Pharmacology of plasma expanders

Plasma expanders are used to restore the circulating volume of a hypovolaemic patient. Typically, colloids are used to expand the plasma volume, although combinations of hypertonic crystalloid and colloid have recently been used. The currently available colloids vary in their physico-chemical, pharmaco-dynamic and pharmaco-kinetic properties. In particular, they differ in molecular weight, which partly determines their duration of action, and in their ability to expand the plasma volume. Dextran, hydroxyethyl starch and hypertonic colloid solutions improve oxygen flux within the microcirculation. Despite their benefits, the use of dextran and high molecular weight starches is limited by their negative impact on coagulation. In addition, these macro-molecules may also induce acute renal failure in susceptible patients. Current research focuses on the development of artificial oxygen-carriers as plasma expanders. These substances, which include modified stromal-free haemoglobin and perfluorocarbon emulsions, are undergoing clinical trials.     

Rapid volume expansion in patients with interstitial lung diseases

Rapid administration of intravascular volume expanders is often necessary during anesthesia. Significant controversy still exists on the relative values of different volume expanders. Fifteen hypoxemic patients (Pao2 less than 70 torr on room air) were studied preoperatively. They were randomized into three groups. One group received 1.5 ml/kg of 25% salt-poor human albumin, a second group, 7 ml/kg of fresh frozen plasma; a third group, 7 ml/kg of 0.9% NaCl in water (normal saline). The infusions were given intravenously and completed in 20 minutes. Changes in hemodynamic pressures and flows, blood chemistries, and oxygen uptake and transport variables were studied. It was concluded that fresh frozen plasma afforded the greatest increase in cardiac output and oxygen availability with the least increase in left ventricular stroke work. Colloid osmotic pressure was more significantly increased by fresh frozen plasma than by salt-poor human albumin. Normal saline caused both a decrease in oxygen availability and colloid osmotic pressure. Pulmonary venous admixture increased to some extent in all patients receiving fresh frozen plasma or normal saline. In three patients, this increase was very marked and accompanied by severe arterial hypoxemia.     

Colloid solutions: a clinical update

Albumin, dextran, gelatin, and hydroxyethyl starch (HES) solutions are colloids that efficiently expand the circulating blood volume. The administration of colloids restores the intravascular volume with minimal risk of tissue edema in comparison with crystalloid solutions alone. However, colloids are always given for surgical and critically ill patients. The type of the colloid, volumes applied, aggressiveness of fluid resuscitation, and the volume status at the initial phase of administration determine their clinical responses. The outcome after fluid resuscitation with various colloids in critically ill patients seems to be comparable according to systematic reviews. A randomized, adequately powered clinical trial comparing modern nonprotein colloid to albumin is still lacking. Rapidly degradable HES solutions have good hemodynamic effects, and the risk of adverse renal and coagulation effects, as well as allergic reactions, is minimal. The current investigation has also shown the beneficial effect of HES solution (especially HES 130/0.4) on inflammatory response, postoperative nausea and vomiting, and postoperative outcome. The indication of colloids with an assessment of the degree of hypovolemia and safety profiles should thus be taken into consideration before colloid administration.     

Néphrotoxicité des produits de remplissage

Expansion of extracellular volume is a treatment traditionally proposed to correct abnormalities of renal perfusion and prevent ischemic injury. However, vascular filling is not at risk for tissue oxygenation and renal function. The use of synthetic colloids exposes the patient to the risk of developing lesions such as osmotic nephrosis. Hyperoncotic colloids reduce glomerular filtration pressure. The nephrotoxicity of hydroxyethyl starches is now clearly established regardless of their characteristics. Colloids have never demonstrated their superiority as plasma volume expanders, they should be abandoned in favour of crystalloid solutions.     

