Fluid Management in Sepsis: Colloids or Crystalloids? G. Marx, T. Schuerholz, and K. Reinhart

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G. Marx, T. Schuerholz, and K. Reinhart

Introduction

Sepsis and septic shock are associated with both a relative and an absolute intravascular volume deficit [1]. The absolute volume deficit occurs with fever, and includes perspiration and increased insensible loss, vomiting, diarrhea, and 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 edema [2]. In this situation, hypoalbuminemia 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 [3]. Sepsis and septic shock are, therefore, characterized by a reduction in 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 restoration and maintenance of an adequate intravascular volume in order to improve tissue perfusion and nutritive microcirculatory flow [4]. The recognition of the degree of hypovole- mia is of utmost importance. Failure to identify the extent of fluid deficit in this situation is an error resulting in low cardiac output state and multiple organ dysfunction or failure. Circulatory stability following fluid resuscitation in the septic patient is usually achieved at the expense of tissue edema formation, which may significantly influence vital organ function [5].

The risk of edema has been used to discredit each type of fluid [6]. Because crystalloid fluid distributes primarily in the interstitial space, edema is an expected fea- ture 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, 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 [7].

Fluid therapy in sepsis is aimed at restoration of intravascular volume status, hemodynamic stability, and organ perfusion. The type of fluid resuscitation, crystal-

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loid or colloid, in sepsis remains an area of intensive and controversial discussion [8]. Despite its clinical relevance and ongoing discussion for decades there has been a striking lack of studies investigating the optimal fluid strategy and including suffi- cient numbers of patients.

In four meta-analyses comparing the effects of crystalloids and colloids on patient outcome, either no clear difference between crystalloids and colloids [9 – 11], or a slight benefit of crystalloids [12], has been found [12]. However, in the meta-analysis of Velanovich [12] there was a 12.3 % difference in mortality rate in trauma patients in favor of crystalloids and for non-trauma patients, there was a 7.8 % difference in mortality rate in favor of colloid treatment. Cook and Guyatt pointed out in one edi- torial that “...original research may be more likely to advance this field than will addi- tional meta-analyses. Finally, participation in well-designed clinical trials represents the optimal approach to resolving continued controversies in patient care [13]”. Since 2001, several experimental and clinical studies have addressed the issue of fluid resuscitation in sepsis which we will discuss in this chapter.

Fluid Resuscitation in Experimental Sepsis

Evidence from experimental models can make an important contribution to under- standing the underlying pathophysiological phenomenon in fluid replacement strat- egies [14]. 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 [15]; the authors demonstrated no difference in the degree of capillary leakage between septic rats treated with normal saline or gelatin. Morisaki and colleagues, however, did not find a difference between infused crystalloid or colloid solutions in the maintenance of plasma volume using a hyperdynamic sepsis model in sheep [16]. Furthermore, using the same model, Morisaki and colleagues investigated the effects of colloid and crystalloid fluid infusion for 48 h on microvascular integrity and cellular structures in the left ventricle and gastroc- nemius muscle [16]. Despite similar circulatory response and increased organ blood flows, septic sheep treated with pentastarch (molecular weight [MW] 63 – 264 kDa) had greater capillary luminal areas with less endothelial swelling and less parenchy- mal injury than septic sheep treated with Ringer’s lactate infusion, in both muscle types. In accordance, there are more data indicating a beneficial effect of colloid solutions in sepsis under well-defined experimental conditions. It has even been suggested that a particular hydroxyethyl starch (HES) solution called pentafraction (MW 120 – 280 kDa), containing a selected category of medium weight molecules, compared to pentastarch may reduce capillary leakage by a direct sealing effect [17].

This hypothesis implies that appropriately sized HES molecules might act as plugs and seal or even restore microvascular integrity at capillary-endothelial junctions.

