Mild or moderate hypothermia, but not increased oxygen breathing, increases long-term survival after uncontrolled hemorrhagic shock in rats

OBJECTIVE: To test the hypotheses that, for uncontrolled hemorrhagic shock (UHS) in rats, mild hypothermia, compared with normothermia, would increase long-term survival as well as moderate hypothermia, oxygen breathing would increase survival further, and hypothermia and oxygen would mitigate visceral ischemia (dysoxia) during UHS. DESIGN: Prospective, randomized study. SETTING: Animal research laboratory. SUBJECTS: A total of 54 male Sprague-Dawley rats. INTERVENTIONS: Under light anesthesia and spontaneous breathing, rats underwent UHS phase I of 75 mins, with initial withdrawal of 3 mL/100 g of blood over 15 mins, followed by UHS via tail amputation and limited fluid resuscitation to maintain mean arterial pressure at > or =40 mm Hg; resuscitation phase II of 60 mins (from 75 mins to 135 mins) with hemostasis and aggressive fluid resuscitation to normalize hemodynamics; and observation phase III to 72 hrs. Rats were randomly divided into nine groups (n = 6 each) with three rectal temperature levels (38 degrees C [normothermia] vs. 34 degrees C [mild hypothermia] vs. 30 degrees C [moderate hypothermia]) by surface cooling; each with 3 FIO2 levels (0.25 vs. 0.5 vs. 1.0). MEASUREMENTS AND MAIN RESULTS: Hypothermia increased blood pressure compared with normothermia. Increased FIO2 had no effect on blood pressure. Additional blood loss from the tail cut was small, with no differences among groups. Hypothermia and FIO2 of 0.5 decreased visceral hypoxia, as measured by the difference between visceral (liver and jejunum) surface Pco2 and PaCO2 during UHS. Compared with normothermia, mild hypothermia increased the survival time and rate as well as moderate hypothermia (p < .01 by life table), without a significant difference between mild and moderate hypothermia. Increased FIO2 had no effect on survival time or rate. CONCLUSIONS: After severe UHS and resuscitation in rats, mild hypothermia during UHS, compared with normothermia, increases blood pressure, survival time and 72-hr survival rate as well as moderate hypothermia. Mild hypothermia is clinically more feasible and safer than moderate hypothermia. Increased FIO2 seems to have no significant effect on outcome.     

Mild hypothermia prolongs the survival time during uncontrolled hemorrhagic shock in rats

OBJECTIVE: To test our hypothesis that during lethal uncontrolled hemorrhagic shock (UHS) in rats, mild hypothermia of either 36 or 34 degrees C would prolong the survival time in comparison with normotherma of 38 degrees C. METHODS: Twenty-four rats were lightly anesthetized with halothane and maintained spontaneous breathing. UHS was induced by blood withdrawal of 2.5 ml/100 g over 15 min, followed by 75% tail amputation. Immediately after the tail cut, the rats were randomly divided into three groups (eight rats for each); normothermic Group 1 (control, rectal temperature 38 degrees C), and mild hypothermic Groups 2 (36 degrees C) and 3 (34 degrees C). Hypothermia was induced and maintained by body surface cooling. The rats were then observed without fluid resuscitation until their death (apnea and no pulse) or for a period of 240 min maximum. RESULTS: The rectal temperature was cooled down to 36 and 34 degrees C in 5 and 10 min, respectively. The mean survival time, which was 76+/-26 min in the control group (38 degrees C), was nearly doubled by mild hypothermia, 178+/-65 min for Group 2 (36 degrees C) (P<0.01 vs. control) and 144+/-54 min for Group 3 (34 degrees C) (P<0.05 vs. control) (no significant difference between Group 2 and 3). Additional blood losses from tail stumps were not significantly different among the three groups. CONCLUSION: Mild hypothermia of either 36 or 34 degrees C prolongs the survival time during lethal UHS in rats.     

Improved survival of hemorrhagic shock with oxygen and hypothermia in rats.

A previously established model in awake rats of hemorrhagic shock (HS) with 25% spontaneous survival rate (without resuscitation) was used to evaluate the effects of 4 novel life-supporting first aid (LSFA) measures on survival time and rate. After shed blood volume (SBV) of 3.25 ml/100 g, withdrawn over 20 min, hemodynamic and respiratory responses were recorded to 3 h and survival to 24 h. The 5 groups of 20 rats each (total n = 100) were as follows: group I, controls without treatment; II, oxygen 100% inhalation; III, external cooling to rectal temperature 30 degrees C; IV, Ringer's solution 5 ml/100 g rectally; and V, acoustic and surface stimuli for arousal. Survival rates were: control group I, 35% at 3 h and 15% at 24 h; oxygen group II, 75% (P less than 0.05 compared with group I) at 3 h and 60% (P less than 0.05 compared with group I) at 24 h; hypothermia group III, 65% at 3 h and 45% (P less than 0.05 compared with group I) at 24 h; rectal fluid group IV, 50% at 3 h and 40% at 24 h; stimulated group V, 15% at 3 h and 15% at 24 h. Compared with group I, median survival times during HS 0-3 h were longer in groups II and III; and self-resuscitation attempts were longer in groups II, III and IV. We conclude that in untreated severe hemorrhagic shock, chances of survival to delayed arrival of advanced life support with i.v. fluid resuscitation might be increased with O2 inhalation and/or moderate external cooling.     

