Trauma 2000; 2: 125134

Albumin: friend or foe?

Peter Gosling

In the absence of red blood cells or any other colloid, human albumin has saved thousands of lives since its rst use in 1941. However, for general volume expansion purposes including trauma resuscitation, published evidence suggests that albumin has now been superseded by synthetic colloids, which are more effective volume expanders, have vascular protective effects and are cheaper. Key words: human albumin solution; resuscitation; thermal injuries; trauma

History of human albumin for uid resuscitation

During World War II there was an urgent need for a stable blood substitute that could be used on the battleeld. In his book All about albumin, written in 1996, Theordore Peters Jr graphically describes the early work on human albumin purication. Albumin was selected by the American Subcommittee on Blood Substitutes of the Committee on Transfusion as being less viscous, less antigenic and more stable than whole plasma (Coates and McFetridge, 1964). Purication of albumin from whole blood using cold ethanol precipitation was developed by EJ Cohn at the Plasma Fractionation Laboratory of the Harvard Department of Physical Chemistry (Peters, 1996, p. 3). Preparation of human albumin was started in 1941, from blood provided by the American Red Cross. Following the attack on Pearl Harbor in 1941, almost the entire stock of human albumin was used on seven severely burned sailors, all of whom survived. The entry of the USA into the war enhanced the scale of the programme, and 600 000 12.5-g units of 25% human albumin were prepared from over 2 million units of blood. Twentyve per cent albumin was prepared to save space to make it easily portable under battle conditions, and was preserved with thiomersal giving it a long shelf-life.
University Hospital Birmingham NHS Trust, Birmingham, UK. Address for correspondence: P Gosling, Clinical Biochemistry Department, University Hospital Birmingham NHS Trust, Birmingham B29 6JD, UK. E-mail: Peter.Gosling@universityb.wmids.nhs.uk Arnold 2000

Concentrated albumin solutions were also thought to be safe. Peters (1996, p. 5) writes:
In 185 injections into volunteers there were no reactions of any kind; to this day there have been no cases of transmission of viral disease from properly prepared commercial albumin.

From the postwar period onwards, human albumin solution was quickly adopted in the civilian arena for correction of hypovolaemia. Despite the wide demand for human albumin for clinical use, before 1975, there were few formal randomized clinical studies comparing albumin with other solutions. Enthusiasts for albumin quoted in vitro or animal studies to justify its use and emphasized its safety. The demand for albumin was such that there were difculties in supply, and its cost formed a large proportion of the pharmaceutical budget. In the USA, production rose from 15 000 kg during World War II to 76 000 kg in 1974, to 311 000 kg in 1990, with a market value of $937 million rising to $1.1 billion in 1992 (Peters, 1996, p. 278). As early as 1975, it was recognized that albumin cost 10 times more than articial macromolecular colloids, and cheaper synthetic alternatives such as hydroxyethyl starch were evaluated (Thompson, 1975). The rising cost of medical care drew attention to the use of human albumin. Workshops were convened in the USA under the joint sponsorship of the Division of Blood Diseases and Resources, National Heart and Lung Institute and the Division of Blood and Blood Products, Bureau of Biologics. Tullis (1977a, b) published a two-part prcis of the ndings and recommendations of these bodies, which represented the views of 59 contributors. In human
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bowel It should not be assumed that albumin has more than a transitory hyperoncotic effect of moving water out of the interstitial space and into the plasma. The large pore size of the pulmonary vasculature permits easy passage of macromolecules in both directions so that rapid equilibration occurs. The primary goal of therapy should be careful maintenance of a constant body weight and avoidance of net uid increase.

studies of respiratory failure, albumin solutions showed better prevention of pulmonary oedema than saline-treated patients (Bushnell, 1975). Tullis pointed out that saline resuscitation in the armed forces with accompanying hypoalbuminaemia, may have been tolerated because of the previous high level of tness of the patients, yet this may not be the case in elderly surgical patients. By this time it was well recognized that following thermal injuries there was a massive shift of protein and water into the interstitial space, and many burn resuscitation regimes recommended predominantly crystalloid resuscitation for the rst 24 h until the capillary leak had subsided. Tullis (1977b) writes that after 24 h:
nearly all treatment programs call for the addition of albumin or some other oncotic solution. At this point the vascular bed has usually regained its impermeability, and the intravenous administration of albumin results in more or less a volume for volume increase in the previously depleted circulating plasma mass. Because of the long term depression of protein synthesis, which sometimes lasts 60 days or more after burns, additional albumin often is needed for certain patients.

