Acute CSF interleukin-6 trajectories after TBI: associations with neuroinflammation, polytrauma, and outcome.

Traumatic brain injury (TBI) results in a significant inflammatory burden that perpetuates the production of inflammatory mediators and biomarkers. Interleukin-6 (IL-6) is a pro-inflammatory cytokine known to be elevated after trauma, and a major contributor to the inflammatory response following TBI. Previous studies have investigated associations between IL-6 and outcome following TBI, but to date, studies have been inconsistent in their conclusions. We hypothesized that cohort heterogeneity, temporal inflammatory profiles, and concurrent inflammatory marker associations are critical to characterize when targeting subpopulations for anti-inflammatory therapies. Toward this objective, we used serial cerebrospinal fluid (CSF) samples to generate temporal acute IL-6 trajectory (TRAJ) profiles in a prospective cohort of adults with severe TBI (n=114). We examined the impact of injury type on IL-6 profiles, and how IL-6 profiles impact sub-acute (2weeks-3months) serum inflammatory marker load and long-term global outcome 6-12months post-injury. There were two distinct acute CSF IL-6 profiles, a high and low TRAJ group. Individuals in the high TRAJ had increased odds of unfavorable Glasgow Outcome Scale (GOS) scores at 6months (adjusted OR=3.436, 95% CI: 1.259, 9.380). Individuals in the high TRAJ also had higher mean acute CSF inflammatory load compared to individuals in the low TRAJ (p⩽0.05). The two groups did not differ with respect acute serum profiles; however, individuals in the high CSF IL-6 TRAJ also had higher mean sub-acute serum IL-1ß and IL-6 levels compared with the low TRAJ group (p⩽0.05). Lastly, injury type (isolated TBI vs. TBI+polytrauma) was associated with IL-6 TRAJ group (χ(2)=5.31, p=0.02). Specifically, there was 70% concordance between those with TBI+polytrauma and the low TRAJ; in contrast, isolated TBI was similarly distributed between TRAJ groups. These data provide evidence that sustained, elevated levels of CSF IL-6 are associated with an increased inflammatory load, and these increases are associated with increased odds for unfavorable global outcomes in the first year following TBI. Future studies should explore additional factors contributing to IL-6 elevations, and therapies to mitigate its detrimental effects on outcome.

Intensivist-led management of brain-dead donors is associated with an increase in organ recovery for transplantation.

The disparity between the number of patients in need of organ transplantation and the number of available organs is steadily rising. We hypothesized that intensivist-led management of brain dead donors would increase the number of organs recovered for transplantation. We retrospectively analyzed data from all consented adult brain dead patients in the year before (n = 35) and after (n = 43) implementation of an intensivist-led donor management program. Donor characteristics before and after implementation were similar. After implementation of the organ donor support team, the overall number of organs recovered for transplantation increased significantly (66 out of 210 potentially available organs vs. 113 out of 258 potentially available organs, p = 0.008). This was largely due to an increase in the number of lungs (8 out of 70 potentially available lungs vs. 21 out of 86 potentially available lungs; p = 0.039) and kidneys (31 out of 70 potentially available kidneys vs. 52 out of 86 potentially available kidneys; p = 0.044) recovered for transplantation. The number of hearts and livers recovered for transplantation did not change significantly. Institution of an intensivist-led organ donor support team may be a new and viable strategy to increase the number of organs available for transplantations.

Fructose-1,6-bisphosphate and MK-801 by aortic arch flush for cerebral preservation during exsanguination cardiac arrest of 20 min in dogs. An exploratory study.

In our exsanguination cardiac arrest (CA) outcome model in dogs we are systematically exploring suspended animation (SA), i.e. preservation of brain and heart immediately after the onset of CA to enable transport and resuscitative surgery during CA, followed by delayed resuscitation. We have shown in dogs that inducing moderate cerebral hypothermia with an aortic arch flush of 500 ml normal saline solution at 4 degrees C, at start of CA 20 min no-flow, leads to normal functional outcome. We hypothesized that, using the same model, but with the saline flush at 24 degrees C inducing minimal cerebral hypothermia (which would be more readily available in the field), adding either fructose-1,6-bisphosphate (FBP, a more efficient energy substrate) or MK-801 (an N-methyl-D-aspartate (NMDA) receptor blocker) would also achieve normal functional outcome. Dogs (range 19-30 kg) were exsanguinated over 5 min to CA of 20 min no-flow, and resuscitated by closed-chest cardiopulmonary bypass (CPB). They received assisted circulation to 2 h, mild systemic hypothermia (34 degrees C) post-CA to 12 h, controlled ventilation to 20 h, and intensive care to 72 h. At CA 2 min, the dogs received an aortic arch flush of 500 ml saline at 24 degrees C by a balloon-tipped catheter, inserted through the femoral artery (control group, n=6). In the FBP group (n=5), FBP (total 1440 or 4090 mg/kg) was given by flush and with reperfusion. In the MK-801 group (n=5), MK-801 (2, 4, or 8 mg/kg) was given by flush and with reperfusion. Outcome was assessed in terms of overall performance categories (OPC 1, normal; 2, moderate disability; 3, severe disability; 4, coma; 5, brain death or death), neurologic deficit scores (NDS 0-10%, normal; 100%, brain death), and brain histologic damage scores (HDS, total HDS 0, no damage; >100, extensive damage; 1064, maximal damage). In the control group, one dog achieved OPC 2, one OPC 3, and four OPC 4; in the FBP group, two dogs achieved OPC 3, and three OPC 4; in the MK-801 group, two dogs achieved OPC 3, and three OPC 4 (P=1.0). Median NDS were 62% (range 8-67) in the control group; 55% (range 34-66) in the FBP group; and 50% (range 26-59) in the MK-801 group (P=0.2). Median total HDS were 130 (range 56-140) in the control group; 96 (range 64-104) in the FBP group; and 80 (range 34-122) in the MK-801 group (P=0.2). There was no difference in regional HDS between groups. We conclude that neither FBP nor MK-801 by aortic arch flush at the start of CA, plus an additional i.v. infusion of the same drug during reperfusion, can provide cerebral preservation during CA 20 min no-flow. Other drugs and drug-combinations should be tested with this model in search for a breakthrough effect.

