摘要:

ABSTRACTSeveral studies indicate that norepinephrine (NE) may be more effective than dopamine for the treatment of septic shock. Nonetheless, many consider dopamine to be the pressor of choice for shock refractory to volume resuscitation. Owing to fear of excessive vasoconstriction, accentuated end-organ hypoperfusion, and the development of multiple organ dysfunction syndrome (MODS), it is contended that NE may be deleterious. We analyzed the duration of NE use and the variables that predict mortality in a consecutive cohort of 406 surgical intensive care unit patients treated with NE for shock. Study parameters included age, acute physiology and chronic health evaluation (APACHE) II and APACHE III scores, hospital (HLOS) and intensive care unit (ULOS) length of stay, maximal and daily multiple organ dysfunction (MOD) scores, MOD score minus cardiovascular points (MOD-CV), duration of NE infusion, and survival. The duration of NE infusion was stratified into six subsets (1, 2, 3–5, 6–10,11–20, and ≥21 days). An age- and APACHE II and III score-matched cohort of 195 patients, in whom NE was not utilized, was identified retrospectively for comparison. The prevalence of NE use was 10.9%. NE patients developed MODS to a greater degree (11.7 ± .3 vs. 5.9 ± .4 points, p < .0001). NE patients had a greater degree (p < .0001) of noncardiovascular MOD as well. When stratified by survival, a greater degree of MOD occurred in both nonsurvivors and survivors of NE (both, p < .0001) compared with comparably ill patients without pressor-dependent shock. MOD scores, ULOS, and HLOS increased progressively with prolonged NE therapy (all, p < .0005), whereas mortality increased significantly only when the duration of NE infusion exceeded 10 days (p = .05). By multivariate analysis of variance (ANOVA), MOD score (p < .0001), and APACHE III (p < .01) predicted mortality, but notably the duration of NE therapy failed to attain predictive value (p = .3192). Only the MOD score was predictive of HLOS (p = .0001) and ULOS (p = .003). Daily MOD scores revealed that nonsurvivors of NE therapy were admitted to the intensive care unit with a greater degree of baseline organ dysfunction than NE survivors (7.5 ± .4 vs. 5.1 ± .2 for survivors, p < .0001). In addition, whereas survivors showed significant improvement by Day 5 (p < .01), MOD amongst nonsurvivors remained unchanged (p = .993). Although critically ill surgical patients requiring NE support have significantly greater degrees of organ dysfunction than patients not requiring pressors, much of the organ dysfunction is present on admission. The data contradict the notion that NE facilitates the development of MODS.

ISSN:1073-2322    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

ABSTRACTSince nitric oxide (NO) contributes to both circulatory disorders and host defense, we analyzed the NO production in (poly)trauma patients (pts) in a prospective (pre)clinical study starting as early as at the scene of accident. Upon approval of the local IRB/EC, 85 multiple injured pts were enrolled. Subsets were performed according to trauma severity (ISS) and injury pattern, and between survivors versus nonsurvivors. The first blood sample was collected at the scene of accident, then in hourly to daily intervals. NO production was assessed by measuring nitrate+nitrite plasma levels. To estimate dilution effects, all values were calculated according to the actual plasma protein content. The extent of trauma was appraised by C-reactive protein (CRP) levels. Immediately after trauma, N02-+ N03-plasma levels were always elevated. This was most pronounced in thoracic injury, irrespective of whether it was combined with multiple trauma. Nitrate+nitrite levels returned to normal within 24 h. CRP generation increased during 12 h following trauma and was most marked in severest trauma (ISS >50). For the first time, we show very early data following major trauma that demonstrate that NO overproduction starts immediately after trauma. However, systemic N02-+ N03-levels actually reflect the severity of injury only during the first 2 h. Thereafter, NO generation is rather related to the individual trauma pattern, e.g., chest trauma. Nonetheless, the role of NO after severe trauma and especially in thoracic injury remains unclear and should further be elucidated in a specific study.

