Sepsis has a high mortality rate even when the infecting organism is known and appropriate antimicrobial therapy used [1,2]. A recent epidemiology survey of severe sepsis in the USA estimated there were 751000 cases every year, with a mortality rate of 28.6%, which increased with age, ranging from 10% in children to 38.4% in those over 85 yr old. The incidence rate is also projected to increase by 1.5% per annum . Moreover, sepsis is associated with prolonged stay in both the intensive care unit and in hospital . Over the first year following an episode of sepsis, the mortality rates remain high and sepsis-associated increased risk of dying may persist for up to 5 yr after hospitalization . Additionally, the long-term quality of life of sepsis survivors is reduced compared with age- and sex-matched controls . Given the reported morbidity and mortality, the economic burden associated with sepsis has recently been estimated at US$17 billion (€;16.8 billion) each year in the USA alone .
Sepsis and septic shock are associated with both a relative and an absolute intravascular volume deficit . The absolute volume deficit occurs with fever including perspiration and increased insensible loss, vomiting, diarrhoea, volume loss by drains or sequestration. The relative volume deficit is due to vasodilatation, venous pooling and alterations in the endothelial barrier. The functional disturbances induced by sepsis are reflected by increased blood lactate concentrations, oliguria, coagulation abnormalities and altered mental state.
Inflammatory cascading reactions including a variety of mediators that occur in sepsis induce increased microvascular permeability and capillary leakage which, in turn, result in interstitial fluid accumulation, loss of protein and tissue oedema . In this situation, hypoalbuminaemia frequently occurs as a result of transcapillary loss and impaired hepatic synthesis of albumin resulting in reduced intravascular colloid osmotic pressure (COP), which further compromises the ability to preserve intravascular volume . Sepsis and septic shock are therefore characterized by a reduction of the cardiac preload and cardiac output resulting in arterial hypotension associated with impaired tissue perfusion and organ oxygenation causing organ dysfunction.
In this clinical situation, fluid resuscitation is essential for the restoration and maintenance of an adequate intravascular volume in order to improve tissue perfusion and nutritive microcirculatory flow . The recognition of the degree of hypovolaemia is of utmost importance. Failure to identify the extent of fluid deficit in this situation is a detrimental error resulting in low cardiac output state and multiorgan dysfunction or failure. Circulatory stability following fluid resuscitation in the septic patient is usually achieved at the expense of tissue oedema formation that may significantly influence vital organ function .
The risk of oedema has been used to discredit each type of fluid. Because crystalloid fluid distributes primarily in the interstitial space, oedema is an expected feature of crystalloid fluid resuscitation. However, oedema 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, advocates of colloid therapy in sepsis argue that by maintenance of an increased COP, fluid is retained in the intravascular space, even in the presence of increased permeability .
Two main questions are asked:
- What are the possibilities to assess increased microvascular permeability?
- What is the optimal type of fluid resuscitation in this situation?
Transvascular macromolecular transport
One of the main characteristics of inflammationinduced organ injury is increased capillary leakage and oedema . Bacteraemia or endotoxaemia are associated with an increase leakage to albumin in a variety of organs [13,14]. Owing to the increased capillary permeability, enhancing transcapillary loss of macromolecules will lead to intravascular fluid loss, lower intravascular COP and hypovolaemia. The physiological background is based on Starling's hypothesis for the filtration and reabsorption of water in capillaries and the formation of lymph . Starling's hypothesis was that the difference in concentration of plasma proteins between the plasma and tissue was responsible for an oncotic pressure, which opposed the hydrostatic filtration. Thus, the driving force for fluid filtration rate across the vessel wall is determined by four pressures: the hydraulic and COPs in the vessel and in the tissue space:
JV/A = LP[Pc − Pi − σ(πc − πi)],
where JV/A is the fluid filtration flux across the capillary wall per unit area, LP is the hydraulic permeability of the capillary wall, σ is the oncotic reflection coefficient, and Pc, Pi, πc and πi are global values for the hydrostatic and COPs in the capillary and interstitial compartments. Thus, oedema formation in any tissue may be the result of increased hydrostatic driving pressures or altered integrity of the microvascular membrane . Starling's equation has been applied across the entire transendothelial barrier. However, there is growing recognition that the application of Starling's equation is much subtler than has been previously realised. While specialised pathways between and through endothelial cells enable water and small solutes such as ions, lactate, urea and glucose to pass, the passage of macromolecules (i.e. proteins) is restricted. Transvascular macromolecular transport involves convective (i.e. by large pores) and diffusive (i.e. paracellular transport through intercellular junctional pathways or via small pores) forces . The transport of solutes across the microvascular walls depends, in part, on mechanical pressure or shear stress forces, plasma and interstitial protein concentration, wall thickness, and perivascular barriers to albumin diffusion . Furthermore, certain intrinsic properties of the endothelium such as the presence of surface binding proteins, the charge of subendothelial matrix proteins and the surface charge are important . Theoretical aspects of increased microvascular permeability have recently been reviewed in detail .
