Effect of hemodiafiltration on pulmonary hemodynamics in endotoxic shock

Hemofiltration can improve pulmonary hemodynamics during septic shock. The main objective of the study was to determine whether hemodiafiltration (HDF) would also have beneficial effects on pulmonary hemodynamics during septic shock. In the Endo group, six anesthetized pigs received a 0.5 mg/kg endotoxin infusion over 30 min. In the HDF group (n = 6), HDF was started 30 min after the end of the endotoxin infusion, while in the Control group (n = 4) they received HDF but no endotoxin infusion. Pulmonary hemodynamics were analyzed in detail with a four-element windkessel model. Although in the Control group, HDF did not alter pulmonary hemodynamic parameters, in the HDF group, it was responsible for an amplification of the deleterious pulmonary vascular response to endotoxin insult. Our results show that HDF must be used cautiously in septic shock since it can precipitate right heart failure by increasing pulmonary vascular resistance.     

不同剂量血液滤过对内毒素休克猪生存时间和细胞因子水平的影响

目的 探讨不同剂量连续性血液滤过（CVVH）对细胞因子的清除作用以及对血浆细胞因子水平的影响。 方法 采用静脉注射内毒素（E.coli O111: B4,15.7 μg/kg）的方法诱导内毒素休克猪模型。将内毒素休克猪按随机数字表法分为对照组(n=6)、 CVVH组 (n=6,前稀释法,等于后稀释法的45 ml·kg-1·h-1）和高容量血液滤过（HVHF）组 (n=6,前稀释法,等于后稀释法的70 ml·kg-1·h-1）。于造模前（基线）、成模时（T0）,成模后1 h（T1）、6 h（T6）、12 h（T12）、24 h（T24）分别测定血浆肿瘤坏死因子α（TNF-α）、白细胞介素（IL）6、IL-10和IL-18水平。 结果 对照组动物平均生存时间为（15.4±5.2） h;CVVH 组为(21.4±7.1) h;HVHF组为（22.4±6.7） h,CVVH组和HVHF组的生存时间显著高于对照组（均P < 0.05）。3组动物的心率（HR）、平均动脉压（MAP）、中心静脉压（CVP）和心排出量（CO）之间差异无统计学意义（P > 0.05）。内毒素休克猪成模后出现BUN和Scr的进行性升高,两治疗组的BUN和Scr水平显著低于对照组（P < 0.05）,但两者之间差异无统计学意义（P > 0.05）。对照组TNF-α和IL-6水平在T1时达高峰,IL-10水平在T0时最高,随后不断下降。IL-18水平在成模后上升,后无明显变化。CVVH组血浆IL-10（T6、T12、T24）水平低于对照组（P < 0.05）。HVHF组TNF-α（T6）和IL-10（T6、T12、T24）水平低于对照组和CVVH组（P < 0.05）,3组的IL-6和IL-18水平差异无统计学意义,IL-6（T6、T12）水平和动物生存时间呈负相关（P < 0.05）。 结论 CVVH和HVHF治疗均能显著延长内毒素休克猪的生存时间。CVVH能有效清除IL-10;HVHF治疗能清除TNF-α和IL-10;但CVVH和HVHF对IL-6和IL-18水平无明显影响;CVVH和HVHF均能有效清除BUN和Scr。IL-6水平是预测内毒素休克预后的独立指标。     

Continuous venovenous hemofiltration improves arterial oxygenation in endotoxin-induced lung injury in pigs

