Resuscitation Of Hemorrhagic Shock Research Articles

Resuscitation from hemorrhagic shock after traumatic brain injury with polymerized hemoglobin

Traumatic brain injury (TBI) is often accompanied by hemorrhage, and treatment of hemorrhagic shock (HS) after TBI is particularly challenging because the two therapeutic treatment strategies for TBI and HS often conflict. Ischemia/reperfusion injury from HS resuscitation can be exaggerated by TBI-induced loss of autoregulation. In HS resuscitation, the goal is to restore lost blood volume, while in the treatment of TBI the priority is focused on maintenance of adequate cerebral perfusion pressure and avoidance of secondary bleeding. In this study, we investigate the responses to resuscitation from severe HS after TBI in rats, using fresh blood, polymerized human hemoglobin (PolyhHb), and lactated Ringer’s (LR). Rats were subjected to TBI by pneumatic controlled cortical impact. Shortly after TBI, HS was induced by blood withdrawal to reduce mean arterial pressure (MAP) to 35–40 mmHg for 90 min before resuscitation. Resuscitation fluids were delivered to restore MAP to ~ 65 mmHg and animals were monitored for 120 min. Increased systolic blood pressure variability (SBPV) confirmed TBI-induced loss of autoregulation. MAP after resuscitation was significantly higher in the blood and PolyhHb groups compared to the LR group. Furthermore, blood and PolyhHb restored diastolic pressure, while this remained depressed for the LR group, indicating a loss of vascular tone. Lactate increased in all groups during HS, and only returned to baseline level in the blood reperfused group. The PolyhHb group possessed lower SBPV compared to LR and blood groups. Finally, sympathetic nervous system (SNS) modulation was higher for the LR group and lower for the PolyhHb group compared to the blood group after reperfusion. In conclusion, our results suggest that PolyhHb could be an alternative to blood for resuscitation from HS after TBI when blood is not available, assuming additional testing demonstrate similar favorable results. PolyhHb restored hemodynamics and oxygen delivery, without the logistical constraints of refrigerated blood.

Selective brain cooling achieves peripheral organs protection in hemorrhagic shock resuscitation via preserving the integrity of the brain-gut axis.

Background: Although whole-body cooling has been reported to improve the ischemic/reperfusion injury in hemorrhagic shock (HS) resuscitation, it is limited by its adverse reactions following therapeutic hypothermia. HS affects the experimental and clinical bowel disorders via activation of the brain-gut axis. It is unknown whether selective brain cooling achieves beneficial effects in HS resuscitation via preserving the integrity of the brain-gut axis.Methods: Male Sprague-Dawley rats were bled to hypovolemic HS and resuscitated with blood transfusion followed by retrograde jugular vein flush (RJVF) with 4 °C or 36 °C normal saline. The mean arterial blood pressure, cerebral blood flow, and brain and core temperature were measured. The integrity of intestinal tight junction proteins and permeability, blood pro-inflammatory cytokines, and multiple organs damage score were determined.Results: Following blood transfusion resuscitation, HS rats displayed gut barrier disruption, increased blood levels of pro-inflammatory cytokines, and peripheral vital organ injuries. Intrajugular-based infusion cooled the brain robustly with a minimal effect on body temperature. This brain cooling significantly reduced the HS resuscitation-induced gut disruption, systemic inflammation, and peripheral vital organ injuries in rats.Conclusion: Resuscitation with selective brain cooling achieves peripheral vital organs protection in hemorrhagic shock resuscitation via preserving the integrity of the brain-gut axis.

Shen-fu injection alleviates acute renal injury by reducing cytokine levels and modulating apoptosis in a porcine hemorrhagic shock model.

ABSTRACTPurposeShen-fu injection (SFI) was used to intervene in the resuscitation of porcine hemorrhagic shock (HS) model to study its protective effects on acute kidney injury.MethodsAfter 60 min of HS, 28 animals were randomly assigned into four groups. The groups were as follows: hemorrhagic shock group (HS); HS resuscitation with shed-blood group (HSR); HS resuscitation with shed-blood and SFI (1 mL·kg–1) group (HSR-SFI); and the sham operation group (Sham). The bloods were analyzed for serum creatinine (sCr), cystatin C (CysC) and neutrophil gelatinase-associated lipocalin (NGAL). BAX, Bcl-2, and caspase-3 protein expressions by Western blot analysis and immunohistochemical staining. The renal tissues were removed and pathologic changes were observed.ResultsMean aortic pressure (MAP) in HSR-SFI groups were higher than that in HSR groups after shock. At the 6th hour after shock, the urine volume per hour in the HSR-SFI groups was more than that in the HSR groups. The sCr, NGAL, CysC and cytokine levels of HSR-SFI groups were lower. The Bcl-2 expression was increased in the HSR-SFI groups. The BAX and caspase-3 expressions were reduced. The histopathologic score in the HSR-SFI was lower.ConclusionsSFI may reduce the risk of acute kidney injury (AKI) following hemorrhagic shock by attenuating systemic inflammatory responses, and regulating the expression of apoptosis-related proteins.

