Influencing factors of early cognitive deficits after ambulatory anesthesia.

BACKGROUND: Anesthesia has an influence on early postoperative cognitive function. This is specifically relevant in ambulatory surgery. At discharge, patients must return to their normal life and manage simple tasks. Goal was to detect influencing factors of early postoperative cognitive dysfunction after ambulatory anesthesia. METHODS: With approval of the local ethics committee, 102 individuals scheduled for ambulatory anesthesia were examined with a specific test battery. Cued and uncued reaction time, divided and selective attention were tested prior to anesthesia and at the time of discharge. Differences between the two examinations and potential influencing factors including age, premedication, type and duration of anesthesia were evaluated with the Student t-test and linear regression. P < 0.05 considered significant. RESULTS: In all, 86 individuals completed the study. Both reaction times were reduced after anesthesia compared to before. No differences were seen for divided and selective attention. Age influenced on the post-anesthesia reaction time while all other factors did not. CONCLUSION: Reaction time but not attention as more complex cognitive function is influenced by anesthesia. Age seems to be an important factor in early postoperative cognitive dysfunction.

Carbon monoxide, but not endothelin-1, plays a major role for the hepatic microcirculation in a murine model of early systemic inflammation.

OBJECTIVE: Endothelin-1 and carbon monoxide play a major role in the regulation of liver microcirculation in numerous disease states. During sepsis and endotoxemia, elevated formation of endothelin-1 results in reduced sinusoidal blood flow. However, the role of carbon monoxide and endothelin-1 and its receptors endothelin receptor A and endothelin receptor B in the deranged liver microcirculation during early systemic inflammation remains unclear. DESIGN: Prospective, randomized, controlled experiment. SETTING: University animal laboratory. SUBJECTS: Male C57/BL6 mice, weighing 23-27 g. INTERVENTIONS: To induce a systemic inflammation, mice were treated with 1 hr of bilateral hind limb ischemia followed by 3 hrs or 6 hrs of reperfusion. Animals were randomly exposed to the nonselective endothelin receptor antagonist Ro-61-6612 (Tezosentan) and/or a continuous endothelin-1 infusion. Different animals were randomized to methylene chloride gavage or carbon monoxide inhalation during the reperfusion period. MEASUREMENTS AND MAIN RESULTS: After ischemia/reperfusion, endothelin-1 plasma concentrations, endothelin-1 messenger RNA expression, and endothelin receptor A and B messenger RNA expression revealed no significant changes when compared with sham animals. After 6 hrs of ischemia/reperfusion, hepatic microcirculatory variables (sinusoidal density, sinusoidal diameter, and red blood cell velocity) deteriorated. Tezosentan after 6 hrs of ischemia/reperfusion did not improve the liver microcirculation, whereas the continuous infusion of endothelin-1 after 6 hrs of ischemia/reperfusion further impaired sinusoidal blood flow. Tezosentan treatment did not produce any alterations in hepatocellular injury or hepatic redox status when compared with the untreated animals receiving 6 hrs of ischemia/reperfusion. Animals receiving 6 hrs of ischemia/reperfusion and exposed to methylene chloride gavage or inhaled carbon monoxide during limb reperfusion showed significantly improved microcirculatory variables, hepatic redox status, and attenuated hepatocellular injury. CONCLUSIONS: These data suggest that endothelin-1 and the endothelin receptors A and B are not responsible for the observed hepatic microcirculatory and cellular dysfunction during early systemic inflammation, but exposure to exogenous carbon monoxide protected the hepatic microcirculation and improved the impaired hepatic cellular integrity and the hepatocellular redox status.

A remission spectroscopy system for in vivo monitoring of hemoglobin oxygen saturation in murine hepatic sinusoids, in early systemic inflammation.

