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In this study, (23)Na- and (31)P- nuclear magnetic resonance (NMR) spectra were examined in perfused rat hearts harvested 1, 2, 4, and 24 h after 40% total body surface area burn trauma and lactated Ringer resuscitation, 4 ml. kg(-1). %(-1) burn. (23)Na-NMR spectroscopy monitored myocardial intracellular Na+ using the paramagnetic shift reagent thulium 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra(methylenephosphonic acid). Left ventricular function, cardiac high-energy phosphates (ATP/PCr), and myocyte intracellular pH were studied by using (31)P NMR spectroscopy to examine the hypothesis that burn-mediated acidification of cardiomyocytes contributes to subsequent Na+ accumulation by this cell population. Intracellular Na+ accumulation was confirmed by sodium-binding benzofuran isophthalate loading and fluorescence spectroscopy in cardiomyocytes isolated 1, 2, 4, 8, 12, 18, and 24 h postburn. This myocyte Na+ accumulation as early as 2 h postburn occurred despite no changes in cardiac ATP/PCr and intracellular pH. Left ventricular function progressively decreased after burn trauma. Cardiomyocyte Na+ accumulation paralleled cardiac contractile dysfunction, suggesting that myocardial Na+ overload contributes, in part, to the progressive postburn decrease in ventricular performance.

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Alveolar macrophages from New Zealand white rabbits were incubated with twice the MIC of amikacin, ciprofloxacin, aztreonam, ceftazidime and imipenem and exposed to either 10(4), 10(5) or 10(6) cfu/mL live Pseudomonas aeruginosa ATCC 27853 or 0.1, 1 or 10 mg/L purified lipopolysaccharide (LPS) derived from P. aeruginosa to determine the effects of different classes of antimicrobial agent on production of tumour necrosis factor (TNF). Incubation of macrophages with ciprofloxacin and amikacin resulted in less TNF activity after exposure to live P. aeruginosa than was found for saline, aztreonam, ceftazidime or imipenem (P < 0.05). However, no significant differences were found between any of the agents after macrophages had been exposed to purified LPS. Different antimicrobial agents therefore appear to exert different effects in vitro on the TNF response of macrophages to bacterial stimulation.

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Inflammation and microvascular injury in the areas adjacent to burn wounds produces extension of postburn tissue necrosis. Leukocytes are potent mediators of the local inflammatory response preceding tissue necrosis, and the selectin and integrin adhesion molecules have been implicated in leukocyte-mediated tissue destruction. We sought to examine the role of L-selectin (CD62-L) and CD18 in leukocyte accumulation and tissue necrosis following burn injury. New Zealand White rabbits (n = 36) were subjected to burn injury and were randomized to treatment with saline (control) or monoclonal antibodies to L-selectin or CD18. Animals given the anti-L-selectin antibody demonstrated reduced immunohistochemical evidence of leukocyte accumulation at 24 hr postinjury but did not show improved wound perfusion or reduced tissue necrosis. Animals in the anti-CD18 group showed significantly improved tissue survival and improved tissue perfusion but had grades of leukocyte accumulation similar to those in the control group. These observations suggest that leukocyte accumulation is partially L-selectin dependent and that leukocyte accumulation alone is not sufficient to cause changes in blood flow and tissue destruction, both of which appear to be largely CD18 mediated.

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Partial and full thickness burns with intervening zones of stasis were created on the backs on New Zealand White rabbits (n = 23). Either saline or the bradykinin receptor antagonist, NPC 17731, was administered. Skin blood flow was measured hourly using a laser Doppler blood flowmeter. After 4 h skin samples were harvested for assessment of tissue oedema (wet/dry weights) and leucocyte accumulation (immunohistochemistry). Statistical analysis was performed using Analysis of variance (ANOVA) and Mann-Whitney U test with a level of significance at P < 0.05. It was found that blood flow was decreased postburn in all groups. Bradykinin antagonist resulted in increased blood flow in partial thickness burns and zones of stasis compared to saline-treated animals (P < 0.05). Pretreatment with bradykinin antagonist showed reduced tissue oedema in full thickness burns (P < 0.05). No significant difference was observed in leucocyte accumulation between both groups. These data suggest a role for bradykinin in the pathogenesis of postburn microvascular changes which is independent of leucocyte-mediated injury.

