[The efficiency of reamberinum in infusion therapy of acetonemic syndrome in children].

The current paper presents the results of monitoring of 69 patients with acute respiratory viral infection, acetonemic syndrome. It was shown the effectiveness of inclusion of Reamberinum into complex therapy as a means for reduction of with acetonemic syndrome and for detoxic effect.

[Impact of the combined application of elastic bandaging of the lower extremities and autohemotransfusion on biochemical indices of the blood and severity of endogenous intoxication in patients with concomitant cardiovascular insufficiency].

Venous congestion in abdominal inner organs in surgical diseases in patients with heart insufficiency may additionally impact biochemical indices of the blood and severity of endogenous intoxication (EI). Basing on the data obtained in the investigations, th was established, that the lower extremities bandaging promotes exit of the blood from depot, where it resides in a concentrated state in cellular and biochemical aspects. It promotes more effective accomplishment of hemodilution as well as reduction of the EI severity in taking of the autologous blood.

Host defense against bacterial endotoxemia: mechanism in normal animals.

The present study defines the early response of normal rabbits to the intravenous injection of a single, sublethal dose of endotoxin. Within the first few hours following endotoxin there occurs in the circulating plasma of recipients a decrease in ionized calcium, a threefold increase in the heat-stable, organo-phosphate-resistant esterase level, and a striking increase in the endotoxin-detoxifying capacity. These results are fully consistent with the thesis that circulating plasma represents a principal site of detoxification and that plasma esterases of the nonspecific, carboxylic type are of major concern in defense against circulating endotoxins.

Dissociation of systemic and renal effects in endotoxemia. Prostaglandin inhibition uncovers an important role of renal nerves.

To elucidate the mechanisms responsible for systemic and renal hemodynamic changes in early endotoxemia, the roles of prostaglandins (PG) and renal nerves were investigated. Endotoxin (E, 3 micrograms/kg i.v.) was given to two groups of anesthetized dogs that had undergone unilateral renal denervation: Group I (n = 9) E only; Group II (n = 11) E + indomethacin (10 mg/kg i.v.) or meclofenamate (5 mg/kg i.v.). A third group of dogs (Group III, n = 5) received indomethacin (10 mg/kg i.v.) only. 1 h after E group I dogs, mean arterial pressure (MAP) decreased from 126 to 94 mm Hg (P less than 0.001), and prostacyclin (6-keto-Fl alpha metabolite, PGI2) increased (from 0.64 to 2.08 ng/ml, P less than 0.005). Glomerular filtration rate (GFR) and renal blood flow (RBF) declined comparably both in innervated and denervated kidneys. In marked contrast, group II dogs had a stable MAP (136-144 mm Hg, NS) and no increase in PGI2 levels. Plasma renin activity (0.7-2.5 ng/ml per h, P less than 0.005) increased, and renin secretion was greater in innervated compared with denervated kidneys (255 vs. 74 U/min, P less than 0.01) in these PG-inhibited dogs. In addition, denervated kidneys in group II dogs had a greater GFR (42 vs. 34 ml/min, P less than 0.01) and RFB (241 vs. 182 ml/min, P less than 0.01) than innervated kidneys after E. Group III animals had no significant changes in systemic or renal hemodynamics, plasma renin activity or PGI2 during the study. These results suggest that PGI2 mediates the systemic hypotension of early endotoxemia in the PG-intact animal. Moreover, PG inhibition uncovers an important effect of E to increase efferent renal nerve activity with a consequent decline in GFR and RBF independent of changes in MAP. Finally, the results demonstrate that renal nerves are important stimuli to renin secretion in early endotoxemia via pathways that are PG-independent.

Prevention by granulocyte depletion of increased vascular permeability of sheep lung following endotoxemia.

