Pharmacology of Crystalloids and Colloids

INTRODUCTION



Blood volume is a critical factor in maintaining hemodynamic equilibrium and tissue oxygenation. Intravascular volume is regulated very closely by means of several complex mechanisms, for which the onset of action varies widely. In some situations, such as acute bleeding, sepsis or with the use of certain drugs, the body must withstand absolute or relative changes in blood volume that cannot be immediately compensated for by the regulatory mechanisms. In these situations, the main goal of volume therapy is to temporarily increase plasma volume until the bodys own mechanisms can correct the hypovolemia.



Treatment of hypovolemia has changed significantly in recent years. In the past, fresh frozen plasma (FFP) or its equivalent was long the volume expander most commonly used. Now, indications for FFP are limited to the correction of some hemostatic disorders. A by-product of this legitimate change in practice was increased use of human albumin. Because of the financial consequences of this strategy, several consensus conferences have issued recommendations on the best indications for the use of various plasma volume expanders.



Despite these recommendations, the choice of the appropriate agent in the treatment of hypovolemia has not yet been settled. The debate on crystalloids versus colloids continues, besides a debate on the choice of colloid.



HYPOVOLEMIC SHOCK



Absolute hypovolemia may be defined as a reduction in the normal blood volume. Initially, the body responds by activating neurohormonal compensatory mechanisms. These mechanisms are designed to counteract the drop in arterial pressure and maintain blood flow to the vital organs at the expense of the muscular, cutaneous and splanchnic tissue beds which are then under-perfused. Subsequently, the true volume-regulating mechanisms take effect. Depending on the extent of the volume loss, hypovolemia may be compensated and changes in hemodynamic status minimal or undetectable, or it may be uncompensated and produce objective hemodynamic signs.



Relative hypovolemia occurs when increased arterial and venous compliance leads to a reduction in venous return. Relative hypovolemia is involved in the pathophysiology of septic shock and anaphylactic shock. In shock associated with infection and anaphylaxis and in the late phase of hemorrhagic shock, capillary permeability also increases to varying degrees.



Reduced blood volume leads to reduced venous return and thus to reduced cardiac output. The hemodynamic and neuro-hormonal responses to acute hypovolemia have two phases which occur progressively in conscious humans <|[1]|>. During the first phase, mechanisms regulating blood pressure intervene rapidly to maintain blood pressure. Baroreceptor-mediated responses produce peripheral adrenergic vasoconstriction that compensates for the fall in cardiac output and keeps arterial pressure near normal. Stimulation of the renin-angiotensin system augments the sympathetic system effect, although vasopressin and the adrenal catecholamines have little direct involvement at this point. Sympathetic vasoconstriction is accompanied by a complex vascular redistribution which initially favors cerebral, coronary and renal circulation and subsequently only cerebral and coronary circulation. Vasoconstriction affects mainly the muscular, cutaneous and splanchnic tissue beds.



If a critical level of hypovolemia is reached and remains untreated, the second phase of the physiologic response occurs abruptly. It is characterized by absolute or relative bradycardia and a profound fall in arterial pressure with a sudden drop in systemic resistance. This phase occurs when blood volume has dropped by more than 30% to 50%. The drop in blood pressure is independent of bradycardia since atropine will counteract the bradycardia but does not restore blood pressure <|[2]|>. Several phenomena are associated with this phase <|[1]|>. The most important appears to be a central inhibition of the sympathetic activation seen during the first phase. During this hypotensive phase, medulloadrenal secretion of adrenalin becomes significant. The renin-angiotensin system becomes highly active, releasing angiotensin II and significant amounts of vasopressin. It appears that receptors in the cardiopulmonary system are responsible for the development of this sympathetic-inhibiting phase. The bradycardia is the result of a vagovagal reflex loop due to stimulation of intracardiac mechanoreceptors. Activation of these receptors is also thought to cause vasodilatation by inducing central inhibition of the sympathetic system. It has been suggested that these mecha-noreceptors are stimulated by mechanical distortion of the left ventricle, which has a practically non-existant volume at end of systole. Bradycardia could allow for better diastolic ventricular filling in conditions of extreme hypovolemia. Central serotoninergic and opioid mechanisms have also been implicated in this phase of hemorrhagic shock <|[1]|>.



Major fluid shifts occur during hypovolemic shock as the body attempts to restore plasma volume. Hormonal responses (the renin-angiotensin system, vasopressin) are actively involved in this phase, but are not effective in the short term. Sympathetic vasoconstriction reduces capillary hydrostatic pressure and thus facilitates movement of interstitial fluid into the plasma compartment. Secondarily, however, changes in cell membranes result in a capillary plasma leak into the interstitial space with an accumulation of non-exchangeable water in some parts of the interstitial space (third-space losses) and the intracellular environment.



When hypovolemic shock is prolonged, a number of abnormalities develop that may become irreversible and promote the secondary development of a multiorgan failure syndrome. Severe trauma is responsible for a major inflammatory reaction triggered by reperfusion of ischemic tissue and tissue attrition <|[3]|>. Ischemia-reperfusion injury occurs as oxygen metabolites activate macrophages and neutrophils. Tissue attrition occurs as tissue factors and the complement system become involved. As well, various mechanisms lead to an irreversible reduction in the microcirculatory flow. The edema of endothelial cells reduces the patency of capillaries, and neutrophils adhere to the vascular endothelium. The gastrointestinal tract appears to play a central role in ischemia-reperfusion phenomena and their consequences at distant locations. Splanchnic circulation is very rapidly sacrificed during shock, and the consequences of this under-perfusion may be catastrophic, as myocardial depressant factors are released, bacteria are translocated and endotoxemia is facilitated. Translocation of bacteria to portal blood and mesenteric lymph nodes is rare in humans, but may be seen at an advanced stage of shock <|[4, 5]|>. Impaired perfusion of the gastrointestinal tract may persist following severe hypovolemia despite an apparent normalization of systemic hemodynamics <|[6]|>. Increased peripheral oxygen demand results from this severe reactive inflammatory syndrome and often is accompanied by peripheral vasoplegia <|[7]|>. Inability to adapt to these secondary impairments appears to indicate a poor prognosis. This inability is reflected in lower cardiac output and arterial oxygen transport in the patients who do not survive <|[8]|> and higher mortality in patients whose initial oxygen consumption is low <|[9]|>.



FLUID COMPARTMENTS AND FLUID SHIFTS



Water accounts for a total of 60-70% of body weight and is contained in three compartments: intracellular, interstitial and intravascular. Intracellular water accounts for about 40% of body weight and 70% of total body water. Extracellular water accounts for 30% of body weight and includes the interstitial space (with about 23% of total body water) and the intravascular space (with 7% of total body water). Despite significant differences in their ionic composition, intracellular and extracellular fluids have the same osmolarity. Intracellular osmolarity remains quite stable, whereas changes in extracellular osmolarity result in the movement of water between these two sectors. Infusion of a hypotonic solution will reduce extracellular osmolarity and thus result in the movement of water into the intracellular compartment in proportion to the electrolyte level gradient. Conversely, infusion of a hypertonic solution results in an increase in extracellular osmolarity that leads to the movement of water out of the intracellular space into the extracellular sector.



The ionic composition of interstitial and intravascular fluids is the same. Proteins, however, are kept with the vascular compartment, at least to a degree, by the vascular wall, which is a semi-permeable membrane. The concentration of proteins is much higher in the plasma sector than in the interstitial sector. About 70% of the oncotic pressure of plasma is created by albumin. Starling defined the factors that determine flows of fluid between the intravascular and interstitial spaces. The overall result is that the oncotic pressure gradient opposes the hydrostatic pressure gradient. As a result, there is a net flow of water into the interstitial space that supplies the lymphatic circulation. However, the capillary membrane is not totally impermeable to proteins. Movement of protein depends on the membranes coefficient of osmotic reflection, which in turn depends on the size, shape and charge of the molecule.



ISOTONIC CRYSTALLOIDS



An isotonic solution does not alter extracellular osmolarity, has a volume of distribution limited and equal to the extracellular sector, and increases plasma volume by about 200 mL for every 1,000 mL given <|[10, 11]|>. Recent research using a pharmacokinetic model adapted for fluid spaces suggests that the volume of distribution is more limited, i.e. about twice the plasma volume, and especially that elimination is significantly slower when hypovolemia is present prior to administration <|[12, 13]|>. These findings could explain why crystalloids have been found quite effective in the treatment of hypovolemia.



Isotonic solutions (physiological saline, Ringers lactate) are widely used as volume expanders. Their use inevitably results in an increase in the volume of interstitial fluid. The subsequent increase in lymphatic return is responsible for interstitial albumin being drawn into the plasma sector. Because of these effects, along with a lack of adverse effects, crystalloid solutions are the first choice for intravenous infusion solutions.



The efficacy of crystalloids, however, is limited in some situations. Cervera et al. showed that the amount of crystalloid infusion required to maintain normovolemia when compensating for blood loss during bleeding that gradually resulted in a loss of 15% to 40% of blood volume was equal to 5 times the volume of blood lost <|[14]|>. For greater losses, the amount of crystalloid required to maintain normovolemia increases exponentially <|(Figure 1)|>. These large amounts are required because of the accumulation of fluid in part of the interstitial space that is not completely drained by the lymphatic circulation, the rate of which reaches its limit. Furthermore, even massive use of crystalloid is not effective in restoring normal microcirculatory perfusion. In an animal study of normovolemic hemodilution, infusion of an amount of Ringers lactate equal to 4 times the amount of blood withdrawn did maintain arterial pressure and filling pressures <|[15]|>. However, tissue perfusion as determined by counting the number of capillaries perfused was significantly reduced by 62% and tissue oxygen partial pressure was reduced from 19 to 8 mm Hg <|(Figure 2)|>. In a group of animals treated by exchange with an equal volume of dextran, capillary counts and tissue oxygenation did not change. Wang et al. studied the quality of reperfusion using laser Doppler in a hemorrhagic shock model <|[16]|>. Microvascular blood flow was significantly reduced during hemorrhagic shock and remained depressed in all organs examined for the two hours following resuscitation using an amount of Ringers lactate equal to 4 times the volume of blood withdrawn, which doubled central venous pressures compared to baseline, pre-shock values <|(Figure 3)|>. These authors also studied hepatic clearance in similar experimental conditions and showed that this function did not return to normal despite volume expansion with Ringers lactate <|[17]|>. They concluded that the persistence of such microvascular and hepatic impairment could be the basis of organ failure following hemorrhagic shock.



Controversy persists, however, with some authors recommending colloids and others crystalloids, using arguments essentially based on measurements of hemodynamic parameters. However, as has been shown, these data are not adequate to judge the quality of resuscitation. There has been no study with sufficient statistical power to compare the various fluids in terms of morbidity or mortality. Several meta-analyses have been undertaken with the aim of assessing the impact of choice of volume expander on mortality.



The first such study was published by Velanovitch in 1989 <|[18]|>. This analysis combined the mortality data from 8 earlier published studies in which the efficacy of colloid was compared to crystalloid in resuscitation from traumatic or septic shock. Overall, the analysis showed a 5.7% difference in mortality rate in favor of crystalloids. When only studies on shock in trauma patients were analyzed, there was a 12.3% difference in mortality rate in favor of crystalloids. Conversely, when only the studies on resuscitation of non-trauma patients were included, there was a 7.8% difference in mortality rate in favor of colloids. The authors found that colloids did not appear to have any advantages in resuscitating trauma patients, but in patients with capillary permeability disorders, colloids could be more effective.



