Volume 25, Issue 3 , Pages 407-414, June 2011
Efficacy and Safety of Hydroxyethyl Starch 6% 130/0.4 in a Balanced Electrolyte Solution (Volulyte) During Cardiac Surgery
Article Outline
Objective
The infusion of large amounts of saline-based solutions may contribute to the development of hyperchloremic metabolic acidosis and the use of a balanced carrier for colloid solutions might improve postoperative acid-base status. The equivalence of 2 hydroxyethyl starch (HES) solutions and the influence on chloride levels and acid-base status by selectively changing the carrier of rapidly degradable modern 6% HES 130/0.4 were studied in cardiac surgery patients.
Design
A prospective, randomized, double-blinded study.
Setting
A clinical study in 2 cardiac surgery institutions.
Participants
Eighty-one patients.
Intervention
Patients received either 6% HES130/0.4 balanced (Volulyte; Fresenius Kabi, Bad Homburg, Germany) or 6% HES130/0.4 saline (Voluven; Fresenius Kabi, Bad Homburg, Germany) for intra- and postoperative hemodynamic stabilization.
Measurements and Main Results
The therapeutic equivalence of both HES formulations regarding volume effect and superiority of the balanced electrolyte solution regarding serum chloride levels and acid-base status were measured. Similar volumes of both HES 130/0.4 balanced and HES 130/0.4 saline were administered until 6 hours after surgery, 2,391 ± 518 mL in the HES 130/0.4 balanced group versus 2,241 ± 512 mL in the HES 130/0.4 saline group. The 95% confidence interval for the difference between treatments (−77; 377 mL; mean, 150 mL) was contained entirely in the predefined interval (−500, 500 mL), thereby proving equivalence. The serum chloride level (mmol/L) was lower (p < 0.05 at the end of surgery), and arterial pH was higher in the balanced group at all time points except baseline, and base excess was less negative at all time points after baseline (p < 0.01).
Conclusions
Volumes of HES needed for hemodynamic stabilization were equivalent between treatment groups. Significantly lower serum chloride levels in the HES balanced group reflected the lower chloride load of similar infusion volumes. The HES balanced group had significantly less acidosis.
Key Words: balanced solutions, hydroxyethyl starches, cardiac surgery
HYDROXYETHYL STARCH (HES) solutions frequently are used to restore intravascular volume depletion during surgery in order to prevent organ dysfunction and organ failure.1 Compared with crystalloid solutions, colloids have a smaller volume of distribution and, therefore, less amounts of fluid and time are needed to restore intravascular volume deficits.2, 3 Colloids also have been shown to improve oxygen transport, myocardial contractility, cardiac output, and tissue oxygenation4, 5, 6, 7; 6% HES 130/0.4 (Voluven; Fresenius Kabi, Bad Homburg, Germany) represents an HES type with optimized pharmacokinetics and an improved safety profile as compared with other HES products, which are less rapidly metabolized because of a higher molar substitution with hydroxyethyl residues.8, 9 Although volume efficacy is equivalent, clearance of the latest generation HES (molar substitution 0.4) is more than 23 times higher than for first-generation hetastarch and almost 5 times higher than for pentastarch (second generation).10 At the same time, recent clinical data indicate an increased safety margin of tetrastarch compared with older HES types. This is suggested by the higher maximum doses and a reduced influence on coagulation, leading to significantly reduced red blood cell transfusion requirements.11 The exclusive use of normal saline-based crystalloids might be associated with the development of hyperchloremic metabolic acidosis resulting from the high chloride load in these solutions.12, 13 The clinical relevance of hyperchloremic acidosis is unclear; however, several studies and animal data suggest that it might be associated with a dose-dependent increased morbidity such as reductions in gastrointestinal motility14 and urinary flow14, 15, 16 as well as increased bleeding.17, 18, 19, 20 In an experimental sepsis model using rats, hyperchloremia also has been reported to cause an increase in plasma levels of proinflammatory cytokines (eg, interleukin-6 and tumor necrosis factor α).21 Usually, much larger volumes of crystalloids compared with colloids have to be given to achieve a defined volume effect, and the relative contribution of electrolytes given with crystalloids is likely to be larger than that given with colloids. Nevertheless, the colloid carrier solution might be of importance.12 In principle, the use of colloids plus crystalloids instead of large volumes of crystalloids only can reduce the calculated chloride load of a patient. HES dissolved in balanced electrolyte solution could further help to prevent hyperchloremic acidosis in case of large-dose infusions. Volulyte (Fresenius Kabi, Bad Homburg, Germany) contains 6% HES 130/0.4 in a balanced electrolyte solution. The carrier solution is physiologically more similar to plasma than saline and has a lower chloride load compared with other solutions.22 The electrolyte carrier solution does not alter the pharmacodynamic and pharmacokinetic properties of HES as studies with hetastarch (HES 670/0.75) have shown.23, 24
This prospective, randomized, double-blind, bicenter, parallel group study was designed to prove therapeutic equivalence of both HES formulations regarding the volume effect within a predefined interval and to test superiority of the balanced electrolyte solution regarding serum chloride levels and acid-base status in patients undergoing cardiac surgery.
