Circulatory HMGB1 is an early predictive and prognostic biomarker of ARDS and mortality in a swine model of polytrauma.

Acute respiratory distress syndrome (ARDS) is a leading cause of morbidity and mortality in polytrauma patients. Pharmacological treatments of ARDS are lacking, and ARDS patients rely on supportive care. Accurate diagnosis of ARDS is vital for early intervention and improved outcomes but is presently delayed up to days. The use of biomarkers for early identification of ARDS development is a potential solution. Inflammatory mediators high-mobility group box 1 (HMGB1), syndecan-1 (SDC-1), and C3a have been previously proposed as potential biomarkers. For this study, we analyzed these biomarkers in animals undergoing smoke inhalation and 40% total body surface area burns, followed by intensive care for 72 h post-injury (PI) to determine their association with ARDS and mortality. We found that the levels of inflammatory mediators in serum were affected, as well as the degree of HMGB1 and Toll-like receptor 4 (TLR4) signal activation in the lung. The results showed significantly increased HMGB1 expression levels in animals that developed ARDS compared with those that did not. Receiver operating characteristic (ROC) analysis showed that HMGB1 levels at 6 h PI were significantly associated with ARDS development (AUROC=0.77) and mortality (AUROC=0.82). Logistic regression analysis revealed that levels of HMGB1 ≥24.10 ng/ml are associated with a 13-fold higher incidence of ARDS [OR:13.57 (2.76-104.3)], whereas the levels of HMGB1 ≥31.39 ng/ml are associated with a 12-fold increase in mortality [OR: 12.00 (2.36-93.47)]. In addition, we found that mesenchymal stem cell (MSC) therapeutic treatment led to a significant decrease in systemic HMGB1 elevation but failed to block SDC-1 and C3a increases. Immunohistochemistry analyses showed that smoke inhalation and burn injury induced the expression of HMGB1 and TLR4 and stimulated co-localization of HMGB1 and TLR4 in the lung. Interestingly, MSC treatment reduced the presence of HMGB1, TLR4, and the HMGB1-TLR4 co-localization. These results show that serum HMGB1 is a prognostic biomarker for predicting the incidence of ARDS and mortality in swine with smoke inhalation and burn injury. Therapeutically blocking HMGB1 signal activation might be an effective approach for attenuating ARDS development in combat casualties or civilian patients.

Immunopathological Alterations after Blast Injury and Hemorrhage in a Swine Model of Prolonged Damage Control Resuscitation.

Trauma-related hemorrhagic shock (HS) remains a leading cause of death among military and civilian trauma patients. We have previously shown that administration of complement and HMGB1 inhibitors attenuate morbidity and mortality 24 h after injury in a rat model of blast injury (BI) and HS. To further validate these results, this study aimed to develop a swine model and evaluate BI+HS-induced pathophysiology. Anesthetized Yucatan minipigs underwent combined BI and volume-controlled hemorrhage. After 30 min of shock, animals received an intravenous bolus of PlasmaLyte A and a continuous PlasmaLyte A infusion. The survival rate was 80% (4/5), and the non-survivor expired 72 min post-BI. Circulating organ-functional biomarkers, inflammatory biomarkers, histopathological evaluation, and CT scans indicated evidence of multiple-organ damage, systemic innate immunological activation, and local tissue inflammation in the injured animals. Interestingly, a rapid and dramatic increase in plasma levels of HMGB1 and C3a and markedly early myocarditis and encephalitis were associated with early death post-BI+HS. This study suggests that this model reflects the immunopathological alterations of polytrauma in humans during shock and prolonged damage control resuscitation. This experimental protocol could be helpful in the assessment of immunological damage control resuscitation approaches during the prolonged care of warfighters.

Mitigating Ischemia-Reperfusion Injury Using a Bilobed Partial REBOA Catheter: Controlled Lower-Body Hypotension.

