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Anesth Analg 2003;97:555-563
© 2003 International Anesthesia Research Society

CRITICAL CARE AND TRAUMA

Apparent Heterogeneity of Regional Blood Flow and Metabolic Changes Within Splanchnic Tissues During Experimental Endotoxin Shock

Jyrki J. Tenhunen, MD PhD*, Ari Uusaro, MD PhD, MHSc (Epid)*, Vesa Kärjä, MD PhD{dagger}, Niku Oksala, MD{ddagger}, Stephan M. Jakob, MD PhD*, and Esko Ruokonen, MD PhD*

Departments of *Anesthesiology and Intensive Care, {dagger}Clinical Pathology, and {ddagger}Surgery, Kuopio University Hospital, Kuopio, Finland

Address correspondence and reprint requests to Jyrki Tenhunen, MD, PhD, Department of Critical Care Medicine, Room 1055, Scaife Hall, 3550 Terrace St., University of Pittsburgh School of Medicine, Pittsburgh, PA 15261. Address e-mail to tenhjj{at}anes.upmc.edu


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
We conducted a randomized, controlled experiment of prolonged lethal endotoxin shock in pigs aiming at 1) simultaneously measuring perfusion at different parts of the gut to study the potential heterogeneity of blood flow within the splanchnic region; 2) studying the association among regional blood flows, oxygen supply, and different metabolic markers of perfusion; and 3) analyzing the association between histological gut injury and markers of perfusion and metabolism. The primary response to endotoxin was a decrease in systemic and splanchnic blood flow followed by hyperdynamic systemic circulation. Redistribution of blood flows occurred within the splanchnic circulation: superior mesenteric artery blood flow was maintained, whereas celiac trunk blood flow was compromised. Mucosal to arterial PCO2 gradients did not reflect changes in total splanchnic perfusion, but they were associated with regional blood flows during the hypodynamic phase of shock. During hyperdynamic systemic circulation, PCO2 gradients increased heterogeneously in the gastrointestinal tract, whereas luminal lactate increased only in the colon. Histological analysis revealed mucosal epithelial injury only in the colon. We conclude that markers of perfusion and metabolism over one visceral region do not reflect perfusion and metabolism in other splanchnic vascular areas. Intestinal mucosal epithelial injury occurs in the colon during 12 h of endotoxin shock while the epithelial injury is still absent in the jejunum. Hyperdynamic and hypotensive shock induces gut luminal lactate release in the colon but not in the jejunum. The association or causality between the mucosal epithelial injury and luminal lactate release remains to be elucidated.

IMPLICATIONS:Surrogate regional markers of tissue perfusion over one region do not reflect the state of perfusion over another. Therefore, regional metabolic monitoring (microdialysis) in multiple locations is needed. Although tonometry does not differentiate between macro-level regional perfusion defect and tissue injury, intestinal luminal microdialysis detects mucosal lactate release, which may be associated with epithelial injury. The degree of correlation or causality between the two remains to be evaluated.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Splanchnic hypoperfusion in critical illness is associated with poor outcome (1). Despite hyperdynamic systemic circulation, gastric (2), small intestinal (3), and colonic (4) mucosal hypoperfusion develop in sepsis, according to some investigators (2–4), whereas others report preferentially sustained mucosal blood flow (5,6). Most studies on splanchnic circulation in sepsis focus on one location only, whereas a few have simultaneously assessed perfusion in different areas with a different arterial supply of the gastrointestinal (GI) tract (7,8). One study suggests that regional blood flow changes within the splanchnic region in sepsis are not uniform (8).

There does not seem to be a clear association between whole-body or local blood flow and markers of metabolism of the gut (9). Some studies suggest that gut mucosa turns acidotic in endotoxin shock despite maintained regional oxygen delivery (6), and an increasing body of evidence suggests that cells are unable to use oxygen in sepsis, even though the oxygen delivery is adequate (4,6,10). Furthermore, the associations among gut perfusion, different laboratory biochemical markers reflecting perfusion and oxygenation, and the actual gut injury are not well documented in sepsis.

