BJA Advance Access originally published online on February 27, 2008
British Journal of Anaesthesia 2008 100(4):457-464; doi:10.1093/bja/aen016
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Comparison of the effects of gelatin and a modern hydroxyethyl starch solution on renal function and inflammatory response in elderly cardiac surgery patients
Department of Anaesthesiology and Intensive Care Medicine, Klinikum der Stadt Ludwigshafen, Bremserstr. 79, D-67063 Ludwigshafen, Germany
* Corresponding author. E-mail: boldtj{at}gmx.net/ jboldt{at}gmx.net
Accepted for publication January 18, 2008.
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Abstract |
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Background: The effects of hydroxyethylstarch (HES) 130/0.4 6% and gelatin 4% on inflammation, endothelial integrity, and renal function after cardiac surgery were compared.
Methods: Sixty patients aged >80 yr undergoing cardiac surgery were randomized to receive gelatin (n=30) or HES 130/0.4 (n=30). The colloid was used in the priming of the cardiopulmonary bypass circuit (500 ml) and for volume replacement until the second postoperative day (POD). Serum creatinine, creatinine clearance, IL-6, IL-10, intercellular adhesion molecule-1 (sICAM-1), urinary glutathione transferase-
, and neutrophil gelatinase-associated lipocalin (NGAL) were measured perioperatively. Serum creatinine was also reported 
60 days after discharge.
Results: The mean(SD) volume of gelatin infused was 4180(440) ml, which was greater than the volume of HES infused 2910(330) ml (P=0.002). The mean(SD) volume of serum creatinine on the first POD was 151(24) µmol litre–1 in the gelatin group and 126(13) µmol litre–1 in the HES group (P=0.004). Values for the second POD were 161(0.26) and 133(16) µmol litre–1, respectively (P=0.004). Creatinine clearance was lower in the gelatin group on the first POD [37(7) vs 46(8) ml min–1 1.73 m2 (P=0.004)] and the second POD [32(8) vs 45(10) ml min–1 1.73 m2 (P=0.002)]. Kidney function 60 days after discharge did not differ between the groups. IL-6, IL-10, and sICAM-1 were significantly lower in the HES group than in the gelatin group on the first and second PODs. Urinary -GST increased in both groups to a comparable extent. Urinary NGAL concentrations were higher in the gelatin than in the HES patients 5 h after surgery and on the first and second PODs.
Conclusions: In cardiac surgery patients aged >80 years, volume therapy with HES 130/0.4 6% was associated with less marked changes in kidney function and a less marked endothelial inflammatory response than gelatin 4%.
Keywords: cardiovascular system, effects; complications, renal; immune response; kidney, failure; surgery, cardiovascular
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Introduction |
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Cardiac surgery is associated with the risk of volume deficits resulting in impaired systemic haemodynamics and tissue perfusion. Aside from major blood loss, preoperative medication, anaesthetics, vasoactive substances, and the extent of the surgical trauma may all alter the patient’s intravascular volume status. Patients undergoing cardiac surgery using cardiopulmonary bypass (CPB) often show a systemic inflammatory response resulting in a panendothelial injury with development of increased endothelial permeability, loss of proteins, and interstitial oedema.
Appropriate intravascular volume replacement is a fundamental component of managing these patients, because failure to treat hypovolaemia adequately may lead to organ dysfunction.1 Controversy still surrounds the ideal volume replacement regimen in cardiac surgery patients. This debate does not only include a crystalloid/colloid controvery, but also must be enlarged to a colloid/colloid debate. The physico-chemical properties of the different plasma substitutes differ markedly. When discussing different volume replacement strategies in cardiac surgery patients, not only do their influence on systemic haemodynamics have to be taken into account, but also adverse effects, inflammatory response, effects on endothelial integrity, and the influence on organ function (e.g. kidneys) are of equal importance.
Gelatins are polydispersed polypeptides produced by degradation of bovine collagen. Three types of modified gelatin products are now available: cross-linked or oxypolygelatins (e.g. Gelofundiol®), urea-crosslinked (e.g. Haemacel®), and succinylated or modified fluid gelatins (e.g. Gelofusine®). Molecular weight (MW) range from 5000 to 50 000 Da with a weight-average MW of 30–35 000 Da. The various gelatin solutions have comparable volume-expanding power, and all are said to be safe with regard to coagulation and organ function (including kidney function).2
Hydroxyethylstarch (HES) is a widely used plasma substitute for correcting hypovolaemia also in cardiac surgery patients. HES preparations vary with regard to concentration, mean MW, molar substitution, C2/C2 ratio, and the solvent. HES solutions with a low MW and a low molar substitution are said to be safe with regard to coagulation, and increased bleeding tendency no longer appears to be a problem with these HES preparations even when higher doses are given.3 Correcting hypovolaemia with HES has been suggested to be associated with an increased risk of acute renal failure, and interest has recently focused on the influence of HES solutions on renal function.4
The present study was designed to compare the two volume replacement strategies using a gelatin and a modern HES preparation with a low MW and a low molar substitution, on inflammatory responses, endothelial injury, and kidney function in elderly patients undergoing cardiac surgery.
