Intensive Care Medicine

, Volume 35, Issue 3, pp 462–470

RETRACTED ARTICLE: The influence of a balanced volume replacement concept on inflammation, endothelial activation, and kidney integrity in elderly cardiac surgery patients

Authors

    • Department of Anesthesiology and Intensive Care MedicineKlinikum der Stadt Ludwigshafen
  • Stephan Suttner
    • Department of Anesthesiology and Intensive Care MedicineKlinikum der Stadt Ludwigshafen
  • Christian Brosch
    • Department of Anesthesiology and Intensive Care MedicineKlinikum der Stadt Ludwigshafen
  • Andreas Lehmann
    • Department of Anesthesiology and Intensive Care MedicineKlinikum der Stadt Ludwigshafen
  • Kerstin Röhm
    • Department of Anesthesiology and Intensive Care MedicineKlinikum der Stadt Ludwigshafen
  • Andinet Mengistu
    • Department of Anesthesiology and Intensive Care MedicineKlinikum der Stadt Ludwigshafen
Original

DOI: 10.1007/s00134-008-1287-1

Cite this article as:
Boldt, J., Suttner, S., Brosch, C. et al. Intensive Care Med (2009) 35: 462. doi:10.1007/s00134-008-1287-1

Abstract

Purpose

A balanced fluid replacement strategy appears to be promising for correcting hypovolemia. The benefits of a balanced fluid replacement regimen were studied in elderly cardiac surgery patients.

Methods

In a randomized clinical trial, 50 patients aged >75 years undergoing cardiac surgery received a balanced 6% HES 130/0.42 plus a balanced crystalloid solution (n = 25) or a non-balanced HES in saline plus saline solution (n = 25) to keep pulmonary capillary wedge pressure/central venous pressure between 12–14 mmHg. Acid-base status, inflammation, endothelial activation (soluble intercellular adhesion molecule-1, kidney integrity (kidney-specific proteins glutathione transferase-alpha; neutrophil gelatinase-associated lipocalin) were studied after induction of anesthesia, 5 h after surgery, 1 and 2 days thereafter. Serum creatinine (sCr) was measured approximately 60 days after discharge.

Results

A total of 2,750 ± 640 mL of balanced and 2,820 ± 550 mL of unbalanced HES were given until the second POD. Base excess (BE) was significantly reduced in the unbalanced (from +1.21 ± 0.3 to −4.39 ± 1.0 mmol L−1 5 h after surgery; P < 0.001) and remained unchanged in the balanced group (from 1.04 ± 0.3 to −0.81 ± 0.3 mmol L−1 5 h after surgery). Evolution of the BE was significantly different. Inflammatory response and endothelial activation were significantly less pronounced in the balanced than the unbalanced group. Concentrations of kidney-specific proteins after surgery indicated less alterations of kidney integrity in the balanced than in the unbalanced group.

Conclusions

A total balanced volume replacement strategy including a balanced HES and a balanced crystalloid solution resulted in moderate beneficial effects on acid-base status, inflammation, endothelial activation, and kidney integrity compared to a conventional unbalanced volume replacement regimen.

Keywords

Volume replacementBalanced volume replacementHydroxethylstarchInflammationKidney functionCardiac surgery

Introduction

The importance of an appropriate volume replacement therapy in cardiac surgery is generally accepted. By using cardiopulmonary bypass (CPB), several mediators are released and an inflammatory process is generated leading to altered endothelial integrity with leakage of fluids resulting in hypovolemia without obvious fluid loss [1]. Adequate fluid replacement improves venous return, cardiac output, tissue perfusion, and subsequently may preserve organ function [24].

Controversy still refer to the kind of volume replacement in the cardiac surgery patient [5, 6]. This controversy does not only include a crystalloid/colloid debate, but also a colloid/colloid debate. New light on this issue was shed by the increasing knowledge that certain fluids may produce metabolic (hyperchloremic) acidosis associated with altered inflammatory response, deteriorated organ function or impaired coagulation [7]. This led to the idea of developing a total balanced volume replacement concept including balanced crystalloids and balanced colloids.

