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.     

Hypercarbic arterial acidemia following resuscitation from severe hemorrhagic shock

Arteriovenous pH and PCO2 gradients can develop during low cardiac output states. We have seen a transient rise in arterial PCO2 and a fall in arterial pH in humans receiving closed-chest cardiopulmonary resuscitation immediately following restoration of spontaneous circulation. Using a hemorrhagic shock model in sheep, serial arterial and mixed venous blood gases were sampled and CO2 elimination was measured. When cardiac output was less than 30% of the baseline value and the arteriovenous PCO2 difference was greater than 20 mmHg, the animals were rapidly resuscitated with intravenous 0.9% NaCl and dopamine. Following resuscitation, there was a transient arterial acidosis and hypercarbia due to passage of venous blood with a high CO2 content into arterial blood. The clinical implications in the setting of hemorrhagic shock are that (1) arterial blood gases are poor indicators of the systemic acid-base state, (2) arterial blood gases drawn immediately following volume resuscitation may be misinterpreted and should probably not be used to guide therapy and (3) there is a transient hypercarbic arterial acidosis following volume resuscitation that may have deleterious effects on cardiac and cerebral function in the early post-resuscitative period.     

Low-volume resuscitation cocktail extends survival after severe hemorrhagic shock

After severe hemorrhage, low-volume resuscitation with hypertonic fluids is increasingly preferred to more aggressive resuscitation strategies. Oxygen delivery to the tissues may be improved by augmentation with hemoglobin [Hb]-based oxygen-carrying compounds (HBOCs); however, previous studies have reported negative outcomes presumably related to extravasation of tetrameric Hb. The purpose of this study was to evaluate a novel large molecular weight polymer of cross-linked bovine Hb (OxyVita; OXYVITA Inc, New Windsor, NY) in a cocktail of hypertonic saline and Hextend (HX; HBOC-C) as an alternative to standard small-volume resuscitation using Hextend (HX) only. Outcomes were survival to 3 h and duration of MAP support more than 60 mmHg without additional fluid support. Conscious male Long-Evans rats were hemorrhaged to 60% total blood volume over 40 min. There were 4 groups: HBOC-C administered in a pressure-titrated infusion, HX titration, HBOC-C administered as a bolus, and HX bolus. Cardiovascular parameters, arterial gases, acid-base status, metabolites, electrolytes, Hb level, and oxygen saturation were measured at baseline, during each 20% hemorrhage increment, and 1, 2, and 3 h after the initiation of hemorrhage. Small-volume resuscitation with HBOC-C significantly improved survival to 3 h and improved MAP support times regardless of method of administration. However, physiological status at the end of hemorrhage significantly influenced survival regardless of resuscitation treatment. These results suggest that HBOC-augmented hypertonic cocktails are of promise in improving survival and providing target MAP support during small-volume resuscitation. Experimental evaluation of any resuscitation therapy should account for the degree of preexisting physiological compromise before therapy is initiated.     

Dying pattern in volume-controlled hemorrhagic shock in awake rats.

We previously determined that in awake, unmonitored Sprague-Dawley rats, bleeding of 2.5 ml/100 g over 20 min resulted in hemorrhagic shock (HS) with about a 75% survival rate over 24 h, and bleeding of 3.0 ml/100 g in about 25% survival to 24 h. In the present study, we monitored systolic and mean arterial pressure (MAP), central venous pressure (CVP), breathing movements, electroencephalogram (EEG), and arterial blood gases to 3 h in order to study dying patterns. After cannulation under light anesthesia and awakening for 2 h, the rats were bled over 20 min. Ten rats in each of four groups were studied. Shed blood volume (SBV) in group I was 2.0 ml/100 g; in group II, 2.5 ml; in group III, 3.0 ml; and in group IV, 3.5 ml. Three hour survival rates were 100% for group I, 80% for group II (survival time 149 +/- 65 [106-180] min), 40% for group III (survival time 116 +/- 72 [93-180] min), and 0% for group IV (survival time 32 +/- 38 [5-69] min). MAP decreased at end of bleeding, increased transiently to moderately hypotensive levels (attempted self-resuscitation), and then either recovered to normotension or declined to cardiac arrest (death), which was defined as simultaneous apnea, systolic arterial pressure less than or equal to 30 mmHg without pulsations, and isoelectric EEG. EEG depression began with hypotension to MAP less than or equal to 50 mmHg. During HS, PaO2 increased, and PaCO2, pHa, and Hct all decreased. The results suggest that this model with SBV of 3.25 ml/100 g would give a low, but not zero 3 h survival, and therefore would be suitable for the study of responses to field resuscitation potentials.     

