Vasopressin improves survival in a pig model of hypothermic cardiopulmonary resuscitation

OBJECTIVE: During hypothermic cardiopulmonary resuscitation with a body core temperature <30 degrees C administration of a vasopressor to support coronary perfusion pressure is controversial. The purpose of the current study was to assess the effects of a single 0.4-unit/kg dose of vasopressin on coronary perfusion pressure, defibrillation success, and 1-hr survival in a pig model of hypothermic closed-chest cardiopulmonary resuscitation combined with rewarming. DESIGN: Prospective, randomized study in an established pig model. SETTING: University hospital research laboratory. SUBJECTS: Fifteen 12- to 16-wk-old domestic pigs. INTERVENTIONS: Pigs were surface cooled to a body core temperature of 26 degrees C and ventricular fibrillation was induced. After 15 mins of untreated cardiac arrest, manual closed-chest cardiopulmonary resuscitation and thoracic lavage with 40 degrees C warmed tap water were started. After 3 mins of external chest compression, animals were assigned randomly to receive vasopressin (0.4 units/kg, n = 8; or saline placebo, n = 7). Defibrillation was attempted 10 mins after drug administration. MEASUREMENTS AND MAIN RESULTS: Compared with saline placebo treated-animals, coronary perfusion pressure in vasopressin-treated pigs was significantly higher 90 secs (36 +/- 5 mm Hg vs. 7 +/- 4 mm Hg, p =.000) to 10 mins (24 +/- 4 mm Hg vs. 8 +/- 4 mm Hg, p =.000) after drug administration. Restoration of spontaneous circulation and 1 hr survival were significantly higher in vasopressin animals compared with saline placebo (8 of 8 vasopressin pigs vs. 0 of 7 placebo pigs, p <.001). CONCLUSIONS: A single 0.4-unit/kg dose of vasopressin administered at a body core temperature <30 degrees C significantly improved defibrillation success and 1-hr survival in a pig model of hypothermic cardiopulmonary resuscitation.     

Vasopressin improves survival in a porcine model of abdominal vascular injury

Introduction  

We sought to determine and compare the effects of vasopressin, fluid resuscitation and saline placebo on haemodynamic variables and short-term survival in an abdominal vascular injury model with uncontrolled haemorrhagic shock in pigs.     

提高急性心肌梗死大鼠模型存活率的实验研究

目的:建立一种简便、轻创、存活率高的急性心肌梗死大鼠实验模型。方法:SD大鼠戊巴比妥钠复合麻醉,经口气管插管,左胸第3、4肋间开胸,结扎左冠状动脉前降支。8周后行心电图观察及血流动力学、左心室功能、病理检测。结果:本法术后24h内大鼠死亡率为11.82%;存活8周的心肌梗死者大鼠可达80.65%。与假手术组相比,心肌梗死组左室重、左室舒张末压、心率均显著升高,收缩压、舒张压、平均压、左室收缩压、左室内压最大收缩和舒张速率均显著降低(P<0.05)。结论:此法简单、有效、重复性好,对研究心肌梗死后左心室重构有重要意义。     

Treatment with interleukin 12 in combination with atovaquone or clindamycin significantly increases survival of mice with acute toxoplasmosis.

The capacity of interleukin 12 (IL-12) to potentiate drugs in the treatment of murine toxoplasmosis was examined. IL-12 (100 ng/injection), atovaquone (10 mg/kg of body weight/day), or clindamycin (5 mg/kg/day) administered alone caused delayed time to death or minimal survival rates. In contrast, significant survival rates resulted when the same dose of IL-12 was used in combination the same doses of atovaquone (P=0.01) or clindamycin (P=0.001). Infected mice treated with IL-12 plus drug produced significantly higher levels of gamma interferon than controls. Although IL-12 was effective only when administered before infection, these results suggest that this cytokine may be a useful adjunct in the therapy of human toxoplasmosis in situations when cysts reactivate and tachyzoites start multiplying in immunocompromised patients.     

