Adequate volume replacement appears to be fundamental in the management of trauma, surgical, and ICU patients. Apart from blood loss, fluid deficits may also occur in the absence of obvious fluid loss secondary to vasodilation or generalized alteration of the endothelial barrier, resulting in diffuse capillary leak with a subsequent shift of fluids from the intravascular to the interstitial space. Although the importance of adequate volume replacement has been widely accepted, the optimal strategy is still the focus of debate.
For several reasons, use of blood should be restricted to correct severe anaemia and fresh frozen plasma should be used to correct coagulopathy only and not hypovolaemia. Various crystalloids are used to restore circulating volume; isotonic saline solution should not be administered so as to avoid unwanted development of metabolic derangements (hyperchloraemic acidosis).1 Human albumin is the most expensive plasma substitute and the value of human albumin to correct hypovolaemia is controversially discussed.2,3 The different nonprotein (synthetic) plasma substitutes have to be distinguished as they vary widely with regard to their physicochemical properties, efficacy, and unwanted side-effects.4,5 Among the ‘group’ of gelatins (3.5% urea cross-linked gelatin; 5.5% urea cross-linked gelatin; 4% succinylated gelatin) and the ‘group’ of dextrans (10% dextran 70; 6% dextran 40), there are some not very important substance-specific effects, whereas hydroxyethyl starch (HES) comprises a group of compounds that show several differences.6,7 HES preparations must be distinguished as to different mean molecular weight [low-molecular weight (LMW) HES: 70 kDa; medium-molecular weight (MMW) HES: 130–260 kDa; high-molecular weight (HMW) HES: >450 kDa], molar substitution (low: <0.5; medium: 0.5; high: >0.5), ratio of C2/C6 hydroxyethylation, the origin (potato versus waxy maize starch), and the solvent [plasma-adapted (balanced) versus nonplasma-adapted (unbalanced) HES].
The most frequent arguments against the use of nonprotein plasma substitutes for correcting hypovolaemia are the risk of severe anaphylaxis, coagulation disturbances with increased bleeding, accumulation, and renal dysfunction.8–10 Apart from these major problems, there are some less often addressed questions on safety issues in connection with the use of nonblood plasma substitutes that also have to be considered.
Can plasma substitutes be used safely in pregnancy?
Severe hypovolaemia occurs seldom in the pregnant woman – trauma and emergency surgery are the most often nonpregnancy-related reasons for extensive bleeding. Three different scenarios can be considered when looking at the use of plasma substitutes in pregnancy: first, volume therapy during pregnancy until delivery; second, caesarean section with large blood loss; and, third, volume preloading prior to spinal anaesthesia for caesarean section.
Product information for the different plasma substitutes varies widely from country to country and even within one ‘group’ of plasma substitutes (e.g. among the different HES preparations). Generally, information on all the products includes nonspecific warnings regarding the use in (early) pregnancy (http://www.emea.europa.eu/pdfs/human/bpwg/223199en.pdf.,http://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/NewDrugApplicationsNDAs/UCM083138.pdf). Animal studies are insufficient to assess the safety with respect to reproduction, development of the embryo or fetus, the course of gestation, and perinatal and postnatal development. It is very unlikely that there will be specific approval for one of the colloids in (early) pregnancy in the future because of the enormous efforts and costs that are associated with drug approval in pregnancy.
None of the colloids are approved for volume therapy during pregnancy. For example, HES 130/0.4 is in Pregnancy Category C.11 The product has been shown to cause embryocidal or other adverse reactions in animal models at doses 1.7 times the human dose due to maternal toxicity (fluid overload), although the starch itself has no teratogenic effects.11 This, however, does not mean that it is strictly contraindicated for correcting hypovolaemia in this setting. It should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.11 It is not known whether HES is excreted in human milk. Thus, caution is advised if the product is administered to a breast-feeding woman.11
There is no evidence of an embryotoxic effect of gelatins (B. Braun Product Information, B. Braun, Melsungen, Germany) – clinical studies on this issue, however, are lacking. Because the possibility of allergic reactions cannot be excluded, administration should be carried out during pregnancy only after critical evaluation of the risks and benefits. No information is available concerning the passage of gelatins into the mother's milk.
