Procedure

Selection of priming solutions for cardiopulmonary bypass in adults

Department of Cardiothoracic Surgery, University Medical Centre Groningen, Groningen, The Netherlands

^* Corresponding author: ^* Tel.: +31-50-361 1719; fax: +31-50-361 1347. E-mail: p.w.boonstra{at}thorax.umcg.nl

	Summary

Top Summary Introduction Crystalloids as priming solution Colloids as priming solution Clinical efficiency and safety Selection of priming solutions References

 
The issue of choosing the right priming solution for adult cardiopulmonary bypass patients has been studied and argued for at least three decades. However, there is still no general consensus with regard to making the right choice. Basically, priming solutions can be classified into two categories, i.e. crystalloids and colloids. The former consists of dextrose, balanced crystalloid fluids, and mannitol, and the latter consists of albumin, dextrans, gelatins, and hydroxyethyl starch. In general, crystalloids are simple volume expanding solutions that mimic the normal plasma electrolyte concentrations. They can be used as clear priming solutions resulting in effective hemodilution but they lack oncotic activity. On the contrary, colloids have the advantage in maintaining the colloid oncotic pressure and reducing tissue oedema. However, colloids have been associated with increased incidence of anaphylactoid reactions and clinical coagulopathy. In this paper, we will describe the basic characteristics, the clinical efficiency and the safety of different types of priming fluids and make an overview on how to select the ideal priming solution for cardiopulmonary bypass in adults.

Key Words: Cardiopulmonary bypass • Colloids • Crystalloids • Priming solution

	Introduction

Top Summary Introduction Crystalloids as priming solution Colloids as priming solution Clinical efficiency and safety Selection of priming solutions References

 
Since hemodilution was introduced into cardiac surgery in the early 1960s, there have been continuous efforts in searching for the right priming solution for cardiopulmonary bypass [1]. During the early years, the complete extracorporeal circuit was primed with ‘fresh’ heparinised homologous blood that is known to have many disadvantages, such as the usage of high numbers of donors, danger of transmission of infectious diseases, and the generation of high level of free haemoglobin. Afterwards, the disadvantages and complications associated with blood priming demanded a search for alternative priming solutions. Nowadays, after at least three decades of research and development on various types of crystalloids (Table 1) and colloids (Table 2), there is still a lack of straight forward guidelines in choosing the right priming solution for adult cardiopulmonary bypass. Similarly, continuous controversies remain in choosing the ideal intravascular volume replacement regimens for other surgical patients and critically ill patients in the intensive care unit, as described by two recent comprehensive reviews [2,3].

	Crystalloids as priming solution

Top Summary Introduction Crystalloids as priming solution Colloids as priming solution Clinical efficiency and safety Selection of priming solutions References

Balanced crystalloid fluids
Balanced crystalloids are fluids formulated to have a neutral pH and concentrations of electrolyte ions similar to that of human plasma. Ringer's lactate fluid, or Hartmann's solution, is a typical example of a balanced crystalloid, and contains lactate as a source of bicarbonate. However, a large volume of fluid containing lactate should be used with caution in diabetic patients, as lactate may be converted into glucose in vivo through the gluconeogenic pathway. A further example of a balanced crystalloid is plasmolyte solution, which contains acetate and gluconate for bicarbonate production. It also contains magnesium which is an important intracellular cation involved in cellular process of energy transfer and in myocardial adenosine triphosphate metabolism.

Mannitol
Mannitol is a hypertonic, low molecular weight crystalloid widely used in clinical practice to stimulate diuresis. As a volume expander, mannitol draws fluid initially across the capillary into the plasma. Then it rapidly diffuses into the interstitial fluid and increases the volume of the whole extracellular phase by withdrawing water from the body cells. A particular advantage of mannitol is its protective effect on renal function. During cardiopulmonary bypass in adults, priming fluid containing 10 g of mannitol provided only a transient diuresis during the bypass period, compared to control patients who did not receive mannitol. However, an increased dose of 20 g of mannitol resulted in a significantly greater diuresis than both the control group and the 10 g group, and this diuretic effect continued for 3 h during the post bypass period. Furthermore, patients receiving 30 g of mannitol had an even greater diuresis which lasted for about 4 h. The diuretic effect of mannitol lasted for up to 12 h after patients' arrival in the intensive care unit despite indications that the crystalloid had already been cleared from the body.

