Subcutaneous perfusion before and during surgery in obese and nonobese patients.

Hypoxia at the surgical site impairs wound healing and oxidative killing of microbes. Surgical site infections are more common in obese patients. We hypothesized that subcutaneous oxygen tension (Psq O2) would decrease substantially in both obese and non-obese patients following induction of anesthesia and after surgical incision. We performed a prospective observational study that enrolled obese and non-obese surgical patients and measured serial Psq O2 before and during surgery. Seven morbidly obese and seven non-obese patients were enrolled. At baseline breathing room air, Psq O2 values were not significantly different (p = 0.66) between obese (6.8 kPa) and non-obese (6.5 kPa) patients. The targeted arterial oxygen tension (40 kPa) was successfully achieved in both groups with an expected significant increase in Psq O2 (obese 16.1 kPa and non-obese 13.4 kPa; p = 0.001). After induction of anesthesia and endotracheal intubation, Psq O2 did not change significantly in either cohort in comparison to levels right before induction (obese 15.5, non-obese 13.5 kPa; p = 0.95), but decreased significantly during surgery (obese 10.1, non-obese 9.3 kPa; p = 0.01). In both morbidly obese and non-obese patients, Psq O2 does not decrease appreciably following induction of anesthesia, but decreases markedly (∼33%) after commencement of surgery. Given the theoretical risks associated with low Psq O2 , future research should investigate how Psq O2 can be maintained after surgical incision.

Hypotension during fluid-restricted abdominal surgery: effects of norepinephrine treatment on regional and microcirculatory blood flow in the intestinal tract.

BACKGROUND: Vasopressors, such as norepinephrine, are frequently used to treat perioperative hypotension. Increasing perfusion pressure with norepinephrine may increase blood flow in regions at risk. However, the resulting vasoconstriction could deteriorate microcirculatory blood flow in the intestinal tract and kidneys. This animal study was designed to investigate the effects of treating perioperative hypotension with norepinephrine during laparotomy with low fluid volume replacement. METHODS: Twenty anesthetized and ventilated pigs were randomly assigned to a control or treatment (norepinephrine) group. Both groups received 3 ml · kg⁻¹ · h⁻¹ Ringer's lactate solution. In addition, the norepinephrine group received norepinephrine to stepwise increase blood pressure to 65 and 75 mmHg. Regional blood flow was measured in the splanchnic arteries. In the small bowel and colon, microcirculatory blood flow was measured using laser Doppler flowmetry. Intestinal tissue oxygen tension was measured with intramural Clark-type electrodes. RESULTS: Hepatosplanchnic and kidney blood flow remained unchanged after reversal of arterial hypotension to a mean arterial pressure of 75 mmHg with norepinephrine. For the norepinephrine group versus the control group, the mean ± SD microcirculatory blood flow in the jejunum (96 ± 41% vs. 93 ± 18%) and colon (98 ± 19% vs. 97 ± 28%) and intestinal tissue oxygen tension (jejunum, 45 ± 13 vs. 43 ± 5 mmHg; colon, 50 ± 10 vs. 45 ± 8 mmHg) were comparable. CONCLUSIONS: In this model of abdominal surgery in which clinical conditions were imitated as close as possible, treatment of perioperative hypotension with norepinephrine had no adverse effects on microcirculatory blood flow or tissue oxygen tension in the intestinal tract.

Hemodynamic parameters change earlier than tissue oxygen tension in hemorrhage.

