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Vele aandoeningen die opname op een icu noodzakelijk maken kunnen worden gecompliceerd door een functionele stoornis in een of meerdere orgaansystemen die niet betrokken zijn bij het primaire ziekteproces. Wanneer een patient op een icu overlijdt is dat meestal niet ten gevolge van de ziekte of aandoening die de indicatie tot opname vormde, maar van deze complicatie. De dood treedt dan in na een min of meer langdurige ziekteperiode waarin het falen van orgaansystemen steeds meer op de voorgrond komt te staan.

To assess the potential role of interleukin-6 (IL-6) in the pathogenesis of dengue virus infection, levels of this cytokine were measured in children with dengue virus infection on admission to the hospital. As presumed surrogate markers of IL-6, C-reactive protein (CRP) and secretory phospholipase A2 (sPLA2) were measured. Three groups were studied: 33 apparently healthy children as negative controls, 11 children with bacterial infections as positive controls, and 186 children with serologically documented dengue virus infection. One-hundred and fifteen patients had dengue fever (DF) and 71 had dengue hemorrhagic fever (DHF). Compared with healthy controls, dengue shock syndrome (DSS) patients had significantly higher levels of IL-6 on admission (P < 0.05), comparable with those in positive controls. Dengue patients with shock had significantly higher levels of IL-6 than normotensive patients (P < 0.001) and higher levels of IL-6 were associated with a higher incidence of ascites. C-reactive protein concentrations in dengue patients and in healthy children were not different, but lower than in children with bacterial infections (P = 0.008). Secretory phospholipase A2 levels were higher in dengue patients than in apparently healthy children (P < or = 0.05) and similar to those in children with bacterial infection. Dengue shock syndrome patients had significantly higher sPLA2 concentrations than normotensive patients (P = 0.02). These data indicate that IL-6 and sPLA2 may have a pathogenetic role only in the most severe forms of dengue virus infection.

OBJECTIVE Arginine is the sole precursor in the generation of the vasodilating agent nitric oxide. Arginine plasma levels are low in situations associated with endotoxemia such as major trauma, sepsis, and experimental obstructive jaundice. The aim of the study was to evaluate hemodynamics at low arginine plasma levels during a low-grade endotoxemia. DESIGN Randomized, placebo-controlled animal laboratory investigation. SUBJECTS Male Wistar rats (n = 29), anesthetized. INTERVENTIONS Rats were randomly assigned to receive (at t = 0 mins) an intravenous infusion of 1.5 mL of 0.9% NaCl (SAL, n = 12) or 1.5 mL of an arginase (3200 IU) solution (ASE, n = 17) over a 20-min period. After the SAL or ASE infusion, rats were randomly assigned to receive an intravenous endotoxin (lipopolysaccharide [LPS], 150 microg/kg in 1.0 mL of 0.9% NaCl; ASE/LPS, n = 10 and SAL/LPS, n = 6) challenge or a control infusion (1.0 mL of 0.9% NaCl; ASE/SAL, n = 7 and SAL/SAL, n = 6) at t = 30 mins. MEASUREMENTS AND MAIN RESULTS Organ blood flow was measured at t = 270 mins, using radiolabeled microspheres. At this time point, arginine plasma levels were lower in the ASE-treated rats (ASE/SAL vs. SAL/SAL and ASE/LPS vs. SAL/LPS, both p < .005, respectively). Cardiac output, mean arterial pressure, and therefore total peripheral resistance were similar for all groups. In the LPS-treated animals (SAL/LPS and ASE/LPS), cardiac output was maintained by a higher heart rate compensating the lower stroke volume. Organ blood flow to the small intestine and splanchnic blood flow was lower in the ASE/LPS-treated rats (both p < .05 when compared with other groups). Total liver blood flow was similar for all groups; the lower splanchnic blood flow was compensated for by a higher hepatic arterial blood flow. CONCLUSION The present study shows that low arginine plasma levels do not influence organ blood flow, whereas, during a low-grade endotoxemia, low arginine plasma levels result in reduced blood flow to the small intestine.

The chemokine interleukin-8 (IL-8) has chemoattractant activity for neutrophils and is able to activate and degranulate these cells. We investigated whether IL-8 may exert these effects in children with dengue virus infection. Circulating levels of IL-8, neutrophilic elastase (a constituent of the azurophilic granula of neutrophils), and lactoferrin, released from specific granula, were measured in 186 children with dengue virus infection, 33 healthy children as negative controls and 11 children with bacterial infections as positive controls. Levels of IL-8 on admission were elevated in 71% of the dengue patients, while the elastase and lactoferrin levels were increased in 68 and 17% of patients, respectively. These levels were significantly higher than in healthy children (P< 0.05) for IL-8 and elastase but not for lactoferrin (by the Wilcoxon-Mann-Whitney [WMW] U test). Similar levels of IL-8 were found in patients with bacterial infections. Levels of IL-8 and elastase in patients with shock were significantly higher than in patients without shock (P= 0.02; WMW), but those of lactoferrin were not. IL-8 correlated with elastase and lactoferrin (r= 0.19 andP= 0.009 versusr= 0.24 andP= 0.001, respectively; two-tailed Spearman rank correlation). Thus, IL-8 levels are increased in most patients with dengue virus infection and correlate with degranulation of neutrophils as well as with some clinical and hemodynamic variables. These findings suggest a role for IL-8 in the pathogenesis of dengue virus infection.