Effect of resuscitative mild hypothermia and oxygen concentration on the survival time during lethal uncontrolled haemorrhagic shock in mechanically ventilated rats.

OBJECTIVE: To test the hypothesis that resuscitative mild hypothermia (MH) (34 degrees C) or breathing fractional inspired oxygen (FIo2) of 1.0 would prolong survival time during lethal uncontrolled haemorrhagic shock (UHS) in mechanically ventilated rats. METHODS: Forty Wistar rats were anaesthetized with halothane, nitrous oxide and oxygen (70/30%), intubated and mechanically ventilated. UHS was induced by volume-controlled blood withdrawal of 3 ml/100 g over 15 min, followed by 75% tail amputation of its length. The animals were randomly divided into four UHS treatment groups (10 rats in each group): group 1 was maintained on an FIo2 of 0.21 and rectal temperature of 37.5 degrees C. Group 2 was maintained on an FIo2 of 0.21 and induced MH. Group 3 was maintained on an FIo2 of 1.0 and 37.5 degrees C. Group 4 was maintained on an FIo2 of 1.0 and MH. Rats were observed otherwise untreated until death. RESULTS: During the initial blood withdrawal, mean arterial pressure (MAP) decreased to 40 mmHg, and the heart rate (HR) increased up to 400 beats/min. The induction of MH increased MAP to 60 mmHg and increased survival time. Moreover, it reduced the HR to 300 beats/min but did not increase bleeding. Ventilation with an FIo2 of 1.0 did not influence MAP, blood loss or survival time, but increased arterial oxygen tension. The mean survival time was 62, 202, 68 and 209 min in groups 1, 2, 3 and 4, respectively. Blood loss from the tail was 1.0, 1.2, 0.9 and 0.7 ml, respectively, in groups 1, 2, 3 and 4. CONCLUSION: MH prolonged the survival time during UHS in mechanically ventilated rats. However, an FIo2 of 1.0 did not influence the survival time or blood loss from the tail.     

Mild hypothermia during hemorrhagic shock in rats improves survival without significant effects on inflammatory responses

OBJECTIVE: To explore the hypothesis that the survival benefit of mild, therapeutic hypothermia during hemorrhagic shock is associated with inhibition of lipid peroxidation and the acute inflammatory response. DESIGN: Prospective and randomized. SETTING: Animal research facility. SUBJECTS: Male Sprague-Dawley rats. INTERVENTIONS: Rats underwent pressure-controlled (mean arterial pressure 40 mm Hg) hemorrhagic shock for 90 mins. They were randomized to normothermia (38.0 +/- 0.5 degrees C) or mild hypothermia (33-34 degrees C from hemorrhagic shock 20 mins to resuscitation time 12 hrs). Rats were killed at resuscitation time 3 or 24 hrs. MEASUREMENTS AND MAIN RESULTS: All seven rats in the hypothermia group and seven of 15 rats in the normothermia group survived to 24 hrs (p <.05). Hypothermic rats had lower serum potassium and higher blood glucose concentrations at 90 mins of hemorrhagic shock (p <.05). At resuscitation time 24 hrs, the hypothermia group had less liver injury (based on serum concentrations of ornithine carbamolytransferase and liver histology) and higher blood glucose than the normothermia group (p <.05). There were no differences in serum free 8-isoprostane (a marker of lipid peroxidation by free radicals) between the two groups at either baseline or resuscitation time 1 hr. Serum concentrations of interleukin- 1 beta, interleukin-6, and tumor necrosis factor-alpha peaked at resuscitation time 1 hr. Tumor necrosis factor-alpha concentrations were higher (p <.05) at resuscitation time 1 hr in the hypothermia group compared with the normothermic group. Serum cytokine concentrations were not different between survivors and nonsurvivors in the normothermia group. Serum cytokine concentrations returned to baseline values in both groups by 24 hrs. There were no differences in the number of neutrophils in the lungs or the small intestine between the groups. More neutrophils were found in the lungs at resuscitation time 3 hrs than at resuscitation time 24 hrs in both groups (p <.01). CONCLUSIONS: These data suggest that lipid peroxidation and systemic inflammatory responses to hemorrhagic shock are minimally influenced by mild hypothermia, although liver injury is mitigated and survival improved. Other mechanisms of benefit from mild hypothermia need to be explored.     