	Colloids as priming solution

Top Summary Introduction Crystalloids as priming solution Colloids as priming solution Clinical efficiency and safety Selection of priming solutions References

 
Albumin
Albumin is a naturally occurring colloid product that has a molecular weight of about 69,000 daltons. Under physiological circumstances, albumin accounts for 75% to 80% of the plasma oncotic pressure responsible for the maintenance of body plasma volume. When used as priming fluid, albumin is often used in combination with crystalloid fluid. The amount of albumin used in pump prime is usually based on the calculation that it should be able to compensate for the decrease of the intravascular colloid osmotic pressure caused by the infusion of crystalloid fluid. Despite its theoretical advantages in preserving the colloid oncotic pressure, an early study showed that the addition of 200 ml of 25% albumin in the bypass circuit had no beneficial effect on perioperative fluid balance, cardiopulmonary function and renal function. However, a recent meta-analysis focussed on the usage of albumin in priming solution for cardiac surgery showed favourable results of albumin in keeping the colloid oncotic pressure on a physiological level as compared with that of crystalloid [4]. Furthermore, albumin prime reduced postoperative bleeding whereas hydroxyethyl starch prime did not [5]. Albumin may induce anaphylactic or anaphylactoid reactions and may also carry the risk of transmission of viral disease. For these reasons, and also because albumin is rather expensive, a number of synthetic colloid fluids are chosen as priming fluids.

Dextrans
Dextrans are also naturally occurring colloids with an average molecular weight of either 40,000 daltons (Dextran 40) or 70,000 daltons (Dextran 70). The dextran molecule is a polysaccharide, produced from sucrose by the bacterium Leuconostoc mesenteroides. Dextran 40 has a colloid osmotic pressure twice as high as that of plasma, and so has a strong effect in mobilising water from the extravascular into the intravascular space. Dextran 40 prepared in 10% solution is a more effective volume expander than dextran 70 is, as it contains almost twice as much colloid per litre. However, the action of the dextran 40 is much less sustained, as the small molecules allow it to be rapidly eliminated by the kidneys. As a priming fluid for cardiopulmonary bypass, dextrans reduce blood viscosity and prevent the adhesion of leukocytes in the microcirculation. It is recommended that the total dose of dextran infusion does not exceed 1.5 g/kg/day as dextrans may impair haemostasis. This dose should be further limited in patients undergoing cardiopulmonary bypass because heparin is used in these patients. Anaphylactoid reactions to dextrans may occur, but the incidence of reaction is much lower than that caused by gelatin.

Gelatins
Gelatins are manufactured from bovine collagen and have an average molecular weight of 30,000 to 35,000 dalton. Two types of gelatins are used as priming fluid for cardiopulmonary bypass: urea-linked gelatin and succinyl-linked gelatin. The former is the result of cross-linking polypeptides with hexamathyl di-isocyanate, whereas the latter is modified by the addition of succinic acid anhydride to become succinylated or modified fluid gelatin. This modification results in a lower isoelectric point with a corresponding increase in the net negative charge, so that the retention time within the circulation is significantly prolonged. An important difference between these two solutions is that the urea-linked gelatin contains calcium, and thus it should not be mixed with citrated blood in order to prevent clot formation. In addition, plasma calcium concentration may increase as a result of using urea-linked gelatin as priming solution, and high concentrations of calcium at the end of cardiopulmonary bypass may lead to coronary vasoconstriction. Although gelatins were originally considered to be free of adverse effects on hemostasis, more recent studies have indicated that there is a negative effect on blood coagulation both in healthy volunteers [6] and in patients undergoing cardiopulmonary bypass [7]. This is particularly true when patients receive a total dose of more than 3.5 litres of gelatin perioperatively [8]. A further disadvantage of gelatin is its relatively high incidence of anaphylactoid reactions compared with other artificial colloids.