A second meta-analysis was published recently by Schierhout et al. <|[19]|>. It focused on intensive care patients. Of the 37 studies selected for inclusion, 26 compared crystalloids to colloids (n = 1,622) and 11 studied hypertonic solutions (n = 1,460). Resuscitation with colloids was associated with an increased absolute risk of mortality of 4% (95% confidence interval: 0% to 8%). The authors did not find any differences regardless of the initial pathology, notably in trauma patients.



Overall, these meta-analyses consistently find crystalloids to be preferable. However, they do have important limitations that deserve mention: the studies included for analysis were often very old, and the treatment used then is no longer the standard of care; the colloids used were previous generation products, not modern colloids; and, these meta-analyses included a very diverse array of pathologies. In short, the issues raised by the meta-analyses are relevant, but the answers they provide are not satisfactory given the inadequacies of the original studies.



Crystalloids remain the volume replacement solutions of first choice, and their use provides essential benefit in the compensation of blood losses by correcting water and sodium deficits in the interstitial compartment. In the context of major hypovolemia, however, their use is not appropriate since the amounts required do not allow for adequate treatment of shock and especially of microcirculatory disturbances, a key factor in limiting the effects of shock on tissues.



HYPERTONIC CRYSTALLOIDS



Hypertonic crystalloids (2500 m0sm/L), often in combination with colloids, have been studied both experimentally and clinically. They produce increased osmolarity in extracellular fluid which results in movement of water from the intracellular compartment to the interstitial and vascular compartments <|[20]|>. Plasma volume expansion, however, does not suffice to explain the efficacy of hypertonic solutions, particularly as this effect is transitory. Their sustained duration of action is due to reflex mechanisms responsible for venous constriction and increased cardiac contractility <|[21]|>. The pathways and centers of these reflex mechanisms continue to be discussed. The presence of intact vagus nerves and the orthosympathetic system appears essential. The increase in cardiac contractility could also be a reflex or it could result from a direct action of hyperosmolarity on myocardial fibers <|[22]|>. Hyperosmolarity vasodilates the splanchnic and renal tissue beds <|[23]|>, an effect that is particularly useful in the setting of hemorrhagic and septic shock. As well, the shrinking of erythrocytes and of swollen vascular epithelium could facilitate tissue oxygenation <|[20, 24]|>. Furthermore, hypertonic saline solutions decrease intracranial pressure <|[25]|>. Hypertonic solutions should be considered to be not only volume expanders, but also real drugs with systemic and regional cardiovascular effects.



Several trials have compared initial resuscitation of trauma patients with hypertonic saline combined with dextran to resuscitation with isotonic crystalloid alone, but no significant difference in mortality has been found. A meta-analysis was published recently <|[26]|>, which included 14 different randomized studies, 8 trials of hypertonic saline with dextran and 6 trials of hypertonic saline. In each case, control patients were given isotonic crystalloid. Overall, the use of hypertonic saline alone for resuscitation from hemorrhagic shock was not associated with improvement in mortality rates. However, a trend to improvement was found with the combination of hypertonic saline and dextran. The difference in the survival rate was 3.5% and the odds ratio estimated to be 1.20 in favor of the combination (95% confidence interval: 0.94 to 1.57). Ultimately, the authors found that treatment of hemorrhagic shock with hypertonic saline and dextran was equivalent or superior to standard treatment with crystalloid. However, hypertonic solutions have one major drawback: they cannot be administered repeatedly because of the hypernatremia that results after a single dose.



In cardiovascular surgical intensive care, several trials have compared the use of hypertonic saline combined with hydroxyethyl starch to standard treatment with colloids <|[27-29]|>. The use of the combination solutions prior to cardiovascular bypass appears to have several advantages. The volume needed to maintain or increase filling pressures was clearly less with hypertonic solutions <|[28, 29]|>. The total volume of fluids administered during the procedure was significantly less in the groups treated with the hypertonic saline-starch solution. A negative fluid balance compared to the use of standard colloids could explain the better pulmonary gas exchange found with this therapy <|[29]|>. Higher cardiac output after coming off bypass was also observed <|[28]|>. This effect may be related to increased venous return <|[30]|>, arterial vasodilatation which facilitates cardiac ejection <|[31]|>, improvement of myocardial contractility <|[22]|>, and increased activity of the orthosympathetic system <|[32]|>. Tolerance of hypertonic-hyperoncotic solutions in cardiovascular surgical trials has generally been good. Some episodes of arterial hypotension or rhythm disturbances related to overly rapid administration have been reported however <|[27, 33]|>.



Hypertonic saline solutions combined with dextran or hydroxyethylstarch are available in several European countries and are currently in the process of being registered in France.



HUMAN ALBUMIN



Human albumin is a protein composed of a simple chain of amino acids with a quaternary helix-like structure. The center of the molecule is made up of hydrophobic radicals which are binding sites for many ligands. The outer part of the molecute is composed of hydrophilic radicals. Albumin is a relatively small molecule in terms of space, but its size is sufficient to prevent it from crossing the capillary membrane. At physiological concentrations (40-45 g/L), albumin accounts for 70% of plasmas oncotic pressure, or about 18 to 22 mm Hg of which 5 to 9 mm Hg are related to the Donnan effect (the molecules electrically neutral charge). Albumins binding capability affects many different areas. For instance, albumin can bind the products of degradation processes such as bilirubin or free fatty acids. Through binding, it can regulate the ionized fraction of some cations such as calcium and magnesium, trap free radicals and serve as a transport protein carrying amino acids and drugs.



Body stores of albumin are about 4.5 to 5.0 g/kg and are divided between the intravascular and interstitial compartments. About a third of the store of exchangeable albumin is located in the intravascular compartment, and the rest is in the interstitial compartment. Whereas distribution of albumin is uniform within the intravascular compartment, its distribution within the interstitial space is uneven depending on the tissue because of large polysaccharides, glycosaminoglycans. Albumin distribution and metabolism have been studied using various models <|[34-37]|>. Following an intravenous injection, plasma activity falls gradually with a distribution half-life of 4 h, which corresponds to the time necessary for equilibration with the interstitial sector, and an elimination half-life of 17 to 18 days which corresponds to the time for catabolism by the reticuloendothelial system. The normal rate of transcapillary escape is 5%/h, meaning that every hour, 5% of the intravascular albumin is transferred to the interstitial sector. The rate of transcapillary exchange can be higher in many disease states such as hypertension, heart failure or sepsis. About 10% of albumin is catabolized, meaning that about 14 g of albumin are broken down daily. To maintain serum albumin levels, mobilization of extravascular albumin by the lymphatic circulation and albumin synthesis must compensate for losses by transcapillary passage and catabolism. Every day, about 90% of the extravascular albumin returns to the intravascular compartment via the lymphatic circulation. Under physiological conditions, the liver does not store albumin; instead, synthesis compensates for metabolic losses. Synthesis of albumin occurs exclusively in the liver and takes 1 to 2 minutes. Excretion of albumin takes about 30 minutes. Regulation of albumin synthesis is complex and involves many different hormones along with the plasma colloid osmotic pressure as an essential regulatory factor.



Abnormalities of water and albumin distribution in the postoperative period have been documented <|[35, 36, 38-40]|>. These abnormalities are particularly pronounced after major abdominal, cardiac or vascular surgery. During the postoperative period, the reduction in plasma volume is greater than that of red cell volume, which indicates a plasma leak into the interstitial space <|[39]|>. Actually, the reduction in plasma volume is associated with a reduction in exchangeable interstitial water because of the development of edema which is not drained by the lymphatic circulation. The reduction in exchangeable interstitial water diminishes lymphatic output, thus limiting the mobilization of extravascular albumin. Reduced lymphatic output is a first factor leading to postoperative hypoalbuminemia. Increased capillary permeability, however, is the main mechanism responsible for hypoalbuminemia since it tends to equilibrate albumin concentrations of the the vascular and interstitial compartments <|[41]|>. In some inflammatory or septic contexts, increased catabolism of albumin may be a third cause of hypoalbuminemia.



A number of studies have been performed to measure the volume expansion properties of albumin <|[34, 37]|>. It is generally accepted that the theoretical volume expanding power of albumin is 18 to 20 mL per g, or 400 mL for a 500 mL infusion of a 4% albumin solution. Actually, volume expansion differs depending on the population studied, and the patients hydration status and body stores of albumin. In patients undergoing minor surgery <|[34]|>, infusion of 50 g of albumin resulted in an increase of plasma volume of about 500 mL. The same degree of volume expansion was observed regardless of the concentration of the albumin solution used, i.e. 1,000 mL at 5%, 250 mL at 20% or 200 mL at 25%. Schwartzkopff et al. measured volume expansion in surgical patients and healthy volunteers <|[37]|>. Based on their findings, the authors determined that 5 to 8 g of albumin are lost from the intravascular space per hour. Albumin leak is greater in normovolemic, hypoprotidemic subjects. Duration of volume expansion is extremely complex to study and depends on blood volume, protein levels and capillary permeability, among other factors.



Albumin is often used to treat hypoalbuminemia in intensive care patients <|[42]|>. The administration of albumin, however, does not improve morbidity or mortality <|[43, 44]|>. Golub et al. performed a prospective, randomized study of 219 surgical intensive care patients comparing albumin supplementation to non-supplementation <|[45]|>. The complication rate was 44% in the albumin group, compared to 36.9% in the control group; the mortality rate was 10.3% in the albumin group vs 5.8% in the control group (p = 0.22). No significant difference was found in the length of time on ventilatory support or length of stay in intensive care. The authors found that albumin replacement therapy offered no benefit in this context and should be abandoned.



A recent British meta-analysis <|[46]|> found very negative results with the use of albumin as a volume expander. This analysis included 30 randomized studies and a total of 1,419 patients treated for hypovolemia, burns or hypoprotidemia with either albumin or similar products (plasma protein fractions), compared to crystalloids. The pooled results showed an excess risk of death of 6% (95% confidence interval: 3% to 9%) with a relative risk of 2.40 (95% confidence interval: 1.11 to 5.19). The authors found that there was no evidence of the efficacy of albumin over crystalloid; instead, albumin appeared to carry additional risk. As a result, the authors called for rigorously conducted randomized trials to determine the appropriate indications for human albumin. This study was widely criticized in letters to the editor published in the British Medical Journal. Criticism mainly focused on the poor selection of studies, i.e. the inclusion of studies of not only albumin but also fractionation products of varying quality, and the use of mortality as a main study outcome measure. While these criticisms are valid, doubts remain and merely serve to confirm the position taken by the consensus conferences that use of albumin should be restricted to a few well-defined situations and albumin used as a second-choice infusion solution when other products are not indicated, are contraindicated or have been used up to their maximum dose.



Albumin can now be extracted only from plasma collected by phlebotomy. In the near future, it will probably be obtained from transgenic animals. Most techniques currently used are based on the Cohn principle and involve sequential fractionation of plasma proteins. Concentrated preparations of 4%, 5%, 20% or 25% albumin solutions are pasteurized.



The frequency of anaphylactoid reactions is significantly lower than that seen with the other colloids, except for hydroxyethyl starch <|[47]|>. The incidence of reactions, which are of the chills-and-fever type, appears to be largely related to the degree of product purity. Reports of other side effects, such as a negative inotropic effect, aluminum overload or hemostatic effects, are anecdoctal or controversial.



DEXTRANS



Of all the colloids used in clinical practice, dextrans are those with which we have the most experience. The physical, chemical and pharmacological properties of dextrans are particularly well known and among the most studied of all plasma substitutes. The use of dextrans has been declining noticeably in Europe because of their side effects.



Dextran is a single-chain polysaccharide of bacterial origin. The average molecular weight of these of variably dispersed solutions is an important product characteristic. The average molecular weight in weight (Mw), which is the arithmetic mean of molecular weights of the constituent particles, is different from the molecular weight in number (Mn), which is the average molecular weight of the particles with colloid oncotic power. The main types of dextran solutions are designated according to their Mw: 70,000 D (dextran 70), 60,000 D (dextran 60) and 40,000 D (dextran 40).



