Splanchnic Microcirculation Research Articles

Microcirculation-driven mitochondrion dysfunction during the progression of experimental sepsis

Sepsis is accompanied by a less-known mismatch between hemodynamics and mitochondrial respiration. We aimed to characterize the relationship and time dependency of microcirculatory and mitochondrial functions in a rodent model of intraabdominal sepsis. Fecal peritonitis was induced in rats, and multi-organ failure (MOF) was evaluated 12, 16, 20, 24 or 28 h later (n = 8/group, each) using rat-specific organ failure assessment (ROFA) scores. Ileal microcirculation (proportion of perfused microvessels (PPV), microvascular flow index (MFI) and heterogeneity index (HI)) was monitored by intravital video microscopy, and mitochondrial respiration (OxPhos) and outer membrane (mtOM) damage were measured with high-resolution respirometry. MOF progression was evidenced by increased ROFA scores; microcirculatory parameters followed a parallel time course from the 16th to 28th h. Mitochondrial dysfunction commenced with a 4-h time lag with signs of mtOM damage, which correlated significantly with PPV, while no correlation was found between HI and OxPhos. High diagnostic value was demonstrated for PPV, mtOM damage and lactate levels for predicting MOF. Our findings indicate insufficient splanchnic microcirculation to be a possible predictor for MOF that develops before the start of mitochondrial dysfunction. The adequate subcellular compensatory capacity suggests the presence of mitochondrial subpopulations with differing sensitivity to septic insults.

Liver Function Following Carbon-Di-Oxide Pneumoperitoneum in Laparoscopic Cholecystectomy

Background: Laparoscopic surgery is performed by the insufflation of gas like carbon di oxide (CO2) into the peritoneal cavity by artificial port which is called creating pneumoperitoneum. The CO2 pneumoperitoneum causes changes in the splanchnic microcirculation and can affect liver physiology. Although laparoscopic cholecystectomy offered many advantages over laparotomy, new concerns arose regarding the effects of CO2 pneumoperitoneum on liver function. Knowledge of the effects of CO2 pneumoperitoneum on liver function can help minimize complications while profiting from the benefits of LC without concerns about its safety. It was noticed in many studies that following laparoscopic cholecystectomy (LC), liver function parameters were disturbed. Aims: To observe any alteration in liver function by carbon dioxide pneumoperitoneum in laparoscopic cholecystectomy. Methods: Ninety-four patients with cholelithiasis having normal liver function enrolled in this study. Test obtained preoperatively including serum bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) then 24 &72 hour post operatively to compare and proceed. Statistical analyses of the results were obtained by using window-based computer software devised with Statistical Packages for Social Sciences (SPSS22). Results: The findings showed that mean duration of pneumoperitoneum was 43.8±9.1minutes. The mean serum bilirubin pre-operatively was 0.75±0.21 (mg/dL), post-operative 24 hours value was 0.77±0.23 (mg/dL) and post-operative 72 hours value was 0.73±0.18 (mg/dL). No significant difference was observed in pre-operative and postoperative values. The mean serum ALT preoperatively was 33.81±7.83 (IU/L), post-operative 24 hours value was 52.51±25.9 (IU/L) and postoperative 72 hours value was 46.3±21.33 (IU/L). The mean serum AST pre-operatively was 33.84±6.83 (IU/L), post-operative 24 hours value was 48.94±19.23 (IU/L) and post-operative 72 hours value was 44.36±15.7 (IU/L). The mean serum alkaline phosphatase pre-operatively was 72.57±25.95 (IU/L), post-operative 24 hours value was 88.26±41.69 (IU/L) and post-operative 72 hours value was 85.32±38.85 (IU/L). There were significant increase of post-operative 24 hours and 72 hours value of liver enzymes when compared to preoperatively. Conclusion: There was significant increase in, AST, ALT, ALP post-operative 24 hours and 72 hours after doing laparoscopic cholecystectomy when compared to preoperatively. There may be a transient elevation of hepatic enzymes after LC and the major causative factor seemed to be CO2 pneumoperitoneum.

