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.     

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 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.     

Delayed, spontaneous hypothermia reduces neuronal damage after asphyxial cardiac arrest in rats

OBJECTIVE: Core temperature is reduced spontaneously after asphyxial cardiac arrest in rats. To determine whether spontaneous hypothermia influences neurologic damage after asphyxial arrest, we compared neurologic outcome in rats permitted to develop spontaneous hypothermia vs. rats managed with controlled normothermia. INTERVENTIONS: Male Sprague-Dawley rats were asphyxiated for 8 mins and resuscitated. After extubation, a cohort of rats was managed with controlled normothermia (CN) by placement in a servo-controlled incubator set to maintain rectal temperature at 37.4 degrees C for 48 hrs. CN rats were compared with permissive hypothermia (PH) rats that were returned to an ambient temperature environment after extubation. Rats were killed at either 72 hrs (PH72hr, n = 14; CN72hr, n = 9) or 6 wks (PH6wk, n = 6, CN6wk, n = 6) after resuscitation. PH72 rats were historic controls for the CN72 rats, whereas PH6 and CN6 rats were randomized and studied contemporaneously. MEASUREMENTS: A clinical neurodeficit score (NDS) was determined daily. A pathologist blinded to group scored 40 hematoxylin and eosin -stained brain regions for damage by using a 5-point scale (0 = none, 5 = severe). Quantitative analysis of CA1 hippocampus injury was performed by counting normal-appearing neurons in a defined subsection of CA1. MAIN RESULTS: Mean rectal temperatures measured in the PH6wk rats (n = 6) were 36.9, 34.8, 35.5, 36.7, and 37.4 degrees C at 2, 8, 12, 24, and 36 hrs, respectively. Mortality rate (before termination) was lower in PH compared with CN (0/20 vs. 7/15; p < .005). PH demonstrated a more favorable progression of NDS (p = .04) and less weight loss (p < .005) compared with CN. Median histopathology scores were lower (less damage) in PH72hr vs. CN72hr for temporal cortex (0 vs. 2.5), parietal cortex (0 vs. 2), thalamus (0 vs. 3), CA1 hippocampus (1.5 vs. 4.5), CA2 hippocampus (0 vs. 3.5), subiculum (0 vs. 4), and cerebellar Purkinje cell layer (2 vs. 4) (all p < .05). There was almost complete loss of normal-appearing CA1 neurons in CN72hr rats (6 +/- 2 [mean +/- SD] normal neurons compared with 109 +/- 12 in na?ve controls). In contrast, PH72hr rats demonstrated marked protection (97 +/- 23 normal-appearing neurons) that was still evident, although attenuated, at 6 wks (42 +/- 24 normal-appearing neurons, PH6wk). CONCLUSION: Rats resuscitated from asphyxial cardiac arrest develop delayed, mild to moderate, prolonged hypothermia that is neuroprotective.     

Mild preseptic hypothermia is detrimental in rats

OBJECTIVE: We evaluated the effects of mild hypothermia (32 degrees C), established before experimental intra-abdominal sepsis, on outcome, cytokine pattern, and muscle tissue oxygenation. DESIGN: Clinic modeling randomized laboratory trial. SETTING: University laboratory. SUBJECTS: Ninety-six male rats. INTERVENTIONS: In a group-sequential design, using 42 rats per group, we compared mild hypothermia with normothermia before peritonitis. Peritoneal inoculation with human stool bacteria was performed to simulate clinical trial conditions. Additionally, 12 rats underwent preoperative mild hypothermia without infection. MEASUREMENTS AND MAIN RESULTS: Primary end point was mortality at 120 hrs. Secondary end points were systemic cytokine concentrations, granulocyte counts, and muscle oxygen partial pressure. Survival rate was 40% (16 of 42) after preseptic hypothermia and 62% (26 of 42) after preseptic normothermia (p =.048). All hypothermic rats without infection survived. Interleukin-10 concentrations were 1843 +/- 96 pg/mL after preseptic hypothermia, 945 +/- 225 pg/mL with preseptic normothermia, and 520 +/- 121 pg/mL after hypothermia without infection (p<.001). Macrophage inflammatory protein-2 was comparable in the treatment groups. Interleukin-6 concentrations were 106 +/- 24 pg/mL after preseptic hypothermia and 276 +/- 76 pg/mL with preseptic normothermia (p<.05). Postinfection granulocyte count was 1.7 x 10(9)/L after hypothermia and 2.4 x 10(9)/L after normothermia (p =.2). After infection, muscle oxygen partial pressure was 47 +/- 10 mm Hg with preseptic hypothermia, 85 +/- 12 mm Hg in preseptic normothermia, and 49 +/- 9 mm Hg after hypothermia without infection (p =.7). CONCLUSIONS: In this rat model of intra-abdominal sepsis, mild preseptic hypothermia (32 degrees C) reduced survival, impaired granulocyte recruitment, and changed cytokine balance, suggesting immunosuppression.     