Diagnostic ultrasound treatment increases the bone fracture-healing rate in an internally fixed rat femoral osteotomy model.

OBJECTIVE: To investigate the healing effects of diagnostic ultrasound in a standardized rat femur fracture model. METHODS: Thirty-two male rats aged 14 weeks were used, and each rat's right femur was osteotomized and stabilized under anesthesia. The rats were then divided into 4 groups. Five days after surgery, ultrasound was applied every fifth day with diagnostic sonographic equipment and a probe with a 7.5-MHz frequency and 11.8-mW/cm2 total output intensity for 10 minutes in each session. Ultrasound was applied 8 times in group A, 3 times in group B, and only once in group C. Ultrasound was not applied to sham-operated group D. Healing and callus formation of the rats' femur fractures were evaluated by radiography and dual-energy x-ray absorptiometry. RESULTS: Dual-energy x-ray absorptiometric and radiographic results showed that the ultrasound therapy accelerated the fracture healing. Radiographically, groups A and B showed better fracture healing than groups C and D. Ultrasound exposure increased both the whole-bone mineral density and the density at the fracture region, increasing in parallel with the exposure period. CONCLUSIONS: This study confirms the previously shown efficacy of low-intensity ultrasonic stimulation in acceleration of the normal fracture repair process even when performed with a diagnostic sonographic device.     

Spontaneous high systemic oxygen delivery increases survival rate in awake sheep during sustained endotoxemia

OBJECTIVE: To study the natural evolution of systemic oxygen delivery (Do2) and oxygen consumption (Vo2) in sheep infused with low or high doses of endotoxin. DESIGN: Prospective, controlled experimental study. SETTING: Animal research laboratory at a medical university. SUBJECTS: Twenty-nine chronically instrumented awake sheep (25-35 kg). INTERVENTIONS: Awake animals were continuously infused with saline (n = 8) or two doses of Escherichia coli endotoxin (20 or 40 ng/kg/min; n = 21) for 72 hrs. No attempt was made to increase Do2, but respiratory failure was treated by mechanical ventilation and metabolic acidosis was corrected. MEASUREMENTS AND MAIN RESULTS: The mortality rate was 25% in the group infused with the low dose and 89% in the group infused with the high dose of endotoxin. During the first 12 hrs of endotoxemia, both surviving (S group; n = 10) and nonsurviving (NS group; n = 11) sheep developed similar pulmonary hypertension, left ventricular failure, and hypotension with low systemic vascular resistance. However, S sheep had less interstitial lung edema (pulmonary lymph protein clearance at 8 hrs was 13+/-3 mL/hr vs. 27+/-6 mL/hr in the NS group and 4+/-1 mL/hr in the control group). During this early phase of endotoxemia, Do2, Vo2, and oxygen extraction ratio did not change significantly in any group. After this phase, animals that ultimately survived had a persistent hyperdynamic syndrome with high cardiac output and hypotension. In this group, the Do2 increase was greater than the Do2 measured in controls and remained steady up to 48 hrs after the start of the endotoxin infusion. Because systemic Vo2 did not change significantly, oxygen extraction ratio decreased progressively to values less than those measured in controls. In contrast, animals that ultimately died had a hypotensive and normokinetic syndrome associated with pulmonary hypertension, persistent depressed left ventricular function, hypothermia, and a progressive deterioration of gas exchange. Systemic Do2 was not significantly different from that in the control group. In contrast, Vo2 decreased progressively to values significantly lower than those measured in controls and remained low until death. CONCLUSIONS: Our results indicate that in the absence of treatment such as fluid challenge or inotropic drugs in sheep infused with endotoxin, the occurrence of spontaneous hyperdynamic syndrome and high Do2 improves the survival rate.     