Use of Acetate-Buffered Crystalloid Solutions for Fluid Therapy in Abdominal Surgery (Review)

Infusion therapy is one of the most frequently prescribed treatments in hospitalized patients. Fluid maintenance and resuscitation is an important strategy in major surgery. Acetate-buffered balanced crystalloid fluids may influence acid-base status, intracellular and extracellular water content, plasma electrolyte composition and have a favorable impact on renal, hepatic, and splanchnic microcirculation. Aim was to evaluate current evidence of efficacy and safety of acetate-buffered crystalloid solutions for fluid therapy in abdominal surgery in adults. Materials and methods . Medline, the Cochrane Library, eLIBRARY.ru were searched up to 31 May 2020 (additional search in November 2020) using the key words «acetate» AND «buffers» OR «buffered» AND «crys-talloid solutions» OR «crystalloids». Studies published after 2009 in English and Russian were included. Systematic review was conducted in accordance with PRISMA guidelines using specified PICO(S) criteria. Results . The total of 62 studies were identified from all databases. Out of them 11 full-text publications were considered eligible, 6 of them were included into the final review. Acetate-buffered crystalloid solutions have a favorable impact on microcirculation. Metabolic alkalosis after the fluid infusion did not occur in all the studies; potassium levels remained stable, also. Conclusion . Efficacy (based on acid-base status, hemodynamic parameters) of the acetate-buffered crystalloid solutions for fluid therapy during the abdominal surgery in adults patients was confirmed with the A level of evidence.

An observational study on effect of carbon dioxide pneumoperitoneum on liver function test in laparoscopic cholecystectomy

Background: In many studies it was noticed that following a laparoscopic cholecystectomy (LC), liver function parameters were disturbed. The carbon dioxide pneumoperitoneum causes changes in the splanchnic microcirculation and can affect cardiac, pulmonary, liver and kidney physiology. Alterations in intracranial pressure, blood acid- base control and the immune system have also been seen. This study was done to know the effects of carbon dioxide pneumoperitoneum on liver function tests in LC. Aim of the study was to study the significance of alterations in Liver function tests and procedure’s safetyMethods: Blood samples of 100 patients who underwent laparoscopic cholecystectomy preoperatively once and post operatively after 24 hours were collected. These blood samples were tested for LFT. The pre op and post op levels of these liver function test values were compared.Results: The level of serum AST, ALT, bilirubin (total) and ALP were increased significantly during the first 24 hrs. Postoperatively after laparoscopic cholecystectomy as compared to baseline values and the levels of serum albumin and total proteins were decreased.Conclusions: There may be a transient elevation of hepatic enzymes after LC and the major causative factor seemed to be CO2 pneumoperitoneum.

Local gastric RAAS inhibition improves gastric microvascular perfusion in dogs.

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.

Evaluation of Gastric Microcirculation by Laser Speckle Contrast Imaging During Esophagectomy

Thoracic epidural anesthesia (TEA) may provoke hypotension, and that, as well as the use of vasopressors and the surgical technique, could affect splanchnic microcirculation, in which the surgical target organ is of particular interest. This study used laser speckle contrast imaging (LSCI) to monitor gastric microcirculation during esophagectomy. Forty-five patients undergoing open esophagectomy were randomized to primary activation (EA; 25 patients) or no intraoperative activation (LA; 20 patients) of TEA. Phenylephrine managed intraoperative hypotension and gastric microcirculation was assessed at antrum and corpus area by LSCI. Antrum microcirculation (mean ± SD) was lower in the EA group at baseline (1,150 ± 189 laser speckle perfusion units [LSPU] vs LA group: 1,265 ± 163 LSPU; p= 0.036). In both groups, antrum microcirculation tended to decrease in response to anesthesia, TEA, and surgical procedure (LA: 1,265 ± 163 to 1,097 ± 184 LSPU, p= 0.021; EA: 1,150 ± 189 to 1,064 ± 177 LSPU, p= 0.093), with no difference between groups during the remaining laparotomy. Corpus microcirculation decreased in both groups from baseline to gastric pull-up in response to anesthesia, TEA, and surgery (LA: 1,081 ± 236 to 649 ± 165 LSPU, p < 0.001; EA: 1,011 ± 208 to 675 ± 178 LSPU, p < 0.001), but recovered after gastric continuity was re-established (EA to 795 ± 162 LSPU, p= 0.027; LA to 815 ± 166 LSPU, p= 0.014), with no significant differences between groups (p > 0.05). The EA group needed continued phenylephrine support to maintain blood pressure (216 ± 86 vs 58 ± 91 minutes; p < 0.001). During esophagectomy, gastric microcirculation can be followed in real-time by LSCI. Flow changes in the stomach seemed related more to surgery than to TEA/vasopressor support. Laser speckle contrast imaging could form basis for directing procedures to maintain the microcirculation.