Mild hypothermia during prolonged cardiopulmonary cerebral resuscitation increases conscious survival in dogs

OBJECTIVE: Therapeutic hypothermia during cardiac arrest and after restoration of spontaneous circulation enables intact survival after prolonged cardiopulmonary cerebral resuscitation (CPCR). The effect of cooling during CPCR is not known. We hypothesized that mild to moderate hypothermia during CPCR would increase the rate of neurologically intact survival after prolonged cardiac arrest in dogs. DESIGN: Randomized, controlled study using a clinically relevant cardiac arrest outcome model in dogs. SETTING: University research laboratory. SUBJECTS: Twenty-seven custom-bred hunting dogs (19-29 kg; three were excluded from outcome evaluation). INTERVENTIONS: Dogs were subjected to cardiac arrest no-flow of 3 mins, followed by 7 mins of basic life support and 10 mins of simulated unsuccessful advanced life support attempts. Another 20 mins of advanced life support continued with four treatments: In control group 1 (n = 7), CPCR was with normothermia; in group 2 (n = 6, 1 of 7 excluded), with moderate hypothermia via venovenous extracorporeal shunt cooling to tympanic temperature 27 degrees C; in group 3 (n = 6, 2 of 8 excluded), the same as group 2 but with mild hypothermia, that is, tympanic temperature 34 degrees C; and in group 4 (n = 5), with normothermic venovenous shunt. After 40 mins of ventricular fibrillation, reperfusion was with cardiopulmonary bypass for 4 hrs, including defibrillation to achieve spontaneous circulation. All dogs were maintained at mild hypothermia (tympanic temperature 34 degrees C) to 12 hrs. Intensive care was to 96 hrs. MEASUREMENTS AND MAIN RESULTS: Overall performance categories and neurologic deficit scores were assessed from 24 to 96 hrs. Regional and total brain histologic damage scores and extracerebral organ damage were assessed at 96 hrs.In normothermic groups 1 and 4, all 12 dogs achieved spontaneous circulation but remained comatose and (except one) died within 58 hrs with multiple organ failure. In hypothermia groups 2 and 3, all 12 dogs survived to 96 hrs without gross extracerebral organ damage (p < .0001). In group 2, all but one dog achieved overall performance category 1 (normal); four of six dogs had no neurologic deficit and normal brain histology. In group 3, all dogs achieved good functional outcome with normal or near-normal brain histology. Myocardial damage scores were worse in the normothermic groups compared with both hypothermic groups (p < .01). CONCLUSION: Mild or moderate hypothermia during prolonged CPCR in dogs preserves viability of extracerebral organs and improves outcome.     

Neurotensin-induced hypothermia improves neurologic outcome after hypoxic-ischemia