Dextran 70 and 60 are generally prepared as 6% solutions, while dextran 40 is available in a 10% concentration. The colloid oncotic power of the various dextran solutions is very high: 1 g of dextran 40 retains 30 mL of water and 1 g of dextran 70, 20 to 25 mL of water. Following intravenous administration, dextran is eliminated by three routes. Most is eliminated by the kidneys. A smaller fraction enters the interstitial space and returns to the bloodstream via lymphatic drainage or is metabolized by certain organs. A third, even smaller fraction is eliminated via the gastrointestinal tract. The variety of routes of elimination and the influence of Mw on most of these routes mean that the pharmcokinetics of dextrans are very complex. Briefly, following intravenous administration of dextran 40, half of the dose given is eliminated within 2 h and 80% within 6 h. Following intravenous administration of dextran 70, 50% of the dose infused is eliminated within 24 h.



The rheologic effect of dextran 40 solutions is especially pronounced since these solutions reduce viscosity of whole blood more for the same degree of hemodilution compared to other plasma substitutes <|[48]|>. Following dilution with various colloid plasma substitutes, low shear-rate viscosity is reduced with dextran 40, whereas it is increased with dextran 70 and dextran 60. Dextran 40 solutions also have a beneficial effect on red cell rouleau formation since they increase the time of red cell aggregation, unlike dextran 60 et 70. A new finding regarding beneficial rheologic effects of dextrans involves leukocyte adherence, an effect that may be useful in the setting of ischemia-reperfusion injury <|[49]|>.



Longer bleeding time is generally seen after administration of more than 1.5 g/kg of dextran <|[50]|>. This effect is greater with high molecular weight dextrans. Reduction of platelet adhesiveness is related to a reduction of factor VIII which acts as a cofactor for ristocetine aggregation activity, likened to the von Willebrand factor. Hemostatic abnormalities induced by dextrans are similar to those seen in type I von Willebrand syndrome. This explains why this side effect can be reversed by the administration of desmopressin. Dextran also impairs the polymerization of fibrin.



Onset of oliguric or anuric kidney failure is exceptional and has been reported exclusively with the use of 10% dextran 40 solutions. Analysis of most published case reports has revealed contributing factors such as age, repeated infusion of large quantities and arteritis <|[51]|>. Experimental models have enabled us to understand the pathophysiology of this type of kidney failure, which is an acute hyperoncotic syndrome.



Anaphylactoid reactions appear to be frequent with dextrans <|[47]|>. The mechanisms of allergic reactions have been thoroughly studied, particularly by Hedin and Richter <|[52]|> who showed the role of dextran antibodies. These pathophysiological findings are the basis for preventing allergic reactions to dextrans by means of hapten inhibition <|[53]|>. Several studies have shown that prior injection of 20 mL of dextran 1,000 D (Promit) a few minutes before a dextran infusion will considerably reduce the incidence of reactions, especially severe reactions. This step should always be taken before infusion of any type of dextran.



Furthermore, signs of acute fetal distress due to uterine hypertonia have been described when dextrans have been used during delivery <|[54]|>. Dextrans are therefore absolutely contraindicated in this setting.



Use of dextrans is declining in most European countries because of dextrans side effects.



GELATINS



The use of gelatins as volume expanders was described in the treatment of hypovolemic shock as early as 1915. It was not until the 1950s, however, that gelatins became available for clinical use, including the current products, modified fluid gelatins and urea-bridge gelatins.



Gelatins are a product of bovine origin. Consequently, there is the problem of the potential risk related to the pathogen involved in spongiform encephalopathy. The French national agency for develoment of medical evaluation (ANDEM) has made the following comments, in accord with the viral safety group of the government drug agency and an opinion issued by the European Medicine Evaluation Agency. Three factors combine to contribute to the safety of gelatins used in pharmaceuticals: manufacturers must not use raw material from the United Kingdom; the tissues used as raw material are classified as not having any detectable level of infectiousness; the method of preparation which includes extended acid and alcaline processing and filtration is sufficient to eliminate any risk. Nevertheless, although gelatin has never been implicated in the transmission of known non-conventional disease agents, the biological risk can never be zero. The residual risk, however small it may be, must therefore be taken into account in a risk/benefit analysis.



The pharmacokinetics of gelatins is not fully understood. Data on all products are fragmentary. Gelatins are cleared essentially by glomerular filtration <|[55]|>. About 20 to 30% of the dose given travels from the intravascular compartment into the interstitial space. From there, it can return to the bloodstream via the lymphatic circulation. Gelatins may also be broken down by proteases into small peptides and amino acids in the reticuloendothelial system <|[56]|>. Gelatins do not accumulate in the body <|[57]|>. These data indicate that the plasma half-life of both urea-bridge gelatins and modified fluid gelatins is 2-3 hours <|[58]|>.



The various gelatin solutions have comparable volume-expanding power. Using old data <|[59]|>, it was estimated that in the most favorable case, which is a hypovolemic subject without any disturbance of capillary permeability, a 500 mL infusion of gelatin would increase plasma volume by a volume equal to the amount infused. Four hours later, volume expansion would be only half that much. Other studies show more limited volume expansion, often much less than the volume infused, due to rapid passage of the gelatin into the interstitial space. In a comparative study in healthy volunteers, Kolher et al. found less volume expansion with gelatin than with dextran 40 or low molecular weight starches <|[60]|>. Loss of volume expansion was also found to be faster than with the other expanders.



A randomized study compared gelatin to albumin in intensive care patients <|[61, 62]|>. Despite the difference in albumin levels, no significant difference in pulmonary edema, kidney failure or mortality was found between the 2 groups. Plasma albumin levels were significantly lower in survivors than in patients who died.



It was long thought that gelatins had no side effects on hemostasis regardless of the daily dose. However, a recent study performed in the setting of progressive hemodilution showed that compared to physiological saline, gelatin, like hydroxyethyl starch and albumin, induced significant changes in the thromboelastrogram that compromised coagulation <|[63]|>. Another study showed that urea-bridge gelatins (Haemaccel) result in greater reduction of platelet aggregation than do modified fluid gelatins <|[64]|>. The incidence of allergic reactions with gelatins is higher than that seen with hydroxyethyl starches and comparable to that with dextrans <|[47]|>. The mechanism involved in these reactions is not as well understood as that associated with dextrans.



In conclusion, clinical use of gelatins is declining because of their modest effectiveness as volume expanders and because their theoretical advantages are gradually being outweighed by their effects on coagulation.



HYDROXYETHYL STARCHES



Hydroxyethyl starches are modified natural polysaccharides. Solutions of natural starch are unstable and are rapidly hydrolyzed by α-amylase. Hydroxylation or etherification are used to stablize the solution and slow hydrolysis <|[65]|>, and increase the molecules hydrophilia considerably and expand its conformation. The extent of hydroxyethylation may be measured by two features: the degree of substitution and molar substitution ratio. This second characteristic takes into account the di- and tri-substitutions that occur with some molecules of glucose and better reflects the starchs resistance to hydrolysis by α-amylase. The site of hydoxyethylation on the glucose molecule is preferentially C2, but etherification at C3 or C6 is also possible. Hydroxyethylation at C2 gives the most resistance to α-amylase. The ratio of C2/C6 reflects the types of hydroxyethylation. An important characteristic of these products is also molecular weight in weight (Mw) and molecular weight in number (Mn). However, molecular weight is not the parameter that determines the starchs pharmacokinetics, which depend mainly on the degree and type of hydroxyethylation. However, molecular weight is a major determinant of the solutions side effects.



The first hydroxyethyl starch was marketed in Germany and the United States and had a high Mw (450 kD). However, this starch had side effects on hemostasis that led to its being withdrawn from the market. Other starches with a lower molecular weight have now been developed. In France, the main products are Elohes , Lomol , Heafusine and Haes-Steril. These products have similar although differing characteristics. Elohes is a 6% solution, has a Mw of 200 kD and a molar substitution rate of 0.62. Lomol is a 10% solution, has a Mw of 250 kD and a molar substitution rate of 0.45. Haes-Steril and Heafusine have similar although not identical characteristics to Lomol and are 6% solutions.



Unlike the dextrans, the pharmacokinetics of hydroxyethyl starches are not influenced mainly by Mw, but depend mainly on the degree of hydroxyethylation <|[66, 67]|> <|(Figure 4)|>. The main route of elimination of hydroxyethyl starches is urinary. A fraction is taken up by the reticuloendothelial system where the starch is slowly broken down. The rate of uriniary excretion in the 24 h following administration of hydroxyethyl starch depends mainly on the degree of hydroxylation. For Elohes, the elimination half-life of the medium-size molecules is 7 h and 5 days for the large molecules. For Lomol, the elimination half-life of the medium-size molecules is 3 h and 2 days for the large molecules. Actually, the usual data are poorly suited to describing the pharmacokinetics of these variably dispersed solutions, since they describe the average kinetics of the solution rather than of its various fractions. It has been shown that after an infusion of hydoxyethyl starch, the dispersion of the Mw molecules changes, first because the smaller molecules are rapidly eliminated and then because the large molecules are partially hydrolyzed to become medium-sized molecules. This partial hydrolysis tends to increase or stabilize plasma volume expansion over time. This phenomenon is reported to predominate for 2 to 4 h following infusion. Intravascular hydrolysis by α-amylase is more limited with some hydroxyethyl starches because of their high degree of hydroxyethylation <|[68]|>. Tissue distribution of these starch solutions has been studied in an animal model. The reticuloendothelial system, including the spleen, accumulates hydroxyethyl starch for a long time and catabolizes it gradually by means of maltases and the sucrase-isomaltase complex.



Metabolism of hydroxyethyl starches has been studied by monitoring blood glucose and urine glucose, and no change has been seen <|[69]|>. In animals, the molecular weight of molecules excreted in urine is low, but it is much higher than the weight of glucose molecules. In vitro, the addition of hydroxyethyl starch to serum or solution containing amylase does not result in any increase in the glucose level. Together, these data indicate that metabolism of hydroxyethyl starches occurs by means of the production of increasingly smaller molecules down to a weight of about 40,000 to 50,000 D, at which point the molecules are small enough to be excreted in urine, without metabolism continuing to the point of formation of glucose or hydroxyethyl glucose. Based on these data, it may be concluded that hydroxyethyl starch infusions do not change blood glucose levels. However, cases of hyperglycemia and even glycosuria have been reported in non-insulin-dependent diabetics. Of course, volume expanders are used in patients under conditions (shock, surgery) in which other factors that disturb glucose metabolism are already present, such that hydroxyethyl starch is not necessarily responsible for disturbing glucose metabolism.



Given the number of hydroxyethyl starches on the market and the variety of their physical and chemical characteristics, comparison of different products is difficult. A classification by in vitro Mw, i.e. high Mw (450 kD), medium Mw (200 kD) and low Mw (70 kD) does not take into consideration the degree of hydroxyethyl substitution or the C2/C6 ratio. It would make more sense to compare hydroxyethyl starches according to their in vivo Mw after partial hydrolysis of the original solution <|[66]|>. The in vivo Mw depends on the original Mw, the extent of hydroxyethylation and the C2/C6 ratio. The higher the values for all three of these characteristics, the higher the in vivo Mw. This approach would allow for easy comparisons between products since a single feature could be used to differentiate one hydroxyethyl starch from another. Furthermore, in vivo Mw is the key parameter for evaluating colloid osmotic power, pharmacokinetics, accumulation in plasma and tissue and side effects on coagulation and renal function. Colloid osmotic power depends on the number of molecules present, a value that can be determined by dividing the mass concentration by the average in vivo Mw. If we look at two hydroxyethyl starches, one of which has an in vivo Mw that is half that of the others, this means that for the same concentration, the solution with the smaller Mw has twice the colloid osmotic power of the other. In other words, for the solution with the smaller Mw, half of the concentration would suffice to produce an equivalent effect <|[70]|>. As well, a lower Mw means that the solution will be cleared more rapidly, and less will accumulate in the plasma and the reticuloendothelial system. Side effects on coagulation and perhaps renal function also depend on the in vivo Mw and plasma concentration. The lower the in vivo Mw, the less starch accumulates in plasma in the event of repeated administration and the fewer the disturbances of coagulation <|[71, 72]|>. It would seem that the best hydroxyethyl starch is the one will the lowest in vivo Mw above the threshold of renal eliminiation, which is 50-60 kD. The in vivo Mw of Elohes is 140-150 kD <|[68, 71]|>, higher than that of Haes-Steril, at 110-120 kD <|[71]|>.