Hydroxyethyl starch
Hydroxyethyl starch is a synthetic colloid that consists of hydroxyethylated polymers of glucose, derived from amylopectin. The physical and chemical characteristics of hydroxyethyl starch can be defined by both their average molecular weight and their molar substitution ratio, i.e. the ratio of replacement of glucose group by hydroxyethyl group during production. For instance, hetastarch has an average molecular weight of 450,000 daltons with a molar substitution of 0.7, so that it is labelled as 450/0.7. Similarly, pentastarch is labelled as 200/0.5, which means that it has a relatively low molecular weight of 250,000 daltons with a low molar substitution ratio of 0.5. In principle, the average molecular weight of hydroxyethyl starch determines its colloidal effect whereas the molar substitution ratio determines its half-life and pharmacokinetics in vivo. Therefore, hydroxyethyl starch with a relative lower average molecular weight and lower ratio of molar substitution has a greater oncotic pressure and a shorter plasma half-life than the starch with a higher molecular weight and a higher molar substitution ratio.

Hetastarch (450/0.7) was the first hydroxyethyl starch introduced in 1975 as priming solution for cardiopulmonary bypass and was found to be as effective and safe as crystalloid priming fluids. Compared with albumin as a colloid priming fluid, hydroxyethyl starch appeared to achieve the similar clinical effects of volume expansion in cardiac surgical patients with low incidence of anaphylactoid reactions. However, it was found to be retained in the reticulo-endothelial system and to be associated with an impairment of haemostasis. The medium molecular weight hydroxyethyl starch pentastarch (200/0.5) was introduced in the late 1980s and has become popular in recent years. However, adverse effects of the 200/0.5 starch solution on haemostasis have also been reported. Several preparations of medium molecular weight hydroxyethyl starch solution that have desirable pharmacologic and pharmacokinetic properties are commercially available in Europe [9]. A low molecular weight hydroxyethyl starch Voluven (130/0.4) was introduced into the European market recently. It was developed with an improved metabolic elimination profile [10] (Table 3). Preliminary evaluation using this solution as priming fluid in patients undergoing cardiopulmonary bypass revealed that this so-called third-generation starch solution was associated with improved haemostasis and that it was safe to be used in cardiac surgical patients in volumes up to 3 l during the complete perioperative period [11]. As the search for improved composition of hydroxyethyl starch solution continues, Hextend was introduced in the United States recently [12]. This is a high molecular weight, high molar substitution hydroxyethyl starch solution (670/0.75) containing balanced electrolytes sodium, chloride, calcium, magnesium, and potassium, as well as glucose and lactate [13] (Table 3). Initial clinical reports revealed that Hextend was as effective as hetastarch as a volume expander but it could deliver a favourable metabolic balance and reduced blood loss in patients with major selective surgery [12]. However, another study showed a less favourable hemostatic profile for Hextend than for Voluven in a randomised study in patients with major abdominal surgery [14]. So far, there is no clinical report about Hextend used as priming solution for cardiopulmonary bypass.

	Clinical efficiency and safety

Top Summary Introduction Crystalloids as priming solution Colloids as priming solution Clinical efficiency and safety Selection of priming solutions References

Theoretically, an ideal artificial colloid used as priming fluid should exert an effect on colloid osmotic pressure and viscosity similar to that of plasma. In reality, however, there are considerable differences between colloids with regard to their weight average molecular weight (Mw) and their number average molecular weight (Mn) (Table 2). Usually, Mw is greater than Mn because the large molecules contribute more to the measured effect than the smaller ones. Albumin solution contains an equal size of molecules, so that their Mw and Mn are the same. In contrast, artificial colloids almost always differ in Mw and Mn because of different particle size and shape during chemical preparation. The theoretical advantage of this is that the smaller molecules may reduce blood viscosity and promote blood flow distribution, whereas the larger ones may serve to prolong the effect of plasma expansion.

During cardiopulmonary bypass, the colloid osmotic pressure may drop as a result of haemodilution. This is particularly the case when large proportions of crystalloids are used in the priming solution. A low intravascular colloid osmotic pressure may result in the shift of water from the intravascular compartment to the interstitial compartment, leading to tissue oedema. The normal reference range of colloid osmotic pressure is 25 to 30 mmHg. However, in patients undergoing cardiopulmonary bypass, a lower limit of 15 to 16 mmHg can be tolerated without leading to tissue oedema and organ dysfunction.

