Uncontrolled Hemorrhagic Shock In Rats Research Articles

Fresh Frozen Plasma Increases Hemorrhage in Blunt Traumatic Brain Injury and Uncontrolled Hemorrhagic Shock

Blunt traumatic brain injury (bTBI) and uncontrolled hemorrhagic shock (UCHS) are common causes of mortality in polytrauma. We studied the influence of fresh frozen plasma (FFP) resuscitation in a rat model with both bTBI and UCHS before achieving hemorrhage control. The bTBI was induced by an external weight drop (200 g) onto the bare skull of anesthetized male Lewis (Lew/SdNHsd) rats; UCHS was induced by resection of two-thirds of the rats' tails. Fifteen minutes following trauma, bTBI+UCHS rats underwent resuscitation with FFP or lactated Ringer's solution (LR). Eight groups were evaluated: (1) Sham; (2) bTBI; (3) UCHS; (4) UCHS+FFP; (5) UCHS+LR; (6) bTBI+UCHS; (7) bTBI+UCHS+FFP; and (8) bTBI+UCHS+LR. Bleeding volume, hematocrit, lactate, mean arterial pressure (MAP), heart rate, and mortality were measured. The study included 97 rats that survived the immediate trauma. Mean blood loss up to the start of resuscitation was similar among UCHS only and bTBI+UCHS rats (P=0.361). Following resuscitation, bleeding was more extensive in bTBI+UCHS+FFP rats (5.2 mL, 95% confidence interval [CI] 3.7, 6.6) than in bTBI+UCHS+LR rats (2.5 mL, 95% CI 1.2, 3.8) and bTBI+UCHS rats (1.9 mL, 95% CI 0, 3.9) (P=0.005). Overall mortality increased if bleeding was above 4.5 mL (92.3% versus 8%; P<0.001). Mortality was 83.3% (10/12) in bTBI+UCHS+FFP rats, 41.7% (5/12) in bTBI+UCHS+LR rats, and 64.3% (9/14) in bTBI+UCHS rats. The bTBI did not exacerbate bleeding in rats undergoing UCHS. Compared to LR, FFP resuscitation was associated with a significantly increased blood loss in bTBI+UCHS rats.

Low-dose norepinephrine in combination with hypotensive resuscitation may prolong the golden window for uncontrolled hemorrhagic shock in rats.

Hypotension resuscitation is an important principle for the treatment after trauma. Current hypotensive resuscitation strategies cannot obtain an ideal outcome for remote regions. With the uncontrolled hemorrhagic shock (UHS) model in rats, the effects of norepinephrine (NE) on the tolerance time of hypotensive resuscitation, blood loss, vital organ functions, and animal survival were observed. Before bleeding was controlled, only the LR infusion could effectively maintain the MAP to 50–60 mmHg for 1 h, while the MAP gradually decreased with prolonging time, even with increasing infusion volume. Low-dose NE during hypotensive resuscitation prolonged the hypotensive tolerance time to 2–3 h, and the effect of 0.3 μg/kg/min NE was the best. Further studies showed that 0.3 μg/kg/min NE during hypotensive resuscitation significantly lightened the damage of organ function induced by UHS via protecting mitochondrial function, while the LR infusion did not. At the same time, NE administration improved Hb content, DO2, and VO2, and restored liver and kidney blood flow. The survival results showed that low-dose NE administration increased the survival rate and prolonged the survival time. Together, low-dose NE during hypotensive resuscitation was suitable for the early treatment of UHS, which can strive for the golden window of emergency treatment for serious trauma patients by reducing blood loss and protecting vital organ functions.

A Novel Cross-Linked Hemoglobin-Based Oxygen Carrier, YQ23, Extended the Golden Hour for Uncontrolled Hemorrhagic Shock in Rats and Miniature Pigs.

