Hextend attenuates hypercoagulability after severe liver injury in swine

BACKGROUND: Hypercoagulability is a major source of morbidity and mortality after injury. A resuscitation regimen that modulates this coagulopathy may prove beneficial. We sought to evaluate the effects of lactated Ringer's (LR) solution and Hextend on the resuscitation of uncontrolled hemorrhagic shock. METHODS: Twenty swine underwent invasive line placement, midline celiotomy, and splenectomy. After a 15-minute stabilization period, we recorded a baseline mean arterial pressure and created a grade V liver injury. The animals bled freely for 30 minutes, after which we measured the initial blood loss (that after injury). We blindly randomized the swine to receive LR solution or Hextend to achieve and maintain the baseline mean arterial pressure for 90 minutes postinjury. Laboratory values were obtained at baseline and on completion of the 2-hour study period. RESULTS: The initial blood loss (before resuscitation) was 22 mL/kg in both treatment groups (p = 0.97). Animals required 119 +/- 78 mL/kg of fluid in the LR group and 40 +/- 21 mL/kg in the Hextend group (p = 0.01). After resuscitation, the secondary blood loss was 3.7 +/- 1.7 mL/kg in the LR group and 4.7 +/- 1.1 mL/kg in the Hextend group (p = 0.1). Thrombelastography revealed a hypercoagulable state in all animals after injury. This was less pronounced in those animals resuscitated with Hextend. Routine tests of coagulation did not reveal a hypercoagulable state. CONCLUSION: Modulation and restoration of normal coagulation is critical in the management of trauma patients. The patient's coagulation profile might determine the type of fluid to be used at various times during their course. Thrombelastography is superior to routine coagulation assays for the detection of a hypercoagulable state. Resuscitation with Hextend results in a decreased fluid requirement and attenuation of hypercoagulability after injury without increased blood loss.     

Resuscitation with normal saline (NS) vs. lactated ringers (LR) modulates hypercoagulability and leads to increased blood loss in an uncontrolled hemorrhagic shock swine model

BACKGROUND: Lactated ringers (LR) and normal saline (NS) are used interchangeably in many trauma centers. The purpose of this study was to compare the effects of LR and NS on coagulation in an uncontrolled hemorrhagic swine model. We hypothesized resuscitation with LR would produce hypercoagulability. METHODS: There were 20 anesthetized swine (35 +/- 3 kg) that underwent central venous and arterial catheterization, celiotomy, and splenectomy. After splenectomy blinded study fluid equal to 3 mL per gram of splenic weight was administered. A grade V liver injury was made and animals bled without resuscitation for 30 minutes. Animals were resuscitated with the respective study fluid to, and maintained, at the preinjury MAP until study end. Prothrombin Time (PT), Partial Thromboplastin Time (PTT), and fibrinogen were collected at baseline (0') and study end (120'). Thrombelastography was performed at 0'and postinjury at 30', 60', 90', and 120'. RESULTS: There were no significant baseline group differences in R value, PT, PTT, and fibrinogen. There was no significant difference between baseline and 30 minutes R value with NS (p = 0.17). There was a significant R value reduction from baseline to 30 minutes with LR (p = 0.02). At 60 minutes, R value (p = 0.002) was shorter while alpha angle, maximum amplitude, and clotting index were higher (p < 0.05) in the LR versus the NS group. R value, PT, and PTT were significantly decreased at study end in the LR group compared with the NS group (p < 0.05). Overall blood loss was significantly higher in the NS versus LR group (p = 0.009). CONCLUSIONS: This data indicates that resuscitation with LR leads to greater hypercoagulability and less blood loss than resuscitation with NS in uncontrolled hemorrhagic shock.     

