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Anesth Analg 2006;103:191-199 © 2006 International Anesthesia Research Society doi: 10.1213/01.ane.0000221179.07006.06
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Abstract |
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 Top Abstract IntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
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The value of human albumin (HA) for treating hypovolemia is controversial. Less expensive alternatives such as hydroxyethyl starch (HES) are sometimes refused because of unwanted side effects. We prospectively randomized 50 patients older than 70 years old undergoing major abdominal surgery to receive either 5% HA (n = 25) or a third generation HES preparation (6% HES 130/0.4; n = 25) when mean arterial blood pressure was <60 mm Hg and central venous pressure was <10 mm Hg. Hemodynamics, inflammation (interleukin-6), endothelial activation-integrity (adhesion molecules), coagulation (thrombelastography), and renal function (including kidney-specific proteins) were monitored after the induction of anesthesia, after surgery, 5 h in the intensive care unit, and on the first postoperative day. HA patients received 3960 ± 590 mL of HA and 5070 ± 1030 mL of Ringer’s lactate solution, and HES patients received 3500 ± 530 mL of HES and 4550 ± 880 mL of Ringer’s lactate solution. Total protein remained normal only in the HA-treated patients. No significant differences (P > 0.1) between the groups were seen with regard to hemodynamics, coagulation, and kidney function. Plasma levels of interleukin-6 and soluble adhesion molecules were significantly (P < 0.05) higher in the HA- than in the HES-treated patients. We conclude that HA in elderly patients undergoing major abdominal surgery can easily be replaced by a modern HES preparation. Because of the decreased inflammatory response and endothelial activation-injury, HES 130/0.4 seems to be the more appropriate fluid strategy for these patients.
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Introduction |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
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In patients undergoing major surgery, intravascular volume depletion is already often seen before surgery for several reasons. This hypovolemia may be aggravated during and after surgery by blood and fluid loss (absolute hypovolemia) or by fluid shift into the extravascular compartment (relative hypovolemia). Hypovolemia is associated with pathophysiological changes that may lead to organ dysfunction or organ failure. Thus, correction of hypovolemia seems to be essential for preventing organ damage in this situation.
The age-old "crystalloid-colloid" debate has been enlarged by a "colloid-colloid" controversy, and in addition to the natural colloid (human albumin [HA]), several synthetic colloids (e.g., dextrans, gelatins, and hydroxyethyl starch [HES]) are available to treat hypovolemia. Among the colloids, HA may offer several advantages compared with nonprotein colloids, including less restrictive dose limitations, decreased risk of impaired hemostasis, absence of tissue deposition leading to severe prolonged pruritus, and reduced incidence of anaphylactoid reactions (1,2). Additionally, the non-oncotic, beneficial effects of HA (e.g., antiinflammatory and antioxidant properties) have been demonstrated in some experimental and animal studies (3). The value of HA as an intravascular volume replacement strategy, however, has been frequently questioned by the "SAFE" study that did not show a benefit of 4% HA in intensive care patients (4). Nevertheless, approximately 112 million doses of HA were administered worldwide from 1990 to 1997, and from 1998 to 2000 approximately 107 doses of 40 g of HA were given (5). The lack of any financial constraints on albumin use in many countries may have contributed to this still frequent use of HA. The continuing interest in albumin is demonstrated by the increasing number of meta-analyses concerning the use of HA (6). Most meta-analyses used old-to-very-old studies because more actual, prospective studies of HA in the perioperative period in humans are lacking. Another problem with these meta-analyses is the mixing of patients suffering from different diseases. In a meta-analysis of HA (6), a subgroup analysis of noncardiac surgery included four papers on HA in major abdominal, noncardiovascular surgery. All studies were 10–20 years old, and most did not include a control group. The hypothesis of the present study was that a HA-based intravascular volume replacement strategy in elderly patients undergoing major abdominal surgery is advantageous compared with a modern third generation HES preparation with regard to inflammation, endothelial activation, coagulation, and kidney function.
