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We have previously shown a sequence of events after unilateral pulmonary contusion that suggests the release of blood-borne prostanoid mediators and that culminates in refractory bilateral pulmonary failure.To determine the role of platelet-derived thromboxane and endothelial-derived prostacyclin in the primary and secondary injury after unilateral blunt chest trauma, and to determine whether pretreatment with the cyclooxygenase inhibitor indomethacin alters the progression of secondary injury.Anesthetized, ventilated (FIO2 = 0.50) pigs received a unilateral, blunt injury to the right thorax (n = 20) or sham injury (n = 5) and were monitored for 24 hours. Either indomethacin (5 mg/kg i.v.; n = 10) or its saline vehicle (n = 10) were administered 15 minutes before injury. Serial bronchoalveolar lavages of each lung were analyzed for protein and neutrophil (polymorphonuclear neutrophil (PMN)) content.Contusion caused profound hypoxemia; PaO2 partially recovered within 1 hour of injury to 50% of baseline. Thereafter, worsening hypoxemia required positive end-expiratory pressure. With indomethacin compared with vehicle, PaO2 was higher at any given level of positive end-expiratory pressure (p0.05). There was an early increase in serial bronchoalveolar lavage protein on the injured side (peak at 2 hours), with a delayed pulmonary capillary leak on the contralateral side (peak at 6 hours), which correlated with increasing PMN infiltration; this was reduced by 40 to 60% with indomethacin (p0.05). Thromboxane peaked within 1 hour after contusion at 800% baseline, then fell off rapidly. This peak preceded the maximal increase in permeability and was completely blocked by indomethacin. Prostacyclin slowly rose to 300% baseline by 3 hours and remained elevated; this change was blocked by indomethacin for 18 hours.Contusion of the right thorax induced a delayed pulmonary capillary leak in the left lung, which reflects a progressive secondary inflammatory response. Elevations in thromboxane and prostacyclin preceded progressive bilateral PMN infiltration. Indomethacin blocked thromboxane and prostacyclin and attenuated, but did not prevent, the progression to pulmonary failure. Overall, these data suggest that prostanoids are released soon after unilateral contusion and initiate an inflammatory response in both lungs that is sustained by PMN infiltration.

To determine properties of acadesine, the prototype adenosine regulating agent, in an experimental model in which abdominal sepsis is superimposed onto hemorrhagic shock.Randomized, blinded animal study.University-based animal research facility.Twenty-eight anesthetized mongrel pigs (35.5 +/- 1.1 kg).The cecum was ligated and punctured to produce abdominal sepsis. To produce hemorrhagic shock, 45% to 47% of the estimated blood volume was withdrawn. After 1 hr, shed blood plus supplemental crystalloid (twice the shed blood volume) plus either acadesine (5 mg/kg bolus + 1 mg/kg x 60 min, n = 10) or its vehicle (n = 10) was administered. All animals were awakened and observed for 48 hrs. At 48 hrs, cardiac function, bacterial cultures from the septic focus, and inflammatory changes in the abdomen were quantified.After resuscitation with acadesine vs. vehicle, we observed the following: a) arterial blood pressure and cardiac filling pressures were similar but cardiac index, systemic oxygen delivery, and systemic oxygen consumption were increased; b) plasma lactate was higher, systemic vascular resistance was lower, but ileal mucosal blood flow was not measurably altered; c) lipopolysaccharide-evoked tumor necrosis factor production in whole blood ex vivo was reduced; d) in those animals that survived 48 hrs (10/10 vs. 8/10), sepsis-induced cardiac depression, amount of free intraperitoneal fluid, extra abscess inflammatory reaction, abscess wall formation, abscess bacterial counts, and peritoneal bacterial counts, were all similar, but blood bacterial counts were higher.Fluid resuscitation with acadesine produced no adverse hemodynamic consequences and probably improved washout of metabolites from the reperfused microcirculation in sites other than the small intestine or heart. Taken together, these observations suggest that adenosine regulating agents might have therapeutic potential during fluid resuscitation from trauma. However, at least in these extreme conditions, the acute salutary effects of acadesine were probably overwhelmed by polymicrobial sepsis. Further studies must determine whether supplemental adjuvants to boost host defense during recovery from trauma will optimize adenosine-based resuscitation solutions.

in the 14 years since the landmark report from the Institute of Medicine ([17][1]), much has been learned about the role of gender in patient outcomes. Women typically have lower mortality rates than men from many chronic diseases at any age ([5][2]). An increasing amount of data have described a

Objective: To determine whether blood lactate, base deficit, or oxygen-derived hemodynamic variables correlate with morbidity and mortality rates in a clinically-relevant LD 50 model of penetrating trauma. Design: Prospective, controlled study. Setting: University research laboratory. Subjects: Anesthetized, mechanically-ventilated mongrel pigs (30 ± 2 kg, n = 29). Interventions: A captive bolt gun delivered a penetrating injury to the thigh, followed immediately by a 40% to 60% hemorrhage. After 1 hr, shed blood and supplemental crystalloid were administered for resuscitation. Measurements and Main Results: After penetrating injury, 50.7 ± 0.3% hemorrhage (range 50% to 52.5%), and a 1-hr shock period, seven of 14 animals died, compared with six of six animals after 55% to 60% hemorrhage, and 0 of nine animals after ≤47.5% hemorrhage. Only two of 13 deaths occurred during fluid resuscitation. At the LD 50 hemorrhage, peak lactate concentration and base deficit were 11.2 ± 0,8 mM and 9.3 ± 1.5 mmol/L, respectively, and minimum mixed venous oxygen saturation, systemic oxygen delivery, and systemic oxygen consumption were 33 ± 5%, 380 ± 83 mL/min/kg, and 177 ± 35 mL/min/kg, respectively. For comparison, baseline preinjury values were 1.6 ± 0.1 mM, -6.7 ± 0.6 mmol/L, 71 ± 3%, 2189 ± 198 mL/min/kg, and 628 ± 102 mL/min/kg, respectively. Of all the variables, only lactate was significantly related to blood loss before and after fluid resuscitation in the 16 survivors. However, r 2 values were relatively low (.20 to.50), which indicates that only a small fraction of the hyperlactacidemia was directly related to tissue hypoperfusion. In the whole population of survivors and nonsurvivors, both lactate and base deficit (but none of the oxygen-derived variables) correlated with blood loss. Conclusions: Arterial lactate is a stronger index of blood loss after penetrating trauma than base deficit or oxygen-derived hemodynamic variables. The reliability of arterial lactate depends on several factors, such as the time after injury, the proportion of survivors and nonsurvivors in the study population, and on factors other than tissue hypoxia.

Purpose: To compare the effects of mechanical ventilation with either positive end-expiratory pressure (PEEP) or partial liquid ventilation (PLV) on cardiopulmonary function after severe pulmonary contusion. Methods: Mongrel pigs (32 ± 1 kg) were anesthetized, paralyzed, and mechanically ventilated (8-10 mL/kg tidal volume; 12 breaths/min; Fio 2 = 0.5). Systemic hemodynamics and pulmonary function were measured for 7 hours after a captive bolt gun delivered a blunt injury to the right chest. After 5 hours, Fio 2 was increased to 1.0 and either PEEP (n = 7) in titrated increments to 25 cm H 2 O or PLV with perflubron (LiquiVent, 30 mL/kg, endotracheal) and no PEEP (n = 7) was administered for 2 hours. Two control groups received injury without treatment (n = 6) or no injury with PLV (n = 3). Fluids were liberalized with PEEP versus PLV (27 ± 3 vs. 18 ± 2 mL.kg -1 .h -1 ) to maintain cardiac filling pressures. Results: Before treatment at 5 hours after injury, physiologic dead space fraction (30 ± 4%), pulmonary vascular resistance (224 ± 20% of baseline), and airway resistance (437 ± 110% of baseline) were all increased (p < 0.05). In addition, Pao 2 /Fio 2 had decreased to 112 ± 18 mm Hg, compliance was depressed to 11 ± 1 mL/cm H 2 O (36 ± 3% of baseline), and shunt fraction was increased to 22 ± 4% (all p < 0.05). Blood pressure and cardiac index remained stable relative to baseline, but stroke index and systemic oxygen delivery were depressed by 15 to 30% (both p < 0.05). After 2 hours of treatment with PEEP versus PLV, Po 2 /Fio 2 was higher (427 ± 20 vs. 263 ± 37) and dead space ventilation was lower (4 ± 3 vs. 28 + 7%) (both p < 0.05), whereas compliance tended to be higher (26 + 2 vs. 20 ± 2) and shunt fraction tended to be lower (0 ± 0 vs. 7 ± 4). With PEEP versus PLV, however, cardiac index, stroke index, and systemic oxygen delivery were 30 to 60% lower (all p < 0.05). Furthermore, although contused lungs showed similar damage with either treatment, the secondary injury in the contralateral lung (as manifested by intra-alveolar hemorrhage) was more severe with PEEP than with PLV. Conclusions: Both PEEP and PLV improved pulmonary function after severe unilateral pulmonary contusion, but negative hemodynamic and histologic changes were associated with PEEP and not with PLV. These data suggest that PLV is a promising novel ventilatory strategy for unilateral pulmonary contusion that might ameliorate secondary injury in the contralateral uninjured lung.