ISSN:1073-2322    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

ABSTRACTAdrenomedullin (AM) is a potent vasorelaxing peptide isolated from human pheochromocytoma. It is proposed that AM dilates the blood vessels by autocrine or paracrine mechanisms. Our investigation concerned whether the vasodilating function of AM accounts for the hypotension occurring in endotoxin shock. The effect of endotoxin shock on AM gene expression in the cardiovascular system was probed using a canine model. The cDNA encoding the AM precursor in dogs was isolated from cDNA libraries of the adrenal gland and was sequenced. The canine AM precursor is constituted of 188 amino acids and its AM consists of 52 amino acids, similar to human and porcine AM. The dogs were injected intravenously with 2 mg/kg of lipopolysaccharide (LPS) after being anesthetized and intubated. After 4 h, we collected whole blood, the large and small blood vessels, and the heart from our canine model of endotoxin shock, and extracted RNA from those tissues for Northern blot analysis. In the endotoxin shock model, the mRNA levels of the AM had increased in almost all of the blood vessels. These results suggest that AM may dilate the blood vessels systemically, even if AM acts as a local modulator of vascular tone. In addition, the plasma concentrations of the AM were high enough to allow for AM to act as a vasodilating hormone. Consequently, AM may be one of the factors facilitating severe hypotension complicated with endotoxin shock.

ISSN:1073-2322    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

ABSTRACTThe CXC chemokines have well-documented neutrophil chemotactic, angiogenic, and mitogenic properties. The current investigations evaluate the effects of interleukin-8 (IL-8), epithelial neutrophil activating protein (ENA-78), and macrophage inflammatory peptide-2 (MIP-2) on hepatocyte proliferation in vitro and liver regeneration in vivo. Primary rat hepatocytes were isolated by collagenase digestion and exposed to incremental doses of IL-8, ENA-78, or MIP-2, and cellular proliferation was measured via tritiated thymidine incorporation. These experiments demonstrated significant increases in hepatocyte proliferation in response to IL-8, ENA-78, and MIP-2. Next, rats were sacrificed in a time-dependent manner following 70% hepatectomy or sham laparotomy, and hepatic tissue levels of MIP-2 and ENA-78 were measured using an ELISA. ENA-78 and MIP-2 were significantly elevated following 70% hepatectomy as compared with sham-operated control animals. Rats undergoing 70% hepatectomy were then treated with neutralizing anti-ENA-78 serum, anti-MIP-2 serum, or preimmune control serum, and liver regeneration was evaluated. These experiments demonstrated that neutralization of ENA-78 or MIP-2 slowed the rate of liver regeneration. These data suggest that the CXC chemokines may be important agents for the induction of hepatocyte proliferation and may be important molecules in vivo in the setting of liver injury, repair, and regeneration.

ISSN:1073-2322    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

ABSTRACTThis study tested the hypothesis that tissue factor pathway inhibitor (TFPI) would improve mortality and morbidity evoked by peritonitis-induced bacteremia in pigs. Secondarily, it sought to determine if TFPI treatment would attenuate cardiodynamic abnormalities produced by this septic model. 32 pigs were chronically instrumented with intracardiac transducers to measure left ventricular pressure and diameter, pulmonary and aortic pressures, and cardiac output. At least 5 days after surgery to implant transducers, basal cardiovascular readings and blood samples were obtained. Using a randomized, blinded study design, either purified, reconstituted TFPI (1 mg/kg bolus, 10 mg/kg/min for 48 h), placebo (arginine buffer), or saline was administered to pigs immediately after Escherichia coli 0111.B4 (3.0–11 ± 109colony-forming U/kg)-laden fibrin clots were implanted intraperitoneally, producing peritonitis and bacteremia. Pigs did not receive antibiotics or supportive therapy. No significant differences in primary or secondary endpoints were noted between the arginine and saline groups, so these data were combined into a control group (N = 20). 5 of 12 TFPI pigs survived (42%), while 5 of 20 control pigs survived (25%); this difference was not significant (p = .714, Fisher's exact test). TFPI treatment augmented cardiac output in surviving pigs, but did not affect any other cardiovascular performance variable (heart rate, % diameter shortening, or systemic and pulmonary vascular resistance). In controls, peritonitis induced rapid increase in plasma tumor necrosis factor-± (428 ± 771 to 5,933 ± 559 pg/mL at 2 h) and interleukin-8 (180 ± 153 to 1,393 ± 145 pg/mL at 2 h). TFPI treatment significantly attenuated cytokine responses to sepsis, reducing peak tumor necrosis factor-± to 2,103 ± 813 pg/mL and reducing peak interleukin-8 levels to 534 ± 211 pg/mL at 2 h (p < .05, Tukey test, two-way ANOVA). In conclusion, TFPI treatment attenuated important mediator components of the inflammatory response but did not provide significant survival benefit.

