Dopexamine improves liver oxygenation during crystalloid resuscitation from experimental hemorrhagic shock

OBJECTIVE: To evaluate the effects of dopexamine administration on hemodynamic variables and tissue oxygen tensions during crystalloid resuscitation from hemorrhagic shock. DESIGN: Randomized, control trial. SETTING: An animal laboratory at a university center. SUBJECTS: Twelve piglets, mean weight 22 kg. INTERVENTIONS: The animals were anesthetized and bled to a state of hemorrhagic shock and resuscitated, using a crystalloid solution infused at a rate of approximately 2.6 mL/min/kg (total amount 208 mL/kg). Cardiac output and mean arterial pressure (MAP were measured as indicators of volume filling during the 20- to 30-min resuscitation period and during the follow-up period until 80 mins from the start of resuscitation. Dopexamine was administered by infusion at 6 micrograms/kg-min from the start of volume replacement (dopexamine group, n = 6). The rest of the animals (control group, n = 6) were given volume replacement only. MEASUREMENTS AND MAIN RESULTS: Systemic oxygen transport variables were calculated. Tissue oxygen tensions were continuously recorded from the liver, conjunctival layer, and via subcutaneous and transcutaneous electrodes in the abdominal region. MAP decreased from 119 +/- 2 (SEM) to 44 +/- 2 mm Hg and cardiac output decreased by 77% during the shock period. During resuscitation, cardiac output was restored in both groups. MAP increased close to the baseline during the early resuscitation period and decreased slowly during follow-up. Oxygen delivery remained at 46% of baseline, whereas systemic oxygen consumption was restored during resuscitation in both groups. Liver tissue oxygen tension increased well above baseline during resuscitation in the dopexamine group, and liver tissue oxygen tension was significantly higher than in the control group. After 60 mins of resuscitation, the liver oxygen tension decreased to control group values. None of the other tissue oxygen tensions showed any differences between groups. CONCLUSIONS: Dopexamine administration during crystalloid resuscitation from hemorrhagic shock was well tolerated and resulted in significant and specific, although transient, improvement in liver oxygenation.     

Effects of dobutamine, norepinephrine and epinephrine on intramucosal pH and hemodynamics of dogs during endotoxic shock

This study assessed the effects of dobutamine (DOB), epinephrine (EPI) and norepinephrine (NE) on gastric tissue oxygenation indicated by gastric intramucosal pH (pHi) and hemodynamics in dogs subjected to endotoxic shock. Twenty-four dogs were assigned to four groups of 6 dogs each: endotoxin without catecholamine and endotoxin with DOB, or EPI or NE. Endotoxic shock was induced by intravenous injection of 3 mg/kg of E. coli over 1 min, with an additional 3 mg/kg over the next 2 hrs. Dogs were resuscitated with normal saline to maintain pulmonary capillary wedge pressure (PCWP) near baseline levels. Catecholamines were infused at 0.1, 0.4 and 1.6 micrograms/kg/min (EPI and NE) and 2.5, 5.0 and 10.0 micrograms/kg/min (DOB) for 30 min at each rate. After 2 hrs of endotoxemia, mean arterial pressure (MAP) and cardiac index (CI) and oxygenation delivery index (DO2I) for all dogs decreased by 46.5%, 43.9% and 15.1% respectively, while pHi decreased from 7.47 to 7.10. Endotoxemia increased blood lactate by 142%. Following fluid resuscitation, EPI (1.6 micrograms/kg/min) further increased lactate by 178% (1.22 to 3.4 mmol/L). No correlation was found between tonometry pHi and lactate (R2 = 0.003), pHi and pHa (R2 = 0.231), pHi and DO2I (R2 = 0.056) nor between intramucosal PCO2 and PaCO2 (R2 = 0.005). pHi did not reflect the improvements in cardiovascular hemodynamics observed following administration of catecholamines. NE improved MAP, CI and DO2I whereas DOB produced similar effects as NE but further reduced SVR. EPI produced similar effects as NE. DOB, NE and EPI further decreased pHi. EPI significantly (P < 0.05) increased blood lactate levels more than DOB and NE.     

