Perioperative Coagulation Changes in Total Pancreatectomy and Islet Autotransplantation.

OBJECTIVES: Thrombotic complications after total pancreatectomy with islet autotransplantation (TPIAT) are common. However, the systemic changes to coagulation in the perioperative period have not been well studied. Our objective was to evaluate the derangements in coagulation in the perioperative period for this procedure. METHODS: This was a prospective observational study of patients undergoing elective TPIAT for chronic pancreatitis. Multiple methods of evaluating coagulation, including 2 viscoelastic assays and standard laboratory assays were obtained at defined intraoperative and postoperative intervals. RESULTS: Fifteen patients were enrolled. Laboratory values demonstrated initial intraoperative hypercoagulability before significant systemic anticoagulation after islet infusion with heparin. Hypercoagulability is again seen at postoperative days 3 and 7. Subgroup analysis did not identify any major coagulation parameters associated with portal vein thrombosis formation. CONCLUSIONS: Apart from the immediate period after islet cell and heparin infusion, patients undergoing TPIAT are generally hypercoagulable leading to a high rate of thrombotic complications. Portal vein thrombosis development had minimal association with systemic derangements in coagulation as it is likely driven by localized inflammation at the time of islet cell infusion. This study may provide the groundwork for future studies to identify improvements in thrombotic complications.

Alterations in Enteroendocrine Hormones After Total Pancreatectomy With Islet Autotransplantation.

OBJECTIVE: When total pancreatectomy with islet autotransplantation (TPIAT) is performed for chronic pancreatitis, the pancreas and most of the duodenum are removed, with Roux-en-Y reconstruction of the gastrointestinal tract. Enteroendocrine cells in the intestines and pancreas secrete hormones coordinating digestion and motility, but anatomic reconstruction alters transit of nutrients to these cells. We hypothesized that TPIAT leads to changes in enteroendocrine hormones. METHODS: Glucagon-like peptide 1 (GLP-1), peptide YY (PYY), and pancreatic polypeptide (PP) were measured from mixed-meal tolerance tests of 34 clinical trial participants before and 18 months after TPIAT. Area under the curve of GLP-1 and PYY-stimulated responses were calculated by trapezoidal method, and the PP response was measured as the stimulated max minus baseline (ΔPP). RESULTS: Area under the curve of GLP-1 and PYY increased significantly after TPIAT (GLP-1 average +553.1 pg/mL per minute, P = 0.004; PYY average +4647.9 pg/mL per minute, P = 0.02). ΔPP trended toward lower after TPIAT (average, -52.2 pg/mL, P = 0.06). CONCLUSIONS: In this novel study of enteroendocrine hormones in TPIAT patients, stimulated levels of GLP-1 and PYY were significantly higher after versus before TPIAT. ΔPP was lower after TPIAT, but not significantly. These hormone changes have potential clinical implications that warrant further research.

Evaluation of novel formulations of d-ß-hydroxybutyrate and melatonin in a rat model of hemorrhagic shock.

d-ß-hydroxybutyrate and melatonin (BHB/MLT) infusion improves survival in hemorrhagic shock models. The original BHB/MLT formulation contains dimethyl sulfoxide (DMSO) to increase melatonin solubility. We formulated BHB/MLT solutions wherein DMSO was replaced either with 10% polyvinylpyrrolidone (BHB/MLT/PVP) or with 5% hydroxypropyl-ß-cyclodextrin/2.5% PVP/2.5% polyethylene glycol 400 (BHB/MLT/CD). Safety and efficacy of the new and the original BHB/MLT solution were tested in a lethal rat hemorrhagic shock model, with seven groups: 1) sham, 2) shock, untreated, 3) shock, lactated Ringer's solution (LR), 4) shock, 4 M BHB/MLT/DMSO, 5) shock, 2 M BHB/MLT/DMSO, 6) shock, BHB/MLT/PVP and 7) shock, BHB/MLT/CD. BHB/MLT/DMSO was given at full strength and 1:1 dilution to match the concentration of the novel formulations. Rats were anesthetized, instrumented, and 40% of the total blood volume was withdrawn in three steps, followed by four-hour long shock. Treatment boluses were infused half-way throughout hemorrhage. Survival was highest in BHB/MLT/CD-treated rats (8/10), followed by the BHB/MLT/PVP (6/10), 4 M BHB/MLT/DMSO (5/10) or 2 M BHB/MLT/DMSO (5/10), LR (3/10) and the untreated group (0/11). Survival did not differ significantly between BHB/MLT groups (p > 0.05), but was significantly higher in BHB/MLT/CD than in LR-treated animals (p = 0.018). BHB/MLT/PVP and BHB/MLT/CD constitute promising candidates for clinical hemorrhagic shock treatment.

