Absolute or relative blood volume deficits

Transcription

1 REVIEWS MINERVA ANESTESIOL 2005;71: Adequate restoration of intravascular volume remains an important therapeutic manoeuvre in managing the surgical, medical and the critically ill intensive care patient. Definition of the ideal volume replacement strategy still remains one of the burning problems. The choice between colloid and crystalloid solutions continues to generate controversy. The highly controversial crystalloid/colloid dispute has been enlarged to a colloid/colloid debate because aside of the natural colloid albumin several non-protein (synthetic) colloids are available as plasma substitutes (e.g. dextrans, gelatins, hydroxyethyl starch [HES] solutions). Due to their varying physico-chemical properties, these solutions widely differ with regard to their pharmacokinetic and pharmacodynamic properties as well as to their hemodynamic efficacy and side-effects. HES is the most intensively studied plasma substitute. The different HES preparations are defined by concentration, molar substitution (MS), mean molecular weight (MW), and the C 2 /C 6 ratio of substitution. Two new HES specification, a third-generation HES with a lower Mw and a lower MS (6% HES 130/0.4) than all other HES preparation and a first-generation HES prepared in a balanced solution, may be promising by improving the therapy of the hypovolemic patient. Albumin cannot be recommended for correction of hypovolemia because of ist extreme costs and because it can easily be replaced by other no-protein colloids. Dextrans should also not be used Address reprint requests to: Prof. Dr. J. Boldt, Department of Anesthesiology and Intensive Care Medicine, Klinikum der Stadt Ludwigshafen, Bremserstr. 79, D Ludwigshafen (Germany). BoldtJ@gmx.net Plasma substitutes J. BOLDT, S. SUTTNER Department of Anesthesiology and Intensive Care Medicine, Klinikum der Stadt, Ludwigshafen, Germany any more due to the negative effects on coagulation and its high anaphylactic potency. The historical crystalloid/colloid controversy has been focused primarily on outcome. There is increasing evidence that outcome (mortality) is not the correct measure when assessing the ideal volume replacement strategy. New concepts about critical care such as organ perfusion and organ function, the role of inflammation, immunological aspects, and wound healing may change this point of view. Volume replacement has been hitherto often based on art, dogma and personal beliefs. Further well-performed studies in this area will help more to shed new light on the ideal volume replacement strategy of the hypovolemic patient than more meta-analyses that are pooling old-to-very old studies to solve this problem. Key words: Plasma substitutes - Albumin - Dextran - Gelatin - Hydroxyethylstarch - Volume replacement - Hypovolemia. Absolute or relative blood volume deficits often occur in the surgical, trauma, and medical patient as well as in the critically ill intensive care unit (ICU) patient. Bleeding may cause absolute volume deficits, vasodilation mediated by vasodilating substances Vol. 71, N. 12 MINERVA ANESTESIOLOGICA 741

2 BOLDT PLASMA SUBSTITUTES (e.g., anesthetics) or rewarming is involved in producing relative volume deficits. Fluid deficits may also develop in the absence of obvious fluid loss secondary to generalized impairment of the endothelial barrier (e.g., during inflammation) resulting in diffuse capillary leakage and shifting of fluid from the intravascular to the interstitial compartment. Hypovolemia is associated with alterations in flow that are inadequate to fulfil the nutritive role of the circulation. During hypovolemia-related hemodynamic dysfunction, the organism tries to compensate for perfusion deficits by redistribution of flow to vital organs (e.g. heart and brain) resulting in underperfusion of other organs such as the gut, kidneys, muscles and skin. Activation of the sympathetic nervous system and the renin-aldosterone-angiotensin system (RAAS) are compensatory mechanisms to maintain peripheral perfusion. Various circulating vasoactive substances and inflammatory mediators are additionally released in this situation. Although this compensatory neurohumoral activation is initially beneficial, it becomes deleterious and may be related to a bad outcome of the hypovolemic critically ill. Because the failure to treat hypovolemia adequately may progress to organ dysfunction or death, an appropriate intravascular volume replacement therapy is a fundamental component in managing the critically ill surgical or ICU patient. 1, 2 A prospective study of patients who died in the hospital after admission for treatment of injuries showed that inadequate fluid resuscitation was the most common mismanagement. 3 An adequate intravascular volume replacement therapy may help to improve organ function and reduce patient morbidity or even mortality: in approximately 50% of septic patients, adequate volume replacement alone can reverse hypotension and restore hemodynamics. 4 It is crucial to distinguish correction of 2 deficits: 1) intravascular volume deficit (correction by volume replacement) and 2) interstitial/intracellular fluid deficit (correction by fluid replacement). Beside (hypo-, iso-, and hypertonic) crystalloids, (hypo-, iso-, and hyperoncotic) human albumin (HA) and various (hypo-, iso-, and hyperoncotic) synthetic colloids (dextrans, gelatins, hydroxyethyl starch [HES] preparations) are available to treat volume deficits. The tonicity and oncotic pressure of a substance mainly determinate the volume expanding efficacy. Thus the term plasma expander should be omitted because isotonic and isooncotic substances have almost no volume expanding rather than volume replacing effects, whereas hypertonic and hyperoncotic substances do have considerable volume expanding capacity. In recent years, the crystalloid/colloid dispute has been enlarged to a colloid/colloid debate because of the increasing number of colloids that are available. The following overview is not focused on whether high or low volume replacement strategies are favorable for the surgical patient nor should be discussed the scoop and run or stay and play debate for managing the trauma patient. It was the aim of this overview to present the different solutions for treating the hypovolemic patient and to facilitate the choice of a specific volume replacement regimen. Principles of volume replacement Administered fluid may stay in the intravascular compartment or equilibrate with the interstitial/intracellular fluid compartments. The antinatriuretic system (atrial natriuretic hormone, ANH), the renin-aldosteroneangiotensin system (RAAS), and the sympathetic nervous system (SNS) are involved in the control of volume and the composition of each body compartment. The principal action of these neurohumoral systems is to retain water in order to restore water or intravascular volume deficits, to retain sodium in order to restore the intravascular volume, and to increase the hydrostatic perfusion pressure through vasoconstriction. Enhanced activity of ANH, RAAS and SNS is known to occur in stress situations, e.g. during surgery. Although the normal response to surgery and starvation results in increased metabolic activity, it can be expected that a 742 MINERVA ANESTESIOLOGICA December 2005

