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Electroencephalograms (EEG) were recorded in fourteen patients who experienced a severe septic encephalopathy (SE). EEG analysis included visual inspection, spectral analysis and a recently developed nonlinear analysis (the Kaplan test). All EEGs showed decreased fast activity and an increase of slow wave activity on visual inspection. There was a nonsignificant trend of negative correlation between the spectral EEG analysis and the severity of the acute systemic illness (based on the sum score of 14 variables known as APACHE II score) (standard coefficient = -0.43, p = 0.118). However, a much more pronounced and significant negative correlation was observed between the Kaplan test and the APACHE II score (standard coefficient = -0.94, p = 0.005). The EEG abnormalities seen in these patients were independent of the sedation level. Neither the EEG parameters, nor the APACHE II score, predicted outcome. Nonlinear analysis is more powerful than spectral analysis to extract clinical relevant information from EEGs in patients who experience a severe SE. The nonlinear EEG analysis suggest that brain dynamics in SE may be characterized by a shift into a fundamentally different level of cortical information exchange which can be summarized in nonlinear terminology as a loss of deterministic structure in the EEG.

The 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-antithrombin III complexes (TAT), the plasmin-alpha2-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.

In patients with sepsis abnormalities in hemostatic variables indicating systemic activation of coagulation and early activation with subsequent inhibition of fibrinolysis, are common features [1-5]. The most important clinical manifestation of these processes is disseminated intravascular coagulation (DIC), which is characterized by generation and deposition of fibrin in the microvasculature with widespread microvascular thrombosis in various organ systems. The bipha- sic effect on the fibrinolytic system may result in impaired fibrin dissolution and aggravate the formation of microthrombi. There is evidence that DIC contributes to the development of (multiple) organ dysfunction and failure [3, 5]. In addition, depletion of coagulation proteins and platelets, mainly due to the extensive and ongoing coagulation activation, may induce severe bleeding complications [6]. The impressive extreme of the clinical spectrum of manifestations of DIC is purpura fulminans, which presents with hemorrhagic skin necrosis and peripheral gangrene and is most often seen in meningococcal sepsis [7].

Publisher Summary This chapter reviews the role of cytokines in the pathogenesis of sepsis. The various models for sepsis are also discussed, including the human models and animal models. The human model for sepsis most frequently studied is the experimental human endotoxemia. Cytokines usually have an auto- or paracrine-mode of action, although in some situations, in particular in sepsis, they exert effects at a distance from their site of production. Cytokines may be grouped based on their main biological effects: (1) those with main effects on the activation and proliferation of lymphocytes, (2) those with effects on hematopoiesis, (3) those with pro- and anti-inflammatory properties, and (4) those that orchestrate cell growth and differentiation during tissue repair. The notion that cytokines are involved in the pathogenesis of sepsis is based on several lines of evidence: (1) the intravenous administration of cytokines [TNF, IL1, and IL2] induces a septic shock-like syndrome in animals or humans, (2) the inhibition of the effects of some cytokines—by administration of neutralizing antibodies, soluble cytokine receptors, or receptor antagonists—attenuates sepsis in animal models, and (3) the administration of anti-inflammatory cytokines, such as IL10, mitigates severe sepsis in animals.

Quality improvement may be defined as the effort to improve the level of performance of key processes in the ICU. Based on knowledge of the current level of performance and on systematic analysis of organizational aspects of the ICU, quality improvement will include the implementation of standards, the formulation and analysis of quality indicators (e.g. scores, rate of complications such as nosocomial infections) and the possible introduction of data management systems.

We studied the value of a noninvasive, bedside, dual-radionuclide method (67Ga-circulating transferrin and 99mTc-red blood cells) to measure pulmonary microvascular permeability in efforts to discriminate between pulmonary edema due to adult respiratory distress syndrome (ARDS) and hydrostatic pulmonary edema (HPE).Patients had respiratory insufficiency and bilateral alveolar pulmonary edema on chest radiographs. All patients, except one, were mechanically ventilated. Patients, were divided into groups according to various sets of etiologic, hemodynamic and ventilatory factors. Group 1 (n = 8) had risk factors for HPE only. Group 2 (n = 5) had risk factors for both ARDS and HPE, such as a pulmonary capillary wedge pressure (PCWP) above 18 torr. Group 3 (n = 13) had risk factors for ARDS only and a PCWP below 18 torr. Patients were also classified on the basis of a lung injury score, using radiographic and ventilatory variables. Group 4 (n = 12) had a score below 2.5 and Group 5 (n = 14) above 2.5, arbitrarily defined as ARDS. Any radioactivity measurements over the lungs and in blood within 72 hr after admission were used to calculate the 1 hr pulmonary leak index as a measure of microvascular permeability (upper limit of normal 14.1 x 10(-3).min-1).The PLI ( x 10(-3).min-1) was median 10.2 (range 4.4-16.2) in Group 1, 26.8 (14.2-31.9) in Group 2 and 32.3 (23.0-52.4) in Group 3 (p0.001). It was 13.3 (4.4-39.9) in Group 4 and 31.1 (14.2-52.4) in Group 5 (p0.01). Using the various definitions, the sensitivity of a supranormal pulmonary leak index for ARDS was 100% and the specificity varied between 46% and 75%. In receiver operating characteristic curves, the pulmonary leak index performed best when ARDS and HPE were defined on the basis of risk factors only, and performed better than hemodynamic and equally well as ventilatory variables in discriminating between edema types, if definitions of the latter were mainly based on hemodynamic and ventilatory variables, respectively.The 67Ga pulmonary leak index is a useful tool to differentiate ARDS from HPE.

