Balanced Volume Replacement Strategy: Fact or Fiction?

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Fact or Fiction?

J. Boldt

Introduction

Adequate volume restoration in the hypovolemic patient appears to be essential to stave non-compensatory, irreversible shock and subsequently to avoid development of multiple organ dysfunction syndrome. Vigorous optimization of the circulation is a prerequisite in the management of such patients. This maneuver is aimed at guar- anteeing stable macro- and micro-hemodynamics, while avoiding excessive fluid accumulation in the interstitial tissue. The choice of fluid for this purpose engenders considerable controversy and there is still a dispute over the beneficial and adverse effects of each fluid type.

What is ‘Standard Therapy’ Today?

Today’s correction of hypovolemia is based on either exclusively using crystalloids or using a combination of crystalloids and colloids. When crystalloids are given, normal saline is often preferred because it is isotonic and cheap. However, substan- tial alterations in acid-base balance develop in patients in whom large volumes of saline solution are infused. This effect has been described as ‘hyperchloremic acidosis’ [1, 2]. Little information exists as to the clinical importance of this type of acidosis:

) It may impair end-organ perfusion (e.g., splanchnic perfusion [3]).

) It may interfere with cellular exchange mechanisms [4].

) In animal experiments, hyperchloremic acidosis was associated with a reduction in renal blood flow (by vasoconstriction) and a negative effect on glomerular filtration rate [4].

) In healthy volunteers, in whom 50 ml/kg normal saline was infused, metabolic acidosis developed. In these patients, time to first urination was significantly increased [5].

) Negative consequences of hyperchloremic acidosis on organ function have been elucidated in some studies: In patients undergoing abdominal aortic aneurysm repair, lactated Ringer‘s solution (total dose 6,800 ml) or normal saline (total dose 7000 ml) was used for volume replacement in a double-blinded fashion [6].

Only the normal saline-treated patients developed hyperchloremic acidosis; they needed significantly more blood products than the Ringer’s lactate patients.

) Scheingraber et al. [7] studied 24 patients scheduled for elective lower abdominal gynecologic surgery. Approximately 6,000 ml of either normal saline or

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Table 1. Electrolyte concentration of plasma and some plasma substitutes

Plasma 0.9 NaCl Ringer RL HES

(6%, 130/0.4)

Na⁺mmol/l 140 154 154 131 154

K⁺mmol/l 4.2 – 4.0 5.4 –

Ca⁺⁺mmol/l 2.35 – 2.7 1.8 –

Magnesium mmol/l 0.9 – – 0,5 –

Phosphate mmol/l 1.25 – – – –

Cl^–mmol/l 103 154 163 112 154

Bicarbonate/anion 35 – – 28 –

Na⁺/Cl^–-ratio 1.36 1.0 0.94 1.17 1.0

Osmolality (mosmol/l) 295 308 324 280 308

RL: Ringer‘s lactate; HES: hydroxyethyl starch

Ringer’s lactate were infused over 2 hrs. Normal saline-treated patients showed a smaller (not significant) urine output (approx. 700 ml) than Ringer’s lactate- treated patients (approx. 1100 ml).

Almost all colloids (e.g., albumin, hydroxyethyl starch [HES], dextrans) are prepared in saline solution containing non-physiological high concentrations of sodium (154 mmol/l) and chloride (154 mmol/l) (Table 1), which may result in acid-base derangements (‘unbalanced colloids’). Thus, use of considerable amounts of these colloids may be associated with hyperchloremic acidosis: Acute normovolemic hemodilution (aim: hematocrit 22 %) in patients undergoing gynecologic surgery using either (unbalanced) 5 % albumin or (unbalanced) 6 % HES 200/0.5 resulted in metabolic acidosis in both groups [8]. A dilution of extracellular bicarbonate or changes in strong ion differences and albumin concentration may be explanations for this type of acidosis. Others found decreases in base excess after use of standard unbalanced high molecular weight HES solution but not with albumin [9].

New Approaches to Volume Therapy

Colloids have been shown to be more effective for correcting intravascular volume deficits and subsequently for improving systemic and microcirculatory hemodynamics than crystalloids [10, 11]. Recently, there has been increasing interest on another aspect with respect to treating hypovolemia: Plasma-adapted, balanced solutions have been reported to possess considerable advantages compared to conventional, unbalanced plasma substitutes [3, 12, 13].