Diaspirin cross-linked hemoglobin resuscitation improves cerebral perfusion after head injury and shock

BACKGROUND: Shock associated with traumatic brain injury (TBI) doubles the mortality of TBI alone by inducing a secondary ischemic injury. Rapid correction of cerebral perfusion pressure (CPP) is thought to be essential to improving outcome. Diaspirin cross-linked hemoglobin (DCLHb) has been shown to improve cerebral blood flow, increase mean arterial pressure (MAP), and reduce lesion size in models of occlusive cerebral ischemia but has not been evaluated in a model of TBI combined with hemorrhagic shock. METHODS: We studied the effects of DCLHb resuscitation in a porcine model of cryogenic TBI and hemorrhagic shock (MAP = 50 mmHg). After combined insults, animals were randomized to receive a bolus of 4 mliters/kg of either lactated Ringer's solution (n = 5) or DCLHb (n = 6). Lactated Ringer's solution was then infused in both groups to maintain MAP at baseline. Shed blood was returned 1 hour after the initiation of resuscitation (R1). Animals were studied for 24 hours. RESULTS: DCLHb infusion resulted in a significantly greater MAP at R1 and R24 (95 +/- 4 vs. 82 +/- 2 and 99 +/- 3 vs. 85 +/- 3 mm Hg, respectively) and a significantly greater CPP at R1 and R24 (83 +/- 10 vs. 68 +/- 5 and 89 +/- 6 vs. 71 +/- 11 mm Hg, respectively). Intracranial pressure was lower in the DCLHb group, but this difference was not significant. There was no significant difference between the groups in cerebral oxygen delivery. DCLHb animals required less fluid to maintain MAP (12,094 +/- 552 vs. 15,542 +/- 1094 mliters, p < 0.05). CONCLUSION: These data suggest that DCLHb is beneficial in the early resuscitation of head injury and shock and that further investigation is warranted. Key Words: Diaspirin cross-linked hemoglobin, Head injury, Shock, Cerebral perfusion pressure.     

A new salutary resuscitative fluid: liposome encapsulated hemoglobin/hypertonic saline solution

Low-volume resuscitation with hypertonic (7.5%) saline (HTS) is an evolving therapeutic modality for patients with hemorrhagic shock. This solution has been shown to exert protective hemodynamic effects in models of controlled hemorrhagic shock and in several clinical trials. However, HTS has no oxygen-carrying capacity and therefore does not improve oxygen delivery directly. One of the leading strategies in developing an oxygen-carrying resuscitative fluid is the encapsulation of hemoglobin within phospholipid vesicles (LEH). This preparation has the advantage of being blood type and antigen free, easily adaptable to scale-up production, and remarkably stable with a long shelf life. We therefore tested the hypothesis that lyophilized LEH reconstituted with HTS will improve tissue oxygenation and survival in rats exposed to a lethal controlled hemorrhagic shock. Shock was induced by withdrawal of 70% of blood volume and therapy (n = 10-16) with HTS (5 mL/kg), LEH (5 mL/kg), lactated Ringer's solution (vol:vol = 1:3), LEH-HTS (5 mL/kg), or oxygen (100%) was initiated 15 minutes later. The LEH-HTS improved skeletal muscle oxygen tension directly measured using a thin-film chamber oxygen sensor (PO2 87 +/- 13 mm Hg vs. 40-50 mm Hg in other groups, p < 0.05). This was associated with improved blood pressure, reduced acidosis, and increased survival at 24 hours (75% vs. 6%-25% in other groups, p < 0.05). In conclusion, the study demonstrates a remarkably salutary effect of LEH reconstituted with HTS as a blood substitute in the treatment of hemorrhagic shock.     

Superiority of blood over saline resuscitation from hemorrhagic shock: a 31P magnetic resonance spectroscopy study

