Biomedical subjects

Kenneth G Proctor

Publications and source records attributed to Kenneth G Proctor.

At least 19 recordsLinked to original sources

PubMed2006

Extracellular ubiquitin increases in packed red blood cell units during storage.

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-alpha, 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; r(2) = 0.82, P < 0.001) 20-fold to 2170 +/- 268 ng/mL on day 42. Plasma inhibited TNF-alpha production but stimulated IL-8 production of normal whole blood, which correlated with time-dependent Ub release (TNFalpha: 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-alpha 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.

Adult↗

PubMed2006

Effects of arginine vasopressin during resuscitation from hemorrhagic hypotension after traumatic brain injury.

OBJECTIVE: Two series of experiments were designed to evaluate whether early arginine vasopressin improves acute outcome following resuscitation from traumatic brain injury and severe hemorrhagic hypotension. DESIGN: Prospective randomized, blinded animal study. SETTING: University laboratory. SUBJECTS: Thirty-three swine. INTERVENTIONS: In series 1 (n = 19), after traumatic brain injury with hemorrhage and 12 mins of shock (mean arterial pressure approximately 20 mm Hg), survivors (n = 16) were initially resuscitated with 10 mL/kg crystalloid. After 30 mins, crystalloid and blood with either 0.1 unit x kg(-1) x hr(-1) arginine vasopressin or placebo was titrated to a mean arterial pressure target >or=60 mm Hg. After 90 mins, all received mannitol and the target was cerebral perfusion pressure >or=60 mm Hg. To test cerebrovascular function, 7.5% inhaled CO2 was administered periodically. In series 2 (n = 14), the identical protocol was followed except the shock period was 20 mins and survivors (n = 10) received a bolus of either arginine vasopressin (0.2 units/kg) or placebo during the initial fluid resuscitation. MEASUREMENTS AND MAIN RESULTS: In series 1, by 300 mins after traumatic brain injury with arginine vasopressin (n = 8) vs. placebo (n = 8), the fluid and transfusion requirements were reduced (both p < .01), intracranial pressure was improved (11 +/- 1 vs. 23 +/- 2 mmHg; p < .0001), and the CO2-evoked intracranial pressure elevation was reduced (7 +/- 2 vs. 26 +/- 3 mm Hg, p < .001), suggesting improved compliance. In series 2, with arginine vasopressin vs. placebo, cerebral perfusion pressure was more rapidly corrected (p < .05). With arginine vasopressin, five of five animals survived 300 mins, whereas three of five placebo animals died. The survival time with placebo was 54 +/- 4 mins (p < .05 vs. arginine vasopressin). CONCLUSIONS: Early supplemental arginine vasopressin rapidly corrected cerebral perfusion pressure, improved cerebrovascular compliance, and prevented circulatory collapse during fluid resuscitation of hemorrhagic shock after traumatic brain injury.

Animals↗

PubMed2006

Prehospital HBOC-201 after traumatic brain injury and hemorrhagic shock in swine.

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 PO2 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 PO2 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.

Analysis of Variance↗

PubMed2006

Simulation training for a mass casualty incident: two-year experience at the Army Trauma Training Center.

BACKGROUND: Civilian and military mass casualty incidents (MCI) are an unfortunate reality in the 21st century, but there are few situational training exercises (STX) to prepare for them. To fill this gap, we developed a MCI STX for U.S. Army Forward Surgical Teams (FST) in conjunction with the U.S. Army Trauma Training Center. METHODS: After a standardized briefing, each FST has 60 minutes to unpack, setup, and organize a standard equipment cache into an emergency room, operating room, and intensive care unit. In an adjacent room, five anesthetized swine are prepared with standardized, combat-relevant injuries. The number and acuity of the total casualties are unknown to the FST and arrive in waves and without warning. A realistic combat environment is simulated by creating resource limitations, power outages, security breaches, and other stressors. The STX concludes when all casualties have died or are successfully treated. FSTs complete a teamwork self-assessment card, while staff and FST surgeons evaluate organization, resource allocation, communication, treatment, and overall performance. Feedback from each FST can be incorporated into an updated design for the next STX. RESULTS: From 2003-2005, 16 FSTs have completed the STX. All FSTs have had collapses in situational triage, primary/ secondary surveys, and/or ATLS principles (basic ABCs), resulting in approximately 20% preventable deaths. CONCLUSIONS: We concluded (1) a MCI can overwhelm even combat- experienced FSTs; (2) adherence to basic principles of emergency trauma care by all FST members is essential to effectively and efficiently respond to this MCI; (3) by prospectively identifying deficiencies, future military or civilian performance during an actual MCI may be improved; and (4) this MCI STX could provide a template for similar programs to develop, train, and evaluate civilian surgical disaster response teams.