Background: Hypotensive resuscitation is widely applied for trauma and war injury to reduce bleeding during damage-control resuscitation, but the treatment time window is limited in order to avoid hypoxia-associated organ injury. Whether a novel hemoglobin-based oxygen carrier (HBOC), YQ23 in this study, could protect organ function, and extend the Golden Hour for treatment is unclear. Method: Uncontrolled hemorrhagic shock rats and miniature pigs were infused with 0.5, 2, and 5% YQ23 before bleeding was controlled, while Lactate Ringer’s solution (LR) and fresh whole blood plus LR (WB + LR) were set as controls. During hypotensive resuscitation the mean blood pressure was maintained at 50–60 mmHg for 60 min. Hemodynamics, oxygen delivery and utilization, blood loss, fluid demand, organ function, animal survival as well as side effects were observed. Besides, in order to observe whether YQ23 could extend the Golden Hour, the hypotensive resuscitation duration was extended to 180 min and animal survival was observed. Results: Compared with LR, infusion of YQ23 in the 60 min pre-hospital hypotensive resuscitation significantly reduced blood loss and the fluid demand in both rats and pigs. Besides, YQ23 could effectively stabilize hemodynamics, and increase tissue oxygen consumption, increase the cardiac output, reduce liver and kidney injury, which helped to reduce the early death and improve animal survival. In addition, the hypotensive resuscitation duration could be extended to 180 min using YQ23. Side effects such as vasoconstriction and renal injury were not observed. The beneficial effects of 5% YQ23 are equivalent to similar volume of WB + LR. Conclusion: HBOC, such as YQ23, played vital roles in damage-control resuscitation for emergency care and benefited the uncontrolled hemorrhagic shock in the pre-hospital treatment by increasing oxygen delivery, reducing organ injury. Besides, HBOC could benefit the injured and trauma patients by extending the Golden Hour.

Beneficial effects of hemoglobin-based oxygen carriers on early resuscitation in rats with uncontrolled hemorrhagic shock