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OBJECTIVE: To determine if the shock-induced alterations in whole blood monocyte tumor necrosis factor (TNF) response are mediated by the CD14 receptor. DESIGN: Prospective controlled animals experiments. MATERIALS AND METHODS: New Zealand White rabbits (n = 15) were subjected to hemorrhage and resuscitation. Blood samples obtained before shock and 24, 72, and 120 hours after shock were stimulated with lipopolysaccharide in the presence or absence of the anti-CD14 monoclonal antibody, 63D3. Tumor necrosis factor was assayed using L929 cells. MEASUREMENTS AND MAIN RESULTS: There are no detectable TNF activity in unstimulated blood. The CD14 inhibition resulted in a 55% reduction in baseline TNF activity. After shock, there was a marked increase in TNF activity with lipopolysaccharide stimulation. Addition of 63D3 resulted in a dose-dependent 95% reduction in TNF activity at 24 and 72 hours after shock, (p < 0.05). CONCLUSION: The enhanced whole blood monocyte TNF response after hemorrhage is CD14 dependent.

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The most common cause of intraperitoneal adhesions is previous abdominal surgery. Postoperative adhesion formation results from a fibroproliferative inflammatory reaction that begins with an influx of polymorphonuclear leukocytes (PMNs) into the peritoneal cavity. Adherence of the PMNs to the endothelial cells (EC) is necessary for PMN migration into the tissue in response to a stimulus. Several receptor-counterreceptor pairs of ligands such as CD11/CD18 on the PMN and ICAM-1 (CD54) on EC have been identified. Monoclonal antibody against CD11/CD18 (R15.7) inhibits PMN adherence and migration and consequently protects against PMN-induced tissue injuries. We therefore studied the effect of preventing PMN-EC adherence, using anti-CD18 monoclonal antibody, on postoperative adhesion formation in rabbits. Group 1 was a control receiving physiologic saline, and group 2 received anti-CD18 antibody (R15.7, 2 mg/kg). The treatment was administered iv at the end of surgery and repeated on the first and second postoperative days. Peritoneal adhesions were induced at laparotomy by repairing two peritoneal defects, by oversewing the defect (model 1), and by resuturing the removed parietal peritoneum in its place as an ischemic graft (model 2). Adhesions were evaluated blindly at 10 days after operation by measuring the percentage of the suture line covered with adhesions (model 1) or by a scoring system (model 2). All control animals developed intraperitoneal adhesions and the percentage of the suture line covered with adhesions was 25 +/- 5.9% (mean +/- SEM) and the mean score in model 2 was 0.9 +/- 0.2. Anti-CD18 antibody, R15.7, increased the degree of postoperative adhesion formation in both models, but the results were significant only in model 2. Also, anti-CD18 antibody significantly decreased peritoneal neutrophils from 11.1 x 10(7) +/- 1.8 x 10(7) to 2.2 x 10(7) +/- 0.4 x 10(7) (P < 0.001) on the first postoperative day. It is concluded that inhibition of PMN-EC adherence does influence the postoperative adhesion formation. These results might suggest that PMNs have a role in modulating postoperative adhesion formation.

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The purpose of this study was to determine if hemorrhagic shock alters the alveolar macrophage (M phi) tumor necrosis factor (TNF) response to lipopolysaccharide (LPS) stimulation. New Zealand White rabbits underwent hemorrhage and resuscitation. At 1, 2, 3, 5, and 7 days post-shock, both M phis and peripheral whole blood monocytes were incubated in vitro with saline or Escherichia coli LPS. The supernatants were assayed for TNF activity using the L929 bioassay. Alveolar M phis from hemorrhaged animals showed reduced TNF activity during the first 5 days post-hemorrhage. Maximal depression of TNF activity was observed on days 3 and 5 post-hemorrhage (p < .05). In comparison, peripheral whole blood monocytes showed an increased TNF response on post-shock days 2 and 3. These results suggest that hemorrhagic shock and resuscitation differentially affect TNF response in alveolar and peripheral blood M phi populations.