To assess the frequency of hypernatremia in patients who were admitted to an intensive care unit (ICU) and to determine the correlation of hypernatremia with the clinical outcomes, durations of the patients' stays in the ICU, and other clinical variables.Retrospective survey.University teaching hospital.All patients (total, 389) who were admitted to the medical ICU of the department of internal medicine during 1 yr.The database of our hospital's mainframe computer was searched for sodium valuesor = 150 mmol/L that were registered in the year 1995. These data were then matched with the registration numbers of all patients who were admitted to our medical ICU between January 1 and December 31, 1995. In this way, we identified all patients in whom hypernatremia was present at admission or those who developed hypernatremia in the course of their stay in our ICU. The prevalence and duration of hypernatremia (defined as a serum sodium concentration ofor = 150 mmol/L or more) were determined; the correlation of hypernatremia with clinical outcome, duration of ICU stay, Acute Physiology and Chronic Health Evaluation II scores, and other clinical variables were evaluated; and changes in fluid administration in response to hypernatremia and fluid regimens in the period preceding hypernatremia were examined.Of a total of 389 patients who were admitted in 1995, hypernatremia was present at admission in 34 patients (8.9%). The average duration of hypernatremia in these patients was 16.2 (range, 4-56) hrs. A total of 22 patients (5.7%) developed hypernatremia in the course of their stay in the ICU. The average duration of hypernatremia in this group was 34.7 (range, 4-89) hrs. Moderately elevated levels of sodium had been detected in most of these patients (n = 21) in the days before the development of severe hypernatremia; however, adjustments in fluid infusion aimed at preventing the occurrence of hypernatremia were either lacking (n = 7) or inadequate (n = 11). Hospital-acquired hypernatremia vs. hypernatremia present at admission to the ICU was associated with a higher mortality rate (32% vs. 20.3%, respectively; p.01).Despite frequent measurement of sodium levels in patients in the ICU, hypernatremia is a relatively common occurrence. Initial treatment of hypernatremia is often inadequate, and sometimes treatment is delayed. The development of hypernatremia is associated with adverse outcomes for patients developing hypernatremia in the ICU. Hypernatremia could potentially be used as an indicator of quality of care in the medical ICU.

In bile duct ligated rats, arginase (ASE) release from damaged hepatocytes results in low arginine (ARG) levels despite maximal renal ARG production. Plasma ARG levels were restored by reducing gut-derived endotoxemia that lowered circulating ASE activity although maintaining increased renal production. From this it was not clear if the higher renal ARG production was induced by the low grade endotoxemia or the low arginine plasma levels. The separate and combined influence of both factors on ARG metabolism was studied in the rat. Male Wistar rats received either bovine liver ASE, to lower ARG levels, or saline (SAL). Following the ASE or SAL infusion, rats were randomized to receive a low dose endotoxin (LPS) or SAL infusion. In ASE/SAL- and ASE/LPS-treated rats, ARG levels were lower compared with SAL/SAL (p

Activation of the nitric oxide (NO) pathway over that of endothelin in the vessel wall, as judged from circulating endothelin and nitrate-nitrite (NN) levels, may partly account for the hypotension associated with vasodilation, diminished catecholamine sensitiveness and O 2 extraction, and lactic acidemia in human septic shock. In a prospective study, 14 consecutive patients with septic shock and a pulmonary artery catheter in place were included. For 3 days after admission, serial measurements of hemodynamic variables and plasma levels of endothelin and NN were done. The patients had a hyperdynamic circulation. Except for a higher final blood lactate level and more treatment with vasoconstricting catecholamines in nonsurvivors, global hemodynamic and O 2 -related variables did not differ between outcome groups. On the day of admission, circulating endothelin and NN levels were elevated and related to elevated levels of tumor necrosis factor-α and interleukin-6. The levels of endothelin increased in time in nonsurvivors as compared with survivors. The NN levels declined in survivors but not in nonsurvivors. The systemic vascular resistance indices (SVRI), global O 2 extraction ratios, and blood lactate levels directly related to the endothelin levels. SVRI and global O 2 extraction ratios inversely, and the lactate blood levels directly, related to NN levels, and the hemodynamic and metabolic parameters related directly to the ratio between endothelin and NN plasma levels on the days of the study. The vessel wall factors did not relate to the creatinine levels. The results suggest that the hemodynamic and metabolic peripheral abnormalities of human septic shock are mediated in part by cytokine-activated endothelin and NO systems in the vessel wall. They also suggest that increased production rather than diminished renal clearance accounts for elevated levels of NN and endothelin and that the latter are associated with a poor outcome.

Objective: To evaluate the performance of total maximum sequential organ failure assessment (SOFA) score and a derived measure, delta SOFA (total maximum SOFA score minus admission total SOFA) as a descriptor of multiple organ dysfunction/failure in intensive care. Design: Prospective, multicentre and multinational study. Setting: Forty intensive care units (ICUs) from Australia, Europe, North and South America. Patients: Data on 1,449 patients, evaluated at admission and then consecutively every 24 h until ICU discharge (11,417 records) during May 1995. Excluded from data collection were all patients with a length of stay in the ICU less than 2 days following uncomplicated scheduled surgery. Main outcome measure: Survival status at ICU discharge. Interventions: The collection of raw data necessary for the computation of a SOFA score on admission and then every 24 h, and basic demographic and clinical statistics. Measurements and main results: Mean total maximum SOFA score presented a very good correlation to ICU outcome, with mortality rates ranging from 3.2 % in patients without organ failure to 91.3 % in patients with failure of all the six organs analysed. A maximum score was reached 1.1 ± 0.2 days after admission for all the organ systems analysed. The total maximum SOFA score presented an area under the ROC curve of 0.847 (SE 0.012), which was significantly higher than any of its individual components. The cardiovascular score (odds ratio 1.68) was associated with the highest relative contribution to outcome. No independent contribution could be demonstrated for the hepatic score. No significant interactions were found. Principal components analysis demonstrated the existence of a two-factor structure that became clearer when analysis was limited to the presence or absence of organ failure (SOFA score ≥ 3 points) during the ICU stay. The first factor comprises respiratory, cardiovascular and neurological systems and the second coagulation, hepatic and renal systems. Delta SOFA also presented a good correlation to outcome. The area under the receiver operating characteristic (ROC) curve was 0.742 (SE 0.017) for delta SOFA, lower than the total maximum SOFA score or admission total SOFA score. The impact of delta SOFA on prognosis remained significant after correction for admission total SOFA. Conclusions: The results show that total maximum SOFA score and delta SOFA can be used to quantify the degree of dysfunction/failure already present on ICU admission, the degree of dysfunction/failure that appears during the ICU stay and the cumulative insult suffered by the patient. These properties make it a good instrument to be used in the evaluation of organ dysfunction/failure.