Shenfu injection improves cerebral microcirculation and reduces brain injury in a porcine model of hemorrhagic shock.

Shenfu injection (SFI) is a traditional Chinese herbal medicine which has been clinically used for treatment of septic shock and cardiac shock. The aim of this study was to clarify effects of SFI on cerebral microcirculation and brain injury after hemorrhagic shock (HS). Twenty-one domestic male Beijing Landrace pigs were randomly divided into three groups: SFI group (SFI, n = 8), saline group (SA, n = 8) or sham operation group (SO, n = 5). In the SFI group, animals were induced to HS by rapid bleeding to a mean arterial pressure of 40 mmHg within 10 minutes and maintained at 40±3 mmHg for 60 minutes. Volume resuscitation (shed blood and crystalloid) and SFI were given after 1 hour of HS. In the SA group, animals received the same dose of saline instead of SFI. In the SO group, the same surgical procedure was performed but without inducing HS and volume resuscitation. The cerebral microvascular flow index (MFI), nitric oxide synthase (NOS) expression, aquaporin-4 expression, interleukin-6, tumor necrosis factor-α (TNF-α) and ultrastructural of microvascular endothelia were measured. Compared with the SA group, SFI significantly improved cerebral MFI after HS. SFI up regulated cerebral endothelial NOS expression, but down regulated interleukin-6, TNF-α, inducible NOS and aquaporin-4 expression compared with the SA group. The cerebral microvascular endothelial injury and interstitial edema in the SFI group were lighter than those in the SA group. Combined application of SFI with volume resuscitation after HS can improve cerebral microcirculation and reduce brain injury.

Penetrating Injury from Interpersonal Violence and Related Haemorrhagic Shock Resuscitation Practices in An Urban South African Emergency Medical Service

Introduction Physical injury is a major cause of premature death and/or disability worldwide. South African mortality statistics indicate approximately half of all injury-related deaths were intentional, often from sharp-force injuries. Injury surveillance data for victims of penetrating injury is scarce in low- to middle-income countries with a reliance on mortality data. The aim was to provide an epidemiological description of penetrating injury and the related haemorrhagic shock resuscitation practice in a South African emergency medical service. Methods A prospective, observational, descriptive study was conducted in urban Cape Town. ‘R’ statistical computing was used. Emergency care providers voluntarily documented parameters for mechanism of injury, vital signs, intravenous fluid resuscitation and demographic information for patients with penetrating injury. Results Of 2884 (N) penetrating trauma cases, 143 (n) cases were sampled from providers. The chest (35.7%) and upper-limbs (31.5%) were the most common anatomy for penetrating injuries. The estimated mean crystalloid fluid volume administered for penetrating abdominal and chest injuries was 1010.6 mL and 925.3 mL respectively. A statistically significant association was observed between fluid administration and clinical indications such as systolic and diastolic blood pressure, heart rate, capillary refill time, level of consciousness estimation from the scene of the incident to the hospital after intravenous fluid administration. Most emergency medical service call outs (56%) were likely to occur between 20:00 and 02:00. Conclusion The intravenous fluid management by pre-hospital emergency care providers for patients with penetrating traumatic injuries, do not cohere with hypotensive resuscitative recommendations. Future research must include clinical practice guideline implementation efficacy and pre-hospital surveillance mechanisms. This study informs hospital clinician expectations for penetrating trauma care by pre-hospital providers.

Hypocalcemia in trauma patients: A systematic review.

During hemorrhagic shock and subsequent resuscitation, pathways reliant upon calcium such as platelet function, intrinsic and extrinsic hemostasis, and cardiac contractility are disrupted. The objective of this systematic review was to examine current literature for associations between pretransfusion, admission ionized hypocalcemia, and composite outcomes including mortality, blood transfusion requirements, and coagulopathy in adult trauma patients. This review was reported using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist. We searched Ovid MEDLINE and grey literature from database inception till May 3, 2020. Case series and reports were excluded. Reference lists of appraised studies were also screened for articles that the aforementioned databases might not have captured. The Newcastle-Ottawa Scale was used to assess study quality. A total of 585 abstracts were screened through database searching and alternative sources. Six unique full-text studies were reviewed, of which three were excluded. Admission ionized hypocalcemia was present in up to 56.2% of the population in studies included in this review. Admission ionized hypocalcemia was also associated with increased mortality in all three studies, with increased blood transfusion requirements in two studies, and with coagulopathy in one study. Hypocalcemia is a common finding in shocked trauma patients. While an association between admission ionized hypocalcemia and mortality, blood transfusion requirements, and coagulopathy has been identified, further prospective trials are essential to corroborating this association. Systematic review, level III.

