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CARDIOVASCULAR ANESTHESIOLOGY

Is Albumin Administration in Hypoalbuminemic Elderly Cardiac Surgery Patients of Benefit with Regard to Inflammation, Endothelial Activation, and Long-Term Kidney Function?

From the Department of Anesthesiology and Intensive Care Medicine, Klinikum der Stadt Ludwigshafen, Ludwigshafen, Germany.

Address correspondence and reprint requests to Joachim Boldt, MD, Department of Anesthesiology and Intensive Care Medicine, Klinikum der Stadt Ludwigshafen, Bremserstr. 7, D-67063 Ludwigshafen, Germany. Address e-mail to BoldtJ{at}gmx.net.

Abstract

BACKGROUND: Because patients with low albumin levels may benefit from human albumin (HA) administration, we studied correction of hypovolemia with HA in hypoalbuminic elderly cardiac surgery patients.

METHODS: In a prospective, randomized study, 50 patients aged >80 yr undergoing cardiac surgery using cardiopulmonary bypass with a preoperative serum albumin concentration of <3.5 mg/dL, received either 5% HA (n = 25) or hydroxyethyl starch (6% HES 130/0.4) (n = 25). Volume was added to the priming (500 mL) and given until the morning of the second postoperative day to keep pulmonary capillary wedge pressure or central venous pressure between 12 and 14 mm Hg.

RESULTS: Inflammatory response (interleukins-6, -10), endothelial activation (intercellular adhesion molecule-1), and kidney function (including glutathione transferase- and neutrophil gelatinase-associated lipocalin) were measured after induction of anesthesia, 5 h after surgery, and the first and second postoperative day. A follow-up, approximately 60 days after discharge from the hospital, was done.

Two thousand nine hundred eighty ± 430 mL of HA and 3060 ± 680 mL of HES 130/0.4 were given. Serum albumin concentration was significantly increased by HA (to 4.5 ± 0.3 mg/dL). Serum creatinine, glomerular filtration rate, and urinary levels of -glutathione transferase and neutrophil gelatinase-associated lipocalin were not different in the HA-compared to the HES-treated patients. The inflammatory response was similar in both groups, whereas endothelial activation was less in the HES group. None of the patients developed renal failure requiring renal replacement therapy.

CONCLUSION: Use of HA in hypoalbuminemic cardiac surgery patients aged >80 yr was without benefit with regard to inflammatory response, endothelial activation, and renal function compared to 6% HES 130/0.4.

In cardiac surgery, the patient's circulating blood volume may be altered by bleeding, cooling/rewarming, anesthesia, and use of vasoactive substances. When cardiopulmonary bypass (CPB) is used, mediators are released and an inflammatory process is generated leading to altered endothelial integrity. This increased capillary permeability causes fluids to leak from the intravascular to the interstitial compartment resulting in hypovolemia.1 Hypovolemia is associated with the risk of organ perfusion deficits subsequently leading to organ dysfunction, e.g., acute renal failure.2

The value of albumin for correcting hypovolemia is still a matter of discussion.3 A reduced serum albumin level is also generally accepted to be a marker of poor outcome in cardiac surgery patients.4 In a meta-analysis of cohort studies and controlled trials in acute illness, each 1 mg/dL decline in serum albumin concentration was shown to increase the odds of mortality by 137%, morbidity by 89%, prolonged intensive care unit (ICU) and hospital stay by 28% and 71%, and increase resource utilization by 66%.5 Albumin may have additional effects beyond correcting hypovolemia, e.g., reducing an inflammatory response in hemorrhagic shock and free radical scavenging by which membrane permeability is beneficially modified.6,7

Although use of albumin was never reported to be of benefit for patients' outcome (e.g., mortality or morbidity), albumin is recommended for correcting hypovolemia instead of using less expensive nonprotein alternatives.3,8 The Saline versus Albumin Fluid Evaluation (SAFE) study9 was done in ICU patients and evaluated safety only and thus is not representative for assessing the value of albumin in cardiac surgery.