Effects of mild hypothermia on survival and serum cytokines in uncontrolled hemorrhagic shock in rats

Previous studies have suggested benefit of mild hypothermia during hemorrhagic shock (HS). This finding needs additional confirmation and investigation into possible mechanisms. Proinflammatory cytokines are mediators of multiple organ failure following traumatic hemorrhagic shock and resuscitation. We hypothesized that mild hypothermia would improve survival from HS and may affect the pro- and anti-inflammatory cytokine response in a rat model of uncontrolled HS. Under light halothane anesthesia, uncontrolled HS was induced by blood withdrawal of 3 mL/100 g over 15 min followed by tail amputation. Hypotensive (limited) fluid resuscitation (to prevent mean arterial pressure [MAP] from decreasing below 40 mmHg) with blood was started at 30 min and continued to 90 min. After hemostasis and resuscitation with initially shed blood and Ringer's solution, the rats were observed for 72 h. The animals were randomized into two HS groups (n = 10 each): normothermia (38 degrees C +/- 0.5 degrees C) and mild hypothermia (34 degrees C +/- 0.5 degrees C) from HS 30 min until resuscitation time (RT) 60 min; and a sham group (n = 3). Venous blood samples were taken at baseline, RT 60 min, and days 1, 2, and 3. Serum interleukin (IL)-1beta, IL-6, IL-10, and tumor necrosis factor (TNF)-alpha concentrations were quantified by ELISA. Values are expressed as median and interquartile range. Survival time by life table analysis was greater in the hypothermia group (P = 0.04). Survival rates to 72 h were 1 of 10 vs. 6 of 10 in the normothermia vs. hypothermia groups, respectively (P = 0.057). All cytokine concentrations were significantly increased from baseline at RT 60 min in both HS groups, but not in the shams. At RT 60 min, in the normothermia vs. hypothermia groups, respectively, IL-1beta levels were 185 (119-252) vs. 96 (57-135) pg/mL (P = 0.15); IL-6 levels were 2242 (1903-3777) vs. 1746 (585-2480) pg/mL (P = 0.20); TNF-alpha levels were 97 (81-156) vs. 394 (280-406) pg/mL (P= 0.02); and IL-10 levels were 1.7 (0-13.3) vs. 15.8 (1.9-23.0) pg/mL (P = 0.09). IL-10 remained increased until day 3 in the hypothermia group. High IL-1beta levels (>100 pg/mL) at RT 60 min were associated with death before 72 h (odds ratio 66, C.I. 3.5-1255). We conclude that mild hypothermia improves survival time after uncontrolled HS. Uncontrolled HS induces a robust proinflammatory cytokine response. The unexpected increase in TNF-alpha with hypothermia deserves further investigation.     

Arginine vasopressin,but not epinephrine,improves survival in uncontrolled hemorrhagic shock after liver trauma in pigs

OBJECTIVE: Epinephrine is widely used for treatment of life-threatening hypotension, although new vasopressor drugs may merit evaluation. The purpose of this study was to determine the effects of vasopressin vs. epinephrine vs. saline placebo on hemodynamic variables, regional blood flow, and short-term survival in an animal model of uncontrolled hemorrhagic shock and delayed fluid resuscitation. DESIGN: Prospective, randomized, laboratory investigation that used a porcine model for measurement of hemodynamic variables and regional abdominal organ blood flow. SETTING: University hospital laboratory. SUBJECTS: A total of 21 pigs weighing 32 +/- 3 kg. INTERVENTIONS: The anesthetized pigs were subjected to a penetrating liver injury, which resulted in a mean +/- sem loss of 40% +/- 5% of estimated whole blood volume within 30 mins and mean arterial pressures of <20 mm Hg. When heart rate declined progressively, pigs randomly received a bolus dose and continuous infusion of either vasopressin (0.4 units/kg and 0.04 units.kg-1.min-1, n = 7), or epinephrine (45 microg/kg and 5 microg.kg(-1).min(-1), n = 7), or an equal volume of saline placebo (n = 7), respectively. At 30 mins after drug administration, all surviving animals were fluid resuscitated while bleeding was surgically controlled. MEASUREMENTS AND MAIN RESULTS: Mean +/- sem arterial blood pressure at 2.5 and 10 mins was significantly (p <.001) higher after vasopressin vs. epinephrine vs. saline placebo (82 +/- 14 vs. 23 +/- 4 vs. 11 +/- 3 mm Hg, and 42 +/- 4 vs. 10 +/- 5 vs. 6 +/- 3 mm Hg, respectively). Although portal vein blood flow was temporarily impaired by vasopressin, it was subsequently restored and significantly (p <.01) higher when compared with epinephrine or saline placebo (9 +/- 5 vs. 121 +/- 3 vs. 54 +/- 22 mL/min and 150 +/- 20 vs. 31 +/- 17 vs. 0 +/- 0 mL/min, respectively). Hepatic and renal artery blood flow was significantly higher throughout the study in the vasopressin group; however, no further bleeding was observed. Despite a second bolus dose, all epinephrine- and saline placebo-treated animals died within 15 mins after drug administration. By contrast, seven of seven vasopressin-treated animals survived until fluid replacement, and 60 mins thereafter, without further vasopressor therapy (p <.01). Moreover, blood flow to liver, gut, and kidney returned to normal values in the postshock phase. CONCLUSIONS: Vasopressin, but not epinephrine or saline placebo, improved short-term survival in a porcine model of uncontrolled hemorrhagic shock after liver injury when surgical intervention and fluid replacement was delayed.     