This suggestion has been supported mainly by laboratory investigations using ischemia-reperfusion models [18 – 22]. During sepsis using a porcine fecal peritonitis model, less pentafraction was required in comparison to pentastarch to prevent hemoconcentration [23] and pentafraction was associated with less hepatic and pulmonary structural damage [24]. In an established porcine septic shock model [25]

we used ⁵¹Cr to determine red blood cell volume and plasma volume because this technique has been shown to be accurate even in septic shock with increased microvascular permeability [26], whereas using a plasma-indicator may be associated with a marked overestimation of the plasma volume due to an increased transcapillary

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Fig. 1. Levels of plasma volume (PV) at baseline, and 6 h after induction of experimental sepsis in pigs [29]. RS: Ringer’s solution; HES 130 kDa: 6 % hydroxyethyl starch 130/0.4. All values are given as mean „ SD. * p e 0.05 versus control group; # p e 0.05 RS versus HES 130 kDa

loss of the indicator [27]. We were able to show that in this model HES and gelatin solutions maintained plasma volume suggesting the intravascular persistence of artificial colloids in the presence of capillary leakage [25]. In addition, use of Ringer’s solution was associated with an increased formation of platelet-derived microvesi- cles compared to use of artificial colloids [28]. These results suggest that the intravascular activation of platelets in experimental sepsis may be enhanced using the crystalloid, Ringer’s solution.

A HES solution with a low MW (130 kDa) has been developed with the aim of improving the pharmacokinetic effects while preserving the efficacy of the volume effect. Using our porcine septic shock model, we tested the effects of HES 130 kDa and a crystalloid regimen with Ringer’s solution on plasma volume maintenance as well as on systemic hemodynamics [29]. We found that it was possible in the presence of marked capillary leakage not only to maintain plasma volume and COP by HES 130 kDa but also as a consequence to preserve systemic oxygenation and hemodynamics (Fig. 1). Neither was the case using Ringer’s solution.

In our study, animals receiving HES 130 kDa showed a significantly higher cardiac output, oxygen delivery, and mixed venous oxygen saturation (SvO₂) than those receiving Ringer’s solution. Thus, these global parameters for tissue oxygenation indicate beneficial effects of HES 130 kDa compared to Ringer’s solution. Further- more it was not possible to prevent respiratory acidosis and arterial hypoxia in the Ringer’s solution group by the preset ventilatory pattern. The underlying reasons for this remain speculative: Ringer’s solution may increase tissue edema compared to hyperoncotic HES 130 kDa. One effect of such edema would be to retard oxygen uptake by increasing the distance from blood vessels to the mitochondria; this in turn, potentially could reduce functional capacity and contribute to the development of multiple organ failure (MOF) [30]. The basic components of the different solutions may be important as well. Recently, it has been shown that a crystalloid solution, in which lactate was substituted by ethyl pyruvate, ameliorated intestinal hyperpermeability in rats [31]. Pyruvate probably serves as an endogenous scaven- ger of reactive oxygen species (ROS), which have been implicated in the pathogene- sis of sepsis. In a murine model of lethal endotoxemia, treatment with a Ringer’s ethyl pyruvate solution instead of a Ringer’s lactate solution prolonged survival and blunted the release of interleukin (IL)-6 [32].

Investigating the effects of HES 130/0.42 and HES 200/0.5, we demonstrated that it was possible in our porcine septic shock model to significantly attenuate systemic capillary leakage by HES 130/0.42 in comparison to HES 200/0.5 [33] (Fig. 2). Both

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Fig. 2. Albumin escape rate (AER) 6 h after induction of experimental sepsis in pigs and administration of 6 % hydroxyethyl starch 200/0.5 (HES 200 kDa), 6 % hydroxyethyl starch 130/0.4 (HES 130 kDa), or control [33]. All values are given as mean „ SD. P e 0.05 versus control group; # p e 0.05 HES 200/0.5 versus HES 130/0.42. From [33] with permission

solutions were similar effective in maintaining systemic hemodynamics and oxygenation. Attenuation of systemic capillary leakage is in line with a higher plasma volume and a less pronounced positive fluid balance in the HES 130/0.42 group compared to the HES 200/0.5 group, although it needs to be stressed that the latter two differences were not statistically significant. Our result of reduced macromolecular leakage after HES 130/0.42 treatment is furthermore in agreement with other experimental observations demonstrating prevention of capillary leak syndrome by specific HES preparations in post-ischemic and septic conditions [20, 34]. Recently, Hoffmann et al. demonstrated, in a normotensive endotoxic model in hamsters, an attenuation of macromolecular leakage using HES 130/0.42 compared to crystalloid resuscitation [34]. Collis et al. showed in an in vitro model using cultured umbilical vein and arterial cells that pentafraction compared to albumin inhibited lipopolysaccharide (LPS)-stimulated von Willebrand factor (vWF) release in a dose-dependent manner but not endothelial E-selectin and neutrophil CD11b/CD18 expression, suggesting an inhibition of endothelial cell activation by pentafraction [35]. Recently, Lv et al. reported that HES 200/0.5 in septic rats may downregulate hepatic inflammatory mediator production and that these anti-inflammatory effects may be induced by inhibition of nuclear factorκB (NF-κB) and activator protein (AP)-1 [36]. In line with our results, Holbeck et al. demonstrated in an in vivo model using cat skeletal muscle that HES 200/0.5 had no direct effect on albumin microvascular permeability [37].

