Resuscitation Group Research Articles

Effects of propofol on activation of c-Jun N-terminal kinase in hippocampus following asphyxial cardiac arrest-resuscitation in rats

Objective To investigate the effect of propofol on the activation of c-Jun N-terminal kinase (JNK) in hippocampus following asphyxial cardiac arrest-resuscitation in rats.Methods Forty male Sprague-Dawley rats,aged 6 months,weighing 350-380 g,were randomly divided into 4 groups (n =l0 each):sham operation group (group S),asphyxial cardiac arrest-cardiopulmonary resuscitation group (group CA-CPR),propofol group (group P) and normal saline group (group NS).All the rats were tracheostomized and mechanically ventilated after anesthetization.Cardiac arrest was induced by clamping the tracheal tube at the end of exhalation until ECG activity disappeared and MAP ＜ 10 mm Hg.Resuscitation was started 3 min later.MAP ＞ 60 mm Hg and HR ＞ 250 bpm were considered to be signs of successful resuscitation.Propofol 2 mg/kg was injected intravenously at 30 min before asphyxia,followed by propofol infusion at a rate of 4 mg· kg-1 · h-1 until the start of resuscitation in group P,while the equal volume of normal saline was given in group NS.At 12 h after successful resuscitation,the animals were sacrificed and brains were harvested for determination of wet/dry brain weight (W/D) ratio in brain tissues and expression of phosphor-JNK (p-JNK) in hippocampus (by immuno-histochemistry and Western blot),and for examination of the pathological changes of hippocampus.Results Compared with group S,W/D ratio was significantly increased and the expression of p-JNK in hippocampus was up-regulated in CA-CPR,P and NS groups (P ＜ 0.05 or 0.01).Compared with group CA-CPR,W/D ratio was significantly decreased and the expression of p-JNK in hippocampus was down-regnlated in group P (P ＜ 0.05 or 0.01),and no significant change was found in the indexes mentioned above in group NS (P ＞ 0.05).The pathological changes of hippocampus were significantly attenuated in group P compared with group CA-CPR.Conclusion Propofol can inhibit the activation of JNK in hippocampus following asphyxial cardiac arrest-resuscitation in rats and thus reducing brain injury. Key words: Propofol; JNK mitogen-activated protein kinases; Heart arrest; Cardiopulmonary resuscitation ; Reperfusion injury ; Brain

Effects of different resuscitation fluids on pulmonary expression of aquaporin1 and aquaporin5 in a rat model of uncontrolled hemorrhagic shock and infection.

BackgroundTo investigate the effects of fluids resuscitation on pulmonary expression of aquaporin1 and aquaporin5 in a rat model of uncontrolled hemorrhagic shock and infection.MethodsSixty Sprague-Dawley rats were randomly assigned to five groups, sham operation group (Group C) and four treated groups: no fluid resuscitation group (Group NF), groups resuscitated with Lactated Ringer's (LR),7.5% NaCl (HTS) and Hydroxyl ethyl starch (HES) respectively. Three-phased uncontrolled hemorrhagic shock and infection model was used. Phase I: Massive hemorrhage with a mean arterial pressure of 35–40 mmHg for 60 min, and followed by infection of lipopolysaccharide. Then some animals were resuscitated with solutions mentioned above, until 90 min. Phase II: At hemorrhagic shock 90 minutes, phase II of 60 minutes began with hemostasis and returning of all the initial shed blood. Phase III: Observation phase for 3.5 hours. After phase III, arterial blood gas analysis and the survival rates of the rats were recorded, Wet-to-dry lung weight ratio, BALF protein, pulmonary permeability index, and expressions of aquaporin1 and aquaporin5 were tested.ResultsThe expressions of aquaporin1 and aquaporin5 were decreased in treatment groups comparing with sham operation group. Group HES and Group HTS decreased pulmonary vascular permeability and Wet-to-dry lung weight ratio, improved arterial blood gas analysis and survival rates, and attenuated the decreased pulmonary expression of aquaporin1 and aquaporin5 after the “two-hit”, comparing with groups NF and LR,but these beneficial effects were blunted in group HTS.ConclusionThe expression of aquaporin1 and aquaporin5 may play important roles in formation of pulmonary edema. Resuscitation with HTS and HES, especially HES can reduce lung injury after hemorrhagic shock, partly by up-regulating the expressions of aquaporin1 and aquaporin5.