Fluid resuscitation improves hemodynamics without increased bleeding in a model of uncontrolled hemorrhage induced by an iliac artery tear in dogs

BACKGROUND: Fluid resuscitation administered before hemorrhage control for trauma victims sustaining penetrating abdominal injury is controversial. Our objective was to evaluate intra-abdominal blood loss and hemodynamic and metabolic effects of no fluid resuscitation, small-volume 7.5% sodium chloride/6% dextran-70 (HSD), or large-volume lactated Ringer's (LR) solution during intra-abdominal vascular injury and uncontrolled hemorrhage. METHODS: In pentobarbital-anesthetized dogs (n = 26, 17 +/- 0.3 kg), a suture was placed through the common iliac artery to produce a 3-mm tear when the exteriorized suture lines were pulled after incision closure. Dogs were randomized to three groups, according to the treatment used after 20 minutes of uncontrolled hemorrhage: controls, no fluid resuscitation (CT group) (n = 6); the HSD group (4 mL/kg over 4 minutes, n = 6); and the LR group (32 mL/kg over 15 minutes, n = 6). After 40 minutes of uncontrolled bleeding, animals were killed, and intra-abdominal blood loss was measured. RESULTS: Eight dogs died from severe hemorrhagic shock before randomization and were excluded. After 20 minutes, animals presented lower blood pressure (approximately 35 mm Hg), low cardiac output (approximately 1.0 L/min/m(2)), and metabolic acidosis (pH approximately 7.23, base excess approximately -9 mmol/L). After HSD and LR solution, arterial pressure presented a transient increase, but remained below baseline. Two animals died before the end of the experiment, both in the LR group. Cardiac index was partially improved in the LR and HSD groups, whereas the CT group sustained a low-flow state. There were no significant differences between groups regarding intra-abdominal blood loss (CT group, 47.8 +/- 5.9 mL/kg; HSD group, 41.7 +/- 2.3 mL/kg; and LR group, 49.4 +/- 0.7 mL/kg). CONCLUSION: Fluid resuscitation with either large-volume LR solution or small-volume HSD, during uncontrolled hemorrhage from intra-abdominal vascular injury, produced hemodynamic and metabolic benefits, without additional blood loss, whereas no fluid resuscitation was associated with sustained low cardiac output and hypotension.     

Hepatic and pulmonary apoptosis after hemorrhagic shock in swine can be reduced through modifications of conventional Ringer's solution

BACKGROUND: Cytotoxic properties of racemic (D-,L-isomers) lactated Ringer's solution detected in vitro and in small animal experiments, have not been confirmed in large animal models. Our hypothesis was that in a clinically relevant large animal model of hemorrhage, resuscitation with racemic lactated Ringer's solution would induce cellular apoptosis, which can be attenuated by elimination of d-lactate. METHODS: Yorkshire swine (n = 49, weight 40-58 kg) were subjected to uncontrolled (iliac arterial and venous injuries) and controlled hemorrhage, totaling 40% of estimated blood volume. They were randomized (n = 7/group) to control groups, which consisted of (1) no hemorrhage (NH), (2) no resuscitation (NR), or resuscitation groups, which consisted of (3) 0.9% saline (NS), (4) racemic lactated Ringer's (DL-LR), (5) L-isomer lactated Ringer's (L-LR), (6) Ketone Ringer's (KR), (7) 6% hetastarch in 0.9% saline (Hespan). KR was identical to LR except for equimolar substitution of lactate with beta-hydroxybutyrate. Resuscitation was performed in three phases, simulating (1) prehospital, (2) operative, (3) postoperative/recovery periods. Arterial blood gasses, circulating cytokines (TNF-alpha, IL-1, -6, -10), and markers of organ injury were serially measured. Metabolic activity of brain, and liver, was measured with microdialysis. Four hours postinjury, organs were harvested for Western blotting, ELISA, TUNEL assay, and immunohistochemistry. RESULTS: All resuscitation strategies restored blood pressure, but clearance of lactic acidosis was impeded following DL-LR resuscitation. Metabolic activity decreased during shock and improved with resuscitation, without any significant inter-group differences. Levels of cytokines in circulation were similar, but tissue levels of TNF in liver and lung increased six- and threefolds (p < 0.05) in NR group. In liver, all resuscitation strategies significantly decreased TNF levels compared with the NR group, but in the lung resuscitation with lactated Ringer (DL and L isomers) failed to decrease tissue TNF levels. DL-LR resuscitation also increased apoptosis (p < 0.05) in liver and lung, which was not seen after resuscitation with other solutions. CONCLUSIONS: In this large animal model of hemorrhagic shock, resuscitation with conventional (racemic) LR solution increased apoptotic cell death in liver and lung. This effect can be prevented by simple elimination of D-lactate from the Ringer's solution.     