BACKGROUND: Non-compressible torso hemorrhage (NCTH) is the leading cause of potentially preventable death on the battlefield. Resuscitative endovascular balloon occlusion of the aorta (REBOA) aims to restore central blood pressure and control NCTH below the balloon, but risks ischemia-reperfusion injury to distal organs when prolonged. We tested a bilobed partial REBOA catheter (pREBOA), which permits some of the blood to flow past the balloon. METHODS: Female swine (n = 37, 6 groups, n = 5-8/group), anesthetized and instrumented, were exponentially hemorrhaged 50% of estimated blood volume (all except time controls [TC]). Negative controls (NC) did not receive REBOA or resuscitation. Positive controls (PC) received retransfusion after 120 min. REBOA groups received REBOA for 120 min, then retransfusion. Balloon was fully inflated in the full REBOA group (FR), and was partially inflated in partial REBOA groups (P45 and P60) to achieve a distal systolic blood pressure of 45 mm Hg or 60 mm Hg. RESULTS: Aortic occlusion restored baseline values of proximal mean arterial pressure, cardiac output, and carotid flow in pREBOA groups. Lactate reached high values during occlusion in all REBOA groups (9.9 ±â€Š4.2, 8.0 ±â€Š4.1, and 10.7 ±â€Š2.9 for P45, P60, and FR), but normalized by 6 to 12 h post-deflation in the partial groups. All TC and P60 animals survived 24 h. The NC, PC, and P45 groups survived 18.2 ±â€Š9.5, 19.3 ±â€Š10.6, and 21.0 ±â€Š8.4 h. For FR animals mean survival was 6.2 ±â€Š5.8 h, significantly worse than all other animals (P < 0.01, logrank test). CONCLUSIONS: In this porcine model of hemorrhagic shock, animals undergoing partial REBOA for 120 min survived longer than those undergoing full occlusion.

Distal organ inflammation and injury after resuscitative endovascular balloon occlusion of the aorta in a porcine model of severe hemorrhagic shock.

BACKGROUND AND OBJECTIVE: Resuscitative Endovascular Balloon Occlusion of Aorta (REBOA) has emerged as a potential life-saving maneuver for the management of non-compressible torso hemorrhage in trauma patients. Complete REBOA (cREBOA) is inherently associated with the burden of ischemia reperfusion injury (IRI) and organ dysfunction. However, the distal organ inflammation and its association with organ injury have been little investigated. This study was conducted to assess these adverse effects of cREBOA following massive hemorrhage in swine. METHODS: Spontaneously breathing and consciously sedated Sinclair pigs were subjected to exponential hemorrhage of 65% total blood volume over 60 minutes. Animals were randomized into 3 groups (n = 7): (1) Positive control (PC) received immediate transfusion of shed blood after hemorrhage, (2) 30min-cREBOA (A30) received Zone 1 cREBOA for 30 minutes, and (3) 60min-cREBOA (A60) given Zone 1 cREBOA for 60 minutes. The A30 and A60 groups were followed by resuscitation with shed blood post-cREBOA and observed for 4h. Metabolic and hemodynamic effects, coagulation parameters, inflammatory and end organ consequences were monitored and assessed. RESULTS: Compared with 30min-cREBOA, 60min-cREBOA resulted in (1) increased IL-6, TNF-α, and IL-1ß in distal organs (kidney, jejunum, and liver) (p < 0.05) and decreased reduced glutathione in kidney and liver (p < 0.05), (2) leukopenia, neutropenia, and coagulopathy (p < 0.05), (3) blood pressure decline (p < 0.05), (4) metabolic acidosis and hyperkalemia (p < 0.05), and (5) histological injury of kidney and jejunum (p < 0.05) as well as higher levels of creatinine, AST, and ALT (p < 0.05). CONCLUSION: 30min-cREBOA seems to be a feasible and effective adjunct in supporting central perfusion during severe hemorrhage. However, prolonged cREBOA (60min) adverse effects such as distal organ inflammation and injury must be taken into serious consideration.

Dynamics of acute respiratory distress syndrome development due to smoke inhalation injury: Implications for prolonged field care.