We have compared three priming solutions on their clinical efficiency in keeping the colloid oncotic pressure on a physiological level during cardiopulmonary bypass [15]. In patients receiving gelatin prime the colloid osmotic pressure was maintained on the preoperative level throughout the operation. However, in patients receiving either hydroxyethyl starch or human albumin, colloid oncotic pressure decreased significantly after infusion of crystalloid cardioplegic solution. The lowest level of colloid osmotic pressure detected during operation was 12.8 mmHg but it returned to the baseline of around 20 mmHg in all three groups 6 h after bypass in the intensive care unit. A colloid osmotic pressure of as low as 9 mmHg has been observed in patients undergoing cardiopulmonary bypass without any postoperative problems. However, such a low level should be avoided in patients who have already additional risk factors for postoperative pulmonary dysfunction.

Anaphylactoid reactions
The typical clinical symptoms of anaphylactoid reaction include skin flush, urticaria, tachycardia, and hypotension. Very occasionally, life-threatening events such as shock and cardiorespiratory arrest may occur. In general, the occurrence of anaphylactoid reaction to synthetic colloid substitutes is very low, at around 0.033%. In a large scale German study [16] performed in 1977 including 200,906 infusions of colloid volume substitutes in 31 hospitals, the incidence of a severe reaction was found to be 0.008% for dextran, 0.038% for gelatin, and 0.006% for hydroxyethyl starch. A somewhat higher incidence was reported in 1994 in a French multicentre study [17], showing an overall frequency of the severe form of anaphylactoid reaction of 0.219% in 19,593 patients. The various synthetic colloids did differ in their incidence for anaphylactoid reactions, being 0.273% for dextrans, 0.345% for gelatins, and only 0.058% for hydroxyethyl starch. Anaphylactoid reaction to the natural product albumin was found to be 0.099%.

According to its definition, anaphylactoid reaction is similar to anaphylactic reaction in its clinical manifestation but is not mediated immunologically by an antigen-antibody reaction. However, involvement of specific antibodies against these synthetic colloids were repeatedly reported. Antibodies against dextrans were found in about 70% of healthy volunteers or surgical patients who received dextran infusion. These dextran-reactive antibodies predominantly belong to the IgG class and may induce an immune-complex anaphylaxis clinically resembling as a type III allergic reaction. Antibodies against either urea-linked gelatin or the succinyl-linked gelatin were not thoroughly documented in the literature although antibodies to raw unmodified gelatin were found both in animals and man. Anaphylactoid reaction to hydroxyethyl starch is usually not considered to be associated with antibodies until a recent report demonstrated that high titres of antibodies against hydroxyethyl starch were found in serum of an aortic surgical patient at the time of reaction [18]. However, such an incidence is considered extremely rare and it does not seem to have a clinical relevance [19].

Blood coagulation and haemostasis
Priming fluids, either crystalloids or colloids, may influence the normal blood coagulation system and haemostasis. These effects are more marked when a large volume of priming is applied. Due to a decreased concentration of clotting factors, it may be anticipated that there should be some degree of coagulopathy and impairment of haemostasis as a result of haemodilution. However, during the early years of haemodilution, it was observed that haemodilution with crystalloid solution actually enhanced blood coagulation. This hypercoagulable state induced by haemodilution was independent on the nature of the crystalloid diluent and all crystalloid solutions produced similar effects. The mechanism of enhanced blood coagulation by haemodilution is most likely due to the imbalance of plasma thrombin and anti-thrombin concentration resulting in a relative decrease in the anti-thrombin capacity. A recent in vivo study on healthy volunteers has further demonstrated that infusion of 1,000 ml saline solution over a period of 30 min resulted in a significant increase of platelet aggregation. This increased platelet aggregation was accompanied by a drop in circulating antithrombin III which was far more marked than could be explained by the haemodilution itself [20].