D-ß-Hydroxybutyrate and melatonin for treatment of porcine hemorrhagic shock and injury: a melatonin dose-ranging study.

OBJECTIVE: Treatment with a combination of D-ß-hydroxybutyrate (BHB) and melatonin (M) improves survival in hemorrhagic shock models. Our objective was to find the most effective melatonin concentration in combination with 4 molar BHB (4 M BHB). Survival and markers of organ injury were analyzed in pigs exposed to pulmonary contusion, liver crush injury, and hemorrhagic shock and treated with lactated Ringer's solution; 4 M BHB/43 mM M; 4 M BHB/20 mM M; 4 M BHB/10 mM M; 4 M BHB/4.3 mM M; or 4 M BHB/0.43 mM M. This work is an extension of a previously published research study. RESULTS: Survival was highest in pigs receiving 4 M BHB/43 mM M (13/14), followed by lactated Ringer's solution (11/16) and BHB/M with decreased melatonin concentrations (4 M BHB/20 mM M 3/6, 4 M BHB/10 mM M 2/6, 4 M BHB/4.3 mM M 3/6, 4 M BHB/0.43 mM M 1/6, p = 0.011). High mortality was associated with increases in serum lactate, higher liver and muscle injury markers and decreases in PaO2:FiO2 ratios. Our study indicates that treatment with 4 M BHB and melatonin concentrations below 43 mM lack the survival benefit observed from 4 M BHB/43 mM melatonin in pigs experiencing hemorrhagic shock and polytrauma.

Metabolomic analysis of survival in carbohydrate pre-fed pigs subjected to shock and polytrauma.

Hemorrhagic shock, a result of extensive blood loss, is a dominant factor in battlefield morbidity and mortality. Early rodent studies in hemorrhagic shock reported carbohydrate feeding prior to the induction of hemorrhagic shock decreased mortality. When repeated in our laboratory with a porcine model, carbohydrate pre-feed resulted in a 60% increase in death rate following hemorrhagic shock with trauma when compared to fasted animals (15/32 or 47% vs. 9/32 or 28%). In an attempt to explain the unexpected death rate for pre-fed animals, we further investigated the metabolic profiles of pre-fed non-survivors (n = 15) across 4 compartments (liver, muscle, serum, and urine) at specific time intervals (pre-shock, shock, and resuscitation) and compared them to pre-fed survivors (n = 17). As hypothesized, pre-fed pigs that died as a result of hemorrhage and trauma showed differences in their metabolic and physiologic profiles at all time intervals and in all compartments when compared to pre-fed survivors. Our data suggest that, although all animals were subjected to the same shock and trauma protocol, non-survivors exhibited altered carbohydrate processing as early as the pre-shock sampling point. This was evident in (for example) the higher levels of ATP and markers of greater anabolic activity in the muscle at the pre-shock time point. Based on the metabolic findings, we propose two mechanisms that connect pre-fed status to a higher death rate: (1) animals that die are more susceptible to opening of the mitochondrial permeability transition pore, a major factor in ischemia/reperfusion injury; and (2) loss of fasting-associated survival mechanisms in pre-fed animals.

Safety of D-ß-Hydroxybutyrate and Melatonin for the Treatment of Hemorrhagic Shock With Polytrauma.