Early Fluid Resuscitation With Hypertonic Solution in a Rat Crush Injury Model

The aim of the study was to evaluate the effects of bolus infusion of hypertonic hydroxyethyl starches (HHESs) and continuous infusion of hypertonic saline (HTS) in the early resuscitation in crush syndrome. A rat model of crush injury was established. Rats were randomly divided into five groups: (1) HHES group, (2) HTS group, (3) volume resuscitation group, (4) normal resuscitation (NR) group, and (5) sham group. Blood samples were collected 6 h after the crush period for biochemical evaluation. Blood pressure was monitored throughout this experiment. Muscles and kidneys were evaluated morphologically 24 h after reperfusion. Twenty rats in each group were taken for survival observation for 72 h. Compared with the NR and HTS groups, the HHES group had significantly increased the survival rate 72 h after release (P < 0.05). In the first 2 h after release, mean arterial blood pressure in the HHES group was significantly higher than in HTS, volume resuscitation, and NR groups (respectively, P < 0.05). Animals that received HHES infusion showed a better acid-base balance and renal function. However, there was no significant difference in survival rate between the HTS and NR groups. Furthermore, animals in the HTS group showed a bad acid-base balance and a higher serum sodium level. Bolus infusion of HHES combined with normal saline could be an effective therapy for crush syndrome in the early resuscitation period. However, continuous HTS injection was not seemed to be a suitable choice particularly in the absence of monitoring equipment for serum irons or blood gases (institutional protocol no. ZN5R20110016).

Extracorporeal Cardiopulmonary Resuscitation for Patients With Out-of-Hospital Cardiac Arrest of Cardiac Origin

Encouraging results of extracorporeal cardiopulmonary resuscitation for patients with refractory cardiac arrest have been shown. However, the independent impact on the neurologic outcome remains unknown in the out-of-hospital population. Our objective was to compare the neurologic outcome following extracorporeal cardiopulmonary resuscitation and conventional cardiopulmonary resuscitation and determine potential predictors that can identify candidates for extracorporeal cardiopulmonary resuscitation among patients with out-of-hospital cardiac arrest of cardiac origin. Post hoc analysis of data from a prospective observational cohort. A tertiary care university hospital in Sapporo, Japan (January 2000 to September 2004). A total of 162 adult patients with witnessed cardiac arrest of cardiac origin who had undergone cardiopulmonary resuscitation for longer than 20 minutes (53 in the extracorporeal cardiopulmonary resuscitation group and 109 in the conventional cardiopulmonary resuscitation group). None. The primary endpoint was neurologically intact survival at three months after cardiac arrest. We used propensity score matching to reduce selection bias and balance the baseline characteristics and clinical variables that could potentially affect outcome. This matching process selected 24 patients from each group. The impact of extracorporeal cardiopulmonary resuscitation was estimated in matched patients. Intact survival rate was higher in the matched extracorporeal cardiopulmonary resuscitation group than in the matched conventional cardiopulmonary resuscitation group (29.2% [7/24] vs. 8.3% [2/24], log-rank p = 0.018). According to the predictor analysis, only pupil diameter on hospital arrival was associated with neurologic outcome (adjusted hazard ratio, 1.39 per 1-mm increase; 95% confidence interval, 1.09-1.78; p = 0.008). Extracorporeal cardiopulmonary resuscitation can improve neurologic outcome after out-of-hospital cardiac arrest of cardiac origin; furthermore, pupil diameter on hospital arrival may be a key predictor to identify extracorporeal cardiopulmonary resuscitation candidates.

Protection of anisodamine on the mitochondrial injury induced by oxidative stress in swine with cardiac arrest

To investigate the protection of anisodamine on cardiac ischemia/reperfusion (I/R) injury by oxidative stress by observing the changes in oxidation and antioxidant markers in plasma and myocardium, and the damage of cardiac mitochondria structure in pigs with cardiac arrest (CA). Twenty-three healthy male swine were divided into three groups using random digits table: sham group (n=5), epinephrine group (n=9), and anisodamine group (n=9). The CA model was reproduced by alternating current. Blood samples were collected before CA, 8 minutes after CA, and 0 minute, 30 minutes, 24 hours after recovery of spontaneous circulation (ROSC), and hearts were harvested at 24 hours after ROSC. The content of malondialdehyde (MDA) and the enzyme activity of superoxide dismutase (SOD) were analyzed by spectrophotography, the cardiac ATP content was assayed by high performance liquid chromatography, the generation of reactive oxygen species (ROS) was detected by laser confocal microscope, and the myocardial ultrastructures were observed with transmission electron microscope to assess mitochondrial damage score. At 30 minutes and 24 hours after ROSC, plasma MDA level of anisodamine group was lower than that of epinephrine group (30 minutes: 43.38±8.12 μmol/L vs. 55.47±10.97 μmol/L, 24 hours: 29.96±6.04 μmol/L vs. 37.87±7.85 μmol/L, both P<0.05). Compared with epinephrine group, the cardiac SOD activity and ATP content of anisodamine group were elevated (SOD: 1.35±0.50 U/mg vs. 0.54±0.19 U/mg, ATP: 4.17±1.06 μmol/g vs. 2.95±0.94 μmol/g, P<0.01 and P<0.05), and the mitochondrial ROS level (RFU) was lowered (88.00±17.67 vs. 107.00±21.35, P<0.05). Although the cardiac MDA content was also reduced, but the difference between two resuscitation groups showed no statistical significance (16.66±2.89 μmol/mg vs. 19.28±3.90 μmol/mg, P>0.05). Using electron microscope, in epinephrine group disordered arrangement of cardiac myocyte arrangement was observed, and the mitochondrial alignment and morphology were significantly different from the sham group (mitochondrial damage score: 0.41±0.08 vs. 0.12±0.01, P<0.01). The level of mitochondrial injury in anisodamine group was milder than that of epinephrine group (mitochondrial damage score: 0.21±0.05 vs. 0.41±0.08, P<0.05). Through regulating oxygen radical metabolism, anisodamine alleviates the injury to myocardial mitochondria structure and function injury as induced by oxidative stress.