The mechanism by which HES 130/0.42 attenuates capillary leakage is not known.

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. Regulation of paracellular transport is associated with actin-based systems that link cells by cadherins, proteins that are important for tight junction formation. It has been shown in vitro that vascular cellular adhesion mole- cule-1 (VCAM-1), upregulated during sepsis, induces an increase in permeability by modulating cadherin function through the production of ROS [38]. 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 [39]. It has been speculated, on the basis of experimental work, that the presence of surface binding proteins, the charge of subendothelial matrix proteins, and the surface charge may be important [40]. The loss of negative endothelial charge in sepsis due to an increased protein extravasation has been demonstrated in a hyperdynamic sepsis model in rats [41].

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One might speculate that the less altered pharmacokinetics of HES 130/0.42 compared to HES 200/0.5 when administered repeatedly [42] might be a potential reason for the differences in the albumin escape rate demonstrated in our study. It appears that the differences in degree of substitution, mean MW, and concentration may be important for specific effects on capillary leakage syndrome and microcirculation [43]. HES 130/0.42 provides a relatively small range of distribution of the mean MW as well as of the degree of substitution [34]. Comparing HES 200/0.5, which accumu- lates only slightly after repetitive administration, with 6 % HES 130/0.42, a faster elimination of HES 130/0.42 did not lead to a reduction in clinical efficacy. In patients undergoing cardiac surgery, Gallandat Huet et al. [44] reported similar HES volume requirements for hemodynamic stabilization (2466 „ 516 ml for 200/0.5 versus 2550 „ 561 ml for HES 130/0.4) in both groups until 16 hours after the end of surgery.

Jungheinrich et al. found that infusion volumes of 2000 „ 424 for HES 200/0.5 and 2035 „ 446 for HES 130/0.4 were equally effective for hemodynamic stabilization up to the first postoperative day in patients undergoing orthopedic surgery [45]. Several studies have documented comparable courses of COP for HES 200/0.5 versus HES 130/0.4 [44, 45]. Jungheinrich et al. [45] showed a significantly lower in vivo MW in the HES 130/0.4 group accompanied by lower HES plasma concentrations postopera- tively, as expected from the comparison of pharmacokinetics of the two HES types.

COP depends on the concentration of oncotically active molecules, not on the HES concentration per se. For example, in the case of an in vivo molecular weight for HES 130/0.4 of about half the value for HES 200/0.5 and a difference in HES concentration of a factor of two at a certain time point, the number of oncotic active molecules in similar plasma volumes, and hence contribution to total COP, will be similar [46].

Thus, HES 130/0.42 may be more efficacious for volume expansion and even the differences in albumin escape rate might be explained by these pharmocodynamic differences between HES 200/0.5 versus HES 130/0.42.

On the other hand, the release of endotoxin in sepsis activates leukocyte-endothelial cell adhesion, capillary leakage, and changes in vascular micro-hemodynamics [47]. Hoffmann et al. demonstrated a reduction in endotoxin-induced leukocyte- endothelial cell interaction in endotoxemic hamsters using HES 130/0.42, thereby ameliorating endothelial damage [34]. Lang et al. demonstrated recently that human serum albumin preparations show modest intrinsic non-thiol-dependent anti- inflammatory properties in vitro, a phenomenon that was not observed with HES 200/0.5 [48]. The binding of neutrophil-derived myeloperoxidase to bovine aortic endothelial cells, a mediator of multiple oxidative and nitric oxide (NO)-consuming reactions, was also enhanced by HES 200/0.5 [48]. Increased NO production through inducible NO synthase (iNOS) activity was shown to decrease the expression of tight junction proteins and decrease tight junction localization in endotoxemic mice [49].

These effects were associated with gut epithelial barrier dysfunction as evidenced by increased ileal mucosal permeability. Hence, there is experimental evidence that different HES solutions may have different effects on sepsis-induced microcirculatory disorders: HES 200/0.5 may further microvascular permeability and according to Hoffmann et al. [34] one might speculate that HES 130/0.42 may have some effects on the inflammatory process, which might contribute to its beneficial effects on sepsis-induced microcirculatory disorders.

