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The original version of this article unfortunately contained mistakes. The Tables 1–3 were missing. The correct versions of Tables 1, 2 and 3 are given below. Bettina Standhartinger was unfortunately not correctly named in the acknowledgments of the original version of this article. The correct acknowledgements are as follows: The authors would like to thank Bettina Standhartinger for her valuable assistance in organizing the Wiggers–Bernard Conference.

A bioreactor for the mechanical stimulation of silk based scaffolds has been developed. The bioreactor simulates the natural movement of the anterior cruciate ligament by applying a biaxial movement on the scaffold. The silk scaffolds are prepared in a way that mimicks the mechanical properties (strength, stiffness) of natural anterior cruciate ligaments. The influence of degumming on the mechanical properties of the scaffolds is investigated and first results on cell cultivation experiments with fibroblasts are presented.

Use of intramedullary reamers (IR) is typically associated with pressure generation during the reaming process, which may result in the introduction of fat and marrow particles into the venous system. Thus, a new System was designed in order to avoid pressure generation and thus to reduce the risk of embolic events. In vitro testing was carried out using pig femura. Intramedullary pressure was recorded during drilling with either the new pressure-free intramedullary reamer (PF-IR; n = 10) or a Standard AO-IR (n = 10). For in vivo testing, nailing of the femur was performed in sheep using either the PF-IR (n = 7) or the Standard AO-IR (n = 7). Fat intravasation was measured using echocardiography and the Gurd test. Hemodynamic and pulmonary parameters as well as intramedullary pressure were continuously recorded during the experiments. The animals were then sacrificed and tissue samples were taken from all regions of the lungs. The incidence of lung fat emboli in histological sections was scored in a blinded manner. A finite element analysis was carried out to assess Performance of the PF-IR under load. The in vitro tests showed that the new PF-IR resulted in significantly less intramedullary pressure (15 ± 12 mm Hg) than the Standard AO-IR (813 ±247 mm Hg; p< 0.001, Mann-Whitney-U test). These results were confirmed in vivo. Moreover, the PF-IR group had significantly less fat intravasation (Gurd test) and better hemodynamic and pulmonary values than the AO-IR group. The incidence of fat microemboli in the lungs was reduced by 90% in the PF-IR group. Finite element analysis showed that the new drilling System performed well under load. The newly developed pressure-free IR clearly outperformed a Standard AO-IR. Use of the new PF-IR was associated with low intramedullary pressures, significantly less fat intravasation, and a markedly lower incidence of fat emboli in the lung. This, in turn, may have been the reason for the better hemodynamic and pulmonary values in the PF-IR group.

Nitric oxide (NO) as both a vasodilator and under certain circumstances a cyto-toxic molecule is suggested as one of the critical mediators of severe sepsis and septic shock. Whether NO is really a central molecule in sepsis and whether inhibition/scavenging has more beneficial or detrimental effects are, however, controversial questions with conflicting data. Many studies demonstrate either one or both effects; these have been thoroughly reviewed recently [1].

The progression of multiple organ failure (MOF) in patients with various underlying diseases continues to pose a life-threatening problem in intensive care units. Despite being the subject of an exponentially increasing number of experimental and clinical investigations during recent decades, the precise mechanisms leading to the development of MOF are not yet clearly understood. While several authors had earlier suggested that systemic sepsis due to uncontrolled infection is the leading cause of MOF (Baue 1975; Fry et al. 1980; Polk and Shields 1973), it has become increasingly clear that an infectious focus cannot be identified in all patients with MOF (Carrico et al. 1986; Faist et al. 1983; Goriset al. 1985).