Fluid resuscitation in traumatic hemorrhagic shock.

Fluid resuscitation from traumatic hemorrhagic shock is a critical component of therapy for the critically injured patient. Therapy is aimed at restoring hemodynamic stability and oxygen delivery to tissues. The route and rate of fluid infusion, the temperature of the fluid infused, the type of asanguineous fluids chosen, and the timing of red cell transfusion may all impact substantially on the patient outcome. Complications of fluid therapy, especially edema, may be related to the choice of fluid infused. Identification of hypovolemia and methods to monitor tissue are important aspects of patient care.     

Bovine polymerized hemoglobin versus Hextend resuscitation in a swine model of severe controlled hemorrhagic shock with delay to definitive care

To compare the efficacy of low-volume resuscitation with bovine polymerized hemoglobin (HBOC-201) versus hetastarch (HEX) in an intermediate severity combat-relevant hemorrhagic shock swine model with a simulated delay to hospital care. Twenty-four anesthetized pigs were hemorrhaged 55% estimated blood volume in conjunction with a 5-min rectus abdominus crush. At 20 min, pigs were resuscitated with 10 mL/kg of HBOC-201 or HEX or nothing (NON); resuscitated pigs received additional infusions (5 mL/kg) at 30, 60, 120, or 180 min if hypotension or tachycardia persisted. Pigs were monitored for a 4-h "prehospital" period. At 4-h, hospital arrival was simulated: surgical sites were repaired, blood, or saline provided, and pigs were recovered from anesthesia. Pigs were monitored for 72 h and then killed for histological evaluation. One hundred percent (8/8) of HBOC-201-, 75% (6/8) of HEX-, and 25% (2/8) of NON-resuscitated pigs survived to 72 h (P = 0.007 overall, HBOC vs. HEX P > 0.05). Mean arterial pressure and mean pulmonary arterial pressure were highest in the HBOC-201 group (P < 0.001), and HR was lowest (P < 0.001). HBOC-201- and HEX-resuscitated pigs had comparable cardiac index and prehospital fluid requirements. HBOC-201 pigs had higher transcutaneous tissue oxygen tension, P < 0.001) and lower urine output (P < 0.001). At simulated hospital arrival, no HBOC-201 pigs required additional fluids or blood transfusion. In contrast, 100% of HEX pigs required blood transfusions (P < 0.01). In this swine model of controlled hemorrhage with low-volume resuscitation and delayed definitive care, HBOC-201 pigs had improved hemodynamics, transcutaneous tissue oxygen tension, and transfusion avoidance compared with HEX.     

Fluid resuscitation therapy for hemorrhagic shock.

Hemorrhagic shock is a severe life-threatening emergency affecting all organ systems of the body by depriving tissue of sufficient oxygen and nutrients by decreasing cardiac output. This article is a short review of the different types of shock, followed by information specifically referring to hemorrhagic shock. The American College of Surgeons categorized shock into 4 classes: (1) distributive; (2) obstructive; (3) cardiogenic; and (4) hemorrhagic. Similarly, the classes of hemorrhagic shock are grouped by signs and symptoms, amount of blood loss, and the type of fluid replacement. This updated review is helpful to trauma nurses in understanding the various clinical aspects of shock and the current recommendations for fluid resuscitation therapy following hemorrhagic shock.     

Adaptive closed-loop resuscitation controllers for hemorrhagic shock resuscitation

Background

After hemorrhage control, fluid resuscitation is the most important intervention for hemorrhage. Even skilled providers can find resuscitation challenging to manage, especially when multiple patients require care. In the future, attention-demanding medical tasks like fluid resuscitation for hemorrhage patients may be reassigned to autonomous medical systems when availability of skilled human providers is limited, such as in austere military settings and mass casualty incidents. Central to this endeavor is the development and optimization of control architectures for physiological closed-loop control systems (PCLCs). PCLCs can take many forms, from simple table look-up methods to widely used proportional–integral–derivative or fuzzy-logic control theory. Here, we describe the design and optimization of multiple adaptive resuscitation controllers (ARCs) that we have purpose-built for the resuscitation of hemorrhaging patients.

Study Design and Methods

Three ARC designs were evaluated that measured pressure–volume responsiveness using different methodologies during resuscitation from which adapted infusion rates were calculated. These controllers were adaptive in that they estimated required infusion flow rates based on measured volume responsiveness. A previously developed hardware-in-loop test platform was used to evaluate the ARCs implementations across several hemorrhage scenarios.

Results

After optimization, we found that our purpose-built controllers outperformed traditional control system architecture as embodied in our previously developed dual-input fuzzy-logic controller.

