Hypovolaemia is reported to be the most important avoidable cause of organ dysfunction and death [1,2]. Delayed and inadequate restoration of intravascular circulating volume may worsen systemic haemodynamics, microvascular flow and subsequently organ function . Thus, hypovolaemia should be treated urgently and sufficiently in the perioperative period. Colloids have been shown to be more effective for correcting intravascular volume deficits and for improving systemic and microcirculatory haemodynamics than crystalloids [4,5].
Recent papers have shed light on another interesting aspect with regard to treating hypovolaemia with colloids: the use of a first generation hydroxyethyl starch (HES) preparation formulated in a balanced electrolyte solution (‘balanced’ HES preparation) was reported to possess considerable advantages compared with a conventional, first generation HES solution prepared in 0.9% sodium chloride (‘unbalanced’ HES preparation) [5–7]. Thus, it may be assumed that a modern volume replacement regimen should be based on both a balanced crystalloid and a balanced colloid. Unfortunately, most of the available colloids are not balanced, include unphysiologically high concentrations of sodium and chloride and do not fit into the concept of a total balanced volume replacement strategy. The present study was designed to assess the effects of a complete balanced volume replacement concept including a new, not-yet approved (potato-derived) balanced third generation HES preparation on haemodynamics, acid–base status, kidney function and coagulation in comparison with a control group in whom a conventional, unbalanced volume replacement strategy was used.
Patients and grouping
After approval by the Ethics Committee of the hospital and written informed consent was obtained from all patients, 30 consecutive patients scheduled for elective first-time major abdominal surgery for intestine cancer were studied. Patients with myocardial infarction within the previous 3 months, renal insufficiency (serum creatinine >2.0 mmol L−1), liver insufficiency (aspartate aminotransferase >40 U L−1, alanine aminotransferase >40 U L−1), diabetes mellitus, anaemia (haemoglobin <8.0 g dL−1) and use of aspirin, corticosteroids, diuretics or angiotensin-converting enzyme inhibitors (ACEI) prior to surgery were not included.
The patients were enrolled in a prospective, randomized, double-blind study. The blinding of the substances was done by a pharmaceutical company (B. Braun, Melsungen, Germany). Using a closed-envelope system, the patients were preoperatively allocated to one of the two volume replacement strategies: patients of Group A (‘balanced group’; n = 15) received a ‘colloid-A’ (a new not-yet approved balanced, potato-derived 6% HES 130/0.42 containing Na+ 140 mmol L−1, Cl− 118 mmol L−1, K+ 4 mmol L−1, Ca2+ 2.5 mmol L−1, Mg2+ 1 mmol, acetate 24 mmol L−1, malate 5 mmol L−1; B. Braun, Melsungen, Germany) and a ‘crystalloid-A’ containing Na+ 140 mmol L−1, Cl− 127 mmol L−1, K+ 4 mmol L−1, Ca2+ 2.5 mmol L−1, Mg2+ 1 mmol, acetate 24 mmol L−1, malate 5 mmol L−1; a balanced crystalloid, Ringerfundin M, B. Braun, Melsungen, Germany), patients of Group B (‘unbalanced’ group; n = 15) received a ‘colloid-B’ (conventional potato-derived 6% HES 130/0.42 [Venofundin®; B. Braun, Melsungen, Germany] prepared in Na+ 154 mmol L−1 and Cl− 154 mmol L−1) and a ‘crystalloid-B’ (normal saline (NS) solution containing Na+ 154 mmol L−1 and Cl− 154 mmol L−1). The contents of solutions ‘A’ and ‘B’ were unknown for the users and the code was broken after finishing the study. The statistician who perform all statistical analyses was also blinded to the grouping.