Adult respiratory distress syndrome (ARDS) (Fig. 1) is the pulmonary manifestation of a diffuse microcirculatory injury that causes exudation of a protein-rich fluid into the pulmonary interstitium and alveolar space. This statement by Meduri et al. (1991) is a very adequate characterization of the morphologic development of ARDS. During trauma, there are short intervals characterized by morphologic alterations that precede typical ARDS, e.g., the stage of “lung in shock” which constitutes the substrate for microcirculatory injury and may reoccur in ARDS itself with stronger intensity. During “early organ failure lung,” actual microcirculatory injury, reflected by the coinvolvement of the alveolar space, may also constitute the morphologic substrate for the subsequent development of ARDS, which is still associated with a mortality of 60%–70% (Bell et al. 1983; Montgomery et al. 1985). The characteristic inflammatory fibrotic process is seen at a later point of time and may be the cause of permanent lung damage.

Endotoxin, bacteria, and immune complexes lead to activation of the complement cascade. As an ef fect of complement activation the anaphylatoxins C3a and C5a and the terminal C5b-9 complement complex are formed. The anaphylatoxins increase contraction of smooth muscles, enhance vascular permeability, and release histamine from mast cells [1–4]. Once formed in the blood, the C3a and C5a molecules are converted to spasmogenically inac tive C3adesArginine and C5adesArginine derivates [5]. C5a is a potent activator of leukocytes and is che-motactically active. In addition, the desArginine form is able to stimulate neutrophil Chemotaxis [5, 6]. C5a induces secretion of lysosomal enzymes from macrophages and neutrophils and may also induce interleukin and prostaglandin production from macrophages [7–9].

Trauma and hemorrhage should closely mimic human polytrauma to create a valid basis for defin itive conclusions on the pathomechanisms and pathophysiology of polytrauma.

Sepsis and septic shock are usually complex conditions in which the overall picture heavily depends on numerous interrelationships among all organ systems and tissues. In the study of such a complicated problem it seems important to eliminate as many variables as possible. In this respect, the use of experimental animals which phylogenetically are as close to humans as possible would appear to be an important initial goal.

Many pathways have led to the discovery of interleukin-1 (IL-1) as a distinct molecule. In the 1940s Menkin (1945) suggested that fever was caus ed by a soluble factor released by activated perito neal exudate cells. The substance was called pyrexin and later granulocytic pyrogen. Subsequently a cir culating pyrogen called endogenous pyrogen was demonstrated in rabbits. After some years a macrophage product, leukocyte endogenous medi ator, was found to induce the acute phase response. In 1972 an apparently unrelated biological re sponse, augmentation of thymocyte proliferation, was ascribed to the lymphocyte activating factor (Gery et al. 1972). At that time there was increasing confusion about the terminology as all the afore mentioned activities were supposed to be caused by the same molecule, or a family of closely related molecules. This led to an agreement in 1979 that all the factors described above should be termed IL-1 (Aarden et al. 1979). An importent step forward in the history of IL-1 was the cloning and expression of the gene encoding human IL-1, which was achieved by several groups in 1984–1985. It was found that two different genes were capable of ex pressing IL-1 activities, and the proteins were termed IL-1α and IL-1 β.

Despite improved diagnostic monitoring and new therapeutic modalities, sepsis remains a serious cause of mortality in most surgical intensive care units (Parker and Parillo 1983). While the patient’s outcome following severe injury or transplantation has been improved, patients still run the risk of developing sepsis due to immunesuppressive therapy and to the increasing use of intravenous catheters (e.g., for various parenteral applications).

Sepsis is a major cause of morbidity, mortality, and financial loss in the world today. As the AIDS epidemic spreads, the incidence of sepsis can only be expected to increase since the victims of the immune deficiency syndrome are harbingers of organisms that are resistant to antibiotics (Fife et al. 1990). Despite this urgent need for an understanding of the cardiopulmonary lesions of sepsis, little progress has been made to improve the lot of the septic individual. Although many experiments have been accomplished in the areas of bacteremia, endotoxemia, and sepsis, much of this work has not been transferable to the human situation. The animal models which were used in many of the previous studies were inappropriate to the human situation. There is a major need for a relevant model for the study of the cardiopulmonary lesions of sepsis and for the development of therapeutic regimen to combat the disorder.