Background: The goals were (1) to characterize physiologic changes after a combined insult of hemorrhage plus sepsis in a large animal model and (2) to determine whether transient inhibition of the neutrophil CD18 adherence receptor during fluid resuscitation impairs host defense during recovery from this injury. Methods: Two series of experiments were performed in anesthetized swine. In the first series (n = 22), the cecum was ligated and incised immediately before 35% hemorrhage. After 1 hour, shed blood plus supplemental fluid was administered to restore and stabilize hemodynamics. On the basis of these results, a second series examined effects of anti-CD18 (2 mg/kg R15.7; n = 9) or its saline placebo (n = 10) administered during fluid resuscitation. Results: In the first series the mortality rate was 41% (9 of 22). Early deaths occurred 3.0 ± 0.8 days after injury and were distinguished by significantly lower neutrophil counts on resuscitation. Those alive at 7 days had intraabdominal abscesses and bacteremia. Alveoli and peribronchial spaces were congested, with edema and fibrin deposition in capillaries and alveoli. Livers were congested with biliary stasis. Despite these pathologic findings, hemodynamic, electrolyte, and serum enzyme changes were minimal. In the second series the mortality rate at 4 days was 30% with placebo (3 of 10) versus 33% with anti-CD18 (3 of 9). Lung changes (i.e., pneumonia, pleuritis, thrombosis, and edema) were similar in both groups, but liver congestion and hemorrhage were attenuated by anti-CD18. Some aspects of host defense were altered by anti-CD18. At 24 and 48 hours the oxidative burst potential for circulating granulocytes was 208% ± 57% and 383% ± 73% with placebo versus 1273% ± 351% and 762% ± 226% in anti-CD18. At 72 hours the granularity of circulating neutrophils was unchanged from baseline with placebo but was reduced to 82% ± 5% by anti-CD18. At 48 hours lipopolysaccharide-evoked tumor necrosis factor production in vitro was reduced to 62% ± 22% with placebo but was increased to 148% ± 16% with anti-CD18. Conclusions: Anti-CD18 during fluid resuscitation did not increase vulnerability to endogenous pathogens because the transient inhibition of neutrophil demargination was balanced by enhanced oxidative burst, degranulation, and production of tumor necrosis factor in circulating cells later during recovery. Thus a single administration of antiadhesion therapy does not worsen posttrauma outcome even if given during ongoing sepsis. (Surgery 1998;123:679-91.)

Background: Granulocyte colony-stimulating factor (G-CSF) increases production and release of neutrophil precursors and activates multiple functions of circulating polymorphonuclear neutrophils (PMNs). G-CSF has therapeutic effects in many experimental models of sepsis; its actions with superimposed reperfusion insults are unknown. In traumatic conditions, G-CSF could exacerbate unregulated, PMN-dependent injury to otherwise normal host tissue or, it could partially reverse trauma-induced immune suppression, which may improve long-term outcome. This study tested whether stimulating PMN proliferation and function with G-CSF during recovery from trauma + sepsis potentiated reperfusion injury or whether it improved host defense. Methods: Anesthetized swine were subjected to cecal ligation and incision, 35% hemorrhage, and 1 hr of hypotension. Resuscitation consisted of intravenous G-CSF (5 μg/kg) or placebo followed by shed blood and 40 mL/kg of lactated Ringer's solution. The control group received laparotomy only. G-CSF or placebo was given daily. Animals were killed at 4 days. Observers, blind to the protocol, graded autopsy samples for localization of infection and quality of abscess wall formation. Data included complete blood count, granulocyte oxidative burst after phorbol myristate acetate stimulation in vitro (GO 2 B), bronchoalveolar lavage (BAL) cell count, BAL noncellular protein, lipopolysaccharide-stimulated tumor necrosis factor production in whole blood in vitro(lipopolysaccharide-tumor necrosis factor), and lung tissue myeloperoxidase (MPO). Results: Neutrophilia and localization of infection, were significantly improved by G-CSF. Variables altered by G-CSF, though not significantly, showed GO 2 B potential increased by 50%, lipopolysaccharide-tumor necrosis factor decreased by 50%, and improved survival versus placebo (100% vs. 70%). G-CSF did not increase lung MPO, BAL cell count, or BAL protein. Both arterial and venous O 2 saturations were unaltered. Conclusions: Our data show that G-CSF initiated at the time of resuscitation reduced the sequelae of posttrauma sepsis by increasing PMN proliferation and function without potentiating PMN-mediated lung reperfusion injury.

A miniature wireless vital signs monitor (MWVSM, www.athena.gtx.com) has been designed according to US Special Operations Command specifications for field monitoring of combat casualties. It incorporates an injury acuity algorithm termed the Murphy Factor (MF), which is calculated from whatever vital signs are available at the moment and changes in the last 30 seconds. We tested the hypothesis that MF can identify civilian trauma patients during prehospital transport who will require a lifesaving intervention (LSI) upon hospital admission.From December 2011 to June 2013, a prospective trial was conducted in collaboration with prehospital providers. The MWVSM detects skin temperature, pulse oximetry (SpO2), heart rate (HR), pulse wave transit time, and MF. LSIs included: intubation, tube thoracostomy, central line insertion, blood product transfusion, and operative intervention. Prehospital MWVSM data were compared with simultaneous vital signs (SaO2, systolic blood pressure (SBP), and HR) from a conventional vital signs monitor. Sensitivity, specificity, negative predictive value, positive predictive value, and area under the receiving operating characteristic curves were calculated.Ninety-six trauma patients experienced predominantly blunt trauma (n = 80, 84%), were mostly male (n = 79, 82%), and had a mean ± SD age of 48 ± 19 years and an Injury Severity Score (ISS) of 10 (17). Those who received an LSI (n = 48) had similar demographics but higher ISS (18 vs. 5) and mortality (23% vs. 0%) (all p0.05). The most common LSIs were intubation (n = 24, 25%), blood product transfusion (n = 19, 20%), and emergency surgery (n = 19, 20%). Compared with HR100 beats/min, SBP90 mm Hg, SaO295% alone or in combination, MF3 during the entire transport time had the largest area under the receiving operating characteristic curves (0.620, p = 0.081). MF greater than 3 had a specificity of 81%, sensitivity of 39%, positive predictive value of 68%, and negative predictive value of 57% for the need for LSI.A single numeric value has the potential to summarize overall patient status and identify prehospital trauma patients who need an LSI. Prehospital monitoring combined with algorithms that include trends over time could improve prehospital care for both civilian and military trauma.Prospective observational, level II.

Thromboelastography (TEG) on hospital admission can identify hypercoagulable trauma patients at risk for venous thromboembolism (VTE), but the value of TEGs obtained after multiple interventions, including tranexamic acid (TXA), has not been defined. We test the following hypotheses. (1) TEG on intensive care unit (ICU) admission can help stratify patients screened with Greenfield's risk assessment profile (RAP) for VTE. (2) TXA is a VTE risk factor, and its effect on fibrinolysis can be identified with TEG.Trauma patients who survived to the ICU with RAP ≥ 10 received serial venous duplex ultrasound examinations and blood samples for coagulation analysis at admission to the ICU and weekly thereafter.Six hundred seventy-eight patients were screened and 121 were enrolled; 76% blunt injury, Injury Severity Score (ISS) 27, 13% mortality. Thromboprophylaxis was administered to 90% of the patients and was started a median of 2 days after hospital admission. VTE was detected in 28% (n = 34) of the patients (27 deep vein thrombosis and 7 pulmonary emboli) and occurred a median 10 days after admission. Twenty-nine percent (n = 10) of VTE occurred within 2 days of admission. Most variables were similar between those with and without VTE, but the VTE group received more operations (3 (2) vs. 2 (2), p = 0.044), had increased ICU days (25 (34) days vs. 15 (18) days, p = 0.004), and was more likely to have abdominal injury with Abbreviated Injury Scale (AIS) score2 (59% vs. 39%, p = 0.050). Upon ICU admission, standard coagulation markers were within normal limits, while TEG demonstrated hypercoagulability, but neither was associated with VTE. Repeat TEG one week after admission (n = 58) remained hypercoagulable but transitioned to a different pattern with increased clot strength. TXA was associated with reduced fibrinolysis on initial TEG (p0.05) but was not associated with VTE.Trauma ICU patients with RAP ≥ 10 are hypercoagulable at admission to ICU and remain so during recovery. They have a ≥ 25% rate of VTE, despite thromboprophylaxis. TXA is associated with reduced fibrinolysis but does not increase VTE rates. Neither TEG nor standard coagulation markers (measured on ICU admission) stratify high-risk patients who develop VTE from those who do not.Prognostic study, level III.

Background. The purpose of this experimental study was to test whether transfusion potentiated physiologic changes associated with fluid resuscitated trauma in controlled conditions. Methods. Anesthetized and ventilated mongrel pigs were subjected to soft-tissue injury plus 35% hemorrhage and 1 hour shock and then were resuscitated with either autologous (shed) or heterologous (crosstransfused) fresh whole blood. Leukocyte differential counts, T-lymphocyte subsets, neutrophil adherence molecule (CD18) expression, granulocyte oxidative burst, plasma cortisol, and serum chemistries were monitored in awake animals with indwelling catheters on 3 consecutive days. Changes were referenced to preinjury baseline values and to a control group that received heterologous transfusion but no shock. To determine whether these changes might have influenced host defense, a low-dose challenge with Escherichia coli endotoxin (lipopolysaccharide [LPS]; 1 to 2 μg/kgfor 30 minutes) was administered on day 4. Results. During recovery, neutrophil counts, neutrophil CD18 expression, and granulocyte oxidative burst were generally increased, but the changes were not potentiated by transfusion. Lymphocyte subpopulations remained relatively constant. Serum enzyme markers were elevated with trauma plus shed blood or trauma plus cross-transfusion, but they remained essentially unchanged after heterologous transfusion only. Plasma cortisol, a nonspecific index of stress, peaked at 3 to 6 times higher than baseline. The increases tended to be higher and later with heterologous transfusion only, relative to trauma plus shed blood or trauma plus cross-transfusion. The delayed LPS challenge evoked profound but transient pulmonary hypertension and leukopenia, followed by subsequent hypoxemia; the time courses and magnitude of these changes were similar in all groups. Conclusions. If these measured variables before and after LPS challenge are a valid index of host defense in this species, then a 35% transfusion does not potentiate the risk for posttrauma immune dysfunction when the magnitude of injury is constant. Thus the predisposition to infection after human trauma might be due to cold storage of blood, separation of blood into components, or other transfusion-related practices rather than to transfusion per se.

