Slow as Compared to Rapid Rewarming After Mild Hypothermia Improves Survival in Experimental Shock.

BACKGROUND: Accidental hypothermia following trauma is an independent risk factor for mortality. However, in most experimental studies, hypothermia clearly improves outcome. We hypothesized that slow rewarming is beneficial over rapid rewarming following mild hypothermia in a rodent model of hemorrhagic shock. MATERIALS AND METHODS: We subjected 32 male Wistar rats to severe hemorrhagic shock (25-30 mmHg for 30 min). Rats were assigned to four experimental groups (normothermia, hypothermia, rapid rewarming [RW], and slow RW). During induction of severe shock, all but the normothermia group were cooled to 34°C. After 60 min of shock, rats were resuscitated with Ringer's solution. The two RW groups were rewarmed at differing rates (6°C/h versus 2°C/h). RESULTS: Slow RW animals exhibit a significantly prolonged survival compared with the rapid RW animals (P < 0.05). Nevertheless, hypothermic animals show a significant survival benefit as compared to all other experimental groups. Whereas seven animals of the hypothermia group survived to the end of the experiment, none of the other animals did (P < 0.001). No significant differences were found regarding acid base status, metabolism, parameters of organ injury, and coagulation. CONCLUSIONS: The results indicate that even slow RW with 2°C/h may be still too fast in the setting of experimental hemorrhage. Too rapid rewarming may result in a loss of the protective effects of hypothermia. As rewarming is ultimately inevitable in patients with trauma, potential effects of rewarming on patient outcome should be further investigated in clinical studies.

Tranexamic acid prolongs survival after controlled hemorrhage in rats.

BACKGROUND: The plasmin/plasminogen inhibitor tranexamic acid (TXA) is mainly used in elective surgeries with a higher blood loss to avoid uncontrolled bleeding. Recently, TXA has also been shown to reduce mortality in trauma patients. It is assumed that its beneficial effects are principally caused by its antifibrinolytic properties. We hypothesize that TXA also improves survival in a modified Wigger's model of hemorrhagic shock by a mechanism other than antifibrinolysis. MATERIALS AND METHODS: Male Wistar rats were intermittently bled until the mean arterial blood pressure was dropped to 25-30 mm Hg (severe shock). After shock induction, the animals received either 0.14-0.15 mL TXA (30 mg/kg) i.v. or the equivalent volume of 0.9% NaCl given as bolus. Adjacent to the shock period, the rats were resuscitated with Ringer's solution within 30 min and observed for another 150 min unless the animals died earlier. RESULTS: In the animals treated with TXA, survival was clearly prolonged and acid-base parameters showed some differences as compared to the animals receiving only NaCl. In the model used, coagulation slightly declined, but an increased fibrinolysis was not observed. CONCLUSIONS: Since in the applied shock model fibrinolysis is negligible, we postulate that TXA is capable of providing protection against hemorrhagic shock independent from its antifibrinolytic properties.

Hypokalemia during acute metabolic acidosis on hemodilution with succinylated gelatin in rats.

BACKGROUND: Extracellular metabolic acidosis of mineral origin is commonly associated with plasma hyperkalemia. Nevertheless, in previous experiments, animals subjected to acute metabolic acidosis induced by normovolemic hemodilution using a colloidal volume replacement solution containing succinylated gelatin (gelafundin), developed a hypokalemic state with concomitant marked increases in diuresis and renal potassium excretion. In the present study, the succinylated gelatin's impact on diuresis and consequently potassium excretion was studied. MATERIAL AND METHODS: Anesthetized Wistar rats were subjected to acute metabolic acidosis either due to normovolemic hemodilution with gelafundin (group I) or HCl application (groups II and III). Animals of group III received mannitol in addition. Blood gas analyses were performed regularly. Urine was continuously collected, and the excreted volume as well as potassium concentration was measured. RESULTS: In all groups, mean base excess value was about -3.0 mEq/L. Plasma potassium concentration decreased from 5.0 mM to 4.5 mM in group I, whereas it was almost constant in groups II and III. The urine volume amounted to 2300 µL in groups I and III and 1000 µL in group II. Excreted total amount of potassium in urine was 340 µmol (group I), 125 µmol (group II), and 230 µmol (group III), respectively. CONCLUSIONS: The employed volume replacement solution leads to increased diuresis induced by excretion of succinylated gelatin, which also sufficiently accounts for enhanced potassium loss into urine and decreased plasma potassium concentration. Therefore, generalization of the connection between acute metabolic acidosis and plasma hyperkalemia, as often stated in literature, is not justified.

