Reduced Fluid Requirements Research Articles

25% HUMAN SERUM ALBUMIN IMPROVES HEMODYNAMICS AND PREVENTS THE NEED FOR NEARLY ALL PREHOSPITAL RESUSCITATION IN A RAT ( RATTUS NORVEGICUS ) MODEL OF TRAUMA AND HEMORRHAGE.

Combat casualty care can be complicated by transport times exceeding the "golden hour," with intervention and resuscitation limited to what the medic can carry. Pharmaceutical albumin comes highly saturated with nonesterified fatty acids (NEFAs). We recently showed that treatment with 25% bovine serum albumin (BSA) loaded with oleic acid, but not NEFA-free BSA, improved survival for hours after severe hemorrhage and often eliminated the need for resuscitation in rats. However, it was unknown whether pharmaceutical albumin, derived from human sources and loaded with caprylic acid (CA), would have the same benefits. We compared adjunct treatment with oleic acid-saturated BSA, CA-saturated BSA, pharmaceutical human serum albumin, or a no-albumin control in a similar rat hemorrhagic shock model to determine whether the three NEFA-albumin groups provided the same benefits relative to control. We found almost no significant differences among the NEFA-albumin groups in any measure. Mortality in controls was too low to allow for detection of improvement in survival, but NEFA-albumin groups had significantly improved hemodynamics, lactate clearance, and greatly reduced fluid requirements compared with controls. Contrary to expectations of "dehydration," 25% albumins shifted little additional fluid into the vasculature. Rather, they restored protein to the autotransfusion fluid. Nonesterified fatty acids-albumin did not worsen lung permeability, but we observed a loss of circulating protein suggesting it may have increased overall vascular permeability. Our findings suggest that, though imperfect, 25% human serum albumin could be a solution for resuscitation in austere conditions requiring prolonged field care.

Effects of chemokine (C-C motif) receptor 2 and 3 antagonists in rat models of hemorrhagic shock.

Systemic concentrations of chemokine CCL2, an agonist at chemokine receptors CCR2/3/5, have been associated with hemodynamic instability after traumatic-hemorrhagic shock. We reported previously that the CCR2 antagonist INCB3284 prevents cardiovascular collapse and reduces fluid requirements after 30min of hemorrhagic shock (HS), whereas the CCR5 antagonist Maraviroc was ineffective. The effects of CCR3 blockade after HS are unknown and information on the therapeutic potential of INCB3284 after longer periods of HS and in HS models in the absence of fluid resuscitation (FR) is lacking. The aims of the present study were to assess the effects of CCR3 blockade with SB328437 and to further define the therapeutic efficacy of INCB3284. In series 1-3, Sprague-Dawley rats were hemorrhaged to a mean arterial blood pressure (MAP) of 30mmHg, followed by FR to MAP of 60mmHg or systolic blood pressure of 90mmHg. Series 1: 30min HS and FR until t = 90min. SB328437 at t = 30min dose-dependently reduced fluid requirements by >60%. Series 2: 60min HS and FR until t = 300min. INCB3284 and SB328437 at t = 60min reduced fluid requirements by more than 65% (p<0.05 vs. vehicle) and 25% (p>0.05 vs. vehicle), respectively, until t = 220min. Thereafter, all animals developed a steep increase in fluid requirements. Median survival time was 290min with SB328437 and >300min after vehicle and INCB3284 treatment (p<0.05). Series 3: HS/FR as in series 2. INCB3284 at t = 60min and t = 200min reduced fluid requirements by 75% until t = 300min (p<0.05 vs. vehicle). Mortality was 70% with vehicle and zero with INCB3284 treatment (p<0.05). Series 4: INCB3284 and SB328437 did not affect survival time in a lethal HS model without FR. Our findings further support the assumption that blockade of the major CCL2 receptor CCR2 is a promising approach to improve FR after HS and document that the dosing of INCB3284 can be optimized.

