Ovine Model Of Septic Shock Research Articles

Effects of resuscitation with human albumin 5%, hydroxyethyl starch 130/0.4 6%, or crystalloid on kidney damage in an ovine model of septic shock

BackgroundColloid solutions have been associated with kidney dysfunction in septic animals and humans. The present study investigated the influence of resuscitation with human albumin (HA) 5%, hydroxyethyl starch (HES) 130/0.4 6%, and balanced crystalloids on ultrastructural kidney damage, kidney function, and survival in a model of ovine septic shock. MethodsAfter induction of peritoneal septic shock, animals were randomised to one of the following groups: (1) HA 5%, (2) HES 130/0.4 6%, (3) balanced crystalloid, and (4) control (each n=10). Causal therapy included re-laparotomy, peritoneal lavage, and antimicrobial therapy. Sequential kidney biopsies were obtained for the assessment of the electron microscopic tubular injury (EMTI) score. ResultsSerum creatinine and urea were highest in the control group, and there were no differences between the intervention groups. Cumulative diuresis was significantly higher in the HA group [1.0 ml kg−1 h−1 (0.6; 1.2)] compared with control [0.7 ml kg−1 h−1 (0.6; 0.9), P<0.05]. Creatinine clearance was highest in the HA and crystalloid groups. Ultrastructural kidney damage was highest in the control group [EMTI score 7.8 (6.7; 9.0)] without differences between intervention groups. Survival was 100% in the colloid groups vs 90% (crystalloid) and 60% (control, all P<0.05). ConclusionIn an ovine model of septic shock, kidney function and cumulative diuresis were preserved in the 5% albumin and crystalloid resuscitation groups, whereas HES 130/0.4 6% resulted in diminished creatinine clearance. Differences in kidney function between resuscitation fluids could not be explained by differences in ultrastructural kidney damage. Clinical trial registration84-02.04.2011.A300.

The Harmful Effects of Hypertonic Sodium Lactate Administration in Hyperdynamic Septic Shock.

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 Ringer's 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.

Triiodothyronine Administration in a Model of Septic Shock: A Randomized Blinded Placebo-Controlled Trial.

Triiodothyronine concentration in plasma decreases during septic shock and may contribute to multiple organ dysfunction. We sought to determine the safety and efficacy of administering triiodothyronine, with and without hydrocortisone, in a model of septic shock. Randomized blinded placebo-controlled trial. Preclinical research laboratory. Thirty-two sheep rendered septic with IV Escherichia coli and receiving protocol-guided sedation, ventilation, IV fluids, and norepinephrine infusion. Two hours following induction of sepsis, 32 sheep received a 24-hour IV infusion of 1) placebo + placebo, 2) triiodothyronine + placebo, 3) hydrocortisone + placebo, or 4) triiodothyronine + hydrocortisone. Primary outcome was the total amount of norepinephrine required to maintain a target mean arterial pressure; secondary outcomes included hemodynamic and metabolic indices. Plasma triiodothyronine levels increased to supraphysiological concentrations with hormonal therapy. Following 24 hours of study drug infusion, the amount of norepinephrine required was no different between the study groups (mean ± SD μg/kg; placebo + placebo group 208 ± 392; triiodothyronine + placebo group 501 ± 370; hydrocortisone + placebo group 167 ± 286; triiodothyronine + hydrocortisone group 466 ± 495; p = 0.20). There was no significant treatment effect on any hemodynamic variable, metabolic parameter, or measure of organ function. A 24-hour infusion of triiodothyronine, with or without hydrocortisone, in an ovine model of septic shock did not markedly alter norepinephrine requirement or any other physiological parameter.

Acute renal denervation does not ameliorate renal function in an ovine model of septic shock

Although obstructive sleep apnea (OSA) is common and pneumonia is a frequent cause of acute respiratory failure requiring admission to the intensive care unit, little is known about the effect of OSA on this patient population. This study examined outcomes associated with OSA in patients with pneumonia requiring invasive mechanical ventilation.The Nationwide Inpatient Sample was investigated for discharges with a primary diagnosis of pneumonia requiring invasive mechanical ventilation between 2009 and 2011. Persons aged 18 to 75 years with OSA were compared with patients without OSA. Outcomes included in-hospital mortality and nonroutine discharges.Among 74 032 hospitalizations, 13.8% (10 227) were obese, and 10.3% (7610) had OSA. Obstructive sleep apnea patients had decreased in-hospital mortality (17.0% vs 25.8%; P < .01) and nonroutine discharge (74.4% vs 79.4%; P < .01) when compared with non-OSA patients. In adjusted logistic models, OSA was associated with a 27% decreased risk of in-hospital mortality (odds ratio, 0.73; 95% confidence interval, 0.68-0.79; P < .01) and a 21% decreased risk of nonroutine discharge (odds ratio, 0.79; 95% confidence interval, 0.74-0.84; P < .01).In mechanically ventilated patients with pneumonia, OSA was associated decreased in-hospital mortality and nonroutine discharge. It is possible that differences in treatment pattern may partially explain improved survival.

