Drug Therapy

Fluids

Sepsis is associated with a profound intravascular fluid deficit due to microvascular leak syndrome. In this clinical situation, fluid therapy is essential for restoration and maintenance of an adequate intravascular volume in order to improve tissue perfusion and nutritive microcirculatory flow. Circulatory stability following fluid resuscitation in the septic patient is usually achieved at the expense of tissue edema formation that may significantly influence vital organ function. The risk of edema has been used to discredit each type of fluid. Because crystalloid fluid distributes primarily in the interstitial space, edema is an expected feature of crystalloid fluid resuscitation. However, edema is also a risk with colloid fluid resuscitation, especially in the presence of increased microvascular permeability, as colloids do not remain in the intravascular compartment and the leakage of macromolecules might result in an increase of interstitial oncotic pressure and the expansion of the interstitial compartment. On the other hand, the advocates of colloid therapy in sepsis argue that by maintenance of an increased colloid osmotic pressure, fluid is retained in the intravascular space, even in the presence of increased permeability.

Until today, there has been no definitive answer to this question. In four meta-analyses comparing the effects of crystalloids and colloids on patient outcome, either no clear difference between crystalloids and colloids, or a slight benefit related to crystalloids, has been found. In view of the clinical relevance and the fact that this has been an ongoing discussion for decades, there is a striking lack of contemporary studies including sufficient numbers of patients aiming at the investigation of the optimal fluid strategy. One reason is the lack of appropriate clinical study end points for fluid resuscitation. Although mortality is an obvious end point, fluid therapy is only one factor within a very complex situation, which may influence the outcome. Considering these problems it is not surprising that there are more data from animal models available in comparison to clinical studies.

In a hyperdynamic porcine septic shock small-volume model, hypertonic saline-dextran or 6 percent dextran 60 was superior in restoring intravascular volume at constant plasma COP in comparison to Ringers' lactate, resulting in higher cardiac output and intestinal blood flow. In septic hamsters hypertonic saline attenuated plasma volume loss with or without dextran. A relationship could be confirmed between reduced colloid osmotic pressure and intestinal hypoxia and development of edema. In an in vivo model, using cat skeletal muscle, synthetic colloids such as HES, gelatin, and dextran had no direct effect on albumin microvascular permeability. A particular HES solution called pentafraction, containing a selected category of medium-weight molecules, might reduce microvascular leakage by a direct sealing effect. This hypothesis, which implies that appropriately sized HES molecules might act as plugs and seal or even restore microvascular integrity at capillary-endothelial junctions, is mainly based on laboratory investigations using ischemia-reperfusion models. In septic pigs less pentafraction in comparison to pentastarch was required to prevent hemoconcentration. Pentafraction was associated with less hepatic and pulmonary structural damage. In septic sheep pentafraction diminished tissue injury, but did not show an advantage in comparison to pen-tastarch. However, very few investigators used accurate methods such as radionuclide tracers in order to evaluate the interaction between fluid therapy and microvascular leak syndrome in sepsis. In endotoxemic rodents, plasma volume decreased after infusion of a crystalloid solution and increased after the administration of gelatin. Interestingly, no difference in the degree of microvascular leakage between septic rats treated with normal saline or gelatin could be demonstrated. In septic sheep similar amounts of crystalloid or colloid solutions were required to maintain plasma volume. Despite similar circulatory response and increased organ blood flows, colloid infusion for 48 hours preserved microvascular integrity and cellular structures in the left ventricle and gastrocnemius muscle. In accordance there are more data indicating beneficial effects of colloid solutions in sepsis under well-defined experimental conditions. Recently, our group demonstrated, in a porcine model of septic shock with concomitant microvascular leak syn drome, that it is possible to maintain plasma volume by the artificial colloids modified fluid gelatin 4 percent and 8 percent (MFG4%, MFG8%), and 6 percent HES 200/0.5, but not with Ringer's solution despite increased microvascular permeability [8].

Theoretically, in the presence of a microvascular leak— which allows the escape of albumin—one would have expected the escape of the smaller gelatin molecules, as well as the escape of HES 200/0.5, which contains a substantial fraction of molecules smaller than albumin. Some experimental work suggest that the presence of surface binding proteins, the charge of subendothelial matrix proteins, and the surface charge are important. The loss of negative endothelial charge in sepsis due to an increased protein extravasation was demonstrated in a hyperdynamic septic rats. Although this may have contributed to the retention of colloids, the explanation seems to be speculative at the moment and further studies are needed to elucidate the exact mechanism involved in the intravascular retention of colloids in microvascular leak syndrome.