BACKGROUND: Hypoxemia is common in septic acute lung failure. Therapy is mainly supportive, and most trials using specific inhibitors of key inflammatory mediators (ie., tumor necrosis factor alpha, interleukin 1) have failed to prove beneficial. The authors investigated if a nonspecific blood purification technique, using zero-balanced high-volume continuous venovenous hemofiltration (CWH), might improve arterial oxygenation in a fluid-resuscitated porcine model of endotoxin-induced acute lung injury. METHODS: Piglets of both sexes weighing 25-30 kg were anesthetized and mechanically ventilated. After baseline measurements, animals received an intravenous infusion of 0.5 mg/kg endotoxin (Escherichia coli lipopolysaccharide). One hour after endotoxin, animals were randomly assigned to either treatment with CWH (endotoxin + hemofiltration, n = 6) or spontaneous course (endotoxin, n = 6). At 4 h after randomization, animals were killed. Hemofiltration was performed from femoral vein to femoral vein using a standard circuit with an EF60 polysulphone hemofilter. RESULTS: Endotoxin challenge induced arterial hypoxemia, an increase in peak inspiratory pressure, pulmonary hypertension, and systemic hypotension. Treatment with CWH did not improve systemic or pulmonary hemodynamics. However, arterial oxygenation was increased in endotoxin-challenged animals at 5 h after completion of endotoxin infusion, as compared with animals not receiving CVVH (arterialoxygen tension, 268+/-33 vs. 176+/-67 mm/Hg, respectively, P < 0.01). In addition, treatment with CWH attenuated the endotoxin-induced increase in peak inspiratory pressure and increased lung compliance. CONCLUSION: These results suggest that nonspecific blood purification with high-volume CWH improves arterial oxygenation and lung function in endotoxin-induced acute lung injury in pigs, independent of improved hemodynamics, fluid removal, or body temperature.     

Continuous Venovenous Hemofiltration Improves Arterial Oxygenation in Endotoxin-induced Lung Injury in Pigs

Background: Hypoxemia is common in septic acute lung failure. Therapy is mainly supportive, and most trials using specific inhibitors of key inflammatory mediators (i.e., tumor necrosis factor [alpha], interleukin 1) have failed to prove beneficial. The authors investigated if a nonspecific blood purification technique, using zero-balanced high-volume continuous venovenous hemofiltration (CVVH), might improve arterial oxygenation in a fluid-resuscitated porcine model of endotoxin-induced acute lung injury.

Methods: Piglets of both sexes weighing 25-30 kg were anesthetized and mechanically ventilated. After baseline measurements, animals received an intravenous infusion of 0.5 mg/kg endotoxin (Escherichia coli lipopolysaccharide). One hour after endotoxin, animals were randomly assigned to either treatment with CVVH (endotoxin + hemofiltration, n = 6) or spontaneous course (endotoxin, n = 6). At 4 h after randomization, animals were killed. Hemofiltration was performed from femoral vein to femoral vein using a standard circuit with an EF60 polysulphone hemofilter.

Results: Endotoxin challenge induced arterial hypoxemia, an increase in peak inspiratory pressure, pulmonary hypertension, and systemic hypotension. Treatment with CVVH did not improve systemic or pulmonary hemodynamics. However, arterial oxygenation was increased in endotoxin-challenged animals at 5 h after completion of endotoxin infusion, as compared with animals not receiving CVVH (arterial oxygen tension, 268 +/- 33 vs. 176 +/- 67 mmHg, respectively, P < 0.01). In addition, treatment with CVVH attenuated the endotoxin-induced increase in peak inspiratory pressure and increased lung compliance.     

Intestinal and hepatic perfusion and metabolism in hypodynamic endotoxic shock. Effects of nitric oxide synthase inhibition