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METHODS |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
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After IRB approval and patients’ written informed consent was obtained, 50 consecutive patients older than 70 years old undergoing major intestine surgery for malignancies were included into the study. Patients with cardiac insufficiency (NY Heart Association class III–IV), renal insufficiency (serum creatinine >200 µmol/L), altered liver function (aspartate aminotransferase >40 U/L and alanine aminotransferase >40 U/L), preoperative anemia (hemoglobin [Hgb] <10g/dL), preoperative coagulation abnormalities, and chronic use of corticosteroids and diuretics were not included.
Using a computerized random number generator, patients were prospectively randomized to receive either 5% HA (n = 25; Baxter, Germany) or a third-generation small-molecular weight (MW) HES (mean MW, 130 kD) with a low molar substitution (MS; 0.4) (6% HES 130/0.4; n = 25; Fresenius Kabi, Bad Homburg, Germany). Intravascular volume replacement was given during and after surgery within 24 h when mean arterial blood pressure (MAP) was <60 mm Hg and central venous pressure (CVP) was <10 mm Hg (aim for CVP, 10–15 mm Hg). Ringer’s lactate (RL) solution was given in a 2:1 ratio to the colloid and to compensate fluid loss by gastric tubes or as a solvent for drugs (e.g., antibiotics). Packed red blood cells (one unit of 300 mL) were transfused when Hgb was <9 g/dL, fresh frozen plasma (one unit of 200 mL) was administered when bleeding occurred, and activated partial thrombin time was >70 s, fibrinogen was <2 g/dL, or antithrombin III was <40%.
Midazolam (7.5 mg) was given 1 h before surgery. Thoracic epidural anesthesia was used for all patients according to a standardized protocol using bupivacaine and sufentanil during surgery. Postoperatively, a patient-controlled analgesia system consisting of ropivacaine and sufentanil was used to control pain. Thiopental (5 mg/kg), fentanyl (3 µg/kg), and vecuronium (0.1 mg/kg) were given for the induction of anesthesia, and anesthesia was maintained with fentanyl, desflurane, and vecuronium titrated according to the patient’s need. Mechanical ventilation was performed in all patients with 50% oxygen in air to keep Sao2 >95% and end-expiratory CO2 between 35 and 40 mm Hg. A rewarming cover blanket system and fluid warmers were used to avoid hypothermia. All patients received metronidazole-cefazolin as single-shot antibiosis after the induction of anesthesia.
After surgery, all patients were transferred to the intensive care unit (ICU). Controlled mechanical ventilation was continued after surgery when required, and the patients were tracheally extubated when hemodynamics remained stable, they showed sufficient spontaneous breathing, and core temperature was >36°C. When MAP was <60 mm Hg despite sufficient intravascular volume (CVP, 10–15 mm Hg), norepinephrine was given. Dobutamine was added when volume replacement therapy plus norepinephrine was not effective to keep MAP >60 mm Hg. All patients were managed by anesthesiologists and intensivists who were not involved in the study and were blinded to the aim of the study.
Intra- and postoperative hemodynamic monitoring included continuous measurement of electrocardiogram, MAP, and CVP. C-reactive protein (CRP; determined by nephelometry; normal values <0.5 mg/dL) and interleukin (IL)-6 (determined by enzyme-linked immunoabsorbent assay) were measured from arterial blood samples. IL-6 was measured in duplicate 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. Plasma levels of soluble (s) endothelial leukocyte adhesion molecule-1 (sELAM-1; normal range, 30–60 ng/mL) and intercellular adhesion molecule-1 (sICAM-1; normal range, 200–300 ng/mL) were measured from arterial blood samples using enzyme-linked immunosorbent assays (ELISA; British Bio-technology Products, Abington, UK). All results of measurements represent the means from duplicate measurements.
