Search

Background: Mechanisms underlying hemodynamic disturbance in hemorrhagic shock are not completely understood. Transient receptor potential vanilloid 1-expressing afferents are involved in hemorrhagic shock pathology, and transient receptor potential vanilloid 1 antagonist, capsazepine, acts on the central nervous system to improve mortality in a rat hemorrhagic shock model. In contrast, transient receptor potential vanilloid 1-positive efferents promote vasoactive reactions through the release of neuropeptides, including calcitonin gene-related peptides. This study aimed to investigate whether transient receptor potential vanilloid 1-positive peripheral sensory efferents are involved in hemodynamic responses after hemorrhagic shock., Methods: Male rats underwent hemorrhagic shock (mean arterial pressure 30 mm Hg for 90 min, followed by resuscitation for 30 min) and received capsazepine (5 μM/kg) 30 min after shock induction. A separate cohort of rats subjected to hemorrhagic shock received hCGRP 8-37 (300 μg/kg), a calcitonin gene-related peptide receptor antagonist, at 30, 60, or 90 minutes after shock induction. The 24-hour survival rate, mean arterial pressure, heart rate, arterial blood gas, and plasma calcitonin gene-related peptide levels were measured. Tissue blood flow and oxygenation both in the mesentery and skeletal muscle were also assessed., Results: Capsazepine treatment prevented the hemorrhagic shock-induced increase in plasma calcitonin gene-related peptide levels, and hCGRP 8-37 treatment improved the 24-h survival rates after hemorrhagic shock at a time-dependent manner. The hCGRP 8-37 - or capsazepine-treated rats exhibited tissue oxygenation and metabolic conditions comparable to those in control rats at the end of the experiment., Conclusion: Transient receptor potential vanilloid 1 plays a crucial role in hemodynamic responses to hemorrhagic shock, partly via calcitonin gene-related peptide release, involved in its peripheral sensory-efferent functions. The hCGRP 8-37 appears to improve peripheral circulatory failure, which may be useful as adjunct treatment after hemorrhagic shock., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Severe injury can lead to immune dysfunction and predispose patients to infection and death. Micro-RNAs regulate gene expression and may act as biomarkers for susceptibility to infection. The aim of this study was to examine the temporal and differential expression of previously identified dysregulated micro-RNAs in patients with severe injury., Methods: Fourteen severely injured patients requiring transfusion were enrolled prospectively in this study approved by our institutional review board. Inclusion criteria consisted of adult patients deemed clinically to be in hemorrhagic shock necessitating transfusion in the acute phase of their injury care. Peripheral blood samples were obtained after admission to the surgical intensive care unit and again at 6, 12, 24, and 48 hours after admission. The samples obtained at arrival to the intensive care unit and 24 and 48 hours later were analyzed in this data set. Fourteen healthy volunteers served as controls. The 10 dysregulated micro-RNAs identified in a prior study at the 12-hour time point and important genes in innate immunity were measured using quantitative reverse transcription-polymerase chain reaction., Results: The participants were 21-77 years old (median, 42), 78% were male, and their Injury Severity Score ranged from 11 to 43 (median, 27); 11 had blunt and 3 had penetrating injuries. Three were intubated and 5 had received blood products before arrival at the hospital. Base deficit on hospital admission was 3-20 (median, 9). All patients required blood transfusion secondary to blood loss sustained during injury. Eleven of the 14 patients went directly to the operating room from the emergency department for control of the source of hemorrhage. Survival to discharge was 93%. Seven patients developed infection. Compared with healthy controls, miR-106a was downregulated at all time points compared with controls (P < .05). miR-618 was upregulated in initial blood draws (P < .05) and at 24 and 48 hours (P < .06). Tumor necrosis factor α and human leukocyte antigen-DR (HLA-DR) were downregulated, and interleukin-10 and PD-L1 were upregulated (P < .05). In patients who developed infection, miR-106a levels appeared more downregulated than those who did not develop infection., Conclusion: miR-106a was downregulated in trauma patients after major injury for up to 48 hours after intensive care unit admission. Tumor necrosis factor α and interleukin-10 are targeted by miR-106a, which are regulators of the immune response. Manipulation of micro-RNA expression may be a therapeutic target for immune dysfunction., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Propranolol has been shown previously to restore bone marrow function and improve anemia after lung contusion/hemorrhagic shock. We hypothesized that daily clonidine administration would inhibit central sympathetic outflow and restore bone marrow function in our rodent model of lung contusion/hemorrhagic shock with chronic stress., Methods: Male Sprague-Dawley rats underwent 