Fragestellung: Ziel der Untersuchung war es, die Folgen des frühen SIRS (Systemic Inflammatory Response Syndrom) auf die sinusoidale HbsO2 (Hämoglobin-O2-Sättigung) sowie auf die mitochondriale O2-Verwertung in den Hepatozyten der Maus zu quantifizieren. Im Rahmen der Intravitalen Fluoreszenzvideomikroskopie wurde die hepatische Mikrozirkulation untersucht, die Veränderung der sinusoidalen HbsO2 gemessen und die NADH-Autofluoreszenz als Maß für den mitochondrialen Redoxstatus erfasst.

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.

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 (HbsO 2 ) 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 HbsO 2 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 HbsO 2 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 HbsO 2 . The detected NAD(P)H autofluorescence correlated with the detected HbsO 2 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 HbsO 2 values correlated with all markers of hepatocellular injury. Conclusion During the early stages of systemic inflammation, there is a significant decrease in hepatic sinusoidal HbsO 2 . 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.

More than 50% of all patients on intensive care units acquire a systemic inflammation such as systemic inflammatory response syndrome (SIRS) or sepsis. The development of hepatic microcirculatory failure with consecutive organ damage might occur during the course of the systemic inflammation. The liver microcirculation is regulated by a complex network of cellular components and specific mediators. The perfusion in liver sinusoids is regulated by the tonus of the contractile Ito cells. Nitric oxide (NO) and carbon monoxide (CO) influence each other and cause the Ito cells to dilate while endothelin results in a contraction of the Ito cells. On-going studies are investigating the role of angiotensin II, catecholamines and prostaglandins for the regulation of the hepatic microcirculatory system during systemic inflammation. Some investigations aim to determine the impact of sedatives and analgesics on the hepatic microcirculation in sepsis and SIRS. Therefore, a decisive recommendation about the choice and dosage of sedatives and analgesics for these patients is not possible. Nevertheless, ketamine, midazolam and fentanyl with their potential anti-inflammatory properties seem to be suitable for patients with systemic inflammation.

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.

OBJECTIVE:Prospective examination whether changes in interleukin (IL)-6, IL-10 or procalcitonin (PCT) concentrations correlate with poor outcome in patients with severe sepsis in comparison with APACHE III or SAPS II.METHODS:33 patients who fulfilled the criteria for severe sepsis have been included in the study. Blood samples were collected for cytokine and PCT determinations. The Acute Physiology, Age and Chronic Health Evaluation (APACHE) III score and the Simplified Acute Physiology Score (SAPS) II were calculated for 3 consecutive days.RESULTS:14 out of 33 patients died of multiple organ failure. The areas under the ROC-curves for APACHE III and SAPS II indicated a poor discrimination between survivors and non-survivors. Plasma PCT and IL-10 concentrations were higher in non-survivors than in survivors. IL-6 levels showed no differences between groups. The multivariate analysis of the APACHE III, SAPS II, IL-10 and PCT data showed a significant relationship between APACHE III, PCT plasma levels and outcome.CONCLUSIONS:The data suggest that non-surviving patients have higher PCT and IL-10 values. Only APACHE III score and PCT plasma levels correlated with a poor outcome. Therefore, routine measurements of plasma PCT concentrations might be helpful to improve the mortality risk prediction in patients with severe sepsis.

Mehr als die Hälfte aller Intensivpatienten entwickelt eine systemische Entzündungsreaktion. Im Verlauf dieser systemischen Inflammation kann es zu einer Störung der hepatischen Mikrozirkulation und einer konsekutiven Schädigung der Leber kommen. Die Lebermikrozirkulation im Rahmen systemischer Entzündungsreaktionen wird durch ein komplexes Zusammenspiel zwischen zellulären Komponenten und spezifischen Mediatoren reguliert. Die Durchblutung der Lebersinusoide wird durch den Tonus der sog. Ito-Zellen beeinflusst. Stickstoffmonoxid (NO) sowie Kohlenmonoxid (CO) beeinflussen sich gegenseitig und führen zu einer Vasodilatation, während Endothelin zu einer Vasokonstriktion der Ito-Zellen führt. Welche Rolle Angiotensin II, Katecholamine und Prostaglandine in der Regulation der hepatischen Mikrozirkulation im „systemic inflammatory response syndrome“ (SIRS) und in der Sepsis spielen, ist Gegenstand aktueller Forschung. Die limitierte Anzahl von Studien über den Einfluss von Sedativa und Analgetika auf die Lebermikrozirkulation bei Patienten mit systemischen Entzündungsreaktionen erlaubt keine abschließende Auswahl oder Dosierungsempfehlung. Ketamin, Midazolam und Fentanyl sind aufgrund ihrer potenziell antiinflammatorischen Eigenschaften für die Analgosedierung von Patienten mit einem SIRS oder einer Sepsis gut geeignet.