OBJECTIVE: To study the relation between blood and saline administration, postresuscitation hematocrit (Hct) level, and metabolic recovery after hemorrhagic shock. SUMMARY BACKGROUND DATA: It is generally believed that crystalloid can be substituted, in whole or in part, for blood during resuscitation of hemorrhagic shock. This is based on the belief that Hct can be safely reduced but should not fall below a critical level. METHODS: Male rats weighing 200 g were subjected to an isobaric hemorrhagic shock at a mean arterial pressure of 30 mmHg for 14 minutes, after which they were randomized to one of three resuscitation regimens. Control group (n = 36) were resuscitated by return of all shed blood. Mid-Hct (n = 39) and low-Hct (n = 60) groups were depleted of one third and one half of their circulating blood volumes, respectively, and were resuscitated with three times that volume of normal saline. Skeletal muscle intracellular energetics and pH were measured serially using 31P magnetic resonance spectroscopy at baseline, during shock, and after resuscitation. Arterial blood was sampled at the same time points. The number of surviving animals in each group at 24 hours was recorded. RESULTS: After resuscitation, surviving rats in the low-Hct group demonstrated a greater consumption of high-energy phosphocreatine stores than did the other groups (control = 0.479 +/- 0.003, mid-Hct = 0.465 +/- 0.004, low-Hct = 0.457 +/- 0.007, mean +/- standard error of the mean; p < 0.01 low-Hct vs. other groups by analysis of variance). The rats that received saline resuscitation developed a relative intracellular acidosis (control = 7.29 +/- 0.02, mid-Hct = 7.25 +/- 0.02, low-Hct = 7.23 +/- 0.02; p < 0.05 controls vs. other groups by analysis of variance). At 24 hours, the death rates were significantly different among the groups: control = 1 of 36 rats (2.8%), mid-Hct = 6 of 39 (15.4%), and low-Hct = 14 of 60 (23.3%) (p < 0.05 by chi square analysis). CONCLUSION: The oxygen-carrying capacity of resuscitation fluid has an important impact on intracellular metabolism and outcome.     

Differing effects of anesthetics on splanchnic arterial blood flow during hemorrhagic shock

The effect of anesthesia on splanchnic blood flow was examined during hemorrhagic shock and resuscitation. Sprague-Dawley rats were anesthetized with the inhalation anesthetic, methoxyflurane, or pentobarbital (65 mg/kg). Transonic Doppler flow probes were placed around the superior mesenteric artery (SMA) and the abdominal aorta, and the animals were subjected to acute hemorrhage (or sham) to 30 mmHg for 90 min followed by 30 min of resuscitation with shed blood (n = 6/group). At 90, 105, and 120 min, sham animals in both anesthetic groups showed comparable blood pressures with a 50% decrease in SMA and aortic blood flow. Acute hemorrhage decreased SMA blood flow by 94.5 +/- 0.01 and 86.0 +/- 2.8%, respectively, in the pentobarbital and methoxyflurane groups, with similar changes occurring in aortic blood flow. During resuscitation, arterial pressure remained significantly depressed and SMA blood flow decreased by 65% in the pentobarbital group, whereas blood pressure returned to control levels and SMA blood flow increased to 56% of control values (P < 0.001) in the methoxyflurane group. The findings indicate that the choice of anesthetic agent may significantly impact splanchnic blood flow and needs to be taken into account when designing experiments examining effects of hemorrhagic shock.     

The effects of prostacyclin on gastric intramucosal pH in patients with septic shock

OBJECTIVE: To investigate whether infusing prostacyclin (PGI2) in patients with septic shock improves splanchnic oxygenation as assessed by gastric intramucosal pH (pHi). DESIGN: Interventional clinical study. SETTING: Surgical ICU in a university hospital. PATIENTS: 16 consecutive patients with septic shock according to the criteria of the ACCP/SCCM consensus conference all requiring norepinephrine to maintain arterial blood pressure. INTERVENTIONS: All patients received PGI2 (10 ng/kg x min) after no further increase in oxygen delivery could be obtained by volume expansion, red cell transfusion and dobutamine infusion. The results were compared with those before and after conventional resuscitation. The patients received continuous PGI2 infusion for 33-32 days. MEASUREMENTS AND RESULTS: O2 uptake was measured directly in the respiratory gases, pHi was determined by tonometry. Baseline O2 delivery, O2 uptake and pHi were 466 +/- 122 ml/min.m2, 158 +/- 38 ml/min.m2, and 7.29 +/- 0.09, respectively. While O2 uptake remained unchanged, infusing PGI2 increased O2 delivery (from 610 +/- 140 to 682 +/- 155 ml/min.m2, p < 0.01) and pHi (from 7.32 +/- 0.09 to 7.38 +/- 0.08, p < 0.001) beyond the values obtained by conventional resuscitation. While 9 of 11 patients with final pHi > 7.35 survived, all patients with final pHi < 7.35 died (p < 0.01). CONCLUSIONS: Infusing PGI2 in patients with septic shock increases pHi probably by enhancing blood flow to the splanchnic bed and thereby improves splanchnic oxygenation even when conventional resuscitation goals have been achieved.     