6 days of restraint stress after lung contusion/hemorrhagic shock during which the animals received clonidine (75 μg/kg) after the restraint stress. On postinjury day 7, we assessed urine norepinephrine, blood hemoglobin, plasma granulocyte colony stimulating factor, and peripheral blood mobilization of hematopoietic progenitor cells, as well as bone marrow cellularity and erythroid progenitor cell growth., Results: The addition of clonidine to lung contusion/hemorrhagic shock with chronic restraint stress significantly decreased urine norepinephrine levels, improved bone marrow cellularity, restored erythroid progenitor colony growth, and improved hemoglobin (14.1 ± 0.6 vs 10.8 ± 0.6 g/dL). The addition of clonidine to lung contusion/hemorrhagic shock with chronic restraint stress significantly decreased hematopoietic progenitor cells mobilization and restored granulocyte colony stimulating factor levels., Conclusion: After lung contusion/hemorrhagic shock with chronic restraint stress, daily administration of clonidine restored bone marrow function and improved anemia. Alleviating chronic stress and decreasing norepinephrine is a key therapeutic target to improve bone marrow function after severe injury., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Introduction: Systemic hyperfibrinolysis (accelerated clot degradation) and fibrinolysis shutdown (impaired clot degradation) are associated with increased mortality compared with physiologic fibrinolysis after trauma. Animal models have not reproduced these changes. We hypothesize rodents have a shutdown phenotype that require an exogenous profibrinolytic to differentiate mechanisms that promote or inhibit fibrinolysis., Methods: Fibrinolysis resistance was assessed by thrombelastography (TEG) using exogenous tissue plasminogen activator (tPA) titrations in whole blood. There were 3 experimental groups: (1) tissue injury (laparotomy/bowel crush), (2) shock (hemorrhage to mean arterial pressure of 20 mmHg), and (3) control (arterial cannulation and tracheostomy). Baseline and 30-minute postintervention blood samples were collected, and assayed with TEG challenged with taurocholic acid (TUCA)., Results: Rats were resistant to exogenous tPA; the percent clot remaining 30 minutes after maximum amplitude (CL30) at 150 ng/mL (P = .511) and 300 ng/mL (P = .931) was similar to baseline, whereas 600 ng/mL (P = .046) provoked fibrinolysis. Using the TUCA challenge, the percent change in CL30 from baseline was increased in tissue injury compared with control (P = .048.), whereas CL30 decreased in shock versus control (P = .048). tPA increased in the shock group compared with tissue injury (P = .009) and control (P = .012)., Conclusion: Rats have an innate fibrinolysis shutdown phenotype. The TEG TUCA challenge is capable of differentiating changes in clot stability with rats undergoing different procedures. Tissue injury inhibits fibrinolysis, whereas shock promotes tPA-mediated fibrinolysis., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: Severe injury initiates an inflammatory response that can perpetuate immunological dysfunction, uncontrolled inflammation, and subsequent multisystem organ failure. MicroRNAs (miRNAs) have recently been identified as regulators of this inflammatory response. Our study sought to identify the differential expression of unique miRNAs and their correlations with genes of the Toll-like receptor (TLR) pathways, and clinical parameters in the severely injured., Methods: Fourteen trauma patients requiring transfusion were prospectively enrolled in this institutional review board-approved study. Inclusion criteria consisted of adult patients deemed clinically to be in hemorrhagic shock necessitating transfusion in the acute phase of their injury care. Peripheral blood samples were obtained after admission to the surgical intensive care unit. Expression of circulating mature miRNA from each patient, as well as from 10 healthy, age-matched controls, was determined and compared using the HiSeq 2500 sequencing system and the R software system. Gene expression of TLR signaling pathways for each patient was examined using custom gene expression polymerase chain reaction arrays. Statistical analyses were performed using general linear models and empirical Bayes methods to determine differential expression and Spearman's nonparametric correlation analysis., Results: Subjects were 21-77 years old (mean, 42), 80% male, Injury Severity Score 11-43 (mean, 26), with 11 blunt and 3 penetrating injuries. Three were intubated and 5 received blood products before arrival. Base deficit upon hospital admission was 3 to 20 (mean, 9). All patients required blood transfusion secondary to blood loss sustained during injury. Survival to discharge was 93%. Controls were 27-64 years old (mean, 40) and 60% male. Sequencing analysis revealed 69 differentially expressed miRNAs (P < .05) in the severely injured. Within the differentially expressed miRNAs, there were 12 direct and 6 indirect correlations with multiple genes involved in the TLR3 and TLR4 signaling pathways. The relationships between these same miRNAs and clinical parameters were also analyzed. We discovered 4 direct