Types of intravenous fluid
Principally, there are three different types of crystalloid fluid solutions: hypotonic (e.g. glucose 5% in water), isotonic (e.g. ‘normal’ or physiological NaCl 0.9% ‘saline’) and hypertonic solutions (e.g. NaCl 7.5% solution). Hypotonic solutions such as glucose 5% do not contain electrolytes and are therefore distributed throughout the total body space, including the intracellular space. After 1 h, about 8% of infused glucose 5% is retained in the intravascular compartment and therefore this solution should not be used for fluid resuscitation in sepsis . The most commonly used isotonic crystalloid solutions for fluid resuscitation are normal saline (NaCl 0.9%) and lactated Ringer's solution . Crystalloid solutions are freely permeable across the endothelial cell barrier and are thus distributed throughout the plasma and interstitial fluid. Therefore, already after a comparably short period of equilibration (20–40 min), only about 20% of an intravenously infused crystalloid solution will remain in the intravascular space to support plasma volume [20,21]. Thus, crystalloids need to be administered in volumes approximately three- to fourfold greater than those of colloids in order to achieve comparable resuscitation end-points. Obviously, this will lower the COP in the plasma . Additionally, it is important to be aware that some crystalloids may alter blood pH. Rapid infusion of unbuffered normal saline but not Ringer's lactate resulted in hyperchloraemic acidosis in patients undergoing gynaecological surgery .
Small-volume resuscitation with hypertonic saline solutions has been suggested for the immediate treatment of haemorrhagic/traumatic shock [23,24]. A small infusion of hypertonic saline rapidly decreases intracellular fluid volume, which shifts fluid into the extracellular space and therefore expands the plasma volume.
Albumin is a natural colloid with a molecular weight of about 69 000 Da. It is a comparatively small protein, which is highly soluble, with a strong net negative charge of −17 . Under normal physiological conditions albumin accounts for about 75% of the normal plasma COP because of its high concentration and small size. In human beings, the body stores of albumin are about 4.5–5.0gkg−1 and are divided between the interstitial and intravascular compartments. It is predominantly an extravascular protein: about two-thirds of the store of exchangeable albumin is in the interstitial space. It has been demonstrated that there is a circulation of albumin between the intravascular and interstitial space and a return via the lymphatic vessels . Measurement of this movement has been described in terms of circulation half-life (normally between 16 and 18h) or as a transcapillary escape rate . The transcapillary escape rate is defined as the percentage of intravascular albumin leaving the intravascular compartment per hour and a rate of 5% has been measured in healthy volunteers.
Albumin used as resuscitation fluid is derived from pooled human plasma. There should be no risk of disease transmission as albumin is heated and sterilized by ultrafiltration . Albumin solutions are monomeric, thus all molecules are of the same size and weight. There is an albumin 5% solution available that is isooncotic with a COP of about 20 mmHg and which remains within the intravascular space when the capillary membrane is intact. Albumin solutions of 20 or 25% are hyperoncotic with a COP of 80–100 mmHg, and therefore total plasma volume is expanded as fluid is pulled from the interstitial to the intravascular space.
Although albumin, from a physiological point of view, may be considered an ideal natural colloid, its use to treat hypoalbuminaemia in intensive care patients has not been shown to have beneficial effect on either mortality or morbidity [28–30]. There are already two meta-analysis published with albumin administration in the critically ill with respect to mortality. The Cochrane Injuries Group Albumin Reviewers (Cochrane Group) compared albumin administration with either crystalloid or no albumin and suggested a higher mortality in albumin recipients . A recent review analysed the use of albumin in surgical and trauma patients, as well as in patients with serious burns, hypoalbuminaemia, in high-risk neonates, in patients with ascites and other serious indications . In this meta-analysis, the relative risk for mortality for the overall population was 1.11 for all but one of the subgroups indicating a trend towards harm associated with albumin . The authors, Wilkes and Navickis, concluded that their results indicated that albumin therapy had no significant effect on overall mortality.