Lactated ringer's is superior to normal saline in a model of massive hemorrhage and resuscitation

BACKGROUND: Previous models comparing normal saline (NS) with lactated Ringer's solution (LR) for resuscitation use only mild or moderate hemorrhage and do not address the clinical situation of massive hemorrhage and resuscitation (MHR). This work compares NS and LR by using a new rat model of MHR. METHODS: NS and LR were compared by using both a traditional model of moderate pressure-controlled hemorrhage and a model of MHR. Moderate hemorrhage animals were bled to mean arterial pressure (MAP) = 60 mm Hg x 2 hour then resuscitated with crystalloid (NS or LR) for 1 hour. MHR animals were bled at a rate of 1 estimated blood volume (EBV) per hour for 2 hours with simultaneous resuscitation by using washed red blood cells (B) and crystalloid (LR+B or NS+B). MAP was kept at 60 mm Hg during the 2 hours of hemorrhage. Bleeding was then stopped, and animals were resuscitated for 1 additional hour with blood and crystalloid to MAP more than 90 mm Hg or until 10x EBV was given. Group means were compared with Student's t test (p < 0.01 significant) and 2-week survival rates were compared by using Fisher's exact test (p < 0.05 significant). RESULTS: The moderate hemorrhage group was bled 36% of EBV. In this setting, resuscitation with NS and LR was equivalent. The final hematocrit, pH, and base excess were not different, and all animals survived in both groups. MHR animals were bled 218% of EBV. Animals resuscitated with NS+B were significantly more acidotic than animals resuscitated with equal volumes of LR+B (pH 7.14+/-.06 vs. 7.39+/-.04, respectively) and had significantly worse survival (50% vs. 100%, respectively). CONCLUSION: With moderate hemorrhage, NS and LR are equivalent, but in the setting of massive hemorrhage and resuscitation, significantly more physiologic derangement and mortality occurs with NS than LR. LR is superior to NS for use in massive resuscitation.     

Effect of hemorrhagic shock on endotoxin-inducing TNF production and intra-tissue lipopolysaccharide-binding protein mRNA expression and their relationship

In order to further elucidate effect of hemorrhagic shock on endotoxin-inducing cytokine production, the present study was designed to investigate the production of tumor necrosis factor alpha (TNF alpha) induced by low-dose (1 microgram/kg) of lipopolysaccharide (LPS) and its cellular sources after hemorrhagic shock (HS) in rats. With combination of expression of lipopolysaccharide-binding protein (LBP) mRNA in the liver, lungs, and kidneys, we further analyzed a possible mechanism for increasing sensitivity to LPS by shock. We found in vivo that plasma TNF alpha levels in the HS + LPS group were 20-fold higher than those in the HS group (p < .01) and 2.7-fold higher than those in the LPS group (p < .05). It was shown in vitro that the capacity of the peripheral white blood cells to produce TNF alpha in response to LPS stimulation was significantly decreased by 126% (p < .01) and 57% (p < .05) compared with the pre-shock levels and sham group, respectively, at the end of resuscitation following shock, and still markedly inhibited 3 h after resuscitation, while the capacity of hepatic Kupffer's cells to produce TNF alpha was significantly increased by 110% compared with the sham group (p < .01) after shock and resuscitation. Results from RT-PCR showed that expression of LBP mRNA in the liver, lungs, and kidneys was increased after shock and resuscitation. It is suggested that hemorrhagic shock could significantly strengthen endotoxin to induce TNF alpha production, which might be due to up-regulation of LBP expression in tissues after shock, and the tissue macrophage population may be the main source for cytokine production in shock.     