When mean arterial pressure (MAP) was 65 mmHg and central venous pressure (CVP) minus the actual positive end-expiratoric pressure (PEEP) was <10 mmHg, colloid-A or B was infused. Volume administration was started after beginning of anaesthesia and continued until the morning of the first postoperative day (POD) when necessary. When colloids were used, crystalloid-A or B was given in a 1 : 1 ratio along with the colloid infusion. To compensate fluid loss by sweating, gastric tubes and urine output or as a dissolvent for drugs (e.g. antibiotics), either crystalloid-A or B was given. During surgery, 500 mL h−1 of either of the crystalloids was infused according to the grouping of the patients. Buffering (administration of sodium bicarbonate) and diuretics were not allowed within the entire study period.
All patients received a continuous epidural anaesthesia. A mixture of ropivacaine and sufentanil was continuously administered by the catheter using a standard protocol. Postoperatively, a patient-controlled anaesthesia (PCA) delivery system was used in all patients that was initially controlled by the nurses of the intensive care unit (ICU). Anaesthesia was induced by weight-related doses of thiopentone (5 mg kg−1), fentanyl (3 μg kg−1) and vecuronium (0.1 mg kg−1) for neuromuscular blockade. Fentanyl, desflurane and vecuronium, titrated according to the patient’s need were used to maintain anaesthesia. Mechanical ventilation was performed in all patients (50% air in oxygen) to keep SaO2 >95% and end-expiratory CO2 between 35 and 40 mmHg. A re-warming cover-blanket system was used to guarantee normothermia during surgery. After surgery, all patients were transferred to the ICU. When necessary, mechanical ventilation was continued until the patients were ready for tracheal extubation (stable haemodynamics, sufficient spontaneous breathing, warmed up to 36°C).
When MAP was <50 mmHg in spite of sufficient intravascular volume (CVP > 10 mmHg), dobutamine was given. Norepinephrine was added when volume therapy and dobutamine were not successful to keep MAP >50 mmHg. Packed red blood cells (PRBC) were given when haemoglobin was <8 g dL−1, fresh frozen plasma (FFP) was used when a PTT was >70 s, fibrinogen was <2 g dL−1, antithrombin III (AT III) was <40% and bleeding occurred.
Intraoperative and postoperative haemodynamic monitoring included continuous measurement of electrocardiogram and arterial pressure (A. radialis cannula), and CVP (V. jugularis interna).
Standard laboratory parameters
Standard laboratory techniques were used to measure haemoglobin, blood gases, acid–base status and electrolytes from arterial blood samples and urine specimen, respectively.
Measures to assess kidney function
Serum and urine creatinine levels were measured using Jaffé reaction. Creatinine clearance was measured from Ucrea× Uvol/Pcrea duration of urine-collection period (Ucrea: urine creatinine concentration; Uvol: urine volume during the collection period; Pcrea: serum creatinine concentration). In all the patients, a bladder catheter was placed after induction of anaesthesia before the start of volume infusion. Kidney-specific proteins beta-NAG (analysed by a spectrophotometric method; Hoffmann-La Roche, Basel, Switzerland; normal value in healthy volunteers: <4 U g−1 creatinine) and alpha-1-microglobulin (measured by immunonephelometry, Behring Werke, Marburg, Germany; normal value in healthy volunteers: <14 mg L−1) were measured.
Measures to assess coagulation
From arterial blood samples, standard coagulation data (AT III, fibrinogen, platelet count and activated partial thromboplastin time) were measured using routine laboratory tests.
Activated thrombelastography (TEG) was carried out using a four-channel analyser (roTEMTM, Pentapharm, Germany). TEG measurements were performed within 10 min after blood sampling using a semi-automatic pipetting system. The roTEMTM system uses a different power-transduction system than conventional TEG machines that makes it less susceptible to mechanical stress, movement and vibration. The roTEMTM analysis relies on the continuous assessment of clot firmness, allowing the determination of the onset of coagulation (coagulation time (CT) – standard TEG: reaction time (r)), kinetics of clot formation (clot formation time (CFT) – standard TEG : CT (k)) and maximum clot firmness (MCF) (standard TEG : maximal amplitude (MA)). Clot formation was measured adding a surface activator (partial thromboplastin from rabbit brain (20 μL)) for monitoring the intrinsic system (factors XII, XI, IX, VIII, X, II, I + platelets) according to the manufacturer’s instructions (intrinsic TEG).