Of more clinical significance are those colloid fluids that may impair postoperative haemostasis. Dextrans are known to affect both the antihaemophilic factor (factor VIII) and platelet function and thus have been used as an antithrombotic agent for deep venous thrombosis prophylaxis. Due to these inhibitory effects on blood coagulation system, a dose limitation of 1.0 to 1.5 g/kg/day of dextrans is usually recommended. Although gelatins were considered to have no adverse effects on haemostasis in early years, it may diminish the efficacy of aprotinin on haemostasis in cardiac surgical patients [8]. When albumin was used as priming solution, aprotinin significantly decreased postoperative blood loss. However, this hemostatic effect by aprotinin disappeared in patients who received gelatin prime. The inhibitory effect of gelatin on hemostasis is largely due to its inhibition on platelet ristocetin agglutination during the bypass period. Platelet aggregation capacity induced by ADP showed no difference between gelatin and albumin [7]. This negative effect of gelatin on ristocetin-induced platelet aggregation has recently been demonstrated in healthy volunteers who received 1 l of gelatin-based plasma substitute [6]. Also, the circulating levels of both von Willebrand factor and the ristocetin cofactor dropped significantly after gelatin infusion, suggesting that gelatin impairs the primary haemostasis mediated by von Willebrand factor.

The effect of hydroxyethyl starch on blood coagulation and on haemostasis was well recognised during the early years of observation as reflected by reduced platelet function and prolonged bleeding time. These negative effects on hemostasis are likely to be attributed to the chemical characteristics of hydroxyethyl starch, which is quite similar to dextran. A remarkable inhibitory effect of hydroxyethyl starch was noticed on factor VIII. According to some reports, hydroxyethyl starch may induce a type I von Willebrand-like syndrome recognised by a marked reduction in factor VIII coagulant activity, von Willebrand's factor antigen, and factor VIII-related riscocetin cofactor. The inhibitory effects of hydroxyethyl starch on hemostasis and von Willebrand factor seem to be not only associated with its in vitro molecular weight, but also associated with the so-called ‘in vivo molecular weight’, a description depending on its degree of substitution [21]. However, this view is challenged by a recent experimental study indicating that the negative effect of hydroxyethyl starch on blood coagulation does not seem to be associated with its high or low molecular weight but with its degree of substitution [22].

Clinically, high molecular weight starch (450/0.7) has been associated with a greater impairment on hemostasis than the medium molecular weight starch solution (200/0.5). The adverse effects of hydroxyethyl starch on hemostasis (represented by high blood loss) have also been reported in patients receiving the 200/0.5 starch as priming solution, whereas other observations indicating that this medium molecular weight starch solution did not significantly increase postoperative bleeding [2]. More recently, the third-generation low molecular weight starch (130/0.4) has been found to be associated with even better hemostatic profiles than either the 200/05 starch or gelatin as it is used as priming solution for cardiopulmonary bypass [11,23]. Nevertheless, according to the recently published meta-analysis and evidence-based consensus statement, hydroxyethyl starch solutions should be used with caution when they are applied as priming fluids for cardiopulmonary bypass [24].The clinical effects of various priming solutionson haemostasis are summarised in Table 4 [7,11,25,26,27,28,29,30,31,32].

	Selection of priming solutions

Top Summary Introduction Crystalloids as priming solution Colloids as priming solution Clinical efficiency and safety Selection of priming solutions References

Overall, the selection of priming fluids for cardiopulmonary bypass varies from institution to institution. In 1994, a British survey containing 38 cardiac surgical teams working in 32 centres revealed that almost all the teams used crystalloids as priming fluids [33]. Among them, 54% used crystalloids alone and 44% used synthetic colloids mixed with crystalloids (Table 5). Recently, another comprehensive survey [34] including 31 adult cardiac surgical centres in the United Kingdom and Ireland showed that the tendency of using crystalloids as priming solution basically remained the same as compared with the survey almost a decade ago. Again, a majority of the centres (58%) used a combined strategy of crystalloid and synthetic colloid with an average ratio of 3:2. Mannitol was used as priming additive in 81% of these centres. However, only 6% of the centres add human albumin routinely in the priming. Decision making on how to select priming solution is mainly depending on cost, ease of use and maintenance of colloid oncotic pressure. Around one quarter of the centres keep using the historical priming protocol because of lack of scientific and evidence-based guidelines to start a new strategy. One remarkable finding of this survey was that there was not any single centre that had the similar composition of priming as compared with any other individual institution.

	References

Top Summary Introduction Crystalloids as priming solution Colloids as priming solution Clinical efficiency and safety Selection of priming solutions References

 

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