Effects of increased oxygen breathing in a volume controlled hemorrhagic shock outcome model in rats

It is believed that victims of traumatic hemorrhagic shock (HS) benefit from breathing 100% O(2). Supplying bottled O(2) for military and civilian first aid is difficult and expensive. We tested the hypothesis that increased FiO(2) both during severe volume-controlled HS and after resuscitation in rats would: (1) increase blood pressure; (2) mitigate visceral dysoxia and thereby prevent post-shock multiple organ failure; and (3) increase survival time and rate. Thirty rats, under light anesthesia with halothane (0. 5% throughout), with spontaneous breathing of air, underwent blood withdrawal of 3 ml/100 g over 15 min. After HS phase I of 60 min, resuscitation phase II of 180 min with normotensive intravenous fluid resuscitation (shed blood plus lactated Ringer's solution), was followed by an observation phase III to 72 h and necropsy. Rats were randomly divided into three groups of ten rats each: group 1 with FiO(2) 0.21 (air) throughout; group 2 with FiO(2) 0.5; and group 3 with FiO(2) 1.0, from HS 15 min to the end of phase II. Visceral dysoxia was monitored during phases I and II in terms of liver and gut surface PCO(2) increase. The main outcome variables were survival time and rate. PaO(2) values at the end of HS averaged 88 mmHg with FiO(2) 0.21; 217 with FiO(2) 0.5; and 348 with FiO(2) 1. 0 (P<0.001). During HS phase I, FiO(2) 0.5 increased mean arterial pressure (MAP) (NS) and kept arterial lactate lower (P<0.05), compared with FiO(2) 0.21 or 1.0. During phase II, FiO(2) 0.5 and 1. 0 increased MAP compared with FiO(2) 0.21 (P<0.01). Heart rate was transiently slower during phases I and II in oxygen groups 2 and 3, compared with air group 1 (P<0.05). During HS, FiO(2) 0.5 and 1.0 mitigated visceral dysoxia (tissue PCO(2) rise) transiently, compared with FiO(2) 0.21 (P<0.05). Survival time (by life table analysis) was longer after FiO(2) 0.5 than after FiO(2) 0.21 (P<0. 05) or 1.0 (NS), without a significant difference between FiO(2) 0. 21 and 1.0. Survival rate to 72 h was achieved by two of ten rats in FiO(2) 0.21 group 1, by four of ten rats in FiO(2) 0.5 group 2 (NS); and by four of ten rats of FiO(2) 1.0 group 3 (NS). In late deaths macroscopic necroses of the small intestine were less frequent in FiO(2) 0.5 group 2. We conclude that in rats, in the absence of hypoxemia, increasing FiO(2) from 0.21 to 0.5 or 1.0 does not increase the chance to achieve long-term survival. Breathing FiO(2) 0.5, however, might increase survival time in untreated HS, as it can mitigate hypotension, lactacidemia and visceral dysoxia.     

Intraperitoneal, but not enteric, adenosine administration improves survival after volume-controlled hemorrhagic shock in rats

OBJECTIVE: To circumvent the potential adverse systemic side effects of adenosine, this study explored the potential benefit of intraperitoneal or enteric adenosine on survival and inflammatory responses after volume-controlled hemorrhagic shock. DESIGN: Prospective, randomized, and blinded. A three-phase, volume-controlled hemorrhagic shock model was used: hemorrhagic shock phase (120 mins), resuscitation phase (60 mins), and observation phase (72 hrs). Three groups were compared: controls, intraperitoneal adenosine, and enteric adenosine. SETTING: Animal research facility. SUBJECTS: Male Sprague-Dawley rats. INTERVENTIONS: Starting at 20 mins of hemorrhagic shock and continuing through the resuscitation phase, all three groups received both intraperitoneal lavage and repeated bolus injections into the ileum of vehicle (normal saline) or adenosine. In the intraperitoneal adenosine group (n = 10), adenosine solution (0.1 mM) was used for intraperitoneal lavage. In the enteric adenosine group (n = 10), adenosine (1.0 mM) was injected into the ileum. Blood cytokine concentrations and leukocyte infiltration in lungs and liver were studied in 12 separate rats (control and intraperitoneal adenosine, n = 6 each) with the same hemorrhagic shock model at resuscitation time 1 hr or 4 hrs. MEASUREMENTS AND MAIN RESULTS: Mean arterial pressure and heart rate were similar between the three groups during hemorrhagic shock and resuscitation. Potassium, lactate, and blood urea nitrogen concentrations were lower and arterial pH was higher in the intraperitoneal and enteric adenosine groups compared with the control group (both p <.05). Survival time to 72 hrs was longer in the intraperitoneal adenosine group than in the control group(p <.05). Neither plasma interleukin-1beta, interleukin-6, interleukin-10, and tumor necrosis factor-alpha concentrations nor leukocyte infiltration in the lungs and liver was different between the control and intraperitoneal adenosine groups. CONCLUSIONS: The administration of adenosine via the intraperitoneal route improves survival time after severe volume-controlled hemorrhagic shock in rats without worsening hypotension or bradycardia. This beneficial effect may not be attributable to effects of adenosine on the inflammatory response.     