3 PLASMA SUBSTITUTES BOLDT pre-existing deficit of water or intravascular volume may further increase this activity. If water or intravascular volume deficits and the stress-related stimulus of ANH, RAA and SNS are additive, fluid management could inhibit this process through counter-regulatory mechanisms. Several attempts to inhibit or attenuate the activity of ANH and RAAS by administering different volumes of isotonic crystalloid solutions have been made. It is known that ANH production is dependent on the maintenance of the extracellular volume and, in particular, the intravascular compartment (preload). Administration of a restricted amount of crystalloid solution could possibly replace previous deficit of water, but the replacement of a previous intravascular volume deficit would require much more volume in order to inhibit the secretory stimulus of all the hormones committed to maintain it. Thus it can be expected that the replacement of water alone will not inhibit the normal response of ANH and RAAS, whereas administration of a combination of crystalloid and colloid solutions (replacement of water deficit simultaneously with improvement in the effective intravascular volume) may achieve this goal. The primary goal of volume administration is to guarantee stable hemodynamics by rapidly restorating circulating plasma volume. Excessive fluid accumulation, particularly in the interstitial issue should be avoided. Starling s hypothesis describes and analyses the exchange of fluid across biological membranes. Colloid oncotic pressure (COP) is an important factor in determining fluid flux across the capillary membrane between the intravascular and interstitial space. Thus manipulation of COP appears to be useful for guaranteeing adequate circulating intravascular volume. The magnitude and duration of this volume effect will depend on the specific water binding capacity of the plasma substitute, and how much of the infused solution stays in the intravascular space. Because of varying physico-chemical properties, the commonly used solutions for volume replacement differ widely with regard to COP, initial volume effects, and duration of intravascular persistence. Possible strategies of volume replacement Crystalloids Hypotonic (e.g. dextrose in water), isotonic (e.g. normal saline [NS] solution; Ringer s solution [Ringer s lactate, RL]) and hypertonic crystalloids (e.g. 7.5% saline solution) have to be distinguished when using crystalloids for volume replacement. Crystalloids are freely permeable to the vascular membrane and are therefore distributed mainly in the interstitial and/or intercellular compartment. Only 25% of the infused crystalloid solution remains in the intravascular space, whereas 75% extravasates into the interstitium. 5 Dilution of plasma protein concentration may also be accompanied by a reduction in plasma COP subsequently leading to tissue edema. It has been shown in animal exeriments that even a massive crystalloid resuscitation is less likely to achieve adequate restoration of microcirculatory blood flow compared to a colloidal-based volume replacement strategy. 6 In a study in patients who underwent major abdominal surgery and in whom crystalloids (RL) or colloids were used for volume replacement, Prien et al. 7 demonstrated a significantly larger intestinal edema with the use of RL than with colloids. In an experimental trauma-hemorrhage model either colloids (dextran) or crystalloids (Ringer`s acetate) were used to replace blood loss after surgical trauma. 8 The crystalloid group showed significantly larger amounts of tissue water in muscle and jejunum than the colloid-treated group of animals. Crystalloids are frequently preferred because they are inexpensive and appear to be almost free of significant negative side-effects, especially with regard to coagulation. Interest has recently been focused on the influence of crystalloids on hemostasis. There is convincing evidence that use of crystalloids have a substantial influence on coagulation. Ruttmann et al. 9, 10 and Ng et al. 11 showed that in vivo dilution with crystalloids resulted in significant enhancement of coagulation. The reason for the hypercoagulable state appears to be an imbalance between naturally Vol. 71, N. 12 MINERVA ANESTESIOLOGICA 743