With Elohes, initial volume expansion greater than the volume infused has been documented by several studies on postoperative volume expansion or normovolemic hemodilution <|[65, 68, 73]|>. These studies confirm that the effectiveness of this solution equals or surpasses that of human albumin in terms of volume expansion or cardiovascular efficacy <|[68, 73]|>. The duration of action is about 24 h. Degrmont et al. ont found that infusion of 500 mLof Elohes initially expanded volume postoperatively by 693 mL. Volume expansion lasted for 24 hours, although the concentration of Elohes gradually fell to 35% of peak concentration at 24 hours. In vivo Mw fell within the hour following administration and then remained stable for 24 hours. The albumin concentration initially fell following the Elohes infusion, and then gradually rose until 24 hours. These findings indicate that although the products duration of action is certainly related to its intravascular persistance, other mechanisms are involved and help explain the long duration of action of Elohes, i.e. intravascular hydrolysis that reduces the in vivo Mw and, even more importantly, mobilization of interstitial albumin and renal adaptations. Comparative studies that measure intravascular volume of other hydroxyethyl starches are not available. As a result, only indirect comparisons may be made. With products such as Lomol ou Haes-Steril, volume expansion equal to or greater than the amount infused has been reported <|[74]|>. The duration of action is not as long as that of Elohes, being about 6 hours. Kolher et al. <|[75]|> compared a 200/0.5 hydroxyethyl starch in 6% and 10% solutions to a dextran 40 in 10% solution and a polygelatin in 5.5% solution <|(Figure 5)|>. This study showed volume expansion of at least 6 hoursduration with this hydroxye-thyl starch, longer than that of the gelatin which was eliminated in 3 hours.



The effectiveness of hydroxyethyl starch 200 has been shown in several clinical settings: normovolemic hemodilution, intraoperative blood loss replacement, cardiac surgery, and sepsis <|[24, 76, 77]|>. In intensive care, the concept of impaired capillary permeability has often been used as an argument against colloid use. The reasoning is that colloids do not remain in the intravascular compartment; instead, they increase the interstitial oncotic pressure and promote the development of edema. However, Rackow et al. studied 26 septic patients and found a lower incidence of pulmonary edema in the group treated with hydroxyethyl starch compared to the group treated with crystalloids <|[78]|>. However, these results were obtained with hetastarch which has a particularly high in vivo Mw. Using an experimental model of ischemia and reperfusion, Zikria showed a reduction in the infarct and less myocardial edema in the group treated with hydroxyethyl starch <|[79]|>. This study was performed using a particular hydroxyethyl starch called pentastarch because the product mainly contains a select category of Mw molecules. Various publications have confirmed the ability of this particular product to reduce edema in experimental models of burns <|[80]|>, ischemia-reperfusion injury <|[79, 81-84]|> or sepsis <|[85, 86]|>. Only one published study describes the use of pentastarch in patients with sepsis, but this study compared the product to albumin and did not look at pulmonary edema. Regardless of experimental evidence, it cannot be concluded that pentastarch has demonstrated ability to reduce edema clinically. As well, this product is not yet on the market. Interestingly, however, the experimental studies suggest that the anti-edema properties of pentastarch are not related to the products colloid osmotic power, but to other properties that are not yet fully understood. Other research with currently available medium Mw hydroxyethyl starches, not pentastarch, provides evidence for this. For instance, using cultured endothelial cells, Collis et al. showed that hydroxyethyl starch could inhibit endothelial cell activation and limit adverse change in capillary permeability, compared to albumin <|[87]|>. Hydroxyethyl starches might also reduce adherence of leukocytes <|[76]|> which play an important role in ischemic-reperfusion events. Schmand et al. found that hydroxyethyl starch had no negative effects on cell-mediated immune functions and macrophage function following resuscitation from hemorrhagic shock <|[88]|>. Eastlund et al. found that cytokine release, chemotaxis and monocyte migration were not affected by resuscitation with hydroxyethyl starch following hemorrhagic shock <|[89]|>. A body of experimental evidence thus suggests that hydroxyethyl starches would in fact have a beneficial effect on the inflammatory processes associated with hypovolemic shock. A clinical study conducted on septic patients appeared to support this indirectly by showing better splanchnic oxygenation as measured by the gastric intramucosal pH in patients treated with hydroxyethyl starch, as compared to those treated with albumin <|[77]|> <|(Figure 6)|>. Overall, the evidence supports the use of hydroxyethyl starches in intensive care patients. Their beneficial effects seem to be more related to their action on inflammatory processes than to their colloid osmotic power. In a risk/benefit analysis of hydroxyethyl starches, however, their side effects should also be weighed.



The effects of hydroxyethyl starches on hemostasis have been studied by many authors <|[63, 67, 90, 91]|>. Hydroxyethyl starches with a high in vivo Mw should be distinguished from other hydroxyethyl starches. Numerous cases of abnormal bleeding have been reported with use of one such product, Hetastarch <|[66]|>. Lengthened APTT and decreased levels of factor VIII and von Willebrand factor have been documented <|[92-94]|>. These findings and case reports of side effects would justify no longer using this product. Case reports involving Elohes are more complex since occasional use does not result in hematologic changes even at high doses (33 mL/kg) for 24 h <|[95]|>. Repeated use for 10 days, however, has been associated with clearly abnormal laboratory findings, including reduced levels of factor VIII and von Willebrand factor <|[66]|>. Furthermore, one drug safety monitoring report contains about a dozen cases of bleeding events related to repeated use of Elohes over several days, most often in a neurosurgical setting. Most of these cases were characterized by hematologic disturbances, particularly reduced levels of von Willebrand factor. Following this report, the marketing authorization and labeling information were amended to indicate that the use of Elohes should be limited to a maximum of 3 consecutive days.



Treib et al. investigated the effects of various hydroxyethyl starches on hemostasis extensively and showed the influence of in vivo Mw on the type and extent of coagulation disorders. Coagulation abnormalities are seen after repeated administration as part of 10-day hemodilution therapy with products that have a high in vivo Mw compared to initial (in vitro) Mw, high degree of hydroxyethyl substitution or high C2/C6 ratio <|[66, 71, 96]|>. The typical product in this category is Elohes. Such products were found to accumulate in the body with a gradual increase in plasma concentrations. Adverse effects on coagulation parameters were proportional to plasma concentration. Shortened thrombin time and decreased fibrinogen levels are probably the result of accelerated polymerization of fibrinogen. Prolonged partial prothrombin time is mainly the result of reduced factor VIII and von Willebrand factor levels. The most likely mechanism for this effect is accelerated clearance of factor VIII-von Willebrand complex after binding by hydroxyethyl starch molecules. Decreased levels of factors XI and XII are seen only with very high in vivo Mw hydroxyethyl starches. These coagulation abnormalities are particularly pronounced after repeated administration of Elohes over 10 days and are minor or non-existant with products of the Haes-Steril or Heafusine type <|[66]|>. In summary, the data show that hydroxyethyl starches with a low in vivo Mw (Haes-Steril or Heafusine) have little or no effects on hemostasis, even when given repeatedly for 10 days. The same is not true for Elohes; its use in this way is to be avoided.



The effects of hydroxyethyl starches on kidney function have been discussed in recent publications. Two types of situations should be distinguished: the perioperative setting and the special case of kidney transplantation. The acute hyperoncotic kidney failure syndrom was first reported with dextran use <|[97]|>. This syndrome occurs when colloid osmotic pressure rises to a level where it offsets the hydraulic pressure of glomerular filtration and thereby suppresses urine output. Such a situation occurs when a high plasma level of colloid is reached, generally after repeated administration. Anuria occurs more readily in any situation in which renal perfusion pressure may decrease, such as shock, arteriopathy, or renal artery stenosis <|[98]|>. This syndrome has now been reported with nearly all colloids: gelatins <|[99]|>, dextrans <|[97]|>, starches <|[100]|>, and concentrated albumin <|[101]|>. In the case of starches, the development of this syndrome may theoretically be promoted by the repeated administration of a hydroxyethyl starch with a high in vivo Mw leading to a gradual increase in plasma levels. However, these products do not appear to increase the risk of postoperative renal failure even when used in large amounts intraoperatively in thoracic aortic or thora-coabdominal aortic surgery <|[102]|> or orthopedic surgery <|[103]|>.



In the setting of kidney transplantation, osmotic-nephrosis-like damage has been seen on biopsy of transplanted kidneys when the donor had been resuscitated with hydroxyethyl starch. These lesions appear to be more frequent than in historical series in which donors were not treated with hydroxyethyl starches <|[104]|>. A prospective, randomized study comparing a gelatin to Elohes showed poorer recovery of kidney function after transplantation and a greater number of patients requiring hemodialysis in the groups with kidneys exposed to hydroxyethyl starch <|[105]|>. The mechanism for impaired renal function might be an accumulation of hydroxyethyl starch in the tubular cells. The presence of hydroxyethyl starch in the osmotic-nephrosis-like lesions has not been shown, however, and many other drugs, especially cyclosporin, can produce the same type of damage. Furthermore, another study showed that the incidence of osmotic-nephrosis-like lesions was apparently not influenced by the use of hydroxyethyl starch <|[106]|>. As well, a multicenter retrospective study did not confirm any adverse effects of hydroxyethyl starch on graft function after kidney transplantation <|[107]|>.



The immunological tolerance of hydroxyethyl starches appears to be excellent <|[47]|>. The frequency of allergic reactions is lower than with dextrans and gelatins. Severe reactions are particularly rare.



CONCLUSION



Crystalloids remain the intravenous solutions of first choice, and their use provides essential benefit in the replacement of blood losses by correcting water and sodium deficits in the interstitial compartment. In major hypovolemia, the use of crystalloids is inappropriate since the amounts needed do not sufficiently treat the shock, especially the microcirculatory disturbances, a key factor in limiting the consequences of shock on tissues. Evidence is building that albumin should be restricted to a few well-defined situations and be considered as a infusion solution of second choice, for use when other products are not indicated, are contraindicated or have been used up to their maximum dose. In particular, it seems that the use of albumin to correct hypoalbuminemia should be abandoned. Hydroxyethyl starches are the synthetic colloids with the pharmcological properties that are the closest to natural colloids. In addition, there is evidence to support the use of hydroxyethyl starches in intensive care patients. Their beneficial effects appear to be related more to their action on inflammatory processes than to their colloid osmotic power. In a risk/benefit analysis of hydroxyethyl starches, their side effects should also be weighed. Side effects are limited when hydroxyethyl starches with a low in vivo Mw are used.



References



1. Schadt JC, Ludbrook J. Hemodynamic and neurohumoral responses to acute hypovolemia in conscious mammals. Am J Physiol, 1991; 260: H305-318.