To see whether circulating granulocytes are necessary for the lung vascular reaction to endotoxin, we measured the endotoxin response in chronically instrumented sheep before and after granulocyte depletion with hydroxyurea. Granulocyte depletion did not affect the pulmonary hypertension caused by endotoxin (peak mean pulmonary artery pressures = 38 +/- 2 cm H2O before depletion and 42 +/- 2 after depletion, P = NS). The late phase increase in lung lymph flow after endotoxin was significantly lower in the granulocytopenic animals as reflected by lung lymph flow (mean steady state lymph flow before depletion = 30.6 +/- 2.0 SE ml/h; mean steady state lymph flow after granulocyte depletion = 15.4 +/- 1.0; P less than 0.01) even though late phase pulmonary vascular pressures were similar before and after granulocyte depletion. Lung lymph protein clearance (lymph flow x lymph/plasma protein concentration) was also significantly lower after granulocyte depletion (mean steady state before depletion = 2.14 +/- 1.4 SE ml/h; and after depletion = 10.4 +/- 1.0; P less than 0.01). We conclude that circulating granulocytes are necessary for the development of increased lung vascular permeability to fluid and protein following endotoxin. The pulmonary vasopressor effects of endotoxin in sheep are independent of granulocytes.

Histomorphometric study of placental villi vascular volume in toxemia and diabetes.

The quantitative changes in the vascular tree in placentas from pregnancies complicated by diabetes mellitus and preeclampsia (PE) are not well defined. The purpose of this study was to quantify placental villi cross-sectional area of capillaries assessed by a computerized morphometry system in pregnancies complicated by PE (n = 23), well-controlled pregestational diabetes mellitus (PGDM; n = 10), and healthy controls (n = 13). Our aims were to test whether villous capillarization volume was changed in PE without intrauterine growth restriction or PGDM compared with the control group and to study these effects in 3 different areas of the placenta. Examination of placentas in women with PGDM and PE revealed limited pathological changes on light microscopic examination. However, the morphometric analysis revealed a more than 5-fold decrease of villous vascular volume in PGDM compared with controls (P = .003) and a 1.6-fold decrease in the PE group that did not reach statistical significance. These findings show quantitative changes in the villous vascular tree in PGDM that are not detectable by conventional light microscopy and suggest that morphometric analysis of the capillary tree may have diagnostic importance in this entity. The findings differ significantly from those previously reported in pregestational diabetes and do not differ significantly from those reported in PE without intrauterine growth restriction.

Distinct biochemical responses of hepatic macrophages and endothelial cells to platelet-activating factor during endotoxemia.

Acute endotoxemia is associated with activation of hepatic macrophages and endothelial cells. These cells release a variety of inflammatory mediators that have been implicated in tissue injury. In the present studies, we analyzed the biochemical responses of these cells to platelet-activating factor (PAF), a lipid autacoid released during hepatic inflammatory responses. To induce acute endotoxemia, rats were injected intravenously with lipopolysaccharide (LPS). Using the calcium sensitive fluorescent indicator dye Indo-1, we found that PAF induced a rapid and transient increase in intracellular calcium in both hepatic macrophages and endothelial cells. Induction of acute endotoxemia resulted in an increase in the amount of calcium mobilized by both cell types. Although endothelial cells from control rats were less responsive to PAF than macrophages, these cells were more sensitive to in vivo endotoxin. PAF was also found to cause a rapid decrease in intracellular pH in hepatic macrophages that was quantified by fluorescence image analysis using the pH sensitive dye SNAFL-calcein. This decrease occurred more rapidly in macrophages from endotoxemic rats. In cells from both control and endotoxemic rats, the effects of PAF on intracellular pH were inhibited by the specific PAF antagonist triazolam. In contrast to hepatic macrophages, PAF had no effect on intracellular pH in endothelial cells from either control or endotoxemic rats. Ligand binding studies demonstrated that both hepatic macrophages and endothelial cells possess high affinity binding sites for PAF. Macrophages expressed 6- to 7-fold more binding sites/cell than endothelial cells and exhibited a higher Kd. Whereas treatment of rats with LPS had no effect on the Kd for PAF binding to macrophages or on the number of binding sites, a significant increase in both of these receptor characteristics was observed in endothelial cells. Taken together, the present data suggest that the biochemical responses of endothelial cells and macrophages to PAF are distinct. Furthermore, cellular activation induced by PAF in endothelial cells appears to be independent of changes in intracellular pH.

Depletion of surfactant tubular myelin with pulmonary dysfunction in a rat model for acute endotoxemia.