4 BOLDT PLASMA SUBSTITUTES occuring anticoagulants and activated procoagulants with a reduction in antithrombin III probably being the most important. 9 Others have also documented hypercoagulability with the use of crystalloids. 12 This increase in coagulation seems to be independent from the type of crystalloid that have been used. 12 An early study reported that the increase in coagulation in patient in whom crystalloids were given during surgery was associate with an increased incidence of deep vein thrombosis. 13 Thus taking new data into account, crystalloids cannot longer be considered as the good with regard to the coagulation process. Use of large amounts the physiological, NS solution (0.9%) should be urgently avoided because of the risk of producing hyperchloremic acidosis. One recent study in patients undergoing major spine surgery, showed that this phenomenon occurs only when considerable amounts of NS solution is infused. The use of RL as a crystalloid was not associated with hyperchloremic acidosis. 14 However, there is little information as to the clinical relevance of this type of acidosis. Negative consequences of hyperchloremic acidosis on organ function have been elucidated by some studies: in patients undergoing abdominal aortic aneurysm repair, either lacated Ringer s solution (RL; total dose: ml) or NS (total dose: ml) was used for volume replacement in a double-blinded fashion. 15 Only the NS-treated patients developed hyperchloremic acidosis. They needed significantly more blood products than the RL-treated patients. There is also some evidence that hyperchloremic acidosis may impair end organ perfusion and organ function. Colloids PROTEIN-COLLOIDS Albumin. Albumin is a naturally-occurring plasma protein and has for long been judged to be the kind of solution by which patients would most profit (defined as the gold-standard). Commercially available human albumin solutions (HA) contain approximately 96% of albumin, purified protein fraction (PPF) contains approximately 83% albumin, the remainder in both products being globulins. Although albumin is derived from pooled human plasma, there should be no risk of disease transmission because albumin is heated and sterilized by ultrafiltration. Thus albumin is generally considered to be safe. 16 The future production of recombinant albumin may be an alternative to today s production process. The molecular weight (MW) of albumin is approximately Da. Albumin 4% is slightly hypooncotic, 5% albumin is isooncotic, whereas 20% and 25% solutions are markedly hyperoncotic, so that total plasma volume is expanded by shifting of fluid from the interstitial/intercellular to the intravascular compartment. One-hundred milliliters of albumin 25% increases intravascular volume to a total volume of approximately 450 ml. 17 Five hundred milliliters of albumin 5% expands plasma volume by approximately 490 ml or 750 ml. The volume effect of albumin are not predictable and depend on blood volume, proteins levels, and capillary permeability. Should hypoalbuminemia be treated with albumin? In the USA, approximately 26% of all albumin is given to treat acute hypovolemia (e.g. surgical blood loss, cardiac surgery, trauma). Approximately 12% of all albumin is used to treat hypovolemia for other reasons (e.g. inflammation). Thus hypovolemia appears to be an important reason to administer albumin. Albumin is used to increase intravascular COP in order to prevent extravasation of fluid from the the intravascular space. Albumin, however, may aggravate interstitial edema because it is not confined to the vascular space but is likely to leak into the interstitial space. Consequently, albumin may be without benefit as a plasma substitute in hypovolemic patients showing capillary leakage (e.g. in inflammatory situation [e.g. sepsis, cardiac surgery]). Another question rises whether the critically ill intensive care unit patient showing hypoalbuminemia should be treated with albumin? Major surgery, trauma, and infection decrease albumin plasma levels. Administration of excess albumin does not alter albumin synthesis but increases the rate of degrada- 744 MINERVA ANESTESIOLOGICA December 2005

5 PLASMA SUBSTITUTES BOLDT TABLE I. Characteristics of dextran solutions. tion. Administered albumin is completely distributed within the extravascular space in 7 to 10 days. 18 Injury and infection have been reported to result in a decrease of serum albumin level of approximately 1.0 to 1.5 g/dl within 3 to 7 days. 18 Half-life of albumin is approximantely 20 days - thus this decrease can less likely be explained by a reduced albumin synthesis. Vascular leakage associated with increased distribution to the extravascular space is the most important mechanism why which albumin concentration is deceased in septic states. 19 Ten percent of the administered albumin leaves the vascular space whithin 2 h. More rapid equilibration occurs in inflammation associated with capillary leakage (e.g. in sepsis). Low serum albumin is definitely a marker of poor outcome A serum albumin level of <2 g/dl was associated with a mortality of approximately 100%. 23 Albumin appears to be a non-specific marker of the seriousness of an illness and thus hypoalbuminemia can be regarded as a normal phenomenon in the critically ill. Several studies have shown that supplementation of albumin in the hypoalbuminemic ICU patient has no apparent effects on morbidity and outcome. 24 However, it is still unknown whether a dangerous (low) level of albumin concentration exists. People have been born without albumin (congenital analbuminemia) and most of these patients are remarkable asymptomatic. 25 Thus what is the role of albumin: vital component or place-holder, hero or poseur? Side-effects of albumin. Certain commercially available albumins contain remarkable quantities of ions from the preparation process. In patients with acute renal failure, potentially toxic concentrations of aluminium occur after massive albumin administration. 26 Hypotension has occured after albumin administration and is most likely caused by vasoactive peptides. 27 Although considered to be the colloid with the least influence on coagulation, albumin may exert some coagulatory or anticoagulatory effects (e.g. by inhibiting platelet aggregation and enhancing the inhibition of factor Xa by antithrombin III). 28, 29 Tobias et al. 30 showed in an in vitro study using serial hemodilution and thrombelastography that albumin may also produce early and profound hypocoagulable effects. Using in vitro bleeding time to test primary hemostasis albumin showed an increased bleeding time. 31 Finally, certain batches of albumin preparations affect the expression of endothelial cell adhesion molecules. 32 The mechanism and importance of this effect is uncertain, although increased plasma levels of endothelial adhesion molecules in the circulating blood may be regarded as markers of nonsurvival. However, overall side-effects of albumin are very rare and it there are no absolute contraindications for the use of human albumin in the hypovolemic patient. NON-PROTEIN, SYNTHETIC COLLOIDS The terms synthetic colloids or artificial colloids may be confusing because all of the following substances are not produced from artificial material, but the raw material is from biological (but non-human) origin. Thus the name non-protein colloids should be preferred (also albumin is synthethized from human plasma). Dextrans. Dextran is a mixture of glucose polymers of various sizes and MWs derived from Leuconostoc mesenteroides, bacteria isolated originally from contaminated sugar beets. The formulations currently available are 10% dextran 40 and 6% dextran 70 (Table I). The colloid onctic power of the dextran solutions is very high, due to a high waterbinding capacity. One gram of dextran 40 retains 30 ml of water and 1 g dextran 70 about ml of water. Following intravenous administration dextran is almost exclusively eliminated by the kidneys. Only a small fraction transiently enters the interstitial space 6% 10% Dextran Dextran Mean molecular weight (Dalton) Volume effect (hours) (approx.) Volume efficacy (%) (approx.) (200) Maximum daily dose (g/kg) Vol. 71, N. 12 MINERVA ANESTESIOLOGICA 745