Manifold points of criticisms have been voiced as a response to these meta-analysis. The limitations of these meta-analysis have been reviewed elsewhere [34,35]. The proper indications for albumin as a plasma expander have been discussed in numerous consensus conferences [36–38]. It has been concluded that there is at present time no clear indication for albumin administration. The usefulness of these conferences has been questioned .
Gelatins are derived from collagen. Several types of gelatin preparations are available (3.5–5.5% solutions): succinylated, urea-linked and cross-linked. The different preparations have different electrolyte concentrations. Urea-linked gelatin is high in calcium and potassium, while succinylated preparations have low calcium and potassium contents. Gelatin preparations contain an average molecular weight of about 35 000 Da and consist of a high proportion of low molecular components which are poorly retained in the intravascular compartment. Gelatin preparations are rapidly cleared mainly by glomerular filtration and furthermore may be broken down by proteases into small peptides and amino acids in the reticuloendothelial system . Gelatin preparations do not accumulate in the body . The intravascular half-life of gelatin preparations is about 2–3 h  and therefore in order to maintain an adequate intravascular volume re-infusions are necessary . This disadvantage may be balanced by the fact that there is no dose limitation with gelatins [9,44]. The incidence of allergic reactions with gelatins is higher compared with other colloids due to their capacity for histamine release .
Dextran is a single-chain polysaccharide of bacterial origin with various molecular weights. The main types of dextran solutions are dextran 70 (average molecular weight 70 000) and dextran 40 (40 000). Dextran 70 is generally prepared as a 6% solution, while dextran 40 is available as a 10% solution. The initial plasma volume expansion provided by dextrans is high due to their high water-binding capacity: 1 g dextran 40 retains 30 mL water; 1g dextran 70 retains 20–25 mL water . Dextrans are eliminated by three different routes after intravenous administration: mostly the route is through the kidneys , whereas a smaller fraction enters the interstitial space and returns to the blood stream via the lymphatic drainage or is metabolized by certain organs . The third and smallest fraction is eliminated via the gastrointestinal tract.
Dextrans, especially dextran 40, have been reported to produce a decrease in blood viscosity , and another rheological effect of dextrans is a reduction of leukocyte adherence under ischaemic conditions . Those effects of dextrans result in a reduction of endothelial cell-blood cell interaction which may be of importance for the maintenance of good microcirculatory blood flow . Dextrans have well-described side-effects such as interference with plasma coagulation and an increased risk of bleeding , and anaphylactic reactions due to dextran antibodies [45, 53,54]. Several studies have shown that an initial injection of hapten dextran (mean molecular weight 1000 Da) before the infusion of dextran solutions will considerably reduce the incidence of anaphylactic reactions  Owing to their side-effects, the use of dextrans is declining in most European countries .