In summary there is a limited but encouraging body of experimental evidence suggesting beneficial effects of colloid resuscitation, especially with 6 % HES 130/

0.42, in short term models of sepsis.

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Fluid Resuscitation in Clinical Sepsis

Major advances in the research of fluid resuscitation have been achieved recently.

The Saline versus Albumin Fluid Evaluation (SAFE) trial including 6997 critically ill patients in Australian intensive care units (ICUs) demonstrated that the use of 4 % albumin or normal saline for fluid resuscitation resulted in similar outcomes after 28 days [50]. This was an adequately powered study to provide reliable estimates of the relative treatment effects of different resuscitation fluids. Inclusion criteria were rather non-specific, thus almost all hypovolemic patients were eligible. Patients who had undergone cardiac surgery or liver transplantation and those with burns were excluded. The primary outcome was also reported in six pre-defined subgroups, including severe sepsis, trauma, and acute respiratory distress syndrome (ARDS).

Both groups were well matched at baseline. It is noteworthy that the patients randomized to 4 % albumin received significantly less study fluid in the first three days after inclusion compared to those receiving normal saline, resulting in a greater positive fluid balance in the latter group. The two groups had similar 28-day mor- talities: albumin 20.9 % and saline 21.1 % (RR 0.99; 95 % CI 0.91 – 1.09). There was no difference in survival time, the number of patients developing MOF, ICU or hospital stay, days of mechanical ventilation, or days of renal replacement therapy. Sub- group analysis in the patients with trauma and brain injury revealed an excess of deaths with albumin use (mortality for albumin 24.5 %, mortality for saline 15.1 %;

RR 1.62; 95 % CI 1.12 – 2.34; p = 0.009). Comparing the 28-day mortality in patients with severe sepsis, the authors revealed a mortality of 30.7 % for albumin and 35.3 % for saline (RR 0.87; 95 % CI 0.74 – 1.02; p = 0.009). This study demonstrated powerful evidence that, with the exception of trauma patients with associated brain injury, it is safe to give 4 % albumin as well as saline to a heterogeneous group of critically ill patients.

Incorporating the results and data of the recruited 6997 patients from the SAFE study, the Cochrane reviewers had to remove the earlier suggestion that administration of albumin is associated with an increased risk of death [51]. They concluded against the use of albumin on the basis of cost; that in view of the absence of any evidence of a mortality benefit from albumin and the increased cost of albumin compared to alternatives such as saline, it would seem reasonable that albumin should only be used within the context of well concealed and adequately powered randomized, controlled trials. In an interesting meta-analysis, Vincent et al. deter- mined the effect of albumin administration on morbidity defined as the incidence of complications, including death in acutely ill hospitalized patients [52]. The authors identified 71 randomized, controlled trials including 3782 patients comparing the administration of albumin with that of crystalloid, no albumin, or lower-dose albumin. Patients in the included trials experienced a total of 3,287 complications, including 515 deaths and 2,772 cardiovascular, gastrointestinal, hepatic, infectious, renal, respiratory, and other complications. Albumin significantly reduced overall morbidity, with a risk ratio of 0.92 (CI 0.86 – 0.98). Control group albumin dose significantly affected the incidence of complications (p = 0.002). In 32 trials with no albumin administered to the control group, the risk ratio was 0.77 (CI: 0.67 – 0.88) compared with 0.89 (CI: 0.80 – 1.00) in 20 trials with control patients receiving low- dose albumin and 1.07 (CI, 0.96 – 1.20) in 19 trials with control group patients receiving moderate-dose albumin.

In a randomized, controlled, non blinded trial including patients with cirrhosis and spontaneous bacterial peritonitis, treatment with albumin significantly improved

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outcome in terms of morbidity and mortality [53]. 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 three months, the mortality rates were 41 % and 22 %. Yet again, the methodology has been questioned, especially the monitoring of fluid therapy and the potential lack of fluid administration in the control group [54].