6 BOLDT PLASMA SUBSTITUTES or is eliminated via the gastrointestinal tract. The length of time that dextran stays in the intravascular compartment is based on particle size. Approximately 60% to 70% of dextran 40 is cleared within 5 h. Dextran 70 has a duration of action of 6 to 8 h. Hemorheologic effects of dextrans. Dextran solutions were widely used to maintain circulatory dynamics during various types of shock and in the setting of ischemia-reperfusion injury. They were also used to improve blood rheologic properties, especially for decreasing blood viscosity, which should ultimately translate into improvements of blood flows in the microcirculation and then tissue perfusion. The rheologic effect of dextran 40 is especially pronounced since these solutions reduce whole blood viscosity more for the same degree of hemodilution than any other plasma substitute. 33 Moreover, dextran tends to reduce harmful interactions between activated leukocytes and the microvascular endothelium (leukocyte sticking). These interactions play an important role in ischemiareperfusion injury, since activated leukocytes release intermediates which are known to damage the endothelial cell membrane. Experimental studies using intravital microscopy have shown a significant reduction in this type of leukocyte-endothelium interaction at very low doses of dextran. Despite these positive macro- and microhemodynamic effects, the use of dextrans is declining in most countries because of their significant side effects. Anaphylactic/anaphylactoid reactions. Dextrans cause more severe anaphylactic reactions than gelatins or the starches. 34 The reactions are due to dextran reactive antibodies which trigger the release of vasoactive mediators. The incidence of these reactions can be reduced by pretreatment with a hapten. Injection of 20 ml of dextran (Promit ) a few minutes before any kind of dextran infusion should be mandatory and significantly reduces severe allergic reactions. Renal function. Impaired renal function may be another problem with the use of dextran solutions. 35, 36 Renal dysfunction and acute renal failure after dextran infusion have been reported in patients who share several risk factors, such as preexisting renal disease, low urine output prior to dextran administration, hemodynamic instability, advanced age in combination with dehydration, or treatment with high doses of dextran for several days. Since there is no chemical toxicity of dextrans, the most likely mechanism for dextran-induced renal dysfunction may be swelling and vacuolization of tubular cells and tubular obstruction due to the production of a hyperviscous urine. Importantly, all hyperoncotic colloids (albumin 20% or 25%, hydroxyethly starch 10%) can induce this type of renal dysfunction. Hemostatic abnormalities. Dextrans have well-documented negative effects on blood coagulation, resulting in an increased bleeding tendency. 37 Dextran infusion induces a dose-dependent acquired von Willebrand s syndrome, with decreased levels of von Willebrand factor (vwf) and associated factor VIII (VIII:c) coagulant activity. The fall in vwf and factor VIII:c after dextran administration is more than can be explained by its dilutional effects. Besides this, dextrans also enhance fibrinolysis. These effects are greater with high MW dextrans. It is therefore not surprising that in several clinical studies the administration of high doses of dextran (>1.5 g dextran/kg body weight) was associated with increased postoperative blood loss and higher transfusion requirements. Consequently, there is a maximal dosage recommendation of 1.5 g dextran/kg body weight/day (about ml for initial fluid resuscitation in an adult) to avoid serious bleeding complications. Gelatins. Gelatins are polydispersed polypeptides produced by degradation of bovine collagen. Gelatin solutions were first used as colloids in the treatment of hypovolemic shock as early as The early solutions had a high MW, which had the advantage of a significant oncotic effect but the disadvantages of a high viscosity and a tendency to gel and solidify if stored at low temperatures. Reducing the MW reduced the tendency to gel but smaller MW molecules could not exert a significant oncotic effect. 746 MINERVA ANESTESIOLOGICA December 2005

7 PLASMA SUBSTITUTES BOLDT TABLE II. Characteristics of the gelatin solutions. Three types of modified gelatin products are now available: cross-linked or oxypolygelatins (e.g. Gelofundiol ), urea-crosslinked (e.g. Haemacel ), and succinylated or modified fluid gelatins (e.g. Gelofusine ) (Table II). Although gelatins are products of bovine origin, they are sterile, pyrogen free, contain no preservatives and have a recommended shelf-life of 3 years when stored at temperatures less than 30 C. The MW ranges from to Da with a weight-average MW of Da. The various gelatin solutions have comparable volume-restoring efficacy. However, the increase in blood volume is less than the infused volume of gelatin, due to a rapid, but transient passage of gelatins in the interstitial space. Moreover, gelatins are rapidly cleared from the bloodstream by glomerular filtration and, to a lesser part, undergo cleavage by proteases into small peptides in the reticuloendthelial system. Therefore, repeated infusions of gelatin are necessary to maintain adequate blood volume. This disadvantage is balanced by the fact that there are no dose limitations with gelatins as occurs with dextrans and HES solutions. Gelatins do not accumulate in the body and appear to be almost without adverse on kidney function. Although for a long time gelatins were considered not to influence blood coagulation other than by dilution, there is some evidence that gelatins do influence platelet function and blood coagulation. In a recent study comparing the effects of progressive hemodilution with gelatin, saline, HES, and albumin on blood coagulation, significant changes in the thromboelastogram were found after the infusion of gelatin solutions. 37 The clinical relevance of Urea-crosslinked Cross-linked Succinylated gelatin gelatin gelatin Concentration (%) Mean molecular weight (Dalton) Volume effect (hours) (approx.) Volume efficacy (%) (approx.) Osmolarity (mosmol/l) the impairment of hemostasis after gelatin infusion, however, is uncertain. HES. HES refers to a class of synthetic colloid solutions that are modified natural polysaccharides and similar to glycogen (Figure 1). HES is derived from amylopectin, a highly branched starch which is obtained from maize or potatoes. Polymerised D-glucose units are joined primarily by 1-4 linkages with occasional 1-6 branching linkages. The degree of branching is approximately 1:20, which means that there is one 1-6 branch for every 20 glucose monomer units. Natural starches cannot be used as plasma substitutes because they are unstable and rapidly hydrolyzed by circulating amylase. Substitut-ing hydroxyethyl for hydroxyl groups results in highly increased solubility and retards hydrolysis of the compound by amylase, thereby delaying its breakdown and elimination from the blood. The hydroxyethyl groups are introduced mainly at carbon position C 2, C 3, and C 6 of the anhydroglucose residues (Figure 1). Unlike the dextrans, which are mainly characterized by their concentration and the weight-averaged mean MW, the pharmacokinetics of HES preparations are characterized also by other patterns: concentration (3%, 6%, 10%); weight averaged mean MW (the arithmetic mean of the MW of all HES molecules): low-molecular weight [LMW]-HES: 70 kd; medium-molecular weight [MMW]-HES: from 130 to 270 kd; high-molecular weight [HMW]-HES: >450 kd); number averaged MW (Mn: the median MW of all HES molecules); MS (the molar ratio of the total number of Vol. 71, N. 12 MINERVA ANESTESIOLOGICA 747