correlations with base deficit and HCO3, and 7 indirect correlations involving total fresh frozen plasma transfused, base deficit, HCO3, and PaCO2 levels., Conclusion: Differential expression and correlations between miRNAs, genes of the TLR pathways, and clinical parameters are unique findings in the severely injured and may lead to a greater understanding of the regulation of sterile inflammation after severe injury., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Hemorrhagic shock leads to a complex cascade of metabolic and hormonal processes that may result in hypoperfusion, end organ damage, and death even when blood pressure is restored. Studies have shown that morbidity and mortality could be attributable to a diminished availability of endothelial-derived nitric oxide (eNO). It is unclear whether adequate levels of citrulline (CIT) and arginine (ARG)--the precursors of eNO synthesis--are available to sustain the eNO needed to maintain adequate perfusion in severe shock. An indirect measure of eNO is the ratio between the levels of ARG and its inhibitor asymmetric dimethylarginine (ARG/ADMA). The purpose of the study was to identify the temporal impact of the ARG/ADMA ratio, ARG, CIT, and ADMA in response to hemorrhage and crystalloid fluid resuscitation by the use of a porcine model of severe hemorrhagic shock., Methods: Hemorrhagic shock was induced in Yorkshire cross pigs by mimicking a bleeding pattern of rapid uncontrolled hemorrhage to achieve a shed volume of 30 mL/kg, a 50% decrease in mean arterial pressure, and an oxygen debt of >60 mL/kg. Normal saline, up to 2 times the shed blood volume, was started 1 hour after the start of hemorrhage with the goal of restoring mean arterial pressure to >50 mm Hg. Hemodynamics, blood gas measurements, and plasma samples were obtained at baseline, 1 hour after the start of hemorrhage, and 1 hour after resuscitation. Amino acids were measured by liquid chromatography coupled to mass spectrometry., Results: During hemorrhage, a distinct subset of pigs was better able to tolerate ischemia than the rest. These pigs required less resuscitation, had evidence of better organ perfusion, and exhibited less of an increase in interleukin-6 (IL-6) after resuscitation. Compared with their less-tolerant counterparts, this group had a greater increase in CIT above baseline (analysis of variance, P < .05) with hemorrhage. ARG levels were similar and remained stable with hemorrhage, which indicated the similar availability of substrate for eNO synthesis but differences in the quantity produced in response to the blood volume loss. With crystalloid fluid resuscitation, ARG levels and ARG/ADMA decreased (analysis of variance, P < .05), whereas CIT remained increased in the group less able to tolerate hemorrhage. ARG/ADMA decreased proportional to greater oxygen debt during hemorrhage and greater IL-6 levels with fluid resuscitation., Conclusion: Our results suggest that a sufficient decrease in MAP during hemorrhagic shock is associated with a subsequent increase in IL-6, persisting impairment of end organ perfusion, and evidence of ongoing eNO deficit and an increase in ADMA despite resuscitation. The ARG/ADMA ratio reflects both of these parameters and corresponds to the increase in IL-6 and persistent ischemia after resuscitation. We propose that the mechanism of IL-6 increase in trauma derives from eNO deficiency, and the ARG/ADMA ratio more accurately depicts the pathologic mechanism responsible for increased morbidity and mortality in trauma., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Traumatic brain injury (TBI) and hemorrhagic shock (HS) are the leading causes of trauma-related deaths. These insults disrupt coagulation and endothelial systems. This study investigated whether previously reported differences in lesion size and brain swelling during normal saline (NS), colloids (Hextend [HEX]), and fresh frozen plasma (FFP) resuscitation are associated with differential effects on coagulation and endothelial systems., Methods: We subjected 15 Yorkshire swine to TBI and HS (40% blood volume), and kept in HS for 2 hours before resuscitation with NS, HEX, or FFP. Markers of endothelial activation (E-selectin, Intercellular adhesion molecule [ICAM]-1), coagulation activation (prothrombin fragment 1 + 2), and natural anticoagulation (activated protein C [aPC]) were determined in serum and brain whole cell lysates., Results: Serum levels of aPC were greater in the NS group (203 ± 30 pg/mL) compared with HEX (77 ± 28 pg/mL; P = .02) and FFP (110 ± 28 pg/mL; P = .09), as was PF 1 + 2 in the brain when compared with FFP (PF 1 + 2, 89 ± 46 vs 37 ± 14 ng/mL; P = .035). Brain E-selectin was greater in the NS group compared with FFP (3.36 ± 0.02 vs 3.31 ± 0.01 ng/mL; P = .029). Circulating ICAM-1 levels were increased in the NS group (151 ± 9 ng/mL) compared with the HEX (100 ± 9 ng/mL; P < .01) and FFP (108 ± 9 ng/mL; P = .01)., Conclusion: In this clinically realistic large animal model of TBI + HS, NS resuscitation was associated with an early activation of coagulation, natural anticoagulation, and endothelial systems, compared with HEX and FFP., (Copyright © 2014 Mosby, Inc. All rights reserved.)

