBO2) of the intestinal mucosa worsens outcome of septic patients. Hypercapnia ameliorates μHBO2, mediated via endogenous vasopressin release. Under physiological conditions, blockade of the endogenous sympathetic nervous system abolishes this protective effect of hypercapnia. The aim of our study was therefore to evaluate the role of the endogenous sympathetic nervous system during hypercapnia on intestinal μHBO2 under septic conditions. Methods We randomized 80 male Wistar rats into eight groups. Sepsis was induced via colon ascendens stent peritonitis. The animals were subjected to 120 min of normocapnic (pCO2 35 mm Hg-45 mm Hg) or moderate hypercapnic (pCO2 65 mm Hg-75 mm Hg) ventilation 24 h after surgery. Animals received sympathetic blockade (hexamethonium 15 mg · kg (bolus) followed by 15 mg · kg · h (infusion) intravenously) or the same volume as vehicle (NaCl 0.9%). Microcirculatory oxygenation (μHBO2) and perfusion (μflow) were recorded using tissue reflectance spectrophotometry and laser Doppler. Results In septic animals, μHBO2 decreased during normocapnia (-8.9 ± 4%) and increased during hypercapnia (+7.8 ± 7.5%). The additional application of hexamethonium did not influence these effects. μHBO2 declined in normocapnic septic animals treated with hexamethonium similar to normocapnia alone (-6.1 ± 5.4%) and increased in hypercapnic animals treated with hexamethonium similar to hypercapnia alone (+7.9 ± 11.7%). Furthermore, hypercapnic ventilation ameliorated microcirculatory perfusion (μflow) irrespective of whether animals received hexamethonium (from 113 ± 54 [AU] to 206 ± 87 [AU]) or vehicle (from 97 ± 37 [AU]-169 ± 52 [AU]). Conclusion The amelioration of the intestinal microcirculation during hypercapnia in sepsis is independent of the endogenous sympathetic nervous system.

Introduction The deterioration of microcirculatory oxygenation of the gut plays a vital role in the development of sepsis. Acute hypercapnia enhances the microcirculatory oxygenation of the splanchnic region under physiological conditions, while the effect of hypercapnia under sepsis is unknown. The aim of this study was to investigate the effects of acute hypercapnia and hypercapnic acidosis on the colonic microcirculation and early cytokine response in polymicrobial sepsis. Methods Experiments were performed on 103 male Wistar rats. Colon ascendens stent peritonitis (CASP) surgery with varying stent diameters was conducted to establish a moderate polymicrobial sepsis model. In a second series, 24 h of sepsis development induced by CASP surgery was followed by 120 min of volume-controlled and pressure-limited ventilation with either normocapnic (pCO2 45 ± 5 mm Hg) or moderate hypercapnic ventilation targets (pCO2 75 ± 5 mm Hg) via exogenous carbon dioxide application. The effect of acidosis was investigated by metabolically buffering the hypercapnic acidosis with tromethamine. Microcirculatory oxygenation of the colon wall (tissue reflectance spectrophotometry) and hemodynamic variables were recorded continuously and arterial blood gas and cytokine (TNF-α, IL-6, IL-10) levels were analyzed intermittently. Results In septic animals the microcirculatory oxygenation of the colon deteriorated under normocapnia (− 7.0 ± 7.6% at 90 min) but was maintained under hypercapnic acidosis (+ 3.6 ± 7.6%) and buffered hypercapnia (+ 1.5 ± 4.4%). Cytokine levels were significantly higher in septic animals as opposed to sham animals but did not differ between normocapnic and hypercapnic groups. Conclusions Acute hypercapnic acidosis and buffered hypercapnia both improve splanchnic microcirculatory oxygenation in a septic animal model, thereby counteracting the adverse effect induced by sepsis. The circulating pro- and anti-inflammatory cytokine levels are not modulated after 120 min of hypercapnia.

The aim of this study was to evaluate a newly developed infrared side-stream capnograph with minimal sample volume for the continuous measurement of end-tidal carbon dioxide (CO2) concentrations in small rodents. Thirty-four male Wistar rats (weight 345 ± 70 g) were treated in accordance with the National Institutes of Health (NIH) guidelines for animal care. All experiments were performed with approval of the local animal care and use committee. Sepsis was induced by implanting an 18 gauge stent into the colon 24 h prior to the experiments, allowing a constant fecal leakage into the peritoneal cavity (25 septic and nine control animals). Hemodynamic variables and end-tidal CO2 were recorded continuously and arterial blood (5 × 120 µL) was sampled periodically for arterial blood gas analysis. After baseline controlled mechanical ventilation was randomized and titrated to either normocapnia (35–45 mmHg) or hypercapnia (65–75 mmHg) with exogenous application of CO2. A total of 155 paired CO2 measurements comparing end-tidal and arterial partial pressure were conducted. Side-stream capnography underestimated the CO2 partial pressure with a bias of −6.1 mmHg and a 95% limit of agreement from 6.7 to –19.1 mmHg. Our results suggest that side-stream end-tidal CO2 monitoring with a low dead space could be utilized in rats as a surrogate for the arterial CO2 measurement over a wide range of partial pressures in normal and septic animals.

Background Little is known about the incidence of severe critical events in children undergoing general anaesthesia in Europe. We aimed to identify the incidence, nature, and outcome of severe critical events in children undergoing anaesthesia, and the associated potential risk factors. Methods The APRICOT study was a prospective observational multicentre cohort study of children from birth to 15 years of age undergoing elective or urgent anaesthesia for diagnostic or surgical procedures. Children were eligible for inclusion during a 2-week period determined prospectively by each centre. There were 261 participating centres across 33 European countries. The primary endpoint was the occurence of perioperative severe critical events requiring immediate intervention. A severe critical event was defined as the occurrence of respiratory, cardiac, allergic, or neurological complications requiring immediate intervention and that led (or could have led) to major disability or death. This study is registered with ClinicalTrials.gov, number NCT01878760. Findings Between April 1, 2014, and Jan 31, 2015, 31 127 anaesthetic procedures in 30 874 children with a mean age of 6·35 years (SD 4·50) were included. The incidence of perioperative severe critical events was 5·2% (95% CI 5·0–5·5) with an incidence of respiratory critical events of 3·1% (2·9–3·3). Cardiovascular instability occurred in 1·9% (1·7–2·1), with an immediate poor outcome in 5·4% (3·7–7·5) of these cases. The all-cause 30-day in-hospital mortality rate was 10 in 10 000. This was independent of type of anaesthesia. Age (relative risk 0·88, 95% CI 0·86–0·90; p

OBJECTIVE Melatonin improves hepatic perfusion after hemorrhagic shock and may reduce stress-induced gastric lesions. This study was designed to investigate whether pretreatment with melatonin may influence gastric mucosal microcirculatory perfusion (μflow), oxygenation (μHbO2 ), or intestinal barrier function during physiological and hemorrhagic conditions in dogs. METHODS In a randomized crossover study, five anesthetized foxhounds received melatonin 100 μg kg-1 or vehicle (ethanol 5%) intravenously in the absence or presence of hemorrhagic shock (60 minutes, -20% blood volume). Systemic hemodynamic variables, gastric mucosal perfusion, and oxygenation were recorded continuously; intestinal barrier function was assessed intermittently via xylose absorption. RESULTS During hemorrhagic shock, melatonin significantly attenuated the decrease in μflow, compared with vehicle (-19±9 vs -43±10 aU, P

