Effects of dopexamine on the intestinal microvascular blood flow and leukocyte activation in a sepsis model in rats.

INTRODUCTION: The administration of dopexamine may constitute a therapeutical option to improve hepatosplanchnic perfusion in sepsis. In order to verify this hypothesis, we administered dopexamine in an experimental sepsis model in rats. METHODS: This prospective, randomized, controlled laboratory study was conducted in 42 Wistar rats. The animals were divided into 3 groups. Group 1 (CON group) served as control group. The Animals of groups 2 (LPS Group) and 3 received an endotoxin infusion (20 mg/kgfor 15 min). In addition, in group 3 (DPX group) dopexamine was administered 0.5 microg/kg/minover 4 hours. One half of the animals of each group underwent studies of intestinal microvascular blood flow (IMBF) using laser Doppler fluxmetry. In the other half an intravital microscopic evaluation of the leukocyte endothelium cell interaction in the intestinal microcirculation was performed. Functional capillary denstity (FCD) in the intestinal mucosaand the circular as well as the longitudinal muscle layer was estimated. RESULTS: One hour after endotoxin challenge IMBF decreased significantly in the untreated LPS group to 51% compared to baseline (p<0.05). In DPX treated endotoxin animals we found significantly higher values at the level of CON group. The after endotoxin challenge impaired FCD was improved by dopexamine in the longitudinal (DPX + 33% vs. LPS; p <0.05) and in the circular muscle layer (DPX + 48% vs. LPS; p < 0.05) as a result of dopexamine administration. The administration of dopexamine reduced the count of firmly adherent leukocytes when compared to the untreated LPS group (-31%, p<0.05). TNF-alpha plasma levels were reduced by dopexamine infusion (LPS group 3637 +/- 553 pg/mL; DPXgroup 1933 +/- 201 pg/mL) one hour after endotoxin challenge. CONCLUSIONS: The administration of dopexamine improved IMBF and FCD as parameters of intestinal microcirculation and reduced leukocyte activation as a parameter of inflammation in experimental sepsis.

Effects of coagulation factor XIII on intestinal functional capillary density, leukocyte adherence and mesenteric plasma extravasation in experimental endotoxemia.

INTRODUCTION: The objective of this study was to determine the effects of the administration of the coagulation factor XIII (F XIII) on intestinal functional capillary density, leukocyte adherence and mesenteric plasma extravasation during experimental endotoxemia. METHODS: In a prospective, randomized, controlled animal study 42 male Wistar rats were divided into three groups. Group 1 served as the control group. Groups 2 (lipopolysaccharide (LPS) group) and 3 (F XIII group) received endotoxin infusions (2.5 mg/kg/h for 2 hours). In group 3, 50 U/kg body weight F XIII was continuously administered during the first 30 minutes of endotoxemia. F XIII levels were measured in all animals. One half of the animals of each group were studied for intestinal functional capillary density (FCD) and leukocyte adherence on venular endothelium by intravital fluorescence microscopy (IVM). In the other half of each group, mesenteric plasma extravasation (FITC-albumin) was determined by IVM. RESULTS: The F XIII level was significantly increased in the F XIII treatment group. In the LPS group, endotoxemia led to a significant reduction of mucosal FCD (-18.5%; p < 0.01 versus control group). F XIII administration in the F XIII group attenuated the decrease in mucosal FCD (-3.7% compared to control; p < 0.05 versus LPS group). During endotoxemia, a significant increase of leukocyte adherence at the endothelium could be noted in the LPS group compared to the control group. Leukocyte adherence at the endothelium and plasma extravasation in the F XIII group did not differ significantly from the LPS group. CONCLUSION: Factor XIII protected mucosal capillary perfusion against endotoxin-induced impairment in an experimental sepsis model in rats, whereas leukocyte adherence and plasma extravasation remained unchanged.

Electroencephalographic mapping during routine clinical practice: cortical arousal during tracheal intubation?