Thoracic epidural analgesia reduces gastric microcirculation in the pig.

BackgroundThoracic epidural analgesia (TEA) is used for pain relief during and after abdominal surgery, but the effect of TEA on the splanchnic microcirculation remains debated. We evaluated whether TEA affects splanchnic microcirculation in the pig.MethodsSplanchnic microcirculation was assessed in nine pigs prior to and 15 and 30 min after induction of TEA. Regional blood flow was assessed by neutron activated microspheres and changes in microcirculation by laser speckle contrast imaging (LSCI).ResultsAs assessed by LSCI 15 min following TEA, gastric arteriolar flow decreased by 22 % at the antrum (p = 0.020) and by 19 % at the corpus (p = 0.029) of the stomach. In parallel, the microcirculation decreased by 19 % at the antrum (p = 0.015) and by 20 % at the corpus (p = 0.028). Reduced arteriolar flow and microcirculation at the antrum was confirmed by a reduction in microsphere assessed regional blood flow 30 min following induction of TEA (p = 0.048). These manifestations took place along with a drop in systolic blood pressure (p = 0.030), but with no significant change in mean arterial pressure, cardiac output, or heart rate.ConclusionThe results indicate that TEA may have an adverse effect on gastric arteriolar blood flow and microcirculation. LSCI is a non-touch technique and displays changes in blood flow in real-time and may be important for further evaluation of the concern regarding the effect of thoracic epidural anesthesia on gastric microcirculation in humans.Trial registrationsNot applicable, non-human study.

Effect of transgastric natural orifice transluminal endoscopic surgery peritoneoscopy on abdominal organ microcirculation: an experimental controlled study

On-demand insufflation during endoscopic peritoneoscopy causes wide variations in intra-abdominal pressure. Its effects on splanchnic microcirculation may differ from those of steady intra-abdominal pressure, because pressure characteristics affect crucial intravascular hemodynamic forces--pressure and shear--adapting flow to local metabolic needs. Our aim was to assess the effect of natural orifice transluminal endoscopic surgery (NOTES) peritoneoscopy on splanchnic microcirculatory blood flow. Twenty-one swine were randomized to the following: cholecystectomy by transgastric NOTES (n = 8), cholecystectomy by standard laparoscopy (Lap) (n = 8), and a sham group (n = 5). During NOTES, CO2 was manually insufflated with a maximum allowed pressure of 30 mm Hg. In the Lap group, intra-abdominal pressure was maintained at 14 mm Hg. Systemic hemodynamics were measured, and microcirculatory blood flow was quantified by using colored microspheres. Mean intra-abdominal pressure was lower in NOTES than in the Lap group (P = .038). In both groups, cardiac index and preload remained unchanged, whereas systemic vascular resistances increased over time, with a lesser increase in the Lap group (2-way analysis of variance; P = .041). In pneumoperitoneum groups, microcirculatory blood flow decreased similarly in the renal medulla, stomach, small bowel, colon, and mesocolon by 30%, 45%, 34%, 32%, and 37%, respectively. In NOTES, there was a greater microcirculatory blood flow decrease in the renal cortex (NOTES 41% vs Lap 35%; P = .044) and mesentery (NOTES 44% vs Lap 38%; P = .041). These findings suggest that both types of pneumoperitoneum have similar physiologic effects on microcirculatory blood flow. However, on-demand pneumoperitoneum (NOTES group) caused a greater microcirculatory blood flow decrease in areas with low metabolic needs, redistributing blood flow toward metabolically active areas.