OBJECTIVE: External cooling is commonly used to force induction of mild hypothermia but requires equipment, has a slow onset of action, and must be prolonged to provide permanent neurologic benefits after hypoxic-ischemia. It is unknown whether the method for inducing mild hypothermia affects neurologic outcome after near-drowning. The objective of the study was to induce mild hypothermia with neurotensin analog NT77 or external cooling in a rat model of near-drowning. We hypothesize that NT77 would be more effective for improving neurologic outcome than external cooling of the same duration. DESIGN: Rats were randomized to a normothermic control, neurotensin-induced hypothermia, brief external cooling, or prolonged external cooling group after asphyxial cardiac arrest. SETTING: Laboratory investigation. SUBJECTS: Forty-eight rats. INTERVENTIONS: Mild hypothermia was induced by external cooling for 4 hrs (brief external cooling) or 24 hrs (prolonged external cooling) or by neurotensin-induced hypothermia administration 30 mins after asphyxial cardiac arrest in rats. MEASUREMENTS: Outcome was assessed by a neurologic deficit score, the Morris water maze, and CA1 hippocampus histology 15 days after resuscitation. MAIN RESULTS: Neurologic deficit score at 72 hrs after asphyxial cardiac arrest was lower with neurotensin-induced hypothermia (score, 0) and prolonged external cooling (score, 0) vs. normothermic control (score, 20) and brief external cooling (score, 18; p <.05). Latency time in the Morris water maze 15 days after asphyxial cardiac arrest was decreased with neurotensin-induced hypothermia (14+/-11 secs) and prolonged external cooling (18+/-9 secs) vs. normothermic control (74+/-17 secs) and brief external cooling (78+/-18 secs, p <.05). There was less ischemic neuronal damage with neurotensin-induced hypothermia (28+/-24%) and prolonged external cooling (21+/-14%) vs. normothermic control (61+/-32%) and brief external cooling (51+/-32%). CONCLUSIONS: Neurotensin-induced hypothermia improved neurologic outcome after asphyxial cardiac arrest in rats vs. brief external cooling but was comparable to prolonged external cooling.     

Effects of mild hypothermia on survival and serum cytokines in uncontrolled hemorrhagic shock in rats

Previous studies have suggested benefit of mild hypothermia during hemorrhagic shock (HS). This finding needs additional confirmation and investigation into possible mechanisms. Proinflammatory cytokines are mediators of multiple organ failure following traumatic hemorrhagic shock and resuscitation. We hypothesized that mild hypothermia would improve survival from HS and may affect the pro- and anti-inflammatory cytokine response in a rat model of uncontrolled HS. Under light halothane anesthesia, uncontrolled HS was induced by blood withdrawal of 3 mL/100 g over 15 min followed by tail amputation. Hypotensive (limited) fluid resuscitation (to prevent mean arterial pressure [MAP] from decreasing below 40 mmHg) with blood was started at 30 min and continued to 90 min. After hemostasis and resuscitation with initially shed blood and Ringer's solution, the rats were observed for 72 h. The animals were randomized into two HS groups (n = 10 each): normothermia (38 degrees C +/- 0.5 degrees C) and mild hypothermia (34 degrees C +/- 0.5 degrees C) from HS 30 min until resuscitation time (RT) 60 min; and a sham group (n = 3). Venous blood samples were taken at baseline, RT 60 min, and days 1, 2, and 3. Serum interleukin (IL)-1beta, IL-6, IL-10, and tumor necrosis factor (TNF)-alpha concentrations were quantified by ELISA. Values are expressed as median and interquartile range. Survival time by life table analysis was greater in the hypothermia group (P = 0.04). Survival rates to 72 h were 1 of 10 vs. 6 of 10 in the normothermia vs. hypothermia groups, respectively (P = 0.057). All cytokine concentrations were significantly increased from baseline at RT 60 min in both HS groups, but not in the shams. At RT 60 min, in the normothermia vs. hypothermia groups, respectively, IL-1beta levels were 185 (119-252) vs. 96 (57-135) pg/mL (P = 0.15); IL-6 levels were 2242 (1903-3777) vs. 1746 (585-2480) pg/mL (P = 0.20); TNF-alpha levels were 97 (81-156) vs. 394 (280-406) pg/mL (P= 0.02); and IL-10 levels were 1.7 (0-13.3) vs. 15.8 (1.9-23.0) pg/mL (P = 0.09). IL-10 remained increased until day 3 in the hypothermia group. High IL-1beta levels (>100 pg/mL) at RT 60 min were associated with death before 72 h (odds ratio 66, C.I. 3.5-1255). We conclude that mild hypothermia improves survival time after uncontrolled HS. Uncontrolled HS induces a robust proinflammatory cytokine response. The unexpected increase in TNF-alpha with hypothermia deserves further investigation.     