BACKGROUND: Untreated hypovolemia results in impaired outcome. This study tests our hypothesis whether general hemodynamic parameters detect acute blood loss earlier than monitoring parameters of regional tissue beds. MATERIALS AND METHODS: Eight pigs (23-25 kg) were anesthetized and mechanically ventilated. A pulmonary artery catheter and an arterial catheter were inserted. Tissue oxygen tension was measured with Clark-type electrodes in the jejunal and colonic wall, in the liver, and subcutaneously. Jejunal microcirculation was assessed by laser Doppler flowmetry (LDF). Intravascular volume was optimized using difference in pulse pressure (dPP) to keep dPP below 13%. Sixty minutes after preparation, baseline measurements were taken. At first, 5% of total blood volume was withdrawn, followed by another 5% increment, and then in 10% increments until death. RESULTS: After withdrawal of 5% of estimated blood volume, dPP increased from 6.1% +/- 3.0% to 20.8% +/- 2.7% (P < 0.01). Mean arterial pressure (MAP), mean pulmonary artery pressure (PAP) and pulmonary artery occlusion pressure (PAOP) decreased with a blood loss of 10% (P < 0.01). Cardiac output (CO) changed after a blood loss of 20% (P < 0.05). Tissue oxygen tension in central organs, and blood flow in the jejunal muscularis decreased (P < 0.05) after a blood loss of 20%. Tissue oxygen tension in the skin, and jejunal mucosa blood flow decreased (P < 0.05) after a blood loss of 40% and 50%, respectively. CONCLUSIONS: In this hemorrhagic pig model systemic hemodynamic parameters were more sensitive to detect acute hypovolemia than tissue oxygen tension measurements or jejunal LDF measurements. Acute blood loss was detected first by dPP.

Crystalloids versus colloids for goal-directed fluid therapy in major surgery.

INTRODUCTION: Perioperative hypovolemia arises frequently and contributes to intestinal hypoperfusion and subsequent postoperative complications. Goal-directed fluid therapy might reduce these complications. The aim of this study was to compare the effects of goal-directed administration of crystalloids and colloids on the distribution of systemic, hepatosplanchnic, and microcirculatory (small intestine) blood flow after major abdominal surgery in a clinically relevant pig model. METHODS: Twenty-seven pigs were anesthetized and mechanically ventilated and underwent open laparotomy. They were randomly assigned to one of three treatment groups: the restricted Ringer lactate (R-RL) group (n = 9) received 3 mL/kg per hour of RL, the goal-directed RL (GD-RL) group (n = 9) received 3 mL/kg per hour of RL and intermittent boluses of 250 mL of RL, and the goal-directed colloid (GD-C) group (n = 9) received 3 mL/kg per hour of RL and boluses of 250 mL of 6% hydroxyethyl starch (130/0.4). The latter two groups received a bolus infusion when mixed venous oxygen saturation was below 60% ('lockout' time of 30 minutes). Regional blood flow was measured in the superior mesenteric artery and the celiac trunk. In the small bowel, microcirculatory blood flow was measured using laser Doppler flowmetry. Intestinal tissue oxygen tension was measured with intramural Clark-type electrodes. RESULTS: After 4 hours of treatment, arterial blood pressure, cardiac output, mesenteric artery flow, and mixed oxygen saturation were significantly higher in the GD-C and GD-RL groups than in the R-RL group. Microcirculatory flow in the intestinal mucosa increased by 50% in the GD-C group but remained unchanged in the other two groups. Likewise, tissue oxygen tension in the intestine increased by 30% in the GD-C group but remained unchanged in the GD-RL group and decreased by 18% in the R-RL group. Mesenteric venous glucose concentrations were higher and lactate levels were lower in the GD-C group compared with the two crystalloid groups. CONCLUSIONS: Goal-directed colloid administration markedly increased microcirculatory blood flow in the small intestine and intestinal tissue oxygen tension after abdominal surgery. In contrast, goal-directed crystalloid and restricted crystalloid administrations had no such effects. Additionally, mesenteric venous glucose and lactate concentrations suggest that intestinal cellular substrate levels were higher in the colloid-treated than in the crystalloid-treated animals. These results support the notion that perioperative goal-directed therapy with colloids might be beneficial during major abdominal surgery.

Effect of fluid resuscitation on mortality and organ function in experimental sepsis models.