Most colloids [including human albumin (HA)] are formulated in saline solution and use of considerable amounts of these colloids having unphysiological high sodium and chloride concentrations may be associated with development of (hyperchloremic) metabolic acidosis [7]. The first colloid prepared in a balanced solution was a first-generation HES preparation with a high mean molecular-weight (Mw > 550 kD) and a high molar substitution (MS > 0.7) (Hextend®) [810]. This plasma substitute is based on a HES preparation that is known to accumulate after repetitive infusions and to result in impaired coagulation including platelet dysfunction [11]. Consequently, a modern lower Mw HES (Mw 130 kD) with a lower MS (<0.5) has been developed showing favorable physico-chemical characteristics compared to older HES generations [12], and that is now dissolved in a balanced preparation. The present study was designed to assess the effects of a total balanced volume replacement regimen including a new balanced HES preparation on base excess (BE), inflammation, endothelial activation, and kidney integrity in comparison to a non-balanced fluid regimen in elderly patients undergoing cardiac surgery. The hypothesis was that a total balanced volume replacement strategy reduces BE less, reduces inflammatory response and endothelial injury as well as beneficially influences kidney integrity.

Materials and methods

Patients

Following approval of the Institutional Review Board (IRB) and written patients informed consent were taken, 50 patients aged >75 years and undergoing elective cardiac surgery were studied. Serum creatinine concentration (sCr) of >2.0 g dL−1, chronic oliguric/anuric kidney dysfunction requiring dialysis, liver insufficiency (aspartate amino-transferase (ASA) >40 U L−1, alanine aminotransferase (ALA) >40 U L−1), and chronic use of corticosteroids were defined as exclusion criterion.

Preoperative randomization of patients was done using a sealed envelope system. Patients received either a balanced volume replacement regimen (n = 25) consisting of a balanced 6% HES 130/0.42 dissolved in a balanced preparation (Na+ 140 mmol L−1, Cl 118 mmol L−1, K+ 4 mmol L−1, Ca2+ 2.5 mmol L−1, Mg2+ 1 mmol L−1, acetate 24 mmol L−1, malate 5 mmol L−1 [Tetraspan®, B. Braun, Melsungen Germany]) plus a balanced crystalloid solution (Na+ 140 mmol L−1, Cl 127 mmol L−1, K+ 4 mmol L−1, Ca2+ 2.5 mmol L−1, Mg2+ 1 mmol L−1, acetate 24 mmol L−1, malate 5 mmol L−1 [Sterofundin® Iso; B. Braun, Melsungen, Germany]) or a non-balanced volume replacement strategy (n = 25) consisting of 6% HES 130 prepared in saline solution (Na+ 154 mmol L−1, Cl154 mmol L−1) plus an unbalanced crystalloid (saline solution). The fluids were not blinded and administered perioperatively until the second postoperative day when mean arterial pressure (MAP) was <60 mmHg and pulmonary capillary wedge pressure (PCWP) or central venous pressure (CVP, after removal of the pulmonary artery catheter at the second postoperative day) was <10 mmHg (aim, 10–15 mmHg). Crystalloids and HES were administered in a 2:1 ratio. To compensate fluid loss by sweating, gastric tubes, and urine output or as a solvent for drugs (e.g., antibiotics) either the balanced crystalloid or saline solution was given according to the grouping of the patients. During surgery, 250 mL h−1 of either crystalloid were administered routinely in both groups.