Initiating prehospital resuscitation with plasma in patients with trauma-associated hemorrhagic shock will result in more rapid and durable clot formation and, thus, the need for fewer packed cell infusions, less frequent use of cryoprecipitate, and more ventilator-free hospital days compared with those of patients randomized to standard crystalloid field resuscitation., (Copyright © 2013 Mosby, Inc. All rights reserved.)

Background: Circulating proteins may serve as biomarkers for the early diagnosis and treatment of shock. We have recently demonstrated that treatment with suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, significantly improves survival in a rodent model of lipopolysaccharide (LPS)-induced septic shock. Preliminary proteomic data showed that LPS-induced shock altered a number of proteins in circulation, including histone H3 (H3) and citrullinated histone H3 (Cit H3). The present study was designed to confirm these findings and to test whether the pro-survival phenotype could be detected by an early alteration in serum biomarkers., Methods: Three experiments were performed. In experiment I, Western blotting was performed on serum samples from male C57B1/6J mice (n = 9, 3/group) that belonged to the following groups: (a) LPS (20 mg/kg)-induced septic shock, (b) SAHA-treated septic shock, and (c) sham (no LPS, no SAHA). In experiment II, HL-60 granulocytes were cultured and treated with LPS (100 ng/m1) in the absence or presence of SAHA (10 μmol/L). Sham (no LPS, no SAHA) granulocytes served as controls. The medium and cells were harvested at 3 hours, and proteins were measured with Western blots. In experiment III, a large dose (LD, 35 mg/kg) or small dose (SD, 10 mg/kg) of LPS was injected intraperitoneally into the C57B1/6J mice (n = 10 per group). Blood was collected at 3 hours, and serum proteins were determined by Western blots or enzyme-linked immunosorbent assay (ELISA). All of the Western blots were performed with antibodies against H3, Cit H3, and acetylated H3 (Ac H3). ELISA was performed with antibody against tumor necrosis factor (TNF)-α. Survival rates were recorded over 7 days., Results: In experiment I, intraperitoneal (IP) injection of LPS (20 mg/kg) significantly increased serum levels of H3, which was prevented by SAHA treatment. In experiment II, LPS (100 ng/mL) induced expression and secretion of Cit H3 and H3 proteins in neutrophilic HL-60 cells, which was decreased by SAHA treatment. In experiment III, administration of LPS (LD) caused a rise in serum H3 and Cit H3 but not Ac H3 at 3 hours, and all of these animals died within 23 hours (100% mortality). Decreasing the dose of LPS (SD) significantly reduced the mortality rate (10% mortality) as well as the circulating levels of Cit H3 (non detectable) and H3. An increase in serum TNF-α was found in both LPS (LD) and (SD) groups, but in a non-dose-dependent fashion., Conclusion: Our results reveal for the first time that Cit H3 is released into circulation during the early stages of LPS-induced shock. Moreover, serum levels of Cit H3 are significantly associated with severity of LPS-induced shock. Therefore, Cit H3 could serve as a potential protein biomarker for early diagnosis of septic shock, and for predicting its lethality., (Copyright © 2011 Mosby, Inc. All rights reserved.)