Terlipressin with Limited Fluid Resuscitation in a Swine Model of Hemorrhage

BackgroundPrinciples of damage control resuscitation include minimizing intravenous fluid (IVF) administration while correcting perfusion pressure as quickly as possible. Recent studies have identified a potential advantage of vasopressin over catecholamines in traumatic shock. Terlipressin (TP) is a vasopressin analogue used to reverse certain shock etiologies in some European countries. Study ObjectiveWe evaluated three dosages of TP when combined with a limited colloid resuscitation strategy on mean arterial pressure (MAP) and lactatemia in a swine model of isolated hemorrhage. MethodsSixty anesthetized swine underwent intubation and severe hemorrhage. Subjects were randomized to one of four resuscitation groups: 4 mL/kg Hextend® (Hospira Inc, Lake Forest, IL) only, 3.75 μg/kg TP + Hextend, 7.5 μg/kg TP + Hextend, or 15 μg/kg TP + Hextend. MAP and heart rate were recorded every 5 min. Baseline and serial lactate values at 30-min intervals were recorded and compared. ResultsSubjects receiving 7.5 μg/kg TP had significantly higher MAPs at times t15 (p = 0.012), t20 (p = 0.004), t25 (p = 0.018), t30 (p = 0.032), t35 (p = 0.030), and t40 (p = 0.021). No statistically significant differences in lactate values between TP groups and controls were observed. ConclusionSubjects receiving 7.5 μg/kg of TP demonstrated improved MAP within 10 min of administration. When combined with minimal IVF resuscitation, TP doses between 3.75 and 15 μg/kg do not elevate lactate levels in hemorrhaged swine.

Effect of Hyperoxia on Resuscitation of Experimental Combined Traumatic Brain Injury and Hemorrhagic Shock in Mice

Hypotension and hypoxemia worsen traumatic brain injury outcomes. Hyperoxic resuscitation is controversial. The authors proposed that hyperoxia would improve hemodynamics and neuronal survival by augmenting oxygen delivery despite increased oxidative stress and neuroinflammation in experimental combined controlled cortical impact plus hemorrhagic shock in mice. Adult C57BL6 mice received controlled cortical impact followed by 35 min of hemorrhagic shock (mean arterial pressure, 25-27 mmHg). The resuscitation phase consisted of lactated Ringer's boluses titrated to mean arterial pressure greater than 70 mmHg. Definitive care included returning shed blood. Either oxygen or room air was administered during the resuscitation phases. Brain tissue levels of oxidative stress and inflammatory markers were measured at 24 h and hippocampal neuronal survival was quantified at 7 days. Hyperoxia markedly increased brain tissue oxygen tension approximately four- to fivefold (n = 8) and reduced resuscitation fluid requirements approximately 15% (n = 53; both P < 0.05). Systemic and cerebral physiologic variables were not significantly affected by hyperoxia. Hippocampal neuron survival was approximately 40% greater with oxygen versus room air (n = 18, P = 0.03). However, ascorbate depletion doubled with oxygen versus room air (n = 11, P < 0.05). Brain tissue cytokines and chemokines were increased approximately 2- to 20-fold (n = 10) after combined controlled cortical impact injury plus hemorrhagic shock, whereas hyperoxia shifted cytokines toward a proinflammatory profile. Hyperoxic resuscitation of cortical impact plus hemorrhagic shock reduced fluid requirements and increased brain tissue oxygen tension and hippocampal neuronal survival but exacerbated ascorbate depletion and neuroinflammation. The benefits of enhanced oxygen delivery during resuscitation of traumatic brain injury may outweigh detrimental increases in oxidative stress and neuroinflammation.