Although prolonged Gram-negative sepsis with high permeability alveolar edema, a well documented cause of adult respiratory distress syndrome, has been shown to result in surfactant alterations, the effects of acute endotoxemia on the lung surfactant system are largely unknown. In this study, lethal endotoxemia (> 80% mortality at 24 h) resulting in severe, rapid leukopenia with progressive thrombocytopenia was achieved through intraperitoneal injection of adult Fischer 344 rats with 3.5 mg of Escherichia coli endotoxin/kg. After assessment of pulmonary mechanics under general anesthesia, endotoxin-injected rats and appropriate controls were killed at 4, 8, and 12 h for morphological and biochemical analyses. Morphometric estimation of surfactant membrane subtypes in bronchoalveolar lavage fluid revealed prominent alterations including significant decrease (45%) in tubular myelin 12 h post-endotoxin, with a threefold increase in lamellar body-like forms at 8 and 12 h. Acute endotoxicosis resulted in decrease of total dynamic compliance, whereas pulmonary resistance remained unchanged. These changes were associated with margination of polymorphonuclear leukocytes in lung microcirculation, multifocal septal edema, and decrease in lamellar body lysozyme specific activity at 12 h. Alveolar edema, as determined by measurement of total protein in cell-free bronchoalveolar lavage fluid, was absent in both controls and endotoxin-injected rats. The results indicate that bloodborne lung injury induced by lethal endotoxicosis initiates acute perturbation of secreted surfactant membranes with pulmonary dysfunction in the absence of high protein alveolar edema.

The influence of sympathoadrenal activation on skeletal muscle oxygen extraction during endotoxemia.

We have previously shown a direct relationship (r = .97) between the fall in arterial blood pressure and the increase in skeletal muscle oxygen extraction (MVO2) during canine endotoxemia. Since it is well known that hypotension activates the sympathetic system, the primary aim of these experiments was to determine if the increase in MVO2 during endotoxemia is a result of elevated levels of catecholamines due to increased sympathetic neural and/or humoral activity (sympathoadrenal system). Canine gracilis muscles were vascularly isolated and perfused in situ at a constant flow (6-7 ml/min/100 g). Endotoxemia was induced by a 30 min intravenous infusion of Escherichia coli endotoxin (2 mg/kg), which induced a 50% reduction in arterial pressure. Perfusion pressure, mean arterial pressure, and arteriovenous oxygen difference (a-v O2) were continuously measured. We found 1) no significant difference between the amount of O2 extracted by an innervated or a denervated muscle during endotoxemia; 2) the intra-arterial infusion of norepinephrine or epinephrine into a denervated gracilis muscle (plasma molar concentrations of; 10(-11), 10(-9), 10(-7), and 10(-5) failed to increase MVO2 to the level observed during endotoxemia; 3) pretreatment of a muscle with propranolol to block skeletal muscle beta-adrenergic receptors, did not suppress the endotoxin-induced rise in MVO2. We concluded that the increase in MVO2 seen after the administration of endotoxin is not due to either increased sympathetic nerve activity or elevated levels of circulating catecholamines. We speculate that the increased MVO2 during endotoxemia is caused by nonadrenergic mediators released by endotoxin rather than the hypotensive stimulus.

The role of histamine in the increased cardiac output in hyperdynamic endotoxemia.

The role of histamine in the hyperdynamic circulatory response to endotoxin (ETX) was investigated in 32 anesthetized dogs by means of histamine H1- and H2-receptor blockade. A hyperdynamic circulation was elicited with a prolonged, slow infusion of a low dose of ETX, and hemodynamic parameters were examined in control and histamine receptor-blocked groups. The following groups were studied: Group ETX received a 2 h infusion of Escherichia coli 055:B5 endotoxin in a total dose of 13.75 micrograms/kg at a rate of 10 micrograms/kg for 45 min and then 5 micrograms/kg for 75 min. In addition to the same dose of ETX, Groups ETX+TPA and ETX+RAN received 0.5 mg/kg of the H1-blocker tripelennamine (TPA) or 2 mg/kg of the H2-blocker ranitidine (RAN), respectively. Infusion of ETX caused a moderate decrease in arterial pressure in Group ETX, whereas TPA but not RAN inhibited this pressure fall. The cardiac output (CO) increased by 41% above the baseline level in Group ETX. Both TPA and RAN prevented this rise in CO. The total peripheral resistance was considerably lowered by ETX, but this decrease was significantly attenuated in the TPA or RAN-treated groups. The heart rate rose significantly after ETX infusion and was unaffected by TPA or RAN. The stroke volume remained unchanged following ETX but was decreased both by TPA and by RAN. TPA or RAN, when given alone, did not affect any of the measured hemodynamic parameters. These experiments provide evidence of the participation of histamine in the hyperdynamic circulatory response in endotoxemia.