Elamipretide mitigates ischemia-reperfusion injury in a swine model of hemorrhagic shock

ischemia-reperfusion injury (IRI) after hemorrhage is potentiated by aortic occlusion or resuscitative endovascular balloon occlusion of the aorta (REBOA). Given the central role of mitochondrial injury in shock, we hypothesized that Elamipretide, a peptide that protects mitochondria, would mitigate IRI after hemorrhagic shock and REBOA. Twelve pigs were subjected to hemorrhagic shock and 45 min of REBOA. After 25 min of REBOA, animals received either saline or Elamipretide. Animals were transfused with autologous blood during balloon deflation, and pigs were resuscitated with isotonic crystalloids and norepinephrine for 4.25 h. Elamipretide-treated animals required less crystalloids than the controls (62.5 [50–90] and 25 [5–30] mL/kg, respectively), but similar amounts of norepinephrine (24.7 [8.6–39.3] and 9.7 [2.1–12.5] mcg/kg, respectively). Treatment animals had a significant reduction in serum creatinine (control: 2.7 [2.6–2.8]; Elamipretide: 2.4 [2.4–2.5] mg/dL; p = 0.04), troponin (control: 3.20 [2.14–5.47] ng/mL, Elamipretide: 0.22 [0.1–1.91] ng/mL; p = 0.03), and interleukin-6 concentrations at the end of the study. There were no differences in final plasma lactate concentration. Elamipretide reduced fluid requirements and protected the kidney and heart after profound IRI. Further understanding the subcellular consequences of REBOA and mitochondrial rescue will open new therapeutic avenues for patients suffering from IRI after hemorrhage.

The Chemokine (C-C Motif) Receptor 2 Antagonist INCB3284 Reduces Fluid Requirements and Protects From Hemodynamic Decompensation During Resuscitation From Hemorrhagic Shock.

OBJECTIVES:Clinical correlations suggest that systemic chemokine (C-C motif) ligand (CCL) 2 release may contribute to blood pressure regulation and the development of hemodynamic instability during the early inflammatory response to traumatic-hemorrhagic shock. Thus, we investigated whether blockade of the principal CCL2 receptor chemokine (C-C motif) receptor (CCR) 2 affects blood pressure in normal animals, and hemodynamics and resuscitation fluid requirements in hemorrhagic shock models.DESIGN:Randomized prospective treatment study.SETTING:University laboratory.SUBJECTS:Male Sprague-Dawley rats.INTERVENTIONS:First, treatment of healthy anesthetized rats with increasing doses of INCB3284 or vehicle. Second, rats were hemorrhaged for 30 minutes, followed by treatment with the CCR2 antagonist INCB3284 (1.1 and 5.5 μmol/kg), the CCR5 antagonist Maraviroc (=control, 5.5 μmol/kg) or vehicle, and subsequent fluid resuscitation to maintain blood pressure until t = 90 minutes. Third, treatment of rats with 5 μmol/kg INCB3284 or vehicle after hemorrhage and fluid resuscitation until t = 300 minutes.MEASUREMENTS AND MAIN RESULTS:INCB3284 did not affect intrinsic function of isolated rat resistance arteries in pressure myography experiments. Blood pressure in anesthetized vehicle-treated animals continuously decreased by 0.09 ± 0.01 mm Hg/min (p < 0.001) but remained constant after INCB3284 injections. Systemic concentrations of the CCR2 agonists CCL2, CCL5, and CCL11 increased during hemorrhage and fluid resuscitation. INCB3284 dose-dependently reduced fluid requirements by 58% ± 11% in short-term experiments, whereas Maraviroc and vehicle-treated animals were indistinguishable. When resuscitation was performed until t = 300 minutes, INCB3284 reduced fluid requirements by 62% ± 6%, prevented from hemodynamic decompensation, reduced mortality from 50% with vehicle treatment to zero, and reduced overall tissue wet-weight/dry-weight ratios.CONCLUSIONS:Our findings suggest that CCR2 is involved in the regulation of normal cardiovascular function and during the cardiovascular stress response to hemorrhagic shock and fluid resuscitation. The present study identifies CCR2 as a drug target to reduce fluid requirements and to prevent death from hemodynamic decompensation during resuscitation from hemorrhagic shock.

Choice of Whole Blood versus Lactated Ringer's Resuscitation Modifies the Relationship between Blood Pressure Target and Functional Outcome after Traumatic Brain Injury plus Hemorrhagic Shock in Mice.