Hydroxyethyl starch (HES) is a widely used inexpensive alternative to albumin for correcting hypovolemia. HES preparations are available with varying concentrations, mean molecular weights (Mw), molar substitutions (MS), substitution ratios, and solvents. Altered coagulation10 and renal dysfunction11 are the most often reported concerns from the use of HES in cardiac surgery patients. In the United States, the Food and Drug Administration approved a major change in the labeling of the first generation HES with a high Mw and high MS (6% Hetastarch in saline), applying specifically to CPB surgeries and not recommending Hetastarch in this situation.12

The present study was designed to compare the benefits of human albumin (HA) and low Mw HES administration for correcting hypovolemia in elderly patients undergoing cardiac surgery with a low preoperative serum albumin level. The hypothesis was that an albumin-based intravascular volume replacement regimen reduces inflammatory cytokine release (interleukin 6 [IL-6]). Secondary end points were the influence of albumin on endothelial injury and kidney function compared to 6% HES 130/0.4.

METHODS

Patients
After approval of the IRB and patients' informed consent, 50 consecutive patients aged >80 yr undergoing elective cardiac surgery and showing an albumin serum level of <3.5 mg/dL (normal value in our laboratory: 3.5–5.0 mg/dL) the day before surgery were included. Patients with oliguric/anuric kidney dysfunction requiring dialysis, myocardial infarction within the previous 3 wk, liver insufficiency (aspartate amino-transferase >40 U/L, alanine aminotransferase >40 U/L), insulin-dependent diabetes mellitus, and chronic use of corticosteroids or nonsteroidal antiinflammatory substances were not included.

The patients were prospectively randomized (closed envelope system) into two groups: in Group I (n = 25) intravascular volume replacement (including 500 mL added to the priming of the CPB circuit) was performed by 6% HES 130/0.4 (Voluven®; Fresenius-Kabi, Bad Homburg, Germany) and in Group II (n = 25) by 5% HA (Baxter, Unterschleissheim, Germany). The infusion containers were not blinded. Volume was administered perioperatively and during the first 48 h after surgery to keep pulmonary capillary wedge pressure (PCWP) or central venous pressure (CVP) between 12 and 14 mm Hg. To compensate fluid loss from sweating, gastric tubes or as a solvent for drugs, Ringer's lactate solution (RL) was given in both groups. During surgery, 250 mL/h of RL was 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 nonpulsatile pump and a membrane oxygenator. The circuit was primed with 1000 mL of RL plus 500 mL of either 5% HA or 6% HES 130/0.4. 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 prime) was used in all patients. Temperature was kept at mild hypothermia (bladder temperature >33°C) and a flow rate of 2.4 L/min · m² was 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, 6% HES or HA was added. When hemoglobin (Hgb) was <7 g/dL, packed red blood cells were given. During weaning off bypass, as much pump blood as necessary to keep PCWP between 10 and 14 mm Hg was infused. After termination of CPB, the blood from the CPB circuit was salvaged (cell saving system) and retransfused after sternal closure. Shed mediastinal blood was not retransfused in the postoperative period. After surgery, all patients were transferred to the ICU and controlled mechanical ventilation was continued. Tracheal extubation was performed when hemodynamics were stable for at least 1/2 h, temperature was >36°C, and the patient breathed spontaneously reaching adequate blood gases.

Postoperatively, fluid volume (6% HES 130/0.4 or HA) was given to keep PCWP/CVP between 10 and 14 mm Hg. Packed red blood cells were given when Hgb was <9 g/dL. When bleeding occurred (>500 mL/h over three consecutive hours), activated partial thromboplastin time was >70 s and antithrombin III was <40%, fresh frozen plasma was given. Epinephrine or dobutamine were given when MAP was <60 mm Hg and cardiac index (CI) was <2.5 L/min · m² despite sufficient volume infusion (target for CI: 2.5–3.0 L/min · m²). Norepinephrine was administered when systemic vascular resistance (SVR) was <600 dyn · sec · cm^–5 and MAP was <60 torr (target for SVR: 600–800 dyn · sec · cm^–5). The patients' perioperative management was performed by physicians who were not involved in the study and who did not know its purpose. Serum albumin levels are not measured routinely in our ICU, thus the physicians were not aware of serum albumin levels.

Measured Parameters
Hemodynamics
All patients had a pulmonary artery catheter and a central venous catheter. The pulmonary artery catheter was removed during the first postoperative day (POD), then the CVP was used to guide intravascular volume therapy. Heart rate, MAP, pulmonary artery pressure, PCWP, CVP, and cardiac output were monitored and derived hemodynamic variables (SVR, CI) were calculated using standard formulae.