Background. The hypothesis that renal failure during septic shock may occur as a result of hypoxia-related cell dysfunction was investigated in two rat models of distributive shock. Methods. Pentobarbitone-anaesthetized rats received either a bolus (1 ml) of living Escherichia coli bacteria (hospital-acquired strain, I x 10 9 CFU/ml; BA-group, n = 7), or a 1-h infusion of endotoxin (E. coli 0127.B8: 8 mg/kg; ET-group, n=7), or saline to serve as time matched controls (C-group, n =7). Results. Urine flow in the BA- and ET-group reached a nadir at 1 h, but thereafter increased and reached values higher than control at 3 h. At this time point, renal oxygen delivery had decreased, in the BA-group mainly due to a fall in arterial oxygen content and in the ET-group to a fall in renal plasma flow (clearance of 131 I-hippurate). However, renal oxygen extraction had significantly increased, by 31% in the BA and by 59% in the ET group, while renal oxygen consumption remained the same. Net tubular sodium reabsorption had decreased by 55% in the BA and by 25% in the ET group, due to a fall in glomerular filtration rate (clearance of creatinine). Hence, an excess oxygen consumption was found which was caused neither by an increased renal glucose release nor by the presence of an increased number of leukocytes stuck in the glomeruli. Renal tubular cells showed normal morphology. An indication that proximal tubular function in the BA and ET group remained largely intact were normal ATP levels, absence of urinary glucose, and a normal fractional excretion of sodium. However, since urine flow had increased in shocked rats at 3 h, water appeared selectively lost. Conclusions. Our data indicate that in rat models of septic shock renal failure is not caused by cortical hypoxia or a shortage of cellular energy supply.

SummaryThe authors sought to evaluate the pathogenetic and prognostic role of a procoagulant and hypofibrinolytic state in the adult respiratory distress syndrome (ARDS). Twenty-two consecutive patients admitted to the intensive care unit (ICU) for respiratory monitoring (n = 2) or mechanical ventilation (n = 20) were studied, of whom 13 had ARDS and 9 were at risk for the syndrome. Plasma levels of thrombin-anti- thrombin III complexes (TAT), the plasmin-α2-antiplasmin complexes (PAP), tissue-type plasminogen activator (tPA) and plasminogen activator inhibitor type 1 (PAI-1) were measured within 48 h after admission, together with respiratory variables allowing computation of the lung injury score (LIS), and pulmonary microvascular permeability [67Gallium-transferrin pulmonary leak index (PLI)], as measures of pulmonary dysfunction. Blood was also sampled 6-hourly until 2 days after admission. The LIS and PLI were higher in ARDS than at risk patients, in the presence of similar systemic morbidity and mortality. TAT complexes were elevated in a minority of patients of both groups, whereas the PAP, tPA and PAI levels were elevated above normal in the majority of ARDS and at risk patients, but groups did not differ. Neither circulating coagulation nor fibrinolysis variables correlated to either LIS or PLI. Furthermore, the course of haemostatic variables did not relate to outcome. These data indicate that systemic activation of coagulation and impaired fibrinolysis do not play a major role in ARDS development and outcome in patients with acute lung injury.

The involvement of C-reactive protein (CRP) in the activation of complement in patients with sepsis was investigated. In 104 patients with infections of varying severity, circulating levels of CRPcomplement complexes, which are specific indicators for CRP-mediated complement activation, were assessed. Complement-CRP complexes were increased in almost all patients and correlated significantly with levels of C3a (r A .59; P o .001) and C-reactive protein (r A .76; P o .001). In addition, they correlated with levels of secretory phospholipase A2 (r A .59; P o .001). Levels of complement-CRP complexes in patients with a pneumococcal type of infection were similar to those in patients with other types of infections. Complement-CRP complexes were significantly higher in patients with shock (P A .01) and in patients who died (P A .03). These results demonstrate that part of the complement activation in patients with sepsis is independent from a direct interaction with microorganisms but rather results from an endogenous mechanism involving CRP. Excessive activation of inflammatory mediators in patients protein (CRP) may be involved: First, in vitro CRP is able to activate the classical complement pathway on binding to an with sepsis may lead to life-threatening complications such as shock and multiple organ failure. One of the mediator systems appropriate ligand [6]; second, we have observed a biphasic activation of complement in a baboon model of septic shock, activated during sepsis is the complement system. Patients with sepsis have decreased plasma levels of complement proteins the later phase coinciding with increases of circulating CRP [7]; and finally, lymphocytes from patients with an IL-2 ‐ induced

Objective : To establish the value of the 67 Gallium (Ga) pulmonary leak index, a marker of increased permeability edema of the lungs, in assessing the severity and course of the adult respiratory distress syndrome (ARDS). Design : Prospective observational study. Setting : Medical intensive care unit of a university hospital. Patients : Seventeen consecutive, mechanically-ventilated ARDS patients. Eleven patients (recovering from ARDS) improved, as defined by the ability to taper the level of positive end-expiratory pressure (PEEP) to 0 cm H 2 O at a median of 7 days after admission. Ten patients survived. Six patients did not recover and died a median of 3.5 days after admission. Interventions : None. Measurements and Main Results : The pulmonary leak index (i.e., upper limit of normal 14.1 x 10 -3 /min) was measured within 72 hrs after admission, and repeated within 48 hrs at the time of recovery in recovering patients. At admission and recovery, respiratory variables were recorded and a lung injury score was calculated. At admission, the pulmonary leak index was increased in each patient to 32.3 (range 15.6 to 52.4) and 28.7 (range 26.0 to 40.8) x 10 -3 /min in recovering and nonrecovering patients, respectively (NS). Groups did not differ with respect to the oxygenation ratio, the level of PEEP, radiographic abnormalities, and the lung injury score. At recovery, the pulmonary leak index in recovering patients had decreased in each patient and had normalized in four patients, averaging 15.2 (range 5.6 to 25.9)x 10 -3 /min, concomitantly with an increased oxygenation ratio, less radiographic abnormalities, and a decreased lung injury score (p

Because of their effects on monocytes, monocyte chemotactic proteins-1 and -2 (MCP-1 and MCP-2) may participate in the pathophysiology of sepsis. We measured circulating MCP-1 and MCP-2 levels in 42 septic patients having positive local or blood cultures. MCP-1 and MCP-2 levels were elevated in 24 (57%) and 25 (59%) of 42 septic patients, respectively, compared with healthy volunteers. Both patients with gram- positive and gram-negative infections had elevated MCP-1 plasma levels (P = .0001) and P < .0001), respectively; Mann-Whitney-U test), whereas patients with gram-positive infection, but not those with gram-negative infection, had increased MCP-2 plasma levels (P= .0182). No relative differences in MCP-1 and MCP-2 plasma levels were observed between several subgroups of patients (sepsis v septic shock; survivors v nonsurvivors), although levels of MCP-1 were the highest in patients with the more severe forms of sepsis, ie, those with shock or a lethal outcome. Serial observations showed that MCP-1 and MCP-2 plasma levels remained elevated for at least 48 hours. MCP-1 correlated weakly with interleukin-8 and MCP-2, the correlations for which were most pronounced in patients with septic shock. MCP-2 correlated with interleukin-8, and surprisingly, with the complement activation product C3a; these correlations further improved when analyzing patients with septic shock or when applying gram-positive infections. Thus, our results not only show increased MCP-1 and MCP-2 levels in patients with sepsis, but also suggest that the synthesis and release of MCP-1 and MCP-2 in sepsis are differently regulated in part.