Inhibition of endothelium-dependent vasodilation by Escherichia coli endotoxemia.

To test the hypothesis that release of endothelium-derived relaxing factor/nitric oxide is inhibited by Gram-negative lipopolysaccharide (LPS; endotoxin), we examined endothelium-independent and endothelium-dependent vasodilator agents in aortic vascular smooth muscle isolated from guinea pigs 4 h after injection of saline (controls) or induction of Escherichia coli endotoxemia. LPS significantly inhibited vasodilator responses to the endothelium-dependent agonists acetylcholine (ACh; 10(-10)-10(-5) M) and ADP (10(-8)-10(-5) M). However, LPS did not affect vasodilator responses to the endothelium-independent agonist nitroprusside (10(-10)-10(-4) M). The nitric oxide synthase (NOS) inhibitor N gamma-nitro-L-arginine methyl ester (L-NAME) inhibited the vasodilator response to ACh; whereas, the cyclooxygenase inhibitor indomethacin (INDO) did not reduce vasodilator effects of ACh. Neither L-NAME nor INDO affected the vasodilator effects of nitroprusside in LPS or control vessels. In contrast, L-NAME converted the vasodilator action of ADP to a vasoconstrictor response that was blocked individually by INDO and the thromboxane synthase inhibitor dazoxiben, suggesting that ADP releases NO and also the vasoconstrictor and platelet aggregating eicosanoid thromboxane A2. These findings suggest that acute (4 h) endotoxemia inhibits function of the constitutive isoform of NOS in vascular endothelial cells. Since L-NAME unmasked a vasoconstrictor action of the endogenous purinoceptor agonist ADP, pharmacologic agents that inhibit NOS may exacerbate LPS-induced inhibition of endothelial NOS; this series of events could lead to diminution of vasodilator reserves and perhaps to augmentation of platelet aggregation during Gram-negative sepsis.

Dose-related pattern of sinusoidal leukocyte adhesion in sublobular regions of the liver after systemic endotoxin challenge in the rat.

The unique arrangement of large numbers of fixed tissue macrophages, endothelial, and parenchymal cells along hepatic sinusoids as well as their key role in the acute phase response makes the liver a primary target organ in endotoxemia. Pathogenesis of hepatic failure in endotoxemia is incompletely understood, but microcirculatory failure as well as leukocyte-endothelial interaction in response to inflammatory mediators may relate to it. Using intravital fluorescence microscopy, sinusoidal widths, leukocyte flow velocity, and sublobular leukocyte (white blood cell (WBC)) adhesion characteristics 1 h after randomized intravenous application of 0, 0.1, 1, or 5 mg/kg b.w. Escherichia coli endotoxin O 111 B4 (ETX) were evaluated in female Sprague-Dawley rats (n = 6-8/group). Whereas the bolus injection of ETX caused only minor concurrent macrohemodynamic effects, a significant increase of permanent WBC adhesion especially in periportal areas (0 mg, 2.1 +/- 0.7%; 0.1 mg, 16.2 +/- 3.6%**; 1 mg, 15.5 +/- 1.0%**; 5 mg, 13.2 +/- 2.3%* (**p < .01, *p < .05, compared to vehicle)) was found in all groups 60 min after ETX challenge. In contrast, an increase of WBC margination in midzonal and pericentral regions was only seen with the higher doses of 1 or 5 mg/kg ETX, respectively. The sublobular pattern of WBC margination is consistent with the concept of regulation of WBC adhesion by inflammatory mediators released by lipopolysaccharide-stimulated Kupffer cells in vivo. We propose that overwhelming the detoxifying capacity of predominantly periportally located Kupffer cells with large amounts of ETX may lead to activation of pericentral-located resting macrophages paralleled by a rise of adhering leukocytes.

Escherichia coli endotoxemia alters coronary and pulmonary arteriolar responses to platelet products.

