Hemodynamic effects of naloxone in anaphylactic shock

Recent reports suggest that endorphins may contribute to hemodynamic depression in septic and hemorrhagic shock. There is also evidence that reversal of endorphin effects with high dose naloxone may improve hemodynamic function and improve survival in shock states. The purpose of this study was to examine the effects of naloxone on hemodynamic parameters in anaphylactic shock. Anaphylactic shock was induced in sensitized rabbits with horse serum. Three minutes after serum challenge, rabbits were treated with a 3 mg/kg bolus of naloxone followed by a 3 mg/kg per h infusion (group I, n = 8), or by injection with an equal volume of saline (group II, n = 8). Cardiac output, blood pressure, heart rate and body temperature were monitored continuously for 60 min and the experiment was terminated. There was a significant increase in cardiac index in group I animals at 10 min (P less than 0.01) and 15 min (P less than 0.01). Stroke volume index was also higher in naloxone treated animals at 10 min and 15 min (P less than 0.05). Although mean blood pressure was higher in group I animals at all time intervals after naloxone was begun, the difference was statistically significant only at 60 min (P less than 0.05). Peripheral vascular resistance index was not significantly different for the two groups.     

纳洛酮联合血必净治疗感染性休克的临床疗效及作用机制研究

目的:观察纳洛酮联合血必净治疗感染性休克的临床疗效,并探讨其可能的作用机制.方法:对45例感染性休克患者,随机分为2组,治疗组23例,对照组22例,治疗组患者在常规抗休克治疗的基础上加用纳洛酮联合血必净治疗.结果:治疗组总有效率为91.3％,明显好于对照组72. 7％(P＜0.05),监测血液动力学变化△CVP、△MAP、△UA、△ScvO2治疗组明显好于对照组(P＜0.05).治疗组MODS的发生率为30.4％(7/23).病死率为13.0％(3/23),对照组MODS的发生率为54.6％(12/22),病死率为27.3％(6/22),两组MODS的发生率比较差异有统计学意义(P＜0.05).结论:纳洛酮联合血必净能够显著改善感染性休克患者的病情,提高生存率.作用机制可能与纳洛酮能拮抗β内啡肽,血必净能降低内毒素的水平有关.     

Efficacy and safety of naloxone in septic shock

We evaluated the effectiveness and safety of iv naloxone in 12 septic patients who remained hypotensive despite volume replacement, appropriate antibiotics, and vasopressor therapy. Only four patients responded positively to naloxone, by increases in mean arterial pressure of between 10 to 15 mm Hg that lasted for 15 to 60 min. These patients could not be distinguished from the others on the basis of underlying illness, laboratory or physical findings, length of preceding hypotension, or glucocorticoid therapy. Four patients had adverse reactions: one developed pulmonary edema, one patient had a grand-mal seizure, and two patients became severely hypotensive. We conclude that in patients with well-established septic shock, naloxone does not reliably improve mean arterial pressure or other physiologic variables, and may cause severe adverse reactions.     

创伤性休克IL-6动态变化 意义及纳洛酮的治疗作用

目的探讨创伤性休克IL-6动态变化、意义及纳洛酮的治疗作用。方法制作家兔创伤性休克模型。70只家兔随机分为休克组和治疗组,每组35只。治疗组于休克后30min予以纳洛酮,剂量2mg/kg。治疗组、休克组于休克前后不同时间点先采血2ml,再杀死家兔,收集肺泡灌洗液。每次杀死5只家兔。采用放免法测定各时刻血浆及肺泡灌洗液IL-6水平。结果休克组血浆和肺泡灌洗液IL-6水平均明显高于休克前,具有显著性差异(p<0.01)。相同时刻点肺泡灌洗液IL-6水平明显高于血浆水平(p<0.01)。休克组IL-6呈双峰改变,于休克后3h和24h达到峰值,并且第二峰高于第一峰,至本研究结束仍高于休克前。治疗组创伤性休克后IL-6水平高于休克前,但明显低于休克组,具有显著性差异(p<0.01)。该组IL-6不具有明显峰值改变。休克后5h有下降趋势。治疗组48h全部存活,休克组7h生存率65%,24h生存率48%,48h生存率32%。结论创伤性休克可导致机体IL-6大量表达,IL-6是反映休克严重程度的标记物。纳洛酮可抑制IL-6的产生,具有抗休克作用。     