Materials and Methods
The study was performed in accordance with the revised Declaration of Helsinki and with the principles of Good Clinical Practice. Eighty-one patients scheduled for cardiac surgery were recruited in 2 cardiac centers (University Hospitals of Vienna, Austria, and Hamburg, Germany). The protocol was approved by the Institutional Review Board of the University of Vienna and the Ethics Committee of the Medical Association of Hamburg, and written informed consent from the patients was obtained. Inclusion criteria were male and female patients undergoing either elective valve surgery, coronary artery bypass surgery, or both, with a body weight between 55 and 100 kg, a body mass index between 19 and 35 kg/m2, and an expected time of cardiopulmonary bypass between 30 minutes and 3.5 hours. Exclusion criteria were a history of cardiac surgery, severe congestive heart failure (ejection fraction <25%), hemoglobin concentration <12 g/dL and >17 g/dL before study admission, a known allergy to HES, renal insufficiency (serum creatinine of >2.5 mg/dL), significant hepatic disease (liver function tests >3× upper limit of normal), or a history of coagulation disorders.
Anesthesia was induced with midazolam (0.1 mg/kg), propofol (1.0-1.5 mg/kg), fentanyl (3-10 μg/kg), and rocuronium bromide (1 mg/kg) and maintained with an infusion of propofol (50-100 μg/kg/min) and fentanyl (0.05-0.1 μg/kg/min). No volatile anesthetics were used. The cardiopulmonary bypass circuit was prepared with 1,000 mL of HES study solution and 500 mL of Ringer's solution, 5,000 IU of heparin, 100 mL of mannitol, and 106 IU of aprotinin. After anticoagulation with heparin (300 IU/kg), cardiopulmonary bypass was performed using nonpulsatile blood flow at 2.5 L/min/m2, a non–heparin-coated circuit, and a membrane oxygenator (Quadrox, Maquet, Hirrlingen, Germany; Dideco Compactflow, Mirandola, Italy; or Hilite 7000, Medos, Stollberg, Germany). Mild-to-moderate hypothermia was induced (30°-32°C) and norepinephrine was given to maintain a mean arterial pressure >60 mmHg. St Thomas crystalloid cardioplegic solution (Hamburg) and Buckberg cardioplegic solution (Vienna) were used for myocardial preservation.
