Enteral administration of high-fat nutrition before and directly after hemorrhagic shock reduces endotoxemia and bacterial translocation

OBJECTIVE: To determine whether potential enhancement of endotoxin neutralization via high-fat enteral nutrition affects endotoxemia and bacterial translocation after hemorrhage. SUMMARY BACKGROUND DATA: Endotoxin and bacterial translocation due to gut barrier failure are important initiating events in the pathogenesis of sepsis after hemorrhage. Systemic inhibition of endotoxin activity attenuates bacterial translocation and distant organ damage. Triacylglycerol-rich lipoproteins constitute a physiological means of binding and neutralizing endotoxin effectively. We hypothesized that enhancement of triacylglycerol-rich lipoproteins via high-fat enteral nutrition would reduce endotoxemia and prevent bacterial translocation. METHODS: A rat model of nonlethal hemorrhagic shock was used. Hemorrhagic shock (HS) rats were divided into 3 groups: rats starved overnight (HS-S); rats fed with a low-fat enteral diet (HS-LF), and rats receiving a high-fat enteral diet (HS-HF). RESULTS: Circulating triacylglycerol and apolipoprotein B, reflecting the amount of triacylglycerol-rich lipoproteins, were elevated in HS-HF rats compared with both HS-S rats (P 相似文献   

Translocation of endotoxin and acute-phase proteins in malleolar fractures

BACKGROUND AND OBJECTIVE: Translocation of endotoxins was demonstrated for multiple injury but not for minor trauma such as isolated malleolar fractures. Major trauma leads to substantial changes in the plasma concentration of acute-phase proteins. However, isolated malleolar fractures are minor trauma. The objective of this study was to elucidate the kinetics of endotoxemia and the ability of plasma to inactivate endotoxin of patients operated on malleolar fractures and to demonstrate the early time course of the acute-phase proteins C-reactive protein, transferrin, alpha1-acid glycoprotein, haptoglobin, and interleukin-6 and to correlate them with the amount of endotoxemia. METHODS: Thirty patients with malleolar fractures were operated on within 6 hours after injury. Blood was collected immediately after admission and regularly up to 96 hours after surgery. RESULTS: Preoperative endotoxin plasma levels were increased compared with that of healthy individuals (0.05 +/- 0.017 vs. 0.02 EU/mL). Endotoxemia peaked 0.5 hours after the surgical procedure at 0.096 +/- 0.03 (p < 0.05 vs. healthy) and decreased to almost normal values after 24 hours. The ability of the plasma to inactivate endotoxin was significantly reduced after the surgical procedure compared with normal subjects (recovery, 0.17 +/- 0.028 EU/mL vs. 0.04 +/- 0.01 EU/mL; p < 0.05). Plasma interleukin-6 peaked 0.5 hours postoperatively (114 +/- 11 pg/mL, p < 0.05 vs. healthy), decreasing thereafter. C-Reactive protein peaked at 45 +/- 5 mg/mL (p < 0.05) 48 hours after injury. Transferrin decreased significantly postoperatively (2.41 +/- 0.12 mg/mL vs. pre-OP 2.65 +/- 0.1 mg/mL) and remained on this level for 96 hours. Both, alpha1-acid glycoprotein and haptoglobin increased postoperatively until day 4 (0.78 +/- 0.06 mg/mL to 1.15 +/- 0.08 mg/mL and 1.51 +/- 0.12 mg/mL to 3.24 +/- 0.22 mg/mL). There was no correlation between endotoxemia and the concentrations of the acute-phase proteins and interleukin-6. CONCLUSION: Surgery for malleolar fractures is associated with temporary endotoxemia and temporary reduced endotoxin inactivation capacity of the plasma. The injury and the surgical procedure leads to substantial changes in the plasma concentrations of acute-phase proteins. The relation between endotoxemia and acute-phase response is not dose dependent.     

