Disorders in blood rheological properties in the post-resuscitation period after the agonal state

It has been discovered in experiments on anesthetized dogs that the early postresuscitation period following agony after a two-hour hypovolemic hypotension was characterized by pronounced disturbances of blood rheological properties: blood viscosity was significantly increased as compared with initial values under the shift rate 1.34 s-1; the limit of blood fluidity was twice as increased. Insignificantly changed was the magnitude of hematocrit following the recovery of the blood volume. Infusion of polyglucin (20-25 ml/kg) promptly after the blood volume recovery and on the first day after it (10 ml/kg) decreased the hematocrit magnitude to 0.26 l/l (days 5-7) but did not make blood fluidity return to normal. A significant increase of blood viscosity and fluidity could be observed for 1-3 months after resuscitation, the hematocrit magnitude being equal to 0.55 l/l instead of 0.47 l/l in an initial state (P less than 0.005).     

Changes in the concentrations of total RNA and DNA in the cerebral cortex and internal organs (liver and heart) after prolonged hypovolemic hypotension and in the post-resuscitation period

It was shown in experiments on dogs that after 4-hour hypovolemic hypotension the content of total RNA in brain cortex and myocardium homogenates decreased. In the liver, there was a significant decrease both in RNA and DNA content. In the postresuscitation period, the content of nucleic acids in the myocardium returned to normal after 14--21 days, and that in the liver after 3--4 months. The gray matter of the brain manifested a delayed lowering of DNA content (after 14--21 days), and the level of nucleic acid did not return ot normal over 3--4 months after resuscitation.     

Absorption and release of biogenic amines by the lung during the restorative period after hypovolemic hypotension

The processes of serotonin and histamine absorption and release by the lungs were studied in dogs during 1 to 3.5 hour hypovolemic hypotension and during 24 hours after blood retains fusion. Absorption of biogenic amines by the lungs tended to increase in all the animals under hypovolemic hypotension. In the group of non-survivors the serotonin absorption by the lungs in the post-terminal period remained increased, while in the group of survivors it came down to normal soon, though the histamine release was increased. The above processes were aggravated in the group of animals whose lungs were affected by oleic acid. It resulted in the absorption of histamine instead of its release. The intensified absorption of biogenic amines by the lungs was accompanied by a quick fall in cardiac output, by the increase in resistance of systemic and pulmonary circulation.     

Survival rate of dogs in the recovery period after prolonged hypovolemic hypotension]

Survival and completeness of the central nervous system functional restoration were investigated during the postreanimation period in 76 dogs, depending upon the duration of the hypovolemic hypotension, arterial pressure level and the subsequent transfusion therapy. Early polyglucine infusion to dogs who suffered 4 hours of hypovolemic hypotension increased the percentage of survived dogs and of dogs with complete neurological restoration as compared to the animals untreated with polyglucine.     

Changes in serum lysozyme activity in terminal states caused by blood loss]

A study was made of the dynamics of the lysozyme activity of the serum in dogs which sustained clinical death on the background of a 2-hour hypovolemic hypotension due to blood loss. There was revealed a progressive increase in the lysozyme activity of the serum during the hypotension and during the first 30 minutes of the postreanimation period. Lysozyme activity of the serum was increased in the course of 4 days after the revival. The significance of the lysozyme activity of the serum as an index of hypoxic injury of the internal organs in terminal conditions is discussed.     

Mechanisms of Responses of Systemic Circulation: Role of the Endothelial Factor of Vascular Tone Control

Experimental data on the effect of NO synthase inhibition on hemodynamic changes (blood pressure, cardiac output, and peripheral resistance) induced by an increased (polyglucin infusion) or decreased (orthostasis) cardiac output are presented. Under conditions of NO synthase inhibition, the pressor effects of polyglucin and orthostatic hypotension increased by 70 and 72%, respectively. The response of peripheral resistance had a similar trend. Significance of NO secretion by vascular endothelium for the development of systemic hemodynamic responses is proposed.     

Hemodynamic response and oxygen transport in pigs resuscitated with maleimide-polyethylene glycol-modified hemoglobin (MP4).