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OBJECTIVE: To determine if thermal injury alters the expression of leukocyte adhesion molecules. DESIGN: This is a controlled experimental animal study. MATERIALS AND METHODS: Partial thickness burns were created on the backs of New Zealand White rabbits. At 30 minutes, 2 hours, 4 hours, and 24 hours after burn, skin was harvested for immunohistochemistry. Monoclonal antibodies were used to study changes in intercellular adhesion molecule 1 (ICAM-1), E-selectin, and leukocyte CD11a. Staining was graded on a scale of 0 to 4. MEASUREMENTS AND MAIN RESULTS: ICAM-1 was significantly decreased at 24 hours after burn (p < 0.007, Wilcoxon signed rank test). CD11a was increased at 30 minutes (p < 0.02), 2 hours (p < 0.02), and 24 hours (p < 0.006). E-selectin was increased at 2 hours (p < 0.03). CONCLUSION: Thermal injury alters the expression of leukocyte adhesion molecules.

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Postoperative adhesion formation results from a fibroproliferative inflammatory reaction. Macrophages are critical in the final resolution of the inflammatory process and tissue repair, including modulation of proliferation and differentiation of fibroblasts and secretion of neutral proteases like plasminogen activator. We, therefore, studied the influence of peritoneal macrophage enhancement on postoperative adhesion formation in five groups of rabbits. Group 1 was a control with normal peritoneum. Animals in group 2 had increased macrophage population in their peritoneum by intraperitoneal injection of protease peptone 3 days before adhesion induction. In group 3, animals were treated by protease peptone as in group 2 and then depleted of the increased macrophage population by peritoneal lavage before adhesion induction. In group 4 macrophages were transplanted from animals enriched as in group 2 into a nonenriched peritoneum at the time of adhesion induction. Group 5 had a normal peritoneum with peritoneal lavage before adhesion induction. Peritoneal adhesions were induced at laparotomy by repairing a peritoneal defect in two different models. It was found that enhancement of peritoneal macrophages by protease peptone reduced markedly the degree of postoperative adhesion formation. After depletion of the enhanced peritoneal macrophages by peritoneal lavage the degree of adhesion formation was equivalent to that of controls. Finally, macrophage transplantation into a nonenhanced macrophage peritoneum also reduced the degree of postoperative adhesion formation. It is concluded that enhancement of peritoneal macrophages reduces postoperative peritoneal adhesion formation.

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Traumatic brain injury challenges the health care team to employ treatment modalities to prevent secondary brain damage. Initially, the focus was on controlling intracranial pressure and maintaining cerebral perfusion pressure. It is now known it is more critical to determine whether flow matches the brain's metabolic needs as indicated by the cerebral metabolic rate of oxygen. Measuring cerebral metabolic rate of oxygen, the brain's oxygen consumption, is not attained easily due to technical reasons; therefore, it is calculated from more easily attained values (cerebral blood flow x arteriovenous oxygen content difference [AVDO2]). Continuous monitoring of cerebral venous O2 saturation is accomplished via the jugular vein. In most incidences where arterial O2 saturation is stable, then AVDO2 is inversely proportional to the jugular bulb O2 saturation. Jugular bulb O2 saturation, and therefore AVDO2, can be used to evaluate cerebral O2 supply and demand balance as it correlates with cerebral blood flow, with important exceptions as discussed. The most immediate value of jugular bulb O2 saturation monitoring lies in its ability to guide the effects of therapy on O2 supply and demand balance.