D-ß-hydroxybutyrate (BHB) and melatonin (M) treatment improves survival in animal models of hemorrhagic shock. Here, we evaluated the safety of BHB/M via 2 routes of administration in a porcine hemorrhagic shock/polytrauma model. Furthermore, we assessed BHB/M serum concentrations after intravenous and intraosseous infusion of different BHB/M doses in healthy pigs. Pigs underwent pulmonary contusion, liver injury, and hemorrhage. Injured animals were treated with an intravenous or intraosseous bolus of BHB/M or lactated Ringer's solution (LR), followed by 4 h of continuous infusion of the respective fluid (n = 12 per group). Pigs were resuscitated with LR (1 h) and then LR and shed blood (20 h). Physiological data and blood samples were analyzed throughout the experiment. In a second study, we infused healthy pigs intravenously or intraosseously with BHB/M at 3 different doses (n = 4 per group). There were no differences between groups in physiologic measurements (heart rate, mean arterial pressure, and cardiac output), organ function markers (alanine aminotransferase, aspartate aminotransferase, serum urea nitrogen, total creatinine kinase, and lactate dehydrogenase), or histopathology. The BHB/M-treated animals exhibited transient changes in blood Na, K, pH, and lactate. Differences in survival were not statistically significant. There was a trend toward decreased survival after intraosseous infusion, potentially related to lower circulating BHB and melatonin levels. Healthy pigs had higher drug serum concentrations after intravenous than after intraosseous infusion of BHB/M at the standard, but not the double dose. D-ß-hydroxybutyrate /M in doses previously shown to be associated with improved survival is safe in a porcine hemorrhagic shock/polytrauma model. Intravenous infusion is the preferred route of administration at standard doses.

Preinjury Fed State Alters the Physiologic Response in a Porcine Model of Hemorrhagic Shock and Polytrauma.

INTRODUCTION: Hemorrhagic shock and injury lead to dramatic changes in metabolic demands and continue to be a leading cause of death. We hypothesized that altering the preinjury metabolic state with a carbohydrate load prior to injury would affect subsequent metabolic responses to injury and lead to improved survival. METHODS: Sixty-four pigs were randomized to fasted (F) or carbohydrate prefeeding (CPF) groups and fasted 12 h prior to experiment. The CPF pigs received an oral carbohydrate load 1 h prior to anesthesia. All pigs underwent a standardized injury/hemorrhagic shock protocol. Physiologic parameters and laboratory values were obtained at set time points. RESULTS: Carbohydrate prefeeding did not convey a survival benefit; instead, CPF animals had greater mortality rates (47% vs. 28%; P = 0.153; log-rank [Mantel-Cox]). Carbohydrate prefeeding animals also had higher rates of acute lung injury (odds ratio, 4.23; 95% confidence interval, 1.1-16.3) and altered oxygen utilization. Prior to shock and throughout resuscitation, CPF animals had significantly higher serum glucose levels than did the F animals. CONCLUSIONS: Carbohydrate prefeeding did not provide a survival benefit to swine subjected to hemorrhagic shock and polytrauma. Carbohydrate prefeeding led to significantly different metabolic profile than in fasted animals, and prefeeding led to a greater incidence of lung injury, increased multiorgan dysfunction, and altered oxygen utilization.

Bovine serum albumin as a molecular sensor for the discrimination of complex metabolite samples.

The potential for using serum albumin (SA) as a broadly applicable molecular sensor was explored in an effort to develop a method for rapid analysis of complex metabolite samples. SA is a protein present at high concentration in blood, which transports a diverse set of compounds including fatty acids, hormones, and drugs. The effectiveness of the bovine ortholog (BSA) as a molecular sensor was tested by analyzing the pool of small molecules bound to the protein after a brief incubation with complex fluids of biological origin. As an initial test, three varietals of red wine were readily distinguished. Further analysis using four varietals of white wine also showed clear separation. In a second analysis using urine, animals in hemorrhagic shock were separated from a group of comparably treated controls. A time course analysis showed that recovery from injury could also be followed using the assay. This finding is significant as there currently is no method or biomarker for predicting the onset of shock. Comparison of samples was based on liquid chromatography mass spectrometry (LCMS) analysis of compounds selectively bound by BSA. Analysis of the samples after protein selection revealed a significant reduction in complexity and clear separation of groups by Principle Component Analysis (PCA). These results show the potential for using cargo-carrying proteins as molecular sensors for screening complex samples without the need for prior knowledge of sample composition or concentration and may streamline elucidation of biomarkers.