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Patients
The study was approved by the Institutional Review Board (IRB) and informed consent was obtained from all patients. Sixty consecutive patients aged >80 yr undergoing elective cardiac surgery were included. Exclusion criteria were oliguric or anuric kidney dysfunction requiring dialysis, serum creatinine >180 µmol litre–1, myocardial infarction within the previous 3 weeks, liver insufficiency (aspartate aminotransferase >40 U litre–1, alanine aminotransferase >40 U litre–1), insulin-dependent diabetes mellitus, and chronic use of corticosteroids or non-steriodal anti-inflammatory substances.
Patients were randomized to volume replacement with either gelatin or HES 130/0.4 6%. Randomization was done with sealed envelopes and there were 30 patients in each group. Patients received either succinylated gelatin 4% (MW, 30 000 kDa; Gelafundin®; B. Braun, Melsungen, Germany) used for volume replacement (including 500 ml added to the priming of the CPB circuit) or HES 130/0.4 6% solved in saline solution (Voluven®; Fresenius-Kabi, Bad Homburg, Germany) was administered (including 500 ml added to priming). Volume was given perioperatively and during the first 24 h after surgery to keep pulmonary capillary wedge pressure (PCWP) between 12 and 14 mm Hg. Pulmonary artery catheters are used routinely in our elderly patients and are removed on the morning of the second postoperative day (POD), volume was then given to keep central venous pressure (CVP) between 12 and 14 mm Hg. Ringer’s lactate (RL) was given in both groups throughout the entire study period to compensate fluid loss from sweating, nasogastric tubes, and urine output. RL was also used as a solvent for drugs (e.g. antibiotics). During surgery, 250 ml h–1 of RL was administered routinely in both groups. There was no dose limitation per day for each colloid.
Weight-related doses of sufentanil, midazolam, and pancuronium bromide were used for induction and maintenance of anaesthesia. A non-pulsatile pump and a membrane oxygenator were used for CPB. The circuit was primed with 1000 ml of Ringer’s solution plus 500 ml of either gelatin 4% or HES 130/0.4 6%. Tranexamic acid (2 g as a bolus after induction of anaesthesia followed by a continuous infusion of 6 mg kg–1 h–1, 1 g added to the priming) was used in all patients. Mild hypothermia (bladder temperature, >33°C) and a flow rate of 2.4 litre min–1 m–2 were used. Mean arterial blood pressure (MAP) was kept between 50 and 70 mm Hg by adding norepinephrine when necessary. To maintain filling volume of the circuit, gelatin 4% or HES 130/0.4 6% was added as necessary. When the haemoglobin concentration was >7 g dl–1, packed red blood cells (PRBCs) were given. During weaning off bypass, as much pump blood as necessary to keep PCWP between 10 and 14 mm Hg was infused. After weaning off CPB, blood from the CPB circuit was salvaged by a cell saving system and transfused after sternal closure. Shed mediastinal blood was not retransfused in the postoperative period. After surgery, all patients were transferred to the intensive care unit (ICU) and controlled mechanical ventilation was continued until the patient was haemodynamically stable for at least 30 min, core temperature was >36°C, and the patient was breathing spontaneously with adequate blood gases.
In the postoperative period, volume (gelatin 4% or HES 130/0.4 6%) was given to keep PCWP or CVP between 10 and 14 mm Hg. PRBCs were given when haemoglobin was <9 g dl–1, fresh frozen plasma (FFP) was given only when bleeding occurred with normal activated partial thromboplastin time (aPTT) and normal activated clotting time. Epinephrine or dobutamine were given when MAP was <60 mm Hg and cardiac index was <2.5 litre min–1 m–2 in spite of sufficient volume infusion (target for cardiac index: 2.5–3.0 litre min–1 m–2). Norepinephrine was administered when systemic vascular resistance (SVR) was <600 dyn s–1 cm–5 and MAP was <60 mm Hg (target for SVR: 600–800 dyn s–1 cm–5). The patients’ perioperative management was carried out by staff who were blinded to the purpose of the study.