Civilian traumatic brain injury (TBI) guidelines recommend resuscitation of patients with hypotensive TBI with crystalloids. Increasing evidence, however, suggests that whole blood (WB) resuscitation may improve physiological and survival outcomes at lower resuscitation volumes, and potentially at a lower mean arterial blood pressure (MAP), than crystalloid after TBI and hemorrhagic shock (HS). The objective of this study was to assess whether WB resuscitation with two different MAP targets improved behavioral and histological outcomes compared with lactated Ringer's (LR) in a mouse model of TBI+HS. Anesthetized mice (n = 40) underwent controlled cortical impact (CCI) followed by HS (MAP = 25-27 mm Hg; 25 min) and were randomized to five groups for a 90 min resuscitation: LR with MAP target of 70 mm Hg (LR70), LR60, WB70, WB60, and monitored sham. Mice received a 20 mL/kg bolus of LR or autologous WB followed by LR boluses (10 mL/kg) every 5 min for MAP below target. Shed blood was reinfused after 90 min. Morris Water Maze testing was performed on days 14-20 post-injury. Mice were euthanized (21 d) to assess contusion and total brain volumes. Latency to find the hidden platform was greater versus sham for LR60 (p < 0.002) and WB70 (p < 0.007) but not LR70 or WB60. The WB resuscitation did not reduce contusion volume or brain tissue loss. The WB targeting a MAP of 60 mm Hg did not compromise function versus a 70 mm Hg target after CCI+HS, but further reduced fluid requirements (p < 0.03). Using LR, higher achieved MAP was associated with better behavioral performance (rho = -0.67, p = 0.028). Use of WB may allow lower MAP targets without compromising functional outcome, which could facilitate pre-hospital TBI resuscitation.

Linopirdine-supplemented resuscitation fluids reduce mortality in a model of ischemia-reperfusion injury induced acute respiratory distress syndrome.

Previously, we demonstrated that supplementation of resuscitation fluids with the Kv7 voltage-activated potassium channel inhibitor linopirdine reduces fluid resuscitation requirements and stabilizes hemodynamics in various rat models of hemorrhagic shock. To further evaluate the therapeutic potential of linopirdine, we tested the effects of linopirdine-supplemented resuscitation fluids in a rat model of ischemia-reperfusion injury-induced acute respiratory distress syndrome (ARDS). Ventilated rats underwent unilateral lung ischemia from t=0-75 min, followed by lung reperfusion and fluid resuscitation to a mean arterial blood pressure of 60 mmHg with normal saline (NS, n=9) or NS supplemented with 50 µg/ml linopridine (NS-L), n=7) until t=360 min. As compared with NS, fluid resuscitation with NS-L stabilized blood pressure and reduced fluid requirements by 40% (p<0.05 vs. NS at t=240-360 min). While NS-L did not affect ARDS development, it reduced mortality from 66% with NS to 14% with NS-L (p=0.03, hazard ratio 0.14; 95% confidence interval of the hazard ratio: 0.03-0.65). Median survival time was 240 min with NS and >360 min with NS-L. As compared with NS treated animals that survived the observation period (n=3), however, plasma lactate and creatinine concentrations at t=360 min were higher with NS-L (n=6; p<0.05). Our findings extend therapeutic potential of NS-L from hypovolemic/hemorrhagic shock to hemodynamic instability under normovolemic conditions during organ ischemia-reperfusion injury. Possible adverse effects of NS-L, such as impairment of renal function and/or organ hypoperfusion, require further evaluation in long-term pre-clinical models.