To investigate the early resuscitation effect of hemoglobin-based oxygen carriers (HBOC) in rats with uncontrolled hemorrhagic shock. 170 Sprague-Dawley (SD) rats were randomly divided into five groups: lactate Ringer solution (LR) control group, whole blood control group, and 0.5%, 2.0%, 5.0% HBOC groups, with 34 rats in each group. The uncontrolled hemorrhagic shock model in SD rats was reproduced by cutting off the splenic artery branch, and induced mean arterial pressure (MAP) reducing to 40 mmHg (1 mmHg = 0.133 kPa). The corresponding solution was infused after model reproduction in each group, maintaining MAP at 50 mmHg for 1 hour, then completely ligating and hemostasis, and maintaining MAP at 70 mmHg for 1 hour and 80 mmHg for 1 hour respectively, after maintaining MAP 80 mmHg, all were supplemented with LR to 2 times blood loss volume. The survival rate and blood loss rate were observed in 16 rats in each group, hemodynamics parameters including MAP, left ventricular systolic pressure (LVSP) and the maximum rate of left ventricular pressure rise (+dp/dt max) were determined in another 10 rats, and cardiac output (CO) and tissue oxygen supply (DO2) were observed in the rest 8 rats. (1) When resuscitation by LR alone, the blood loss rate of animals was as high as 60% to 70%. Compared with the LR control group, whole blood recovery could significantly reduce the blood loss rate before hemostasis in uncontrolled hemorrhagic shock rats [(46.6±4.5)% vs. (62.3±4.0)%, P < 0.01]; 0.5%, 2.0%, 5.0% HBOC could significantly decrease the blood loss rate, especially in 5.0% HBOC group with significant difference as compared with that in the LR control group [(45.6±4.1)% vs. (62.3±4.0)%, P < 0.01]. (2) When LR was used alone for resuscitation, the rats died quickly and survived for a short time. Only one rat survived for 12 hours, and no rat survived for more than 24 hours. Compared with the LR control group, whole blood resuscitation could improve the survival rate of uncontrolled hemorrhagic shock rats, and the survival time was significantly prolonged (hours: 20.4±4.6 vs. 3.5±1.1, P < 0.01); 0.5%, 2.0% and 5.0% HBOC also significantly prolonged the survival time of rats. The 5.0% HBOC group had the best effect, 4 rats survived in 24 hours, and the survival time was significantly longer than that of the LR control group (hours: 18.4±4.0 vs. 3.5±1.1, P < 0.01), and it was the same as the whole blood control group. (3) Compared with pre-shock, CO, DO2 and hemodynamic parameters of uncontrolled hemorrhagic shock rats were significantly decreased, and the above parameters were gradually increased with the prolongation of rehydration time. Compared with the LR control group, whole blood resuscitation could significantly increase CO and DO2, and improve hemodynamics in rats with uncontrolled hemorrhagic shock at different time points. Three concentrations of HBOC could also increase CO, DO2 and other hemodynamic parameters of rats at 1 hour of maintaining MAP of 80 mmHg after hemostasis and 1 hour and 2 hours after resuscitation. The effect of 5.0% HBOC group was more significant than that of the LR control group with statistically significant difference [CO (×10-3, L/min): 72.84±2.84 vs. 63.11±2.38 at 1 hour of maintaining MAP of 80 mmHg, 70.25±4.55 vs. 59.88±9.31 at 1 hour after resuscitation, 71.51±2.90 vs. 53.24±6.32 at 2 hours after resuscitation; DO2 (L×min-1×m-2): 271.9±13.5 vs. 159.1±25.4 at 1 hour of maintaining MAP of 80 mmHg, 261.0±15.0 vs. 145.7±20.1 at 1 hour after resuscitation, 249.6±12.0 vs. 107.4±18.2 at 2 hours after resuscitation; MAP (mmHg): 82.1±2.1 vs. 74.0±2.8 at 1 hour of maintaining MAP of 80 mmHg, 107.5±9.3 vs. 64.0±5.7 at 1 hour after resuscitation, 104.0±9.7 vs. 73.0±4.2 at 2 hours after resuscitation; LVSP (mmHg): 128.6±7.9 vs. 103.8±0.8 at 1 hour of maintaining MAP of 80 mmHg, 129.3±15.0 vs. 99.4±0.0 at 1 hour after resuscitation, 127.5±11.3 vs. 97.4±0.0 at 2 hours after resuscitation; +dp/dt max (mmHg/s): 6 534.2±787.6 vs. 5 074.0±71.7 at 1 hour of maintaining MAP of 80 mmHg, 5 961.5±545.4 vs. 4 934.5±510.2 at 1 hour after resuscitation, 5 897.4±350.5 vs. 4 534.7±489.2 at 2 hours after resuscitation, all P < 0.05]. HBOC infusion prolonged the survival time, increased survival rate, and improved hemodynamics, cardiac function and tissue oxygen supply in a dose-dependent manner in the early stage of uncontrolled hemorrhagic shock. The recovery effect of 5.0% HBOC was similar to that of the whole blood.

Acute high-altitude exposure shortens survival after uncontrolled hemorrhagic shock in rats

BackgroundUncontrolled hemorrhage (UH) remains the most common cause of death on the battlefield. This study examined the pathophysiological characteristics of UH in rats acutely exposed to high altitude. Material and methodsRats raised at sea level were randomly divided into two groups. Rats in the high-altitude group were exposed to hypobaric hypoxia in a hypobaric chamber (simulating 4000 m above sea level) for 2 d and then were performed a hemorrhagic shock protocol in the hypobaric chamber. Rats that underwent the same hemorrhage procedure at sea level were used as control. Anesthetized rats were bled to maintain their mean arterial pressure at 45 mmHg for 1 h. The distal quarter of the tail was amputated to allow free blood loss. After 1 h, the tail cut was ligated to induce hemostasis. mean arterial pressure, acid–base balance, blood loss, and survival were recorded. Rats were killed, and tissues were obtained for histological analysis. ResultsRats in the high-altitude group suffered less uncontrolled blood loss, more severe acidosis (lower pH and base excess), and inferior tissue oxygen supply (lower oxygen saturation and higher arterial lactate concentration) during the hemorrhage periods compared with the control group. Survival rates were significantly lower in the high-altitude group than those in the control group (P < 0.05), which was consistent with the results of pathological tissue injury. ConclusionsIn this rat model of hemorrhagic shock, acute high-altitude exposure resulted in decreased UH but more serious hemorrhagic shock injuries than that at sea level.