We used quantitative analysis of the electroencephalogram (EEG) in 42 patients to assess the effect of tracheal intubation after induction of anesthesia with etomidate and sufentanil using standard clinical practice. The EEG was recorded from eight bipolar electrode derivations and Z-transformed relative to age expected normative data for relative power in the delta, theta, alpha, and beta frequency bands. Tracheal intubation resulted in classical cortical arousal, as indicated by acceleration of the EEG frequencies. Significant effects were seen in all frequency bands, most pronounced in the alpha frequency band, with the largest increase bilaterally in the fronto-temporal regions (F-values: Delta - 9.592, P < 0.001; theta - 1.691, P < 0.001; alpha - 18.439, P < 0.001; beta - 4.504, P < 0.001). Changes in alpha and delta power during induction of anesthesia were correlated with the dose of etomidate (P < 0.05). Changes in alpha after tracheal intubation were correlated at the parietooccipital brain regions to the dose of sufentanil (P < 0.05). Individual titration of the dose of etomidate and sufentanil, as during routine clinical practice, is not sufficient to block the strong noxious stimulation of tracheal intubation and results in cortical arousal. The clinical impact of this cortical wake-up phenomenon is undetermined.

Postoperative analgesia after major spine surgery: patient-controlled epidural analgesia versus patient-controlled intravenous analgesia.

BACKGROUND: Spinal fusion surgery causes severe postoperative pain, hampering reconvalescense. We investigated the efficacy of patient-controlled epidural analgesia (PCEA) in a prospective, double-blind, randomized, controlled comparison with patient-controlled IV analgesia (PCIA). METHODS: After lumbar anterior-posterior fusion receiving an epidural catheter intraoperatively, 72 patients were given either PCEA (ropivacaine 0.125% and sufentanil 1.0 microg/mL at 14 mL/h; bolus: 5 mL; lockout time: 15 min) and IV placebo or PCIA (morphine 2.0 mg/mL; bolus: 3 mg; lockout time: 15 min) and epidural placebo. Pain levels (visual analog scale 0-10), functional capabilities (turning in bed, standing, and walking), analgesic consumption, and side effects were evaluated until 72 h after surgery. RESULTS: Fourteen patients were excluded by predetermined criteria, leaving 58 patients for data analysis. Pain levels at rest and during mobilization were significantly lower in the PCEA when compared with that in the PCIA group throughout the study period (P < 0.0001 in all cases). Time until able to turn in bed was achieved earlier in the PCEA group (P < 0.05). Patients in the PCEA group were significantly more satisfied with pain therapy (P < 0.01). CONCLUSION: We conclude that PCEA with ropivacaine and sufentanil, using intraoperatively placed epidural catheters, provides superior analgesia and higher patient satisfaction when compared with PCIA after spinal fusion surgery.

Xenon prevents cellular damage in differentiated PC-12 cells exposed to hypoxia.

BACKGROUND: The neuroprotective effect of xenon has been demonstrated for glutamatergic neurons. In the present study it is investigated if dopaminergic neurons, i.e. nerve-growth-factor differentiated PC-12 cells, are protected as well against hypoxia-induced cell damage in the presence of xenon. RESULTS: Pheochromocytoma cells differentiated by addition of nerve growth factor were placed in a N2-saturated atmosphere, a treatment that induced release of dopamine, reaching a maximum after 30 min. By determining extracellular lactate dehydrogenase concentration as marker for concomitant cellular damage, a substantial increase of enzymatic activity was found for N2-treated cells. Replacement of N2 by xenon in such a hypoxic atmosphere resulted in complete protection against cellular damage and prevention of hypoxia-induced dopamine release. Intracellular buffering of Ca2+ using the Ca-chelator 1, 2-bis(2-Aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakis(acetoxymethyl) ester (BAPTA) reduced the neuroprotective effect of xenon indicating the essential participation of intracellular Ca2+-ions in the process of xenon-induced neuroprotection. CONCLUSIONS: The results presented demonstrate the outstanding property of xenon to protect neuron-like cells in a hypoxic situation.

Renal replacement therapy with high-cutoff hemofilters: Impact of convection and diffusion on cytokine clearances and protein status.