Obesity and impaired barrier function after shock: A biomimetic in vitro model using microfluidics.

Impaired microvascular perfusion in the obese patient has been linked to chronic adverse health consequences. The impact on acute illnesses including trauma, sepsis, and hemorrhagic shock (HS) is uncertain. Studies have shown that endothelial glycocalyx and vascular endothelial derangements are causally linked to perfusion abnormalities. Trauma and HS are also associated with impaired microvascular perfusion in which glycocalyx injury and endothelial dysfunction are sentinel events. We postulate that obesity may impact the adverse consequences of HS on the vascular barrier. This was studied in vivo in a biomimetic model of HS using microfluidic technology. Human umbilical vein endothelial cell monolayers were established in a microfluidic device. Cells were exposed to standard or biomimetic shock conditions (hypoxia plus epinephrine) followed by perfusion from plasma obtained from obese or nonobese subjects. Endothelial glycocalyx and endothelial cellular injury were then determined. Plasma from nonobese patients completely reversed glycocalyx and endothelial vascular barrier injury. Plasma from obese patients was only partially protective and was associated with differences in adipokines and other substances in the plasma of these patients. Our study supports that obesity impairs HS resuscitation. This may be due to microrheological differences between nonobese and obese individuals and may contribute to the poorer outcome in this patient population.

Topical Melatonin Improves Gastric Microcirculatory Oxygenation During Hemorrhagic Shock in Dogs but Does Not Alter Barrier Integrity of Caco-2 Monolayers

Systemic administration of melatonin exerts tissue protective effects in the context of hemorrhagic shock. Intravenous application of melatonin prior to hemorrhage improves gastric microcirculatory perfusion and maintains intestinal barrier function in dogs. The aim of the present study was to analyze the effects of a topical mucosal melatonin application on gastric microcirculation during hemorrhagic shock in vivo and on mucosal barrier function in vitro. In a randomized cross-over study, six anesthetized female foxhounds received 3.3 mg melatonin or the vehicle as a bolus to the gastric and oral mucosa during physiological and hemorrhagic (−20% blood volume) conditions. Microcirculation was analyzed with reflectance spectrometry and laser doppler flowmetry. Systemic hemodynamic variables were measured with transpulmonary thermodilution. For analysis of intestinal mucosal barrier function in vitro Caco-2 monolayers were used. The transepithelial electrical resistance (TEER) and the passage of Lucifer Yellow (LY) from the apical to the basolateral compartment of Transwell chambers were measured. Potential barrier protective effects of melatonin against oxidative stress were investigated in the presence of the oxidant H2O2. During physiologic conditions topical application of melatonin had no effect on gastric and oral microcirculation in vivo. During hemorrhagic shock, gastric microcirculatory oxygenation (μHbO2) was decreased from 81 ± 8% to 50 ± 15%. Topical treatment with melatonin led to a significant increase in μHbO2 to 60 ± 13%. Topical melatonin treatment had no effect on gastric microcirculatory perfusion, oral microcirculation or systemic hemodynamics. Incubation of H2O2 stressed Caco-2 monolayers with melatonin did neither influence transepithelial electrical resistance nor LY translocation. Topical treatment of the gastric mucosa with melatonin attenuates the shock induced decrease in microcirculatory oxygenation. As no effects on local microcirculatory and systemic perfusion were recorded, the improved μHbO2 is most likely caused by a modulation of local oxygen consumption. In vitro melatonin treatment did not improve intestinal barrier integrity in the context of oxidative stress. These results extend the current knowledge on melatonin's protective effects during hemorrhage in vivo. Topical application of melatonin exerts differential effects on local microcirculation compared to systemic pretreatment and might be suitable as an adjunct for resuscitation of hemorrhagic shock.

Therapeutic interventions to restore microcirculatory perfusion following experimental hemorrhagic shock and fluid resuscitation: A systematic review.