The present study outlines the relationship between cerebral and systemic hemodynamics in patients with septic shock. Sepsis is an immune mediated systemic disease in which the systemic vascular resistance (SVR) often decreases as a result of a Gram negative sepsis. The result is a hyperdynamic systemic circulation with redistribution phenomena in different organ systems. In order to study the effect of sepsis on cerebral vessels 20 patients with septic shock (12 men, 8 women, mean age 57.9 years) were subjected to both pulmonary artery catheter and transcranial Doppler (TCD) monitoring. The data were correlated to the APACHE II score and outcome. The study showed that cerebral mean and end-diastolic blood flow velocities (BFV) in the middle cerebral arteries significantly enhanced if the SVR-index decreases. In some patients a severely reduced SVRI (below 500 dynes.s/cm5.m2) was observed in combination with a downstroke latent steal phenomenon. TCD abnormalities were strongly related to disease severity and outcome. The increased BFV are explained by a mild vasospasm of the basal cerebral arteries. TCD appears to be a valuable tool to monitor the cerebral hemodynamics in these patients. They are particularly at risk for ischemic brain damage if they are subjected to therapeutic or spontaneous hyperventilation, which can potentially be detected by TCD.

In the late 1960s several reports appeared describing remote organ failure (e.g., pulmonary or liver failure) as a complication of severe sepsis (Clowes et al. 1968; Skillman et al. 1969). Stimulated by the observation of Tilney et al. (1973) that sequential failure of initially uninvolved organ systems may follow operations for ruptured aortic aneurysm, the concept emerged that severe injury can result in damage to distant organ systems. In a classical editorial by Baue (1975) entitled“Multiple, Progressive or Sequential Systems Failure: A Syndrome of the 1970s,”this concept was formulated as the basis of a“new”clinical syndrome. Several terms were coined thereafter, such as multiple organ failure (Eiseman et al. 1977), multiple system(s) organ failure (Border et al. 1976), and multiple organ system failure (Bell et al. 1983), to describe this evolving clinical syndrome of otherwise unexplained progressive physiological failure of several interdependent organ systems. More recently the term multiple organ dysfunction syndrome has been proposed as a more appropriate description (Bone et al. 1992).

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.

In severe sepsis, a network of proinflammatory cytokines (TNF, IL-1 beta, IL-6, IL-8) is activated and blood levels of these cytokines are elevated, albeit inconsistently and with large individual variations. In addition, elevated blood levels of anti-inflammatory cytokines (IL-10), as well as of soluble cytokine receptors (sTNF-RI and II, IL-1ra), have been found. They seem to have a regulatory function in the host response. Levels of TNF and IL-6 are usually highest at the time of admission, whereas the time course of IL-1 beta levels (when detectable) can vary considerably. Limited data on IL-8 levels suggest that they may remain elevated for longer periods. Elevated levels of sTNFR and IL-1ra may also persist for a prolonged period of time. The pathogenetic significance of these observations is still unclear, but persistingly high levels of proinflammatory cytokines may be associated with organ failure and mortality.

The interaction between activated neutrophils and pulmonary endothelium is thought to contribute to the pathogenesis of the adult respiratory distress syndrome (ARDS), but its relation to ARDS severity, which may support a pathogenetic role, is unclear. Therefore, circulating inflammatory mediators, including the neutrophil chemoattractant and activator interleukin 8 (IL-8), the acute phase cytokine IL-6, and the neutrophil product elastase complexed to alpha 1-antitrypsin (alpha 1-AT), were measured prospectively, together with gas exchange, ventilatory and radiographic variables, in 13 mechanically ventilated patients with ARDS, mostly owing to sepsis, at admission into the intensive care unit. Measurements were repeated in the eight improving patients at the time that positive end-expiratory pressure could be reduced to 0 cm H2O. From the gas exchange, ventilatory and radiographic abnormalities, a lung injury score (LIS) was calculated. For pooled data, the LIS and the arterial PO2/inspiratory O2 fraction, the oxygenation ratio, correlated with plasma levels of IL-8 (rs = 0.60, P < 0.01 and rs = -0.65, P < 0.005, respectively), with levels of IL-6 (rs = 0.60, P < 0.01, and rs = -0.68, P < 0.005, respectively), and the oxygenation ratio related to elastase-alpha 1-AT (rs = -0.70, P < 0.005). Levels of IL-8 and IL-6 interrelated (rs = 0.61, P < 0.01) and related to the elastase complexes (rs = 0.45, P < 0.05). Hence, our data support a role of cytokine-induced activation of neutrophils in the clinical severity of ARDS.

We report a case of invasive pulmonary aspergillosis after near-drowning complicated by systemic disseminated disease to the heart, kidneys, left adrenal gland and brain. Detection of fungal micro-organisms in the sputum of near-drowning patients should be taken seriously.