BACKGROUND: Smoke inhalation injury (SII) causes 30% to 40% mortality and will increase as a cause of death during prolonged field care. We used a combat relevant model of acute respiratory distress syndrome due to SII to study temporal changes in ventilation-perfusion (V/Q) matching, computed tomography (CT) scan data, and histopathology and hypothesized that SII leads to increase in shunt (Qshunt), V/Q mismatch, lung consolidation, and diffuse alveolar damage. METHODS: Swine received severe SII and airway pressure release ventilation (APRV, n = 6), or conventional ARDSNet mechanical ventilation (MV) (CMV, n = 8). A control group without injury received volume controlled MV (CTRL, n = 6), The multiple inert gas elimination technique and CT were performed at baseline (BL), 0.5 hours, 1 hours, 2 hours, 24 hours, and 48 hours after injury. Diffuse alveolar damage scoring was performed post mortem. Significance at p less than 0.05: APRV versus CTRL; CMV versus CTRL; APRV versus CMV*; denotes changes versus BL. RESULTS: (1) SII caused increases in Qshunt more so in APRV than CMV group. Qshunt did not change in CTRL. (2) PaO2-to-FIO2 ratio (PFR) was lower in APRV versus CTRL at 2 hours (375 ± 62‡ vs. 549 ± 40) and 24 hours (126 ± 34‡* vs. 445 ± 5) and 48 hours (120 ± 41‡& vs. 430 ± 13). In CMV animals, PFR was lower versus CTRL and BL at 24 hours (238 ± 33) and 48 hours (98 ± 27). Qshunt correlated with PFR (r = 0.75, p < 0.0001, APRV and (r = 0.65, p < 0.0001, CMV). CT showed decrease in normally aerated lung, while poorly and nonaerated lung increased. CONCLUSION: Smoke inhalation injury leads to early development of shunt, V/Q mismatch, lung consolidation, and diffuse alveolar damage. These data substantiate the need for new point of injury interventions in the prolonged field care setting. LEVEL OF EVIDENCE: Animal research.

Point-of-care endoscopic optical coherence tomography detects changes in mucosal thickness in ARDS due to smoke inhalation and burns.

BACKGROUND: The prevalence of acute respiratory distress syndrome (ARDS) in mechanically ventilated burn patients is 33%, with mortality varying from 11-46% depending on ARDS severity. Despite the new Berlin definition for ARDS, prompt bedside diagnosis is lacking. We developed and tested a bedside technique of fiberoptic-bronchoscopy-based optical coherence tomography (OCT) measurement of airway mucosal thickness (MT) for diagnosis of ARDS following smoke inhalation injury (SII) and burns. METHODS: 16 female Yorkshire pigs received SII and 40% thermal burns. OCT MT and PaO2-to-FiO2 ratio (PFR) measurements were taken at baseline, after injury, and at 24, 48, and 72h after injury. RESULTS: Injury led to thickening of MT which was sustained in animals that developed ARDS. Significant correlations were found between MT, PFR, peak inspiratory pressure (PIP), and total infused fluid volume. CONCLUSIONS: OCT is a useful tool to quantify MT changes in the airway following SII and burns. OCT may be effective as a diagnostic tool in the early stages of SII-induced ARDS and should be tested in humans.

Your Metric Matters! Choose Wisely to Assess User Performance With Tourniquets in Simulated First Aid.

BACKGROUND: Readiness to perform lifesaving interventions during emergencies is based on a person's preparation to proficiently execute the skills required. Graphically plotting the performance of a tourniquet user in simulation has previously aided us in developing our understanding of how the user actually behaves. The purpose of this study was to explore performance assessment and learning curves to better understand how to develop best teaching practices. METHODS: These were retrospective analyses of a convenience sample of data from a prior manikin study of 200 tourniquet uses among 10 users. We sought to generate hypotheses about performance assessments relevant to developing best teaching practices. The focus was on different metrics of user performance. RESULTS: When one metric was chosen over another, failure counts summed cumulatively over 200 uses differed as much as 12-fold. That difference also indicated that the degree of challenge posed to user performance differed by the metric chosen. When we ranked user performance with one metric and then with another, most (90%; nine of 10) users changed rank: five rose and four fell. Substantial differences in performance outcomes resulted from the difference in metric chosen, which, in turn, changed how the outcome was portrayed and thus interpreted. Hypotheses generated included the following: The usefulness of a specific metric may vary by the user's level of skill from novice to expert; demonstration of the step order in skill performance may suffice for initial training of novices; a mechanical metric of effectiveness, like pulse stoppage, may aid in later training of novices; and training users how to practice on their own and self-assess performance may aid their self-development. CONCLUSION: The outcome of the performance assessments varied depending on the choice of metric in this study of simulated use of tourniquets.

Resuscitative endovascular balloon occlusion of the aorta (REBOA): Comparison with immediate transfusion following massive hemorrhage in swine.