ObjectiveMicrocirculatory perfusion disturbances following hemorrhagic shock and fluid resuscitation contribute to multiple organ dysfunction and mortality. Standard fluid resuscitation is insufficient to restore microcirculatory perfusion; however, additional therapies are lacking. We conducted a systematic search to provide an overview of potential non‐fluid‐based therapeutic interventions to restore microcirculatory perfusion following hemorrhagic shock.MethodsA structured search of PubMed, EMBASE, and Cochrane Library was performed in March 2020. Animal studies needed to report at least one parameter of microcirculatory flow (perfusion, red blood cell velocity, functional capillary density).ResultsThe search identified 1269 records of which 48 fulfilled all eligibility criteria. In total, 62 drugs were tested of which 29 were able to restore microcirculatory perfusion. Particularly, complement inhibitors (75% of drugs tested successfully restored blood flow), endothelial barrier modulators (100% successful), antioxidants (66% successful), drugs targeting cell metabolism (83% successful), and sex hormones (75% successful) restored microcirculatory perfusion. Other drugs consisted of attenuation of inflammation (100% not successful), vasoactive agents (68% not successful), and steroid hormones (75% not successful).ConclusionImproving mitochondrial function, inhibition of complement inhibition, and reducing microvascular leakage via restoration of endothelial barrier function seem beneficial to restore microcirculatory perfusion following hemorrhagic shock and fluid resuscitation.

Therapeutic Hypothermia Improves Long-Term Survival and Blunts Inflammation in Rats During Resuscitation of Hemorrhagic Shock.

We tested the hypothesis that therapeutic hypothermia (TH) improves survival and blunts inflammation in rats undergoing experimental hemorrhagic shock. Rats were randomized to TH (n = 16) or normothermia (n = 15). Hemorrhagic shock was induced by withdrawing blood to a fixed mean blood pressure (MBP) of 30 mmHg for 30 minutes followed by reinfusion of shed blood for the next 30 minutes. TH (target 32°C) was started at 5 minutes after MBP reached 30 mmHg and was maintained throughout blood volume resuscitation. In the normothermic control group, body temperature was maintained at 37°C during the procedure. Rats were allowed to recover for 6 weeks. TH significantly improved survival: 4 of 15 (26.7%) rats in the normothermic group and 11 of 16 (68.8%; p = 0.032) rats in the TH group survived 6 weeks. Recovery of MBP during the resuscitation phase was significantly improved and left ventricular fractional shortening was markedly increased in the TH group compared with the normothermic group. Brain infarction was observed in 3 of 4 surviving rats (75%) in normothermic group, and in only 1 of the 11 surviving rats (9%) in TH group. The neutrophil-to-lymphocyte ratio was lower in TH group (0.20 ± 0.02) compared with the normothermic group (0.32 ± 0.03; p = 0.003). TH influenced the levels of blood gases and blood counts, favoring hypothermia over control. TH significantly improved long-term survival and blunted the inflammatory response in experimental hemorrhagic shock.

Liquid plasma: A solution to optimizing early and balanced plasma resuscitation in massive transfusion

Early and balanced resuscitation for traumatic hemorrhagic shock is associated with decreased mortality, making timely plasma administration imperative. However, fresh frozen plasma (FFP) thaw time can delay administration, and the shelf life of thawed FFP limits supply and may incur wastage. Liquid plasma (LP) offers an attractive alternative given immediate transfusion potential and extended shelf life. As such, we hypothesized that the use of LP in the massive transfusion protocol (MTP) would improve optimal plasma/red blood cell (RBC) ratios, initial plasma transfusion times, and clinical outcomes in the severely injured patient. Using Trauma Quality Improvement Program data from our level 1 trauma center, we evaluated MTP activations from 2016 to 2018. Type A LP use was instated April 2017. Before this, thawed FFP was solely used. Plasma/RBC ratios and initial plasma transfusion times were compared in MTP patients before and after LP implementation. Patient and injury characteristics were accounted for using linear regression analysis. Secondary outcomes of mortality, 28-day recovery, and complications were evaluated using Cox proportional hazards regression. A total of 95 patients were included (pre-LP, 39; post-LP, 56). Time to initial plasma transfusion and plasma/RBC ratios at 4 and 24 hours were improved post-LP implementation with a coinciding reduction in RBC units transfused (p < 0.05). In a 28-day Cox proportional hazards regression LP implementation was associated with favorable recovery (hazard ratio, 3.16; 95% confidence interval, 1.60-6.24; p < 0.001) and reduction in acute kidney injury (hazard ratio, 0.092; 95% confidence interval, 0.011-0.77; p = 0.027). No post-LP patients with blood group type B or AB (n = 9) demonstrated evidence of hemolysis within 24 hours of type A LP transfusion. Initial resuscitation with LP optimizes early plasma administration and improves adherence to transfusion ratio guidelines. Furthermore, LP offers a solution to inherent delays with FFP and is associated with improved clinical outcomes, particularly 28-day recovery and odds of acute kidney injury. Liquid plasma should be considered as an alternative to FFP in MTPs. Therapeutic/care management, level IV.