Intraperitoneal, but not enteric, adenosine administration improves survival after volume-controlled hemorrhagic shock in rats.

OBJECTIVE: To circumvent the potential adverse systemic side effects of adenosine, this study explored the potential benefit of intraperitoneal or enteric adenosine on survival and inflammatory responses after volume-controlled hemorrhagic shock. DESIGN: Prospective, randomized, and blinded. A three-phase, volume-controlled hemorrhagic shock model was used: hemorrhagic shock phase (120 mins), resuscitation phase (60 mins), and observation phase (72 hrs). Three groups were compared: controls, intraperitoneal adenosine, and enteric adenosine. SETTING: Animal research facility. SUBJECTS: Male Sprague-Dawley rats. INTERVENTIONS: Starting at 20 mins of hemorrhagic shock and continuing through the resuscitation phase, all three groups received both intraperitoneal lavage and repeated bolus injections into the ileum of vehicle (normal saline) or adenosine. In the intraperitoneal adenosine group (n = 10), adenosine solution (0.1 mM) was used for intraperitoneal lavage. In the enteric adenosine group (n = 10), adenosine (1.0 mM) was injected into the ileum. Blood cytokine concentrations and leukocyte infiltration in lungs and liver were studied in 12 separate rats (control and intraperitoneal adenosine, n = 6 each) with the same hemorrhagic shock model at resuscitation time 1 hr or 4 hrs. MEASUREMENTS AND MAIN RESULTS: Mean arterial pressure and heart rate were similar between the three groups during hemorrhagic shock and resuscitation. Potassium, lactate, and blood urea nitrogen concentrations were lower and arterial pH was higher in the intraperitoneal and enteric adenosine groups compared with the control group (both p <.05). Survival time to 72 hrs was longer in the intraperitoneal adenosine group than in the control group(p <.05). Neither plasma interleukin-1beta, interleukin-6, interleukin-10, and tumor necrosis factor-alpha concentrations nor leukocyte infiltration in the lungs and liver was different between the control and intraperitoneal adenosine groups. CONCLUSIONS: The administration of adenosine via the intraperitoneal route improves survival time after severe volume-controlled hemorrhagic shock in rats without worsening hypotension or bradycardia. This beneficial effect may not be attributable to effects of adenosine on the inflammatory response.

Thiopental and phenytoin by aortic arch flush for cerebral preservation during exsanguination cardiac arrest of 20 minutes in dogs. An exploratory study.

We are systematically exploring in our exsanguination cardiac arrest (CA) outcome model in dogs suspended animation (SA), i.e. immediate preservation of brain and heart for resuscitative surgery during CA, with delayed resuscitation. We have shown in dogs that inducing moderate cerebral hypothermia with an aortic arch flush of 500 ml normal saline solution of 4 degrees C, at start of CA 20 min no-flow, leads to normal functional outcome. We hypothesized that, using the same model, adding thiopental (or even better thiopental plus phenytoin) to the flush at ambient temperature (24 degrees C), which would be more readily available in the field, will also achieve normal functional outcome. Thirty dogs (20-28 kg) were exsanguinated over 5 min to CA of 20 min no-flow, and resuscitated by closed-chest cardiopulmonary bypass. They received assisted circulation to 2 h, 34 degrees C post-CA to 12 h, controlled ventilation to 20 h, and intensive care to 72 h. At CA 2 min, the dogs received an aortic arch flush of 500 ml saline at 24 degrees C by a balloon-tipped catheter, inserted through the femoral artery (control group 1, n=14). In group 2 (n=9), thiopental (variable total doses of 15-120 mg/kg) was added to the flush and given with reperfusion. In group 3 (n=7), thiopental (15 or 45 mg/kg) plus phenytoin (10, 20, or 30 mg/kg) was given by flush and with reperfusion. Outcome was assessed in terms of overall performance categories (OPC 1, normal; 2, moderate disability; 3, severe disability; 4, coma; 5, brain death), neurologic deficit scores (NDS 0-10%, normal; 100%, brain death), and histologic deficit scores (HDS, total and regional). The flush reduced tympanic temperature to about 36 degrees C in all groups. In control group 1, one dog achieved OPC 1, three OPC 2, six OPC 3, and four OPC 4. In thiopental group 2, two dogs achieved OPC 1, two OPC 3, and five OPC 4. In thiopental/phenytoin group 3, one dog achieved OPC 1, two OPC 3, and four OPC 4 (p=0.5). Median NDS were 36% (IQR 22-62%) in group 1; 51% (IQR 22-56%) in group 2; and 55% (IQR 38-59%) in group 3 (p=0.7). Median total HDS were 67 (IQR 56-127) in group 1; 60 (IQR 52-138) in group 2; and 76 (IQR 48-132) in group 3 (p=1.0). Thiopental and thiopental/phenytoin dogs achieved significantly lower HDS only in the putamen. Thiopental in large doses caused side effects. We conclude that neither thiopental alone nor thiopental plus phenytoin by flush, with or without additional intravenous infusion, can consistently provide 'clinically significant' cerebral preservation for 20 min no-flow. Other drugs and drug-combinations should be tested with this model in search for a breakthrough effect.