HES is a plasma expander derived from a high-polymer glucose compound produced by hydrolysis and hydroxyethylation of a highly branched starch, amylopectin. Therefore, the HESs are of vegetable origin . HES is slowly metabolized intravascularly by amylase. Small weight particles of HES are mostly eliminated by the kidneys and larger weight particles are phagocytosed in the reticuloendothelial system. HES consists of glucose units linked within the chain by α-1,4 and at the branching points by α-1,6 glycosidic bonds. The molar substitution ratio describes the average number of hydroxyethyl groups per glucose unit. The hydroxyethyl groups can be linked with the carbons 2,3 and 6 of the glucose molecule and the ratio of the C2:C6 hydroxyethylation seems to be an important factor for the breakdown rate by the alpha-amylases and other pharmacokinetic reactions . Numerous types of HES preparations with different concentrations (3, 6, 10%), and different weight averages (MW) (70 000, 130 000, 200 000, 450 000 Da) and different degrees of molar substitution ratio (0.4, 0.5, 0.62, 0.7) are available. The different HES solutions have different effects on plasma volume expansion, intravascular half-life, coagulation, COP and rheology [58,59]. Comparison of the different studies using HES solutions appears to be difficult because of their variation in the type of used solutions, group of patients and end-points of fluid therapy . For a detailed analysis of theoretical properties of HES, see . Side-effects discussed in association with HES administration include anaphylactic reactions, storage, pruritus, and interference with haemostasis and renal dysfunction. According to the data of several large prospective trials, the risk for an anaphylactic reaction associated with HES administration is low [62,63]. Data from a French multicentre survey of more than 15 000 patients reported the risk of an anaphylactic reaction associated with HES to be 0.058% per patient . The adverse effects of HES on coagulation have been well-documented [64,65]. It is caused by an interference with the factor VIII and the von Willebrand complex. This effect can be limited by using HES solutions with a lower in vivo molecular weight [66,67]. In critically ill patients, the use of albumin versus lower molecular weight HES (200/0.5) had no effect on coagulation parameters despite an administration of 4L over 5 days . HES is partly eliminated by the reticuloendothelial system, and a dose-dependent uptake in macrophages, endothelial and epithelial has been detected . Pruritus is a reported side-effect after HES administration . Assessment of the pruritus incidence after surgery is difficult as it appears weeks after the administration. In a recent study, including more than 700 patients undergoing minor elective surgery, there was no increase in pruritus 2 months afterwards when comparing HES 6% 200/0.5 with Ringer's solution . Tissue deposition of HES seems to be transitory and dose-dependent [69,71]. The effects of HES administration on renal function are under continuous discussion. Whereas in the perioperative situation no renal dysfunction was evident following HES administration , Schortgen and colleagues showed HES to be an independent risk factor for acute renal failure in severe sepsis . The methodology of this study has been questioned although being randomized and controlled [74–76]. In the situation of kidney transplantation, osmotic nephrosis-like histological lesions have been noticed retrospectively in kidney transplant recipients when HES was used for fluid resuscitation of non heart-beating cadaveric donors . A recent prospective trial using HES 200/0.62 demonstrated a detrimental effect of this HES on initial graft function . In two other studies using HES, 200/0.5 did not impair early graft function after kidney transplantation [79,80]. These data suggest that low molecular weight HES solutions, such as HES 200/0.5, may be safe.
Monitoring of fluid resuscitation
Adequate monitoring of fluid resuscitation in the critically ill patient and especially in septic patients remains a challenge. The goal of fluid resuscitation in sepsis is the restoration of tissue perfusion and normalization of cellular metabolism. The assessment of preload is one of the key haemodynamic variables in the process of haemodynamic monitoring. Fluid resuscitation in sepsis is aimed at an increase of preload in order to achieve a maximal increase in cardiac output. Clinically fluid resuscitation is frequently titrated to easy access parameters such as heart rate, mean arterial pressure and urine output.
The use of the pulmonary artery catheter has been the subject of much discussion . The usefulness of filling pressures pulmonary arterial occlusion pressure (PAOP) and central venous pressure derived from the pulmonary artery catheter has been questioned. In particular, it presumes a predictable relationship between measurements of cardiac filling pressures and actual cardiac volumes. Central venous pressure and PAOP are assumed to be equivalent to right and left ventricular end-diastolic pressure, which again are assumed to reflect the right and left ventricular enddiastolic volumes. This is not always the case especially in critically ill patients, e.g. septic patients who have an abnormality of compliance of the left or right ventricle .
Echocardiography seems to be a highly specific monitoring instrument that is not yet available for every critically ill patient due to its expense and high requirements on training to use the technique appropriately.
The arterial transpulmonary thermodilution technique offers the possibility of measuring intrathoracic blood volume as a preload marker . Experimental and clinical data suggest that intrathoracic blood volume may be a better indicator of the cardiac preload in ventilated patients compared with traditional PAC-derived central venous pressure and PAOP [84,85]. A dynamic parameter of volume responsiveness may be the variation of stroke volume. The increase of intrathoracic pressure during inspiration in the mechanically ventilated patient leads to a temporary reduction of cardiac preload, and in consequence to a temporarily reduced stroke volume. This phenomenon can be visualized as undulating variations in the course of the arterial pressure curve in hypovolaemic patients. The stroke volume variation has been described as a highly sensitive parameter to quantify responsiveness to preload changes [86,87].