Animal reproduction studies have not been conducted with human albumin [e.g. product information Plasbumin (www.talecris-pi.info/inserts/plasbumin20la.pdf)]. It is not known whether albumin solutions can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Controlled clinical trials with albumin for correcting hypovolaemia in pregnant women are missing. In the Guideline on the Core Summary of Product Characteristics (SPC) for Human Albumin Solution (http://www.emea.europa.eu/pdfs/human/bpwg/223199en.pdf.), it is documented that ‘clinical experience with albumin suggests that no harmful effects on the course of pregnancy, or on the foetus and the neonate are to be expected’.
The limitations and warnings for using plasma substitutes for guaranteeing normovolaemia change at the end of pregnancy. Although the value of volume preloading prior to spinal anaesthesia for caesarean section has been controversially discussed,12 different substances have been used for this purpose. Volume preloading has been reported with gelatins or HES and no negative side-effects for the mother or the newborn have been demonstrated with this volume replacement strategy.13,14
Does hydroxyethyl starch have an influence on blood sugar level?
HES refers to a class of synthetic colloids that are modified natural polysaccharides and that are similar to glycogen. HES is derived from amylopectin, a highly branched starch, which is obtained from waxy maize or potatoes. HES is mainly characterized by its concentration and the weight-averaged mean molecular weight; the pharmacokinetics of HES preparations are further characterized by the pattern of hydroxyethylation, in particular by the molar substitution and by the degree of substitution. The molar substitution is computed by counting the total number of hydroxyethyl groups present and dividing the number by the quantity of glucose molecules. The degree of substitution is determined by measuring the number of substituted glucose molecules and dividing this number by the total number of glucose molecules present. Because of its glucose molecules, questions may arise about HES and its potential to modify blood sugar level. In a study on 150 American Society of Anesthesiologists (ASA) class I, nondiabetic patients undergoing elective surgery, patients received either 20 ml kg−1 of Ringer's lactate, 10 ml kg−1 of 6% HES 450/0.7 or 10 ml kg−1 of 6% HES 200/0.5 for preloading prior to spinal anaesthesia over a period of 1 h.15 No significant changes in blood sugar levels until 360 min after the end of infusion were seen in the Ringer's lactate group, whereas blood sugar levels significantly increased in the HES 450/0.7 (maximum increase +37 ± 3 mg%) and HES 200/0.5 group (maximum increase +31 ± 3 mg%). Although this increase was statistically significant, blood sugar concentration remained always within normal range. In contrast to these data in humans, Hofer and Lanier16 found no significant influence of HES administration on blood sugar level in rats. Although clinically relevant changes in blood sugar level appear to be unlikely, large clinical trials including patients with established diabetes mellitus and using new HES preparations would be helpful to finally answer this question.
Is itching a problem when using plasma substitutes?
Itching has been reported after infusion of HES.17,18 Special features of HES-induced pruritus include long latency of onset and persistence. A dose-dependent uptake of HES was first detected in macrophages and, thereafter, in endothelial and epithelial cells. Patients with pruritus consistently showed additional deposition of HES in small peripheral nerves.17 Pruritus has been reported after use of large doses of HES over a long period, mostly using HES with a high molecular weight or a high molar substitution. The incidence of pruritus after surgery is not clearly known because it may occur weeks or even months after administration. Reports on pruritus have been published even after single use of approximately 2000 ml of HES.18 In a prospective multicentre study, 497 patients with different indications for HES infusion and 47 patients without HES were observed over 3–9 weeks after the end of surgery.19 No significant differences with regard to pruritus between the HES-treated and control patients were seen. In a study including more than 700 patients undergoing minor elective surgery, the incidence of pruritus after infusion of HES 200/0.5 from two different manufacturers was compared with that with Ringer's lactate.20 There was no episode of pruritus after the 5th postoperative day. The incidence of pruritus after 8 weeks was without significant group differences: 9.1%/12.0% in the two HES groups and 11.5% in the Ringer's lactate group.