Effect of alpha(alpha)-cross-linked hemoglobin and pyridoxalated hemoglobin polyoxyethylene conjugate solutions on gastrointestinal regional perfusion in hemorrhagic shock

BACKGROUND: Hemoglobin-based blood substitutes may cause vasoconstriction, which could limit organ perfusion during trauma resuscitation. We investigated the effect of two hemoglobin solutions on regional blood flow and mucosal perfusion in the gastrointestinal tract in a hemorrhagic shock model. METHODS: Twenty-four swine were bled 30% of blood volume over 1 hour. Six additional animals were anesthetized and monitored but did not undergo hemorrhage. Bled animals were resuscitated with alpha(alpha)-hemoglobin (alpha(alpha)Hb), pyridoxalated hemoglobin polyoxyethylene conjugate (PHP), shed blood, or lactated Ringer's solution. Regional blood flow was measured by radiolabeled microspheres. Gastric mucosal perfusion was estimated by measuring intramucosal pH (pHi) by tonometry. RESULTS: PHP and shed blood restored small-bowel flows to sham values, whereas lactated Ringer's solution and alpha(alpha)Hb did not. Shed blood and PHP, but not alpha(alpha)Hb, restored cardiac index (CI) to baseline (p < 0.05). Mean pulmonary artery pressure was elevated over baseline with alpha(alpha)Hb and PHP and remained elevated with alpha(alpha)Hb (p < 0.05). pHi was significantly lower after resuscitation with PHP than with other fluids. CONCLUSION: PHP was efficacious in restoring CI and small-bowel flow, but the pHi remained low, indicating possible continued mucosal ischemia. Alpha(alpha)Hb led to limited recovery of CI and small-bowel blood flow but restored pHi close to baseline. Shed blood was efficacious in restoration of pHi, gastrointestinal blood flows, and systemic hemodynamics.     

Isolated domain II and III from the Bacillus thuringiensis Cry1Ab delta-endotoxin binds to lepidopteran midgut membranes

BACKGROUND: Little is known about the changes in the hepatic microcirculation and the leukocyte-endothelial adhesion processes during the early reperfusion period after resuscitation in hemorrhagic shock. P-selectin and its natural ligand Sialyl Lewis(x) (SLe(x)) are involved in the early stages of reperfusion events leading to neutrophil migration. Therefore, the aim of this study was to investigate the effect of the administration of CY-1503 [corrected], a synthetic SLe(x) analog, in the liver inflammatory response and neutrophil migration after hemorrhagic shock. MATERIALS AND METHODS: Rats, each weighing 275 to 300 grams, were subjected to 60 minutes of pressure controlled hemorrhagic shock. After this period, animals were resuscitated according to the following protocol: shed blood was reinfused to equal 50% of the total volume bled, and the other 50% was replaced with 3x volume of Ringer's lactated solution. Animals were divided into sham and two study groups to receive vehicle (controls) and CY-1503 [corrected] (10 mg/kg intravenously) diluted in 1 mL of normal saline 45 minutes after initiating hemorrhagic shock. The following parameters were analyzed: 7-day survival, liver injury tests, liver tissue myeloperoxidase as an index of neutrophil infiltration, and liver histology. RESULTS: Survival was significantly increased from 48% in the controls to 90% in the CY-1503 [corrected] treated group. Animals treated with the SLe(x) analog showed significantly better mean arterial blood pressure after 15 minutes after resuscitation. Also, the treated group showed a marked decrease in liver enzymes levels at 5 minutes and 4 hours after reperfusion. Neutrophil migration was significantly ameliorated as reflected by decreased myeloperoxidase levels in the SLe(x) analog treated group. Furthermore, we observed improved histologic damage scores in the treated group when compared with controls. CONCLUSIONS: The SLe(x) analog, CY-1503 [corrected], had a protective effect in ischemic livers by decreasing neutrophil migration after hemorrhagic shock and resuscitation. This protective effect also resulted in improved survival and mean arterial blood pressure after resuscitation.     