We have shown that therapy directed at polymorphonuclear neutrophil (PMN) CD18 receptors attenuates sequelae associated with a post-trauma endotoxin (lipopolysaccharide [LPS]) challenge. Platelet activating factor (PAF) stimulates PMNs by CD18-independent pathways, and WEB-2086, a PAF receptor antagonist, blunts septic symptoms in many experimental models. This study tested the hypothesis that the blockade of non-CD18 dependent PMN adherence attenuates trauma- and LPS-evoked pulmonary dysfunction.We performed three experiments. First, anesthetized swine were subjected to hind-limb trauma and 30% hemorrhage. After 1 hour animals were resuscitated with shed blood, lactated Ringer's solution (LRS), and WEB-2086 (10 mg/kg/hr) or vehicle. After a 72-hour recovery period, LPS was administered. LPS was then administered without an earlier episode of traumatic shock to animals treated with WEB-2086 or vehicle. Finally, PAF was infused before and after trauma and a dose response curve was obtained.Surprisingly, PAF blockade increased mortality after trauma (5 of 11 WEB-2086 animals versus 1 of 9 vehicle animals; p = 0.15) and depressed cardiac index and O2 delivery at 72 hours (p0.05). After LPS administration WEB-2086 treated pigs were unable to manifest the hyperdynamic circulatory compensation seen in the vehicle pigs. In the absence of traumatic shock, WEB-2086 was associated with reduced mortality (four of five WEB-2086 treated pigs versus two of five vehicle pigs survived 5 hours; p = 0.07) and improved arterial PO2 (p = 0.05) and base excess (p = 0.04) 60 minutes after LPS administration. The dose response curve for PAF infusion on the cardiac index was altered after trauma compared with the nontraumatized state.Because WEB-2086 had unexpected and fundamentally opposite properties before and after trauma, PAF may have a previously undescribed homeostatic role in the compensatory response to injury. These results also suggest that blockade of endogenous inflammatory mediators can have a positive or negative action, depending on the timing of administration and the preexisting condition.

Dehydroepiandrosterone (DHEA), an endogenous immune modulator, reduces mortality after endotoxin (lipopolysaccharide (LPS)) administration in rodents. However, there have been no studies in clinically relevant large-animal models. A unique experimental model is used to study the effects of DHEA in resuscitated trauma and to evaluate the protective effect of DHEA on the systemic inflammatory response induced by a delayed LPS challenge. Anesthetized, ventilated pigs were instrumented and then subjected to local hind-limb trauma and 35% hemorrhage. After 1 h, animals were resuscitated with shed blood, supplemental Ringers solution, and in a randomized, blinded fashion, 4 mg/kg of DHEA or vehicle. Two additional groups received 10 mg/kg or 20 mg/kg of DHEA. Animals were dosed again at 24, 48, and 72 h. After 75 h, Escherichia coli LPS was administered. LPS caused a fall in DHEA levels (0.23 +/- .05 ng/mL (60 min post-LPS) versus .94 +/- 35 ng/mL (72 h), p = .01). DHEA levels 60 min post-LPS were significantly higher in treated animals (p < .002). After LPS, all groups manifested progressive septic symptoms with a hyperdynamic state and pulmonary failure. These symptoms were not blunted by the administration of DHEA. DHEA levels are suppressed by LPS in this two-stage model of trauma and delayed sepsis; however, exogenous DHEA administration fails to blunt the associated systemic inflammatory response and pulmonary failure.

The purpose of this study was to evaluate the long-term coagulation status of patients undergoing malignancy resection.A prospective observational trial was conducted with informed consent in 52 patients (age 66 ± 10 years and 60% male) with thoracoabdominal tumors (pancreas [n = 18, 35%], esophagus [n = 13, 25%], liver [n = 7, 14%], stomach [n = 6, 12%], bile duct [n = 3, 6%], retroperitoneal [n = 3, 6%], and duodenum [n = 2, 4%]) with 6- to 12-month follow-up. Coagulation was evaluated with rotational thromboelastography (ROTEM) on whole blood and with a panel of hemostatic markers on stored plasma.Maximum clot firmness (MCF) in the intrinsic, extrinsic, and fibrinogen pathways increased immediately postoperatively and then decreased by 9.2 ± 4.1 months (p0.05). Markers of thrombin generation (prothrombin fragment 1 + 2, fibrinolysis [D-dimer], and endothelial activation [coagulation factor VIII]) were elevated at all time points. The ROTEM pattern depended on histologic type and cancer location. All esophageal tumors were adenocarcinoma and demonstrated similar patterns to the overall population, with MCF differences over time in all 3 pathways (all p0.05). Regarding tumors of the pancreas or liver, there were no statistically significant differences when comparing all 3 time periods, but there were time-related differences when evaluating only primary adenocarcinomas of the liver (all p0.05). Three patients (6%) developed venous thromboembolism (VTE) and had decreased clot formation time, increased angle, and increased MCF (all p0.05).Cancer patients at risk for VTE can be identified with a point-of-care ROTEM test and may benefit from additional anticoagulation. Biomarkers reflecting different functional hemostasis activity groups (fibrinolysis, thrombin generation, and endothelial activation) confirm the ongoing prothrombotic state. The ROTEM demonstrated increased hypercoagulability postoperatively, which returned to baseline in long-term follow-up. Reversal of cancer-induced hypercoagulability occurred in some patients and varied with tumor histology and location.

This study tests the hypothesis that a change in hematocrit (ΔHct) during initial trauma work-up is as reliable as conventional vital signs for detecting bleeding, even with ongoing fluid resuscitation. Consecutive trauma patients admitted to a Level I trauma center receiving two Hct measurements during initial resuscitation between January 2010 and January 2011 were stratified based on estimated blood loss greater than 250 mL (bleeding) or nonbleeding. Sensitivity, specificity, and receiver operating characteristic curves were calculated for systolic blood pressure (SBP), heart rate, base deficit, and ΔHct. In 168 (72%) nonbleeding versus 64 (28%) bleeding patients, age and gender were similar. Arrival SBP was highly specific (90 to 99%) but poorly sensitive (13 to 31%) for detecting bleeding. Combinations of vital signs increased specificity, albeit at the expense of sensitivity. For bleeding versus nonbleeding patients (all receiving resuscitation fluid), ΔHct was 9.0 versus 1.8, ΔHct/liter was 4.8 versus 1.5, and ΔHct/liter/hour was 2.8 vs 0.6 (all P0.001). Only SBP (area under the curve [AUC] 0.608 to 0.695) and ΔHct (AUC 0.731 to 0.921) were significant for identifying bleeding with ΔHct 6 or greater being the best predictor (sensitivity 89%, specificity 95%, AUC 0.921). During ongoing fluid resuscitation of a trauma victim, ΔHct is the single most reliable indicator of continuing blood loss. A ΔHct 6 or greater during initial resuscitation is highly suspicious for ongoing blood loss, but even lesser changes have predictive value. Altogether, these results support the idea that fluid shifts are rapid after hemorrhage and Hct can be valuable during initial trauma assessment.

In this era of cost containment, the value of routine repeat head computed tomography (CT) in patients with mild TBI (mTBI) and no interval neurologic change has been challenged. The purpose of this study was to test the hypothesis that routine repeat head CT provides critical information after mTBI even with no neurologic change.From January 1996 to May 2010, records from all patients admitted to our Level I trauma center with an arrival Glasgow Coma Scale (GCS) score of 13 to 15 and at least one head CT were retrospectively reviewed.In 360 patients with mTBI and positive initial head CT finding, the most common abnormalities were subarachnoid hemorrhage (64%), intraparenchymal hemorrhage (57%), and subdural hemorrhage (40%). Scans were repeated in 8 ± 6 hours; 11% were recalled, 59% remained stable, but 30% showed injury progression. Those patients with worsening repeat head CT finding had higher Injury Severity Score (ISS), were more likely to be intubated and require craniotomy, had longer stay, and had higher mortality (all p0.001). On multiple logistic regression, altered GCS score (odds ratio, 3.1-4.0), ISS (odds ratio, 1.1), and presence of mass effect (odds ratio, 2.0) were independently associated with worsening repeat head CT finding. In patients receiving a neurosurgical operative intervention, 32% to 59% had no clinical decline before the worsening repeat CT finding.After mTBI, worsening of repeat head CT finding is seen in a third of patients and is associated with worse outcomes. A substantial fraction of patients who require operative intervention will have no clinical changes in the first 8 hours, supporting the value of repeat head CT within this time frame.Care management study, level III.

Background Rotational thromboelastometry (ROTEM) is a new point-of-care test that allows a rapid and comprehensive evaluation of coagulation. We were among the first to show that ROTEM identifies baseline hypercoagulability in 40% of patients with intra-abdominal malignancies and that hypercoagulability persists for ≥1 month after resection. The purpose of this follow-up study was to confirm and extend these observations to a larger population in outpatient preoperative clinics. The hypothesis is that pre-existing hypercoagulability is present in patients undergoing surgery for malignant disease and that coagulation status varies by tumor type. Methods After informed consent, preoperative blood samples were drawn from patients undergoing exploratory laparotomies for intra-abdominal malignancies and analyzed with ROTEM. Results Eighty-two patients were enrolled, including 72 with a confirmed pathologic diagnosis and 10 age-matched controls with benign disease. The most common cancers involved the pancreas ( n = 23; 32%), esophagus ( n = 19; 26%), liver ( n = 12; 17%), stomach ( n = 7; 10%), and bile ducts ( n = 5; 7%). Preoperative hypercoagulability was detected in 31% ( n = 22); these patients were more likely to have lymphovascular invasion (88% vs 50%; P = .011), perineural invasion (77% vs 36%; P = .007), and stage III/IV disease (80% vs 62%; P = .039). More patients with pancreatic tumors (9/23, 39%) were hypercoagulable than with esophageal (3/19, 16%) or liver (2/13, 15%, P = .034) tumors. When only resectable malignancies were considered, clot formation was more rapid (low clot formation time, high alpha) with enhanced maximum clot strength (high maximum clot firmness) in pancreatic versus esophageal or liver cancers and in all cancers versus those with benign disease. Conclusion Preoperative hypercoagulability can be identified with ROTEM and is associated with lymphovascular/perineural invasion and advanced-staged disease in cancer. Compared with other tumor types, pancreatic adenocarcinomas have the greatest risk for hypercoagulability.