Measurements were made after induction of anaesthesia (before volume was administered) (T0), at the end of surgery (T1), 5 h after surgery (on the ICU) (T2) and 24 h after surgery on the first POD (T3).
Between the two data points ‘baseline’ and ‘5 h after end of surgery’, a smaller rise in the serum chloride (Cl−) concentration and a lower base excess (BE) were expected with the balanced volume replacement concept compared with the non-balanced group. The study aimed at determining both primary end-points: chloride and BE (in consideration of the necessary correction of the level of significance according to Bonferroni). A sample-size calculation based on the results of the study from Wilkes and colleagues  leads to a minimum sample size of n = 2 × 9 (two-sided question using the U-test (rank sum test according to Wilcoxon/Mann–Whitney)). Considering a drop out rate of 20% and in view of the limited comparability of the study conditions, sample-size calculation resulted in n = 2 × 15 patients. Data are expressed as mean and standard deviation (SD) unless otherwise indicated. A SPSS/PC+ software package was used for statistical analyses (v 4.0. SPSS, Inc., Chicago, IL, USA). Categorical variables were tested by X2-test. Normally distributed data (tested by Kolmogorov–Smirnov test) were analysed using t-test. One-way and two-way analysis of variance (ANOVA) with repeated measures and post hoc Scheffé’s test were used to determine the effects of group, time and group–time interaction. U-test or the Kruskal–Wallis test were also used when appropriate. A P value <0.05 was considered significant.
Biometric data, type of surgery, as well as duration of anaesthesia and surgery were without significant differences between the two groups (Table 1). Group A received a total of 3533 ± 1302 mL of HES and 5333 ± 1063 mL of crystalloids, whereas in Group B, 3866 ± 1674 mL of HES and 5966 ± 1202 mL of crystalloids were given (Table 2). Blood loss, use of PRBC and FFP until the end of the study did not differ significantly within the two groups (Table 2). Haemodynamics were comparable in both groups throughout the study period (Table 3). Haemoglobin and standard coagulation data were also similar for the two groups (Table 4). Changes in TEG (CT, CFT, MCF) from baseline until the end of the study (first POD) did not show significant differences between the two groups (Fig. 1). Creatinine clearance and urine concentrations of kidney-specific proteins were similar in the two groups and without significant differences between the groups (Fig. 2).
BE was significantly more negative in patients of Group B than in patients of Group A (end of surgery: −5 ± 2.4 vs. 0.4 ± 2.4 mmol L−1) (Fig. 3). A BE of <−5 mmol L−1 was seen in seven patients of Group B (maximum: −11.5 mmol L−1). Cl− plasma concentration was significantly higher in patients of Group B than in patients of Group A (Fig. 3). A Cl− plasma level of >115 mmol L−1 was seen in one patient of Group A (maximum: 116 mmol L−1) compared with 14 patients of Group B (maximum: 128 mmol L−1). Sodium plasma levels were also significantly higher in patients of the unbalanced than of the balanced Group A. Potassium (K+) plasma concentrations remained within normal range in all patients throughout the study period.
No adverse effects (e.g. anaphylactic reactions, postoperative itching) related to infusion of the new HES preparation were documented. None of the patients died within a period of 30 days.