Bacterial translocation secondary to gut damage caused by traumatic shock is a source of posttraumatic sepsis. Enteral bacterial translocation has been implicated as a possible cause of the subsequent development of organ failure. In several series, only one third of multiorgan failure patients with clinical manifestations of sepsis had an identifiable focus of infection (Goris et al. 1985). The majority of intensive care patients show the picture of clinical sepsis without a focus. In these patients, the gut frequently plays an important part as a shock organ involved in the development of sepsis.

Leukocytes, in particular polymorphonuclear neutrophils (PMNs), release important mediators of microvascular injury seen after ischemia/reperfusion, hemorrhage, and sepsis. Adherence of PMNs to the endothelium is thought to be crucial in PMN-mediated injury and results in an increase in permeability and edema. Adhesion is also an in tegral part of the beneficial role of leukocytes during migration, phagocytosis and bacterial killing.

The liver in acute shock is usually enlarged and may be purplish in congestive heart failure (Sherlock 1987) or pale in hypovolemic-traumatic shock. Sometimes the surface of the shocked liver shows a patchy appearance with anemic spots because of circumscribed ischemic areas. The edges of the liver are rounded and because of the interstitial edema the liver weight is increased. Spotty subcapsular hemorrhages may also occur, especially in septic shock, with consumption of coagulation factors resulting in hemorrhagic diathesis. The cut surface of the liver is grayish and pale in pure hypovolemic shock or reveals distended hepatic veins in congestive heart failure. In addition the cut surface may show anemic spots or hemorrhagic patches. Pale and dry areas of yellow color represent necrotic foci; however, such macroscopically detectable necrotic foci are usually rare since they must become quite large to be detectable in this way.

In this book current knowledge of the pathophysiology of shock, sepsis and multi organ failure is presented. The rapid progress which has been made and the results achieved in intensive care medicine are based on sound basic research, which is duly reflected in these chapters. Multiorgan failure is the foremost cause of postoperative and posttraumatic death and many complex mechanisms are involved. Only with a good foundation of basic research can abnormalities in the physiological, biochemical, and morphological course of shock be recognized and the necessary conclusions for treatment drawn. Therapy must proceed from profound knowledge of the multi variant physiological events in order to influence shock, sepsis and organ failure. Although numerous possibilities for therapy have arisen from pharmaceutical research in recent years, they are beyond the scope of this book and are not discussed here. To gain a better understanding of the pathophysiological events it was necessary to examine and to describe different models that simulate and reproduce these events. Here we describe the causative agents (shock) and the consequences (sepsis, organ failure) in two main sections, divided on the basis of their pathophysiology.

In the pathophysiology of polytrauma, the “organs in shock” fundamentally affect the patient’s-post-traumatic course. Polytrauma is commonly associated with hypovolemic-traumatic shock and/or with thoracic injury involving the lung. In the traumatic setting, the pulmonary vessels play an important role due to the involvement of two pathomechanisms: either direct trauma (lung contusion, aspiration or inhalation injury) or indirect trauma due to release of tissue-damaging mediators. A combination of both mechanisms is possible. It stands to reason that due to the physiologic role of the lung, its involvement in the traumatic series of events has a highly relevant impact on the post-traumatic course, among other things because of the high associated mortality (>50%).

During infection and sepsis the genes for many cytokines are expressed and some of the proteins are also released both locally and into plasma. Teleologically, such cytokine response must be beneficial to the host. However, from a certain threshold level of activation there might be an overactivation and imbalance of the cytokine sys tem, which then tends to be harmful to the host. It is difficult to make a strict classification of cyto kines, but nevertheless some of them can be seen as proinflammatory (e.g., tumor necrosis factor, TNF) and some as anti-inflammatory molecules (e.g., in-terleukin 4, transforming growth factor-β?). In considering the role of cytokines in sepsis, it should be emphasized that some of these molecules occur in sequence in vivo, with possible reciprocal amplification or inhibition cascade.