Recorded variables
Haemodynamics
Heart rate, MAP, pulmonary artery pressure, PCWP, CVP, and cardiac output (CO) were recorded.
Markers of kidney function
Serum creatinine concentrations (sCrs) were estimated by the Jaffé reaction (normal values for our laboratory: 62–85 µmol litre–1), and haemoglobin, blood gases, and electrolytes were measured using standard laboratory techniques. To assess creatinine clearance (CrCl) we used the Cockcroft–Gault formula (if female): CrCl = {[(140–age)xweight]/(0.814xsCr)}x0.85.5 Urinary glutathione transferase- (-GST) was measured by enzyme immunoassay with NephkitTM-Alpha (Biotrin International, Sinsheim-Reihen, Germany). Normal -GST values in healthy volunteers are 3.5(SD 11.1) µg litre–1 (mean±2SD). Urinary neutrophil gelatinase-associated lipocalin (NGAL) was measured with a sandwich enzyme-linked immonosorbent assay (ELISA) using microwells coated with monoclonal antibody against human NGAL (Kit 0236, Antibody Shop, Grusbakken, Denmark). Normal NGAL values in healthy volunteers given by the manufacturer of the assay are 5.3 ng ml–1 [range 0.7–9.8 ng ml–1].
Markers of inflammation
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 are <5 pg dl–1 and 2–24 pg ml–1 for IL-10.
Endothelial activation/injury
Plasma concentrations of soluble intercellular adhesion molecule-1 (sICAM-1; normal range: 200–300 ng ml–1) were measured from arterial blood samples using ELISA (British Bio-technology Products, Abington, UK).
Results from laboratory measurements represent the means from duplicate measurements and were performed by laboratory staff who were blinded to the grouping of the patients.
Data collection points
Haemodynamic measurements were made and samples taken for laboratory analysis after induction of anaesthesia (before volume was administered), at the end of surgery, 5 h after surgery (on the ICU), and at the first and second PODs on the ICU. Serum creatinine, IL-6, IL-10, and ICAM-1 plasma concentrations were also measured at discharge from hospital. A questionnaire was sent to the patients’ physicians 60 days after discharge from the hospital, requesting details of the patients’ sCr, renal failure requiring renal replacement therapy (RRT), and mortality after discharge from the hospital.
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The primary outcome variable used for the power calculation for this study was the estimated CrCl at 24 h after surgery. Based on the assumption of an SD for CrCl of 20 ml min–1 and a mean difference of 20 ml min–1 considered as a clinically significant difference between groups and taking power 0.8 and alpha error 0.05, a minimum sample size of 22 patients was calculated for each group.6 A total of 30 patients in each group were included to compensate possible drop outs. Data are expressed as mean(SD) unless otherwise indicated. The
2 test was used to analyse categorical data. Normally distributed data (tested by Kolmogorov–Smirnov test) were analysed using Student’s t-test. Two-way analysis of variance (ANOVA) with repeated measures and post hoc Scheffé’s tests were used to determine the effects of group, time, and group–time interaction. When multiple comparisons were made on serially measured data (e.g. for haemodynamics, biochemical data), the Bonferroni correction was used. The Mann–Whitney U-test or the Kruskal–Wallis H-test was also used when appropriate. MedCalc 4.30 (MedCalc Software, Mariakerke, Belgium) was used for statistical analyses. To account for the five and seven time points, Bonferroni-corrected values of P<0.01 and <0.007 were used as the criteria for statistical significance. |
Results |
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Biometric data and type of surgery were similar between the two groups (Table 1). There were no important differences in preoperative medication between the groups that could have biased the results of the study. Times of anaesthesia, surgery, and cross-clamping were also similar in both groups (Table 1). Two patients died during ICU stay (one patient in each group), both died from multiple organ failure more than 2 days after surgery. There were no drop-outs during the study period. The response rate from our postoperative questionnaire was 82%. We received information on patients’ sCr 55–65 days after discharge from the hospital. One patient of each group needed RRT during the stay on the ICU (starting at the third and fourth POD), one patient of the gelatin group needed RRT after discharge from the hospital—patients requiring RRT were not included in the data analysis after hospital discharge.
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The mean(SD) volume of gelatin 4% given in the study period was 4180(440) ml and was significantly more than the amount of HES 130/0.4 given in the same period which was 2910(330) ml (Table 2) (P=0.002). The use of crystalloids, urine output, PRBCs, and FFP did not differ between the two groups (Table 2). Haemodynamic variables were comparable differences between the groups as was the need for inotropes, vasopressors, and diuretics (Table 3).