Cardiopulmonary bypass: for preoperative pump priming, Bushnell (1975) wrote:

When the plasma oncotic pressure falls below 20 mmHg the risk of complications increases when the oncotic pressure drops below this level, it should be treated with concentrated albumin and diuretics, especially in high risk patients who have undergone abdominal, cardiovascularthoracic, or urologic surgery or who have acute bacteremia.

However, there is little hard clinical evidence for the working partys recommendations. In the introduction to part 2, Guidelines for clinical use, Tullis (1977b) writes:
Partly on the basis of the physiologic information given in part 1 and partly on the basis of empiric observations derived from uncontrolled clinical administration, it is believed pertinent to propose guidelines for the contemporary therapeutic use of albumin, an important plasma protein.

Acute liver failure: during rapid loss of liver function with or without coma, to support plasma oncotic pressure and bind excessive bilirubin. After surgery: especially abdominal surgery for malignancy. Acute nephrosis: in patients who do not respond to cyclophosphamide or steroid therapy, 25% albumin and a diuretic were recommended. Renal dialysis: where there is shock or hypotension, or in patients who are uid overloaded and who cannot tolerate substantial volumes of salt solution. The only unjustied uses were hypoalbuminaemia associated with undernutrition, chronic nephrosis and chronic cirrhosis. Not surprisingly, albumin usage continued to rise. In 1977, Alexander et al. (1979) found that in a 3month period, 91% of albumin use was in surgical patients and that 41% of the total amount administered was deemed to be inappropriate. However, the cost of albumin continued to drain pharmacy budgets to an extent that stimulated formulation of further guidelines for appropriate use of albumin (Klapp and Harrison, 1979; Lewis, 1980; Doweiko and Nompleggi, 1991; Victorian Drug Use Advisory Committee, 1991; Yim et al., 1995). There was limited impact on well-established albumin usage, and guidelines are still being published 25 years later (Debrix et al., 1999). Randomized controlled studies were carried out in an attempt to provide a scientic basis for rational use of albumin in various clinical settings. In 1991, Erstad et al. reviewed 18 randomized studies, the majority of which could nd no signicant benet from albumin compared with the control uid. Evaluation of these

Albumin solutions were then recommended in the following conditions (Bushnell, 1975) unsupported by citation of any clinical studies: Shock, especially in older subjects who will not tolerate large volumes of crystalloids. Extensive burns, after the rst 24 h, with the aim of maintaining serum albumin levels around 25 g/l (5 g/l) and oncotic pressure of about 20 mmHg. Adult respiratory distress syndrome (ARDS): where there is a postdiuretic fall in plasma volume when treating uid overload, 25% albumin should be used in sufcient quantity to maintain vital signs. The caveat was added that in patients having undergone extensive abdominal surgery where there is
additional sequestration in the lumen of the
Trauma 2000; 2: 125134