Mild hypothermia increases survival from severe pressure-controlled hemorrhagic shock in rats.

BACKGROUND: In previous studies, mild hypothermia (34 degrees C) during uncontrolled hemorrhagic shock (HS) increased survival. Hypothermia also increased mean arterial pressure (MAP), which may have contributed to its beneficial effect. We hypothesized that hypothermia would improve survival in a pressure-controlled HS model and that prolonged hypothermia would further improve survival. METHODS: Thirty rats were prepared under light nitrous oxide/halothane anesthesia with spontaneous breathing. The rats underwent HS with an initial blood withdrawal of 2 mL/100 g over 10 minutes and pressure-controlled HS at a MAP of 40 mm Hg over 90 minutes (without anticoagulation), followed by return of shed blood and additional lactated Ringer's solution to achieve normotension. Hemodynamic monitoring and anesthesia were continued to 1 hour, temperature control to 12 hours, and observation without anesthesia to 72 hours. After HS of 15 minutes, 10 rats each were randomized to group 1, with normothermia (38 degrees C) throughout; group 2, with brief mild hypothermia (34 degrees C during HS 15-90 minutes plus 30 minutes after reperfusion); and group 3, with prolonged mild hypothermia (same as group 2, then 35 degrees C [possible without shivering] from 30 minutes after reperfusion to 12 hours). RESULTS: MAP during HS and initial resuscitation was the same in all three groups, but was higher in the hypothermia groups 2 and 3, compared with the normothermia group 1, at 45 and 60 minutes after reperfusion. Group 1 required less blood withdrawal to maintain MAP 40 mm Hg during HS and more lactated Ringer's solution for resuscitation. At end of HS, lactate levels were higher in group 1 than in groups 2 and 3 (p < 0.02). Temperatures were according to protocol. Survival to 72 hours was achieved in group 1 by 3 of 10 rats, in group 2 by 7 of 10 rats (p = 0.18 vs. group 1), and in group 3 by 9 of 10 rats (p = 0.02 vs. group 1, p = 0.58 vs. group 2). Survival time was longer in group 2 (p = 0.09) and group 3 (p = 0.007) compared with group 1. CONCLUSION: Brief hypothermia had physiologic benefit and a trend toward improved survival. Prolonged mild hypothermia significantly increased survival after severe HS even with controlled MAP. Extending the duration of hypothermia beyond the acute phases of shock and resuscitation may be needed to ensure improved outcome after prolonged HS.

Gut damage during hemorrhagic shock: effects on survival of oral or enteral interleukin-6.

It has been reported that oral interleukin (IL)-6, without deleterious systemic side effects, prevents bacteremia and gut epithelial apoptosis after hemorrhagic shock (HS) in rodents. The goal of this study was to explore potential benefit of oral or enteral IL-6 on the gut and, consequently, on survival in a long-term outcome model of HS in rats. In Study A, 20 rats (control and IL-6, n = 10 per group) were anesthetized by spontaneous breathing of halothane and N2O. The left femoral vein and artery were cannulated. HS was initiated with withdrawal of 3 mL of blood per 100 g body weight over 15 min, and mean arterial pressure was maintained at 40 to 50 mmHg for another 75 min (total HS 90 min) by blood withdrawal or infusion of Ringer's solution. At HS 90 min, resuscitation included reinfusion of shed blood and additional Ringer's solution to restore normotension for 30 min. After awakening at resuscitation time 30 min, the rats received either 300 units IL-6 or the same volume of vehicle (controls) injected into the stomach via a feeding cannula. In Study B, 20 rats (control and IL-6, n = 10 per group), fasted overnight, were prepared and treated as in Study A, except that HS was initiated with withdrawal of 2 mL blood per 100 g over 10 min, and mean arterial pressure was maintained at 35-40 mmHg. IL-6 rats received 3,000 units IL-6 in 5 mL of normal saline injected directly into the ileum lumen 20 min after induction of shock and again at resuscitation time 60 min. Control rats received normal saline alone. In both studies, survival was observed to 72 h. In Study A, 7 of 10 rats in the control group and 5 of 10 in the IL-6 group survived to 72 h (NS). Macroscopic assessment of gut injury was not different between the two groups. In Study B, 6 of 10 rats survived to 72 h in each group. Frequency of bacteria growth in liver tissue of 72 h survivors was not different between the two groups. IL-6, administered into the stomach or directly injected into the small intestine lumen, did not protect the gut from ischemic injury, nor did it improve survival following severe HS in rats.