Small volume resuscitation with tempol is detrimental during uncontrolled hemorrhagic shock in rats

BACKGROUND: In a previous study, titration of a hypertonic saline (HTS) solution during severe uncontrolled hemorrhagic shock (UHS) failed to reduce mortality. In a separate study, a novel antioxidant, polynitroxylated albumin (PNA) plus tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl), infused during shock increased long-term survival. We hypothesized that combining potent antioxidants with a hypertonic solution during UHS would preserve the logistical advantage of small volume resuscitation and improve survival. METHODS: An UHS outcome model in rats was used. UHS phase I (90 min) included blood withdrawal of 30 ml/kg over 15 min, followed by tail amputation for uncontrolled bleeding. At 20 min, rats were randomized to four groups (n=10 each) for hypotensive resuscitation from 20 to 90 min (mean arterial pressure [MAP] > or = 40 mmHg): HTS/starch group received 7.2% NaCl/10% hydroxyethyl starch; HTS/albumin group received 7.5% NaCl/20% albumin; HTS/PNA group received 7.5% NaCl/20% PNA; HTS/albumin+tempol group received 7.5% NaCl/20% albumin plus tempol. Resuscitation phase II (180 min) included hemostasis, return of shed blood and administration of fluids to restore MAP > or = 80 mmHg. Observation phase III was to 72 h. RESULTS: The total amount of fluid required to maintain hypotensive MAP during HS was low and did not differ between groups (range: 3.4+/-1.9 to 5.3+/-2.5 ml/kg). The rate of fluid administration required was higher in the HTS/albumin+tempol group compared to all other groups (p=0.006). Additional uncontrolled blood loss was highest in the HTS/PNA group (16.2+/-5.7 ml/kg [p=0.01] versus 10.4+/-7.9 ml/kg in the HTS/starch group, 7.7+/-5.2 ml/kg in the HTS/albumin group and 8.2+/-7.1 ml/kg in the HTS/albumin+tempol group). MAP after start of resuscitation in phase I was lower in the HTS/albumin+tempol group than the HTS/albumin or HTS/PNA groups (p<0.01). This group was also less tachycardic. Long-term survival was low in all groups (2 of 10 after HTS/starch and 1 of 10 after HTS/albumin, 3 of 10 after HTS/PNA, 1 of 10 after HTS/albumin+tempol). Median survival time was shortest in the HTS/albumin+tempol group (72 min [CI 34-190]) compared to all other groups (p=0.01). CONCLUSIONS: Despite its benefits in other model systems, free tempol is potentially hazardous when combined with hypertonic fluids. PNA abrogates these deleterious effects on acute mortality but may lead to increased blood loss in the setting of UHS.     

Therapeutic hypothermia limited to the resuscitation period does not prolong survival after severe hemorrhagic shock in rats

OBJECTIVE: Controlled hypothermia induced during hemorrhagic shock (HS) has been shown previously to improve survival in HS rat outcome models. We hypothesized that hypothermia (34 degrees C) induced immediately with reperfusion would also improve survival. METHODS: Twenty-four rats were lightly anesthetized with halothane and maintained spontaneous breathing. The rats underwent: an HS phase I of 75 min, with an initial blood withdrawal of 2.5 mL/100 g over 15 min, followed by either additional blood withdrawal or re-infusion in order to maintain a mean arterial pressure (MAP) of 30 mmHg over 60 min; a resuscitation phase II of 60 min with return of shed blood and infusion of lactated Ringer's solution to maintain a MAP of 75 mmHg; and an observation phase III without anesthesia for 72 h. Five minutes before the start of phase II, 12 rats were randomized into either a normothermia (38 degrees C) group or hypothermia (34 degrees C) group. The rectal temperature in each group was carefully maintained during the 60-min period of phase II. Survival at 72 h, as well as gut damage were assessed. RESULTS: All 24 rats survived beyond phases I and II. At 72 h, 8 of 12 rats survived in the hypothermia group, while and 6 of 12 survived in the normothermia group (p=0.64). Intestines of the 72 h survivors were macroscopically normal. In rats that died during phase III, total gut scores did not differ statistically between the groups (1.2+/-0.6 versus 1.0+/-0.9). CONCLUSION: Brief resuscitative hypothermia of 60 min duration induced immediately with reperfusion after HS did not improve survival in this model.     