Purpose To study the effects of pretreatment with levosimendan (LEVO, a Ca2+-sensitizer and KATP+ channel opener) and/or the KATP+ channel antagonist glibenclamide (GLIB) on systemic hemodynamics, metabolism, and regional gastromucosal oxygenation during hypoxic hypoxemia. Methods Chronically instrumented, healthy dogs (24–32 kg, n = 6 per group, randomized cross-over design) were repeatedly sedated, mechanically ventilated (FiO2 ~0.3) and subjected to the following interventions: no pretreatment, LEVO pretreatment, GLIB pretreatment, or combined LEVO + GLIB pretreatment, each followed by hypoxic hypoxemia (FiO2 ~0.1). We measured cardiac output (CO, ultrasonic flow probes), oxygen consumption (VO2, indirect calorimetry), and gastromucosal microvascular hemoglobin oxygenation (μHbO2, spectrophotometry). Statistics: data are presented as mean ± SEM and compared by one-way ANOVA (direct drug effects within group) and two-way ANOVA (between all hypoxic conditions) both with Bonferroni corrections; p

Microcirculatory dysfunction, reduced oxygen supply and thus impaired hepatosplanchnic organ function, play a pivotal role in the clinical manifestation of sepsis and septic shock. Early correction of the perfusion mismatch is essential to maintain end-organ and gut mu-cosa barrier function and thus to prevent bacterial translocation, bacteraemia and possible multiple organ failure. This review will outline the clinical tightrope-walk optimizing hepa-tosplanchnic oxygen supply while maintaining adequate end-organ perfusion pressure and highlight the diagnostic challenges and limitations faced in clinical practice.

Objective Hypothermia preserves gastric mucosal microvascular oxygenation (μHbO 2 ) during hemorrhagic shock. Additionally, hypothermia activates the sympathetic nervous system that leads to the release of vasopressin. The aim of this study was to evaluate whether the effect of hypothermia is mediated via the sympathetic nervous system and/or via vasopressin. Methods In prospective and randomized experiments on five anesthetized dogs (foxhounds, cross-over design, 6 groups with n = 5 per group) we analyzed the effects of hemorrhage on μHbO 2 during mild hypothermia (HT, 34 °C), during additional thoracic epidural anesthesia (HT/TEA) and during additional vasopressin V1 receptor blockade (HT/VB). As control groups, effects of hemorrhage were studied under normothermia alone (NT), during additional thoracic epidural anesthesia (NT/TEA) and during additional vasopressin V1 receptor blockade (NT/VB). Results Hemorrhage decreased μHbO 2 from 81 ± 3 to 49 ± 8%. In contrast, in the presence of hypothermia, μHbO 2 was significantly higher during hemorrhagic shock (from 79 ± 3 to 66 ± 9%) despite a similar decrease in DO 2 . The effect of hypothermia on μHbO 2 was reduced in the presence of thoracic epidural anesthesia or vasopressin receptor blockade. Conclusions Hypothermia preserves μHbO 2 during hemorrhagic shock. This effect is partially abolished during thoracic epidural anesthesia or during vasopressin receptor blockade. The sympathetic nervous system and the vasopressin V1 receptor are partially involved in mediating the effect of hypothermia on gastric oxygenation during hemorrhage.

Background Microvascular oxygen saturation (μHBO 2 ) plays an essential role in the development and outcome of sepsis. Hypercapnia (HC) improves the microvascular oxygenation of the mucosa in both healthy and septic animals. Vasopressin V 1A receptor blockade prevents this positive effect under otherwise physiological conditions. The aim of this study was to investigate the effects and mechanisms of the vasopressin system during hypercapnia under septic conditions. Methods 80 rats were randomized into 8 groups (N = 10). Colon ascendens stent peritonitis (CASP) or sham surgery was performed on 40 animals each to establish a moderate polymicrobial sepsis or sham control, respectively. 24 h after sepsis induction the animals were subjected to 120 min of volume-controlled and pressure-limited ventilation with either normocapnic (pCO 2 35–45 mm Hg) or moderate hypercapnic (pCO 2 of 65–75 mm Hg) ventilation targets. Animals received either vasopressin V 1A receptor blockade (SR 49059, 1 mg kg − 1 i.v.) or vehicle solution (dimethyl sulfoxide, 1%). Blood pressure, heart rate, pO 2 and pCO 2 were measured and microcirculatory oxygenation (μHBO 2 ) and microcirculatory flow (μflow) were recorded using tissue reflectance spectrophotometry. Oxygen supply (μDO 2 ) and consumption (μVO 2 ) were calculated from intermittent blood gas analysis. Results In septic animals, μHBO 2 declined during normocapnia (− 11 ± 10.3) but remained unchanged during hypercapnia. μHBO 2 declined with vasopressin V 1A receptor blockade both during normocapnia (− 7.4 ± 10.6) and hypercapnia (− 9.2 ± 9.8). Microcirculatory oxygen consumption was significantly reduced by hypercapnia in septic animals (− 2.4 · 10 5 [AU] ± 2.4 · 10 5 [AU]). In sham animals, μHBO 2 and μVO 2 did not change. Conclusion Vasopressin V 1A receptors mediate the beneficial effects of hypercapnia on microcirculatory oxygenation during sepsis. The effects of vasopressin on μHBO 2 might be related to decreased oxygen consumption during hypercapnia.

Objective: To compare the effects of dopamine, both in the presence and absence of α1-blockade, and fenoldopam on microvascular gastric mucosal oxygenation and systemic oxygen transport under compromised circulatory conditions, both without and with fluid resuscitation. Design: Randomized controlled animal study. Setting: University department of anesthesiology. Subjects: Eight anesthetized dogs with chronically implanted ultrasound flow probes around the pulmonary artery for continuous measurement of cardiac output. Interventions: On different days, the dogs received in random order either dopamine (2.5 and 5.0 μg·kg-1 ·min-1, with or without α1-blocker pretreatment), the selective DA1-agonist fenoldopam (0.1 and 1.0 μg·kg-1·min-1, with and without DA 1-blocker pretreatment), or saline (control). These interventions were performed under compromised cardiocirculatory conditions (induced by ventilation with positive end-expiratory pressure [PEEP] of 10 cm H 2O), both without and with fluid resuscitation. Measurements and Main Results: We continuously measured regional microvascular hemoglobin saturation (μHbO2) in gastric mucosa by reflectance spectrophotometry and systemic oxygen transport (ḊO2). Ventilation with PEEP significantly decreased ḊO2 (from 19 ± 2 to 9 ± 1 mL·kg-1·min-1, mean ± SEM) and gastric mucosal μHbO2 (from 57 ± 2% to 37 ± 3%). Fluid resuscitation restored ḊO2 back to baseline (from 9 ± 1 to 19 ± 2 mL·kg-1 ·min-1) but only partially restored μHbO2 (from 37 ± 3% to 50 ± 4%). Under both conditions, dopamine with and without α1-blockade significantly increased ḊO 2 (by about 5 mL·kg-1·min-1 in the nonresuscitated state and 10 mL·kg-1·min -1 in the fluid resuscitated state, respectively), but only dopamine in the presence of α1-blockade also significantly increased gastric mucosal μHbO2 (by 5 ± 1% and 7 ± 2% in the nonresuscitated and fluid resuscitated states, respectively). Fenoldopam under all study conditions did not significantly affect ḊO2 or μHbO2, either in the presence or absence of DA1- blockade. Conclusions: During compromised cardiocirculatory conditions, α1-receptor activation during dopamine infusion prevented an increase in gastric mucosal oxygenation. Furthermore, selective DA 1-stimulation (by fenoldopam) was insufficient to overcome the PEEP-induced depression of μHbO2. The responses of gastric mucosal oxygenation did not parallel changes in systemic oxygen transport. These findings were independent of fluid resuscitation.