Suspended animation for delayed resuscitation from prolonged cardiac arrest that is unresuscitable by standard cardiopulmonary-cerebral resuscitation.

Standard cardiopulmonary-cerebral resuscitation fails to achieve restoration of spontaneous circulation in approximately 50% of normovolemic sudden cardiac arrests outside hospitals and in essentially all victims of penetrating truncal trauma who exsanguinate rapidly to cardiac arrest. Among cardiopulmonary-cerebral resuscitation innovations since the 1960s, automatic external defibrillation, mild hypothermia, emergency (portable) cardiopulmonary bypass, and suspended animation have potentials for clinical breakthrough effects. Suspended animation has been suggested for presently unresuscitable conditions and consists of the rapid induction of preservation (using hypothermia with or without drugs) of viability of the brain, heart, and organism (within 5 mins of normothermic cardiac arrest no-flow), which increases the time available for transport and resuscitative surgery, followed by delayed resuscitation. Since 1988, we have developed and used novel dog models of exsanguination cardiac arrest to explore suspended animation potentials with hypothermic and pharmacologic strategies using aortic cold flush and emergency portable cardiopulmonary bypass. Outcome evaluation was at 72 or 96 hrs after cardiac arrest. Cardiopulmonary bypass cannot be initiated rapidly. A single aortic flush of cold saline (4 degrees C) at the start of cardiac arrest rapidly induced (depending on flush volume) mild-to-deep cerebral hypothermia (35 degrees to 10 degrees C), without cardiopulmonary bypass, and preserved viability during a cardiac arrest no-flow period of up to 120 mins. In contrast, except for one antioxidant (Tempol), explorations of 14 different drugs added to the aortic flush at room temperature (24 degrees C) have thus far had disappointing outcome results. Profound hypothermia (10 degrees C) during 60-min cardiac arrest induced and reversed with cardiopulmonary bypass achieved survival without functional or histologic brain damage. Further plans for the systematic development of suspended animation include the following: a) aortic flush, combining hypothermia with mechanism-specific drugs and novel fluids; b) extension of suspended animation by ultraprofound hypothermic preservation (0 degrees to 5 degrees C) with cardiopulmonary bypass; c) development of the most effective suspended animation protocol for clinical trials in trauma patients with cardiac arrest; and d) modification of suspended animation protocols for possible use in normovolemic ventricular fibrillation cardiac arrest, in which attempts to achieve restoration of spontaneous circulation by standard external cardiopulmonary resuscitation-advanced life support have failed.

Rapid induction of mild cerebral hypothermia by cold aortic flush achieves normal recovery in a dog outcome model with 20-minute exsanguination cardiac arrest.

OBJECTIVES: Resuscitation attempts in trauma victims who suffer cardiac arrest (CA) from exsanguination almost always fail. The authors hypothesized that an aortic arch flush with cold normal saline solution (NSS) at the start of exsanguination CA can preserve cerebral viability during 20-minute no-flow. METHODS: Twelve dogs were exsanguinated over 5 minutes to CA of 20-minute no-flow, resuscitated by cardiopulmonary bypass, followed by post-CA mild hypothermia (34 degrees C) continued to 12 hours, controlled ventilation to 20 hours, and intensive care to 72 hours. At CA 2 minutes, the dogs received a 500-mL flush of NSS at either 24 degrees C (group 1, n = 6) or 4 degrees C (group 2, n = 6), using a balloon-tipped catheter inserted via the femoral artery into the descending thoracic aorta. RESULTS: The flush at 24 degrees C (group 1) decreased tympanic membrane temperature [mean (+/-SD)] from 37.5 degrees C (+/-0.1) to 35.7 degrees C (+/-0.2); the flush at 4 degrees C (group 2) to 34.0 degrees C (+/-1.1) (p = 0.005). In group 1, one dog achieved overall performance category (OPC) 2 (moderate disability), one OPC 3 (severe disability), and four OPC 4 (coma). In group 2, four dogs achieved OPC 1 (normal), one OPC 2, and one OPC 3 (p = 0.008). Neurologic deficit scores (0-10% normal, 100% brain death) [median (25th-75th percentile)] were 62% (40-66) in group 1 and 5% (0-19) in group 2 (p = 0.01). Total brain histologic damage scores were 130 (62-137) in group 1 and 24 (10-55) in group 2 (p = 0.008). CONCLUSIONS: Aortic arch flush of 4 degrees C at the start of CA of 20 minutes rapidly induces mild cerebral hypothermia and can lead to normal functional recovery with minimal histologic brain damage. The same model with aortic arch flush of 24 degrees C results in survival with brain damage in all dogs, which makes it suitable for testing other (e.g., pharmacologic) preservation potentials.