Effects of a Novel Anticoagulant Compound (TV7130) in an Ovine Model of Septic Shock

Effects of a Novel Anticoagulant Compound (TV7130) in an Ovine Model of Septic Shock

Sympatho‐inhibition in an Ovine Model of Septic Shock: Cardiovascular and Renal Effects

There is evidence that inhibition of the increased sympathetic outflow in sepsis is beneficial, but the mechanisms are unclear. In conscious sheep, at 24 hours of septic shock induced by intravenous infusion of live E. coli, the effect of intravenous infusion of clonidine for 8 hours on cardiovascular and renal function was examined. Administration of E. coli caused hyperdynamic septic shock: hypotension, tachycardia, increased cardiac output, increased renal blood flow, oliguria and decreased glomerular filtration rate. During sepsis, clonidine (1.0 μg/kg/h) reduced cardiac index (from 7.5±0.8 to 5.9±0.5 L/min), heart rate (from 146±9 to 124±8 b/min), but mean arterial pressure did not significantly fall (79±4 vs. 73±5 mmHg). Clonidine reduced renal blood flow (363±9 to 312±30 mL/min) and increased urine output (22±5 to 46±19 mL/h), but did not improve creatinine clearance (42±4 to 29±9 mL/min). In hyperdynamic sepsis, clonidine treatment did not increase the degree of hypotension despite a fall in cardiac output, it increased urine output but did not improve glomerular filtration rate.This research was supported by the NHMRC, Australia.

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

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. Randomized animal study. University hospital animal research laboratory. Fourteen adult female sheep. Fecal peritonitis was induced, and the sheep were randomized to receive tetrahydrobiopterin (n=7), given intravenously as 20 mg/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. 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). 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.

Combination Therapeutics

Combination Therapeutics

The peroxynitrite catalyst WW-85 improves microcirculation in ovine smoke inhalation injury and septic shock

This prospective, randomized, controlled experimental study examined the effects of the peroxynitrite decomposition catalyst WW-85 on global hemodynamics and regional microvascular blood flow (RMBF) in an established ovine model of septic shock following severe smoke inhalation injury. Twenty-one sheep were randomized into a sham group (no injury), a control group (smoke/sepsis), and a treatment group (smoke/sepsis/WW-85; n = 7 each). WW-85 was administered 1 h after injury as a bolus (0.1 mg/kg), followed by a continuous infusion of 0.02 mg/kg/h RMBF was analyzed using colored microspheres. All control animals developed a hypotensive, hyperdynamic circulation and increased plasma levels of nitrate/-nitrite (NOx). All hemodynamic variables and NOx levels were significantly improved in the treatment group. In visceral organs of controls, blood flow to trachea, ileum, and spleen significantly increased ( p < 0.05). Blood flow to kidneys and pancreas significantly decreased ( p < 0.05). Treatment with WW-85 stabilized blood flow to ileum, spleen, and kidneys on baseline levels and was significantly improved compared to controls ( p < 0.05). Cerebral blood flow deteriorated in controls, but was significantly improved in cerebral cortex, cerebellum, pons, medulla oblongata, and thalamus ( p < 0.05) by WW-85. These results provide evidence that WW-85 blocks NO production, thereby improving cardiovascular function and microcirculation.

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 sheep's 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.

Acute Hypercapnia Improves Indices of Tissue Oxygenation More than Dobutamine in Septic Shock

Hypercapnia has similar hemodynamic effects to those of a dobutamine infusion and may have relevance in the management of septic shock. To compare the effects induced by hypercapnia with those of dobutamine in a clinically relevant model of septic shock. Fecal peritonitis was induced in 21 anesthetized, invasively monitored, mechanically ventilated female sheep. A combination of Ringer's lactate and 6% hydroxyethyl starch solution was titrated to maintain constant cardiac filling throughout the experiments. Two hours after feces spillage, animals were randomized to one of three groups (each, n = 7): (1) hypercapnia: carbon dioxide given to maintain partial pressure of carbon dioxide between 55 and 65 mm Hg throughout the experiment; (2) dobutamine: dobutamine infused intravenously (7 microg/kg/min); (3) control: no treatment. In the dobutamine and control groups, the partial pressure of carbon dioxide was kept between 35 and 45 mm Hg. All animals were monitored until spontaneous death. The animals in the hypercapnia group had significantly lower arterial pH than the other two groups (P < 0.05). Hypercapnic and dobutamine-treated animals developed significantly higher heart rate, cardiac index, and oxygen delivery, and lower lactate concentrations than control animals (P < 0.05). Hypercapnic animals had lower post mortem lung wet/dry ratio than the control animals (P < 0.05). The alveolar-arterial oxygen partial pressure difference and shunt fraction were significantly lower in hypercapnic animals than in the other groups (P < 0.05). In this clinically relevant ovine model of septic shock, hypercapnia had similar effects to dobutamine on hemodynamic variables and lactic acidosis. Hypercapnia improved tissue oxygenation and reduced lung edema formation more than dobutamine administration.