Objective: To compare the effects of fenoldopam and dopamine on gastric mucosal and systemic oxygenation, and to identify the receptors involved. Design: Randomized controlled animal study. Setting: University research department of experimental anesthesiology. Subjects: Seven anesthetized dogs with chronically implanted ultrasound flow probes around the pulmonary artery for continuous measurement of cardiac output. Interventions: On different days, the dogs received in random order either the selective DA1-agonist fenoldopam (0.1 and 1.0 μg·kg-1·min-1, with or without DA1-blocker pretreatment), dopamine (2.5 and 5.0 μg·kg-1·min-1, with or without α1-blocker pretreatment), or saline (control). Measurements and Main Results: We continuously measured regional microvascular hemoglobin oxygen saturation (μHbO2) In gastric mucosa by reflectance spectrophotometry, and systemic oxygen delivery. Fenoldopam increased gastric mucosal μHbO2 by approximately 20%, and this effect was prevented by selective DA1-receptor blockade. In contrast, dopamine neither alone nor during α1-blockade altered μHbO2. With respect to systemic measures of oxygen transport, fenoldopam had negligible effects, whereas dopamine (with and without α1-blocker pretreatment) dose-dependently increased cardiac output and systemic oxygen delivery by approximately 30%. Conclusions: Fenoldopam dose-dependently increased microvascular oxygenation of the gastric mucosa without changing systemic oxygen transport, i.e., this drug acted selectively on the splanchnic mucosa. The increase in gastric mucosal oxygenation was mediated by DA1-receptors. In contrast, dopamine markedly increased systemic oxygen transport, but did not affect microvascular oxygenation of gastric mucosa. This lacking effect on gastric mucosal oxygenation was not caused by α1-mediated vasoconstriction. The regional effects of both catecholamines could not be deduced from systemic hemodynamics and oxygenation.

Objective: To compare the effects of dopamine and dopexamine on gastric mucosal oxygenation during mechanical ventilation without and with positive end-expiratory airway pressure (PEEP) and after compensation of the PEEP-induced hemodynamic suppression. Design: Randomized controlled animal study. Setting: University research department of experimental anesthesiology. Subjects: Ten anesthetized dogs with chronically implanted ultrasound flow probes around the pulmonary artery for continuous measurement of cardiac output. Interventions: On different days, the dogs randomly received dopamine (2.5 and 5.0 μg·kg-1·min-1, n = 10), dopexamine (0.5 and 1.0 μg·kg-1·min-1) without (n = 8) or with pretreatment with a selective β2-adrenoceptor antagonist (ICI 118,551, n = 7), or saline (control, n = 7). To simulate common clinical situations, these interventions were performed during different ventilation modes: during mechanical ventilation without and with high levels of PEEP, and after compensation of the PEEP-induced systemic hemodynamic suppression by titrated volume resuscitation with hydroxyethyl starch. Measurements and Main Results: We continuously measured microvascular hemoglobin saturation (μHbo2) by light-guide spectrophotometry in the gastric mucosa. Dopexamine, but not dopamine, significantly increased gastric mucosal μHbo2 by about 20%, regardless of the dose and the ventilation mode. Both catecholamines dose-dependently increased cardiac output and oxygen delivery by up to 75% without effects on systemic oxygen saturation. The effects of dopexamine on μHbo2 as well as on cardiac output and oxygen delivery were prevented by selective β2-adrenoceptor-blockade. Conclusions: Dopexamine but not dopamine improved gastric mucosal oxygenation in dogs. This effect was independent of the dosage and the ventilation mode. Thus, dopexamine may reverse a decrease in splanchnic oxygenation induced by ventilation with PEEP. The dopexamine-induced increase in gastric mucosal oxygenation was mediated by β2-adrenoceptors, which explains the superior effects of dopexamine to dopamine on μHbo2. The regional effects of both catecholamines were not mirrored by systemic hemodynamics.

Background Acute hypercapnia maintains the microcirculatory oxygenation of the splanchnic region during sepsis. The first aim of this study was to characterize the role of K + ATP channels on the microcirculatory flow and oxygenation during acute moderate hypercapnia. The second aim was to investigate whether a short period of hypercapnia induces detrimental effects in an otherwise undamaged rodent lung. Methods Experiments were performed on 60 male Wistar rats. A moderate polymicrobial sepsis was induced by colon ascendens stent peritonitis (CASP) surgery. 24 h after induction of sepsis volume-controlled and pressure-limited ventilation was established for 120 min, with either normocapnic (pCO 2 35–45 mm Hg) or moderate hypercapnic ventilation targets (pCO 2 65–75 mm Hg) and with or without non-selective K + ATP channel blockade with glibenclamide. Microcirculatory blood flow of the colonic wall as well as oxygen delivery and consumption were assessed with tissue laser Doppler and reflectance spectrophotometry. Hemodynamic variables were recorded and plasma cytokine levels and myeloperoxidase levels of the lungs were analyzed. Results In septic animals microcirculatory oxygenation deteriorated progressively with normocapnia (− 11.7 ± 11.8%) but was maintained (− 2.9 ± 5.6%) with hypercapnia. This effect was associated with an increased microcirculatory oxygen consumption in septic animals with normocapnia (+ 25.7 ± 37.1%) that was decreased in the hypercapnia groups (− 7.2 ± 28.1%). The effect of hypercapnia in septic animals was not altered by additional K + ATP channel blockade (− 5.7 ± 32.7%). Hypercapnia neither induced an inflammatory response in lungs nor altered the systemic cytokine response. Conclusions The observed beneficial effect of hypercapnia on microvascular oxygenation of the colon in sepsis does not seem to be mediated via K + ATP channels.

Objective: Using indocyanine green (ICG), blood volume can be determined within minutes according to the mass conservation principle by back-extrapolation of the concentration/time curve to the time of injection (BVTinj) or by the transit time approach (BVMTT) as the product of cardiac output and mean transit time (MTT) of ICG through the circulation. To see which factor accounts for the difference between the two methods we measured cardiac output and MTT independently and compared the volumes with those obtained by dilution of Evans blue (BVEB). Design: Prospective animal study. Settings: University department of experimental anaesthesiology. Animals: Six anaesthetised, spontaneously breathing dogs with chronically implanted ultrasound flow probes around the pulmonary artery. Measurements and results: BVMTT and BVTinj agreed closely (48±2 ml·kg–1 and 49±2 ml·kg–1), but underestimated blood volume by about 40% compared with BVEB (75±1 ml·kg–1). Transit times measured were 33±1 s and should be about 50 s as calculated from the quotient of BVEB and cardiac output. Conclusions: Both methods underestimate blood volume by about the same extent compared with BVEB, probably because slowly perfused compartments are not detected during the short measurement period of 4 min. In the case of the transit time approach, rather short transit times result and in the case of the mass conservation principle, back-extrapolation yields rather high plasma concentrations of ICG at the time of injection. Accordingly, the two methods seem to be equivalent for measuring blood volume rapidly, although the absolute volume is underestimated by about 40%.