Aortic surgery results in ischemia/reperfusion of the lower body. This may liberate inflammatory mediators that activate neutrophils, and may result in lung microvascular changes with increased permeability and respiratory failure. We studied circulating inflammatory mediators and the pulmonary leak index (PLI) of 67Ga, a measure of transvascular transferrin transport and permeability, in patients scheduled for elective aortic and peripheral vascular surgery, before and after surgery. Aortic surgery patients in Groups 1 (n = 10) and 2 (n = 7) were studied before and at a median of 2.5 and 21.0 h after surgery, respectively. A control Group 3 (n = 6) was studied before and at a median of 2.9 h after peripheral vascular surgery. The PLI (median) increased from a median of 9.1 (range, 6.6 to 14.7) before to a median of 23.4 (range, 18.7 to 86.4) x 10(-3)/min after surgery in Group 1 but not in the other groups (p < 0.001). The postoperative increase in circulating neutrophils and elastase-alpha 1-antitrypsin, a marker of neutrophil activation, was similar among the groups. Plasma levels of activated complement 3a and tumor necrosis factor (TNF-alpha) did not change in any of the groups. In contrast, plasma levels of interleukin-8 (IL-8) increased in Group 1 from < 3 (range, < 3 to 37) before to 324 (range, 36 to 868) pg/ml after surgery, but did not change in the other groups (p < 0.005). The decrease in plasma levels of angiotensin converting enzyme (ACE) was greater in Group 1 than in the other groups (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Aortic surgery results in ischemia/reperfusion of the lower body. This may liberate inflammatory mediators that activate neutrophils, and may result in lung microvascular changes with increased permeability and respiratory failure. We studied circulating inflammatory mediators and the pulmonary leak index (PLI) of 67Ga, a measure of transvascular transferrin transport and permeability, in patients scheduled for elective aortic and peripheral vascular surgery, before and after surgery. Aortic surgery patients in Groups 1 (n = 10) and 2 (n = 7) were studied before and at a median of 2.5 and 21.0 h after surgery, respectively. A control Group 3 (n = 6) was studied before and at a median of 2.9 h after peripheral vascular surgery. The PLI (median) increased from a median of 9.1 (range, 6.6 to 14.7) before to a median of 23.4 (range, 18.7 to 86.4) x 10(-3)/min after surgery in Group 1 but not in the other groups (p < 0.001). The postoperative increase in circulating neutrophils and elastase-alpha 1-antitrypsin, a marker of neutrophil activation, was similar among the groups. Plasma levels of activated complement 3a and tumor necrosis factor (TNF-alpha) did not change in any of the groups. In contrast, plasma levels of interleukin-8 (IL-8) increased in Group 1 from < 3 (range, < 3 to 37) before to 324 (range, 36 to 868) pg/ml after surgery, but did not change in the other groups (p < 0.005). The decrease in plasma levels of angiotensin converting enzyme (ACE) was greater in Group 1 than in the other groups (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

We studied microvascular permeability in the lung in 16 patients with the Adult Respiratory Distress Syndrome (ARDS) and in 8 patients with cardiogenic pulmonary edema. Studies were performed with 99mTc-labeled erythrocytes and 67Gallium, for in vivo labelling of circulating transferrin. The mean pulmonary leak index (PLI) was significantly increased in patients with ARDS, but not in patients with cardiogenic pulmonary edema. We conclude that the transvascular 67Ga flux is specifically increased in patients with ARDS and not in patients with cardiogenic pulmonary edema.

1. Mabs with a high affinity for free lipid A do not bind when it is covalently linked, i.e. in the form of LPS. 2. Lipid A-binding Mabs may be divided into three categories: I. Monoreactive Mabs that bind to the hydrophillic backbone of lipid A II. Polyreactive Kdo Mabs III. Polyreactive Mabs that bind by hydrophobic interactions 3. rBPI23 binds either free or covalently linked lipid A.

In patients with septic shock, hypovolemia is a major factor contributing to circulatory instability. In the early phase, cardiac filling pressures are often lowered, due to a decrease in venous return, compromising cardiac output and tissue perfusion [1, 2]. A decline in effective circulating volume can be induced by a variety of sepsis-related mechanisms. First, generalized vasodilation increases total vascular capacitance with subsequent relative hypovolemia. A decline in systemic vascular resistance, mainly due to arteriolar vasodilation, is a constant feature in human septic shock [3]. Alterations in the venous capacitance system, by far the largest part of the intravascular compartment, are however difficult to assess. The concept of venous pooling as a major factor limiting effective venous return stems from animal experiments [4, 5]. Experimental studies in endotoxin and sepsis models have indicated that in several body areas venous capacitance increases. Although significant increases in venous capacitance in the forearm could not be demonstrated in the clinical study [6], it is likely that also in human septic shock venous pooling in vascular beds other than skeletal muscle (e.g. the splanchnic area) is an important mechanism. The evidence for this is, however, only circumstantial. The observation that large amounts of fluids are usually required for initial resuscitation supports such a concept. Secondly, absolute hypovolemia may contribute to a defect in effective circulating volume. This could be due to fever with perspiration and increased insensible loss, vomiting, diarrhea, volume loss by drains or sequestration (e.g. in the gut), and inadequate oral intake.

Pulmonary edema is defined as an excess of extravascular fluid, caused by increased fluid flux from the intravascular into the interstitial space. An elevated hydrostatic pressure in the pulmonary microcirculation, following left ventricular failure for instance, may result in hydrostatic pulmonary edema, while injury of the pulmonary microvasculature may lead to increased transvascular flux of proteins and fluid with resultant permeability-edema [1].