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Mean serum creatinine and CrCl were abnormal at baseline prior to volume therapy (Fig. 1). In 11 patients of the gelatin group and 12 patients of the HES group, sCr was between 133 and 156 µmol litre–1 before the start of the study. Serum creatinine was significantly higher in the gelatin than in the HES-treated patients on the first and second PODs. On the first POD, mean(SD) values were 151(24) µmol litre–1 in the gelatine group and 126(13) µmol litre–1 in the HES group (P=0.004). On the second POD, sCr values were 161(0.26) and 133(16) µmol litre–1, respectively, in the two groups (P=0.004). At discharge from the hospital and
60 days after discharge, there was no longer a difference between the two groups. CrCl was significantly lower in the gelatin group compared with the HES group on the first and second PODs. Values for the gelatin and HES groups were 37(7) and 46(8) ml min–1 1.73 m2 (P=0.004), respectively, on the first POD and 32(8) and 45(10) ml min–1 1.73 m2 (P=0.002), respectively, on the second POD (Fig. 1).
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The urinary concentration of
-GST was within normal range at baseline in both groups (Fig. 2). It was similarly increased in both groups 5 h after surgery (P=0.004) and on the first POD (P=0.004).
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NGAL urine concentrations were slightly elevated in both groups at baseline (Fig. 2). In the gelatin group, NGAL increased from 16.9(2.5) ng ml–1 at baseline to 61.1(19) ng ml–1 on the first POD (P=0.0002). In the HES group, it increased from 13.2(2.2) ng ml–1 at baseline to 28.4(10) ng ml–1 on the first POD (P=0.002). Urinary NGAL concentrations were higher in the gelatin than in the HES patients 5 h after surgery, the first, and second POD (P<0.01).
In the gelatin group, IL-6 increased from 4.8(2.1) pg dl–1 at baseline to 250(51) pg dl–1 5 h after surgery (P=0.0002). In the HES-treated patients, IL-6 increased from 4.3 (1.9) pg dl–1 at baseline to 173(39) pg dl–1 5 h after surgery (P=0.0002) (Fig. 3). Both IL-6 and IL-10 levels were significantly higher on the second POD in the gelatin group than in the HES group (both P=0.004). There was no longer any difference between the two groups on the day of discharge from the hospital.
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Starting from normal plasma levels at baseline, postoperative sICAM-1 was significantly higher in the gelatin group than in the HES group on the first POD (P=0.002) and on the second POD day (P=0.002) (Fig. 4). At discharge from the hospital, sICAM-1 plasma concentrations have reached baseline data in both groups.
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Discussion |
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The main result from the present study was that volume therapy in elderly cardiac surgery patients using HES 130/0.4 6% showed more beneficial effects on inflammatory response, endothelial integrity, and short-term kidney function than gelatin 4%.
We have studied patients aged >80 years, because an increased risk postoperative acute renal failure has been reported in this population.7 Moreover, there are cellular defects and dysfunctions in the elderly that may result in an altered immune response and an increased inflammatory response.8 In patients aged >70 years undergoing unselected cardiac surgery procedures, the 30 day postoperative mortality rate was 6.8% compared with 2.5% in younger patients.9
There is increasing evidence that the choice of the ideal plasma substitute for treating hypovolaemia goes beyond simple haemodynamic effects.1,10 Perioperative fluid optimization represents an approach to limit the incidence and severity of systemic inflammation and organ dysfunction after major surgery.1 In contrast to HES, there are only sporadic reports exploring the effects of gelatins on inflammation and endothelial injury.10 In the present study, gelatin 4% showed significantly less beneficial effects on inflammatory response than HES 130/0.4. Postoperative sICAM-1 plasma concentration indicating endothelial injury was also significantly lower in our HES-treated group than in our gelatin-treated group. Improved endothelial function and less impaired endothelial integrity with HES 130/0.4 6% have also been shown by others.11 HES solutions with a narrow range of MWs were reported to be effective in reducing capillary oedema in experimental12 and clinical models of increased permeability.13 In cat skeletal muscles, it was demonstrated that capillary fluid permeability was decreased by albumin and dextran, unchanged by HES, but increased by gelatin.14 Allison and colleagues15 studied the influence of volume resuscitation with gelatin or HES 200/0.5 6% on renal albumin excretion rate in trauma patients. They found a significantly higher excretion in the gelatin group and concluded that this represented decreased capillary permeability in the HES-treated group. Significantly improved microcirculation and tissue oxygenation secondary to HES infusion16 are possible explanations for these effects. Another mechanism by which HES may have beneficially affected endothelial integrity is a direct effect of HES on inflammation (e.g. via a reduction in NF-
