John O. Hwabejire

Traumatic brain injury and hemorrhagic shock: evaluation of different resuscitation strategies in a large animal model of combined insults.

ABSTRACT Traumatic brain injury (TBI) and hemorrhagic shock (HS) are the leading causes of trauma-related mortality and morbidity. Combination of TBI and HS (TBI + HS) is highly lethal, and the optimal resuscitation strategy for this combined insult remains unclear. A critical limitation is the lack of suitable large animal models to test different treatment strategies. We have developed a clinically relevant large animal model of TBI + HS, which was used to evaluate the impact of different treatments on brain lesion size and associated edema. Yorkshire swine (42–50 kg) were instrumented to measure hemodynamic parameters and intracranial pressure. A computer-controlled cortical impact device was used to create a TBI through a 20-mm craniotomy: 15-mm cylindrical tip impactor at 4 m/s velocity, 100-ms dwell time, and 12-mm penetration depth. Volume-controlled hemorrhage was started (40% blood volume) concurrent with the TBI. After 2 h of shock, animals were randomized to one of three resuscitation groups (n = 5/group): (a) normal saline (NS); (b) 6% hetastarch, Hextend (Hex); and (c) fresh frozen plasma (FFP). Volumes of Hex and FFP matched the shed blood, whereas NS was three times the volume. After 6 h of postresuscitation monitoring, brains were sectioned into 5-mm slices and stained with TTC (2,3,5-triphenyltetrazolium chloride) to quantify the lesion size and brain swelling. Combination of 40% blood loss with cortical impact and a period of shock (2 h) resulted in a highly reproducible brain injury. Total fluid requirements were lower in the Hex and FFP groups. Lesion size and brain swelling in the FFP group (2,160 ± 202.6 mm3 and 22% ± 1.0%, respectively) were significantly smaller than those in the NS group (3,285 ± 130.8 mm3 and 37% ± 1.6%, respectively) (P < 0.05). Hex treatment decreased the swelling (29% ± 1.6%) without reducing the lesion size. Early administration of FFP reduces the size of brain lesion and associated swelling in a large animal model of TBI + HS. In contrast, artificial colloid (Hex) decreases swelling without reducing the actual size of the brain lesion.

Assessment of coagulopathy, endothelial injury, and inflammation after traumatic brain injury and hemorrhage in a porcine model

BACKGROUND Traumatic brain injury (TBI) and hemorrhagic shock (HS) can be associated with coagulopathy and inflammation, but the mechanisms are poorly understood. We hypothesized that a combination of TBI and HS would disturb coagulation, damage the endothelium, and activate inflammatory and complement systems. METHODS A total of 33 swine were allocated to either TBI + HS (n = 27, TBI and volume-controlled 40% blood loss) or controls (n = 6, anesthesia and instrumentation). TBI + HS animals were left hypotensive (mean arterial pressure, 30–35 mm Hg) for 2 hours. Blood samples were drawn at baseline, 3 minutes and 15 minutes after injury, as well as following 2 hours of hypotension. Markers of coagulation, anticoagulation, endothelial activation/glycocalyx shedding, inflammation, complement, and sympathoadrenal function were measured. RESULTS The TBI + HS group demonstrated an immediate (3 minutes after injury) activation of coagulation (prothrombin fragment 1 + 2, 289 ng/mL vs. 232 ng/mL, p = 0.03) and complement (C5a, 2.83 ng/mL vs. 2.05 ng/mL, p = 0.05). Shedding of the endothelial glycocalyx (syndecan 1) was evident 15 minutes after injury (851.0 ng/ml vs. 715.5 ng/ml, p = 0.03) while inflammation (tumor necrosis factor &agr; [TNF-&agr;], 81.1 pg/mL vs. 50.8 pg/mL, p = 0.03) and activation of the protein C system (activated protein C, 56.7 ng/mL vs. 26.1 ng/mL, p = 0.01) were evident following the 2-hour hypotension phase. CONCLUSION The combination of TBI and shock results in an immediate activation of coagulation and complement systems with subsequent endothelial shedding, protein C activation, and inflammation.

Pharmacologic resuscitation for hemorrhagic shock combined with traumatic brain injury.