Background: Inhibition of nitric oxide synthase (NOS) has been claimed to be beneficial in septic shock. We investigated the overall and regional effects of a NOS-inhibitor on perfusion and metabolism during severe endotoxic shock.
Methods: Nineteen anaesthetised pigs were catheterised and ultrasonic flow-probes were placed around the portal vein, the hepatic artery, and the superior mesenteric artery. Thirteen animals were given a 3-h infusion of endotoxin; in 6 of these an infusion of N^G-nitro-L-arginine-methyl-ester (L-NAME) was started an hour after the start of endotoxin while 7 animals served as controls and received endotoxin only. Six animals were sham operated with no further intervention.
Results: Endotoxin produced a hypodynamic shock with pulmonary hypertension. L-NAME did not increase arterial blood pressure, but deepened the fall in cardiac output and enhanced the increase in systemic and pulmonary vascular resistance. The infusion of endotoxin caused a decrease in flows in all regions. The addition of L-NAME induced a further decrease in the mesenteric artery flow only. L-NAME had no additional effect on hepatic artery flow ratio, while a transient decrease was seen in mesenteric flow ratio. Portal flow ratio decreased in the control group only. Global as well as regional oxygen extraction increased in both groups, more so in the L-NAME group. Lactate levels increased with no differences between the groups.
Conclusion: In hypodynamic endotoxic shock, L-NAME infusion enhanced pulmonary vasoconstriction and increased left ventricular afterload. The resulting hypoperfusion caused an increase in mortality. The effects of L-NAME on global and mesenteric blood flow and metabolism were similar, while L-NAME had no additional effects on hepatic hypoperfusion or oxygen extraction. Thus, nitric oxide does not seem to be a major factor in the preservation of hepatic perfusion during unresuscitated endotoxic shock.     

Anatomic arterial-venous shunting in endotoxic and septic shock in dogs.

Shunting of radionuclide labeled 9 micron diameter microspheres by the systemic circulation, and 6 body regions was measured in two dog shock models: endotoxic shock (1 mg/kg E. Coli endotoxin intravenously) and sepsis and septic shock (5 days after cecal ligation). Mean systemic arterial blood pressure was significantly lower than control in both the endotoxic and septic shock groups. Mean systemic shunting was 7.7% in the control group and 7.3% and 4.3% respectively in the endotoxic and septic shock groups. Regional shunting of the head, heart, and skeletal muscle were not significantly different in the three groups. However, mean shunting in the splanchnic circulation was 36.5% in the septic shock group as compared to 18.6% in the control group (p less than 0.05). Mean kidney shunting in the endotoxic group was 15.1% compared to 4% in the control group (p less than 0.05). During resuscitation with crystalloid, mannitol, blood, and cortiocosteroids mean aterial blood pressure and cardiac index increased but systemic arterial-venous shunting was 3.8 and 4.3% in endotoxic and septic shock respectively. These data show that systemic anatomic arterial-venous shunting is small and not different from control in both dog shock models, and regional arterial-venous shunting is increased only in the splanchnic circulation in the septic model and in the kidney in the endotoxin model.     

Effects of Large‐Pore Hemofiltration in a Swine Model of Fulminant Hepatic Failure

Among the different potential mechanisms that could lead to brain edema and intracranial hypertension in fulminant hepatic failure (FHF), the inflammatory hypothesis implies that systemic inflammation might be in part responsible for an increase in cerebral blood flow (CBF) and brain water content. In this study, the authors used a validated ischemic FHF swine model to evaluate the effects of 80 kDa large‐pore membrane hemofiltration (LPHF) on intracranial pressure (ICP) and CBF, in relation with the clearance of proinflammatory cytokines and blood liver tests, as primary end points. Fifteen pigs were randomized into one of three groups: SHAM, FHF, and FHF + LPHF. All experiments lasted 6 h. In the FHF groups, liver failure was induced by liver ischemia. After 2 h, the FHF + LPHF group underwent 4 h of a zero‐balance continuous veno‐venous hemofiltration using a 0.7‐m², large‐pore (78 Å) membrane with a cutoff of 80 kDa. ICP, CBF, mean arterial pressure, central venous pressure, and heart rate were continuously monitored and recorded. Arterial aspartate aminotransferase, total bilirubin, creatinine, international normalized ratio, glucose, lactate and serum cytokines interleukin (IL)‐6, IL‐10, and tumor necrosis factor‐α were measured at T0, T120, and T360. Over the 6 h following liver ischemia, the FHF group developed a significant increase in ICP. This ICP rise was not observed in the SHAM group and was attenuated in the FHF + LDHF group. However, the ICP levels were not different at T360 in the FHF + LDHF group compared to the FHF group. No significant effect of LPHF on liver tests or levels of proinflammatory cytokines could be demonstrated. In this model, 80 kDa LPHF was not efficient to control FHF intracranial hypertension and to decrease serum cytokine levels.     

