Xinrong He

Cerebral microcirculation is impaired during sepsis: an experimental study

IntroductionPathophysiology of brain dysfunction due to sepsis remains poorly understood. Cerebral microcirculatory alterations may play a role; however, experimental data are scarce. This study sought to investigate whether the cerebral microcirculation is altered in a clinically relevant animal model of septic shock.MethodsFifteen anesthetized, invasively monitored, and mechanically ventilated female sheep were allocated to a sham procedure (n = 5) or sepsis (n = 10), in which peritonitis was induced by intra-abdominal injection of autologous faeces. Animals were observed until spontaneous death or for a maximum of 20 hours. In addition to global hemodynamic assessment, the microcirculation of the cerebral cortex was evaluated using Sidestream Dark-Field (SDF) videomicroscopy at baseline, 6 hours, 12 hours and at shock onset. At least five images of 20 seconds each from separate areas were recorded at each time point and stored under a random number to be analyzed, using a semi-quantitative method, by an investigator blinded to time and condition.ResultsAll septic animals developed a hyperdynamic state associated with organ dysfunction and, ultimately, septic shock. In the septic animals, there was a progressive decrease in cerebral total perfused vessel density (from 5.9 ± 0.9 at baseline to 4.8 ± 0.7 n/mm at shock onset, P = 0.009), functional capillary density (from 2.8 ± 0.4 to 2.1 ± 0.7 n/mm, P = 0.049), the proportion of small perfused vessels (from 95 ± 3 to 85 ± 8%, P = 0.02), and the total number of perfused capillaries (from 22.7 ± 2.7 to 17.5 ± 5.2 n/mm, P = 0.04). There were no significant changes in microcirculatory flow index over time. In sham animals, the cerebral microcirculation was unaltered during the study period.ConclusionsIn this model of peritonitis, the cerebral microcirculation was impaired during sepsis, with a significant reduction in perfused small vessels at the onset of septic shock. These alterations may play a role in the pathogenesis of septic encephalopathy.

Sepsis is associated with altered cerebral microcirculation and tissue hypoxia in experimental peritonitis.

Objective:Alterations in cerebral microvascular blood flow may develop during sepsis, but the consequences of these abnormalities on tissue oxygenation and metabolism are not well defined. We studied the evolution of microvascular blood flow, brain oxygen tension (PbO2), and metabolism in a clinically relevant animal model of septic shock. Design:Prospective randomized animal study. Setting:University hospital research laboratory. Subjects:Fifteen invasively monitored and mechanically ventilated female sheep. Interventions:The sheep were randomized to fecal peritonitis (n = 10) or a sham procedure (n = 5), and craniectomies were performed to enable evaluation of cerebral microvascular blood flow, PbO2, and metabolism. The microvascular network of the left frontal cortex was evaluated (at baseline, 6, 12, and 18 hr) using sidestream dark-field videomicroscopy. Using an off-line semiquantitative method, functional capillary density and the proportion of small perfused vessels were calculated. PbO2 was measured hourly by a parenchymal Clark electrode, and cerebral metabolism was assessed by the lactate/pyruvate ratio using brain microdialysis; both these systems were placed in the right frontal cortex. Measurement and Main Results:In septic animals, cerebral functional capillary density (from 3.1 ± 0.5 to 1.9 ± 0.4 n/mm, p < 0.001) and proportion of small perfused vessels (from 98% ± 2% to 84% ± 7%, p = 0.004) decreased over the 18-hour study period. Concomitantly, PbO2 decreased (61 ± 5 to 41 ± 7 mm Hg, p < 0.001) and lactate/pyruvate ratio increased (23 ± 5 to 36 ± 19, p < 0.001). At 18 hours, when shock was present, animals with a mean arterial pressure less than 65 mm Hg (n = 6) had similar functional capillary density, proportion of small perfused vessels, and PbO2 values but significantly higher lactate/pyruvate ratio (46 ± 18 vs 20 ± 4, p = 0.009) compared with animals with an mean arterial pressure of 65–70 mm Hg (n = 4). Conclusions:Impaired cerebral microcirculation during sepsis is associated with progressive impairment in PbO2 and brain metabolism. Development of severe hypotension was responsible for a further increase in anaerobic metabolism. These alterations may play an important role in the pathogenesis of brain dysfunction during sepsis.

Administration of tetrahydrobiopterin improves the microcirculation and outcome in an ovine model of septic shock.