Kidney Function
Standard laboratory techniques were used to measure albumin serum levels, serum creatinine concentrations (sCr; by Jaffé reaction), Hgb, blood gases, and electrolytes. The glomerular filtration rate (GFR) was calculated according to the Cockcroft-Gault formula (GFR = [(140 – age) x weight]/(72 sCr), multiplied by 0.85 if female gender).13 From urine specimens, glutathione transferase- (-GST, was analyzed by enzyme immunoassay with Nephkit^TM-Alpha (Biotrin International, Sinsheim-Reihen, Germany) normal values in healthy volunteers are <11 µg/L [mean ±2 sd] and neutrophil gelatinase-associated lipocalin (NGAL, analyzed by sandwich enzyme-linked immonosorbent assay using microwells coated with monoclonal antibody against human NGAL [Kit 0236], Antibody Shop, Grusbakken, Denmark; normal values in healthy volunteers 5.3 ng/mL [range 0.7–9.8 ng/mL]) were measured.

Inflammation and Endothelial Activation/Injury
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; Los Angeles, CA). Normal values for IL-6 are <5 pg/dL and for IL-10 2–24 pg/mL. Plasma levels of soluble intercellular adhesion molecule-1 (sICAM-1; normal range: 200–300 ng/mL) were measured from arterial blood samples using enzyme-linked immonosorbent assay (British Bio-technology Products, Abington, UK).

Data Points
All results from laboratory measurements represent the means from duplicate measurements and were performed by laboratory staff that was blinded to patient grouping. Measurements were made after induction of anesthesia (before volume replacement was administered), at the end of surgery, 5 h after surgery (on the ICU), at the morning of the first and the second POD in the ICU. sCr was also measured at discharge from the hospital. A questionnaire was sent to the patients' physicians to retrieve patients' information on sCr, the need for renal replacement therapy (hemofiltration, hemodialysis), and mortality after discharge from the hospital (approximately 60 days after discharge).

Statistics
The primary objective of this study was to evaluate whether the administration of HA would be superior to 6% HES 130/0.4 with regard to the release of IL-6. The null hypothesis was that inflammatory cytokine release would be equal for HA patients versus HES-treated patients. The alternative hypothesis was that intravascular volume replacement with HA would reduce inflammatory cytokine release. An a priori power analysis14 indicated that 21 patients needed to be enrolled in each group to obtain an 80% chance of detecting a mean difference in IL-6 release of 45 pg/mL (approximate sd: 50 pg/mL) between patient groups at the P < 0.05 level of significance. Twenty-five patients were included to compensate for possible drop-outs. The sample size calculation was based on the primary end point using a Type I error () of 0.05, a Type II error () of 0.2.

All data are expressed as mean and sd unless otherwise indicated. Categorical variables were assessed using ² test. Normally distributed data (tested by Kolmogorov-Smirnov test) were analyzed using Student's t-test. Two-way analysis of variance 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 was also used when appropriate. A SPSS/PC+ software package was used for statistical analyses (V 10 SPSS, Chicago, IL). A P value <0.05 was considered significant.

RESULTS

Twenty-five patients were included in each group, no patient was excluded from the study. The patients did not differ with regard to co-morbidities, preoperative medication, and type of surgery (Table 1). Duration of surgery, cross-clamping, CPB, anesthesia, and stay in the ICU and in the hospital were also without differences between the two groups (Table 1). ICU and in-hospital mortality, as well as mortality after discharge form the hospital, did not differ between the groups: one patient in each group died after the end of the infusion period. No patient had renal failure requiring renal replacement therapy (hemofiltration, hemodialysis) during hospital stay and thereafter (physicians' response rate: 82%).

A total of 2980 ± 430 mL of albumin and 3060 ± 680 mL of HES 130/0.4 were given until the second POD (Table 2). Urine output was without significant differences between groups (Table 2). Total use of blood and blood products was also similar between groups (Table 2). Hemodynamics were comparable at each data point in both groups (Table 3). The need for inotrophic support and use of vasopressors did not differ between the groups within the entire study period (Table 4).

The serum albumin concentration was similar at baseline in both groups (Fig. 1). It decreased significantly in the HES group (lowest serum albumin level: 2.63 ± 0.3 mg/dL 5 h after submission in the ICU), whereas it increased significantly in the HA-treated patients (to 4.5 ± 0.3 mg/dL at the first POD (Fig. 1).