Hypotensive resuscitation in combination with arginine vasopressin may prolong the hypotensive resuscitation time in uncontrolled hemorrhagic shock rats.

The optimal resuscitation strategy for traumatic hemorrhagic shock is not completely determined. The objective of the present study was to investigate whether hypotensive resuscitation in combination with arginine vasopressin (AVP) can prolong the hypotensive resuscitation time by minimizing blood loss and stabilizing hemodynamics for uncontrolled hemorrhagic shock. With an established rat model of uncontrolled hemorrhagic shock, we compared the beneficial effects of hypotensive resuscitation in combination with AVP to maintain blood pressure at 50 mm Hg for 3 hours to hypotensive resuscitation alone on animal survival, blood loss, and vital organ functions. Hypotensive resuscitation in combination with AVP maintenance for 3 hours significantly reduced total blood loss and fluid requirement during hypotensive resuscitation period and significantly improved the survival of shock rats as compared with hypotensive resuscitation alone. Among the four concentrations of AVP, 5 × 10 U/mL had the best effect: it significantly improved hemodynamics and increased cardiac function, oxygen delivery, as well as hepatic blood flow and hepatic function in the shock rats. However, renal blood flow in the hypotensive resuscitation + AVP group was lower than that in the hypotensive resuscitation alone group. Hypotensive resuscitation in combination with early application of AVP could prolong the tolerance time of hypotensive resuscitation and "buy" longer safe prehospital transport time by reducing blood loss and stabilizing hemodynamics. This strategy may be a promising strategy for the early management of trauma patients with active bleeding.

Small Doses of Arginine Vasopressin in Combination With Norepinephrine “Buy” Time for Definitive Treatment for Uncontrolled Hemorrhagic Shock in Rats

Implementation of fluid resuscitation and blood transfusion are greatly limited in prehospital or evacuation settings after severe trauma or war wounds. With uncontrolled hemorrhagic shock rats, we investigated if arginine vasopressin (AVP) in combination with norepinephrine (NE) is independent (or slightly dependent) of fluid resuscitation and can "buy" time for the subsequently definitive treatment of traumatic hemorrhagic shock in the present study. The results showed that AVP (0.4 U/kg) alone or with NE (3 μg/kg) with one-eighth and one-fourth volumes of total blood volume of lactated Ringer's infusion significantly increased and maintained the mean arterial pressure. Among all groups, 0.4 U/kg of AVP + NE (3 μg/kg) with one-eighth volume of lactated Ringer's infusion had the best effect: it significantly increased and maintained hemodynamics and prolonged the survival time. This early treatment strategy significantly improved the effects of subsequently definitive treatments (after bleeding controlled): it increased the subsequent survival, improved the hemodynamic parameters, improved the cardiac function, and increased the tissue blood flow and oxygen delivery. These results suggested that early application of small doses of AVP (0.4 U/kg) + NE before bleeding control can "buy" time for the definitive treatment of uncontrolled hemorrhagic shock, which may be an effective measure for the early treatment of traumatic hemorrhagic shock.

δ Opioid Receptor Antagonist, ICI 174,864, Is Suitable for the Early Treatment of Uncontrolled Hemorrhagic Shock in Rats