BACKGROUND: High-cutoff hemofilters are characterized by an increased effective pore size designed to facilitate the elimination of inflammatory mediators in sepsis. This study compares diffusive versus convective high-cutoff renal replacement therapy (RRT) in terms of cytokine clearance rates and effects on plasma protein levels. METHODS: Twenty-four patients with sepsis-induced acute renal failure were studied. A polyflux hemofilter with a cutoff point of approximately 60 kd was used for RRT. Patients were randomly allocated to either continuous venovenous hemofiltration (CVVH) with an ultrafiltration rate of 1 L/h (group 1) or 2.5 L/h (group 2) or continuous venovenous hemodialysis (CVVHD) with a dialysate flow rate of 1 L/h (group 3) or 2.5 L/h (group 4). Interleukin-1 (IL-1) receptor antagonist (IL-1ra), IL-1beta, IL-6, tumor necrosis factor-alpha (TNF-alpha), and plasma proteins were measured daily. RESULTS: CVVH achieved significantly greater IL-1ra clearance compared with CVVHD (P = 0.0003). No difference was found for IL-6 (P = 0.935). Increasing ultrafiltration volume or dialysate flow led to a highly significant increase in IL-1ra and IL-6 clearance rates (P < 0.00001). Peak clearances were 46 mL/min for IL-1ra and 51 mL/min for IL-6. TNF-alpha clearance was poor for both RRT modalities. A significant decline in plasma IL-1ra and IL-6 clearance was observed in patients with high baseline levels. Protein and albumin losses were greatest during the 2.5-L/h hemofiltration mode. CONCLUSION: High-cutoff RRT is a novel strategy to clear cytokines more effectively. Convection has an advantage over diffusion in the clearance capacity of IL-1ra, but is associated with greater plasma protein losses.

Uncoupling protein 2 (UCP2) lowers alcohol sensitivity and pain threshold.

Abuse of ethanol is a major risk factor in medicine, in part because of its widespread effect on the activity of the central nervous system, including behavior, pain, and temperature sensation. Uncoupling protein 2 (UCP2) is a mitochondrial protonophore that regulates cellular energy homeostasis. Its expression in mitochondria of axons and axon terminals of basal forebrain areas suggests that UCP2 may be involved in the regulation of complex neuronal responses to ethanol. We employed a paradigm in which acute exposure to ethanol induces tolerance and altered pain and temperature sensation. In UCP2 overexpressing mice, sensitivity to ethanol was decreased compared to that of wild-type animals, while UCP2 knockouts had increased ethanol sensitivity. In addition, UCP2 expression was inversely correlated with the impairment of pain and temperature sensation induced by ethanol. Taken together, these results indicate that UCP2, a mitochondrial uncoupling protein previously associated with peripheral energy expenditure, is involved in the mediation of acute ethanol exposure on the central nervous system. Enhancement of UCP2 activation after acute alcohol consumption might decrease the time of recovery from intoxication, whereas UCP2 inhibition might decrease the tolerance to ethanol.

Bioactive oxidized lipids in the plasma of cardiac surgical intensive care patients.

Critical illness is associated with increased oxidative stress that may give rise to the formation of lipid hydroperoxides (LOOH) and various secondary degradation products such as fragmented phosphatidylcholine (FPC) and lipids related to the platelet-activating factor (PAF). Because some oxidized phospholipids are potent proinflammatory agents, we measured the concentration of LOOH, FPC, and PAF-like activity in blood plasma of 36 patients who had undergone cardiac surgery and developed postoperative complications associated with systemic inflammatory response syndrome (SIRS) or multiple organ failure (MOF). These patients were compared to two control groups, namely preoperative patients scheduled for cardiac surgery (n = 13), and postoperative patients without complications (n = 19). Postoperative patents had higher concentrations of LOOH and lower concentrations of FPC than preoperative patients (P < 0.01). However, SIRS and MOF had no significant effect on the concentration of oxidatively modified lipids. This is despite the fact that MOF patients showed evidence of increased lipid peroxidation (7-fold higher ratio of alpha-tocoquinone/alpha-tocopherol compared to control). LOOH correlated positively with the white blood cell count. Postoperative patients had 4-fold higher plasma activities of phospholipase A2 and this activity was further increased in patients with SIRS (P < 0.04). Phospholipase A2 activity correlated negatively with the concentration of FPC. The data suggest that oxidatively modified lipids do not accumulate in patients with SIRS and MOF, perhaps because enhanced peroxidation of lipids is offset by enhanced lipolytic activity.

Alcohol withdrawal severity is decreased by symptom-orientated adjusted bolus therapy in the ICU.