Animals↗

PubMed2005

Resuscitation with pressors after traumatic brain injury.

BACKGROUND: 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. STUDY DESIGN: Anesthetized, ventilated swine (n = 39, 30 +/- 2 kg) underwent fluid percussion traumatic brain injury followed by hemorrhage (30 +/- 2mL/kg) to a mean arterial pressure < 30mmHg, then were randomized to 1 of 5 groups to maintain mean arterial pressure > 60mmHg for 30 to 60minutes, then cerebral perfusion pressure > 60mmHg 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 was < 13, and mannitol was administered if intracranial pressure was > 20 mmHg. Cerebrovascular reactivity was evaluated with serial CO(2) challenges. RESULTS: 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 p < 0.05 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 (p < 0.05). With either pressor only, intracranial pressure remained low, but mixed venous O(2) saturation, cardiac output, and urine output were decreased (all p < 0.05 versus other groups). CONCLUSIONS: 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.

Analysis of Variance↗

PubMed2005

Ubiquitin reduces fluid shifts after traumatic brain injury.

BACKGROUND: Ubiquitin has well-described intracellular properties. Recent data also suggest pleiotropic effects of extracellular ubiquitin, including induction of apoptosis, regulation of immune functions, and therapeutic potential during fluid resuscitation from severe trauma. However, the actions of exogenous ubiquitin after traumatic brain injury (TBI) are unknown. METHODS: Series 1: Thirty-five minutes after TBI and hemorrhage, 1.5 mg ubiquitin/kg (n = 5) or albumin (n = 5) intravenous was followed by fluid resuscitation to maintain mean arterial and cerebral perfusion pressure. Series 2: Ubiquitin (n = 5) or vehicle (n = 6) was administered after TBI only. Ubiquitin was measured with enzyme-linked immunosorbent assay in serum, urine (series 1), and cerebrospinal fluid (series 2) for 300 minutes. RESULTS: Series 1: After intravenous bolus, serum ubiquitin peaked at t = 45 minutes with a half-life of 54 minutes. Recovery in urine was 10%. With albumin versus ubiquitin, 85% more resuscitation fluid was required to stabilize systemic and cerebral hemodynamics (P < .05 for t = 150 to 300 minutes), but hematocrit was similar. With albumin there were progressive increases in intracranial pressure, peak inspiratory pressure, and decreases in oxygenation. All were significantly attenuated by ubiquitin (all P < .05 vs albumin). Series 2: Intravenous ubiquitin altered cerebrospinal fluid ubiquitin with an increased time to peak (t = 88 +/- 13 min vs 45 +/- 7 min, P < .05) and area under the concentration-time curve (82 +/- 22 vs 23 +/- 11 microg/min(1)/mL(-1), P < .05). CONCLUSIONS: After TBI, intravenous ubiquitin crossed the blood-brain barrier and significantly reduced third spacing of fluid into the brain and lung during resuscitation.

Animals↗

PubMed2005

Ubiquitin immunoreactivity in cerebrospinal fluid after traumatic brain injury: clinical and experimental findings.

OBJECTIVE: 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. DESIGN AND SETTING: Prospective observational study of patients, with a subsequent interventional study of animals. SUBJECTS: The subjects were 14 patients with TBI, five patients with nontraumatic subarachnoid hemorrhage, ten nonneurologic controls, and seven cross-bred swine. INTERVENTIONS: Standardized TBI. MEASUREMENTS AND MAIN RESULTS: 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. CONCLUSIONS: 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.

Adult↗

PubMed2005

Can near-infrared spectroscopy identify the severity of shock in trauma patients?

