Vladimir Krejci

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 &mgr;g/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 &mgr;g/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 &mgr;g/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.

Dynamic study of the distribution of microcirculatory blood flow in multiple splanchnic organs in septic shock.

ObjectivesTo study dynamic distribution of microcirculatory blood flow in multiple splanchnic organs during septic shock; to test the hypothesis that changes in microcirculatory blood flow in splanchnic organs correlate with changes in regional flow during septic shock. DesignA prospective, controlled, animal study. SettingAnimal laboratory in a university medical center. SubjectsNine anesthetized and mechanically ventilated domestic pigs. InterventionsSystemic flow (cardiac output) was measured with thermodilution and regional (superior mesenteric artery) flow with transit time flowmetry. Local blood flow (microcirculatory flow) was continuously measured in splanchnic organs (gastric, jejunal, and colon mucosa, liver, and pancreas) and the kidney with multichannel laser Doppler flowmetry. Septic shock was induced with fecal peritonitis. After 240 mins of sepsis, intravenous fluids were administered to alter hypodynamic shock to hyperdynamic septic shock. Measurements and Main ResultsIn this severe septic shock model, systemic and regional flows decreased by ∼50% during the first 240 mins. Similar reductions were recorded in microcirculatory flow in the mucosa of the stomach (−41%;p < .001) and colon (−47%;p < .001). In the jejunal mucosa, on the other hand, flow remained virtually unchanged. Microcirculatory flow was also significantly decreased in the liver (−49%;p < .001), pancreas (−56%;p < .001), and kidney (−44%;p < .001). Administration of intravenous fluids at 240 mins was followed by three-fold increases in systemic and regional flows (∼70% above baseline). In the jejunal mucosa, flow also increased significantly above baseline (42%;p < .001), whereas in the stomach and the colon, it barely reached baseline. Kidney blood flow increased to baseline, whereas pancreas and liver flows remained 26% (p < .05) and 34% (p < .001), respectively, below baseline. ConclusionChanges in microcirculatory blood flow in the splanchnic organs are heterogeneous, both in early hypodynamic and in hyperdynamic septic shock, and cannot be predicted from changes in systemic or regional flows. Microcirculatory blood flow in the jejunal mucosa remains constant during early septic shock, whereas pancreatic blood flow decreases significantly more than regional 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 μg · kg−1 · min−1 dopamine, 5 and 10 μg · kg−1 · min−1 dobutamine, and 1 and 2 μg · kg−1 · min−1 dopex-amine. 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.

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

IntroductionSeveral 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.Methods48 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, Ringers lactate, n = 8); high-volume (15 + 5 ml/kg/h, Ringers 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.ResultsMortality 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.ConclusionsHigh-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.

Effects of Sodium Nitroprusside and Phenylephrine on Blood Flow in Free Musculocutaneous Flaps during General Anesthesia

Background: Hypoperfusion and necrosis in free flaps used to correct tissue defects remain important clinical problems The authors studied the effects of two vasoactive drugs, sodium nitroprusside and phenylephrine, which are used frequently in anesthetic practice, on total blood flow and microcirculatory flow in free musculocutaneous flaps during general anesthesia Metbods : In a porcine model (n = 9) in which clinical conditions for anesthesia and microvascular surgery were simulated, latissimus dorsi free flaps were transferred to the lower extremity. Total blood flow in the flaps was measured using ultrasound flowmetry and microcirculatory flow was measured using laser Doppler flowmetry. The effects of sodium nitroprusside and phenylephrine were studied during local infusion through the feeding artery of the flap and during systemic administration. Results: Systemic sodium nitroprusside caused a 30% decrease in mean arterial pressure, but cardiac output did not change. The total flow in the flap decreased by 40% (P < 0.01), and microcirculatory flow decreased by 23% in the skin (P < 0.01) and by 30% in the muscle (P < 0.01) of the flap. Sodium nitroprusside infused locally into the flap artery increased the total flap flow by 20% (P < 0.01). Systemic phenylephrine caused a 30% increase in mean arterial pressure, whereas heart rate, cardiac output, and flap blood flow did not change, local phenylephrine caused a 30% decrease (P < 0.01) in the total flap flow. Conclusions: Systemic phenylephrine in a dose increasing the systemic vascular resistance and arterial pressure by 30% appears to have no adverse effects on blood flow in free musculocutaneous flaps. Sodium nitroprusside, however, in a dose causing a 30% decrease in systemic vascular resistance and arterial pressure, causes a severe reduction in free flap blood flow despite maintaining cardiac output.

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

ObjectiveSplanchnic 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. DesignProspective, controlled animal study. SettingUniversity-affiliated research laboratory. SubjectsFifteen anesthetized and mechanically ventilated pigs. InterventionsSeptic 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·kg−1·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 ResultsMicrocirculatory 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. ConclusionsThe 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.

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 &agr;-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−1 · h−1 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.

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.

Comparison of calibrated and uncalibrated arterial pressure-based cardiac output monitors during orthotopic liver transplantation.

Arterial pressure–based cardiac output monitors (APCOs) are increasingly used as alternatives to thermodilution. Validation of these evolving technologies in high‐risk surgery is still ongoing. In liver transplantation, FloTrac‐Vigileo (Edwards Lifesciences) has limited correlation with thermodilution, whereas LiDCO Plus (LiDCO Ltd.) has not been tested intraoperatively. Our goal was to directly compare the 2 proprietary APCO algorithms as alternatives to pulmonary artery catheter thermodilution in orthotopic liver transplantation (OLT). The cardiac index (CI) was measured simultaneously in 20 OLT patients at prospectively defined surgical landmarks with the LiDCO Plus monitor (CIL) and the FloTrac‐Vigileo monitor (CIV). LiDCO Plus was calibrated according to the manufacturers instructions. FloTrac‐Vigileo did not require calibration. The reference CI was derived from pulmonary artery catheter intermittent thermodilution (CITD). CIV‐CITD bias ranged from −1.38 (95% confidence interval = −2.02 to −0.75 L/minute/m2, P = 0.02) to −2.51 L/minute/m2 (95% confidence interval = −3.36 to −1.65 L/minute/m2, P < 0.001), and CIL‐CITD bias ranged from −0.65 (95% confidence interval = −1.29 to −0.01 L/minute/m2, P = 0.047) to −1.48 L/minute/m2 (95% confidence interval = −2.37 to −0.60 L/minute/m2, P < 0.01). For both APCOs, bias to CITD was correlated with the systemic vascular resistance index, with a stronger dependence for FloTrac‐Vigileo. The capability of the APCOs for tracking changes in CITD was assessed with a 4‐quadrant plot for directional changes and with receiver operating characteristic curves for specificity and sensitivity. The performance of both APCOs was poor in detecting increases and fair in detecting decreases in CITD. In conclusion, the calibrated and uncalibrated APCOs perform differently during OLT. Although the calibrated APCO is less influenced by changes in the systemic vascular resistance, neither device can be used interchangeably with thermodilution to monitor cardiac output during liver transplantation. Liver Transpl 16:773‐782, 2010.

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

IntroductionVasopressin 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.MethodsThirty-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.ResultsIn 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.ConclusionVasopressin 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.