Hypertonic saline resuscitation of head injury: effects on cerebral water content

Ideal resuscitation would simultaneously replete intravascular volume and minimize cerebral edema. We assessed the effects of hypertonic saline (HS) shock resuscitation on cerebral edema after head injury. Rats were subjected to hemorrhagic shock (40 mm Hg for 1 hour) in the presence or absence of mechanical brain injury, followed by 1 hour of resuscitation with either hypertonic saline (6.5%) or lactated Ringer's (LR). After resuscitation, animals were sacrificed and brain water contents determined. Results: Less HS than LR was needed for resuscitation both in animals without brain injury (7 +/- 2 ml/kg vs. 97 +/- 16 ml/kg; p less than 0.0003) and with brain injury (10 +/- 1 ml/kg vs. 68 +/- 6 ml/kg; p less than 0.0001). Brain water content (ml H2O/gm dry wt) after HS resuscitation was decreased compared to LR resuscitation in animals without brain injury (3.36 +/- 0.12 vs. 3.74 +/- 0.08; p less than 0.025) and in the uninjured hemisphere of head-injured animals (3.29 +/- 0.11 vs. 3.78 +/- 0.09; p less than 0.025). Brain water content was increased in injured brain in both resuscitation groups, but the increase was the same (HS 4.10 +/- 0.13; LR 4.25 +/- 0.17; p greater than 0.05). Conclusions: HS resuscitation of hemorrhagic shock decreases brain water content in uninjured but not injured brain. HS may be useful in resuscitation of combined hemorrhagic shock and head injury.     

Treatment of uncontrolled hemorrhagic shock after liver trauma: fatal effects of fluid resuscitation versus improved outcome after vasopressin

In a porcine model of uncontrolled hemorrhagic shock, we evaluated the effects of vasopressin versus an equal volume of saline placebo versus fluid resuscitation on hemodynamic variables and short-term survival. Twenty-one anesthetized pigs were subjected to severe liver injury. When mean arterial blood pressure was <20 mm Hg and heart rate decreased, pigs randomly received either vasopressin IV (0.4 U/kg; n = 7), an equal volume of saline placebo (n = 7), or fluid resuscitation (1000 mL each of lactated Ringer's solution and hetastarch; n = 7). Thirty minutes after intervention, surviving pigs were fluid resuscitated while bleeding was surgically controlled. Mean (+/- SEM) arterial blood pressure 5 min after the intervention was significantly (P < 0.05) higher after vasopressin than with saline placebo or fluid resuscitation (58 +/- 9 versus 7 +/- 3 versus 32 +/- 6 mm Hg, respectively). Vasopressin improved abdominal organ blood flow but did not cause further blood loss (vasopressin versus saline placebo versus fluid resuscitation 10 min after intervention, 1343 +/- 60 versus 1350 +/- 22 versus 2536 +/- 93 mL, respectively; P < 0.01). Seven of 7 vasopressin pigs survived until bleeding was controlled and 60 min thereafter, whereas 7 of 7 saline placebo and 7 of 7 fluid resuscitation pigs died (P < 0.01). We conclude that vasopressin, but not saline placebo or fluid resuscitation, significantly improves short-term survival during uncontrolled hemorrhagic shock. IMPLICATIONS: Although IV fluid administration is the mainstay of nonsurgical management of trauma patients with uncontrolled hemorrhagic shock, the efficacy of this strategy has been discussed controversially. In this animal model of severe liver trauma with uncontrolled hemorrhagic shock, vasopressin, but not saline placebo or fluid resuscitation, improved short-term survival.     