Weight-related doses of sufentanil, midazolam, and pancuronium bromide were used for induction and maintenance of anesthesia. CPB was performed using a non-pulsatile pump and a membrane oxygenator. The circuit was primed either with 1,000 mL of the balanced crystalloid plus 500 mL of the balanced 6% HES 130/0.42 or 1,000 mL of saline plus the non-balanced 6% HES 130. Tranexamic acid (2 g as a bolus after induction of anesthesia followed by a continuous infusion of 6 mg kg−1 h−1, 1 g added to the priming) was used in all patients. MAP was kept between 50 and 70 mmHg by adding norepinephrine when necessary. To maintain filling volume of the circuit, HES corresponding to the grouping was added. When hemoglobin (Hb) was <7 g dL−1, packed red blood cells (PRBC) were given. During weaning off bypass, as much pump blood as necessary to keep PCWP between 10 and 14 mmHg was infused. After termination of CPB, the blood from the CPB circuit was salvaged (cell saving system) and retransfused after sternal closure. After surgery, all patients were transferred to the intensive care unit (ICU) and controlled mechanical ventilation was continued. Tracheal extubation was performed when hemodynamics were stable, temperature was >36°C, and the patient breathed spontaneously reaching adequate blood gases.

Postoperatively, balanced or unbalanced HES were given when MAP was <60 mmHg and PCWP (first postoperative day) or CVP (after removal of the pulmonary artery catheter) was <10 mmHg. PRBC were given when hemoglobin was <9 g dL−1, fresh frozen plasma (FFP) was given only when bleeding occurred with activated partial thromboplastin time (aPTT) >60 s inspite of a normal activated clotting time (ACT). Epinephrine or dobutamine were used when mean arterial blood pressure was <60 mmHg and cardiac index was <2.5 L min−1 m−2 in spite of sufficient volume infusion (target for cardiac index: 2.5 to 3.0 L min−1 m2). Norepinephrine was administered when systemic vascular resistance (SVR) was <600 dyn sec cm−5 and MAP was <60 mmHg (target for SVR, 600 to 800 dyn sec cm−5). Sodium bicarbonate was not used within the entire study period.

Measurements

Hemodynamics

Heart rate (HR), MAP, pulmonary artery pressure (PAP), PCWP, CVP, and cardiac output (using a pulmonary artery catheter) were monitored and derived hemodynamic parameters (SVR, CI) were calculated using standard formulae.

Inflammation

From arterial blood samples, interleukin-6 (IL-6) and interleukin 10 (IL-10) plasma levels were measured using commercially available solid-phase two site chemiluminescent enzyme immunometric assays [Diagnostic Product Corporation (DPC), Los Angeles, USA; normal values for IL-6, <5 pg dL−1 and for IL-10, 2–24 pg mL−1].

Endothelial activation/injury

Plasma levels of soluble intercellular adhesion molecule-1 (sICAM-1; normal range, 200–300 ng mL−1) were measured using enzyme-linked immuno-sorbent assays (ELISA; British Bio-technology Products, Abington, UK).

Kidney integrity/function

Serum creatinine concentrations (sCr; by Jaffé reaction), hemoglobin (hgb), blood gases, and electrolytes were measured using standard laboratory techniques. From urine specimen, glutathione transferase-alpha [alpha-GST, by enzyme immunoassay (EIA) with Nephkit™Alpha, Biotrin International, Sinsheim-Reihen, Germany, normal values in healthy volunteers, 3.5 ± 11.1 μg L−1 (mean ± 2SD)] and neutrophil gelatinase-associated lipocalin [NGAL, analyzed by sandwich enzyme-linked-immuno-sorbent-assay (ELISA) using microwells coated with monoclonal antibody against human NGAL (Kit 0236), Antibody Shop, Grusbakken, Denmark; normal values in healthy volunteers 5.3 ng mL−1 (range 0.7–9.8 ng mL−1)] were measured.

Data points

Measurements were done after induction of anesthesia (before volume was administered), at the end of surgery, 5 h after surgery (on the ICU), at the first and second postoperative day (POD) on the ICU. sCr was measured also before discharge from the hospital. A questionnaire was sent to the patient's physicians to get information on the patient's sCr, the need for renal replacement therapy, and mortality approximately 60 days after discharge from the hospital.