BACKGROUND: Our recent experimental study showed that peripheral muscle tissue oxygen saturation (StO2), determined noninvasively by near-infrared spectroscopy (NIRS), was more reliable than systemic hemodynamics or invasive oxygenation variables as an index of traumatic shock. The purpose of this study was to establish the normal range of thenar muscle StO2 in humans and the relationship between shock state and StO2 in trauma patients. METHODS: This was a prospective, nonrandomized, observational, descriptive study in normal human volunteers (n = 707) and patients admitted to the resuscitation area of our Level I trauma center (n = 150). To establish a normal StO2 range, an NIRS probe was applied to the thenar eminence of volunteers (normals). Subsequently, in a group of trauma patients, an NIRS probe was applied to the thenar eminence and data were collected and stored for offline analysis. StO2 monitoring was performed continuously and noninvasively, and values were recorded at 2-minute intervals. Five moribund trauma patients were excluded. Members of our trauma faculty, blinded to StO2 values, classified each patient into one of four groups (no shock, mild shock, moderate shock, and severe shock) using conventional physiologic parameters. RESULTS: Mean +/- SD thenar StO2 values for each group were as follows: normals, 87 +/- 6% (n = 707); no shock, 83 +/- 10% (n = 85); mild shock, 83 +/- 10% (n = 19); moderate shock, 80 +/- 12% (n = 14); and severe shock, 45 +/- 26% (n = 14). The thenar StO2 values clearly discriminated the normals or no shock patients and the patients with severe shock (p < 0.05). CONCLUSION: Decreased thenar muscle tissue oxygen saturation reflects the presence of severe hypoperfusion and near-infrared spectroscopy may be a novel method for rapidly and noninvasively assessing changes in tissue dysoxia.

Adult↗

PubMed2005

Early vasopressin improves short-term survival after pulmonary contusion.

UNLABELLED: Arginine vasopressin (AVP) is a promising treatment for several types of irreversible shock, but its therapeutic potential has not been examined after severe chest trauma. Two series of experiments were performed to fill this gap. METHODS: Series 1: anesthetized, mechanically-ventilated pigs (n = 20, 29 +/- 1 kg) received a blast to the chest, followed by a "controlled" arterial hemorrhage to a mean arterial pressure (MAP) <30 mm Hg. At 20 minutes, a 10 mL/kg normal saline (NS) bolus was followed by either 0.1 U/kg AVP bolus or NS, in randomized, blinded fashion. From 30-300 minutes, either AVP (0.4 U/kg/hr plus NS) or NS alone was infused as needed to MAP>70 mm Hg. Series 2: Swine (n = 15) received the chest injury followed by partial left hepatectomy to produce "uncontrolled" hemorrhage. Resuscitation was the same as in series 1. RESULTS: The blast created bilateral parenchymal contusions (R > L), hemo/pneumothorax and progressive cardiopulmonary distress. In Series 1, there were 3/20 deaths before randomization, 0/8 deaths after resuscitation with AVP versus 4/9 deaths with NS (p = 0.029). In surviving animals, with AVP versus NS, fluid requirements and peak airway pressures were lower while P/F was higher (all p < 0.05). In Series 2, with uncontrolled hemorrhage, there were 5/15 deaths before randomization. Upon resuscitation with AVP versus NS, survival time and blood loss were both improved, but the differences did not reach statistical significance. CONCLUSIONS: After severe chest trauma with controlled hemorrhage, early AVP decreased mortality, reduced fluid requirements and improved pulmonary function. With uncontrolled hemorrhage, early AVP did not increase the risk for bleeding.

Animals↗

PubMed2005

Systemic coagulation changes caused by pulmonary artery catheters: laboratory findings and clinical correlation.