Early postoperative respiratory acidosis after large intravascular volume infusion of lactated ringer's solution during major spine surgery

In this study, we compared the effects of large intravascular volume infusion of 0.9% saline (NS) or lactated Ringer's (LR) solution on electrolytes and acid base balance during major spine surgery and evaluated the postoperative effects. Thirty patients aged 18-70 yr were included in the study. General anesthesia was induced with 5 mg/kg thiopental and 0.1 mg/kg vecuronium IV. Anesthesia was maintained with oxygen in 70% nitrous oxide and 1.5%-2% sevoflurane. In Group I, the NS solution, and in Group II, the LR solution were infused 20 mL. kg(-1). h(-1) during the operation and 2.5 mL. kg(-1). h(-1), postoperatively. Electrolytes (Na+, K+, Cl-) and arterial blood gases were measured preoperatively, every hour intraoperatively and at the 1st, 2nd, 4th, 6th, and 12th hours postoperatively. In the NS group, pHa, HCO3 and base excess decreased, and Cl- values increased significantly at the 2nd hour and Na+ values increased at the 4th hour intraoperatively (P < 0.001). The values returned to normal ranges at the 12th hour postoperatively. In the LR group, blood gas analysis and electrolyte values did not show any significant difference intraoperatively, but the increase in PaCO2 and the decrease in pHa and serum Na+ was significant at the 1st hour postoperatively. Although intraoperative 20 mL. kg(-1). h(-1) LR infusion does not cause hyperchloremic metabolic acidosis as does NS infusion, it leads to postoperative respiratory acidosis and mild hyponatremia. IMPLICATIONS: The infusion of large-volume lactated Ringer's solution does not cause hyperchloremic metabolic acidosis as does 0.9% saline during major surgery, but leads to postoperative mild hyponatremia and respiratory acidosis.     

Impact of shock and fluid resuscitation on the morphology and apoptosis of bone marrow: an experimental study

BACKGROUND: We hypothesized that bone marrow failure after hemorrhagic shock might be secondary to impaired apoptosis regulation. Our objective was to assess the morphologic alterations and the rate of apoptosis in bone marrow after hemorrhagic shock and resuscitation. METHODS: Under pentobarbital anesthesia, Wistar rats (n = 70) underwent femoral vessel cannulation. The hemorrhagic shock model involved a controlled retrieval of blood, maintaining mean blood pressure at 40 +/- 5 mm Hg during 50 minutes. During the resuscitation period, lactated Ringer's (twice the blood volume retrieved, group LR) or NaCl 7.5% (4 mL/kg, group HS) was infused, followed by the previously retrieved blood. Bone marrow was collected through left femoral puncture. Morphology was assessed by Leishmann-stained smears, and apoptosis was assessed through terminal deoxynucleotide transferase-mediated dUTP nick-end labeling assay. Analysis of variance and Tukey's test were applied for statistical treatment, considering p < 0.05 as significant. RESULTS: LR animals presented a statistically significant decrease in the lymphocytic series (LR, 24.2 +/- 4.2%; Sham, 55.1 +/- 6.6%), together with an increase in the percentage of granulocyte (LR, 51.4% +/- 2.3%; Sham, 31.5 +/- 2.9%) and monocyte precursors (LR, 7.3 +/- 1.3%; Sham, 3.3 +/- 1.1%), detected 72 hours after shock (p < 0.05). Both LR and HS groups presented a significant increase in apoptosis, when compared with the sham group (LR, 13.1 +/- 0.5%; HS, 12.2 +/- 0.7%; Sham, 6.8 +/- 0.4%). The alterations detected in the bone marrow morphology of LR group were not observed in HS animals. CONCLUSION: There was an increase in bone marrow apoptosis after hemorrhagic shock. The type of resuscitation scheme used did influence bone marrow morphology.     