BACKGROUND: Resuscitative endovascular balloon occlusion of the aorta (REBOA) is less invasive than emergency department thoracotomy for the treatment of massive hemorrhage. We evaluated the effects of REBOA on carotid blood flow (Qcarotid) in a porcine model of massive hemorrhage. We hypothesized that REBOA restores Qcarotid faster than reinfusion of blood. METHODS: Spontaneously breathing sedated Sinclair pigs underwent exponential hemorrhage of 65% total blood volume in 1 hour. They were randomized into three groups. Positive control (PC, n = 7) underwent immediate transfusion of shed blood. REBOA (n = 21) received a novel 7 Fr ER-REBOA catheter (Pryor Medical, Arvada, CO) placed into aortic Zone 1 via a femoral artery introducer for 30 minutes or 60 minutes, with transfusion either after deflation or midway through inflation. Negative control (n = 7) received no resuscitation. Qcarotid was recorded continuously using an ultrasonic flow probe. Survival and time between Qcarotid, min and both a stable maximal value (Qcarotid, max) and restoration of baseline flow (Qcarotid, new BL) were compared by Kaplan-Meier analysis. RESULTS: Median time to Qcarotid, max was 3.0 minutes in the REBOA group versus 9.6 minutes in the control group (p = 0.006). Median time to Qcarotid, new BL was 6.0 minutes in the REBOA group versus 20.5 minutes in the PC group (p = 0.11). Slope of the linear regression between Qcarotid, min and Qcarotid, new BL was 16.7 in REBOA and 10.4 in PC (p = 0.31). Four-hour survival was 95% (20 of 21) in the REBOA group versus 71% (5 of 7) in the PC group (p = 0.06) and 0% in the negative control group. CONCLUSION: REBOA resulted in the restoration of Qcarotid ("cerebrovascular resuscitation") at least as rapidly as retransfusion of shed blood, with equivalent 4-hour survival. Further studies of REBOA, to include mitigation of end-organ effects and longer follow-up, are needed.

Comparison of virtual bronchoscopy to fiber-optic bronchoscopy for assessment of inhalation injury severity.

PURPOSE: Compare virtual bronchoscopy (VB) to fiberoptic bronchoscopy (FOB) for scoring smoke inhalation injury (SII). METHODS: Swine underwent computerized tomography (CT) with VB and FOB before (0) and 24 and 48 h after SII. VB and FOB images were scored by 5 providers off line. RESULTS: FOB and VB scores increased over time (p<0.001) with FOB scoring higher than VB at 0 (0.30±0.79 vs. 0.03±0.17), 24 h (4.21±1.68 vs. 2.47±1.50), and 48h (4.55±1.83 vs. 1.94±1.29). FOB and VB showed association with PaO2-to-FiO2 ratios (PFR) with areas under receiver operating characteristic curves (ROC): for PFR≤300, VB 0.830, FOB 0.863; for PFR≤200, VB 0.794, FOB 0.825; for PFR≤100, VB 0.747, FOB 0.777 (all p<0.001). FOB showed 80.3% specificity, 77% sensitivity, 88.8% negative-predictive value (NPV), and 62.3% positive-predictive value (PPV) for PFR≤300 and VB showed 67.2% specificity, 85.5% sensitivity, 91.3% NPV, and 53.4% PPV. CONCLUSIONS: VB provided similar injury severity scores to FOB, correlated with PFR, and reliably detected airway narrowing. VB performed during admission CT may be a useful screening tool specifically to demonstrate airway narrowing induced by SII.

Relationships of intraosseous and systemic pressure waveforms in a Swine model.

BACKGROUND: Despite some focus on the use of intraosseous (IO) catheters to obtain laboratory samples, very little is known about the potential for obtaining other forms of clinical data. Largely unstudied is the relationship between IO pressures (IOPs) and systemic hemodynamic pressures such as mean arterial pressure (MAP) and central venous pressures (CVP). OBJECTIVES: The objective was to explore the relationship between hemodynamic parameters (blood pressures) measured through an IO catheter and intravascular catheters placed in the arterial and central venous circulation. METHODS: Eight pigs (Sus scrofa) weighing 30 to 45 kg were sedated with a short-acting agent, intubated with a cuffed endotracheal tube, and anesthetized with 2% to 3% isoflurane. Intravascular catheters were placed into the femoral or carotid artery and the femoral or jugular vein for MAP and CVP measurements. IO catheters, 15 mm for the sternum and 25 mm for the long bones, were placed percutaneously into the proximal tibia, proximal femur, proximal humerus, right proximal ulna, and/or sternum. Pressures were recorded during normotension, hypotension, and hypertension. RESULTS: Averaged across all eight animals, the means (ranges) for baseline systemic pressures were as follows: MAP = 66.5 (55.6 to 76.7) mm Hg, tibia IOP = 17.4 (9.3 to 34.5) mm Hg, femur IOP =18.4 (3.3 to 33.1) mm Hg, humerus IOP = 15.7 (2.8 to 28.9) mm Hg, ulna IOP = 16.0 (7.9 to 25.6) mm Hg, sternum IOP = 5.7 (-0.5 to 47.9) mm Hg, and CVP = 2.7 mm Hg (-3.3 to 7.9) mm Hg. The best median correlation occurred between femur IOP and mean MAP (r = 0.65). The four highest correlations between IOP and MAP were associated with mean femur IOP. Only one IO site had a correlation coefficient over 0.50 for CVP. The long bones tended to correlate better with the MAP and the sternum tended to correlate better with the CVP. Nonlinearity was observed in the actively rising pressure phases, which can be explained by a hysteresis model. CONCLUSIONS: The relationship between IOP and MAP or CVP is variable by site, with the MAP and CVP tending to be estimated by the femur and sternum, respectively. The relationship to actively rising pressures is nonlinear and a hysteresis model is proposed to explain the phase change. Further experimentation is needed to refine the IOP relationship to the MAP and CVP and assess the potential of these measurements to provide clinically relevant information.