Moderate hypothermia may be detrimental after traumatic brain injury in fentanyl-anesthetized rats

OBJECTIVES: To determine whether transient, moderate hypothermia is beneficial after traumatic brain injury in fentanyl-anesthetized rats. DESIGN: Prospective, randomized study. SETTING: University-based animal research facility. SUBJECTS: Adult male Sprague-Dawley rats. INTERVENTIONS: All rats were intubated, mechanically ventilated, and anesthetized with fentanyl (10 microg/kg intravenous bolus and then 50 microg.kg(-1).hr(-1) infusion). Controlled cortical impact was performed to the left parietal cortex, followed immediately by 1 hr of either normothermia (brain temperature 37 +/- 0.5 degrees C) or hypothermia (brain temperature 32 +/- 0.5 degrees C). Hypothermic rats were rewarmed gradually over 1 hr. Fentanyl anesthesia and mechanical ventilation were continued in both groups until the end of rewarming (2 hrs after traumatic brain injury). MEASUREMENTS AND MAIN RESULTS: Histologic assessment performed 72 hrs after traumatic brain injury was the primary outcome variable. Secondary outcome variables were physiologic variables monitored during the first 2 hrs after traumatic brain injury and plasma catecholamine and serum fentanyl concentrations measured at the end of both hypothermia and rewarming (1 and 2 hrs after traumatic brain injury). Contusion volume was larger in hypothermic vs. normothermic rats (44.3 +/- 4.2 vs. 28.6 +/- 4.0 mm, p <.05), but hippocampal neuronal survival did not differ between groups. Physiologic variables did not differ between groups. Plasma dopamine and norepinephrine concentrations were increased at the end of hypothermia in hypothermic (vs. normothermic) rats (p <.05), indicating that hypothermia augmented the systemic stress response. Similarly, serum fentanyl concentrations were higher in hypothermic (vs. normothermic) rats at the end of both hypothermia and rewarming (p <.05), demonstrating that hypothermia reduced the clearance and/or metabolism of fentanyl. CONCLUSIONS: Moderate hypothermia was detrimental after experimental traumatic brain injury in fentanyl-anesthetized rats. Since treatment with hypothermia has provided reliable benefit in experimental traumatic brain injury with inhalational anesthetics, these results indicate that the choice of anesthesia/analgesia after traumatic brain injury may dramatically influence response to other therapeutic interventions, such as hypothermia. Given that narcotics commonly are administered to patients after severe traumatic brain injury, this study may have clinical implications.     

Influence of heme-based solutions on stress protein expression and organ failure after hemorrhagic shock

OBJECTIVE: Hemoglobin-based oxygen carriers (e.g., diaspirin-cross-linked hemoglobin [DCLHb] and hemoglobin glutamer-200 [HbG]) may have potential in the treatment of hemorrhagic shock. The nitric oxide scavenging and direct vasoconstrictive side effects of free hemoglobin of currently available preparations may increase organ injury after shock in contrast to non-oxygen-carrying heme solutions (e.g., hemin arginate [HAR]). However, both classes of substances might induce the protective enzyme heme oxygenase (HO)-1, particularly in the liver. The aim of the study was to assess the role of pretreatment with DCLHb, HbG, or HAR on HO-1 expression and organ injury after hemorrhagic shock. DESIGN: Prospective controlled laboratory study. SETTING: Animal research laboratory at a university hospital. SUBJECTS: Male Sprague-Dawley rats (200-300 g body weight, n = 5-12/group). INTERVENTIONS: Twenty-four hours after different doses of DCLHb, HbG (each 1, 2, or 3 g/kg of body weight), or HAR (5, 25, or 75 mg/kg of body weight), the protein expression of HO-1 and heat shock protein-70 in liver, kidney, heart, lungs, and aorta was determined. Twenty-four hours after pretreatment with DCLHb, HbG, or HAR, rats were subjected to hemorrhage (mean arterial blood pressure, 35-40 mm Hg for 1 or 2 hrs)/resuscitation (5 or 4 hrs, respectively). Animals treated with Ringer's solution (30 mL/kg of body weight) served as controls. In additional experiments, HO activity was blocked with tin mesoporphyrin-IX. MEASUREMENTS AND MAIN RESULTS: DCLHb, HbG, and HAR dose-dependently induced HO-1 protein but not heat shock protein-70. Pretreatment with DCLHb or HbG shortened the onset of decompensation in shock (DCLHb, 40 +/- 11 mins; HbG, 36 +/- 4 mins) compared with vehicle (68 +/- 4 mins, p < .05) and HAR pretreatment (81 +/- 7 mins, p < .05). High doses of DCLHb pretreatment increased mortality (2 hrs of shock, 80%; p < .05 vs. vehicle or HAR). Pretreatment with HAR led to higher shed blood volumes (p < .05) and higher hepatocellular ATP levels (2 hrs of shock, p < .05 vs. DCLHb and HbG). Blockade of HO activity by tin mesoporphyrin-IX abolished the protection mediated by HAR. CONCLUSIONS: Although DCLHb, HbG, and HAR induce HO-1 in the absence of an unspecific stress response, only HAR pretreatment protects against shock-induced organ failure. Although the underlying mechanisms of positive HAR priming are not completely understood, the induction of HO-1 expression and the lack of nitric oxide scavenging through HAR may play an important role.     