Small-volume hypertonic saline dextran resuscitation from canine endotoxin shock.

This study evaluated resuscitation of endotoxin shock with 7.5% hypertonic saline dextran (HSD 2400 mOsm) by measuring hemodynamic and regional blood flow responses. Endotoxin challenge (1 mg/kg) in adult dogs caused a significant decrease in mean arterial blood pressure (MABP), cardiac output (CO), left ventricular +/- dP/dt max, and regional blood flow (radioactive microspheres). Cardiocirculatory dysfunction and acid-base derangements persisted throughout the experimental period in untreated endotoxin shock (group 1, n = 10). In contrast both regimens of fluid resuscitation (group 2, n = 11: bolus of 4 mL/kg HSD followed by a constant infusion of lactated Ringer's [LR] to maintain MABP and CO at baseline values; group 3, n = 10; LR alone given as described for group 2) improved regional perfusion and corrected acid-base disturbances similarly in all dogs. Hypertonic saline dextran enhanced all indices of cardiac contraction and relaxation more than LR alone. The total volume of LR required to maintain MABP and CO at baseline values was less in the HSD group (59.2 +/- 6.8 mL/kg) than in the LR alone group (158 +/- 16 mL/kg, p = 0.01). The net fluid gain (infused volume minus urine output and normalized for kilogram body weight) was five times greater in the LR (24.8 +/- 6.2 mL/kg) than in the HSD group (4.6 +/- 1.2 mL/kg, p = 0.01). Lung water was similar in all dogs, regardless of the regimen of fluid resuscitation. Hypertonic saline dextran effectively resuscitates endotoxin shock in this canine model.     

Effect of hydroxyethyl starch on coagulopathy in a swine model of hemorrhagic shock resuscitation.

BACKGROUND: Hydroxyethyl starch (HES) has a known dose-dependant effect on coagulopathy. The purpose of this study was to determine the effect of HES on coagulopathy after a period of hemorrhagic shock. METHODS: Anesthetized swine underwent a 15-minute, 40% blood volume hemorrhage (28 mL/kg) and a 1-hour shock period, followed by resuscitation with sham resuscitation (group I); 6% HES, 15 mL/kg (group II); 5% albumin, 15 mL/kg (group III); lactated Ringer's solution, 39 mL/kg, and 6% HES, 15 mL/kg (group IV); and lactated Ringer's solution, 39 mL/kg, and 5% albumin, 15 mL/kg (group V). Coagulation function was measured by bleeding time, prothrombin time, partial thromboplastin time, fibrinogen, platelet count, and thromboelastography. RESULTS: Platelet counts decreased significantly (p < 0.05) in all resuscitation groups except the sham resuscitation group. A significant decrease in platelets, fibrinogen levels, and maximum amplitude on thromboelastography was related to a dilutional effect of the fluid given and not a result of HES at the dose tested. CONCLUSION: The linear dose-related coagulopathic effects of HES when given at moderate doses does not seem to be worsened by prolonged periods of hemorrhagic shock. The coagulopathy seen during resuscitation from hemorrhagic shock seems to be a dilutional effect.     