8 BOLDT PLASMA SUBSTITUTES O CH 2 -CH 2 OH O O CH 2 -CH 2 OH hydroxyethyl groups to the total number of glucose units): low MS: 0.4 and 0.5; high MS: 0.62 and 0.7 (for example Voluven, a newly designed third-generation medium MW HES with a MS of 0.4 has 4 hydroxyethyl groups for every 10 glucose units); the degree of substitution (DS: the ratio of substituted glucose units to the total number of glucose molecules); the C 2 /C 6 -ratio: there is convincing evidence that the α-amylase activity depends on the position of the hydroxyethyl groups on the glucose molecule (C 2, C 3, C 6 ). The ratio of O O binding O CH 2 -CH 2 OH CH 2 -CH 2 OH Degradation dependent on: 1. Molar substitution (MS) (high MS: slow degredation) ( ) 2. C 2 /C 5 -ratio (high: slow degredation) Figure 1. Structure of hydroxyethyl starch (HES). Hydroxyethyl starch (HES) degradation by serum α-1.4-amylase TABLE III. Characteristics of hydroxyethyl starch (HES) solutions. O O O O O binding C 2 :C 6 hydroxyethylation appears to be an important factor for the pharmacokinetic behaviour of HES and possibly also for its side-effects (e.g. accumulation, tissue accumulation and bleeding complications). In Europe, numerous HES preparations with different combinations of concentration, MW, MS, and hydroxyethylation pattern (C 2 /C 6 -ratio) are available (Table III). Hextend is another development of HES preparations (Figure 2). It is a modified, physiologically balanced first-generation HMW- HES preparation (MS: 0.7; weight average MW: approximately 670 kd, mean MW 550 kd) containing balanced electrolytes (Na + : CH 2 -CH 2 OH 3. Mean molecular weight (Mw) - LMW-HES: 70 kd - MMW-HES kd - HMW-HES: 450 kd HES HES HES HES HES HES 70/ / / / / /0.7 Concentration (%) Volume efficacy (%) (approx.) Volume effect (hours) (approx.) Mean molecular weight (kd) Molar substitution (MS) C 2 /C 6 ratio 4:1 9:1 6:1 6:1 9:1 4.6:1 KD: kilo Dalton. 748 MINERVA ANESTESIOLOGICA December 2005

9 PLASMA SUBSTITUTES BOLDT 143 mmol/l, Cl-: 124 mmol/l, lactate: 28 mmol/l, Ca ++ : 2.5 mmol/l, K + : 3 mmol/l, Mg ++ : 0.45 mmol/l, glucose: 5 mmol/l). The balancing of a HMW-HES should eliminate the negative side-effects known from standard HMW-HES (e.g. bleeding complications known from hetastarch). It is important to distinguish between the different HES preparations, because the extent and duration of plasma volume expansion, as well as their effects on blood rheology, the coagulation system, and other likely clinical variables differs with respect to the specific physico-chemical properties of a HES preparation. The water-binding capacity of HES ranges between 20 and 30 ml/g. Therefore, HES solutions have a good plasma volume expanding capacity. Following the infusion of HES there is initially a rapid amylasedependent breakdown and renal excretion of up to 50% of the administered dose within 24 h. The hydroxyethyl residues, especially when bound to the C 2 carbon position of glucose, hinder the plasma amylase, hence increasing the intravascular half-life of the HES solution. A higher MW range and a more extensive degree of substitution result in slower elimination. Smaller HES molecules (<50-60 kd) are eliminated rapidly by glomerular filtration. Renal elimination by filtration continues as larger HES molecules are hydrolysed to smaller molecules. A small amount of the administered dose is forced into the interstitial space for later redistribution and elimination. Another fraction is taken up by the reticuloendothelial system where the starch is slowly broken down. Thus, trace amounts of the preparations can be detected for several weeks after administration. Plasma and tissue accumulation are markedly dependent on the type of HES preparation (Figures 3, 4). Microcirculatory effects of HES solutions Hypovolemia may initiate a complex pathophysiologic process (e.g. stimulation of the sympathoadrenergic and renin-angiotensin systems) that may result in an inadequate tissue perfusion and decreased tissue oxygen supply. Therefore, fluid therapy 450/0.7 First generation HES Development of HES 70/ / /0.62 Second generation HES should not only stabilize macrohemodynamics, but also have beneficial effects on microcirculation and tissue oxygenation. HES preparations have been successfully used for both, the treatment of intravascular volume deficits and to improve microcirculatory blood flow. The hemorheologic effects of HES are determined by their high hemodilutional capacity in combination with their specific pharmacological effects on red cell aggregation, platelet function, plasma viscosity, and blood corpuscle-endothelial cell interactions. Vascular resistance is reduced by lowering whole blood viscosity, which will enhance venous return and increase cardiac output. The net result would be improved blood fluidity, which might beneficially influence tissue perfusion and oxygenation. Intravascular volume replacement with the third-generation MMW HES 130/0.4 has been shown to improved tissue oxygenation in patients undergoing major abdominal surgery. 41 In contrast, equivalent volumes of a crystalloid solution (lactated Ringer s solution) were associated with a significant decrease of tissue oxygen tensions. Increased tissue oxygen tension may have a clinical Balanced HES 450/0.7 (Hextend TM ) 130/0.4 Third generation HES Figure 2. Development of hydroxyethyl starch (HES). Vol. 71, N. 12 MINERVA ANESTESIOLOGICA 749