INTRODUCTION: Several recent studies have shown that a positive fluid balance in critical illness is associated with worse outcome. We tested the effects of moderate vs. high-volume resuscitation strategies on mortality, systemic and regional blood flows, mitochondrial respiration, and organ function in two experimental sepsis models. METHODS: 48 pigs were randomized to continuous endotoxin infusion, fecal peritonitis, and a control group (n = 16 each), and each group further to two different basal rates of volume supply for 24 hours [moderate-volume (10 ml/kg/h, Ringer's lactate, n = 8); high-volume (15 + 5 ml/kg/h, Ringer's lactate and hydroxyethyl starch (HES), n = 8)], both supplemented by additional volume boli, as guided by urinary output, filling pressures, and responses in stroke volume. Systemic and regional hemodynamics were measured and tissue specimens taken for mitochondrial function assessment and histological analysis. RESULTS: Mortality in high-volume groups was 87% (peritonitis), 75% (endotoxemia), and 13% (controls). In moderate-volume groups mortality was 50% (peritonitis), 13% (endotoxemia) and 0% (controls). Both septic groups became hyperdynamic. While neither sepsis nor volume resuscitation strategy was associated with altered hepatic or muscle mitochondrial complex I- and II-dependent respiration, non-survivors had lower hepatic complex II-dependent respiratory control ratios (2.6 +/- 0.7, vs. 3.3 +/- 0.9 in survivors; P = 0.01). Histology revealed moderate damage in all organs, colloid plaques in lung tissue of high-volume groups, and severe kidney damage in endotoxin high-volume animals. CONCLUSIONS: High-volume resuscitation including HES in experimental peritonitis and endotoxemia increased mortality despite better initial hemodynamic stability. This suggests that the strategy of early fluid management influences outcome in sepsis. The high mortality was not associated with reduced mitochondrial complex I- or II-dependent muscle and hepatic respiration.

Automatic algorithm for monitoring systolic pressure variation and difference in pulse pressure.

BACKGROUND: Difference in pulse pressure (dPP) reliably predicts fluid responsiveness in patients. We have developed a respiratory variation (RV) monitoring device (RV monitor), which continuously records both airway pressure and arterial blood pressure (ABP). We compared the RV monitor measurements with manual dPP measurements. METHODS: ABP and airway pressure (PAW) from 24 patients were recorded. Data were fed to the RV monitor to calculate dPP and systolic pressure variation in two different ways: (a) considering both ABP and PAW (RV algorithm) and (b) ABP only (RV(slim) algorithm). Additionally, ABP and PAW were recorded intraoperatively in 10-min intervals for later calculation of dPP by manual assessment. Interobserver variability was determined. Manual dPP assessments were used for comparison with automated measurements. To estimate the importance of the PAW signal, RV(slim) measurements were compared with RV measurements. RESULTS: For the 24 patients, 174 measurements (6-10 per patient) were recorded. Six observers assessed dPP manually in the first 8 patients (10-min interval, 53 measurements); no interobserver variability occurred using a computer-assisted method. Bland-Altman analysis showed acceptable bias and limits of agreement of the 2 automated methods compared with the manual method (RV: -0.33% +/- 8.72% and RV(slim): -1.74% +/- 7.97%). The difference between RV measurements and RV(slim) measurements is small (bias -1.05%, limits of agreement 5.67%). CONCLUSIONS: Measurements of the automated device are comparable with measurements obtained by human observers, who use a computer-assisted method. The importance of the PAW signal is questionable.

Subcutaneous oxygen pressure in spontaneously breathing lean and obese volunteers: a pilot study.

BACKGROUND: Oxidative killing is the primary defense against surgical pathogens; risk of infection is inversely related to tissue oxygenation. Subcutaneous tissue oxygenation in obese patients is significantly less than in lean patients during general anesthesia. However, it remains unknown whether reduced intraoperative tissue oxygenation in obese patients results from obesity per se or from a combination of anesthesia and surgery. In a pilot study, we tested the hypothesis that tissue oxygenation is reduced in spontaneously breathing, unanesthetized obese volunteers. METHODS: Seven lean volunteers with a body mass index (BMI) of 22 +/- 2 kg/m(2) were compared to seven volunteers with a BMI of 46 +/- 4 kg/m(2). Volunteers were subjected to the following oxygen challenges: (1) room air; (2) 2 l/min oxygen via nasal prongs, (3) 6 l/min oxygen through a rebreathing face mask; (4) oxygen as needed to achieve an arterial oxygen pressure (arterial pO(2)) of 200 mmHg; and (5) oxygen as needed to achieve an arterial pO(2) of 300 mmHg. The oxygen challenges were randomized. Arterial pO(2) was measured with a continuous intraarterial blood gas analyzer (Paratrend 7); deltoid subcutaneous tissue oxygenation was measured with a polarographic microoxygen sensor (Licox). RESULTS: Subcutaneous tissue oxygenation was similar in lean and obese volunteers: (1) room air, 52 +/- 10 vs 58 +/- 8 mmHg; (2) 2 l/min, 77 +/- 25 vs 79 +/- 24 mmHg; (3) 6 l/min, 125 +/- 43 vs 121 +/- 25 mmHg; (4) arterial pO(2) = 200 mmHg, 115 +/- 42 vs 144 +/- 23 mmHg; (5) arterial pO(2) = 300 mmHg, 145 +/- 41 vs 154 +/- 32 mmHg. CONCLUSION: In this pilot study, we could not identify significant differences in deltoid subcutaneous tissue oxygen pressure between lean and morbidly obese volunteers.