View larger version (9K): [in this window] [in a new window]   Figure 1. Changes in albumin plasma level (normal values in our laboratory: 3.5–5.0 mg/dL). Mean ± sd, POD: postoperative day; +P < 0.05 different from baseline data; *P < 0.05 different between the two groups.

sCr was slightly higher than normal at baseline in both groups (Fig. 2). After CPB and in the ICU, sCr was slightly higher than at baseline in both groups. Calculated GFR was similar at baseline in both groups (Fig. 2), it decreased slightly postoperatively in both groups. Three months after discharge from the hospital, both, sCr and GFR, almost reached baseline levels (Fig. 2).

View larger version (16K): [in this window] [in a new window]   Figure 2. a and b, Changes in serum creatinine (sCr) (a, normal value: <1.3 mg/dL) and calculated glomerular filtration rate (GFR) in the two groups (b). Mean ± sd; POD: postoperative day.

Urine levels of -GST were normal at baseline and increased significantly until the second POD in both groups (HA: from 6.88 ± 12.7 µg/L; HES: from 8.46 ± 1.8 µg/L to 14.1 ± 3.2 µg/mL); this increase, however, was without group differences (Fig. 3). NGAL urine level increased only in HA-treated patients (from 6.89 ± 1.23 ng/mL to 19.6 ± 2.8 ng/mL at the second POD), whereas it remained almost unchanged in the HES group (from 8.04 ± 1.3 ng/mL to 11.8 ± 1.9 ng/mL) (Fig. 3).

View larger version (11K): [in this window] [in a new window]   Figure 3. a and b, Changes in glutathione transferase- (-GST, normal value: 3.5 ± 11.1 µg/L [mean ± 2 sd]) (a) and neutrophil gelatinase-associated lipocalin (NGAL) (normal values in healthy volunteers 5.3 ng/mL [range, 0.7–9.8 ng/mL]) (b) in the two groups. Mean ± sd, POD: postoperative day; +P < 0.05 different from baseline data; *P < 0.05 different between the two groups.

IL-6 plasma levels were almost normal at baseline and increased similarly in both groups after bypass (HA: from 6 ± 2 pg/dL to 180 ± 32 pg/dL 5 hr after surgery; HES: from 5 ± 2 pg/dL to 193 ± 36 pg/dL) (Fig. 4). IL-10 plasma levels showed a similar course and were without group differences (Fig. 4).

View larger version (13K): [in this window] [in a new window]   Figure 4. a and b, Plasma levels of interleukin-6 (IL-6) (a) and interleukin-10 (IL-10) (b) in the two groups (normal values for IL-6 are <5 pg/dL and for IL-10, 2–24 pg/mL). Mean ± sd, POD: postoperative day. +P < 0.05 different from baseline data.

ICAM-1 plasma levels were slightly increased from normal at baseline (Fig. 5). Postoperatively, soluble ICAM was significantly lower in the HES than the HA-treated patients until the end of the study (Fig. 5).

View larger version (12K): [in this window] [in a new window]   Figure 5. Changes in plasma levels of soluble intercellular adhesion molecule-1 (sICAM-1; normal range, 200–300 ng/mL). Mean ± sd, POD: postoperative day. *P < 0.05 different between the two groups.

DISCUSSION

The major result from the present study was that use of albumin in hypoalbuminemic patients aged >80 yr undergoing cardiac surgery lacked significant advantages compared to an intravascular volume replacement strategy using a HES preparation with a low Mw and low MS. Postoperative serum albumin concentrations were always significantly higher in our HA-treated patients. However, this had no beneficial negative effects on inflammatory response, endothelial integrity, and kidney function.

We included patients aged >80 yr because elderly cardiac surgery patients are at increased risk to develop postoperative organ dysfunction, e.g., acute renal failure.15 Moreover, altered immune responses have been reported in the elderly.16

Our results are somewhat in contrast to other studies showing significant negative effects of a low serum albumin level. In a cohort study of 9352 cardiac surgery surgery patients, an univariate and logistic regression analyses for infectious outcome identified low preoperative albumin level among other factors such as age, banked blood requirement, duration of operation, and diabetes mellitus as predictive of postoperative infection.17 Others also showed that a reduced serum albumin concentration is an important marker of a poor prognosis not a pathogenic factor itself.18 In the present study, we measured pro-(IL-6) and antiinflammatory (IL-10) cytokines to assess the influence of albumin on inflammatory response. Soluble adhesion molecule ICAM-1 was measured as a marker of endothelial injury/activation. In our elderly patients, HA-based intravascular volume replacement did not attenuate the inflammatory response and endothelial injury/activation that are often associated with CPB. By contrast, ICAM-1 plasma levels were even significantly lower in the HES than in the albumin group. This is in agreement with others who also found improved endothelial function and less impaired endothelial integrity by using the same HES preparation as we used.18,19 One explanation may be an improved microcirculation, another may be direct beneficial effect of HES on inflammation, e.g., via a reduction in NF-kappaB release.20