Standard coagulation variables (antithrombin III, platelet count, and activated partial thrombin time) were measured from arterial blood samples using routine laboratory methods. Another 5 mL of citrated blood was taken for performing activated thrombelastography (TEG®) using a four-channel TEG® analyzer (ROTEM® Whole Blood Hemostasis Analyser; Pentapharm Diagnostic Division, Munich, Germany). This modification of the conventional TEG® system uses a different power transduction system that makes it less susceptible to mechanical stress, movement, and vibration. It uses a technique based on optical detection of the movement of a disposable plastic sensor attached to a short axis guided by a ball bearing, which is inserted into the clotting blood. TEG® monitoring using the ROTEM® analyser relies on the continuous assessment of clot firmness, allowing the determination of the onset of coagulation (coagulation time – standard TEG®: reaction time [r]), kinetics of clot formation (clot formation time [CFT] – standard TEG®: coagulation time [k]), and maximum clot firmness (standard TEG®: maximal amplitude [MA]). TEG® was measured after the addition of different activators: (a) Intrinsic TEG® (InTEG®) = clot formation was measured after recalcification of 300 µL of whole blood with 20 µL of 0.2 M calcium chloride and adding a surface activator (partial thromboplastin from rabbit brain [20 µL]) for monitoring the intrinsic system (factors XII, XI, IX, VIII, X, II, and I + platelets); and (b) Extrinsic TEG® (ExTEG®) = clot formation was monitored after the addition of tissue thromboplastin (rabbit brain extract) for monitoring the extrinsic system (factors VII, X, V, II, and I + platelets).
Serum and urine creatinine levels were measured using the Jaffé reaction. Creatinine clearance was measured from standard formula: Ucrea x Uvol/Pcrea x duration of urine collection period; (Ucrea = urine creatinine concentration; Uvol = urine volume during the collection period; Pcrea = serum creatinine concentration). Sampling periods for urine were defined as the following: evening of preoperative day until end of the induction of anesthesia (baseline), end of the induction of anesthesia until end of surgery, end of surgery until 5 h in the ICU, 5 h in the ICU until the morning of the first postoperative day (POD).
Urine concentrations of N-acetyl-ß-d-glucosaminidase (ß-NAG; analyzed by a spectrophotometric method; Hoffmann La-Roche, Basel, Switzerland; normal values in healthy volunteers, <7 U/L), 
-1-microglobuline (analyzed by immunonephelometry; Behring Werke, Marburg, Germany; normal values in healthy volunteers, <14 mg/L), and glutathione transferase- (GST-; analyzed by enzyme immunoassay using NephkitTM-Alpha; Biotrin International, Sinsheim-Reihen, Germany; normal values in healthy volunteers, <5 µg/L) were measured to assess tubular integrity.
All measurements were performed after the induction of anesthesia (before intravascular volume administration), at the end of surgery, 5 h after arrival in the ICU, and on the morning of the first POD. A follow-up (morbidity and mortality) was performed when the patient was transferred to the normal ward, when the patient left the hospital, and 1 yr after surgery.
The number of patients that are required to assess whether HA is of value for our patients compared with a less expensive alternative was not based on mortality or morbidity because thousands of patients would have been required for this purpose (4). Thus, the formal sample-size calculation performed before the start of the study was based on previous studies concerning the release of IL-6 in elderly patients (7). We hypothesized that intravascular volume replacement with HES compared with HA would reduce the IL-6 response by 30%. The approximate standard deviation of IL-6 levels in elderly patients undergoing major abdominal surgery was demonstrated to be 50 pg/mL (7). The error was set at 0.05 (two-sided), and type II error was set at 0.2. Based on this assumption, a minimum of 21 patients per group was required. For statistical analysis, software package SPSS/PC+ (V 4.0. SPSS, Inc., Chicago, IL) was used. 
2 analyses with Fisher’s exact test were used for categoric data if appropriate (e.g., differences in the complication rates were tested by 2 test). A nonparametric test (Wilcoxon rank sum) was used for variables not normally distributed (tested by Kolmogorov-Smirnov test). Differences from baseline and between the groups were evaluated by two-way analysis of variance for repeated measures (followed by Scheffé test). A P value <0.05 was considered significant.