2. Barriot P, Riou B. Hemorrhagic shock with paradoxical bradycardia. Intensive Care Med, 1987; 13: 203-207.


3. Moore FA, Moore EE. Evolving concepts in the pathogenesis of postinjury multiple organ failure. Surg Clin North Am, 1995; 75: 257-277.


4. Moore FA. Posttraumatic complications and changes in blood lymphocyte populations after multiple trauma. Crit Care Med, 1999; 27: 674-675.


5. Peitzman AB, Udekwu AO, Ochoa J, Smith S. Bacterial translocation in trauma patients. J Trauma, 1991; 31: 1083-1086.


6. Edouard AR, Degremont AC, Duranteau J, Pussard E, Berdeaux A, Samii K. Heterogeneous regional vascular responses to simulated transient hypovolemia in man. Intensive Care Med, 1994; 20: 414-420.


7. Abou-Khalil B, Scalea TM, Trooskin SZ, Henry SM, Hitchcock R. Hemodynamic responses to shock in young trauma patients: need for invasive monitoring. Crit Care Med, 1994; 22: 633-639.


8. Rady MY, Edwards JD, Nightingale P. Early cardiorespiratory findings after severe blunt thoracic trauma and their relation to outcome. Br J Surg, 1992; 79: 65-68.


9. Moore FA, Haenel JB, Moore EE, Whitehill TA. Incommensurate oxygen consumption in response to maximal oxygen availability predicts postinjury multiple organ failure. J Trauma, 1992; 33: 58-65.


10. Haupt MT. The use of crystalloidal and colloidal solutions for volume replacement in hypovolemic shock. Crit Rev Clin Lab Sci, 1989; 27: 1-26.


11. Haupt MT. Colloidal and crystalloidal fluid resuscitation in shock associated with increased capillary permeability. Curr Stud Hematol Blood Transfus, 1986; 53: 86-100.


12. Drobin D, Hahn RG. Volume kinetics of Ringers solution in hypovolemic volunteers. Anesthesiology, 1999; 90: 81-91.


13. Svensen C, Hahn RG. Volume kinetics of Ringer solution, dextran 70, and hypertonic saline in male volunteers. Anesthesiology, 1997; 87: 204-212.


14. Cervera AL, Moss G. Crystalloid distribution following hemorrhage and hemodilution: mathematical model and prediction of optimum volumes for equilibration at normovolemia. J Trauma, 1974; 14: 506-520.


15. Funk W, Baldinger V. Microcirculatory perfusion during volume therapy.A comparative study using crystalloid or colloid in awake animals. Anesthesiology, 1995; 82: 975-982.


16. Wang P, Hauptman JG, Chaudry IH. Hemorrhage produces depression in microvascular blood flow which persists despite fluid resuscitation. Circ Shock, 1990; 32: 307-318.


17. Wang P, Ayala A, Dean RE, Hauptman JG, Ba ZF, DeJong GK, Chaudry IH. Adequate crystalloid resuscitation restores but fails to maintain the active hepatocellular function following hemorrhagic shock. J Trauma, 1991; 31: 601-607.


18. Velanovich V. Crystalloid versus colloid fluid resuscitation: a meta-analysis of mortality. Surgery, 1989; 105: 65-71.


19. Schierhout G, Roberts I. Fluid resuscitation with colloid or crystalloid solutions in critically ill patients: a systematic review of randomised trials. BMJ, 1998; 316: 961-964.


20. Mazzoni MC, Borgstrom P, Arfors KE, Intaglietta M. Dynamic fluid redistribution in hyperosmotic resuscitation of hypovolemic hemorrhage. Am J Physiol, 1988; 255: H629-637.


21. Lopes OU, Pontieri V, Rochae Silva M, Jr., Velasco IT. Hyperosmotic NaCl and severe hemorrhagic shock: role of the innervated lung. Am J Physiol, 1981; 241: H883-890.


22. Mouren S, Delayance S, Mion G, Souktani R, Fellahi JL, Arthaud M, Baron JF, Viars P. Mechanisms of increased myocardial contractility with hypertonic saline solutions in isolated blood-perfused rabbit hearts. Anesth Analg, 1995; 81: 777-782.


23. Kien ND, Reitan JA, White DA, Wu CH, Eisele JH. Cardiac contractility and blood flow distribution following resuscitation with 7.5% hypertonic saline in anesthetized dogs. Circ Shock, 1991; 35: 109-116.


24. Boldt J, Zickmann B, Rapin J, Hammermann H, Dapper F, Hempelmann G. Influence of volume replacement with different HES-solutions on microcirculatory blood flow in cardiac surgery. Acta Anaesthesiol Scand, 1994; 38: 432-438.


25. Prough DS, Whitley JM, Taylor CL, Deal DD, DeWitt DS. Regional cerebral blood flow following resuscitation from hemorrhagic shock with hypertonic saline. Influence of a subdural mass. Anesthesiology, 1991; 75: 319-327.


26. Wade CE, Kramer GC, Grady JJ, Fabian TC, Younes RN. Efficacy of hypertonic 7.5% saline and 6% dextran-70 in treating trauma: a meta-analysis of controlled clinical studies.Surgery, 1997; 122: 609-616.


27. Sirieix D, Hongnat JM, Delayance S, DAttellis N, Vicaut E, Brbi A, Paris M, Fabiani JN, Carpentier A, Baron JF. The comparison of the acute hemodynamic effects of hypertonic or colloid infusions immediately after mitral valve repair. Intensive Care Medicine 1999: (In Press).


28. Boldt J, Kling D, Herold C, Dapper F, Hempelmann G. Volume therapy with hypertonic saline hydroxyethyl starch solution in cardiac surgery. Anaesthesia, 1990; 45: 928-934.


29. Boldt J, Kling D, Weidler B, Zickmann B, Herold C, Dapper F, Hempelmann G. Acute preoperative hemodilution in cardiac surgery: volume replacement with a hypertonic saline-hydroxyethyl starch solution. J Cardiothorac Vasc Anesth, 1991; 5: 23-28.


30. Tollofsrud S, Tonnessen T, Skraastad O, Noddeland H. Hypertonic saline and dextran in normovolaemic and hypovolaemic healthy volunteers increases interstitial and intravascular fluid volumes. Acta Anaesthesiol Scand, 1998; 42: 145-153.


31. Hellyer PW, Meyer RE. Effects of hypertonic saline on myocardial contractility in anaesthetized pigs. J Vet Pharmacol Ther, 1994; 17: 211-217.


32. Seki K, Aibiki M, Ogura S. 3.5% hypertonic saline produces sympathetic activation in hemorrhaged rabbits. J Auton Nerv Syst, 1997; 64: 49-56.


33. Ellinger K, Fahnle M, Schroth M, Albrecht DM. Optimal preoperative titrated dosage of hypertonic-hyperoncotic solutions in cardiac risk patients. Shock, 1995; 3: 167-172.


34. Lamke LO, Liljedahl SO. Plasma volume expansion after infusion of 5%, 20% and 25% albumin solutions in patients. Resuscitation, 1976; 5: 85-92.


35. Hoye RC, Paulson DF, Ketcham AS. Total circulating albumin deficits occurring with extensive surgical procedures.Surg Gynecol Obstet, 1970; 131: 943-952.


36. Hoye RC, Voightlander V, Plantin LO, Birke G. Changes in the total circulating albumin, plasma volume and extracellular fluid volume with hemorrhage and the response to hydrocortisone. Acta Chir Scand, 1971; 137: 299-304.


37. Schwartzkopff W, Schwartzkopff B, Wurm W, Frisius H. Physiological aspects of the role of human albumin in the treatment of chronic and acute blood loss. Dev Biol Stand, 1980; 48: 7-30.


38. Hoye RC. Simultaneous measurement of red cell, plasma, and extracellular fluid volume in the surgical patient. J Lab Clin Med, 1967; 69: 683-688.


39. Hoye RC, Ketcham AS. Shifts in boyd fluids during radical surgery. Cancer, 1967; 20: 1827-1831.


40. Hoye RC, Bennett SH, Geelhoed GW, Gorschboth C. Fluid volume and albumin kinetics occurring with major surgery.JAMA, 1972; 222: 1255-1261.


41. Fleck A, Raines G, Hawker F, Trotter J, Wallace PI, Ledingham IM, Calman KC. Increased vascular permeability: a major cause of hypoalbuminaemia in disease and injury.Lancet, 1985; 1: 781-784.


42. Boldt J, Lenz M, Kumle B, Papsdorf M. Volume replacement strategies on intensive care units: results from a postal survey. Intensive Care Med, 1998; 24: 147-151.


43. Foley EF, Borlase BC, Dzik WH, Bistrian BR, Benotti PN. Albumin supplementation in the critically ill. A prospective, randomized trial. Arch Surg, 1990; 125: 739-742.


44. Rubin H, Carlson S, DeMeo M, Ganger D, Craig RM. Randomized, double-blind study of intravenous human albumin in hypoalbuminemic patients receiving total parenteral nutrition. Crit Care Med, 1997; 25: 249-252.


45. Golub R, Sorrento JJ, Jr., Cantu R, Jr., Nierman DM, Moideen A, Stein HD. Efficacy of albumin supplementation in the surgical intensive care unit: a prospective, randomized study. Crit Care Med, 1994; 22: 613-619.


46. Reviewers CIGA. Human albumin administration in critically ill patients: systematic review of randomised controlled trials. BMJ, 1998; 317: 235-240.


47. Laxenaire MC, Charpentier C, Feldman L. Anaphylactoid reactions to colloid plasma substitutes: incidence, risk factors, mechanisms. A French multicenter prospective study. Ann Fr Anesth Reanim, 1994; 13: 301-310.


48. Dewachter P, Laxenaire MC, Donner M, Kurtz M, Stoltz JF. In vivo rheologic studies of plasma substitutes. Ann Fr Anesth Reanim 1992; 11: 516-525.


49. Steinbauer M, Harris AG, Leidere r R, Abels C, Messmer K. Impact of dextran on microvascular disturbances and tissue injury following ischemia/reperfusion in striated muscle. Shock, 1998; 9: 345-351.


50. Aberg M, Hedner U, Bergentz SE. Effect of dextran 70 on factor VIII and platelet function in von Willebrands disease.Thromb Res, 1978; 12: 629-634.


51. Mailloux L, Swartz CD, Capizzi R, Kim KE, Onesti G, Ramirez O, Brest AN. Acute renal failure after administration of low-molecular weight dextran. N Engl J Med, 1967; 277: 1113-1118.


52. Hedin H, Richter W, Ring J. Dextran-induced anaphylactoid reactions in man: role of dextran reactive antibodies.Int Arch Allergy Appl Immunol, 1976; 52: 145-159.


53. Hedin H, Ljungstrom KG. Prevention of dextran anaphylaxis. Ten years experience with hapten dextran. Int Arch Allergy Immunol, 1997; 113: 358-359.


54. Barbier P, Jonville AP, Autret E, Coureau C. Fetal risks with dextrans during delivery. Drug Saf, 1992; 7: 71-73.


55. Kohler H, Kirch W, Fuchs P, Stalder K . Pharmacokinetics of urea complexed gelatin in patients with normal and with reduced kidney function. Verh Dtsch Ges Inn Med, 1978; 84: 1479-1481.


56. Schildt B, Bouveng R, Sollenberg M. Plasma substitute induced impairment of the reticuloendothelial system function.Acta Chir Scand, 1975; 141: 7-13.


57. Muchmore E, Bonhard K, Kothe N. Distribution and clearance from the body of an oxypolygelatin plasma substitute determined by radioactive tracer study in chimpanzees.Arzneimittelforschung, 1983; 33: 1552-1554.


58. Klotz U, Kroemer H. Clinical pharmacokinetic considerations in the use of plasma expanders. Clin Pharmacokinet,1987; 12: 123-135.