Background Therapeutic hypothermia, used primarily for protective effects after hypoxia, improves oral and gastric mucosal microvascular oxygenation (μHbO2) during additional haemorrhage. Therefore, we questioned whether hypothermia likewise improves μHbO2 during hypoxic challenges. Since both hypothermia and hypoxia reduce cardiac output (e.g. by myofilament Ca2+ desensitization), and modulate vasomotor tone via K+ATP channels, we hypothesized that the Ca2+ sensitizer levosimendan and K+ATP channel blocker glibenclamide would support the cardiovascular system. Methods The effects of mild hypothermia (34°C) on μHbO2 during hypoxia ( F I O 2 = 0. 12 , 15 min) were analysed in a cross-over study on five anaesthetized dogs and compared with normothermia (37.5°C) and hypoxia. During hypothermia, but before hypoxia, glibenclamide (0.2 mg kg−1) or levosimendan (20 µg kg−1+0.25 µg kg−1 min−1) was administered. Systemic haemodynamic variables, gastric and oral mucosal microvascular oxygenation (reflectance spectrophotometry), and perfusion (laser Doppler flowmetry) were recorded continuously. Data are presented as mean ( sem ), P Results Hypoxia during normothermia reduced gastric μHbO2 by 27 (3)% and oral μHbO2 by 28 (3)% (absolute change). During hypothermia, this reduction was attenuated to 16 (3)% and 13 (1)% (absolute change). This effect was independent of microvascular flow that did not change during hypoxia and hypothermia. Additional administration of levosimendan during hypothermia restored reduced cardiac output but did not change flow or μHbO2 compared with hypothermia alone. Glibenclamide did not exert any additional effects during hypothermia. Conclusions Hypothermia attenuates the decrease in μHbO2 during additional hypoxic challenges independent of systemic or regional flow changes. A reduction in cardiac output during hypothermia is prevented by Ca2+ sensitization with levosimendan but not by K+ATP channel blockade with glibenclamide.

Hypercapnia (HC) increases systemic oxygen delivery (DO2) and gastric mucosal oxygenation. However, it activates the renin–angiotensin–aldosterone system (RAAS), which conversely reduces mesenteric perfusion. The aims of this study were to evaluate the effect of RAAS inhibition during normocapnia and HC on oral and gastric mucosal oxygenation (μHbO2) and to assess the effect of blood pressure under these circumstances. Five dogs were repeatedly anesthetized to study the effects of ACE inhibition (ACE-I; 5 mg/kg captopril, followed by 0.25 mg/kg per h) on μHbO2(reflectance spectrophotometry) and hemodynamic variables during normocapnia (end-tidal CO2=35 mmHg) and HC (end-expiratory carbon dioxide (etCO2)=70 mmHg). In the control group, the dogs were subjected to HC alone. To exclude the effects of reduced blood pressure, in one group, blood pressure was maintained at baseline values via titrated phenylephrine (PHE) infusion during HC and additional captopril infusion. ACE-I strongly reduced gastric μHbO2from 72±2 to 65±2% and mean arterial pressure (MAP) from 64±2 to 48±4 mmHg, while DO2remained unchanged. This effect was counteracted in the presence of HC, which increased gastric μHbO2from 73±3 to 79±6% and DO2from 15±2 to 22±4 ml/kg per min during ACE-I without differences during HC alone. However, MAP decreased similar to that observed during ACE-I alone from 66±3 to 47±5 mmHg, while left ventricular contractility (dPmax) increased from 492±63 to 758±119 mmHg/s. Titrated infusion of PHE had no additional effects on μHbO2. In summary, our data suggest that RAAS inhibition reduces gastric mucosal oxygenation in healthy dogs. HC not only abolishes this effect, but also increases μHbO2, DO2, and dPmax. The increase in μHbO2during ACE-I under HC is in accordance with our results independent of blood pressure.

Hypercapnia (HC) improves systemic oxygen delivery (DO2) and microvascular hemoglobin oxygenation of the mucosa (μHbO2). Simultaneously, HC increases plasma levels of vasopressin. Although vasopressin is generally regarded a potent vasoconstrictor particularly in the splanchnic region, its effects on splanchnic microcirculation during HC is unclear. The aim of this study was to evaluate the role of endogenous vasopressin on gastric mucosal oxygenation and hemodynamic variables during physiological (normocapnia) and hypercapnic conditions. Five dogs were repeatedly anesthetized to study the effect of vasopressin V1A receptor blockade ([Pmp1,Tyr(Me)2]-Arg8-Vasopressin, 35 μg/kg) on hemodynamic variables and μHbO2 during normocapnia or HC (end-tidal CO2 70 mmHg). In a control group, animals were subjected to HC alone. μHbO2 was measured by reflectance spectrophotometry, systemic DO2 was calculated from intermittent blood gas analysis, and cardiac output was measured by transpulmonary thermodilution. Data are presented as mean±s.e.m. for n=5 animals. During HC alone, DO2 increased from 12±1 to 16±1 ml/kg per min and μHbO2 from 70±4 to 80±2%. By contrast, additional vasopressin V1A receptor blockade abolished the increase in μHbO2 (80±2 vs 69±2%) without altering the increase in DO2 (16±1 vs 19±2 ml/kg per min). Vasopressin V1A receptor blockade (VB) during normocapnia neither affected DO2 (13±1 vs 14±1 ml/kg per min) nor μHbO2 (75±3 vs 71±5%). Vasopressin V1A receptor blockade abolished the increase in μHbO2 during HC independent of DO2. Thus, in contrast to its generally vasoconstrictive properties, the vasopressin V1A receptors seem to mediate the increase in gastric microcirculatory mucosal oxygenation induced by acute HC.

Hypothermia is known to improve tissue function in different organs during physiological and pathological conditions. The aim of this study was to evaluate the effects of hypothermia on oral and gastric mucosal microvascular oxygenation (μHbO2) and perfusion (μflow) under physiological and hemorrhagic conditions. Five dogs were repeatedly anesthetized. All animals underwent each experimental protocol (randomized cross-over design): hypothermia (34°C), hypothermia during hemorrhage, normothermia, and normothermia during hemorrhage. Microcirculatory and hemodynamic variables were recorded. Systemic (DO2) and oral mucosal (μDO2) oxygen delivery were calculated. Hypothermia increased oralμHbO2with no effect on gastricμHbO2. Hemorrhage reduced oral and gastricμHbO2during normothermia (−36 ± 4% and −27 ± 7%); however, this effect was attenuated during additional hypothermia (−15 ± 5% and −11 ± 5%). The improvedμHbO2might be based on an attenuated reduction inμflow during hemorrhage and additional hypothermia (−51 ± 21 aU) compared to hemorrhage and normothermia (−106 ± 19 aU).μDO2was accordingly attenuated under hypothermia during hemorrhage whereas DO2did not change. Thus, in this study hypothermia alone improves oralμHbO2and attenuates the effects of hemorrhage on oral and gastricμHbO2. This effect seems to be mediated by an increasedμDO2on the basis of increasedμflow.