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RESULTS |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
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Demographic data, type of surgery, and use of catecholamines were similar in both groups (Table 1). In none of the patients was diuretics used during the study period. Costs of the entire fluid management were significantly more expensive for the HA- (4869 Euro) than for the HES-treated group (1064 Euro) (Table 1).
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Morbidity and mortality (outcome) during the stay in the ICU and during the entire hospital stay were without significant differences in both groups (Table 2).
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Patients of the HA group received a total of 3960 ± 590 mL of HA and 5070 ± 1030 mL of RL, whereas HES-treated patients received a total of 3500 ± 530 mL of HES and 4550 ± 880 mL of RL (Table 3). Use of blood-blood products (Table 3) and hemodynamics were without significant differences between groups (Table 4).
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Total protein was significantly higher in the HA group than in the HES-treated patients until the end of the study period (Table 5). CRP was significantly more increased in the HA- than in the HES-treated patients (Table 5). Hemoglobin and standard coagulation data were without significant differences between the two groups (Table 5).
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IL-6 plasma levels increased significantly in both groups (Fig. 1). This increase was significantly larger in the HA-treated (from 0.4 ± 0.2 pg/mL at baseline to 320 ± 70 pg/mL 5 h in the ICU) than in the HES-treated patients (from 0.3. ± 0.2 at baseline to 185 ± 38 pg/mL 5 h in the ICU). The plasma concentration of both measured endothelial adhesion molecules increased significantly during surgery (Fig. 1), showing a significantly higher increase in the HA- than in the HES-treated patients. On the morning of the first POD, plasma levels of adhesion molecules had returned to baseline vales in the HES group, whereas sELAM-1 and sICAM-1 plasma levels remained increased in the HA patients.
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Creatinine clearance decreased during surgery without showing significant differences between groups (Fig. 2). Kidney-specific proteins (-1-microglobuline, -GST, and ß-NAG) were without differences between groups and remained for normal range during the entire study period (Figs. 2 and 3).
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InTEG®-CFT and Ex-TEG®-CFT increased during surgery and during the postoperative period without showing significant differences between groups (Figs. 4 and 5). All other data of TEG monitoring remained almost unchanged and without differences between volume groups.
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DISCUSSION |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
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In the United States, the indications for which HA therapy is considered include hypovolemia or shock, burns, hypoalbuminemia, surgery or trauma, cardiopulmonary bypass, acute respiratory distress syndrome, hemodialysis, and sequestration of protein-rich fluids (1). The more ill the patients are, the more often HA is considered to be of benefit (1,3,8). We have included elderly patients because there is a tendency to assume that older patients have a worse prognosis because of the presence of preexisting diseases (9). In addition to the established lung, kidney, and cardiovascular function changes that occur with increased age, there seems to also be more pronounced changes in hemostasis and inflammation. We decided to include patients undergoing abdominal surgery because this is associated with more inflammatory response than non-intestine, minor surgery (10).
One result from the present study was that hemodynamics in both intravascular volume replacement groups were similar within the entire study period. HA-treated patients required slightly (nonsignificant) more 5% HA to keep CVP between 10 and 15 mm Hg than 6% HES 130/0.4-treated patients required. This is in contrast to a laboratory study, in which plasma-expanding effects after hemorrhage were significantly greater with 20 mL/kg of 5% HA (21.1 ± 3.6 mL/kg) than with the same amount of 6% HES 130/0.4 (13.8 ± 2.2 mL/kg) (11).