Volume replacement and microhemodynamic changes in polytrauma

Though fluid administration is one of the most basic concepts in resuscitation, there is ongoing controversy and continuing research on the definition of the ideal fluid for resuscitation of trauma and hemorrhage and for intraoperative volume support. In general, crystalloids and colloids, as well as blood, blood substitutes and oxygen therapeutics, are available. This report briefly revisits the physiological mechanisms underlying resuscitation with crystalloids and colloids, emphasizing colloid-supplemented resuscitation with hypertonic saline. Finally, potential applications of oxygen therapeutics are briefly considered.     

The efficacy and safety of colloid resuscitation in the critically ill

Despite evidence from clinical studies and meta-analyses that resuscitation with colloids or crystalloids is equally effective in critically ill patients, and despite reports from high-quality clinical trials and meta-analyses regarding nephrotoxic effects, increased risk of bleeding, and a trend toward higher mortality in these patients after the use of hydroxyethyl starch (HES) solutions, colloids remain popular and the use of HES solutions is increasing worldwide. We investigated the major rationales for colloid use, namely that colloids are more effective plasma expanders than crystalloids, that synthetic colloids are as safe as albumin, that HES solutions have the best risk/benefit profile among the synthetic colloids, and that the third-generation HES 130/0.4 has fewer adverse effects than older starches. Evidence from clinical studies shows that comparable resuscitation is achieved with considerably less crystalloid volumes than frequently suggested, namely, <2-fold the volume of colloids. Albumin is safe in intensive care unit patients except in patients with closed head injury. All synthetic colloids, namely, dextran, gelatin, and HES have dose-related side effects, which are coagulopathy, renal failure, and tissue storage. In patients with severe sepsis, higher doses of HES may be associated with excess mortality. The assumption that third-generation HES 130/0.4 has fewer adverse effects is yet unproven. Clinical trials on HES 130/0.4 have notable shortcomings. Mostly, they were not performed in intensive care unit or emergency department patients, had short observation periods of 24 to 48 hours, used cumulative doses below 1 daily dose limit (50 mL/kg), and used unsuitable control fluids such as other HES solutions or gelatins. In conclusion, the preferred use of colloidal solutions for resuscitation of patients with acute hypovolemia is based on rationales that are not supported by clinical evidence. Synthetic colloids are not superior in critically ill adults and children but must be considered harmful depending on the cumulative dose administered. Safe threshold doses need to be determined in studies in high-risk patients and observation periods of 90 days. Such studies on HES 130/0.4 are still lacking despite its widespread and increasing use. Because there are safer and equally effective alternatives in the form of crystalloids, use of synthetic colloids should be avoided except in the context of clinical studies.     

Plasma substitutes

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 C2/C6 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 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.     

Fluid management in burn patients: results from a European survey-more questions than answers

Many strategies were proposed for fluid management in burn patients with different composition containing saline solution, colloids, or plasma. The actual clinical use of volume replacement regimen in burn patients in Europe was analysed by an international survey. A total of 187 questionnaires consisting of 20 multiple-choice questions were sent to 187 burn units listed by the European Burn Association. The response rate was 43%. The answers came from a total of 20 European countries. Volume replacement is mostly exclusively with crystalloids (always: 58%; often: 28%). The majority still use fixed formulae: 12% always use the traditional Baxter formula, in 50% modifications of this formula are used. The most often used colloid is albumin (always: 17%, often: 38%), followed by HES (always: 4%, often: 34%). Gelatins, dextrans, and hypertonic saline are used only very rarely. Fresh frozen plasma (FFP) is given in 12% of the units as the colloid of choice. Albumin was named most often to be able to improve patients' outcome (64%), followed by HES (53%), and the exclusive use of crystalloids (45%). Central venous pressure (CVP) is most often used to monitor volume therapy (35%), followed by the PiCCO-system (23%), and mixed-venous saturation (ScVO2; 10%). It is concluded that the kind of volume therapy differs widely among European burn units. This survey supported that no generally accepted volume replacement strategy in burn patients exists. New results, e.g. importance of goal-directed therapy or data concerning use of albumin in the critically ill, have not yet influenced strategies of volume replacement in the burn patient.     