Most of the fluids used for resuscitation or for correction of hypovolemia do not meet the criteria of an ‘ideal’ volume replacement strategy. Volume therapy with HES has become an established approach to correct hypovolemia under a variety of conditions in several countries. It is generally suspected, however, that HES significantly alters plasma coagulation and platelet function, leading to an increased bleeding tendency [14, 15]. HES with a high mean molecular weight (MW) and a high molar substitution (e.g., Hetastarch: Mw 450 kDa, molar substitution 0.7) diminished factor VIII related antigen and factor VIII ristocetin cofactor more than HES with lower MW and lower molar substitution [6, 7]. Platelet function abnor- malities were also more commonly associated with infusion of high MW HES [16, 17].

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One way to improve safety of HES with regard to coagulation is to modify the solvent. Not only the physico-chemical characteristics of the HES preparation may affect platelet function, the electrolyte composition of the solvent of the HES preparation may also influence platelet function [18]. Hextend® is a first generation, high molecular weight HES (weight average MW approximately 670 kDa) with a high molar substitution (0.75) that is dissolved in a physiologically ‘balanced’ solution containing 143 mmol/l Na⁺, 124 mmol/l Cl^–, 28 mmol/l lactate, 2.5 mmol/l Ca⁺⁺,3 mmol/l K⁺, 0.45 mmol/l Mg⁺⁺, and 5 mmol/l glucose [12, 19]. This specific HES preparation is reported to deteriorate coagulation significantly less than standard high-molecular weight (HMW), highly substituted HES solutions (Hetastarch) [3, 20]. Others, however, could not verify that modification of a first-generation HMW (MW 8 550 kDa), highly-substituted (molar substitution 8 0.7) HES preparation (Hextend®) eliminated the negative effects on coagulation [21]. The slowly degradable, HMW HES (MW 8 550 kDa) with a high molar substitution (8 0.7) (Hextend®) is predisposed to exert negative effects on platelet function in a balanced solution;

platelet glycoprotein IIb-IIIa availability increased significantly after hemodilution with this solution [23]. This unexpected platelet stimulating effect is unique among the currently available starches and is most likely induced by the calcium chloride dihydrate (2.5 mmol/l) contained in its solvent.

Balancing the volume replacement regimen also showed other beneficial effects aside from those on coagulation: In elderly patients undergoing elective open surgical procedures, conventional HMW-HES (Hetastarch) or a hetastarch in a balanced electrolyte and glucose formulation (Hextend®) was used [3]. Only patients treated with the conventional hetastarch developed hyperchloremic acidosis (postoperative base excess: -0.2 versus -3.8 mmol/l). Gastric tonometry indicated improved gastric mucosal perfusion with the balanced solution (Hextend®) when compared to the saline-based hetastarch [3].

Modifying the solvent of a first-generation HES with a high MW and a high molar substitution does not eliminate the problems that are generally associated with such a solution [14, 15], e.g., slow degradation, plasma and tissue accumulation, coagulation disturbances. Subsequently, a more rapidly degradable third generation HES with a lower MW (130 kDa), a lower molar substitution (0.4 – 0.42), and a lower C2/C6 ratio has been developed to improve safety and reduce the negative

Fig. 1. Development of hydroxyethyl starch (HES) solutions since their introduction in the 1960s.

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impact on coagulation [14, 23, 24] (Fig. 1). These solutions show more favorable physico-chemical properties than other HES preparations, but similar hemodynamic efficacy [25, 26]. They are, however, still dissolved in non-physiologic saline solution. Consequently, a new third generation HES solution with a low MW (130 kDa) and a low molar substitution (0.42) prepared in a plasma-adapted solution (containing 140 mmol/l Na⁺, 118 mmol/l Cl^–, 4 mmol/l K⁺, 2.5 mmol/l Ca⁺⁺, 1 mmol/l Mg⁺⁺, 24 mmol/l acetate, 5 mmol/l malate; B. Braun, Melsungen, Germany) has been developed [27]. This new, balanced HES solution is associated with similar hemodynamic effects to a conventional unbalanced HES preparation [27, 28]. Used in a total plasma-adapted volume replacement strategy and given in high doses, the balanced HES preparation showed more favorable effects on electrolyte concentrations and base excess: A total balanced, high-dose volume replacement strategy resulted in significantly less alterations in acid-base status (base excess, pH) and chloride concentration than a non-balanced regimen (Fig. 2). In the patients who received a non- balanced replacement strategy, infusion of the high, non-physiological amounts of sodium and chloride of the colloid and the crystalloid were not compensated for, resulting in hyperchloremic acidosis. The unbalanced volume replacement concept was associated with a base excess of ‹ –5 mmol/l in 7 out of 15 patients and significantly elevated plasma Cl^–levels of 8115 mmol/l in 14 out of 15 patients. Because base excess may also serve as an important marker to identify patients with malper- fused tissues, limiting acid-base alterations by the choice of volume replacement regimen may be helpful in this context: Producing (hyperchloremic) acidosis by admin-