Endotoxemia and acute-phase proteins in major abdominal surgery

BACKGROUND: Translocation of endotoxin is a controversial issue. The ability of plasma to inactivate endotoxin is an indirect measure of endotoxemia. Endotoxin is a potent stimulator of the inflammatory response and affects the innate immune system. OBJECTIVE: To elucidate the kinetics of endotoxemia and the ability of plasma to inactivate endotoxin in patients with major abdominal operations. To demonstrate the early time course of the acute-phase proteins C-reactive protein (CRP), serum amyloid A (SAA), alpha(1)-antitrypsin, alpha(2)-macroglobulin, transferrin, and interleukin 6 (IL-6), and to correlate them with the amount of endotoxemia. METHODS: Twenty patients with elective major abdominal operation and 10 healthy controls were investigated. Blood was collected preoperatively, during the operation and regularly up to 12 days after surgery. Endotoxin was measured by Limulus amebocyte lysate test (LAL), the ability of plasma to inactivate endotoxin by modified LAL, the acute-phase proteins nephelometrically, and IL-6 by enzyme-linked immunosorbent assay (ELISA). RESULTS: Preoperative endotoxin plasma level (0.026 +/- 0.004 EU/mL) did not differ from healthy volunteers but increased during operation (0.09 +/- 0.02 EU/mL, P = 0.02). Endotoxemia peaked 1 hour after the surgical procedure (0.16 +/- 0.03 EU/mL; P <0.0001 versus preoperative) and decreased to almost normal values after 48 hours. The capability of plasma to inactivate endotoxin was significantly reduced during (recovery, 0.16 +/- 0.03 EU/mL), 1 hour (0.25 +/- 0.04 EU/mL) and 24 hours (0.16 +/- 0.02 EU/mL) after the operation compared with preoperative (0.068 +/- 0.01 EU/mL) values. Plasma IL-6 was significantly increased for 48 hours with a peak 1 hour after surgery (470 +/- 108 pg/mL). CRP peaked at 210 +/- 19 mg/L (P <0.0001 versus preoperative) 48 hours after operation and was significantly elevated for the rest of the observation period. SAA was significantly increased 24 hours after surgery (249 +/- 45 mg/L) and peaked additional 48 hours later (456 +/- 86 mg/L). alpha(1)-Antitrypsin, although a positive acute-phase protein, decreased initially to 1.38 +/- 0.1 g/L (preoperative, 2.33 +/- 0.18 g/L; P <0.0001) and increased thereafter until day 12 (3.05 +/- 0.35 g/L, P = 0.11 versus preoperative). The same was true for alpha(2)-macroglobulin (preoperative, 2.2 +/- 0.16 g/L; intraoperative, 1.36 +/- 0.13 g/L; day 5, 2.8 +/- 0.4 g/L). Transferrin decreased already during surgery (1.6 +/- 0.1 g/L versus preoperative 2.8 +/- 0.17 g/L, P <0.0001) and remained on this level for 5 days. Correlation analysis revealed a relationship between endotoxemia and the ability of plasma to inactivate endotoxin (r = 0.67, P <0.0001) and also a relation between intraoperative endotoxemia on one hand and alpha(2)-macroglobulin (-0.53 > r > -0.6, P <0.05) as well as alpha(1)-antitrypsin (0.64 > r >0.55, P <0.05) on the other. CONCLUSION: Major abdominal surgery is associated with transient endotoxemia and a transient reduced endotoxin inactivation capacity of the plasma. Endotoxemia correlates with the endotoxin inactivation capacity. The surgical procedure causes substantial changes in plasma concentrations of acute-phase proteins. alpha(2)-Macroglobulin and alpha(1)-antitrypsin correlate moderately with endotoxemia.     

The nitric oxide donor molsidomine improves survival and reduces hepatocyte apoptosis in cholestasis and endotoxemia

BACKGROUND: Cholestasis and endotoxemia have been demonstrated to cause hepatocyte apoptosis through caspase-mediated pathways. In vitro nitric oxide (NO) donors reduce hepatocyte apoptosis and caspase activation in several models. The nitric oxide donor molsidomine improves survival in an in vivo model of endotoxemia. We tested the effect of molsidomine on survival and hepatocyte apoptosis in a model of obstructive jaundice and endotoxemia. STUDY DESIGN: Sprague-Dawley rats underwent common bile duct ligation on day 1. On day 3, animals were given either 100 mg/kg of molsidomine or an equivalent volume of saline, and 30 minutes later they were given endotoxin 3 mg/kg or 10 mg/kg intravenously. Animals were sacrificed 4 or 16 hours after endotoxin injection. Serum samples were analyzed for alanine aminotransferase and frozen liver samples were analyzed for caspase 3 activity. Paraffin-embedded liver sections were assayed for apoptosis using the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling assay. Survival was measured in a separate experiment in which animals underwent the same protocol, but were given three different doses of endotoxin and were observed for 72 hours before sacrifice. RESULTS: At endotoxin 3 mg/kg, the 72-hour survival in saline-treated animals was 92%, which decreased to 45% at 10 mg/kg and to 29% at 15 mg/kg. All of the molsidomine-treated animals survived all endotoxin doses. Alanine aminotransferase was reduced in molsidomine-treated animals compared with those treated with saline. Apoptosis was attenuated in molsidomine-treated animals. Caspase 3 activity was decreased in molsidomine-treated animals compared with those given saline. CONCLUSIONS: Molsidomine attenuates caspase activation and hepatocyte apoptosis and improves survival after cholestatic endotoxic injury.     