Low StO2 measurements in surgical intensive care unit patients is associated with poor outcomes.

BACKGROUND: Near-infrared spectroscopy-derived tissue hemoglobin saturation (StO2) is a noninvasive measurement that reflects changes in microcirculatory tissue perfusion. Previous studies in trauma patients have shown a correlation between low StO2 levels and mortality, organ failure, and severity of injury. The goals of this study were to identify the incidence of low StO2 in the critically ill patient population of a surgical intensive care unit (SICU) and evaluate the relationship of low StO2 and clinical outcomes. METHODS: We conducted a prospective cohort study at the University of Minnesota Medical Center. After institutional review board approval, 620 patients admitted to the SICU between July 2010 and July 2011 were screened for enrollment. Patients with an expected ICU length of stay of less than 24 hours were excluded. In the 490 patients who met inclusion criteria, StO2 measurements were obtained from the thenar eminence one to three times daily for the length of the ICU stay, up to 14 days. Outcome data included 28-day hospital mortality; ICU readmission; ventilator-free, ICU-free, and hospital-free days; and the need for lifesaving interventions. RESULTS: The overall incidence of low StO2 (<70%) was 11% of the patients per day. Patients with at least 1 day in the SICU with an StO2 measurement of less than 70% had higher rates of ICU readmission and fewer ventilator-free, ICU-free, and hospital-free days compared with those who did not. Mortality (28-day in-hospital) trended higher for these patients but was not statistically significant. An increase in the number of days with StO2 less than 70% was also associated with fewer ventilator-free, ICU-free, and hospital-free days. CONCLUSION: Low StO2 (<70%) is common and associated with poor outcomes in SICU patients. Near-infrared spectroscopy represents a potentially useful, noninvasive adjunct to monitoring of critically ill patients. LEVEL OF EVIDENCE: Prognostic study, level II.

Prolonged induced hypothermia in hemorrhagic shock is associated with decreased muscle metabolism: a nuclear magnetic resonance-based metabolomics study.

Hemorrhagic shock is a leading cause of trauma-related death in war and is associated with significant alterations in metabolism. Using archived serum samples from a previous study, the purpose of this work was to identify metabolic changes associated with induced hypothermia in a porcine model of hemorrhagic shock. Twelve Yorkshire pigs underwent a standardized hemorrhagic shock and resuscitation protocol to simulate battlefield injury with prolonged evacuation to definitive care in cold environments. Animals were randomized to receive either hypothermic (33°C) or normothermic (39°C) limited resuscitation for 8 h, followed by standard resuscitation. Proton nuclear magnetic resonance spectroscopy was used to evaluate serum metabolites from these animals at intervals throughout the hypothermic resuscitation period. Animals in the hypothermic group had a significantly higher survival rate (P = 0.02) than normothermic animals. Using random forest analysis, a difference in metabolic response between hypothermic and normothermic animals was identified. Hypothermic resuscitation was characterized by decreased concentrations of several muscle-related metabolites including taurine, creatine, creatinine, and amino acids. This study suggests that a decrease in muscle metabolism as a result of induced hypothermia is associated with improved survival.

Metabolomics classifies phase of care and identifies risk for mortality in a porcine model of multiple injuries and hemorrhagic shock.