Effects of increased oxygen breathing in a volume controlled hemorrhagic shock outcome model in rats.

It is believed that victims of traumatic hemorrhagic shock (HS) benefit from breathing 100% O(2). Supplying bottled O(2) for military and civilian first aid is difficult and expensive. We tested the hypothesis that increased FiO(2) both during severe volume-controlled HS and after resuscitation in rats would: (1) increase blood pressure; (2) mitigate visceral dysoxia and thereby prevent post-shock multiple organ failure; and (3) increase survival time and rate. Thirty rats, under light anesthesia with halothane (0. 5% throughout), with spontaneous breathing of air, underwent blood withdrawal of 3 ml/100 g over 15 min. After HS phase I of 60 min, resuscitation phase II of 180 min with normotensive intravenous fluid resuscitation (shed blood plus lactated Ringer's solution), was followed by an observation phase III to 72 h and necropsy. Rats were randomly divided into three groups of ten rats each: group 1 with FiO(2) 0.21 (air) throughout; group 2 with FiO(2) 0.5; and group 3 with FiO(2) 1.0, from HS 15 min to the end of phase II. Visceral dysoxia was monitored during phases I and II in terms of liver and gut surface PCO(2) increase. The main outcome variables were survival time and rate. PaO(2) values at the end of HS averaged 88 mmHg with FiO(2) 0.21; 217 with FiO(2) 0.5; and 348 with FiO(2) 1. 0 (P<0.001). During HS phase I, FiO(2) 0.5 increased mean arterial pressure (MAP) (NS) and kept arterial lactate lower (P<0.05), compared with FiO(2) 0.21 or 1.0. During phase II, FiO(2) 0.5 and 1. 0 increased MAP compared with FiO(2) 0.21 (P<0.01). Heart rate was transiently slower during phases I and II in oxygen groups 2 and 3, compared with air group 1 (P<0.05). During HS, FiO(2) 0.5 and 1.0 mitigated visceral dysoxia (tissue PCO(2) rise) transiently, compared with FiO(2) 0.21 (P<0.05). Survival time (by life table analysis) was longer after FiO(2) 0.5 than after FiO(2) 0.21 (P<0. 05) or 1.0 (NS), without a significant difference between FiO(2) 0. 21 and 1.0. Survival rate to 72 h was achieved by two of ten rats in FiO(2) 0.21 group 1, by four of ten rats in FiO(2) 0.5 group 2 (NS); and by four of ten rats of FiO(2) 1.0 group 3 (NS). In late deaths macroscopic necroses of the small intestine were less frequent in FiO(2) 0.5 group 2. We conclude that in rats, in the absence of hypoxemia, increasing FiO(2) from 0.21 to 0.5 or 1.0 does not increase the chance to achieve long-term survival. Breathing FiO(2) 0.5, however, might increase survival time in untreated HS, as it can mitigate hypotension, lactacidemia and visceral dysoxia.

Mild or moderate hypothermia, but not increased oxygen breathing, increases long-term survival after uncontrolled hemorrhagic shock in rats.

OBJECTIVE: To test the hypotheses that, for uncontrolled hemorrhagic shock (UHS) in rats, mild hypothermia, compared with normothermia, would increase long-term survival as well as moderate hypothermia, oxygen breathing would increase survival further, and hypothermia and oxygen would mitigate visceral ischemia (dysoxia) during UHS. DESIGN: Prospective, randomized study. SETTING: Animal research laboratory. SUBJECTS: A total of 54 male Sprague-Dawley rats. INTERVENTIONS: Under light anesthesia and spontaneous breathing, rats underwent UHS phase I of 75 mins, with initial withdrawal of 3 mL/100 g of blood over 15 mins, followed by UHS via tail amputation and limited fluid resuscitation to maintain mean arterial pressure at > or =40 mm Hg; resuscitation phase II of 60 mins (from 75 mins to 135 mins) with hemostasis and aggressive fluid resuscitation to normalize hemodynamics; and observation phase III to 72 hrs. Rats were randomly divided into nine groups (n = 6 each) with three rectal temperature levels (38 degrees C [normothermia] vs. 34 degrees C [mild hypothermia] vs. 30 degrees C [moderate hypothermia]) by surface cooling; each with 3 FIO2 levels (0.25 vs. 0.5 vs. 1.0). MEASUREMENTS AND MAIN RESULTS: Hypothermia increased blood pressure compared with normothermia. Increased FIO2 had no effect on blood pressure. Additional blood loss from the tail cut was small, with no differences among groups. Hypothermia and FIO2 of 0.5 decreased visceral hypoxia, as measured by the difference between visceral (liver and jejunum) surface Pco2 and PaCO2 during UHS. Compared with normothermia, mild hypothermia increased the survival time and rate as well as moderate hypothermia (p < .01 by life table), without a significant difference between mild and moderate hypothermia. Increased FIO2 had no effect on survival time or rate. CONCLUSIONS: After severe UHS and resuscitation in rats, mild hypothermia during UHS, compared with normothermia, increases blood pressure, survival time and 72-hr survival rate as well as moderate hypothermia. Mild hypothermia is clinically more feasible and safer than moderate hypothermia. Increased FIO2 seems to have no significant effect on outcome.