In order to examine the effects of Escherichia coli endotoxemia on coronary and pulmonary microvascular responses to serotonin (5-HT) and ADP, arterioles (80-190 micros diameter) were isolated from pigs 3 h after administration of E. coli endotoxin (150 micrograms/kg, intravenously over 1 h, n = 8) or Ringer's lactate (control, n = 8). Arterioles were studied in vitro in a pressurized, partially contracted, no-flow state with video-microscopy. Precontracted (30-50% of baseline diameter) control coronary arterioles dilated in responses to either 5-HT (24 +/- 2%) or ADP (89 +/- 2%). These relaxations were partially inhibited by indomethacin, but were markedly reduced with nitric oxide synthase inhibition. After 3 h of endotoxemia, 5-HT caused contraction of coronary arterioles which was inhibited with indomethacin. In the presence of indomethacin, coronary vessels from endotoxic pigs relaxed slightly, but significantly, more to 5-HT than did control vessels exposed to indomethacin. In contrast, the relaxation response to ADP was unchanged following endotoxemia. Precontracted (15-30% of baseline diameter) pulmonary arterioles dilated in response to 5-HT (13 +/- 1%) or ADP (67 +/- 3%). Following 3 h of endotoxemia, the pulmonary arteriolar relaxation induced by 5-HT was reduced, whereas the response to ADP was not altered. In both coronary and pulmonary arterioles, relaxation induced by the endothelium-independent vasodilator, sodium nitroprusside, was unaffected by endotoxemia. Thus, coronary and pulmonary microvascular relaxation response to ADP are minimally affected by 3 h of endotoxemia, but relaxation responses to 5-HT are significantly reduced or converted to contractile responses.

Inhibition of nitric oxide synthesis aggravates reperfusion injury after hepatic ischemia and endotoxemia.

The potential role of nitric oxide (NO) was investigated in the pathophysiology of liver injury after priming with 20 min hepatic ischemia-reperfusion and administration of .5 mg/kg Salmonella enteritidis endotoxin. Liver injury during the early reperfusion phase of 4 h was characterized by severe vascular oxidant stress, lipid peroxidation (LPO), neutrophil infiltration, and a 33% reduction of the microvascular blood flow in the liver. Inhibition of NO synthesis with N omega-nitro-L-arginine methyl ester hydrochloride (L-NAME) aggravated liver injury by 90%, reduced LPO, and did not affect liver neutrophils but further impaired microvascular blood flow. Treatment with the NO-donor spermine-NONOate or L-arginine did not affect these parameters in postischemic animals, however, treatment did restore all values of L-NAME-treated animals back to disease control levels. These data suggest that endogenous NO formation is sufficient to limit ischemic liver injury during reperfusion but inhibition of NO synthesis will result in additional ischemic damage. NO may also be involved in scavenging of superoxide in the vasculature and in inducing LPO.

Effect of endotoxemia on contrast media reactions.

Since complement activation is sharply temperature-dependent, we have examined the effects of fever produced by a very small dose of endotoxin on contrast media lethality in rabbits. After the injection of 8.2 ml/kg of 52% methylglucamine iodipamide, a group of rabbits exhibiting an average temperature elevation of 1.5 degrees C had a 100% mortality rate. This was contrasted to a 30% mortality in control rabbits receiving contrast alone, and no mortality in rabbits receiving endotoxin alone. The rabbits with fever and increased mortality exhibited increased activation of serum complement. From this preliminary data it appears that caution should be observed in performing a contrast examination in a patient with endotoxemia and/or a fever.

The exchange of small molecules as a measure of normal and abnormal lung microvascular function.

Evidence exists for the utility of measures of small-molecule exchange in assessing the normal and abnormal transport status of the lung vasculature. The evidence for the usefulness of PS for 14C-urea is: 1. PSu compares to other small molecules as would be expected from free-diffusion coefficients. 2. The extraction of 14C-urea decreases with increase flow as would be expected of a diffusion-limited indicator. 3. PSu is unaffected by moderate pressure increase, it increases when lymph protein flow indicated permeability increase, and it decreases when surface area is reduced. 4. Lung injuries such as E. coli endotoxemia in sheep and ARDS in patients can both reduce PSu, presumably through surface area reduction, and increase PSu, through increased permeability. Two events that accompany clinically important vascular injury complicate the interpretation of lung MT curves. These events are surface area loss and heterogeneity of flow and transport properties in the lung. Additional work is needed to precisely measure these variables and assess their importance.