BACKGROUND We have previously demonstrated that valproic acid (VPA), a histone deacetylase inhibitor, can improve survival after hemorrhagic shock (HS), protect neurons from hypoxia-induced apoptosis, and attenuate the inflammatory response. We have also shown that administration of 6% hetastarch (Hextend [Hex]) after traumatic brain injury (TBI) decreases brain swelling, without affecting size of the lesion. This study was performed to determine whether addition of VPA to Hex would decrease the lesion size in a clinically relevant large animal model of TBI + HS. METHODS Yorkshire swine (42–50 kg) were instrumented to measure hemodynamic parameters, intracranial pressure, and brain tissue oxygenation. A custom-designed, computer-controlled cortical impact device was used to create a TBI through a 20-mm craniotomy: 15-mm cylindrical tip impactor at 4-m/s velocity, 100-millisecond dwell time, and 12-mm penetration depth. Volume-controlled hemorrhage was started (40% blood volume) concurrent with the TBI. After 2 hours of shock, animals were randomized to one of three resuscitation groups (n = 7 per group) as follows: (1) isotonic sodium chloride solution; (2) 6% hetastarch, Hex; and (3) Hex and VPA 300 mg/kg (Hex + VPA). Volumes of Hex matched the shed blood, whereas that of the isotonic sodium chloride solution was three times the volume. VPA treatment was started after an hour of shock. After 6 hours of postresuscitation monitoring, brains were sectioned into 5-mm slices and stained with 2, 3, 5-Triphenyltetrazolium chloride to quantify the lesion size (mm3) and brain swelling (percent change compared with uninjured side). Levels of acetylated histone H3 were determined to quantify acetylation, and myeloperoxidase and interleukine-1&bgr; (IL-1&bgr;) levels were measured as markers of brain inflammation. RESULTS Combination of 40% blood loss with cortical impact and a period of shock (2 hours) and resuscitation resulted in a highly reproducible brain injury. Lesion size and brain swelling in the Hex + VPA group (1,989 [156.8] mm3, and 19% [1.6%], respectively) were significantly smaller than the isotonic sodium chloride solution group (3,335 [287.9] mm3 and 36% [2.2%], respectively). Hex alone treatment significantly decreased the swelling (27% [1.6%]) without reducing the lesion size. The number of CD11b-positive cells as well as myeloperoxidase and IL-1 levels in the brains were significantly reduced by the VPA treatment. CONCLUSION In a combined HS and TBI model, treatment with artificial colloid (Hex) improves hemodynamic parameters and reduces swelling, without affecting the actual size of the brain lesion. Addition of VPA effectively reduces both the size of brain lesion and associated swelling by attenuating the inflammatory response.

Platelet activation and dysfunction in a large-animal model of traumatic brain injury and hemorrhage

BACKGROUND: Traumatic brain injury (TBI) and hemorrhage are the leading causes of trauma‐related mortality. Both TBI and hemorrhage are associated with coagulation disturbances, including platelet dysfunction. We hypothesized that platelet dysfunction could be detected early after injury, and that this dysfunction would be associated with early activation, as measured by circulating levels of platelet activation markers. METHODS: A total of 33 swine were allocated to TBI and hypotension (n = 27, TBI and volume‐controlled 40% blood loss) or controls (n = 6, anesthesia and instrumentation only). Animals in the TBI/Hemorrhage group were left hypotensive, defined as mean arterial pressure of 35 mm Hg, for 2 hours. Blood samples were drawn at baseline and 3 minutes and 15 minutes following injury as well as following 2 hours of shock. Samples were analyzed for platelet aggregation using impedance aggregometry with agonists collagen, arachidonic acid, and adenosine diphosphate (ADP) and thromboelastography (TEG) and circulating levels of platelet activation markers transforming growth factor‐[beta] (TGF‐[beta]), CD40 ligand, and sP‐selectin. RESULTS: Platelet ADP aggregation was significantly lower in the TBI/Hemorrhage group when compared with the control group 15 minutes following injury (62.4 vs. 80.4 U, p = 0.03) as well as following 2 hours of hypotension (59.9 vs. 73.5 U, p < 0.01). The latter was associated with lower TEG measured clot strength (TEG‐MA, 74.1 vs. 79.4 mm, p = 0.05). No difference in collagen or arachidonic acid aggregation was observed. TGF‐[beta] levels were significantly higher in the TBI/Hemorrhage group following 2 hours of hypotension (1,764 vs. 1,252 pg/mL, p = 0.01). No differences in CD40 ligand or sP‐selectin levels were observed. CONCLUSION: In this combined model of TBI and hemorrhage, a significantly lower ADP‐induced platelet aggregation was detected 15 minutes following injury that was further aggravated during the 2‐hour shock period. This dysfunction was associated with an increase in platelet activation marker TGF‐[beta].

Excessively Long Hospital Stays After Trauma Are Not Related to the Severity of Illness: Let’s Aim to the Right Target!