Background: Extremity wounds account for most battlefield injuries. Clinical examination may be unreliable by medics or first responders, and continuous assessment by experienced practitioners may not be possible on the frontline or during transport. Near-infrared spectroscopy (NIRS) provides continuous, noninvasive monitoring of tissue oxygen saturation (StO2), but its use is limited by inter-patient and intra-patient variability. We tested the hypothesis that bilateral NIRS partially addresses the variability problem and can reliably identify vascular injury after extremity trauma. Materials and methods: This prospective study consisted of 30 subjects: 20 trauma patients with extremity injury and 10 healthy volunteers. Bilateral StO2 tissue sensors were placed on the thenar eminence or medial plantar surface. Injured and non-injured extremities within the same patient (DStO2) were compared using Wilcoxon signed ranks test. Receiver operating characteristic curves were generated and areas under the curve (AUCs) were calculated for DStO2 of 6, 10, and 15. Values are expressed as median (interquartile range). Results: Trauma patients were age 31 y (23 y), 85% male, with injury severity score of 9 (5). There were seven arterial and three venous injuries. Most involved the lower extremity (n ¼ 16; 80%) and resulted from a penetrating mechanism (n ¼ 14; 70%). DStO2 between limbs was 20.4 (10.4) versus 2.4 (3.0) (P < 0.001) for all patients with vascular injury versus patients and volunteers with no vascular injury. DStO2 reliably identified any vascular injury (AUC, 0.975; P < 0.001), whereas pulse examination alone or in combination with Doppler exam could detect only arterial injury. A DStO2 of 6 had the greatest sensitivity and specificity (AUC, 0.900; P < 0.001). Conclusions: Continuous monitoring of bilateral limbs with NIRS detects changes in perfusion resulting from arterial or venous injury and may offer advantages over serial manual measurements of pulses or Doppler signals. This technique may be most relevant in military and disaster scenarios or during transport, in which the ability to monitor limb perfusion is difficult or experienced clinical judgment is unavailable.

Blood substitutes such as hemoglobin-based oxygen carriers (HBOC) have tremendous potential to improve pre hospital fluid resuscitation in both civilian and military populations. This chapter reviews goals and current recommendations of pre hospital resuscitation, the historical development of HBOC and initial clinical trials, and future developments that may improve pre hospital resuscitation.

Background. Histamine H 2 antagonists (e.g., ranitidine) are generally thought to specifically reduce gastric acid secretion and are commonly used for stress ulcer prophylaxis in critically ill patients because of their efficacy and safety profile. A few reports suggest that ranitidine might also bind to extragastric sites and/or act as an immunomodulator. The potential effects on posttraumatic sepsis are unknoum. Methods. Mongrel pigs (n=24) were anesthetized with fentanyl, injured by a 10 kg steel bar dropped from a height of 1 m onto the fleshy portion of the posterior thigh, and then 35% of their blood volume was drained through the arterial catheter. All the shed blood plus two times the hemorrhage volume as lactated Ringer's solution was infused after a 1-hour shock period. Either vehicle or ranitidine (1.5 mg/kg) was intravenously administered at the time of resuscitation and every 12 hours thereafter in a blinded fashion. After 72 hours a septic challenge was administered (15 μg/kg Escherichia coli lipopolysaccharide [LPS]×30 min). Serial gastroscopy, gastric pH, hemodynamics leukocyte counts, cortisol, and tumor necrosis factor were recorded for 180 minutes after LPS. Results. Immediately before LPS all hemodynamic variables were identical between treatments, but gastric pH was slightly higher and stress gastritis was marginally lower with ranitidine. LPS caused profound leukopenia and a hyperdynamic circulatory response (i.e., tachycardia, increased cardiac output, and decreased peripheral vascular resistance at relatively constant blood pressure); these changes were not altered by ranitidine. Gastric pH remained elevated after LPS with ranitidine, but LPS-induced gastritis was not modified. Ranitidine delayed the LPS-induced ventilation-perfusion imbalance and attenuated the peak increase in the proinflammatory cytokine, tumor necrosis factor, without altering its antiinflammatory opponent, cortisol. Similar changes were observed in four additional animals treated with cimetidine. The proportion of circulating neutrophils and lymphocytes was slightly altered 180 minutes after LPS, but there was no obvious effect on T lymphocytes in vivo, and no effect on the LPS-induced increase in neutrophil CD18 expression in vitro was seen. Conclusions. (1) Ranitidine increased gastric pH, which blunted the stress gastritis caused by trauma but not that caused by LPS; (2) ranitidine delayed the early LPS-evoked pulmonary changes and reduced the tumor necrosis factor spike, which is consistent with a favorable immunomodulatory action that has been reported in patients who are critically ill or are undergoing an elective abdominal surgical procedure; (3) the mechanism is probably related to H 2 receptor antagonism rather than to a nonspecific side effect of ranitidine, which suggests that histamine may have a previously unrecognized role in posttraumatic septic responses; and (4) the site of action is probably not in the heart or peripheral resistance vessels, but salutary effects on circulating lymphocytes or neutrophils cannot be excluded.

In the late 1990s, a Department of Defense subcommittee screened more than 100 civilian trauma centers according to the number of admissions, percentage of penetrating trauma, and institutional interest in relation to the specific training missions of each of the three service branches. By the end of 2001, the Army started a program at University of Miami/Ryder Trauma Center, the Navy began a similar program at University of Southern California/Los Angeles County Medical Center, and the Air Force initiated three Centers for the Sustainment of Trauma and Readiness Skills (C-STARS) at busy academic medical centers: R. Adams Cowley Shock Trauma Center at the University of Maryland (C-STARS Baltimore), Saint Louis University (C-STARS St. Louis), and The University Hospital/University of Cincinnati (C-STARS Cincinnati). Each center focuses on three key areas, didactic training, state-of-the-art simulation and expeditionary equipment training, as well as actual clinical experience in the acute management of trauma patients. Each is integral to delivering lifesaving combat casualty care in theater. Initially, there were growing pains and the struggle to develop an effective curriculum in a short period. With the foresight of each trauma training center director and a dynamic exchange of information with civilian trauma leaders and frontline war fighters, there has been a continuous evolution and improvement of each center's curriculum. Now, it is clear that the longest military conflict in US history and the first of the 21st century has led to numerous innovations in cutting edge trauma training on a comprehensive array of topics. This report provides an overview of the decade-long evolutionary process in providing the highest-quality medical care for our injured heroes.

Trauma center performance depends on quality metrics, such as mortality rates, but there have been few studies on how an exact definition of death can influence these statistics. The purpose of this study was to test the hypothesis that the mortality rate at one trauma center could be influenced by the interpretation of "dead on arrival." Personal communication suggests that this definition is applied variably throughout our state.All deaths at our Level I trauma center from January 2009 to April 2011 were reviewed.There were 11,121 trauma admissions, predominantly male (75%), with mean +/- SD of 39 +/- 20, 72% blunt, 22% penetrating, and 7% burn injuries. There were 661 deaths, of which 582 were "hospital deaths" and an additional 79 were classified as "dead on arrival," defined as patients arriving with no vital signs and receiving no hospital intervention. However, 23% (n = 136) of the hospital deaths also arrived with no vital signs but received some lifesaving intervention, for example, tube thoracostomy (n = 95, 70%), thoracotomy (n = 48, 35%), and/or central venous catheter (n = 21, 15%). The state-reported mortality rate each month was 5.3 +/- 1.4%. If those who arrived with no vital signs were excluded, the mortality rate each month was 4.0 +/- 1.2% (p0.001).At this trauma center, approximately one fourth of the deaths reported to the state were patients who arrived with no vital signs. If any lifesaving intervention is attempted in these moribund patients, even if it is futile, it is termed "hospital death," rather than "dead on arrival." State regulations exclude patients who received any intervention from being classified as dead on arrival, but compliance with this definition is not audited. Therefore, unless there is strict compliance and standardized definitions, any comparison of trauma center quality based on mortality could be questioned.Epidemiologic study, level III.