59. Giebel O, Horatz K. Behaviour of blood volume and its components after replacement with dextran and gelatin plasma substitutes following bleeding in the health young male.Bibl Haematol, 1969; 33: 171-183.


60. Kohler H, Zschiedrich H, Linfante A, Appel F, Pitz H, Clasen R. The elimination of hydroxyethyl starch 200/0.5, dextran 40 and oxypolygelatine. Klin Wochenschr, 1982; 60:293-301.


61. Stockwell MA, Scott A, Day A, Riley B, Soni N. Colloid solutions in the critically ill. A randomised comparison of albumin and polygeline 2. Serum albumin concentration and incidences of pulmonary oedema and acute renal failure.Anaesthesia, 1992; 47: 7-9.


62. Stockwell MA, Soni N, Riley B. Colloid solutions in the critically ill. A randomised comparison of albumin and polygeline. 1. Outcome and duration of stay in the intensive care unit. Anaesthesia, 1992; 47: 3-6.


63. Egli GA, Zollinger A, Seifert B, Popovic D, Pasch T, Spahn DR. Effect of progressive haemodilution with hydroxyethyl starch, gelatin and albumin on blood coagulation.Br J Anaesth, 1997; 78: 684-689.


64. Evans PA, Glenn JR, Heptinstall S, Madira W. Effects of gelatin-based resuscitation fluids on platelet aggregation.Br J Anaesth, 1998; 81: 198-202.


65. Baron JF. Pharmacology of low molecular weight hydroxyethyl starch. Ann Fr Anesth Reanim, 1992; 11: 509-515.


66. Treib J, Baron JF, Grauer MT, Strauss RG. An international view of hydroxyethyl starches. Intensive Care Med, 1999; 25: 258-268.


67. Treib J, Baron JF. Hydroxethyl starch: effects on hemostasis.Ann Fr Anesth Reanim, 1998; 17: 72-81.


68. Degrmont AC, Ismal M, Arthaud M, Oulare B, Mundler O, Paris M, Baron JF. Mechanisms of postoperative prolonged plasma volume expansion with low molecular weight hydroxethy starch (HES 200/0.62, 6%). Intensive Care Med, 1995; 21: 577-583.


69. Hulse JD, Yacobi A. Hetastarch: an overview of the colloid and its metabolism. Drug Intell Clin Pharm, 1983; 17: 334-341.


70. Waitzinger J, Bepperling F, Pabst G, Opitz J, Muller M, Baron JF. Pharmacokinetics and tolerability of a new hydroxyethyl starch (HES) specification [(HES (130/0.4)] after single dose infusion of 6% and 10% solutions in healthy volonteers. Clin. Drug Invest, 1998; 16: 151-160.


71. Treib J, Haass A, Pindur G, Grauer MT, Wenzel E, Schimrigk K. All medium starches are not the same: influence of the degree of hydroxyethyl substitution of hydroxyethyl starch on plasma volume, hemorrheologic conditions, and coagulation. Transfusion, 1996; 36: 450-455.


72. Treib J, Haass A, Pindur G. Coagulation disorders caused by hydroxyethyl starch. Thrombosis And Haemostasis, 1997; 78: 974-983.


73. Baron JF, De Kegel D, Prost AC, Mundler O, Arthaud M, Basset G, Maistre G, Masson F, Carayon A, Landault C et al. Low molecular weight hydroxyethyl starch 6% compared to albumin 4% during intentional hemodilution. Intensive Care Med, 1991; 17: 141-148.


74. Mishler JMT. Synthetic plasma volume expanders - their pharmacology, safety and clinical efficacy. Clin Haematol, 1984; 13: 75-92.


75. Kohler H, Zschiedrich H, Clasen R, Linfante A, Gamm H. The effects of 500 ml 10% hydroxyethyl starch 200/0.5 and 10% dextran 40 on blood volume, colloid osmotic pressure and renal function in human volunteers. Anaesthesist, 1982; 31: 61-67.


76. Boldt J, Muller M, Heesen M, Neumann K, Hempelmann GG. Influence of different volume therapies and pentoxifylline infusion on circulating soluble adhesion molecules in critically ill patients. Crit Care Med, 1996; 24: 385-391.


77. Boldt J, Heesen M, Mller M, Pabsdorf M, Hempelmann G. The effects of albumin versus hydroxyethyl starch solution on cardiorespiratory and circulatory variables in critically ill patients. Anesth Analg, 1996; 83: 254-261.


78. Rackow EC, Falk JL, Fein IA, Siegel JS, Packman MI, Haupt MT, Kaufman BS, Putnam D. Fluid resuscitation in circulatory shock: a comparison of the cardiorespiratory effects of albumin, hetastarch, and saline solutions in patients with hypovolemic and septic shock. Crit Care Med, 1983; 11: 839-850.


79. Zikria BA, Subbarao C, Oz MC, Popilkis SJ, Sachdev R, Chauhan P, Freeman HP, King TC. Hydroxyethyl starch macromolecules reduce myocardial reperfusion injury. Arch Surg, 1990; 125: 930-934.


80. Zikria BA, King TC, Stanford J, Freeman HP. A biophysical approach to capillary permeability. Surgery, 1989; 105: 625-631.


81. Wisselink W, Patetsios P, Panetta TF, Ramirez JA, Rodino W, Kirwin JD, Zikria BA. Medium molecular weight pentastarch reduces reperfusion injury by decreasing capillary leak in an animal model of spinal cord ischemia. J Vasc Surg, 1998; 27: 109-116.


82. Oz MC, FitzPatrick MF, Zikria BA, Pinsky DJ, Duran WN. Attenuation of microvascular permeability dysfunction in postischemic striated muscle by hydroxyethyl starch. Microvasc Res, 1995; 50: 71-79.


83. Oz MC, Zikria BA, McLeod PF, Popilkis SJ. Hydroxyethyl starch macromolecule and superoxide dismutase effects on myocardial reperfusion injury. Am J Surg, 1991; 162: 59-62.


84. Zikria BA, Subbarao C, Oz MC, Shih ST, McLeod PF, Sachdev R, Freeman HP, Hardy MA. Macromolecules reduce abnormal microvascular permeability in rat limb ischemia-reperfusion injury. Crit Care Med, 1989; 17: 1306-1309.


85. Webb AR, Tighe D, Moss RF, al-Saady N, Hynd JW, Bennett ED. Advantages of a narrow-range, medium molecular weight hydroxyethyl starch for volume maintenance in a porcine model of fecal peritonitis. Crit Care Med, 1991; 19:409-416.


86. Webb AR, Moss RF,Tighe D, Mythen MG, al-Saady N, Joseph AE, Bennett ED. A narrow range, medium molecular weight pentastarch reduces structural organ damage in a hyperdynamic porcine model of sepsis. Intensive Care Med, 1992; 18: 348-355.


87. Collis RE, Collins PW, Gutteridge CN, Kaul A , Newland AC, Williams DM, Webb AR. The effect of hydroxyethyl starch and other plasma volume substitutes on endothelial cell activation; an in vitro study. Intensive Care Med, 1994; 20: 37-41.


88. Schmand JF, Ayala A, Morrison MH, Chaudry IH. E ffects of hydroxyethyl starch after trauma-hemorrhagic shock: restoration of macrophage integrity and prevention of increased circulating interleukin-6 levels [see comments]. Critical Care Med, 1995; 23: 806-814.


89. Eastlund DT, Douglas MS, Choper JZ. Monocyte chemotaxis and chemotactic cytokine release after exposure to hydroxyethyl starch. Transfusion, 1992; 32: 855-860.


90. Jamnicki M, Zollinger A, Seifert B, Popovic D, Pasch T, Spahn DR. Compromised blood coagulation: an in vitro comparison of hydroxyethyl starch 130/0.4 and hydroxyethyl starch 200/0.5 using thrombelastography. Anesth Analg, 1998; 87: 989-993.


91. Boldt J, Knothe C, Zickmann B, Andres P, Dapper F, Hempelmann G. Influence of different intravascular volume therapies on platelet function in patients undergoing cardio-pulmonary bypass. Anesth Analg, 1993; 76: 1185-1190.


92. Stump DC, Strauss RG, Henriksen RA, Petersen RE, Saunders R. Effects of hydroxyethyl starch on blood coagulation, particularly factor VIII. Transfusion, 1985; 25: 349-354.


93. Strauss RG, Stump DC, Henriksen RA, Saunders R. Effects of hydroxyethyl starch on fibrinogen, fibrin clot formation, and fibrinolysis. Transfusion, 1985; 25: 230-234.


94. Strauss RG, Stump DC, Henriksen RA. Hydroxyethyl starch accentuates von Willebrands disease. Transfusion, 1985; 25: 235-237.


95. Rosencher N, Vassilieff N, Guigonis V, Toulon P, Conseiller C. Comparison of effects of Elohes and albumin on hemostasis in orthopedic surgery. Ann Fr Anesth Reanim, 1992; 11: 526-530.


96. Treib J, Haass A, Pindur G, Seyfert UT, Treib W, Grauer MT, Jung F, Wenzel E, Schimrigk K. HES 200/0.5 is not HES 200/0.5. Influence of the C2/C6 hydroxyethylation ratio of hydroxyethyl starch (HES) on hemorheology, coagulation and elimination kinetics. Thromb Haemost, 1995; 74: 1452-1456.


97. Moran SM, Myers BD. Pathophysiology of protracted acute renal failure in man. J Clin Invest, 1985; 76: 1440-1448.


98. Matheson NA, Diomi P. Renal failure after the administration of dextran 40. Surg Gynecol Obstet, 1970; 131: 661-668.


99. Hussain SF, Drew PJ. Acute renal failure after infusion of gelatins. BMJ, 1989; 299: 1137-1138.


100. Waldhausen P, Kiesewetter H, Leipnitz G, Scielny J, Jung F, Bambauer R, von Blohn G. Hydroxyethyl starch-induced transient renal failure in preexisting glomerular damage. Acta Med Austriaca, 1991; 18: 52-55.


101. Rozich JD, Paul RV. Acute renalfailure precipitated by elevated colloid osmotic pressure. Am J Med, 1989; 87: 359-360.


102. Godet G, Fleron MH, Vicaut E, Zubicki A, Bertrand M, Riou B, Kieffer E, Coriat P. Risk factors for acute post-operative renal failure in thoracic or thoracoabdominal aortic surgery: a prospective study. Anesth Analg, 1997; 85: 1227-1232.


103. Vogt NH, Bothner U, Lerch G, Lindner K H , Georgieff M. Large-dose administration of 6% hydroxyethyl starch 200/0.5 total hip arthroplasty: plasma homeostasis, hemostasis, and renal function compared to use of 5% human albumin. Anesth Analg, 1996; 83: 262-268.


104. Legendre C, Thervet E, Page B, Percheron A, Noel LH, Kreis H. Hydroxyethylstarch and osmotic-nephrosis-like lesions in kidney transplantation. Lancet, 1993; 342: 248-249.


105. Cittanova ML, Leblanc I, Legendre C, Mouquet C, Riou B, Coriat P. Effect of hydroxyethylstarch in brain-dead kidney donors on renal function in kidney-transplant recipients. Lancet, 1996; 348: 1620-1622.


106. Coronel B, Mercatello A, Martin X, Lefrancois N. Hydroxyethylstarch and renal function in kidney transplant recipients. Lancet, 1997; 349: 884.


107. Deman A, Peeters P, Sennesael J. Hydroxyethyl starch does not impair immediate renal function in kidney transplant recipients: a retrospective, multicentre analysis. Nephrol Dial Transplant, 1999; 14: 1517-1520.

Appendix: 



References



1. Schadt JC, Ludbrook J. Hemodynamic and neurohumoral responses to acute hypovolemia in conscious mammals. Am J Physiol, 1991; 260: H305-318.