Hemostatic potential of cold-stored non-leukoreduced whole blood over time: An assessment of platelet function and thrombin generation for optimal shelf life.

Cold-stored low-titer whole blood (WB) is becoming increasingly used as the preferred product for initial hemorrhagic shock resuscitation. The purpose of this study was to identify whether the current 21-day shelf life is the optimal duration for storage of WB, maintaining hemostatic efficacy. Five units of fresh low-titer group O WB (non-leukoreduced) were acquired from our regional blood center. These units were stored at 4°C for up to 21 days as per current clinical storage guidelines in our emergency department. Hemostatic parameters were measured in vitro at 0 days, 7 days, 14 days, and 21 days. Assessments of hemostatic potential included cell count, rapid thrombelastography (r-TEG) and kaolin thrombelastography (TEG), multiplate impedance aggregometry, and calibrated automated thrombogram (CAT). Univariate analysis, including one-way analysis of variance with repeated measures, was performed (STATA 12.1). Compared with baseline product (0 days), both platelet count and platelet function of WB showed sharp decreases at 7 days and again at 14 days. Platelet function deterioration was noted by r-TEG c (MA), TEG-MA, and multiplate arachidonic acid and adenosine diphosphate (all p < 0.001). With respect to clot initiation, r-TEG ACT and TEG R-time were similar over the 21-day shelf life (p = 0.058 and p = 0.620, respectively). Thrombin generation assessed by CAT demonstrated stable endogenous thrombin potential over the course of storage (p = 0.162), but increased peak thrombin generation and quicker time to peak generation after 7 days. While the platelet function of WB degrades significantly at 7 days (and again at 14 days), clot initiation remains stable over time, and thrombin generation appears to be improved at 7 days. This study supports a current storage limit for cold-stored, low-titer WB of 14 days.

Improved Hemodynamic Recovery and 72-Hour Survival Following Low-Volume Resuscitation with a PEGylated Carboxyhemoglobin in a Rat Model of Severe Hemorrhagic Shock.

Hemorrhage is a leading cause of death from potentially survivable civilian and military trauma. As projected conflicts move from settings of tactical and logistical supremacy to hyper-dynamic tactical zones against peer and near-peer adversaries, protracted medical evacuation times are expected. Treatment at the point-of-injury is critical. Although crystalloids like Lactated Ringer's (LR) are ubiquitous, whole blood (WB) is the preferred resuscitation fluid following hemorrhage; however, logistical constraints limit the availability of WB in prehospital settings. Hemoglobin-based oxygen carriers (HBOCs) offer both hemodynamic support and oxygen-carrying capacity while avoiding logistical constraints of WB. We hypothesized that low-volume resuscitation of severe hemorrhagic shock with an HBOC (PEGylated carboxyhemoglobin, [PC]) would improve hemodynamic recovery and 72-hour survival; comparable to WB and superior to LR. A total of 21 anesthetized male Sprague-Dawley rats underwent severe hemorrhagic shock followed by randomly assigned low-volume resuscitation with LR, WB, or PC, and then recovered from anesthesia for up to 72-hour observation. Mean arterial pressure (MAP) was recorded continuously under anesthesia, and arterial blood gases were measured at baseline (BL), 60minutes post-hemorrhage (HS1h), and 24hours post-resuscitation (PR24h). Survival was presented on a Kaplan-Meier plot and significance determined with a log-rank test. Cardiovascular and blood gas data were assessed with one-way analysis of variance and post hoc analysis where appropriate. All measured cardiovascular and blood chemistry parameters were equivalent between groups at BL and HS1h. BL MAP values were 90±3, 86±1, and 89±2mmHg for LR, PC, and WB, respectively. Immediately following resuscitation, MAP values were 57±4, 74±5, and 62±3mmHg, with PC equivalent to WB and higher than LR (P<0.05). WB and LR were both lower than BL (P<0.0001), whereas PC was not (P=0.13). The PC group's survival to 72hours was 57%, which was not different from WB (43%) and higher than LR (14%; P<0.05). A single bolus infusion of PC produced superior survival and MAP response compared to LR, which is the standard fluid resuscitant carried by combat medics. PC was not different from WB in terms of survival and MAP, which is encouraging because its reduced logistical constraints make it viable for field deployment. These promising findings warrant further development and investigation of PC as a low-volume, early treatment for hemorrhagic shock in scenarios where blood products may not be available.