Fluid resuscitation is the essential step for early treatment of traumatic hemorrhagic shock. However, its implementation is greatly limited before hospital or during evacuation. The authors investigated whether δ opioid receptor antagonist ICI 174,864 was suitable for the early treatment of traumatic hemorrhagic shock. With uncontrolled hemorrhagic-shock rats, the antishock effects of six dosages of ICI 174,864 (0.1, 0.3, 0.5, 1, 3, and 5 mg/kg) infused with or without a small volume of lactated Ringer's solution (LR) before bleeding controlled or bleeding cessation at different times were observed. ICI 174,864 (0.1-3 mg/kg) with or without 1/4 volume of LR infusion showed dose-dependent increase in the mean arterial blood pressure, and significantly prolonged the survival time and 8-h survival rate, as compared with ICI 174,864 plus 1/2 volume of LR infusion. The best effect was shown with 3 mg/kg of ICI 174,864. Bleeding cessation at 1, 2, or 3 h during infusion of ICI 174,864 (3 mg/kg) plus 1/4 volume of LR improved subsequent treatment (70% 24-h survival rate vs. 50 and 10% 24-h survival rate in hypotensive resuscitation and LR group, respectively). There was significant improvement in hemodynamic parameters, oxygen delivery, and tissue perfusion of hemorrhagic-shock rats with 3 mg/kg of ICI 174,864 plus 1/4 volume of LR infusion. δ Opioid receptor antagonist ICI 174,864 alone or with small volume of fluid infusion has good beneficial effect on uncontrolled hemorrhagic shock. Its early application can "buy" time for subsequent treatment of traumatic shock.

Arginine vasopressin in combination with norepinephrine for uncontrolled hemorrhagic shock in rats

Objective To investigate the effects of arginine vasopressin (AVP) combined with norepinephrine (NE) in treatment of uncontrolled hemorrhagic shock (UHS) in rats.Methods UHS models were produced in rats and divided into three groups according to the random number table,which were resuscitated with LR equivalent to 1/2 (17.5 ml/kg) of shed blood,LR equivalent to 1/4 (8.75 mL/kg) of shed blood and without LR respectively.Each group was subdivided into six groups:AVP1 (0.04 U/kg) group,AVP2 (0.4 U/kg) group,NE (3 μg/kg) group,AVP1 + NE group,AVP2 + NE group and LR control group,with 10 rats per group.Effects of single AVP or NE infusion or combined infusion respectively grouped with different doses of LR on survival time and hemodynamics of UHS rats were observed.Results Compared with AVP,NE and AVP + NE groups without LR or with LR equivalent to 1/2 of shed blood respectively,AVP2 + NE group with LR equivalent to 1/4 of shed blood provided better main artery pressure (MAP),prolonged survival time and enhanced 4-hour survival rate in treatment of UHS rats.Moreover,survival time and 24-hour survival rate were increased significantly and hemodynamic parameters like MAP,left intraventricular systolic pressure (LVSP) and maximal change rate of left intraventricular pressure (± dp/dt max) were improved after hemostasis.Conclusion AVP (0.04 U/kg) + NE (3 μg/kg) infusion with LR equivalent to 1/4 of shed blood prior to hematosis can win the time for definitive treatment and improve the treatment outcome. Key words: Shock, hemorrhagic ; Resuscitation ; Arginine vasopressin; Norepinephrine

Short-term, Mild Hypothermia Can Increase the Beneficial Effect of Permissive Hypotension on Uncontrolled Hemorrhagic Shock in Rats

Our previous and other studies have shown that hypotensive or hypothermic resuscitation have beneficial effects on uncontrolled hemorrhagic shock. Whether hypothermia can increase the beneficial effect of hypotensive resuscitation on hemorrhagic shock is not known. Two-hundred and twenty Sprague-Dawley rats were used to make uncontrolled hemorrhagic shock. Before bleeding was controlled, rats received normotensive or hypotensive resuscitation (target mean arterial pressure at 80 or 50 mmHg) in combination with normal (37°C) or mild hypothermia (34°C) (phase II). After bleeding was controlled, rats received whole blood and lactated Ringer's solution resuscitation for 2 h (phase III). The animal survival, blood loss, fluid requirement, cardiac output, and coagulation functions, as well as vital organ function, mitochondrial function, and energy metabolism of liver, kidney and intestines, were noted. Short-term, mild hypothermia before bleeding was controlled increased the beneficial effect of hypotensive resuscitation. Hypothermia further decreased blood loss, oxygen consumption, and functional damage to the liver, kidney, and intestines during hypotensive resuscitation, protected mitochondrial function and energy metabolism (activity of Na(+)-K(+)-ATPase), and further improved survival time and survival rate (hypothermic/hypotensive combined group: survival rate, 9/10; survival time, 616 min; normothermic/normotensive group: 1/10, 256 min; hypothermic/normotensive group: 4/10, 293 min). Hypothermia slightly inhibited coagulation function. Mild hypothermia before bleeding is controlled can increase the beneficial effect of hypotensive resuscitation on uncontrolled hemorrhagic shock. The mechanism underlying the benefits of short-term hypothermia may be related to the decrease in oxygen consumption and metabolism, and protection of mitochondrial and organ functions.