Objective: Supplementation with tetrahydrobiopterin, a nitric oxide synthase cofactor, may reduce microvascular endothelial dysfunction in severe sepsis. We studied whether tetrahydrobiopterin administration exerts beneficial effects in an ovine septic shock model. Design: Randomized animal study. Setting: University hospital animal research laboratory. Subjects: Fourteen adult female sheep. Interventions: Fecal peritonitis was induced, and the sheep were randomized to receive tetrahydrobiopterin (n = 7), given intravenously as 20mg/kg boluses at 4 and 12 hrs after sepsis induction, or placebo (n = 7). All animals were fluid resuscitated. The experiment was continued until death or for a maximum of 30 hrs. Measurements and Main Results: In addition to standard hemodynamic assessment, the sublingual microcirculation was evaluated using sidestream dark-field videomicroscopy. The first bolus of tetrahydrobiopterin blunted the increase in heart rate and cardiac index seen in the control group without affecting mean arterial pressure, and the second bolus of tetrahydrobiopterin prevented the decreases in cardiac index and mean arterial pressure. The reduction in mixed venous blood oxygen saturation and the increase in blood lactate seen in the control group were also delayed. Tetrahydrobiopterin significantly attenuated the deterioration in perfused small vessel proportion and density, microvascular flow index, and the increase in microvascular heterogeneity observed in the control group. Tetrahydrobiopterin was associated with better preserved lung compliance and PaO2/FIO2 ratio, which were associated with a lower lung wet/dry weight ratio at the end of the study. Median survival time was significantly prolonged in the tetrahydrobiopterin group (25.0 vs. 17.8 hrs, p < .01). Conclusion: In this clinically relevant model of sepsis, tetrahydrobiopterin supplementation attenuated the impairment in sublingual microvascular perfusion and permeability, which was accompanied by better preserved gas exchange, renal flow and urine output, and prolonged survival.

A selective V1A receptor agonist, selepressin, is superior to arginine vasopressin and to norepinephrine in ovine septic shock

Objective:Selective vasopressin V1A receptor agonists may have advantages over arginine vasopressin in the treatment of septic shock. We compared the effects of selepressin, a selective V1A receptor agonist, arginine vasopressin, and norepinephrine on hemodynamics, organ function, and survival in an ovine septic shock model. Design:Randomized animal study. Setting:University hospital animal research laboratory. Subjects:Forty-six adult female sheep. Interventions:Fecal peritonitis was induced in the anesthetized, mechanically ventilated, fluid-resuscitated sheep, and they were randomized in two successive phases. Three late-intervention groups (each n = 6) received IV selepressin (1 pmol/kg/min), arginine vasopressin (0.25 pmol [0.1 mU]/kg/min), or norepinephrine (3 nmol [0.5 &mgr;g]/kg/min) when mean arterial pressure remained less than 70 mm Hg despite fluid challenge; study drugs were thereafter titrated to keep mean arterial pressure at 70–80 mm Hg. Three early-intervention groups (each n = 7) received selepressin, arginine vasopressin, or norepinephrine at the same initial infusion rates as for the late intervention, but already when mean arterial pressure had decreased by 10% from baseline; doses were then titrated as for the late intervention. A control group (n = 7) received saline. All animals were observed until death or for a maximum of 30 hours. Measurements and Main Results:In addition to hemodynamic and organ function assessment, plasma interleukin-6 and nitrite/nitrate levels were measured. In the late-intervention groups, selepressin delayed the decrease in mean arterial pressure and was associated with lower lung wet/dry weight ratios than in the other two groups. In the early-intervention groups, selepressin maintained mean arterial pressure and cardiac index better than arginine vasopressin or norepinephrine, slowed the increase in blood lactate levels, and was associated with less lung edema, lower cumulative fluid balance, and lower interleukin-6 and nitrite/nitrate levels. Selepressin-treated animals survived longer than the other animals. Conclusions:In this clinically relevant model, selepressin, a selective V1A receptor agonist, was superior to arginine vasopressin and to norepinephrine in the treatment of septic shock, especially when administered early.

