Left panel: Plasma volume expansion from infusion of 10 ml/kg of hydroxyethyl starch (HES) 130/0.4 (Voluven) in 10 male volunteers. The thick curve is the modeled average and the thin lines each of the underlying experiments. Middle and right panels: Kinetic parameters of 32 experiments where male volunteers received either 5 ml/kg of 6% dextran 70, 10 ml/kg 5% albumin, or 10 ml/kg hydroxyethyl starch 130/0.4 in saline. The half-life is the inverse of the elimination rate constant times 0.693, which becomes 160, 90, and 110 min, respectively. All calculations were performed in a single run with a mixed models analytical program, Phoenix NLME, without correction for evaporation.
An infusion of 10 ml/kg of albumin 5% increases the serum albumin concentration by 10%, and this remains unchanged for more than 8 hours.[1] Restoration of normal blood volume is governed by translocation of albumin molecules from the plasma to the interstitial fluid space. Moreover, the plasma volume expansion per se has a diuretic effect. The albumin is gradually transported back to the plasma via lymphatic pathways, and the half-life of blood-derived albumin in the body is much longer (16 hours) than the half-life of the accompanying plasma volume expansion.
Clinical use
Albumin is a “natural” colloid and remains an effective means of restoring the plasma volume and normal hemodynamics in hypovolemic shock.
Despite high cost and limited supply, the use of albumin in adults has undergone a revival in recent years. The main reason is that the adverse effects of the artificial colloids on kidney function do not seem to be shared by albumin.[2] Albumin also has a scavenger effect that is appreciated in intensive care. Acute reduction of serum albumin is a sign of capillary leak in inflammatory disorders, such as sepsis. The leakage rate is normally 5% per hour but can be raised to 20% per hour in septic patients.[3] The reason seems to be breakdown (shedding) of the glycocalyx layer of the endothelium, which binds the plasma proteins and other colloid particles more firmly to the vascular system.[4]
The use of albumin as a plasma volume expander in situations of increased capillary leak is a double-edged sword. The solution expands the plasma volume transiently, but the infused albumin creates peripheral edema later on, as the lymphatic drainage might not be able to catch up with the increased loss of protein from the plasma. In these situations, one should select colloids based on macromolecules that are eliminated from the blood by metabolism or renal excretion rather than by capillary leak, and that have a shorter half-life in the body than albumin (16 hours).
In intensive care, albumin infusions have been used to treat hypoalbuminemia. This therapy has gradually been taken out of practice as low serum albumin is a sign of severe disease rather than a problem in itself. The added albumin will soon be subject to catabolism and used in the same way as amino acids in the body. Albumin may be used to replace excessive albumin losses in special medical conditions, such as nephritis. Albumin is also the most commonly used plasma volume expander in children.
Hyperoncotic (20%) albumin does not improve survival in septic patients (ALBIOS study),[2] but both ALBIOS and the earlier SAFE study suggested a survival benefit for albumin treatment in patients with septic shock.[2,5]
The “albumin debate”
Treatment of the critically ill with albumin has been the subject of lively debate over the years.[6,7] In 1998, the Cochrane Library published a meta-analysis of 1,419 patients from 30 studies in which albumin was used. The results were surprising, since albumin treatment seemed to increase the mortality. The relative risk of death was 1.46 when albumin was given to treat hypovolemia, 1.69 if the indication was hypoalbuminemia, and 2.40 when albumin was given for burns.[8] In the United Kingdom, the use of albumin decreased by 40% during the months following publication of the meta-analysis.[9]
A later review of the same topic indicated that the risk of death associated with the use of albumin appeared to be lower the better the study was conducted. The best studies did not support that albumin increases the risk of death.[10]
These meta-analyses were followed by a randomized study (the SAFE study) that compared albumin 4% with normal saline.[5] No difference in outcome depending on the choice of infusion fluid was found in 7,000 intensive care patients. The mortality after 28 days was virtually identical in the groups (726 vs. 729).