Resuscitation With Aged Blood Exacerbates Liver Injury in a Hemorrhagic Rat Model*

Blood loss and transfusion are frequent among patients undergoing liver surgery. Concerns have been raised about the safety and efficacy of transfusing stored blood. The influence of transfusing fresh vs. stored blood on the liver has not been studied to date. We tested the hypothesis that transfusion of stored, but not fresh blood, adversely affects liver outcome in vivo following acute hemorrhage. Additionally, possible mechanisms linking adverse liver outcome with increased storage duration were evaluated. Prospective, controlled, animal study. University research laboratory. Adult male Sprague-Dawley rats Anesthetized rats were randomized to control, hemorrhagic and shock group (acute bleeding; HSG), or hemorrhagic and blood resuscitation groups (BR) (with fresh blood [BR-d0], blood stored for 4 [BR-d4] or 7 [BR-d7] days, or packed RBCs stored for 7 days [packed RBC-d7]). Administration of blood or packed RBC stored for 7 days exacerbated liver injury as reflected by liver necrosis and enhanced apoptosis (p < 0.001). Functional MRI analysis of the liver demonstrated significant improvement in liver perfusion with fresh blood (% change in functional MRI signal intensity due to hyperoxia was 16% ± 3% in BR-d0 vs. 4% ± 3% in hemorrhagic group, p < 0.001) but not with stored blood (12% ± 2% and 9% ± 5% for BR-d4 and BR-d7, respectively). Analysis of stored blood showed reduction in RBC deformability at 7 days of storage, reflecting a five-fold increase in the number of undeformable cells. Liver injury is exacerbated by the transfusion of stored blood, primarily due to the change in the rheological properties of RBC. This data call for clinical studies in patients undergoing liver resection or transplantation.

Impact of inverse ratios on patients with exsanguinating vascular injuries

Resuscitation strategies in patients with severe hemorrhage have evolved throughout the years. Optimal resuscitation ratios for civilian exsanguinating vascular injuries has not been determined. We hypothesize improved outcomes in patients with exsanguinating vascular injuries when an aggressive hemostatic resuscitation is used with an inverse ratio of fresh frozen plasma (FFP) to packed red blood cell (PRBC). This is a 5-year retrospective analysis of vascular injuries requiring hemostatic resuscitation. Resuscitation groups by ratios of FFP/PRBC were inverse (>1:1), high (1-1:2), and low (<1:2). Patients with 10 or greater units of PRBC (massively transfused patients) were evaluated in each of the resuscitation groups. Demographics and complications throughout hospital length of stay and were compared between the resuscitation groups. Survivability Kaplan-Meier curves were generated at 6 hours and 5 days. A total of 258 patients with vascular injuries required component therapy resuscitation (low, n = 78; high, n = 156; inverse, n = 24). Massively transfused patients (n = 162, 62.7%) showed a significant Kaplan-Meier survivability difference at 6 hours (low, 65.0% vs. high, 75.0% vs. inverse, 100%, p = 0.024) and at 5 days (low, 52.5% vs. high, 62.0% vs. inverse, 100%, p = 0.008). Moreover, for massively transfused patients with extremity vascular injuries (n = 65, 39%), a relationship between resuscitation ratio and amputations was significant (low vs. high vs. inverse was 36.8% vs. 12.8% vs. 0%, respectively; p = 0.033). This is the first study that highlights the potential outcomes benefits of an inverse ratio of FFP-PRBC in patients with exsanguinating vascular injuries. Multi-institutional prospective analysis is needed to potentially elucidate the cytoprotective effect of FFP to validate these results. Therapeutic study, level IV; diagnostic study, level III.

Even Four Minutes of Poor Quality of CPR Compromises Outcome in a Porcine Model of Prolonged Cardiac Arrest

Objective. Untrained bystanders usually delivered suboptimal chest compression to victims who suffered from cardiac arrest in out-of-hospital settings. We therefore investigated the hemodynamics and resuscitation outcome of initial suboptimal quality of chest compressions compared to the optimal ones in a porcine model of cardiac arrest. Methods. Fourteen Yorkshire pigs weighted 30 ± 2 kg were randomized into good and poor cardiopulmonary resuscitation (CPR) groups. Ventricular fibrillation was electrically induced and untreated for 6 mins. In good CPR group, animals received high quality manual chest compressions according to the Guidelines (25% of animal's anterior-posterior thoracic diameter) during first two minutes of CPR compared with poor (70% of the optimal depth) compressions. After that, a 120-J biphasic shock was delivered. If the animal did not acquire return of spontaneous circulation, another 2 mins of CPR and shock followed. Four minutes later, both groups received optimal CPR until total 10 mins of CPR has been finished. Results. All seven animals in good CPR group were resuscitated compared with only two in poor CPR group (P < 0.05). The delayed optimal compressions which followed 4 mins of suboptimal compressions failed to increase the lower coronary perfusion pressure of five non-survival animals in poor CPR group. Conclusions. In a porcine model of prolonged cardiac arrest, even four minutes of initial poor quality of CPR compromises the hemodynamics and survival outcome.