Ghrelin Attenuates Brain Injury after Traumatic Brain Injury and Uncontrolled Hemorrhagic Shock in Rats

Ghrelin Attenuates Brain Injury after Traumatic Brain Injury and Uncontrolled Hemorrhagic Shock in Rats

Ghrelin attenuates brain injury after traumatic brain injury and uncontrolled hemorrhagic shock in rats.

Traumatic brain injury (TBI) and hemorrhagic shock often occur concomitantly due to multiple injuries. Gastrointestinal dysfunction occurs frequently in patients with TBI. However, whether alterations in the gastrointestinal system are involved in modulating neuronal damage and recovery after TBI is largely neglected. Ghrelin is a "gut-brain" hormone with multiple functions including antiinflammation and antiapoptosis. The purpose of this study was to determine whether ghrelin attenuates brain injury in a rat model of TBI and uncontrolled hemorrhage (UH). To study this, brain injury was induced by dropping a 450-g weight from 1.5 m onto a steel helmet attached to the skull of male adult rats. Immediately after TBI, a midline laparotomy was performed and both lumbar veins were isolated and severed at the junction with the vena cava. At 45 min after TBI/UH, ghrelin (4, 8 or 16 nmol/rat) or 1 mL normal saline (vehicle) was intravenously administered. Brain levels of TNF-α and IL-6, and cleaved PARP-1 levels in the cortex were measured at 4 h after TBI/UH. Beam balance test, forelimb placing test and hindlimb placing test were used to assess sensorimotor and reflex function. In additional groups of animals, ghrelin (16 nmol/rat) or vehicle was subcutaneously (s.c.) administered daily for 10 d after TBI/UH. The animals were monitored for 28 d to record body weight changes, neurological severity scale and survival. Our results showed that ghrelin downregulated brain levels of TNF-α and IL-6, reduced cortical levels of cleaved PARP-1, improved sensorimotor and reflex functions, and decreased mortality after TBI/UH. Thus, ghrelin has a great potential to be further developed as an effective resuscitation approach for the trauma victims with brain injury and severe blood loss.

Resuscitation: When Less Is More

Resuscitation: When Less Is More

Ideal Permissive Hypotension to Resuscitate Uncontrolled Hemorrhagic Shock and the Tolerance Time in Rats

Studies have shown that permissive hypotension for uncontrolled hemorrhagic shock can result in good resuscitation outcome. The ideal target mean arterial pressure (MAP) and the tolerance time for permissive hypotension have not been determined. To elucidate the ideal target MAP and tolerance time for permissive hypotension with uncontrolled hemorrhagic shock rats, the effects of different target MAPs (40, 50, 60, 70, 80, and 100 mmHg) and 60-, 90-, and 120-min permissive hypotension (50 mmHg) on uncontrolled hemorrhagic shock were observed. Rats in normotensive groups (80 and 100 mmHg) had increased blood loss (101%, 126% of total blood volume), decreased hematocrit, decreased vital organ (liver and kidney) and mitochondrial function, and decreased animal survival rate (1 of 10). Rats in the 50- and 60-mmHg target MAP groups had decreased blood loss (52% and 69%, respectively), good hematocrit and vital organ and mitochondrial function, stable hemodynamics, and increased animal survival (8 of 10 and 6 of 10, respectively). Rats in the 40-mmHg target MAP group, although having decreased blood loss (39%), appeared to have very inferior organ function and animal survival (2 of 10). Animal survival (1 of 10) and vital organ function in the 120-min permissive hypotension group were significantly inferior to the 60- and 90-min groups. The 60- and 90-min groups had similar animal survival (8 of 10 and 6 of 10) and vital organ function. A target resuscitation pressure of 50-60 mmHg is the ideal blood pressure for uncontrolled hemorrhagic shock. Ninety minutes of permissive hypotension is the tolerance limit; 120 min of hypotensive resuscitation can cause severe organ damage and should be avoided.