Dopamine and intestinal mucosal tissue oxygenation in a porcine model of haemorrhage

Haemorrhage is associated with intestinal mucosal hypoxia and impaired gut barrier function. Dopamine increases oxygen delivery to the intestinal mucosa and may thus counteract haemorrhage-induced mucosal hypoxia. Jejunal mucosal tissue oxygen tension (mucosal PO2) and jejunal oxygen saturation of mucosal microvascular haemoglobin (mucosal HbO2) were measured in 14 anaesthetized pigs. Seven animals served as controls (group C) and seven received continuous infusion of dopamine 16 micrograms kg-1 min-1 (group D) while 45% of blood volume was removed in three equal increments. Resuscitation was performed using shed blood and fluid. Mean arterial pressure and systemic oxygen delivery decreasing significantly during haemorrhage and returned to baseline after resuscitation in both groups. Mucosal PO2 decreased from 4.4 to 1.7 kPa after haemorrhage (P < 0.01) and further to 1.5 kPa after resuscitation (P < 0.01) in group C whereas group D showed an increase from 3.9 to 5.9 kPa after the start of the dopamine infusion (P < 0.05), but no significant difference from baseline after haemorrhage (2.3 kPa) (ns) or resuscitation (3.1 kPa) (ns). Mucosal HbO2 decreased from 52 to 32% after haemorrhage (P < 0.05) and increased to near baseline (37%) (ns) after resuscitation in group C whereas group D showed no significant changes from baseline (54%) throughout the experiment. Comparison between groups showed higher mucosal PO2 and HbO2 values for group D animals after the start of the dopamine infusion (P < 0.05 each), after the first two steps of haemorrhage (P < 0.01 each) and after resuscitation (P < 0.05 each). We conclude that i.v. dopamine 16 micrograms kg-1 min-1 improved tissue oxygenation of the small intestinal mucosa during moderate haemorrhage and subsequent resuscitation.     

Dose-dependent character of the effect of hydrocortisone on energy metabolism of rat thymocytes

OBJECTIVES: Pancreatic hypoxia/ischemia, as a consequence of shock-induced microcirculatory failure, is considered a causative factor in the initiation and/or progression of pancreatic tissue injury. The aim of this study was to compare the effects of "small volume resuscitation" with conventional isovolemic colloid and hypervolemic crystalloid resuscitation on pancreatic microcirculation after hemorrhagic shock. DESIGN: Randomized, controlled intervention trial. SETTING: University laboratory. SUBJECTS: Twenty-three male Sprague-Dawley rats anesthetized with á-chloralose mechanically and ventilated. Interventions: Rats subjected to 1 hr of hemorrhagic shock (mean arterial pressure of 40 mm Hg) were resuscitated with lactated Ringer's solution (four-fold shed volume/20 mins), 10% hydroxyethyl starch (shed volume/5 mins), or 7.2% sodium chloride-10% hydroxyethyl starch (10% shed volume/2 mins). MEASUREMENTS AND MAIN RESULTS: The microcirculation of pancreatic acinar tissue was studied by means of intravital fluorescence microscopy and laser Doppler flowmetry. At 1 hr after resuscitation, mean arterial pressure, pancreatic capillary erythrocyte velocity, and erythrocyte flux were found to be significantly increased when compared with those values in the shock state. However, mean arterial pressure, pancreatic capillary erythrocyte velocity, and erythrocyte flux did not completely return to preshock values, regardless of the type of fluid used for resuscitation. At 15 mins and 1 hr after resuscitation, shock-induced capillary perfusion failure (reduction of functional capillary density) was restored to 91% to 94% of baseline values in all groups. Pancreatic capillary narrowing, indicating microvascular endothelial cell swelling, was abolished by resuscitation with both isotonic hydroxyethyl starch and hypertonic hydroxyethyl starch (p<.05 vs. lactated Ringer's solution). CONCLUSIONS: Despite replacement of only 10% of actual blood loss, small-volume resuscitation with hypertonic hydroxyethyl starch is as effective as the ten-fold volume of isotonic hydroxyethyl starch and, due to prevention of microvascular endothelial cell swelling, superior to the 40-fold volume of isotonic lactated Ringer's solution in regard to restoration of the shock-induced microcirculatory disturbances of rat pancreatic acinar tissue.     