Cell-free Hb increases systemic and pulmonary pressure and resistance and reduces cardiac output and heart rate in animals and humans, effects that have limited their clinical development as "blood substitutes." The primary aim of this study was to evaluate the hemodynamic response to infusion of several formulations of a new polyethylene glycol (PEG)-modified human Hb [maleimide PEG Hb (MalPEGHb)] in swine, an animal known to be sensitive to Hb-induced vasoconstriction. Anesthetized animals underwent controlled hemorrhage (50% of blood volume), followed by resuscitation (70% of shed volume) with 10% pentastarch (PS), 4% MalPEG-Hb in lactated Ringer (MP4), 4% MalPEG-Hb in pentastarch (HS4), 2% MalPEG-Hb in pentastarch (HS2), or 4% stroma-free Hb in lactated Ringer solution (SFH). Compared with baseline, restoration of blood volume after resuscitation was similar and not significantly different for the PS (103%), HS2 (99%), HS4 (106%), and MP4 (87%) animals but significantly less for the SFH animals (66%) (P < 0.05). All solutions that contained MalPEG-Hb restored mean arterial and pulmonary pressure and cardiac output. Systemic vascular resistance was unchanged, and pulmonary arterial pressure and resistance were increased slightly. Both systemic and pulmonary vascular resistance increased significantly in animals that received SFH, despite less adequate blood volume restoration. Oxygen consumption was maintained in all animals that received MalPEG-Hb, but not PS. Base excess improved only with MalPEG-Hb and PS, but not SFH. Red blood cell O2 extraction was significantly increased in animals that received Hb, regardless of formulation. These data demonstrate resuscitation with MalPEG-human Hb without increasing systemic vascular resistance and support our previous observations in animals suggesting that the efficacy of low concentrations of PEG-Hb in the plasma results from reduced vasoconstriction.     

Restoration of microcirculation in the brain during ischemia

The work shows that, after slinging two carotids in rats, the blood pressure in the circle of Willis decreases to approximately 40 mm Hg. The developing ischemia is accompanied by a mass adhesion of leukocytes to the walls of the brain venules and smallest veins. In two hours after slinging, the blood pressure in the vessels of the circle of Willis decreases to 16-20 mm Hg. The rate of adhesion increases abruptly. In these vessels the leukocyte conglomerates are formed which results in complete occlusion of the vessels and the death of animals. These processes are shown to be reversible. The insertion of 4.0-4.5 ml of plasmosubstituent polyglucin into the vessels of the circle of Willis "washes away" the leukocyte conglomerates as well as a part of adhered leukocytes and restores the blood flow in the venules and smallest veins for 10-15 min.     

Effects of verapamil on the activity of Ca2+, Mg2+-dependent endonucleases in the nuclei of the dog liver during prolonged hypovolemic shock]

In the experiments of 23 mongrel anesthetized dogs it was established that the blockade of calcium channels with verapamil (0.1 mg/kg) significantly decreased the activity of Ca2+, Mg(2+)-dependent endonucleases in the nuclei of canine liver (after four hours of arterial hypotension, arterial pressure--40 mm Hg). Verapamil was injected intravenously 30 min before the beginning of haemorrhage. The infusion of verapamil to intact animals does not change the activity of the investigated DNA-endonucleases. The obtained experimental data demonstrate that verapamil effectively blocks the activity of endonucleases in the nuclei of canine liver in the conditions of an increasing permeability of hepatocytes' membranes which integrity is deranged during hypovolemic shock. The present investigation reveals a new molecular mechanism of defense of hepatocytes from the damaging effect of one of the pathogenetic factors of a terminal process, namely an increase in the activity of Ca2+, Mg(2+)-dependent endonucleases in the nuclei of the liver.     