Natural and engineered chemokine (C-X-C motif) receptor 4 agonists prevent acute respiratory distress syndrome after lung ischemia\u2013reperfusion injury and hemorrhage

We compared therapeutic properties of natural and engineered chemokine (C-X-C motif) receptor 4 (CXCR4) agonists in a rat acute respiratory distress syndrome (ARDS) model utilizing the PaO2/FiO2-ratio as a clinically relevant primary outcome criterion. Ventilated rats underwent unilateral lung ischemia from t = 0–70 min plus hemorrhage to a mean arterial blood pressure (MAP) of 30 mmHg from t = 40–70 min, followed by reperfusion/fluid resuscitation until t = 300 min. Natural CXCR4 agonists (CXCL12, ubiquitin) and engineered CXCL12 variants (CXCL121, CXCL22, CXCL12K27A/R41A/R47A, CXCL12 (3–68)) were administered within 5 min of fluid resuscitation. Animals treated with vehicle or CXCL12 (3–68) reached criteria for mild and moderate ARDS between t = 90–120 min and t = 120–180 min, respectively, and remained in moderate ARDS until t = 300 min. Ubiquitin, CXCL12, CXCL121 and CXCL122 prevented ARDS development. Potencies of CXCL12/CXCL121/CXCL122 were higher than the potency of ubiquitin. CXCL12K27A/R41A/R47A was inefficacious. CXCL121 > CXCL12 stabilized MAP and reduced fluid requirements. CXCR4 agonists at doses that preserved lung function reduced histological injury of the post-ischemic lung and reduced mortality from 55 to 9%. Our findings suggest that CXCR4 protein agonists prevent development of ARDS and reduce mortality in a rat model, and that development of new engineered protein therapeutics with improved pharmacological properties for ARDS is possible.

Fatty Acid-Saturated Albumin Reduces High Mortality and Fluid Requirements in a Rat Model of Hemorrhagic Shock Plus Tourniquet and Hypotensive Resuscitation.

Military prehospital care for hemorrhage is often characterized by use of tourniquets (TQ) and permissive hypotensive resuscitation (PHR) with crystalloids or colloids, but these treatments have not been previously combined in an animal model. Although albumin resuscitation solutions have been tested, the potential effects of nonesterified fatty acids (NEFAs) bound to albumin have not been evaluated in vivo, and few studies have investigated concentrated albumin solutions to reduce fluid requirements. We created a militarily relevant rat model of trauma and hemorrhagic shock (T/HS) (27 mL/kg hemorrhage) with TQ and PHR. We investigated the ability of resuscitation with concentrated (250 mg/mL) albumin, followed by Plasmalyte as needed to maintain PHR, to reduce fluid volumes (vs. Plasmalyte alone, N = 17). Albumin was free of nonesterified fatty acids (N = 15) or saturated with oleic acid (OA; N = 13). The model resulted in high (53%) mortality within 3 h of injury. Only OA-saturated albumin was able to significantly reduce mortality (from 47% to 8%) and fluid requirements (from 56 to 6 mL/kg) compared to Plasmalyte alone. Plasma NEFA-binding capacity was saturated earliest in the OA-saturated albumin group. Likewise, OA-saturated albumin tended to increase cell-free hemoglobin in the broncheoalveolar lavage fluid, which was significantly associated with survival. Our findings suggest incorporating TQ and PHR in T/HS models may result in high mortality and fluid requirements and that OA-saturated albumin, but not NEFA-free albumin or Plasmalyte alone, may provide a benefit to early survival and resuscitation volume, though a hemolytic mechanism may have later consequences, so caution is advised.

Effects of the Kv7 voltage-activated potassium channel inhibitor linopirdine in rat models of haemorrhagic shock.

Recently, we demonstrated that Kv7 voltage-activated potassium channel inhibitors reduce fluid resuscitation requirements in short-term rat models of haemorrhagic shock. The aim of the present study was to further delineate the therapeutic potential and side effect profile of the Kv7 channel blocker linopirdine in various rat models of severe haemorrhagic shock over clinically relevant time periods. Intravenous administration of linopirdine, either before (1 or 3mg/kg) or after (3mg/kg) a 40% blood volume haemorrhage, did not affect blood pressure and survival in lethal haemorrhage models without fluid resuscitation. A single bolus of linopirdine (3mg/kg) at the beginning of fluid resuscitation after haemorrhagic shock transiently reduced early fluid requirements in spontaneously breathing animals that were resuscitated for 3.5hours. When mechanically ventilated rats were resuscitated after haemorrhagic shock with normal saline (NS) or with linopirdine-supplemented (10, 25 or 50μg/mL) NS for 4.5hours, linopirdine significantly and dose-dependently reduced fluid requirements by 14%, 45% and 55%, respectively. Lung and colon wet/dry weight ratios were reduced with linopirdine (25/50μg/mL). There was no evidence for toxicity or adverse effects based on measurements of routine laboratory parameters and inflammation markers in plasma and tissue homogenates. Our findings support the concept that linopirdine-supplementation of resuscitation fluids is a safe and effective approach to reduce fluid requirements and tissue oedema formation during resuscitation from haemorrhagic shock.