Resuscitation with a blood substitute causes vasoconstriction without nitric oxide scavenging in a model of arterial hemorrhage

BACKGROUND: The purpose of this study was to determine if a hemoglobin-based oxygen carrier, HBOC-201 (Hemopure, Biopure Corp), alters endothelial function and nitric oxide physiology when used for hemorrhagic shock. STUDY DESIGN: Female swine (Sus scrofa) underwent catheterization of the femoral, circumflex iliac, and pulmonary arteries. Control animals (n = 3) underwent instrumentation only. Study animals underwent hemorrhage to mean arterial pressure of 30 +/- 5 mmHg, were maintained for 45 minutes, and resuscitated to the baseline mean arterial pressure for 4 hours. Resuscitation fluids included: shed blood (SB) (n = 8), lactated Ringers plus shed blood (LRSB) (n = 8), and HBOC (n = 8). At baseline, 1, and 4 hours after resuscitation, acetylcholine was infused into the proximal iliac artery and endothelial-dependent relaxation was measured with M-mode ultrasonography. Nitric oxide levels were determined using a chemiluminescent assay. RESULTS: HBOC, SB, and LRSB provided equivalent survival and resuscitation as measured by mean arterial pressures (65.3 +/- 2.48 mmHg); pulmonary artery mean pressures (15.8 +/- 0.84 mmHg); and lactate levels (1.22 +/- 0.19 mmol/L). HBOC group animals required the lowest resuscitation volume (SB, 41.5 +/- 3.5 mL/kg; LRSB, 76.4 +/- 1.1 mL/kg, HBOC, 14.6 +/- 2.1 mL/kg, p < 0.001). Response to acetylcholine was normal in the SB and LRSB groups, but the HBOC group had diminished acetylcholine response (29.5% endothelial-dependent relaxation end resuscitation, p < 0.001). Arterial nitric oxide levels did not differ between study groups (p = 0.69). CONCLUSIONS: HBOC might be an alternative resuscitation agent in patients with hemorrhagic shock. Resuscitation with HBOC requires less volume than blood or crystalloid. These data suggest HBOC-201 has a vasoconstrictive effect that cannot be attributed soley to nitric oxide scavenging.     

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.     

Combined hemorrhagic shock and head injury: effects of hypertonic saline (7.5%) resuscitation

Hypertonic saline resuscitation was compared to isotonic fluid resuscitation in a large animal model combining hemorrhagic shock with head injury. Sheep were subjected to a freeze injury of one cerebral hemisphere as well as 2 hours of hypotension at a mean arterial pressure (MAP) of 40 mm Hg. Resuscitation was then carried out (MAP = 80 mm Hg) for 1 hour with either lactated Ringer's (LR, n = 6) or 7.5% hypertonic saline (HS, n = 6). Hemodynamic parameters and intracranial pressure (ICP) were followed. At the end of resuscitation brain water content was determined in injured and uninjured hemispheres. No differences were detected in cardiovascular parameters; however, ICPs were lower in animals resuscitated with HS (4.2 +/- 1.5 mm Hg) compared to LR (15.2 +/- 2.2 mm Hg, p less than 0.05). Additionally, brain water content (ml H2O/gm dry weight) in uninjured brain hemispheres was lower after HS resuscitation (HS = 3.3 +/- 0.1; LR = 4.0 +/- 0.1; p less than 0.05). No differences were detected in the injured hemispheres. We conclude that hypertonic saline abolishes increases in ICP seen during resuscitation in a model combining hemorrhagic shock with brain injury by dehydrating areas where the blood-brain barrier is still intact. Hypertonic saline may prove useful in the early management of multiple trauma patients.     

Rapid body cooling by cold fluid infusion prolongs survival time during uncontrolled hemorrhagic shock in pigs