However, a subgroup analysis of the SAFE study comprising the 460 patients with head injury showed that albumin 4% was followed by a higher mortality than normal saline (33% vs. 20%). The difference was greatest in the most severe cases.[11]
The research group of Marcus Rehm and Matthias Jacob of Munich has presented evidence that colloid solutions, and among them albumin 5%, only have an 80–100% volume effect when infused in normovolemic (bleeding) patients, while the volume effect is poorer in hypervolemic states. The reason is that marked hypervolemia raises the atrial natriuretic peptide (ANP) concentration, which negatively affects the glycocalyx layer.[12,13] They advocate the use of albumin as the colloid that helps to maintain the glycocalyx layer.
Starch
Hydroxyethyl starch (HES) consists of polysaccharides and is prepared from plants such as grain or maize.
HES is the only type of colloid preparation that has undergone a company-driven development to achieve refinement during the past 30 years. Several different formulations may be marketed, both old and new. They vary in concentration, usually being 6% or 10%. They also vary in chemical composition with respect to molecular weight, the number of hydroxyethyl groups per unit of glucose (substitution), and the placement of these hydroxyethyl groups on the carbon atoms of the glucose molecules (C2/C6 ratio).
The variability in chemical composition determines the differences in clinical effect between the solutions. Over the past decades, the trend has been to use molecules of smaller size to reduce the half-life and the risk of hemorrhagic complications. Hetastarch contains the largest molecules (450 kDa) and pentastarch contains intermediate-sized molecules (260 kDa). The most recently developed HES preparations have an even lower molecular size, on average 130 kDa. The degree of substitution may be low (0.45–0.60) or high (0.62–0.70), and the C2/C6 ratio is low if less than 8.
The preparations are usually described with the key characteristics of molecular size and substitution, which may or may not be followed by the C2/C6 ratio. Hence, currently the most widely promoted HES preparations are denoted HES 130/0.4/9:1 (Voluven from Fresenius-Kabi) and HES 130/0.62/6:1 (Venofundin from B. Braun). A modern adaptation is to mix the HES in balanced crystalloid solutions instead of in normal saline, which is to be preferred when several fluid bags are prescribed.
The degree of substitution is the key determinant for half-life. Higher molecular size increases risk of adverse effects in the form of anaphylactoid reactions, coagulopathy, and postoperative itching.
HES (6%) mixed in hypertonic (7.5%) saline is also marketed for emergency and trauma situations. Such a solution expands the plasma by much more than the infused volume, by virtue of osmotic volume transfer from the intracellular fluid space.
Pharmacokinetics
A 6% HES solution in iso-osmotic saline or balanced electrolytes expands the plasma volume by as much as the infused volume (Figure 3.1). Considerable variability in this respect may be encountered when administered to intensive care patients.[14]
The elimination of the HES molecules is a complex issue. They have a spectrum of sizes of which the smallest (<60–70 kDa) are quickly eliminated by renal excretion. Larger molecules first need to be cleaved by endogenous alpha-amylase into smaller fragments before being excreted, a process that increases the osmotic strength per gram of polysaccharide. The HES molecules are also subjected to phagocytosis by the reticuloendothelial system, and remnants may be found in the liver and spleen even after several years. Hence, the half-life of the HES molecules does not correspond closely with the plasma volume expansion over time.
The half-life of the HES molecules in Venofundin was 3.8 hours when administered to volunteers.[15] The half-life of the HES molecules of Voluven in plasma is said to be shorter, 1.4 hours, although the terminal half-life is 12 hours. After 72 hours, approximately 60% of the molecules can be recovered in the urine.[16]
The decay of the plasma volume expansion for HES 130/0.4 (Voluven) occurs with a half-life of 2 hours in volunteers [17] (Figure 3.1) and a similar duration of the intravascular persistence was found in laparoscopic cholecystectomy [18] and hip replacement surgery.[19] Hence, the intravascular persistence of the fluid volume is much shorter than the half-life of the HES molecules, which suggests that the molecules reside outside the circulation for many hours before being eliminated.