Ulinastatin Suppresses Burn-Induced Lipid Peroxidation and Reduces Fluid Requirements in a Swine Model

Objective. Lipid peroxidation plays a critical role in burn-induced plasma leakage, and ulinastatin has been reported to reduce lipid peroxidation in various models. This study aims to examine whether ulinastatin reduces fluid requirements through inhibition of lipid peroxidation in a swine burn model. Methods. Forty miniature swine were subjected to 40% TBSA burns and were randomly allocated to the following four groups: immediate lactated Ringer's resuscitation (ILR), immediate LR containing ulinastatin (ILR/ULI), delayed LR resuscitation (DLR), and delayed LR containing ulinastatin (DLR/ULI). Hemodynamic variables, net fluid accumulation, and plasma thiobarbituric acid reactive substances (TBARS) concentrations were measured. Heart, liver, lung, skeletal muscle, and ileum were harvested at 48 hours after burn for evaluation of TBARS concentrations, activities of antioxidant enzymes, and tissue water content. Results. Ulinastatin significantly reduced pulmonary vascular permeability index (PVPI) and extravascular lung water index (ELWI), net fluid accumulation, and water content of heart, lung, and ileum in both immediate or delayed resuscitation groups. Furthermore, ulinastatin infusion significantly reduced plasma and tissue concentrations of TBARS in both immediate or delayed resuscitation groups. Conclusions. These results indicate that ulinastatin can reduce fluid requirements through inhibition of lipid peroxidation.

Effect of Rescue Breathing During Cardiopulmonary Resuscitation on Lung Function After Restoration of Spontaneous Circulation in a Porcine Model of Prolonged Cardiac Arrest*

The destruction of the pulmonary structure after cardiopulmonary resuscitation may lead to lung function breakdown. The aim of this study was to investigate lung function after cardiopulmonary resuscitation and the influence of rescue breathing on lung function. Prospective, randomized animal study. A university animal research laboratory. Twenty-eight male domestic pigs weighing 30 ± 2 kg. The animals were randomized into three groups: continuous compressions (n = 12), 30:2 compression/rescue ventilation cardiopulmonary resuscitation (n = 12), and sham cardiopulmonary resuscitation (n = 4). Ventricular fibrillation was induced in the continuous compressions and compression/rescue ventilation groups. Cardiac output, extravascular lung water, and airway resistance were measured at baseline and 1, 2, and 4 hrs after restoration of spontaneous circulation. Thoracopulmonary compliance, lower inflection point, and dead space were calculated. Lung ventilation/perfusion scans with Tc were performed 48 hrs before the experiment and 24 hrs after restoration of spontaneous circulation. Conventional histopathology evaluation was performed. Dead space, airway resistance, lower inflection point, and extravascular lung water significantly increased and compliance decreased after restoration of spontaneous circulation in the continuous compressions and compression/rescue ventilation groups. Lung injury was more severe in the continuous compressions group. Significant differences were found between the two groups in the three time points after restoration of spontaneous circulation (p < 0.05). Variables of the sham cardiopulmonary resuscitation group remained stable during the whole protocol. Poor ventilation/perfusion and mismatch were found after restoration of spontaneous circulation, but the injury was mitigated in the compression/rescue ventilation group. Histopathology injury in the compression/rescue ventilation group was also improved. Appropriate rescue breathing during cardiopulmonary resuscitation does not influence the prognosis of cardiac arrest or the hemodynamics after restoration of spontaneous circulation but can improve lung function and alleviate lung injury.

Pharmacologic resuscitation for hemorrhagic shock combined with traumatic brain injury

We have previously demonstrated that valproic acid (VPA), a histone deacetylase inhibitor, can improve survival after hemorrhagic shock (HS), protect neurons from hypoxia-induced apoptosis, and attenuate the inflammatory response. We have also shown that administration of 6% hetastarch (Hextend [Hex]) after traumatic brain injury (TBI) decreases brain swelling, without affecting size of the lesion. This study was performed to determine whether addition of VPA to Hex would decrease the lesion size in a clinically relevant large animal model of TBI + HS. Yorkshire swine (42-50 kg) were instrumented to measure hemodynamic parameters, intracranial pressure, and brain tissue oxygenation. A custom-designed, computer-controlled cortical impact device was used to create a TBI through a 20-mm craniotomy: 15-mm cylindrical tip impactor at 4-m/s velocity, 100-millisecond dwell time, and 12-mm penetration depth. Volume-controlled hemorrhage was started (40% blood volume) concurrent with the TBI. After 2 hours of shock, animals were randomized to one of three resuscitation groups (n = 7 per group) as follows: (1) isotonic sodium chloride solution; (2) 6% hetastarch, Hex; and (3) Hex and VPA 300 mg/kg (Hex + VPA). Volumes of Hex matched the shed blood, whereas that of the isotonic sodium chloride solution was three times the volume. VPA treatment was started after an hour of shock. After 6 hours of postresuscitation monitoring, brains were sectioned into 5-mm slices and stained with 2, 3, 5-Triphenyltetrazolium chloride to quantify the lesion size (mm) and brain swelling (percent change compared with uninjured side). Levels of acetylated histone H3 were determined to quantify acetylation, and myeloperoxidase and interleukine-1β (IL-1β) levels were measured as markers of brain inflammation. Combination of 40% blood loss with cortical impact and a period of shock (2 hours) and resuscitation resulted in a highly reproducible brain injury. Lesion size and brain swelling in the Hex + VPA group (1,989 [156.8] mm, and 19% [1.6%], respectively) were significantly smaller than the isotonic sodium chloride solution group (3,335 [287.9] mm and 36% [2.2%], respectively). Hex alone treatment significantly decreased the swelling (27% [1.6%]) without reducing the lesion size. The number of CD11b-positive cells as well as myeloperoxidase and IL-1 levels in the brains were significantly reduced by the VPA treatment. In a combined HS and TBI model, treatment with artificial colloid (Hex) improves hemodynamic parameters and reduces swelling, without affecting the actual size of the brain lesion. Addition of VPA effectively reduces both the size of brain lesion and associated swelling by attenuating the inflammatory response.