B release).17 Modulation of inflammatory response reflected by a reduction of TNF-, IL-1β, and MIP-2 was reported with HES 130/0.4 6%, whereas no anti-inflammatory properties were demonstrated with gelatin.18 HES also markedly decreased ICAM-1 mRNA, whereas gelatin did not show inhibitory effects on ICAM-1.18
Renal dysfunction is one of the most serious organ complications after cardiac surgery. There is continuing concern about the influence of HES on kidney function, whereas gelatin is supposed to have no adverse effects on kidney function.19 After infusion of HES, reversible swelling of tubular cells of the kidneys (‘osmotic nephrosis like-lesion’) has been shown.20 A retrospective study including 95 coronary artery bypass patients found impaired renal function seen by a slight reduction in estimated GFR after infusion of high-MW HES with a high molar substitution (HES 670/0.75; Hextend®).21
When insensitive markers of kidney dysfunction are measured, possible negative effects of plasma substitutes may be masked. We did not only measure sCr and calculated CrCl, but also measured urinary concentrations of kidney-specific proteins -GST and NGAL to assess the influence of our volume replacement strategies on tubular integrity. Urine -GST is considered as a marker of proximal tubular injury.22 As -GST concentration increased 1–2 days before sCr did, -GST appears to be useful in the detection of early renal injury.22 NGAL is a member of the lipocalin superfamily. It is a 25 kDa protein covalently bound to gelatinase from human neutrophils23 that are usually barely detectable in human tissues including the kidney. NGAL is upregulated by ischaemia, predominantly in proximal tubules.23 It precedes any increase in sCr by 1–3 days and thus appears to be an early biomarker of acute renal injury. By measuring kidney-specific proteins, subclinical alterations in renal function have been reported in the absence of overt changes in serum sCr and CrCl.22 SCr and CrCl at the first and second POD were significantly less changed in the HES 130/0.4 6% than in the gelatin-treated group. The patients’ follow-up after hospital discharge revealed no differences in sCr and CrCl or need of RRT in the two volume replacement groups. Postoperative urinary concentrations of NGAL were higher in the gelatin than in the HES 130/0.4 6%-treated patients, suggesting more damage of distal tubule in the gelatin-treated patients. The explanations for this difference may include improved microcirculation and tissue oxygenation and less inflammatory response in patients who received HES 130/0.4 6%. Others have reported that HES 130/0.4 6%-based volume therapy is superior to gelatin administration with regard to kidney function. In patients undergoing abdominal aortic aneurysm surgery, administering HES 130/0.4 6% maintained glomerular and tubular function over the following five PODs better than gelatin 4%.24
We needed significantly more gelatin than HES 130/0.4 6% to fulfil our criteria for volume therapy, indicating that HES 130/0.4 6% may display a better intravascular volume effect than gelatin 4%.25 Others also found a better volume effect with HES 130/0.4 6%: in an animal study in sheep, HES 130/0.4 6% resulted in higher CO, oxygen delivery, and lower blood lactate levels than similar amounts of gelatin 3%.26 In contrast, in animal experiments in rats, Dubniks and collegues27 found similar volume-expending effects of gelatin 4% and HES 130/0.4 6%.
One objection to the present study is that only surrogate markers for identifying patient’s volume status have been used. Filling pressures (PCWP and CVP) do not definitely confirm or exclude hypovolaemia. Although they have only a limited relevance for guiding volume therapy, they are used routinely in several centres for this purpose. As both groups showed similar filling pressures, major differences in volume status appear unlikely.
This study was not designed to find differences of the two volume replacement strategies on overall mortality. It has been doubted whether we can make a meaningful statement on comparative mortality with regard to different plasma substitutes.28 Mortality might not represent the optimal endpoint for studying the effects of different volume replacement strategies—inflammatory response, altered endothelial integrity—organ dysfunction might represent more sensitive means of determining a beneficial effect.29 It is summarized that in our elderly cardiac surgery patients aged >80 years, a gelatin-based volume replacement strategy showed higher inflammatory response, more endothelial injury, and more short-term impaired kidney integrity than HES 130/0.4 6%. There was no difference in renal function between the two groups 60 days after discharge from hospital.
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This study was not supported by a pharmaceutical company, but by a hospital grant (ANA 05104G).
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18 Feng X, Yan W, Wang Z, et al. Hydroxyethyl starch, but not modified fluid gelatin, affects inflammatory response in a rat model of polymicrobial sepsis with capillary leakage. Anesth Analg (2007) 104:624–30.
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