The aims of our investigation were 1) to simultaneously measure perfusion in different areas of the gut to study the potential heterogeneity of blood flow within the splanchnic region during the progression of septic shock; 2) to study the association among regional blood flows, oxygen supply, and different metabolic markers of gut perfusion; and, finally, 3) to analyze the association between histological gut injury and markers of gut perfusion and metabolism.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
The institutional animal use and care committee of the University of Kuopio approved the study protocol. The same material was previously used to describe the effect of increasing dead space ventilation on the gastric mucosal to end-tidal partial pressure of carbon dioxide (PCO2) gradient as a surrogate for the gastric mucosal to arterial PCO2 gradient (11).

Fourteen Finnish female landrace pigs (range, 28–38 kg) were fasted for 48 h with free access to water. The animals were anesthetized and normoventilated as described previously (11). No paralyzing drugs were used. Normothermia, normovolemia, and normoglycemia were maintained.

Arterial and venous cannulations were performed as previously described (11). In addition, the descending aorta, celiac trunk, superior mesenteric artery, hepatic artery, and portal vein were prepared and visualized through a midline laparotomy. Transit-time flowprobes (Transonic Systems Inc., Ithaca, NY) were applied around the vessels. A gastric tonometer with microdialysis capillaries (Tonometrics, Datex Instrumentarium, Helsinki, Finland) was guided through the mouth into the stomach. Veins from the jejunum, gastric wall, and mid colon, as well as the portal and splenic veins, were cannulated. A hepatic venous catheter was guided manually to the hepatic vein. Finally, tonometers with microdialysis capillaries for jejunal and colonic PCO2 monitoring were inserted through antimesenteric incisions in the gut wall. The tip of the tonometer catheter was guided proximally from the enterotomy, which was then carefully sutured. The laparotomy was closed in two layers, and pleural drains were inserted through lateral incisions.

After stabilization, the animals were randomly allocated to two groups: endotoxin (n = 7), with Escherichia coli endotoxin infusion (lipopolysaccharide B O111:B4; Difco Laboratories, Detroit, MI); or control (n = 7). Infusion of E. coli endotoxin (20 µg/mL in 5% glucose; endotoxin group) was started at a rate of 1.0 µg · kg-1 · h-1. After 2–4 h, the infusion rate was increased (doubled) stepwise to induce systemic hypotension (mean arterial blood pressure, <60 mm Hg). Mean pulmonary arterial pressure was not allowed >40 mm Hg. We aimed at hyperdynamic hypotensive shock mimicking a clinical picture of septic shock with frequent mortality if untreated. At the end of the experiment, the animals were killed with IV magnesium sulfate while they were still anesthetized.

Tissue samples for routine histopathological assessment were taken from the colon and jejunum before the laparotomy was closed and at the end of the experiment. A pathologist (VK) who had no data of the experimental setting graded all sections for mucosal injury in a blinded fashion according to Chiu et al.’s classification (12) and further evaluated the samples with special emphasis on changes in mucosal epithelium, villi, and crypts.

Regional blood flows (descending aortic, celiac trunk, hepatic arterial, superior mesenteric arterial, and portal venous) were measured by transit-time probes (Transonic Systems Inc.). Of note is that gastric wall blood flow was estimated as hepatic arterial blood flow subtracted from trunk blood flow.

Gastric, jejunal, and colonic mucosal PCO2 values were measured with a semiautomatic gas analyzer (Tonocap®; Datex-Ohmeda, Helsinki, Finland) every 10 min. Arterial PCO2 was determined (ABL; Radiometer, Copenhagen, Denmark), and tonometric-arterial PCO2 gradients were calculated. Regional venoarterial CO2 content differences were calculated by an iterative procedure introduced by Giovannini et al.(13). Corresponding CO2 production was calculated by using the regional blood flow data. The microdialysis capillary, which was attached on the surface of the tonometer balloon, was designed and manufactured in our laboratory. It has been validated previously for lactate sampling both in vitro and in vivo (14).

We used the enzymatic lactate oxidase method with polarographic detection for L-lactate measurement (YSI 2300 Stat Plus; Yellow Springs Instruments Co. Inc., Yellow Springs, OH). We measured whole blood pyruvate enzymatically (Sigma UV-706 kit; Sigma Diagnostics, St. Louis, MO) with spectrophotometric detection (Shimadzu CL-750; Shimadzu Corp., Kyoto, Japan). Regional lactate and pyruvate exchange were calculated for each region. Plasma ketone bodies (KB), acetoacetate, and ß-hydroxybutyrate were determined enzymatically with ultraviolet detection at a 340-nm wavelength (Kone Pro; Kone Instruments, Espoo, Finland). Plasma endotoxin concentrations were determined by the limulus amebocyte lysate assay (Charles River Endosafe, Charleston, SC) with chromogenic quantitation (Coatest endotoxin; Chromogenix AB, Mölndal, Sweden). Arterial serum cytokine concentrations (interleukin [IL]-1ß and IL-6) were determined with porcine immunoassay for IL-1ß (Quantikine P; R&D Systems, Inc., Minneapolis, MN).