In a prospective clinical study, septic patients were randomized to fluid resuscitation with albumin 5 % or HES 10 % 260/0.5 with a study endpoint of pulmonary artery occlusion pressure (PAOP) of 15 mmHg [55]. There were no differences in resulting hemodynamic status between the groups. Hankeln and colleagues compared, in a cross-over study, the effects of HES 10 % 200/0.5 and lactated Ringer’s solution on hemodynamics and oxygen transport in critically ill patients, of whom 50 % were septic [56]. Following HES administration these investigators found a significant improvement in cardiac index and oxygen transport variables, which 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 gastric intramucosal pH (pHi) measurements could be preserved, whereas the pHi decreased in patients receiving albumin 20 % indicating worsened splanchnic perfusion [57]. In another prospective, randomized study in patients with sepsis, administration of HES 10 % 200/0.5 resulted in a lower plasma concentration of adhesion molecules compared to administration of 20 % albumin [58].

Thus, a body of short-term studies support the hypothesis that the administration of HES might be beneficial for hemodynamic stabilization in patients with severe sepsis or septic shock. In comparison with gelatin, however, treatment with HES did not show a survival benefit but a higher rate of renal failure [59]. Recently, a randomized, multicenter German study, the Efficacy of Volume Substitution and Insulin Therapy in Severe Sepsis (VISEP) trial, investigated whether volume resuscitation with either modified Ringer’s lactate (n = 275) or 10 % HES 200/0.5 (n = 262) would have an effect on the morbidity and mortality of patients with severe sepsis/

septic shock [60]. It has to be stressed that this work has only been published as an abstract so far. HES administration was limited to 20 ml/kg/day, and further volume therapy in the HES group was allowed with modified Ringer’s lactate. Between 0 – 96 hours, hemodynamic goals were applied according to the algorithm introduced by Rivers et al. [61]: mean arterial pressure (MAP) 870 mmHg, central venous pressure (CVP) 88 mmHg, central venous oxygen saturation (ScvO₂) 870 %. Primary study endpoints were 28-day mortality and mean sequential organ failure assessment score (SOFA) score. At the time of the first interim analysis with 537 patients, enrollment was suspended because of differences in the frequency of acute renal failure and renal replacement therapy. Administration of 10 % HES 200/0.5 resulted in significantly faster normalization of CVP, but not of MAP and ScvO₂. There was no difference in 28-day mortality. Multivariate analysis showed that adverse renal effects were associated with the cumulative dose of HES. The authors concluded that therapy with 10 % HES 200/0.5 cannot be recommended in patients with severe sepsis/

septic shock because 10 % HES 200/0.5 is associated with development of acute renal failure in a dose-dependent fashion.

Recently, it was shown that large amounts of HES aggravate macrophage enzyme release in patients with impaired renal function. This can result in an acquired lysosomal storage disease [62]. Further adverse effects associated with the use of HES solutions are effects on clotting [63], and dose-dependent tissue deposition in many tissues but especially in the reticuloendothelial system [64]. This effect has been

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associated with MOF and death [65, 66]. Taking the results of the VISEP study and the previous study by Schortgen et al. [59], there is evidence from two large randomized trials that use of 10 % HES 200/0.5 and 6 % HES 200/0.6 – 0.66, respectively compared with Ringer’s lactate or gelatin, is associated with acute renal failure in patients with severe septsis. In view of the recent data, the safest options for colloi- dal fluid resuscitation in sepsis for early hemodynamic stabilization appear to be modified fluid gelatin and albumin used in combination with crystalloids or crystalloids alone.

Whether 6 % HES 130/0.4 can be used safely in septic patients needs to be eluci- dated. There is some experimental evidence suggesting differences between HES 130 and HES 200 [33], but this remains to be tested in adequately powered long-term (90 days) clinical studies.

Conclusion

In conclusion, based on the evidence available, achieving adequate volume loading in septic patients seems more important than the type of fluid used [67, 68]. Admin- istration of albumin is safe in septic patients, but not cost-effective in comparison with crystalloids or artificial colloids. Colloid administration may restore hemodynamic stability in patients with severe sepsis more rapidly than crystalloids. 10 % HES 200/0.5 and 6 % HES 200/0.6 – 0.66 are associated with an increased incidence of acute renal failure and need for renal replacement therapy in severe septic patients and should not be used in this group of patients. Higher cumulative doses of HES have been reported to result in life-threatening organ dysfunction and increased mortality. Colloids have various non-oncotic properties that may influence vascular integrity, inflammation, and pharmacokinetics. The clinical relevance of these properties is unknown.

As so often, further research is needed to elucidate the effects of different fluid types in sepsis. Additionally, this research must take into account the physico- chemical properties of the various colloids. Last, but not least, the paucity of high quality, well powered, long-term, randomized controlled trials needs to be empha- sized in order to address further clinical research questions on fluid resuscitation in sepsis.

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