Volume expanders for spontaneous bacterial peritonitis: Are we comparing oranges with oranges?
Authors: Florence Wong
Journal: Hepatology (2005)

Spontaneous bacterial peritonitis (SBP) is a common and often fatal complication occurring in approximately 20%-30% of patients with cirrhosis and ascites.1 It is associated with significant morbidity and mortality.2 In addition to the usual problems associated with infection, patients with SBP are particularly susceptible to the development of hepatorenal syndrome (HRS), a functional but potentially reversible form of renal failure that is seen in patients with advanced cirrhosis.3 It is estimated that at least 30% of patients with SBP will develop hepatorenal syndrome despite adequate treatment of their infection.3 SBP, spontaneous bacterial peritonitis; HRS, hepatorenal syndrome; NO, nitrous oxide; HES, hydroxyethyl starch; vWF-Ag, von Willebrand related antigen. The pathophysiology leading to the development of HRS in patients with SBP is complex. It probably begins with translocation of bacteria from the intestinal lumen to the systemic circulation and then to the ascitic fluid.4 Once in the ascitic fluid, various bacterial derived toxins incite the production of proinflammatory cytokines,5 responsible for many pathophysiological changes that ultimately lead to tissue injury and organ failure.6 One such response is an exaggeration of the systemic arterial vasodilatation already present in advanced cirrhosis. These hemodynamic changes are closely related to an increase in the production of vasodilators, including nitric oxide (NO), which are abundantly released following stimulation with cytokines and endotoxins.7, 8 This exaggerated systemic arterial vasodilatation is associated with a decreased systemic vascular resistance, which further reduces the already diminished effective arterial blood volume. This vasodilatation leads to further activation of the already elevated vasoconstrictive neurohumoral systems and, in an attempt to replenish the circulatory volume, results in more sodium and water retention.9 The renal circulation is particularly sensitive to the effects of these vasoconstrictor systems. The final response is reduced renal blood flow and glomerular filtration and, ultimately, renal failure. Therefore, it stands to reason that in patients with SBP, the effective circulation should be adequately filled to reduce the likelihood of development of HRS. Indeed, volume expansion has been advocated as an adjunct to antibiotic therapy in the management of SBP.10 In a study assessing the effect of albumin infusion on renal function and survival in patients with SBP, 126 patients were randomized to receive either cefotaxime or cefotaxime with albumin.10 Albumin infusions prevented the rise in renin, decreased the incidence of renal failure and improved mortality from 29% to 10% when compared to cefotaxime alone. These findings suggest that filling the intravascular volume improved circulatory parameters and reduced the risk of renal failure. The patients who benefited the most were those with elevated baseline urea levels, that is, those patients who were at a higher risk for developing HRS fared the best. It is unclear whether albumin infusions were necessary in patients with normal baseline urea, bilirubin <4 mg/dL or Protime >60% of control, as their mortality rate was only 4% without versus 0% with albumin. The study did not explore whether fluid support with crystalloids or other colloids would have produced the same results. The reason why albumin is effective in the prevention of HRS in patients with SBP lies in its many unique properties.11 Although albumin is a relatively small protein, it accounts for 75% of protein molecules in plasma in healthy individuals, and therefore it is also responsible for 75% of plasma colloid oncotic pressure.11 As albumin is also a negatively charged molecule, it attracts sodium and hence water, becoming a major contributor to plasma osmotic pressure. Thus, albumin is a very good plasma volume expander, especially in situations of reduced intravascular volume such as shock or vascular collapse. In addition, albumin participates in many other functions independent of its effects on oncotic pressure.12 For example, the negative charges on albumin will attract positively charged cations, thus allowing albumin to function as a transport protein. Albumin also binds many endogenous and exogenous substances including many vasodilators such as NO and bile acids.13 Albumin contains thiol groups, avid scavengers of reactive oxygen and nitrogen species, thereby reducing oxidative stress. Albumin also stabilizes capillaries, reduces capillary permeability and interferes with neutrophil adhesion to the capillary endothelium.12 All of these actions tend to reduce the inflammatory response. Therefore, albumin has been favored by some as the solution of choice for resuscitation in critical care units, especially when sepsis is also present.14 However, many critics question the use of albumin in situations of reduced intravascular volume. An international survey of intensivists from mostly European countries reported that starch was the preferred volume expander compared to albumin.15 A recent large clinical trial including 7,000 critically ill patients showed that normal saline was equally effective as 4% albumin as resuscitation fluid, with no differences in terms of morbidity, length of stay in either intensive care units or in hospital, and survival.16 A Cochrane review actually reported an increased risk of death with albumin administration to critically ill patients.17 Because albumin is derived from human serum, there are concerns with the transmission of known and unknown infections with albumin infusions.18 Finally, bolus administration of 20% albumin to patients with sepsis can lead to a faster decline in plasma albumin concentrations, suggesting faster degradation and reduced effectiveness of albumin in these patients.19 In its defense, a recent metaanalysis on the use of albumin in critically ill patients showed that at least patient survival was no worse in those who received albumin when compared to those who did not.20 Therefore, until further clinical trials are completed, the use of albumin as a volume expander appears to be here to stay, especially if it has not been shown to be definitively