Another result from our study was that total protein concentration was kept almost normal and at baseline values in the HA patients, whereas a significant decrease was seen in the HES-treated group. The importance of HA may be related to its transport function for various drugs and endogenous substances, e.g., bilirubin or free fatty acids (3). HA has also been reported to have beneficial effects on membrane permeability secondary to antiinflammatory properties and free radical scavenging (3). The possibly stabilizing effect of HA on the endothelium was studied in 12 adult patients fulfilling American College of Chest Physicians/Society of Critical Care Medicine criteria for septic shock (12). HA supplementation sufficient to nearly double serum concentrations in profoundly hypoalbuminemic septic patients had no clinically significant effects in reducing microvascular permeability. HA favorably influenced antioxidant status compared with normal saline (13). This influence may protect against oxidative stress and beneficially influence inflammatory response. HA, however, may also have negative effects in patients with acute respiratory distress syndrome because it contains a variety of ligands, including reactive metals, and HA may have pro-oxidant properties with proinflammatory consequences (13). Optimization of the patient’s intravascular volume status may generally have important effects on immune response and endothelial activation and injury (14,15). The definite influence of resuscitation fluids on immune function, inflammatory response, and endothelial activation and injury, however, is not clear. We have measured CRP, proinflammatory cytokine IL-6, and plasma levels of adhesion molecules (sICAM-1 and sELAM-1) as markers of inflammation and endothelial activation and injury. In our HA-treated patients, CRP and plasma levels of IL-6, sICAM-1, and sELAM-1 were significantly more increased than in the HES 130/0.4-treated group, indicating some attenuation of inflammation and endothelial activation and injury by HES but not HA. These results are in agreement with a study by Collis et al. (16) in which the influence of HES (HES 280/0.5 and HES 450/0.7) and HA on endothelial cell activation was studied using endothelial cell cultures (human umbilical vein endothelial cells. Lipopolysaccharide-stimulated expression of the adhesion ligand P-selectin was significantly inhibited by both HES preparations. In a septic animal model, administration of 6% HES 130/0.4 resulted in significantly reduced lipopolysaccharide-induced arteriolar and venular leukocyte adherence with subsequently improved microcirculation and attenuated capillary leak, whereas saline resuscitation had no beneficial effects when compared with nontreated control animals (17). In a study of patients undergoing abdominal surgery, inflammatory response and endothelial activation were significantly less in HES 130/0.4-treated patients than in those in whom only crystalloids (RL) were perioperatively used (18).
The reason why HA was not as effective as HES 130/0.4 in blunting the inflammatory process and endothelial activation and injury can only be speculated upon to be that the HES molecule may exert some direct, substance-specific beneficial effects on endothelial cells resulting in less release of adhesion molecules (16). Delayed and inadequate restoration of intravascular circulating volume may worsen microvascular flow, endothelial integrity, and subsequently organ function. Better organ blood flow (e.g., gut perfusion) and tissue perfusion at the microcirculatory level with HES 130/0.4 than with HA may be another reason for the beneficial effects of HES 130/0.4 on inflammation and endothelial activation and injury. Finally, it has been demonstrated that certain batches of HA preparations affect the expression of endothelial cell adhesion molecules (19); this may have also contributed to the increased levels of adhesion molecules after HA administration in our study.
Coagulation was not negatively affected with HA or with the latest generation of HES. HA has no negative effects on coagulation, and thus, it is generally considered to be the gold-standard when assessing the influence of plasma substitutes on hemostasis. The lack of acceptance of HES for intravascular volume replacement is often based on reports of abnormal coagulation (8,20). All HES solutions are not created equally, and they differ widely with regard to their physico-chemical characteristics (concentration, mean MW, MS, and C2/C6-substitution ratio). These differences cause important consequences such as alterations of the coagulation process. Neither standard coagulation data nor TEG® monitoring revealed differences between our HA- and HES 130/0.4-treated patients. Several studies have shown that the third generation of HES is almost free of negative effects on hemostasis (21). Some studies, however, have also reported negative effects with this HES preparation: In a prospective, double-blind, placebo-controlled, crossover study, the influence of HES 130/0.4, HES 200/0.62, and RL (10 mL/kg within 30 minutes) on hemodynamics and platelet function (using platelet function analyzer [PFATM]-100) were compared for chronic low back pain patients scheduled for peridural blockades (22). An antiplatelet effect of HES 130/0.4 was a significant increase in adenosine diphosphate-induced closure time from approximately 90 seconds at baseline to 98 seconds after the infusion. These changes, however, were within the normal range of 70–120 seconds. In our study, the two groups did not differ with regard to coagulation monitoring or bleeding tendency and use of blood-blood products. In a recently published overview of starches and coagulation, it was stated that rapidly degradable HES preparations (such as the HES 130/0.4) have minimal influence, if any, on hemostasis (21). Our elderly patients did not profit from an HA-based fluid replacement strategy in terms of their hemostasis or bleeding tendency compared with the HES-based intravascular volume replacement regimen.