BACKGROUND: A higher rate of pulmonary embolism has been associated with pulmonary artery (PA) catheters; however, no mechanism has been described. Conventional tests of coagulation reveal no changes related to PA catheterization. The purpose of this study was to determine whether PA catheterization resulted in a hypercoagulable state detectable by thrombelastography (TEG). METHODS ANIMAL: Healthy, anesthetized, swine (n = 19) underwent PA catheterization. Samples were drawn from 7F femoral arterial catheters before and two hours after PA catheterization, at 5 mL/min, and analyzed (native whole blood, n = 15, kaolin activated blood, n = 4) by TEG (Hemoscope, Niles, IL) at precisely two minutes. Human: An IRB-approved prospective, observational trial was conducted in critically ill patients (n = 19). Samples were drawn from 22-gauge radial artery catheters, before and three hours after PA catheterization. Kaolin-activated TEG samples were analyzed at precisely five minutes. Data are mean +/- SE; Groups were compared with analysis of variance and significance was assessed at the 95% confidence interval. RESULTS: In both animals and patients, PA catheterization truncated R times (time to initial fibrin formation). In swine, the R times were 17.6 +/- 1.3 minutes (native) and 3.8 +/- 0.4 (kaolin) before PA catheterization, and decreased to 6.3 +/- 1.0 minutes (p = 0.002) and 1.9 +/- 0.5 minutes (p = 0.010) afterward. There were no changes in pH or temperature during the experiment. In patients, 4 of 19 were excluded for protocol violations. The R time was 6.3 +/- 1.0 minutes (kaolin) before and 3.0 +/- 0.3 minutes after catheterization (p = 0.003). No changes were observed in conventional coagulation parameters, temperature or pH. CONCLUSION: In healthy swine, and critically ill patients, PA catheters may enhance thrombin formation and fibrin polymerization, indicating a systemic hypercoagulable state. This may explain why PA catheters are associated with an increased risk of pulmonary emboli.

Adult↗

PubMed2005

Resuscitation with a hemoglobin-based oxygen carrier after traumatic brain injury.

BACKGROUND: 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. METHODS: 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 to > or = 100 mm Hg and heart rate (HR) to < or = 100 beats/min. After 60 minutes, fluid was given to maintain mean arterial pressure (MAP) at > or = 70 mm Hg and heterologous whole blood (red blood cells [RBCs], 10 mL/kg) was transfused for hemoglobin at < or = 5 g/dL. After 90 minutes, mannitol (MAN, 1 g/kg) was given for intracranial pressure > or = 20 mm Hg, LR solution was given to maintain cerebral perfusion pressure at > or = 70 mm Hg, and RBCs were given for hemoglobin of < or = 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. RESULTS: 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 p < 0.05). Cerebrovascular reactivity and intracranial compliance were improved with LR + HBOC (p < 0.05) and fluid requirements were reduced (30 +/- 12 vs. 280 +/- 40 mL/kg; p < 0.05). 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. CONCLUSION: 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.

Analysis of Variance↗

PubMed2004

Effects of exogenous ubiquitin in lethal endotoxemia.

BACKGROUND: Recent data indicated a potential role for extracellular ubiquitin in hematopoiesis and inflammation. The biological significance and therapeutic potential of these findings in vivo are unknown. Based on its in vitro abilities to inhibit endotoxin-stimulated tumor necrosis factor alpha (TNFalpha) production, we hypothesized that exogenous ubiquitin has salutary effects on sequelae caused by endotoxin in vivo. METHODS: Anesthetized and mechanically ventilated swine were infused with endotoxin for 3 hours. Ubiquitin was administered intravenously either 15 minutes before or 45 minutes after the endotoxin infusion was started. Albumin was administered to a control group. An additional control group received only ubiquitin. Ex vivo endotoxin evoked TNFalpha production was measured using a whole blood assay. Ubiquitin and TNFalpha concentrations were determined by enzyme-linked immunosorbent assay. RESULTS: Ubiquitin reduced mortality (P <.05), prevented development of pulmonary failure (P <.05), reduced fluid requirements (P <.05), and diminished erythema and edema formation. Ubiquitin pretreatment was more effective than treatment 45 minutes after an endotoxin infusion was started. In vivo ubiquitin administration alone inhibited ex vivo endotoxin-evoked TNFalpha secretion, but had no effect on TNFalpha serum levels after endotoxin infusion. CONCLUSION: In vivo ubiquitin administration has salutary actions during lethal endotoxemia and inhibits ex vivo whole blood TNFalpha production upon endotoxin stimulation. The clinical appearance after ubiquitin treatment in endotoxemia indicates the endothelium as another potential target cell population for interactions with ubiquitin. A novel therapeutic approach to a broad variety of diseases, in which endotoxin triggers immune activation, is suggested.

Animals↗

PubMed2004

Noninvasive muscle oxygenation to guide fluid resuscitation after traumatic shock.