Statistics

It was hypothezised that the difference of the base excess (BE) between data points “baseline” and “5 h after end of surgery” is >4 mmol L−1 in the unbalanced compared to the balanced group (13). A sample size calculation based on the BE led to a minimum sample size of n = 2 × 10 [two-sided question using the U test (rank sum test according to Wilcoxon/Mann–Whitney)]. To compensate possible dropouts, a total of 25 patients in each group were included.

All data are expressed as mean and standard deviation (SD) unless otherwise indicated. Categorical variables were assessed using Chi-square test. Normally distributed data (tested by Kolmogorov–Smirnov test) were analyzed using student’s t test. 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. Mann–Whitney U test or the Kruskal–Wallis H test were also used when appropriate. A P value <0.05 was considered significant. A MedCalc 4.30 software package (MedCalc Software, Mariakerke, Belgium) was used for statistical analysis.

Results

The patients did not differ with regard to demographic data, preoperative medication, type of surgery, duration of surgery/anesthesia, time of postoperative ventilation, and duration of stay on the ICU (Table 1). One patient from the balanced group could not be weanend from bypass, two patients died secondary to multi-organ failure (MOF) during the stay on the ICU (>5 days after surgery) (Table 1). Two patients from the unbalanced group died secondary to MOF on the ICU (>5 days after surgery) (Table 1). One patient from the unbalanced group died after discharge from the ICU secondary to acute myocardial infarction (Table 1). No patient died approximately 60 days after discharge from the hospital. Two patients in each group showed acute renal failure (ARF) requiring renal replacement therapy more than 5 days after surgery. No more renal failure was seen on the normal ward and after discharge from the hospital (physicians response rate: 78%) (Table 1).
Table 1

Demographic data and data from the perioperative period

 

Balanced group (n = 25)

Unbalanced group (n = 25)

Demographics

 Age (years) (range)

82 ± 4 (76–85)

81 ± 2 (75–85)

 Weight (kg)

78 ± 14

76 ± 13

 Height (cm)

166 ± 9

168 ± 11

 Gender (f/m)

14/11

13/12

Type of surgery

 CABG

9

11

 AVR

7

6

 MVR

3

4

 AVR + MVR

2

1

 CABG + AVR

4

3

Preoperative cardiac function

 LVEF (%)

45 ± 11

41 ± 14

 LVEDP (mmHg)

24 ± 10

22 ± 13

Chronic preoperative medication

 Beta-blockers

14

15

 ACE inhibitors

12

11

 Nitrates

10

13

 AT1-inhibitors

11

10

 Oral antidiabetics

8

6

 Other antihypertonic drugs

8

9

 Diuretics

10

12

 Statins

8

9

Time of (min)

 Anesthesia (range)

247 ± 54 (190–390)

255 ± 45 (181–351)

 CPB (range)

75 ± 26 (50–155)

77 ± 22 (55–141)

 Cross-clamp (range)

58 ± 15 (44–75)

55 ± 14 (45–70)

Time of

 Postoperative ventilation

3–339

4–444

 ICU stay [median (range)]

14 (12–339)

13 (14–444)

Patients requiring renal replacement therapy

 During ICU stay

2 (>5 days after surgery)

2 (>5 days after surgery)

 During hospital stay

 30 days after surgery

 60 days after surgery

Death

 During surgery

1

 During ICU stay

2 (MOF)

2 (MOF)

 During hospital stay

1

 30 days after discharge

 60 days after discharge

CABG coronary artery bypass grafting, AVR aortic valve replacement, MVR mitral valve replacement, f female, m male, CPB cardiopulmonary bypass, LVEF left ventricular ejection fraction, LVDP left ventricular enddiastolic pressure, first POD first postoperative day, ICU intensive care unit, ACE angiotensin converting enzyme, AT angiotensin, MOF multi-organ-failure, mean ± standard deviation (SD)