中心静脉-动脉二氧化碳分压差与动脉-中心静脉氧含量差的比值(Pcv-aCO2/Ca-cvO2)变化率对急诊重症监护室脓毒症患者预后的评估价值

目的:探讨中心静脉动脉二氧化碳分压差/氧含量差(Pcv-aCO_2/Ca-cvO_2)变化率在急诊重症监护室(EICU)高乳酸脓毒血症患者病情及预后评估中的临床应用价值。方法:选择2017年1月到2018年9月入住急诊重症监护室的48例高乳酸(乳酸大于4 mmol/h)脓毒血症患者,均按2016年脓毒症指南进行液体复苏治疗。采集复苏前(T0h)和开始复苏后6h(T6h)、24h(T24h)的动脉血、上腔静脉血气分析以及动脉血乳酸浓度。计算并记录各时间点的乳酸,乳酸清除率,中心静脉动脉二氧化碳分压差(Pcv-aCO_2)值,中心静脉动脉二氧化碳分压差/氧含量(Pcv-aCO_2/Ca-cvO_2)值及其变化率。根据治疗24h改良SOFA评分是否改善将患者分为两组,即改良SOFA改善组和未改善组,观察和比较两组间基本临床资料及化验参数,并分析各时间点各参数之间的相关性,以及这些参数能否有效预测高乳酸脓毒血症患者病情危重程度和预后。结果:45例患者纳入最终分析,3例因为24h内死亡或者自动出院脱落。其中,17例24hSOFA改善,28例未改善;20例死亡,25例存活。两组患者复苏前各项一般临床资料指标比较差异均无统计学意义(P0.01)。24hSOFA改善组与未改善组患者Pcv-aCO_2/Ca-cvO_2(T24h)、Pcv-aCO_2/Ca-cvO_2变化率(0-24h)存在组间差异(P0.01)。45例患者的乳酸清除率(0-24h)与Pcv-aCO_2/Ca-cvO_2变化率(0-24h)呈显著相关性(r=0.906,P=0.034)。ROC分析显示Pcv-aCO_2/Ca-vO_2变化率(0-24h)能有效预测24hSOFA评分改善,同其他指标相比,曲线下面积最大(AUROC=0.851),最佳界值是0.307(30.7%),敏感度是76.5%,特异度是92.9%;Pcv-aCO_2/Ca-vO_2变化率(0-24h)也能有效预测脓毒症患者院内死亡,AUROC=0.696,AUROC较24h乳酸值小,但不存在统计学差异,最佳界值是0.181(18.1%),敏感度是65%,特异度是68%。结论:液体复苏前到开始复苏后24h的Pcv-aCO_2/Ca-cvO_2变化率可以有效预测高乳酸脓毒症患者的器官功能改善情况,也能有效预测脓毒症患者院内死亡的发生。     

Incidence of delayed ovulation in Holstein heifers and its effects on fertility and early luteal function

In the first of 3 experiments 134 first-service and 108 repeat-breeder Holstein heifers were palpated at 12-hour intervals starting 24 hours after insemination to compare the incidence of delayed ovulation in the 2 groups. Delayed ovulation was defined as failure to ovulate within the first 24 hours after insemination. Ovulation occurred within 24 hours post insemination in 92.1% of the animals and was delayed in 7.9% of the cases, with no differences between first-service and repeat-breeder heifers, indicating that the subfertility of the repeat-breeder animals was not due to delayed ovulation. The duration of the delay was at most 12 hours since all the animals had ovulated by 36 hours post insemination. Conception rate of the 19 animals with delayed ovulation (42.1%) was not different (P>0.05) from that of the 223 heifers that ovulated on time (44.8%). In a second experiment, no differences were detected between 15 heifers with delayed ovulation and 15 animals that ovulated on time with respect to their progesterone concentrations during the first 8 days post insemination, indicating that delayed ovulation is not associated with delayed luteinization or subnormal early luteal function. In the third experiment, the conception rate of 126 repeat-breeder heifers that were treated with hCG at the time of insemination was 26.7%; the conception rate of 101 repeat-breeder heifers that were inseminated twice, at 12 and 24 hours after the onset of estrus, was 34.6%; and the conception rate of 105 repeat-breeder heifers which were not treated with hCG and which were inseminated only once was 30.5% (P>0.05) It is concluded that delayed ovulation is not an important cause of infertility and does not constitute an important component of the repeat-breeding syndrome in Holstein heifers.     