Furthermore, there is evidence that assessment of central venous oxygen saturation may be helpful in sepsis . The measurement of regional perfusion in order to detect inadequate tissue perfusion has been suggested as being helpful in guidance of fluid resuscitation. Gastric tonometry has been proposed as a method to assess regional perfusion in the gut by measuring ΔPCO2 . However, the relationship between gastric tonometry and gastrointestinal perfusion seems to be more complex than previously thought . Convincing data that demonstrate the ability of tonometry-guided therapy to improve outcome remain elusive .
Assessment of capillary leakage in sepsis
An increase of microvascular permeability is an early sign of endothelial damage . During severe sepsis and septic shock, an increased microvascular permeability, the extravasation of albumin and other macromolecules from the plasma into the interstitial space result in hypovolaemia, haemodynamic instability and generalized oedema due to intravascular fluid losses .
Staub and colleagues analysed lung microvascular permeability in sheep , measuring plasma and lung lymphatic flow and protein concentration. Using the same model, Brigham and colleagues demonstrated the increased microvascular permeability caused by Pseudomonas bacteraemia . Measurement of wet weight: dry ratios has been performed frequently for experimental assessment of pulmonary oedema . In experimental settings, radioactive tracers have been used to measure increased microvascular permeability accurately. Gorin and colleagues measured pulmonary transvascular protein flux in sheep using 113mindium labelled transferrin and 99mtechnetium-labelled erythrocytes using a gamma camera .
After the initial evaluation of a sepsis-induced increased microvascular permeability in the pulmonary circulation, histological and ultrastructural changes in non-pulmonary organs during early hyperdynamic sepsis could be demonstrated . Groeneveld and colleagues analysed the capillary leakage syndrome (CLS) in the lung and abdomen during endotoxaemia in pigs using a dual radionuclide method (99mtechnetium and 131iodine serum albumin) . A tissue/ organ- and insult-dependent alteration in radioiodine-labelled albumin flux was demonstrated in a rodent model of sepsis . Following an abdominal bacteraemia or endotoxic challenge, capillary permeability increased mainly in the liver, heart, colon and kidneys. There were also regional differences in permeability dependent on time. Filep introduced a method to evaluate the albumin escape rate by using 51chromium-tagged erythrocytes and 125iodine albumin to measure the systemic increase of capillary permeability to albumin in a rodent model . Marx and colleagues modified this method, evaluating systemic capillary leakage in a porcine faecal peritonitis model of sepsis .
Another measurement of capillary leakage involves monitoring (with video images) the leakage of fluorescein (FITC)-labelled albumin and rhodamine dye from the pulmonary capillaries into the alveoli . This method has been used in different experimental settings, for example, to evaluate pulmonary microvascular changes during sepsis  or to assess the modulation of coronary venular permeability to albumin by different flow rates .
Sakai and colleagues suggested simultaneous measurement of initial distribution volume of indocyanin green (ICG) and glucose as a method to determine generalized capillary protein leakage in septic dogs .
Papadopoulos and colleagues recently showed (by investigating brain tissue using light and electron microscopy) that faecal peritonitis causes substantial oedema in pig cerebral cortex . Sepsis also resulted in neuronal injury, disruption of astrocytic end-feet and swollen rounded erythrocytes. The authors suggested that these morphological changes might be sufficient to underlie the clinical features seen in septic encephalopathy.