Randomization was performed using SAS Version 8.2 (SAS, Cary, CA). Patients were randomized to treatment groups per study center in blocks of 6 and received either 6% HES 130/0.4 in a balanced electrolyte solution (Volulyte) or 6% HES 130/0.4 in NaCl 0.9% (Voluven, HES 130 saline group). Study medication was blinded by the manufacturer. Study drugs were used for intra- and postoperative volume therapy and priming of the cardiopulmonary bypass circuit as indicated earlier. A maximum study drug dose of 50 mL/kg within 24 hours was allowed. If additional volume was needed, Ringer solution was given. Colloid infusion was adjusted individually for each patient to achieve hemodynamic stability, which was defined as a systolic blood pressure >90 mmHg and avoidance of decrease of systolic blood pressure >20% from baseline, a heart rate <100 beats/min and avoidance of an increase in heart rate of 30% from baseline, a cardiac index >2 L/min/m2, normal hemodynamic filling pressures (central venous pressure 5-12 mmHg and pulmonary artery occlusion pressure 10-15 mmHg), and urine output >0.5 mL/kg/h. Additional crystalloid (Ringer's solution) was used concomitantly for fluid maintenance in both groups. The ventilator was set to achieve a target alveolar partial carbon dioxide pressure between 35 and 40 mmHg. The use of sodium bicarbonate was only allowed if arterial pH was <7.2. Regarding concomitant medication, the use of colloids other than the study drug was forbidden until 6 hours after surgery. For fluid therapy with crystalloids including preoperative hydration, Ringer's solution was to be used exclusively, except in the case of hyperkalemia (>5.1 mmol/L) when normal saline was allowed. If further colloids were needed from 24 hours postoperatively until hospital discharge, standard 6% HES 130/0.4 (in NaCl 0.9%) was used. Transfusion triggers for the transfusion of allogeneic red blood cells were hemoglobin concentrations of ≤7.0 g/dL (during cardiopulmonary bypass), 7.5 to 8.0 g/dL after weaning from cardiopulmonary bypass, and 8.0 to 8.5 g/dL after the end of surgery. Fresh frozen plasma, platelets, or coagulation factor concentrates were to be given for the correction of microvascular bleeding, which was defined by a chest tube drainage >200 mL/h for 2 consecutive hours in the presence of abnormal coagulation values (either Quick test <50%, an activated partial thromboplastin time >60 seconds, a platelet count <50 × 109/L, and a fibrinogen concentration <1 g/L).
The primary variable for assessing therapeutic equivalence was the volume of the study drug in milliliters needed for hemodynamic stabilization until 6 hours after the end of surgery (ie, the cumulative volume of the study drug in milliliters administered up to this time point). Therapeutic equivalence regarding the primary variable was defined as the treatment difference ≤500 mL in the amount of the study drug.
Consecutive variables analyzed were the chloride level and arterial pH at the end of surgery. The serum chloride levels were measured at each time point from enrollment to the first postoperative morning and 48 hours postoperatively. Arterial pH was measured at each time point from the induction of anesthesia to 1 hour after arrival in the intensive care unit (ICU) and on the first postoperative morning. In addition, base excess values were measured at the same time points as arterial pH. All blood gas analysis samples were measured at 37°C. Secondary efficacy parameters were the volume of the study drug needed for adequate volume therapy until the end of surgery and the volume needed until 24 hours postoperatively. Further secondary parameters were hemodynamic parameters, blood gases, fluid balance, and concomitant vasoactive medication. Safety parameters were coagulation variables (eg, platelet count, fibrinogen, prothrombin time, thrombin time, and activated partial thromboplastin time), hematology parameters (eg, hemoglobin, hematocrit, erythrocytes, and leukocytes), clinical chemistry parameters (eg, creatinine, urea, albumin, aspartataminotransaminase, alaninaminotransaminase, gamma-glutamyltransferase, and lactatedehydrogenase), urine analysis, creatinine clearance, and adverse events. With regard to patient outcome, the duration of mechanical ventilation, the length of ICU stay and hospital stay, and mortality were recorded. Patients were contacted by telephone 30 days after surgery in order to obtain data on potential delayed adverse events.
Based on a 2-sided significance level of 5%, a power of 90%, an expected treatment difference of 0 mL, and a common treatment standard deviation of 750 mL, 80 patients were required for the demonstration of equivalence (ie, treatment difference ≤500 mL or less than one bottle because complete bags or bottles usually are given to adult patients in clinical practice). For the statistical analysis program, SAS Version 8.2 was used.
Primary therapeutic equivalence variable was the accumulated study drug volume in milliliters administered up to 6 hours after the end of surgery. Consecutive variables used for the confirmatory analysis were chloride levels and arterial pH at the end of surgery. A confirmatory analysis was performed to assess the therapeutic equivalence and differences between treatments regarding chloride and arterial pH at a 2-sided significance level of 5% or a 1-sided significance level of 2.5%. Analysis of variance with treatment and center effects was used for confirmatory testing of the primary variable. Baseline values were included as covariates in the analyses of chloride and arterial pH. When analyzing chloride, the concomitant chloride administration was included in the model as a further covariate. Data are presented as means ± standard deviation.