Brain natriuretic peptide has vasodilatory properties and may thus increase splanchnic perfusion and oxygenation. We compared the effects of recombinant brain natriuretic peptide on gastric mucosal microvascular haemoglobin oxygenation (reflectance spectrophotometry) and systemic variables with those of equi-hypotensive doses of two other vasodilators (nitroglycerine and dihydralazine). Chronically instrumented, healthy dogs were randomly allocated to receive on different days, one of the three drugs (nitroglycerine and dihydralazine doses titrated to reduce mean arterial pressure by similar to 20%). Brain natriuretic peptide significantly increased gastric mucosal microvascular haemoglobin oxygenation selectively, i.e. without concomitant haemodynamic effects. In contrast, the other vasodilators either did not increase gastric mucosal microvascular haemoglobin oxygenation at all (nitroglycerine), or did so only with marked increases in other systemic haemodynamic variables (dihydralazine). Our data suggest a potential role of recombinant brain natriuretic peptide selectively for increasing microvascular mucosal oxygenation. Studies are required to extend these findings to the clinical setting.

The authors aimed to clarify the effects of hypercapnic acidosis and its timing on gastric mucosal oxygenation in a canine model of hemorrhage. This was designed as a prospective, controlled, randomized animal study set in a university research laboratory. Five chronically instrumented dogs were used. Dogs were repeatedly anesthetized (sevoflurane 1.5 MAC), mechanically ventilated, and randomized to each of the following protocols. In a control series (CON), animals underwent hemorrhage during normoventilation (etCO(2), 35 mmHg). In a second series, hypercapnia (etCO(2), 70 mmHg) was applied before onset of hemorrhage (prophylactic hypercapnia), whereas in the third series, hypercapnia was applied after hemorrhage (therapeutic hypercapnia, THE). Microvascular oxygenation (mu HbO(2)) of the gastric mucosa was continuously assessed by tissue reflectance spectrophotometry. Cardiac output was continuously measured, and oxygen delivery (DO2) was intermittently calculated. In CON, hemorrhage decreased DO2 (from 11 +/- 3 mL.kg(-1).min(-1) to 8 +/- 2 mL.kg(-1).min(-1) and 8 +/- 2 mL.kg(-1).min(-1) after 30 and 75 min, respectively) and mu HbO(2) (from 57% +/- 4% to 43% +/- 11% and 50% +/- 11%). Prophylactic hypercapnia attenuated the effects of hemorrhage on DO2 (12 +/- 2 mL.kg(-1).min(-1) to 10 +/- 2 mL.kg(-1).min(-1) and 11 +/- 2 mL.kg(-1).min(-1)) and preserved mu HbO(2) (52% +/- 3% to 47% +/- 5% and 57% T 3%). Initial effects of hemorrhage in THE were comparable to CON (DO2 from 11 +/- 2 mL.kg(-1).min(-1) to 8 +/- 1 mL.kg(-1).min(-1); mu HbO(2) from 56% +/- 7% to 43% +/- 9%), but after application of hypercapnic acidosis, baseline levels were restored (DO2 10 +/- 3 mL.kg(-1).min(-1); mu HbO(2) 52% +/- 14%). Hypercapnic acidosis applied before or after hemorrhage (THE) preserves microvascular mucosal oxygenation. If these experimental findings may be transferred to the clinical setting, deliberate hypercapnic acidosis could serve to augment oxygenation of the splanchnic region in states of compromised circulation, e. g., hemorrhage.

Summary Background Several studies have assessed the effects of training using patient simulation systems on medical skills. However, endocrine and psychological stress responses in a patient simulation situation and the relationship between stress reactivity and medical performance have been studied rarely, so far. Methods Medical students (18 males and 16 females) who had completed at least two months anaesthesiology training participated in the study. In a counterbalanced cross-over design they were subjected to three conditions: rest, laboratory stress (LS; public speaking), and simulated emergency situation (SIM; myocardial ischemia and ventricular fibrillation). Salivary cortisol and psychological responses (visual analogue scales, VAS) were assessed every 15 min from 15 min prior to until 60 min after intervention. Differences between stress and rest conditions were analysed. Medical performance was assessed according to the European Resuscitation Council's Guidelines for Resuscitation. Results As compared to rest, cortisol increased significantly in both stress conditions with different time courses in LS and SIM. Psychological responses in SIM exceeded those in LS. Cortisol increase in LS ( r s = .486; p = .019) but not in SIM ( r s = .106; p = .631) correlated significantly with medical performance. Discussion A simulated emergency situation is a profound stressor. The positive relationship between endocrine stress responsiveness in a standard laboratory situation and medical performance in a simulated emergency situation indicates that high stress responsiveness might be a predictor of good performance. At the same time the high stress response might counteract educational efforts associated with training using high-fidelity patient simulation.

Purpose of review This review presents important pathophysiological alterations associated with impaired liver function and discusses protective perioperative strategies and the various anaesthetic agents recommended. Recent findings Perioperative liver impairment is a serious complication of anaesthesia and surgery. Unfortunately, clinicians are provided with only crude macrohaemodynamic monitoring devices to optimize their therapy. Technical improvements have revealed some complex mysteries of perioperative microcirculatory alterations and have disclosed a large heterogeneity between different vascular beds. The present review will critically discuss current clinical concepts of optimizing global haemodynamic variables and the often contrasting effects of vasoactive agents on the microcirculatory nutritional blood flow. Finally, promising protective experimental interventions of pharmacological or ischaemic preconditioning are presented and their often disillusioning transition into recent clinical trials is highlighted. Summary Targeted perioperative liver protection still lacks adequate monitoring tools and is currently based on optimization of global haemodynamic variables. While there is currently no evidence suggesting a positive effect of ischaemic preconditioning, promising experimental results of pharmacological preconditioning and therapeutic hypothermia require further evaluation in larger randomized clinical trials.

Background:Adequate gastrointestinal mucosal oxygenation is regarded to be crucial in the prevention and therapy of critical illness. Epinephrine and norepinephrine are used for perioperative haemodynamic support. However, their per se effects on gastromucosal haemoglobin oxygenation (mu HbO(2)) remain unclear. Moreover, respective effects of epinephrine and norepinephrine may be affected by the type of underlying anaesthesia. Thus, we studied the effects of epinephrine and norepinephrine during anaesthesia with sevoflurane or propofol on regional gastromucosal mu HbO(2) and systemic O(2)-derived variables.Methods:In a double-randomized cross-over study, chronically instrumented dogs (n=6 per group) were anaesthetized randomly with sevoflurane or propofol, ventilated, and then randomly received either epinephrine or norepinephrine (0, 0.05, 0.1, and 0.2 mu g kg(-1) min(-1)). We measured gastromucosal mu HbO(2), systemic haemodynamics, and O(2)-derived variables.Results:During sevoflurane anaesthesia, norepinephrine markedly increased mu HbO(2) (P Conclusions:The effects of epinephrine and norepinephrine depended on the type of anaesthesia. In addition, regional effects (i.e. mu HbO(2)) were not predictable from systemic effects (i.e. DO(2)).