Hemoglobin concentration and hemoglobin oxygen saturation were measured within 5 min of sampling with an analyzer in pig mode (Hemoxymeter OSM3; Radiometer). Oxygen contents and transport variables were calculated according to standard formulas.

One control animal was excluded from data analysis because pneumothorax occurred during manipulation of pleural drainage. Results are given as median (interquartile range) because of small sample size. Accordingly, we chose to use nonparametric statistical tests. We estimated the differences between the groups (histology) at baseline with the Mann-Whitney U-test. Nonparametric analysis of variance for repeated measurements (Friedman) was used for within-group comparison from baseline to 4 h and from 4 h until 10 and 12 h because of a biphasic response to endotoxin. A P value <0.05 was chosen to indicate statistical significance. We used SPSS 9.0 for Windows (SPSS Inc., Chicago, IL).


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
The total amount of endotoxin required per animal varied from 7 to 660 µg/kg until 12 h or death. Two animals died in the endotoxin group because of cardiac failure after 6 and 10 h of endotoxin infusion. At baseline, endotoxin concentrations were 57 pg/mL (interquartile range, 49–68 pg/mL) and 67 pg/mL (interquartile range, 55–75 pg/mL) (P = 0.5) in the endotoxin and control groups, respectively. At the end of the experiment, the endotoxin concentration exceeded 400 pg/mL in each animal in the endotoxin group, whereas endotoxin concentration decreased to 18 pg/mL (range 16–41 pg/mL) (P = 0.018) in the control group. Arterial plasma IL-1ß increased from <10 pg/mL to 654 pg/mL (range, 403–1,010 pg/mL) (P = 0.018) and IL-6 increased from 74 pg/mL (range, 27–120 pg/mL) to 15,580 pg/mL (range, 6,822–24,232 pg/mL) (P = 0.018) in response to endotoxin infusion. The control animals remained stable: arterial plasma IL-1ß was <10 pg/mL both at baseline and at the end of the experiment, and IL-6 was 46 pg/mL (range, 37–113 pg/mL) before and 124 pg/mL (range, 72–246 pg/mL) after the experiment (P = 0.116). Normovolemia was maintained. Pulmonary arterial occlusion pressure increased from 5 mm Hg (range, 4–6 mm Hg) at baseline to 7 mm Hg (range, 7–7 mm Hg) (P = 0.012) at 4 h and thereafter remained constant at approximately 7 mm Hg (range, 7–8.5 mm Hg) (P = 0.62) after 12 h in the endotoxin group.

We observed a biphasic hemodynamic response to endotoxin infusion: primarily hypodynamic circulation, characterized by low stroke volume, developed into hyperdynamic, hypotensive systemic circulation after 12 h of endotoxin infusion (Fig. 1). Mean arterial blood pressure decreased from the basal 90 mm Hg (range, 89–91 mm Hg) to 64 mm Hg (range, 62–67 mm Hg) after 12 h of endotoxin infusion (P = 0.04). Systemic vascular resistance decreased from 2336 dynes · s-1 · cm-5 (range, 2231–2698 dynes · s-1 · cm-5) to 726 dynes · s-1 · cm-5 (range, 648–837 dynes · s-1 · cm-5) (P < 0.0001). Core temperature had a tendency to increase from 38.2°C (range, 37.9°C–38.4°C) to 38.4°C (range, 38.4°C–38.5°C) (P = 0.05). Blood glucose was 5.7 mM (range, 4.7–6.4 mM) at baseline, 7.0 mM (range, 6.6–7.9 mM) at 4 h, and 8.3 mM (range, 6.0–9.9 mM) (not significant) at 12 h in the endotoxin group. Control animals remained stable. Systemic oxygen delivery was maintained during the endotoxin challenge (Fig. 1). Systemic CO2 production increased. Arterial hyperlactatemia developed, with a concomitant increase in the lactate/pyruvate ratio. The arterial KB ratio decreased from 1.3 (range, 0.9–1.5) to 0.4 (range, 0.4–0.7) (4 h) and 0.6 (range, 0.4–0.9) (12 h) (P = 0.007, 0–4 h; P = 0.005, 4–12 h).