Vasopressin V1A receptors mediate the increase in gastric mucosal oxygenation during hypercapnia

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 V(1A) 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 V(1A) 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 V(1A) 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.

Interruption of the intestinal immune route to the systemic circulation associated with early hyperhydration minimized splanchnic microcirculation damage and improved sepsis survival

Interruption of the intestinal immune route to the systemic circulation associated with early hyperhydration minimized splanchnic microcirculation damage and improved sepsis survival

Inhibition of Rho-kinase attenuates endothelial–leukocyte interaction during ischemia–reperfusion injury

Resuscitation from hemorrhagic shock induces endothelial dysfunction and activates inflammatory cascades leading to organ damage. Following restoration of blood flow to ischemic vascular beds, leukocyte-endothelium interactions leading to leukocyte infiltration into the vascular wall occur very early due, in part, to the loss of endothelium-derived nitric oxide (NO). The mechanism by which ischemia-reperfusion injury impairs endothelium-derived NO is not completely understood. We hypothesized that inhibition of Rho-kinase could exert beneficial effects following hemorrhagic shock by preserving endothelial function and attenuating leukocyte trafficking in the microcirculation. Using intravital microscopy, we found that resuscitation from hemorrhage acutely increased the number of rolling and adherent leukocytes in the mouse splanchnic microcirculation. Treatment of mice with the Rho-kinase inhibitor fasudil, markedly attenuated leukocyte-endothelium interaction in response to hemorrhage/reinfusion. The beneficial effect of fasudil was not observed in endothelial nitric oxide synthase (eNOS)(-/-) mice. In conclusion, inhibition of Rho-kinase prevents inflammatory leukocyte trafficking in the microcirculation via an eNOS-dependent mechanism. Our data support a role for Rho-kinase inhibitors in the treatment of ischemia-reperfusion injury.

Monitoring the microcirculation in the critically ill patient: reflectance spectroscopy

Dear Editor, I read with great interest and pleasure the excellent overview of the most common methods currently used to monitor the microcirculation by De Backer and colleagues [1]. The expertise of this group of authors with most of the methods described in their review of innumerable original publications was clearly evident. However, the section on reflectance spectroscopy is rather short, suggesting that they may lack in-depth practical experience with that specific method. In particular, the last sentence on recent developments in the technique is incorrect and needs to be explained more specifically. The first device using reflectance spectroscopy (EMPHO) was limited to perpendicular probes for mucosa measurements and was based on spectrophotometry only. Nevertheless, it has been used in numerous experimental and clinical studies performed by our group for assessing the effects of various factors and agents, such as positive airway pressure, intraabdominal pressure, hypercapnia, cardiopulmonary bypass, vasoactive drugs and anaesthetics, on the splanchnic microcirculation [for references, see the Electronic Supplementary Material (ESM)]. The latest development using reflectance spectroscopy is incorporated in the O2C (oxygen to see) device (Lea, Giessen, Germany). The technology of the O2C device is based on two physical principles: reflection spectroscopy and the laser Doppler technique. Compared to the EMPHO device, the O2C instrument integrates both techniques in a much smaller device because the rotating filter wheel has been replaced by a CCD-spectrometer and the xenon high-pressure lamp by a small light source optimised for fibre optics. Specific probes are used to introduce white light (wavelengths 500–800 nm) and laser light (wavelength 830 nm) simultaneously into the tissue. A part of the light spectrum is absorbed when the white light interacts with the erythrocytes, and this absorbed portion assumes the colour of the haemoglobin as a measure of its oxygen saturation. The laser light experiences a frequency displacement due to the moving erythrocytes (the so-called Doppler Shift), and this displacement is a measure of their velocity. The sum of all erythrocytes and their velocity is a measure of blood flow (volume flow) in the complex network of capillaries. With this device the following parameters can be measured simultaneously in tissue: the oxygen saturation of haemoglobin (μHbO2) at the venous end of the capillaries (the so-called “last meadow”); the regional amount of haemoglobin (rHb) in the micro-blood vessels as a measure of its blood volume and for capillary density; the velocity of the blood in microcirculation; the flow of blood in the microcirculation. The main advantage of this technology when assessing microvascular blood flow is that this combination of parameters allows the determination of regional oxygen consumption (rVO2) in the tissue as a direct measure of tissue viability. The metabolism may be a more important parameter than the heterogeneity of perfusion, which is considered to be a key to monitor sepsis (for details, see ESM). The method has been used clinically to assess the microvascular response in patients with septic shock [2], to monitor the effects of extreme anaemia [3] or flap viability [4] and to predict wound healing in burn injury [5]. In conclusion, the combination of reflection spectroscopy and laser Doppler (O2C) may offer a useful enlargement of the diagnostic tools available to the clinician for assessing microvascular blood flow and tissue oxygen consumption.

