II. The balanced concept of fluid resuscitation
In trauma, burn, surgical, and intensive care patients with hypovolaemia, adequate volume restoration is essential to avoid development of organ failure. This manoeuvre is aimed at guaranteeing stable macro- and micro-haemodynamics while avoiding excessive interstitial fluid overload. The choice of fluid engenders much controversy and there is considerable dispute over the pros and cons of each type. Most crystalloids consist of a non-physiological mixture of electrolytes.1 In the beginning of the 1990s, substantial alterations in acid–base status were described in patients who had large amounts of saline (NS) infused.2 This has been defined as ‘hyperchloraemic acidosis’.3 Colloids have been shown to be more effective than crystalloids for correcting intravascular volume deficits and for improving systemic and microcirculatory haemodynamics.4 5 Consequently, colloids are often preferred for correcting hypovolaemia.6 Almost all colloids [albumin, hydroxyethylstarch (HES), gelatins] are prepared in non-physiological solutions and can be defined as ‘unbalanced colloids’. The use of large amounts of these colloids may be associated with unwanted electrolyte or acid–base disturbances. Our emerging understanding of the (patho-) physiology of the different volume replacement strategies leads to the question as to why infusion solutions are so poorly compounded.Avoidance of acid–base alterations by the choice of volume replacement regimen is important as base excess (BE) may serve as an important marker to identify patients with under-perfused tissues. Producing severe (hyperchloraemic) acidosis by giving large amounts of unbalanced fluids may mask diagnosis of perfusion deficits or may result in inappropriate clinical interventions due to the erroneous presumption of ongoing tissue hypoxia secondary to hyovolaemia.7 In a study in intensive care unit (ICU) patients, the BE was shown to predict outcome and to identify patients who have a high risk for mortality and thus should be admitted to ICU.8 In patients undergoing cardiac surgery with cardiopulmonary bypass, the BE measured during the first hour after surgery correlated with the length of stay on the ICU.9
The clinical relevance of hyperchloraemic acidosis is not fully elucidated. While some authors emphasized that infusion-related hyperchloraemic acidosis is benign,10 other's stress the importance of this type of acid–base upset.
Benefit of avoiding hyperchloraemia: data from animal studies
In an animal model of massive haemorrhage (removal of approximately 200% of the estimated blood volume), resuscitation with normal saline (NS) (n = 10) resulted in severe acidosis (BE – 19 mmol litre–1) compared with Ringer's lactate (RL) (n = 10; BE – 5.5 mmol litre–1).11 Survival was significantly higher with RL (100%) than with NS (50%). In an endotoxaemia study in rats, i.v. infusion of a balanced HES (Hextend®; n = 25) resulted in significantly less negative BE (– 12.1 mmol litre–1; pH 7.15) than resuscitation using NS (BE – 19.3 mmol litre–1, pH 7.02).12 Survival was significantly improved by Hextend® when compared with NS. In experiments in greyhounds, hyperchloraemic acidosis was associated with a reduction in renal blood flow and a negative effect on glomerular filtration rate.13 In a porcine model of uncontrolled haemorrhage, resuscitation with saline [n = 10, 331 (38) ml kg–1] modified hypercoagulability secondary to trauma and resulted in increased blood loss and fluid requirements compared with use of RL [n = 10, 148 (20) ml kg–1].14 These effects were most likely to be related to acidosis associated with the infusion of saline only.