The intensive care unit as a trauma unit.

The ICU plays a pivotal role in the care of the critically injured patient. From the resuscitative phase of care through the life-support phases and finally the recovery phase, advances in ICU care have been made in recent years. As a result, an improved outcome for traumatically injured patients often is seen, and the third peak in the trimodal distribution of trauma deaths has been affected significantly.

Outcome and quality of life of patients with acute pancreatitis requiring intensive care.

BACKGROUND: Patients with severe acute pancreatitis often require intensive care unit (ICU) admission, have multiple complications, spend weeks to months in the hospital, and consume a large amount of resources. The aim of this study was to evaluate the ICU course, costs, mortality, and quality of life of patients who require ICU admission for acute pancreatitis. METHODS: Patients with acute pancreatitis requiring ICU admission were identified retrospectively. Data regarding in-hospital morbidity, mortality, and hospital costs were obtained. Long-term quality of life was assessed using the Short Form-36 Health Survey (SF-36). RESULTS: Fifty-two patients were identified. There were 31 men and 21 women: the mean age was 53 years (range, 22-89). The most common causes of acute pancreatitis were gallstones (44%) and alcoholism (17%). Pulmonary failure (52% required mechanical ventilation) and renal failure (21% required dialysis) were common. There were 39 (75%) hospital survivors and 13 (25%) nonsurvivors. In the first 24 h, the mean Acute Physiology and Chronic Health Evaluation (APACHE) II scores were 10 +/- 6 in survivors and 16 +/- 4 in the nonsurvivors (<0.01). Mean length of ICU (15 +/- 18 and 28 +/- 31 days) and hospital (40 +/- 34 and 38 +/- 34 days) stays were similar in survivors and nonsurvivors, respectively (NS). The mean hospital cost for survivors was $83,611 +/- 88,434 and that for nonsurvivors was $136,730 +/- 95,045 (P = 0. 09). The estimated cost to obtain one hospital survivor was $129,188. Of the 39 hospital survivors, 5 died later, 21 completed the SF-36, and 13 were lost to follow-up. Long-term quality of life (SF-36) was similar to that of an age-matched population. Twenty of twenty-one felt their general health was at least as good as it had been 1 year previously. CONCLUSIONS: Patients with severe acute pancreatitis need prolonged ICU and hospital stays. APACHE II may be a good predictor of outcome; further, prospective evaluation is needed. Although resource utilization is high, most patients survive and have good long-term quality of life.

Adenosine by aortic flush fails to augment the brain preservation effect of mild hypothermia during exsanguination cardiac arrest in dogs - an exploratory study.

Most trauma cases with rapid exsanguination to cardiac arrest (CA) in the field, as well as many cases of normovolemic sudden cardiac death are 'unresuscitable' by standard cardiopulmonary-cerebral resuscitation (CPCR). We are presenting a dog model for exploring pharmacological strategies for the rapid induction by aortic arch flush of suspended animation (SA), i.e. preservation of cerebral viability for 15 min or longer. This can be extended by profound hypothermic circulatory arrest of at least 60 min, induced and reversed with (portable) cardiopulmonary bypass (CPB). SA is meant to buy time for transport and repair during pulselessness, to be followed by delayed resuscitation to survival without brain damage. This model with exsanguination over 5 min to CA of 15-min no-flow, is to evaluate rapid SA induction by aortic flush of normal saline solution (NSS) at room temperature (24 degrees C) at 2-min no-flow. This previously achieved normal functional recovery, but with histologic brain damage. We hypothesized that the addition of adenosine would achieve recovery with no histologic damage, because adenosine delays energy failure and helps repair brain injury. This dog model included reversal of 15-min no-flow with closed-chest CPB, controlled ventilation to 20 h, and intensive care to 72 h. Outcome was evaluated by overall performance, neurologic deficit, and brain histologic damage. At 2 min of CA, 500 ml of NSS at 24 degrees C was flushed (over 1 min) into the brain and heart via an aortic balloon catheter. Controls (n=5) received no drug. The adenosine group (n=5) received 2-chloro-adenosine (long acting adenosine analogue), 30 mg in the flush solution, and, after reperfusion, adenosine i.v. over 12 h (210 microg/kg per min for 3 h, 140 microg/kg per min for 9 h). The 24 degrees C flush reduced tympanic membrane temperature (T(ty)) within 2 min of CA from 37.5 to approximately 36.0 degrees C in both groups. At 72 h, final overall performance category (OPC) 1 (normal) was achieved by all ten dogs of the two groups. Final neurologic deficit scores (NDS; 0-10% normal, 100% brain death) were 5+/-3% in the control group versus 6+/-5% in the adenosine group (NS). Total brain histologic damage scores (HDS) at 72 h were 74+/-9 (64-80) in the control group versus 68+/-19 (40-88) in the adenosine group (NS). In both groups, ischemic neurons were as prevalent in the basal ganglia and neocortex as in the cerebellum and hippocampus. The mild hypothermic aortic flush protocol is feasible in dogs. The adenosine strategy used does not abolish the mild histologic brain damage.