The impact of early administration of vasopressor agents for the resuscitation of severe hemorrhagic shock following blunt trauma

BackgroundWhen resuscitating patients with hemorrhagic shock following trauma, fluid volume restriction and permissive hypotension prior to bleeding control are emphasized along with the good outcome especially for penetrating trauma patients. However, evidence that these concepts apply well to the management of blunt trauma is lacking, and their use in blunt trauma remains controversial. This study aimed to assess the impact of vasopressor use in patients with blunt trauma in severe hemorrhagic shock.MethodsIn this single-center retrospective study, we reviewed records of blunt trauma patients with hemorrhagic shock and included patients with a probability of survival < 0.6. Vital signs on arrival, characteristics, examinations, concomitant injuries and severity, vasopressor use and dose, and volumes of crystalloids and blood infused were compared between survivors and non-survivors. Data are described as median (25–75% interquartile range) or number.ResultsForty patients admitted from April 2014 to September 2019 were included. Median Injury Severity Score in survivors vs non-survivors was 41 (36–48) vs 45 (34–51) (p = 0.48), with no significant difference in probability of survival between the two groups (0.22 [0.12–0.48] vs 0.21 [0.08–0.46]; p = 0.93). Despite no significant difference in patient characteristics and injury severity, non-survivors were administered vasopressors significantly earlier after admission and at significantly higher doses. Total blood transfusion amount administered within 24 h after admission was significantly higher in survivors (8430 [5680–9320] vs 6540 [4550–7880] mL; p = 0.03). Max catecholamine index was significantly higher in non-survivors (2 [0–4] vs 14 [10–18]; p = 0.008), and administered vasopressors were terminated significantly earlier (12 [4–26] vs 34 [10–74] hours; p = 0.026) in survivors.Although the variables of severity of the patients had no significant differences, vasopressor use (Odds ratio [OR] = 21.32, 95% confident interval [CI]: 3.71–121.6; p = 0.0001) and its early administration (OR = 10.56, 95%CI: 1.90–58.5; p = 0.005) indicated significant higher risk of death in this study.ConclusionVasopressor administration and high-dose use for resuscitation of hemorrhagic shock following severe blunt trauma are potentially associated with increased mortality. Although the transfused volume of blood products tends to be increased when resuscitating these patients, early termination of vasopressor had better to be considered.

Cold-stored Whole Blood: A Better Method of Trauma Resuscitation?

In the setting of trauma with hemorrhagic shock, balanced blood product resuscitation requires transfusing a high ratio of plasma and platelets to red blood cells. Multiple units of blood products must be transfused rapidly, each product is separately packaged, and each product has a different volume, preparation method, shelf-life, and availability. Despite limited initial data comparing whole blood (WB) to blood component therapy (BCT), recent military medicine shows both a survival benefit and safety of warm WB transfusion over component therapy. This has sparked a renewed interest in the practice of using cold-stored type-O WB (CWB) for resuscitation of hemorrhagic shock in the civilian setting. While recent studies have demonstrated benefits and safety when comparing type-specific and type-O CWB verses component therapy, they have not evaluated the acute resuscitative period. The purpose of this study was to report the impact of CWB on initial resuscitation.

Resuscitation with Hydroxyethyl Starch Maintains Hemodynamic Coherence in Ovine Hemorrhagic Shock.

Fluid resuscitation in hemorrhagic shock aims to restore hemodynamics and repair altered microcirculation. Hemodynamic coherence is the concordant performance of macro- and microcirculation. The present study on fluid therapy in hemorrhagic shock hypothesized that the choice of fluid (0.9% sodium chloride [saline group] or balanced 6% hydroxyethyl starch 130/0.4 [hydroxyethyl starch group]) impacts on hemodynamic coherence. After instrumentation, 10 sheep were bled up to 30 ml/kg body weight of blood stopping at a mean arterial pressure of 30 mmHg to establish hemorrhagic shock. To reestablish baseline mean arterial pressure, they received either saline or hydroxyethyl starch (each n = 5). Hemodynamic coherence was assessed by comparison of changes in mean arterial pressure and both perfused vessel density and microvascular flow index. Bleeding of 23 ml/kg blood [21; 30] (median [25th; 75th percentile]) in the saline group and 24 ml/kg [22; 25] (P = 0.916) in the hydroxyethyl starch group led to hemorrhagic shock. Fluid resuscitation reestablished baseline mean arterial pressure in all sheep of the hydroxyethyl starch group and in one sheep of the saline group. In the saline group 4,980 ml [3,312; 5,700] and in the hydroxyethyl starch group 610 ml [489; 615] of fluid were needed (P = 0.009). In hemorrhagic shock perfused vessel density (saline from 100% to 83% [49; 86]; hydroxyethyl starch from 100% to 74% [61; 80]) and microvascular flow index (saline from 3.1 [2.5; 3.3] to 2.0 [1.6; 2.3]; hydroxyethyl starch from 2.9 [2.9; 3.1] to 2.5 [2.3; 2.7]) decreased in both groups. After resuscitation both variables improved in the hydroxyethyl starch group (perfused vessel density: 125% [120; 147]; microvascular flow index: 3.4 [3.2; 3.5]), whereas in the saline group perfused vessel density further decreased (64% [62; 79]) and microvascular flow index increased less than in the hydroxyethyl starch group (2.7 [2.4; 2.8]; both P < 0.001 for saline vs. hydroxyethyl starch). Resuscitation with hydroxyethyl starch maintained coherence in hemorrhagic shock. In contrast, saline only improved macro- but not microcirculation. Hemodynamic coherence might be influenced by the choice of resuscitation fluid.