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Leukocyte (WBC) adherence to endothelial cells has been implicated in the pathogenesis of microvascular injury. The process of leukocyte adherence is mediated by both the integrin and selectin families of molecules, and their interaction with specific endothelial ligands. Antibodies directed against the leukocyte integrin CD18 and L-selectin have been developed and functionally inhibit leukocyte adherence in models of inflammatory injury. We asked the question: Does inhibition of leukocyte adherence by administration of monoclonal antibody directed against either CD18, integrins (R15.7, R7.1) or against L-selectin (DREG 200) increase susceptibility to infection? New Zealand white rabbits were shaved and injected subcutaneously on their dorsum with Pseudomonas aeruginosa (ATCC#27853) at two sites each of 10(8) and 10(7) colony forming units. Animals were monitored with daily determination of weight, temperature, WBC counts, hematocrit, and killed at 1 week for determination of abscess formation. There were four blinded experimental groups: (1) Saline (2 mL/kg); (2) DREG 200 (2 mg/kg); (3) R7.1 (2 mg/kg); or (4) R15.7 (2 mg/kg). At the 10(7) and 10(8) injection sites the R15.7 group had an increased rate and size of abscess formation compared with controls. The R7.1 group had an increased rate at the 10(8) injection site. There was no significant difference in the percentage of the abscess formation or mean area between the controls and DREG 200-treated groups. We conclude that giving antibody to CD18 increased susceptibility to infection while giving antibody to L-selectin does not.

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Leukocytes and the process of leukocyte adherence have been implicated in the pathogenesis of organ dysfunction after ischemic injury and inflammation. We asked the question: Will inhibition of leukocyte adherence by administration of a monoclonal antibody to intercellular adhesion molecule alter the systemic response to major thermal injury? New Zealand white rabbits instrumented to measure mean arterial pressure, cardiac output, urine output, and arterial oxygenation were deeply anesthetized, and 30% total body surface area full-thickness burn was created by applying brass probes heated to 100 degrees C to the animals' backs for 15 seconds. The animals were continuously monitored, resuscitated, and given analgesic for 24 hours. There were three experimental groups: I-controls (n = 7), anesthetized and monitored; II-30% burn (n = 7) given 30% total body surface area + vehicle (saline solution 1.0 ml/kg every 8 hours); III-30% burn + R6.5 (n = 6) animals given a monoclonal antibody (R6.5, 2.0 mg/kg every 8 hours) directed against the intercellular adhesion molecule beginning 30 minutes after burn. This model of a 30% total body surface area burn injury resulted in hypotension and hypoxemia in the burn group. The animals given the antibody R6.5 maintained higher mean arterial pressure and arterial oxygenation at several points. These results suggest that leukocytes and leukocyte adherence may be involved in the pathogenesis of the systemic sequellae of major thermal injury.

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Leukocyte (WBC) adherence to endothelial cells (EC) has been implicated in the pathogenesis of microvascular injury. WBC-EC adherence is largely dependent on interaction between the WBC-CD18 complex and the endothelial ligand, intercellular adhesion molecule-1 (ICAM-1). Administration of monoclonal antibodies directed against CD18 and/or ICAM-1 inhibit WBC-EC adherence and have been reported to modulate ischemia-reperfusion and inflammatory injury. We asked the question, does inhibition of WBC-EC adherence by administration of monoclonal antibody directed against either CD18 (R15.7) or against ICAM-1 (R6.5) increase susceptibility to infection. New Zealand white rabbits were shaved and injected subcutaneously on their dorsum with Staphylococcus aureus (ATCC No. 25923) at two sites each with 10(9), 10(8), 10(7), and 10(6) colony-forming units (CFUs). A second set of rabbits were injected subcutaneously with Pseudomonas aeruginosa (ATCC No. 27853) at two sites each of 10(8) and 10(7) CFUs. Animals were monitored for 1 week with daily determination of weight, temperature, WBC counts, hematocrit, and gross evidence of abscess formation. There were three blinded experimental groups; animals given R15.7 (2.0 mg/kg), animals given R6.5 (2.0 mg/kg), and controls given saline (2.0 ml/kg). Administration of the anti-CD18 antibody, R15.7, resulted in significantly increased rates of abscess formation following innoculation with S. aureus and with P. aeruginosa, compared to controls and to the animals given the antibody to ICAM-1, R6.5. The administration of R6.5 did not increase the incidence or severity of abscess formation.