High-Dose Ascorbic Acid for Burn Shock Resuscitation May Not Improve Outcomes

High dose ascorbic acid (HDAA) has been touted to ameliorate inflammation and reduce fluid requirements during burn shock resuscitation (BSR). Whether this leads to improved outcomes is not known. The authors' aim for this study was to compare ventilator days, ventilator-associated pneumonia, and mortality between patients who did and did not receive HDAA during BSR.The authors performed a retrospective case control study from 2012 to 2015. They identified 38 patients (HDAA) who received HDAA during BSR. Using age and %TBSA, the authors identified and matched 42 control patients (CTL) who did not receive HDAA for BSR during that same time period. The authors collected data for age, %TBSA, hospital days (LOS), ventilator days (VENT), inhalation injury (INH), ventilator-associated pneumonia (VAP), and mortality (MORT).There were no differences in age and %TBSA or %TBSA of third-degree burn injury between groups. There was no significant difference in the incidence of INH (HDAA-52% vs CTL-36%, P = .17) and the groups had similar LOS and VENT. Additionally, there was no significant difference in VAP incidence (HDAA-29% vs CTL-14%, P = .13) or mortality (HDAA-26% vs CTL-23%, P = .8). HDAA patients had a numerically higher incidence of acute renal failure requiring dialysis (23 vs 7%, P = .06) which was confirmed in a multivariate analysis (odds ratio 5.4; 95% confidence interval 1.1-26). HDAA, while potentially reducing inflammation and fluid requirements during BSR, may not improve any meaningful outcomes such as ventilator requirements, ventilator-associated pneumonia, and mortality.

Treatment of severe cholera: a review of strategies to reduce stool output and volumes of rehydration fluid.

Severe cholera is a life-threatening illness of hypovolemic shock and metabolic acidosis due to rapid and profuse diarrheal fluid loss. Emergency life-saving therapy is i.v. saline, optionally supplemented with potassium and alkali to correct the fluid deficit, potassium losses and acidosis. After this initial rehydration, for the next 2 days ongoing stool losses are replaced with oral rehydration solution (ORS), which contains sodium chloride, potassium and alkali together with glucose or rice powder as a source of glucose to serve as a carrier for sodium. In actual field trials, antibiotics are given to reduce fluid requirements, but large volumes averaging about 7 liters of i.v. fluid followed by about 14 liters of ORS have been given to adult patients. Disturbing trends during therapy have included overhydration, hyponatremia and polyuria. It is suggested that stool output and fluid requirements could be reduced, if borne out in future research, by avoiding overhydration by restricting ORS intake to match stool output and promoting intestinal reabsorption of luminal fluid by early introduction of glucose without salts into the intestine, more gradual correction of dehydration, giving mineralocorticoid and vasopressin, and infusing glucose or short-chain fatty acids into the proximal colon.

Xuebijing injection treatment inhibits vasopermeability and reduces fluid requirements in a canine burn model