The noninvasive carbon dioxide gradient (NICO2G) during hemorrhagic shock.

Hemorrhagic shock (HS) is a setting in which both pulmonary and cutaneous perfusion may be impaired. The goals of this study were to evaluate the relationship between end-tidal (etCO2), transcutaneous (tPCO2), arterial carbon dioxide (PaCO2) and lactate during lethal HS and to assess the effect of progressive HS on those variables and on a new variable, the noninvasive CO2 gradient ([NICO2G] or the difference between tPCO2 and etCO2). Ten consciously sedated swine were hemorrhaged, by means of a computerized exponential protocol, of up to 80% estimated blood volume for 20 min. End-tidal carbon dioxide, tPCO2, PaCO2, and lactate measurements were taken at baseline and every 5 min thereafter, that is, after 25%, 44%, and 62% total blood volume hemorrhage (TBVH) and at cardiac arrest. Cardiac arrest occurred on average at 67% TBVH. Data were analyzed by linear regression and one-way repeated-measures analysis of variance and are presented as means ± SD. Forty-nine paired measurements were made. There was no overall relationship between NICO2 variables and PaCO2: PaCO2 vs. tPCO2 (r2 = 0.002, P = 0.78); PaCO2 vs. etCO2 (r2 = 0.0002, P = 0.93). Rather, NICO2G increased at each level of blood loss: 4.0 ± 24.9 at baseline, 6.3 ± 35.7 at 25% TBVH, 25.0 ± 37.6 at 44% TBVH, 55.0 ± 33.9 at 62% TBVH, and 70.0 ± 33.2 at cardiac arrest (P < 0.05). Similarly, tPCO2 increased and etCO2 decreased at each level. Linear regression of NICO2G and lactate showed a better correlation than was observed for the other two variables: NICO2G, r2 = 0.58; tPCO2, r2 = 0.46; etCO2, r2 = 0.26. During HS, NICO2 monitors lose accuracy for approximating the PaCO2 but gain usefulness as hemodynamic monitors. Also, by combining data from two different organ systems, NICO2G demonstrated improved correlation with lactate than did either etCO2 or tPCO2 alone.

Comparison of airway pressure release ventilation to conventional mechanical ventilation in the early management of smoke inhalation injury in swine.

