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.

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.

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.

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.

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.