Using the latest generation of HES, only occasional reports on pruritus are available, mostly after high or repetitive doses of HES 130/0.4 in the nonsurgical, non-ICU setting. Out of 12 volunteers who received 500 ml of 10% HES 130/0.4 on 10 consecutive days, one patient showed mild itching.21 In a randomized, double-blind study, 40 patients with acute ischaemic stroke received either 6% HES 130/0.4 or crystalloid over 4 days with a total dose of 6.5 l.22 Itching was noticed in three patients in the HES group and two patients in the crystalloid group. In a controlled, double-blind, randomized, multicentre study, 106 patients with acute ischaemic stroke received high-dose HES 130/0.4 or placebo within 6 h of symptom onset.23 Approximately 5 l of HES had been infused within 6.3 days and, in one of the 70 HES-treated patients, pruritus was reported. In a randomized, double-blind, multicentre study including 210 patients with unilateral idiopathic sudden sensorineural hearing loss, 158 patients received HES 130/0.4 (45, 30, and 15 g per day) or glucose over 6 days.24 Only one patient in the high-dose HES group presented with severe pruritus. In 60 patients undergoing preoperative autologous blood donation [acute normovolaemic haemodilution (ANH)], withdrawn blood was replaced by either HES 130/0.4 or HES 200/0.5.25 In a questionnaire completed 24 h after ANH, one patient in each group reported a new itching phenomenon. All in all, the risk of producing itching by using modern HES preparations in surgery and ICU patients appears to be very low.
Why some plasma substitutes have a dose limitation and others not?
There is a large difference in the recommended daily maximum dose of plasma substitutes ranging from 20 ml kg−1 per day to no dose limitations. Specific recommendations on dose limitations are expressed by the manufacturers for dextrans and all HES preparations, but not for gelatins and albumin solutions.
Dextran was the first nonprotein plasma substitute with a recommended dose limitation (6% dextran 70 and 10% dextran 40: 1.5 g kg−1 per day). A recommended daily dose limitation of isooncotioc 6% HES with a molecular weight of 200 kDa and a molar substitution of 0.5 (second-generation HES) is 33 ml kg−1 per day (for 10% HES 200/0.5: 20 ml kg−1 per day), whereas the recommended dose limitation for the latest generation HES showing a lower molecular weight (130 kD) and a lower molar substitution (<0.5) is 50 ml kg−1 per day for the isooncotic 6% HES preparation and 33 ml kg−1 per day for the hyperoncotic 10% HES preparation.
Recommendations on dose limitations for the different synthetic colloids appear to have no definite scientific basis, but can mostly be explained from history. Gelatins were introduced in 1915 during the First World War and no studies on dose limitations to show possible side-effects were necessary. Dextrans were frequently used during the Korean war and dose limitations of 1.5 g kg−1 per day were expressed because of the fear of producing increased bleeding. Apart from their dilutional effects on haemostasis, dextrans possess substance-specific negative effects on kidney function and coagulation26,27 that resulted in a recommendation for the maximum daily dose of dextrans (approximately 1500 ml per day).
The first generation of HES with a high molecular weight (450 kD) and a high molar substitution (0.7) was approved in the early 1960s and dose limitations were adapted to those of dextrans as all nonprotein (colloidal) plasma substitutes were considered as one ‘family’ and thus dose limitations from dextrans were extrapolated to HES. By modifying the physicochemical characteristics of the HES molecule, safety has been improved. The likelihood of substance-specific coagulation disturbances and kidney dysfunction has been reduced and the risk of plasma or tissue accumulation/storage has been significantly lowered by these modifications.6,21,26–33 There is no evidence that the recommended dose limitations are meaningful in all kinds of patients. It is unclear whether in young trauma patients an identical dose limitation can be justified to that in elderly septic patients with kidney dysfunction. There are some sporadic reports exploring the use of much higher doses of modern HES preparations. In patients without relevant comorbidities, much higher doses of 6% HES 130/0.4 have been safely used without affecting morbidity (e.g. renal function) or mortality.34 Determining the safe upper dose limit in surgery and critically ill patients is still a challenge and this issue will remain a potent topic of debate that needs to be addressed in future studies.