Objectives: To study the effects of growth hormone administration on insulin-like growth factor I concentration, nitrogen balance, and fuel utilization, and to study its safety in critically ill nonseptic patients. Design: Prospective, randomized, placebo-controlled trial. Setting: Medical intensive care unit of a university hospital. Patients: Eighteen critically ill nonseptic patients were studied for 8 days after admission. Interventions: Growth hormone (0.1 mg/kg/day) or placebo was administered as a continuous intravenous infusion on the second, third, and fourth days after admission. The study period was 8 days. Measurements and Main Results: Plasma hormone concentrations were measured every 6 hrs and average daily values were calculated. The 24-hr urinary nitrogen and 3-methylhistidine excretion were measured. Indirect calorimetry was used to calculate fuel utilization. Insulin-like growth factor I concentrations increased in the treatment group from subnormal to normal values and remained increased despite discontinuation of growth hormone treatment (p=.02). Nitrogen balance differed between the groups upon admission: growth hormone group (3.9±4.1 g/day) vs. controls (13.8±5.4 g/day), but improved with growth hormone. This finding appeared independent of the imbalance between the groups. The 3-methylhistidine excretion was not different between the groups and did not change during growth hormone administration. Free fatty acids and glycerol concentrations increased during growth hormone treatment, but calculated fuel utilization did not change. During growth hormone treatment, insulin concentrations increased, due to the increased administration of insulin necessary for glycemic control. Side effects other than hyperglycemia were not observed. Conclusions: Growth hormone administration in a heterogeneous group of critically ill nonseptic patients resulted in normalization of insulin-like growth factor I levels, even after cessation of growth hormone treatment. Nitrogen balance improved, but this change was transient. Hence, growth hormone affects nitrogen balance, probably partly independent of insulin-like growth factor I

Considerable time and energy has been invested in the conception, modelling and evaluation of sophisticated severity scoring systems for ICU patients. These systems are created to enhance the precise estimation of hospital mortality for large ICU patient populations. Their current low sensitivity precludes their use for predicting out-come for individual ICU patients. However, severity scores can already be valuable for predicting mortality in groups of general ICU patients, and are very useful in the clinical trial setting. Outcome of ICU therapy, however, should incorporate more than mortality. Morbidity, disability and quality of life should also be taken into account; these factors were not taken into consideration in the design of the currently available severity scoring systems. At present, the severity scores have a very limited or no role in clinical decision-making for an individual patient, because they are based on a number of physiological and disease-oriented variables collected during the first 24 h after ICU admission. Future developments and subsequent validation of the dynamic process of clinical, physiological and organ-specific variables could improve the sensitivity and the value of severity scoring. Further collaborative developmental work in this field should be encouraged and supported across Europe and North America.

A monoclonal antibody (MAb) raised against Salmonella minnesota R595 and specific for alpha-3-deoxy-D-manno-octulosonic acid (alpha-Kdo) of the inner core was tested for binding to lipopolysaccharides (LPS) of Klebsiella pneumoniae. The MAb was tested in several assay systems (enzyme-linked immunosorbent assay, passive hemolysis, and inhibition of passive hemolysis) with a large panel (n = 23) of K. pneumoniae LPS representing all nine currently known O serotypes. MAb 20 showed reactivity with almost all O serotypes of K. pneumoniae LPS, and this reactivity could be inhibited by synthetic Kdo. This suggests an epitope in the cores of these Klebsiella LPS much like that in the inner core of LPS of S. minnesota. Large differences in reactivity between LPS of different strains belonging to the same O serotype were observed. After sodium dodecyl sulfate-polyacrylamide gel electrophoresis of LPS followed by immunoblotting, reactivity of MAb 20 was observed only with the fast-moving fraction possibly representing the nonsubstituted core. No binding was seen with the high-molecular-weight fraction that contained core material substituted with several units of O-antigen building blocks. The chemical basis for these differences in reactivity remains to be established. As far as we know, this is the first report containing comprehensive immunochemical data on the LPS core of K. pneumoniae.

The objective of this study was to evaluate the safety and the effect of recombinant exogenous growth hormone (GH) on nitrogen production in patients with severe sepsis. It was designed as a prospective, randomized, placebo-controlled trial, and performed in the medical intensive care unit of a university hospital. Twenty patients admitted with septic shock and receiving standard parenteral nutrition served as subjects. Treatment consisted of GH 0.1 mg/kg/day or placebo administered as continuous intravenous infusion on the second, third, and fourth days after admission. The study period was eight days. During GH administration, nitrogen production decreased significantly in the GH group and increased in controls (p < 0.01). Nitrogen balance became slightly positive in the GH group during treatment: 1.2 +/- 6.4 versus controls -3.7 +/- 3.8 g/day (day 3) (p < 0.05). Within 24 hours after cessation of treatment, differences between GH and controls disappeared. 3-Methylhistidine excretion as a measure of absolute muscle breakdown declined during the study period, but did not differ between groups. The levels of insulin, insulinlike growth factor 1, glycerol, free fatty acids, and beta-hydroxybutyrate increased during treatment. Despite continuous intravenous administration, GH levels gradually declined during the 3 treatment days, indicating increased metabolic clearance. Side effects other than insulin resistance were not observed. Growth hormone administration reduces nitrogen production and improves nitrogen balance in patients with severe sepsis. These effects are not sustained after cessation of treatment.