High vasopermeability and excessive inflammation following severe burns may result in tissue edema, organ dysfunction and the loss of circulatory plasma volume, which can influence the doctor to do the prognosis to the patients. The study aims to examine whether Xuebijing injection (XBJ), an extracts of a traditional Chinese medicine used to treat sepsis in clinic, can reduces fluid requirements by inhibiting vasopermeability and tissue edema in a canine model after burn injury. Twenty-four beagle dogs were subjected to 50% TBSA burns, and then were randomly allocated to the following three groups: lactated Ringer's resuscitation (LR) group (n=8), immediate LR containing Xuebijing injection (LR/XBJ) group (n=8), and operation control group (n=8). Hemodynamic variables and net fluid accumulation were measured. Blood samples were collected for measurement of hematocrit and circulatory plasma volume (PV). At 24h after burn injury, heart, lung, small intestine and kidney were harvested for evaluation of the activities of myeloperoxidase (MPO) and neutrophil elastase (NE), vasopermeability, tissue water content and the amount of neutrophil infiltration. XBJ treatment significantly reduced net fluid accumulation, and pulmonary vascular permeability index (PVPI), extravascular lung water index (ELWI), and water content of heart, small intestine, kidney and lung compared with LR group. Furthermore, XBJ infusion significantly reduced tissue activities of MPO and NE compared with LR group. The amount of neutrophil infiltration in LR/XBJ group was lower than that in LR group. These results indicate that XBJ injection can reduce fluid requirements by inhibition of neutrophil protease-induced high vasopermeability and tissue edema.

Outcomes associated with stroke volume variation versus central venous pressure guided fluid replacements during major abdominal surgery.

Background and Aims:There is limited data on the impact of perioperative fluid therapy guided by dynamic preload variables like stroke volume variation (SVV) on outcomes after abdominal surgery. We studied the effect of SVV guided versus central venous pressure (CVP) guided perioperative fluid administration on outcomes after major abdominal surgery.Material and Methods:Sixty patients undergoing major abdominal surgeries were randomized into two equal groups in this prospective single blind randomized study. In the standard care group, the CVP was maintained at 10-12 mmHg while in the intervention group a SVV of 10% was achieved by the administration of fluids. The primary end-points were the length of Intensive Care Unit (ICU) and hospital stay. The secondary end points were intraoperative lactate, intravenous fluid use, requirement for inotropes, postoperative ventilation and return of bowel function.Results:The ICU stay was significantly shorter in the intervention group as compared to the control group (2.9 ± 1.15 vs. 5.4 ± 2.71 days). The length of hospital stay was also shorter in the intervention group, (9.9 ± 2.68 vs. 11.96 ± 5.15 days) though not statistically significant. The use of intraoperative fluids was significantly lower in the intervention group than the control group (7721.5 ± 4138.9 vs. 9216.33 ± 2821.38 ml). Other secondary outcomes were comparable between the two groups.Conclusion:Implementation of fluid replacement guided by a dynamic preload variable (SVV) versus conventional static variables (CVP) is associated with lesser postoperative ICU stay and reduced fluid requirements in major abdominal surgery.

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.

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.

Adenocaine and Mg2+ reduce fluid requirement to maintain hypotensive resuscitation and improve cardiac and renal function in a porcine model of severe hemorrhagic shock*

Hypotensive resuscitation is gaining clinical acceptance in the treatment of hemorrhagic shock. Our aims were to investigate: 1) the effect of 7.5% NaCl with adenocaine (adenosine and lidocaine, AL) and AL with Mg (ALM) on fluid requirement to maintain a minimum mean arterial pressure of 50 mm Hg, and 2) the effect of a second bolus of 0.9% NaCl with AL during return of shed blood on cardiac and renal function in a porcine model of hemorrhagic shock. Pigs were randomized to: Sham (n = 5), Sham + ALM/AL (n = 5), hemorrhage control (n = 11), or hemorrhage + ALM/AL (n = 9). Hemorrhage animals were bled to a mean arterial pressure of 35 mm Hg. After 90 mins, pigs were fluid resuscitated with Ringers acetate and 20 mL 7.5% NaCl with ALM to maintain a target mean arterial pressure of minimum 50 mm Hg. Shed blood and 0.9% NaCl with AL were infused 30 mins later. Hemorrhage control group was subjected to the same protocol but without ALM/AL. Hemodynamics, cardiodynamics (pressure-volume analysis), oxygen consumption, and kidney function were measured for 6 hrs. University hospital laboratory. Female farm-bred pigs. Fluid volume infused during hypotensive resuscitation was 40% less in the 7.5% NaCl-/ALM-treated pigs than controls (25 vs. 41 mL/kg, p < .05). ALM was associated with a significant increase in dp/dtmax, end-systolic blood pressure, and systemic vascular resistance. Return of shed blood and 0.9% NaCl/AL reduced whole body oxygen consumption by 27% (p < .05), and significantly improved the end-systolic pressure-volume relationship and preload recruitable stroke work compared to controls. Glomerular filtration rate in the ALM/AL group returned to 83% of baseline compared to 54% in controls (p = .01). Resuscitation with 7.5% NaCl ALM increases cardiac function and reduces fluid requirements during hypotensive resuscitation, whereas a second AL infusion during blood resuscitation transiently reduces whole body oxygen consumption and improves cardiac and renal function.