IMPORTANCE Reduction in length of hospital stay is a veritable target in reducing the overall costs of health care. However, many existing approaches are flawed because the assumptions of what cause excessive length of stay are incorrect; we methodically identified the right targets in this study. OBJECTIVE To identify the causes of excessively prolonged hospitalization (ExProH) in trauma patients. DESIGN The trauma registry, billing databases, and medical records of trauma admissions were reviewed. Excessively prolonged hospitalization was defined by the standard method used by insurers, which is a hospital stay that exceeds the Diagnosis Related Group-based trim point. The causes of ExProH were explored in a unique potentially avoidable days database, used by our hospitals case managers to track discharge delays. SETTING Level I academic trauma center. PARTICIPANTS Adult trauma patients admitted between January 1, 2006, and December 31, 2010. MAIN OUTCOMES AND MEASURES Excessively prolonged hospitalization and hospital cost. RESULTS Of 3237 patients, 155 (5%) had ExProH. The patients with ExProH compared with non-ExProH patients were older (mean [SD] age, 53 [21] vs 47 [22] years, respectively; P = .001), were more likely to have blunt trauma (92% vs 84%, respectively; P = .03), were more likely to be self-payers (16% vs 11%, respectively; P = .02) or covered by Medicare/Medicaid (41% vs 30%, respectively; P = .002), were more likely to be discharged to post-acute care facilities than home (65% vs 35%, respectively; P < .001), and had higher hospitalization cost (mean,

Early treatment with lyophilized plasma protects the brain in a large animal model of combined traumatic brain injury and hemorrhagic shock

54 646 vs

Fresh frozen plasma resuscitation attenuates platelet dysfunction compared with normal saline in a large animal model of multisystem trauma.

18 444, respectively; P < .001). Both groups had similar Injury Severity Scores, Revised Trauma Scores, baseline comorbidities, and in-hospital complication rates. Independent predictors of mortality were discharge to a rehabilitation facility (odds ratio = 4.66; 95% CI, 2.71-8.00; P < .001) or other post-acute care facility (odds ratio = 5.04; 95% CI, 2.52-10.05; P < .001) as well as insurance type that was Medicare/Medicaid (odds ratio = 1.70; 95% CI, 1.06-2.72; P = .03) or self-pay (odds ratio = 2.43; 95% CI, 1.35-4.37; P = .003). The reasons for discharge delays were clinical in only 20% of the cases. The remaining discharges were excessively delayed because of difficulties in rehabilitation facility placement (47%), in-hospital operational delays (26%), or payer-related issues (7%). CONCLUSIONS AND RELEVANCE System-related issues, not severity of illness, prolong hospital stay excessively. Cost-reduction efforts should target operational bottlenecks between acute and postacute care.

Self-expanding foam for prehospital treatment of severe intra-abdominal hemorrhage: dose finding study.

BACKGROUND Combination of traumatic brain injury (TBI) and hemorrhagic shock (HS) can result in significant morbidity and mortality. We have previously shown that early administration of fresh frozen plasma (FFP) in a large animal model of TBI and HS reduces the size of the brain lesion as well as the associated edema. However, FFP is a perishable product that is not well suited for use in the austere prehospital settings. In this study, we tested whether a shelf-stable, low-volume, lyophilized plasma (LSP) product was as effective as FFP. METHODS Yorkshire swine (42–50 kg) were instrumented to measure hemodynamic parameters, intracranial pressure, and brain tissue oxygenation. A prototype, computerized, cortical impact device was used to create TBI through a 20-mm craniotomy: 15-mm cylindrical tip impactor at 4 m/s velocity, 100-millisecond dwell time, and 12-mm penetration depth. Volume-controlled hemorrhage was induced (40–45% total blood volume) concurrent with the TBI. After 2 hours of shock, animals were treated with (1) normal saline (NS, n = 5), (2) FFP (n = 5), and (3) LSP (n = 5). The volume of FFP and LSP matched the shed blood volume, whereas NS was 3 times the volume. Six hours after resuscitation, brains were sectioned and stained with TTC (2, 3, 5-Triphenyltetrazolium chloride), and lesion size (mm3) and swelling (percent change in volume compared with the contralateral, uninjured side) were measured. RESULTS This protocol resulted in a highly reproducible brain injury, with clinically relevant changes in blood pressure, cardiac output, tissue hypoperfusion, intracranial pressure, and brain tissue oxygenation. Compared with NS, treatment with LSP significantly (p < 0.05) decreased brain lesion size and swelling (51% and 54%, respectively). CONCLUSION In a clinically realistic combined TBI + HS model, early administration of plasma products decreases brain lesion size and edema. LSP is as effective as FFP, while offering many logistic advantages. LEVEL OF EVIDENCE Therapeutic study, level V.