Effects of mild induced hypothermia during experimental sepsis

OBJECTIVES: The potential advantages of lowering core temperature during sepsis are to lower energy requirement and to activate various cell-protecting pathways. We experimentally investigated whether postconditioning temperature modifications influence survival duration during experimental sepsis. DESIGN: A prospective, randomized, experimental animal study. SETTING: University laboratory. SUBJECTS: Eighteen male Sprague-Dawley rats (median 326 g, range 310-347 g). INTERVENTIONS: After anesthesia, experimental sepsis was induced by cecal ligation and perforation. The animals were subsequently assigned a core temperature range: normothermia (37 degrees C), hyperthermia (42 degrees C), and mild hypothermia (32 degrees C). Anesthesia and analgesia were continuously maintained until death. MEASUREMENTS AND MAIN RESULTS: Plasma lactate and pyruvate concentrations were measured at sepsis induction (H0), 4 hrs later (H4), and/or at the time of death. A significant increase in lactate concentration was observed at the time of death in the 42 degrees C group (p = .04). Lactate-to-pyruvate ratio increased in the 32 degrees C (at H4) and 42 degrees C (at the time of death) groups (p = .04). A linear correlation between a longer survival duration and a lower assigned core temperature was observed (from 61 +/- 10 mins at 42 degrees C to 289 +/- 17 mins at 37 degrees C and to 533 +/- 69 mins at 32 degrees C; R = .959, p < .0001). CONCLUSIONS: The current results demonstrate that postconditioning hypothermia was associated with increased survival duration during experimental sepsis. Whether the observed benefits on survival duration are due to potential impacts on energy metabolism or to an anti-inflammatory effect of hypothermia requires further investigation.     

Effect of experimental hemorrhagic shock on hepatic drug elimination.

OBJECTIVE: Exogenous substrates were used to measure hepatic function for the purposes of determining organ dysfunction and to evaluate the effect of experimental hemorrhagic shock with resuscitation on hepatic drug elimination. DESIGN: Prospective, controlled, non-randomized crossover trial. INTERVENTIONS: Eleven chronically instrumented immature swine were studied using a fixed-volume hemorrhage model (45 mL/kg blood removal over 15 mins) followed by resuscitation with lactated Ringer's solution at three times the volume of shed blood. One week before and immediately after hemorrhage and resuscitation, hepatic function markers (indocyanine green and antipyrine) were simultaneously administered intravenously. MEASUREMENTS: Physiologic data and blood samples were collected over 12 hrs after drug administration. Drug clearances, volumes of distribution, and half-lives were determined. MAIN RESULTS: For indocyanine green, there was no substantial change in pharmacokinetics from preshock to postshock, suggesting minimal change in hepatic blood flow. For antipyrine, clearance was decreased by 30% after shock and resuscitation (p = .05), suggesting that oxidative metabolism was acutely impaired. CONCLUSIONS: The information indicates that hepatic oxidative drug metabolism may be impaired early after hemorrhagic shock and that dosages of drugs in this class should be carefully examined when administered to patients who have sustained injury with hemorrhagic shock.     