Epinephrine and endotoxin tolerance differentially modulate serum cytokine levels to high-dose lipopolysaccharide challenge in a murine model

BACKGROUND: The epinephrine tolerance state has been demonstrated to increase survival in endotoxic shock and was claimed to have cross-tolerance with endotoxin tolerance. With use of these data, we aimed to determine the effect of epinephrine and endotoxin tolerance on major cytokine levels in a lipopolysaccharide challenge in mice. METHODS: Epinephrine tolerance was induced by beginning with a low dose and gradually increasing to a lethal dose. Endotoxin tolerance was induced by injecting saline solution for 4 days and lipopolysaccharide 1 mg/kg on the fifth day. After these procedures, saline solution or 20 mg/kg lipopolysaccharide was injected into animals. Peak serum levels of tumor necrosis factor-alpha (TNF-alpha), interleukin 1 beta, interleukin 6 (IL-6), interleukin 10 (IL-10), and interleukin 12 (IL-12) were assayed. RESULTS: The lipopolysaccharide injection increased the levels of all the cytokines in the control and epinephrine-tolerant animals. TNF-alpha, IL-6, and IL-10 levels were lower in endotoxin-tolerant animals compared with controls. Epinephrine-tolerant animals had higher levels of TNF-alpha, IL-6, and IL-12 than the controls did. CONCLUSION: Epinephrine tolerance primes for an exaggerated release of TNF-alpha, IL-6, and IL-12 in response to lipopolysaccharide challenge, suggesting anti-inflammatory and immunosuppressive effects by epinephrine. The anti-inflammatory effect was not mediated through increased IL-10 release. Endotoxin tolerance selectively modulated cytokine release.     

High‐Volume Hemofiltration Reduces the Expression of Myocardial Tumor Necrosis Factor‐Alpha in Septic Shock Pigs

Increasing evidence indicates that the expression of tumor necrosis factor‐α (TNF‐α) in myocardium correlates with the severity of cardiac dysfunction in septic shock. The aim of this study was to investigate the impact of high‐volume hemofiltration (HVHF) on the expression of TNF‐α in myocardium in septic shock pigs. Sixteen male Landrace pigs weighing 31 ± 5 kg were randomly assigned to control group (n = 4), septic shock group (n = 6), and HVHF group (septic shock + HVHF, n = 6). All animals were anesthetized and mechanically ventilated. After baseline examinations, septic shock group and HVHF group underwent induction of peritonitis. One hour later, the animals in HVHF group received treatment with HVHF and the treatment was continued for 12 h. As the control of HVHF group, the animals in septic shock group received the same support but hemofiltration. Twelve hours after HVHF therapy, all the animals were sacrificed. TNF‐α and nitric oxide (NO) levels in both circulation and myocardium were measured. Compared with those of septic shock animals, the levels of cardiac output, stroke volume, and mean arterial pressure were better maintained in HVHF group. The expression of TNF‐α in myocardium in HVHF group was lower than that in septic shock group (44.17 ± 18.70 vs. 92.50 ± 33.89 pg/mg protein, P = 0.015). The difference of TNF‐α in circulation between HVHF group and septic shock group was no significance at different time. However, circulating NO in HVHF group was lower than that in septic shock group. These results suggest that HVHF improves hemodynamics and heart dysfunction in septic shock pigs, which may be attributed to reduction of TNF‐α in myocardium but not in circulation.     