Is mixing of drugs with plasma substitutes safe?
There is general agreement that no other drugs should be added to nonprotein plasma substitutes as the compatibility has not been established. Precipitations or chelations modifying the efficacy of the added drug is the most important problem. Owing to the different electrolyte composition of balanced crystalloids (e.g. with/without calcium) and the different pH levels, it is not suitable to mix them with other drugs. Isotonic saline solution is still the fluid of choice to mix other drugs with.
Is it permissible to warm up plasma substitutes?
Warming up fluids before infusion to approximately 40°C is an important issue as infusion of high volumes of not warmed fluids administered to correct severe hypovolaemia may result in considerable hypothermia. Hypothermia is an important factor for inducing coagulopathy35 and thus should be stringently avoided. It has become common practice in many institutions to warm up fluids in warming cabinets. Moderate warming is safely possible with crystalloids, HES preparations, dextrans, and gelatins according to the product information from the different manufacturers. Human albumin solutions must be stored at room temperature and 30°C should not be exceeded (product information Buminate; Baxter, Deerfield, Illinois, USA).
Do calcium-containing plasma substitutes induce blood clotting?
There is a tendency in todays's volume replacement strategies to use plasma-adapted (balanced) fluids, instead of using isotonic saline solution, which is nonplasma-adapted (nonbalanced) fluid containing an unphysiological electrolyte composition. Some balanced fluids (crystalloids or colloids) contain some calcium to conform with the idea of a fully plasma-adapted fluid replacement strategy. The addition of calcium-containing fluids to citrated blood products poses a potential risk whenever the level of ionized calcium reaches a concentration capable of catalysing the coagulation cascade. Thus, mixing of these fluids with packed red blood cells (PRBCs) has not been recommended due to a theoretical risk of blood clotting.36,37 It has to be distinguished whether calcium-containing solutions are used to dilute blood products or whether calcium-containing infusions are administered along with PRBCs via the same infusion line. Some old in-vitro clotting studies showed that Ringer's lactate should not be administered concurrently with blood anticoagulated with citrate–phosphate–dextrose (CPD).36,37 Recently, it was shown in an in-vitro model simulating the clinical setting of extensive transfusion that mixing of calcium-containing Ringer's lactate with AS-3 preserved PRBCs did not lead to visible or molecular evidence of activation of the clotting cascade.38 In a recent communication, no blood clotting was reported by infusing expired blood followed by Hartmann's solution (a calcium-containing crystalloid) through a warming device.39 Whenever PRBCs are administered, use of two different lines is the easiest way to avoid any problems with possible clotting in the infusion lines.
Is cross-matching and blood-typing influenced by plasma substitutes?
In the early 1970s, it was reported that dextrans modified blood-typing and cross-matching.40,41 In an in-vitro study, the influence of 6% dextran, 6% HES 450/0.7, and 6% HES 70/0.5 on subsequent blood-typing and serological tolerance tests was studied.40 None of the plasma substitutes tested caused false-positive agglutination. The higher molecular weight 6% dextran and the high molecular weight HES preparation had positive blood-group serological reactions. With low molecular weight HES 70/0.5, no alterations occurred in all tests of cross-matching. Others, however, did not find an influence of dextrans on blood typing. The effects of dextran therapy on pretransfusion compatibility testing were evaluated in 24 patients with a variety of vascular disorders.42 In no instance could any interference by dextran with pretransfusion tests, even at high serum levels of dextran, be demonstrated.