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).

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.

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.

Reductions in red blood cell membrane deformability (RBC(D)) may perturb microcirculatory blood flow and impair tissue O(2)-availability. We investigated the effect of assay temperature on the distribution of RBC(D) in endotoxin (LPS) incubated and control RBCs. Fresh blood from healthy rats was incubated with and without the presence of LPS for 6 hrs. An index of red blood cell membrane deformability, delta, was measured via the micropipette aspiration technique at 25 degrees C and 37 degrees C at 0, 2 and 6 hrs of incubation. The ATP content of RBC was measured by the luciferin-luciferase technique. At 25 degrees C, LPS caused a significant decrease in mean delta after 2 and 6 hours incubation compared to controls (-10.0%, p=0.03 and -24.0%, p=0.03, respectively) characterized by a left shift in the distribution (skewness: -1.4). However, at 37 degrees C a significant decrease in delta was only detected after 6 hrs of LPS incubation (-13.8%, p=0.01, compared to -5.1%, p=0.7 at 2 hours) and lacked the left shifted distribution (skewness: 0.2). No significant difference in ATP content of RBCs was observed between groups. We have shown that LPS incubation results in a significant decrease in RBC(D) and that room temperature measurement of physical membrane properties may exaggerate the differences between normal and perturbed RBCs.

Objective To investigate the effects of endotoxin on adhesion of human red blood cells to human vascular endothelial cells under conditions of flow. Design Prospective, randomized, controlled in vitro study. Settings University-affiliated cell biology laboratory. Subjects Human erythrocytes and human vascular endothelial cells. Interventions Fresh human erythrocytes and human vascular endothelial cells grown as monolayers were incubated with either saline or endotoxin. After incubation, endothelial monolayers were superfused with erythrocytes, and the number of erythrocytes adhering to the endothelial monolayer was quantified. Measurements and Main Results Adhesion of erythrocytes to vascular endothelium was measured under conditions of continuous flow in different settings: a) exposure of both endothelial cells and erythrocytes to saline; b) incubation of both erythrocytes and endothelial cells with endotoxin; c) exposure of erythrocytes only to endotoxin; d) incubation of endothelial cells only to endotoxin; and e) both the endothelial cells and erythrocytes incubated with different concentrations of endotoxin. Erythrocyte adhesion in the saline control group was 71 ± 8 cells/mm2. Incubation of both components with endotoxin increased the number of adhesive erythrocytes to 172 ± 9 cells/mm2 (p < .05). When only the endothelial cells were treated with endotoxin, 142 ± 8 cells/mm2 adhered to the endothelial monolayer, whereas the incubation of the erythrocytes only to endotoxin resulted in adhesion of 102 ± 3 cells/mm2. Decreasing concentrations of endotoxin reduced adhesion from 172 ± 9 cells/mm2 (endotoxin, 75 &mgr;g/mL) to 165 ± 9 cells/mm2 (endotoxin, 25 &mgr;g/mL), 153 ± 4 cells/mm2 (endotoxin, 1 &mgr;g/mL), and 146 ± 6.1 cells/mm2 (endotoxin, 5 ng/mL). Conclusions Exposure of human erythrocytes and human venous vascular endothelial cells to an inflammatory stimulus such as endotoxin promotes a dose-dependent adhesion of erythrocytes to endothelium in a dynamic environment. These adhesive erythrocyte-endothelium interactions can be produced by exposure of either red blood cells or endothelial cells to endotoxin, with a higher degree of adhesion after activation of the endothelial cell component.