Rapid hypothermic aortic flush can achieve survival without brain damage after 30 minutes cardiac arrest in dogs.

BACKGROUND: Neither exsanguination to pulselessness nor cardiac arrest of 30 min duration can be reversed with complete neurologic recovery using conventional resuscitation methods. Techniques that might buy time for transport, surgical hemostasis, and initiation of cardiopulmonary bypass or other resuscitation methods would be valuable. We hypothesized that an aortic flush with high-volume cold normal saline solution at the start of exsanguination cardiac arrest could rapidly preserve cerebral viability during 30 min of complete global ischemia and achieve good outcome. METHODS: Sixteen dogs weighing 20-25 kg were exsanguinated to pulselessness over 5 min, and circulatory arrest was maintained for another 30 min. They were then resuscitated using closed-chest cardiopulmonary bypass and had assisted circulation for 2 h, mild hypothermia (34 degrees C) for 12 h, controlled ventilation for 20 h, and intensive care to outcome evaluation at 72 h. Two minutes after the onset of circulatory arrest, the dogs received a flush of normal saline solution at 4 degrees C into the aorta (cephalad) via a balloon catheter. Group I (n = 6) received a flush of 25 ml/kg saline with the balloon in the thoracic aorta; group II (n = 7) received a flush of 100 ml/kg saline with the balloon in the abdominal aorta. RESULTS: The aortic flush decreased mean tympanic membrane temperature (Tty) in group I from 37.6 +/- 0.1 to 33.3 +/- 1.6 degrees C and in group II from 37.5 +/- 0.1 to 28.3 +/- 2.4 degrees C (P = 0.001). In group 1, four dogs achieved overall performance category (OPC) 4 (coma), and 2 dogs achieved OPC 5 (brain death). In group II, 4 dogs achieved OPC 1 (normal), and 3 dogs achieved OPC 2 (moderate disability). Median (interquartile range [IQR]) neurologic deficit scores (NDS 0-10% = normal; NDS 100% = brain death) were 69% (56-99%) in group I versus 4% (0-15%) in group II (P = 0.003). Median total brain histologic damage scores (HDS 0 = no damage; > 100 = extensive damage; 1,064 = maximal damage) were 144 (74-168) in group I versus 18 (3-36) in group II (P = 0.004); in three dogs from group II, the brain was histologically normal (HDS 0-5). CONCLUSIONS: A single high-volume flush of cold saline (4 degrees C) into the abdominal aorta given 2 min after the onset of cardiac arrest rapidly induces moderate-to-deep cerebral hypothermia and can result in survival without functional or histologic brain damage, even after 30 min of no blood flow.

Peritoneal ventilation with oxygen improves outcome after hemorrhagic shock in rats.

OBJECTIVE: In experimental pulmonary consolidation with hypoxemia in rabbits, peritoneal ventilation (PV) with 100% oxygen (PV-O2) improved PaO2. We hypothesized that PV-O2 could improve outcome after hemorrhagic shock (HS) with normal lungs, by mitigating dysoxia of the abdominal viscera. DESIGN: Randomized, controlled, laboratory animal study. SETTING: University animal research facility. SUBJECTIVE: Male Sprague-Dawley rats. INTERVENTIONS: Thirty rats under light anesthesia (N2O/oxygen plus halothane) and spontaneous breathing underwent blood withdrawal of 3 mL/100 g over 15 mins. After volume-controlled HS phase 1 of 60 mins, resuscitation phase 2 of 60 mins included infusion of shed blood and, if necessary, additional lactated Ringer's solution intravenously to control normotension from 60 to 120 mins. This was followed by observation phase 3 for 7 days. We randomized three groups of ten rats each: group I received PV-O2, starting at 15 mins of HS at a rate of 40 inflations/min, and a peritoneal "tidal volume" of 6 mL, until the end of phase 2. Group II received the same PV with room air (PV-Air). Control group III was treated without PV. MEASUREMENTS AND MAIN RESULTS: During the second half of HS phase 1, mean arterial pressures were higher in the PV-O2 group I compared with the PV-Air group II and control group III (p < .05). All 30 rats survived the 120 mins of phases 1 and 2. Survival to 7 days was achieved by ten of ten rats in PV-O2 group I; by nine of ten in PV-Air group II; and by five of ten in control group III (p < .05 vs. group I; NS vs. group II). Survival times of <7 days were 5 days in the one death of group II and ranged between 6 hrs and 4 days in the five deaths of group III. In 7-day survivors, neurologic deficit scores (0% to 10% = normal, 100% = death) were normal, ranging between zero and 8%. Necropsies of rats that died during phase 3 showed multiple areas of necrosis of the gut, some with perforations. Necropsies in the five survivors to 7 days of group III showed marked macroscopic and microscopic changes (scattered areas of necrosis of stomach and intestine, adhesions, and pale areas in the liver). These changes were absent or less severe in the nine survivors of group II. Viscera appeared normal in all ten rats of PV-O2 group I. CONCLUSIONS: Peritoneal ventilation with oxygen during and after severe hemorrhagic shock in rats seems to decrease morbidity and mortality by helping preserve viability of abdominal viscera.