When a colloid-based volume replacement strategy is chosen, HES prepared in 0.9% saline solution is mostly used. These HES preparations contain high (unphysiological) concentrations of sodium (154 mmol L−1) and chloride (154 mmol L−1). Thus, the requirements on a total balanced volume replacement regimen cannot be fulfilled with this plasma substitutes. When crystalloids are given, NS is often preferred because it is isotonic and cheap. It also, however, contains high chloride and sodium concentrations. Administration of large amounts of such fluids (combined HES prepared in NS plus NS) is associated with the risk of development of hyperchloraemic acidosis [8,9]. The clinical relevance of hyperchloraemic acidosis still remains unclear: it may impair organ perfusion (e.g. splanchnic perfusion ) or may interfere with cellular exchange mechanism . Hyperchloraemic acidosis in animal experiments was associated with a reduction in renal blood flow (most likely due to vasoconstriction) and a negative effect on glomerular filtration rate . In non-cardiac surgical patients, Bennett-Guerrero and colleagues  demonstrated that administration of unbalanced salt solutions resulted in reduced urine output and increased serum creatinine levels postoperatively.
In our balanced solutions, maleate and acetate were used instead of adding lactate, because lactate metabolism is dependent on a well-functioning liver, whereas maleate and acetate are also metabolized also in other organs apart from the liver. This may have an important impact in shock situations in that excessive lactate added by the fluid replacement regimen may accumulate and lactic acidosis cannot be used any longer as a diagnostic tool.
The present study was designed to assess the effects of a total balanced volume replacement strategy including a new, not yet approved balanced third generation HES preparation on acid–base status, coagulation and renal function. We created a ‘balanced’ group (Group A) by adding a balanced crystalloid to the balanced new HES preparation and compared it with an ‘unbalanced’ group containing an unbalanced modern HES preparation and an unbalanced crystalloid NS.
It is difficult to compare our study with other studies assessing the importance of balanced plasma substitutes. The only balanced HES preparation that is available in very few countries (Hextend®; Abbott Lab, North Chicago, IL, USA) is based on a first HES with a high molecular weight (HMW-HES: mean molecular weight (Mw) 670 kD) and a high molar substitution (MS: 0.75). HMW-HES with such high MS is known to be associated with several unwanted adverse effects such as high plasma/tissue accumulation and negative effects on coagulation [12,13]. Whether modification of the diluent (a balanced solution instead of NS with high sodium and chloride concentrations) is able to beneficially modify the substance-specific negative effects of a HMW-HES with a high MS [14,15] has been doubted . In the few studies using Hextend® in patients, smaller amounts of these HES preparations (1301 ± 1079 mL , 1596 ± 923 mL ) have been given compared with the amounts of the new third generation HES that have been given in the present study. We used a new (potato-derived) third generation HES with a lower mean molecular weight (Mw: 130 kD) and a lower MS (0.42) in high doses (3866 ± 1674 mL (range: 1500–7000)). HES specifications with a low Mw and low MS are known to have favourable physico-chemical characteristics: they are associated with almost no negative effects on accumulation even after repetitive dosing, and possess almost no negative effects on coagulation [17–19].
One finding of the present study was the new balanced HES solution given along with a balanced crystalloid showed similar haemodynamics compared with a conventional, unbalanced HES preparation plus an unbalanced crystalloid. CVP was similar and also the total volumes of HES were similar in both groups. The new HES solution embedded in a total plasma-adapted volume replacement strategy and given in high doses was not associated with significant adverse effects on coagulation and kidney function. Since certain HES preparations have been reported to possess considerable negative effects on coagulation and kidney function [20–22], we not only measured routine laboratory data but also used more sophisticated measures such as TEG monitoring and urine levels of specific renal tubule enzymes to assess the effects of the new HES solution on haemostasis and kidney integrity.
Another finding of our study was that using a total balanced, high-dose volume replacement strategy resulted in significantly less alterations in acid–base status (BE, pH) and chloride concentration than a non-balanced regimen. In our patients, who have received a non-balanced replacement strategy, infusion of the high, unphysiological amounts of sodium and chloride of the colloid and the crystalloid were not compensated resulting in hyperchloraemic acidosis. The unbalanced volume replacement concept was associated with a BE of <−5 mmol L−1 in seven patients and significantly elevated Cl− plasma levels of >115 mmol L−1 in 14 patients. Although not definitely known at present, avoiding hyperchloraemic acidosis may have considerable advantages for patients’ comfort and organ function [5,6,8]. Because BE may also serve as an important marker to identify patients with malperfused tissues, avoidance of acid–base alterations, by the choice of volume replacement regimen, may be helpful in this context.