A total of 2,750 ± 640 mL of balanced and 2,820 ± 550 mL of unbalanced HES were administered until the second POD (Table 2). Use of PRBC was without group differences, whereas significantly more FFP was used in the unbalanced than in the balanced group (Table 2). Hemodynamics and oxygenation were without group differences at each data point in both groups (Table 3). Need for inotropic support and use or vasopressors did not differ between the groups within the entire study period (Table 4).
Table 2

Fluid input and output (cumulative)

 

Until end of surgery+

5 h after surgery

First POD

second POD

Crystalloids (mL)

 Balanced group

2,270 ± 520

3,240 ± 510

4,850 ± 440

5,200 ± 610

 Unbalanced group

2,090 ± 440

3,080 ± 400

5,000 ± 390

5,150 ± 570

Colloids (mL)

 Balanced group

1,425 ± 220

1,720 ± 450

2,450 ± 560

2,750 ± 640

 Unbalanced group

1,380 ± 240

1,650 ± 390

2,550 ± 430

2,820 ± 550

Total blood loss (mL)

 Balanced group

510 ± 140

930 ± 290

1,210 ± 330

1,380 ± 460

 Unbalanced group

620 ± 120

1,030 ± 220

1,360 ± 290

1,510 ± 410

Urine output (mL)

 Balanced group

705 ± 330

2,870 ± 640

3,920 ± 870

6,870 ± 1,160

 Unbalanced group

890 ± 340

2,620 ± 620

4,110 ± 610

7,020 ± 1,190

Blood/blood products (units)

 PRBC (total number/group)

  Balanced group

49

62

70

72

  Unbalanced group

55

68

72

79

 FFP (total number/group)

  Balanced group

10*

18*

24*

30*

  Unbalanced group

20

30

36

42

+, including priming; HES hydroxyethylstarch, FFP fresh frozen plasma, PRBC packed red blood cells, POD postoperative day, mean ± standard deviation (SD)

* P < 0.05 different between the groups

Table 3

Hemodynamics and oxygenation in the two groups

 

Prior to surgery

End of surgery

5 h after surgery

First POD

Second POD

MAP (mmHg)

 Balanced group

76 ± 14

70 ± 6

70 ± 11

76 ± 8

75 ± 12

 Unbalanced group

73 ± 11

73 ± 14

78 ± 14

79 ± 12

80 ± 12

HR (min−1)

 Balanced group

65 ± 12

89 ± 11

90 ± 13

93 ± 11

87 ± 11

 Unbalanced group

63 ± 9

90 ± 14

88 ± 12

88 ± 12

87 ± 9

PAP (mmHg)

 Balanced group

22 ± 6

25 ± 8

24 ± 8

24 ± 7

 Unbalanced group

23 ± 4

25 ± 6

27 ± 7

24 ± 6

PCWP (mmHg)

 Balanced group

9 ± 5

13 ± 3

14 ± 2

12 ± 5

 Unbalanced group

10 ± 2

14 ± 3

12 ± 3

12 ± 4

CVP (mmHg)

 Balanced group

11 ± 5

12 ± 4

13 ± 3

13 ± 3

12 ± 4

 Unbalanced group

10 ± 2

11 ± 3

12 ± 3

13 ± 4

12 ± 4

CI (L min−1 m−2)

 Balanced group

1.95 ± 0.2

2.36 ± 0.3

2.55 ± 0.3

2.57 ± 0.5

 Unbalanced group

2.05 ± 0.2

2.47 ± 0.3

2.49 ± 0.3

2.69 ± 0.4

paO2/FiO2 (mmHg)

 Balanced group

505 ± 55

458 ± 45

486 ± 66

 Unbalanced group

488 ± 52

492 ± 67

492 ± 53

MAP mean arterial blood pressure, HR heart rate (HR), PAP pulmonary artery pressure, PCWP pulmonary capillary wedge pressure, CVP central venous pressure, PAP mean pulmonary artery pressure, CI cardiac index, POD postoperative day

Table 4

Use of catecholamines

 

End of surgery

5 h after surgery

At the first POD

At the second POD

Norepinephrine (number of patients/range) (μg kg−1 min−1)