The differential induction of two immediate early genes, c-fos and c-jun, after systemic hypovolemic shock/resuscitation in the rat liver and kidney

The aim of this study was to investigate the expression of the immediate early genes (IEGs), c-fos and c-jun, in the rat kidney and liver in two types of hemorrhage shock/resuscitation models. In the first group, hemorrhagic shock was induced by the withdrawal of blood through the carotid artery. A mean arterial blood pressure (MAP) of 40mmHg was maintained for 1h before blood was reperfused. In the second group, the MAP was maintained at the same level for 2h. Animals were resuscitated with Ringer's lactate solution. In the first group, a rapid and transient induction of c-fos and c-jun mRNAs in both the liver and kidney was observed, peaking 0 to 2 h after reperfusion. In the second group, a more protracted pattern of induction was evident in both organs. In both models, the induction of c-fos mRNA was distinctly different in the liver and kidney. These results indicated, first, that with respect to IEG expression, organs respond differently to a systemic shock/resuscitation stimuli, and second, that alterations in the pattern of IEG expression might represent an indication of the degree of organ damage or the repair processes subsequent to hypotension/reperfusion.     

Drug-induced vasodilation: the effects of sodium nitroprusside, hydralazine, and cromakalin on the rabbit carotid artery: in vitro and in vivo study

Hemorrhagic shock results in hepatocellular dysfunction and hepatic injury that may contribute to the development of liver failure and multiple organ dysfunction in trauma patients. The specific mediators involved in this process remain incompletely defined. We have previously demonstrated that inhibition of nitric oxide (NO) synthesis in a rat model of moderately severe hemorrhagic shock increases hepatic injury, suggesting that NO synthesis is beneficial after hemorrhage. To further define the role of NO in hepatic function during hemorrhagic shock, rats were subjected to a severe hemorrhagic shock insult in which they were bled to a mean arterial pressure of 40 mmHg until 40% of their shed blood had been returned and then were resuscitated. Rats were treated with the NO synthase inhibitor L-nitroarginine methyl ester (L-NAME) or the NO donor S-nitroso-N-acetylpenicillamine beginning either during the hypotensive period or after resuscitation. When instituted during the hypotensive period, low dose L-NAME infusion significantly increased hepatic injury. When L-NAME was infused after resuscitation, no increase in hepatic injury was detected even when the L-NAME dose was increased by a factor of four. The increased hepatic injury produced by L-NAME was associated with increased myeloperoxidase content in the lung, suggesting that L-NAME led to a greater accumulation of neutrophils during shock. Administration of the NO donor S-nitroso-N-acetylpenicillamine reduced hepatocellular enzyme release. Our results suggest that ongoing NO synthesis during the hypotensive phase of hemorrhagic shock is essential in preventing shock-induced hepatic injury and this may be due, in part, to the interaction between NO and circulating neutrophils.     

Subcutaneous and gut tissue perfusion and oxygenation changes as related to oxygen transport in experimental peritonitis

Peritonitis and septic shock may lead to tissue hypoxia, but this risk is not identical in all organ systems. This study was undertaken to measure changes in tissue oxygenation and perfusion in the gut wall and subcutaneous tissue, respectively, and to examine their relation to oxygen delivery and consumption. Twelve pigs were anesthesized and mechanically ventilated. An ultrasonic flow probe was placed around the superior mesenteric artery for registration of blood flow. A mesenteric vein was cannulated for blood sampling. For calculation of gut intramural pH (pHi), a Silastic balloon (Tonomitor) was placed in the lumen of the midileum. pHi was calculated from tonometrically measured PCO2 and arterial bicarbonate concentration. The subcutaneous PO2 was measured by means of an oxygen-permeable Silastic tube implanted in the subcutis of the abdominal wall. Oxygen delivery (DO2) and consumption (VO2) were determined for the gut as well as for the whole body. In six randomly allocated animals, peritonitis was induced after a stabilization period of at least 1 hr, by instillation of autologous faeces into the abdominal cavity, while the other six animals served as controls. The animals were then followed for 5 hr. pHi remained stable in the control group, whereas a drop from 7.37 to 7.02 took place in the peritonitis group. In the test group, subcutaneous oxygen tension (PscO2) already began to fall 1 hr after the induction of peritonitis, and gained the minimum at the end of the study. In peritonitis, a moderate correlation was seen between pHi and DO2 (r = 0.51 +/- 0.16); no statistical difference was noted if pHi was correlated to gut DO2 (r = 0.56 +/- 0.18).(ABSTRACT TRUNCATED AT 250 WORDS)     