Treatment of Pre-eclampsia and Eclampsia as a Hypoperfusion Syndrome

A therapeutical program in pre-eclampsia and eclampsia is presented. The results in 10 patients suggest that the same basic program as is used in the hypoperfusion syndrome can be used in pre-eclampsia and eclampsia:
Chlorpromazin to combat vasoconstriction and dilate the vascular bed. Plasma expanders, plasma, albumin and glucose with electrolytes to fill up the dilated vascular bed and restore the tissue perfusion.
Buffers to combat acidosis, oxygen to combat hypoxemia, hypertonic Mannitol to mobilize edema.
Furosemide to force diuresis.     

危重患者胶体复苏的有效性和安全性

尽管已有临床研究和荟萃分析的证据表明在危重患者中使用胶体复苏和晶体复苏同样有效,而且有来自于高水平的临床试验和荟萃分析的报告称,使用羟乙基淀粉（hydroxyethylstarch,HES）溶液会出现肾毒性反应、出血风险增加以及死亡率增高的趋势,但胶体治疗依然流行,在世界范围内HES溶液的使用与日俱增。我们主要探讨使用胶体的优势,即胶体是比晶体更为有效的血浆扩容剂、合成胶体与白蛋白一样安全、HES溶液在合成胶体中的风险／效益比最优而且第三代的HES130／0．4比前两代HES不良反应发生率更低等。临床研究表明用晶体溶液达到类似复苏效果的用量比通常认为的要少,即少于2倍胶体用量。白蛋白对于闭合性脑损伤以外的重症监护室（intensiveunitcare,ICU）患者安全性都很高。所有的合成胶体,如右旋糖酐、明胶和HES等都有剂量依赖的副作用,例如凝血障碍、肾衰竭和组织蓄积。在严重脓毒症患者中使用大剂量HES可能导致过高的死亡率。第三代HES130／0．4副作用更小的假设目前还未经证实。有关HES130／0．4的临床试验有着显著缺陷,主要因为并未针对ICU或急诊科患者;仅有24—48小时的短暂观察期;累积使用剂量小于每日剂量限值（50ml／kg）;并且使用了不合适的对照液体如其他HES溶液或明胶。总之,首选胶体溶液对急性血容量减少的患者进行复苏治疗的理论缺乏临床证据的支持。基于给药剂量的限制,合成胶体治疗危重成人及儿童患者的效果并非有益而是有害。安全剂量需通过对高风险患者进行长达90天观察期的研究来确定。尽管HES130／0．4的使用日益增加,但是它还缺乏研究证实。由于有晶体作为等效并且更为安全的选择方案,因此除进行临床研究外应避免使用胶体。     

Indications et place de l'albumine dans le cadre du remplissage vasculaire au bloc opératoire

Prospective clinical studies on albumin and non human colloids, administered peroperatively, were analysed. Only those with a level of evidence I or II were considered. On the basis of the cost-effectiveness ratio, albumin should not be the first choice treatment for peroperative plasma volume expansion. Low molecular weight hydroxyethylstarch is as efficient for restoration and maintenance of volaemia and colloid osmotic pressure. Albumin is administered when other colloids are contra-indicated or when their upper limit of volume has been reached.     