Beneficial effects of hypertonic saline/dextran on early survival in porcine endotoxin shock

BACKGROUND: Hypertonic saline/dextran (HSD) has been shown to have beneficial effects in haemorrhagic shock. These effects, with improved haemodynamics and organ perfusion, would in theory also be of benefit in septic shock. However, this is less studied. We have therefore further evaluated the effect of additional treatment with HSD in a porcine endotoxin shock model. METHODS: Sixteen anaesthetized pigs were used. A continuous infusion of endotoxin (LPS EC) was increased stepwise during 30 min to a rate of 5 microg/kg/h. The infusion was discontinued after 3 h and the animals were observed for another 2 h. The animals received continuous basal fluid resuscitation with isotonic Ringer's glucose 2.5% at a rate of 20 ml/kg/h throughout the experiment. After 1 h of endotoxin infusion, the animals were randomized to additional treatment with HSD, 4 ml/kg over 5 min, or the same volume of isotonic saline. Every 30 min, haemodynamics and mixed venous saturation (SvO2) were measured via a pulmonary artery catheter. Regional blood flow rates were measured continuously by perivascular ultrasonic flow probes. The metabolic response was measured by arterial blood gas analysis. RESULTS: The endotoxin put all animals into a progressive hypodynamic circulatory shock during the experiment. Treatment with HSD improved survival rate to 8/8 compared with controls 3/8. There was a transient circulatory recovery with improved central and regional haemodynamics, accompanied by stabilized metabolic response. CONCLUSION: Treatment with additional HSD improves survival in an early phase of endotoxin shock. Generally improved haemodynamics and oxygenation of peripheral tissues are suggested as possible mechanisms.     

Insulin tolerance during endotoxic shock in 10-day-old rats

PURPOSE: The purpose was to investigate insulin tolerance during endotoxic shock in 10-day-old rats. MATERIALS AND METHODS: [(14)C]Deoxy-glucose (2DG) with or without insulin (1 unit/kg) was injected to 10-day-old and 6-week-old rats 3 h after an injection of endotoxin (lipopolysaccharide: LPS). Plasma concentrations of glucose and 2DG were serially measured for 45 min. Gluconeogenesis was measured in hepatocytes isolated from control and endotoxic 10-day-old rats to evaluate effects of insulin on gluconeogenesis. RESULTS: In endotoxic 10-day-old rats, plasma glucose concentration at 45 min was 48 +/- 3% (P < 0.05) of value at 0 min, and when insulin was injected with 2DG, it was 29 +/- 4% (P < 0.05) after insulin injection. Plasma 2DG disappearance was enhanced by insulin injection in the control (t(1/2) = 17.9 vs 20.5 min, P < 0.05), but not in the endotoxic rats (t(1/2) = 17.9 vs 18.4 min), indicating the presence of insulin tolerance in septic rats. Insulin decreased gluconeogenesis (P < 0.05) in hepatocytes from both control and endotoxic 10-day-old rats. In endotoxic 6-week-old rats, plasma glucose concentration was decreased to 46 +/- 10% at 45 min and further decreased to 38 +/- 4% (P < 0.05) by insulin injection. Plasma 2DG disappearance was enhanced by insulin injection in the control (t(1/2) = 11.8 vs 17.4 min, P < 0.05) and in the septic rats (t(1/2) = 14.8 vs 12.2 min). However, the enhancement of plasma 2DG disappearance by insulin was less (P < 0.05) in the septic rats than in the control, confirming reports of other investigators which showed insulin tolerance in septic shock. CONCLUSION: Although hepatocytes from endotoxic rats retained insulin sensitivity, insulin tolerance which was evaluated by 2DG disappearance occurred during septic shock in newborn rats.     

The 21-aminosteroid U74389G enhances hepatic blood flow and preserves sinusoidal endothelial cell function and structure in endotoxin-shocked dogs.