Activation of the complement and contact systems occur in patients with septic shock and is associated with a poor outcome. Activation of both systems is regulated by a common inhibitor, C1-esterase inhibitor (C1-Inh). Functional levels of C1-Inh are normal or slightly decreased in septic patients although this inhibitor is an acute phase protein. Moreover, an increased turn-over of C1-Inh in sepsis likely occurs since levels of proteolytically inactivated ("modified") C1-Inh are increased in this syndrome. One may therefore postulate that in sepsis there is a relative deficiency of C1-Inh. Here we will summarize our preliminary studies in 11 patients with septic shock, who received high doses of C1-Inh for up to 5 days. Activation of complement and contact systems also occurs in "a human model for septic shock" i.e., the vascular leak syndrome (VLS) induced by immunotherapy with the cytokine interleukin-2 (IL-2). The similarity between VLS and sepsis is not only reflected by similar patterns of complement and contact activation, but also by comparable hemodynamic and biochemical changes, and by the involvement of a number of other inflammatory mediators, such as the release of pro-inflammatory cytokines, and activation of coagulation and fibrinolysis and of neutrophils. Here we will also summarize our initial studies of the effect of C1-Inh administration to 6 patients with the VLS induced by IL-2. Our results indicate that high doses of C1-Inh can be safely administered to patients with septic shock or with the VLS, and may attenuate complement and contact activation in these conditions. Whether this therapy may reduce mortality and or morbidity of either syndrome has to be established by double-blind controlled studies.

To evaluate the role of platelet activating factor (PAF) during endotoxin shock, we compared its effects with those of endotoxin. We measured arterial pressure (MAP), heart rate (HR), cardiac output (CO; thermodilution), arterial lactate (Calact), organ blood flow (radioactive microspheres), and organ vascular resistance in four groups of anesthetized (pentobarbital) male Wistar rats (n = 7 per group), infused from t = 0 to t = 60 min with saline (group C: time matched control), endotoxin Escherichia coli O127:B8, 8 mg.kg-1 (group E), a "low PAF dose" (1 microgram.kg-1) to cause the same decrease in MAP as in group E (group PL), or a "high PAF dose" (3 micrograms.kg-1) to cause the same decrease in CO as in group E (group PH). At t = 60 min, MAP had decreased by 33% in E and PL, and by 55% in PH group. CO had decreased by 41% in the E and PH group. Calact had increased in the E and PH group by 300 and 200%, respectively. In the E, PL and PH group, coronary vascular resistance decreased. In the splanchnic organs, endotoxin caused a decrease in blood flow due to vasoconstriction, whereas PAF (both concentrations) caused vasodilation (except for spleen). Renal vascular resistance decreased (P0.05) in the PL group. In all groups, vascular resistance had increased (P0.05) in skin, and not changed in skeletal muscle (P0.05). Thus, hemodynamic changes after PAF infusion were partially similar to those after endotoxin infusion (coronary vasodilation and vasoconstriction in spleen and skin).(ABSTRACT TRUNCATED AT 250 WORDS)

In trauma patients a specific pattern of the hormone endocrine response to injury has been described. Conflicting data exist regarding the hormonal changes during sepsis. We studied the time course and variability of the hormonal and metabolic responses to severe sepsis in twelve medical patients.Hormone levels were measured every 6 hours. Urinary nitrogen and 3-methylhistidine excretion were measured daily. Indirect calorimetry was used to calculate energy production rate (EPR).None of the hormones measured showed a time course in individual patients. Growth hormone (1.69 +/- 0.17 ng/ml) and insulin (48 +/- 5 mU/L) values were within normal range. Cortisol value (474 +/- 44 nmol/L) was in the upper normal range. Insulin-like growth factor 1 level (12.5 +/- 5.7 nmol/L) was decreased. Nitrogen balance was negative and did not change during the study period. Neither oxygen consumption (VO2) (318 +/- 20 ml/min), carbon dioxide output (283 +/- 10 ml/min), EPR (2064 +/- 435 kcal/day), nor fuel utilization showed a time course. The variability during the study period compared with values on admission ranged from 20% (insulin-like growth factor 1) to 74% (growth hormone). The variability of calculated fuel utilization ranged from 35% (protein) to 180% (fat). The variability of VO2, carbon dioxide production, and EPR was for less, 8%.A specific pattern in the endocrine and metabolic responses as observed in trauma patients does not occur in medical patients with severe sepsis. Hormones and calculated fuel utilization show large variations when compared with values on admission. VO2 and EPR vary for less. Nutritional needs in patients with sepsis, therefore, can be calculated on admission and need not be recalculated during the first week after admission.

The abnormal dependence of O2 uptake (VO2) on O2 delivery (QO2) during severe sepsis, and the adult respiratory distress syndrome (ARDS) may be caused by impaired vascular reactivity, following release of vasodilating prostaglandins. Infusion of these compounds, however, may improve tissue oxygenation. We studied the effect of vasodilating prostaglandin E1 (PGE1; 0.2 microgram/kg/min) on the critical O2 extraction ratio (ERO2c) and the critical QO2 (QO2c) in a saline-controlled, crossover study in 12 barbiturate-anesthetized pigs. QO2, VO2 (independently from QO2), and blood lactate concentrations were measured during graded cardiac output reductions by incremental positive end-expiratory pressure (0-20 cm H2O PEEP, raised by 5 cm H2O at 15 min intervals). At 0 cm H2O PEEP, PGE1 decreased arterial blood pressure, mainly due to a fall in systemic vascular resistance. From 0 to 20 cm H2O PEEP, the fall in QO2 was greater in the PGE1 than in the saline series (P0.005), since ventricular filling and the rise in heart rate were less in the former. The decrease in VO2 (P0.005) did not differ between series. As estimated from bilinear regression on paired VO2/QO2 data in individual pigs, the QO2c was 9.8 +/- 3.6 (mean +/- SD) during PGE1 and 14.6 +/- 3.8 ml/kg/min during saline infusion (P = 0.008), with ERO2c 68% +/- 16% and 48% +/- 12%, respectively (P0.005). The QO2c, estimated from bilinear regression on paired lactate/QO2 data during the first treatment period, was 7.1 +/- 1.2 for PGE1 and 12.8 +/- 4.5 ml/kg/min for saline (P0.05), at similar lactate concentrations (2.0 +/- 0.5 and 1.7 +/- 0.5 mmol/liter, respectively). PGE1-induced vasodilation thus decreases QO2c, because of increased ERO2c, probably resulting from capillary recruitment, an increased surface area available for O2 exchange, and decreased O2 diffusion distances. Hence, a reduced ERO2 and abnormal supply dependence of VO2 during severe sepsis and ARDS are not caused by release of vasodilating prostaglandins. In contrast, our results partly explain improved tissue oxygenation with these compounds during abnormal VO2 supply dependence, following sepsis and ARDS.