 Balanced group

11/1–6

8/2–8

8/2–6

2/1–3

 Unbalanced group

10/2–10

10/2–8

7/3

1/2

Epinephrine (number of patients/range) (μg kg−1 min−1)

 Balanced group

3/1–4

4/4–6

3/1–3

 Unbalanced group

4/1–6

3/2–6

2/3

Dobutamine (number of patients/range) (μg kg−1 min−1)

 Balanced group

16/2–8

14/2–5

12/2–5

4/2–3

 Unbalanced group

16/2–7

13/3–7

11/2–7

3/1–4

POD postoperative day

BE decreased significantly in the unbalanced group (from +1.21 ± 0.3 at baseline to −4.39 ± 1.0 mmol L−1 5 h after surgery) and remained almost unchanged in the balanced group (from 1.16 ± 0.3 to −0.81 ± 0.3 mmol L−1 5 h after surgery) (Fig. 1). Evolution of the BE was significantly different at the end of surgery, 5 h after after surgery on the ICU, and on the first POD.
https://static-content.springer.com/image/art%3A10.1007%2Fs00134-008-1287-1/MediaObjects/134_2008_1287_Fig1_HTML.gif
Fig. 1

Base excess (BE) in the two groups. Mean ± standard deviation (SD); POD postoperative day. +P < 0.05 different to baseline; *P < 0.05 different to the other group Evolution of the BE in the two groups was significantly different

IL-6 plasma levels increased in both groups after CPB showing significantly higher levels in the unbalanced than the balanced group (277 ± 48 vs. 186 ± 42 pg mL−1 at the first POD (Fig. 4). IL-10 plasma level showed a similar course and also showed highest levels in the unbalanced group (Fig. 2).
https://static-content.springer.com/image/art%3A10.1007%2Fs00134-008-1287-1/MediaObjects/134_2008_1287_Fig2_HTML.gif
Fig. 2

Plasma levels of interleukin-6 (IL-6) and interleukin-10 (IL-10) in the two groups (normal value for IL-6 is <5 pg dL−1 and for IL-10 2–24 pg mL−1). Mean ± standard deviation (SD), POD postoperative day. +P < 0.05 different to baseline; *P < 0.05 different to the other group. Evolution of the interleukins in the two groups was significantly different

At the first and second POD, ICAM-1 plasma levels increased significantly in both groups (Fig. 3). sICAM was significantly more elevated in the unbalanced than in the balanced group (380 ± 40  vs. 299 ± 46 ng mL−1).
https://static-content.springer.com/image/art%3A10.1007%2Fs00134-008-1287-1/MediaObjects/134_2008_1287_Fig3_HTML.gif
Fig. 3

Changes in plasma levels of soluble intercellular adhesion molecule-1 (sICAM-1; normal range, 200–300 ng mL−1). Mean ± standard deviation (SD), POD postoperative day. +P < 0.05 different to baseline; *P < 0.05 different to the other group. Evolution of the adhesion molecules in the two groups was significantly different

At baseline, mean sCr was evelated beyond normal without showing significant differences between the both groups (Fig. 4). At the first and second POD, sCr slightly increased in both groups without showing significant differences between the two groups. Approximately 60 days after discharge form the hospital, sCr had reached baseline in both groups (Fig. 4).
https://static-content.springer.com/image/art%3A10.1007%2Fs00134-008-1287-1/MediaObjects/134_2008_1287_Fig4_HTML.gif
Fig. 4

Changes in serum creatinine (sCr) in the two groups. Mean ± standard deviation (SD); POD postoperative day. +P < 0.05 different to baseline; *P < 0.05 different to the other group. Evolution of the sCr in the two groups was significantly different