Objective: To evaluate the impact of clonidine on mucosal red cell flux during baseline sedation with propofol or sevoflurane, respectively. Materials and Methods:Six healthy, chronically instrumented dogs for the measurement of cardiac output (CO) were repeatedly studied. During baseline sedation with either propofol (15 mg kg -1 h -1) or sevoflurane (1.5 MAC), local tissue cell flux was assessed using laser Doppler flowmetry at the enoral mucosa. After baseline measurements, a bolus of clonidine (2.0 μ g/kg) was infused within 1 min. Data are presented as mean ± SEM; Statistics: ANOVA, Scheffé's post hoc test, p < 0.05. Results:Clonidine significantly reduced CO from 75 ± 4 and 75 ± 6 ml kg -1 min -1 (sedation with propofol or sevoflurane, respectively) to 40 ± 3 and 49 ± 5 ml kg -1 min -1 , however, with almost complete recovery to baseline after 30 min (70 ± 4 and 71 ± 6 ml kg -1 min -1 , NS from baseline). Similarly, clonidine decreased mucosal red cell flux by 44 ± 8% and 54 ± 4%. However, mucosal perfusion did not return to baseline (-25 ± 5% and -27 ± 3%). Conclusions:In spite of the rapid return to baseline in systemic perfusion, the mucosal red cell flux of the enoral mucosa remained markedly reduced after a single bolus of clonidine. Given the crucial role of preserved microcirculatory perfusion for an intact mucosal barrier function, our data suggest that clonidine might impair this important mechanism to prevent the translocation of bacteria and endotoxins into the systemic circulation.

To clarify the effects of hypercapnia (increased PaCO2) on gastric mucosal oxygenation during anaesthesia in dogs.Prospective, controlled animal study.Experimental research laboratory of an university hospital.Six chronically instrumented dogs.Dogs were anaesthetized (sevoflurane 1.5 MAC), mechanically ventilated (etCO2 = 35 mmHg) and randomly assigned to the following protocols: in a first series, ventilation was adjusted to increase etCO(2) to 45, 55, 65 and 70 mmHg. In a second series, animals were ventilated to achieve 70 mmHg of etCO2, which was maintained for 120 min to test if effects are transient or prolonged and to achieve a similar time course in both protocols.Gastric mucosal oxygenation (microHbO2) was assessed continuously by tissue reflectance spectrophotometry. Mean arterial blood pressure (MAP) and cardiac output (CO) were continuously measured. Blood was sampled for blood gas analysis and lactate concentration. Hypercapnia increased gastric mucosal oxygenation concentration dependently from 48 +/- 6% (35 mmHg etCO2) to 51 +/- 4, 54 +/- 5, 56 +/- 5 and 59 +/- 3% (etCO2 45, 55, 65 and 70 mmHg, respectively). This reflected changes in CO (68 +/- 16, 74 +/- 16, 82 +/- 12, 91 +/- 11 and 97 +/- 16 ml kg(-1) min(-1), respectively) and systemic oxygen delivery (10 +/- 2, 11 +/- 3, 13 +/- 2, 14 +/- 2 and 14 +/- 2 ml kg(-1) min(-1), respectively). These effects persisted for 2 h (microHbO2 53 +/- 6 vs. 64 +/- 4%, CO 73 +/- 16 vs. 92 +/- 15 ml kg(-1) min(-1), DO2 12 +/- 4 vs. 14 +/- 3 ml kg(-1) min(-1), etCO2 35 and 70 mmHg, respectively).Hypercapnia increased systemic and regional oxygenation. If this experimental finding may be transferred to the clinical setting, permissive hypercapnia might be used to augment the oxygenation of the splanchnic region, e.g. gastrointestinal mucosa.

Background and objective: During high epidural anaesthesia, endothelin only contributes minimally to blood pressure stabilization. This phenomenon could result from the inhibitory action of nitric oxide on the endothelin system. To clarify this, we studied the interaction between nitric oxide and endothelin during high epidural anaesthesia in conscious dogs, in comparison to the interaction of nitric oxide and vasopressin. Methods: Six animals were used in 45 individual experiments randomly arranged as follows: N-ω-nitro- arginine-methylester 0.3-10 mg kg-1 under physiological conditions or during high epidural anaesthesia (lidocaine 1%) and N-ω-nitro-arginine- methylester (L-NAME) 0.3-10 mg kg-1 after preceding endothelin (Tezosentan®) or vasopressin (β-mercapto-β,β-cyclo-penta- methylene-propionyl-O-Me-Tyr-Arg-vasopressin) receptor blockade under physiological conditions or during high epidural anaesthesia. During control experiments normal saline was injected either intravenously (n = 5) or into the epidural space (n = 4). Results: N-ω-nitro-arginine-methylester increased mean arterial pressure dose-dependently in all groups. However, this effect was substantially reduced in the presence of the endothelin receptor antagonist compared to N-ω-nitro-arginine-methylester alone, both under control conditions (7 ± 3 vs. 21 ± 3 mmHg; P < 0.05) and during high epidural anaesthesia (17 ± 3 vs. 30 ± 1 mmHg; P < 0.05). Blockade of vasopressin showed no similar relationship with N-ω-nitro- arginine-methylester. Conclusions: The diminished increase in mean arterial pressure after injection of N-ω-nitro-arginine-methylester only during endothelin receptor blockade indicates that endogenous nitric oxide inhibits the action of endothelin during high epidural anaesthesia and might thus explain the reduced efficacy of endothelin in maintaining blood pressure during high epidural anaesthesia.

Objective: The effect of levosimendan, a novel inotropic vasodilator (inodilator), on the microvascular gastric mucosal hemoglobin oxygenation (μHbO2) is unknown. A possible effect could thereby be selective for the splanchnic region or could primarily reflect changes in systemic oxygen transport (ḊO2) and/or oxygen consumption (V̇O2). We compared systemic and regional effects of levosimendan with those of established inotropes, milrinone and dobutamine. Design: Laboratory experiment. Setting: University animal research laboratory of experimental anesthesiology. Subjects: Chronically instrumented dogs with flow probes for cardiac output measurement. Interventions: Anesthetized, mechanically ventilated dogs (each group n = 6) on different days randomly received levosimendan (10 μg·kg-1, followed by four infusion steps: 0.125-1.0 μg·kg-1·min-1), milrinone (5.0 μg·kg-1, followed by 1.25-10 μg·kg -1·min-1), or dobutamine (2.5-10.0 μg·kg-1·min-1). Since these drugs may modify regional or systemic responses to fluid load, an additional predefined volume challenge was subsequently performed with hydroxyethyl starch 6% (10 mL·kg-1). Measurements and Main Results: We measured μHbO2 (reflectance spectrophotometry), ḊO2, V̇O2, and systemic hemodynamics. Levosimendan significantly increased μHbO2 from baseline (∼55% for all groups) to 64 ± 4% and further to 69 ± 2% with volume challenge (mean ± SEM). At the systemic level, levosimendan alone only slightly increased ḊO2 at a stable V̇O2. Milrinone elicited similar systemic effects (ḊO2, V̇O2, hemodynamics) but failed to increase μHbO2. Dobutamine, conversely, increased μHbO2 to a similar extent as levosimendan; however, this was accompanied by marked increases in ḊO2 and V̇O2. The gastric mucosa selectivity of these interventions, expressed as slope of the μHbO2/ḊO2 relation, was highest for levosimendan (+1.89 and +1.14, without and with volume challenge), compared with milrinone (+0.45 and + 0.47) and dobutamine (+0.48 and + 0.33). Conclusions: Levosimendan is superior to milrinone (no significant regional effects) and dobutamine (marked systemic effects) in increasing gastric mucosal oxygenation selectiveiy (i.e., at only moderately increased ḊO2 and stable V̇O 2). If our experimental data apply to the clinical setting, levosimendan may serve as an option to selectively increase gastrointestinal mucosa oxygenation in patients at risk to develop splanchnic ischemia.