L-Malate's Plasma and Excretion Profile in the Treatment of Moderate and Severe Hemorrhagic Shock in Rats.

Introduction. Malate is a standard component in fluid therapy within a wide range of medical applications. To date, there are insufficient data regarding its plasma distribution, renal excretion, and metabolism after infusion. This study aimed to investigate these three aspects in a rat model of moderate and severe hemorrhagic shock (HS). Methods. Male Wistar rats were subjected to HS by dropping the mean arterial blood pressure to 25-30 mmHg (severe) and 40-45 mmHg (moderate), respectively, for 60 minutes. Subsequently, reperfusion with Ringer-saline or a malate containing crystalloid solution (7 mM, 13.6 mM, and 21 mM, resp.) was performed within 30 minutes, followed by an observation period of 150 minutes. Results. In the present experiments, malate rapidly disappeared from the blood, while only 5% of the infused malate was renally excreted. In the resuscitation interval the urinary citrate and succinate amounts significantly increased compared to control. Conclusion. Malate's half-life is between 30 and 60 minutes in both, moderate and severe HS. Thus, even under traumatic conditions malate seems to be subjected to rapid metabolism with participation of the kidneys.

Comparison of Malated Ringer's with Two Other Balanced Crystalloid Solutions in Resuscitation of Both Severe and Moderate Hemorrhagic Shock in Rats.

In preclinical treatment of polytraumatized patients crystalloids are preferentially used. To avoid metabolic acidosis, metabolizable anions like lactate or acetate are used to replace chloride in these solutions. We here studied the effects of malated Ringer's in resuscitation of both shock severities in comparison to lactated and acetated Ringer's. Male Wistar rats underwent severe (mean arterial blood pressure (MAP) of 25-30 mmHg) or moderate (MAP 40-45 mmHg) hemorrhagic shock. Adjacent to the shock period animals were resuscitated with acetated (AR), lactated (LR), or malated Ringer's (MR) and observed for 150 min. MR improved survival compared with LR and AR in severe hemorrhagic shock whereas it was equally effective to LR and superior to AR in moderate hemorrhagic shock. In all other parameters tested, MR was also effective similar to the other solutions under these conditions. We conclude that MR is preferable to AR and LR in resuscitation of hemorrhagic shock independent of shock depth. The positive effects of MR may stem from the absence of any adverse impact on energy metabolism under both conditions.

Volume replacement with Ringer-lactate is detrimental in severe hemorrhagic shock but protective in moderate hemorrhagic shock: studies in a rat model.

INTRODUCTION: To date, there are insufficient data demonstrating the benefits of preclinically administered Ringer-lactate (RL) for the treatment of hemorrhagic shock following trauma. Recent animal experiments have shown that lactate tends to have toxic effects in severe hemorrhagic shock. This study aimed to compare the effects of RL administered in a rat model of severe hemorrhagic shock (mean arterial blood pressure (MAP): 25 to 30 mmHg) and moderate hemorrhagic shock (MAP: 40 to 45 mmHg). METHODS: Four experimental groups of eight male Wistar rats each (moderate shock with Ringer-saline (RS), moderate shock with RL, severe shock with RS, severe shock with RL) were established. After achieving the specified depth of shock, animals were maintained under the shock conditions for 60 minutes. Subsequently, reperfusion with RS or RL was performed for 30 minutes, and the animals were observed for an additional 150 minutes. RESULTS: All animals with moderate shock that received RL survived the entire study period, while six animals with moderate shock that received RS died before the end of the experiment. Furthermore, animals with moderate shock that received RL exhibited considerable improvements in their acid-base parameters and reduced organ damage. CONCLUSIONS: The preclinical use of RL for volume replacement has different effects depending on the severity of hemorrhagic shock. RL exhibits detrimental effects in cases of severe shock, whereas it has pronounced protective effects in cases of moderate shock.