BACKGROUND: Early recognition and intervention in hemorrhagic shock is essential to improved outcomes. However, the lack of robust diagnostic tools readily available to identify patients in the field inhibits the ability to provide timely intervention. Therefore, the development of a reliable prognostic indicator, such as a serum biomarker or a metabolic profile, has significant potential to improve far-forward trauma care. In this study, we used metabolomics as a tool to identify a metabolic state associated with the hemorrhagic shock and outcome in our porcine model of multiple injuries, shock, and resuscitation. METHODS: Proton nuclear magnetic resonance spectroscopy was used to evaluate serum metabolites from 23 animals that underwent multiple injuries, controlled hemorrhage, and 20 hours of a standard resuscitation protocol. Serum samples were collected from the animals at baseline (before hemorrhage), at shock (after 45 minutes of shock), and at 8 hours of full resuscitation. RESULTS: We were able to demonstrate shifts in the metabolome throughout different time points and construct a metabolic profile associated with mortality using partial least squares discriminate analysis. The metabolites most responsible for the classification of hemorrhagic shock in our model serve as markers for ischemia, changes in energy production, and cellular damage. Hemorrhagic shock was characterized by marked increases in tricarboxylic acid cycle intermediates, glycolytic-gluconeogenic by-products, purine-pyrimidine catabolism, and fatty acid oxidation. CONCLUSION: The results of this study demonstrate the potential for metabolomics as a tool to classify the metabolic flux, to identify relevant biochemical pathways, and to identify clinically useful biomarkers.

Environmental hypothermia in porcine polytrauma and hemorrhagic shock is safe.

We have previously demonstrated survival benefit to induced hypothermia in a porcine model of controlled hemorrhagic shock simulating an associated delay to definitive care. In the current study, we wished to evaluate the effects of environmental hypothermia in a porcine model of hemorrhagic shock with the addition of polytrauma. Sixteen pigs were randomized to normothermic (39°C, n = 7) or hypothermic (34°C, n = 9) groups. The model included instrumentation, chest injury (captive bolt device), hemorrhage to systolic blood pressure (SBP) of ∼50 mmHg, and crush liver injury. Animals received limited fluid resuscitation for a 1-h period with goal SBP of greater than 80 mmHg and ice packs or warming blankets to achieve goal temperatures, followed by full resuscitation with goal SBP of greater than 90 mmHg, adequate urine output, and hemoglobin by protocol for 20 h. Survivors were observed for an additional 24 h with end points including mortality, markers of organ injury, and neurologic function. There were no differences in survival between the groups (mortality = 1/9, hypothermia group vs. 2/7, normothermia group, P = 0.39). Markers of organ injury were elevated in the hypothermia group at 24 h after injury but were identical between groups at the end of the experimental protocol (48 h after injury). There were no noted differences in neurologic function between the two groups. Environmental hypothermia in a model of polytrauma and hemorrhagic shock was not associated with worse outcomes.

Analysis of biomarkers characteristic of porcine liver injury--from biomolecular logic gates to an animal model.

A biocatalytic cascade for the analysis of the simultaneous increase in the concentration of two biomarkers characteristic of liver injury (alanine transaminase, ALT, and lactate dehydrogenase, LDH) was tested on real samples acquired from an animal model (domestic pigs, Sus scrofa domesticus) suffering from traumatic liver injury. A two-step reaction biocatalyzed in the presence of both enzyme-biomarkers resulted in the oxidation of NADH followed by optical absorbance measurements. A simple qualitative, YES/NO, test allowed for distinction between animals with and without the presence of liver injury with the probability of 92%. These data represent the first demonstration of applying binary logic systems for the analysis of real biomedical samples.

Hypercoagulability in porcine hemorrhagic shock is present early after trauma and resuscitation.

INTRODUCTION: The understanding of coagulopathy associated with trauma continues to evolve. Trauma patients are frequently coagulopathic early after injury and become hypercoagulable within days of injury. Thrombelastography (TEG) allows real-time evaluation of the coagulation status of patients. We hypothesized that TEG will identify post-traumatic hypercoagulable state in our porcine model of hemorrhagic shock and resuscitation. METHODS: Fourteen male Yorkshire pigs were sedated, instrumented, and splenectomized via laparotomy. Eight of these animals underwent a shock protocol consisting of a pulmonary contusion via captive bolt gun, 35% hemorrhage and two liver fractures. Vitals, hemodynamics, physiologic parameters and TEG were measured at baseline, after shock and at intervals after injury thru 72 h post-injury. RESULTS: Animals undergoing surgery and instrumentation demonstrated the same hypercoagulable patterns as animals that received shock, injury, and resuscitation. In this model, hypercoagulability was present in both groups at 4 h after injury and continued for 72 h post-injury (increased angle and maximum amplitude, P < 0.05, compared to baseline). Statistically significant differences between the groups were noted at both 16 and 48 h post-injury. CONCLUSIONS: Hypercoagulability is present early after surgical intervention and trauma. This finding has implications for use of deep venous thrombosis (DVT) prophylaxis in trauma patients.