Abnormalities in coagulation and fibrinolysis are frequently observed in septic shock. The most pronounced clinical manifestation is disseminated intravascular coagulation. Recent studies in human volunteers and animal models have clarified the early dynamics and route of activation of both coagulation and fibrinolytic pathways. In healthy subjects subjected to a low dose of either endotoxin or TNF an imbalance in the procoagulant and the fibrinolytic mechanisms is apparent, resulting in a procoagulant state. Also in patients with septic shock a dynamic process of coagulation and fibrinolysis is ongoing with evidence of impaired fibrinolysis. These abnormalities have prognostic significance; the extent of disturbances of coagulation and fibrinolysis is related to the development of multiple organ failure and death.

Trauma, sepsis, surgery and hypocaloric feeding all increase catabolic rate, resulting in a loss of body protein. Both the increase in metabolic rate and proteolysis are thought to result from hormonal changes and the production of mediators. Prevention of erosion of lean body mass may result in shorter weaning periods from mechanical Ventilation and reconvalescense periods. Furthermore, protein loss is associated with loss of immunocompetence, increased incidence of infection, poor wound healing, muscle weakness, and even mortality. Amelioration of loss of body protein may thus improve patient outcome. Aggressive nutritional support is not effective in increasing or even maintaining body protein. Research has therefore focused on adjunctive therapy to enteral and parenteral nutrition.

C1-inhibitor (C1-INH) is the major plasma inhibitor of the complement and contact systems. Activation of either system has been shown to occur in patients with septic shock and is associated with a poor outcome. Functional levels of C1-INH tend to be normal in septic patients although paradoxically this inhibitor is an acute phase protein. Moreover, levels of proteolytically inactivated C1-INH are increased in sepsis pointing to an increased turn-over. These observations suggest a relative deficiency of biologically active C1-INH in sepsis. Complement and contact activation have also been shown to occur in the vascular leak syndrome (VLS) induced by immunotherapy with the cytokine interleukin-2 (IL-2), which syndrome may be regarded as a human model for septic shock. The similarity between VLS and sepsis encompasses more than complement and contact activation since a number of other inflammatory mediators considered to play a role in the pathogenesis of septic shock, are also involved in the development of VLS. The role and the mechanisms of complement and contact activation in sepsis and in the VLS are reviewed in this paper. Initial results of intervention therapy with high doses of C1-INH in these syndromes are also reported. It is concluded that high doses of C1-INH can be safely administered to patients with septic shock or with the VLS and may attenuate complement and contact activation in these conditions. Double-blind controlled studies are needed to definitely proved these effects and to establish whether this treatment is able to reduce mortality and morbidity of these syndromes.

Critical illness, surgery and hypocaloric feeding are accompanied by a high rate of total body nitrogen loss. Loss of body protein, occurring despite adequate nutrition, results in increased incidence of infection, poor wound healing, skeletal muscle weakness and increased mortality. Growth hormone (GH) administration together with nutritional support attenuates protein catabolism. This review focuses on normal GH physiology and the administration of GH in adult catabolic patients.

The ability of murine monoclonal antibodies (mAbs), directed to the inner core of Gram-negative bacterial lipopolysaccharide (LPS, endotoxin), to enhance complement-mediated killing of bacteria, was investigated. The mAbs were tested as present in ascitic fluid. It was found that ascites contains an factor that inhibited the activity of complement. This effect was evident in assays for complement-mediated lysis of antibody-coated Gram-negative bacteria (bacterial killing) or of opsonised red blood cells. Moreover, the amount of inhibitor was found to vary from one ascites to another and spanned a 60-fold range. Thus, in vitro or in vivo experiments where complement is known to play a determining role may yield incorrect results when ascites is used as a source of antibody; the use of ascites prepared from irrelevant antibody as a negative control does not eliminate this problem.

Because of its neutrophil-activating properties, interleukin-8 (IL-8) may play an important role in the pathophysiology of sepsis. We measured circulating IL-8 levels in 47 patients with clinical sepsis. Levels on admission were elevated in 42 of the 47 patients (89%) and were comparable in patients with gram-positive or gram-negative infections. Patients with shock had significantly higher IL-8 levels than normotensive patients (P = 0.0014, Wilcoxon-Mann-Whitney test), whereas no differences in IL-8 levels were found between patients with or without adult respiratory distress syndrome. Patients who died had higher IL-8 levels on admission than the patients who survived. The largest differences in IL-8 levels between survivors and nonsurvivors was found when only patients with positive cultures were considered (P = 0.0342). IL-8 levels appeared to correlate significantly with lactate levels and inversely with leukocyte and platelet numbers and mean arterial pressure. In addition, the IL-8 level in the sepsis patients was found to correlate significantly with levels of IL-6, elastase-alpha 1-antitrypsin, and C3a. Serial observations revealed that in most patients IL-8 levels decreased, irrespective of the outcome. Thus, our results demonstrate that IL-8 levels are increased in most patients with sepsis and correlate with some important clinical, biochemical, and inflammatory parameters. These findings suggest a role for IL-8 in the pathophysiology of sepsis.