Background: Resuscitation fluids containing beta-hydroxybutyrate (BHB) have been shown to decrease cellular injury after hemorrhagic shock and resuscitation through an unknown mechanism. We tested whether this effect was related to BHB-induced metabolic modulations., Methods: Male Sprague Dawley rats (n=30) were subjected to volume-controlled hemorrhage (27 mL/kg during 10 minutes followed by 75 minutes of shock during which another 8 mL/kg of blood was withdrawn). Experimental groups included the following: (1) sham, (2) no resuscitation (NR), (3) racemic lactated Ringer's (DL-LR) solution, (4) LR containing L-isomer only (L-LR), (5) ketone Ringer's solution with lactate substituted by BHB (KR), and (6) pyruvate Ringer's solution with lactate substituted by pyruvate (PR). The resuscitation fluids were infused during 45 minutes simultaneously with additional hemorrhage of 8 mL/kg. Hemodynamic and physiologic parameters and the plasma levels of BHB were serially measured. The animals were killed 2 hours after resuscitation, and tissues were frozen instantaneously for cellular adenylate extraction and adenosine triphosphate (ATP) and adenosine diphosphate analysis. Pulmonary apoptosis was studied using Western blotting, immunohistochemistry, and reverse transcriptase-polymerase chain reaction. Expression of enzymes involved in ketogenesis and ketolysis was analyzed by reverse transcriptase-polymerase chain reaction., Results: NR and resuscitation with DL-LR increased the expression of apoptotic markers, whereas resuscitation with KR and PR significantly decreased the expression of apoptotic markers in rat lungs. Resuscitation with KR was followed by a profound increase in plasma BHB levels; however, the expression levels of ketolytic enzymes were essentially unaffected. KR infusion did not induce significant improvements in tissue ATP levels., Conclusions: Resuscitation with KR and PR protects against pulmonary apoptosis without improving tissue ATP content. Therefore, metabolic modulation is unlikely to be the major mechanism by which BHB exerts its protective effects during reperfusion.