BACKGROUND: 21-Aminosteroids are potent anti-inflammatory and antioxidant drugs that provide remarkable endothelial protection in different models of tissue ischemia-reperfusion and inflammation. The effects of 21-aminosteroids in sepsis, a highly inflammatory condition leading to panendothelial activation and injury, are largely uninvestigated. We therefore explored the effects of the 21-aminosteroid U74386G on hepatic blood flow, endothelial cell function, and sinusoidal structure in a canine model of fluid-resuscitated, hyperdynamic endotoxic shock. MATERIALS AND METHODS: Following invasive hemodynamic monitoring and placement of ultrasonic flow probes around the common hepatic artery and the portal vein, 12 anesthetized dogs received 2 mg/kg iv of Escherichia coli endotoxin, followed by generous saline infusion, before randomization into two groups. One group (N = 6) received U74389G as an iv bolus of 80 microg/kg, followed by a continuous infusion of 10 microg/kg. min. The other group (N = 6) received an equivalent volume of vehicle. Hyaluronic acid was measured in plasma for in vivo evaluation of endothelial cell function. Liver biopsies were taken after 4 h of endotoxic shock and prepared for light and electron microscopic examination. RESULTS: Compared with the vehicle-treated controls, U74389G maintained a higher blood flow in the hepatic artery and in the portal vein, without markedly influencing the systemic hemodynamic response. The endotoxin-induced increase in plasma hyaluronic acid levels was significantly attenuated following U74389G treatment (70 +/- 14 vs 188 +/- 24 ng/mL after 3 h of endotoxic shock; P < 0.05). Morphological studies showed that the U74389G-treated group had less sinusoidal endothelial cell damage together with a dramatic reduction of neutrophil infiltration into the liver tissue. CONCLUSION: U74389G can preserve the functional and structural integrity of endothelial cells in the hepatic sinusoid during hyperdynamic endotoxic shock. This endothelial-protective effect was associated with a better maintained hepatic blood flow and a significant attenuation of inflammatory liver injury.     

Cytokine serum level during severe sepsis in human IL-6 as a marker of severity.

Forty critically ill surgical patients with documented infections were studied during their stay in an intensive care unit. Among these patients, 19 developed septic shock and 16 died, 9 of them from septic shock. Interleukin 1 beta (IL-1 beta), tumor necrosis factor (TNF alpha), and interleukin 6 (IL-6) were measured each day and every 1 or 2 hours when septic shock occurred. Although IL-1 beta was never found, TNF alpha was most often observed in the serum at a level under 100 pg/mL except during septic shock. During these acute episodes TNF alpha level reached several hundred pg/mL, but only for a few hours. In contrast, IL-6 was always increased in the serum of acutely ill patients (peak to 500,000 pg/mL). There was a direct correlation between IL-6 peak serum level and TNF alpha peak serum level during septic shock and between IL-6 serum level and temperature or C-reactive protein serum level. Moreover, IL-6 correlated well with APACHE II score, and the mortality rate increased significantly in the group of patients who presented with IL-6 serum level above 1000 pg/mL. Thus, IL-6 appears to be a good marker of severity during bacterial infection.     

Bioartificial kidney ameliorates gram-negative bacteria-induced septic shock in uremic animals

The bioartificial kidney (BAK) consists of a conventional hemofiltration cartridge in series with a renal tubule assist device (RAD) containing 10(9) porcine renal proximal tubule cells. BAK replaces filtration, transport, and metabolic and endocrinologic activities of a kidney. Previous work in an acutely uremic dog model demonstrated that BAK ameliorated endotoxin (lipopolysaccharide [LPS])-induced hypotension and altered plasma cytokine levels. To further assess the role of BAK in sepsis in acute renal failure, dogs were nephrectomized and 48 h later administered intraperitoneally with 30 x 10(10) bacteria/kg of E. coli. One hour after bacterial administration, animals were placed in a continuous venovenous hemofiltration circuit with either a sham RAD without cells (n = 6) or a RAD with cells (n = 6). BP, cardiac output, heart rate, pulmonary capillary wedge pressure, and systemic vascular resistance were measured throughout the study. All animals tested were in renal failure, with blood urea nitrogen and serum creatinine concentrations greater than 60 and 6 mg/dl, respectively. RAD treatment maintained significantly better cardiovascular performance, as determined by arterial BP (P < 0.05) and cardiac output (P < 0.02), for longer periods than sham RAD therapy. Consistently, all sham RAD-treated animals, except one, expired within 2 to 9 h after bacterial administration, whereas all RAD-treated animals survived more than 10 h. Plasma levels of TNF-alpha, IL-10, and C-reactive protein (CRP) were measured during cell RAD and sham RAD treatment. IL-10 levels were significantly higher (P < 0.01) during the entire treatment interval in the RAD animals compared with sham controls. These data demonstrated in a pilot large animal experiment that the BAK with RAD altered plasma cytokine levels in acutely uremic animals with septic shock. This change was associated with improved cardiovascular performance and increased survival time. These results demonstrate that the addition of cell therapy to hemofiltration in an acutely uremic animal model with septic shock ameliorates cardiovascular dysfunction, alters systemic cytokine balance, and improves survival time.     