OBJECTIVE: The purpose of this study was to examine whether cold fluid infusion could rapidly decrease the core temperature and prolong survival during uncontrolled hemorrhagic shock in pigs. METHODS: Fourteen pigs under light halothane anesthesia and spontaneous breathing underwent initial blood withdrawal of 25 mL/kg over 15 minutes, followed by uncontrolled hemorrhage (5-mm aortotomy). Immediately after the aortotomy, the pigs were randomized to receive 500 mL lactated Ringer's solution at either 4 degrees C (group 1, n = 7) or 37 degrees C (group 2, n = 7) over 20 minutes through the internal jugular vein and observed until their death or for a maximum of 240 minutes. RESULTS: The pulmonary artery temperature of group 1 decreased to 35.5 degrees +/- 0.3 degrees C after the infusion, then remained at 35.5 degrees C during the observation period. Pulmonary artery temperature values of group 2 remained at around 37.5 degrees C throughout the experiment. The mean survival time was 220 +/- 45 minutes in group 1 versus 136 +/- 64 minutes in group 2 (p < 0.05, life table analysis). The additional intraperitoneal blood loss of group 1 was similar to that of group 2 (9 +/- 4 g/kg vs. 10 +/- 5 g/kg). CONCLUSION: In lightly anesthetized pigs during uncontrolled hemorrhagic shock, infusion with 4 degrees C lactated Ringer's solution (which seems to be feasible in the clinical setting) decreases the core temperature rapidly and prolongs survival.     

Prolonged low-volume resuscitation with HBOC-201 in a large-animal survival model of controlled hemorrhage

BACKGROUND: Military guidelines call for two 500-mL boluses of Hextend for resuscitation in far-forward environments. This study compared a hemoglobin-based oxygen carrier (HBOC-201; Hemopure) to Hextend when used to treat hemorrhagic shock in situations of delayed definitive care military operations. METHODS: Yorkshire swine (55-65 kg) were hemorrhaged to a mean arterial blood pressure (MAP) of 30 mmHg. Hypotension was maintained for 45 minutes followed by resuscitation with either Hextend (HEX) (n = 8) or HBOC-201 (HBOC) (n = 8). Over 8 hours, animals received up to 1,000 mL of either fluid in an effort to sustain an MAP of 60 mmHg. At the end of 8 hours, HEX animals received 2 L of lactated Ringer's solution followed by shed blood. HBOC animals received 4 L of lactated Ringer's solution only. Animals were killed and necropsied on postprocedure day 5. Hemodynamic data were collected during shock and resuscitation. Complete blood counts, amylase, lactate, coagulation studies, and renal and liver function were measured throughout the experiment. RESULTS: Equivalent volumes were hemorrhaged from each group (HBOC, 44.3 +/- 2.2 mL/kg; HEX, 47.4 +/- 3.0 mL/kg). The HBOC group achieved the goal MAP (HBOC, 60.0 +/- 2.3 mmHg; HEX, 46.4 +/- 2.3 mmHg; p < 0.01) and required less volume during the initial 8 hours (HBOC, 12.4 +/- 1.4 mL/kg; HEX, 17.3 +/- 0.3 mL/kg; p < 0.01). The HBOC group had lower SvO2 (HBOC, 46.3 +/- 2.4%; HEX, 50.7 +/- 2.5%; p = 0.12) and cardiac output (HBOC, 5.8 +/- 0.4 L/min; HEX, 7.2 +/- 0.6 L/min; p = 0.05), but higher systemic vascular resistance (HBOC, 821.4 +/- 110.7 dynes . s . cm-5; HEX, 489.6 +/- 40.6 dynes . s . cm-5; p = 0.01). Base excess, pH, lactate, and urine output did not differ between groups. HEX group survival was 50% (four of eight) versus 88% for the HBOC group (seven of eight). All animals survived the initial 8 hours. Animals surviving 5 days displayed no clinical or laboratory evidence of organ dysfunction in either group. CONCLUSION: HBOC-201 more effectively restored and maintained perfusion pressures with lower volumes, and allowed for improved survival. These data suggest that hemoglobin-based oxygen carriers are superior to the current standard of care for resuscitation in far-forward military operations.     

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.     

Resuscitation from hemorrhagic shock. Alterations of the intracranial pressure after normal saline, 3% saline and dextran-40.