低血容量性休克大鼠全身氧动力学的变化研究

目的：研究低血容量性休克时全身氧动力学的变化特点。方法：按４ｍｌ／ｋｇ,每隔０．５分次从静脉放血,观察大鼠休克过程中全身氧供给（ＤＯ２）,氧消耗（ＶＯ２）和氧摄取率（ＥｘｔＯ２）的变化。结果：失血后１．５小时血红蛋白浓度开始显著降低,心率明显加快,失血２．０小时平均动脉压明显下降,此时ＤＯ２亦开始进行性下降,由于ＥｘｔＯ２出现代偿升高,ＶＯ２维持相对不变;     

Effects of various concentrations of inhaled oxygen on tissue dysoxia,oxidative stress,and survival in a rat hemorrhagic shock model

Objective

To test the hypothesis that a fractional inspired oxygen (F_IO₂) of 1.0 compared to 0.4 during hemorrhagic shock (HS) and fluid resuscitation (FR): mitigates tissue dysoxia; however, enhances the oxidative stress; therefore, offsets the benefit on survival.

Methods

Thirty rats underwent: HS for 75 min, during which 3.0 mL/100 g of blood was withdrawn, followed by FR for 75 min, during which 1.0 mL/100 g of shed blood and 3.0 mL/100 g of crystalloid solution were infused. Ten rats were randomized into one of three F_IO₂ (0.21 vs. 0.4 vs. 1.0) groups, and observed for survival until 72 h in each group. Hemodynamics, liver tissue PO₂ (P_TO₂), and, plasma antioxidants levels were also monitored.

Results

Oxygen inhalation increased mean arterial pressure (MAP) and decreased heart rate (HR) during HS and FR. Liver P_TO₂ was less than 10 Torr in all groups throughout HS; while it increased to average 26–35 Torr in oxygen groups during FR, it remained at 10 Torr with F_IO₂ 0.21 (P < 0.01). MAP, HR, and P_TO₂ did not differ significantly between oxygen groups. Plasma antioxidants levels did not differ among the three groups. All rats treated with oxygen, but eight of 10 rats with F_IO₂ 0.21 survived up to 72 h (NS).

Conclusions

Supplemental oxygen does not mitigate tissue dysoxia during HS, but does reduce tissue dysoxia without enhancing oxidative stress during subsequent FR. Increased F_IO₂ appears to prolong survival. These beneficial effects of supplemental oxygen do not differ between an F_IO₂ of 0.4 and 1.0.     

中度低温对急性出血坏死性胰腺炎大鼠胰腺损伤的保护作用

目的 观察中度低温对急性出血坏死性胰腺炎(AHNP)大鼠胰腺损伤和死亡率的影响。方法将112只大鼠随机分为假手术组(n=24)、AHNP常温组(n=44)和AHNP低温组(n=44)。以牛磺胆酸钠逆行注射制备大鼠AHNP模型,低温组诱导AHNP后通过体表降温将体温控制在32.0-33.0℃。各组中24只大鼠分别在AHNP诱导后第2和5 h取标本,观察血清淀粉酶、脂肪酶以及胰腺血管通透性变化、病理形态学改变和胰腺组织湿重／干重比值。AHNP常温组和低温组中余20只大鼠将体温控制在预定范围12 h,观察大鼠72 h的生存率。结果 与AHNP常温组比较,低温组AHNP后2、5 h血清淀粉酶和脂肪酶水平、血管渗透指数及AHNP后5 h胰腺组织水肿程度均明显降低(P均<0.05)。AHNP常温组平均生存时间是7.5 h(3.0-18.0 h),而低温组则延长至25.5 h(13.0-72.0 h)。低温组大鼠生存率显著高于常温组(P=0.000 1)。结论 急性胰腺炎应用中度低温可减轻胰腺损伤,延长大鼠生存时间,提示低温有可能作为一项有益的辅助措施用于急性胰腺炎的治疗中。     

Extending the golden hour of hemorrhagic shock tolerance with oxygen plus hypothermia in awake rats. An exploratory study