Treatment with beta-hydroxybutyrate and melatonin is associated with improved survival in a porcine model of hemorrhagic shock.

INTRODUCTION: The neuroprotective ketone ß-hydroxybutyrate (BHB) and the antioxidant melatonin have been found at elevated levels in hibernating mammals. Previous studies in rat models of hemorrhagic shock have suggested a benefit. We compared infusion of 4M BHB and 43 mM melatonin (BHB/M) to 4M sodium chloride and 20% DMSO (control solution) to evaluate for potential benefits in porcine hemorrhagic shock. METHODS: Hemorrhagic shock was induced to obtain systolic blood pressures <50 mmHg for 60 min. Pigs were treated with a bolus of either BHB/M (n=9) or control solution (n=8) followed by 4-h infusion of the either BHB/M or control solution. All animals were then resuscitated for 20 h after shock. Physiological data were continually recorded, and blood samples were taken at intervals throughout the experiment. Serum samples were analyzed via high resolution NMR for metabolomic response. RESULTS: BHB/M treatment significantly increased 24-h survival time when compared to treatment with control solution (100% versus 62%; p=0.050), with a trend toward decreased volume of resuscitative fluid administered to animals receiving BHB/M. BHB/M-treated animals had lower base deficit and higher oxygen consumption when compared to animals receiving control solution. Serum metabolite profiles revealed increases in ß-hydroxybutyrate (BHB), succinate, 2-oxovalerate and adipate with BHB/M treatment as compared with animals treated with control infusion. CONCLUSION: Infusion of BHB/M conferred a survival benefit over infusion of control solution in hemorrhagic shock. BHB and its products of metabolism are identified in serum of animals subjected to shock and treated with BHB/M. Further preclinical studies are needed to clarify the mechanisms of action of this promising treatment strategy.

Liver metabolomic changes identify biochemical pathways in hemorrhagic shock.

BACKGROUND: Despite ongoing advances in treatment, thousands of patients still die annually from complications due to hemorrhagic shock, a condition causing dramatic physiologic and metabolic changes as cells switch to anaerobic metabolism in response to oxygen deprivation. As the shift from aerobic to anaerobic metabolism occurs in the peripheral tissues during shock, the liver must increase production of endogenous glucose as well as process excess lactate produced in the periphery. This places the liver at the center of metabolic regulation in the body during hemorrhagic shock. Therefore, we hypothesized that liver tissue from pigs during an in vivo model of hemorrhagic shock (n = 6) would reflect resultant metabolic changes. MATERIALS AND METHODS: The in vivo model of shock consisted of 45 min of shock followed by 8 h of hypotensive resuscitation (80 mmHg) and subsequent normotensive resuscitation (90 mmHg) ending 48 h after the shock period. Control groups of pigs (n = 3) (1) shock with no resuscitation, and (2) only anesthesia and instrumentation, also were included. Metabolic changes within the liver after shock and during resuscitation were investigated using both proton ((1)H) and phosphorous ((31)P) nuclear magnetic resonance (NMR) spectroscopy. RESULTS: Concentrations of glycerylphosphorylcholine (GPC) and glycerylphosphorylethanolamine (GPE) were significantly lower at 8 h after shock, with recovery to baseline by 23 and 48 h after shock. Uridine diphosphate-glucose (UDP-glucose), and phosphoenolpyruvate (PEP) were elevated 23 h after shock. CONCLUSIONS: These results indicate that (1)H and (31)P NMR spectroscopy can be used to identify differences in liver metabolites in an in vivo model of hemorrhagic shock, indicating that metabolomic analysis can be used to elucidate biochemical events occurring during this complex disease process.