OBJECTIVE: The role of airway pressure release ventilation in the management of early smoke inhalation injury has not been studied. We compared the effects of airway pressure release ventilation and conventional mechanical ventilation on oxygenation in a porcine model of acute respiratory distress syndrome induced by wood smoke inhalation. DESIGN: Prospective animal study. SETTING: Government laboratory animal intensive care unit. PATIENTS: Thirty-three Yorkshire pigs. INTERVENTIONS: Smoke inhalation injury. MEASUREMENTS AND MAIN RESULTS: Anesthetized female Yorkshire pigs (n = 33) inhaled room-temperature pine-bark smoke. Before injury, the pigs were randomized to receive conventional mechanical ventilation (n = 15) or airway pressure release ventilation (n = 12) for 48 hrs after smoke inhalation. As acute respiratory distress syndrome developed (PaO2/Fio2 ratio <200), plateau pressures were limited to <35 cm H2O. Six uninjured pigs received conventional mechanical ventilation for 48 hrs and served as time controls. Changes in PaO2/Fio2 ratio, tidal volume, respiratory rate, mean airway pressure, plateau pressure, and hemodynamic variables were recorded. Survival was assessed using Kaplan-Meier analysis. PaO2/Fio2 ratio was lower in airway pressure release ventilation vs. conventional mechanical ventilation pigs at 12, 18, and 24 hrs (p < .05) but not at 48 hrs. Tidal volumes were lower in conventional mechanical ventilation animals between 30 and 48 hrs post injury (p < .05). Respiratory rates were lower in airway pressure release ventilation at 24, 42, and 48 hrs (p < .05). Mean airway pressures were higher in airway pressure release ventilation animals between 6 and 48 hrs (p < .05). There was no difference in plateau pressures, hemodynamic variables, or survival between conventional mechanical ventilation and airway pressure release ventilation pigs. CONCLUSIONS: In this model of acute respiratory distress syndrome caused by severe smoke inhalation in swine, airway pressure release ventilation-treated animals developed acute respiratory distress syndrome faster than conventional mechanical ventilation-treated animals, showing a lower PaO2/Fio2 ratio at 12, 18, and 24 hrs after injury. At other time points, PaO2/Fio2 ratio was not different between conventional mechanical ventilation and airway pressure release ventilation.

Respiratory dialysis: reduction in dependence on mechanical ventilation by venovenous extracorporeal CO2 removal.

OBJECTIVES: Mechanical ventilation is injurious to the lung. Use of lung-protective strategies may complicate patient management, motivating a search for better lung-replacement approaches. We investigated the ability of a novel extracorporeal venovenous CO2 removal device to reduce minute ventilation while maintaining normocarbia. DESIGN: Prospective animal study. SETTING: Government laboratory animal intensive care unit. SUBJECTS: Seven sedated swine. INTERVENTIONS: Tracheostomy, volume-controlled mechanical ventilation, and 72 hrs of round-the-clock intensive care unit care. A 15-F dual-lumen catheter was inserted in the external jugular vein and connected to the Hemolung, an extracorporeal pump-driven venovenous CO2 removal device. Minute ventilation was reduced, and normocarbia (Paco2 35-45 mm Hg) maintained. Heparinization was maintained at an activated clotting time of 150-180 secs. MEASUREMENTS AND MAIN RESULTS: Minute ventilation (L/min), CO2 removal by Hemolung (mL/min), Hemolung blood flow, O2 consumption (mL/min), CO2 production by the lung (mL/min), Paco2, and plasma-free hemoglobin (g/dL) were measured at baseline (where applicable), 2 hrs after device insertion, and every 6 hrs thereafter. Minute ventilation was reduced from 5.6 L/min at baseline to 2.6 L/min 2 hrs after device insertion and was maintained at 3 L/min until the end of the study. CO2 removal by Hemolung remained steady over 72 hrs, averaging 72 ± 1.2 mL/min at blood flows of 447 ± 5 mL/min. After insertion, O2 consumption did not change; CO2 production by the lung decreased by 50% and stayed at that level (p < .001). As the arterial PCO2 rose or fell, so did CO2 removal by Hemolung. Plasma-free hemoglobin did not change. CONCLUSIONS: Venovenous CO2 removal enabled a 50% reduction in minute ventilation while maintaining normocarbia and may be an effective lung-protective adjunct to mechanical ventilation.

Development and resuscitation of a sedated, mature male miniature swine severe hemorrhage model.

BACKGROUND: A sedated, mature male miniature swine hemorrhage model has been specifically developed to evaluate resuscitation products for the Defense Advanced Research Projects Agency Surviving Blood Loss program. METHODS: Animals were placed in a sling, sedated with midazolam, and hemorrhaged 60% of estimated blood volume (∼39 mL/kg) exponentially for 1 hour with no resuscitation (control; n = 16). An additional 26 swine were treated similarly, then resuscitated with 1 mL/kg/min of Hextend to a systolic blood pressure of either 65 mm Hg ± 2 mm Hg (n = 7) or 80 mm Hg ± 5 mm Hg (n = 7) and with 17ß-estradiol (E2) at 1 mg/kg (n = 6) or 10 mg/kg (n = 6). Animals were observed for 3 hours with periodic blood sampling. Survival times for the two E2 groups were not significantly different (p = 0.59); therefore, the groups were combined for comparison with control. RESULTS: Hemorrhage resulted in a characteristic hypotension and metabolic acidosis. Survival time for the control swine was 64 minutes ± 11.5 minutes with a 6% survival at 180 minutes. The 180 minutes Hextend survival was 86% for 65 mm Hg and 100% for 80 mm Hg. E2 survival was 125 minutes ± 15.3 minutes, significantly different from control (p = 0.01), but E2 survival of 25% at 180 minutes was not different from control. CONCLUSION: A sedated, sexually mature male miniature swine severe hemorrhage model has been successfully developed, resuscitated with Hextend and used to evaluate E2 as a small volume resuscitation product.