Discussion

Future efforts will focus on engineering our purpose-built control systems to be robust to noise in the physiological signal coming to the controller from the patient as well as testing controller performance across a range of test scenarios and in vivo.     

Fluid resuscitation with hemoglobin vesicles in a rabbit model of acute hemorrhagic shock

Several hemoglobin (Hb)-based oxygen carriers are available for use in clinical situations, but their use risks inducing cardiovascular dysfunction as a result of Hb interacting with nitric oxide. Hb vesicles (HbV) are liposome-encapsulated purified human Hb with polyethylene glycol chains at the surface. This study evaluated the effects of HbV on hemodynamics, tissue and systemic oxygenation, and osmotic pressure after fluid resuscitation in an acute hemorrhagic shock model. Hemorrhagic shock was induced in 24 anesthetized mechanically ventilated male rabbits by withdrawing blood to a mean arterial blood pressure (MAP) of 30 to 35 mmHg over 15 min and maintaining this state for 30 min. The animals were resuscitated by replacing the blood with equal volumes of HbV in recombinant human albumin solution (HbV/rHSA), rHSA alone, or Ringer lactated solution (RL), or with three times the withdrawn volume of RL and observed for 2 h. Fluid resuscitation restored MAP, central venous pressure, and cardiac index values, but these fell again within 2 h in rabbits treated with RL. Fluid resuscitation using HbV/rHSA immediately increased MAP and cardiac index but not systemic vascular resistance, maintained a high level of oxygen consumption, and reduced the blood glucose level, which increased after hemorrhage. Fluid resuscitation using HbV/rHSA did not disturb microoxygenation in the brain, kidneys, liver, or muscle; allowed an immediate recovery of tissue oxygenation without decreasing cardiac output or increasing systemic vascular resistance, and increased the oxygen consumption. HbV solution offers the advantages of systemic oxygenation without impairing microcirculation in the treatment of hemorrhagic shock.     

重度未控制性失血性休克三种复苏策略的比较

目的：比较重度未控制性失血性休克（UHS）早期延迟复苏、低压液体复苏和垂体后叶素复苏的效果。方法犬24只,采用股动脉穿刺放血使平均动脉压降至50 mm Hg,随机分为三组（n=8）：延迟复苏组（A组）不采用任何复苏措施,低压液体复苏组（B组）静脉输注羟乙基淀粉（HES200/0.5）、垂体后叶素组（C组）每次静注垂体后叶素0.1～0.4 U/kg,使MAP≥50 mm Hg,1 h后全部停止放血行充分容量复苏。监测放血前即刻（T0）、达到目标血压时（T1）、实施三种复苏方法后1 h（T2）、复苏平稳后2 h（T3）各时点的血流动力学指标及动脉血气参数,同时采血样本检测TNF-α和IL-10。观察实验犬出血量、存活率并取死亡或存活超过72 h立即处死后的心肌、肺、肾组织进行病理学检查。结果（1）血流动力学指标：在T2时点,A组的SBP、DBP、MAP、CVP、HR明显低于B组和C组（P〈0.05）,且大多数动物（6/8）死亡。（2）炎症介质及动脉血气参数：T1和 T2时点,三组的碱缺失（BD）、血乳酸（BL）和 SvO2均与T0有明显差别（P〈0.01）;在T3时点,三组的BD和BL仍处在T1和T2之间,但SvO2恢复正常。三组TNF-α和IL-10的变化规律与BD和BL一致,但在T2和T3时点,A组与B、C两组之间有统计学差异（P〈0.05）。（3）出血量及成活率：在未控制性失血期,A组的失血量少于B和C组,但仅与B组有统计学差异（P〈0.05）。A组72 h的成活率为25%,明显低于B组的87.5%和C组的100%（P〈0.01）。（4）病理学检查：A组心、肺、肾病理损害程度都明显重于B、C两组,但C组的损害程度略轻于B组。结论在重度UHS条件下,垂体后叶素和低压液体复苏均为早期有效的复苏方式,两者复苏后的存活率均高且无统计学差异;但低压复苏组的失血和组织损伤程度比垂体后叶素组明显,复苏质量不如后者。延迟复苏不适宜用于重度UHS。     

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.     