Vasopressin in septic shock: effects on pancreatic, renal, and hepatic blood flow.

INTRODUCTION: Vasopressin has been shown to increase blood pressure in catecholamine-resistant septic shock. The aim of this study was to measure the effects of low-dose vasopressin on regional (hepato-splanchnic and renal) and microcirculatory (liver, pancreas, and kidney) blood flow in septic shock. METHODS: Thirty-two pigs were anesthetized, mechanically ventilated, and randomly assigned to one of four groups (n = 8 in each). Group S (sepsis) and group SV (sepsis/vasopressin) were exposed to fecal peritonitis. Group C and group V were non-septic controls. After 240 minutes, both septic groups were resuscitated with intravenous fluids. After 300 minutes, groups V and SV received intravenous vasopressin 0.06 IU/kg per hour. Regional blood flow was measured in the hepatic and renal arteries, the portal vein, and the celiac trunk by means of ultrasonic transit time flowmetry. Microcirculatory blood flow was measured in the liver, kidney, and pancreas by means of laser Doppler flowmetry. RESULTS: In septic shock, vasopressin markedly decreased blood flow in the portal vein, by 58% after 1 hour and by 45% after 3 hours (p < 0.01), whereas flow remained virtually unchanged in the hepatic artery and increased in the celiac trunk. Microcirculatory blood flow decreased in the pancreas by 45% (p < 0.01) and in the kidney by 16% (p < 0.01) but remained unchanged in the liver. CONCLUSION: Vasopressin caused marked redistribution of splanchnic regional and microcirculatory blood flow, including a significant decrease in portal, pancreatic, and renal blood flows, whereas hepatic artery flow remained virtually unchanged. This study also showed that increased urine output does not necessarily reflect increased renal blood flow.

Assessing intravascular volume by difference in pulse pressure in pigs submitted to graded hemorrhage.

We assessed changes in intravascular volume monitored by difference in pulse pressure (dPP%) after stepwise hemorrhage in an experimental pig model. Six pigs (23-25 kg) were anesthetized (isoflurane 1.5 vol%) and mechanically ventilated to keep end-tidal CO2 (etCO2) at 35 mmHg. A PA-catheter and an arterial catheter were placed via femoral access. During and after surgery, animals received lactated Ringer's solution as long as they were considered volume responders (dPP>13%). Then animals were allowed to stabilize from the induction of anesthesia and insertion of catheters for 30 min. After stabilization, baseline measurements were taken. Five percent of blood volume was withdrawn, followed by another 5%, and then in 10%-increments until death from exsanguination occurred. After withdrawal of 5% of blood volume, all pigs were considered volume responders (dPP>13%); dPP rose significantly from 6.1+/-3.3% to 19.4+/-4.2%. The regression analysis of stepwise hemorrhage revealed a linear relation between blood loss (hemorrhage in %) and dPP (y=0.99*x+14; R2=0.7764; P<.0001). In addition, dPP was the only parameter that changed significantly between baseline and a blood loss of 5% (P<0.01), whereas cardiac output, stroke volume, heart rate, MAP, central venous pressure, pulmonary artery occlusion pressure, and systemic vascular resistance, respectively, remained unchanged. We conclude that in an experimental hypovolemic pig model, dPP correlates well with blood loss.

Effects of endotoxin and catecholamines on hepatic mitochondrial respiration.

