Crystalloid Versus Colloid Versus Colloid

Administration of various types of fluid intravenously is frequently required to resuscitate perioperatively or critically ill patients. Crystalloids, plasma, albumin, or synthetic colloids such as gelatin, dextran, or hydroxyethyl starches (HESs) are the current options for this purpose. Intravenous fluid administration is well tolerated if the microvascular integrity is preserved, but the inflammatory response that occurs in sepsis, trauma, shock, and anaphylaxis results in increased vascular permeability. Significant vascular leakage causes interstitial edema, which may adversely affect organ function: cerebral edema causes mental status changes, pulmonary edema impairs gas exchange, myocardial edema decreases compliance, edematous tissues have impaired wound healing, and gut edema decreases nutrient absorption and increases bacterial translocation. Mitchell et al. [1] reported a negative correlation between survival and positive fluid balance in critically ill patients. Maintenance of stable hemodynamics requires 2 to 6 times the volume of crystalloid compared with colloid solutions [2]. Although studies have not clearly demonstrated the superiority of one solution over another, recent clinical trials have suggested that colloid solutions are at least as beneficial as crystalloid solutions for volume replacement in critically ill and perioperative patients [3-6]. Although the crystalloid-colloid controversy has not focused on the specific colloid used, it is increasingly clear that the effects of different colloids are different. Colloids vary markedly in their size, number average molecular weight (the arithmetic mean of all particle molecular weights), and weight average molecular weight (the sum of the number of molecules at each weight times the particle weight divided by the total weight of all molecules). Monodisperse solutions have one size of particle so that weight average and number average molecular weight are similar. Polydisperse solutions have a diverse range of molecular sizes and shapes, causing disparity between the weight average and the number average molecular weight. There are many colloid suspensions available with varying molecular sizes, half-lives, colloid oncotic pressures, side effects, and costs Table 1.Table 1: Comparison of Colloid Solutions in Terms of the Initial Plasma Volume Increase Relative to the Amount of Colloid Administered, the Weight Average Molecular Weight (MW), the Number Average MW, the Colloid Oncotic Pressure (COP), the Molar Substitution Ratio, and the Half-LifeAlbumin accounts for 60%-80% of normal plasma oncotic pressure. Albumin is expensive because it is derived from pooled human plasma. Despite its multiple physiologic roles, albumin levels are best used as a prognostic indicator rather than as an absolute value to be maintained with exogenous albumin administration. Recent studies show that albumin administration can maintain oncotic pressure but does not decrease morbidity or mortality in critically ill patients [7-9]. One explanation for the lack of benefit is continued extravascular leak of albumin, a monodisperse compound with a low molecular weight. Dextrans are composed of linear polysaccharide molecules whose molecular weight ranges from 10 to 90 kilodaltons (kd). Dextrans can improve microvascular circulation by decreasing blood viscosity and by coating vascular endothelial cells to minimize platelet and red blood cell aggregation. However, dextrans may produce bleeding by the same mechanism and are associated with a 1%-5% risk of anaphylaxis. Gelatins are polypeptides with a molecular weight of 35 kd. They have limited utility as plasma expanders due to rapid migration from the intravascular space. HES compounds are synthetic polymers derived from amylopectin, a branched polysaccharide polymer. The attachment of hydroxyethyl ether groups to the glucose units slows degradation by serum amylase [10]. The pharmacokinetic properties of HES are directly related to the size and the molar substitution ratio (the number of hydroxyethyl groups per molecule of glucose). A higher degree of substitution results in slower breakdown and elimination of the molecule. Particles less than 50 kd are filtered by the kidneys within 48 hours, while larger particles are hydrolyzed by amylase and then excreted in urine and bile or phagocytized by the reticuloendothelial system. The standard HES solution used in the United States (HES 450/0.7) has a high weight average molecular weight (450 kd) and a high molar substitution ratio (0.7). Pentastarch is a modified HES that is diafiltered to eliminate molecules outside a strict size range (10-1000 kd). Pentafraction is even more homogenous than pentastarch, with a molecular weight range from 100-500 kd. Recent studies suggest less adverse effects with the more homogeneous solutions [2,11,12]. A modified HES solution (HES 200/0.5) with a medium molecular weight and molar substitution ratio similar to pentastarch has been used in Europe. Two studies in this issue of Anesthesia & Analgesia suggest similar beneficial effects from this solution [13,14]. Previous studies have shown both medium and high molecular weight starches to be as effective as 5% albumin when used for volume replacement [2,15-17]. Early studies had suggested worsening of noncardiogenic pulmonary edema with the use of colloid solutions due to vascular leak of the colloid into the pulmonary interstitium. However, clinical studies have shown decreased pulmonary edema in septic patients treated with hetastarch [15] and no adverse pulmonary, biochemical, or outcome events with pentastarch [18]. Unfortunately, current recommendations limit the maximum dose of HES to 20 mg centered dot kg-1 centered dot d-1 due to concerns of adverse hematological, immunologic, renal, and reticuloendothelial function [2,10,19]. For many years, there was concern that hetastarch might be associated with a bleeding diathesis. Observed coagulation abnormalities included hemodilution reduction of clotting factors and decreased Factor VIII and von Willebrand factor (vWF) levels. However, studies of cardiovascular patients compared the use of HES with the use of albumin as a pump priming solution and found no differences in bleeding, chest tube drainage, or transfusion requirements [20]. Claes et al. [21] studies the effects of albumin versus HES in neurosurgical and gynecological patients. Coagulation variables remained within the physiological range, but factor VIII and vWF levels decreased from baseline values. This decrease may be clinically relevant in patients with initially low levels as in disseminated intravascular coagulation, hemophilia, and von Willebrand's disease [22]. Doses of HES larger than recommended have been used, resulting in moderate abnormalities in coagulation variables but no clinical bleeding or