Sesame oil attenuates multiple organ failure and increases survival rate during endotoxemia in rats

OBJECTIVE: To investigate the effects and the possible mechanism of sesame oil on multiple organ failure induced by lipopolysaccharide in rats. DESIGN: Laboratory in vivo study of the effects of sesame oil on serum aspartate aminotransferase, gamma-glutamyltransferase, alkaline phosphatase, total bilirubin, blood urea nitrogen, creatinine, lipid peroxide, and nitric oxide concentrations. To assess the effect of sesame oil on xanthine oxidase, serum uric acid was measured. Furthermore, lipid peroxide concentrations in liver and kidney were determined. SETTING: University laboratory. SUBJECTS: Male Wistar rats. INTERVENTIONS: Blood testing. MEASUREMENT AND MAIN RESULTS: Serum aspartate aminotransferase, gamma-glutamyltransferase, alkaline phosphatase, total bilirubin, blood urea nitrogen, creatinine, and uric acid concentrations were determined. Lipid peroxide was analyzed by using a commercial kit. Nitric oxide production was estimated by Griess reaction. Sesame oil ameliorated hepatic and renal damage in a dose-dependent manner and increased animal survival in lipopolysaccharide-treated rats. Sesame oil decreased lipid peroxide concentration in serum but not in liver and kidney. Serum nitrite production was unaffected by sesame oil ingestion. Furthermore, the activity of xanthine oxidase was reduced by sesame oil in lipopolysaccharide-challenged rats. CONCLUSION: Sesame oil ameliorated multiple organ failure and mortality via its inhibition of xanthine oxidase in lipopolysaccharide-dosed rats. Xanthine oxidase may play a critical role in sesame oil-associated organ protection during endotoxemia in rats.     

Propofol increases morbidity and mortality in a rat model of sepsis

IntroductionSevere sepsis is associated with approximately 50% mortality and accounts for tremendous healthcare costs. Most patients require ventilatory support and propofol is commonly used to sedate mechanically ventilated patients. Volatile anesthetics have been shown to attenuate inflammation in a variety of different settings. We therefore hypothesized that volatile anesthetic agents may offer beneficial immunomodulatory effects during the course of long-term intra-abdominal sepsis in rats under continuous sedation and ventilation for up to 24 hours.MethodsSham operation or cecal ligation and puncture (CLP) was performed in adult male Wistar rats followed by mechanical ventilation. Animals were sedated for 24 hours with propofol (7 to 20 mg/kg/h), sevoflurane, desflurane or isoflurane (0.7 minimal alveolar concentration each).ResultsSeptic animals sedated with propofol showed a mean survival time of 12 hours, whereas >56% of all animals in the volatile groups survived 24 hours (P <0.001). After 18 hours, base excess in propofol + CLP animals (−20.6 ± 2.0) was lower than in the volatile groups (isoflurane + CLP: -11.7 ± 4.2, sevoflurane + CLP: -11.8 ± 3.5, desflurane + CLP -14.2 ± 3.7; all P <0.03). Plasma endotoxin levels reached 2-fold higher levels in propofol + CLP compared to isoflurane + CLP animals at 12 hours (P <0.001). Also blood levels of inflammatory mediators (tumor necrosis factor-α, interleukin-1β, interleukin-10, CXCL-2, interferon-γ and high mobility group protein-1) were accentuated in propofol + CLP rats compared to the isoflurane + CLP group at the same time point (P <0.04).ConclusionsThis is the first study to assess prolonged effects of sepsis and long-term application of volatile sedatives compared to propofol on survival, cardiovascular, inflammatory and end organ parameters. Results indicate that volatile anesthetics dramatically improved survival and attenuate systemic inflammation as compared to propofol. The main mechanism responsible for adverse propofol effects could be an enhanced plasma endotoxin concentration, leading to profound hypotension, which was unresponsive to fluid resuscitation.

Electronic supplementary material

The online version of this article (doi:10.1186/s13054-015-0751-x) contains supplementary material, which is available to authorized users.     