Regardless of its clinical importance, there are no standardized criteria available for diagnosis of capillary leakage. Assessment of fluid distribution and balance in septic patients with massive fluid retention is very difficult . Early diagnosis of capillary leakage is of particular interest because capillary leakage would increase the possibility for early and specified treatment and the evaluation of the efficacy of therapeutic efforts. It is important to distinguish between capillary leakage and other hypo-oncotic conditions or clinical situations presenting fluid retention like renal or hepatic failure. For a better understanding of the pathophysiology and for the development of new therapeutic approaches, a more defined description of CLS is needed. The proposed criteria for clinical assessment of CLS so far have be non-specific or have limited bedside applicability: capillary leakage has been defined as non-cardiogenic generalized oedema and haemodynamic instability  or >3% increase of body weight within 24h, combined with generalized oedema . It must be stressed that calculated fluid balances are not predictive for actual weight changes in critically ill patients . Raijmakers and colleagues reported about the value of a dualradionuclide method using 67gallium transferrin and 99mtechnetium-labelled erythrocytes to measure pulmonary oedema  (Table 1). This is considered as an interesting approach, but obviously this sophisticated technique is not widely available. Margarson and Soni used the transcapillary escape rate of 125iodine-labelled albumin as a surrogate measurement of CLS . The limitations of this method are the recirculation of radiolabelled albumin from the tissues via the lymphatic system of which the degree cannot be measured. As albumin is distributed throughout extracellular compartments, synthesis and catabolism is influenced by many different factors. Thus, maintenance and the increase of serum albumin concentrations in critically ill patients may be due to a subsequent redistribution. This redistribution may cause secondary to increased vascular permeability a less rapid reduction in serum albumin concentrations. As a compensatory mechanism, there might be an increased clearance of interstitial fluid by increased lymphatic flow . Moreover, the clinical applicability of any radioactive tracers is limited due to radioactive contamination and dye accumulation and the disadvantages especially in repeated measurements are obvious.
An increased amount of extravascular lung water has been suggested as a morphological correlate for pulmonary oedema  and been used for analysis of pulmonary capillary leakage . Currently, available clinical systems measure extravascular lung water by a double indicator (indocyanin green and heat) or a single indicator thermodilution (heat) technique. The accuracy of both, double [114–116] and single  indicator thermodilution techniques have been demonstrated gravimetrically. In animals, the sensitivity rate has been estimated to be 81% and the specificity rate as 97% . The coefficient of variation for repeated measurements of extravascular lung water has been reported to be 8–9% in human beings and 6–7% in animals, respectively . There are limitations of the thermal-dye method including overestimation of the extravascular lung water at normal levels of water content  and perfusion dependence. Thus, severe alterations of lung perfusion may lead to an underestimation of the water content using the thermal dye dilution method . When significant proportions of pulmonary tissue are excluded from the pulmonary circulation, the indicators do not reach non-perfused areas and therefore both intra- and extravascular fluid pools may be undetected by the indicators .
Christ and colleagues  modified the technique of venous congestion plethysmography first described by Whitney to assess non-invasively the filtration capacity as a measure of microvascular water permeability and isovolumetric venous pressure, a value related to the balance of filtration forces across the microvasculature [122,123]. Using this method, the authors could demonstrate an increased microvascular water permeability in patients with septic shock . However, the technique of venous congestion plethysmography comprises some limitations. It requires a sedated or co-operative patient, because movement would cause artefacts. Furthermore, if the isovolumetric venous pressure is high and the diastolic blood pressure low (as in some septic patients), the measurement of the filtration capacity is not accurate because fluid filtration is only observed at high cuff pressures that are close to the diastolic arterial pressure . The above-mentioned method of simultaneous measurement of the initial distribution volume of indocyanin green and glucose as a method to determine generalized capillary protein leakage in animals  has been also evaluated in septic patients . In a clinical study in non-septic blunt trauma patients, renal albumin excretion has been used as a surrogate for capillary leakage . However, this approach is not recommended in septic patients owing to the frequent occurrence of renal dysfunction/failure. Recently, a set of non-invasive diagnostic determinants for the CLS has been suggested  (Table 1). Initially, the reliability of a non-invasive measurement of extracellular fluid volume using bioelectrical impedance analysis compared with inulin was assessed. Thereafter, measurement of an increased extracellular fluid volume using bioelectrical impedance analysis combined with the response of COP to albumin infusion in septic shock patients has been demonstrated as a non-invasive method to diagnose the CLS applicable at the bedside. Nevertheless, despite recent developments in non-invasive measurements of capillary leakage, the diagnosis of the CLS in septic patients remains difficult and challenging in daily clinical routine.
Fluid resuscitation in sepsis with capillary leakage
Sepsis is associated with a profound intravascular fluid deficit due to capillary leakage. Fluid therapy is aimed at restoration of intravascular volume status, haemodynamic stability and organ perfusion. The type of fluid resuscitation, crystalloid or colloid, in sepsis with capillary leakage remains an area of intensive and controversial discussion . Until today, there are no definitive clinical prospective studies available to answer this question. In four meta-analyses comparing the effects of crystalloids and colloids on patient outcome, either no clear difference between crystalloids and colloids [129–131] or a slight benefit by crystalloids has been found . However, in this meta-analysis of Velanovich, there was a 12.3% difference in mortality rate in trauma patients in favour of crystalloids, and for non-trauma patients there was a 7.8% difference in mortality rate in favour of colloid treatment.