Hemodynamic and metabolic effects of low-dose vasopressin infusions in vasodilatory septic shock

OBJECTIVE: To investigate the physiologic effects of exogenous vasopressin as a potential alternative to traditional high-dose catecholamine therapy for septic patients with vascular hyporeactivity to catecholamines. DESIGN: Prospective, case-controlled study. SETTING: Intensive care unit of a university hospital. PATIENTS: Vasopressin was infused in 16 critically ill septic patients who remained persistently hypotensive despite infusions of pharmacologic doses of catecholamines. INTERVENTION: Continuous intravenous infusion of vasopressin at 0.04 units/min for 16 hrs, in place of escalating the amount of catecholamines being infused. MEASUREMENTS AND MAIN RESULTS: After administration of vasopressin, systemic vascular resistance and mean arterial pressure were immediately and significantly increased in comparison with the values obtained just before vasopressin. When the vasopressin infusions were discontinued, mean arterial pressure decreased immediately and dramatically. We did not detect any obvious adverse cardiac effects during the vasopressin infusions. Vasopressin had no effect on other hemodynamic parameters or any of the metabolic parameters studied, including measures of oxygenation, plasma glucose, or electrolytes. Urine output increased significantly during the administration of vasopressin, although this effect may be nonspecific. Lactate concentrations decreased, particularly in the survival group, but the decreases were not significant. Overall survival was 56%. CONCLUSIONS: Low-dose vasopressin infusions increased mean arterial pressure, systemic vascular resistance, and urine output in patients with vasodilatory septic shock and hyporesponsiveness to catecholamines. The data indicate that low-dose vasopressin infusions may be useful in treating hypotension in these patients.     

The haemodynamic and metabolic effects of epinephrine in experimental hyperdynamic septic shock

Objective To study the effect of epinephrine (EPI) infusion on vital organ blood flow and metabolic variables during sepsis.Design and setting Randomised placebo-controlled animal trial in an animal laboratory.Animals Seven merino cross-ewes.Interventions Chronic implantation of flow probes (aorta, renal, mesenteric and coronary artery and sagittal sinus). Induction of sepsis by intravenous injection of E. coli. Random allocation of sheep to EPI (0.4 µg kg^–1 min^–1) or vehicle for 6 h.Measurements and results E. coli induced hypotension and hyperlactataemia and increased cardiac output, renal, mesenteric and coronary blood flows. Compared to vehicle, EPI restored mean arterial blood pressure (69 vs. 86 mmHg) and further increased cardiac output (6.4 vs. 7.1 l/min). EPI, however, decreased renal blood flow (330 vs. 247 ml/min) and renal conductance. EPI also reduced mesenteric and coronary conductance without changes in flows. Compared to vehicle, EPI increased urine output (293 vs. 544 ml/6 h) but not creatinine clearance. EPI increased lactate (1.8 vs. 15.7 mmol/l) with accompanying acidosis (serum bicarbonate: 25.2 vs. 15.7 mmol/l), hyperglycaemia (2.6 vs. 13.5 mmol/l) and hypokalaemia (4.3 vs. 3.0 mmol/l).Conclusions Hyperdynamic sepsis increased blood flow to heart, gut and kidney. Although EPI infusion further increased cardiac output, blood pressure and myocardial performance, it was also associated with potent metabolic effects, decreased mesenteric, coronary and renal conductance and a significant reduction in renal blood flow.This study was supported by an institute grant (no. 983001) from the National Health & Medical Research Council of Australia and by grants from the Intensive Care Foundation of the Australian and New Zealand Intensive Care Society, the Laerdal Foundation (Norway) and the ARMC Anaesthesia and Intensive Care Trust Fund.     

The haemodynamic effects of metabolic acidosis in the rat.

1. The effect of metabolic acidosis of 4-6 h duration on cardiac output, blood pressure, heart rate, and hepatic and renal blood flow has been studied in the rat. 2. In anaesthetized rats, blood pressure and heart rate fell linearly with blood pH in both sham-operated and nephrectomized rats. There was no significant difference between the two groups in the effect of acidosis on either variable. 3. Cardiac output showed a significant fall with increasing acidosis in the conscious rat. 4. Estimated hepatic blood flow in conscious rats showed a significant positive correlation with blood pH in both sham-operated and nephrectomized animals. There was no significant difference in estimated hepatic blood flow between the two groups of animals at any blood pH. 5. In conscious rats, increasing acidosis caused a progressive decrease in estimated renal blood flow. 6.It is concluded that the increase in the previously described apparent renal contribution to lactate removal in the acidotic rat cannot be explained by any circulatory effect mediated by the kidney. The possible relevance of the findings to lactate homeostasis is discussed.     