OBJECTIVE: To examine the effect of bolus vs. continuous infusion adjustment on severity and duration of alcohol withdrawal syndrome (AWS), the medication requirements for AWS treatment, and the effect on ICU stay in surgical intensive care unit (ICU) patients. DESIGN AND SETTING: Prospective randomized, double-blind controlled trial in a surgical ICU. PATIENTS: 44 patients who developed AWS after admission to the ICU. INTERVENTIONS: Patients were randomized to either (a). a continuous infusion course of intravenous flunitrazepam (agitation), intravenous clonidine (sympathetic hyperactivity), and intravenous haloperidol (productive psychotic symptoms) if needed (infusion-titrated group), or (b). the same medication (flunitrazepam, clonidine, or haloperidol) bolus adjusted in response to the development of the signs and symptoms of AWS (bolus-titrated group). MEASUREMENTS AND RESULTS: The administration of "as-needed" medication was determined using a validated measure of the severity of AWS (Clinical Institute of Withdrawal Assessment). Although the severity of AWS did not differ between groups initially, it significantly worsened over time in the infusion-titrated group. This required a higher amount of flunitrazepam, clonidine, and haloperidol. ICU treatment was significantly shorter in the bolus-titrated group (median difference 6 days) due to a lower incidence of pneumonia (26% vs. 43%). CONCLUSIONS: We conclude that symptom-orientated bolus-titrated therapy decreases the severity and duration of AWS and of medication requirements, with clinically relevant benefits such as fewer days of ventilation, lower incidence of pneumonia, and shorter ICU stay.

Antibiotic-mediated release of tumour necrosis factor alpha and norharman in patients with hospital-acquired pneumonia and septic encephalopathy.

OBJECTIVE: To investigate antibiotic-mediated release of tumour necrosis factor (TNF)-alpha and norharman in patients with hospital-acquired pneumonia with and without additional septic encephalopathy. DESIGN: Prospective observational study with a retrospective post hoc analysis. SETTING: Surgical intensive care unit (ICU) at a university hospital. PATIENTS: Thirty-seven patients were consecutively included (9 patients with hospital-acquired pneumonia, 11 patients with hospital-acquired pneumonia and septic encephalopathy, 17 control patients) in the study. Pneumonia was defined according to the criteria of the American Thoracic Society. INTERVENTIONS: Patients received cephalosporins for antibiotic treatment of hospital-acquired pneumonia. Blood samples were taken before, immediately after and 4 h after application of cephalosporins. MEASUREMENTS AND RESULTS: Of the pneumonia patients, 55% developed septic encephalopathy. ICU stay, complications and mortality were significantly increased. An increased release of TNF-alpha was immediately seen in all pneumonia patients after antibiotics compared to controls, whereas the level did not differ between patients with and without septic encephalopathy. Norharman was significantly increased in pneumonia patients 4 h after antibiotic treatment, in tendency more enhanced in the pneumonia patients without encephalopathy. CONCLUSIONS: Patients with hospital-acquired pneumonia and septic encephalopathy had a significantly longer ICU stay with higher mortality rate compared to patients with hospital-acquired pneumonia alone. Antibiotic-mediated TNF-alpha release may induce the kynurenine pathway. TNF-alpha activates indolamine-2,3-dioxygenase with neurotoxic quinolinic acid as the end product. Norharman seems to counteract this mechanism and seems to play a role in neuroprotection. The worse outcome of patients with encephalopathy expresses the need to investigate protective factors and mechanisms.

Blood alcohol concentration for monitoring ethanol treatment to prevent alcohol withdrawal in the intensive care unit.

OBJECTIVE: Alcohol withdrawal syndrome (AWS) is a serious complication during postoperative treatment in chronic alcoholics. Despite prophylactic treatment, AWS occurs in at least 25% of these patients after elective surgery. An established protocol for the prevention of AWS is ethanol administration. The aim of this study was to evaluate possible differences in ethanol dose and levels between successfully treated patients and those who developed AWS. DESIGN: Prospective, observational study with retrospective post hoc analysis. SETTING: Intensive care unit (ICU). PATIENTS: Thirty-two alcohol-dependent patients undergoing elective or emergency surgery after trauma with postoperative admission to ICU. INTERVENTIONS: Continuous postoperative i.v. ethanol substitution. MEASUREMENTS AND RESULTS: Despite treatment, 13 patients developed AWS (failure group) and therapy was successful in the other 19 patients (success group). Major complications occurred more frequently in the failure group. The total dose of ethanol treatment and ethanol levels did not differ between the groups. Ethanol levels were determined in whole arterial blood (aBAC) and simultaneously taken in venous blood (vBAC), urine (UAC) and exhaled air (EAC). The following bias and precision, compared with aBAC, were found: vBAC less than UAC less than EAC. CONCLUSIONS: There is a high failure rate for i.v. ethanol prophylaxis. None of the methods to determine alcohol concentration were sufficient to monitor suitable ethanol treatment. It therefore seems to be more useful to titrate the individual dose for each patient by closer monitoring of the clinical status, adding additional therapy to counteract AWS if higher ethanol doses are required.