Cardiovascular and microvascular responses to mild hypothermia in an ovine model

AIMS Hypothermia is used for brain protection after resuscitation from cardiac arrest and other forms of brain injury, but its impact on systemic and tissue perfusion has not been well defined. The aim of this study was to evaluate the cardiovascular and microvascular responses to mild therapeutic hypothermia (MTH) in an ovine model. METHODS Seven anaesthetised, mechanically ventilated, invasively monitored sheep were cooled from a baseline temperature of 39-40°C to 34°C using cold intravenous fluids, ice packs and transnasal cooling. After 6h of MTH, sheep were progressively re-warmed to baseline temperature. Positive fluid balance was maintained during the entire study period to avoid hypovolemia. In addition to standard haemodynamic assessment, the sublingual microcirculation was evaluated using sidestream dark-field (SDF) videomicroscopy. RESULTS MTH was associated with significant decreases in cardiac index and left (LVSWI) and right (RVSWI) ventricular stroke work indexes. There was a downward shift in the relationship between LVSWI and pulmonary artery occlusion pressure during MTH, indicating myocardial depression. During MTH, mixed venous oxygen saturation increased, in association with reduced oxygen consumption, but blood lactate concentrations increased significantly. There was a significant decrease in the proportion and density of small perfused vessels. All variables returned to baseline levels during the re-warming phase. CONCLUSION In this large animal model, MTH was associated with decreased ventricular function, oxygen extraction and microvascular flow compared to normothermia. These changes were associated with increased blood lactate levels. These observations suggest that MTH may impair tissue oxygen delivery through maldistribution of capillary flow.

Sublingual microcirculatory effects of enalaprilat in an ovine model of septic shock.

Severe sepsis is frequently associated with microcirculatory abnormalities despite seemingly adequate hemodynamic resuscitation. As increased serum angiotensin II levels may play a role in this dysfunction, we evaluated the microcirculatory effects of enalaprilat in an experimental model of septic shock. One hour after injection of 1.5 g/kg body weight of feces into the abdominal cavity, 16 adult female anesthetized, mechanically ventilated sheep were randomized to receive 2.5 mg enalaprilat or saline. When fluid-resistant hypotension (mean arterial pressure, <65 mmHg) developed, norepinephrine was given up to a maximal dose of 3 &mgr;g·kg−1·min−1. The sublingual microcirculation was evaluated using sidestream dark-field videomicroscopy. A cutoff of 20 &mgr;m was used to differentiate small and large vessels. Experiments were pursued until the sheeps spontaneous death or for a maximum of 30 h. There were progressive and significant reductions in the proportion of small perfused vessels and in the microvascular flow index for small vessels (both P < 0.01 for trend) during shock and the first 2 h of norepinephrine infusion in the placebo group, which were prevented by the administration of enalaprilat. There were no differences between treated and placebo groups in global hemodynamic variables, time to shock or median survival time (21.8 [18.6-28.8] vs. 22.9 [21.8-30.0] h; P = 0.45). However, oxygen exchange was worse (PaO2/FiO2 ratio, 224 [128-297] vs. 332 [187-450]; P < 0.05), and creatinine concentrations increased more in the treated group (from 0.51 [0.42-0.75] to 1.19 [0.64-1.50] mg·dL−1; P = 0.04) than in the control group (from 0.55 [0.45-0.62] to 0.78 [0.46-1.78] mg·dL−1; P = 0.12), Enalaprilat therefore prevented the worsening of sublingual microcirculatory variables in this fluid-resuscitated, hyperdynamic model of septic shock, without significant effect on arterial pressure, but with a possible deleterious effect on renal and lung function.

Effects of Different Crystalloid Solutions on Hemodynamics, Peripheral Perfusion, and the Microcirculation in Experimental Abdominal Sepsis.

Background:Crystalloid solutions are used to restore intravascular volume in septic patients, but each solution has limitations. The authors compared the effects of three crystalloid solutions on hemodynamics, organ function, microcirculation, and survival in a sepsis model. Methods:Peritonitis was induced by injection of autologous feces in 21 anesthetized, mechanically ventilated adult sheep. After baseline measurements, animals were randomized to lactated Ringer’s (LR), normal saline (NS), or PlasmaLyte as resuscitation fluid. The sublingual microcirculation was assessed using sidestream dark field videomicroscopy and muscle tissue oxygen saturation with near-infrared spectroscopy. Results:NS administration was associated with hyperchloremic acidosis. NS-treated animals had lower cardiac index and left ventricular stroke work index than LR-treated animals from 8 h and lower mean arterial pressure than LR-treated animals from 12 h. NS-treated animals had a lower proportion of perfused vessels than LR-treated animals after 12 h (median, 82 [71 to 83] vs. 85 [82 to 89], P = 0.04) and greater heterogeneity of proportion of perfused vessels than PlasmaLyte or LR groups at 18 h. Muscle tissue oxygen saturation was lower at 16 h in the NS group than in the other groups. The survival time of NS-treated animals was shorter than that of the LR group (17 [14 to 20] vs. 26 [23 to 29] h, P < 0.01) but similar to that of the PlasmaLyte group (20 [12 to 28] h, P = 0.74). Conclusions:In this abdominal sepsis model, resuscitation with NS was associated with hyperchloremic acidosis, greater hemodynamic instability, a more altered microcirculation, and more severe organ dysfunction than with balanced fluids. Survival time was shorter than in the LR group.