纳洛酮在大鼠肠缺血再灌流致肺损伤中保护作用的初步研究

目的 探讨纳洛酮在大鼠肠缺血再灌流致肺损伤中的作用。方法 成年雄性SD大鼠,随机分为以下四组：假手术组、肠缺血再灌流组及分别用生理盐水和纳洛酮干预后的肠缺血再灌流组。分别测各组大鼠血浆β-内啡肽及肺组织丙二醛含量、髓过氧化酶活性和肺毛细血管通透性。结果 肠缺血再灌流组血浆β-内啡肽及肺组织丙二醛含量、髓过氧化酶活性和肺毛细血管通透性高于假手术组,而用纳洛酮干预后各指标测定值较生理盐水对照组明显降低。结论 纳洛酮对肠缺血再灌流时肺损伤有明显的保护作用。     

Modulation of hemorrhagic shock by intestinal mucosal NG-nitro-L-arginine and L-arginine in the anesthetized rat.

Maintaining intestinal function protects against shock of various origins. Nitric oxide (NO) can protect tissues. The present research examined whether the presence of 50 microM NG-nitro-L-arginine (NOLARG), a nitric oxide synthase (NOS) inhibitor, or L-arginine (LARG), the substrate of NOS, in the jejunal lumen of the anesthetized rat could affect the progress of hemorrhagic shock. The jejunal lumen was perfused with saline containing 14C-inulin and 3H2O to measure net H2O absorption and absorptive site blood flow (ASBF). Luminal NOx (NO3- +NO2-) secretion into the gut effluent and blood pressure (BP) were also measured. The animals were bled to and maintained at 40 mmHg for 60 min and then reinfused. Survival time was significantly decreased in luminally-perfused NOLARG animals, but was significantly increased in LARG perfused animals. Most deaths occurred during the hemorrhage periods. Animals perfused with LARG through the ileal lumen required significantly less blood to be reinfused to maintain blood pressure during the hemorrhage periods. There were not significant differences in BP among surviving animals. Net H2O absorption and ASBF were significantly decreased only in NOLARG-perfused animals in the period just before and after reinfusion. There were no significant differences in luminal NOx secretion among the groups. Thus, intestinal mucosal NOS substrates or antagonists modulate the progress of hemorrhagic shock, but the mechanism was not defined in these experiments.     

Comparative effects of nitric oxide synthesis inhibition and catecholamine treatment in a rat model of endotoxin shock

Catecholamines and volume repletion are currently used for the treatment of septic shock. However, the prognosis of patients suffering from this condition is very poor. An overproduction of nitric oxide (NO) seems to be related to the hypotension and tissue damage of endotoxin shock. Thus, treatment with NO synthase inhibitors has been proposed. Using a rat model of septic shock we have studied the effects of noradrenaline or the NO synthase inhibitor, N^G-nitro-l -arginine methylester (l -NMMA) on arterial pressure, tissue damage and NO production. Anaesthetized rats treated with Salmonella typhosa showed a decrease in blood pressure accompanied by an increase in the plasma concentration of cytosolic enzymes (transaminases and lactate dehydrogenase, markers of cell disruption) and nitrite plus nitrate (NO^?₂/NO^?₃, markers of NO production). A large proportion of these animals (40%) died before the end of the experiment. Co-treatment with noradrenaline resulted in temporary maintenance of arterial pressure followed by a decline, despite the dose being increased progressively. No differences were observed in plasma cytosolic enzymes, NO^?₂/NO^?₃ or mortality compared with animals treated with lipopolysaccharide (LPS) alone. In contrast, administration of l -NMMA (10 mg kg^?1) to septic animals prevented the fall in blood pressure and death caused by endotoxin. This treatment markedly diminished cell disruption, as measured by the plasma levels of necrosis enzymes, and partially, but significantly, reduced the production of NO as assessed by plasma NO^?₂/NO^?₃. We conclude that tissue damage in septic shock is related to the overproduction of NO and not exclusively to the hypotension that follows this increased production. Thus, maintenance of blood pressure with catecholamines fails to improve cellular damage. Instead, partial inhibition of NO generation is sufficient to ameliorate the haemodynamic and tissue-damaging effects of septic shock and improves survival in this model of endotoxaemia.     