BACKGROUND: During the early stages of systemic inflammation, the liver integrity is compromised by microcirculatory disturbances and subsequent hepatocellular injury. Little is known about the relationship between the hemoglobin oxygen saturation (HbsO2) in sinusoids and the hepatocellular mitochondrial redox state, in early systemic inflammation. In a murine model of early systemic inflammation, we have explored the association between the sinusoidal HbsO2 detected with a remission spectroscopy system and 1.) the NAD(P)H autofluorescence (an indicator of the intracellular mitochondrial redox state) and 2.) the markers of hepatocellular injury. RESULTS: Animals submitted to 1 hour bilateral hindlimb ischemia (I) and 3 hours of reperfusion (R) (3.0 h I/R) exhibited lower HbsO2 values when compared with sham. Six hours I/R (1 hour bilateral hindlimb ischemia and 6 hours of reperfusion) and the continuous infusion of endothelin-1 (ET-1) further aggravated the hypoxia in HbsO2. The detected NAD(P)H autofluorescence correlated with the detected HbsO2 values and showed the same developing. Three hours I/R resulted in elevated NAD(P)H autofluorescence compared with sham animals. Animals after 6.0 h I/R and continuous infusion of ET-1 revealed higher NAD(P)H autofluorescence compared with 3.0 h I/R animals. Overall the analysed HbsO2 values correlated with all markers of hepatocellular injury. CONCLUSION: During the early stages of systemic inflammation, there is a significant decrease in hepatic sinusoidal HbsO2. In parallel, we detected an increasing NAD(P)H autofluorescence representing an intracellular inadequate oxygen supply. Both changes are accompanied by increasing markers of liver cell injury. Therefore, remission spectroscopy in combination with NAD(P)H autofluorescence provides information on the oxygen distribution, the metabolic state and the mitochondrial redox potential, within the mouse liver.

Heme oxygenase modulates hepatic leukocyte sequestration via changes in sinusoidal tone in systemic inflammation in mice.

Heme oxygenase (HO) modulates the accumulation of leukocytes within the liver during the early stages of a systemic inflammatory response syndrome (SIRS), but the anti-inflammatory mechanism(s) remain to be tested. The influence of HO on the adhesion molecule expression within the liver and on circulating leukocytes was assessed. In addition, the effect of HO and nitric oxide synthase (NOS) on the liver microcirculation was tested. Mice were subjected to 1 h bilateral hindlimb ischemia followed by 3 h of reperfusion, at which time blood samples and the liver were harvested and adhesion molecule expression determined (ICAM-1, CD49d and CD11b). Direct measures of sinusoidal diameter and estimates of volumetric blood flow were obtained using intravital microscopy. HO was specifically induced and inhibited by hemin and chromium mesoporphyrin (CrMP), respectively, whereas NOS was inhibited by N-nitro-L-arginine methyl ester (L-NAME). ICAM-1 expression was increased following hindlimb ischemia-reperfusion. Hemin caused only a modest, but significant decrease in ICAM-1 expression, whereas inhibition of HO had no effect. However, HO inhibition significantly reduced sinusoidal diameters and volumetric flow and such vessels were correlated with significantly increased numbers of stationary leukocytes. Inhibition of NOS had no effect on sinusoidal diameter or volumetric flow. In conclusion, the anti-inflammatory benefits afforded by HO activity within the liver appear to involve the control of sinusoidal diameter and volumetric blood flow rather than altered adhesion molecule expression during the early stages of SIRS.

Intermittent flow increases endotoxin-induced adhesion of human erythrocytes to vascular endothelial cells.

OBJECTIVE: To investigate the effects of different conditions of flow on endotoxin induced adhesion of human red blood cells (RBC) to human umbilical vein endothelial cells (HUVEC). DESIGN AND SETTING: Prospective, randomized, controlled in vitro study in a university-affiliated cell biology laboratory. SUBJECTS. Human erythrocytes, human vascular endothelial cells. INTERVENTIONS: Superfusion of HUVEC monolayers with human erythrocytes incubated with either saline (CON) or endotoxin (ETX) with different flow pattern (basic flow rates of 0.65 or 1.3 ml/min; intermittent flow, IMF). The CON/0.6, CON/1.3, CON-IMF/1.3 ( n=7/group) groups served as control, and in test groups ETX/0.6, ETX/1.3, ETX-IMF/0.6, and ETX-IMF/1.3 ( n=7/group) both RBC and HUVECs were incubated with ETX and flow pattern and rates varied. In the IMF experiments flow rates of 0.65 and 1.3 ml/min were combined with stop-and-go flow pattern. MEASUREMENTS AND RESULTS: At continuous flow of 0.65 ml/min erythrocyte adhesion was 61+/-5 cells/mm(2) in CON and 172+/-25 cells/mm(2) after ETX. When flow rate was increased to 1.3 ml/min, adhesion decreased to 27+/-4 cells/mm(2) in CON and 93+/-18 cells/mm(2) after ETX. IMF conditions had no effect on RBC adhesion of naive RBC but increased the number of adhesive erythrocytes after incubation with ETX both at 0.65 ml/min (287+/-33 cells/mm(2)) and at 1.3 ml/min (148+/-13 cells/mm(2)). CONCLUSIONS: RBC adhesion to vascular endothelium is affected by rate and pattern of blood flow. Higher flow rates or shear forces reduce RBC adhesion while stop-and-go flow pattern favored adhesion of ETX-treated erythrocytes to HUVECs. These findings suggest that altered RBCs interact with altered flow patterns potentially contributing to the microcirculatory injury observed in sepsis.