Dynamic changes in shunt and ventilation-perfusion mismatch following experimental pulmonary contusion.

The objective of this study was to investigate early changes in oxygenation by means of the multiple inert gas elimination technique and in coagulation by means of thromboelastography (TEG) after right-sided pulmonary contusion (PC) in swine. Anesthetized swine (group 1; n = 8) sustained a right-chest PC by a captive-bolt stunner. Multiple inert gas elimination technique, TEG, and thoracic computed tomography (CT) scans were performed before and 10, 30, 60, and 120 min after injury. Three-dimensional CT scan reconstruction enabled measurement of volumes of poorly (Vol(Poor)) and nonaerated (Vol(Non)) lung. Eight animals (group 0) were used as uninjured controls. Pulmonary contusion led to sustained tachycardia and transient hypotension. Partial pressure of arterial oxygen (PaO2) decreased from 83.9 +/- 4.2 mmHg at baseline to 51.3 +/- 2.8 mmHg 10 min after PC (P < 0.001). Vol(Poor) and Vol(Non) on the right increased significantly after PC, followed by gradual progression in injury marked by decreased Vol(Poor) and increased Vol(Non). By the multiple inert gas elimination technique, blood flow to the true shunt compartment increased from 4.4% +/- 1.0% at baseline to 21.2% +/- 4.9% 10 min after PC, P < 0.001, peaked at 33.2% +/- 7.5% 30 min after PC, P < 0.001, and remained significantly higher compared with controls. Transient increase in blood flow to low and very low ventilation-perfusion (V/Q) compartments was also seen. Clot reaction time and formation rate by TEG increased at 2 h after PC. True shunt is the major cause of hypoxemia after PC, but V/Q mismatch also contributes significantly early after injury. By CT, PC leads to significant loss of functional lung volume on the side of injury. A mild hypocoagulable state was identified 2 h after injury.

New measures of heart-rate complexity: effect of chest trauma and hemorrhage.

BACKGROUND: Traditional vital signs such as heart rate, blood pressure, and oxygen saturation are not ideal for timely and accurate assessment of physiologic status after trauma (TR) and hemorrhagic shock (HS). Analysis of the complex beat-to-beat variability present in the heart-rate time series has been proposed as a "new vital sign" in this setting. We determined the effect of chest TR and HS on heart-rate complexity (HRC) in a porcine model. METHODS: Anesthetized swine in group II (n = 20) underwent blunt right chest TR with a modified captive-bolt stunner; then, 10 minutes later, hemorrhage of 12 mL/kg over 10 minutes, followed by resuscitation with lactated Ringer's solution, and reinfusion of blood. Group I (n = 15) served as time controls. Two hundred beat sections of EKG waveforms were analyzed at 7 time points: at baseline, after TR, immediately after hemorrhage (HS), and 1 hour, 2 hours, 4 hours, and 5 hours after HS. Several computationally different measures of HRC were calculated, including sample entropy, similarity of distribution, and point correlation dimension. RESULTS: HRC was decreased after TR, HS, and at 1 hour, manifested by decreased sample entropy and point correlation dimension and increased similarity of distribution. These HRC measures were all restored by resuscitation. CONCLUSIONS: Several independent measures demonstrated decreased HRC after combined TR/HS and restored HRC with resuscitation. Complexity analysis may be useful for diagnosis of TR/HS and for monitoring resuscitation.

Ventilation-perfusion relationships following experimental pulmonary contusion.