早期肠黏膜屏障功能障碍对感染性休克的影响

目的探讨严重感染患者血二胺氧化酶活性（DAO）的变化规律及其对发生感染性休克的预测作用。方法采用分光光度法测定49例严重感染患者于全身性感染、严重全身性感染和感染性休克后第1天、第3天和第5天的DAO活性,并选择16例同期健康志愿者作为对照,将患者分为对照组、全身性感染组、严重全身性感染组和感染性休克组;另根据感染性休克发生与否分为非休克组和休克组,并分别比较组间差异。结果与对照组（1．92±0．42）相比,全身性感染组DAO活性（2．50±0．98）,严重全身性感染组DAO活性（2．80±1．06）和感染性休克组DAO活性（3．42±1．19）明显升高,P〈0．05;分别同全身性感染组（2．50±0．98）和严重全身性感染组（2．80±1．06）相比,感染性休克组DAO活性（3．42±1．19）明显升高,P〈0．05。发生感染性休克患者入选研究时的DAO活性升高较未发生感染性休克更为显著[（3．17±1．12）vs（2．35±0．85）,P〈0．05],且第3天的DAO活性明显升高[（3．34±1．03）vs（2．31±0．83）,P〈0．05],ROC曲线下面积为0．83,最佳阈值为2．7U／ml。结论肠黏膜屏障功能障碍在严重感染的发病机制中起着重要作用,且血DAO活性可以预测感染性休克的发生。     

Hepato-splanchnic metabolic effects of the stable prostacyclin analogue iloprost in patients with septic shock

OBJECTIVE: To evaluate the effects of the stable prostacyclin analogue iloprost on hepato-splanchnic blood flow, oxygen exchange and metabolism in patients with septic shock. DESIGN: Prospective clinical study. SETTING: Intensive care unit in a university clinic. PATIENTS: Eleven patients with septic shock requiring norepinephrine to maintain mean arterial pressure above 70 mmHg. INTERVENTIONS: Iloprost was incrementally infused to increase cardiac index by 15%. MEASUREMENTS AND MAIN RESULTS: Splanchnic blood flow (Qspl) was measured using the steady-state indocyanine-green infusion technique and endogenous glucose production rate (EGP) using a stable isotope approach. Systemic and splanchnic oxygen consumption (VO2), the hepato-splanchnic uptake rates of the glucose precursors lactate, pyruvate, alanine and glutamine, the hepatic venous redox state and gastric mucosal-arterial PCO2 gradients were determined. After a baseline measurement, iloprost infusion was started. After 90 min all measurements were repeated and a third measurement was obtained after another 90 min following iloprost withdrawal. Qspl (baseline I: 0.82/0.75-1.08 l x min x m2; iloprost: 0.94/0.88-1.29 l x min x m2; baseline II: 0.87/0.74-1.09 l x min x m2) and splanchnic oxygen delivery (baseline I: 122/103-166 ml x min x m2; iloprost: 134/117-203 ml x min x m2; baseline II: 130/98-158 ml x min x m2) significantly increased. While systemic VO2 significantly increased (baseline I: 139/131-142 ml x min x m2; iloprost: 147/136-164 ml x min x m2; baseline II: 143/133-154 ml x min x m2) splanchnic VO2 increased in 9 of 11 patients which, however, did not reach statistical significance. EGP significantly decreased (baseline I: 23/16-26 micromol x kg x min; iloprost: 16/14-21 micromol x kg x min; baseline II: 18/12-20 micromol x kg x min), whereas all other parameters of energy metabolism remained unchanged. CONCLUSION: In patients with septic shock an iloprost-induced increase in cardiac index increased splanchnic blood flow and shifted oxygen utilization from the energy requiring de novo glucose production rate to other oxygen-demanding metabolic pathways.     