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  		Figure 1. Systemic hemodynamic and metabolic variables in endotoxin (black line) and control (gray line, n = 6) animals: (A) cardiac index (CI), (B) stroke volume, (C) systemic oxygen delivery (DO2), (D) systemic CO2 production (VCO2), (E) arterial lactate concentration, and (F) lactate/pyruvate ratio (L/P ratio). n = 6 after 8 h and n = 5 after 10 h in the endotoxin group. *P < 0.05 for within-group tests (Friedman) over 4 h from baseline; {dagger}P < 0.05 over the remaining 8 h (4–12 h).

 
Total splanchnic blood flow decreased during the hypodynamic systemic circulation and increased to baseline levels during the hyperdynamic phase of shock. The proportional splanchnic blood flow remained low throughout the endotoxin infusion. Portal venous blood flow increased over baseline during hyperdynamic shock, whereas hepatic arterial flow barely reached the baseline (Fig. 2). After the initial decrease, the oxygen delivery to the liver returned to baseline at the end of the experiment. Both prehepatic and total splanchnic CO2 content difference increased during the hypodynamic phase, but the actual CO2 production did not increase. Prehepatic lactate release decreased during the hypodynamic phase, whereas hepatic lactate uptake remained fairly constant (details in on-line data supplement). The hepatic venous KB ratio decreased from 0.7 (range, 0.4–1.1) to 0.4 (range, 0.3–0.4) (4 h) and to 0.3 (range, 0.2–0.6) (12 h) (P = 0.156, 0–4 h; P = 0.07, 4–12 h).



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  		Figure 2. Total splanchnic and hepatic hemodynamics and metabolism in endotoxin shock (black line) and control animals (gray line). (A) Total splanchnic blood flow (Qsplanchnic), (B) proportional splanchnic blood flow from aortic blood flow (Qsplanchnic/CO), (C) absolute portal blood flow (Qporta), (D) absolute hepatic arterial blood flow (Qhepa), (E) hepatic oxygen delivery (DO2liver), (F) splanchnic v-a CO2 content gradient (hepatic venous to arterial CO2 content gradient; splanchnic cCO2 gap), (G) prehepatic v-a CO2 content gradient (prehepatic cCO2 gap), (H) prehepatic CO2 production (prehepatic VCO2), and (I) prehepatic (portal venous) lactate to pyruvate ratio (prehepatic L/P ratio). n = 6 after 8 h and n = 5 after 10 h in the endotoxin group. *P < 0.05 for within-group tests (Friedman) over 4 h from baseline; {dagger}P < 0.05 over the remaining 8 h (4–12 h).

 
During the hypodynamic phase, celiac trunk blood flow decreased, but it increased toward the end of the experiment to baseline level. Proportional trunk blood flow decreased and remained low during endotoxin infusion (Fig. 3). Accordingly, oxygen delivery through the trunk decreased and remained low. The estimated oxygen delivery to the gastric wall (extrahepatic trunk blood flow) decreased similarly. The gastric mucosal to arterial PCO2 gradient increased both during hypodynamic and hyperdynamic shock. Gastric venous to arterial CO2 content gradient increased and remained high. The estimated gastric wall CO2 production had a tendency to increase only in hyperdynamic shock. The gastric venous lactate/pyruvate ratio increased slightly with concomitant uptake of both lactate and pyruvate into the gastric wall (Fig. 3). The gastric venous KB ratio was 0.4 (range, 0.4–0.5) at baseline and remained constant at 4 h (0.4; range, 0.3–0.4) and at 12 h (0.5; range, 0.4–1.1) (P = 0.016, 0–4 h; P = 0.11, 4–12 h).