Superiority of acetate compared with lactate in a rodent model of severe hemorrhagic shock.

BACKGROUND: Recently, we have shown that the use of lactated Ringer's (LR) solution is inferior to pure Ringer's solution (RS) in treatment of severe hemorrhagic shock in rats. The present study was performed to evaluate whether this is a specific effect of lactate or also applies to another metabolizable anion, namely acetate. MATERIAL AND METHODS: We subjected male Wistar rats to hemorrhagic shock by dropping the mean arterial blood pressure to 25-30 mm Hg for 60 min, resuscitated with acetated Ringer's (AR) solution, LR solution, RS, or normal saline (NS) within 30 min, and further observed the animals for 180 min. RESULTS: Administration of AR solution prolonged median survival to 115 min compared with 50 min for resuscitation with LR solution or 85 and 90 min for NS and RS, respectively. Resuscitation with AR solution and LR solution clearly improved metabolic acidosis compared with NS and RS but tissue injury, indicated by plasma enzyme activities, was most pronounced in the LR solution group, medium in the NS and RS groups, and least in the AR solution group. CONCLUSIONS: In severe hemorrhagic shock, resuscitation with both RS and NS is superior to administration of LR solution but initial outcome is even further improved if AR solution is used. Mere amelioration of the acid-base status by AR solution may explain its superior role compared with RS and NS but cannot be responsible for its superiority compared with LR solution. Here, direct injury by lactate has to be discussed.

Molecular effects of baicalein in Hct116 cells and Caenorhabditis elegans : activation of the Nrf2 signaling pathway and prolongation of lifespan.

Baicalein is a major compound of extracts derived from Scutellaria baicalensis Lamiaceae, which are used as food supplements. Baicalein possesses a high radical scavenging activity and decreases intracellular reactive oxygen species in Hct116 human colon carcinoma cells and in Caenorhabditis elegans . It activates Nrf2, a key transcription factor that binds to the antioxidant responsive element (ARE): Baicalein causes a nuclear accumulation of Nrf2, increases ARE-dependent luciferase activity, and enhances the expression of heme oxygenase-1 in Hct116 cells. Additionally, accumulation of the Nrf2 homologue SKN-1 in nuclei of intestinal cells of C. elegans was observed. Lifespan analysis revealed that baicalein extends the mean, median, and maximum lifespans of the nematode by 45, 57 and 24%, respectively. Because SKN-1 activation is associated with prolongation of lifespan, the results suggest that baicalein increases the lifespan of C. elegans by activation of the Nrf2/SKN-1 signaling pathway.

Adverse effects of resuscitation with lactated ringer compared with ringer solution after severe hemorrhagic shock in rats.

Lactated Ringer (LR) is a widely used resuscitation fluid that is known to mediate beneficial effects on acid-base balance when compared with normal saline. We here compared LR with the more physiological Ringer solution (RS) regarding acid-base status, hemodynamics, survival, and organ injury following fluid resuscitation subsequent to severe hemorrhagic shock. Anesthetized rats were hemorrhaged to a mean arterial blood pressure of 25 to 30 mmHg within 30 min. After 60 min, they were resuscitated with either RS or LR (three times the shed blood volume) or with RS or LR plus blood (shed blood plus twice its volume) within 30 min. Subsequently, the animals were observed for further 150 min. When the rats were resuscitated with pure LR or RS, all animals of the shock/LR group, but only three of eight shock/RS group rats were dead 100 min later (median survival, 50 ± 13.1 vs. 120 ± 14.1 min; P < 0.05). Coadministration of the shed blood with RS or LR increased the survival rates to 100%. In these blood-resuscitated groups, organ injury, especially of the kidney, was diminished by the use of RS compared with LR. Time-matched acid-base parameters were not different in all shock groups until death of the animals or euthanasia at the end of experimental time. We conclude that, in severe hemorrhagic shock, resuscitation with RS leads to an improved outcome compared with resuscitation with LR, regardless whether blood is coadministered or not.