Management of shock in trauma

Shock is a state of acute circulatory failure, with inadequate tissue perfusion causing cellular hypoxia. Hypovolaemia from haemorrhage is the most common cause after trauma, but other mechanisms must be excluded. Initially, sympathetic and neurohumoral mechanisms compensate for the reduced pre-load, but eventually, negatively inotropic products of anaerobic metabolism, have direct cytotoxic effects, leading to failure of membrane pumps and the initiation of the inflammatory cascade. The final common pathway is arteriolar vasodilatation, refractory to further fluids or catecholamines. The priorities are to ensure adequate ventilation and oxygenation, to stop further blood loss and to restore the circulating volume with warmed fluids. There is no evidence to support the use of one fluid over another, provided they are given in sufficient quantity. Adequacy of fluid repletion can initially be judged by simple physiological measures, guided by the base deficit and plasma lactate. In the critical care setting, transoesophageal Doppler or continuous cardiac output monitors can provide additional valuable information on volume status and the requirement for inotropes. Isotonic crystalloids are cheap, but poor volume expanders, which need to be given in repeated boluses, often leading to tissue oedema with gut and pulmonary dysfunction. Colloids give better plasma expansion at smaller doses with good volume-stabilizing abilities. However, they are expensive and side-effects include hypersensitivity reactions, coagulopathies and storage lesions. A novel approach is low volume resuscitation using a combination of colloid and hypertonic saline. These solutions lead to rapid improvement in cardiac output and mean arterial pressure with increased capillary blood flow and reduced cellular oedema; however, there are side-effects. Permissive hypotension is a resuscitation technique designed to prevent further blood loss by limiting fluid boluses to a target systolic blood pressure of 80, until haemostasis has been achieved. The risk and benefits of tissue perfusion against further bleeding have to be assessed for each patient. This technique is best suited to young patients without co-morbidities, but is contraindicated in the presence of traumatic brain injury. It is possible that developments in blood substitutes, will enable low volume resuscitation while allowing for increased oxygen delivery.     

Perioperative colloid administration: a survey of Spanish anesthesiologists' attitudes

OBJECTIVES: To determine the availability of intravascular fluid volume replacement solutions in Spanish hospitals, to survey the extent of use of colloids by anesthesiologists, to ascertain the possible adverse effects they seek to prevent when using each solution, and to assess their level of knowledge about the subject. MATERIAL AND METHODS: A questionnaire was administered over a period of 6 months (July 2004-January 2005). The questionnaire was available online at www.encuestacoloides.com. The address was distributed by e-mail to anesthesiologists of all the Spanish autonomous communities and published in the Revista Espa?ola de Anestesiología y Reanimación. RESULTS: One hundred forty-two anesthesiologists responded. Crystalloids and colloids were widely available in most hospitals. Hydroxyethyl starch (HES) solutions were the colloids most often used (73%), followed by gelatins (28%). Dextran solutions, on the other hand, were no longer being used. The reasons the respondents gave for using these solutions were related to the time they remained in the vascular system, their greater effect of volume expansion, and the preservation of hemostasis. The most-feared complication was anaphylactic reaction to gelatins and there were concerns about the dose limit for infusion of HES solutions and about hemodynamic instability caused by dextran solutions. Fifty-four percent felt that scientific meetings provide little information about colloids and volume replacement. CONCLUSIONS: There is widespread use of colloids other than dextran along with crystalloids for plasma volume replacement. Spanish anesthesiologists are clear about important concepts related to colloid use. However, a high percentage have doubts about certain fundamental issues. Continuing professional development opportunities related to intravascular fluid replacement therapy should be increased.     

Preferences for colloid use in Scandinavian intensive care units

Background: Fluid resuscitation is a frequent intervention in intensive care. Colloids are widely used, but recent data suggest harm by some of these solutions. This calls for more clinical studies on this matter, but the current preferences for colloid use in Scandinavian intensive care units (ICUs) are unknown.
Methods: In March–May 2007, 120 Scandinavian ICUs were invited to answer a web-based survey consisting of 18 questions on types of colloids, indications, contraindications and rationale of use.
Results: Seventy-three ICUs, of which 31 were university hospital units, answered the questionnaire. Most ICUs used both synthetic and natural colloids, and hydroxyethyl starch (HES) 130/0.4 was the preferred colloid in 59 units. Eleven ICUs had protocols for colloid use. The most frequent indication was second-line fluid for hypovolaemia, but one in three ICUs used colloids as first-line fluid. Thirty-five ICUs had contraindications, which were mainly for the use of synthetic colloids (acute renal failure 25 units, bleeding 15 units). Most units based the use of colloids on theoretical knowledge and tradition. Sixty-five and 54 ICUs were ready to change colloid use based on data from randomised trials of ICU patients showing changes in mortality or renal function, respectively.
Conclusion: Most Scandinavian ICUs use both synthetic and natural colloids, but HES 130/0.4 is by far the preferred colloid. Few units have protocols for colloid use, but most use them for hypovolaemia, and the majority have no contraindications. Most ICUs are ready to change colloid use if randomised trials in ICU patients show changes in mortality or renal function.     