2. Barriot P, Riou B. Hemorrhagic shock with paradoxical bradycardia. Intensive Care Med, 1987; 13: 203-207.


3. Moore FA, Moore EE. Evolving concepts in the pathogenesis of postinjury multiple organ failure. Surg Clin North Am, 1995; 75: 257-277.


4. Moore FA. Posttraumatic complications and changes in blood lymphocyte populations after multiple trauma. Crit Care Med, 1999; 27: 674-675.


5. Peitzman AB, Udekwu AO, Ochoa J, Smith S. Bacterial translocation in trauma patients. J Trauma, 1991; 31: 1083-1086.


6. Edouard AR, Degremont AC, Duranteau J, Pussard E, Berdeaux A, Samii K. Heterogeneous regional vascular responses to simulated transient hypovolemia in man. Intensive Care Med, 1994; 20: 414-420.


7. Abou-Khalil B, Scalea TM, Trooskin SZ, Henry SM, Hitchcock R. Hemodynamic responses to shock in young trauma patients: need for invasive monitoring. Crit Care Med, 1994; 22: 633-639.


8. Rady MY, Edwards JD, Nightingale P. Early cardiorespiratory findings after severe blunt thoracic trauma and their relation to outcome. Br J Surg, 1992; 79: 65-68.


9. Moore FA, Haenel JB, Moore EE, Whitehill TA. Incommensurate oxygen consumption in response to maximal oxygen availability predicts postinjury multiple organ failure. J Trauma, 1992; 33: 58-65.


10. Haupt MT. The use of crystalloidal and colloidal solutions for volume replacement in hypovolemic shock. Crit Rev Clin Lab Sci, 1989; 27: 1-26.


11. Haupt MT. Colloidal and crystalloidal fluid resuscitation in shock associated with increased capillary permeability. Curr Stud Hematol Blood Transfus, 1986; 53: 86-100.


12. Drobin D, Hahn RG. Volume kinetics of Ringers solution in hypovolemic volunteers. Anesthesiology, 1999; 90: 81-91.


13. Svensen C, Hahn RG. Volume kinetics of Ringer solution, dextran 70, and hypertonic saline in male volunteers. Anesthesiology, 1997; 87: 204-212.


14. Cervera AL, Moss G. Crystalloid distribution following hemorrhage and hemodilution: mathematical model and prediction of optimum volumes for equilibration at normovolemia. J Trauma, 1974; 14: 506-520.


15. Funk W, Baldinger V. Microcirculatory perfusion during volume therapy.A comparative study using crystalloid or colloid in awake animals. Anesthesiology, 1995; 82: 975-982.


16. Wang P, Hauptman JG, Chaudry IH. Hemorrhage produces depression in microvascular blood flow which persists despite fluid resuscitation. Circ Shock, 1990; 32: 307-318.


17. Wang P, Ayala A, Dean RE, Hauptman JG, Ba ZF, DeJong GK, Chaudry IH. Adequate crystalloid resuscitation restores but fails to maintain the active hepatocellular function following hemorrhagic shock. J Trauma, 1991; 31: 601-607.


18. Velanovich V. Crystalloid versus colloid fluid resuscitation: a meta-analysis of mortality. Surgery, 1989; 105: 65-71.


19. Schierhout G, Roberts I. Fluid resuscitation with colloid or crystalloid solutions in critically ill patients: a systematic review of randomised trials. BMJ, 1998; 316: 961-964.


20. Mazzoni MC, Borgstrom P, Arfors KE, Intaglietta M. Dynamic fluid redistribution in hyperosmotic resuscitation of hypovolemic hemorrhage. Am J Physiol, 1988; 255: H629-637.


21. Lopes OU, Pontieri V, Rochae Silva M, Jr., Velasco IT. Hyperosmotic NaCl and severe hemorrhagic shock: role of the innervated lung. Am J Physiol, 1981; 241: H883-890.


22. Mouren S, Delayance S, Mion G, Souktani R, Fellahi JL, Arthaud M, Baron JF, Viars P. Mechanisms of increased myocardial contractility with hypertonic saline solutions in isolated blood-perfused rabbit hearts. Anesth Analg, 1995; 81: 777-782.


23. Kien ND, Reitan JA, White DA, Wu CH, Eisele JH. Cardiac contractility and blood flow distribution following resuscitation with 7.5% hypertonic saline in anesthetized dogs. Circ Shock, 1991; 35: 109-116.


24. Boldt J, Zickmann B, Rapin J, Hammermann H, Dapper F, Hempelmann G. Influence of volume replacement with different HES-solutions on microcirculatory blood flow in cardiac surgery. Acta Anaesthesiol Scand, 1994; 38: 432-438.


25. Prough DS, Whitley JM, Taylor CL, Deal DD, DeWitt DS. Regional cerebral blood flow following resuscitation from hemorrhagic shock with hypertonic saline. Influence of a subdural mass. Anesthesiology, 1991; 75: 319-327.


26. Wade CE, Kramer GC, Grady JJ, Fabian TC, Younes RN. Efficacy of hypertonic 7.5% saline and 6% dextran-70 in treating trauma: a meta-analysis of controlled clinical studies.Surgery, 1997; 122: 609-616.


27. Sirieix D, Hongnat JM, Delayance S, DAttellis N, Vicaut E, Brbi A, Paris M, Fabiani JN, Carpentier A, Baron JF. The comparison of the acute hemodynamic effects of hypertonic or colloid infusions immediately after mitral valve repair. Intensive Care Medicine 1999: (In Press).


28. Boldt J, Kling D, Herold C, Dapper F, Hempelmann G. Volume therapy with hypertonic saline hydroxyethyl starch solution in cardiac surgery. Anaesthesia, 1990; 45: 928-934.


29. Boldt J, Kling D, Weidler B, Zickmann B, Herold C, Dapper F, Hempelmann G. Acute preoperative hemodilution in cardiac surgery: volume replacement with a hypertonic saline-hydroxyethyl starch solution. J Cardiothorac Vasc Anesth, 1991; 5: 23-28.


30. Tollofsrud S, Tonnessen T, Skraastad O, Noddeland H. Hypertonic saline and dextran in normovolaemic and hypovolaemic healthy volunteers increases interstitial and intravascular fluid volumes. Acta Anaesthesiol Scand, 1998; 42: 145-153.


31. Hellyer PW, Meyer RE. Effects of hypertonic saline on myocardial contractility in anaesthetized pigs. J Vet Pharmacol Ther, 1994; 17: 211-217.


32. Seki K, Aibiki M, Ogura S. 3.5% hypertonic saline produces sympathetic activation in hemorrhaged rabbits. J Auton Nerv Syst, 1997; 64: 49-56.


33. Ellinger K, Fahnle M, Schroth M, Albrecht DM. Optimal preoperative titrated dosage of hypertonic-hyperoncotic solutions in cardiac risk patients. Shock, 1995; 3: 167-172.


34. Lamke LO, Liljedahl SO. Plasma volume expansion after infusion of 5%, 20% and 25% albumin solutions in patients. Resuscitation, 1976; 5: 85-92.


35. Hoye RC, Paulson DF, Ketcham AS. Total circulating albumin deficits occurring with extensive surgical procedures.Surg Gynecol Obstet, 1970; 131: 943-952.


36. Hoye RC, Voightlander V, Plantin LO, Birke G. Changes in the total circulating albumin, plasma volume and extracellular fluid volume with hemorrhage and the response to hydrocortisone. Acta Chir Scand, 1971; 137: 299-304.


37. Schwartzkopff W, Schwartzkopff B, Wurm W, Frisius H. Physiological aspects of the role of human albumin in the treatment of chronic and acute blood loss. Dev Biol Stand, 1980; 48: 7-30.


38. Hoye RC. Simultaneous measurement of red cell, plasma, and extracellular fluid volume in the surgical patient. J Lab Clin Med, 1967; 69: 683-688.


39. Hoye RC, Ketcham AS. Shifts in boyd fluids during radical surgery. Cancer, 1967; 20: 1827-1831.


40. Hoye RC, Bennett SH, Geelhoed GW, Gorschboth C. Fluid volume and albumin kinetics occurring with major surgery.JAMA, 1972; 222: 1255-1261.


41. Fleck A, Raines G, Hawker F, Trotter J, Wallace PI, Ledingham IM, Calman KC. Increased vascular permeability: a major cause of hypoalbuminaemia in disease and injury.Lancet, 1985; 1: 781-784.


42. Boldt J, Lenz M, Kumle B, Papsdorf M. Volume replacement strategies on intensive care units: results from a postal survey. Intensive Care Med, 1998; 24: 147-151.


43. Foley EF, Borlase BC, Dzik WH, Bistrian BR, Benotti PN. Albumin supplementation in the critically ill. A prospective, randomized trial. Arch Surg, 1990; 125: 739-742.


44. Rubin H, Carlson S, DeMeo M, Ganger D, Craig RM. Randomized, double-blind study of intravenous human albumin in hypoalbuminemic patients receiving total parenteral nutrition. Crit Care Med, 1997; 25: 249-252.


45. Golub R, Sorrento JJ, Jr., Cantu R, Jr., Nierman DM, Moideen A, Stein HD. Efficacy of albumin supplementation in the surgical intensive care unit: a prospective, randomized study. Crit Care Med, 1994; 22: 613-619.


46. Reviewers CIGA. Human albumin administration in critically ill patients: systematic review of randomised controlled trials. BMJ, 1998; 317: 235-240.


47. Laxenaire MC, Charpentier C, Feldman L. Anaphylactoid reactions to colloid plasma substitutes: incidence, risk factors, mechanisms. A French multicenter prospective study. Ann Fr Anesth Reanim, 1994; 13: 301-310.


48. Dewachter P, Laxenaire MC, Donner M, Kurtz M, Stoltz JF. In vivo rheologic studies of plasma substitutes. Ann Fr Anesth Reanim 1992; 11: 516-525.


49. Steinbauer M, Harris AG, Leidere r R, Abels C, Messmer K. Impact of dextran on microvascular disturbances and tissue injury following ischemia/reperfusion in striated muscle. Shock, 1998; 9: 345-351.


50. Aberg M, Hedner U, Bergentz SE. Effect of dextran 70 on factor VIII and platelet function in von Willebrands disease.Thromb Res, 1978; 12: 629-634.


51. Mailloux L, Swartz CD, Capizzi R, Kim KE, Onesti G, Ramirez O, Brest AN. Acute renal failure after administration of low-molecular weight dextran. N Engl J Med, 1967; 277: 1113-1118.


52. Hedin H, Richter W, Ring J. Dextran-induced anaphylactoid reactions in man: role of dextran reactive antibodies.Int Arch Allergy Appl Immunol, 1976; 52: 145-159.


53. Hedin H, Ljungstrom KG. Prevention of dextran anaphylaxis. Ten years experience with hapten dextran. Int Arch Allergy Immunol, 1997; 113: 358-359.


54. Barbier P, Jonville AP, Autret E, Coureau C. Fetal risks with dextrans during delivery. Drug Saf, 1992; 7: 71-73.


55. Kohler H, Kirch W, Fuchs P, Stalder K . Pharmacokinetics of urea complexed gelatin in patients with normal and with reduced kidney function. Verh Dtsch Ges Inn Med, 1978; 84: 1479-1481.


56. Schildt B, Bouveng R, Sollenberg M. Plasma substitute induced impairment of the reticuloendothelial system function.Acta Chir Scand, 1975; 141: 7-13.


57. Muchmore E, Bonhard K, Kothe N. Distribution and clearance from the body of an oxypolygelatin plasma substitute determined by radioactive tracer study in chimpanzees.Arzneimittelforschung, 1983; 33: 1552-1554.