Resuscitation from hemorrhagic shock by infusion of isotonic (normal) saline (NS) is accompanied by a transient elevation in intracranial pressure (ICP), although cerebral edema, as measured by brain weights at 24 hours, is prevented by adequate volume resuscitation. The transient increase in ICP is not observed during hypertonic saline (HS) resuscitation. The effect of colloid resuscitation on ICP is unknown. Beagles were anesthetized, intubated, and ventilated, maintaining pCO2 between 30-45 torr. Femoral artery, pulmonary artery, and urethral catheters were positioned. ICP was measured with a subarachnoid bolt. Forty per cent of the dog's blood volume was shed and the shock state maintained for 1 hour. Resuscitation was done with shed blood and a volume of either NS (n = 5), 3% HS (n = 5), or 10% dextran-40 (D-40, n = 5) equal to the amount of shed blood. Intravascular volume was then maintained with NS. ICP fell from baseline values (4.7 +/- 3.13 mmHg) during the shock state and increased greatly during initial fluid resuscitation in NS and D-40 groups, to 16.0 +/- 5.83 mmHg and 16.2 +/- 2.68 mmHg, respectively. ICP returned to baseline values of 3.0 +/- 1.73 mmHg in the HS group with initial resuscitation and remained at baseline values throughout resuscitation. NS and D-40 ICP were greater than HS ICP at 1 hour (p less than .001) and 2 hours (p less than .05) after resuscitation. These results demonstrate that NS or colloid resuscitation from hemorrhagic shock elevates ICP and that HS prevents elevated ICP.     

A comparison of lactated ringer's solution to hydroxyethyl starch 6% in a model of severe hemorrhagic shock and continuous bleeding in dogs

In this randomized, controlled study in dogs, we examined the short-term effects of blood pressure targeted fluid resuscitation with colloids or crystalloids solutions on systemic oxygen delivery, and lactate blood concentration. Fluid resuscitation using hydroxyethyl starch (HES) 6% to a mean arterial blood pressure (MAP) of 60 mm Hg was compared with lactated Ringer's solution (LR) to a MAP of 60 or 80 mm Hg (LR60 and LR80, respectively). The model was one of withdrawal of blood to a MAP of 40 mm Hg through an arterial catheter that was then connected to a system allowing bleeding to occur throughout the study whenever MAP exceeded 40 mm Hg. Target MAP was maintained for 60 min with a continuous infusion of the designated fluid replacement. All 15 dogs (5 in each group) survived until the last measurement. Blood loss in the LR80 group (2980 +/- 503 mL) (all values mean +/- SD) was larger than in the LR60 and HES60 groups (1800 +/- 389 mL, and 1820 +/- 219 mL, respectively) (P < 0.001). Whereas 840 +/- 219 mL of HES60 was needed to maintain target MAP, 1880 +/- 425 mL of LR was needed in the LR60 group, and 4590 +/- 930 mL in the LR80 group (P < 0.001). Lactate blood concentrations were smaller and delivered O(2) higher in the HES60 group (35 +/- 17 mg/dL and 239 +/- 61 mL/min, respectively) in comparison to the LR60 group (89 +/- 18 mg/dL and 140 +/- 48 mL/min, respectively) and the LR80 group (75 +/- 23 mg/dL and 153 +/- 17 mL/min, respectively) (P = 0.02 and P = 0.026). In conclusion, fluid resuscitation during uncontrolled bleeding, to a target MAP of 60 mm Hg, using HES60 resulted in larger oxygen delivery and smaller systemic lactate A resuscitation to a target MAP of 60 or 80 mm Hg using LR. IMPLICATIONS: Fluid resuscitation to a target mean arterial blood pressure of 60 mm Hg during uncontrolled bleeding resulted in larger oxygen delivery and smaller systemic lactate concentrations when hydroxyethyl starch 6% was used, in comparison to lactated Ringer's solution resuscitation to a target mean arterial blood pressure of 60 or 80 mm Hg.     

Early vasopressin improves short-term survival after pulmonary contusion

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.