Harmful Effects of Hyperoxia in Postcardiac Arrest, Sepsis, Traumatic Brain Injury, or Stroke: The Importance of Individualized Oxygen Therapy in Critically Ill Patients

The beneficial effects of oxygen are widely known, but the potentially harmful effects of high oxygenation concentrations in blood and tissues have been less widely discussed. Providing supplementary oxygen can increase oxygen delivery in hypoxaemic patients, thus supporting cell function and metabolism and limiting organ dysfunction, but, in patients who are not hypoxaemic, supplemental oxygen will increase oxygen concentrations into nonphysiological hyperoxaemic ranges and may be associated with harmful effects. Here, we discuss the potentially harmful effects of hyperoxaemia in various groups of critically ill patients, including postcardiac arrest, traumatic brain injury or stroke, and sepsis. In all these groups, there is evidence that hyperoxia can be harmful and that oxygen prescription should be individualized according to repeated assessment of ongoing oxygen requirements.

The harmful effects of hypertonic sodium lactate administration in hyperdynamic septic shock

ABSTRACT Hypertonic sodium lactate (HTL) expands intravascular volume and may provide an alternative substrate for cellular metabolism in sepsis. We compared the effects of HTL, hypertonic saline (HTS), 0.9% (“normal”) saline (NS) and Ringers lactate (RL) on hemodynamics, sublingual and renal microcirculation, renal, mesenteric and brain perfusion, renal and cerebral metabolism, and survival in anesthetized, mechanically ventilated, adult female sheep. Animals (7 in each group) were randomized to receive a bolus (over 15-min) of 3 mL/kg 0.5 M HTL, 3 mL/kg 3% HTS, 10.8 mL/kg NS, or 10.8 mL/kg RL at 2, 6, and 10 h after induction of fecal peritonitis, followed by 2-h infusions of 1 mL/kg/h (HTL/HTS groups) or 3.6 mL/kg/h (NS/RL groups). Animals also received RL and hydroxyethyl starch (ratio 1:1) titrated to maintain pulmonary artery occlusion pressure at baseline levels throughout the experiment. Animals were observed until their spontaneous death. Fluid balance was lower in the HTL and HTS groups than in the other groups from 4 h. Hemodynamic variables were similar among groups during the first 12 h, but thereafter the HTL group had more pronounced decreases in blood pressure and cardiac function. Sublingual and renal microcirculatory abnormalities occurred earlier in the HTL group. Kidney and brain perfusion decreased more rapidly in the HTL group. Median survival times were significantly shorter in the HTL (17 h) and NS (16 h) groups than in the HTS (22 h) or RL (20 h) groups (P = 0.0029). In conclusion, in an ovine model of septic shock, administration of HTL was associated with earlier onset impaired tissue perfusion and shorter survival time. These observations raise concerns about use of HTL in septic shock.

Effects of a novel anticoagulant compound (TV7130) in an ovine model of septic shock.

We compared the effects of a new compound (TV7130) with those of activated protein C (APC) in a large animal model of septic shock. Thirty-two fasted, anesthetized, invasively monitored, mechanically ventilated female sheep received 1.5 g/kg body weight of feces into the abdomen to induce sepsis. Immediately after feces injection, all animals received a bolus followed by a continuous infusion of saline (n = 8, bolus 1.5 mL for 15 min, infusion 1.5 mL/[kg·h]), low-dose TV7130 (n = 8; 0.4 mg/kg bolus, 0.4 mg/[kg·h] infusion), high-dose TV7130 (n = 8; 0.8 mg/kg bolus, 0.8 mg/[kg·h] infusion), or APC (n = 8; saline bolus, APC infusion of 0.024 mg/[kg·h]). Experiments were pursued until each sheeps spontaneous death. There were no significant differences among groups in heart rate or cardiac index, but mean arterial pressure, systemic vascular resistance index, and left ventricular stroke work index decreased less in the high-dose TV7130 and APC groups than in the other groups. Gas exchange was preserved better in the high-dose TV7130 and APC groups. Interleukin 6 and lactate concentrations were lower in the high-dose TV7130 and APC groups than in the other groups. Functional capillary density and proportion of perfused vessels, evaluated in the sublingual region using sidestream dark-field videomicroscopy, were significantly higher in the TV7130 and APC groups than in the vehicle group at 16 h. Survival time was significantly longer in the high-dose TV7130 and APC groups than in the other groups (log-rank test, P = 0.0002). TV7130 has similar effects to APC and may be a promising agent for the management of severe sepsis.