harmful. The major drawback is its cost. Albumin is expensive whereas other volume expanders are not.12, 15 To prove that albumin is worth the cost, it has to be shown to be superior than other plasma expanders. Therefore, the study by Fernández and colleagues in this issue of HEPATOLOGY is timely.21 They compared the use of albumin versus another colloid solution, namely hydroxyethyl starch (HES), as a volume expander in patients with ascites and SBP. Specifically, the authors studied the effects of albumin versus HES on systemic hemodynamics and renal function in 20 patients with known SBP. Baseline hemodynamic, and laboratory measurements as well as abdominal ultrasound to assess renal vascular resistance were performed within 12 hours of the diagnosis of SBP. Patients were randomly assigned to receive either albumin (10 patients) or HES (10 patients) at the same dose (1.5 g/kg body weight following baseline measurements and 1 g/kg body weight on day 3). The duration of infusion was 6 hours for albumin and 18 hours for HES owing to the higher volume of fluid required for the administration of the latter solution. All measurements were repeated 48 hours after resolution of infection. The authors found that albumin was able to increase plasma volume, improve systemic hemodynamics and renal function. Albumin also had an effect on the endothelium as indicated by a significant decrease in von Willebrand related antigen factor (vWF-Ag). This factor is synthesized by endothelial cells and released in response to mechanisms that also stimulate NO release. Therefore, a reduction in vWF-Ag levels would also suggest less NO released from the endothelium. In contrast, those patients who received HES did not show any changes in their systemic hemodynamics, due primarily to the fact that plasma volume was unchanged. As a consequence, 3 patients in the HES group developed circulatory dysfunction and one developed acute renal failure. Dr. Fernández and colleagues therefore concluded that albumin was superior to HES in preventing deleterious hemodynamic changes in patients with SBP. When one dissects the results of the study, it is obvious that despite its inability to ameliorate systemic hemodynamics nor the hormonal profile, HES infusion did lead to a significant reduction in the serum creatinine levels in these patients, similar to albumin infusion.21 Therefore, it would appear that HES was functioning adequately as a plasma volume expander to counteract the renal vasoconstriction; it just was not effective enough to completely eliminate the mismatch between vascular capacitance and intravascular volume. That is, HES was not able to overcome the reduced effective arterial blood volume present in patients with cirrhosis and SBP. In order to understand this finding, we need to examine the properties of HES solutions. HES solutions are modified natural polymers of amylopectin. Their physical and chemical characteristics are defined by the degree of hydroxyethylation, which is the major determinant of circulating half-life, and also by their molecular weight, which determines colloidal activity. The HES used in the study of Fernández et al. was a 6% solution of HES 200/0.5. This solution has a molecular weight of 200 kd and a 50% substitution of the glucose moieties by hydroxyethyl radicals.22 Hydroxyethylation can occur at carbon positions 2, 3, or 6 of the glucose molecule, and the number of hydroxyethyl radicals attached to carbon position 2 versus position 6 or the C2/C6 hydroxyethylation ratio determines the rate the starch is metabolized. Two HES solutions with the same molecular weights and percentage substitution, but a different C2/C6 ratio will have totally different characteristics. For example, a HES 200/0.5 solution with a C2/C6 ratio of 6 (HES 200/0.5/6) will be metabolized much faster than another HES 200/0.5 solution with a C2/C6 ratio of 13 (HES 200/0.5/13).23 The former also causes minimal, if any, changes in vWF-Ag, whereas the latter can cause an average of 18% reduction in vWF-Ag.22 Because we do not know which HES 200/0.5 solution was used in the study by Fernández et al., we can only assume that it was the fast metabolizing HES 200/0.5/6 solution, especially as the changes in vWF-Ag were minimal.21 Hence, we could expect a lower plasma concentration at any given time after infusion. This may influence its ability to act as a colloid oncotic agent. Irrespective of whether the solution used in this study was HES 200/0.5/13 or HES 200/0.5/6, a 6% solution of HES 200/0.5 only has a half-life of 2 hours,24 whereas albumin has a half-life of days to weeks. Therefore, it is not surprising that the HES solution did not perform as well as albumin. One would not expect measurements made after several half-lives of HES 200/0.5 to show any effects. As there still was a significant reduction in serum creatinine with HES 200/0.5 several days after the last infusion of the HES solution, HES 200/0.5 probably did have a volume expanding effect in these patients. As the inability to induce a reduction in vWF-Ag is probably an intrinsic property of the HES 200/0.5 solution used,22 and a reduction in vWF-Ag is linked to a reduction in NO release, this particular HES solution is also "inferior" to albumin as an agent to decrease the extent of the systemic arterial vasodilatation observed in patients with cirrhosis with SBP. Furthermore, HES solutions do not have any of the ligand-binding, scavenging, and anti-inflammatory characteristics of albumin, and therefore have no specific vasodilatation-reducing properties. Indeed, Fernández et al. reported unchanged systemic hemodynamics and hormonal profile following infusion of the HES solution.21 Therefore, before any valid comparison of volume expanders can be made, one needs to ensure that the physical and physiological properties of the solutions used are comparable. Rapidly degradable medium molecular weight HES solutions such as HES 200/0.5/6 are probably adequate when volume expansion alone is required. However, in situations where exaggerated systemic arterial vasodilatation is present, such as cirrhosis with SBP, albumin or HES solutions with slower metabolic rates would probably be preferred. Whether albumin is indeed superior than HES solutions in conditions of sepsis awaits the results of clinical trials that use comparable compounds.