In order to assess if an oxidant/antioxidant imbalance is involved in human septic shock and its outcome, we measured plasma levels of the lipid peroxides malondialdehyde--as thiobarbituric acid reactive substance--conjugated dienes and fluorescent products, together with the antioxidants alpha-tocopherol, glutathione peroxidase activity and selenium in 12 patients with septic shock and compared them with values of normal controls. At first measurements, malondialdehyde (median 3.9 mumol/l; range 2-38.8) and fluorescent products (median 21.2%; range 9.4-134) were elevated (p less than 0.05), alpha-tocopherol (median 15 mumol/l; range 7-25) and selenium (median 0.76 micrograms/ml; range 0.49-1.09) were depressed (p less than 0.05). Conjugated dienes and glutathione peroxidase activity were in the normal range. In non-survivors (n = 5) initial levels of malondialdehyde and fluorescent products (median 11 versus 3.1 mumol/l; 74 versus 13% respectively) were higher than in survivors (p less than 0.05) and initial selenium levels were lower (median 0.58 versus 0.92 micrograms/l; p less than 0.05). These results are consistent with the concept that an oxidant/antioxidant imbalance--as indicated by elevated plasma lipid peroxides and depressed antioxidants--is involved in human septic shock and a fatal outcome.

SummaryPatients treated with high doses of interleukin-2 (IL-2) because of cancer, develop hemodynamic and vasopermeability changes, that resemble those observed in sepsis. These patients thus provide a unique opportunity to study the early events in the development of septic shock. We analysed the changes that occurred in the contact system of coagulation in plasma from 4 patients, who together received seven 12-day cycles of high doses of IL-2. Levels of factor XII and prekallikrein during the cycles progressively fell to 50 and 30% of their initial levels, respectively, whereas significant increases in plasma factor XIIa-and kallikrein-C1-inhibitor complexes were not observed (in 3 out of 211 samples slightly increased levels of both complexes were found). The reductions in factor XII and prekallikrein were only in part due to protein leakage, since levels were still significantly lower, i. e., 80 and 50%, respectively, when corrected for albumin decreases. Levels of high molecular weight kininogen (HMWK) also decreased during IL-2 therapy, however, this decrease paralleled that of albumin. SDS-PAGE analysis of plasma HMWK did not reveal increased cleavage of this protein. The reduction of factor XII and prekallikrein, corrected for protein leakage, significantly correlated with albumin levels and inversely with daily cumulative weight gain in the patients.Thus, we demonstrate that factor XII and prekallikrein decrease during IL-2 therapy. As these decreases, already observed after 1 day treatment, were disproportional to that of albumin, a negative acute phase reactant, and correlated with signs of the vascular leak syndrome, we favor the explanation that they reflected activation rather than a decreased synthesis of the contact system proteins. Further studies are needed to substantiate this hypothesis.

OBJECTIVE: End-of-life practices vary worldwide. The objective was to demonstrate that there is no clear-cut distinction between treatments administered to relieve pain and suffering and those intended to shorten the dying process. DESIGN: Secondary analysis of a prospective, observational study. SETTING: Thirty-seven intensive care units in 17 European countries. PATIENTS: Consecutive patients dying or with any limitation of therapy. INTERVENTIONS: Evaluation of the type of end-of-life category; dates and times of intensive care unit admission, death, or discharge; and decisions to limit therapy, medication, and doses used for active shortening of the dying process and the intent of the doctors prescribing the medication. MEASUREMENTS AND MAIN RESULTS: Limitation of life-sustaining therapy occurred in 3,086 (72.6%) of 4,248 patients, and 94 (2.2%) underwent active shortening of the dying process. Medication for active shortening of the dying process included administration of opiates (morphine to 71 patients) or benzodiazepines (diazepam to 54 patients) alone or in combination. The median dosage for morphine was 25.0 mg/hr and for diazepam 20.8 mg/hr. Doses of opiates and benzodiazepines were no higher than mean doses used with withdrawal in previous studies in 20 of 66 patients and were within the ranges of doses used in all but one patient. Doctors considered that medications for active shortening of the dying process definitely led to the patient's death in 72 patients (77%), probably led to the patient's death in 11 (12%), and were unlikely to have led to death in 11 (12%) patients. CONCLUSIONS: There is a gray area in end-of-life care between treatments administered to relieve pain and suffering and those intended to shorten the dying process.

Previously we studied levels of the cytokine IL-6 and activation of the complement and contact system and of neutrophils in a group of 48 patients with sepsis. Some of these inflammatory parameters appeared to be associated with a poor prognosis. Here we report on the relationships of C4a and C3a (complement activation products), of factor XII and prekallikrein (contact system proteins), of elastase (a protease released by activated neutrophils) and of the cytokine IL-6 to hemodynamic and biochemical parameters measured in those 48 patients at the time of admission to the Intensive Care Unit. No significant correlations between any inflammatory parameter and either systemic vascular resistance or cardiac index were found. Mean arterial pressure significantly correlated with both factor XII and prekallikrein levels. Lactate correlated with C3a and C4a, with elastase, and in particular, with IL-6, whereas it did not correlate with either factor XII or prekallikrein. Platelet numbers inversely correlated with both C3a and C4a, as well as with elastase and IL-6, whereas they positively correlated with factor XII and prekallikrein. Based on these findings we propose a model for the interplay of these inflammatory mediators in the pathogenesis of sepsis. This model takes into consideration the occurrence of capillary leakage, shock, disseminated intravascular coagulation, thrombocytopenia and of acute phase reactions in sepsis.