Increased oxygen cost of contractility in the endotoxemic porcine left ventricle

OBJECTIVE: Myocardial oxygen consumption (MVO) in the septic myocardium is comparatively high in relation to the sepsis-induced reduction in ventricular work. Our previous studies indicate that this energetic inefficiency is due to increased energy consumption in excitation-contraction (EC) coupling, i.e. myocardial calcium handling. DESIGN: To further confirm this observation, we assessed the oxygen cost of contractility in anesthetized pigs before and 2 h after induction of endotoxemia (1 microg/kg endotoxin infusion over 1 h, Escherichia coli toxin, n=6). Baroreceptor reflexes were blocked by hexamethonium. Contractility was increased by stepwise dopamine infusions at baseline and 2 h after induction of endotoxemia. Oxygen cost of contractility was assessed as the relationship between myocardial contractility (E or elastance) and non-mechanical oxygen consumption (unloaded MVO), a measure of energy consumption in EC coupling or calcium handling. RESULTS: Non-mechanical oxygen consumption (unloaded MVO) was higher after endotoxin infusions than at baseline (0.641 +/- 0.05 vs 0.383 +/- 0.07 J/beat/100 g, p < 0.05). The relationship between unloaded MVO and E, constructed by the dopamine response, was highly linear both at baseline and endotoxemia (r2 =0.76-0.99). However, endotoxin increased oxygen cost of contractility by approximately 45% (baseline 0.06 +/- 0.03 vs endotoxin 0.09 +/- 0.04 J ml/mmHg/beat/100 g). CONCLUSION: Acute endotoxemia increases oxygen cost of contractility, a measure of energy consumed in EC coupling or myocardial calcium handling.     

Mechanism of macrophage injury following traumatic hemorrhagic shock：through PTX—sensitive G—protein—mediated signal transduction pathway

OBJECTIVE: To study the mechanism of macrophage injury after trauma-hemorrhagic shock. METHODS: Wistar male rats underwent trauma (closed bone fracture) and hemorrhage (mean arterial blood pressure of 35 mm Hg+/-5 mm Hg for 60 minutes, following fluid resuscitation). Rats without trauma, hemorrhage or fluid resuscitation served as controls. Peritoneal macrophages were harvested at 6 hours and 1, 2, 3, 7 days after traumatic hemorrhagic shock to determine the effects of pertussis toxin (PTX, as a specific inhibitor to Gi(alpha) and cholera toxin (CTX, as a stimulant to Gs(alpha) on macrophage-Ia expression and TNF-alpha production and levels of Gi(alpha) and Gs(alpha). RESULTS: The macrophages from the injured rats revealed a significant decrease of Ia positive number and TNF-alpha release in response to LPS. Wi th pretreatment with PTX 10-100 ng/ml Ia positive cells and LPS-induced TNFalpha production in both control and impaired macrophages populations were dos e dependently increased. Both macrophages populations were not responding to CTX treatment (10-100 ng/ml). Western blot analyses showed that the levels of Gi(alpha) protein expression increased as much as 116.5%-148.8% of the control level fro m 6 hours through 7 days after traumatic hemorrhage. The levels of Gs protein expression were reduced at 6 hours and decreased to the lowest degree; 36% o f the control at day 1, began to return at day 2 and returned to the normal level at day 7, following traumatic hemorrhagic shock. CONCLUSIONS: PTX-sensitive G-protein may participate in th e modulation of macrophage-Ia expression and TNF-alpha release following traumatic hemorrhagic shock. Analyses of the alteration of Gi(alpha) and Gs protein express ions further supports the concept that G-protein is involved in trauma-induced macrophage signal transduction pathways.     

Endotoxemia after surgery in digestive diseases

The blood level of endotoxin after operations in patients with digestive diseases, mainly liver cirrhosis and obstructive jaundice, and the complications most likely related to the presence of endotoxemia were investigated. Twenty-seven patients without either liver cirrhosis or obstructive jaundice showed a minimal elevation of the endotoxin level in blood, as shown by 6.1 +/- 3.9 pg/ml at the first postoperative day and there was only one anastomotic leakage. On the other hand, 18 patients with liver cirrhosis showed a notable and persistent endotoxemia after surgery. The cirrhotic patients who especially underwent splenectomy and hepatectomy showed marked elevations of endotoxin level at the first postoperative day, with values of 151.0 +/- 46.1 pg/ml and 101.3 +/- 36.2 pg/ml, respectively, and one of these patients died of hepatic failure. Thirteen patients with obstructive jaundice developed endotoxemia evidenced by the value of 21.6 +/- 4.8 pg/ml at the first day after surgery. Among these patients, two had gastrointestinal bleeding and one developed DIC. The markedly high and persistent levels of endotoxin in patients with liver cirrhosis or obstructive jaundice may be possibly related with the development of MOF.     