Sublethal hemorrhagic shock reduces tumor necrosis factor-alpha-producing capacity in different cell compartments

Hemorrhagic shock results in a severe impairment of the immune response. Immunological alterations after hemorrhagic shock thus appear to be responsible for reduced resistance to infectious agents commonly observed after shock and severe injury. In the present study we examined the TNF-alpha-producing capacity of immune cells derived from different organs after sublethal shock in rats. Hemorrhagic shock was established by pressure controlled bleeding to a mean arterial pressure of 35 mm Hg for 35-40 min and consecutive resuscitation in male Sprague-Dawley rats. Twenty four hours after shock, TNF-a production in response to lipopolysaccharide (LPS, Salmonella friedenau) stimulation was measured in isolated spleen, bone marrow and blood cells. TNF-a production could be induced by stimulation with 1 ng/ml, in blood, spleen and bone marrow cells collected from sham-operated animals. A maximal stimulation was observed in all cell types after stimulation with 10 ng/ml LPS and could not be further increased with LPS doses of 100 ng/ml. Hemorrhagic shock of 35 mm Hg for 35-40 min, with consecutive resuscitation did not result in mortality, in contrast to a 4 hours lasting hemorrhagic shock resulting in 80% mortality. Blood, spleen or bone marrow cells, harvested from animals 24 hours after sublethal hemorrhagic shock, showed a significantly reduced TNF-alpha production in all cell populations after LPS stimulation. Serum collected from animals 2 hours after sublethal hemorrhagic shock contained an activity not present either before or 24 hours after shock, that downregulated LPS-induced TNF-alpha production in rat whole blood cultures and the murine macrophage cell line J774. The inhibitory activity present in serum, 2 hours after shock is not IL-10 since this mediator was not detectable in any serum sample. However, in the serum samples with TNF-alpha-inhibitory activity, elevated levels of PGE2 metabolites were found, which suggests the involvement of prostaglandins in trauma-induced immunosuppression. Altered TNF-a expression might be partially explained by an inhibitory activity in the serum already present 2 hours after shock. Since adequate, but not overwhelming TNF-alpha production is essential for host response, the altered cytokine formation might explain local and systemic susceptibility to infections after hemorrhagic shock.     

早期颈内动脉支架置入对动脉粥样硬化脑梗患者血清Lp-PLA2和Hcy水平的影响

摘要 目的：探讨早期颈内动脉支架置入（carotid artery stenting,CAS）对动脉粥样硬化脑梗死患者血清脂蛋白相关磷脂酶2（lipoprotein-associated phospholipase 2,LP-PLA2）和同型半胱氨酸（Homocysteine,Hcy）水平的影响。方法：选择2018年8月到2021年4月在在西安交通大学第一附属医院诊治的颈动脉重度狭窄性脑梗死患者86例作为研究对象,根据治疗方法将患者分为早期CAS组与对照组各43例,对照组给予药物保守治疗,2周后脑梗死稳定后再给予手术,CAS组在对照组基础上治疗3~5 d后给予颈内动脉支架置入治疗,检测两组患者血清Lp-PLA2和Hcy水平变化情况。结果：CAS组治疗后7 d的总有效率为97.7 %,高于对照组的86.0 %（P<0.05）。CAS组治疗后7 d的高灌注综合征、脑出血、低血压、心动过缓等并发症发生率为4.7 %,对照组无出现高灌注综合征、脑出血、低血压、心动过缓等并发症,对比差异无统计学意义(P>0.05)。两组治疗后7 d的颈内动脉相对脑血流量与脑血容量高于治疗前(P<0.05),CAS组高于对照组(P<0.05)。两组治疗后7 d的血清Lp-PLA2、Hcy含量低于治疗前（P<0.05）,CAS组低于对照组（P<0.05）。结论：早期颈内动脉支架置入在动脉粥样硬化脑梗死患者的应用能抑制Lp-PLA2、Hcy的表达,改善患者的血流动力学变化,从而促进提高治疗效果,在临床上的应用具有很好的安全性。     

The following is the abstract of the article discussed in the subsequent letter:.