Albumin: friend or foe? 127 studies is hampered by the large number of variables, which have to be controlled in comparative studies of albumin; some of these are summarized in Table 1. The past decade has seen increasing disquiet about the use of albumin, not simply because of the huge expenditure incurred, but because of the lack of objective clinical evidence of benet over cheaper alternatives (Soni, 1995). Several studies have suggested that albumin performs no better or even worse than either crystalloids, or articial colloids (Kaminski et al., 1990; Guthrie and Hines, 1991; Stockwell et al., 1992; Golub et al., 1994; Wahba et al., 1996; Vogt et al., 1999). In the UK, these suspicions appeared to be conrmed by a meta-analysis of outcome following administration of crystalloids versus colloids, indicating that colloid treatment carried a signicantly higher mortality (Scheirhout and Roberts, 1998), and in a second meta-analysis study, albumin was associated with an increased mortality of 6% compared with patients who had received crystalloids or no treatment (Cochrane Injuries Group Albumin Reviewers, 1998). While these ndings were vigorously challenged, the public spotlight was focused on the use of human albumin solutions in the UK (Offringa, 1998). In 1999, The Committee on Safety of Medicines convened an expert working party, which concluded that:
there is insufcient evidence of harm to warrant withdrawal of albumin products from the market and that the effect of albumin on mortality would only be
Table 1 Variables in comparative studies of the use of human albumin solutions for volume therapy Which albumin preparation is to be compared? E.g. 5%, 20% or 25%. What uid should be used in the control arm? E.g. Ringers lactate, 0.9% saline, gelatin, hetastarch, pentastarch. Which clinical setting? E.g. haemorrhagic shock, elective surgery, nephrotic syndrome, pulmonary insufciency (ARDS), cirrhosis. What targets to use for uid administration? E.g. blood pressure, urine output, cardiac index, pulmonary artery wedge pressure, colloidal oncotic pressure, serum albumin concentration. What outcome measures to use? E.g. mortality, ICU days, pO2/FiO2 ratio, lung water, blood pressure, urine output, cardiac index, pulmonary artery wedge pressure.

answered by conducting large, purpose-designed, randomised controlled clinical trials.

However, the Working Party also recommended that the product information should contain:
a warning that special care should be taken when administering albumin in pathological states which affect capillary integrity .

The intention of this article is to try to assess the performance of albumin in the context of trauma resuscitation.

Properties of albumin
There are several reviews of the properties and albumin and its metabolism, and only an overview can be given here (Whicher and Spence, 1987; Gosling, 1995; Margarson and Soni, 1998). Human albumin is a single polypeptide of 585 amino acids and molecular weight of 66 248 Da. Albumin is synthesized in the liver at a normal rate of 912 g/24 h, which can rise two- to three-fold during maximal stimulation. The primary factors controlling hepatic albumin synthesis are the colloidal oncotic pressure and osmolality of the extravascular liver space. Synthesis is also stimulated by insulin, thyroxine and cortisol. Cytokines (e.g. interleukins 1 and 6, tumour necrosis factor and gamma interferon) stimulate hepatic acute-phase protein production and inhibit albumin synthesis. In man, albumin is predominantly an extravascular protein, with about 165 g in the interstitial space and 120 g in the vascular compartment. There is normally a circulation of albumin between intra- and extravascular pools of about 130 g/24 h, or about 5% per h of the total pool. Albumin moves from the vascular space through the capillary wall, and returns to the circulation via the lymphatic system (Figure 1). Using radiolabelled albumin, this can be accurately determined as the albumin transcapillary escape rate (Parving and Gyntelberg, 1973). There is a profound and rapid increase in transcapillary escape rate of radio-labelled albumin within 6 h of surgery and in patients with septicaemia (Fleck et al., 1985). It is vascular permeability that is the major determinant of serum albumin concentrations in acute illness and following trauma. In normal plasma concentrations, albumin accounts for 80% of the colloidal oncotic pressure, but as albumin concentrations fall (e.g. in the critically ill) albumin becomes progressively less important as an oncotic agent, this role being taken over by other proTrauma 2000; 2: 125134

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Figure 1 Normal albumin distribution and pharmacokinetics

teins. Albumin binds a wide variety of plasma constituents such as bilirubin, long-chain fatty acids, acidic drugs and metal ions (Hallworth and Capps, 1993) (Table 2). In plasma at a hydrogen ion concentration of 40 nmol/l (pH 7.40) albumin carries a net charge of 19 and thus binds metal anions such as calcium and magnesium. The thiol group on the exposed cysteine residue at position 31 within the albumin molecule, scavenges free radical species, in particular superoxide, hydroxy and peroxynitrite radicals. Albumin also binds Cu2+ ions, which catalyse the formation of other free radicals (Strubelt and Younes, 1994). However, the signicance of normal serum albumin concentrations in

limiting free radical mediated damage is unknown.