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  		Figure 3. Celiac axis hemodynamics and metabolism in endotoxin (black line) and control animals (gray line). (A) Absolute celiac trunk blood flow (Qtrunk), (B) proportional trunk blood flow (Qtrunk/CO), (C) oxygen delivery via trunk (DtrunkO2), (D) gastric mucosal to arterial PCO2 gradient (gastric t-a PCO2 gap), (E) gastric venoarterial CO2 content gradient (gastric v-a cCO2 gap), (F) gastric CO2 production, (G) gastric venous lactate/pyruvate ratio (gastric L/P ratio), (H) gastric venoarterial lactate gradient (gastric v-a lactate gap), and (I) gastric lactate exchange. n = 6 after 8 h and n = 5 after 10 h in the endotoxin group. *P < 0.05 for within-group tests (Friedman) over 4 h from baseline; {dagger}P < 0.05 over the remaining 8 h (4–12 h).

 
During hypodynamic shock, superior mesenteric artery flow was maintained, whereas during hyperdynamic shock, superior mesenteric artery blood flow exceeded the baseline level (Fig. 4). Proportional superior mesenteric artery blood flow was 18% (range, 16%–18%) and 14% (range, 11%–17%) at baseline in the endotoxin and control groups, respectively, and remained constant both in the endotoxin group after 4 h (16%; range, 14%–18%) and 12 h (15%; range, 11%–19%) (P = 0.25) and in the control group after 4 h (15%; range, 11%–16%) and 12 h (14%; range, 12%–17%) (P = 0.66). Concomitantly, oxygen delivery through the superior mesenteric artery remained constant in both groups. The jejunal mucosal to arterial PCO2 gradient increased slightly and remained increased. The jejunal venoarterial CO2 content gradient and jejunal CO2 production remained constant. The mesenteric venous lactate/pyruvate ratio increased with concomitant jejunal lactate and uptake during hypodynamic shock (Fig. 4). The mesenteric venous (draining jejunum) KB ratio was 0.7 (range, 0.6–1.1) at baseline and decreased to 0.4 (range, 0.4–0.6) at 4 h and to 0.5 (range, 0.4–0.6) at 12 h (P = 0.005, 0–4 h; P = 1, 4–12 h). The colonic mucosal to arterial PCO2 gradient increased during the hypodynamic phase and returned to the baseline level later during the experiment. The colonic venoarterial CO2 content gradient increased during hypodynamic shock but returned to baseline toward the end of the experiment. Colonic CO2 production remained constant. In the endotoxin group, the colonic venous lactate/pyruvate ratio increased from 14 (range, 12–15) at baseline to 17 (range, 16–19) (P = 0.023) during the hypodynamic phase and remained increased (21; range, 19–24; P = 0.05) after 14 h. Concomitantly, the colonic venous to arterial pyruvate gradient turned negative, from a basal level of 10 µmol/L (range, -1 to 19 µmol/L) to -30 µmol/L (range, -42 to -14 µmol/L) after 4 h and -26 µmol/L (range, -69 to -14 µmol/L) after 14 h (P = 0.017). The colonic venous KB ratio decreased from 1.4 (range, 0.6–2.2) to 0.6 (range, 0.5–0.8) (4 h) and 0.5 (range, 0.5–0.8) (12 h) (P = 0.084, 0–4 h; P = 0.23, 4–12 h).



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  		Figure 4. Superior mesenteric artery axis hemodynamics and metabolism in endotoxin (black line) and control animals (gray line). (A) Absolute superior mesenteric artery blood flow (Qsma), (B) jejunal mucosal to arterial PCO2 gradient (t-a PCO2 gap), (C) jejunal venoarterial CO2 content gradient (jejunal v-a cCO2 gap), (D) jejunal CO2 production (VCO2), (E) mesenteric (jejunal) venous lactate/pyruvate (L/P) ratios, (F) jejunal lactate exchange, (G) colonic mucosal to arterial PCO2 gradient (t-a PCO2 gap), (H) colonic venoarterial CO2 content gradient (v-a cCO2 gap), and (I) colonic CO2 production (VCO2). n = 6 after 8 h and n = 5 after 10 h in the endotoxin group. *P < 0.05 for within-group tests (Friedman) over 4 h from baseline; {dagger}P < 0.05 over the remaining 8 h (4–12 h).

 
The intestinal luminal microdialysate lactate concentration increased at the end of the experiment in the colon in the endotoxin group from undetectable to 0.4 mmol/L (range, 0.2–0.5 mmol/L) (P = 0.001), whereas no colonic luminal lactate release occurred in time controls. Luminal lactate in the jejunum (baseline, 0 mM [range, 0–0.07 mM] versus 0.09 mM [range, 0.06–0.1 mM] after 12 h; P = 0.2) and stomach (baseline, 0 mM [range, 0–0 mM] versus 0 mM [range, 0–0.2 mM] after 12 h; P = 0.1) remained unchanged as compared with small baseline concentrations.