Effects of C1 esterase inhibitor administration on intestinal functional capillary density, leukocyte adherence and mesenteric plasma extravasation during experimental endotoxemia.

OBJECTIVE: To determine the effects of C1 esterase inhibitor (C1-INH) administration on intestinal functional capillary density, leukocyte adherence, and mesenteric plasma extravasation during experimental endotoxemia. DESIGN AND SETTING: Prospective, randomized, controlled animal study in the experimental laboratory of a university. SUBJECTS: 42 male Wistar rats. INTERVENTIONS: The animals were divided into three groups. One half of the animals of each group underwent studies of intestinal functional capillary density and leukocyte adherence on venular endothelium by intravital fluorescence microscopy. In the other half of the animals mesenteric plasma extravasation (FITC albumin) was determined by intravital fluorescence microscopy. Treatment groups received endotoxin infusion of 2.5 mg/kg per hour (group 2 and 3) and 100 U/kg b.w. C1-INH (group 3) during the 2 h of endotoxemia. MEASUREMENTS AND RESULTS: Endotoxemia resulted in a significant decrease in mucosal functional capillary density (18.5% vs. controls), which was reduced by C1-INH administration (9.5%). Treatment with C1-INH also significantly attenuated intestinal leukocyte adherence in submucosal venules (35% vs. endotoxin group) and mesenteric plasma extravasation (44% vs. endotoxin group). CONCLUSIONS: C1-INH administration diminishes endotoxin-induced changes in the intestinal microcirculation during experimental endotoxemia.

Intermittent high permeability hemofiltration in septic patients with acute renal failure.

OBJECTIVE: High permeability hemofiltration (HP-HF) is a new renal replacement modality designed to facilitate the elimination of cytokines in sepsis. Clinical safety data on this new procedure is still lacking. This study investigates the effects of HP-HF on the protein and coagulation status as well as on cardiovascular hemodynamics in patients with septic shock. In addition, the clearance capacity for interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) is analyzed. DESIGN: Prospective, single-center pilot trial. SETTING: University hospital. PATIENTS: Sixteen patients with multiple organ failure (MOF) induced by septic shock were studied. INTERVENTION: Patients were treated by intermittent high permeability hemofiltration (iHP-HF; nominal cut-off point: 60 kilodaltons). Intermittent HP-HF was performed over 5 days for 12 h per day and alternated with conventional hemofiltration. MEASUREMENTS AND RESULTS: Intermittent HP-HF proved to be a safe hemofiltration modality in regard to cardiovascular hemodynamics and its impact on the coagulation status. However, transmembrane protein loss occurred and cumulative 12-h protein loss was 7.60 g (IQR: 6.2-12.0). The filtration capacity for IL-6 was exceptionally high. The IL-6 sieving coefficient approximated 1 throughout the study period. The total plasma IL-6 burden, estimated by area under curve analysis, declined over time ( p<0.001 vs baseline). The TNF-alpha elimination capacity was poor. CONCLUSIONS: High permeability hemofiltration is a new approach in the adjuvant therapy of sepsis that facilitates the elimination of cytokines. HP-HF alternating with conventional hemofiltration is well tolerated. Further studies are needed to analyze whether HP-HF is able to mitigate the course of sepsis.

Recombinant factor VIIa after aortic valve replacement in a patient with osteogenesis imperfecta.

A 26-year-old man with osteogenesis imperfecta and severe aortic regurgitation was scheduled for aortic valve replacement. As previously described by other authors the operation was difficult owing to the friability and weakness of the tissues. Mean blood losses of 153 mL per hour during the first 7 postoperative hours were observed. Despite normal coagulation indicators the bleeding did not stop and recombinant factor VIIa was applied at 40 microg/kg. Bleeding was successfully stopped after this single application.

Prevention of neurotoxicity in hypoxic cortical neurons by the noble gas xenon.