In this paper we review evidence in favor of a protective role for antibodies directed at the lipopolysaccharide (LPS) core region of Gram-negative bacilli. It will be shown that, given the right animal model, polyclonal antisera raised against O-antigen lacking, rough mutant strains, can be shown to protect animals against lethal sepsis due to a variety a bacterial species. Evidence for a protective role obtained from clinical studies will also be discussed. It will be stressed how difficult it is to prove that the antibodies directed against the LPS-core, and not other proteins present in the polyclonal anti-rough strain antisera, were responsible for the observed protective effects. The solution to some of these problems is the production of monoclonal antibodies (Mabs). We will discuss the findings that purified anti-core Mabs may give false-positive outcomes of protection studies, due to the induction of tolerance by small amounts of contaminating endotoxin, present in the antibody preparation. The need to administer the Mab therapeutically instead of prophylactically to the test animals, will be stressed. It will be shown how we succeeded in determining the epitope-specificities of several anti-core antibodies. It will be shown also that use of Elisa alone for characterization of anti-core Mabs may lead to false conclusions concerning epitope specificities. We will prove that synthetic KDO-(=ketodeoxycctanate) and lipid A-containing antigens are indispensable tools for thorough characterization of Mabs. Using this methodology we were able to discriminate between specific antigen-antibody interactions, and the ability of some Mabs to bind “non-specifically” to hydrophobic surfaces. The relationship between epitope specificity and protective effects of anti-core Mabs will be described. Finally, we will demonstrate that a KDO-specific Mabs is capable of protecting mice against lethal sepsis; in other words, it will be shown conclusively that Mabs to defined epitopes in LPS core region are cross-protective.

OBJECTIVE: To determine the influence of religious affiliation and culture on end-of-life decisions in European intensive care units (ICUs). DESIGN AND SETTING: A prospective, observational study of European ICUs was performed on consecutive patients with any limitation of therapy. Prospectively defined end-of-life practices in 37 ICUs in 17 European countries studied from 1 January 1999 to 30 June 2000 were compared for frequencies, patterns, timing, and communication by religious affiliation of physicians and patients and regions. RESULTS: Of the 31,417 patients 3,086 had limitations. Withholding occurred more often than withdrawing if the physician was Jewish (81%), Greek Orthodox (78%), or Moslem (63%). Withdrawing occurred more often for physicians who were Catholic (53%), Protestant (49%), or had no religious affiliation (47%). End-of-life decisions differed for physicians between regions and who had any religious affiliation vs. no religious affiliation in all three geographical regions. Median time from ICU admission to first limitation of therapy was 3.2 days but varied by religious affiliation; from 1.6 days for Protestant to 7.6 days for Greek Orthodox physicians. Median times from limitations to death also varied by physician's religious affiliation. Decisions were discussed with the families more often if the physician was Protestant (80%), Catholic (70%), had no religious affiliation (66%) or was Jewish (63%). CONCLUSIONS: Significant differences associated with religious affiliation and culture were observed for the type of end of life decision, the times to therapy limitation and death, and discussion of decisions with patient families. Intensive Care Med

In critically ill patients coagulation abnormalities often occur. The most pronounced manifestation of these, caused by overwhelming activation of the coagulation system, is disseminated intravascular coagulation (DIC) which is also considered to be a component of the multiple organ dysfunction syndrome (MODS). There is no generally accepted definition of DIC but recently a working definition has been proposed [1]: “DIC is an acquired syndrome characterized by the activation of intravascular coagulation up to intravascular fibrin formation, which may be accompanied by secondary fibrinolysis or inhibited fibrinolysis”. DIC is not a disease entity but rather a syndrome which can complicate a large variety of clinical disorders mostly characterized by high morbidity and mortality. In general, DIC is therefore an indication of severe underlying disease. In critical illness acute, rather than chronic, low grade DIC may complicate the course of disease.

In critically ill patients, the hypothalamic-pituitary-adrenal axis is usually activated, resulting in elevated plasma cortisol levels. This enables the human organism to cope with sepsis, trauma and other forms of stress. During critical illness, total adrenal insufficiency rarely occurs. On the other hand, septic shock can be accompanied by a relative deficit of cortisol. Causes of this relative adrenal insufficiency are a dysfunction of the hypothalamic-pituitary-adrenal axis and/or cortisol resistance. There are no strict biochemical criteria available to diagnose relative adrenal insufficiency; clinical observation is the decisive factor. In randomised trials with patients in septic shock, a more rapid haemodynamic recovery was obtained with physiological doses of hydrocortisone than with a placebo. The observed haemodynamic response following hydrocortisone administration supports the concept of relative adrenal insufficiency.

A case report is described of a patient who developed severe hypercalcemia during slow continuous arterio-venous ultrafiltration (SCUF). Which was instituted because of refractory congestive heart failure with pulmonary edema. The hypercalcemia was due to a preexisting mild hyperparathyroidism and aggressive fluid removal by SCUF. The differential diagnosis of hypercalcemia in the intensive care ward is discussed.

In the early years of intensive care a stress ulcer related bleeding, occurring in 20-30% of the IC population, became recognized as a significant cause of morbidity and mortality. Due to improved intensive care medicine (including adequate early resuscitation, analgesia, sedation) the incidence of stress ulcer-related bleeding in the IC has decreased markedly. Without pharmacological prophylaxis incidences ranging from 0.6 to 6% were reported. It is not recommended to apply stress ulcer prophylaxis on a routine basis, it should be reserved for patients with an increased risk of a stress ulcer-related bleeding. In patients with neurotrauma, severe burn, recent peptic ulcer or bleeding and those with coagulopathy prophylaxis with ranitidine is advised.

The heart plays a central role in multiple organ failure associated with inflammatory conditions during the course of sepsis or after cardiac surgery.1 Although appearing dissimilar at first, the conditions may have in common the generalized inflammatory state and the circulatory (i.e., cardiac) response to it (Fig. 35.1). This chapter describes the epidemiology, pathogenesis, and therapeutic approach to myocardial dysfunction associated with sepsis and cardiopulmonary bypass surgery.