Pathophysiology of hypoalbuminaemia
Several studies have shown the powerful association between hypoalbuminaemia and poor outcome (Reinhardt et al., 1980; Phillips et al., 1989; Gibbs et al., 1999). There are several possible mechanisms for these observations. In patients with active inammation, there will be hepatic suppression of albumin synthesis by inammatory cytokines. In such patients there will be a ten-

Table 2 Drugs, metal ions, hormones and other substances which bind to albumin in plasma Drugs Warfarin Salicylate Clobrate Phenylbutazole Penicillin Phenytoin Sulphonamides Diazepan Frusemide Prednisolone Valproate Trauma 2000; 2: 125134 Metal ions Calcium Magnesium Zinc Copper Nickel Hormones Thyroxine Liothyronine Aldosterone Cortisol Oestrogens Androgens Other substances Bilirubin Haem Long-chain fatty acids Pyridoxal Cystine Porphyrins Uric acid Acetylcholine Bile acids

Albumin: friend or foe? 129

Figure 2 Factors inuencing serum albumin concentration post-trauma

dency for increased albumin catabolism and in some cases increased renal and gut losses. However, the major causes of the rapid fall in plasma albumin concentrations following trauma will be the effects of dilution with resuscitation uids and redistribution due to increased capillary permeability, allowing more albumin to move from the vascular to the interstitial space. Decreased lymphatic ow will delay the return of extravasated albumin to the circulation, and thus prolong hypoalbuminaemia. These effects are summarized in Figure 2. In the light of the known physiological roles of albumin, and the poor outcome associated with hypoalbuminaemia, the desire to improve outcome by treating patients with intravenous human albumin infusion is understandable. However, there is almost no evidence to support this conjecture, and there is increasing evidence that vigorous attempts to correct hypoalbuminaemia by intravenous administration of exogenous albumin has no benet and may be associated with a worse outcome.

Comparative studies of intravenous albumin with other solutions in trauma

Blunt and penetrating injuries
In 1980, Lucas et al. studied 94 trauma victims who were initially resuscitated with lactated Ringers solution, whole blood and fresh frozen plasma. Patients were then randomized to receive additional albumin to bring their serum albumin concentrations into the normal range (mean value 42 g/l) or allowed to become hypoalbuminaemic (mean albumin 28.5 g/l).

In the albumin-supplemented group, mean FiO2/pO2 ratio, pulmonary shunting and mean number of ventilator days were all higher than in the control group. Although the large volumes of albumin solution infused attracted criticism, this study does demonstrate that normalization of serum albumin does not improve pulmonary function. In a comparison of lactated Ringers solution versus lactated Ringers plus albumin, Lowe et al. (1977) studied 141 trauma patients undergoing laparotomy. Eighty-four patients were given lactated Ringers solution and 54 lactated Ringers solution plus albumin. Patients were given washed red blood cells in both arms as required, and volumes of the chosen uids to maintain a urine output at >50 ml/h and normal pulse and blood pressure. Over the subsequent 5 days there were no signicant differences in alveolararterial oxygen gradient, pulmonary shunt or ventilator hours. In a similar study, the same group (Moss et al., 1981) studied 36 patients in shock undergoing laparotomy. Shock was dened as a systolic blood pressure less than or equal to 80 mmHg, or a transfusion requirement of ve or more units of washed red blood cells. Patients were randomized to either lactated Ringers solution or 50 g of 25% human albumin. Endpoints for uid administration in both groups were heart rate, urine output and systolic blood pressure, with washed red cells given to maintain the haematocrit. Again, there were no differences between groups in pulmonary shunt, alveolararterial oxygen gradient, oxygen delivery or ventilator hours. So far, only comparative studies of albumin in the early treatment of trauma victims have been
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P Gosling phy during the rst 48 h postburn. Cardiac index was lower in the 1224-h postburn interval in the crystalloid group, but this difference had disappeared by 48 h postburn. In phase 2 of the study (50 patients), extravascular lung water remained unchanged in the crystalloid-treated patients, but progressively increased in the albumin-treated patients over the 7day study. The authors concluded that:
the addition of colloid to crystalloid resuscitation uids produces no long lasting benet on total body blood ow, and promotes accumulation of lung water when edema uid is being reabsorbed from the burn wound.