Histological grading according to Chiu et al. (12) revealed no subepithelial Gruenhagen’s space or epithelial lifting in either the jejunum or colon. The numbers of plasma cells and lymphocytes in the submucosa were in normal limits in each case, although eosinophilic granulocytes were overexpressed in the jejunum. Further analysis focusing on mucosal epithelial cellular integrity revealed cryptal epithelial injury in the colon, whereas the jejunal mucosal epithelium remained intact (Table 1).


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  		Table 1. Histological Analysis of Colon and Jejunum in Endotoxin Shock (ETX) (n = 5) and Control Animals
 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
There were three main findings in the present study. 1) Regarding regional blood flows, redistribution of blood flows within splanchnic circulation occurred in endotoxin shock. Superior mesenteric artery blood flow (and mesenteric oxygen delivery) was maintained, but celiac trunk blood flow (and celiac oxygen delivery) was compromised. 2) Regarding blood flow versus metabolic markers, local hypoperfusion in hypodynamic shock was associated with an increased local mucosal to arterial PCO2 gradient. In hyperdynamic shock, regional blood flows were either increased or close to baseline levels. There was a discrepancy between mucosal PCO2 and luminal lactate release. Regional visceral lactate production did not occur in the 12-hour experiment. Regional venous lactate to pyruvate ratios increased in endotoxin shock, and this was due to increased intestinal uptake of pyruvate with concomitant hepatic pyruvate release. Regional venous KB ratios were not associated with regional blood flow changes, indicating that there was no major whole gut wall dysoxia. 3) Regarding histological injury and metabolic markers, gut mucosal epithelial injury developed in the mid colon after 12 hours of endotoxin shock, whereas there was no epithelial injury in the jejunum. Concomitantly, we observed gut luminal lactate release in the colon while there was no luminal lactate release in the jejunum, suggesting a further hypothesis that gut luminal lactate release could be associated with intestinal mucosal epithelial injury.

Splanchnic hypoperfusion is presumably one of the triggers of multiple organ dysfunction (15). The adequacy of splanchnic perfusion has been studied experimentally and clinically, mainly by tonometry, laser Doppler, or regional blood flow measurements, usually from only one location at a time. Interpretation of the PCO2 gap is complex. Increasing the total splanchnic blood flow with inotropic drugs does not decrease the gastric mucosal arterial PCO2 gradient and may even do the opposite (9). Mechanisms underlying this discrepancy may be multifactorial, including not only the conceptual problem of the relation between the partial tension of CO2 and the CO2 content (the Haldane effect) (16), but also the anatomical and physiological premises: different visceral tissues are supplied by different arteries. In our study, endotoxin induced a biphasic response in total splanchnic blood flow, with a primary decrease in blood flow followed by an increase over the baseline values. Concomitantly, superior mesenteric arterial blood flow was preserved and later exceeded the baseline, whereas celiac blood flow decreased. Parallel changes in regional oxygen delivery were observed. We found that during hypodynamic shock, an increase in the gastric mucosal arterial PCO2 gradient was associated with decreased celiac trunk blood flow. Increases in jejunal and colonic mucosal arterial PCO2 gradients were associated with short-term decreases in mesenteric perfusion. Also, one has to bear in mind that in this experiment, gross regional blood flows, rather than microcirculatory blood flows, were measured, and, thereby, blood flow and PCO2 gradient changes are not necessarily expected to be associated. However, none of the three PCO2 gradients could be taken per se as a marker for total splanchnic perfusion during hyperdynamic shock. This is in accordance with another study (17). We also found that high mucosal-systemic PCO2 gradients did not correlate with other local markers of ischemia/dysoxia or cellular injury.