In a previous study of volume-controlled hemorrhagic shock (HS) in awake rats, without fluid resuscitation, either breathing of 100% oxygen or moderate hypothermia while breathing air, increased survival time. We hypothesized that combining oxygen and hypothermia can maximally extend the "golden hour" of HS from which resuscitation can be successful in terms of survival rate. Rats were prepared under light general anesthesia, breathing spontaneously via face mask, and then awakened for 2 h. Then, 3.25 ml arterial blood/100 g were withdrawn over 20 min. At the end of HS of 30, 60, 90 or 180 min duration, the shed blood was reinfused. Breathing was spontaneous. Survival endpoint was 24 h or earlier death. HS of 30 or 60 min was used for preliminary experiments; HS of 90 or 180 min for 35 definitive experiments. Control groups A-1 and B-1 had normothermia (rectal temperature 37.5 degrees C) and were breathing air. Treatment groups A-2 and B-2 had total body surface cooling during HS to rectal temperature 32 degrees C and were breathing 100% O(2). Arterial pressure during HS was higher in the hypothermia-O(2) groups. With HS of 90 min, in the normothermia-air group A-1 (n=10), none of the 10 rats survived to 3 h; while in the hypothermia-O(2) group A-2 (n=5), all rats survived to 24 h (P<0.001). With HS of 180 min, in the normothermia-air group B-1 (n=10), three of 10 rats survived to 3 h and 24 h (hypotension during HS in these three survivors was less severe than in the non-survivors); and in the hypothermia-O(2) group B-2 (n=10) all 10 rats survived to 24 h (P<0.003). We conclude that moderate hypothermia (32 degrees C) plus 100% oxygen inhalation during volume-controlled HS in awake rats mitigates hypotension and increases the chance of survival. It enables survival even after 3 h of moderate HS.     

Increased survival with hypotensive resuscitation in a rabbit model of uncontrolled hemorrhagic shock in pregnancy

Aim

We sought to compare the effects of conservative hypotensive and aggressive normotensive resuscitation strategies on blood loss, fluid requirements, blood lactate and survival rate in a clinically relevant model of uncontrolled hemorrhagic shock in pregnancy.

Method

60 anesthetized New Zealand white rabbits at late gestation underwent uncontrolled hemorrhagic shock by transecting a small artery in the mesometrium, followed by blood withdrawal via the carotid artery, to a mean arterial pressure (MAP) of 40–45 mmHg. They were randomly divided into six groups (n = 10 per group): sham shock (group SS); shock without resuscitation (group SH); hypotensive resuscitation in the simulated prehospital phase with Ringer's solution to MAP of 50, 60, or 70 mmHg, respectively (groups RE50, RE60, RE70); and aggressive resuscitation in the prehospital phase with Ringer's solution to MAP of 80 mmHg (group RE80). Finally, in the simulated hospital phase, animals in the resuscitated groups underwent surgical control of bleeding and were fully resuscitated with half of the heparinized shed blood and Ringer's solution to MAP of 80 mmHg.

Results

Hypotensive resuscitation significantly decreased blood loss and subsequent volume infusion, leading to higher hematocrit, lower lactate concentration, and shorter prothrombin time and activated partial thromboplastin time. Median survival time in group RE60 (4.3 ± 0.6 days) was significantly longer than that in groups RE50 (2.7 ± 0.4 days), RE70 (2.3 ± 0.3 days), and RE80 (1.7 ± 0.3 days) (P < 0.05).

Conclusions

We conclude that in this rabbit model of uncontrolled hemorrhage in pregnancy, hypotensive resuscitation to MAP of 60 mmHg may be an optimal target MAP before hemorrhage can be controlled by surgical intervention.     

Combination of therapeutic mild hypothermia and delayed fluid resuscitation improved survival after uncontrolled haemorrhagic shock in mechanically ventilated rats

We challenged the current management of uncontrolled haemorrhagic shock (UHS) and put forward a hypothesis that therapeutic mild hypothermia combined with delayed fluid resuscitation will improve the survival rate. After an initial blood withdrawal of 3 ml/100g for 15 min, the rat's tail was amputated up to 75% to induce UHS phase I. The mean arterial blood pressure (MAP) was maintained at 40 mmHg or 80 mmHg, according to the assigned study group. This was followed by homeostasis of the tail wound and increase of the MAP up to 100 mmHg during resuscitation phase II. Finally, phase III was an observation of phase up to 72 h. Rats were anaesthetised and randomised into four groups. Group 1 received immediate fluid resuscitation and normothermia. Group 2 received immediate fluid resuscitation and therapeutic mild hypothermia. Group 3 received limited fluid solutions to maintain MAP at 40 mmHg and normothermia. Group 4 also received limited fluid solution, but the rats were subjected to therapeutic mild hypothermia. In groups 2 and 4, the body temperature was kept at 34 degrees C throughout the UHS phase I and resuscitation phase II. At the end of the observation phase III, the brains of the animals were fixed and analysed histologically. The blood loss from the tail during the UHS phase I was significantly higher in groups 1 and 2. The survival rate was 33.3, 83.3, 58.3 and 91.7%, respectively in groups 1-4. In all surviving rats, no histological brain damage was observed. These results indicate that therapeutic mild hypothermia or delayed fluid resuscitation increase the survival rate in this model. However, when mild hypothermia and limited fluid resuscitation were combined, the survival rate was the highest.     