Pathophysiological basis of albumin use in cirrhosis

During the course of cirrhosis, a progressive reduction of splanchnic vascular resistance takes place in parallel with a deterioration of cardiac function manifested by the disappearance of the hyperdynamic circulation due to a fall in cardiac output. This compromises arterial pressure and determines a homeostatic activation of endogenous vasoconstrictor systems. Cirrhotic patients are prone to developing renal vasoconstriction, decreased renal perfusion and renal failure in response to insults that impairs the effective arterial blood volume such as severe bacterial infections or other clinical events that produce hypovolemia. Although circulatory dysfunction in cirrhosis predominantly affects the kidney, it has also effects on other organs and systems: brain edema and encephalopathy, increased portal pressure and decreased intestinal motility. Albumin infusion is effective in the prevention of circulatory dysfunction after therapeutic paracentesis or acute bacterial infections and in in the treatment of hepatorenal syndrome. This effectiveness may be related to the dual effect of albumin on the cardio-circulatory function, the increase in the cardiac output and in the systemic vascular resistance. The administration of intravenous albumin not only expands the plasma volume and increases cardiac preload and cardiac output but also induces arterial vasoconstriction at the level of splanchnic microcirculation. Moreover, albumin is a powerful antioxidant as well as plays a crucial role in the transport of physiologic substances and disposal of toxic substances. Impairment of albumin function is one of the most characteristic traits of cirrhosis. Administration of exogenous albumin could be beneficial because of its positive effects on microcirculation.

On the role of ischemia in the pathogenesis of IBD

Inflammatory bowel disease (IBD) is a chronic intestinal disorder comprising 2 distinct but often overlapping diseases: Crohn's disease and ulcerative colitis. Although much research to identify the etiology of IBD has focused on genetic constitution, infectious causes, and immune dysregulation, its exact cause and pathogenesis remain incompletely understood. Mesenteric blood flow, the intestinal microcirculation, and intestinal ischemia also have been proposed as etiologic, although they remain less-explored themes despite evidence suggesting a contributory role in IBD pathogenesis. The anatomy, architecture, and function of the splanchnic microcirculation will be reviewed here with regard to the development of intestinal microvascular ischemia, a pathologic process that appears to precede the classic changes that characterize IBD.

Splanchnic Microcirculation Protection by Hydroxyethyl Starches During Abdominal Aortic Aneurysm Surgery

Objective To specifically compare the effect of two hydroxyethyl starches (HES) on the splanchnic microcirculation and systemic inflammation during abdominal aortic aneurysm (AAA) surgery. Materials and methods A prospective randomised study was carried out on 62 patients who received HES of molecular-weight 200 kDa (HES200/0.62), 130 kDa (HES130/0.4) or gelatine for 24 h peri-operatively. Gastric-mucosal pHi (GpHi) and anti-endotoxin antibody were used as markers of splanchnic perfusion and endotoxaemia respectively. C-reactive protein (CRP) and lung-injury score (LIS) were used as markers of systemic inflammation and end-organ dysfunction respectively. Data was collected prospectively. Results The drop in GpHi was least with HES200/0.62 compared to HES130/0.4 and gelatine at reperfusion (7.32 vs 7.28 and 7.28, p = 0.017 and 0.009 respectively) and compared to gelatine at 2 h as well (7.43 vs 7.28, p = 0.001). GpHi dropped less with HES130/0.4 compared to gelatine at 2 h (7.39 vs 7.28, p = 0.002). Endotoxaemia increased only with gelatine. CRP was lower with HES200/0.62 (178 mg/mL) than gelatine (221 mg/mL) and HES130/0.4 (223 mg/mL) at 48 h ( p = 0.049 and p = 0.009 respectively). There was no difference in LIS but ventilation duration was less with HES200/0.62 compared with gelatine (4 vs 11 h, p = 0.012). Conclusion During AAA surgery, HES200/0.62 provides the best splanchnic microcirculation protection, also reducing inflammation and duration of ventilation (Trial ISRCTN70166506).