The influence of hypotensive resuscitation strategy on gut and lung injury in a rat model of uncontrolled hemorrhagic shock

Objective To investigate the effect of hypotensive resuscitation strategies on the hemorrhagic shock-induced gut and lung injury in an uncontrolled hemorrhagic-shock rat model. Methods Uncontrolled hemorrhagic-shock Sprague-Dawley male rats (n = 16;8 rats per group) were randomly assigned to normotensive resuscitation group ( group Ⅰ ) and hypotensive resuscitation group ( group Ⅱ ). 3h after resuscitation,gut injury and lung injury was assessed. Results The percentage of villous injury in group Ⅰwas ( 33. 13 ± 2. 17 ) %, while it was ( 12. 38 ± 1.69 ) % ( P ＜ 0. 05 ). The incidence of bacterial translocation in both groups was 87.5% (7/8) and 25.0% ( 2/8 ) respectively ( P ＜ 0.05 ). The percentage of Evan' s blue leakage was ( 3.03 ± 0. 28 ) % in group Ⅰ , whereas it was ( 1.25 ± 0. 17 ) % in group Ⅱ ( P ＜0. 05). The lung permeability index in both groups was 0. 140 ± 0. 018 and 0. 085 ± 0. 004 respectively (P＜0.05). Myeloperoxidase (MPO) activity in group Ⅰ was significantly higher than in group Ⅱ,(16.4±2.6) u/gvs(33.8±2.1) u/g(P＜0.05). Conclusion In severe and uncontrolled hemorrhagic shock, hypotensive resuscitation before definitive hemorrhage control is achieved is superior to normotensive resuscitation as it decreases both gut and lung injuries. Key words: Uncontrolled hemorrhagic shock; Resuscitation; Gut injury; Lung injury

Improved Survival Time With Combined Early Blood Transfusion and Fluid Administration in Uncontrolled Hemorrhagic Shock in Rats

To test whether early blood administration combined with crystalloid solution infusion may prolong survival in a clinically relevant model of ongoing uncontrolled life-threatening hemorrhage. Light anesthesia was induced with halothane in 24 rats, and spontaneous breathing was maintained. Uncontrolled hemorrhagic shock was induced by withdrawal of blood at 2.5 mL/100 g over a 15-minute period, followed by 75% tail amputation. At 10 minutes after tail cutting, rats were randomized into four groups (n = 6 each): group 1, receiving 3 mL of shed blood for 5 minutes followed by 9 mL of lactated Ringer's (LR) solution for 15 minutes; group 2, receiving 9 mL of LR solution for 15 minutes followed by 3 mL of shed blood for 5 minutes; group 3, receiving 9 mL of LR solution only for 15 minutes; group 4, receiving neither of shed blood nor LR solution. Rats were then observed until death or a maximum of 180 minutes. Mean survival time was 138 +/- 30 minutes, 108 +/- 22 minutes, 79 +/- 13 minutes, and 55 +/- 18 minutes for groups 1, 2, 3, and 4, respectively (p < 0.05 among the four groups). Additional blood loss from the tail stump did not differ significantly between the three treatment groups. In a model of uncontrolled hemorrhagic shock in rats, a resuscitation regimen using crystalloids agent alone is not ideal, and even a brief delay in blood administration worsens survival. Early blood administration combined with crystalloid solution infusion seems ideal.