Benefit of avoiding hyperchloraemia: data from volunteers/patients
Results from humans also suggested that fluid-related upsets in acid–base status may have adverse effects. In healthy volunteers (n = 18) in whom 50 ml kg–1of either NS or RL were infused more than 1 h, metabolic acidosis developed in the NS group [pH: – 0.04 (0.04) from baseline] and time to first urination was increased significantly.15 Moreover, abdominal discomfort and mental changes were more common with NS than with RL. Scheingraber and colleagues16 studied patients undergoing elective lower abdominal gynaecologic surgery who received approximately 6000 ml of either NS (n = 12) or RL (n = 12) for 2 h. NS-treated patients showed a smaller (not significant) urine output (approximately 700 ml) than RL-treated patients (approximately 1100 ml). In a group of patients undergoing abdominal aortic aneurysm repair who received either lactated Ringer's solution [RL; total dose: 6800 ml (n = 33)] or normal saline [NS; total dose: 7000 ml (n = 33)] in a double-blinded fashion,17 only the NS-treated patients developed hyperchloraemic acidosis [BE –3.8 (3.9) mmol litre–1, pH 7.35] and they needed significantly more blood products than the RL-group. In patients undergoing kidney transplantation, either approximately 6 litre of NS (n = 26) or RL (n = 25) were given.18 Use of high doses of NS was not recommended because this was associated with metabolic acidosis and significant hyperkalemia.
New approach of fluid resuscitation: the total balanced concept
To complete the idea of a total balanced fluid resuscitation concept, balanced colloids are needed aside from balanced, plasma-adapted crystalloids. HES has become an established approach to correct hypovolaemia under a variety of conditions in several countries.6 Apart from substance-specific beneficial effects on haemodynamics and unwanted adverse effects (e.g. on coagulation), there is increasing interest in the issue of balanced, plasma-adapted HES preparations which have been reported to have advantages over conventional, unbalanced HES solutions.19 20 A first-generation high-molecular weight HES [mean molecular weight (Mw) > 650 kD] with a high molar substitution (MS: > 0.7) has been dissolved in a physiologically balanced solution (Hextend®).21 Modifying the solvent of this first-generation HES with a high Mw and MS probably does not eliminate the problems that are generally associated with such a solution, for example, slow degradation, plasma/tissue accumulation, and coagulation disturbances. Subsequently, a more rapidly degradable third generation HES with a lower Mw (130 kD), a lower MS (0.4), and a lower C2/C6 ratio has been developed to improve safety and is prepared in a balanced, plasma-adapted solution.22 23 When used in a plasma-adapted volume replacement strategy (balanced crystalloid plus balanced HES) and given in high doses (approximately 2500 ml of HES within 24 h), this had better effects with regards to electrolyte concentrations and BE compared with a non-balanced strategy including normal saline and a non-balanced HES.23
There is evidence that a balanced colloidal volume replacement concept offers some other important advantages in addition to changes in acid–base status. HES is thought to alter coagulation and platelet function leading to increased bleeding tendency. Coagulation may be affected by both the physico-chemical characteristics of the HES preparation and the electrolyte composition of the solvent. In in vitro studies using serial haemodilution (up to 60% dilution) and thrombelastographyTM to assess changes in haemostasis, a balanced high-Mw HES with a high MS (Hextend®) impaired coagulation significantly less than a conventional high-Mw, high-MS HES prepared in saline (Hetastarch).24 In extensive in vitro coagulation tests using this agent, Bick25 found no alteration in haemostasis, other than those expected by dilution. No adverse effects were seen on aPPT, prothrombin time, functional fibrinogen, factor VIII:C, factor VIII:von Willebrand factor (factor VIII:vW), factor VIII-related antigen (factor VIII:RAG), or von Willebrand multimers. Slow degradable high-Mw HES with a high MS (e.g. Hetastarch) may also alter platelet function. By using a balanced high Mw/high MS HES (Hextend®), the platelets' glycoprotein IIb–IIIa availability increased significantly after 20% haemodilution when compared with Hetastarch.26 This unexpected platelet stimulating effect is unique among the currently available starches and may be due to its solvent containing calcium chloride dihydrate (2.5 mmol litre–1). In a prospective, randomized, double-blinded study in 90 patients undergoing major non-cardiac surgery,27 the use of HES prepared in normal saline (Hetastarch, n = 30, approximately 1300 ml) resulted in significantly more impaired thrombelastographic data than HES prepared in a balanced solution (Hextend®, n = 30, approximately 1450 ml). In an in vitro study, whole blood from 20 healthy volunteers was haemodiluted either with a low-Mw HES (130 kD) with a low MS (0.42) dissolved in a balanced solution (Tetraspan®), a conventional 6% HES 130/0.4 (dissolved in saline), or RL.28 Fifty per cent dilution with the non-balanced HES resulted in significantly more altered platelet aggregation than in the balanced HES group.