Reduced rate of bacterial translocation and improved variables of natural killer cell and T-cell activity in rats surviving controlled hemorrhagic shock and treated with hypertonic saline

OBJECTIVE: To examine the effect of hypertonic saline on bacterial translocation and the number and function of natural killer and T cells in controlled hemorrhagic shock. DESIGN: Randomized controlled study. Duration of follow-up was 24 hrs. SETTING: University research laboratory. SUBJECTS: Adult male Sprague-Dawley rats, weighing 310-390 g. INTERVENTIONS: Controlled hemorrhagic shock was induced by blood withdrawal (mean arterial pressure, 30-40 mm Hg) and maintained for 30 mins. The animals were randomly divided into three groups: group 1 (n = 10) was sham-operated, group 2 (n = 10) was untreated, and group 3 was treated with 5 mL/kg hypertonic saline (n = 10). The rats were killed after 24 hrs. MEASUREMENTS AND MAIN RESULTS: Infusion of hypertonic saline in group 3 was followed by reduced bacterial translocation rate (5.0 +/- 2.2% vs. 18.3 +/- 5.3%, p <.033). The total mass of bacteria isolated from hypertonic saline-treated animals with bacterial translocation was 7.8- to 10.4-fold less than that from untreated rats. Controlled hemorrhagic shock resulted in a low percentage of CD4+ cells in blood (35.2 +/- 3.9%, p <.05) and lymph nodes (44.4 +/- 4.5%, p <.05) and depressed CD4 expression on blood (82 +/- 13 arbitrary units, p <.005) and lymph node (168 +/- 24 arbitrary units, p <.03) cells. A compensatory mobilization of NKR-P1+ cells from lymph nodes (8.6 +/- 2.3%, p <.05) to blood (21.2 +/- 5.2%, p <.01) with down-regulated NKR-P1 expression on blood cells (59 +/- 10 arbitrary units, p <.005) was observed. Natural killer cell-mediated cytotoxicity was decreased (67.9 +/- 9.7%, p <.05). Hypertonic saline treatment greatly stimulated CD4 expression on blood (419 +/- 113 arbitrary units, p <.005) and lymph node (553 +/- 115 arbitrary units, p <.03) cells. Also, normalization of NKR-P1 expression (160 +/- 19 arbitrary units, p <.005) and restoration of natural killer cell-mediated cytotoxicity to near normal values (88.6 +/- 7.4%, p <.05) were demonstrated. CONCLUSION: Controlled hemorrhagic shock was accompanied by CD4+ cells suppression and excessive recruitment of natural killer cells with abnormally low NKR-P1 expression and suppressed cytolytic activity into circulation. Infusion of hypertonic saline reversed these changes and reduced bacterial translocation.     

Posttraumatic hypothermia is neuroprotective in a model of traumatic brain injury complicated by a secondary hypoxic insult.

OBJECTIVE: Human traumatic brain injury frequently results in secondary complications, including hypoxia. In previous studies, we have reported that posttraumatic hypothermia is neuroprotective and that secondary hypoxia exacerbates histopathologic outcome after fluid-percussion brain injury. The purpose of this study was to assess the therapeutic effects of mild (33 degrees C) hypothermia after fluid-percussion injury combined with secondary hypoxia. In addition, the importance of the rewarming period on histopathologic outcome was investigated. DESIGN: Prospective experimental study in rats. SETTING: Experimental laboratory in a university teaching hospital. INTERVENTION: Intubated, anesthetized rats underwent normothermic parasagittal fluid-percussion brain injury (1.8-2.1 atmospheres) followed by either 30 mins of normoxia (n = 6) or hypoxic (n = 6) gas levels and by 4 hrs of normothermia (37 degrees C). In hypothermic rats, brain temperature was reduced immediately after the 30-min hypoxic insult and maintained for 4 hrs. After hypothermia, brain temperature was either rapidly (n = 6) or slowly (n = 5) increased to normothermic levels. Rats were killed 3 days after traumatic brain injury, and contusion volumes were quantitatively assessed. MEASUREMENTS AND MAIN RESULTS: As previously shown, posttraumatic hypoxia significantly increased contusion volume compared with traumatic brain injury-normoxic animals (p <.02). Importantly, although posttraumatic hypothermia followed by rapid rewarming (15 mins) failed to decrease contusion volume, those animals undergoing a slow rewarming period (120 mins) demonstrated significantly (p <.03) reduced contusion volumes, compared with hypoxic normothermic rats. CONCLUSIONS: These data emphasize the beneficial effects of posttraumatic hypothermia in a traumatic brain injury model complicated by secondary hypoxia and stress the importance of the rewarming period in this therapeutic intervention.     