TOLL-LIKE RECEPTOR 4 CONTRIBUTES TO MICROVASCULAR INFLAMMATION AND BARRIER DYSFUNCTION IN THERMAL INJURY

Systemic and microvascular inflammation plays a key role in the development of multiple organ failure after infection, sepsis, and traumatic injury. Toll-like receptors (TLRs) regulate host responses to pathogens and sterile, injury-associated inflammatory responses. We investigated whether TLR-4 contributes to microvascular dysfunction during thermal injury in vivo in anesthetized wild-type or TLR-4 (-/-) mice receiving either a 25% total body surface area full-thickness scald burn or sham treatment on the dorsal skin. Using intravital microscopy, we assessed the hemodynamics and leukocyte dynamics in the mesenteric microvasculature as representative of the splanchnic microcirculation at a site remote from the burn wound. The transvascular flux of fluorescein isothiocyanate-albumin across mesenteric venules was measured as an indicator of microvascular permeability. Furthermore, cultured microvascular endothelial cell models were used to evaluate the endothelial-specific mechanisms involved in TLR-4-mediated barrier dysfunction. The results showed significantly elevated microvascular permeability in wild-type mice after burn, whereas this response was markedly attenuated in TLR-4 (-/-) mice. Burn injury also increased leukocyte adhesion in mesenteric venules of wild-type mice, and a blunted leukocyte response was seen in the TLR-4 mice. Treatment of endothelial cell monolayers with burn plasma induced a rapid reduction in the transendothelial electrical resistance measured by electric cell-substrate impedance sensing, indicative of endothelial cell-cell adhesive barrier dysfunction. Reducing expression of TLR-4 with siRNA treatment attenuated this response. Taken together, these data indicate that TLR-4 plays an important role in microvascular leakage and leukocyte adhesion under the inflammatory condition associated with nonseptic thermal injury.

Effects of sodium nitroprusside on splanchnic microcirculation in a resuscitated porcine model of septic shock

We tested the hypothesis that sodium nitroprusside (SNP) might improve the impairment of hepatosplanchnic microcirculatory blood flow (MBF) in septic shock. Fourteen pigs were anaesthetized and their lungs mechanically ventilated. Sepsis was induced with i.v. infusion of live Pseudomonas aeruginosa [1x10(8) colony forming units (CFU) ml(-1) kg(-1)] for 1 h. Sixty minutes later, the animals received in a random succession either SNP or normal saline for 30 min. Mean arterial pressure (MAP), cardiac index (CI), mean pulmonary artery pressure (MPAP), carbon dioxide tension of the ileal mucosa (PCO2; by gas tonometry), ileal mucosal and hepatic MBF by laser Doppler flowmetry, blood gases, and lactates were assessed before, during administration, and 30 min after discontinuing the test drug. Bacterial infusion promoted hypodynamic shock (MAP -18%, CI -33%, ileal MBF -19%, and hepatic MBF -27%), which was converted to normodynamic shock by resuscitation. During SNP infusion, ileal mucosal MBF significantly increased (+19%) compared with control (P = 0.033). Although hepatic MBF increased (+42% from baseline), this did not differ from control. In order to maintain a constant central venous pressure and MAP, fluid loading and norepinephrine (P < 0.01) were increased. Acid-base status was not altered by SNP. In a resuscitated porcine model of the early phase of septic shock, SNP improved ileal mucosal MBF but required a concomitant increase in fluid and norepinephrine supplements to maintain constant systemic haemodynamic parameters.