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The physiologic and psychologic stress of critical illness produces systemic endocrine responses that affect the body's ability to achieve and maintain homeostasis. Regardless of the nature of the stress or illness, specific hormonal changes occur in thyroid, adrenal, and posterior pituitary activity. This article describes the physiologic and pathophysiologic basis underlying endocrine responses to the stress of critical illness. The critical care nurse is challenged by the complexity of this patient and needs to be familiar with the endocrine responses to critical illness for assessment and clinical interventions to be meaningful.

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We tested the hypothesis that the frequency and amplitude of spontaneous venular contractions in the bat wing could be modulated by changes in transmural pressure. In one series of experiments, venous pressure in the wing was elevated by pressurizing a box containing the body of the animal while the wing was exposed to atmospheric pressure. During this time, venular diameters were continuously recorded using intravital microscopic techniques while venular pressures were measured through servo-null micropipettes. In another series of experiments, single venular segments were dissected from the wing, cannulated, and pressurized in vitro. The results from both experimental protocols were qualitatively similar; alterations in venous pressure over a narrow range (+/- 5 cmH2O from control) produced substantial changes in contraction frequency and amplitude. The product of frequency and cross-sectional area was maximal over the venous pressure range between 10 and 15 cmH2O. Venules demonstrated a rate-sensitive component in their reaction to rapid pressure changes, because contraction bursts occurred immediately after positive pressure steps and quiescent periods often occurred after negative pressure steps. We conclude that venular vasomotion in the bat wing is modulated by intraluminal pressure and involves a bidirectional, rate-sensitive mechanism. In addition, comparisons with arteriolar vasomotion studies suggest that venules are more sensitive to luminal pressure changes than arterioles.

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The arterial myogenic response may consist of both static- and rate-sensitive components. However, in a recent study of bat wing arterioles, we were unable to demonstrate rate-sensitive constrictions when luminal pressure was elevated at rates between 0.06 and 1 mmHg/s. We have now examined this response in isolated arterioles in vitro, where pressure could be elevated more rapidly. Arterioles were dissected from the hamster cheek pouch and cannulated with micropipettes. Diameters were measured using an inverted microscope and video system, while the vessels were pressurized at various rates (up to 120 cmH2O/s) without flow. Most arterioles developed spontaneous tone and vasomotion and showed myogenic responses over the pressure range 40-160 cmH2O. The magnitude and time course of the active diameter response to a rapid pressure change was highly dependent on the amplitude and direction of the pressure step; monophasic constrictions were observed in response to small-amplitude, positive-pressure steps, and biphasic constrictions were consistently observed when box pressure was elevated to values exceeding 120 cmH2O. The time courses of these responses could be partially, but not completely, explained by a myogenic mechanism with static- and rate-sensitive components. The possible mechanism and physiological significance of this behavior in a microvascular network are discussed.

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The responses of three sequential branching orders of arterioles in the bat wing to rapid and slow changes in transmural pressure were studied. Arterial and venous pressures to the wing were elevated simultaneously by pressurizing a box containing the body of the animal, while the wing was exposed to atmospheric pressure. Box pressure was elevated from 0 to +48 mmHg at two rates: 24 and 0.6 mmHg/s. During this time, continuous recordings of hydrostatic pressure and diameter were made in single arterioles using intravital microscopic techniques. Second-order arterioles and arcuate arterioles from skin and skeletal muscle constricted in response to elevated transmural pressure but did not show an enhanced response to rapid pressure changes. There was a trend for terminal arterioles to show a transient peak constriction during rapid stretch, but this response was always associated with a biphasic change in arteriolar pressure. These results suggest that the transient arteriolar resistance changes associated with rapid transmural pressure increases in previous experiments may be primarily a result of transient pressure changes in small arterioles. We find no evidence that arterioles in this preparation exhibit a rate-sensitive component to their myogenic response.

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