reviewed. Metildi et al. (1984) studied 46 patients with established severe pulmonary insufciency for 48 h, to compare the effects of either crystalloid or albumin. By random number, 26 patients received lactated Ringers solution and 20 patients received 5% albumin to maintain haemodynamic stability. Groups were comparable with respect to the cause of pulmonary insufciency, age and sex. For the duration of the study and at 48 h, there was no signicant difference in cardiac index, colloid osmotic pressure, pulmonary capillary wedge pressure, right and left ventricular stroke work indices and positive airway pressure required. Both groups had a signicant improvement in intrapulmonary shunt after 24 h of treatment. The shunt in the albumin-treated patients was signicantly lower than in those given lactated Ringers solution at the termination of the study, but this did not affect outcome. The crystalloid group required more uid than the albumin group, but the difference was not statistically signicant. No clinical advantage was found for either solution in this study.

Thermal injuries
There are few randomized comparisons of albumin versus other uids in burns resuscitation. Jelenko et al. (1979) evaluated three uid regimes administered on the basis of central venous pressure, pulmonary artery pressure, pulmonary artery wedge pressure, pulse rate, blood pressure, and/or urine volume, in burns patients. They compared randomly selected groups of burn patients who were resuscitated using a hypotonic uid alone (seven patients), hypertonic uid alone (ve patients), or the hypertonic uid containing albumin (12.5 g/l) (seven patients). Signicantly, smaller volumes of uid were needed to resuscitate the patients in the albumin group and the authors claimed that there was more rapid normalization of physical, physiological, and biochemical parameters. The very small numbers in the groups and the absence of an isotonic resuscitation arm makes interpretation of these results in the light of modern practice difcult. Goodwin et al. (1983) compared the effects of albumin and crystalloid only resuscitation on the haemodynamic response and lung water following thermal injury. Seventy-nine patients were randomized to lactated Ringers solution or 2.5% albumin-lactated Ringers solution. Crystalloid-treated patients required more uid than those given albumin. In phase 1 of the study (29 patients), cardiac index and myocardial contractility were determined by echocardiograTrauma 2000; 2: 125134

More recently, Greenhalgh et al. (1995) carried out a prospective trial in 70 paediatric patients with > 20% burns over 6 weeks. Patients were randomized to receive either a constant albumin infusion to maintain serum concentrations between 25 and 35 g/l, or only to receive albumin if the albumin concentrations fell below 15 g/l. During the shock phase, the volumes of resuscitation uids required were calculated using the Parkland formula plus the daily basal uid requirements, and most patients in both groups received albumin in order to maintain the albumin concentration >15 g/l. The patients in the low albumin group (36) and in the normal albumin group (34) were matched for burn size, depth of injury, inhalation injury and age. No differences were found in the volume of resuscitation uids required, urine output, nutritional requirements, days of antibiotic therapy or the number of patients requiring mechanical ventilation. There were three deaths in the low-albumin group and seven in the high-albumin group, which failed to reach statistical signicance (p = 0.262). The authors concluded that albumin supplementation to maintain serum albumin levels within the normal range was not warranted in previously healthy children who suffer major burns and who receive adequate nutrition.

Comparison of albumin with newer colloids

The studies summarized above compared human albumin with crystalloids in the treatment of traumaassociated hypovolaemic shock. The general conclusion was that including albumin in the resuscitation regime either makes no difference or tends to be associated with poorer outcome, particularly in terms of lung function. The development of synthetic colloids such as medium molecular weight hydroxyethyl