A simple survival model of volume-controlled hemorrhagic shock in awake rats.

A simple rat model was developed for the study of spontaneous survival after volume-controlled hemorrhage. The objective was to determine in awake, unrestrained rats the shed blood volume (SBV) in ml/100 g body weight that without fluid resuscitation, would result in either a high or a low percentage of survivors within 24 h. About 24 h after cannulation under light anesthesia, the awake rats were insulted with arterial blood withdrawal at a constant rate over 20 min, while mean arterial pressure (MAP) was monitored (N = 78). Then, the arterial catheter was removed, and the rats were observed for 24 h or until death. With increasing SBV, survival rate decreased, SBV of 2.50 ml/100 g (group I) resulted in 74% survivors at 2 h and 24 h; SBV of 2.75 ml/100 g (group II), in 67% survivors at 2 h and 46% at 24 h; SBV of 3.00 ml/100 g (group III), in 35% survivors at 2 h and 20% at 24 h; and SBV of 3.50 ml/100 g (group IV), in no survivors to 2 h. MAP declined similarly over 20 min blood withdrawal in the four insult groups, without difference between ultimate survivors vs. nonsurvivors. All rats survived to the end of 20 min hemorrhage (i.e. hemorrhagic shock [HS] time = 0 min). Deaths at HS time 0-2 h occurred after SBV of 2.50 ml/100 g, at HS time 56 +/- 35 min; after SBV of 2.75 ml/100 g, at HS 81 +/- 26 min; after SBV of 3.00 ml/100 g, at HS 37 +/- 33 min; and after SBV of 3.50 ml/100 g, at HS 11 +/- 2 min. Weight may have affected MAP response and survival. We conclude that a volume-controlled HS model in rats without anesthesia or restraint is feasible. SBV of 2.50 ml/100 g should be suitable for testing additional insults. SBV of 3.00 ml/100 g should be suitable for testing resuscitative therapies. The model should be modified to allow monitoring of key variables after hemorrhage.     

Depletion of myocardial glucose is observed during endotoxemic but not hemorrhagic shock in a porcine model

Introduction

Metabolic dysfunction is one of the hallmarks of sepsis yet little is known about local changes in key organs such as the heart. The aim of this study was to compare myocardial metabolic changes by direct measurements of substrates, such as glucose, lactate and pyruvate, using microdialysis (MD) in in-vivo porcine endotoxemic and hemorrhagic shock. To assess whether these changes were specific to the heart, we simultaneously investigated substrate levels in skeletal muscle.

Methods

Twenty-six female pigs were randomized to three groups: control (C) n = 8, endotoxemic shock (E) n = 9 and hemorrhagic shock (H) n = 9. Interstitial myocardial pyruvate, lactate and glucose were measured using MD. Skeletal muscle MD was also performed in all three groups.

Results

Marked decreases in myocardial glucose were observed in the E group but not in the H group compared to controls (mean difference (CI) in mmol/L: C versus E -1.5(-2.2 to -0.8), P <0.001; H versus E -1.1(-1.8 to -0.4), P = 0.004; C versus H -0.4(-1.1 to 0.3), P = 0.282). Up to four-fold increases in myocardial pyruvate and three-fold increases in lactate were seen in both shock groups with no differences between the two types of shock. There was no evidence of myocardial anaerobic metabolism, with normal lactate:pyruvate (L:P) ratios seen in all animals regardless of the type of shock.In skeletal muscle, decreases in glucose concentrations were observed in the E group only (mean difference: C versus E -0.8(-1.4 to -0.3), P = 0.007). Although skeletal muscle lactate increased in both shock groups, this was accompanied by increases in pyruvate in the E group only (mean difference: C versus E 121(46 to 195), P = 0.003; H versus E 77(7 to 147), P = 0.032; C versus H 43(-30 to 43), P = 0.229). The L:P ratio was increased in skeletal muscle in response to hemorrhagic, but not endotoxemic, shock.

Conclusions

Endotoxemia, but not hemorrhage, induces a rapid decrease of myocardial glucose levels. Despite the decrease in glucose, myocardial lactate and pyruvate concentrations were elevated and not different than in hemorrhagic shock. In skeletal muscle, substrate patterns during endotoxemic shock mimicked those seen in myocardium. During hemorrhagic shock the skeletal muscle response was characterized by a lack of increase in pyruvate and higher L:P ratios.Hence, metabolic patterns in the myocardium during endotoxemic shock are different than those seen during hemorrhagic shock. Skeletal muscle and myocardium displayed similar substrate patterns during endotoxemic shock but differed during hemorrhagic shock.