Synergistic effects of fresh frozen plasma and valproic acid treatment in a combined model of traumatic brain injury and hemorrhagic shock

BACKGROUND Platelet dysfunction following trauma has been identified as an independent predictor of mortality. We hypothesized that fresh frozen plasma (FFP) resuscitation would attenuate platelet dysfunction compared with 0.9% normal saline (NS). METHODS Twelve swine were subjected to multisystem trauma (traumatic brain injury, liver injury, rib fracture, and soft tissue injury) with hemorrhagic shock (40% of estimated blood volume). Animals were left in shock (mean arterial pressure, 30–35 mm Hg) for 2 hours followed by resuscitation with three times shed volume NS (n = 6) or one times volume FFP (n = 6) and monitored for 6 hours. Platelet function was assessed by adenosine diphosphate (ADP)–induced platelet aggregation at baseline, after 2 hours of shock following resuscitation, and 6 hours after resuscitation. Fibrinogen levels and markers of platelet activation (transforming growth factor &bgr; [TGF-&bgr;], sP-Selectin, and CD40L) as well as endothelial injury (intercellular adhesion molecule 1 [ICAM-1], vascular cell adhesion molecule 1 [VCAM-1]) were also assayed. Thromboelastography was used to measure clotting activity. RESULTS ADP-induced platelet aggregation was significantly higher in the FFP group (46.3 U vs. 25.5 U, p < 0.01) following resuscitation. This was associated with higher fibrinogen levels (202 mg/dL vs. 80 mg/dL, p < 0.01) but lower endothelial activation (VCAM-1, 1.25 ng/mL vs. 3.87 ng/mL, p = 0.05). Other markers did not differ. After 6 hours of observation, ADP-induced platelet aggregation remained higher in the FFP group (53.8 U vs. 37.0 U, p = 0.03) as was fibrinogen levels (229 mg/dL vs. 153 mg/dL, p < 0.01). Endothelial activation was lower (ICAM-1, 21.0 ng/mL vs. 24.4 ng/mL, p = 0.05), whereas TGF-&bgr; levels were higher (2,138 pg/mL vs. 1,802 pg/mL, p = 0.03) in the FFP group. Other markers did not differ. Thromboelastography revealed increased clot strength in the FFP group at both postresuscitation time points. CONCLUSION Resuscitation with FFP resulted in an immediate and sustained improvement in platelet function and clot strength compared with high-volume NS resuscitation. This was associated with an increase in fibrinogen levels and an attenuation of endothelial activation.

Pharmacologic modulation of cerebral metabolic derangement and excitotoxicity in a porcine model of traumatic brain injury and hemorrhagic shock

BACKGROUND Noncompressible abdominal bleeding is a significant cause of preventable death on the battlefield and in the civilian trauma environment, with no effective therapies available at point of injury. We previously described the development of a percutaneously administered, self-expanding, poly(urea)urethane foam that improved survival in a lethal Grade V hepatic and portal vein injury model in swine. In this study, we hypothesized that survival with foam treatment is dose dependent. METHODS A high-grade hepatoportal injury was created in a closed abdominal cavity, resulting in massive noncompressible hemorrhage. After injury, the animals were divided into five groups. The control group (n = 12) was treated only with fluid resuscitation, and four polymer groups received different dose volumes (Group 1, n = 6, 64 mL; Group 2, n = 6, 85 mL; Group 3, n = 18, 100 mL; and Group 4, n = 10, 120 mL) in addition to fluids. Ten minutes after injury, the foam was percutaneously administered, and animals were monitored for 3 hours. RESULTS Survival with hepatoportal injury was highest in Group 4 (90%) and decreased in a dose-dependent fashion (Group 3, 72%; Group 2, 33%; Group 1, 17%). All polymer groups survived significantly longer than the controls (8.3%). Hemorrhage rate was reduced in all groups but lowest in Group 4 versus the control group (0.34 [0.052] vs. 3.0 [1.3] mL/kg/min, p < 0.001). Increasing foam dose volume was associated with increased peak intra-abdominal pressure (88.2 [38.9] in Group 4 vs. 9.5 [3.2] in the controls, p < 0.0001) and increased incidence of focal bowel injuries. CONCLUSION The self-expanding foam significantly improves survival in a dose-dependent fashion in an otherwise lethal injury. Higher doses are associated with better survival but resulted in the need for bowel resection.