Increased oxygen cost of contractility in the endotoxemic porcine left ventricle

Objective—Myocardial oxygen consumption (MVO ₂ ) in the septic myocardium is comparatively high in relation to the sepsis‐induced reduction in ventricular work. Our previous studies indicate that this energetic inefficiency is due to increased energy consumption in excitation–contraction (EC) coupling, i.e. myocardial calcium handling.

Design—To further confirm this observation, we assessed the oxygen cost of contractility in anesthetized pigs before and 2?h after induction of endotoxemia (1?μg/kg endotoxin infusion over 1?h, Escherichia coli toxin, n=6). Baroreceptor reflexes were blocked by hexamethonium. Contractility was increased by stepwise dopamine infusions at baseline and 2?h after induction of endotoxemia. Oxygen cost of contractility was assessed as the relationship between myocardial contractility (E _es or elastance) and non‐mechanical oxygen consumption (unloaded MVO ₂ ), a measure of energy consumption in EC coupling or calcium handling.

Results—Non‐mechanical oxygen consumption (unloaded MVO ₂ ) was higher after endotoxin infusions than at baseline (0.641±0.05 vs 0.383±0.07?J/beat/100?g, p?<?0.05). The relationship between unloaded MVO ₂ and E _es , constructed by the dopamine response, was highly linear both at baseline and endotoxemia (r ² =0.76–0.99). However, endotoxin increased oxygen cost of contractility by ～45% (baseline 0.06±0.03 vs endotoxin 0.09±0.04 J?ml/mmHg/beat/100?g).

Conclusion—Acute endotoxemia increases oxygen cost of contractility, a measure of energy consumed in EC coupling or myocardial calcium handling.     

Development and reversal of endotoxemia and endotoxin-related death in obstructive jaundice

Gut-derived endotoxemia has been implicated in postoperative complications in patients with jaundice. It is thought that absence of bile in the gut predisposes to portal absorption of endotoxin and endotoxemia is reversed by oral bile salt replacement or internal biliary drainage and return of bile to the gut, but not by external drainage. We believe that the importance of gastrointestinal bile flow has been overestimated and biliary obstruction and the integrity of hepatocyte and Kupffer cell function are more important in the development and reversal of endotoxemia. In experiment 1, serum endotoxin concentrations were measured in control rats (n = 10) after choledochovesical fistula (n = 15) and bile duct ligation (n = 15) and after relief of biliary obstruction by internal drainage (choledochoduodenostomy; n = 8) and sterile external drainage (choledochovesical fistula; n = 8), with a quantitative limulus assay. In experiment 2, mortality rates were measured in similar groups 48 hours after administration of oral endotoxin (5 mg/100 gm) and intravenous lead acetate (5 mg/100 gm). Bilirubin levels were elevated in bile duct ligation (192 +/- 13 mumols/L) compared with control animals and those with choledochovesical fistula, internal drainage, and external drainage (10.6 +/- 1.5 mumols/L). In experiment 1, significant portal endotoxemia and systemic endotoxemia occurred in bile duct ligation (portal, 130.4 +/- 12.9 pg/ml; systemic, 91.8 +/- 11.0 pg/ml) but not in choledochovesical fistula (portal, 49.3 +/- 17.1 pg/ml; systemic, 27.2 +/- 11.5 pg/ml). Relief of obstruction by both internal and external drainage reversed endotoxemia. In experiment 2, significant death occurred in bile duct ligation (13 of 15) but not in choledochovesical fistula (3 of 15), and relief of obstruction by both internal and external drainage prevented death. These results confirm that biliary obstruction is a more important factor than is gastrointestinal bile flow in the development and reversal of endotoxemia.     