No effects on our patients’ outcome (mortality) by the chosen volume replacement strategy were seen. The aim of the study was to assess the effects of a balanced volume replacement strategy including a new, not-yet approved HES preparation on acid–base status. Alterations in coagulation and kidney function were additionally studied as these are the most often arguments against the use of HES. Thus, the power analysis was based exclusively on changes of the acid–base/electrolyte status. The patient population was definitely too small to draw conclusions with regard to mortality. No convincing data are available at present showing that the choice of a fluid saves someone’s life [23,24].
One objection to the present study is that only surrogate markers for identifying patient’s volume status have been used. The ideal method for recognizing hypovolaemia or for guiding volume therapy still needs to be elucidated. Transoesophegeal echocardiography (TEE) appears to be a very sensitive technique, but is expensive and unreliable for monitoring volume status continuously over time (e.g. over 24 h). It has been shown that CVP does not definitely confirm or exclude hypovolaemia . We not only used CVP for indicating volume administration but also took MAP into account to guide volume therapy. CVP was similar in both groups within the entire study period and in both groups, very similar volumes of colloids (and crystalloids) have been infused – thus, similar volume replacing efficacy of both HES preparations may be assumed.
Another objection is that we used a total balanced volume replacement strategy and the value of the new balanced HES preparation that was given along with a balanced crystalloid preparation is difficult to assess. Certain HES preparations were reported to be associated with substance-specific unwanted side-effects on haemostasis and renal function [13,20,21]. Results from the present study demonstrated that even large volumes of the new HES preparation were as safe with regard to coagulation and kidney function as the already approved, conventional HES solution.
Since apart from differences in the acid–base status, almost no other differences between the two groups were seen, the question on the value of creating a total balanced (‘plasma-adapted’) fluid replacement strategy arises. Because of considerable negative effects, avoiding hyperchloraemic metabolic acidosis appears to be a generally accepted aim when managing the hypovolaemic patient [26–29]. Producing (hyperchloraemic) acidosis by administering unbalanced fluids may also mask diagnosis of perfusion deficits or may result in inappropriate clinical interventions due to the erroneous presumption of ongoing tissue hypoxia . All our patients were in sufficient physical conditions preoperatively. 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 metabolic acidosis and even longer survival . Whether modulation of the acid–base status by a complete balanced volume replacement strategy would have beneficially influenced organ function, morbidity or even mortality in more critically ill patients 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 with a non-balanced regimen.
This study was not focused on the controversy whether patients undergoing abdominal surgery profit from a ‘liberal’ or a more ‘restrictive’ fluid replacement strategy . At present, there does not exist a generally accepted definition for ‘liberal’ or ‘restrictive’ fluid replacement approach. A ‘goal-directed’ fluid replacement strategy that uses surrogates for assessing the patient’s volume status (e.g. blood pressure or filling pressures as in the present study) appears to be much more appropriate than using a fixed ‘liberal’ or ‘restrictive’, non-patient-adapted fluid regimen.
It is concluded that it is imperative to continue the search for the ideal volume replacement regimen. A total balanced volume replacement strategy including a new balanced HES solution resulted in similar haemodynamic effects, but significantly less alterations in acid–base status and electrolyte concentrations than an unbalanced regimen using a conventional HES preparation plus a non-balanced crystalloid solution. 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 in the puzzle of finding the ‘ideal’ fluid therapy in the hypovolaemic critically ill patient.
Fluids used in this study were provided by B. Braun Melsungen, Germany. The study was supported by a grant from B. Braun Melsungen, Germany providing all costs for the measurements (laboratory kits, etc.).
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