Fig. 2. Changes in Na⁺, Cl^–, pH, and base excess (BE) in patients undergoing major abdominal surgery. The patients received either a plasma-adapted crystalloid (140 mmol/l Na⁺, 127 mmol/l Cl^–, 4 mmol/l K⁺, 2.5 mmol/l Ca⁺⁺, 1 mmol Mg⁺⁺, 24 mmol/l acetate, 5 mmol/l malate) plus a plasma-adapted (balanced) 6 % HES 130/0.42 dissolved in 140 mmol/l Na⁺, 118 mmol/l Cl^–, 4 mmol/l K⁺, 2.5 mmol/l Ca⁺⁺, 1 mmol Mg⁺⁺, 24 mmol/l acetate, 5 mmol/l malate) or a non-balanced regimen consisting of saline solution plus a conventional 6 % HES 130/0.42 (dissolved in saline solution). POD: postoperative day. Modified from [28]

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Fig. 3. In vitro studies on platelet function using whole blood aggregometry. Blood from healthy volun- teers was diluted (10 %, 30 %, 50 %) with plasma-adapted (balanced) 6 % HES 130/0.42 dissolved in 140 mmol/l Na⁺, 118 mmol/l Cl^–, 4 mmol/l K⁺, 2.5 mmol/l Ca⁺⁺, 1 mmol Mg⁺⁺, 24 mmol/l acetate, 5 mmol/l malate; conventional 6 % HES 130/0.4 (dissolved in saline solution); or Ringer’s lactate (RL). Induction of platelet aggregation was performed with ADP (ADPTest), collagen (COLTest) or thrombin-receptor-activating protein (TRAPTest). Dilution by 50 % resulted in significant differences in platelet aggregation between balanced and non-balanced HES solutions. Modified from [30]

istering unbalanced fluids may mask the diagnosis of perfusion deficits or may result in inappropriate clinical interventions due to the erroneous presumption of ongoing tissue hypoxia [29].

In in vitro studies using hemodilution, extensively diluting blood (50 %) with such a modern balanced HES preparation (6 % HES 130/0.42) resulted in only mod- erately altered platelet function (similar to dilution with Ringer’s lactate), whereas the most compromised platelet function was seen with an unbalanced HES preparation [30] (Fig. 3).

In the new, balanced HES preparation, maleate and acetate were used instead of adding lactate, because lactate metabolism is dependent on a well functioning liver, whereas maleate and acetate are metabolized in other organs in addition to the liver.

This effect may have an important impact in shock situations in that excessive lactate added by the fluid replacement regimen may accumulate and lactic acidosis can no longer be used as a diagnostic tool.

The value of creating a totally balanced (‘plasma-adapted’) fluid replacement strategy is still unclear. Avoiding hyperchloremic metabolic acidosis appears to be a generally accepted aim when managing the hypovolemic patient. In an animal model of septic shock, volume resuscitation with Hextend® (a balanced first-generation HES preparation) compared with 0.9 % saline was associated with less meta-

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bolic acidosis and even longer survival [31]. Whether modulation of the acid-base status by a completely balanced volume replacement strategy would beneficially influence organ function, morbidity, or even mortality in the critically ill must be evaluated in future studies. It also remains to be elucidated whether prolonged, repetitive use of such a fluid replacement concept would be of advantage compared to a non-balanced regimen.

Conclusion

Disorders of the composition of extracellular fluid occur commonly in the critically ill patient. It is imperative to continue the search for the ideal volume replacement regimen, because the requirements of a totally balanced volume replacement regimen cannot be fulfilled with the presently available plasma substitutes. Recent papers using new HES preparations dissolved in a balanced solution have shed new light on this issue. A modern third generation HES solution prepared in a balanced solution completes the idea of a plasma-adapted volume replacement strategy and may add another piece to the puzzle of finding the ‘ideal‘ fluid therapy in the hypovolemic, critically ill patient.

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