一氧化氮合酶抑制剂L-精氨酸对创伤性休克大鼠存活率的影响

目的　探讨一氧化氮合酶 (NOS)抑制剂左旋精氨酸 (L Arg)对创伤性休克大鼠存活率的影响。方法　通过外力致大鼠双侧股骨骨折 ,建立创伤性休克模型。复苏时分别给予非选择性 NOS抑制剂 L 硝基精氨酸甲酯 (L NAME) 10 m g/kg、选择性诱导型 NOS(i NOS)抑制剂氨基胍 (AG) 10 0 m g/kg和一氧化氮(NO)合成底物 L Arg10 0 mg/kg;观察给药前后血流动力学及组织氧分压变化 ,并记录存活时间和存活率。结果　与休克对照组〔分别为 (18.78± 4 .6 4 ) h和 10 %〕比较 ,L NAME组大鼠存活时间和 2 4 h存活率均无显著变化〔分别为 (2 3.80± 9.0 9) h和 4 0 % ,P均 >0 .0 5〕;AG组和 L Arg组大鼠存活时间均显著延长〔分别为 (2 8.72± 6 .2 5 ) h和 (30 .6 4± 8.77) h,P均 <0 .0 1〕,2 4 h存活率提高 (均为 80 % ,P均 <0 .0 1)。结论　选择性 i NOS抑制剂 AG及 L Arg对创伤性休克具有保护作用。     

癌基因表达对骨肉瘤患者生存率及生活质量的意义

目的目前有关骨肉瘤中跨膜糖蛋白(ErbB2)表达与患者预后的关系的意见尚不一致,对此做进一步的研究。方法采用免疫组化SABC法检测69例骨肉瘤标本中ErbB2表达,并对有关临床及病理指标综合分析。结果骨肉瘤中ErbB2表达阳性率49.3%。大肿瘤组较小肿瘤组ErbB2表达阳性率高;III期骨肉瘤组ErbB2表达阳性率较II期骨肉瘤组高;ErbB2表达阳性组更容易出现肺转移,并且其生存率降低。结论ErbB2在促进骨肉瘤的侵润性生长和促进转移方面起重要的作用,其阳性表达与恶性程度有关。检测ErbB2的表达情况可以预测骨肉瘤的预后。     

Epinephrine, but not vasopressin, improves survival rates in an adult rabbit model of asphyxia cardiac arrest

Although vasopressin has been reported to be more effective than epinephrine for cardiopulmonary resuscitation in ventricular fibrillation animal models, its efficacy in asphyxia model remains controversy. The purpose of this study was to investigate the effectiveness of vasopressin vs epinephrine on restoration of spontaneous circulation (ROSC) in a rabbit model of asphyxia cardiac arrest. Cardiac arrest was induced by clamping endotracheal tube. After 5 minutes of basic life-support cardiopulmonary resuscitation, animals who had no ROSC were randomly assigned to receive either epinephrine alone (epinephrine group; 200 microg/kg) or vasopressin alone (vasopressin group; 0.8 U/kg). The coronary perfusion pressure (CPP) was calculated as the difference between the minimal diastolic aortic and simultaneously recorded right atrial pressure. Restoration of spontaneous circulation was defined as an unassisted pulse with a systolic arterial pressure of 60 mm Hg or higher for 5 minutes or longer. We induced arrest in 62 rabbits, 15 of whom had ROSC before drug administration and were excluded from analysis. The remaining 47 rabbits were randomized to epinephrine group (n = 24) and vasopressin group (n = 23). Before and after drug administration, CPP in epinephrine group increased significantly (from -4 +/- 4 to 36 +/- 9 mm Hg at peak value, P = .000), whereas CPP in vasopressin group increased only slightly (from 9 +/- 5 to 18 +/- 6 mm Hg at peak value, P = .20). After drug administration, 13 of 24 epinephrine rabbit had ROSC, and only 2 of 23 vasopressin rabbit had ROSC (P < .01). Consequently, we conclude that epinephrine, but not vasopressin, increases survival rates in this adult rabbit asphyxia model.     