ISSN:1073-2322    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

ABSTRACTNeutrophil (PMN) influx into the peritoneal cavity in response to bacterial peritonitis is an indispensable aspect of host defense. PMNs also are responsible for the remote organ injury observed after major abdominal infection. The aim of this study was to examine the effect of selectin blockade on PMN migration into the peritoneum and on PMN sequestration in the lungs, early in the course of peritonitis. Cecal ligation and puncture (CLP) was performed on P-selectin-deficient (P-def) mice and their genetic controls (C57). Both groups were treated with anti-E-selectin antibody, anti-L-selectin, or isotypic control immunoglobulin G at the time of CLP. 6 h after CLP, mice were sacrificed. Peritoneal PMN migration decreased in P-def mice compared with C57 controls after CLP. Blockade of E- or L-selectin alone in controls did not alter peritoneal PMN influx or circulating PMNs after CLP. In the P-def mice, treatment with anti-E-antibody or anti-L-antibody nearly eliminated PMN influx into the peritoneum. In contrast, circulating PMNs markedly increased after CLP in P-def mice when compared with baseline values. Lung myeloperoxidase increased in all groups of mice following CLP. Blockade of P-selectin with anti-P-selectin antibody elicited a response similar to that observed in the P-def mice. In conclusion, P-selectin mediates PMN influx into the peritoneal cavity, while E- and L-selectins do not appear to play any significant role in the 6 h time period following CLP. Lung PMN sequestration, after CLP, occurred independent of P-, E-, or L-selectin expression. Blockade of P-selectin during peritonitis appears to be potentially deleterious by preventing early PMN influx into the compartment containing the septic focus.

ISSN:1073-2322    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

ABSTRACTIt is well recognized that bum trauma induces an inflammatory cascade and the release of cytokines including tumor necrosis factor (TNF)-±. The negative inotropic effects of TNF-± on the heart are well recognized, but the cellular mechanisms remain unclear. To examine one aspect of cellular function, we exposed cardiac myocytes isolated from NZW rabbits (collagenase digestion) to either TNF-± (200, 400, or 1000 U/mL) or sham or burn plasma (10% by volume) for 3 to 4 h and measured calcium transient ratios in the isolated, contracting myocytes using the fluorescent indicator Fura-2-acetoxymethyl (1.2 ±M); myocytes treated with media alone served as controls. Cells were placed in a perfusion chamber on the stage of an inverted Nikon microscope and superfused with buffer at 37±C and stimulated at 1 Hz. A Tracor Northern Fluoroplex 1000 microspectrofluorometer and camera system, set to provide excitation of 340 and 380 nm with emission at 450–580 nm, was used to measure Ca2+transients during systole-diastole. [Ca2+]iwas reported as a fluorescence ratio (F340/F380) to minimize effects of different cell thickness and motion artifacts. After recording diastolic/systolic [Ca2+]i, cells were stimulated with isoproterenol, and [Ca2+]i, was again measured. TNF-± produced diastolic and systolic [Ca2+]i, values (1.067 ± .023/1.301 ± .017) that were similar to values seen after myocyte exposure to burn plasma (1.099 ± .024/1.307 ± .028) and significantly greater than values measured in controls (.857 ± .017/1.077 ± .015, p < .05). Our data confirm that burn trauma and TNF-± alter calcium handling by cardiomyocytes. The possible contribution of altered intracellular calcium dynamics to cardiac contractile abnormalities after burn trauma and TNF-± administration warrants further study.