重症胸部创伤合并创伤失血性休克限制性液体复苏的疗效评价

目的评价重症胸部创伤合并创伤性失血性休克(HTS)采用限制性液体复苏的治疗效果,以提高治愈率.方法总结1998-01～2003-09急诊收治的重症胸部创伤合并HTS病人49例,对病人年龄、创伤严重程度评分、休克程度、复苏开始时间、输入液量进行统计学分析,对比常规液体复苏(n=27)与限制性液体复苏(n=22)的疗效及ARDS的发生率与病死率.结果常规液体复苏组平均输液量为(2 965±524)mL,治愈率为77.8%,死亡率为22.2%,其中ARDS发生率为18.5%,死亡率为60%;限制性液体复苏组平均输液量为(2089±328)mL,治愈率为86.4%,死亡率为13.6%,其中ARDS发生率为9.1%,死亡率为0.组间比较均有显著性差异(P＜0.05).结论重症胸部创伤合并HTS采用限制性液体复苏方法救治可降低ARDS发生,提高治愈率.     

Pentoxifylline in resuscitation of experimental hemorrhagic shock

BACKGROUND: Pentoxifylline improves survival in animal models of hemorrhagic shock. The purpose of this study was to determine the physiologic effects of pentoxifylline in hemorrhagic shock that may be responsible for improved survival. METHODS: Randomized, prospective, blinded trials in Sprague-Dawley rats subjected to hemorrhage and resuscitation, with or without pentoxifylline. RESULTS: Pentoxifylline had no effect on BP or cardiac output. However, tissue oxygenation and oxygen consumption were increased with pentoxifylline resuscitation. Pentoxifylline resuscitation also significantly decreased polymorphonuclear leukocyte adhesiveness. CONCLUSIONS: Pentoxifylline improves tissue oxygenation and oxygen consumption posthemorrhage and this effect is not due to increased cardiac output. Therefore, it must be due to improved microcirculatory blood flow. This effect may be due to decreased polymorphonuclear leukocyte adhesiveness induced by pentoxifylline resuscitation.     

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.     

Hypertonic and hyperoncotic resuscitation from severe hemorrhagic shock in dogs: a comparative study

Single bolus injections of hypertonic (7.5%) NaCl (H), hyperoncotic (6%) dextran-70 (D), or of their combination (HD) were given to severely bled (54.2 +/- 1.3 ml/kg) anesthetized dogs. Two shock procedures (30 or 60 min at 35 mm Hg) were tested. Survival was highest (11/12) after HD, lower (9/12) after H, and lowest (7/12) after D; it was higher (15/18 vs. 12/18) after the shorter vs. longer shock procedure. Cardiac index (CI) was restored to 83%-104% of prehemorrhage levels immediately after HD or H; 3 h later it was down to 67%-71% of control; after D, CI was stable at 41% to 50% of control; no differences in the relative performances of the agents tested in the 30 or 60-min shock durations. Arterial pressure recovered to near control levels in all groups; consequently, systemic vascular resistance was reduced after H and HD, but increased after D. Plasma volume recovered to 95% of control after H, 105% of control after HD, but only to 80% after D; however, the response to H was transient. Metabolic acidosis was partially reverted by all solutions. Plasma Na+ was transiently raised by H and HD. Overall differences detected between H vs. HD tend to favor HD as a resuscitative solution.     

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.     

Small-volume resuscitation from hemorrhagic shock with polymerized human serum albumin

Human serum albumin (HSA) is used as a plasma expander; however, albumin is readily eliminated from the intravascular space. The objective of this study was to establish the effects of various-sized polymerized HSAs (PolyHSAs) during small-volume resuscitation from hemorrhagic shock on systemic parameters, microvascular hemodynamics, and functional capillary density in the hamster window chamber model. Polymerized HSA size was controlled by varying the cross-link density (ie, molar ratio of glutaraldehyde to HSA). Hemorrhage was induced by controlled arterial bleeding of 50% of the animal's blood volume (BV), and hypovolemic shock was maintained for 1 hour. Resuscitation was implemented in 2 phases, first, by infusion of 3.5% of the BV of hypertonic saline (7.5% NaCl) then followed by infusion of 10% of the BV of each PolyHSA. Resuscitation provided rapid recovery of blood pressure, blood gas parameters, and microvascular perfusion. Polymerized HSA at a glutaraldehyde-to-HSA molar ratio of 60:1 (PolyHSA(60:1)) provided superior recovery of blood pressure, microvascular blood flow, and functional capillary density, and acid-base balance, with sustained volume expansion in relation to the volume infused. The high molecular weight of PolyHSA(60:1) increased the hydrodynamic radius and solution viscosity. Pharmacokinetic analysis of PolyHSA(60:1) indicates reduced clearance and increased circulatory half-life compared with monomeric HSA and other PolyHSA formulations. In conclusion, HSA molecular size and solution viscosity affect central hemodynamics, microvascular blood flow, volume expansion, and circulation persistence during small-volume resuscitation from hemorrhagic shock. In addition, PolyHSA can be an alternative to HSA in pathophysiological situations with compromised vascular permeability.