Despite its clinical relevance and ongoing discussion for decades, there is a striking lack of contemporary studies including a sufficient number of patients aiming at the investigation of the optimal fluid strategy. This reflects 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 that may influence the outcome . There is a clear need to identify other appropriate end-points enabling conclusive research in this area.
Considering these problems, it is not of surprising that there are more data from animal models available in comparison with clinical studies. As experimental models can make an important contribution in gathering much required evidence in fluid replacement strategies , they will be discussed in the following as well as the clinical studies involving septic patients.
In a hyperdynamic porcine septic shock model, Kreimeier and colleagues  found that smallvolume resuscitation using hypertonic saline dextran or 6% dextran 60 is superior to Ringer's lactate in restoring intravascular volume at constant plasma COP and favours high cardiac output and high intestinal blood flow . In septic hamsters, hypertonic saline attenuated plasma volume loss with or without dextran . A relationship has been confirmed between reduced COP and intestinal hypoxia and the development of oedema . Holbeck and colleagues  demonstrated in an in vivo model (using cat skeletal muscle) that synthetic colloids such as HES, gelatin and dextran have no direct effect on albumin microvascular permeability. It has even been suggested that a particular HES solution called pentafraction, containing a selected category of medium weight molecules, compared with pentastarch may reduce capillary leakage by a direct sealing effect . This hypothesis implies that appropriately sized HES molecules might act as plugs and seal or even restore microvascular integrity at capillary-endothelial junctions. It has been supported mainly by laboratory investigations using ischaemia-reperfusion models [140–144]. During sepsis, pentafraction in comparison with pentastarch was less required to prevent haemoconcentration using a porcine faecal peritonitis model  and was associated with less hepatic and pulmonal structural damage . In septic sheep, pentafraction showed no benefit in tissue injury over pentastarch . However, only very few investigators have used accurate methods as radionuclide tracers in order to evaluate the interaction between a volume replacement solution and capillary leakage in sepsis [97,148]. Van Lambalgen and colleagues reported in a rodent endotoxin model a decrease in plasma volume after infusion of a crystalloid solution and an increase after the administration of gelatin . The authors also demonstrated no difference in the degree of capillary leakage between septic rats treated with normal saline or gelatin, whereas Morisaki and colleagues did not find a difference between infused crystalloid or colloid solutions in the maintenance of plasma volume using a hyperdynamic sepsis model in sheep. However, they investigated the effects of colloid and crystalloid fluid infusion for 48h using this model on microvascular integrity and cellular structures in the left ventricle and gastrocnemius muscle . Despite similar circulatory response and increased organ blood flows, greater capillary luminal areas with less endothelial swelling and less parenchymal injury were found in septic sheep treated with pentastarch versus Ringer lactate infusion in both muscle types. In accordance, there are more data indicating the beneficial effects of colloid solutions in sepsis under well-defined experimental conditions. Recently, we demonstrated in a porcine model of septic shock with concomitant CLS that it is possible to maintain plasma volume by the artificial colloids modified fluid gelatin 4 and 8% (MFG 4%, MFG 8%), and HES 6% 200/0.5, but not with Ringer's solution despite increased microvascular permeability . Whereas in septic patients a reduced COP has been reported , colloid osmotic pressure increased in animals receiving colloids, which indicated a better intravascular persistency. This may be due to the infusion of the colloid solutions being hyperoncotic in pigs .
Theoretically, with a capillary leak – which allows the escape of albumin – one would expect the similar disappearance should have allowed the escape of 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 suggesting that the presence of surface-binding proteins, the charge of subendothelial matrix proteins and the surface charge are important [151–153]. The loss of a negative endothelial charge in sepsis due to an increased protein extravasation has been demonstrated in a hyperdynamic sepsis model in 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 capillary leak syndrome .
In 26 patients, Rackow and colleagues  compared in a randomized controlled trial with hypovolaemic or septic shock crystalloid and colloid resuscitation at a similar PAOP. Resuscitation with crystalloids resulted in a significantly higher incidence of pulmonary oedema diagnosed by chest radiography than did resuscitation with colloids.