Carbon Monoxide–Bound Red Blood Cells Protect Red Blood Cell Transfusion-Induced Hepatic Cytochrome P450 Impairment in Hemorrhagic-Shock Rats

Red blood cell (RBC) transfusions for massive hemorrhage induce systemic ischemic-reperfusion and influence the disposition and pharmacological activity of drugs as a result of a reduction in the level of expression and activity of cytochrome P450s (P450). It was reported that, when organ-preserving solutions are exposed to carbon monoxide (CO), the treatment was effective in suppressing the postreperfusion reduction in renal P450 levels in cases of kidney transplantation. Therefore, we hypothesized that transfusions with RBC that contain bound CO (CO-RBC) would protect the hepatic level of rat P450 during a massive hemorrhage, compared with plasma expanders and RBC resuscitation. To achieve this, we created 40% hemorrhagic-shock model rats, followed by resuscitation, with use of recombinant human serum albumin, RBCs, and CO-RBCs. At 1 hour after resuscitation, the expressions of hepatic P450 isoforms (1A2, 2C11, 2E1, and 3A2) were significantly decreased in the RBC resuscitation group, compared with the sham group. Such alterations in hepatic P450 significantly resulted in an increase in the plasma concentrations of substrate drugs (caffeine [1A2], tolbutamide [2C11], chlorzoxazone [2E1], and midazolam [3A2]) for each P450 isoform, and thus, the hypnotic action of midazolam could be significantly prolonged. Of interest, the reductions in hepatic P450 activity observed in the RBC group were significantly suppressed by CO-RBC resuscitation, and consequently, the pharmacokinetics of substrate drugs and the pharmacological action of midazolam remained at levels similar to those under sham conditions. These results indicate that CO-RBC resuscitation has considerable potential in terms of achieving safe and useful drug therapy during massive hemorrhages.

Load-distributing band improves ventilation and hemodynamics during resuscitation in a porcine model of prolonged cardiac arrest

BackgroundThe use of mechanical cardiopulmonary resuscitation (CPR) has great potential for the clinical setting. The purpose of present study is to compare the hemodynamics and ventilation during and after the load-distributing band CPR, versus the manual CPR in a porcine model of prolonged cardiac arrest, and to investigate the influence of rescue breathing in different CPR protocols.MethodsSixty-four male pigs (n = 16/group), weighing 30 ± 2 kg, were induced ventricular fibrillation and randomized into four resuscitation groups: continuous load-distributing band CPR without rescue ventilation (C-CPR), load-distributing band 30:2 CPR (A-CPR), load-distributing band CPR with continuous rescue breathing (10/min) (V-CPR) or manual 30:2 CPR (M-CPR). Respiratory variables and hemodynamics were recorded continuously; blood gas was analyzed.ResultsTidal volume produced by compressions in the A-, C- and V-CPR groups were significantly higher compared with the M-CPR group (all p < 0.05). Coronary perfusion pressure of the V-CPR group was significantly lower than the C-CPR group (p < 0.01), but higher than the M-CPR group. The increasing of lung dead space after restoration of spontaneous circulation was significantly greater in the M-CPR group compared with the A-, C- and V-CPR groups (p < 0.01). Blood pH gradually decreased and was lower in the M-CPR group than that in the A-, C- and V-CPR groups (p < 0.01). PaO2 of the A-, C- and V-CPR groups were significantly higher and PaCO2 were significantly lower compared with the M-CPR (both p < 0.05). Cerebral performance categories were better in the A-, C- and V-CPR groups compared with the M-CPR group (p < 0.0001).ConclusionsThe load-distributing band CPR significantly improved respiratory parameters during resuscitation by augmenting passive ventilation, and significantly improved coronary perfusion pressure. The volume of ventilation produced by the load-distributing band CPR was adequate to maintain sufficient gas exchange independent of rescue breathing.