Results
Eighty-one patients were included in the study; 43 were treated with 6% HES 130/0.4 balanced, and 38 patients were treated with 6% HES 130/0.4 saline (Fig 1). Treatment groups were comparable regarding age, sex, height, weight, and body mass index. Patient demographics, preoperative medication, and concomitant diseases are presented in Table 1. There were more patients with combined surgery in the HES 130/0.4 balanced group (coronary artery bypass graft plus valve surgery, 16 v 6, Table 2). Regarding concomitant medication including the use of vasoactive drugs, there were no major differences between the 2 centers with 1 exception: 21 of 32 patients (this corresponds to 65.6%) in Hamburg (12 patients with HES 130/0.4 balanced and 9 patients with HES 130/0.4 saline) versus none in Vienna received 300 mg of clopidogrel immediately before surgery.
Fig 1.
Study patient flow.
Table 1. Patient Characteristics
| HES 130 Balanced | HES 130 Saline | |||
|---|---|---|---|---|
| N (%) | Mean (range) | N (%) | Mean (range) | |
| Demographics | ||||
 Sex (M/F) | 33/10(77/23) | — | 29/9(76/24) | — |
| Age (y) | 43(100.0) | 64.6(38-83) | 38(100.0) | 67.9(53-83) |
| Body weight (kg) | 43(100.0) | 80.3(53-115) | 38(100.0) | 79.6(55-100) |
| Body height (cm) | 43(100.0) | 172(158-186) | 38(100.0) | 170(150-183) |
| BMI (kg/m2) males | 33(100.0) | 27.4(21.0-35.0) | 29(100.0) | 27.6(21.5-30.9) |
| BMI (kg/m2) females | 10(100.0) | 25.3(21.2-30.1) | 9(100.0) | 26.9(21.8-30.9) |
| Concomitant diseases | ||||
| Previous myocardial infarction | 5(11.6) | — | 5(13.2) | — |
| Previous cardiac failure | 0(0.0) | — | 2(5.3) | — |
| Hypertension | 30(69.8) | — | 24(63.2) | — |
| COPD | 7(16.3) | — | 6(15.8) | — |
| Diabetes type II | 9(21.0) | — | 10(26.4) | — |
| Concomitant medication (prior surgery) | ||||
| Antithrombotic agents | 34(79.1) | 26(68.4) | — | |
| Lipid-lowering agents | 30(69.8) | 27(71.1) | — | |
| ACE inhibitors | 25(58.1) | 27(71.1) | — | |
| β-Blocker | 23(53.5) | 21(55.3) | — | |
| Diuretics | 11(25.6) | 12(31.6) | — | |
Table 2. Procedures and Duration of Medical Care
| HES 130 Balanced | HES 130 Saline | |||
|---|---|---|---|---|
| N (%) | Mean (range) | N (%) | Mean (range) | |
| Type of procedure | ||||
| Coronary artery bypass graft | 19(44.2) | — | 21(55.3) | — |
| Valve surgery | 8(18.6) | — | 11(28.9) | — |
| Coronary artery bypass graft + valve surgery | 16(37.2) | — | 6(15.8) | — |
| Surgery details | ||||
| Duration of surgery (h) | 43(100.0) | 4.1(2.5-10.3) | 38(100.0) | 3.8(2.1-7.8) |
| Cardiopulmonary bypass time (h) | 43(100.0) | 2.0(1.0-7.7) | 38(100.0) | 1.8(0.6-3.6) |
| Cross-clamp time (h) | 43(100.0) | 1.3(0.7-4.5) | 38(100.0) | 1.1(0.5-2.2) |
| Ventilator time (d) | 43(100.0) | 1.4(0.2-15.2) | 38(100.0) | 0.8(0.3-4.0) |
| Outcome | ||||
| ICU duration of stay (d) | 43(100.0) | 5.5(0.6-87.1) | 38(100.0) | 4.5(0.8 –93) |
| Hospital duration of stay (d) | 43(100.0) | 15.4(7.0-88.0) | 38(100.0) | 11.5(5.0-93) |
| Mortality⁎ | 2(4.7) | — | 1(2.6) | — |
⁎Includes fatalities up to 88 (HES 130 balanced) and 93 (HES 130 saline) days after surgery. |
In view of the primary study endpoint, similar volumes of 6% HES 130/0.4 balanced and 6% HES 130/0.4 saline were administered until 6 hours after surgery. The mean dose was 2,390 ± 520 mL and 2,240 ± 510 mL in the HES 130/0.4 balanced and HES 130/0.4 saline group, respectively. The 95% confidence interval found for the difference HES 130/0.4 balanced minus HES 130/0.4 saline (−77, 377 mL) was entirely contained in the predefined interval (−500, 500 mL), and, therefore, equivalence has been proven statistically. Perioperative infusion volumes grouped by component are presented in Table 3.