Hypothermia is associated with improved outcomes in a porcine model of hemorrhagic shock.

BACKGROUND: : Hypothermia after trauma is, in current medical practice, both avoided and aggressively treated. However, the effects of environmental hypothermia during early resuscitation after hemorrhagic shock have been only poorly characterized. METHODS: : The objective of our study was to compare normothermia versus mild and severe levels of hypothermia in a porcine model of hemorrhagic shock. In a prospective survival study, we anesthetized 19 juvenile male pigs (Yorkshire-Landrace, 15-25 kg) and caused them to hemorrhage until their systolic blood pressure was 45 mm Hg to 55 mm Hg for a duration of 45 minutes. Then, we randomized them into three groups (all of which underwent an 8-hour limited resuscitation period) as follows: normothermic (39 degrees C), mildly hypothermic (36 degrees C), and severely hypothermic (33 degrees C). We used ice packs to achieve surface cooling that mimicked environmental hypothermia. After 8 hours, we rewarmed the pigs and fully resuscitated them for 16 hours. We extubated the survivors and observed them for an additional 24 hours, before killing them. RESULTS: : Surface cooling resulted in significant reduction in core body temperature. The mortality rate was significantly higher in the normothermic group (60%) than in the two hypothermic groups combined (7%) (p = 0.015) or in the severely hypothermic group (0%) (p = 0.023). Hypothermic animals had significantly lower levels of creatinine kinase, lactate dehydrogenase, and lactate in addition to a lower base deficit after shock. However, severely hypothermic animals required greater volumes of colloid infusion and whole blood transfusion to maintain our target systolic blood pressure and hemoglobin levels when compared with normothermic animals. We saw a strong trend toward decreased oxygen consumption with hypothermia. CONCLUSIONS: : In our porcine model, we found that simulating mild and severe levels of environmental hypothermia during early resuscitation after hemorrhage was associated with a significantly decreased mortality rate. Furthermore, markers of cellular stress and organ dysfunction, including lactate levels and the base deficit, were lower in hypothermic animals. Decreasing oxygen consumption with hypothermia may, in part, explain the protective effects observed with hypothermia.

Noninvasive tissue oxygen saturation measurements identify supply dependency.

BACKGROUND: Hemorrhagic shock can lead to multiple organ failure and death. We have previously shown that noninvasive measurement of tissue oxygen saturation (StO(2)) has predictive value for outcomes in patients suffering hemorrhagic shock. Our study objectives were twofold: (1) to compare invasive and noninvasive measurements of local and systemic tissue hemoglobin oxygenation and (2) to compare the effects of various physiologic conditions seen in patients in hemorrhagic shock on tissue hemoglobin oxygenation. MATERIALS AND METHODS: We studied pigs in controlled conditions mimicking shock induced by one of the following: hypothermia, isovolemic hemodilution, or manipulations of vascular tone. We obtained both invasive and noninvasive measurements in a hind limb of StO(2), tissue hemoglobin index, femoral artery and venous flows, blood pressures, temperature, pH, pO(2), pCO(2), oxygen saturation, lactate, hemoglobin, and base excess. In all cases, we measured baseline values in both experimental and control hind limbs. RESULTS: We found that tissue hemoglobin oxygenation did not vary significantly over relevant physiologic temperatures. Under all physiologic conditions tested, we found supply-dependent oxygen consumption at oxygen levels less than 7 mL O(2)/min/kg. Similarly, we found that local oxygen delivery in animals subjected to varying degrees of isovolemic hemodilution or altered vascular tone was correlated with supply-dependent oxygen consumption, as measured by local noninvasive StO(2). CONCLUSIONS: Noninvasive StO(2) measurements are valid and durable over a wide range of physiologic conditions and correlate with invasively-measured oxygen delivery.

Near-infrared spectroscopy in patients with severe sepsis: correlation with invasive hemodynamic measurements.