Effects of combined antibiotic therapy in an ovine model of septic shock with smoke inhalation

OBJECTIVE: Sepsis increases morbidity and mortality of smoke inhalation victims. We test the effect of ciprofloxacin and piperacillin combination therapy in an ovine model of Ps. aeruginosa sepsis with smoke inhalation. METHODS: Sheep were surgically prepared for study. After a tracheotomy, acute lung injury was induced by cotton smoke and instillation of Ps. aeruginosa into lung. After the injury, all sheep were awakened, mechanically ventilated, and resuscitated with fluid. Groups: Control (n=6: injured, untreated); Treated (n=6: injured, treated with ciprofloxacin [0.4g, every 12 h] and piperacillin [3g, every 6h] started 12h post injury). RESULTS: All control sheep died before 36h. 50% treated sheep survived over 96h. All sheep showed severe cardiopulmonary dysfunctions and plasma nitrate/nitrite (NOx) level significantly increased at 12h and peaked at 18h. PaO2/FiO2 ratio, mean arterial pressure, NOx were 167±32, 77±8, 14.0±1.3 at 18h vs. 160±42, 109±7, 5.6±1.8, respectively at 30h in treated group. CONCLUSIONS: The combined antibiotic therapy significantly improved the survival, hemodynamics, plasma NOx, but not improved pulmonary function at 30h post-injury. This combined therapy may be an effective treatment option against Ps. aeruginosa-induced sepsis even with delayed onset. SUPPORT: NIH PO12GM066312, R01GM060688, Shriners Hospitals for Children 8450, 8954, 8820

EFFECTS OF SEVERE SMOKE INHALATION INJURY AND SEPTIC SHOCK ON GLOBAL HEMODYNAMICS AND MICROVASCULAR BLOOD FLOW IN SHEEP

This prospective, randomized, controlled experimental study looks at the effects on global and regional microvascular blood flow (RMBF) in an ovine model of septic shock after severe smoke inhalation injury. Sixteen sheep were randomized into two groups, a control group (no injury, n = 8) and a smoke/sepsis (SS) group (n = 8), which received an insufflation of 4 sets of 12 breaths of cotton smoke (<40 degrees C) followed by instillation of live Pseudomonas aeruginosa into both lung lobes, according to an established protocol. All sheep were mechanically ventilated with 100% oxygen, and fluid resuscitated with lactated Ringer's solution for the entire duration of the 24-h experimental period to maintain hematocrit at baseline (BL) levels. Healthy control animals were not subjected to the injury and received only 4 x 12 breaths of room air and instillation of the vehicle (normal saline). Blood flow was analyzed using colored microspheres. Control animals remained hemodynamically stable and had no statistical changes from BL in visceral or cerebral blood flow during the entire experimental period. All SS animals developed a hypotensive, hyperdynamic circulation, characterized by a significant increase in heart rate and cardiac output with a simultaneous significant fall in mean arterial pressure, which, in combination, led to a fall in systemic vascular resistance index versus BL (P < 0.001, each). In visceral organs, the trachea showed a significant increase in RMBF (P < 0.001). In addition, skeletal muscle significantly increased versus BL and versus controls over time (P < 0.01). Whereas the pancreas displayed a significant drop in RMBF versus BL and controls (P < 0.05), no statistical differences occurred in the renal cortex, spleen, and ileum. All investigated cerebral structures, such as the cortex cerebri, basal ganglia, thalamus, hippocampus, pons, medulla oblongata, and cerebellum showed a significant increase in RMBF versus BL and versus control animals (P < 0.05, each). These data differ in areas of normal, increased, and decreased RMBF during septic shock after smoke inhalation injury and show differences to former studies of our group investigating RMBF in ovine models of either smoke inhalation or P. aeruginosa infusion. The results of this study reflect the complex pathophysiological variances of the combined injury and may provide a basis for future investigations for the treatment of this kind of injury.