Background: Hemorrhagic shock and sepsis are usually studied separately or in rodents. This study combined the two insults in a large animal model., Methods: Anesthetized pigs were bled, held in shock for 1 hour, and then resuscitated with fluid. After 3 days, Escherichia coli endotoxin LPS was infused into the portal vein (150 micrograms/kg x 30 min) to mimic the effect of enteric substances breaching the mucosal barrier. Systemic and splanchnic hemodynamics, circulating leukocytes, and plasma levels of tumor necrosis factor (TNF) were measured in five groups: 40% hemorrhage plus fluid only resuscitation, 40% hemorrhage plus fluid-blood resuscitation, 50% hemorrhage plus fluid-blood resuscitation, sham, or sham plus 5 micrograms/kg LPS priming dose instead of hemorrhage., Results: On day 4 before infusion of LPS, there were no differences between groups in hemodynamics or O2 utilization, but systemic O2 delivery and O2 consumption were each reduced in the hemorrhaged groups because of the hemodilution associated with resuscitation. For 3 hours after infusion of LPS, all animals received aggressive fluid and respiratory support, but arterial blood pressure decreased, and systemic O2 utilization, splanchnic O2 utilization, and arterial lactate level increased; there were no differences between groups. In the 50% group compared with sham, LPS-evoked decreases in cardiac index and stroke index were eliminated, and LPS-evoked tachycardia, pulmonary and systemic vasoconstriction, and increases in hepatic and portal vein lactate levels were blunted. Despite similar leukocyte counts before infusion of LPS and similar leukopenia after LPS infusion, plasma LPS level was higher in the 50% group compared with sham. Furthermore, LPS evoked increases in portal and hepatic vein plasma TNF in the shams, but those changes were reduced in the 50% group., Conclusions: Most responses to LPS were similar after hemorrhagic shock or a sham operation, which is inconsistent with the concept of "priming." LPS-evoked increases in plasma TNF were blunted after shock, probably because of trauma-induced immune dysfunction. A combined shock plus septic challenge in a large animal model may be valuable for investigating the pathogenic mechanism in human beings.

Oxygen consumption (VO2) is dependent on oxygen delivery (DO2) in septic shock. Local hypoxia with later secondary organ failure may develop, however, despite an often hyperdynamic circulation. The splanchnic organs seem to be of vital importance in this context. In experiments performed in pigs we compared total body VO2 and DO2 with oxygen consumption and delivery in the gastrointestinal organs and the liver in two different shock states: (1) septic shock induced by peritonitis (n = 6) and (2) hemorrhagic shock (n = 6). Another group of six animals not in shock served as controls. Total, gastrointestinal, and liver DO2 decreased in a similar pattern in both septic and hemorrhagic shock. Gastrointestinal and liver VO2 increased in sepsis, whereas it was unchanged in hemorrhage. In the later phase of sepsis, liver VO2, but not gastrointestinal VO2, again decreased, because liver oxygen extraction was almost total and liver DO2 decreased further. The development of flow-dependent liver hypoxia was reflected in a decrease in liver lactate turnover (increased liver lactate release) during late sepsis. Early hypoxia in the splanchnic region is suggested as a plausible mechanism behind the development of secondary organ failure, especially in sepsis.

Hypocalcemia often follows resuscitation from hemorrhagic shock. The role of calcium supplementation is controversial, whereas, little data are available regarding the parathyroid (PTH) response. Therefore this response was studied in 41 injured patients who required 15 blood transfusions and 11.7 L balanced electrolyte solution during emergency room and operating room therapy. Postoperative reduced total calcium (7.5 +/- 0.8 mg/dl SD) and ionized calcium 1.85 +/- 0.2 mEq/SD) paralleled a rise in PTH (69.7 +/- 37 microliters Eq/ml SD) and the severity of insult as reflected by shock time and hypoalbuminemia. Renal function was normal. Increased PTH is probably homeostatic and belies the theoretical merits of calcium channel blocker administration after hemorrhagic shock. Calcium supplements may be of benefit during resuscitation when bone flow is low and calcium release from bone in response to PTH is reduced.