Hypoxia-induced neuronal damage and glutamate release were investigated in a N(2)- or in xenon-atmosphere for embryonic rat cortical neurons; cellular damage and glutamate over-release were observed in N(2)-treated cells whereas xenon protected the cells from the hypoxic insult. The protective effect of xenon was strongly reduced by pre-incubating neurons with the calcium-chelator BAPTA-AM indicating a role for calcium in this process. The results demonstrate (a) the neuroprotective properties of xenon, suggest (b) a relationship between the prevention of neurotransmitter release in a hypoxic situation and neuroprotection and present (c) evidence that such neuroprotection may be based on yet other xenon-dependent mechanisms.

Mild hypothermia after near drowning in twin toddlers.

INTRODUCTION: We report a case of twin toddlers who both suffered near drowning but with different post-trauma treatment and course, and different neurological outcomes. METHODS AND RESULTS: Two twin toddlers (a boy and girl, aged 2 years and 3 months) suffered hypothermic near drowning with protracted cardiac arrest and aspiration. The girl was treated with mild hypothermia for 72 hours and developed acute respiratory dysfunction syndrome and sepsis. She recovered without neurological deficit. The boy's treatment was conducted under normothermia without further complications. He developed an apallic syndrome. CONCLUSION: Although the twin toddlers experienced the same near drowning accident together, the outcomes with respect to neurological status and postinjury complications were completely different. One of the factors that possibly influenced the different postinjury course might have been prolonged mild hypothermia.

N-acetylcysteine decreases lactate signal intensities in liver tissue and improves liver function in septic shock patients, as shown by magnetic resonance spectroscopy: extended case report.

BACKGROUND: N-acetylcysteine (NAC) has been shown to improve splanchnic blood flow in experimental studies. This report evaluates the effects of NAC on liver perfusion and lactate signal intensities in the liver tissue of septic shock patients using proton magnetic resonance imaging and spectroscopy. Furthermore, the monoethylglycinexylidide (MEGX) test was used to investigate hepatic function. METHODS: Five septic shock patients received 150 mg/kg body weight NAC as an intravenous bolus injection over 15 min. Lidocaine was injected both prior to and following NAC administration in order to determine MEGX formation. Measurements (hemodynamics, oxygen transport-related variables, blood samples for lactate, liver-related markers) were performed 1 hour before and 1 hour after NAC injection. In addition to the proton magnetic resonance imaging patients received two proton magnetic resonance spectra, one prior to and one 30 min subsequent to the onset of the NAC infusion at a 1.5 Tesla clinical scanner, for measurement of liver perfusion and liver lactate signal intensity. MAIN FINDINGS: Following NAC infusion, the lactate signal intensity in the liver tissue showed a median decrease of 89% (11-99%), there was a median increase in liver perfusion of 41% (-14 to 559%), and the MEGX serum concentration increased three times (1.52-5.91). CONCLUSIONS: A decrease in the lactate signal intensity in the liver tissue and an increase in the MEGX serum concentration and in liver perfusion might indicate improved liver function as a result of NAC administration. Patients with compromised hepatosplanchnic function, such as patients with septic shock due to peritonitis, may therefore benefit from NAC therapy.

Altered immune parameters in chronic alcoholic patients at the onset of infection and of septic shock.

INTRODUCTION: Chronic alcoholic patients have a threefold to fourfold increased risk for developing a severe infection or septic shock after surgery, which might be due to altered immune response. The aim of this outcome matched study was to investigate proinflammatory and anti-inflammatory immune parameters during the course of infection and subsequent septic shock in chronic alcoholic patients, and to compare these parameters with those in nonalcoholic patients. METHODS: Twenty-eight patients from a cohort of fifty-six with either pneumonia or peritonitis and subsequent septic shock were selected. Fourteen patients were chronic alcoholics whereas fourteen were nonalcoholic patients. Chronic alcoholic patients met criteria (Diagnostic and Statistical Manual of Mental Disorders IV, of the American Psychiatric Association) for alcohol abuse or dependence. Measurements were performed during the onset of infection (within 24 hours after the onset of infection), in early septic shock (within 12 hours after onset of septic shock) and in late septic shock (72 hours after the onset). Blood measurements included proinflammatory and anti-inflammatory cytokines. RESULTS: Chronic alcoholic patients exhibited significantly lower plasma levels of IL-8 (P < 0.010) during the onset of infection than did matched nonalcoholic patients. In early septic shock, chronic alcoholic patients had significantly decreased levels of IL-1beta (P < 0.015), IL-6 (P < 0.016) and IL-8 (P < 0.010). The anti-inflammatory parameters IL-10 and tumour necrosis factor receptors I and II did not differ between alcoholic and nonalcoholic patients. CONCLUSION: At the onset of infection and during early septic shock, chronic alcoholic patients had lower levels of proinflammatory immune parameters than did nonalcoholic patients. Therefore, immunomodulatory therapy administered early may be considered in chronic alcoholic patients at the onset of an infection because of their altered proinflammatory immune response.