Table 3. Intraoperative and Postoperative Infusions
| HES 130 Balanced (N = 43) | HES 130 Saline (N = 38) | |
|---|---|---|
| Intraoperative | ||
| HES | 1,665±530 | 1,572±516 |
| Crystalloids | 3,271±956 | 3,079±866 |
| Total fluid input⁎ | 5,644±1,743 | 5,417±1,195 |
| Postoperative (end of surgery until 6 h postoperatively) | ||
| HES | 648±432 | 621±342 |
| Crystalloids | 1,720±1,197 | 1,643±1,066 |
| Total fluid input⁎ | 2,906±1,647 | 2,462±1,290 |
| Postoperative (6-24 h) | ||
| HES | 633±562 | 517±444 |
| Crystalloids | 2,657±1,764 | 2,510±1,935 |
| Total fluid input‡ | 3,654±1,818 | 3,351±1,948 |
⁎Total fluid input includes HES, crystalloids, blood products such as red blood cell concentrates or fresh frozen plasma, and other colloids and medications. |
Consecutive variables analyzed were the chloride level at the end of surgery and the arterial pH at the end of surgery. The serum chloride level (mmol/L) was significantly lower after cardiopulmonary bypass (108.4 ± 4.3 v 110.4 ± 3.8, p = 0.0103) and at the end of surgery (110.0 ± 3.8 v 111.9 ± 4.2, p = 0.0171), as well as highly significantly lower 6 hours postoperatively (110.5 ± 3.7 v 113.5 ± 4.0, p = 0.0003) in the balanced HES 130/0.4 group. Changes of serum chloride levels over time are presented in Figure 2.
Fig 2.
The time course of plasma chloride levels; squares, HES 130 balanced; triangles, HES 130 saline; data are means ± standard deviation; *p < 0.05, ***p < 0.001 for differences between groups; T-1, enrollment; baseline, after anesthesia induction; T1, during extracorporeal circulation; T2, after extracorporeal circulation; T3, end of surgery; T4, 1 hour after arrival at ICU; T6, first postoperative morning; T7, 48 hours postoperatively; p values are results of analysis of covariance-based testing for superiority of HES 130 balanced with the factors center, treatment, baseline, and perioperatively administered chloride (see Methods section for further details).
The arterial pH was higher in the HES 130/0.4 balanced group at all time points after baseline than in the HES 130/0.4 saline group (Fig 3). Significant differences of mean pH were seen during bypass (7.41 ± 0.05 v 7.37 ± 0.06, p = 0.0005) and after extracorporeal circulation (7.40 ± 0.05 v 7.37 ± 0.06, p = 0.0040). For base excess, analysis of covariance yielded highly significant group differences at all time points after baseline (Fig 4).
Fig 3.
The time course of arterial pH; squares, HES 130 balanced; triangles, HES 130 saline; data are means ± standard deviation; **p < 0.01 for differences between groups; baseline, after anesthesia induction; T1, during extracorporeal circulation; T2, after extracorporeal circulation; T3, end of surgery; T4, 1 hour after arrival at ICU; T6, first postoperative morning; p values are the results of analysis of covariance–based testing for superiority of HES 130 balanced with the factors center, treatment, and baseline (see Methods section for further details).
Fig 4.