Genetic analysis of adult-onset cataract in a city-based ophthalmic hospital

When oxygen delivery (DO2) critically decreases, oxygen consumption (VO2) becomes supply dependent. We examined whether end-tidal PCO2 (PetCO2) would identify supply dependency during shock. Five dogs (Group I) underwent progressive hemorrhage to decrease DO2 until they could no longer maintain a stable blood pressure. Five additional animals (Group II) were bled until VO2 decreased to 70% of baseline, followed by resuscitation. The PetCO2 versus time inflection point was compared with the DO2 at onset of supply dependency (DO2crit). DO2crit for Groups I and II were 6.9 +/- .4 and 8.1 +/- 1.3, respectively (p = NS), and not statistically different from the DO2 values at which PetCO2 decreased (6.6 +/- .7 and 6.3 +/- .7 mL/kg per min, respectively). AT constant minute volume, PetCO2 effectively indicated the onset of supply dependency and rapidly increased during resuscitation, paralleling the changes in VO2 in this model of hemorrhagic shock.     

Low-volume resuscitation with a hemoglobin-based oxygen carrier after hemorrhage improves gut microvascular oxygenation in swine

Using palladium-porphyrin quenching of phosphorescence, we investigated the influence of diaspirin cross-linked hemoglobin (DCLHb) on gut microvascular oxygen pressure (microPO2) in anesthetized pigs. Values of gut microPO2 were studied in correlation with regional intestinal as well as global metabolic and circulatory parameters. A controlled hemorrhagic shock (blood withdrawal of 40 mL/kg) was followed by resuscitation with either a combination of lactated Ringer's solution (75 mL/kg) and modified gelatin (15 mL/kg)(lactR/Gel) or 10% DCLHb (5 mL/kg). After resuscitation, gut microPO2 was similarly improved in the lactR/Gel group (from 25 +/- 10 mm Hg to 53 +/- 8 mm Hg) and the DCLHb group (from 23 +/- 9 mm Hg to 46 +/- 6 mm Hg), which was associated with increased gut oxygen delivery. However, the improvement after resuscitation with DCLHb was sustained for longer periods of time (75 vs 30 min). Mesenteric venous PO2 was increased after resuscitation with lactated Ringer's solution and modified gelatin but not with DCLHb, which was associated with an increased gut oxygen consumption in the latter group. We conclude that measurement of microPO2 by the palladium-porphyrin phosphorescence technique revealed DCLHb to be an effective carrier of oxygen to the microcirculation of the gut. Also, this effect can be achieved with a lower volume than is currently used in resuscitation procedures.     

Steroid content in endometrial tissue

Recent studies indicate beneficial effects of androgen depletion in male mice, before trauma-hemorrhage on cell-mediated immunity following soft-tissue trauma and hemorrhagic shock. Nonetheless, it remains unknown whether androgen receptor blockade following the insult has any salutary effects. To study this, male C3H/HeN mice were either sham-operated or subjected to soft-tissue trauma (i.e., 2.5 cm midline laparotomy) followed by hemorrhagic shock (blood pressure 35 +/- 5 mmHg for 90 min) and then adequately resuscitated (shed blood and lactated Ringer's). Immediately after the completion of resuscitation, as well as 24 and 48 h thereafter, the animals received either vehicle, 10 mg/kg body weight (BW) flutamide or 25 mg/kg BW flutamide subcutaneously. At 72 h after resuscitation, all animals were killed. The spleens and peritoneal macrophages (M phi) were then harvested and cultures established to determine IL-2 and IL-3 release, splenocyte proliferative capacity, as well as splenic and peritoneal M phi IL-1 release. Moreover, plasma testosterone and corticosterone levels were measured. Our results indicate that trauma-hemorrhage resulted in significant depression of splenocyte and M phi functions in vehicle-treated and animals receiving 10 mg/kg BW flutamide. Treatment with 25 mg/kg BW flutamide following trauma-hemorrhage, however, resulted in levels of cytokine release which were comparable with those found in sham-operated animals. No significant alterations in plasma corticosterone and testosterone levels were observed in any of the experimental groups. These findings indicate that short-term therapy of males with the androgen receptor blocker, flutamide at 25 mg/kg BW, following trauma-hemorrhage has protective effects on immune functions. This protective effect is dose dependent, since 10 mg/kg BW flutamide did not produce significant salutary effects. Thus, flutamide represents a novel and safe agent for improving the depressed functions in male trauma patients suffering severe blood loss.