Rates of venous thromboembolism as high as 58% have been reported after trauma, but there is no widely accepted screening protocol. If Medicare adds venous thromboembolism to the list of "preventable complications," they will no longer reimburse for treatment, which could have devastating effects on many urban centers. We hypothesized that prescreening with a risk assessment profile followed by routine surveillance with venous duplex ultrasound that could identify asymptomatic venous thromboembolism in trauma patients.Prospective, observational trial with waiver of consent.Level I trauma center intensive care unit.At admission, 534 patients were prescreened with a risk assessment profile.Patients (n = 106) with risk assessment profile scores10 were considered high risk and received routine screening venous duplex ultrasound within 24 hrs and weekly thereafter.In prescreened high-risk patients, 20 asymptomatic deep vein thrombosis were detected with venous duplex ultrasound (19%). An additional ten venous thromboembolisms occurred, including six symptomatic deep vein thrombosis and four pulmonary emboli, resulting in an overall venous thromboembolism rate of 28%. The most common risk factors discriminating venous thromboembolism vs. no venous thromboembolism were femoral central venous catheter (23% vs. 8%), operative intervention2 hrs (77% vs. 46%), complex lower extremity fracture (53% vs. 32%), and pelvic fracture (70% vs. 47%), respectively (all p.05). Risk assessment profile scores were higher in patients with venous thromboembolism (19 ± 6 vs. 14 ± 4, p = .001). Risk assessment profile score (odds ratio 1.14) and the combination of pelvic fracture requiring operative intervention2 hrs (odds ratio 5.75) were independent predictors for development of venous thromboembolism. The rates of venous thromboembolism for no chemical prophylaxis (33%), unfractionated heparin (29%), dalteparin (40%), or inferior vena cava filters (20%) were not statistically different (p = .764).Medicare's inclusion of venous thromboembolism after trauma as a "never event" should be questioned. In trauma patients, high-risk assessment profile score and pelvic fracture with prolonged operative intervention are independent predictors for venous thromboembolism development, despite thromboprophylaxis. Although routine venous duplex ultrasound screening may not be cost-effective for all trauma patients, prescreening using risk assessment profile yielded a cohort of patients with a high prevalence of venous thromboembolism. In such high-risk patients, routine venous duplex ultrasound and/or more aggressive prophylactic regimens may be beneficial.

BACKGROUND: Central venous catheters (CVCs) increase the risk of venous thromboembolism. We have previously demonstrated that pulmonary artery catheters are associated with a hypercoagulable state in an animal model and in patients. The purpose of this study is to determine whether the insertion of a CVC is associated with a similar response. METHODS: Animal: 7F femoral artery catheters were placed in healthy anesthetized swine (N = 16). Serial arterial blood samples were drawn immediately before and after an 8.5F jugular vein CVC and then for 3 hours after CVC removal. Samples were analyzed using kaolin-activated thromboelastography (TEG) at precisely 2 minutes. Human: An institutional review boardYapproved prospective observational trial was conducted, with informed consent, in patients with critical illness (N = 8) at a Level I trauma center. Blood was drawn from indwelling arterial catheters immediately before and 60 minutes after CVC insertion. Samples were stored in sodium citrate for 15 minutes before TEG. Routine and special coagulation tests were performed on stored samples in the hospital pathology laboratory. RESULTS: Insertion of a CVC decreased TEG clotting time (R) by 55% in swine and by 29% in humans (p G 0.001 and 0.019, respectively). Initial clot formation time (K) was reduced by 41% in swine and by 36% in humans (p = 0.003 and 0.019). Fibrin cross-linking (>) was accelerated by 28% in swine and by 17% in humans (p = 0.007 and 0.896), but overall clot strength (maximum amplitude) was not affected. There was no change in routine or special coagulation factors, including von Willebrand factor, antithrombin III, prothrombin time, international normalized ratio, or activated partial thromboplastin time. In animals, the hypercoagulable TEG response was persistent for 3 hours after CVC removal and was prevented by pretreatment with enoxaparin (n = 4) but not heparin (n = 2). CONCLUSION: In healthy swine and patients with critical illness, a systemic hypercoagulable state occurred after CVC insertion, and this may partially account for an increased risk of venous thromboembolism. However, because the sample size was small and not powered to detect changes in coagulation proteins, no inferences can be made about the mechanism for the hypercoagulable response. (J Trauma Acute Care Surg. 2012;73: 385Y390. Copyright * 2012 by Lippincott Williams & Wilkins)

Background Recently, three patients with hemopericardium after severe chest trauma were successfully managed nonoperatively at our institution. This prompted the question whether these were rare or common events. Therefore, we reviewed our experience with similar injuries to test the hypothesis that trauma-induced hemopericardium mandates sternotomy. Method Records were retrospectively reviewed for all patients at a Level I trauma center (December 1996 to November 2011) who sustained chest trauma with pericardial window (PCW, n = 377) and/or median sternotomy (n = 110). Results Fifty-five (15%) patients with positive PCW proceeded to sternotomy. Penetrating injury was the dominant mechanism (n = 49, 89%). Nineteen (35%) were hypotensive on arrival or during initial resuscitation. Most received surgeon-performed focused cardiac ultrasound examinations (n = 43, 78%) with positive results (n = 25, 58%). Ventricular injuries were most common, with equivalent numbers occurring on the right (n = 16, 29%) and left (n = 15, 27%). Six (11%) with positive PCW had isolated pericardial lacerations, but 21 (38%) had no repairable cardiac or great vessel injury. Those with therapeutic versus nontherapeutic sternotomies were similar with respect to age, mechanisms of injury, injury severity scores, presenting laboratory values, resuscitation fluids, and vital signs. Multiple logistic regression revealed that penetrating trauma (odds ratio: 13.3) and hemodynamic instability (odds ratio: 7.8) were independent predictors of therapeutic sternotomy. Conclusion Hemopericardium per se may be overly sensitive for diagnosing cardiac or great vessel injuries after chest trauma. Some stable blunt or penetrating trauma patients without continuing intrapericardial bleeding had nontherapeutic sternotomies, suggesting that this intervention could be avoided in selected cases. Level of evidence Therapeutic study, level III.

Few patients require angiography and therapeutic embolization for bleeding pelvic fractures, but they are risk for significant morbidity and mortality. In hemodynamically unstable trauma patients with pelvic fractures, the decision to proceed to the operating room (OR) to address intraabdominal bleeding, or angiography to address pelvic bleeding (ANGIO), is rarely straightforward. This study tested the hypothesis that outcomes are similar regardless if the sequence was OR-ANGIO or ANGIO-OR.All pelvic fractures between 1999 and 2011 were retrospectively reviewed and stratified by initial management with ANGIO or OR.Of 2,922 patients with pelvic fractures, only 183 (6%) required angiography for suspected bleeding. For OR-ANGIO (n = 49) versus ANGIO (n = 134), injury severity score was similar (40 ± 15 vs. 35 ± 16), but systolic blood pressure (97 ± 28 vs. 108 ± 32 mmHg, p = 0.038) and base excess were both lower (-9 ± 5 vs. -5 ± 5 mEq/L, p0.001). During initial resuscitation and in the first 24 hours, crystalloid, blood product usage and total fluid requirements were all increased 50% to 100% (all p0.001). Despite these differences, lengths of stay (32 ± 32 vs. 26 ± 28 days) and mortality (33% vs. 31%) were similar. The same trends in fluid requirements remained in the subset of patients with unstable pelvic fractures, with an increased mortality (67% vs. 20%, p = 0.011) in those requiring ANGIO-OR versus OR-ANGIO.These data support current management algorithms. In hemodynamically unstable trauma patients with pelvic fractures, those who proceeded immediately to the OR to address intraabdominal bleeding tended to be sicker but had outcomes that were the same or better compared with those who received angiography to address pelvic bleeding.III, retrospective review.

After severe trauma and hemorrhage, it is generally assumed that the rate of fluid shift from the interstitial space into the vasculature is relatively slow and that initial hematocrit (Hct) does not reflect estimated blood loss. This study challenges that idea and tests the hypothesis that initial Hct correlates with signs of shock and hemorrhage in trauma patients.Data were retrospectively reviewed from 198 trauma patients requiring emergency surgery at a Level I center from July 2009 to April 2010. Patients were divided into quartiles based on the initial Hct measured within 10 minutes of arrival. Categorical data were compared using χ(2) test or Fisher's exact test, as appropriate. Normally distributed data were compared using Student's t test or analysis of variance. Nonparametric data were compared with a Mann-Whitney U test or Kruskal-Wallis test. Post hoc analysis was conducted using the Bonferroni correction or paired Mann-Whitney U tests.The study population was 83% male, aged 35 ± 1 years (mean ± SE), with 71% penetrating injuries. Lower initial Hct correlated with hypotension (p0.001), acidosis (p = 0.003), altered mental status (p0.001), Injury Severity Score (p0.001), Revised Trauma Score (p0.001), estimated blood loss (p0.001), and usage of packed red blood cells (p0.001), fresh frozen plasma (p = 0.003), crystalloid (p = 0.021), and vasopressors (p0.001).Admission Hct correlates with signs of shock and hemorrhage in trauma patients requiring emergency surgery because fluid shifts rapidly from the interstitial space into the vasculature. This finding of a rapid Hct change contradicts the current teaching in most trauma textbooks.