Balanced colloidal volume replacement regimen may also have other beneficial effects. In a prospective, randomized, double-blinded clinical trial in elderly patients (> 60 yr) undergoing elective open surgical procedures, a high-Mw, highly substituted HES prepared in a balanced electrolyte formulation improved gastric mucosal perfusion assessed by gastric tonometry more than a conventional high-Mw HES with a high MS.19
Importance of a total balanced volume replacement concept
Although total balanced volume replacement appears to be a promising tool from the physiological point of view, its relevance for patients' outcome is unclear as outcome data (mortality) in patients are lacking. In animal studies, volume resuscitation with a balanced HES preparation [Hextend®, 0.12 (0.09) ml kg–1min–1] was associated with less metabolic acidosis and a longer short-term survival compared with resuscitation using 0.9% saline [0.19 (0.04) ml kg–1min–1].12 As mortality in elective surgical patients has become extremely low, it is unlikely that mortality using total balanced fluid replacement would be significantly different to unbalanced volume replacement. The value of this strategy in the critically ill intensive care patient needing volume therapy over days has not yet been studied. Aside from possible negative sequelae on coagulation and organ function (e.g. kidney function) by using an unbalanced fluid resuscitation regimen, production of a low pH/low BE by the choice of our volume replacement limits our diagnostic process, as BE has been shown to be a valuable tool to diagnose (micro-) circulatory derangements. Subsequently, avoiding therapy-related hyperchloraemic metabolic acidosis is a desirable aim when managing the hypovolaemic patient.10
Administration of large amounts of many of the fluids available for correction of hypovolaemia is associated with unwanted changes of acid–base status. It is imperative to continue the search for a volume replacement regimen that avoids altering our patients' homeostasis. At present, only limited data are available concerning the clinical relevance of total balanced volume replacement in major surgery, burns, or intensive care patients. The subject has no systematic review or meta-analysis as the few studies are very variable with regard to the study structure (in vitro studies, animals, volunteers, and patients), the aim of fluid administration, and the kind of fluid.
It has never been shown that the choice of a plasma substitute has saved a life. Thus, it is doubtful whether we can make a meaningful statement on comparative mortality with regard to different plasma substitutes. Alternatively, we should look more closely at other outcome variables such as patient comfort, organ function, microcirculation, adverse effects and, finally, costs when assessing the optimal plasma substitute. Whether choosing a total balanced volume replacement strategy would beneficially influence organ function, morbidity or even patients' mortality must be evaluated in large controlled studies. It also remains to be elucidated whether repetitive use of such a fluid replacement concept, for example, in the ICU patient, would be of advantage.
To argue against a total balanced volume replacement strategy appears to be difficult. Although the amount of unbalanced fluids required to produce clinically relevant upsets of electrolyte and acid–base status is not known, the question rises why we generally should use a non-balanced concept that is associated with the risk of altering homeostasis when a total balanced concept, including balanced colloids, that does not affect homeostasis is available? This question is appropriate also when using more ‘restrictive’ fluid administration practice during surgery. Primum nil nocere (first do no harm) is the basic doctrine of medicine. The total balanced fluid resuscitation concept is adding another piece in the puzzle of finding the ideal fluid therapy in the hypovolaemic patient. There will be an ongoing controversy with this strategy of fluid resuscitation.
The following pharmaceutical companies which produce plasma substitutes have, in the past, supported studies in the author's department: Fresenius (Germany), Baxter (Germany), Bernburg (Germany), B. Braun (Germany), and Glaxo-Smith-Kline (Canada). None had any involvement in this article.
Department of Anaesthesiology
and Intensive Care Medicine
Klinikum der Stadt
Ludwigshafen
Bremserstr. 79
D-67063 Ludwigshafen
Germany
* E-mail: boldtj{at}gmx.net
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