Increased vasopermeability and vasodilation, presumably the result of endothelial perturbation, are considered among the basic pathogenetic mechanisms in septic shock. Neutrophils have been implicated as a source for mediators in endothelial injury. We measured elastase-alpha 1-antitrypsin (alpha 1AT) complexes and lactoferrin as markers for release of neutrophil granule contents in plasma from patients with sepsis on admission to the Intensive Care Unit, and we delineated the relationship of neutrophil activation to other inflammatory parameters and to hemodynamic and biochemical parameters. Levels of elastase-alpha 1AT and lactoferrin significantly correlated with each other (r = 0.58; p less than 0.008), and were increased (greater than 3.33 and 5 nmol/L, respectively) in 96% and 71% of the patients, respectively. Lactoferrin, but not elastase-alpha 1AT, correlated with the number of white blood cells (r = 0.38; p = 0.008). Elastase-alpha 1 AT levels were significantly higher (p = 0.008), whereas white blood cell counts were lower (p = 0.015) in patients with shock when compared with patients without abnormal blood pressure. Both elastase-alpha 1AT and lactoferrin levels correlated with lactate levels (r = 0.33; p = 0.024 and r = 0.30; p = 0.04), suggesting a role for neutrophil activation in the pathogenesis of hypoxygenation. In addition, elastase-alpha 1AT correlated with the concentrations of interleukin 6 (IL-6) (r = 0.46; p = 0.001) and C3a (r = 0.38; p = 0.009), suggesting that cytokines and complement may contribute to the degranulation of neutrophils in sepsis. Elastase-alpha 1AT complexes were inversely related to C1-inhibitor (r = -0.33; p = 0.028) and to platelet numbers (r = -0.42; p = 0.003). Levels of elastase-alpha 1AT complexes in plasma appeared to be of prognostic significance; levels were higher in 27 patients who died than in 21 patients who survived (p = 0.01). The mortality in 27 patients with concentrations below 10 nM was 37%, whereas it was 81% in 21 patients with higher levels. The overall mortality in this study was 56%. These results provide further evidence that activation and degranulation of neutrophils, induced by multiple agonists, are involved in the development of fatal complications in patients with sepsis.

Activation of the complement system has been implicated as one of the possible mechanisms involved in the extremely complex pathophysiology of septic shock. Bacteria and their products like endotoxin can activate this system even in the absence of antibodies [1]. Complement activation results in the generation of several peptides which have strong biological properties and are called anaphylatoxins [2], Hypotension, leukopenia and increased pulmonary permeability are features of systemic complement activation which are also observed in human septic shock. In this chapter, we will review the available evidence for the role of activation of the complement system in severe sepsis, and some of its sequelae.

Background Translocation of bacteria and their products through the intestinal mucosa during ischaemia–reperfusion (I/R) may contribute to gut I/R injury. Methods In order to study the role of luminal endotoxin in gut I/R injury, two groups of seven germ-free pigs each were studied by clamping of the superior mesenteric artery, with and without luminal administration of endotoxin. Two control groups of seven germ-free pigs, with and without endotoxin, were not clamped. Translocation of an inert indicator (polyethyleneglycol (PEG) 3350), mucosal ischaemia (measured by tonometry) and haemodynamics were assessed. Results Both clamped groups showed ischaemic injury as measured by raised PEG 3350 urinary levels, lowered intestinal pH, and increased intramucosal arterial and intramucosal portal partial pressure of carbon dioxide gradients. Luminal endotoxin application did not aggravate this I/R injury, nor did it influence haemodynamics. The PEG 3350 level in the clamped endotoxin group was significantly lower than that in the clamped control group (mean(s.d.) 0·55(0·37) versus 1·82(0·70); P = 0·001), suggesting a blunting influence of endotoxin on the I/R injury. This might be explained by a desensitizing effect on leucocytes in the gut wall by luminal endotoxin before clamping and diminishing the I/R-induced production of cytokines in the gut wall. Conclusion Endotoxin does not significantly mediate gut I/R injury in the pig and might desensitize the gut wall leucocytes, resulting in decreased translocation of large molecules, including bacterial products and endotoxin.

The purpose of the present study was to determine the effect of volume loading alone (CONTR) vs. volume loading in combination with dobutamine (DOBU) or norepinephrine (NOR) on total body blood volume distribution in septic shock. After instrumentation, injection of in vitro labelled 99mTc red blood cells, and baseline measurements, anesthetized, ventilated pigs (n = 21) received 3-4.10(8).kg-1 live E. coli bacteria intravenously. Images of thorax, abdomen, and hindlimb were obtained by using a gamma camera simultaneously with hemodynamic measurements. E. coli infusion resulted in a decrease in arterial pressure, ventricular filling pressures, and cardiac output with a concomitant increase in pulmonary arterial pressure. Blood volume was redistributed from the heart, lungs, spleen, abdomen, and leg to the liver. After randomization, the CONTR group (I, n = 5) was subjected to volume loading, and treatment groups (each n = 8) received volume loading in combination with DOBU (group II, 5-10 micrograms/kg/min) or NOR (group III, 0.25-0.50 micrograms/kg/min). As compared to volume loading alone, DOBU and NOR increased cardiac output but only NOR restored arterial pressure. Volume loading increased blood volume in all regions studied; however, it was unequally distributed amongst organs with a preference for the liver. Neither DOBU nor NOR influenced the partitioning of the infused volume between organs. However, NOR prevented pooling of blood in the leg.