Microaggregates have been implicated as a contributory cause of respiratory distress syndrome. Blood flow and resistance changes are compared between the right and left lungs following the selective administration of stored autologous heparinized blood into the left pulmonary artery. Eight dogs were bled 1,160 +/- 47 c.c. over 3 days. Following storage for 5 days the volume, number and size of microaggregates were measured by multichannel particle size analyzer and compared to 14-day-old human blood. Distribution of blood flow and resistance were calculated from data derived from injection of radioactively tagged microspheres into the right atrium and determination of cardiac output and pulmonary artery and wedge pressures. These measurements were made during a control period, following resuscitation from a 2 hour hemorrhagic shock period with the stored blood and 3 hours after resuscitation. Despite the administration of stored blood with massive amounts of microaggregates into the left pulmonary artery, the distribution of blood flow immediately and 3 hours following resuscitation was the same as in the control period. The pulmonary vascular resistance increased across both lungs but the increase was the same on the left as the right. These data suggest that microaggregates may not be important in the development of the respiratory distress syndrome.

The effect of fluid resuscitation from hemorrhagic shock on cerebral edema, intracranial pressure (ICP), and blood brain barrier function was investigated in the presence of a simulated head injury. Beagle dogs were anesthetized and ICP was measured via a right subarachnoid bolt while a contralateral epidural balloon was inflated in the left hemicranium to mimic a closed head injury. Forty percent of the dogs' blood was shed and the shock state was maintained for 1 hour. Resuscitation was initiated with shed blood and a volume of either normal saline solution (NS, n = 5), 10% dextran-40 (D-40, n = 6), or hypertonic (3%) saline solution (HS, n = 6) equal to the amount of shed blood. Evans blue solution was infused intravenously, and intravascular volume was then maintained with normal saline solution. Control (n = 5) dogs did not undergo shock, but received equivalent volumes of normal saline solution and Evans blue solution. The dogs were killed after 2 hours of resuscitation, and the brains were removed, weighed, and fixed in formalin. The average intracranial pressure value after epidural balloon inflation was 18.6 +/- 0.80 mm Hg and decreased equally in all groups during the shock period, averaging 10.8 +/- 1.24 mm Hg at the end of the shock period. Fluid resuscitation markedly elevated ICP in the NS and D-40 groups, reaching maximal values of 46.6 +/- 12.11 mm Hg and 45.3 +/- 28.95 mm Hg, respectively. Maximal ICP values in control and HS groups measured 21.8 +/- 1.36 mm Hg and 15.8 +/- 2.04 mm Hg, respectively (p less than 0.25 for HS versus NS control). Wet brain weights were significantly less in the HS group compared with either NS or D-40 groups (p less than 0.05). Coronal sections of fixed HS brains showed deep cortical Evans blue staining on the side of balloon injury. Therefore, in the presence of an intracranial mass lesion, resuscitation with hypertonic (3%) saline solution is accompanied by lower ICP values and less cerebral edema than is isotonic saline or colloid resuscitation. Blood brain barrier function is not restored by hypertonic saline solution resuscitation.

Hemorrhage in dogs to 30 mm. Hg did not produce platelet aggregation. Significant platelet aggregation was shown in stored blood delivered through the standard blood administration set, in the splanchnic circulation in endotoxic shock, and in the inferior vena cava following three hours of aortic cross-clamping. Pulmonary trapping of platelet aggregates could not be shown by serial screen filtration pressure measurements.

Previous studies performed in our laboratory with a constant-pressure model of hemorrhagic shock in the anesthetized rat have failed to find any significant effect of shock on the glycogen or high-energy phosphate content of the soleus muscle that would be consistent with inadequate oxygen supply. The present study examined the extracellular-intracellular lactate concentration gradients under conditions identical to those of our previous studies to determine whether skeletal muscle lactate accumulation might occur under these conditions. Twenty-seven pentobarbital-anesthetized rats were bled to a mean arterial blood pressure of 40 mm Hg during a 10-minute period and maintained at that level by withdrawal or reinfusion of shed blood. Arterial blood samples were taken and soleus muscles rapidly frozen during four defined phases of hemorrhagic shock: the early compensatory (phase I), maximal compensatory (phase II), early decompensatory (phase III), and late decompensatory (phase IV) phases. The results showed that although the plasma lactate and intracellular lactate concentrations change in parallel during all phases of shock, the extracellular--intracellular concentration gradient for lactate was always positive, ranging from 0.64 +/- 0.61 mmol/L in phase I to 6.41 +/- 0.93 mmol/L in phase III. These findings, together with the previous failure to find significant high-energy phosphate or glycogen changes in the soleus muscle, suggest that this skeletal muscle is not metabolizing anaerobically and does not contribute to the observed lactic acidemia in this model of hemorrhagic shock.