58. Klotz U, Kroemer H. Clinical pharmacokinetic considerations in the use of plasma expanders. Clin Pharmacokinet,1987; 12: 123-135.


59. Giebel O, Horatz K. Behaviour of blood volume and its components after replacement with dextran and gelatin plasma substitutes following bleeding in the health young male.Bibl Haematol, 1969; 33: 171-183.


60. Kohler H, Zschiedrich H, Linfante A, Appel F, Pitz H, Clasen R. The elimination of hydroxyethyl starch 200/0.5, dextran 40 and oxypolygelatine. Klin Wochenschr, 1982; 60:293-301.


61. Stockwell MA, Scott A, Day A, Riley B, Soni N. Colloid solutions in the critically ill. A randomised comparison of albumin and polygeline 2. Serum albumin concentration and incidences of pulmonary oedema and acute renal failure.Anaesthesia, 1992; 47: 7-9.


62. Stockwell MA, Soni N, Riley B. Colloid solutions in the critically ill. A randomised comparison of albumin and polygeline. 1. Outcome and duration of stay in the intensive care unit. Anaesthesia, 1992; 47: 3-6.


63. Egli GA, Zollinger A, Seifert B, Popovic D, Pasch T, Spahn DR. Effect of progressive haemodilution with hydroxyethyl starch, gelatin and albumin on blood coagulation.Br J Anaesth, 1997; 78: 684-689.


64. Evans PA, Glenn JR, Heptinstall S, Madira W. Effects of gelatin-based resuscitation fluids on platelet aggregation.Br J Anaesth, 1998; 81: 198-202.


65. Baron JF. Pharmacology of low molecular weight hydroxyethyl starch. Ann Fr Anesth Reanim, 1992; 11: 509-515.


66. Treib J, Baron JF, Grauer MT, Strauss RG. An international view of hydroxyethyl starches. Intensive Care Med, 1999; 25: 258-268.


67. Treib J, Baron JF. Hydroxethyl starch: effects on hemostasis.Ann Fr Anesth Reanim, 1998; 17: 72-81.


68. Degrmont AC, Ismal M, Arthaud M, Oulare B, Mundler O, Paris M, Baron JF. Mechanisms of postoperative prolonged plasma volume expansion with low molecular weight hydroxethy starch (HES 200/0.62, 6%). Intensive Care Med, 1995; 21: 577-583.


69. Hulse JD, Yacobi A. Hetastarch: an overview of the colloid and its metabolism. Drug Intell Clin Pharm, 1983; 17: 334-341.


70. Waitzinger J, Bepperling F, Pabst G, Opitz J, Muller M, Baron JF. Pharmacokinetics and tolerability of a new hydroxyethyl starch (HES) specification [(HES (130/0.4)] after single dose infusion of 6% and 10% solutions in healthy volonteers. Clin. Drug Invest, 1998; 16: 151-160.


71. Treib J, Haass A, Pindur G, Grauer MT, Wenzel E, Schimrigk K. All medium starches are not the same: influence of the degree of hydroxyethyl substitution of hydroxyethyl starch on plasma volume, hemorrheologic conditions, and coagulation. Transfusion, 1996; 36: 450-455.


72. Treib J, Haass A, Pindur G. Coagulation disorders caused by hydroxyethyl starch. Thrombosis And Haemostasis, 1997; 78: 974-983.


73. Baron JF, De Kegel D, Prost AC, Mundler O, Arthaud M, Basset G, Maistre G, Masson F, Carayon A, Landault C et al. Low molecular weight hydroxyethyl starch 6% compared to albumin 4% during intentional hemodilution. Intensive Care Med, 1991; 17: 141-148.


74. Mishler JMT. Synthetic plasma volume expanders - their pharmacology, safety and clinical efficacy. Clin Haematol, 1984; 13: 75-92.


75. Kohler H, Zschiedrich H, Clasen R, Linfante A, Gamm H. The effects of 500 ml 10% hydroxyethyl starch 200/0.5 and 10% dextran 40 on blood volume, colloid osmotic pressure and renal function in human volunteers. Anaesthesist, 1982; 31: 61-67.


76. Boldt J, Muller M, Heesen M, Neumann K, Hempelmann GG. Influence of different volume therapies and pentoxifylline infusion on circulating soluble adhesion molecules in critically ill patients. Crit Care Med, 1996; 24: 385-391.


77. Boldt J, Heesen M, Mller M, Pabsdorf M, Hempelmann G. The effects of albumin versus hydroxyethyl starch solution on cardiorespiratory and circulatory variables in critically ill patients. Anesth Analg, 1996; 83: 254-261.


78. Rackow EC, Falk JL, Fein IA, Siegel JS, Packman MI, Haupt MT, Kaufman BS, Putnam D. Fluid resuscitation in circulatory shock: a comparison of the cardiorespiratory effects of albumin, hetastarch, and saline solutions in patients with hypovolemic and septic shock. Crit Care Med, 1983; 11: 839-850.


79. Zikria BA, Subbarao C, Oz MC, Popilkis SJ, Sachdev R, Chauhan P, Freeman HP, King TC. Hydroxyethyl starch macromolecules reduce myocardial reperfusion injury. Arch Surg, 1990; 125: 930-934.


80. Zikria BA, King TC, Stanford J, Freeman HP. A biophysical approach to capillary permeability. Surgery, 1989; 105: 625-631.


81. Wisselink W, Patetsios P, Panetta TF, Ramirez JA, Rodino W, Kirwin JD, Zikria BA. Medium molecular weight pentastarch reduces reperfusion injury by decreasing capillary leak in an animal model of spinal cord ischemia. J Vasc Surg, 1998; 27: 109-116.


82. Oz MC, FitzPatrick MF, Zikria BA, Pinsky DJ, Duran WN. Attenuation of microvascular permeability dysfunction in postischemic striated muscle by hydroxyethyl starch. Microvasc Res, 1995; 50: 71-79.


83. Oz MC, Zikria BA, McLeod PF, Popilkis SJ. Hydroxyethyl starch macromolecule and superoxide dismutase effects on myocardial reperfusion injury. Am J Surg, 1991; 162: 59-62.


84. Zikria BA, Subbarao C, Oz MC, Shih ST, McLeod PF, Sachdev R, Freeman HP, Hardy MA. Macromolecules reduce abnormal microvascular permeability in rat limb ischemia-reperfusion injury. Crit Care Med, 1989; 17: 1306-1309.


85. Webb AR, Tighe D, Moss RF, al-Saady N, Hynd JW, Bennett ED. Advantages of a narrow-range, medium molecular weight hydroxyethyl starch for volume maintenance in a porcine model of fecal peritonitis. Crit Care Med, 1991; 19:409-416.


86. Webb AR, Moss RF,Tighe D, Mythen MG, al-Saady N, Joseph AE, Bennett ED. A narrow range, medium molecular weight pentastarch reduces structural organ damage in a hyperdynamic porcine model of sepsis. Intensive Care Med, 1992; 18: 348-355.


87. Collis RE, Collins PW, Gutteridge CN, Kaul A , Newland AC, Williams DM, Webb AR. The effect of hydroxyethyl starch and other plasma volume substitutes on endothelial cell activation; an in vitro study. Intensive Care Med, 1994; 20: 37-41.


88. Schmand JF, Ayala A, Morrison MH, Chaudry IH. E ffects of hydroxyethyl starch after trauma-hemorrhagic shock: restoration of macrophage integrity and prevention of increased circulating interleukin-6 levels [see comments]. Critical Care Med, 1995; 23: 806-814.


89. Eastlund DT, Douglas MS, Choper JZ. Monocyte chemotaxis and chemotactic cytokine release after exposure to hydroxyethyl starch. Transfusion, 1992; 32: 855-860.


90. Jamnicki M, Zollinger A, Seifert B, Popovic D, Pasch T, Spahn DR. Compromised blood coagulation: an in vitro comparison of hydroxyethyl starch 130/0.4 and hydroxyethyl starch 200/0.5 using thrombelastography. Anesth Analg, 1998; 87: 989-993.


91. Boldt J, Knothe C, Zickmann B, Andres P, Dapper F, Hempelmann G. Influence of different intravascular volume therapies on platelet function in patients undergoing cardio-pulmonary bypass. Anesth Analg, 1993; 76: 1185-1190.


92. Stump DC, Strauss RG, Henriksen RA, Petersen RE, Saunders R. Effects of hydroxyethyl starch on blood coagulation, particularly factor VIII. Transfusion, 1985; 25: 349-354.


93. Strauss RG, Stump DC, Henriksen RA, Saunders R. Effects of hydroxyethyl starch on fibrinogen, fibrin clot formation, and fibrinolysis. Transfusion, 1985; 25: 230-234.


94. Strauss RG, Stump DC, Henriksen RA. Hydroxyethyl starch accentuates von Willebrands disease. Transfusion, 1985; 25: 235-237.


95. Rosencher N, Vassilieff N, Guigonis V, Toulon P, Conseiller C. Comparison of effects of Elohes and albumin on hemostasis in orthopedic surgery. Ann Fr Anesth Reanim, 1992; 11: 526-530.


96. Treib J, Haass A, Pindur G, Seyfert UT, Treib W, Grauer MT, Jung F, Wenzel E, Schimrigk K. HES 200/0.5 is not HES 200/0.5. Influence of the C2/C6 hydroxyethylation ratio of hydroxyethyl starch (HES) on hemorheology, coagulation and elimination kinetics. Thromb Haemost, 1995; 74: 1452-1456.


97. Moran SM, Myers BD. Pathophysiology of protracted acute renal failure in man. J Clin Invest, 1985; 76: 1440-1448.


98. Matheson NA, Diomi P. Renal failure after the administration of dextran 40. Surg Gynecol Obstet, 1970; 131: 661-668.


99. Hussain SF, Drew PJ. Acute renal failure after infusion of gelatins. BMJ, 1989; 299: 1137-1138.


100. Waldhausen P, Kiesewetter H, Leipnitz G, Scielny J, Jung F, Bambauer R, von Blohn G. Hydroxyethyl starch-induced transient renal failure in preexisting glomerular damage. Acta Med Austriaca, 1991; 18: 52-55.


101. Rozich JD, Paul RV. Acute renalfailure precipitated by elevated colloid osmotic pressure. Am J Med, 1989; 87: 359-360.


102. Godet G, Fleron MH, Vicaut E, Zubicki A, Bertrand M, Riou B, Kieffer E, Coriat P. Risk factors for acute post-operative renal failure in thoracic or thoracoabdominal aortic surgery: a prospective study. Anesth Analg, 1997; 85: 1227-1232.


103. Vogt NH, Bothner U, Lerch G, Lindner K H , Georgieff M. Large-dose administration of 6% hydroxyethyl starch 200/0.5 total hip arthroplasty: plasma homeostasis, hemostasis, and renal function compared to use of 5% human albumin. Anesth Analg, 1996; 83: 262-268.


104. Legendre C, Thervet E, Page B, Percheron A, Noel LH, Kreis H. Hydroxyethylstarch and osmotic-nephrosis-like lesions in kidney transplantation. Lancet, 1993; 342: 248-249.


105. Cittanova ML, Leblanc I, Legendre C, Mouquet C, Riou B, Coriat P. Effect of hydroxyethylstarch in brain-dead kidney donors on renal function in kidney-transplant recipients. Lancet, 1996; 348: 1620-1622.


106. Coronel B, Mercatello A, Martin X, Lefrancois N. Hydroxyethylstarch and renal function in kidney transplant recipients. Lancet, 1997; 349: 884.


107. Deman A, Peeters P, Sennesael J. Hydroxyethyl starch does not impair immediate renal function in kidney transplant recipients: a retrospective, multicentre analysis. Nephrol Dial Transplant, 1999; 14: 1517-1520.