The time course of base excess; squares, HES balanced; triangles, HES saline; data are means ± standard deviation; **p < 0.01 and ***p < 0.001 for differences between groups; baseline, after anesthesia induction; T1, during extracorporeal circulation (p < 0.0001); T2, after extracorporeal circulation (p = 0.0037); T3, end of surgery (p = 0.0032); T4, 1 hour after arrival at ICU (p = 0.0005); T6, first postoperative morning (p = 0.0039); p values are results of analysis of covariance–based testing for the superiority of HES 130 balanced with the factors centre, treatment, and baseline (see Methods section for further details).
Analysis of adverse events, whether or not related to the study drugs, included those that began or worsened between the start of study medication and 30 days after surgery. A total of 57 patients (70.4%) experienced at least 1 adverse event, 29 patients (67.4%) in the HES 130/0.4 balanced group and 28 patients (73.7%) in the HES 130/0.4 saline group. The majority of adverse events were of mild-to-moderate intensity (72.9%) and rated as unlikely related to the study drug in 75.0%. Most frequent events were atrial fibrillation (9 patients in each group, 20.9% for HES 130/0.4 balanced v 23.7% for HES 130/0.4 saline), postprocedural hemorrhage (7 v 4 patients, 16.3% v 10.5%), hemoglobin decrease (4 v 3 patients, 9.3% v 7.9%), and respiratory failure (4 v 1 patients, 9.3 v 2.6%). Adverse events possibly related to the study drugs comprised metabolic acidosis or hyperchloremic acidosis (one of these conditions: 2 v 7 patients, 4.6% v 18.4%), perioperative bleeding (6 v 4 patients, 14.0% v 10.5%), and decreased hemoglobin (1 v 3 patients, 2.3% v 7.9%). Pruritus was experienced by 2 patients in the HES 130/0.4 balanced group and by 1 patient in the HES 130/0.4 saline group and was considered to be related to the study drug only in 1 patient of the HES 130/0.4 balanced group (mild, duration <24 h, alternative explanation: dexpanthenole allergy). There were 2 deaths in the balanced HES 130/0.4 group. One patient died 20 days postoperatively because of cardiac arrest, and another patient died 88 days after surgery because of respiratory failure. There was 1 death in the HES 130/0.4 saline group 93 days after surgery because of multiorgan failure. All fatalities were considered to be unrelated to the study drugs.
Apart from the electrolyte chloride and acid-base status, there were no relevant treatment group differences regarding any laboratory value. Clinically relevant hyperkalemia was reported in 1 HES 130/0.4 saline patient (as transient) and in no HES 130/0.4-balanced patient. The total urine output until 24 hours was 56 ± 26 versus 58 ± 28 mL/kg body weight. Creatinine clearance (measured by urinary collection from 24-48 hours) also was not significantly different between groups (109.7 ± 66.2 v 94.3 ± 42.7 mL/min). Measured blood loss was virtually identical when comparing groups for both the intraoperative period (14.3 ± 12.4 v 14.6 ± 10.0 mL/kg body weight) and the postoperative period (12.1 ± 8.5 v 12.9 ± 11.0 mL/kg body weight).
Parameters of surgical outcome did not show significant differences. Median values were 0.6 versus 0.6 days (intubation time), 1.9 versus 1.1 days (ICU stay), and 9 versus 9 days (hospital stay), respectively. For means and ranges, please refer to Table 2. Slightly higher mean values for the HES 130/0.4-balanced group can be explained by the higher proportion of combined procedures (16 v 6 cases) in this group. Overall, except for fewer cases of hyperchloremic acidosis in the HES 130/0.4-balanced group, both solutions were found to be comparable regarding safety.
Discussion
The major findings of the present study were that therapeutic equivalence of the 2 different formulations, 6% HES 130/0.4 in saline and 6% HES 130/0.4 in a balanced electrolyte solution, could be proven statistically. In addition, lower chloride levels, less negative base excess values, and higher pH during cardiopulmonary bypass were found in the HES 130/0.4 balanced group. Hyperchloremic acidosis was more frequent in the HES 130/0.4 saline group (7 patients) than in the HES 130/0.4 balanced group (2 patients, p = 0.049, χ2). In contrast to others,14, 15, 16 the authors found no difference in renal function parameters.