To examine the role of systemic plasma tumor necrosis factor (TNF) in the septic response following trauma, an endotoxin (lipopolysaccharide (LPS)) challenge was administered to anesthetized mongrel pigs 72 h following either hemorrhagic shock/resuscitation or sham shock. For TNF to be considered a mediator, at least two conditions should be satisfied: a TNF increase should precede other manifestations of the septic response and the magnitude of that increase should correlate with the symptoms. Immediately following resuscitation from shock, hemodynamics were stable, but heart rate, cardiac index (CI), and systemic oxygen delivery (DO2) were elevated 20-60%, and systemic vascular resistance (SVR) was decreased 40%, relative to the preshock baseline. After 72 h, the animals were reanesthetized, reinstrumented, and all hemodynamic values were near normal in both groups. At this point, either 1.5 (shock, n = 2; sham, n = 2), 15 (shock, n = 7; sham, n = 6) or 150 (shock, n = 11; sham, n = 4) micrograms/kg of Escherichia coli LPS was administered intravenously over 30 min. Serial hemodynamic data, complete blood counts, and TNF were recorded for 3 h post-LPS. LPS evoked profound leukopenia and pulmonary hypertension within 15 min that was followed by a hyperdynamic septic response (i.e., progressive arterial desaturation, tachypnea, tachycardia, increased CI, and decreased SVR) and rise in plasma TNF at 60-90 min. In the shock group, LPS-evoked TNF changes were less than or equal to those in the sham group, even though mortality was higher after shock.(ABSTRACT TRUNCATED AT 250 WORDS)

At the end of the 20th century, the Institute of Medicine reviewed the state of the art for combat casualty and civilian trauma care. Intravenous saline (or crystalloid) solutions were typically the first-line therapy for hypovolemic shock patients to compensate for acute blood loss before transfusions could be safely administered.1 In the first decade of the 21st century, little has changed; isotonic crystalloids remain the standard of care. There are promising data on the salutary actions of several different colloid or hypertonic solutions relative to isotonic crystalloids2–6; but to date, virtually no randomized controlled trial has reported a significant survival benefit of these novel solutions. As of 2006, there were at least 32 randomized controlled trials comparing albumin to crystalloid solutions in 8,452 critically ill patients with hypovolemia or burns, and there was no evidence that albumin reduced mortality when compared with cheaper alternatives.7 As of 2007, there were at least 55 randomized controlled trials of colloids compared with crystalloids, and there was no evidence that colloids reduced the risk of death compared with crystalloids in 7,754 patients with trauma or burns or after surgery.8 As of 2008, a review of 70 trials in 4,375 patients found no evidence that any one colloid solution is safer or more effective than any other.9 Because colloids are not associated with an improvement in survival and because they are more expensive than crystalloids, some thought that leaders, especially in the civilian sector, are convinced that continued use of colloids in trauma patients cannot be justified outside the context of randomized controlled trials.8 For the military, on the other hand, colloids and other low-volume resuscitation solutions are attractive alternatives, because they have unique advantages in austere environments where supplies are limited and evacuation times can be delayed. For these logistic reasons because of its reduced weight and size relative to saline solutions, Hextend (HEX, 6% hetastarch in lactated electrolyte buffer; www.hospira.com) was recommended for fluid resuscitation of combat casualties.10,11 HEX is a colloid approved by the US Food and Drug Administration that is indicated for use in hypovolemia during elective surgery.12 Despite these recommendations, saline solutions are still commonly used on the battlefield. Furthermore, many civilian or military clinicians avoid any artificial colloid solutions after trauma because of generalized concerns about anaphylaxis,1 coagulopathy,13 and/or catastrophic bleeding.14 In fact, the few studies that have addressed the coagulation profile of HEX have been inconclusive15–18; and there are no data on the safety and efficacy of HEX at the doses typically used for initial trauma resuscitation, except for several previous studies in various animal models.19–23 Ogilvie et al.24 attempted to fill this gap by examining the safety and efficacy of HEX at a Level I trauma center, with particular focus on the risk of coagulopathy. From June to December 2008, HEX was available as a therapeutic option for all nonburn patients. At the discretion of the admitting surgeon, 500 mL to 1,000 mL of HEX was administered during initial fluid resuscitation. Apart from this initial bolus of HEX, care was otherwise identical in all patients and in exact accordance with advanced trauma life support guidelines. Fluids, blood products, vasopressors, and/or any other drugs were administered as needed. Review of pharmacy records and nursing notes was approved by the Institutional Review Board of the University of Miami and by the Clinical Trials Office of Jackson Memorial Hospital with waiver of informed consent. This study was registered as NCT00527098 on www.clinicaltrials.gov. There were 1,714 admissions; 805 received HEX and 909 did not. The characteristics and demographics were identical between the two groups in terms of age, gender, hemodynamics, laboratory values, Glasgow coma scale score, and Injury Severity Score at the scene and on admission to the trauma resuscitation unit. With standard of care, the population was primarily male (78.9%) with blunt injury (72.8%); with standard of care HEX, the distribution was similar for gender (80.9%) and type of trauma (74.7%). These values are typical for any large, mostly urban, trauma population.24 With HEX versus standard of care, there were reduced early deaths (p 0.0001) and overall mortality (5.2% vs. 8.9%; p 0.0035) by univariate analysis. Results were similar after penetrating injury only (p 0.0016) and in those with severe injury, defined by the Glasgow coma scale score 9 (p 0.0013) or Injury Severity Score 26 (p 0.0142). Consistent with early salvage of otherwise lethal injury, after HEX, more required admission to the intensive care unit (40.9% vs. 34.5%; p 0.0334) and transfusions of blood (34.4% vs. 20.2%; p 0.0014) or plasma (20.7% vs. 12.2%; p 0.0251). Consistent with safety, in the intensive care unit Submitted for publication February 11, 2011. Accepted for publication March 14, 2011. Copyright © 2011 by Lippincott Williams & Wilkins From the Divisions of Trauma and Surgical Critical Care, Dewitt Daughtry Family Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida. Supported, in part, by grant N140610670 from the Office of Naval Research. Address for reprints: Kenneth G. Proctor, PhD, Dewitt Daughtry Family Department of Surgery, Divisions of Trauma and Surgical Critical Care, University of Miami Miller School of Medicine, Miami, FL 33136; email: kproctor@miami.edu.

Heart rate variability (HRV) is a method of physiologic assessment which uses fluctuations in the RR intervals to evaluate modulation of the heart rate by the autonomic nervous system (ANS). Decreased variability has been studied as a marker of increased pathology and a predictor of morbidity and mortality in multiple medical disciplines. HRV is potentially useful in trauma as a tool for prehospital triage, initial patient assessment, and continuous monitoring of critically injured patients. However, several technical limitations and a lack of standardized values have inhibited its clinical implementation in trauma. The purpose of this paper is to describe the three analytical methods (time domain, frequency domain, and entropy) and specific clinical populations that have been evaluated in trauma patients and to identify key issues regarding HRV that must be explored if it is to be widely adopted for the assessment of trauma patients.

Background For logistics, the US Army recommends Hextend (Hospira; 6% hetastarch in buffered electrolyte, HET) for battlefield resuscitation. To support this practice, there are laboratory data, but none in humans. To test the hypothesis that HET is safe and effective in trauma, we reviewed our first 6 months of use at a civilian level 1 trauma center. Study Design From June 2008 to December 2008, trauma patients received standard of care (SOC) ± 500 to 1,000 mL of HET within 2 hours of admission at surgeon discretion. Each case was reviewed, with waiver of consent. Results There were 1,714 admissions; 805 received HET and 909 did not. With HET versus SOC, overall mortality was 5.2% versus 8.9% (p = 0.0035) by univariate analysis. Results were similar after penetrating injury only (p = 0.0016) and in those with severe injury, defined by Glasgow Coma Scale 26 (p = 0.0142). After HET, more patients required ICU admission (40.9% vs. 34.5%; p=0.0334) and transfusions of blood (34.4% vs. 20.2%; p=0.0014) or plasma (20.7% vs. 12.2%; p=0.0251), but there were no treatment-related differences in prothrombin time or partial thromboplastin time. The 24-hour urine outputs and requirements for blood, plasma, and other fluids were similar. However, increased early deaths with SOC implicate possible selection bias. If that factor was controlled for with multivariate analysis, the same trends were present, but the apparent treatment effects of HET were no longer statistically significant. Conclusions In the first trial to date in hemodynamically unstable trauma patients, and the largest trial to date in any population of surgical patients, initial resuscitation with HET was associated with reduced mortality and no obvious coagulopathy. A randomized blinded trial is necessary before these results can be accepted with confidence.

Background: Prehospital triage of patients with trauma is routinely challenging, but more so in mass casualty situations and military operations. The purpose of this study was to prospectively test whether heart rate variability (HRV) could be used as a triage tool during helicopter transport of civilian patients with trauma. Methods: After institutional review board approval and waiver of informed consent, 75 patients with trauma requiring prehospital helicopter transport to our level I center (from December 2007 to November 2008) were prospectively instrumented with a 2-Channel SEER Light recorder (GE Healthcare, Milwaukee, WI). HRV was analyzed with a Mars Holter monitor system and proprietary software. SDNN (standard deviation [SD] of the normal-to-normal R-R interval), as an index of HRV, was correlated with prehospital trauma triage criteria, base deficit, seriousness of injury, operative interventions, outcome, and other data extracted from the patients' medical records. There were no interventions or medical decisions based on HRV. Data were excluded only if there was measurement artifact or technical problems with the recordings. Results: The demographics were mean age 47 years, 63% men, 88% blunt, 25% traumatic brain injury, 9% mortality. Prehospital SDNN predicted patients with base excess ≤-6, those defined as seriously injured and benefiting from trauma center care, as well as patients requiring a life-saving procedure in the operating room. No other available data, including prehospital en-route vital signs, predicted any of these. The sensitivity, specificity, positive predictive value, and negative predictive value were 80%, 75%, 33%, 96%, respectively, with and an overall accuracy of 76% for predicting a life-saving intervention in the operating room. Conclusions: This is the first demonstration that prehospital HRV (specifically SDNN) predicts base excess and operating room life-saving opportunities. HRV triages and discriminates severely injured patients better than routine trauma criteria or en-route prehospital vital signs. HRV may be a useful civilian or military triage tool to avoid unnecessary helicopter evacuation for minimally injured patients. A prospective, randomized trial in a larger patient population is indicated.