血清内毒素检测在经皮肾镜碎石术后感染诊断中的临床意义

目的:探讨血清内毒素水平检测在经皮肾镜碎石术(PCNL)后感染诊断中的临床意义,为临床诊治提供参考。方法:选择收治的肾结石患者122例,分别在B超引导下完成PCNL,留取患者术前、术后血液样本测定内毒素水平值,分析研究血清内毒素水平变化与术后感染的关系。据检验标准设定内毒素小于0.075EU/ml为阴性值,升高为阳性值。结果:所有患者均顺利完成手术,其中19例术后出现发热(发热组),103例术后未出现发热(对照组)。对照组术前测得血清内毒素平均值为(0.023±0.017)EU/ml,阳性率为3.9%,术后平均值为(0.090±0.054)EU/ml,阳性率为39.8%;发热组术前血清内毒素平均值为(0.031±0.029)EU/ml,阳性率为10.5%,术后为(0.728±0.534)EU/ml,阳性率为89.4%。两组对比发现术前血清内毒素水平差异不明显(P0.05),但术后发热组患者血清内毒素水平明显高于对照组(P0.05),其中6例患者在出现持续寒颤高热时检测血清内毒素的平均值为(0.650±0.403)EU/ml,均为阳性值,考虑合并内毒素血症存在。结论:通过检测发现,在经皮肾镜碎石术后检测血清内毒素水平是诊断和监测术后感染的一个重要参数,且具有快速、简便、灵敏度高等优点,适合早期判断病情,对临床治疗具有一定的指导意义。     

The cardiocirculatory and metabolic effects of endotoxin challenge after canine resuscitated hemorrhagic shock

Although adequate volume resuscitation has decreased mortality from hemorrhagic shock, recovery in many patients is complicated by sepsis. To determine whether a subject debilitated by hemorrhagic shock would exhibit greater cardiocirculatory dysfunction when challenged with sepsis, ten dogs (Group I) were hemorrhaged to a mean arterial blood pressure of 30 mm Hg. After 2 hours of hypotension, shed blood and lactated Ringer's solution (50 ml/kg) were given, and the dogs were observed for 3 to 6 days. Ten dogs were sham hemorrhage and served as controls (Group II). On the experimental day, all cardiovascular and hemodynamic parameters were measured in both groups of animals before endotoxin challenge. There was no significant difference in cardiac output, stroke volume, stroke work, +dP/dt max, myocardial blood flow, myocardial oxygen metabolism, or acid-base balance in the two groups. Compared to sham-hemorrhaged dogs, resuscitated shock dogs had a significantly lower mean arterial blood pressure (127 +/- 7 vs. 110 +/- 6 mm Hg; p less than 0.05), and heart rate was significantly higher (86 +/- 6 vs. 109 +/- 7 beats/minute; p less than 0.05). Furthermore, maximal rate of left ventricular pressure fall (-dP/dT max) was significantly lower in the animals previously hemorrhaged, suggesting a persistent defect in left ventricular relaxation. Blood glucose and insulin levels were significantly elevated in the resuscitated shocked dogs, likely due to increased circulating catecholamine concentrations and enhanced glycogenolysis. Endotoxin shock caused significant hypotension, acidosis, and impaired regional perfusion in all dogs. In addition, cardiac output, stroke volume, dP/dT, and left ventricular end-diastolic pressure fell and hyperglycemia and hyperinsulinemia occurred in all dogs after endotoxin injection.(ABSTRACT TRUNCATED AT 250 WORDS)     

TNF-a release capacity is suppressed immediately after hemorrhage andresuscitation

Purpose: It has been suggested that patients with traumatic insults are resuscitated into a state of an early systemic inflammatory response. We aimed to evaluate the influence of hemorrhagic shock and resuscitation (HSR) upon the inflammatory response capacity assessed by overall TNF-a secretion capacity of the host compared to its release from circulating leukocytes in peripheral circulation. Methods: Rats (8/group) subjected to HS (MAP of 30e35 mmHg for 90 min followed by resuscitation over 50 min) were challenged with Lipopolysaccharide (LPS), 1 mg/kg intravenously at the end of resuscitation (HSR-LPS group) or 24 h later (HSR-LPS24 group). Control animals were injected with LPS without bleeding (LPS group). Plasma TNF-a was measured at 90 min after the LPS challenge. In addition, whole blood (WB) was obtained either from healthy controls (CON) immediately after resuscitation (HSR), or at 24 h post-shock (HSR 24). WB was incubated with LPS (100 ng/mL) for 2 h at 37 C. TNF-a concentration and LPS binding capacity (LBC) was determined. Results: Compared to LPS group, HSR followed by LPS challenge resulted in suppression of plasma TNF-a in HSR-LPS and HSR-LPS24 groups (1835 ± 478, 273 ± 77, 498 ± 200 pg/mL, respectively). Compared to CON the LPS-induced TNF-a release capacity of circulating leukocytes ex vivo was strongly declined both at the end of resuscitation (HSR) and 24 h later (HSR24) (1012 ± 259, 313 ± 154, 177 ± 63 ng TNF/mL, respectively). The LBC in WB was similar between CON and HSR and only moderately enhanced in HSR24 (57 ± 6, 56 ± 6, 71 ± 5 %, respectively). Conclusion: Our data suggest that the overall inflammatory response capacity is decreased immediately after HSR, persisting up to 24 h, and is independent of LBC.     