As for crystalloid fluids, the plasma volume expansion is greater if HES is infused during anesthesia-induced hypotension [20] and has a markedly longer duration when given to replace hemorrhage.[21]
The elimination of crystalloid fluid is known to be greatly retarded by anesthesia and surgery, but there are no data on the rate of elimination of colloid fluid volumes in the perioperative setting.
Clinical use
Hydroxyethyl starch is indicated solely for plasma volume expansion in bleeding patients. The colloid is not recommended for use in intensive care.
The first 10–20 ml should be infused slowly and the patient closely observed with respect to allergic reactions, which are rare and less severe than for dextran.
The highest recommended dose of Voluven to be given during 24 hours is 3.5 1iters in an adult of 70 kg. Only half as much should be allowed for dextran and HES preparations that contain larger molecules.
Although small-sized HES (130 kDa) preparations have a shorter persistence in the blood, they have the same clinical efficacy as median-sized HES preparations while being safer.[22]
The “starch debate”
Europe has suffered a painful debate on the clinical use of HES in clinical medicine. In 2001, Schortgen et al. found a greater change in creatinine concentration in patients treated with 6% HES 200/0.60–0.66 (Elohes) as compared with 3% gelatin.[23] A second study, called VISEP, reported lactated Ringer’s to be superior to 10% HES 200/0.5 (Hemohes).[24] In a small study of burn patients the latter hyperoncotic HES preparation also seemed to promote renal failure and even death.[25] These findings were initially thought to be because the tested HES solutions were of an older type and not of the most modern (molecular weight 130 type) HES, and also because the base solution was isotonic saline and not a balanced electrolyte preparation. However, a subsequent Scandinavian trial in septic patients, called the 6S study, found that HES 130/0.4 more often than Ringer’s acetate is followed by renal replacement therapy and even death.[26]
Another study in 2012, the CHEST trial, also reported that HES 130/0.4 in saline (Voluven) was associated with more negative outcomes than isotonic saline in 7,000 patients treated for different diagnoses in the intensive care setting.[27] There was no difference in mortality, but serum creatinine rose more in the HES group. The fraction of the cohorts that fulfilled the criteria for kidney dysfunction (RIFLE-R) and kidney injury (RIFLE-I) was larger among those who received saline, but more patients who received HES fulfilled the criteria for kidney failure (10.5% versus 5.8%) and subsequently received renal replacement therapy (7.0% versus 5.8%). The adverse effect was more than twice as common after HES treatment (5.3% versus 2.8%), which is a more expected finding because colloids but not crystalloids have allergic properties.
These studies made it apparent that no type of HES solution should be used in septic patients. The existence of a negative influence on the clinical course and outcome in other patients is less clear. The only study with mixed diagnoses was the CHEST study, which is the least convincing of these trials. Critics of HES argue that this colloid has a dose-dependent toxic effect on the kidneys that had been demonstrated in several large trials. Defenders of HES pointed out that these trials never compared the fluids when used as first-line treatment, and that the administration often deviated from clinical practice.
In late 2013 the European Medicines Agency published a proposal that was later endorsed by the European Commission, and that put limitations on the use of HES. From then on, these colloids can only be used within the EU to combat hypovolemia in bleeding patients and not at all in the intensive care setting. Sepsis, burn injuries, and renal failure are contraindications. Treatment should be initiated only if crystalloids are insufficient. The lowest effective dose should be used, and treatment should be continued for the shortest period of time, and no longer than 24 hours. Serum creatinine must be monitored in the aftermath of the HES treatment.[28]
Three meta-analyses published during 2014 refuted a negative effect of HES on outcome when used in the operating theatre.[29–31] Naturally, these meta-analyses were mostly based on the same material.