Renal failure often complicates endotoxin shock. This might be due to renal hypoperfusion, but endotoxemia could also have additional effects. We studied in anesthetized rats renal plasma flow (RPF), glomerular filtration rate (GFR), and metabolism (ATP, CrP = creatine phosphate, energy charge = [ATP + 0.5 ADP]/[ATP + ADP + AMP], lactate, glucose) during endotoxin shock (Escherichia coli endotoxin, 10 mg/kg for 60 min; n = 10) and "balloon shock" (balloon inflated in vena cava below renal vein to cause comparable decreases in cardiac output and RPF as in endotoxin-treated rats; n = 10). A third group of rats served as controls (n = 10). At t = 0 infusion of endotoxin was started. At t = 90 min, when cardiac output was low and serum lactate was high (indicating shock), GFR and RPF were obtained from plasma disappearance rates (from t = 90 to t = 135 min) of 125I-thalamate and 131I-hippurate, respectively. Experiments ended at t = 135 min. In both shock groups RPF decreased (by ca. - 75% compared with control rats), but filtration fraction only increased (by 72%) in the "balloon shock" rats. In renal biopsies lactate concentration increased more (by 407 vs. 167%) and ATP decreased more (by -63 vs. - 35%) during endotoxin shock than during "balloon shock"; the endotoxin-treated rats also showed a significant decrease in CrP (by - 58%), energy charge (by - 31%), and glucose concentration (by - 34%), and an increase in the number of leukocytes in the glomeruli (by 730%). Renal function and metabolism thus was more affected in this hypodynamic form of endotoxin shock than in "balloon shock." This may be caused by the effects of endotoxin on sticking of leukocytes and renal metabolism.

The authors sought to determine how hypoperfusion influences acid-base balance in arterial and mixed venous blood. In anesthetized, ventilated pigs (n = 12), we determined hemodynamics, O2 uptake, CO2 output, dead-space ventilation, arterial and mixed venous blood acid-base balances, and lactate concentrations during graded reductions in cardiac output by incremental positive end-expiratory pressure (PEEP, 0-20 cm H2O). Cardiac output decreased from 3.2 +/- 0.2 (mean +/- SEM) to 1.2 +/- 0.1 L/min at 20 cm H2O PEEP. Oxygen delivery declined more than O2 uptake did by 60% +/- 2% and 27% +/- 2%, respectively. The decrease in CO2 output (by 21% +/- 2%) was less than that in O2 uptake. Fractional dead-space ventilation increased. At a slight increase in carbon dioxide tension (PCO2) of 4 +/- 1 mm Hg, pH decreased in arterial blood from 7.54 +/- 0.01 to 7.47 +/- 0.02 mmol/L, and standard bicarbonate decreased from 30.3 +/- 0.5 to 27.5 +/- 0.6 mmol/L. The decrease in standard bicarbonate exceeded the increase in blood lactate concentrations. At a similar decrease in standard bicarbonate, the decrease in pH was larger (P less than 0.005) in mixed venous blood than in arterial blood owing to a larger increase in PCO2 (from 40 +/- 2 to 50 +/- 2 mm Hg, P less than 0.005). The changes were reversed after discontinuing PEEP. The authors conclude that ischemia after incremental PEEP results in tissue metabolic acidosis with superimposed respiratory acidosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Patients 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.(ABSTRACT TRUNCATED AT 250 WORDS)

Alpha 2-macroglobulin (alpha 2 M) in vitro inhibits numerous proteinases that are generated during inflammatory reactions and therefore, probably plays an important role in diseases such as sepsis. To monitor the state of alpha 2 M in sepsis, we developed novel assays for functional and inactive alpha 2M. Functional alpha 2M in plasma was measured by quantitating the binding of alpha 2M to solid-phase trypsin. Inactive alpha 2M (i alpha 2M) was assessed with a monoclonal antibody, mcAb M1, that specifically reacts with a neodeterminant exposed on i alpha 2M. This mcAb in combination with chromogenic substrates was used to detect alpha 2M-proteinase complexes. Functional alpha 2M was reduced in plasma from 48 patients with clinical sepsis compared to healthy controls (p less than 0.0001). Levels of functional alpha 2M on admission and the lowest levels encountered in 23 patients with shock were lower than in 25 normotensive patients (p = 0.023 and p = 0.009, respectively). Increased levels of i alpha 2M (greater than 30 nM) at least on one occasion were found in only 4 of the 48 patients, being not different in hypotensive compared with normotensive patients, and not in patients who died compared with those who survived. Levels of functional alpha 2M correlated significantly with levels of factor XII and prekallikrein suggesting that decreases in alpha 2M at least in part were due to contact activation. Indeed, in two patients with increased i alpha 2M, complexes between alpha 2M and kallikrein were demonstrated in addition to plasmin- and thrombin-alpha 2M complexes.

The changes of hemodynamic and oxygen transport variables in human septic shock are well documented [1]. They are essentially characterized by a hyperdynamic circulatory state associated with an increased cardiac output (CO), a decreased systemic vascular resistance (SVR) and a narrowed arterial-mixed venous oxygen difference (a-vO2) together with elevated arterial blood lactate levels. Therefore, when arterial oxygenation is maintained, oxygen delivery (DO2) is as a consequence usually supranormal. This implies a defective tissue oxygen extraction as the most important mechanism that limits oxygen consumption (\( \dot{V}{{O}_{2}} \)) in septic shock. Throughout a septic episode the basic pathophysiologic problem seems to be a disparity between the uptake of oxygen and the demand of oxygen in the tissues as manifested by increased blood lactate levels. Limitation of oxygen uptake may significantly contribute to morbidity and mortality by predisposing to multiple organ failure. Several observations suggest that inadequate tissue oxygenation is a central mechanism mediating the widespread and irreversible tissue damage that is associated with multiple organ failure and a fatal outcome [2, 3].