Based on studies reporting negative effects of starches on renal function (23), we carefully assessed whether either of the used fluids deteriorated kidney function. Elderly patients seem prone to develop renal dysfunction. After the age of 40 years, creatinine clearance decreases approximately 1% per year, and the ability to compensate disturbances of renal function is limited in the elderly. HA is assumed to be the gold-standard fluid for patients at risk from altered kidney function. We measured not only creatinine clearance, but also urinary excretion of kidney-specific proteins because moderate and transient alterations in renal integrity detected by these markers of tubular damage have been reported in the absence of overt changes in creatinine serum concentrations and creatinine clearance (24). An increased elimination of ß-NAG has been shown to be a sensitive marker for lysosomal tubular damage, indicating subclinical renal tubular injury (25). Urinary excretion of -1-microglobuline is a marker of (subclinical) proximal tubular dysfunction, even when no histologic damage is seen (26); likewise, urine -GST is considered a marker of proximal tubular cell injury (26,27). Our elderly patients seemed to be at considerable risk for developing (moderate) kidney dysfunction during major abdominal surgery, most likely because of preoperatively altered renal function and altered fluid homeostasis during major surgery. Neither creatinine clearance nor urine concentrations of kidney-specific proteins showed differences between HA- and HES 130/0.4-treated patients.
One problem with the present study is that intramuscular volume administration was indicated and guided by measuring standard hemodynamics (MAP and CVP). It is has been shown that CVP is only of limited value as a surrogate of the intramuscular volume status, and hypovolemia can be masked when intramuscular volume status is monitored by filling pressures alone (e.g., CVP) (28). Thus, we not only used CVP for indicating intravascular volume administration, but also MAP to guide intravascular volume therapy. CVP was similar in both groups within the entire study period, and similar amounts of colloids (and crystalloids) were infused. Thus, there seemed to be no major differences in the patients’ intravascular volume status.
Considering the value of the two different intravascular volume replacement regimens, patient outcome is a much-debated issue. Controversy continues as to whether a patient’s life can be saved by the choice of intravascular volume replacement. The patient population of the present study was definitely too small to draw any conclusions with regard to mortality. Compared with the less expensive alternative (HES), use of HA in our elderly patients showed no beneficial affects on general morbidity (e.g., complications) during their ICU stay and during their entire hospital stay. We have also measured laboratory values that are surrogates of organ function (TEG®, coagulation; kidney-specific proteins, kidney function; IL-6, inflammation; adhesion molecules, endothelial activation and injury); all values did not differ between HA- and HES-treated patients, indicating no advantage of HA concerning morbidity.
We conclude that, although total protein concentration was kept within normal limits by administrating HA, elderly patients undergoing major abdominal surgery did not profit from the use of HA compared with a much less expensive nonprotein modern HES preparation, even when rather large doses were used. Inflammatory response and endothelial activation and injury were even more beneficially influenced by HES 130/0.4 than HA. When considering the effects on hemodynamics, organ function (renal), coagulation, inflammatory response, endothelial activation and integrity, and costs, HA cannot be recommended in this patient population, and the use of a modern starch preparation should be favored to correct hypovolemia.
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Footnotes |
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This study was not supported by a pharmaceutical company.
Accepted for publication March 7, 2006.
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