Increasing P(50) does not improve DO(2CRIT) or systemic VO(2) in severe anemia.

Reducing the hemolobin (Hb)-O(2) binding affinity facilitates O(2) unloading from Hb, potentially increasing tissue mitochondrial O(2) availability. We hypothesized that a reduction of Hb-O(2) affinity would increase O(2) extraction when tissues are O(2) supply dependent, reducing the threshold of critical O(2) delivery (DO(2 CRIT)). We investigated the effects of increased O(2) tension at which Hb is 50% saturated (P(50)) on systemic O(2) uptake (VO(2) (SYS)), DO(2 CRIT), lactate production, and acid-base balance during isovolemic hemodilution in conscious rats. After infusion of RSR13, an allosteric modifier of Hb, P(50) increased from 36.6 +/- 0.3 to 48.3 +/- 0.6 but remained unchanged at 35.4 +/- 0.8 mmHg after saline (control, CON). Arterial O(2) saturations were equivalent between RSR13 and saline groups, but venous PO(2) was higher and venous O(2) saturation was lower after RSR13. Convective O(2) delivery progressively declined during hemodilution reaching the DO(2 CRIT) at 3.4 +/- 0.8 ml x min(-1) x 100 g(-1) (CON) and 3.6 +/- 0.6 ml x min(-1) x 100 g(-1) (RSR13). At Hb of 8.1 g/l VO(2) (SYS) started to decrease (CON: 1.9 +/- 0.1; RSR13: 1.8 +/- 0.2 ml x min(-1) x 100 g(-1)) and fell to 0.8 +/- 0.2 (CON) and 0.7 +/- 0.2 ml x min(-1). 100 g(-1) (RSR13). Arterial lactate was lower in RSR13-treated than in control animals when animals were O(2) supply dependent. The decrease in base excess, arterial pH, and bicarbonate during O(2) supply dependence was significantly less after RSR13 than after saline. These findings demonstrate that during O(2) supply dependence caused by severe anemia, reducing Hb-O(2) binding affinity does not affect VO(2) (SYS) or DO(2 CRIT) but appears to have beneficial effects on oxidative metabolism and acid base balance.

Inhibition of haem oxygenase activity increases leukocyte accumulation in the liver following limb ischaemia-reperfusion in mice.

The role of haem oxygenase (HO) in the hepatic accumulation of leukocytes in mice during the initiation of remote organ injury following normotensive limb ischaemia-reperfusion (I-R) was investigated. Remote organ injury was initiated by 1 h bilateral hindlimb ischaemia followed by either 1 or 1.5 h reperfusion (I-R) in male C57BL/6 mice. Mice were randomly assigned to either sham (no I-R, n = 4), I-R (n = 4 for both time points), I-R plus chromium mesoporphyrin (CrMP, n = 4) to inhibit HO or I-R plus haemin (n = 4) to increase HO. Leukocyte accumulation and leukocyte-endothelial interaction were directly measured using fluorescence intravital microscopy. Leukocytes were labelled via an injection of rhodamine 6G. In sinusoids the total number and the number of stationary leukocytes were assessed. In postsinusoidal venules the number of adherent and rolling leukocytes and the velocities of both red blood cells and leukocytes were measured. The total number of leukocytes increased in sinusoids of I-R mice reaching a plateau within 1 h compared with sham animals, while the number of stationary leukocytes progressively increased over the entire study period. Stationary leukocytes in sinusoids increased after 1 and 1.5 h of I-R following CrMP, while they were significantly reduced following haemin treatment compared to animals treated with I-R only. In postsinusoidal venules a progressive increase in adherent leukocytes also occurred. As observed in sinusoids, CrMP significantly increased, while haemin significantly reduced leukocyte adhesion. The number of rolling leukocytes increased after CrMP in both I-R groups (1 and 1.5 h). The velocities of rolling leukocytes declined following 1.5 h of I-R compared with sham. Haemin treatment of 1.5 h I-R animals restored the velocities back to sham levels. The calculated wall shear rates in postsinusoidal venules were significantly lower in all I-R groups in comparison to sham animals. Combination of 1.5 h I-R with CrMP resulted in the lowest shear rates of all I-R groups. The number of stationary leukocytes within sinusoids and adherent leukocytes in postsinusoidal venules were correlated to the corresponding alanine aminotransferase (ALT) levels. In conclusion, endogenous HO reduces leukocyte-endothelial interactions within the liver. Thus, endogenous HO activity provides an important mechanism controlling the hepatic inflammatory response during the initiation of remote organ injury following normotensive limb ischaemia-reperfusion.