Metabolically stable adenosine (ADO) agonists were infused into cannulas chronically implanted in the lateral cerebral ventricle intracerebroventricularly (icv) while responses in skin microcirculation of pentobarbital-anesthetized hamsters were observed with intravital microscopy. Cyclohexyladenosine (CHA; A1-receptor selective; 0.0001-1 pmol) and N-ethylcarboxoamidoadenosine (NECA; A2-receptor selective; 0.01-0.05 pmol) were delivered in 10 microliters of bicarbonate-buffered Ringer vehicle. Mean systemic arterial blood pressure, heart rate, skin arteriolar diameter, and red blood cell velocity were continuously monitored. Blood flow was calculated from measurements of arteriolar diameter (20-40 microns) and red blood cell velocity. CHA icv caused dose-related decreases in blood pressure and heart rate, as well as increases in cutaneous perfusion. Comparable amounts of CHA administered intravenously evoked no response. Pretreatment with an A1-selective antagonist xanthine amine congener (XAC, 5 pmol icv or 1 mg/kg iv) had no effect on the depressor response but antagonized the bradycardia. In contrast, a nonselective antagonist 8-phenyltheophylline (8pTHEO, 5 pmol icv or 0.3 mg/kg iv) had no effect on the bradycardia but attenuated the depressor response. By either route, both antagonists prevented the cutaneous microcirculatory responses evoked by icv CHA. NECA icv produced hypotension but no change in the skin, and the depressor response was not altered by icv XAC. These observations provide direct evidence that chemical stimulation of central nervous system (CNS) ADO receptors is linked to a cutaneous vascular response that can be dissociated from other cardiorespiratory depressant actions of CNS ADO.

We tested the hypothesis that hepatosplanchnic and systemic hemodynamics are improved with equi-effective doses of dopamine (DA) versus norepinephrine (NE) in a brain-dead swine model. Pigs (n = 18) were anesthetized and ventilated. Brain death was induced by epidural balloon inflation, hypoventilation, and hypoxia. After 30 minutes, mechanical ventilation was restored without anesthesia. During 60 and until 480 minutes, half received DA (10 microg/kg/minute) and half received NE (0.1 microg/kg/minute) titrated to a mean arterial pressure (MAP)60 mm Hg with supplemental fluid to maintain a central venous pressure8 mm Hg. Hemodynamics, hepatic laser Doppler blood flow, and hepatic and gastric tissue oxygenation with near-infrared spectroscopy were continuously monitored. Serial blood samples were analyzed for blood gases and electrolytes, coagulation changes, and serum chemistries. Balloon inflation caused brain death and autonomic storm, and 8 of 18 were nonsurvivors. After 30 minutes, the MAP, mixed venous O(2) saturation, and partial pressure of arterial oxygen values decreased to 37 +/- 2 mm Hg, 38 +/- 4, and 49 +/- 8 mm Hg, respectively. Serum lactate increased to 5.4 +/- 0.7 mM. Among survivors (n = 10), MAP stabilized with either pressor. Urine output was maintained (1 mL/kg/hour), but creatinine increased30% with respect to the baseline. Tachyphylaxis developed with NE but not with DA (P0.05). Cardiac index was higher with DA versus NE (P0.05). There were no differences in stroke volume, metabolic indices, or liver blood flow. Liver tissue O(2) was higher with DA versus NE at 8 hours (P0.05). Coagulation tests and liver enzymes were similar with NE versus DA (P0.05). In conclusion, after brain death, cardiac index and hepatic oxygenation were significantly improved with equi-effective doses of DA versus NE.

Phenylephrine is often used for management of cerebral perfusion pressure after traumatic brain injury, but can have undesirable actions. Few studies have evaluated alternatives. The hypothesis was that arginine vasopressin was as effective as phenylephrine for maintaining tissue oxygenation during cerebral perfusion pressure management.Prospective randomized, blinded animal study.University laboratory.Thirty-five anesthetized swine (46 +/- 1 kg).Blunt trauma to the head and bilateral chests (estimated injury severity score was 25-32) was followed by hypoventilation. Resuscitation was divided into phases to simulate treatment in a typical prehospital, emergency room, and intensive care unit. For 30-45 mins postinjury, 1 L of normal saline was administered. For 45-120 mins, normal saline maintained systolic blood pressure100 mm Hg plus mannitol for intracranial hypertension. After 120 mins, phenylephrine or arginine vasopressin was titrated to cerebral perfusion pressure70 mm Hg (randomized and blinded) plus normal saline to maintain filling pressure12 mm Hg plus glucose to maintain normoglycemia.Mortality rate was 37% (13 of 35) within 2 hrs. Before resuscitation, mean arterial pressure was 61 +/- 5 mm Hg, heart rate was 110 +/- 6 beats/min, PaO2 was 46 +/- 2 mm Hg, and lactate was 5.0 +/- 0.4 mM. Intracranial pressure increased from 8 +/- 1 mm Hg to 20 +/- 1 mm Hg and brain tissue PO2 decreased from 19 +/- 1 mm Hg to 8 +/- 1 mm Hg. Resuscitation corrected most variables, as well as mixed venous, renal, portal, and muscle oxygen saturations, but 90% (20 of 22) required pressor support. After 6 hrs with either pressor, hemodynamics were stable. However, with phenylephrine vs. arginine vasopressin, intracranial pressure averaged10 mm Hg higher and brain tissue PO2 was 6 mm Hg lower, whereas tissue oxygen saturations were10% higher in the shoulder and hindlimb muscles (all p0.05).Arginine vasopressin was as effective as phenylephrine for maintaining cerebral perfusion pressure, but intracranial pressure and brain tissue oxygenation were improved at the expense of the periphery.

An island skin flap was designed on the left inferior epigastric neurovascular bundle of anesthetized male rats. Blood flow was measured in situ with a laser Doppler flowmeter at 20 discrete points on a grid system (5 points in each quadrant of the flap) before and after surgery, or before vascular occlusion, during reperfusion, and 48 to 72 hours later. Two series of experiments were performed. In the first series, the raised flap was placed in a bath containing heated Ringer's solution and the left pedicle was cross-clamped. After 30 minutes, adenosine at a concentration that produced supramaximal vasodilatation, or its vehicle, was added to the bath. After 1 hour total occlusion time, the vascular clamp was released and adenosine treatment was continued for the first 30 minutes of reperfusion. In the second series, the protocol was similar except that adenosine, or its vehicle, was infused into the ischemic flap by means of the distal stump of the right inferior epigastric artery. After 48 to 72 hours, fluorescein was injected IV. The data showed a significant regional variation in baseline laser Doppler blood flow that was further altered by surgically raising the flap. Whereas proximal axial laser Doppler blood flow was essentially unchanged from the preoperative baseline, distal axial laser Doppler blood flow decreased 10 to 50 percent, and proximal and distal dependent laser Doppler blood flow decreased 50 to 80 percent. Thus no single value accurately reflected total flap perfusion. Necrosis occurred only in the dependent flap regions, which confirmed previous work. In the dependent regions, especially along the incision line, postoperative laser Doppler blood flow was lowest. Fluorescein penetration at 48 to 72 hours was strongly correlated with laser Doppler blood flow if a correction factor of 2.3 was considered. With adenosine treatment, in contrast to its vehicle, laser Doppler blood flow tended to increase during the postoperative period. We conclude (1) that surgical construction of a skin flap can aggravate a regional variation in perfusion that can be detected with a laser Doppler flowmeter, (2) that continuous monitoring of laser Doppler blood flow at a single site could be misleading unless tissue perfusion is uniform, and (3) that adenosine has a potential beneficial effect in ischemic skin tissue.

Management of severe pulmonary contusion is a challenge for clinicians. The incidence of adult respiratory distress syndrome (5-20%), pneumonia (5-50%), and mortality (5-10%) associated with traumatic lung injury has changed little in the past three decades. Therapeutic options are limited to basic supportive measures such as mechanical ventilation, positive end expiratory pressure, invasive cardiopulmonary monitoring, analgesics and aggressive pulmonary hygiene. Presently, no pharmacological agents can prevent the progressive respiratory embarrassment that is associated with the natural history of the disease, but several drugs have been tested in the laboratory. The purpose of this brief review is to summarize information published since January 2000 related to the clinical management and pathophysiology of lung contusion.

Background: Data are limited on the actions of hemoglobin based oxygen carriers (HBOCs) after traumatic brain injury (TBI). This study evaluates neurotoxicity, vasoactivity, cardiac toxicity, and inflammatory activity of HBOC-201 (Biopure, Cambridge, Mass.) resuscitation in a TBI model. Methods: Swine received TBI and hemorrhage. After 30 minutes, resuscitation was initiated with 10 mL/kg normal saline (NS), followed by either HBOC-201 (6 mL/kg, n = 10) or NS control (n = 10). Supplemental NS was administered to both groups to maintain mean arterial pressure (MAP) >60 mm Hg until 60 minutes, and to maintain cerebral perfusion pressure (CPP) >70 mm Hg from 60 to 300 minutes. The control group received mannitol (1 g/kg) and blood (10 mL/kg) at 90 minutes and half (n = 5) received CPP directed phenylephrine (PE) therapy after 120 minutes. Serum cytokines were measured with ELISA and coagulation was evaluated with thromboelastography. Brains were harvested for neuropathology. Results: With HBOC administration, MAP, CPP, and brain tissue Po 2 were restored within 30 minutes and maintained until 300 minutes. Clot strength and fibrin formation were maintained and 9/10 successfully extubated. In contrast, with control, MAP and brain tissue Po 2 did not correct until 120 minutes, after mannitol, transfusion and 40% more crystalloid. Furthermore, without PE, CPP did not reach target and 0/5 could be extubated. Lactate, heart rate, cardiac output, mixed venous oxygenation, muscle oxygenation, serum cytokines, and histology did not differ between groups. Conclusions: After TBI, a single HBOC-201 bolus with minimal supplements provided rapid resuscitation, while maintaining CPP and improving brain oxygenation, without causing cardiac dysfunction, coagulopathy, cytokine release, or brain structural changes.

To develop clinically-relevant experimental models of 1A and 2A injuries after civilian or military trauma; to determine mechanisms/ therapeutic targets in those models; to develop/evaluate novel resuscitation strategies based on those mechanisms/ therapeutic targets; to translate those findings to patients.