BACKGROUND: Clinicians have begun using near-infrared spectroscopy (NIRS) to monitor tissue perfusion in hemorrhagic shock, as the technique allows continuous noninvasive monitoring of tissue hemoglobin oxygen saturation (StO(2)) and the tissue hemoglobin index (THI). We hypothesized that StO(2) measurements in patients with severe sepsis would be associated with the severity of their illness and would correlate with invasive hemodynamic measurements. METHODS: We measured mean arterial pressure (MAP), serum lactate concentration, blood hemoglobin concentration, StO(2), and THI in nine healthy volunteers and ten patients with septic shock in a surgical intensive care unit (ICU). Enrolled patients had a pulmonary artery catheter, and had family able to give informed consent. The average Acute Physiology and Chronic Health Evaluation (APACHE) II score at enrollment for the patients was 19 +/- 5 (standard deviation) points. Volunteers and patients were similar with respect to age and sex. To collect NIRS data, we used the InSpectra Tissue Spectrometer, Model 325 (Hutchinson Technology, Inc., Hutchinson, MN). For three consecutive days, we obtained invasive hemodynamic measurements three times daily, simultaneously with NIRS measurements, and metabolic cart measurements once daily. RESULTS: Patients with severe sepsis had significantly lower thenar muscle StO(2) values (p = 0.031) than healthy volunteers. Near-infrared spectroscopy-derived mixed venous oxygen saturation (NIRSvO(2)) and StO(2) measured from the thenar eminence in patients with severe sepsis correlated with SvO(2) from the pulmonary artery catheter (p < 0.05). In this group of patients, StO(2) did not correlate significantly with lactate concentration, base deficit, or APACHE II score. CONCLUSIONS: Near-infrared spectroscopic measurements of StO(2) correlated with invasive hemodynamic measurements in patients with severe sepsis but did not correlate with severity of illness. These findings suggest that NIRStO(2) may be a clinically useful measurement in monitoring patients with severe sepsis. Further study of this device in early resuscitation of patients with sepsis is necessary.

Eight hours of hypotensive versus normotensive resuscitation in a porcine model of controlled hemorrhagic shock.

OBJECTIVES: The aim of this study was to compare hypotensive and normotensive resuscitation in a porcine model of hemorrhagic shock. METHODS: This was a prospective, comparative, randomized survival study of controlled hemorrhagic shock using 28 male Yorkshire-Landrace pigs (15 to 25 kg). In 24 splenectomized pigs, the authors induced hemorrhagic shock to a systolic blood pressure (sBP) of 48 to 58 mm Hg (approximately 35% bleed). Pigs were randomized to undergo normotensive resuscitation (sBP of 90 mm Hg, n = 7), mild hypotensive resuscitation (sBP of 80 mm Hg, n = 7), severe hypotensive resuscitation (sBP of 65 mm Hg, n = 6), or no resuscitation (n = 4). The authors also included a sham group of animals that were instrumented and splenectomized, but that did not undergo hemorrhagic shock (n = 4). After the initial 8 hours of randomized pressure-targeted resuscitation, all animals were resuscitated to a sBP of 90 mm Hg for 16 hours. RESULTS: Animals that underwent severe hypotensive resuscitation were less likely to survive, compared with animals that underwent normotensive resuscitation. Mean arterial pressure (MAP) decreased with hemorrhage and increased appropriately with pressure-targeted resuscitation. Base excess (BE) and tissue oxygen saturation (StO2) decreased in all animals that underwent hemorrhagic shock. This decrease persisted only in animals that were pressure target resuscitated to a sBP of 65 mm Hg. CONCLUSIONS: In this model of controlled hemorrhagic shock, initial severe hypotensive pressure-targeted resuscitation for 8 hours was associated with an increased mortality rate and led to a persistent base deficit (BD) and to decreased StO2, suggesting persistent metabolic stress and tissue hypoxia. However, mild hypotensive resuscitation did not lead to a persistent BD or to decreased StO2, suggesting less metabolic stress and less tissue hypoxia.