The object of this article is to assess the value of human serum albumin (HSA) in the initial resuscitation of hypotensive trauma victims. Thirty-six patients (mean age = 30 years) in shock from trauma who underwent laparotomies were randomly assigned to either Ringer's lactate solution (RL) resuscitation or 4% HSA in RL resuscitation. Both groups received approximately 8L of test fluid and 6U of washed red cells. The only death in the study occurred in a patient assigned to the RL group. Two patients in each group required mechanical ventilation for longer than 24 hours. No differences were noted in a battery of pulmonary function tests performed daily for 5 days. These results demonstrate that HSA is not essential in this clinical setting for safe and effective resuscitation.

Primary hemostasis was studied in 22 injured patients in the operating room (OR) after a minimum of 10 transfusions, 6 and 15 hours after surgery, on postoperative days 2 and 4 and during convalescence (mean 25 days after surgery). The platelet count was low in the OR and continued to fall after surgery through the second postoperative day; it began to rise by day 4 and was above normal at convalescence. Most patients had prolonged bleeding time through day 4. Platelet aggregation with adenosine diphosphate and collagen was depressed in the OR and platelet aggregation remained depressed. The platelet-specific proteins, beta-thromboglobulin and platelet factor 4, were elevated in the OR and fell throughout the first 4 postoperative days. A secondary rise in these proteins occurred at convalescence. Despite severe alterations in both the number and function of platelets after massive transfusion for injury, no patient had clinical oozing. Therefore the routine administration of platelets in comparable patients without "medical bleeding" is unwarranted.

One hour of hemorrhagic shock in the dog produces alterations in thyroid hormone metabolism far exceeding those seen after elective surgery or thermal injury. The changes in plasma thyroid hormone levels cannot be fully explained by carrier protein loss. Plasma concentrations of total thyroxine (T4) and triiodothyronine (T3) were significantly decreased after only 20 minutes of shock, continued to decrease throughout shock and resuscitation, and remained depressed for several days thereafter. Both hormones reached nadirs during volume replacement of 42% and 17% of baseline, respectively. The total T4 level normalized by the fifth postshock day, but the T3 concentration was still depressed on the ninth day. Plasma albumin, the principal canine thyroid hormone carrier, was significantly reduced 20 minutes after hemorrhage and remained low throughout convalescence. Concentrations of free T4 and T3 decreased during shock, but not as much as the total T4 and T3 concentrations. Reverse T3 levels, corrected for albumin loss, and T3 uptake values were increased during shock and resuscitation. Similar alterations in circulating thyroid hormone concentrations were seen in three patients with major traumatic injury and/or shock. The thyroid hormone changes in shock may represent another example of the "euthyroid sick syndrome."

Insulin secretory rates (ISR) during intravenous glucose tolerance tests (IVGTT's) were measured in six dogs subjected to hemorrhagic shock and were compared to ISR's from five monkeys subjected to shock of comparable severity. ISR's also were measured in normotensive control dogs and monkeys subjected to the same blood sampling protocol. A sixfold increase in ISR occurred in shocked dogs after glucose loading; however, no ISR response occurred in monkeys subjected to hemorrhage. It is concluded that marked species differences exist in the insulin-glucose metabolic responses to shock. In addition, the dog would appear to be an inappropriate experimental animal as applied to trauma-insulin metabolism in man.