Dobutamine compensates deleterious hemodynamic and metabolic effects of vasopressin in the splanchnic region in endotoxin shock

BACKGROUND: Vasopressin is a potent vasopressor in septic shock, but it may impair splanchnic perfusion. We compared the effects of vasopressin alone and in combination with dobutamine on systemic and splanchnic circulation and metabolism in porcine endotoxin shock. METHODS: Twelve pigs were randomized to receive either vasopressin (VASO, n = 6) or vasopressin in combination with dobutamine (DOBU, n = 6) during endotoxin shock (E. coli endotoxin infusion). Endotoxin infusion rate was increased to induce hypotension after which vasoactive drugs were started. We aimed to keep systemic mean arterial pressure (MAP) >70 mmHg by vasopressin; the goal of dobutamine infusion was to prevent decrease in cardiac output often associated with vasopressin infusion. Regional blood flows, oxygen delivery and consumption, arterial and regional lactate concentrations were measured. RESULTS: Mean arterial pressure >70 mmHg was achieved in both the VASO and DOBU groups. After the primary decrease of cardiac output by vasopressin, systemic blood flow remained stable in vasopressin-treated animals. However, vasopressin as a monotherapy decreased portal venous blood flow. This was prevented by dobutamine. Vasopressin also induced splanchnic lactate release and arterial hyperlactatemia, which were not observed when dobutamine was combined with vasopressin. CONCLUSION: Dobutamine prevents adverse hemodynamic and metabolic effects of vasopressin in septic shock.     

On the value of giving a combination of drugs for the treatment of endotoxaemia in pigs.

OBJECTIVE: To see if treatment with a combination of drugs each directed at a different mediator was successful in preventing activation of those mediators in experimental endotoxic shock. DESIGN: Controlled study. MATERIAL: 40 juvenile pigs. INTERVENTIONS: 33 animals received 0.01 mg/kg endotoxin infusion, the rest being given the same volume of saline; 10 of the 33 received no treatment. Of the remaining 23, 5 were given combination treatment with methylprednisolone, naloxone, ketanserin, promethazine, C1 esterase inhibitor, antithrombin III and aprotinin; 7 were given methylprednisolone only; 6 were given the three protease inhibitors (C1 esterase inhibitor, antithrombin III and aprotinin); and 5 were given naloxone, ketanserin and promethazine. MAIN OUTCOME MEASURES: Assessment of haemodynamic, proteolytic, and cellular effects of endotoxaemia. RESULTS: Only the combination treatment totally blocked all the effects of the infusion of endotoxin. CONCLUSION: As endotoxin affects several mediators, combination treatment is necessary to block all its deleterious effects in pigs.     

己酮可可碱对内毒素休克家兔生物喋呤诱生的干预作用

目的　观察己酮可可碱 (PTX)对内毒素休克家兔休克时生物喋呤诱生的影响。　方法　 2 8只大耳白兔 ,随机分为 3组 ,对照组 (8只 )、内毒素休克组 (10只 )、PTX治疗组 (10只 )。制作内毒素休克模型 ,观察血浆生物喋呤、肿瘤坏死因子及组织三磷酸鸟苷环水解酶I活性的变化 ,同时监测全身血流动力学改变。　结果　内毒素休克大鼠早期给予PTX治疗 ,可显著降低血浆生物喋呤及肿瘤坏死因子水平 ,与对照组及休克组比较 ,差异有显著性意义 (P <0 0 5 ,P <0 0 1) ;不同程度地抑制肝、肺、心等组织三磷酸鸟苷环水解酶I活性 (P <0 0 5 ) ;与此同时 ,治疗组平均动脉压、心输出量及外周血管阻力均比休克组明显提高 ,差异有显著性意义 (P <0 0 5 ,P <0 0 1)。　结论　PTX能有效抑制内毒素休克时体内生物喋呤的合成与释放 ,明显减轻全身血流动力学障碍。     