BACKGROUND: Three different protocols tested the hypothesis that hind limb muscle tissue O(2) saturation (StO(2)), measured noninvasively with near-infrared spectroscopy (NIRS), is as reliable as invasive systemic oxygenation indices to guide fluid resuscitation. METHODS: In series 1, swine (n=30) were hemorrhaged, then received either no fluid, a fixed volume of colloid (15 mL/kg), or shed blood plus lactated Ringer's (LR) titrated to MAP >60 mm Hg. In series 2, swine (n=16) received a penetrating femur injury, a 47% to 55% hemorrhage to determine a median lethal dose (LD(50)) then shed blood plus LR titrated to MAP >60 mm Hg. In series 3, swine (n=5) received the femur injury plus LD(50) hemorrhage, and were resuscitated with LR titrated to StO(2) >50%. RESULTS: In series 1, StO(2) tracked mixed venous O(2) saturation (SvO(2)), but discriminated between 3 survivor groups better than SvO(2), arterial lactate, or arterial base excess. In series 2, StO(2) tracked SvO(2) but discriminated between 2 survivor groups better than SvO(2), arterial lactate, or arterial base excess. In series 3, animals survived to extubation when resuscitated to an StO(2) target. CONCLUSIONS: Noninvasive muscle StO(2) determined by NIRS was more reliable than invasive oxygenation variables as an index of shock. Because muscle StO(2) can be easily monitored in emergency situations, it may represent an improved method to gauge the severity of shock or the adequacy of fluid resuscitation after trauma.

Animals↗

PubMed2004

Changes in intracranial pressure, coagulation, and neurologic outcome after resuscitation from experimental traumatic brain injury with hetastarch.

BACKGROUND: In a model of traumatic brain injury (TBI), 2 protocols compared changes in intracranial pressure (ICP), coagulation, and neurologic outcome after intravenous fluid (IVF) resuscitation with either Hextend (HEX, 6% hetastarch in lactated electrolyte injection) or standard of care, crystalloid plus mannitol (MAN). METHODS: In the nonsurvivor protocol, swine (n = 28) received a fluid percussion TBI and hemorrhage (27 +/- 3 mL/kg). At 30 minutes, resuscitation began with lactated Ringer's (LR) or HEX. After 60 minutes, MAN (1 g/kg) or placebo was given plus supplemental IVF to maintain cerebral perfusion pressure (CPP) > or = 70 mm Hg for 240 minutes. Swine in the survivor group (n = 15) also underwent TBI and hemorrhage, and resuscitation with HEX was compared to that of normal saline (NS)+MAN. Neurologic outcome and coagulation were evaluated for 72 hours. RESULTS: In the nonsurvivor protocol, HEX, LR+MAN, and HEX+MAN attenuated the time-related rise of ICP and prevented ICP >20 mm Hg versus LR alone (P < .05). HEX alone maintained CPP (relative to baseline) and decreased total IVF by 50% versus LR +/- MAN (P < .05). MAN had no additive effect with HEX. Coagulation, measured by thromboelastograph reaction time (R), was 11 +/- 1 and 9 +/- 1 minutes at baseline and after TBI (before randomization). At 240 minutes after HEX or LR+MAN, R was 6 +/- 1 or 7 +/- 2 minutes, which indicates a hypercoagulable state, but there was no difference between treatments. In the survivor protocol, ICP and CPP were similar with NS+MAN versus HEX, but IVF requirement was 161 +/- 20 versus 28 +/- 3 mL/kg (P < .05). Motor scores were higher on days 2 and 3 with HEX (P < .05). At 72 hours, R was 28 +/- 14 versus 26 +/- 6 minutes with NS+MAN versus HEX, which indicates a hypocoagulable state, but there was no difference between treatments. CONCLUSIONS: Hextend as the sole resuscitation fluid after severe TBI reduces fluid requirement, obviates the need for mannitol, improves neurologic outcome, and has no adverse effect on the coagulation profile relative to the crystalloid plus mannitol standard of care.

Animals↗

PubMed2004

Cerebral perfusion pressure elevation with oxygen-carrying pressor after traumatic brain injury and hypotension in Swine.