Albumin: friend or foe? 131 starches (HES), which are well retained by the leaky vasculature and which do not seriously derange coagulation, has led to a number of recent studies in which HES preparations have been compared with crystalloid only, gelatin and albumin resuscitation regimes. These studies suggest that HES may have distinct clinical benet over other uids. Unfortunately, to date there have been few studies of HES in trauma resuscitation; however, the results from randomised controlled studies with albumin in elective surgery are encouraging. Boldt et al. (1996a) randomized 30 trauma patients (injury severity score between 15 and 30) and 30 sepsis patients (secondary to major general surgery) to receive either 10% HES (mean molecular weight 200 000 Da) or human albumin 20% infused over 5 days to keep pulmonary capillary wedge pressure between 12 and 18 mmHg. Central venous pressure and pulmonary capillary wedge pressure were comparable within the subgroups (trauma/sepsis) throughout the entire study period. In both trauma and sepsis patients, cardiac index, oxygen consumption and oxygen delivery signicantly increased only in the HEStreated patients. Right ventricular ejection fraction was reduced (< 40%) in the albumin-treated patients and increased only in the HES group. Intramucosal gastric pHi, a marker of splanchnic perfusion, remained normal (> 7.35) in both trauma groups and in the HES-treated sepsis patients. In the albumintreated sepsis group, pHi, fell below 7.20 within the study period, indicating reduced splanchnic perfusion. The authors concluded that long-term intravascular uid therapy with albumin in trauma and sepsis patients has no advantages in comparison to HES. In both groups, volume replacement with HES resulted in improved systemic haemodynamics, and in sepsis patients improved splanchnic perfusion. In a prospective randomized trial of HES versus crystalloid volume replacement in 30 patients undergoing aortic surgery, Marik et al. (1997) also studied splanchnic perfusion by pHi measurements. The difference between the preoperative pHi and nadir was 0.07 0.03 in the HES group compared with 0.13 0.04 in the crystalloid group (p = 0.001), and the intra-operative positive uid balance was signicantly less in the HES-treated group. These authors also concluded that during major surgery, volume resuscitation with HES could improve microvascular blood ow and tissue oxygenation. In a related study, Boldt et al. (1996b), in addition to measuring pHi and haemodynamic parameters, also studied the effects of albumin and HES resuscitation in trauma (n = 28) and sepsis (n = 28) patients on liver function and circulatory regulators. Plasma concentrations of vasopressin, endothelin-1, adrenaline, noradrenaline, atrial natriuretic peptide and 6-ketoprostaglandin F1 alpha were measured on the day of admission to the intensive care unit (trauma patients) or on diagnosis of sepsis, and daily for the next 5 days. Liver function was assessed daily using the monoethylglycinexylidide test (MEGX). Mean arterial pressure, heart rate and pulmonary capillary wedge pressure did not differ between the corresponding subgroups (trauma/sepsis). Cardiac index increased signicantly more in the HES than in the albumin groups. pHi and MEGX plasma concentrations did not differ in the trauma patients throughout the study, but both were lower than normal in the sepsis groups and increased more markedly in the HES than in the albumin-treated patients. In the trauma patients, concentrations of all vasoactive regulators were very similar in both albumin and HES-treated groups. In both sepsis groups, vasopressors (vasopressin, endothelin-1, noradrenaline and adrenaline) were signicantly increased above normal at baseline and decreased more markedly in HES than in albumin-treated patients. Concentrations of atrial natriuretic peptide increased only in the albumin-treated patients, while plasma concentrations of 6-keto-prostaglandin F1 alpha decreased signicantly only in the HES sepsis patients. These results suggested that HES was a more effective volume expander than albumin, particularly in sepsis patients. Younes et al. (1998) studied trauma patients with haemorrhagic hypovolaemia randomized to HES (n = 12) or isotonic saline (n = 11). Fluid was infusing in 250 ml boluses until systolic blood pressure was >100 mmHg. While mortality rates were similar in both groups, signicantly less uid was required in the HES-treated patients. In a randomized prospective study, the authors group compared resuscitation with HES (n = 20) or gelatin (n = 21) in patients suffering blunt trauma (Allison et al., 1999). Capillary permeability was assessed by the mean 6-hourly urine albumin excretion rate (AER) for the rst 24 h. Pulmonary function was monitored by daily mean pO2/FiO2. Daily serum creactive protein, haemoglobin, white cell and platelet count, prothrombin and activated partial thromboplastin time were compared between groups. Capillary permeability was signicantly lower in HES-treated patients throughout the rst 24 h. The mean (95% CI)
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P Gosling weight HES materials were associated with coagulopathies, this is not a serious problem with modern preparations of mean molecular weight 200 000 Da and substitution of 0.5, and compared with albumin, improves endothelial-associated coagulation in critically ill septic patients (Boldt et al., 1995). The microvascular protecting properties of HES need further study. As with the albumin studies in the past (with the exception of metanalyses), any effect of HES on mortality has not been demonstrated because the numbers of patients in individual studies are too small and the between-study variables too large. However, the difference now is that we understand more about the pathophysiological response to severe illness. Critically ill patients are at risk of systemic inammatory response syndrome and later organ failures, the features of which include exaggerated pro- and antiinammatory mediator release, microvascular failure, capillary leak, interstitial oedema and interstitial uid overload. Randomized controlled clinical studies, which show modern HES preparations to be a safe and more effective volume expander than albumin in terms of tissue oxygenation, capillary patency, lung function, haemodynamics and the acute inammatory response, deserve attention.