Improved Survival after Resuscitation with Norepinephrine in a Murine Model of Uncontrolled Hemorrhagic Shock

Recent studies have challenged current guidelines on fluid resuscitation. However, studies on resuscitation using norepinephrine in uncontrolled hemorrhagic shock are lacking. The authors examined the effects of norepinephrine in combination with saline infusion in uncontrolled hemorrhage in rats. Rats subjected to a 15-min controlled hemorrhage (withdrawal of 3 ml blood/100 g body mass) followed by a 60-min uncontrolled hemorrhage (75% tail amputation) were randomly assigned to one of several treatment groups (10 rats/group) receiving different doses of norepinephrine (0 [NE0], 5 [NE5], 50 [NE50], or 500 [NE500] microg.100 g(-1).h(-1)). In the four hypotensive resuscitation groups (n = 40), mean arterial pressure was not allowed to fall below 40 mmHg by titrated infusion of normal saline. In the four normotensive resuscitation groups (n = 40), it was not allowed to fall below 80 mmHg. The endpoint was survival at 210 min. There was a significant difference (P < 0.05) in survival rate among groups. Among the hypotensive rats, 6 (60%) survived in the NE0 and NE5 dose groups, 9 (90%) survived in the NE50 dose group, and none survived in the NE500 dose group. Among the normotensive rats, none survived in the NE0 group, 4 (40%) survived in the NE5 dose group, all 10 (100%) survived in the NE50 group, and none survived in the NE500 group. The early use of norepinephrine in uncontrolled hemorrhagic shock in rats significantly improved survival when infused at a rate of 50 microg.100 g(-1).h(-1) in normotensive and hypotensive resuscitation strategies.

Effect of Induction Rate for Mild Hypothermia on Survival Time During Uncontrolled Hemorrhagic Shock in Rats

Rapid induction of hypothermia has been shown to improve survival in uncontrolled hemorrhagic shock (UHS) rat studies. We hypothesized that prolonged induction of hypothermia would be equally beneficial for survival during UHS. Light anesthesia was induced with halothane in 30 rats, and spontaneous breathing was maintained. Rectal temperature (Tr) was monitored and maintained at 38 degrees C. UHS was induced by blood withdrawal of 2.5 mL/100 g during a 15-minute period, followed by 75% tail amputation. Immediately after cutting the tail, rats were randomized into three groups of 10 rats each: Group 1, maintained at Tr 38 degrees C; group 2, passively cooled to 34 degrees C by exposure to room temperature (23 degrees C); and group 3, actively cooled to 34 degrees C by applying alcohol to the skin and under an electric fan. Next, rats were controlled at each target Tr and observed without fluid resuscitation until either death or a maximum of 240 minutes. Cooling rate was -0.09 +/- 0.01 degrees C/min in group 2 and -0.36 +/- 0.9 degrees C/min in group 3 (p < 0.01). Mean survival time was 72 +/- 21 minutes in group 1 (38 degrees C), and was nearly doubled by hypothermia to 132 +/- 62 minutes for group 2 (p < 0.01 vs. group 1) and 150 +/- 69 minutes for group 3 (p < 0.01 vs. group 1). No significant difference in survival was noted between groups 2 and 3. Additional blood loss from the tail stump did not differ significantly between groups. Therapeutic mild hypothermia, induced either slowly (approximately -0.1 degrees C/min) or rapidly (approximately -0.4 degrees C/min) prolongs survival during lethal UHS in rats.

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

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. 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. 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). 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.

Effects of hypotensive resuscitation on uncontrolled hemorrhagic shock in rats

目前国内外的动物实验和部分临床研究结果显示,低压复苏是治疗非控制性出血性休克较为合理的方案[1～4],但还没有人从增加血容量,减少应激反应引起的血管收缩、改善组织微循环氧供方面进行研究.本研究拟观察低压及低压扩容复苏对腹腔实质脏器损伤非控制性出血性休克的治疗效果。