Hemodynamic and metabolic manifestations of acute endotoxin infusion in pigs with and without the malignant hyperthermia mutation.

BACKGROUND: The hypermetabolic state induced by acute endotoxemia and malignant hyperthermia (MH) may be indistinguishable. The aims of this study were (1) to investigate the differences between MH and sepsis, (2) to determine whether acute endotoxemia can trigger MH, and (3) to establish the effects of dantrolene in these two disorders. METHODS: Three groups of swine were studied. All pigs were invasively monitored and initially anesthetized with nontriggering agents. A placebo MH-susceptible group (n = 5) received normal saline whereas the endotoxin groups (MH-susceptible, n = 6; MH-negative, n = 4) received intravenous endotoxin (250 microg/kg total) during 2.5 h. Halothane (1.5%) and succinylcholine (2-4 mg/kg) were then administered, followed by two doses of dantrolene (4 mg/kg total). RESULTS: Endotoxin infusion resulted in pulmonary hypertension and systemic hypotension in pigs with and without the MH mutation, but did not trigger MH. Halothane and succinylcholine triggered MH, evidenced by a markedly higher oxygen consumption in the MH-susceptible pigs that received endotoxin (325+/-196 ml/min) and those that did not (374+/-110 ml/min) compared to the MH-negative pigs (69+/-15 ml/min, P<0.0009), as well as muscular rigidity in the susceptible animals. Dantrolene reversed these changes. Three of the six MH-susceptible pigs that received endotoxin died; two died soon after triggering and one after dantrolene administration. In contrast, none of the MH-negative pigs or the MH-susceptible pigs that did not receive endotoxin died (0 of 9 vs. 3 of 6, P = 0.044). CONCLUSION: Endotoxemia does not trigger MH, but may worsen outcome if it occurs.     

Hemodynamic and Metabolic Manifestations of Acute Endotoxin Infusion in Pigs with and without the Malignant Hyperthermia Mutation

Background: The hypermetabolic state induced by acute endotoxemia and malignant hyperthermia (MH) may be indistinguishable. The aims of this study were (1) to investigate the differences between MH and sepsis, (2) to determine whether acute endotoxemia can trigger MH, and (3) to establish the effects of dantrolene in these two disorders.

Methods: Three groups of swine were studied. All pigs were invasively monitored and initially anesthetized with nontriggering agents. A placebo MH-susceptible group (n = 5) received normal saline whereas the endotoxin groups (MH-susceptible, n = 6; MH-negative, n = 4) received intravenous endotoxin (250 [mu]g/kg total) during 2.5 h. Halothane (1.5%) and succinylcholine (2-4 mg/kg) were then administered, followed by two doses of dantrolene (4 mg/kg total).

Results: Endotoxin infusion resulted in pulmonary hypertension and systemic hypotension in pigs with and without the MH mutation, but did not trigger MH. Halothane and succinylcholine triggered MH, evidenced by a markedly higher oxygen consumption in the MH-susceptible pigs that received endotoxin (325 +/- 196 ml/min) and those that did not (374 +/- 110 ml/min) compared to the MH-negative pigs (69 +/- 15 ml/min, P < 0.0009), as well as muscular rigidity in the susceptible animals. Dantrolene reversed these changes. Three of the six MH-susceptible pigs that received endotoxin died; two died soon after triggering and one after dantrolene administration. In contrast, none of the MH-negative pigs or the MH-susceptible pigs that did not receive endotoxin died (0 of 9 vs. 3 of 6, P = 0.044).     

Prospective, randomized trial on the effect of cyclic versus continuous enteral nutrition on postoperative gastric function after pylorus-preserving pancreatoduodenectomy.