Different recovery profiles of coagulation factors, thrombin generation, and coagulation function after hemorrhagic shock in pigs

Hemorrhagic shock contributes to coagulopathy after trauma. We investigated daily changes of coagulation components and coagulation function for 5 days in hemorrhaged and resuscitated pigs. Fourteen pigs were randomized into the sham control (C) and the hemorrhage and lactated Ringer's resuscitation (H-LR) groups. On day 1, hemorrhage was induced in the H-LR group by bleeding 35% of the total blood volume, followed by LR resuscitation at three times the bled volume. Pigs in the C group were not hemorrhaged or resuscitated. Hemodynamics and coagulation were measured daily after H-LR on day 1 to day 5. No changes in hemodynamics and coagulation function occurred in C. Hemorrhage decreased mean arterial pressure and increased heart rate. LR resuscitation corrected these changes within 2 hours. Compared with the baseline values (BL) on day 1, fibrinogen levels were decreased to 76% ± 6% by H-LR on day 1, increased to 217% ± 16% on day 2, and remained increased thereafter; platelet counts were decreased to 63% ± 5% by H-LR on day 1 and remained lower on days 2 and 3 but returned to BL by days 4 and 5 (all p < 0.05). Thrombin generation was decreased by H-LR on days 1 and 2 but then increased to above BL on days 4 and 5. Coagulation factor levels were decreased by H-LR on day 1 but returned to BL on day 3 except for factor XIII. Clot strength was decreased by H-LR on day 1 and returned to BL by day 2. Clot rapidity did not change on day 1 but was decreased on days 2 and 3 and returned to BL on days 4 and 5. Hemorrhage and resuscitation reduced coagulation components and compromised coagulation function, which showed different recovery profiles over the 5-day study period.

Effect of resuscitation strategy based on the early goal directed therapy on the prognosis of patients with shock

To evaluate the effects of fluid management strategies in early goal directed therapy (EGDT) on the prognosis of patients with shock. Clinical data of 79 patients with septic shock or hemorrhagic shock admitted to emergency intensive care unit (EICU) of the First People's Hospital of Yunnan Province were retrospectively analyzed. Patients were divided into continual fluid administrating group (n=41) in accordance with protocol calculating approximating fluid volume and adjust the infusion speed based on blood pressure, heart rate, pulse saturation of blood oxygen (SpO(2)) and urine output with the end of fluid resuscitation was set to restore spontaneous circulation function and wean off vasoactive drugs, and the conservative fluid resuscitation group (n=38) by means of using vasoactive agents to maintenance blood pressure after infusing amount (20 ml/kg) of liquid early, respectively. The 28-day mortality and the time of using pressure agents were compared between two groups. According to the 28-day mortality, patients were further divided into the survival group (n=37) and death group (n=42), and acute physiology and chronic health evaluation II (APACHEII) score was compared between two groups. Logistic regression analysis of prognostic factors was conducted to identify and describe the relationship between the prognosis and fluid resuscitation methods and strategies. The 28-day mortality of continual fluid administrating group was significantly lower than that of the conservative fluid resuscitation group (14.63% vs. 94.74%, P<0.01), total drugs supporting time (hours) was significantly shorter than that in conservative fluid resuscitation group (33.24±17.56 vs. 58.29±34.78, P<0.05). Thirty-six cases of 42 death patients received conservative fluid resuscitation (85.7%), but 35 cases of 37 survival patients received continual fluid administration (94.6%). Logistic regression analysis showed that odds ratio (OR) of brain natriuretic peptide before death or shifted out ICU was 0.9136, 95% confidence interval (95%CI) was 0.8125 to 0.9986, regression coefficient was -0.0931, P=0.0478, OR of procalcitonin before death or shifted out ICU was 0.9095, 95%CI was 0.8294 to 0.9973, regression coefficient was -0.0949, P=0.0436, and OR of blood lactate level before death or shifted out ICU was 0.5023, 95%CI was 0.2833 to 0.8905, regression coefficient was -0.6885, P=0.0184. Ongoing fluid resuscitation early in accordance with method to theoretically calculate fluid volume and to adjust infusion speed based on blood pressure, heart rate, SpO(2) and urine, withdrawal of vasoactive drugs, the mortality of patients with shock was significantly reduced.