organ toxicity [20,23]. The study by Vogt et al. [13] in this issue of Anesthesia & Analgesia demonstrates the safety of HES 200/0.5 at doses significantly larger (20-36 mL/kg) than those recommended for traditional HES therapy. The study is a prospective, randomized trial in patients undergoing total hip arthroplasty. There were no significant differences in colloid oncotic pressure, hemodynamics, renal function, coagulation variables, or total blood loss between the hetastarch group and the albumin group. There was a mild increase in coagulation times in the hetastarch group, but abnormalities resolved within six hours. Although this study suggests that large volume modified HES therapy is safe in healthy patients, the results may not be applicable to sicker patients with increased vascular permeability from shock, sepsis, or trauma. Although the modified HES may have potential long-term benefits such as decreased postoperative infection (see below) and thromboembolism, these were not examined in the current study. Recent animal studies suggest that medium molecular weight HES compounds may decrease edema in inflammatory states. Ischemia and inflammation are known to increase microvascular permeability by increasing endothelial cell junction separation. Zikria et al. [24-26] hypothesized that appropriately sized and shaped biodegradable macromolecules could act as plugs for the leaky capillaries. Animals treated with medium molecular weight HES have higher reflection coefficients, decreased albumin leakage, and less extravascular extravasation compared with animals treated with crystalloid, albumin, or smaller size HES. Other studies have demonstrated preservation of microvascular architecture in septic animals treated with medium molecular weight starches compared with crystalloid [27] and higher molecular weight HES [28]. Starch compounds may blunt the release of thromboxane A2, a vasoconstrictor that contributes to the initial increase in microvascular pressures in response to endotoxin. Traber et al. [29] demonstrated that medium molecular weight starches decreased lung lymph flow after endotoxin administration in septic sheep. Thus, medium weight HES may improve physiology in inflammatory states by plugging leaky vasculature, decreasing release of vasoactive mediators, and improving microcirculatory flow by decreased blood viscosity and maintenance of plasma volume. Immunologic function may also be affected by the choice of resuscitation fluid. In vitro studies show that HES inhibits vWF release from endothelial cells, suggesting inhibition of early endothelial cell activation. Preventing the release of adhesion molecules responsible for binding neutrophils may attenuate the inflammatory cascade reactions of sepsis and adult respiratory distress syndrome. HES administration results in down-regulation of the release of interleukin 6 from liver macrophages in an animal model of shock [30]. Medium molecular weight homogenous HES solutions may beneficially alter membrane stabilization, microvascular function, endothelial activation, and immunologic function in inflammatory states. However, membranes differ between species and organ systems, so human studies are necessary. The report by Boldt et al. [14] in this issue of Anesthesia and Analgesia is the first human study to suggest such benefit. They compared modified 10% HES (colloid oncotic pressure 66 mm Hg) with 20% albumin (colloid oncotic pressure 78 mm Hg) for volume replacement over five days in critically ill patients. They monitored hemodynamics, oxygen delivery and consumption, and gastric intramucosal pH, which has been demonstrated to correlate with mortality [31]. Positive inotropic drugs, blood, and fluids were titrated to achieve optimal hemodynamics. Cardiac index, oxygen delivery, and oxygen consumption significantly increased only in the HES patients despite similar filling pressures in both groups. Septic patients treated with HES had a significant increase in the PaO2/fraction of inspired oxygen ratio, suggesting improved pulmonary function. Patients treated with HES had decreasing APACHE II scores, indicating decreasing severity of illness and risk of death. The septic patients treated with albumin had a decrease in intramucosal pH, suggesting inadequate splanchnic perfusion; no such decrease occurred in the HES group. Overall, HES appeared to significantly improve cardiorespiratory variables and splanchnic perfusion, effects which should improve survival in a large enough cohort of patients. These beneficial effects are consistent with the large body of experimental evidence discussed above. Improved splanchnic perfusion may reflect a decreased inflammatory response, down-regulation of the reticuloendothelial system from hetastarch degradation products, and reduced viscosity, improving microcirculatory flow. Improvement in cardiorespiratory variables may reflect increased intravascular volume due to sealing of leaky capillaries and attenuation of endothelial cell activation. However, these benefits may depend on the specific HES formulation studied. The specific study design used by Boldt et al. [14] raises some important issues. They compared 10% HES and 20% albumin, both of which are hyperoncotic fluids. Would the results have been similar with 6% HES and 5% albumin? Perhaps the key to improved microcirculatory function was the administration of hyperoncotic solutions which can decrease endothelial swelling. Patients resuscitated with HES required a greater volume of fluid than did those resuscitated with albumin, possibly due to the low number average molecular weight of HES. Would intravascular volume requirements have decreased with the use of a more homogenous medium molecular weight HES solution? In the study, there were no adverse effects of HES. However, the study excluded patients with renal dysfunction, liver insufficiency, disseminated intravascular coagulation, or septic shock. Would HES have had further beneficial effects or adverse effects in such patients? Finally, the study required resuscitation to hemodynamic stability prior to entry. Since attenuation of the immune cascade requires early therapy, would additional benefit have occurred from early use of modified HES? These issues will require further clinical studies. In summary, all colloids are not equal. In particular, the development of modified homogeneous medium molecular weight HES solutions appears to allow us to use larger doses of HES for volume administration and possibly to decrease the adverse effects of the systemic inflammatory reaction. Although the modified HES solutions are not currently available in the United States and in many other countries, the two studies in this issue of Anesthesia & Analgesia suggest the potential for marked improvements in intravascular volume resuscitation of perioperatively and critically ill patients.