We hypothesized that support of arterial perfusion pressure with diaspirin cross-linked Hb (DCLHb) would prevent the sepsis-induced attenuation in the systemic O(2) delivery-O(2) uptake relationship. Awake septic rats were treated with a chronic infusion of DCLHb or a reference treatment [norepinephrine (NE)] to increase mean arterial pressure by 10-20% over 18 h. Septic and sham control groups received normal saline. Isovolemic hemodilution to create anemic hypoxia was then performed in a metabolic box during continuous measurement of systemic O(2) uptake. O(2) delivery was calculated from hemodynamic variables, and the critical point of O(2) delivery (DO(2 crit)) was determined using piecewise regression analysis of the O(2) delivery-O(2) uptake relationship. Sepsis increased DO(2 crit) from 4.99 +/- 0.17 to 6.69 +/- 0.42 ml x min(-1) x 100 g(-1) (P < 0.01), while O(2) extraction capacity was decreased (P < 0.05). DCLHb and NE infusion prevented the sepsis-induced increase in DO(2 crit) [4.56 +/- 0.42 ml x min(-1) x 100 g(-1) (P < 0.01) and 5.04 +/- 0.56 ml x min(-1) x 100 g(-1) (P < 0.05), respectively]. This was explained by a 59% increase in O(2) extraction capacity in the DCLHb group compared with septic controls (P < 0.05), whereas NE treatment decreased systemic O(2) uptake in anemic hypoxia (1.51 +/- 0.08 vs. 1.87 +/- 0.1 ml x min(-1) x 100 g(-1) in septic controls, P < 0.05). We conclude that DCLHb ameliorated O(2) extraction capacity in the septic microcirculation, whereas NE decreased the metabolic demands of the tissues.

Objective: To determine the effect of a bolus infusion of diaspirin cross‐linked hemoglobin (DCLHb or hemoglobin crosfumaril) on the ileal mucosal microcirculation in septic rats. Design: Prospective, randomized, single‐blinded study. Setting: University‐affiliated animal research laboratory. Subjects: Twenty‐four male Sprague‐Dawley rats, weighing 320‐380 g. Interventions: Under inhalational anesthesia, arterial and venous catheters were inserted and sepsis was created by cecal ligation and perforation (CLP). Twenty‐four hours later, animals were reanesthetized and ventilated. Via midline abdominal incision, the ileum was mobilized and prepared for intravital microscopy. Post‐CLP hemodynamic values were obtained, and videomicroscopy was performed on four to ten villi. Animals were then randomized to receive 2 mL of DCLHb solution (100 mg/mL; n = 12) or pentastarch (n = 12) intravenously, and measurements were repeated after 20 mins. Rats treated with DCLHb then received nitroprusside to restore mean arterial pressure to post‐CLP levels, and final measurements were obtained 15 mins later. Measurements and Main Results: Cardiac index increased with both treatments (p < .001), whereas systemic vascular resistance index and mean arterial blood pressure were augmented only with DCLHb (p < .0001 compared with pentastarch). Intercapillary areas (ICA; inversely related to capillary density) were determined using computerized image analysis. ICA size decreased after treatment, from 974 ± 79 to 791 ± 106 μm2 with DCLHb and from 1044 ± 90 to 840 ± 82 μm2 with pentastarch (both p < .05). Red blood cell velocity in terminal arterioles, as assessed by velocimetry from the recorded images, increased by 15% with both treatments (p < .05). Restoration of mean arterial pressure to post‐CLP levels in DCLHb animals by nitroprusside infusion abolished the effects of the hemoglobin solution on ICA size and red blood cell velocity. Conclusion: Both DCLHb and pentastarch infusion improved microcirculatory perfusion in the ileum of septic rats. In addition, DCLHb also exhibited vasopressor properties, which in combination with improved perfusion may be particularly useful in the treatment of sepsis.