10 BOLDT PLASMA SUBSTITUTES mg HES 450/0.7 (ml mg HES 200/0.6 (ml A Multiple dosage 6% HES 450/0.7 (500 ml/day for 3 days) Hours Multiple dosage 6% HES 200/0.6 (500 ml/day for 5 days) Hours impact in terms of improved wound healing and less infectious complications, which has been shown in another clinical trial in patients undergoing major colon surgery. Other authors suggested that HES may be able to ameliorate capillary leakage secondary to inflammation. However, whether HES solutions are able to seal the leak in patients with systemic inflammatory response syndrome or sepsis, as proposed by these results, must be clarified. HES and the coagulation system. One major concern with the use of HES solutions is a possible alteration in the coagulation system. Imbalances in the normal hemostatic mechanisms are commonly seen in surgical or ICU patients, secondary to blood loss, hypothermia or activation of inflammatory process with a subsequent imbalance of proand anticoagulatory pathways. Normovolemic volume replacement with synthetic colloids may addionally lead to dilution of red blood cells, platelets, and coagulation factors. Negative effects on coagulation have been reported after the use of HES, 42, 43 but different HES preparations do have different effects on hemostasis. 37, 44 In the majority of studies showing significant negative effects on the coagulation process, the first-generation mg HES/ml % B Plasma concentration after administration of 10% HES 130/ Day 1 6 Day Hours C-HES in the body in % of administered dose -50% * 3-50% Figure 3A, B. Plasma accumulation of different HES preparations after multi-dose infusions. mg HES 200/0.5 ml mg HES 70/0.5 ml Multiple dosage 10% HES 200/0.5 (500 ml/day for 5 days) Hours 10 8 Multiple dosage 6% HES 70/0.5 (500 ml/day for 5 days) Hours Figure 4. Plasma accumulation and tissue accumulation after adminstration of the third. generation HES 130/0.4 in comparison with second generation HES 200/0.5. * -50% * 6% HES 130/0.4 6% HES 200/0.5-75% Days after last HES administration HMW (hetastarch; HES 450) with a high MS (0.7) has been used. 42, 43 Modern HES preparations with a lower MW and a lower MS (0.4) (e.g. HES 130/0.4) appear to be almost free of negative effects on hemostasis. 45, 46 * 750 MINERVA ANESTESIOLOGICA December 2005

11 PLASMA SUBSTITUTES BOLDT There is only very little information available on the mechanisms by which HES affects blood coagulation or platelet function beyond that observed after hemodilution alone. It is hypothesised that large HES molecules induce a specific decrease of vwf and VIII:c by precipitation, leading to a lengthened activated partial thromboplastin time. HES has also been suggested to reduce platelet function by coating the platelet surface or inducing platelet damage. In fact, HES with a HMW, high DS, and with high C 2 /C 6 hydroxyethylation ratio (e.g. HES 450/0.7 or HES 200/0.62) reduced concentrations of vwf and VIII:c more than HES with lower MW and a lower DS (e.g. HES 200/0.5 or HES 130/0.4). Abnormal platelet function also occurs more often after administration of HMW HES (MW 450 kd) or HES with a high MS (0.62; 0.7). Thus, these solutions may induce an increased bleeding tendency, whereas HES with lower MW and a lower MS are probably safe in this respect. HES and renal function. There are some studies showing that patients treated with certain HES solutions (HMW-HES and HES with a high MS) may suffer from renal dysfunction. 47,48 Several hypotheses and risk factors have been proposed to explain the mechanism of renal dysfunction associated with HES administration. Some histological studies have shown reversible swelling of renal tubular cells after the administration of certain HES preparations, most likely related to reabsorption of macromolecules. Swelling of tubular cells causes tubular obstruction and medullary ischemia, 2 important risk factors for the development of acute renal failure. In a retrospective study, Legendre et al. 49 reported an 80% rate of osmotic nephrosislike lesions (vacuolization of the proximal tubular cells) in transplanted kidneys after routine administration of a HES with a MMW (200 kd), a high MS (0.62), and high C 2 /C 6 hydroxyethylation ratio to brain-dead donors. This lesions, however, had no negative influence on graft function or serum creatinine 3 and 6 months after transplantation. Similar tubular lesions have been described with other substances (dextrans, mannitol). The most likely mechanism of causing renal dysfunction is the induction of hyperviscosity of the urine by infusion of hyperoncotic colloids in dehydrated patients. Glomerular filtration of hyperoncotic molecules from colloids causes a hyperviscous urine and stasis of tubular flow, resulting in obstruction of the tubular lumen. Considering this pathogenesis, it can be hypothesized that all hyperoncotic colloid solutions can induce renal impairment (hyperoncotic acute renal failure). In the case of HES, the risk of high plasma COP and thus the risk of acute renal failure are probably increased by high concentrations of the colloid (10% HES) or repeated administration of HES with a high in vivo MW. An adequate hydration using sufficient amount of crystalloids is preventing these adverse effects on renal function. Large amounts (>2 000 ml) of HES preparations with a LMW or MMW (e.g. HES 130/0.4 or HES 200/0.5) and a low MS (0.4; 0.5) have been used safely in patients without altered kidney function. 50, 51 The critical creatinine level when HES should be avoided is not know. New light on this problem is shed by the last generation HES: in volunteers showing mild-to-severe renal dysfunction (mean creatinine clearance 50.6 ml/min/1.73 m 2 ), HES 130/0.4 was used. 52 After 500 ml of HES 130/0.4, kidney function was not affected (creatinine clearance even slightly increased by 7.5 ml/min/1.73 m 2 ) indicating no negative effects of this new preparation with regard to kidney function. HES and accumulation/storage/itching. The degree of accumulation is highly dependent on the type of HES used for volume replacement. Especially HES solutions with a high MS are associated with considerable accumulation, particularly after multiple dosing (Figure 3, Figure 4). Thus HES with low MS (0.4, 0.5) should be preferred when consistent hypovolemia is treated over days in the ICU patient (e.g. in sepsis or septic shock). Depending on the characteristics of the HES preparation, a varying degree of the infused HES leaves the vascular space and is taken up by the reticulo-endothelial system (RES [=mononuclear phagocytic system [MPS]). The sequelae of storage of HES are not well clearified - with regard to function of the MPS, HES storage appears to be without detrimental consequences. 53 The new third- Vol. 71, N. 12 MINERVA ANESTESIOLOGICA 751