Hypothermia reduces resuscitation fluid volumes required to maintain blood pressure in a rat hemorrhagic shock model

To examine the hypothesis that resuscitative hypothermia would (1) reduce fluid requirements and reactive oxygen species production during a period of resuscitation and (2) improve survival after hemorrhagic shock (HS) in rats. Sixteen rats underwent an HS phase (phase I: 0-75 minutes), with pressure-controlled HS at a mean arterial pressure of 30 mm Hg ± 5 mm Hg; a resuscitation phase (phase II: 75-150 minutes), with fluid resuscitation to maintain mean arterial pressure ≥75 mm Hg; and an observation phase (phase III: from 150 minutes to 72 hours). During phase II, eight rats were randomized into a normothermia group (group 1: 38°C) or a hypothermia group (group 2: 34°C). Fluid requirements during phase II and survival at 72 hours were compared between groups. Plasma levels of Vitamin E and %coenzyme Q9 (%CoQ9) were also assessed. The fluid requirement during resuscitation in phase II was 8.2 ± 1.4 mL/100 g in group 1 versus 2.1 mL/100 g ± 0.7 mL/100 g in group 2 (p < 0.01). Vitamin E level decreased to 10.8 μmol/L ± 1.8 μmol/L during HS in all rats. After resuscitation, it was restored to a baseline level of 15.9 μmol/L ± 3.1 μmol/L in group 2 but remained at 10.2 μmol/L ± 0.8 μmol/L in group 1 (p < 0.05). %CoQ9 did not differ significantly between the groups. At 72 hours, six of eight rats in group 1, and all rats in group 2 survived (NS). In a rat HS model, hypothermia during resuscitation from HS reduces resuscitation fluid volume required to maintain blood pressure and restores Vitamin E to the baseline level, and appears to have no adverse impact on long survival after HS.

Abstract 4: Resuscitation with Adenocaine and Magnesium Reduces Fluid Requirement and Improves Cardiac Function Following 72% Blood Loss in the Pig

Introduction: Fluid therapy following severe hemorrhagic shock triggers ischemia-reperfusion (I/R) injury and multi-organ dysfunction. The combination of adenocaine (adenosine and lidocaine), and Mg2+ (ALM) has been shown to stabilize cardiac function and hemodynamics after myocardial I/R. Hypothesis: ALM in 7.5%NaCl at resuscitation: 1) reduces fluid requirements during permissive hypotension and 2) improves post-resuscitation cardiac function. Methods: Pigs (38kg) were randomized to: Sham (n=5), Sham + ALM (n=5), hemorrhage (n=11), and hemorrhage + ALM (n=9). Animals were subjected to pressure controlled hemorrhage at a target MAP of 35mmHg. After 90 min Ringers acetate and 20ml 7.5% NaCl ± ALM (Adenosine 0.23 mg/kg; Lidocaine 0.64 mg/kg; Mg2+ 0.4 mg/kg) was infused to maintain a target MAP of 50 mmHg (permissive hypotension). After 30min 75% of the shed blood was re-infused ± ALM (Adenosine 0.82 mg/kg; Lidocaine 1.66 mg/kg) and the pigs were observed for 6 hrs. Cardiac function was evaluated by pressure-volume (P-V) analysis. Results: In the ALM group 40% less fluid was required to maintain a MAP of 50mmHg for 30min (hemorrhage: 41.5ml/kg CI: 27.7-61.8 vs. ALM: 24.7ml/kg CI:19.4-31.5*). During permissive hypotension 7.5% NaCl ALM significantly increased end-systolic pressure by 27% (hemorrhage: 70 mmHg ± 3 vs. ALM: 89 mmHg ± 9*) and cardiac contractility by 64% (dP/dtmax) (hemorrhage: 2622 mmHg/sec ± 331 vs. ALM: 4301 mmHg/sec ± 262*). Treatment with ALM at blood infusion reduced whole body O2 consumption by 27% lasting 30 min into infusion (group difference p&lt;0.05). In addition, systolic function after blood reinfusion, evaluated by the end-systolic P-V relationship and preload recruitable stroke work, was significantly improved in ALM vs. hemorrhage. Furthermore, ALM enhanced relaxation (dP/dtmin) during reperfusion (hemorrhage: -1578 mmHg/sec ± 103 vs. ALM -2178 mmHg/sec ± 189*). Conclusion: 7.5% NaCl ALM reduced fluid requirements by 40% during permissive hypotension, improved cardiac function and reduced total body O2 consumption following severe hemorrhage. Administration of ALM is effective in minimizing fluid requirements and I/R injury following hemorrhage. (* p&lt;0.05)