Synthetic colloids attenuate leukocyte-endothelial interactions by inhibition of integrin function

BACKGROUND: It has been suspected that synthetic colloids may interfere with leukocyte adhesion by down-regulation of endothelial cell adhesion molecules. Although inhibition of endothelial inflammation might reduce leukocyte-related tissue injury, the same mechanism may be detrimental for host defense during severe infection. Regarding the widespread use of colloids, the authors performed a laboratory investigation to determine the mechanisms by which synthetic colloids interfere with leukocyte-endothelial interactions. METHODS: Adhesion molecule expression on native and cytokine-activated endothelium from umbilical veins was measured after pretreatment with gelatin and various preparations of dextran or hydroxyethyl starch. Inhibition of neutrophil adhesion to activated endothelium was examined in a flow chamber by perfusion of untreated and colloid-treated neutrophils over colloid-pretreated endothelium at 2 dyn/cm. Comparisons were made between untreated controls, colloid-pretreated endothelium, and colloid-cotreated neutrophils. RESULTS: Intercellular adhesion molecule 1, vascular cell adhesion molecule 1, E-selectin, and P-selectin were not attenuated by any colloid. Accordingly, colloid pretreatment of endothelium alone did not reduce neutrophil adhesion. In contrast, when neutrophils were cotreated by addition of colloids to the perfusate immediately before perfusion, adhesion decreased by 31-51% (P < 0.05) regardless of the colloid type. As indicated by the twofold increased rolling fractions, this reduction was due to an inhibition of neutrophil integrins. CONCLUSIONS: This study shows that synthetic colloids inhibit neutrophil adhesion by a neutrophil-dependent mechanism rather than interfering with endothelial cell activation. This suggests that inhibition of leukocyte sequestration by volume support is a common and transient phenomenon depending on the colloid concentration in plasma.     

Crystalloid or colloid: Does it matter?

The modern version of the crystalloid-colloid debate has continued for more than 25 years, and a current appraisal of the debate is presented here. Although the effect of crystalloids and colloids on intravascular volume is important, their effect on interstitial fluid volume after hemorrhage and hemorrhagic shock is central to the debate. I f reduced, crystalloids are appropriate as part of the resuscitation regime; if increased, colloid therapy is more logical. A brief review of the distribution of crystalloids and currently used colloids (albumin, polygeline, dextran 70, and hydroxyethyl starch) is presented. The problems of pulmonary and peripheral edema also are presented, as is an appraisal of adverse reactions to colloids together with a cost comparison of crystalloids and colloids. The results of a survey of attitudes at the major Australian anesthetic departments are given, and a personal approach to fluids in resuscitation is outlined.     

Fluid choice for resuscitation of the trauma patient: a review of the physiological, pharmacological, and clinical evidence

PURPOSE: Volume replacement regimens are discussed very emotionally. Interpretation of the literature is difficult due to variations in study design, patient population, target for volume replacement, endpoints, and type of fluids. Meta-analyses may not be very helpful because all kinds of patients and very old studies are included. The principles and options for volume replacement were reviewed exclusively in trauma patients and studies from the literature focusing on this problem were analyzed. SOURCE: Using a MEDLINE search, volume replacement therapy in adult trauma patients published in the English language from 1985 to the end of 2002 were identified and analyzed. Studies on prehospital volume replacement, volume replacement in the emergency area or in the operating room, and volume therapy in trauma intensive care unit patients were included. PRINCIPLE FINDINGS: The age-old crystalloid/colloid controvery has still not been resolved but has been enlarged to a colloid/colloid debate. It is now widely accepted that human albumin could easily be replaced by synthetic colloids for volume replacement in trauma patients. No superiority of a specific volume replacement strategy with regard to outcome was found. However, in several studies outcome was not the major endpoint. Although showing some promising results, the importance of hypertonic solutions for volume replacement in the trauma patient is not yet defined. CONCLUSION: The choice of fluid therapy in trauma patients engenders the most controversy and an examination of the body of literature on this subject results in confusion. It is imperative to continue the search for substances that are effective in avoiding the development of post-trauma multi-organ dysfunction syndrome without detrimental side-effects.     