ISSN:1073-2322    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

ABSTRACTEffects of growth hormone (GH) and insulin-like growth factor (IGF)-I on bactericidal capacity of human polymorphonuclear neutrophils (PMNs) were investigated. Venous blood was collected from healthy volunteers. In Experiment 1, PMNs were isolated, incubated with GH or IGF-I, and cocultured with Escherichia coli. E. coli-killing capacity, viability, and CD11b and CD16 expressions of PMNs were then assessed. Both GH and IGF-I enhanced E. coli killing by PMNs. GH preserved PMN viability during E coli killing, whereas IGF-I enhanced PMN CD11b expression before coculture with E. coli. In Experiment 2, whole blood was washed and incubated with GH or IGF-I. PMNs in washed whole blood were then analyzed for phorbol myristate acetate (PMA)-stimulated CD11b, CD35, and CD16 expressions and production of reactive oxygen intermediates (ROI), as well as phagocytosis with/without anti-CD11b antibody. IGF-I enhanced PMN expressions of CD11b and CD35, but not CD16, stimulated with PMA. Both hormones enhanced phagocytosis, which was abrogated by anti-CD11 b antibody, and intracellular ROI production by PMNs. These results indicate that both GH and IGF-I augment human PMN bactericidal capacity, via increased phagocytosis and intracellular ROI production. Preservation of PMN viability by GH and enhanced complement receptor expression by IGF-I may also be associated with augmented PMN bactericidal capacity. Although PMN activation has potentially harmful aspects, these results encourage additional studies to confirm the clinical relevance of exogenous GH or IGF-I for the prevention or management of septic complications in perioperative or critically ill patients especially with low circulating GH and/or IGF-I levels.

ISSN:1073-2322    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

ABSTRACTThe use of end-systolic elastance as a parameter of left ventricular contractility is based on a theory put forward by Sagawa (1) and is limited by an assumed linearity of the model for a time varying compliance. A major problem is the contractility-dependent curvilinearity of the end-systolic pressure-volume relationship (ESPVR), which may result in intercept volumes that are below a passive unstretched volume. Based on the experimental data of Burkhoff et al. (2), we demonstrate the reasons for the lack of correlation of the slope (k) of the end-systolic pressure (Pes)-volume (Ves) relationship with ventricular contractility. A parabolic relation, Pes= a ± Ves2+ b ± Ves+ c, was used for approximation of the ESPVRs, as proposed by Burkhoff et al., and the slope (k = 2 ± a ± Ves+ b), together with the volume axis intercepts (Vo), calculated for the tangents for all Pes/Vespoints of the ESPVRs. The results demonstrate the volume range dependence of the slope and Voof linear regression lines. However, intercepts of the ESPVRs tangents with a midrange constant pressure line (e.g., 80 mmHg or 100 mmHg) justify the use of the shift of the end-systolic pressure-volume relationship as a parameter of left ventricular contractility. This method appears to be valid over a much wider range of end-systolic volumes than is the use of the slope alone.

ISSN:1073-2322    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

ABSTRACTGut mucosal hypoperfusion plays a major role in the pathogenesis of ongoing sepsis and multiple organ dysfunction syndrome. Traditionally, therapy included increasing systemic flow, thus secondarily augmenting blood flow to the gut. Direct manipulation of the gut mucosal microcirculation avoiding systemic effects, i.e., selective gut microcirculatory control (SGMC), has not been tested with a clinically available vasodilating drug. We hypothesized that a topically applied vasoactive drug would affect gut mucosal microcirculation without systemic effects. Twelve Sprague-Dawley rats were randomly assigned to cecal ligation and perforation (CLP), or sham (SC) laparotomy. Twenty-four hours after surgery, mucosal arterioles of a 3–4 cm exteriorized ileal segment were studied using intravital microscopy while suffused with saline followed by sodium nitroprusside (SNP, 100 ±g/mL, 3.4 mM). SNP normalized (to SC saline values, 14.5 ± .6 ±m) the CLP arteriolar diameters, from 11 ± 6 to 14.6 ± .3 ±m (p < .05), while mean arterial pressure (MAP) was stable. Flowmotion patterns were also normalized by SNP, and intercapillary areas (i.e., diffusion distance) were decreased. We conclude that SNP exerted beneficial effects on gut mucosal microcirculation without affecting MAP; therefore, SGMC may be a novel way to affect the course of sepsis.

ISSN:1073-2322    

出版商:OVID    

年代:1998

数据来源: OVID