Septic patients receiving albumin 5 percent had an expansion of the extracellular volume twice the infused volume compared to those receiving normal saline. This suggests that infusing excessive amount of colloid can cause interstitial fluid overload. Indeed, in rats expansion of plasma volume with colloids enhanced transport of plasma protein from the vascular to the interstitial compartment because of dissipative transport of albumin [9].

In the porcine septic shock model just mentioned, animals receiving Ringer's solution demonstrated impaired systemic oxygenation compared to the colloid solutions [8]. The underlying mechanism may be that Ringer's solution increases tissue edema compared to hyperoncotic colloid solutions. One effect of such an edema would be to retard oxygen uptake by increasing distances from the blood vessel to the mitochondria. Furthermore, in the colloid groups HES-infused animals showed a significantly higher cardiac output, systemic oxygen delivery, and lower oxygen extraction ratio compared to those receiving MFG4% and MFG8%. Recent experimental work suggested that HES improves rheology by decreasing blood viscosity. Additionally, HES may improve rheology by removing plasma proteins from the endothelial glycocalix. Impaired systemic hemodynamics in the MFG4 and MFG8% groups might indicate an influence on rheology and impaired tissue oxygenation due to an increase in plasma viscosity in porcine sepsis. In septic patients, there were differences in hemodynamics after receiving albumin 5 percent or HES 10 percent 260/0.5. The administration of HES 10 percent 200/0.5 compared to lactated Ringer's solution improved cardiac index and oxygen transport variables in septic patients, which could not be achieved by the lactated Ringer's solution. In septic patients HES 10 percent 200/0.5 preserved splanchnic perfusion assessed by pHi measurements for more than 5 days, whereas the pHi decreased in patients receiving albumin 20 percent, indicating deteriorated splanchnic perfusion. The administration of HES 10 percent

200/0.5 compared to 20 percent albumin in sepsis resulted in a lower plasma concentration of adhesion molecules. These results suggesting effects of specific fluid therapy on the immune function during inflammation. In vitro HES, compared to albumin, inhibited lipopolysaccharide-stimulated vWF release but not endothelial E-selectin and neutrophil CD11bCD18 expression in a dose-dependent manner, thus suggesting an inhibition of endothelial cell activation by HES. Hence, there is some evidence that HES solutions may have some beneficial effect on the inflammatory process, which might in turn explain beneficial effects on systemic hemodynamics and oxygenation.

Anti-inflammatory Agents

Despite identification of several targets for pharmacological manipulations, at present there are no clinically effective specific therapies available to counteract sepsis-induced microvascular leak. In vitro and experimental data suggest that anti-inflammatory drugs may have the potential to attenuate or even to prevent microvascular leak. A variety of drugs interfering with the proinflammatory response including blockade of TNF-a, blockade platelet activating factor, or b-adrenergic-agent have been shown to effectively attenuate endothelial cell dysfunction in animal models of inflammation, but they generally failed when tested in large trials in septic patients. Recently, more specific targets have been identified [6]. First, the blockade of endothelial receptor is a potential target. Antihistamines and endothelin antagonists, as well as blockers of adhesion molecules and integrin CD11/CD18, are currently under clinical investigation. Furthermore, the administration of angiopoietin-1 has been shown to counteract VEGF and inflammatory-induced microvascular leak.

Modulation of signal transduction has been identified as another promising target to modulate endothelial function. The elevation of cytoplasmic calcium ion concentration of the endothelial cell is central for the induction of the endothelial hyperpermeability. The role of several protein kinases in changing intracellular calcium ion concentration and regulating endothelial permeability has been recognized as well. Another therapeutic strategy could be the enforcement of the barrier function by inhibiting the decrease in cAMP. Suitable agents include b-adrenergic-agents or phosphodiesterase inhibitors. As complement activation contributes significantly to the inflammatory reaction in sepsis, inhibition of complement activation has become a target for pharmacological research [10]. Endogenous soluble complement inhibitors, such as C1 esterase inhibitor, recombinant complement receptor 1, or blocking C5a have been developed to attenuate complement cascade reaction. An example of a successful application of the principle of complement inhibition in treatment of microvascular leak is the clinical use of C1 esterase inhibitor concentrate purified from human plasma. C1 esterase inhibitor concentrate is primarily indicated for the treatment of angioedema, but experimental and clinical evidence suggest that complement inhibition might also be an effective tool in the treatment of sepsis-induced microvascular leak.

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