Talniflumate increases survival in a cystic fibrosis mouse model of distal intestinal obstructive syndrome

Intestinal disease in cystic fibrosis (CF) mice closely mirrors aspects of obstructive syndromes in CF patients. The pathogenesis involves accumulation of mucoid debris in the crypts that fuse with intestinal content to form obstructing mucofeculant impactions. Treatment involves modalities that increase the fluidity of the luminal content, such as osmotic laxatives and liquid diets. We investigated the effects of talniflumate (Lomucin, Genaera Corporation, Plymouth Meeting, PA), a compound that may be beneficial to treatment of CF intestinal disease based on three mechanisms of action: mucus synthesis inhibition by blockade of the murine calcium-activated chloride channel 3 (mCLCA3), nonsteroidal anti-inflammatory effects, and inhibition of Cl(-)/HCO (-)(3) exchanger(s) involved in intestinal NaCl absorption. Cohorts of CF mice were fed control diet or diets containing either talniflumate (0.4 mg/g chow) or ibuprofen (0.4 mg/g chow) for 21 days to assess survival. Talniflumate significantly increased CF mouse survival from 26 to 77%, whereas ibuprofen had no effect (22% survival). Oral talniflumate did not alter crypt goblet cell numbers or change intestinal expression of mCLCA3 but tended to decrease crypt mucoid impaction. Ussing chamber studies indicated that talniflumate slightly increased the basal short-circuit current of CF intestine, but the change was not sensitive to secretagogue stimulation or bumetanide inhibition. In contrast, intracellular pH measurements of intact intestinal villous epithelium indicated that talniflumate significantly inhibited apical membrane Cl(-)/HCO (-)(3) exchange by >50%. We conclude that oral talniflumate increases the survival of CF mice, possibly by the beneficial effects of decreasing small intestinal NaCl absorption through the inhibition of apical membrane Cl(-)/HCO (-)(3) exchanger(s).     

Nitrate tolerance: effect of thiol supplementation during prolonged nitroglycerin infusion in an in vivo rat model

Depletion of intracellular sulfhydryl groups has been considered a main reason for the development of nitrate tolerance during sustained nitrate therapy. Although administration of N-acetyl-cysteine, a sulfhydryl donor, potentiates the acute hypotensive effect of nitroglycerin (NTG), its role in the reversal of nitrate tolerance is controversial. In the present study, we developed a conscious in vivo rat model to study nitrate tolerance and nitrate-thiol interactions. Tolerance to NTG, as assessed by the blood pressure reduction in response to i.v. NTG bolus doses, developed after 24 h of i.v. NTG infusion. After 3 and 5 days of 0.2 mg/h NTG i.v., the dose-response relations for NTG-induced reduction in blood pressure were shifted to 25-fold higher doses (P less than .01). Infusion of N-acetylcysteine (0.245, 1.225 and 6.125 mmol/kg/h for 4 h) and, to a lesser extent, equimolar doses of reduced glutathione, but not N-acetylserine, significantly potentiated the hypotensive effect of NTG, in a dose-dependent manner (P less than .05). However, complete reversal of tolerance was not achieved. This animal model of nitrate tolerance is suitable for further investigations of nitrate-thiol interactions and shares similarities with nitrate tolerance development in humans. The results suggest that sulfhydryl supplementation may enhance the hypotensive effect of NTG in a dose-dependent manner. This effect is more likely to be achieved with N-acetylcysteine than with glutathione and may be related to differences in membrane permeability.     