Positive end-expiratory pressure does not affect indocyanine green plasma disappearance rate or gastric mucosal perfusion after cardiac surgery*

Positive end-expiratory pressure (PEEP) may affect hepato-splanchnic blood flow. We studied whether a PEEP of 10 mbar may negatively influence flow-dependent liver function (indocyanine green plasma disappearance rate, ICG-PDR) and splanchnic microcirculation as estimated by gastric mucosal PCO2 (PRCO2). In a randomized, controlled clinical study, we enrolled 28 patients after elective cardiac surgery using cardiopulmonary bypass. In 14 patients (13 male, 1 female; age 48-74, mean 63 +/- 7 yr) we assessed ICG-PDR and PRCO2 on intensive care unit admission with PEEP 5 mbar, after 2 h with PEEP of 10 mbar and again after 2 h at PEEP 5 mbar. Inspiratory peak pressure was adjusted to maintain normocapnia. Fourteen other patients (8 male, 6 female; age 46-86, mean 68 +/- 11 yr) in whom PEEP was 5 mbar throughout served as controls. All patients underwent haemodynamic monitoring by measurement of central venous pressure, left atrial pressure and cardiac index using pulmonary artery thermodilution. While doses of vasoactive drugs and cardiac filling pressures did not change significantly, cardiac index slightly increased in both groups. ICG-PDR remained unchanged either within or between both groups (PEEP10 group: 24.0 +/- 6.9, 22.0 +/- 7.9 and 25.5 +/- 7.7% min-1 vs. controls: 22.0 +/- 7.5, 23.8 +/- 8.4 and 21.4 +/- 6.5% min-1) (P = 0.05). The difference between PRCO2 and end-tidal PCO2 (PCO2-gap) did not change significantly (PEEP10 group: 1.1 +/- 0.9, 1.3 +/- 0.7 and 1.3 +/- 0.9 kPa vs. controls: 0.8 +/- 0.5, 0.9 +/- 0.5 and 0.9 +/- 0.5 kPa). A PEEP of 10 mbar for 2 h does not compromise liver function and gastric mucosal perfusion in patients after cardiac surgery with maintained cardiac output.

Increasing Cardiac Output by Epinephrine After Cardiac Surgery: Effects on Indocyanine Green Plasma Disappearance Rate and Splanchnic Microcirculation

The effects of increasing cardiac output by epinephrine on indocyanine green plasma disappearance rate (ICG-PDR) and gastric mucosal PCO(2) (P(R)CO(2)) were studied as indicators of splanchnic microcirculation. A prospective clinical study. Intensive care unit of a university hospital. With ethics approval and written consent, 12 elective cardiac surgical patients (5 female, 7 male, 71 +/- 8 years) were studied. Patients underwent pulmonary artery and left atrial catheterization for clinical indications. Measurements were made at intensive care unit admission and 1 hour after (increased) epinephrine treatment. Mean epinephrine dose was changed from 0.02 to 0.08 microg/kg/min. Heart rate significantly increased from 97 +/- 11 to 106 +/- 12 beat/min. Central venous (10 +/- 3 v 10 +/- 4 mmHg) and left atrial (10 +/- 5 v 11 +/- 5 mmHg) pressures were unchanged. Cardiac index and stroke volume index significantly increased from 2.7 +/- 0.5 to 3.2 +/- 0.5 L/min/m(2) and from 28 +/- 6 to 31 +/- 5 mL/m(2), respectively. Although systemic O(2) delivery and O(2) consumption significantly increased, ICG-PDR did not change significantly (ie, from 18.0% +/- 5.6% to 19.5% +/- 6.4% per minute). P(R)CO(2) and PCO(2) gap (difference between regional and end-tidal PCO(2)) significantly increased from 5.4 +/- 1.0 to 5.9 +/- 1.1 kPa and 1.2 +/- 0.8 to 1.5 +/- 0.7 kPa, respectively. Increasing cardiac output by epinephrine in patients after cardiac surgery was not associated with a change in flow-dependent liver function but a deterioration in gastric mucosal perfusion.

Increasing cardiac output by epinephrine after cardiac surgery: effects on indocyanine green plasma disappearance rate and splanchnic microcirculation

Department of Anesthesiology and Intensive Care Medicine, Friedrich-Schiller-University, Jena, Germany