Recently, Ernest and colleagues demonstrated in a randomized controlled trial that patients with sepsis receiving albumin 5% have an expansion of the extracellular volume twice the infused volume compared with those receiving normal saline . This suggests that infusing an excessive amount of colloid can cause interstitial fluid overload. Indeed, in rats, expansion of the plasma volume could be demonstrated with colloids enhancing transport of plasma protein from the vascular to the interstitial compartment due to dissipative transport of albumin . Furthermore, in sepsis, lymphatic propulsive activity is depressed, thus interstitial fluid is cleared with greater difficulty. In contrast, Sibbald and colleagues investigated pulmonary microvascular flux using one low and one high molecular weight radiotracer in patients with adult respiratory distress syndrome (ARDS), of whom many had sepsis. After administration of hyperoncotic albumin – in combination with frusemide if required to avoid an increase of the PAOP – the authors did not detect a difference in clearance of both radiotracers . Thus, they concluded that albumin did not increase pulmonary transmicrovascular flux.
In a recent randomized controlled non-blinded trial, including patients with cirrhosis and spontaneous bacterial peritonitis, treatment with albumin significantly improved outcome in terms of morbidity and mortality . Renal impairment developed in 33% of the patients in the control group but in only 10% of those in the albumin group. The in-hospital mortality rates were 28 and 6%, respectively, and at 3 months the mortality rates were 41 and 22%. Yet again, the methodology has been questioned, especially the monitoring of fluid therapy and fluid administration of the control group .
In the above-mentioned porcine septic shock model, animals receiving Ringer's solution demonstrated impaired systemic oxygenation compared with the colloid solutions . The underlying mechanism may be that the Ringer's solution may increase tissue oedema compared with hyperoncotic colloid solutions. One effect of such an oedema 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 than those receiving MFG4% and MFG8%. Recent experimental work suggested that HES improves rheology by decreasing blood viscosity . Additionally, it has been postulated that HES may improve rheology by removing plasma proteins from the endothelial glycocalix . Impaired systemic haemodynamics 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 contrast, Morisaki and colleagues found in a septic sheep model no difference in DO2 when comparing two starch solutions and one crystalloid solution . In a prospective clinical study, septic patients were randomized to fluid resuscitation with albumin 5% or HES 10% 260/0.5 with a study end-point of PAOP = 15 mmHg . There were no differences in the resulting haemodynamics between the groups. Hankeln and colleagues compared in a cross-over study HES 10% 200/0.5 and lactated Ringer's solution on haemodynamics and oxygen transport in critically ill patients, of whom 50% were septic . Following HES administration, they found a significant improvement in cardiac index and oxygen transport variables that could not be achieved by the lactated Ringer's solution. In septic patients receiving HES 10% 200/0.5 over 5 days, splanchnic perfusion assessed by pHi measurements could be preserved whereas the pHi decreased in patients receiving albumin 20%, indicating deteriorated splanchnic perfusion . In another prospective randomized study, administration of HES 10% 200/0.5 compared with albumin 20% in sepsis resulted in a lower plasma concentration of adhesion molecules . These results suggest the effects of specific fluid therapy on the immune function during inflammation. Collis and colleagues showed in an in vitro model using cultured umbilical vein and arterial cells that HES compared with 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 that might in turn explain beneficial effects on systemic haemodynamics and oxygenation.
In conclusion, based on the evidence available, it is important to guarantee adequate volume loading in septic patients rather than the type of fluid used . Unfortunately, the studies that have been included in the recent meta-analysis are partly flawed. General approaches have substantially changed over the years; types, doses and duration of fluid infusion vary significantly between different studies. Moreover, the studies deal with very heterogeneous patient populations. Although at present it is still impossible to give a specific recommendation about the choice of fluid resuscitation, it is worth noting that there is a limited but encouraging body of experimental and clinical evidence suggesting the beneficial effects of colloid resuscitation in sepsis. As so often, further research is needed to elucidate the effects of different fluid types on increased microvascular permeability, the subsequent effects and morbidity. To be conclusive, these studies must distinguish between septic patients with capillary leakage and other types of critically ill patients. Additionally, they must take into account the physicochemical properties of the various colloids . Lastly, appropriate models and study end-points need to be developed as mortality does not seem a useful study end-point for fluid resuscitation.
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