BACKGROUND: Previously, we had shown that elevation of cerebral perfusion pressure, using pressors, improved short-term outcomes after traumatic brain injury and hemorrhagic shock in swine. The current study evaluates outcomes after resuscitation with diaspirin cross-linked hemoglobin (DCLHb)--a hemoglobin-based oxygen carrier with pressor activity--in the same swine model of traumatic brain injury and hemorrhagic shock. METHODS: Anesthetized and ventilated swine received traumatic brain injury via cortical fluid percussion (6-8 atm) followed by 45% blood volume hemorrhage. One hour later, animals were randomized to either a control group (SAL) resuscitated with normal saline equal to three times shed blood volume or to one of two experimental groups resuscitated with DCLHb. The two experimental groups consisted of a low-dose group, resuscitated with 250 mL of DCLHb (Hb1), and a high-dose group, resuscitated with 500 mL of DCLHb (Hb2). Animals were observed for 210 minutes postresuscitation. Outcomes evaluated were cerebral oxygenation by measuring partial pressure and saturation of oxygen in cerebrovenous blood; cerebral function by evaluating the preservation and magnitude of cerebrovascular carbon dioxide reactivity; and brain structural damage by semiquantitatively assessing beta amyloid precursor protein positive axons. RESULTS: Postresuscitation, cerebral perfusion pressure was higher in the DCLHb groups (p < 0.05, Hb1 and Hb2 vs. SAL), and intracranial pressure was lower in the Hb2 group (p < 0.05 vs. SAL). Cerebrovenous oxygen level was similar in all groups (p > 0.05). At baseline, 5% carbon dioxide evoked a 16 +/- 1% increase in cerebrovenous oxygen saturation, indicating vasodilatation. At 210 minutes, this response was nearly absent in SAL (4 +/- 4%) (p < 0.05 vs. baseline) and Hb1 (1 +/- 5%), but was partially preserved in Hb2 (9 +/- 5%). There was no intergroup difference in beta amyloid precursor protein positive axons. Five of 20 SAL and 0 of 13 DCLHb animals developed brain death (flat electroencephalogram) (p = 0.05, SAL vs. DCLHb). Postresuscitation, DCLHb animals maintained higher mean pulmonary arterial pressure (28 +/- 1 mm Hg, SAL; 42 +/- 1 mm Hg, Hb1; 45 +/- 1 mm Hg, Hb2) (p < 0.05, Hb1 and Hb2 vs. SAL) and lower cardiac output (3.9 +/- 1.6 L/min, SAL; 2.6 +/- 0.1 L/min, Hb1; 2.7 +/- 0.1 L/min, Hb2) (p < 0.05, Hb1 and Hb2 vs. SAL). Three Hb2 animals died as a result of cardiac failure, and one SAL animal died as a result of irreversible shock. CONCLUSION: In this swine model of traumatic brain injury and hemorrhagic shock, resuscitation with DCLHb maintained a higher cerebral perfusion pressure. Low-dose DCLHb (minimal increase in oxygen carriage) failed to significantly improve short-term outcome. With high-dose DCLHb (significant improvement in oxygen carriage), intracranial pressure was lower and cerebrovascular carbon dioxide reactivity was partially preserved; however, this was at the cost of poorer cardiac performance secondary to high afterload.

Amyloid beta-Protein Precursor↗

PubMed2004

Therapeutic potential of exogenous ubiquitin during resuscitation from severe trauma.

BACKGROUND: Recent studies suggest that extracellular ubiquitin could have a physiologic role in immunodepression in sepsis and trauma. The therapeutic potential of exogenous ubiquitin after trauma has not been examined. To fill this gap, we designed a series of experiments in a clinically relevant trauma model. METHODS: Forty minutes after femur fractures and hemorrhage, swine received 1.3 mg of ubiquitin per kilogram or bovine serum albumin intravenously followed by fluid resuscitation to maintain systemic hemodynamics. Leukocyte function and the immunomodulatory capacity of serum were assessed measuring endotoxin-evoked tumor necrosis factor-alpha (TNF alpha) production ex vivo. TNF alpha and ubiquitin were quantified with enzyme-linked immunosorbent assay. RESULTS: Intravenous ubiquitin had no significant hemodynamic effect in normal animals. After injury, ubiquitin significantly reduced fluid requirements by at least 60% (p < 0.05). The injury was associated with transient immunodepression, as reflected by reduced endotoxin-evoked TNF alpha production by 40% to 50%. With ubiquitin, this response remained depressed for 100 to 160 minutes (p < 0.05), but fully recovered to baseline with albumin. CONCLUSION: Ubiquitin is apparently safe and effective for reducing fluid requirements as a measure of diffuse capillary leak. This immunomodulatory property suggests a new therapeutic approach after injury in particular, and for infectious and noninfectious inflammation in general.