Catecholamines are frequently used in sepsis, but their interaction with mitochondrial function is controversial. We incubated isolated native and endotoxin-exposed swine liver mitochondria with either dopamine, dobutamine, noradrenaline or placebo for 1 h. Mitochondrial State 3 and 4 respiration and their ratio (RCR) were determined for respiratory chain complexes I, II and IV. All catecholamines impaired glutamate-dependent RCR (p = 0.046), predominantly in native mitochondria. Endotoxin incubation alone induced a decrease in glutamate-dependent RCR compared to control samples (p = 0.002). We conclude that catecholamines and endotoxin impair the efficiency of mitochondrial complex I respiration in vitro.

Effects of vasopressin on microcirculatory blood flow in the gastrointestinal tract in anesthetized pigs in septic shock.

BACKGROUND: Vasopressin increases arterial pressure in septic shock even when alpha-adrenergic agonists fail. The authors studied the effects of vasopressin on microcirculatory blood flow in the entire gastrointestinal tract in anesthetized pigs during early septic shock. METHODS: Thirty-two pigs were intravenously anesthetized, mechanically ventilated, and randomly assigned to one of four groups (n=8 in each; full factorial design). Group S (sepsis) and group SV (sepsis-vasopressin) were made septic by fecal peritonitis. Group C and group V were nonseptic control groups. After 300 min, group V and group SV received intravenous infusion of 0.06 U.kg.h vasopressin. In all groups, cardiac index and superior mesenteric artery flow were measured. Microcirculatory blood flow was recorded with laser Doppler flowmetry in both mucosa and muscularis of the stomach, jejunum, and colon. RESULTS: While vasopressin significantly increased arterial pressure in group SV (P<0.05), superior mesenteric artery flow decreased by 51+/-16% (P<0.05). Systemic and mesenteric oxygen delivery and consumption decreased and oxygen extraction increased in the SV group. Effects on the microcirculation were very heterogeneous; flow decreased in the stomach mucosa (by 23+/-10%; P<0.05), in the stomach muscularis (by 48+/-16%; P<0.05), and in the jejunal mucosa (by 27+/-9%; P<0.05), whereas no significant changes were seen in the colon. CONCLUSION: Vasopressin decreased regional flow in the superior mesenteric artery and microcirculatory blood flow in the upper gastrointestinal tract. This reduction in flow and a concomitant increase in the jejunal mucosa-to-arterial carbon dioxide gap suggest compromised mucosal blood flow in the upper gastrointestinal tract in septic pigs receiving low-dose vasopressin.

Effects of epinephrine, norepinephrine, and phenylephrine on microcirculatory blood flow in the gastrointestinal tract in sepsis.

OBJECTIVE: The use of vasopressors for treatment of hypotension in sepsis may have adverse effects on microcirculatory blood flow in the gastrointestinal tract. The aim of this study was to measure the effects of three vasopressors, commonly used in clinical practice, on microcirculatory blood flow in multiple abdominal organs in sepsis. DESIGN: Random order, cross-over design. SETTING: University laboratory. SUBJECTS: Eight sedated and mechanically ventilated pigs. INTERVENTIONS: Pigs were exposed to fecal peritonitis-induced septic shock. Mesenteric artery flow was measured using ultrasound transit time flowmetry. Microcirculatory flow was measured in gastric, jejunal, and colon mucosa; jejunal muscularis; and pancreas, liver, and kidney using multiple-channel laser Doppler flowmetry. Each animal received a continuous intravenous infusion of epinephrine, norepinephrine, and phenylephrine in a dose increasing mean arterial pressure by 20%. The animals were allowed to recover for 60 mins after each drug before the next was started. MEASUREMENTS AND MAIN RESULTS: During infusion of epinephrine (0.8 +/- 0.2 mug/kg/hr), mean arterial pressure increased from 66 +/- 5 to 83 +/- 5 mm Hg and cardiac index increased by 43 +/- 9%. Norepinephrine (0.7 +/- 0.3 mug/kg/hr) increased mean arterial pressure from 70 +/- 4 to 87 +/- 5 mm Hg and cardiac index by 41 +/- 8%. Both agents caused a significant reduction in superior mesenteric artery flow (11 +/- 4%, p < .05, and 26 +/- 6%, p < .01, respectively) and in microcirculatory blood flow in the jejunal mucosa (21 +/- 5%, p < .01, and 23 +/- 3%, p < .01, respectively) and in the pancreas (16 +/- 3%, p < .05, and 8 +/- 3%, not significant, respectively). Infusion of phenylephrine (3.1 +/- 1.0 mug/kg/min) increased mean arterial pressure from 69 +/- 5 to 85 +/- 6 mm Hg but had no effects on systemic, regional, or microcirculatory flow except for a 30% increase in jejunal muscularis flow (p < .01). CONCLUSIONS: Administration of the vasopressors phenylephrine, epinephrine, and norepinephrine failed to increase microcirculatory blood flow in most abdominal organs despite increased perfusion pressure and-in the case of epinephrine and norepinephrine-increased systemic blood flow. In fact, norepinephrine and epinephrine appeared to divert blood flow away from the mesenteric circulation and decrease microcirculatory blood flow in the jejunal mucosa and pancreas. Phenylephrine, on the other hand, appeared to increase blood pressure without affecting quantitative blood flow or distribution of blood flow.