Background. Ubiquitin (Ub) is involved in intracellular protein metabolism, but may also have extracellular roles in host defense and immunomodulation. Erythrocytes contain high amounts of Ub and hemolysis is one potential source of extracellular Ub in vivo. Since hemolysis also occurs with storage of packed RBC units (pRBCs) in vitro, we hypothesized that Ub is released during storage and that it correlates with immunological properties of pRBCs. Materials and methods. Daily aliquots were drawn from pRBCs (n = 3) for 42 days and plasma was isolated. Ub was measured by ELISA. Immunomodulatory properties of plasma were assessed by measuring endotoxin-stimulated cytokine (TNF-a, IL-6, IL-8) production of normal whole blood, and cell proliferation in phytohemagglutinin-stimulated peripheral blood mononuclear cells. Results. Plasma Ub linearly increased (49 ± 2 ng/mL/ day; r2 = 0.82, P < 0.001) 20-fold to 2170 ± 268 ng/mL on day 42. Plasma inhibited TNF-a production but stimulated IL-8 production of normal whole blood, which correlated with time-dependent Ub release (TNFa: r spearman = -0.626, P < 0.001; IL-8: r spearman = 0.427, P = 0.004). Addition of exogenous Ub (equaling day 42 concentration) to day 0-4 plasma inhibited TNF-a production by one-third of the effect detected for day 42 plasma, but also inhibited IL-8 production by 40%. IL-6 production and cell proliferation was unchanged between day 0-4 plasma with or without Ub supplementation and day 42 plasma. Conclusions. Extracellular Ub release in pRBCs correlates with in vitro immunomodulatory effects and may partially contribute to transfusion-related immune modulation. Additionally, the linear kinetics of the ubiquitin release during pRBC storage suggest Ub is a suitable in vitro quality control parameter.

Traumatic brain injury (TBI) remains an exclusionary criterion in nearly every clinical trial involving hemoglobin-based oxygen carriers (HBOCs) for traumatic hemorrhage. Furthermore, most HBOCs are vasoactive, and use of pressors in the setting of hemorrhagic shock is generally contraindicated. The purpose of this investigation was to test the hypothesis that low-volume resuscitation with a vasoactive HBOC (hemoglobin glutamer-200 [bovine], HBOC-301; Oxyglobin, BioPure, Inc., Cambridge, MA) would improve outcomes after severe TBI and hemorrhagic shock.In Part 1, anesthetized swine received TBI and hemorrhage (30 +/- 2 mL/kg, n = 15). After 30 minutes, lactated Ringer's (LR) solution (n = 5), HBOC (n = 5), or 10 mL/kg of LR + HBOC (n = 5) was titrated to restore systolic blood pressure toor = 100 mm Hg and heart rate (HR) toor = 100 beats/min. After 60 minutes, fluid was given to maintain mean arterial pressure (MAP) ator = 70 mm Hg and heterologous whole blood (red blood cells [RBCs], 10 mL/kg) was transfused for hemoglobin ator = 5 g/dL. After 90 minutes, mannitol (MAN, 1 g/kg) was given for intracranial pressureor = 20 mm Hg, LR solution was given to maintain cerebral perfusion pressure ator = 70 mm Hg, and RBCs were given for hemoglobin ofor = 5 g/dL. In Part 2, after similar TBI and resuscitation with either LR + MAN + RBCs (n = 3) or HBOC alone (n = 3), animals underwent attempted weaning, extubation, and monitoring for 72 hours.In Part 1, relative to resuscitation with LR + MAN + RBCs, LR + HBOC attenuated intracranial pressure (12 +/- 1 mm Hg vs. 33 +/- 6 mm Hg), improved cerebral perfusion pressure in the initial 4 hours (89 +/- 6 mm Hg vs. 60 +/- 3 mm Hg), and improved brain tissue PO2 (34.2 +/- 3.6 mm Hg vs. 16.1 +/- 1.6 mm Hg; all p0.05). Cerebrovascular reactivity and intracranial compliance were improved with LR + HBOC (p0.05) and fluid requirements were reduced (30 +/- 12 vs. 280 +/- 40 mL/kg; p0.05). Lactate and base excess corrected faster with LR + HBOC despite a 40% reduction in cardiac index. With HBOC alone and LR + HBOC, MAP and HR rapidly corrected and remained normal during observation; however, with HBOC alone, lactate clearance was slower and systemic oxygen extraction was transiently increased. In Part 2, resuscitation with HBOC alone allowed all animals to wean and extubate, whereas none in the LR + MAN + RBCs group was able to wean and extubate. At 72 hours, no HBOC animal had detectable neurologic deficits and all had normal hemodynamics.The use of HBOC-301 supplemented by a crystalloid bolus was clearly superior to the standard of care (LR + MAN + RBCs) after TBI. This may represent a new indication for HBOCs. Use of HBOC eliminated the need for RBC transfusions and mannitol. The inherent vasopressor effect of HBOCs, especially when used alone, may misguide initial resuscitation, leading to transient poor global tissue perfusion despite restoration of MAP and HR. This suggests that MAP and HR are inadequate endpoints with HBOC resuscitation. HBOC use alone after TBI permitted early extubation and excellent 72-hour outcomes.

Recent data indicate that ubiquitin is increased in serum after trauma and might regulate immune functions. Its cellular source is unknown. Because there have been no previous studies after traumatic brain injury (TBI), we determined whether ubiquitin immunoreactivity is increased in cerebrospinal fluid (CSF) after TBI.Prospective observational study of patients, with a subsequent interventional study of animals.The subjects were 14 patients with TBI, five patients with nontraumatic subarachnoid hemorrhage, ten nonneurologic controls, and seven cross-bred swine.Standardized TBI.Ubiquitin immunoreactivity was analyzed by enzyme-linked immunosorbent assay and immunoblotting. Hemolysis was assessed spectrophotometrically. CSF ubiquitin levels (mean +/- sd) were 19 +/- 3 ng/mL in nonneurologic control patients, 81 +/- 48 ng/mL at 7 +/- 2 hrs after TBI (p = .002), and at the end of operation in patients with nontraumatic subarachnoid hemorrhage they were 104 +/- 68 ng/mL (p = .001). CSF and serum ubiquitin were measured for 7 days in six patients with TBI. In survivors (n = 3), CSF ubiquitin levels progressively recovered, whereas in nonsurvivors (n = 3), the levels increased until death. There was no difference in serum ubiquitin levels between survivors/nonsurvivors and there was no correlation between serum and CSF ubiquitin levels. In swine, CSF ubiquitin levels peaked at 8- to 30-fold higher than baseline at 60 min post-TBI and then declined with a half-life of 1.3 hrs. In CSF with hemolysis, peak ubiquitin levels were five-fold higher than without hemolysis (p.05). Ubiquitin and hemoglobin correlations in CSF and after in vitro lysis of erythrocytes suggested that erythrolysis could account for no more than 23 +/- 16% of the CSF ubiquitin.CSF ubiquitin levels are increased more than four-fold in patients after TBI and nontraumatic subarachnoid hemorrhage. Peak CSF ubiquitin measurements in patients with TBI probably underestimated the actual peak, on the basis of data from the animal model. The progressive rise in CSF ubiquitin in patients with TBI who died suggests that lack of clearance could reflect lethal progression to irreversible brain damage. Erythrolysis is one potential source of CSF ubiquitin.

The long term objective is to develop and evaluate new monitoring strategies in clinically-relevant laboratory models of civilian and military trauma then translate the laboratory findings to the bedside. The short term primary objective was to assess the value of a new portable, noninvasive, continuous monitoring device (near-infrared spectroscopy, NIRS) in establishing the adequacy of resuscitation after trauma in an experimental model. That objective was achieved earlier than expected and is now being tested in patients. We are now evaluating proof of concept of other non-invasive monitoring strategies in both animals and patients. Some of these novel strategies could permit minimally-trained medics or other EMS personnel to provide care of trauma patients in the combat or civilian prehospital setting; others provide new perspectives on the diagnosis of injury severity.

The purpose of the study was to compare initial resuscitation with arginine vasopressin (AVP), phenylephrine (PE), or isotonic crystalloid fluid alone after traumatic brain injury and vasodilatory shock.Anesthetized, ventilated swine (n = 39, 30 +/- 2 kg) underwent fluid percussion traumatic brain injury followed by hemorrhage (30 +/- 2mL/kg) to a mean arterial pressure30mmHg, then were randomized to 1 of 5 groups to maintain mean arterial pressure60mmHg for 30 to 60minutes, then cerebral perfusion pressure60mmHg for 60 to 300minutes, either unlimited crystalloid fluid only (n = 9), arginine vasopressin + fluid (n = 9), phenylephrine + fluid (n = 9), arginine vasopressin only (n = 5), or phenylephrine only (n = 5). Heterologous transfusions were administered if hematocrit was13, and mannitol was administered if intracranial pressure was20 mmHg. Cerebrovascular reactivity was evaluated with serial CO(2) challenges.In all groups, physiologic variables were similar at baseline and at the end of shock. On resuscitation, all achieved mean arterial pressure and cerebral perfusion pressure goals. Brain tissue PO(2)s were similar. With fluid only, more blood and mannitol were required, intracranial pressure and peak inspiratory pressure were higher, and cerebrovascular reactivity was decreased (all p0.05 versus pressor + fluid). With either pressor + fluid, cardiac output, heart rate, lactate, and mixed venous O(2) saturation were similar to fluid only, but total fluid requirements and urine output were both reduced (p0.05). With either pressor only, intracranial pressure remained low, but mixed venous O(2) saturation, cardiac output, and urine output were decreased (all p0.05 versus other groups).To correct vasodilatory shock after traumatic brain injury, a resuscitation strategy that combined either phenylephrine or arginine vasopressin plus crystalloid was superior to either fluid alone or pressor alone.