It was expected that the safety and efficacy of 6% HES 130/0.4 in a balanced electrolyte solution were comparable to 6% HES 130/0.4 in saline. The aim was not to compare completely opposite treatment concepts, like completely saline-based versus completely balanced infusion solutions, but to selectively examine the influence of the carrier solution of the colloid on the acid-base status. Therefore, the same type of add-on crystalloid was used in both groups.
According to the proponents of dilutional acidosis, perioperatively measured nonrespiratory acidosis is predictable if caused by hemodilution using buffer-free fluids.25 Base excess and PCO2 are important variables to differentiate and quantify nonrespiratory and respiratory causes of acid-base derangements.26, 27, 28 PCO2 levels were maintained by ventilation and were not different between the groups; the statistically significant lower base excess represented a disturbance in the nonrespiratory (ie, metabolic state) in the HES saline group. The reason for hyperchloremic acidosis in patients receiving saline based fluids can be explained elegantly by using Stewart's acid-base approach.29 This approach allows for the determination of the mathematically independent variables that influence the concentration of H+. According to Stewart, the independent variables that contribute to the pH of body fluids are the strong ion difference (SID, Σ [strong cations] − Σ [strong anions], calculated as Na+ + K+ − Cl− − lactate), the PCO2, and the albumin concentration. The SID is the most important variable in determining metabolic influences on the pH of the body fluid.30 If normal saline solution is administered, an increase in the chloride concentration results in a decrease in the SID and creates an acidosis.31
The definite relevance of hyperchloremic acidosis remains unclear although most published data suggest that there is some clinical impact. Noritomi et al32 showed that patients with severe sepsis and septic shock exhibit a complex metabolic acidosis at ICU admission caused predominantly by hyperchloremic acidosis. Wilkes et al14 performed a study to determine whether crystalloid and colloid solutions with a more physiologically balanced electrolyte formulation can provide a superior metabolic environment and improved indices of organ perfusion when compared with saline-based fluids in elderly surgical patients. The latter authors showed that the use of balanced formulations can prevent the development of hyperchloremic metabolic acidosis and yields better gastric mucosal perfusion compared with saline-based solutions. Ondiveeran and Fox-Robichaud33 reported that pentastarch in a balanced solution, but not in normal saline, significantly reduced hepatic leukocyte recruitment, suggesting that solution composition regarding electrolytes may have impact on the immune response. It was found34, 35 that base excess was significantly more negative in the unbalanced group (6% HES 130 in saline solution + unbalanced saline solution) and remained unchanged in the balanced group (6% HES 130 in balanced solution + balanced crystalloid). In their studies, a “total balanced” regimen consisting of balanced HES plus balanced crystalloid versus unbalanced HES plus unbalanced crystalloid was examined. Therefore, the between-group differences in chloride and acid-base parameters were expectedly larger than those found in the present study.
The first HES in a balanced solution (Hextend; Hospira Inc, Lake forest, IL; product originating from Biotime Inc, Berkeley, CA) used first-generation hetastarch (HES 670/0.75) as the colloid component. It could be shown that HES pharmacokinetics were not influenced by the change of the crystalloid carrier.23 This means in the case of hetastarch that the product accumulates in plasma and tissues after repetitive use to a similar extent to saline-based hetastarch products.8 There were several drivers for the development of this first balanced HES solution including (1) the potential avoidance of hyperchloremic acidosis,14, 35 (2) the reduction of bleeding after hetastarch and overcoming dose limitations,24 and (3) the possibly increased urinary flow using balanced solutions.14, 16
Meanwhile, third-generation HES products (based on HES 130/0.4) have become available and are used widely because of their improved safety profile.8 The aim of the development of HES 130/0.4 in balanced electrolyte solution (Volulyte) was to combine favorable HES pharmacokinetics with an improved carrier solution, while avoiding the unnecessary addition of glucose, which was included in the formulation of Hextend. In the present study, the authors were able to show that the use of a balanced 6% HES 130/0.4 solution reduced the incidence of hyperchloremic acidosis and improved acid-base status in cardiac surgery while the volume needed for adequate therapy was equivalent.