Effects of dopamine, dobutamine, and dopexamine on microcirculatory blood flow in the gastrointestinal tract during sepsis and anesthesia.

BACKGROUND: Insufficient blood flow to the splanchnic organs is believed to be an important contributory factor for the development of organ failure after septic shock. It has been suggested that increasing systemic flow also may improve splanchnic blood flow in septic patients. The aim of this study was to compare the effects of three commonly used inotropic agents, dopamine, dobutamine, and dopexamine, on systemic (cardiac index), regional (superior mesenteric artery), and local (micro-circulatory) blood flow during septic shock in pigs. METHODS: Eight pigs were intravenously anesthetized, mechanically ventilated, and exposed to sepsis induced by fecal peritonitis. Cardiac index was measured with thermodilution, superior mesenteric artery flow was measured with ultrasound transit time flowmetry, and microcirculatory blood flow was continuously measured with a six-channel laser Doppler flowmetry in the gastric, jejunal, and colon mucosa as well as in the kidney, pancreas, and jejunal muscularis. Each animal received, in a random-order, crossover design, the three test drugs, one at a time: 5 and 10 microg x kg(-1) x min(-1) dopamine, 5 and 10 microg x kg(-1) x min(-1) dobutamine, and 1 and 2 microg x kg(-1) x min(-1) dopexamine. Administration of each drug at each dose continued for 30 min and was followed by a 40- to 60-min recovery period. A new baseline was taken before the next drug was administered. RESULTS: All three drugs significantly increased cardiac index; dopamine by 18%, dobutamine by 48%, and dopexamine by 35%, compared with baseline (P < 0.001 for each). At the same time, superior mesenteric artery flow increased by 33% (P < 0.01) with dopamine and 13% (P < 0.01) with dopexamine, whereas it did not change with dobutamine. Microcirculatory blood flow did not change significantly in any of the organs studied with any of the drugs tested. CONCLUSION: All the inotropic agents markedly increased cardiac output in this sepsis model. However, increased systemic flow did not reach the microcirculation in the gastrointestinal tract. This may in part explain why some of the clinical trials, in which systemic oxygen delivery was deliberately increased by administration of inotropic drugs, have failed to improve survival in critically ill patients.

Redistribution of microcirculatory blood flow within the intestinal wall during sepsis and general anesthesia.