Itaconate modulates tricarboxylic acid and redox metabolism to mitigate reperfusion injury

ObjectivesCerebral ischemia/reperfusion (IR) drives oxidative stress and injurious metabolic processes that lead to redox imbalance, inflammation, and tissue damage. However, the key mediators of reperfusion injury remain unclear, and therefore, there is considerable interest in therapeutically targeting metabolism and the cellular response to oxidative stress. MethodsThe objective of this study was to investigate the molecular, metabolic, and physiological impact of itaconate treatment to mitigate reperfusion injuries in in vitro and in vivo model systems. We conducted metabolic flux and bioenergetic studies in response to exogenous itaconate treatment in cultures of primary rat cortical neurons and astrocytes. In addition, we administered itaconate to mouse models of cerebral reperfusion injury with ischemia or traumatic brain injury followed by hemorrhagic shock resuscitation. We quantitatively characterized the metabolite levels, neurological behavior, markers of redox stress, leukocyte adhesion, arterial blood flow, and arteriolar diameter in the brains of the treated/untreated mice. ResultsWe demonstrate that the “immunometabolite” itaconate slowed tricarboxylic acid (TCA) cycle metabolism and buffered redox imbalance via succinate dehydrogenase (SDH) inhibition and induction of anti-oxidative stress response in primary cultures of astrocytes and neurons. The addition of itaconate to reperfusion fluids after mouse cerebral IR injury increased glutathione levels and reduced reactive oxygen/nitrogen species (ROS/RNS) to improve neurological function. Plasma organic acids increased post-reperfusion injury, while administration of itaconate normalized these metabolites. In mouse cranial window models, itaconate significantly improved hemodynamics while reducing leukocyte adhesion. Further, itaconate supplementation increased survival in mice experiencing traumatic brain injury (TBI) and hemorrhagic shock. ConclusionsWe hypothesize that itaconate transiently inhibits SDH to gradually “awaken” mitochondrial function upon reperfusion that minimizes ROS and tissue damage. Collectively, our data indicate that itaconate acts as a mitochondrial regulator that controls redox metabolism to improve physiological outcomes associated with IR injury.

Impact of high-dose norepinephrine during intra-hospital damage control resuscitation of traumatic haemorrhagic shock: A propensity-score analysis

IntroductionThe use of norepinephrine (NE) during uncontrolled haemorrhagic shock (HS) has mostly been investigated in experimental studies. Clinical data including norepinephrine dose and its impact on fluid resuscitation and organ function are scarce. We hypothesized that there is great variability in NE use and that high doses of NE could lead to increased organ dysfunction as measured by the sequential organ failure assessment (SOFA). MethodWe included patients with HS (systolic blood pressure < 90 mmHg in severely injured patients) who required haemostasis surgery and a transfusion of more than 4 packed red blood cells (PRBC) in the first 6 h of admission and the used of norepinephrine infusion to maintain the blood pressure goal, between admission and the end of haemostasis surgery in a prospective trauma database. A ROC curve determined that, using Youden's criterion, a dose of NE ≥ 0.6 µg/kg/min was the optimal threshold associated with intrahospital mortality. Patients were compared according to this threshold in a propensity score (PS) model. In a generalized linear mixed model, we searched for independent factors associated with a SOFA ≥ 9 at 24 h ResultsA total of 89 patients were analysed. Fluid infusion rate ranged from 1.43 to 57.9 mL/kg/h and norepinephrine infusion rate from 0.1 to 2.8 µg/kg/min. The HDNE group received significantly less fluid than the LDNE group. This dose is associated with a higher SOFA score at 24h: 9 (7–10) vs. 7 (6–9) (p = 0.003). Factors independently associated with a SOFA score ≥ 9 at 24 h were maximal norepinephrine rate ≥ 0.6 µg/kg/min (OR 6.69, 95% CI 1.82 – 25.54; p = 0.004), non-blood resuscitation volume < 9 mL/kg/h (OR 3.98, 95% CI 1.14 – 13.95; p = 0.031) and lactate at admission ≥ 5 mmol/L (OR 5.27, 95% CI 1.48 – 18.77; p = 0.010) ConclusionHigh dose of norepinephrine infusion is associated with deleterious effects as attested by a higher SOFA score at 24 h and likely hypovolemia as measured by reduced non-blood resuscitation volume. We did not find any significant difference in mortality over the long term.