Hypothermic aortic arch flush for preservation during exsanguination cardiac arrest of 15 minutes in dogs.

BACKGROUND: Trauma victims rarely survive cardiac arrest from exsanguination. Survivors may suffer neurologic damage. Our hypothesis was that a hypothermic aortic arch flush of 500 mL of isotonic saline solution at 4 degrees C, compared with 24 degrees C (room temperature), administered at the start of prolonged exsanguination cardiac arrest (CA) would improve functional neurologic outcome in dogs. METHODS: Seventeen male hunting dogs were prepared under light N2O-halothane anesthesia. The animals were randomized into two groups: group I (n = 9) received 4 degrees C isotonic saline flush and group II (n = 6) received 24 degrees C flush. Two additional dogs received no flush. While spontaneously breathing, the dogs underwent normothermic (tympanic membrane temperature [Ttm] = 37.5 degrees C) exsanguination over 5 minutes to cardiac arrest, assured by electric induction of ventricular fibrillation. After 2 minutes of arrest, the flush was administered over 1 minute into the aortic arch by means of a 13 French balloon-tipped catheter inserted by means of the femoral artery. After 15 minutes of CA, resuscitation was with closed-chest cardiopulmonary bypass, return of shed blood, and defibrillation. For the first 12 hours after CA, core temperature was maintained at 34 degrees C. Mechanical ventilation was continued to 20 hours and intensive care to 72 hours, when final evaluation and perfusion-fixation killing for brain histologic damage scoring were performed. RESULTS: Three dogs in group I were excluded because of extracerebral complications. All 14 dogs that followed protocol survived. During CA, the Ttm decreased to 33.6 +/- 1.2 degrees C in group I and 35.9 +/- 0.4 degrees C in group II (p = 0.002). At 72 hours, in group I, all dogs achieved an overall performance category (OPC) of 1 (normal). In group II, 1 dog was OPC 2 (moderate disability), 3 dogs were OPC 3 (severe disability), and 2 dogs were OPC 4 (coma). Both dogs without flush were OPC 4. Neurologic deficit scores (NDS 0% = normal, 100% = brain death) were 1 +/- 1% in group I and 41 +/- 12% in group II (p < 0.05). The two dogs without flush achieved an NDS of 47% and 59%. Total brain histologic damage scores were 35 +/- 28 in group I and 82 +/- 17 in group II (p < 0.01); and 124 and 200 in the nonflushed dogs. CONCLUSION: At the start of 15 minutes of exsanguination cardiac arrest in dogs, hypothermic aortic arch flush allows resuscitation to survival with normal neurologic function and histologically almost clean brains.

Mild or moderate hypothermia but not increased oxygen breathing prolongs survival during lethal uncontrolled hemorrhagic shock in rats, with monitoring of visceral dysoxia.

OBJECTIVE: To test the hypotheses that during lethal uncontrolled hemorrhagic shock (UHS) in rats compared with normothermia and room air breathing: a) mild hypothermia would prolong survival time as well as moderate hypothermia; b) oxygen breathing would prolong survival further; and c) hypothermia and oxygen would mitigate visceral ischemia (dysoxia) during UHS. DESIGN: Prospective, randomized, controlled laboratory animal study. SETTING: Animal research facility. SUBJECTS: Male Sprague-Dawley rats. INTERVENTION: Fifty-four rats were lightly anesthetized with halothane during spontaneous breathing. UHS was induced by blood withdrawal of 3 mL/100 g over 15 mins, followed by 75% tail amputation with topical application of heparin. Five minutes after tail cut, rats were randomly divided into nine groups (6 rats each) with three rectal temperature levels (38 degrees C [100.4 degrees F; normothermia] vs. 34 degrees C [93.2 degrees F; mild hypothermia] vs. 30 degrees C [86 degrees F; moderate hypothermia]) by surface cooling; each with 3 FIO2 levels (0.25 vs. 0.5 vs. 1.0). Rats were observed without fluid resuscitation until death (apnea and pulselessness). Visceral ischemia was monitored by observing liver and gut surface PCO2. MEASUREMENTS AND MAIN RESULTS: Mean survival time, which was 51 mins in the control group with normothermia and FIO2 of 0.25, was more than doubled with hypothermia, to 119 mins in the combined mild hypothermia groups (p < .05) and to 132 mins in the combined moderate hypothermia groups (p < .05; NS for moderate vs. mild hypothermia). FIO2 had no statistically significant effect on survival time. Increases in visceral surface PCO2 correlated with hypotension (r2 = .22 for intestine and .40 for liver). Transiently, increased FIO2, not hypothermia, mitigated visceral ischemia. CONCLUSIONS: Both mild and moderate hypothermia prolonged survival time during untreated, lethal UHS in rats. Increased FIO2 had no effect on survival. The effects of hypothermia and increased FIO2 during UHS on viscera, the ability to be resuscitated, and outcome should be explored further.