Eine Aktivierung der Blutgerinnung ebenso wie die Aktivierung und anschliesende Inhibierung der Fibrinolyse findet sich bei Patienten mit schwerer Sepsis und septischem Schock sehr haufig, wie mittels der neu entwickelten hochempfindlichen Gerinnungsassays nachgewiesen werden konnte [25, 37, 48, 55, 86]. Die bei weitem gefahrlichste klinische Manifestation stellt die disseminierte intravasale Gerinnung (DIC) dar [25]. Die Aktivierung des Gerinnungs- und Fibrinolysesystems erfolgt auf getrennten Wegen. Der Gerinnungsprozes wird eingeleitet durch die mediatorinduzierte Expression von Gewebsthromboplastin und geht mit einem Verbrauch der naturlichen Gerinnungsinhibitoren Antithrombin III (AT-III), Protein C (PC) und Protein S (PS) einher. Die Auswirkungen auf das fibrinolytische System werden in hohem Mase von den stark erhohten Werten des Plasminogenaktivatorinhibitors (PAI-1) beeinflust. Obwohl die Spiegel des Plasminogenaktivatorantigens erhoht sind, wird dessen Aktivitat durch den Plasminogenaktivatorinhibitor PAI-1 praktisch vollstandig aufgehoben. Das Ergebnis ist eine Verschiebung des Gleichgewichtes beider Systeme hin zu einem prokoagulatorischen Zustand. So werden bei der DIC nicht selten Fibrinablagerungen in der Mikrozirkulation gefunden, die mit einer disseminierten mikrovaskularen Thrombose verschiedener Organe einhergehen. Dies konnte durchaus fur die Entwicklung eines multiplen Organversagens von ausschlaggebender Bedeutung sein [48]. Zusatzlich kann der Verbrauch an Gerinnungsproteinen und Thrombozyten, hauptsachlich verursacht durch die massive und fortwahrende Aktivierung des Gerinnungssystems, schwere Blutungen auslosen [53]. Die klinisch eindrucksvollste Manifestation der DIC stellt die Purpura fulminans dar, die durch hamorrhagische Hautnekrosen und Gangrane der Extremitaten gekennzeichnet ist. Sie stellt besonders bei Meningokokkensepsis eine gefurchtete Komplikation dar.

Fever suggests the likelihood of severe microbial infection. Abnormal temperature, tachycardia, tachypnea, and abnormal white blood cell counts define the systemic inflammatory response syndrome (SIRS). In 300 hospitalized medical patients with fever, we determined clinical variables and procalcitonin, elastase-alpha1-antitrypsin, and lactoferrin levels in plasma. Of the patients, 71% had clinical infection (by clinical judgment) and 44% had microbial infection (by microbiological testing). SIRS occurred in 95%, and the 28-day mortality rate was 9%. The sensitivity for predicting microbial infection, bacteremia, and mortality was less but the specificity was greater for supranormal procalcitonin, elastase-alpha1-antitrypsin, and lactoferrin levels than for SIRS. The area under the receiver operating characteristic curve (AUC) for microbial infection was higher for procalcitonin and elastase-alpha1-antitrypsin levels than for clinical variables and lactoferrin level. The AUC for bacteremia was also higher for inflammatory factors (0.70; P.001) than for clinical variables. The AUC for mortality (P.05) was 0.79 for the respiratory rate, 0.69 for elastase-alpha1-antitrypsin level, 0.65 for heart rate, 0.61 for procalcitonin level, and 0.60 for white blood cell count. In febrile medical patients, plasma procalcitonin and elastase-alpha1-antitrypsin levels may predict microbial infection and bacteremia better than (and mortality as well as) do clinical symptoms.

To evaluate the effectiveness of lorazepam and midazolam for long-term sedation of critically ill, mechanically ventilated patients.Double-blind, randomized, controlled study.Medical intensive care unit in a university teaching hospital.Sixty-four evaluable adult patients admitted to the intensive care department requiring mechanical ventilation for3 days.Patients were randomized to receive blinded solutions of either lorazepam or midazolam by continuous infusion. The lowest dose that achieved an adequate sedation was infused. The maximum dose allowed for each drug was 60 mg/hr for midazolam and 4 mg/hr for lorazepam. Sedation was assessed initially and at least every 8 hrs thereafter on a seven-point scale if the sedation was adequate and every 2 hrs if it was not.Measurements included the score on the sedation scale, the time between determination of the desired level of sedation and the achievement of that level, and plasma concentrations. It is significantly easier to reach a desired level of sedation with lorazepam than with midazolam. No difference in recovery was found in the 24 hrs after discontinuation of therapy. The fact that there are many factors influencing midazolam pharmacokinetics may explain the more difficult management of desired sedation levels. The equipotent dose of 10 mg of midazolam proved to be 0.7 mg of lorazepam in long-term sedation. The average cost for therapy with midazolam was approximately ten times more than that with lorazepam.Lorazepam is a useful alternative to midazolam for the long-term sedation of patients in the medical intensive care unit and provides easier management of the sedation level. Sedation with lorazepam offers a significant cost-savings.

To compare continuous cardiac output obtained by simulation of an aortic input impedance model to bolus injection thermodilution (TDCO) in critically ill patients with septic shock.In an open study, mechanically ventilated patients with septic shock were monitored for 1 (32 patients), 2 (15 patients), or 3 (5 patients) days. The hemodynamic state was altered by varying the dosages of dopamine, norepinephrine, or dobutamine. TDCO was estimated 189 times as the series average of four automated phase-controlled injections of iced 5% glucose, spread equally over the ventilatory cycle. Continuous model-simulated cardiac output (MCO) was computed from radial or femoral artery pressure. On each day, the first TDCO value was used to calibrate the model.TDCO ranged from 4.1 to 18.2 l/min. The bias (mean difference between MCO and TDCO) on the first day before calibration was -1.92 +/- 2.3 l/min (mean +/- SD; n = 32; 95% limits of agreement, -6.5 to 2.6 l/min). The bias increased at higher levels of cardiac output (P0.05). In 15 patients studied on two consecutive days, the precalibration ratio TDCO:MCO on day 1 was 1.39 +/- 0.28 (mean +/- SD) and did not change on day 2 (1.39 +/- 0.34). After calibration, the bias was -0.1 +/- 0.8 l/min with 82% of the comparisons (n = 112)1 l/min and 58% (n = 79)0.5 l/min, and independent of the level of cardiac output.In mechanically ventilated patients with septic shock, changes in bolus TDCO are reflected by calibrated MCO over a range of cardiac output values. A single calibration of the model appears sufficient to monitor continuous cardiac output over a 2-day period with a bias of -0.1 +/- 0.8 l/min.

In this article arguments are given to stop the current practise of infusing albumin in patients in shock and low levels of serum albumin. Correcting the albumin levels is not correlated with better survival or change in morbidity. Fluid therapy including the use of synthetic plasma expanders is the accepted therapy for patients in sceptic shock.