Isoflurane prevents acute lung injury through ADP-mediated platelet inhibition

Growing evidence suggests platelets are essential in posttraumatic, acute lung injury (ALI). Halogenated ethers interfere with the formation of platelet-granulocyte aggregates. The potential benefit of halogenated ethers has not been investigated in models of trauma/hemorrhagic shock (T/HS). Therefore, we hypothesized that isoflurane decreases T/HS-mediated ALI through platelet inhibition. Sprague-Dawley rats (n = 47) were anesthetized by either pentobarbital or inhaled isoflurane and placed into (1) control, (2) trauma (laparotomy) sham shock, (3) T/HS (mean arterial pressure, 30 mmHg × 45 min), (4) pretreatment with an ADP receptor antagonist, or (5) T/HS with isoflurane initiated during resuscitation groups. ALI was determined by protein and pulmonary immunofluorescence bronchoalveolar lavage (BAL) fluid. Platelet Mapping specifically evaluated thrombin-independent inhibition of the ADP and AA pathways of platelet activation. Pretreatment with isoflurane abrogated ALI as measured by both BAL fluid protein and pulmonary immunofluorescence (P < .001). Platelet Mapping revealed specific inhibition of the platelet ADP-pathway with isoflurane (P < .001). Pretreatment with an ADP receptor antagonist decreased ALI to sham levels, confirming that specific platelet ADP inhibition decreases ALI. Isoflurane initiated during resuscitation also decreased ALI (P < .001). Isoflurane attenuates ALI through an antiplatelet mechanism, in part, through inhibition of the platelet ADP pathway. Isoflurane given postinjury also protects against ALI, and highlights the potential applications of this therapy in various clinical scenarios of ischemia/reperfusion.

Traumatic Brain Injury and Hemorrhagic Shock

Traumatic brain injury (TBI) and hemorrhagic shock (HS) are the leading causes of trauma-related mortality and morbidity. Combination of TBI and HS (TBI + HS) is highly lethal, and the optimal resuscitation strategy for this combined insult remains unclear. A critical limitation is the lack of suitable large animal models to test different treatment strategies. We have developed a clinically relevant large animal model of TBI + HS, which was used to evaluate the impact of different treatments on brain lesion size and associated edema. Yorkshire swine (42-50 kg) were instrumented to measure hemodynamic parameters and intracranial pressure. A computer-controlled cortical impact device was used to create a TBI through a 20-mm craniotomy: 15-mm cylindrical tip impactor at 4 m/s velocity, 100-ms dwell time, and 12-mm penetration depth. Volume-controlled hemorrhage was started (40% blood volume) concurrent with the TBI. After 2 h of shock, animals were randomized to one of three resuscitation groups (n = 5/group): (a) normal saline (NS); (b) 6% hetastarch, Hextend (Hex); and (c) fresh frozen plasma (FFP). Volumes of Hex and FFP matched the shed blood, whereas NS was three times the volume. After 6 h of postresuscitation monitoring, brains were sectioned into 5-mm slices and stained with TTC (2,3,5-triphenyltetrazolium chloride) to quantify the lesion size and brain swelling. Combination of 40% blood loss with cortical impact and a period of shock (2 h) resulted in a highly reproducible brain injury. Total fluid requirements were lower in the Hex and FFP groups. Lesion size and brain swelling in the FFP group (2,160 ± 202.63 mm and 22% ± 1.0%, respectively) were significantly smaller than those in the NS group (3,285 ± 130.8 mm3 and 37% ± 1.6%, respectively) (P < 0.05). Hex treatment decreased the swelling (29% ± 1.6%) without reducing the lesion size. Early administration of FFP reduces the size of brain lesion and associated swelling in a large animal model of TBI + HS. In contrast, artificial colloid (Hex) decreases swelling without reducing the actual size of the brain lesion.

Effects of starch nanospheres solution on hemodynamic values in rats with hemorrhagic shock: A preliminary study in hemorrhagic shock resuscitation

BackgroundThe objective of the present study was to explore the resuscitation effects of starch nanospheres solution on hemodynamics in rats with hemorrhagic shock. MethodsA total of 20 Sprague-Dawley rats were randomly divided into 2 groups: resuscitation group 1 (infusion with Ringer's solution) and resuscitation group 2 (infusion with starch nanospheres solution) with 10 rats per group. The rats in resuscitation groups 1 and 2 were subjected to hemorrhagic shock, and resuscitation was performed with Ringer's solution and starch nanospheres solution. The changes in the hemodynamic values of the rats in both groups were observed and recorded. ResultsThe hemodynamic values included the systolic blood pressure, diastolic blood pressure, mean arterial blood pressure, heart rate, and respiratory rate. After resuscitation, the systolic blood pressure, diastolic blood pressure, mean arterial pressure, and heart rate in resuscitation group 2 had reverted back to the base values (P > 0.05). The systolic blood pressure, diastolic blood pressure, and mean arterial pressure were lower at all points in resuscitation group 1 than in resuscitation group 2 (P < 0.05). The respiratory rate was more rapid after resuscitation at 30 and 60 min in resuscitation group 1 than in resuscitation group 2 (P < 0.05). ConclusionsStarch nanospheres solution expands the circulating blood volume and improves the hemodynamics. It also increases the effective circulating blood volume and improves the shock symptoms of effective hypovolemia.