Intermittent high-permeability hemofiltration modulates inflammatory response in septic patients with multiorgan failure.

BACKGROUND/AIM: Continuous venovenous hemofiltration with high-permeability hemofilters is a novel approach in the adjuvant therapy of septic patients. High-permeability hemofilters are characterized by an increased pore size which facilitates the filtration of inflammatory mediators. The present study examines whether intermittent high-permeability hemofiltration has an immunomodulatory effect on polymorphonuclear leukocytes and mononuclear cells. METHODS: Twenty-eight septic patients with acute renal failure were randomly allocated to either receive intermittent high-permeability or conventional hemofiltration. Intermittent high-permeability hemofiltration consisted of a daily 12-hour course of high-permeability hemofiltration alternated by conventional hemofiltration. For high-permeability hemofiltration, a newly developed high-flux polyamide membrane (P2SH) with a nominal cutoff point of 60 kD was used. For conventional hemofiltration a high-flux polyamide hemofilter (Polyflux 11S, cutoff point 30 kD) was used. RESULTS: The polymorphonuclear leukocyte phagocytosis activity before starting hemofiltration was almost double the rate of healthy controls in both groups (p < 0.001). The phagocytosis rate decreased significantly during the course of intermittent high-permeability hemofiltration (p < 0.05), whereas the values remained unchanged in the conventional hemofiltration group. Incubation of high-permeability filtrates with blood from healthy donors resulted in a significant induction of phagocytosis (p < 0.001), whereas conventional filtrates had no phagocytosis-stimulating effects. In addition, incubation of healthy-donor mononuclear cells with high-permeability but not conventional filtrates resulted in a significant tumor necrosis factor alpha release (p < 0.001). CONCLUSIONS: Intermittent high-permeability hemofiltration is a novel extracorporeal elimination modality which exhibits immunomodulatory effects on leukocytes, attenuating polymorphonuclear neutrophil phagocytosis. Further studies are necessary to elucidate whether these effects translate in a clinical improvement in patients suffering from sepsis.

Sympathetic modulation of intestinal microvascular blood flow oscillations in experimental endotoxemia.

Impairment of the intestinal microcirculation has been recognized as an important factor in the pathogenesis of endotoxin related sepsis syndrome. We investigated the effects of endotoxemia on the variability of intestinal microvascular blood flow (IMBF) and arterial blood pressure (BP) in a prospective, randomized, controlled animal study. Recordings of IMBF (laser Doppler fluxmetry) and BP were performed before, two and four hours after i.v. injection of either placebo or endotoxin (5 mg/kg b.w. lipopolysaccharide from E. coli, serotype O55:B5). Control experiments were performed with systemic (clonidine) and local intestinal (surgery) sympathectomy. Spectral analysis was performed using the autoregressive approach. Spectral power was determined in two frequency bands (low frequency (LF): 0.27-0.74 Hz; high frequency (HF): 0.76-3.00 Hz). Two hours after endotoxin challenge a significant decrease in IMBF was observed. LF spectral power of IMBF and BP increased significantly in the endotoxin challenged group, while no effects were observed in the placebo group. Four hours after endotoxin administration IMBF decreased further and LF spectral power of IMBF and BP remained elevated. Denervation prevented the decrease in IMBF but did not abolish the LF power increase. Clonidine administration attenuated the IMBF decrease and significantly diminished the increase in LF spectral power of IMBF and BP. We conclude that endotoxemia is associated with increased sympathetic outflow to the systemic vasculature, as indicated by the increase in LF spectral power of arterial blood pressure. The increase in LF variability of IMBF is secondary to the increase in LF spectral power of BP, since it could be attenuated by systemic and not by local intestinal sympathectomy.