Objectives: To evaluate the safety and potential efficacy of antithrombin III (AT III) in reducing mortality in patients with severe sepsis. Design: Prospective, randomized, placebo-controlled, double-blind, phase II, multicenter, multinational clinical trial. Setting: Seven academic medical center intensive care units (ICU) in Belgium, Denmark, the Netherlands, Norway and Sweden. Patients: 42 patients with severe sepsis who received standard supportive care and antimicrobial therapy, in addition to the administration of AT III or placebo. Interventions: Patients received either an intravenous loading dose of 3000IU AT III followed by a maintenance dose of 1500 IU every 12 h for 5 days or equivalent amounts of placebo. Measurements and results: All patients were evaluated for safety and for 30-day all-cause mortality. Conclusions: The administration of AT III was safe and well-tolerated. It was followed by a 39 % reduction in 30-day all-cause mortality (NS). The reduction in mortality was accompanied by a considerably shorter stay in the ICU. Patients treated with AT III exhibited a better performance in overall severity of illness and organ failure scores (Acute Physiology and Chronic Health Evaluation II, multiple organ failure, organ system failure), which was noticeable soon after initiation of treatment. Patients treated with AT III demonstrated a better resolution of pre-existing organ failures and a lower incidence of new organ failures during the observation period. A meta-analysis comprising this and two other double-blind, placebo-controlled trials with AT III with a total of 122 patients suffering from severe sepsis confirms the positive trend. The results of the meta-analysis demonstrate a 22.9 % reduction in 30-day all-cause mortality in patients treated with AT III. Although still too small to be confirmative, the meta-analysis clearly points to the fact that a sufficiently powered phase III trial is warranted to prove whether AT III has a beneficial role in the treatment of severe sepsis.

Arginine (ARG) is the precursor of nitric oxide (NO), a potent vasodilator. Arginase (ASE) is released following hepatocellular damage, resulting in low plasma ARG levels. The effect of ASE infusion on hemodynamics was studied. Rats received a 20 min ASE or saline infusion, and systemic hemodynamics and organ blood flow were studied, at 30 and 270 min, using radiolabeled microspheres. Compared with control, ASE resulted (30 min) in 1) undetectable ARG levels; 2) higher mean arterial pressure and total peripheral resistance (both p < .05); 3) higher blood flow to the heart, kidneys, stomach, small intestine (all p < .05), and spleen (p < .001); and 4) lower vascular resistance in the heart, kidneys, stomach, and small intestine (all p < .05) and in the spleen (p < .005). At 270 min, ASE rats had similar organ blood flow and higher nitrate levels in urine and plasma (both p < .05) compared with control. We conclude that ASE reduces ARG levels with simultaneous increase in mean arterial pressure and total peripheral resistance. Higher nitrate production, suggesting higher NO formation in the presence of low ARG plasma levels, is paradoxical but could explain the higher blood flow in some organs. The increased total peripheral resistance during higher nitrate formation suggests regional differences in dependency of NO production on plasma ARG levels.

The aim was to evaluate demographic, clinical, and laboratory variables in febrile patients, with or without a microbiologically confirmed infection, for prediction of death, in comparison to the systemic inflammatory response syndrome (SIRS) and its criteria, such as abnormal temperature, tachycardia, tachypnea, and abnormal WBC count, and to sepsis, that includes SIRS and an infection.A prospective cohort study.Department of internal medicine at a university hospital.In 300 consecutive, hospitalized medical patients with new onset of fever, demographic, clinical, and laboratory variables were obtained during the 2 days after inclusion, while microbiological results for a follow-up period of 7 days were collected. Patients were followed up for survival or death, up to a maximum of 28 days after inclusion.Of all patients, 95% had SIRS, 44% had sepsis with a microbiologically confirmed infection, and 9% died. A model with a set of variables all significantly (p0.01) contributing to the prediction of mortality was derived. The set included the presence of hospital-acquired fever, the peak respiratory rate, the nadir score on the Glasgow coma scale, and the nadir albumin plasma level within the first 2 days after inclusion. This set of variables predicted mortality for febrile patients with microbiologically confirmed infection even better. The predictive values for mortality of SIRS and sepsis were less than that of our set of variables.In comparison to SIRS and sepsis, the new set of variables predicted mortality better for all patients with fever and also for those with microbiologically confirmed infection only. This type of effort may help in refining definitions of SIRS and sepsis, based on prognostically important demographic, clinical, and laboratory variables that are easily obtainable at the bedside.

Postoperative hemodynamic disturbances in obstructive jaundice are associated with complications such as shock and renal failure. Gut-derived endotoxemia may underlie these complications. Recently, we have shown that cholestyramine treatment prevents gut-derived endotoxemia in bile duct-ligated (BDL) rats (Houdijk APJ, Boermeester MA, Wesdorp RIC, Hack CE, van Leeuwen PAM: Tumor necrosis factor unresponsiveness following surgery in bile duct-ligated rats. Am J Physiol 271: G980-G986, 1996).The effect of cholestyramine on systemic hemodynamics and organ blood flows after a laparotomy was studied in 2 wk BDL rats using radioactive microspheres.Compared with sham-operated rats, postoperative BDL rats had 1) lower blood pressure (p.05) and heart rate (p.001) with higher cardiac output (p.05), 2) lower splanchnic blood flow (p.05), 3) lower renal blood flow (p.01), and 4) higher splanchnic organ and renal-vascular resistances. Cholestyramine treatment in BDL rats prevented the postoperative decrease in blood pressure by increasing cardiac output (p.01). In addition, cholestyramine maintained splanchnic blood flow at sham levels (p.05). Furthermore, cholestyramine also prevented the fall in renal blood flow after surgery in BDL rats.Gut endotoxin restriction using cholestyramine treatment maintained normal blood pressure, improved splanchnic blood flow, and completely prevented the fall in renal blood flow in BDL rats. Reducing the gut load of endotoxin in patients with obstructive jaundice scheduled for abdominal surgery may prevent postoperative hemodynamic complications.

Recently in an observational study the use of a pulmonary artery catheter in critically ill patients was associated with an increase in both mortality and utilization of resources when compared with case-matched control patients. The authors corrected for selection bias by using a propensity score. The publication of this article elicited a flood of commentary in both medical journals and the lay press. Critical assessment of this study and other studies about pulmonary artery catheterization in our opinion supports the view that it is probably not the use of the catheter itself, but physicians' insufficient knowledge of right heart catheterization and the specific treatment resulting from its use that is at fault.