Hemodynamic support of the trauma patient

The aim of this review is to address and summarize some key issues and recent insights into the hemodynamic support of the trauma patient related to fluid administration. Colloids are not superior to crystalloids in treating hypovolemia in the trauma patient and show no survival benefit. Furthermore, several adverse effects (renal failure, bleeding complications and anaphylaxis) have been reported with the use of artificial colloids. Hypertonic saline is effective and well tolerated in the treatment of hypovolemic shock and traumatic brain injury. Potential benefits are reduced fluid requirements and immune modulation. Resuscitation strategies should depend on the type of injury (penetrating vs. blunt; concomitant brain injury). Excessive fluid resuscitation, which can cause acute respiratory distress syndrome, abdominal compartment syndrome and brain edema, should be avoided. Dynamic parameters to guide volume therapy are probably more reliable than static parameters and minimally invasive techniques to monitor the microcirculation are becoming more important to determine the endpoints of resuscitation. Hemodynamic support is an early goal in the treatment of the trauma patient. The use of crystalloids is currently recommended in trauma resuscitation. The amount of fluid we give should be tailored to the individual trauma patient in which clear endpoints of resuscitation are of vital importance to maximize the chances of survival.

POLOXAMER 188 PROLONGS SURVIVAL OF HYPOTENSIVE RESUSCITATION AND DECREASES VITAL TISSUE INJURY AFTER FULL RESUSCITATION

Hypotensive resuscitation prolongs survival of patients with severe bleeding until they can undergo hemorrhage control. However, its value is limited by continuing ischemic injury. Purified poloxamer 188 (P188), a copolymer with rheological and cytoprotective activities, was known to reduce mortality of hemorrhagic shock when used as an adjunct to full resuscitation with fresh whole blood and crystalloid. Studies were undertaken to determine if it could prolong survival and reduce reperfusion injury during prolonged hypotensive resuscitation when added to the best regimen currently available. Unanesthetized rats were bled to a MAP of 30 mmHg for 30 min under computer control. They then received hypotensive resuscitation with Hextend or Hextend + P188 to maintain a MAP of 60 mmHg until death. Poloxamer 188 improved autoresuscitation, reduced fluid requirements, and increased the survivable duration of hypotensive resuscitation by more than 3 h (P < 0.01). Additional studies assessed tissue damage after shock and hypotensive resuscitation with Hextend followed by full resuscitation with crystalloid. In these studies, P188 blunted the no-reflow phenomenon and largely prevented myocardial injury, pulmonary inflammation, small bowel damage, renal tubular necrosis, hepatic central lobular necrosis, and apoptosis of splenic germinal centers that occurred during full resuscitation. Additional studies demonstrated that P188 increased survival from 0% to 75% in 50% volume-controlled hemorrhage (P < 0.001). Finally, P188 did not increase bleeding in uncontrolled hemorrhage produced by 75% tail amputation. Because P188 prolongs survival, decreases fluid requirements, and reduces tissue damage, it deserves further consideration as an adjunct to hypotensive resuscitation.