短时程复合亚低温改善长时间室颤家猪复苏预后的研究

目的 比较短时程亚低温对长时间室颤家猪短期复苏预后的影响.方法 采取体质量34～ 36 kg左右健康雄性种猪14头,通过右心室致颤电极诱发室颤并维持11 min,之后采取人工胸外按压及球囊面罩通气,按压通气比为30:2,每2 min轮换操作者.复苏6 min后给予120 J双向波除颤,若未能获得自主循环恢复(return of spontaneous circulation,ROSC),继续给予心肺复苏及必要时电除颤.连续复苏12 min仍无ROSC认为复苏失败.对ROSC家猪,随机(随机数字法)分为常温组(normothermia group,NT)及复合降温组(combined hypothermia group,CH).CH组立即给予4℃生理盐水静脉输注并联合体表物理降温,在120 min内将核心体温降至32 ～ 34℃并维持2h后主动复温,2h将体温升至基础体温水平.记录两组家猪致颤前基础状态下血流动力学、血气及乳酸.记录ROSC后心输出量、心率、核心体温变化.每24h评估动物神经功能直至观察终点.组间比较采用Fisher检验或方差分析,以P＜0.05为差异有统计学意义.结果 两组动物基础状态下体质量、平均动脉压、心输出量、Ph、呼气末二氧化碳水平、血乳酸水平差异均无统计学意义(P＞0.05).在复苏过程中,两组动物在总复苏时间、首次除颤成功率、ROSC比例、首次除颤ROSC比例、总除颤次数及肾上腺素用量差异均无统计学意义(P＞0.05).存活时间上,CH组明显长于NT组[(96.00±0.00) h vs.(49.71 ±43.65)h,P=0.031],同时NT组96 h生存率亦高于NT组,差异有统计学意义(P＜0.05).神经功能方面,CH组在复苏后96 h内各时间段均优于NT组,差异有统计学意义(P＜0.05).结论 即使2h短时程的亚低温,也可以明显改善11 min室颤家猪的短期复苏预后.     

Fluid resuscitation and hyperchloremic acidosis in experimental sepsis: improved short-term survival and acid-base balance with Hextend compared with saline

OBJECTIVE: To compare resuscitation with 0.9% saline with Hextend, a synthetic colloid in a balanced electrolyte solution, in terms of acid-base status and survival time in an experimental model of septic shock in the rat. DESIGN: Randomized, open-label, controlled experiment. SETTING: University research laboratory. SUBJECTS: Sixty adult, male Sprague-Dawley rats. INTERVENTION: Animals were studied for 12 hrs after intravenous infusion of Escherichia coli endotoxin (20 mg/kg). Animals were volume resuscitated to maintain a mean arterial pressure >60 mm Hg using either 0.9% saline (n = 25), Hextend (n = 25), or lactated Ringer's (n = 10). MEASUREMENTS: Arterial blood gases and electrolytes were measured before and after resuscitation (0, 180, 360, and 540 mins after endotoxin infusion). Survival time was measured, up to 12 hrs. RESULTS: Mean survival time among animals treated with saline or Ringer's was 45% less compared with Hextend-treated animals: 391 +/- 151 mins and 362 +/- 94 mins vs. 567 +/- 140 mins, respectively, p <.0001. Overall survival (at 12 hrs) was 0% with saline or Ringer's vs. 20% with Hextend, p =.05. After resuscitation with saline, arterial standard base excess and plasma apparent strong ion difference were both significantly lower (-19.3 +/- 5.2 vs. -12.1 +/- 5.7, p <.001, and 23.0 +/- 6.2 vs. 30.3 +/- 2.9, p <.0001, respectively) and plasma Cl(-) was significantly higher (123 +/- 7 vs. 115 +/- 3 mmol/L, p <.0001) compared with Hextend. Resuscitation with Ringer's solution resulted in a standard base excess, and Cl(-) between that of saline and Hextend (-15.4 +/- 3.1, and 117 +/- 3, respectively). CONCLUSION: Compared with 0.9% saline, volume resuscitation with Hextend was associated with less metabolic acidosis and longer survival in this experimental animal model of septic shock.     