Abstract 218: Therapeutic Hypothermia Alone and Combination With Preconditioning Blunt Inflammation in Experimental Hemorrhagic Shock

Background: Recent studies by our group indicate that preconditioning, therapeutic hypothermia (TH) and TH combined with preconditioning improved long-term survival during resuscitation of hemorrhagic shock. The neutrophil-to-lymphocyte ratio (NLR) is a marker of inflammation associated with increased mortality in patients with severe hemorrhage shock. The aim of this study is to evaluate the effects of these three therapies on NLR level in rats with acute hemorrhagic shock. Methods and Results: In the preconditioning study, Sprague Dawley rats (both genders) were randomized to preconditioning (n=26) or control group (n=27); in the hypothermia study, rats were randomized to TH (n=16) or control group (n=15); in a combination study, rats were randomized to TH plus preconditioning (n=11) or control group (n=10). Rats were anesthetized with intraperitoneal Ketamine and xylazine. After heparinizing, hemorrhagic shock was induced by withdrawing blood to a fixed mean blood pressure (MBP) of 30 mmHg for 30 minutes and then shed blood was reinfused. Preconditioning was induced by 4 cycles of inflating small cuffs around the femoral arteries to 200 mmHg for 5 minutes, followed by 5-minute deflation of the cuffs prior to hemorrhagic shock. TH started at 5 minutes after MBP reached 30 mmHg. Core temperature was maintained at ~32 °C until blood volume was fully restored. In the control group, body temperature was maintained at ~ 37°C. Arterial blood samples were collected 1 hour after resuscitation. The NLR is an easily accessible biomarker, which is calculated by dividing the absolute neutrophil count by the absolute lymphocyte count. The NLR was significantly lower in TH group (0.20 ± 0.02) compared with the control group (0.32 ± 0.03; p=0.003). Similarly, the NLR level was significantly decreased in TH plus preconditioning group (0.19 ± 0.02) versus the control group (0.33 ± 0.02; p= 0.001). There was no difference in NLR level between the preconditioning group (0.41 ± 0.04) and the control group (0.41 ± 0.04; p=0.984). Conclusions: NLR is widely recognized inflammation marker associated with poor prognosis in severe hemorrhagic shock. TH alone and TH combined with preconditioning blunt the inflammation by decreasing the NLR level in experimental hemorrhagic shock.

Abstract 216: Therapeutic Hypothermia Alone and in Combination With Preconditioning Improves Long Term Survival During Resuscitation of Hemorrhagic Shock

Background: We investigated the effects of hypothermia treatment alone and in combination with experimental bilateral lower limb remote ischemic preconditioning (RIPC) in rats undergoing experimental hemorrhagic shock. Previously we showed that RIPC alone improved survival. Methods: In the hypothermia alone study, adult Sprague Dawley rats (both genders) were randomized to hypothermia (n=16) or control group (n=15); in a combination study, rats were randomized to hypothermia plus RIPC (n=11) or control group (n=10). Rats were anesthetized with intraperitoneal ketamine/xylazine. Therapeutic hypothermia (Thermosuit) was started at 5 minutes after mean blood pressure (MBP) reached 30 mmHg. Core temperature was maintained at ~ 32 °C until blood volume was fully restored. RIPC was induced by 4 cycles of inflating small bilateral pressure cuffs to 200 mmHg around the femoral arteries for 5 minutes, followed by 5 minute deflation of the cuffs prior to hemorrhagic shock. In the control group, body temperature was maintained at 37 °C during the procedure. Hemorrhagic shock was induced by withdrawing blood from the carotid artery. Target mean blood pressure of 30 mmHg was maintained for 30 minutes followed by reinfusion of shed blood within the next 30 min. Rats were allowed recovery and the primary endpoint was survival rate at 6 weeks. Results: In the setting of hypothermia alone, 4 of 15 (26.7 %) rats in the control group and 11 of 16 (68.8 %; p = 0.032) rats in the hypothermia group survived at 6 weeks. In the combination study, 1 of 10 (10 %) rats in the control group and 7 of 11 (63.6 %; p = 0.024) rats in the hypothermia plus RIPC group survived at 6 weeks. Kaplan Meier Survival Curves are shown in Fig1. Conclusions: Hypothermia alone and combination with RIPC significantly improved long term survival in rats subjected to hemorrhagic shock. Hypothermia and RIPC did not show survival rates greater than hypothermia alone.