pO2/FiO2 ratio for the HES and gelatin groups 48 h postadmission were 43.2 (5.8) and 35.6 (5.7) kpa, respectively (p = 0.03). The mean (95% CI) serum creactive protein in the HES and gelatin groups 24 h after admission were 72.4 (19.2) and 105.7 (30.1) mg/l, respectively (p = 0.03). There were no signicant differences in any of the haematological parameters during the rst 48 h. The results support other studies, which indicate that, compared with other volume expanders including albumin, resuscitation with medium molecular weight HES reduces post-trauma capillary leak, improves pulmonary gas exchange and may have some anti-inammatory effect. The mechanism by which HES is benecial is as yet unclear. Although HES preparations in the 100200 kD molecular weight range are better retained in the leaky circulation of the critically ill patient than albumin, there may be other factors that improve outcome. Soluble adhesion molecules have been used as markers of the neutrophilendothelial cell interaction during the post-trauma inammatory response (Boldt et al., 1996c). In a study of trauma patients randomized to HES (n = 15) or 20% human albumin (n = 15) for volume therapy, plasma concentrations of soluble adhesion molecules, endothelial leucocyte adhesion molecules (sELAM-1), intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1) and granule membrane protein 140 (sGMP-140) were serially measured over 5 days. At baseline, plasma concentrations of all adhesion molecules were similar in both groups. In the HES group, sELAM-1 and sICAM-1 concentrations decreased signicantly (p < 0.05) reaching normal values during the study period, whereas the mean values increased in the albumin-treated patients. The sGMP140 plasma concentration increased only in those patients receiving albumin and this was signicantly different to the other groups. None of the other haemodynamic or laboratory factors could be correlated with plasma concentrations of the adhesion molecules. It appears that volume therapy with HES resulted in a decrease in circulating adhesion molecules in trauma patients, while volume therapy with albumin did not exert this effect. Evidence from clinical and in vitro studies suggest that HES reduces inammation-induced capillary leak of water and albumin (Oz et al., 1995; Boldt et al., 1996b), possibly by modulating cytokine release (Schmand et al., 1995) and the interaction of leucocytes with vascular endothelium (Collis et al., 1994; Hofbauer et al., 1999). Although early high molecular
Trauma 2000; 2: 125134

Conclusion
In the absence of red blood cells or any other colloid, human albumin has saved thousands of lives since its rst use in 1941. However, for general volume expansion purposes including trauma resuscitation, published evidence suggests that albumin has now been superseded by HES preparations, which are more effective volume expanders, have vascular protective effects and are cheaper. However, care must be used when HES is used to replace albumin, and clinical experience needs to be acquired. A sudden abandonment of established practice must be avoided. Since HES is well retained in the vascular compartment, it is important to ensure that adequate water is also provided. Where HES forms the major component of the uid infused, there is a risk of cellular dehydration (Cittanova et al., 1996). HES has been shown to be of benet in the studies cited in this review when it constituted 3040% of the total volume of uid infused. Additional studies are required to rene future HES and related preparations, and to identify the mechanism by which HES appears to have anti-inammato-

Albumin: friend or foe? 133 ry properties, protecting the microvasculature during acute inammatory states such as trauma and sepsis.
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