Effect of ibuprofen and diethylcarbamazine on the hemodynamic and inflammatory response to endotoxin in the dog

We studied the effects of pretreatment with either ibuprofen (15 mg/kg), diethylcarbamazine (DEC, 15 mg/kg), or vehicle, on the hemodynamic, hematologic, and serum tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-6 responses to a bolus Escherichia coli endotoxin infusion (2 mg/kg) in 21 pentobarbital-anesthetized dogs (n = 7 each group). Hematologic and cytokine data were collected before and 0.5, 1, and 3 h after endotoxin infusion. Endotoxin decreased arterial pressure (P(a)), cardiac output (CO), total leukocyte (WBC) and platelet counts, and increased lactate, TNF-alpha, and IL-6. TNF-alpha levels peaked at 1 h and decreased by 3 h, whereas IL-6 remained elevated. Ibuprofen abolished the endotoxin-induced changes in P(a) and lactate, but did not alter the initial decrease in CO, WBC, and platelets or the increase in TNF-alpha and IL-6. DEC did not alter the response to endotoxin, although the DEC group had higher TNF-alpha and IL-6 levels before endotoxin infusion compared to controls. We conclude that the cardiovascular effects of ibuprofen in the canine model of acute endotoxemia are not due to suppression of the systemic inflammatory response.     

1,6—二磷酸果糖对犬内毒素休克血流动力学的影响

１２只犬随机分为两组：内毒素休克组（ＥＴ），内毒素休克治疗组（ＦＤＰ组）。麻醉后机械通气，分别插入动脉导管及 Ｓｗａｎ－Ｇａｎｚ漂浮导管并联接于 ＢＳＭ－８３０１Ｊ／Ｋ生理记录仪。外周静脉注射灭活大肠杆菌（２．７×１０１２／ｋｇ）。３０、９０分钟后ＦＤＰ经外周静脉输入３７５ｍｇ／ｋｇ。ＥＴ组输入等容量平衡盐液。注射ＥＴ前、后１至８小时测血流动力学及心功能指标。结果。注射ＥＴ前两组各项指标间无明显差异，注射后ＣＩ、ＭＡＰ、ＰＡＭＰ、ＰＣＷＰ、ＳＶＩ、ＬＳＷＩ明显低于注射前，且ＥＴ组呈进行性下降，而ＦＤＰ组则逐渐回升至正常水平。８小时死亡率ＦＤＰ组明显低于ＥＴ组。这说明ＦＤＰ通过改善心功能、恢复血流动力学对ＥＴ休克有较好疗效，能显著延长ＥＴ休克犬存活时间。     

Increased plasma levels of vasoactive intestinal polypeptide in pigs during endotoxinaemia

Vasoactive intestinal polypeptide (VIP) is a highly potent vasodilatator. Cardiovascular changes and plasma VIP levels were studied during endotoxinaemia (Escherichia coli endotoxin 1 mg/kg) in a carefully monitored porcine model. Endotoxin infusion resulted in a profound but reversible shock and a substantial rise in plasma VIP levels. Increased levels of VIP could be demonstrated already after 30 min of endotoxin infusion and increased further during the infusion. Animals followed for a period of 60 h demonstrated slowly declining levels of VIP after endotoxin infusion but significantly elevated levels were usually found 24 h after infusion. Control animals did not show any changes in VIP during a similar procedure. Release of gastrointestinal peptides may be of importance during septic shock.