Background. The effects of thoracic epidural anaesthesia (TEA) on gastric mucosal microvascular haemoglobin oxygenation (μHbO2) are unclear. At the splanchnic level, reduction of sympathetic tone may promote vasodilation and increase μHbO2. However, these splanchnic effects are counteracted by systemic effects of TEA (e.g., decreased cardiac output (CO) and mean arterial pressure (MAP)), thus making the net effect on μHbO2 difficult to predict. In this respect, effects of TEA on μHbO2 may differ between physiological and compromised circulatory conditions, and additionally may depend on adequate fluid resuscitation. Furthermore, TEA may alter the relationship between regional μHbO2 and systemic oxygen-transport (DO2). Methods. Chronically instrumented dogs (flow probes for CO measurement) were anaesthetized, their lungs ventilated and randomly received TEA with lidocaine (n=6) or epidural saline (controls, n=6). Animals were studied under physiological and compromised circulatory conditions (PEEP 10 cm H2O), both with and without fluid resuscitation. We measured gastric mucosal μHbO2 by reflectance spectrophotometry, systemic DO2, and systemic haemodynamics (CO, MAP). Results. Under physiological conditions, TEA preserved μHbO2 (47 (3)% and 49 (5)%, mean (SEM)) despite significantly decreasing DO2 (11.3 (0.8) to 10.0 (0.7) ml kg-1 min-1) and MAP (66 (2) to 59 (3) mm Hg). However, during compromised circulatory conditions, TEA aggravated the reduction in μHbO2 (to 32 (1)%), DO2 (to 6.7 (0.8) ml kg-1 min-1) and MAP (to 52 (4) mm Hg), compared with controls. During TEA, fluid resuscitation completely restored these variables. TEA preserved the correlation between μHbO2 and DO2, compared with controls. Conclusions. TEA maintains μHbO2 under physiological conditions, but aggravates the reduction of μHbO2 induced by cardiocirculatory depression, thereby preserving the relationship between gastric mucosal and systemic oxygenation.

Background. In this study we aimed to clarify the role of endothelin in arterial pressure regulation during anaesthesia with increasing concentrations of sevoflurane (1-3 MAC) and compare it with those of vasopressin and angiotensin. Methods. After an awake control period, on different days, six dogs underwent each of the following four interventions: sevoflurane anaesthesia alone (1-3 MAC), sevoflurane after block of either endothelin receptors using tezosentan (3 mg kg-1 followed by 3 mg kg-1 h-1), vasopressin V1a receptors using [d(CH2)5Tyr(Me2)]AVP (40 μg kg-1) or angiotensin receptors using losartan (6 mg kg-1 h-1). Plasma concentrations of endothelin, big endothelin, vasopressin and renin were measured. Effects of sevoflurane in the presence and absence of the respective receptor block were analysed and compared using analysis of variance for repeated measures (ANOVA followed by Fisher's PLSD (protected least significant difference) (P-1 at 3 MAC as arterial pressure decreased in all groups. Conclusions. At 1 MAC, angiotensin attenuated the decrease in arterial pressure during sevoflurane anaesthesia more than endothelin and vasopressin. However, at higher MAC only vasopressin was specifically activated to partly compensate for the arterial pressure decrease.

Background and objective: Desflurane has been shown to increase sympathetic activity and heart rate (HR) in a concentration-dependent manner. Nevertheless, desflurane, like all other volatile anaesthetics, increased HR in parallel to vagal inhibition in a previous study. Therefore, our hypothesis is that desflurane elicits tachycardia by vagal inhibition rather than by activation of the sympathetic nervous system. Methods: Six dogs were studied awake and during desflurane anaesthesia (1 and 2 MAC) alone, after pretreatment with propranolol (2 mg kg-1 followed by 1 mg kg-1 h -1), or after pre-treatment with atropine (0.1 mg kg-1 followed by 0.05 mg kg-1 h-1). The effects on HR and HR variability were compared by an analysis of variance (P < 0.05). HR variability was analysed in the frequency domain as power in the high-(0.15-0.5 Hz, vagal activity) and low-frequency range (0.04-0.15 Hz, sympathetic and vagal activity). Results: HR increased during 2 MAC of desflurane from about 60 (awake) to 118 ± 2 beats min-1 (mean ± SEM) in controls and to 106 ± 3 beats min-1 in dogs pre-treated with propranolol. In contrast, pretreatment with atropine increased HR from 64 ± 2 to 147 ± 5 beats min-1 (awake) and HR decreased to 120 ± 5 beats min-1 after adding desflurane. High-frequency power correlated inversely with HR (r2 = 0.95/0.93) during desflurane alone and in the presence of β-adrenoceptor blockade, with no significant difference between regression lines. There was no correlation between these variables during atropine/desflurane. Conclusions: The increase in HR elicited by desflurane mainly results from vagal inhibition and not from sympathetic activation.

Background Oxygen consumption ( V ˙ o 2) is rarely measured during anaesthesia, probably because of technical difficulties. Theoretically, oxygen delivery into a closed anaesthesia circuit ( V ˙ o 2-PF; PhysioFlex™ Draeger Medical Company, Germany) should measure V ˙ o 2. We aimed to measure V ˙ o 2-PF in vitro and in vivo. Methods Three sets of experiments were performed. V ˙ o 2-PF was assessed with five values of V ˙ o 2 (0–300 ml min−1) simulated by a calibrated lung model ( V ˙ o 2-Model) at five values of F I O2 (0.25–0.85). The time taken for V ˙ o 2-PF to respond to changes in V ˙ o 2-Model gave a measure of dynamic performance. In six healthy anaesthetized dogs we compared V ˙ o 2-PF with V ˙ o 2 measured by the Fick method ( V ˙ o 2-Fick) during ventilation with nine values of F I O2 (0.21–1.00). V ˙ o 2-PF and V ˙ o 2-Fick were also compared in three dogs when V ˙ o 2 was changed pharmacologically [102 ( sd 14), 121 (17) and 200 (57) ml min−1]. In patients during surgery, we measured V ˙ o 2-PF and V ˙ o 2-Fick simultaneously after induction of anaesthesia (n=21) and during surgery (n=17) (F I O2 0.3–0.5). Results Compared with V ˙ o 2-Model, V ˙ o 2-PF values varied from time to time so that averaging over 10 min is recommended. Furthermore, at an F I O2 >0.8, V ˙ o 2-PF always overestimated V ˙ o 2. With F I O2