Albumin has been shown to improve microcirculation, increase mesenteric blood flow, decrease leukocyte rolling and adherence, and reduce the inflammatory response.8,21 Thus, improved organ function might also have been expected in our elderly cardiac surgery patients receiving HA. Renal dysfunction is one of the most serious organ complications after cardiac surgery.2,15 Albumin has been reported to have protective effects on the kidneys such as inhibition of apoptosis and scavenging of reactive oxygen species.22 By contrast, after infusion of HES, histological studies have shown reversible swelling of tubular cells of the kidneys ("osmotic nephrosis-like lesions").23 Use of 6% HES 200/0.62 in brain-dead donors resulted in impaired renal function in kidney transplant recipients showing larger sCr and a higher need for hemodialysis compared to gelatin-treated patients.24 In a recently published study in patients with severe sepsis, use of very high doses of a hyperoncotic HES preparation (10%) with a medium Mw (200 kDa) and a medium MS (0.5) over a long time resulted in a higher incidence of acute renal failure requiring dialysis compared to a RL-based intravascular volume replacement strategy.25 In a retrospective study including 95 coronary artery bypass patients, infusion of a high-Mw HES with a high MS (HES 670/0.75; Hextend®) resulted in impairment of renal function as seen by a slight reduction in estimated GFR.11

Measuring insensitive markers of kidney dysfunction could mask the possible negative effects of an intravascular volume replacement regimen.26 Thus, we did not only measure sCr and calculated GFR, but also measured urinary concentrations of kidney-specific proteins such as -GST and NGAL to assess the influence of our volume replacement strategies on tubular integrity more closely. Urine -GST is considered as a marker of proximal tubulus injury.27 Urinary -GST concentrations were shown to increase 1–2 days before sCr, thus -GST is considered as useful in the detection of early renal injury.27 NGAL is a member of the lipocalin superfamily; it is a 25 kDa protein covalently bound to gelatinase from human neutrophils28 that is usually barely detectable in human tissues including the kidney. NGAL is upregulated by ischemia in several segments of the nephron, predominantly in proximal tubules.29 It precedes any increase in sCr for 1–3 days and is subsequently suggested to be an early biomarker of acute renal injury.29 By measuring kidney-specific proteins, subclinical alterations in renal function have been reported in the absence of overt changes in sCr and creatinine clearance.29 In the present study, urine concentrations of kidney-specific proteins were not superior in HA-compared to HES 130/0.4-treated patients. The patients' follow-up (approximately 60 days after surgery) revealed no differences in sCr and GFR or need of renal replacement therapy between the two groups. Postoperatively, urinary concentrations of NGAL increased even more in the HA-than in the HES-treated group, indicating more damage of distal tubulus in the HA patients. The reasons for this can only be speculated: urinary NGAL levels have been suggested to serve as an early marker for ischemic renal injury.28,29 Six percent HES 130/0.4 has been shown to improve microcirculation and tissue oxygenation,30 thus one explanation for the lower NGAL urine levels may be an improved blood flow to the kidneys by HES 130/0.4.

One criticism is that our study was not powered to evaluate differences in mortality.31 Other issues aside from mortality, e.g., inflammatory response, altered endothelial integrity or organ dysfunction, including renal insufficiency, have to be considered when assessing the ideal intravascular volume replacement regimen. Another objection is that guiding volume therapy using PCWP and CVP is a problem as filling pressures have been shown to be weak surrogate variables for assessing the patients' volume status. However, as both groups showed similar hemodynamics, including comparable filling pressures, major differences in the patients' volume status by which our results would have been influenced appear unlikely.

We conclude that in patients aged >80 yr showing hypoproteinemia before surgery, a HA-based intravascular volume replacement strategy was without benefit compared to 6% HES 130/0.4 with regard to inflammatory response, endothelial activation, and kidney function. Larger controlled studies are necessary to confirm our data showing no value of HA administration in the cardiac surgery patient.

Footnotes

Accepted for publication June 4, 2008.

Supported by a pharmaceutical company, but by a hospital grant.

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