Polytrauma is commonly associated with hemorrhagic-traumatic shock causing hypoperfusion of vital organs. Reperfusion of these organs occurs following resuscitation. Hypoperfusion/reperfusion events together with phagocyte activation caused by products of humoral cascade systems (e.g., complement) represent the nonbacterial inflammatory events leading to organ failure.

The development of organ failure may occur within the first days after trauma (early organ failure) or after one or two weeks (late organ failure) in ICU patients. The reaction that leads to organ damage and organ failure is a generalized inflammatory event [1]. This inflammation may be non-bacterial in the early stage of organ failure, and be aggravated by the influence of bacterial factors during the development of late organ failure. The non-bacterial inflammatory reaction is induced by the initial injury and is usually based on three factors: tissue ischemia/hypoxia, reperfusion events with generation of oxygen radicals; stimulation of phagocytes by complement split products or other humoral inflammatory factors; and the interaction with endothelial cells. This chapter focuses on PMN/endothelial activation with special emphasis on the PMN-endothelial interaction. The results of these events will be discussed in the trauma and the sepsis situation.

Trauma still constitutes the most frequent cause of death in the first four decades of life and ranks third over all age brackets (Baker et al. 1980, Baue 1990, Chaudry et al. 1990, National Safety Council 1986). Polytrauma plays a key role with a mortality rate ranging from 7 – 37% — depending on the severity of the injury (Nast-Kolb et al. 1991). In the past 20 years these figures have not essentially changed. However, we have to distinguish between early mortality (craniocerebral injuries, massive hemorrhage due to a tear of major vessels) and late mortality. In the latter case death sets in after the first 24 hours post trauma when sepsis is the major non-neurological cause (Chaudry et al. 1990) with a mortality rate of more than 50%. In polytrauma there is always the risk of organ dysfunction or even MODS (multiple organ dysfunction syndrome). Nast-Kolb et al. (1991) recorded 57% organ dysfunction in a group of polytraumatized patients with a fatality of 27%. Organ dysfunction and subsequent organ failure is caused by an infection which can easily lead to sepsis. Today we know that infections are associated with the release of cytokines; in the case of sepsis the toxic effect of the cytokines may lead to organ damage.

In posttraumatic organ failure we distinguish two different phases -early and late organ failure —, which by definition are caused by non-bacterial (early) and bacterial products (late) induced generalized inflammation. Organ failure is the final result of the action of inflammatory mediators, which cause a permeability increase as well as cellular edema.

Im Zuge eines Polytraumas kommt es neben der direkten Gewebsschadigung zur Ausbildung eines hypovolamischen Schockzustands mit einer Minderperfusion von lebenswichtigen Organen. Daruber hinaus werden weniger wichtige Korperteile von der Durchblutung weitgehen ausgeschaltet, wie z. B. die quergestreifte Muskulatur oder die Haut.

Posttraumatic organ damage is related to the effects of a multitude of mediators released via activation of the humoral and blood cell cascade systems. Thus several generations of toxic messengers may be released.

First I would like to express my personal thanks to both Drs. Gunther Schlag and Heinz Redl. They have worked to make this conference a superb scientific session. Its organization and .the ability to publish it are also largely related to their efforts in negotiating with both Immuno and Springer publications. What has come out of this effort is a significant forum which focuses research in the field of shock. Moreover, both the papers and their discussions are important contributions to the literature on this subject, because the discussion gives each participant the chance to interact with a group of excellent minds, each of whom has great experience in his or her respective scientific area. It is in this spirit that I am going to try and present a conceptual organization of what has gone on, not because I think it is necessarily the best, or even a good organization, because by making the attempt, you can have a straw man to challenge and by doing so alter and focus the discussion to achieve some logical conclusions, as to what we agree on and what we do not agree on, and where new directions for research should come.