Other investigators have evaluated the small-intestinal (18), intraperitoneal (4), sigmoid (4), and bladder (19) mucosal arterial PCO2 gradients as indicators of total splanchnic or systemic perfusion. Estimation of adequacy of perfusion in the colon by PCO2 gradients is ambiguous, with the possibility of CO2 supersaturation due to bacterial CO2 production (20). In any part of the gastrointestinal (GI) tract, intraluminal blood interferes with mucosal CO2 measurement (21). Gastric mucosal PCO2 measurement has several pitfalls, including mucosal acid generation and the Haldane effect (16). In this experiment, we saw strikingly different patterns of PCO2 gradients and luminal lactate in different parts of the GI tract: high mucosal PCO2 in the stomach with no luminal lactate release and only a moderately increased PCO2 gradient in the colon with concomitant luminal lactate release. Schlichtig and Bowles (22) suggested that distinguishing aerobic and anaerobic CO2 production is possible by dissociation of mucosal PCO2 from regional PCO2. This seems appealing but can be regarded as applicable only in laboratory conditions. In a more recent in vitro study (23), it was suggested that one of the fundamental acid-base changes in intestinal dysoxia is CO2 retention accompanied by lactate accumulation. In our in vivo experiment, colonic CO2 production tended to increase in parallel with luminal lactate concentration. Consequently, detection of intestinal luminal lactate may be a feasible method of detecting intestinal mucosal epithelial dysoxia, not only in low-flow states (14,24), but also in endotoxin/septic shock.

There was an apparent discrepancy between the regional lactate kinetics and intestinal luminal lactate concentrations. Decreased regional lactate release (colon) or even lactate uptake (stomach and jejunum) occurred during hypodynamic shock, whereas in the hyperdynamic state there was a tendency toward increased lactate release from the gastric wall. At the same time, luminal lactate release occurred only in the colon. We suggest that regional lactate kinetics (and regional venous samples in general) represent the whole intestinal wall, whereas luminal microdialysis monitors mucosal epithelial metabolism. This is supported by our histological findings. We detected gut luminal lactate release only in the colon in the end of the experiment in four of five surviving animals. This implies that mucosal epithelial dysoxia appears in the colon before it appears in the jejunum or stomach. Interestingly, blinded histological analysis revealed no injury in either jejunal or colonic subepithelial mucosa according to Chiu et al.’s classification (12), whereas epithelial injury was present in the colon but not in the jejunum. Thus, cellular injury occurred specifically in the epithelium of colonic mucosa. No causality or timely correlation can be deduced from this study, and thereby this association should be taken as further hypothesis to be tested in future experiments. Small or even decreasing KB ratios (25) over each part of the GI tract give further support to our conclusion that there was no marked dysoxia in the intestinal wall as a whole.

We used a model of normovolemic, hyperdynamic, hypotensive, prolonged endotoxin shock in anesthetized pigs. Twelve hours of endotoxin infusion produced systemic circulation with high cardiac output and low blood pressure and systemic vascular resistance, all of which are characteristic of septic shock. Furthermore, concentrations of biochemical markers of inflammation increased in animals receiving endotoxin, but not in the control animals. In addition, because we aimed at a lethal model of endotoxin challenge, shock was severe by definition; two animals died because no vasoactive drugs were given. However, there are also obvious limitations in our study. First, there may be species differences. Therefore, extrapolating of data to humans has to be performed cautiously. Second, the endotoxin used in this model represents only one specific stimulus for inflammatory response. Third, we did not take tissue samples from the gastric wall for histological analysis. This was considered to be a risk for the validity of the gastric tonometer measurements (21). Jejunal and colonic catheters were guided proximally from the enterotomy, thus preventing blood contamination, and the enterotomy could be sutured easily. Also, our experimental setting did not allow sequential tissue sampling over time to better investigate sequential changes in histology and markers of gut perfusion/metabolism. Furthermore, we want to emphasize that this model represents untreated endotoxin shock. Thereby, comparison to the clinical setting needs to be limited to septic shock before vasoactive treatment. Finally, prolonging the experiment further could have induced tissue injury or pathologic changes in other parts of GI tract in addition to the colon.

We conclude that redistribution of regional blood flow occurs within the visceral circulation in endotoxin shock. Therefore, markers of perfusion over one visceral region do not reflect perfusion over other splanchnic areas. Intestinal mucosal epithelial injury occurs in the colon during 12 hours of endotoxin shock while the epithelial injury is still absent in the jejunum. Hyperdynamic and hypotensive shock induces gut luminal lactate release in the colon, but not in the jejunum, thereby suggesting the hypothesis that gut luminal lactate release may be associated with mucosal epithelial injury. The causal relation between the two remains to be investigated.


   Acknowledgments
 
Supported in part by a grant from Kuopio University Hospital and a grant from the Finnish Medical Society.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication April 1, 2003.




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