Intra-arrest cooling with delayed reperfusion yields higher survival than earlier normothermic resuscitation in a mouse model of cardiac arrest

BACKGROUND: Therapeutic hypothermia (TH) represents an important method to attenuate post-resuscitation injury after cardiac arrest. Laboratory investigations have suggested that induction of hypothermia before return of spontaneous circulation (ROSC) may confer the greatest benefit. We hypothesized that a short delay in resuscitation to induce hypothermia before ROSC, even at the expense of more prolonged ischemia, may yield both physiological and survival advantages. METHODS: Cardiac arrest was induced in C57BL/6 mice using intravenous potassium chloride; resuscitation was attempted with CPR and fluid administration. Animals were randomized into three groups (n=15 each): a normothermic control group, in which 8 min of arrest at 37 degrees C was followed by resuscitation; an early intra-arrest hypothermia group, in which 6.5 min of 37 degrees C arrest were followed by 90s of cooling, with resuscitation attempted at 30 degrees C (8 min total ischemia); and a delayed intra-arrest hypothermia group, with 90s cooling begun after 8 min of 37 degrees C ischemia, so that animals underwent resuscitation at 9.5 min. RESULTS: Animals treated with TH demonstrated improved hemodynamic variables and survival compared to normothermic controls. This was the case even when comparing the delayed intra-arrest hypothermia group with prolonged ischemia time against normothermic controls with shorter ischemia time (7-day survival, 4/15 vs. 0/15, p<0.001). CONCLUSIONS: Short resuscitation delays to allow establishment of hypothermia before ROSC appear beneficial to both cardiac function and survival. This finding supports the concept that post-resuscitation injury processes begin immediately after ROSC, and that intra-arrest cooling may serve as a useful therapeutic approach to improve survival.     

硝酸甘油型偏头痛模型评述

偏头痛是原发性神经血管性头痛之一，是一种常见病、多发病。由于偏头痛的发病机制较为复杂，影响因素多样，因此给研究带来很多困难。目前，偏头痛发病机制的假说有几种，但无论哪种都不能很好地解释其临床表现和实验观察到的现象。尽管如此，人们为探讨偏头痛的防治方法，针对其发病机制，已设计出多种偏头痛动物模型，各有优点和缺点，其中硬脑膜神经炎症模型与目前较为完善的偏头痛发病机制学说——三叉神经血管反射学说比较吻合，故得到国内外学者的一致肯定，成为实验性偏头痛动物模型的首选。但该造模方法对手术的要求相对较高，且对动物的损伤较重，影响因素较多，在短期内不能大量复制。     

Intravenous crocetinate prolongs survival in a rat model of lethal hypoxemia

OBJECTIVE: To examine whether a carotenoid, trans-sodium crocetinate, has beneficial effects on hemodynamic status and short-term outcome in a rat model of lethal hypoxemia. DESIGN: Randomized, placebo-controlled study. SETTING: Medical school laboratory. SUBJECTS: Eighteen spontaneously breathing, anesthetized Sprague-Dawley rats (six per group). INTERVENTIONS: Rats underwent instrumentation to measure blood pressure, aortic and renal blood flow, arterial blood gases, bladder epithelial oxygen tension (by an intraluminal Clark electrode), and hepatic microvascular oxygen tension (measured by porphyrin phosphorescence). After stabilization, the rats were subjected to breathing 10% inspired oxygen concentration. After 10 mins, they were administered 1.25 mL/kg intravenous boluses of either isotonic saline (control), normal strength crocetinate (40 microg/mL), or a concentrated crocetinate solution (60 microg/mL). These boluses were repeated at 30-min intervals until either death or 3 hrs had elapsed. MEASUREMENTS AND MAIN RESULTS: With the onset of hypoxemia, we observed a rapid reduction in blood pressure and renal blood flow, maintenance of aortic blood flow, an increase in arterial base deficit, and falls in oxygen tensions in arterial blood, bladder epithelium, and hepatic microvasculature. A progressive deterioration in the control rats was noted, with only two of the six animals surviving for 3 hrs. However, all 12 rats in the two crocetinate groups survived for 3 hrs, with hemodynamic stability until 150 mins and a slow decline thereafter. CONCLUSIONS: Trans-sodium crocetinate improved hemodynamic status and prolonged survival in this model of severe acute hypoxic hypoxia. To our knowledge, this is the first demonstration of an intravenous agent having such an effect.