Sublingual and intestinal mucosal blood flow and Pco(2) were studied in a canine model of endotoxin-induced circulatory shock and resuscitation. Sublingual Pco(2) (Ps(CO(2))) was measured by using a novel fluorescent optrode-based technique and compared with lingual measurements obtained by using a Stowe-Severinghaus electrode [lingual Pco(2) (Pl(CO(2)))]. Endotoxin caused parallel changes in cardiac output, and in portal, intestinal mucosal, and sublingual blood flow (Q(s)). Different blood flow patterns were observed during resuscitation: intestinal mucosal blood flow returned to near baseline levels postfluid resuscitation and decreased by 21% after vasopressor resuscitation, whereas Q(s) rose to twice that of the preshock level and was maintained throughout the resuscitation period. Electrochemical and fluorescent Pco(2) measurements showed similar changes throughout the experiments. The shock-induced increases in Ps(CO(2)) and Pl(CO(2)) were nearly reversed after fluid resuscitation, despite persistent systemic arterial hypotension. Vasopressor administration induced a rebound of Ps(CO(2)) and Pl(CO(2)) to shock levels, despite higher cardiac output and Q(s), possibly due to blood flow redistribution and shunting. Changes in Pl(CO(2)) and Ps(CO(2)) paralleled gastric and intestinal Pco(2) changes during shock but not during resuscitation. We found that the lingual, splanchnic, and systemic circulations follow a similar pattern of blood flow variations in response to endotoxin shock, although discrepancies were observed during resuscitation. Restoration of systemic, splanchnic, and lingual perfusion can be accompanied by persistent tissue hypercarbia, mainly lingual and intestinal, more so when a vasopressor agent is used to normalize systemic hemodynamic variables.     

Resuscitation affects microcirculatory polymorphonuclear leukocyte behavior after hemorrhagic shock: role of hypertonic saline and pentoxifylline

We have previously shown that lung injury following fluid resuscitation either with hypertonic saline (HS) or lactated Ringer's (LR) plus pentoxifylline (PTX) attenuated acute lung injury when compared with LR resuscitation. The objective of the present study is to determine whether our previous observations are accompanied by changes in polymorphonu-clear leukocyte (PMN) behavior. To study this, PMN-endothelial cell interactions, microcirculatory blood flow, lung histology, lung PMN infiltration (MPO, Myeloperoxidase), and lung intra-cellular adhesion molecule-1 (ICAM-1) expression were assessed in a controlled hemorrhagic shock model followed by LR, HS, and LR+PTX resuscitation in rodents. Rats (240-300 g) were bled to a mean arterial pressure (MAP) of 35 mm Hg for 1 hr and then randomized into three groups: HS (7.5% NaCl, 4 ml/kg); LR (3x shed blood); and LR+PTX (25 mg/kg). Additionally, total shed blood was reinfused. A sham group underwent no shock and no treatment. The internal spermatic fascia was exteriorized and the microcirculation was observed by closed-circuit TV coupled to a microscope, 2 and 6 hrs after treatment. The number of leukocytes sticking to the venular endothelium was determined 2 hrs after fluid resuscitation. Microcirculatory blood flow was measured by an optical Doppler velocimeter. Lung histology and lung MPO immunostaining were assessed at 6 hrs, and lung ICAM-1 expression was determined by immunostaining at 2 hrs following fluid resuscitation. Two hours after treatment, HS (1.4 +/- 0.4), LR+PTX (1.7 +/- 0.3), and sham (0.4 +/- 0.2) groups presented significant reductions in leukocyte adherence (cells/100 microm venule length), compared with the LR group (4.0 +/- 0.9, P < 0.05). No differences were observed 6 hrs after treatment on leukocyte adherence and microcirculatory blood flow. ICAM-1 expression was significantly higher in LR-treated animals compared with the HS, LR+PTX, and sham groups (P < 0.01). PMN infiltration and overall lung injury were significantly attenuated by HS and LR+PTX. These results support earlier studies that indicated the potential application of HS and PTX in shock therapy and the increase in PMN-endothelial cell interaction and lung injury after LR resuscitation.     

Recovery of brain energy metabolism following a period of combined hypoxia and hypotension.