BACKGROUND: Hypoperfusion of the intestinal mucosa remains an important clinical problem during sepsis. Impairment of the autoregulation of microcirculatory blood flow in the intestinal tract has been suggested to play an important role in the development of multiple organ failure during sepsis and surgery. The authors studied microcirculatory blood flow in the gastrointestinal tract in anesthetized subjects during early septic shock. METHODS: Eighteen pigs were intravenously anesthetized and mechanically ventilated. Regional blood flow in the superior mesenteric artery was measured with ultrasound transit time flowmetry. Microcirculatory blood flow was continuously measured with a six-channel laser Doppler flowmetry system in the mucosa and the muscularis of the stomach, jejunum, and colon. Eleven pigs were assigned to the sepsis group, while seven animal served as sham controls. Sepsis was induced with fecal peritonitis, and intravenous fluids were administered after 240 min of sepsis to alter hypodynamic sepsis to hyperdynamic sepsis. RESULTS: In the control group, all monitored flow data remained stable throughout the study. During the hypodynamic phase of sepsis, cardiac output, superior mesenteric artery flow, and microcirculatory blood flow in the gastric mucosa decreased by 45%, 51%, and 40%, respectively, compared to baseline (P < 0.01 in all). Microcirculatory blood flow in the muscularis of the stomach, jejunum, and colon decreased by 55%, 64%, and 70%, respectively (P < 0.001 in all). In contrast, flow in the jejunal and colonic mucosa remained virtually unchanged. During the hyperdynamic phase of sepsis, there was a threefold increase in cardiac output and superior mesenteric artery flow. Blood flow in the gastric, jejunal, and colonic mucosa also increased (22%, 24%, and 31% above baseline, respectively). Flow in the muscularis of the stomach returned to baseline, while in the jejunum and colon, flow in the muscularis remained significantly below baseline (55% and 45%, respectively, P< 0.01). CONCLUSIONS: It appears that in early septic shock, autoregulation of microcirculatory blood flow is largely intact in the intestinal mucosa in anesthetized pigs, explaining why microcirculatory blood flow remained virtually unchanged. This may be facilitated through redistribution of flow within the intestinal wall, from the muscularis toward the mucosa.

Endothelin receptor antagonist bosentan improves microcirculatory blood flow in splanchnic organs in septic shock.

OBJECTIVE: Splanchnic ischemia is believed to play an important role in the development of multiple organ dysfunction in septic shock. The vasoconstrictor peptide endothelin can produce an intense and sustained splanchnic vasoconstriction and is increased in sepsis. The aim of this investigation was to study the effects of an endothelin antagonist on microcirculatory blood flow in multiple abdominal organs during septic shock. DESIGN: Prospective, controlled animal study. SETTING: University-affiliated research laboratory. SUBJECTS: Fifteen anesthetized and mechanically ventilated pigs. INTERVENTIONS: Septic shock was induced by fecal peritonitis. After 120 mins of sepsis, eight animals received 10 mg/kg bosentan intravenously followed by an intravenous infusion at 5 mg x kg-1 x hr-1 whereas seven (controls) received isotonic saline. At 240 mins after induction of sepsis both groups received hydroxyethyl starch, 20 mL/kg intravenously, to convert hypodynamic septic shock to hyperdynamic sepsis. MEASUREMENTS AND MAIN RESULTS: Microcirculatory blood flow was measured simultaneously and continuously in the jejunal muscularis, pancreas, liver, kidney, skeletal muscle, and gastric, jejunal, and colon mucosa by using a multiple-channel laser Doppler flow meter. After 120 mins, all animals had developed signs of hypodynamic sepsis with decreased cardiac index, mean arterial blood pressure, and gastric mucosal pH. Microcirculatory blood flow in the pancreas and liver had decreased by 20% and in the jejunal muscularis by >40% (p <.01) whereas it remained virtually unchanged in the gastric, jejunal, and colonic mucosa. After 240 mins, cardiac index, mean arterial blood pressure, gastric mucosal pH, and microcirculatory blood flow in the gastric mucosa, colon mucosa, jejunal muscularis, and pancreas had all deteriorated in the controls, whereas in the bosentan-treated group, cardiac index and microcirculatory blood flow in the pancreas, gastric, and colon mucosa improved. During hyperdynamic sepsis, cardiac index increased above baseline in both groups but significantly more in the bosentan group. In the control group, microcirculatory flow returned to baseline in most tissues except in skeletal muscle and jejunal muscularis. In the bosentan group, microcirculatory flow returned to or increased above baseline in all tissues except in the muscularis of the jejunum. CONCLUSIONS: The endothelin receptor antagonist bosentan significantly improved microcirculatory blood flow in many splanchnic organs and in peripheral tissues during septic shock. The results of this study are consistent with the hypothesis that endothelin plays an important role in the regulation of microcirculatory blood flow in splanchnic as well as in peripheral tissues during septic shock.