Alpha-GST concentrations were slightly higher than normal at baseline and increased until the first and second POD in both groups with the significantly higher increase in the unbalanced group (balanced: from 4.8 ± 2.2 to 10.2 ± 3.0 μg L−1; unbalanced: from 4.3 ± 2.1 to 18.1 ± 4.1 μg L−1) (Fig. 5). Postoperatively, NGAL urine level increased in both groups showing significantly higher levels in the unbalanced than in the balanced group at the first POD (17.9 ± 4.0 vs. 28.9 ± 6.6 ng mL−1) (Fig. 5).
https://static-content.springer.com/image/art%3A10.1007%2Fs00134-008-1287-1/MediaObjects/134_2008_1287_Fig5_HTML.gif
Fig. 5

Changes in glutathione transferase-alpha [alpha-GST, normal value: 3.5 ± 11.1 μg L−1 (mean ± 2SD)] and neutrophil gelatinase-associated lipocalin (NGAL) [normal values in healthy volunteers 5.3 ng mL−1 (range 0.7–9.8)] in the two groups. Mean ± standard deviation (SD); POD postoperative day. +P < 0.05 different to baseline; *P < 0.05 different to the other group. Evolution of the kidney-specific proteins in the two groups was significantly different

Discussion

Use of HES in cardiac surgery patients is much discussed issue [5, 6]. The Food and Drug Administration (FDA) approved a major change in the labeling of 6% Hetastarch in saline (Mw > 450 kD, MS > 0.7) applying specifically to cardiopulmonary bypass surgeries and not recommending Hetastarch in saline in this situation [14]. It is important to distinguish the different physico-chemical characteristics of the different HES preparations, because the extent and duration of plasma volume expansion as well as unwanted side effects widely differ [12, 15, 16]. Dissolving modern HES preparation in a balanced, plasma-adapted solution instead of in saline may be a further step to improve our volume replacement concepts [13]. We assessed the value of a balanced volume replacement strategy in patients aged >75 years because increased inflammatory response, more pronounced cellular defects, and increased risk to suffer from organ dysfunction have been reported with increasing age [17, 18].

One finding of our study was that a total balanced volume replacement strategy including a balanced HES preparation in our elderly cardiac surgery patients reduced BE significantly less than a coventional, non-balanced fluid replacement strategy. Animal studies have also shown that by choosing a balanced HES, acid-base status was significantly less altered than by HES dissolved in saline [19]. In a prospective, randomized, double-blind study in cardiac surgery patients, a balanced HES 130/0.4 preparation with a slightly different solvent than that HES preparation of our study, was compared to an unbalanced HES 130/0.4 [20]. Approximately 2,500 mL of either HES preparation have been given along with RL in both groups. While hemodynamics did not differ between the two groups, BE at the end of surgery was significantly less negative in the balanced than in the unbalanced HES group.

One of the most serious complications following cardiac surgery is the development of acute renal failure (ARF) [21]. The influence of HES on kidney function remains controversial [22, 23]. Histological studies demonstrated reversible swelling of tubular cells of the kidneys (‘osmotic nephrosis like-lesions’) [24]. The importance of this finding remains unclear as other substances also may induce this effects. In a retrospective study including 95 coronary artery bypass patients, use of a high-Mw HES with a high MS solution (HES 670/0.75; Hextend®) resulted in a slight reduction in glomerular filtration rate (GFR) indicating impaired renal function with this HES preparation [25]. In septic patients, administration of large amounts of a hyperoncotic HES (10%) with a medium Mw (200 kD) and a medium MS (0.5) dissolved in saline was associated with a significant higher incidence of ARF requiring hemodialysis than use of RL [26]. When assessing kidney function with regard to different volume replacement strategies, the composition of the solvent has to be taken into consideration as well. The role of chloride concentration in modulating vasoconstrictor responses to angiotensin II, arginine vasopressin, and phenylephrine was investigated in the rat isolated kidney [27]. The ability of chloride to modify renal responsiveness to vasoconstrictor agents may contribute to the increase in renal vascular resistance and decrease GFR which occurs during infusion of hyperchloremic solutions. In denervated kidneys, it has been shown that hyperchloremia produced a progressive renal vasoconstriction and fall in GFR that is independent of the renal nerves [28]. In humans, plasma renin activity was suppressed by sodium chloride but not by sodium bicarbonate infusion [29]. In the present study, sCr levels were similar in both groups. As sCr is influenced by several factors (e.g., muscle mass and age), we measured urinary concentrations of kidney-specific proteins such as alpha-GST and NGAL to assess the influence of our volume replacement strategies on tubular integrity. Urine alpha-GST is considered as a marker of proximal tubulus injury [30]. Urinary alpha-GST concentrations increased 1–2 days before sCr did and alpha-GST is considered to be useful to detect early renal injury [31]. NGAL is a member of the lipocalin superfamily, it is a 25-kDa protein covalently bound to gelatinase from human neutrophils that is usually barely detectable in human tissues including the kidney [30, 31]. NGAL is upregulated by ischemia in several segments of the nephron, predominantly in proximal tubules [30]. It precedes any increase in sCr 1–3 days and is subsequently suggested to be an early marker of acute renal injury [30, 31]. Measuring kidney-specific proteins, subclinical alterations in renal function have been reported in the absence of overt changes in sCr [30, 31]. We found lesser changes of both kidney-specific proteins in the balanced than the unbalanced group indicating a favorable influence balanced fluids on kidney integrity. The patients follow-up approximately 60 days after surgery revealed no differences in sCr or need of renal replacement therapy between the two groups.