Crit Care 1999, 3 3 ( (s su up pp pl l 1 1) ):P1 I In nt tr ro od du uc ct ti io on n: : Critically ill patients requiring intensive care are at risk of iatrogenic ocular damage.Studies have reported an incidence of eye problems of up to 40% in critically ill ventilated patients.We conducted this study to assess the incidence of ocular complications in our intensive care unit where all patients are cared for according to an eye care standard.M Me et th ho od ds s: : All ventilated patients over a 2 month period were included.Ophthalmic assessment was performed on admission and repeated every other day during the period of ventilation.At each assessment the average Ramsey sedation score over the previous 24 h, the presence of tracheal secretions and the presence of ventilation associated pneumonia was noted.Eye care performed was recorded.R Re es su ul lt ts s: : Sixty patients were included.One patient developed corneal exposure keratopathy.No patient developed conjunctivitis or corneal ulceration.Further advice on appropriate measures of eye care was given in five cases (8%).Nine patients (15%) had large amounts of respiratory secretions with positive microbiological results.C Co on nc cl lu us si io on n: : This study confirms that the use of an eye care standard is associated with a low incidence of ocular surface complications.The incidence of ocular complications in this group of patients is far lower than previously described.

Reduced Hb-O affinity facilitates O release to tissue but may impair pulmonary O uptake, affecting cardiac output and systemic vascular resistance (SVR). We studied the effects of shifting the O-dissociation curve (ODC) to the right with a continuous infusion of RSR13, an allosteric modifier of Hb, and of different inspired Ofractions ([Formula: see text]) on arterial O saturations ([Formula: see text]) in Hb and on hemodynamics in nonanesthetized rats. At an[Formula: see text] of 0.21,[Formula: see text] fell during RSR13 from 95 to 81%. Elevation of [Formula: see text] to 0.30 returned [Formula: see text] to baseline in the RSR13 group. The decrease in mean arterial pressure (MAP) was significantly greater in the control than in the RSR13 group at 30% O. Cardiac index (CI) increased only during RSR13 at 21% O and returned to baseline at 30% O. In contrast, SVR decreased after RSR13 was infused at 21% O but returned to baseline at 30%O, whereas controls showed the opposite, a sustained SVR. In the follow-up period, when 21 O% was reestablished and mild anemia was present, MAP and SVR fell significantly more in controls, whereas CI only increased in controls. Lactate was significantly lower in the RSR13 than in the control group during RSR13 and the follow-up period. These results demonstrate that 1) continuous infusion of RSR13 produces a constant shift in the O tension at which Hb is 50% saturated (P), 2)[Formula: see text] of 0.30 compensates for the effects of increased P on pulmonary O loading, and 3) right-shifted ODC combined with supplemental O may improve tissue O availability.

Reduced Hb-O2 affinity facilitates O2 release to tissue but may impair pulmonary O2 uptake, affecting cardiac output and systemic vascular resistance (SVR). We studied the effects of shifting the O2-dissociation curve (ODC) to the right with a continuous infusion of RSR13, an allosteric modifier of Hb, and of different inspired O2fractions ([Formula: see text]) on arterial O2 saturations ([Formula: see text]) in Hb and on hemodynamics in nonanesthetized rats. At an[Formula: see text] of 0.21,[Formula: see text] fell during RSR13 from 95 to 81%. Elevation of [Formula: see text] to 0.30 returned [Formula: see text] to baseline in the RSR13 group. The decrease in mean arterial pressure (MAP) was significantly greater in the control than in the RSR13 group at 30% O2. Cardiac index (CI) increased only during RSR13 at 21% O2 and returned to baseline at 30% O2. In contrast, SVR decreased after RSR13 was infused at 21% O2 but returned to baseline at 30%O2, whereas controls showed the opposite, a sustained SVR. In the follow-up period, when 21 O2% was reestablished and mild anemia was present, MAP and SVR fell significantly more in controls, whereas CI only increased in controls. Lactate was significantly lower in the RSR13 than in the control group during RSR13 and the follow-up period. These results demonstrate that 1) continuous infusion of RSR13 produces a constant shift in the O2 tension at which Hb is 50% saturated (P50), 2)[Formula: see text] of 0.30 compensates for the effects of increased P50 on pulmonary O2 loading, and 3) right-shifted ODC combined with supplemental O2 may improve tissue O2 availability.