Analysis of Variance↗

PubMed2004

Building a better fluid for emergency resuscitation of traumatic brain injury.

UNLABELLED: Hextend (HEX) is a colloid solution that is FDA-approved for volume expansion during surgery. ATL-146e is a novel adenosine A2A receptor agonist that has anti-inflammatory, neuroprotective, and coronary vasodilator properties. Three series of experiments were designed to evaluate the therapeutic potential of HEX+/-ATL-146e for emergency resuscitation from traumatic brain injury (TBI) + hemorrhagic hypotension. METHODS: In the first two studies in vivo, anesthetized, ventilated pigs (30-45 kg) received a fluid percussion TBI, 45% arterial hemorrhage, and 30 minutes shock period. In Series 1, resuscitation consisted of unlimited crystalloid (n = 8) or HEX (n = 8) to correct systolic arterial pressure >100 mm Hg and heart rate <100 bpm for the first 60 minutes ("emergency phase"), and then maintain cerebral perfusion pressure (CPP) > 70 mm Hg for 60-240 minutes. In Series 2 (n = 31), resuscitation consisted of a 1 L bolus of HEX + ATL-146e (10 ng/kg/min, n = 10) or HEX +placebo (n = 10) followed by crystalloid to the same endpoints. In Series 3 in vivo, the hemodynamic response evoked by 0, 10, 50, or 100 ng/kg/min ATL-146e was measured before or 60 minutes after HEX resuscitation from 45% hemorrhage. RESULTS: Following TBI+hemorrhage, there were 4/22 deaths in series 1 and 11/31 deaths in series 2. In those alive at 30 minutes, mean arterial pressure, cardiac index, mixed venous O2 saturation, and cerebral venous O2 saturation were all reduced by 40-60%, while heart rate and lactate were increased 2-5 fold. With no resuscitation (n = 2), there was minimal hemodynamic compensation and progressive acidosis. Upon resuscitation, these values corrected but intracranial pressure progressively rose from <5 mm Hg to 15-20 mm Hg. Series 1: With HEX (n = 8) versus crystalloid (n = 8), CPP was less labile, acid/base was maintained, and the fluid requirement was reduced by 60% (all p < 0.05) Series 2: With ATL-146e (n = 10) versus placebo (n = 10), stroke volume and cardiac output were improved by 40-60%, and the fluid requirement was reduced by 30% (all p < 0.05). Series 3: ATL-146e caused a dose-related increase (p < 0.05) in stroke volume after, but not before, hemorrhage. The effects on pre-load, afterload, and heart rate were similar before and after hemorrhage. CONCLUSIONS: HEX alone is a safe and efficacious low volume alternative to initial crystalloid resuscitation after TBI. An adenosine A2A agonist combined with 1 L of HEX safely and effectively counteracted a decrease in cardiac performance noted after TBI+hemorrhage without causing hypotension or bradycardia.

Animals↗

PubMed2004

Modified rapid deployment hemostat bandage terminates bleeding in coagulopathic patients with severe visceral injuries.

BACKGROUND: We recently reported that a new dressing, the Modified Rapid Deployment Hemostat (MRDH) controlled bleeding in hypothermic coagulopathic swine after traumatic liver avulsion. The purpose of this study was to evaluate the MRDH in coagulopathic trauma patients undergoing abbreviated laparotomy. METHODS: A prospective, observational clinical trial of the MRDH dressing was performed at our Level One Trauma Center in patients with high-grade visceral injuries with coagulopathy who failed conventional therapy and required packing. Attending surgeons graded the injury and the adequacy of hemostasis following application of the dressing. Patients were followed until discharge or death. RESULTS: Ten patients were enrolled: nine severe hepatic injuries, and one major abdominal vascular injury. All patients were hypothermic, acidotic, and clinically coagulopathic. Intraoperative hemostasis was immediately obtained after MRDH placement in all cases except one. There was one death. CONCLUSION: The Modified Rapid Deployment Hemostat terminates bleeding from severe visceral injuries in coagulopathic patients undergoing abbreviated laparotomy.

Abdominal Injuries↗