Inhalation anaesthetics decrease heart rate in isolated hearts but mostly increase heart rate in the intact organism, although most inhibit sympathetic drive. Differences in the degree of increase in heart rate between agents may be related to differences in their vagolytic action. To test this hypothesis, we studied the effects of halothane (H), isoflurane (I), enflurane (E), sevoflurane (S) and desflurane (D) [1-3 MAC (minimum alveolar concentration)] on heart rate and heart rate variability (HRV) as a measure of cardiac vagal activity in seven dogs. HRV was analysed in the time domain as the standard deviation of the RR interval (SDNN) and in the frequency domain as power in the high-frequency (HF, 0.15-0.5 Hz) and low-frequency (LF, 0.04-0.15 Hz) ranges. Heart rate increased with anaesthetic concentration and there were corresponding decreases in SDNN, HF power and LF power. Heart rate increased most with D (+40 beats min(-1)), least with H (+8 beats min(-1)) and to an intermediate extent with S, I and E. SDNN and HF power, as measures of vagal activity, changed in the opposite direction and decreased in the same order as heart rate increased. However, SDNN and HF power correlated significantly with heart rate [r=-0.81 (0.04) and -0.81 (0.03) respectively] and were independent of the anaesthetic and its concentration (P0.05). Consistent with our hypothesis, these results suggest that differences between agents in the degree of increase in heart rate are explained by differences in their vagolytic action.

UNLABELLED: We studied whether endogenous endothelin, like endogenous vasopressin, helps to maintain blood pressure during high epidural anesthesia when efferent sympathetic drive is diminished. On different days, six awake dogs underwent each of the following five interventions: blockade of vasopressin V(1a) receptors using [d(CH(2))(5)Tyr(Me(2))]AVP, (40 microg/kg) or endothelin receptors using tezosentan (3 mg/kg followed by 3 mg. kg(-1). h(-1)) with or without epidural anesthesia (1% lidocaine, intraindividual dose did not differ between experiments), and epidural saline (n = 5). The effects of endothelin- or vasopressin-receptor blockade were analyzed (means +/- SEM) and compared by an analysis of variance for repeated measures (paired Student's t-test, alpha-adjusted, P < 0.05). Vasopressin-receptor blockade decreased blood pressure (10 +/- 2 mm Hg) only in the presence of epidural anesthesia, whereas endothelin-receptor blockade reduced blood pressure both in the presence and absence of epidural anesthesia (12 +/- 3 versus 10 +/- 1 mm Hg). During baseline and each intervention, plasma concentrations of vasopressin and big-endothelin were measured and compared by a Wilcoxon's rank sum test; P < 0.05. Vasopressin concentrations increased during epidural anesthesia and after additional endothelin receptor blockade, but big-endothelin concentrations remained unchanged during each intervention. We conclude that vasopressin acts as a reserve system, as it stabilizes blood pressure specifically during epidural anesthesia, whereas the unchanged concentrations of big-endothelin indicate that the endothelin system is not specifically activated to support blood pressure during epidural anesthesia. IMPLICATIONS: We studied in awake dogs whether endogenous endothelin, like endogenous vasopressin, helps to maintain blood pressure during resting conditions and epidural anesthesia. Only vasopressin was specifically activated to support blood pressure during epidural anesthesia, whereas endothelin supported blood pressure to the same extent during epidural anesthesia and during resting conditions.

Objective: To assess the accuracy and reproducibility of long-term implanted ultrasound transit-time flow probes for measuring cardiac output. Design: Prospective animal study. Settings: Animal research laboratory in a university department. Animals: Eleven anaesthetised dogs, 24–34 kg. Measurements and results: Flow probes (16–24 mm S-series, Transonic) were implanted around the pulmonary artery for a mean duration of 22 months (range 6–47 months). Comparisons (n = 147) were made between cardiac output thus obtained and that measured by the direct Fick principle using oxygen uptake (Deltatrac II Metabolic Monitor) and the arterial to mixed venous oxygen content difference measured by a galvanic cell (Lex-O2-Con-TL). Measurements were made either during baseline conditions or during pharmacologically altered cardiac output (range 22–180 ml · kg–1· min–1). Regardless of the intervention, the two methods yielded the same results in half of the dogs. In the others, however, cardiac output was underestimated by the flow probes by up to 38 % (probably because of non-perpendicular position of the probe towards the vessel). This difference was constant for the whole range of cardiac output studied and remained constant over the entire observation period for each individual dog, so that a correction factor was used. Thereafter, the mean difference between the two methods was –1.1 ml · kg–1· min–1 with a precision (SD) of 14.2 ml · kg–1· min–1 for all experiments. Conclusions: After in vivo calibration, ultrasound transit-time flow probes measure cardiac output precisely for several years, regardless of the intervention.

Background & Goal: To study the response to acute hypoxia in micro- and macrocirculatory variables during propofol- (PROPO) vs. sevoflurane- (SEVO) anesthesia. Materials and methods: In randomized cross over design, chronically instrumented dogs (24-32 kg, n=6 per group) were anesthetized with PROPO or SEVO (equi-anesthetic dosages), mechanically ventilated (FiO2 ~0.3) and underwent a hypoxemic episode (FiO2 ~0.1 for 15 min [1] ), followed by normoxic recovery (FiO2 ~0.3; 90 min). Microcirculatory perfusion of oral mucosa (µ-mucosa) and hindlimb skin (µ-skin) were measured by laser Doppler fluxmetry. Regional gastric intraluminal PCO2 (PgiCO2) was measured by tonometry. Macro-hemodynamics (cardiac output (CO), blood pressures), metabolism (O2-consumption (VO2); indirect alorimetry) and blood-derived variables (art. O2-content (CaO2), acid/base variables) were also measured. Statistics: Data are mean±sem for n=6 experiments per group, and compared by two-way-ANOVA, corrected for multiple comparisons (Bonferroni). A p< 0.05 was significant. Results and Discussion: During normoxia, both CO and CaO2 were similar (both N.S.) under PROPO and SEVO. In addition, the hypoxia model achieved comparable drops in CaO2 (N.S.) under both anesthesia types. However, hypoxia elicited markedly different responses between PROPO and SEVO: Hypoxia during PROPO significantly increased µ-mucosa and µ-skin, but decreased both during SEVO. After hypoxia under PROPO, PgiCO2 was preserved, whereas under SEVO, PgiCO2 significantly accumulated. During PROPO, hypoxia generally stimulated macro-hemodynamics (e.g., CO increased from 86±3 to 123±8 ml/kg/min), whereas in contrast during SEVO-hypoxia hemodynamics were unresponsive (CO, 72±8 vs. 71±6 ml/kg/min) or even depressed. On the metabolic level, VO2 was maintained during PROPO/hypoxia, but significantly decreased with SEVO/hypoxia. Conclusion: In this dog model, only PROPO permitted hemodynamic stimulation by acute hypoxia, resulting in (compensatory) increased micro- and macrocirculatory perfusion. In line, PROPO-hypoxia maintained VO2 , without aggravating anaerobiosis markers (lactate), and with preservation of PgiCO2. In contrast, SEVO failed to permit hemodynamic stimulation by hypoxia and failed to preserve PgiCO2. If our data can be transferred to the clinical setting, PROPO appears beneficial (vs. SEVO) to support the systemic and regional circulation during acute hypoxia. Reference: 1. Schwarte LA et al, Int Care Med 2011;37:701-10