The debate has been fueled by the CRISTAL study that compared the use of any colloid with any crystalloid fluid in the intensive care setting. There was no difference in 30-day mortality but there was a trend towards a survival benefit in the colloid group at 90 days.[32]
Gelatin
Gelatin solutions consist of polypeptides from bovine raw material. This colloid was already in use during World War I and since then has mostly been used in Great Britain and its former colonies. Gelatin is considered to have a fairly good plasma volume-expanding effect, similar to that of HES.[18] The duration is shorter (approximately 2 hours) because of the relatively small size of the molecules (average 30 kDa), which makes them excretable by the kidneys. Mild anaphylactoid reactions occur at a frequency of 0.3%, which is relatively high, but severe reactions are rare.[33] The effect of gelatin on blood coagulation is small.
Gelatin had a bad reputation for some years because of the risk of spreading slow virus diseases such as “mad cow disease” (bovine spongiform encephalopathy). To prevent this problem, the gelatin preparations are now heated to high temperature before sale.
The two marketed solutions are Haemaccel, which contains 3.5% gelatin, and Gelofusine, which is a plasmion-succinylated gelatin mixed in isotonic saline. The latter is the most widely used gelatin today. The solution is slightly hypo-osmotic (274 mosmol/kg) and contains 154 mmol/l of sodium but only 120 mmol/l of chloride, whereby hyperchloremic acidosis will be less of a problem compared with Voluven and isotonic saline.
Dextran
Long chains of glucose molecules (polysaccharides) are synthesized by bacteria to serve as macromolecules in the group of infusion fluids called the dextrans (sometimes abbreviated to DEX). As with albumin, the osmolality of a water solution containing only the macromolecules is quite low and necessitates that electrolytes are added as well.
Commercially available dextran solutions have an average molecular weight of 70 kDa (dextran 70) or 40 kDa (dextran 40), and concentrations used are 3%, 6%, or 10%. The most widely used, 6% dextran 70, expands the plasma volume by the volume of the infused amount, although the initial volume expansion is slightly larger. The plasma volume expansion subsides with a half-life of almost 3 hours (Figure 3.1). A solution of 10% dextran 40 expands the plasma volume by twice the infused volume. The half-life is shorter than for dextran 70.
The dextran molecules are either excreted by the kidneys or metabolized by an endogenous hydrolase (dextranase) to carbon dioxide and water.
The dextrans decrease blood viscosity and improve microcirculatory blood flow. This can sometimes be noted by visual inspection of the cut surface in a surgical wound as small vessels seem to open up when dextran is infused, increasing the bleeding surface (oozing). This might be disturbing to the surgeon. However, it is debatable whether this oozing really increases the total blood loss, provided that the infused volume is limited to 500–1,000 ml.[34]
Dextran in hypertonic (7.5%) saline is available in some countries as an effective plasma volume expander in emergencies and prehospital trauma care. The dose is 4 ml/kg and should be provided as a fluid bolus. One unit of 250 ml is usually given. Studies performed in the 1980s showed a tendency toward reduced mortality, but more recent studies have not shown any benefit with regard to survival or neurological outcome in the prehospital setting.[35,36]
In volunteers, the effectiveness of this solution in expanding the plasma volume is six to seven times that of normal saline.[37]
Clinical use
Dextran 70 is used to expand the plasma volume and/or to prevent thromboembolism.
Dextran 40 is used to improve the microcirculation after vascular surgery.
The maximum dose is 1.5 g/(kg day), which corresponds to 1.5–2.01 of 6% dextran 70 in an adult. Hemorrhagic complications may ensue if larger amounts are given.
There is a risk of anaphylaxis developing in patients who have irregular antibodies to dextran. This complication occurs in a frequency of 0.27% [33] but severe reactions can be prevented by dextran molecules of very small size (1 kDa). This pretreatment is performed by giving an intravenous injection of dextran 1, which blocks the irregular antibodies (“hapten binding”), just before dextran 40 or 70 is infused. The use of dextran 1 has reduced the number of allergic reactions by 95%.[38] Dextran 1 is less essential when treating prehospital trauma victims, as the associated stress response prevents anaphylaxis.
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