OBJECTIVE: The effect of a cyclic versus a continuous enteral feeding protocol on postoperative delayed gastric emptying, start of normal diet, and hospital stay was assessed in patients undergoing pylorus-preserving pancreatoduodenectomy (PPPD). SUMMARY BACKGROUND DATA: Delayed gastric emptying occurs in approximately 30% of patients after PPPD and causes prolonged hospital stay. Enteral nutrition through a catheter jejunostomy is used to provide postoperative nutritional support. Enteral infusion of fats and proteins activates neurohumoral feedback mechanisms and therefore can potentially impair gastric emptying and prolong postoperative gastroparesis. METHODS: From September 1995 to December 1996, 72 consecutive patients underwent PPPD at the Academic Medical Center, Amsterdam. Fifty-seven patients were included and randomized for either continuous (CON) jejunal nutrition (0-24 hr; 1500 kCal/24 hr) or cyclic (CYC) enteral nutrition (6-24 hr; 1125 kCal/18 hr). Both groups had an equal caloric load of 1 kCal/min. The following parameters were assessed: days of nasogastric intubation, days of enteral nutrition, days until normal diet was tolerated orally, and hospital stay. On postoperative day 10, plasma cholecystokinin (CCK) levels were measured during both feeding protocols. RESULTS: Nasogastric intubation was 9.1 days in the CON group (n = 30) and 6.7 days in the CYC group (n = 27) (not statistically significant). First day of normal diet was earlier for the CYC group (15.7 vs. 12.2 days, p < 0.05). Hospital stay was shorter in the CYC group (21.4 vs. 17.5 days, p < 0.05). CCK levels were lower in CYC patients, before and after feeding, compared with CON patients (p < 0.05). CONCLUSIONS: Cyclic enteral feeding after PPPD is associated with a shorter period of enteral nutrition, a faster return to a normal diet, and a shorter hospital stay. Continuously high CCK levels could be a cause of prolonged time until normal diet is tolerated in patients on continuous enteral nutrition. Cyclic enteral nutrition is therefore the feeding regimen of choice in patients after PPPD.     

Release of Endotoxin-binding Proteins during Major Elective Surgery: Role of Soluble CD14 in Phagocytic Activation

Our previous study demonstrated that soluble CD14 (sCD14) modulates the biologic activity of circulating endotoxin, which appears after surgery. In this study, we examined the behavior of endotoxin-binding proteins, such as sCD14, lipopolysaccharide-binding protein (LBP), and bactericidal/permeability-increasing protein (BPI), in patients' plasma after major abdominal surgery and the phagocytic secretion of sCD14 from peripheral blood mononuclear cells (PBMCs) throughout the observation period. In a prospective study, 15 patients undergoing major abdominal surgery (gastrectomy, n= 3; pancreatectomy, n= 10; colectomy, n= 2) were involved in this study. The endotoxin-binding proteins were perioperatively (preoperatively; postoperative hour 6; days 1, 2, 3, 4, 5, 7, and 10) measured by an enzyme-linked immunosorbent assay (ELISA). To exclude the hemodilution effect of samples, each parameter was corrected by dividing the respective value by the albumin concentration. The phagocytic activity at each time point was tested as an ex vivo sCD14 secretion from PBMCs in the presence and absence of exogenously added endotoxin, Escherichia coli 055B5 (1 ng/ml). Significant endotoxemia (0.35 ± 0.13 EU/ml; p < 0.05) was observed 6 hours after the beginning of surgery. The sCD14/albumin value rapidly increased at 6 hours after surgery, peaked on day 1, and sequentially declined, whereas the BPI/albumin and LBP/albumin ratios increased more gradually and peaked on day 2. The secretion of sCD14 from 2 × 10⁶ PBMCs was significantly enhanced from 6 hours after operation. The increased plasma level of sCD14 may be explained by the parallel-enhanced sCD14 PBMC production. Activated secretion of these endotoxin-binding proteins may play a role in regulating the biologic activity of circulating endotoxin.     

Therapeutic Apheresis for Septic Patients with Organ Dysfunction: Hemoperfusion using a Polymyxin B Immobilized Column

A prospective clinical study was performed to evaluate a new method of treatment of endotoxin shock, a column containing polystyrene fibers with covalently bound immobile polymyxin B. Direct hemoperfusion using the column removes circulating endotoxin by adsorption. All of the patients studied, 37 in the treatment group and 33 in the control group, had endotoxemia and failure of 1 or more organs. The perfusion was performed 1–7 times per patient, 2 h/session. The survival rate was significantly higher in the treatment group (54%) than in the controls (36.4%). The mean plasma endotoxin concentration was significantly lowered by the treatment from 83.7 pg/ml before perfusion to 56.4 pg/ml immediately after and 28.5 pg/ml the day after the treatment, and the posttreatment level was much lower in those who survived (mean, 18.8 pg/ml) compared to those who died (mean, 88 pg/ml). Various parameters of cardiac function also improved after the treatment.     