创伤性休克大鼠中性粒细胞CD18和糖皮质激素受体的变化及纳络酮的治疗作用

目的探讨中性粒细胞粘附分子CD18(PMNCD18)和中性粒细胞糖皮质激素受体(PMNGR)在大鼠创伤性休克早期的动态变化及盐酸纳络酮的治疗作用。方法采取软组织损伤加颈动脉放血作为大鼠创伤性休克动物模型,分别于创伤前、休克后45、90、210、330和450分钟取血,测定各组大鼠的PMNCD18和PMNGR含量。复苏组和纳络酮组则于休克后90分钟开始实施复苏措施。结果休克组休克45分钟PMNCD18表达值明显增高,随后逐渐下降,至休克后450分钟与基础表达值仍相差非常显著(P<0.01);PMNGR随休克时间的延长逐渐下降;复苏120分钟后上述改变最为显著。肝、肺组织切片发现,复苏组复苏后120分钟毛细血管内有大量白细胞粘附于血管内壁,同时血管周围有白细胞浸润,组织细胞浊肿,复苏360分钟后上述改变减轻。纳络酮治疗组复苏后120、240和360分钟PMNCD18较复苏组同时间点的结果明显降低(P均<0.01),PMNGR较复苏组同时间点的结果明显升高(P均<0.01);肝、肺组织学检查显示,纳络酮治疗组复苏后毛细血管内白细胞附壁较复苏组同时间点明显减少。结论创伤性休克及复苏时,PMN与内皮细胞粘附明显增强,与PMNCD18的表达增加有关,PMNGR的减数调节是PMNCD18表达增加的原因之一;纳络酮可通过增加PMNGR密度及抑制PMNCD18表达而对机体起到保护作用。     

High-dose naloxone: pharmacokinetics in patients in septic shock

Naloxone, a commonly used narcotic antagonist, may be beneficial in reversing the hemodynamic alterations seen in septic shock. In normal subjects, naloxone pharmacokinetics are characterized by rapid distribution and elimination. We investigated the pharmacokinetics of high-dose naloxone in four patients with septic shock and multiorgan failure. The pharmacokinetics of naloxone in these patients can be described by a two-compartment model with a rapid alpha distribution similar to that observed in normal humans. However, in these critically ill patients there was virtually no drug elimination as levels were followed for 5 h post-termination of a 6-h infusion of 2.4 mg/kg X h. This dramatic accumulation of naloxone may explain why responses have been reported by others to small doses of naloxone in septic shock patients. No significant side-effects were seen in our patients with plasma naloxone levels as high as 3.78 micrograms/ml. Caution is warranted when one administers naloxone to patients whose ability to eliminate this drug is minimal.     

创伤性休克大鼠中性粒细胞CD18的动态变化及纳洛酮治疗作用的研究

目的 :探讨中性粒细胞粘附分子CD18(PMNCD18)在大鼠创伤性休克早期的动态变化及盐酸纳洛酮 (NLX)的治疗作用。方法 :动物模型采用软组织损伤加颈动脉放血法 ,采用流式细胞仪测定PMNCD18的表达。结果 :休克组休克 45minPMNCD18表达值明显增高 ,随后逐渐下降 ,至休克 7 5h与基础表达值仍相差非常显著 (P <0 0 1) ;复苏后 2hPMNCD18达到最高值 ;肝、肺组织切片发现 ,复苏后 2h毛细血管内有大量白细胞粘附于血管内壁。复苏 6h后上述改变减轻。治疗组复苏后 2、 4、 6hPMNCD18较复苏组同时相点的结果明显降低 (P <0 0 1) ;组织学检查显示治疗组复苏后毛细血管内白细胞附壁较复苏组同时相点明显减少。结论 :创伤性休克及复苏时 ,PMN EC粘附明显增强 ,与PMNCD18的表达增加有关 ,NLX可通过抑制PMNCD18表达而对机体具有保护作用。     

高血糖素样肽-2对大鼠失血性休克复苏后肠道免疫功能的影响

目的 研究高血糖素样肽-2(Glucagon-1ike peptide-2，CLP-2)对大鼠失血性休克复苏后胆汁中分泌型IgA(sIgA)、肠黏膜蛋白质和DNA含量的影响。方法 采用大鼠经股动脉放血及自体血回输的方法复制休克复苏模型，连续腹腔注射GLP-2，7d后收集大鼠胆汁测定sIgA、采集门静脉血测定血内毒素及制备小肠黏膜标本测定小肠黏膜蛋白质和DNA含量。结果 休克复苏组胆汁中sIgA仅为对照组的78％左右，而GLP-2组与对照组接近；小肠黏膜蛋白质和DNA含量GLP-2组显著高于休克复苏组，门静脉血内毒素也显著减少。结论 GLP-2能够改善大鼠休克复苏后肠道免疫功能，从而减轻内毒血症。