In a study in major abdominal surgery, Boldt et al22 compared a “total balanced” volume replacement strategy with an exclusively NaCl 0.9%–based strategy. Besides 3.8 L versus 3.5 L of HES colloid, 6.0 L versus 5.3 L of balanced versus saline-based crystalloids were given. In a similar comparison of concepts in cardiac surgery, Boldt et al used 3.0 L of both balanced and saline-based HES solutions and 5.1 L of balanced crystalloid and 0.9% saline, respectively. Expectedly, the latter studies showed higher differences in Cl− and base excess compared with the present study. Notably, in the present study, only the colloid carrier solution was changed (same crystalloid in both groups) to test for the specific value of using a balanced colloid solution within a volume therapy concept. One further difference of the 2 studies by Boldt et al and the present study was that pH and base excess in the balanced group showed the development of alkalosis, which was in contrast to the present study. Additionally, the 6% HES 130/0.4 saline patients in the present study had slightly less severe acidosis at the end of surgery compared with the saline group in the studies by Boldt et al (mean base excess −3.6 in the present study v −5 mmol/L22 and −4.8 mmol/L35). Jungheinrich et al10, 36 recently published data showing that the infusion of moderate amounts of 6% HES 130/0.4 saline (approximately 2 L) does not necessarily result in hyperchloremic acidosis if the concomitant use of balanced crystalloids is not artificially restricted. Despite the content of potassium, the new carrier solution did not cause clinically relevant hyperkalemia. This is in line with data from O'Malley et al,37 reporting cases of hyperkalemia with the use of saline solution in renal transplant requiring intervention but none with Ringer's lactate.
It has been reported that acidosis delays gastric emptying in animals.38 Less clear, however, is the role of hyperchloremic acidosis in the multifactorial genesis of postoperative gastrointestinal tract dysfunction.14, 16 Nausea or vomiting were not frequent events in the present study and reported for the saline group only (1 patient each). Gunnerson et al39 showed an increased mortality associated with lactate and unidentified anions acidosis. In the latter cohort study, hyperchloremic acidosis was not associated with increased mortality. On the other hand, Noritomi et al32 found that patients with severe sepsis and septic shock exhibited a complex metabolic acidosis at intensive care unit admission, caused predominantly by hyperchloremic acidosis. Therefore, Van Aken et al40 recommended an ionic composition of intravenous infusion solutions, which is as much as possible identical to the extracellular fluid. A preference for balanced crystalloid solutions (or a suitable colloid) is also expressed in the current UK guideline.41 This study had some limitations that the authors want to acknowledge. First, the study was not designed to prove the translation of acid-base status improvements to clinical outcomes. Second, no dramatic differences in acid-base status were to be expected because only the carrier solution of the colloid and not all fluid given to the patients was varied regarding chloride and buffer content. However, given the distribution volume of chloride and the difference in chloride given with the 2 treatment groups (154-110 = 44 mmol/L chloride), the maximum mean chloride difference observed (3 mmol/L at 6 hours) was well in the expected order of magnitude. The specific effect of a modification of the colloid carrier solution only, has, to the authors' knowledge, not been studied previously, and the data show a realistic perspective of this effect.
In summary, this study showed that 6% HES 130/0.4 balanced (Volulyte) and saline-based 6% HES 130/0.4 were equally effective for hemodynamic stabilization. A reduction of hyperchloremia and cases of hyperchloremic acidosis in the balanced group could be shown in cardiac surgery and in a setting in which only the colloid carrier was modified. Differences in chloride concentrations were not large but in the range of what had to be expected with this modification of the colloid carrier only. Outcome measures like ICU stay, hospital stay, and mortality were not different between groups, and safety apart from the surrogate parameters of acid-base status was similar between groups. The use of balanced colloid solutions is probably not uniformly warranted as long as moderate infusion amounts are used, and the use of concomitant balanced crystalloids is not unnecessarily restricted. For large-dose infusions, however, balanced colloids may reduce chloride load and avoid hyperchloremic acidosis. Lower influence of balanced solutions on base excess can be regarded per se because beneficial base excess is an important marker of severity of metabolic derangement that should not be masked.42 Regarding influence on bleeding and renal excretion, the type of HES raw material seems to be more important than the carrier solution.11, 43
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PII: S1053-0770(10)00516-1
doi:10.1053/j.jvca.2010.12.005
© 2011 Elsevier Inc. All rights reserved.
Volume 25, Issue 3 , Pages 407-414, June 2011