12 BOLDT PLASMA SUBSTITUTES TABLE IV. Characteristics of hypertonic saline solutions. generation HES (HES 130/0.4) showed some favorable physico-chemical properties that are associated with less storage than other HES specifications. Itching after administration of HES has been demonstrated in some reports. Special features of HES-induced pruritus include long latency of onset and persistence. A dosedependent uptake of HES was first detected in macrophages and, thereafter, in endothelial and epithelial cells. Patients suffering from pruritus consistently showed additional deposition of HES in small peripheral nerves. 54 Most of these reports originated from patients treated for sudden deafness. These patients has received considerable amount of HES (up to 20 L) over a long period (10 to 20 days) - mostly HMW-HES or HES with a high MS. The incidence of pruritus after surgery is not clearly known because it may occur weeks or even months after administration, when the anesthetist is no longer in contact with the patient. Occasional reports on pruritus have been published after single use of approximately ml of HES. 55 In a questionnaire covering more than 700 patients no increased incidence of pruritus after infusion of 2 different HES preparations (LMW- and MMW-HES) in comparison with lactated Ringer s solution have been shown. 56 HYPERTONIC SOLUTIONS HyperHaes (Fresenius, Germany) Great enthusiasm has been expressed for hypertonic solutions (HS) or hypertonic/colloid solutions (HCS) in the treatment of refractory hypovolemic shock. The physiologic effects of these solutions have been well documented. The positive effects of HS were described in several experimental and clinical studies The sodium concentration ranged from 3% to 7.5%. HS may improve cardiovascular function on multiple levels: displacement of tissue fluid into the blood compartment; direct vasodilatory effects, both in the systemic and pulmonary circulation; reduction in venous capacitance; and positive inotropic effects through direct actions on the myocardial cells. Additionally, HS are able to improve organ blood flow and microcirculation. The main mechanism of action of HS is rapid mobilization of endogenous fluid and subsequent plasma volume expansion. Due to the hypertonicity of the solutions, only a small volume of fluid (approximately 4 ml/kg) is necessary to effectively restore cardiovascular function (small volume resuscitation). The initial improvement in cardiovascular function (e.g., increase in cardiac output) seems to be mediated by the hypertonicity of the solution and subsequently by the increase in ventricular preload, 61 whereas the solute composition does not seem to be important. Volume expanding effects of hypertonic saline solution were reported to be rather transient. Thus, HS were mixed with colloids (with hypertonic dextran solution [HDS= hypertonic/hyperoncotic solution or isotonic HES solution [HHS=hypertonic/isooncotic solution]) (Table IV) and these mixtures show significant prolongation of their efficacy.62 The use of extreme HS (up to mosmol/l) aside from hypovolemic trauma patients has been studied only in some clinical trials, mostly in burns, trauma patients, and occasionally in patients with severe hypovolemia secondary to surgery. RescueFlow (BioPhausia, Sweden) Electrolyte concentration 7.2% NaCl 7.5% NaCl Sodium 1,232 mmol/l 1,283 mmol/l Osmolarity 2,464 mosmol/l 2,567 mosmol/l Colloid Hydroxyethyl starch Dextran Colloid concentration 6% 6% Mean molecular weight (kd) Indication Severe volume deficit Severe volume deficit 752 MINERVA ANESTESIOLOGICA December 2005