Recurrent episodes of gram-negative bacteremia or endotoxemia change reactivity of pre- and post-capillary pulmonary segments to angiotensin or free radicals.

OBJECTIVE: Recurrent episodes of Gram-negative bacteremia (from intraperitoneal abscesses) or endotoxemia cause lung microvascular injury in the rat. Change in vascular reactivity was assessed in response to challenge. DESIGN: In the isolated lung preparation, resistance was partitioned between pre-(PVRa) and post-capillary (PRVv) segments: vasoreactivity was assessed by challenge with Angiotensin II (AII) or reactive oxygen metabolites. Animals received 4 weekly intra-abdominal implants of live E. coli and B. fragilis in a carrier of sterile cecal content and barium sulfate (SEPSIS) or carrier alone (SHAM SEPSIS): or 4 weekly intravenous infusion of E. coli endotoxin (ENDO) or of saline (SHAM ENDO). A fifth group were untreated controls (CONTROL). MEASUREMENTS AND RESULTS: In the SEPSIS and ENDO lungs, PVRa and PVRv before challenge were normal. In the SEPSIS lung, AII increased PVRa more than in the control lung, PVRv to a similar degree in both. In the ENDO lung it increased PVRa compared with its effect on the SHAM ENDO lung: In both it also increased PVRv, to a similar degree and well above the baseline. Always tachyphylaxis developed with increases in dosage (to 25 microns and 50 microns, respectively). Oxygen free radical challenge in the SEPSIS and ENDO lung caused significant vasoconstriction, particularly PVRv, whereas no response was observed in the CONTROL or SHAM-treated lung from either group. CONCLUSION: Abnormal lung vascular reactivity after SEPSIS or ENDOTOXIN is evident on challenge, the two agents used here detecting site specific changes.

Myocardial protection with prostacyclin after lethal endotoxemia.

A previous study of endotoxemia in dogs demonstrated that exogenous prostacyclin (PGI2), normally a product of vascular endothelium, restored the cardiac index to normal and improved survival. To account for these results, a study was undertaken to test whether PGI2 would alter isolated rat or dog cardiac mitochondrial function following incubation with plasma from endotoxemic animals. A group of five animals served as anesthetized controls. A second group of seven mongrel dogs was given 1.75 mg Escherichia coli endotoxin/kg and was observed for 5 hours without treatment. Anesthesia did not alter cardiopulmonary function; however, 30 minutes after endotoxin administration, the cardiac index decreased from 148 +/- 25 (mean +/- SD) to 111 +/- 12 ml/kg . min (P less than 0.05) and further decreased to 89 +/- 20 ml/kg . min after 4 hours. Dog plasma obtained 2 to 5 hours after endotoxin infusion, incubated with rat or dog myocardial mitochondria, decreased succinate dehydrogenase (SDH) activity (P less than 0.05) and depressed mitochondrial respiration in the presence of the substrate succinate and adenosine diphosphate (ADP) from 180 to 87 Natoms oxygen/mg protein . min (P less than 0.05). There was no change in oxygen consumption when substrate alone was present, nor did plasma alter the amount of ADP phosphorylation as a function of oxygen consumption. A third group of seven animals, 30 minutes after administration of 1.75 mg endotoxin/kg, was treated with 100 ng/kg . min PGI2 for 3 hours. PGI2 infusion in this group prevented the decrease in cardiac index. Plasma obtained during and after PGI2 infusion did not decrease mitochondrial SDH activity, which remained higher than that in controls (P less than 0.001); mitochondrial respiration was also not altered. A correlation was observed between cardiac index and SDH activity (r = 0.58, P less than 0.001) and between cardiac index and mitochondrial respiration (r = 0.61, P less than 0.001). In PGI2-treated dogs cardiac mitochondria were functionally and structurally normal in contrast to the depression and disruption produced by endotoxemia, as observed by enzymatic assay as well as electron microscopy. These results suggest that endotoxemia depresses cardiac mitochondrial respiration, an event related to the decrease in cardiac index. In contrast, cardiac function and mitochondrial respiration are maintained with PGI2 treatment.

Gastric and extragastric actions of the histamine antagonist ranitidine during posttraumatic sepsis.