Sepsis is a clinical syndrome that in most cases is induced by severe bacterial infections. Its manifestations may vary and include fever, leukocytosis, thrombocytopenia, tachycardia and tachypnea. Frequently, sepsis is complicated by the development of shock and multiple organ failure. Septic shock still continues to be a challenge for clinical investigators. In spite of advances in intensive care medicine and the availability of a large number of antibiotics, the mortality rate of this condition is still high, in some studies being 50–70%.

Bystander cardiopulmonary resuscitation (CPR) has produced variable results since its introduction in the mid-seventies [1–3]. On the one hand, up to 32% survival has been reported, on the other hand, other studies demonstrated no benefit from the method. Although outcome also depends on time- and patient-related factors, the fact that conventional CPR usually does not even generate sufficient vital organ perfusion to maintain aerobic metabolism [4, 5] contributes to mortality and neurologic damage after circulatory arrest.

Septic shock is the ultimate consequence of overwhelming, predominantly Gram negative infection, and carries a high mortality rate ( = 50%) [1-8]. Hemodynamic changes play a central role in septic shock, so that monitoring of the circulation might allow evaluation of the severity and course of the syndrome and its response to treatment. Conventional hemodynamic monitoring in septic shock pertains to invasive, mostly continuous measurements of arterial blood pressure and pressures in the lesser circulation (central venous, pulmonary arterial and capillary wedge pressures) and to intermittent determinations of cardiac output. In order to obtain the latter variables, insertion of a thermistor, balloon tipped pulmonary artery catheter is required. In conjunction with determinations of arterial and mixed venous oxygen contents, cardiac output measurements with the thermodilution technique allow assessment of peripheral oxygen delivery, extraction and uptake. The indications and implications of hemodynamic monitoring in septic shock are to a large extent dictated by the circulatory pathophysiology involved. Difficulties in the diagnosis and treatment of septic shock may constitute indications for insertion of a pulmonary artery catheter and measurements of filling pressures, pulmonary arterial pressures and blood flow. However, problems may arise in the proper interpretation of hemodynamic and metabolic measurements in septic shock. The impact of these variables on treatment and prognosis is difficult to prove. Hence, it has been doubted whether the benefits of a pulmonary artery catheter outweigh the risks of insertion and whether the use of the catheter improves outcome. Finally, some additional (non-invasive) monitoring devices have been developed, that may be useful in the treatment of septic shock. Before discussing these issues, we will briefly outline the hemodynamic characteristics of septic shock. A discussion of techniques of catheter insertion, maintenance, measurements of blood flow and pressures is provided elsewhere [9–12].

The factors predisposing to and complicating acute renal failure (ARF) in the medical intensive care unit (ICU), and their relative influence on outcome during ARF are unclear. We retrospectively evaluated the relative importance of age, prior chronic disease (including chronic renal failure), sepsis and organ system failure, for development and outcome of ARF in the medical ICU. Of 487 consecutively admitted patients, 78 (16%) had ARF, in 63% treated with renal replacement therapy. Mortality was 63%. Independently from each other, advancing age, prior chronic disease, and cardiovascular and pulmonary failure directly related to the development of ARF, while neurological failure related inversely. Sepsis only contributed to ARF prediction from these variables if cardiopulmonary failure was excluded. Advancing age, cardiovascular failure before and after onset of ARF, pulmonary failure before ARF and use of renal replacement therapy were the major independent factors directly related to ARF mortality, while prior chronic renal failure related inversely and sepsis did not contribute. Hence, the outcome of ARF in a medical ICU is largely dependent on factors predisposing to ARF, even though the severity and complications of ARF may partly contribute. Our results may help in deciding on the prevention and therapy of ARF in a medical ICU.

Endotoxin causes only a limited increase in plasma leakage in rats. This may be due to a concomitant fall in venous pressure. We therefore studied effects of increases in this pressure on plasma loss. After a 60 min. endotoxin (20 mg/kg. hr E coli 0127-B8) or saline (control) infusion anesthetized rats were volume loaded (3 ml/10 min. 100 g for 10 min.) at t = 120 min. with saline (shock group n = 8; control group n = 8) or Haemaccel (shock group n = 6; control group n = 8). At t = 180 min. the experiments ended. We measured mean arterial and central venous pressure, heart rate, arterial lactate, blood volume (51Cr-labeled red cells), hematocrit (conductivity cell), macromolecular extravasation (125I-HSA) and fluid retention (calculated from change in plasma volume). Whole body transcapillary filtration coefficient (Kf) and interstitial compliance (Ci) were obtained from saline retention curves. During volume loading central venous pressure increased, then fell again. At the end of saline loading (t = 130) 50 and 60% of infused volume remained intravascularly in control and endotoxin treated rats, respectively; at the end of Haemaccel infusion retention was 110 and 120%, respectively. Fifty minutes later (t = 180) it was 25 and 30% after saline loading and 50 and 60% after Haemaccel loading in control and endotoxin treated rats, respectively. Between control and endotoxin group filtration coefficients (Kf; .094 vs .111 ml/min.mmHg.100 g, respectively) and compliances (Ci; 1.90 vs 1.58 ml/mmHg.100 g, respectively) were not significantly different. No increase in leakage of 125I-HSA was found in either group. Increased venous pressure thus did not reveal an increase in macromolecular permeability in endotoxin treated rats.