13 PLASMA SUBSTITUTES BOLDT In a meta-analysis of the efficacy of a hypertonic 7.5% saline/6% dextran solution in trauma patients from 1997, 9 original studies were analyzed. 63 The analysis revealed no significant improvement in outcome after the infusion of hypertonic saline solution, whereas the use of hypertonic saline plus dextran (HSD) may be superior compared to isotonic fluid resuscitation. In a recently published meta-analysis (Cochrane Review) from 2002, the use of crystalloids was compared with HS. Five studies in trauma patients were included. No beneficial influence of the HS on outcome was found. 64 Optimal treatment of the hypovolemic patient What kind of solution - can the literature help us? What may be the criticeria for facilitating the decision for the ideal kind of volume replacement solution? Mortality? Morbidity? Organ function? Side-effects? Costs?... Without doubt, outcome (mortality) appears to be the major argument pro or con a specific volume replacement regimen. Unfortunately, up to now no valid study exists that implicates the superiority of a specific solution. In the recently published SAFEstudy (The Saline versus Albumin Fluid Evaluation) from Australia and New Zealand, volume therapy using 4% albumin was compared with NS solution in approximately critically ill ICU patients in a multicenter, randomized double-blind trial. 65 The study included a heterogenous population of ICU patients with approximately 43% surgical and approximately 57% medical patients. The primary outcome measure was death during the 28-day period after randomization. The authors concluded that use of either 4% albumin or NS for fluid resuscitation resulted in similar outcome at 28 days. Length of stay in the ICU and in the hospital as well as days on the ventilator and on renal-replacement therapy were also without differences. This study supports the well-known recommendation that use in of albumin in the critically ill is hard to justify, but the results from this study should not be generalized for all colloids! Whether 4% albumin is the ideal colloid for treating the hypovolemic critically ill must be doubted. Thus also the SAFE-study seems to be unable to solve the age old crystalloid vs colloid debate. We are living in times of evidence-basedmedicine (EBM), meta-analyses, and systematic reviews. What does the literature tell us about the best way to treat our hypovolemic patients: In a Cochrane Review from 2002, a systematic review was made on colloids versus crystalloids for fluid resuscitation in critically ill patients. 66 No study more recent than 2000 was included in this analysis comparing mortality of colloids versus crystalloids for fluid resuscitation in humans. Twenty-six trials comparing crystalloids with different kinds of colloids, 9 trials comparing colloids prepared in hypertonic crystalloids with isotonic crystalloids, and 3 trials comparing hypertonic crystalloids with colloids were included. There was no evidence that resuscitation with colloids reduces the risk of death in patients with trauma, burns, and following surgery. In another systematic review from the Cochrane Group from 2002, hypertonic-based volume replacement regimen was compared with crystalloid-based volume replacement in critically ill patients. 64 Although several of studies have been published on this topic, only 12 studies were included into the analysis. The authors concluded that there is no evidence that one strategy of volume therapy is superior to the other in patients with trauma (5 studies included), burns (3 studies included), or those undergoing surgery (4 studies included). This results concerning trauma patients are in contrast to another meta-analysis on hypertonic volume replacement from 1997 including 12 studies comparing hypertonic salinebased volume therapy with dextran-based volume replacement. 63 This meta-analysis suggests a favorable survival benefit for hypertonic saline treatment of traumatic hypotension. In a meta-analysis from 2001 supported by Vol. 71, N. 12 MINERVA ANESTESIOLOGICA 753

14 BOLDT PLASMA SUBSTITUTES the Plasma Protein Therapeutics Association (PPTA), 67 the influence of expensive albumin-based volume therapy on mortality compared to other less expensive volume replacement strategies was compared. No actual studies before 2000 were included. Trials involving surgery and trauma (27 studies), burns (4 studies), hypoalbuminemia (5 studies), high-risk neonates (6 studies), ascites (5 studies), and other indications (8 studies) were included. None of the analysed factors (outcome, mortality) were significantly influenced by either of the volume replacement regimen. There was overall no beneficial effect of albumin on mortality in this 55 studies including patients in comparison to other plasma substitutes. The authors concluded from their findings that this supports the safety of albumin as a volume replacement strategy. The fact that it does no help to improve patients outcome remained uncommented. One meta-analysis distinguished between trauma patients and other kind of patients (e.g. cardiac surgery, critical care patients). 68 In this analysis from trauma studies were included. Most of them were more than 17 years old. All kinds of colloids were compared to crystalloid-based resuscitation. There were no differences between the 2 volume replacement strategies. Some reviews and meta-analyses were focused only on side-effects. In a review from de Jonge et al., 37 articles were selected that provided data on the effects of all colloids on hemostasis and postoperative blood loss in humans. They concluded that all artifical colloids are potentially associated with an increased bleeding tendency after infusion of very large volumes. Rapidly degradable HES preparations (e.g. HES 200/0.5) and gelatins appear not to significantly impair the coagulation process. New HES products (e.g. HES 130/0.4 or Hextend ) were not included in this analysis. Wilkes et al. 42 carried out a meta-analysis on postoperative bleeding in cardiac surgery patients in whom either albumin or different HES preparations have been given. Both solutions have been used either before or after cardiopulmonary bypass (CPB) or as an addition to the priming. When HMW HES (Hetastarch; HES 450/0.7) was compared to albumin (9 studies with 354 patients), postoperative bleeding was significantly higher in the HMW-HES patients than in the albumintreated group (95% confidence interval [CI]: to -0.05). When HES with a lower Mw (200 kd; HES 200/0.5) was compared with albumin (8 studies with 299 patients), no more statistical difference in postoperative bleeding (95% CI: to +0.01) was obvious. Use of blood and blood products have not been systematically analysed. Serious adverse reports from 1998 to 2000 with albumin were analysed by Vincent et al. 69 They found only very few adverse reports with this very expensive volume replacement regimen. The risks of other much cheaper volume replacement strategies were not documented or analysed. Conclusions Adequate management of the underlying insult is a prerequisite of treating trauma, surgical, medical and critically ill ICU patients - supportive therapy, including sufficient volume therapy, however, appears to be also of high importance. In spite of numerous studies that have been published on the different plasma substitutes, the ideal volume replacement strategy for correcting hypovolemia has still not been yet identified (Table V). Looking on the flood of publications on volume therapy, what did we learn from the recent years? Although the quality of studies have improved (prospective, randomized rather than retrospective studies) standardized protocols for volume replacement are unfortunately still often missing. Criteria for volume infusion such as as determined by the attending clinician are definitely inappropriate to assess the effects of a certain substance on volume status. Although several studies are available assessing the different volume replacement strategies, there are still no convincing guidelines regarding the choice of fluid for volume replacement. 754 MINERVA ANESTESIOLOGICA December 2005