A novel hydroxyethyl starch (Voluven®) for effective perioperative plasma volume substitution in cardiac surgery

PURPOSE: To compare the new hydroxyethyl starch HES 130/0.4 (Voluven) and the standard HES 200/0.5 (pentastarch) regarding effectiveness for plasma volume substitution and safety of large volumes in heart surgery. METHODS: Fifty-nine patients scheduled for coronary artery bypass grafting were enrolled in a prospective, randomised, double-blind, parallel-group, multicentre, clinical, phase III study. Hydroxyethyl starch was used as the exclusive artificial colloid for acute normovolemic hemodilution, priming of the heart lung machine, and for intra- and postoperative plasma volume substitution from induction of anesthesia until 16 hr after the end of surgery. Efficacy was evaluated by comparing the amount of colloid infused, hemodynamics, and colloid osmotic pressure (COP). Safety endpoints were blood loss, the use of allogeneic blood products, coagulation variables, and adverse events. RESULTS: Effectiveness, as assessed by the total amount of infused HES volumes within the treatment period, was similar between HES 130/0.4 and HES 200/0.5 (2,550 mL +/- 561 mL vs 2,466 mL +/- 516 mL). Also, no differences were found for the use of other colloids (pasteurised plasma), hemodynamics, and COP In HES 130/0.4 patients, the postoperative increase of von-Willebrand factor (vWF) was higher (P < 0.01), blood loss was lower, and less packed red blood cells were transfused. CONCLUSION: Hydroxyethyl starch 130/0.4 is an effective plasma volume expander in heart surgery and may be used as the sole artificial colloid to cover the perioperative period. We found a reduced influence of HES 130/0.4 on the physiologic postoperative increase of vWF.     

Immune effect of hypertonic saline: fact or fiction?

Hypertonicity affects many parts of the immune system. Animal studies and experiments in isolated cell cultures show that hypertonicity reversibly suppresses several neutrophil functions and at the same time up-regulates T-lymphocyte function. Infusion of hypertonic saline with or without colloids may thus, besides providing efficient plasma volume expansion, ameliorate the detrimental consequences on the immune function of trauma, shock, reperfusion, and major surgery. However, the few clinical studies conducted to date, specifically addressing the immune effect of hypertonic saline infusion, have shown little, if any, effect on markers of immune function, and larger clinical trials have not demonstrated benefit in terms of morbidity or mortality. Thus, as opposed to animal and cell-culture studies, the immune-modulating properties of hypertonic saline infusion would appear to be of limited value in clinical practice. This review presents in vitro studies, animal experiments, and clinical trials which investigated the consequences of hypertonic saline on markers of immune function.     

Fluid therapy

Peri-operative fluid therapy is a fundamental part of the management of the high-risk surgical patient. Knowledge of the physicochemical and pharmacological effects of the available crystalloid and colloid solutions should guide their use. In addition to differences in tissue distribution and plasma volume expansion many of these solutions have significant effects on haemorrheology, haemostasis, vascular integrity and inflammatory cell function. When considering colloid solutions differentiation between the properties of the carrier solution and the dissolved colloid is important. Pre-operative risk assessment leading to institution of appropriate monitoring to guide fluid therapy is essential. Fluid therapy should be titrated to specific endpoints. Use of techniques which allow optimization of stroke volume, cardiac output and oxygen delivery have been shown to be beneficial. Monitoring of tissue perfusion as an endpoint will become increasingly important.