Apoptosis and necrosis in the development of acute lung injury after hemorrhagic shock

Acute lung injury can be a complication of hemorrhagic shock. Mechanisms of injury include neutrophil-derived inflammatory products that induce necrosis within the lung. Recent data has shown apoptosis, in addition to necrosis, as a pathway leading toward acute lung injury in shock models. This study quantitates apoptotic and necrotic cells in the lung after hemorrhagic shock. Mongrel pigs (20-30 kg) under general anesthesia (with pancuronium and pentobarbital) underwent instrumentation with placement of carotid and external jugular catheters. The animals were randomized to sham hemorrhage (n = 6) and to hemorrhagic shock (n = 7). The hemorrhagic shock group then underwent hemorrhage (40-45% blood volume) to a systolic blood pressure of 40-50 mm Hg for 1 hour. The animals were then resuscitated with shed blood plus crystalloid to normalization of heart rate and blood pressure. The animals were observed under general anesthesia for 6 hours after resuscitation, then sacrificed, and lungs were harvested. Lung injury parameters including histology (H&E stain), apoptosis [terminal deoxynucleotidyl transferase-mediated dUTP biotin nick end labeling (TUNEL)], and myeloperioxidase activity (spectrophotometric assay) were assessed. Hemorrhagic shock induced marked loss of lung architecture, neutrophil infiltration, alveolar septal thickening, hemorrhage, and edema in H&E staining. Furthermore, MPO activity, a marker for neutrophil infiltration and activation, was more than doubled as compared to controls (44.0 vs 20.0 Grisham units activity/g). Apoptosis (cell shrinkage, membrane blebbing, apoptotic bodies) and necrosis (cellular swelling, membrane lysis) in neutrophils, macrophages, as well as in alveolar cells was demonstrated and quantified by H&E staining use. Apoptosis was confirmed and further quantified by positive TUNEL signaling via digital semiquantitative analysis, which revealed a significant increase in apoptotic cells (16.0 vs 2.5 cells/hpf, shock vs control, respectively) and necrotic cells (16.0 vs 2.0 cells/hpf, shock vs control, respectively). Acute lung injury is a complex pathophysiologic process. Apoptosis in cells (neutrophils, macrophages, alveolar cells) is induced within the lung after hemorrhagic shock. The role of apoptosis in pulmonary dysfunction after hemorrhagic shock has yet to be determined.     

Effect of internal biliary drainage on plasma levels of endotoxin,cytokines, and C-reactive protein in patients with obstructive jaundice

Preoperative biliary drainage may improve the cytokine and acute-phase response derangements observed in patients with obstructive jaundice. We conducted a prospective longitudinal, before-after trial in our 600-bed teaching hospital. Twenty-four patients with obstructive jaundice were investigated, 11 with benign obstruction and 13 with malignant disease. Endoscopic internal biliary drainage was performed in all patients (7 by papillotomy and 17 by endoprostheses). Endotoxin, tumor necrosis factor alpha (TNF-a), interleukin-6 (IL-6), nitric oxide production, and C-reactive protein (CRP) were determined at admission and on days 2 and 7 after internal biliary drainage was accomplished. Bile cultures were obtained before and at the time of drainage. Endotoxin, IL-6, TNF-a, and CRP were significantly higher in patients with cancer. After internal drainage, endotoxin (11.4 vs. 2 EU/L; p <0.05), TNF-a (87.5 vs. 48 pg/ml; p = 0.03), and IL-6 (324 vs. 232 pg/ml; p <0.05) plasma levels decreased significantly in the early postdrainage period in patients with cancer. Endotoxin, cytokines, as well as the CRP plasma values, however, increased again on day 7 after drainage. This trend was less marked in patients with benign obstruction. Patients with positive bile cultures after drainage displayed higher levels of CRP (115 vs. 62 mg/L; p = 0.03), IL-6 (598 vs. 330 pg/ml; p = 0.04), and endotoxin (10.6 vs. 4.8 EU/L; p = 0.02) than those with negative bile cultures. Biliary tract obstruction is associated with an increase in endotoxin levels, a positive acute-phase response, and plasma cytokine elevation. After biliary drainage a transitory improvement of these alterations was observed, although values remained high 1 week postdrainage. These findings were associated with positive bile cultures.     

杀菌／通透性增加蛋白对休克大鼠组织细胞因子mRNA表达的影响

作者在大鼠失血性休克模型上,观察了重组杀菌／通透性增加蛋白（ＢＰＩ）对肺组织肿瘤坏死因子（ＴＮＦ）、白人素－６（ＩＬ－６）ｍＲＮＡ表达及急性肺损伤的影响,并对肠源性内毒素血症与炎症细胞因子诱发的关系进行了探讨。结果显示：失血性休克可导致血浆内毒素含量显著升高,肺组织ＴＮＦ,ＩＬ－６ｍＲＮＡ表达分别在复苏后２、８小时明显增多（Ｐ〈０．０５－０．０１）;给予ＢＰＩ治疗则完全中和休克所致内毒素血症,并不