Environmental hypothermia in porcine polytrauma and hemorrhagic shock is safe

ABSTRACT: We have previously demonstrated survival benefit to induced hypothermia in a porcine model of controlled hemorrhagic shock simulating an associated delay to definitive care. In the current study, we wished to evaluate the effects of environmental hypothermia in a porcine model of hemorrhagic shock with the addition of polytrauma. Sixteen pigs were randomized to normothermic (39°C, n = 7) or hypothermic (34°C, n = 9) groups. The model included instrumentation, chest injury (captive bolt device), hemorrhage to systolic blood pressure (SBP) of ～50 mmHg, and crush liver injury. Animals received limited fluid resuscitation for a 1-h period with goal SBP of greater than 80 mmHg and ice packs or warming blankets to achieve goal temperatures, followed by full resuscitation with goal SBP of greater than 90 mmHg, adequate urine output, and hemoglobin by protocol for 20 h. Survivors were observed for an additional 24 h with end points including mortality, markers of organ injury, and neurologic function. There were no differences in survival between the groups (mortality = 1/9, hypothermia group vs. 2/7, normothermia group, P = 0.39). Markers of organ injury were elevated in the hypothermia group at 24 h after injury but were identical between groups at the end of the experimental protocol (48 h after injury). There were no noted differences in neurologic function between the two groups. Environmental hypothermia in a model of polytrauma and hemorrhagic shock was not associated with worse outcomes.     

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.     

The effect of vigorous fluid resuscitation in uncontrolled hemorrhagic shock after massive splenic injury

OBJECTIVE: Using a standardized massive splenic injury model of uncontrolled hemorrhagic shock, we studied the effect of vigorous fluid resuscitation on the hemodynamic response and survival time in rats. DESIGN: Randomized, controlled study. Duration of follow-up was 4 hrs. SETTING: University research laboratory. SUBJECTS: Adult male Sprague-Dawley rats, weighing 240-430 g. INTERVENTIONS: Standardized massive splenic injury was induced by two transverse incisions in the rat's spleen. The animals were randomized into four groups: group 1 (n = 8) underwent sham operation; in group 2 (n = 15), massive splenic injury was untreated; in group 3 (n = 15), massive splenic injury was treated with 41.5 mL/kg 0.9% sodium chloride (large-volume normal saline); and in group 4 (n = 15), massive splenic injury was treated with 5 mL/kg 7.5% sodium chloride (hypertonic saline). MEASUREMENTS AND MAIN RESULTS: The hemodynamic and metabolic variables in the sham-operated group 1 were stable throughout the experiment. Mean arterial pressure in group 2 decreased from 86.5 +/- 4.0 to 50.3 +/- 6.3 mm Hg (p < .001) in the first 15 mins after massive splenic injury. Mean survival time in group 2 was 127.5 +/- 17.0 mins; total blood loss was 33.8% +/-2.6% of blood volume; and the mortality rate at 1 hr was 13.3%. Bolus infusion of large-volume normal saline after 15 mins resulted in an early increase in mean arterial pressure from 48.6 +/-7.4 to 83.3 +/- 7.2 mm Hg (p < .01); it then rapidly decreased to 24.6 +/- 8.6 mm Hg (p < .001) after 60 mins. The mean survival time (95.3 +/- 16.4 mins) was significantly lower than in group 2 (p < .01); total blood loss (48.0% +/- 4.3%) was significantly higher than in group 2 (p < .01); and mortality rate in the first hour was 33.3% (p < .05). Bolus infusion of hypertonic saline also decreased survival time to 93.3 +/- 20.3 mins (p < .01), but total blood loss was 35.2% +/- 3.0%, which was not significantly different from the blood loss in group 2. The mortality rate in the first hour (60.0%) was significantly higher than in group 2 (p < .005). CONCLUSIONS: Vigorous infusion of normal saline after massive splenic injury resulted in a significant increase in intra-abdominal bleeding and decreased survival time. The hemodynamic response to crystalloid infusion in blunt abdominal trauma is primarily dependent on the severity of injury and the rate of blood loss.