Old data showed that it appears unlikely that gelatins modify cross-matching or blood-typing.43
Alterations in cross-matching or blood-typing by the first-generation HES have been shown in eight healthy volunteers undergoing a series of three plasmaphereses with HES 450/0.5 (250, 500, and 750 ml) and the effects on erythrocyte sedimentation rate (ESR), blood-typing, and cross-matching have been tested.44 Administration of either 500 or 750 ml HES produced a significant increase in the ESR. Rouleaux formation was observed to be dose-related and only observed following administration of greater than 500 ml. Blood-typing and cross-matching studies were normal, but caution must be used in regard to false-positive results when the estimated blood concentration of HES exceeds 575 mg dl−1. In another in-vitro study, venous blood was mixed with varying amounts of a 6% high-molecular weight, high molar substitution HES preparation.45 Owing to rouleaux formation, moderate difficulties were encountered in the interpretation of typing and antibody screening in some samples that contained greater than 30% of the HES solution. The authors concluded that, although the apparent difficulties were not extreme, blood bank personnel should be alerted to the potentially misleading effects of HES on test results. Definite data on the influence of modern HES preparations with a lower molecular weight and a lower molar substitution on cross-matching or blood-typing are lacking, but, as data with HES with a low molecular weight (70 kD) and a low molar substitution (0.5) had no influence,40 modern HES preparations appear to be safe with regard to this issue.
Are potassium-containing solutions contraindicated in patients with reduced kidney function?
Administration of large volumes of potassium-containing fluids might be suspected to cause hyperkalaemia in patients with kidney failure.46 Subsequently, isotonic saline solution is preferred in these patients as it is potassium free.47 Isotonic saline solution includes a nonphysiological composition of electrolytes showing abnormally high sodium (154 mmol l−1; plasma: 135–145 mmol l−1) and chloride (154 mmol l−1; plasma: 98–112 mmol l−1) concentrations that are associated with the risk of producing metabolic derangements (hyperchloraemic acidosis).48 Most colloidal plasma substitutes have traditionally been dissolved in isotonic saline solution and use of considerable amounts of these colloids poses the risk of producing metabolic alterations. Subsequently, plasma-adapted, ‘balanced’ crystalloids and colloids have been developed to avoid (hyperchloraemic) acidosis. The electrolyte composition of these fluids widely differs; almost all of them contain potassium ranging from 3.0 to 5.5 mmol l−1. The normal plasma level of potassium (K+) ranges from 3.5 to 5.0 mmol l−1, whereas intracellular potassium concentration is approximately 150 mmol l−1. Thus, it appears to be unlikely that 1000 ml of a solution containing 4 mmol l−1 of K+ will significantly increase the intravascular potassium level. By contrast, administration of considerable amounts of (no potassium containing) isotonic saline solution results in metabolic (hyperchloraemic) acidosis, which may cause hyperkalaemia through an extracellular shift of K+ ions by acute changes in hydrogen ions (H+). In patients undergoing kidney transplantation, either approximately 6 l of isotonic saline (n = 26) or Ringer's lactate (containing 4 mmol l−1 of potassium; n = 25) was given.46 Use of high doses of isotonic saline solution was associated with metabolic acidosis and significant hyperkalaemia, whereas Ringer's lactate was well tolerated and no hyperkalaemia with Ringer's lactate was documented in this study.
Adequate volume replacement is accepted to be fundamental for treating the critically ill. At present, discussion on the side-effects of the commonly used plasma substitutes on haemostasis or kidney function is continuing. Other safety issues such as mixing of drugs, warming of fluids, or the influence on blood sugar level have received less attention, although they are very important for a small group of patients (e.g. pregnant women) or are of interest for many of our patients. Most of the plasma substitutes have been widely used over recent years; thus, it is astonishing that some data on possible side-effects are rare or even lacking. Further input is necessary to also answer those less frequently asked questions concerning the different plasma substitutes. To further improve safety, let us remember: ‘The chapter of knowledge is very short, but the chapter of accident is a very long one’ (Lord Chesterfield 1753).
The present study was supported by a grant from the hospital only.
The author has received support for studies from B. Braun (Germany); Baxter (Europe); Fresenius Kabi (Germany); and Serumwerke Bernburg (Germany).
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