Rats were "stressed" by a 30-min period of hypoxia (FIO2 = 7.5%) and hypotension (x arterial pressure = 30 mm Hg), and then "resusciated" by restoring FIO2 = 30% and reinfusing shed blood to restore arterial pressure toward baseline values. Concentrations of brain phosphocreatine, ATP and lactate were measured after "stress" and 20, 60, and 120 min after "resuscitation". A biphasic response was noted in which ATP was initially restored to baseline values by "resuscitation", and then progressively decreased. Physiologic mechanisms to explain the observed data are presented.     

Possibility of brain recovery after electrically induced cardiac arrest and reanimation in dogs

The changes of aortic blood pressure (BP), carotid artery flow (CAF), power spectrum of analysed EEG, neurologic deficit and survival rate were determinated in dogs after experimental cardiac arrest of different duration. Following artificially induced ventricular fibrillation of 1, 4, 10, 12 and 15 min duration successful cardiopulmonary resuscitation was performed in 30 experimental animals. Alterations of power spectrum during and after reanimation procedures, severity of the neurologic state and the survival rate deteriorated in parallel with the increasing duration of circulatory stop. Advantageous effect of direct heart massage could be demonstrated by the measuring circulatory parameters. Following a 15 min fibrillation, all animals were lost in a few hours despite the successful restoration of circulation and ventilation. Considering the various experimental and clinical conditions experimental cardiac arrest lasting for 12 min seems to be useful in extrapolating the results to human cases. The suggested model allows to study the brain function recovery after circulatory stop and resuscitation.     

Sympathetic innervation of the splanchnic region mediates the beneficial hemodynamic effects of 8-OH-DPAT in hemorrhagic shock

Administration of the 5-HT(1A) receptor agonist, 8-OH-DPAT, improves cardiovascular hemodynamics and tissue oxygenation in conscious rats subjected to hypovolemic shock. This effect is mediated by sympathetic-dependent increases in venous tone. To determine the role of splanchnic nerves in this response, effects of 8-OH-DPAT (30 nmol/kg iv) were measured following fixed-arterial blood pressure hemorrhagic shock (i.e., maintenance of 50 mmHg arterial pressure for 25 min) in rats subjected to bilateral splanchnic nerve denervation (SD). Splanchnic denervation decreased baseline venous tone as measured by mean circulatory filling pressure (MCFP) and accelerated the onset of hypotension during blood loss. Splanchnic denervation did not affect the immediate pressor effect of 8-OH-DPAT but did reverse the drug's lasting pressor effect, as well as its ability to increase MCFP and improve metabolic acidosis. Like SD, adrenal demedullation (ADMX) lowered baseline MCFP and accelerated the hypotensive response to blood withdrawal but also reduced the volume of blood withdrawal required to maintain arterial blood pressure at 50 mmHg. 8-OH-DPAT raised MCFP early after administration in ADMX rats, but the response did not persist throughout the posthemorrhage period. In a fixed-volume hemorrhage model, 8-OH-DPAT continued to raise blood pressure in ADMX rats. However, it produced only a transient and variable rise in MCFP compared with sham-operated animals. The data indicate that 8-OH-DPAT increases venoconstriction and improves acid-base balance in hypovolemic rats through activation of splanchnic nerves. This effect is due, in part, to activation of the adrenal medulla.     

Central hemodynamics of dogs in the early postresuscitation period and the outcome of resuscitation

Variations in central hemodynamics of dogs were compared with the outcome of resuscitation of 18 dogs subjected to 12-minute reversible circulatory arrest because of ventricular fibrillation. Nine survived dogs with completely recovered neurological status during the first 10 minutes after resuscitation had moderate hypertension, the mean arterial pressure (MAP) being 175.0 + 8.9 mm Hg. In the dogs who died within 24-48 hours after resuscitation, the MAP did not rise during this period as compared to the initial level; 2 dogs developed excessive hypertension (MAP about 200 mm Hg). There were also found certain differences in other parameters of central hemodynamics. Moderate hypertension in the first 10 minutes of the postresuscitation period leads to rapid restoration of the adequate level of peripheral blood flow in organs and tissues, thus favouring survival of animals subjected to a long circulatory arrest.