Another result from our study was that the inflammatory response after cardiac surgery using CPB (e.g., increase in pro-inflammatory IL-6 and anti-inflammatory IL-10 plasma levels) was less pronounced in the balanced than the unbalanced volume replacement group. In a septic animal study, Kellum et al. [32] reported that by lowering the BE the inflammatory response was increased. Endothelial cell activation commonly occurs in cardiac surgery patients undergoing CPB [3]. Expression of endothelial cell adhesion molecules is believed to play a key role in the inflammatory process in this patients. In accordance with the less pronounced increase of IL-6 and I-10 plasma levels in the patients in whom the balanced volume replacement concept has been used, sICAM-1 plasma levels also increased less indicating less endothelial damage. It cannot be decided at present whether the composition of the solvent or the BE is responsible for the reduced inflammatory response and less endothelial activation in the balanced group.

Interestingly, the balanced group needed less FFP within the study period than the non-balanced group. The reasons for this can only be speculated because no intensive monitoring of coagulation was performed (e.g., thrombelastography®). There is growing evidence that balanced solutions showed improved coagulation status possibly resulting in less use of blood/blood products [34].

One objection to our study may be that overall mortality or morbidity was not the primary endpoints. It has never been proven that by the choice of a plasma substitute survival would be improved. Even the SAFE-study including approximately 7,000 intensive care patients did not document a difference in survival between two different volume replacement strategies [33]. To assess the effects of different volume replacement strategies on organ dysfunction (e.g., kidney failure requiring renal replacement therapy), several hundreds of patients would have been necessary. Thus, we used surrogate markers such as inflammatory response, alterations of endothelial integrity or influence on concentration of kidney-specific proteins to assess the benefit of a balanced volume replacement strategy. Changes of all of measured markers were only moderate and sometimes only transient. The amount of administered fluids were also only moderate and infusion was limited to a time period of approximately 48 h. However, others also documented the value of reducing the chloride load in cardiac surgery patients. Use of a new solution containing half-molar sodium-lactate (chloride free) 12 h after surgery, resulted in a significantly higher cardiac index, higher urine output, no change in pH, and in a very negative postoperative body fluid balance compared to RL [35].

It is summarized that a total balanced volume replacement strategy including a balanced HES preparation in elderly cardiac surgery patients showed moderate beneficial effects on inflammation, endothelial activation, and short-term renal integrity than a non-balanced volume strategy. Whether larger, repetitive doses of a total a balanced volume replacement strategy offers advantages with regard to patient’s morbidity and safety has to be proven in larger controlled trials.

Acknowledgments

This study was supported only by a hospital grant.

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© Springer-Verlag 2008