BACKGROUND: Histamine H2 antagonists (e.g., ranitidine) are generally thought to specifically reduce gastric acid secretion and are commonly used for stress ulcer prophylaxis in critically ill patients because of their efficacy and safety profile. A few reports suggest that ranitidine might also bind to extragastric sites and/or act as an immunomodulator. The potential effects on posttraumatic sepsis are unknown. METHODS: Mongrel pigs (n = 24) were anesthetized with fentanyl, injured by a 10 kg steel bar dropped from a height of 1 m onto the fleshy portion of the posterior thigh, and then 35% of their blood volume was drained through the arterial catheter. All the shed blood plus two times the hemorrhage volume as lactated Ringer's solution was infused after a 1-hour shock period. Either vehicle or ranitidine (1.5 mg/kg) was intravenously administered at the time of resuscitation and every 12 hours thereafter in a blinded fashion. After 72 hours a septic challenge was administered (15 micrograms/kg Escherichia coli lipopolysaccharide [LPS] x 30 min). Serial gastroscopy, gastric pH, hemodynamics, leukocyte counts, cortisol, and tumor necrosis factor were recorded for 180 minutes after LPS. RESULTS: Immediately before LPS all hemodynamic variables were identical between treatments, but gastric pH was slightly higher and stress gastritis was marginally lower with ranitidine. LPS caused profound leukopenia and a hyperdynamic circulatory response (i.e., tachycardia, increased cardiac output, and decreased peripheral vascular resistance at relatively constant blood pressure); these changes were not altered by ranitidine. Gastric pH remained elevated after LPS with ranitidine, but LPS-induced gastritis was not modified. Ranitidine delayed the LPS-induced ventilation-perfusion imbalance and attenuated the peak increase in the proinflammatory cytokine, tumor necrosis factor, without altering its antiinflammatory opponent, cortisol. Similar changes were observed in four additional animals treated with cimetidine. The proportion of circulating neutrophils and lymphocytes was slightly altered 180 minutes after LPS, but there was no obvious effect on T lymphocytes in vivo, and no effect on the LPS-induced increase in neutrophil CD18 expression in vitro was seen. CONCLUSIONS: (1) Ranitidine increased gastric pH, which blunted the stress gastritis caused by trauma but not that caused by LPS; (2) ranitidine delayed the early LPS-evoked pulmonary changes and reduced the tumor necrosis factor spike, which is consistent with a favorable immunomodulatory action that has been reported in patients who are critically ill or are undergoing an elective abdominal surgical procedure; (3) the mechanism is probably related to H2 receptor antagonism rather than to a nonspecific side effect of ranitidine, which suggests that histamine may have a previously unrecognized role in posttraumatic septic responses; and (4) the site of action is probably not in the heart or peripheral resistance vessels, but salutary effects on circulating lymphocytes or neutrophils cannot be excluded.

Influence of omega-3 fatty acids on splanchnic blood flow and lactate metabolism in an endotoxemic rat model.

Alteration in regional blood flow is important in the pathogenesis of organ failure during endotoxemia and sepsis. In particular, intestinal ischemia is thought to enhance the translocation of bacteria into the systemic circulation. We used radioactive microspheres to measure the influence of two intravenous (IV) dietary fats (vegetable oil containing high levels of omega-6 fatty acids, and fish oil containing high levels of omega-3 fatty acids) on regional blood flow during low-dose Escherichia coli endotoxin infusion (0.1 mg/100 g body weight [BW]) in a rat model. Despite absence of changes in the cardiac output, blood flow rates to the small and large intestines, stomach, and pancreas, and also to the skin and skeletal muscle were significantly reduced after 18 hours of endotoxin infusion in the rats fed standard vegetable oil. Short-term IV feeding during a period of 40 hours with an isonitrogenous, isocaloric nutrient solution containing fish oil as the only lipid source normalized intestinal perfusion and increased blood flow to the liver and spleen. Low-dose endotoxin infusion also resulted in significant increases in glucose, lactate, and pyruvate concentrations. In comparison to standard vegetable fat emulsion, fish oil significantly reduced these parameters. A second experiment was conducted to measure lactate kinetics. Based on the dilution of U-14C-lactate, fish oil feeding was associated with higher lactate clearance than standard vegetable oil feeding during the endotoxin infusion. We conclude that short-term IV feeding with fish oil improves intestinal perfusion and portal blood flow, improves glucose tolerance, and increases lactate clearance in a low-dose endotoxin rat model.