Ventilation-perfusion changes after right-sided pulmonary contusion (PC) in swine were investigated by means of the multiple inert gas elimination technique (MIGET). Anesthetized swine (injury, n = 8; control, n = 6) sustained a right-chest PC by a captive-bolt apparatus. This was followed by a 12-ml/kg hemorrhage, resuscitation, and reinfusion of shed blood. MIGET and thoracic computed tomography (CT) were performed before and 6 h after injury. Three-dimensional CT scan reconstruction enabled determination of the combined fractional volume of poorly aerated and non-aerated lung tissue (VOL), and the mean gray-scale density (MGSD). Six hours after PC in injured animals, Pa(O(2)) decreased from 234.9 +/- 5.1 to 113.9 +/- 13.0 mmHg. Shunt (Q(S)) increased (2.7 +/- 0.4 to 12.3 +/- 2.2%) at the expense of blood flow to normal ventilation/perfusion compartments (97.1 +/- 0.4 to 87.4 +/- 2.2%). Dead space ventilation (V(D)/V(T)) increased (58.7 +/- 1.7% to 67.2 +/- 1.2%). MGSD increased (-696.7 +/- 6.1 to -565.0 +/- 24.3 Hounsfield units), as did VOL (4.3 +/- 0.5 to 33.5 +/- 3.2%). Multivariate linear regression of MGSD, VOL, V(D)/V(T), and Q(S) vs. Pa(O(2)) retained VOL and Q(S) (r(2) = .835) as independent covariates of Pa(O(2)). An increase in Q(S) characterizes lung failure 6 h after pulmonary contusion; Q(S) and VOL correlate independently with Pa(O(2)).

Sympathetic nerve activity and heart rate variability during severe hemorrhagic shock in sheep.

INTRODUCTION: In this study we explored direct and indirect measures of autonomic nervous system function, as well as changes in cardiovascular complexity, during hemorrhagic shock (HS). METHODS: HS was induced in anesthetized sheep (n=8) by removing 40 ml/kg of blood in four 10 ml/kg steps over 40 min. Resuscitation was performed with lactated Ringer's and re-infusion of shed blood. Renal sympathetic nerve activity (RSNA) was measured by microneurography. Spectral analysis of heart rate variability (HRV) employed fast-Fourier transformation of the R-to-R interval (RRI) of the EKG. This generated the normalized high-frequency (HFnu) and low-frequency (LFnu) powers of the RRI, and their ratio (LFnu/HFnu, a proposed index of sympatho-vagal balance). Additionally, non-linear methods were applied: RRI complexity was measured by approximate (ApEn) and sample (SampEn) entropy methods; RRI fractal dimension was measured by curve lengths (FDCL). Plasma catecholamines were determined by HPLC. RESULTS: The model caused profound HS; 2/8 animals survived till the end of resuscitation. RSNA increased in 7/8 sheep and, as HS progressed, multiple burst complexes were identified followed by sympathetic withdrawal. Concomitant decreases in HFnu and increases in LFnu/HFnu occurred after 20 ml/kg blood loss. ApEn and FDCL decreased after withdrawal of 40 ml/kg of blood. Catecholamine concentrations increased throughout HS. LFnu/HFnu and RSNA were not linearly correlated. CONCLUSIONS: HS led to an increase in RSNA with subsequent withdrawal. LFnu/HFnu increased during HS in association with vagal withdrawal and loss of RRI complexity. RRI complexity may in part reflect vagal modulation of the heart rate. Changes in directly measured tonic sympathetic traffic do not correlate with non-invasive measures of autonomic modulation of the heart.

Intestinal and gastric tonometry during experimental burn shock.

INTRODUCTION: The occurrence of organ failure following thermal injury, despite restoration of hemodynamic parameters and urine output during resuscitation, has led to efforts to measure end-organ perfusion. The purpose of this 24-h study was to evaluate the utility of gastrointestinal (GI) tonometry during burn shock and resuscitation. METHODS: Male swine (n=11, 23.3+/-0.9 kg) were anesthetized with ketamine and propofol. A 70% full thickness burn was caused by immersion in 97 degrees C water for 30 s. Resuscitation with lactated Ringer's, 4 ml/kg/% burn, was begun at hour 6 and titrated to urine output (UO). Arterial blood gases and pulmonary artery catheter data were measured every 6 h. Gastric and ileal regional PCO(2) (PrCO(2)) were measured continuously by air tonometry, and the gastric and ileal intramucosal pH (pHi) and PCO(2) gap (PrCO(2)-PaCO(2)) were calculated every 6 h. RESULTS: Gastric pHi, ileal PrCO(2), ileal pHi, and ileal PCO(2) gap (but not gastric PrCO(2) or PCO(2) gap) all decreased with shock and were restored to baseline levels by resuscitation. Changes in ileal PrCO(2) were of greater magnitude and demonstrated decreased variability than those in gastric PrCO(2). CONCLUSIONS: In this model, ileal tonometry outperformed gastric tonometry during burn shock and resuscitation.