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Impact of balanced tetrastarch raw material on perioperative blood loss: a randomized double blind controlled trial†
British Journal of Anaesthesia, 117 (4): 442–9 (2016) doi: 10.1093/bja/aew249 Cardiovascular
CARDIOVASCULAR
A. Joosten1,‡,*, R. Tircoveanu2,‡, S. Arend2, P. Wauthy3, P. Gottignies4 and P. Van der Linden2 1
Department of Anesthesiology and Perioperative Care, Erasme University Hospital, Université Libre de Bruxelles, Brussels, Belgium, 2Department of Anesthesiology and Perioperative Care, CHU Brugmann, Université Libre de Bruxelles, Brussels, Belgium, 3Department of Cardiac Surgery, CHU Brugmann, Université Libre de Bruxelles, Brussels, Belgium, and 4Department of Intensive Care, CHU Brugmann, Université Libre de Bruxelles, Brussels, Belgium *Corresponding author. E-mail: [email protected]
Abstract Background: As 6% hydroxyethyl starch (HES) 130/0.40 or 130/0.42 can originate from different vegetable sources, they might have different clinical effects. The purpose of this prospective, randomized, double-blind controlled trial was to compare two balanced tetrastarch solutions, one maize-derived and one potato-derived, on perioperative blood loss in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). Methods: We randomly assigned 118 patients undergoing elective cardiac surgery into two groups, to receive either a maize- or a potato-derived HES solution. Study fluids were administered perioperatively (including priming of CPB) until the second postoperative day (POD#2) using a goal directed algorithm. The primary outcome was calculated postoperative blood loss up to POD#2. Secondary outcomes included short-term incidence of acute kidney injury (AKI), and long-term effect (up to one yr) on renal function. Results: Preoperative and intraoperative characteristics of the subjects were similar between groups. Similar volumes of HES were administered (1950 ml [1250–2325] for maize-HES and 2000 ml [1500–2700] for potato-HES; P=0.204). Calculated blood loss (504 ml [413–672] for maize-HES vs 530 ml [468–705] for potato-HES; P=0.107) and the need for blood components were not different between groups. The incidence of AKI was similar in both groups (P=0.111). Plasma creatinine concentration and glomerular filtration rates did vary over time, although changes were minimal. Conclusions: Under our study conditions, HES 130/0.4 or 130/0.42 raw material did not have a significant influence on perioperative blood loss. Moreover, we did not find any effect of tetrastarch raw material composition on short and long-term renal function. Clinical trial registration: EudraCT number: 2011-005920-16. Key words: acute kidney injury; blood loss; cardiac surgical procedures; colloids; hydroxyethyl starch
†
This Article is accompanied by Editorial Aew304. A. Joosten and R. Tircoveanu are co-first authors. Accepted: June 5, 2016 ‡
© The Author 2016. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: [email protected]
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Impact of balanced tetrastarch raw material on perioperative blood loss: a randomized double blind controlled trial†
Impact of tetrastarch raw material on perioperative blood loss in cardiac surgery
Editor’s key points • The influence of hydroxyethyl starch (HES) raw material on haemostasis and renal outcome in cardiac surgery is unknown. • Patients undergoing cardiac surgery with cardiopulmonary bypass were prospectively randomized to receive balanced tetrastarch solutions derived from either maize or potato. • Perioperative blood loss, transfusion, and kidney injury did not differ between groups in this study of 118 subjects. • These preliminary findings suggest no significant clinical differences between balanced tetrastarch solutions derived from two different sources.
perioperative and long-term renal function, patient quality of life and occurrence of pruritus.
Methods Ethics The investigation was approved by the Ethics Committee of Brugmann’s Hospital and registered under the EudraCT number: 2011-005920-16. All 118 subjects provided written informed consent the day before surgery.
Patients Inclusion criteria were patients >18 yr undergoing elective cardiac surgery with CPB. Exclusion criteria were patients with an ASA physical status greater than III, heart failure (left ventricular ejection fraction <30%), cardiac arrhythmias, significant aortic regurgitation, coagulation disorders ( platelet count <100 000 µl−1, activated partial thromboplastin time >1.5 normal), preoperative renal dysfunction (serum creatinine >2 mg ml−1, oliguria, anuria, or receiving haemodialysis), impaired hepatic function (aspartate amino-transferase, alanine amino-transferase >2 times normal), current pregnancy or lactation, and known allergy to HES.
Randomization and blinding Randomization of the study was created by our hospital pharmacist in blocks of 10 using an internet-based software (http://www. randomization.com). The morning of surgery, blinded solutions were provided in identical plastic bags (500 ml) which prevented identification of the type of fluid being used. All investigators and people taking care of the patients remained blinded until the completion of the study and finalization of the statistical analysis.
Anaesthesia procedures Premedication was standardized and consisted of 0.5 mg of alprazolam on the morning of surgery. Preoperative medications such as β-blockers, statins and calcium channel blockers were continued until the day of surgery. Preoperative antiplatelet drugs were stopped seven days before surgery, unless medical conditions required them to be maintained until the day of surgery. Angiotensin-converting enzyme inhibitors (ACEI), angiotensin II receptor blockers (ARB) and oral hypoglycaemic agents were stopped 24 to 48 h before surgery. Standard monitoring included 5-lead ECG, pulse oximetry, noninvasive blood pressure, central venous pressure, invasive radial artery catheter (using a Flotrac catheter connected to the Vigileo monitoring device, Edwards Lifesciences, Irvine, CA, USA), rectal temperature, inspiratory and expiratory gas concentrations, urine output, and depth of anaesthesia monitoring (Spectral Entropy, GE Healthcare, Helsinki, Finland). Anaesthesia was induced with lean body weight-adjusted doses of etomidate (0.2 mg kg−1), sufentanil (0.2 mcg kg−1), and rocuronium (0.5 mg kg−1), and was maintained with sufentanil (Geps PK model: 0.7–1.2 ng ml−1) and midazolam (0.05–0.1 mg kg−1 h−1) using a target-controlled infusion pump (Alaris® PK) syringe assessment. After intubation, lungs were ventilated with a tidal volume of 8 ml kg−1 lean body weight, PEEPof 5 cm H2O, and respiratory rate to achieve an end tidal carbon dioxide pressure between 4.3 and 4.8 Kpa. Prophylactic antibiotic (2 g of cefazolin), methylprednisolone (15 mg kg−1) and tranexamic acid (30 mg kg−1 loading dose +2 mg kg−1 pump prime +16 mg kg−1 h−1 maintenance infusion during CPB)14 were administered to all subjects. Anaesthetic drugs were
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Six percent hydroxyethyl starch (HES) 130/0.40 or 130/0.42, commonly known as tetrastarch, has been routinely used to treat hypovolaemia, in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB), as it is considered to be superior for volume expansion compared with crystalloid solutions.1 This fluid consists of large branched glucose molecules substituted with hydroxyethyl groups for increased solubility and intravascular persistence. They are formulated to a concentration of 6%, a mean molecular weight of 130 kDa, and a molar substitution of 0.40 or 0.42. There is an active debate over the use of tetrastarch in high risk surgical patients. However, five recent meta-analyses failed to identify an association between surgical HES administration and postoperative morbidity or mortality.2–6 Newer tetrastarch solutions have been developed in an electrolyte balanced solution. Recent German guidelines recommend that if colloids are used in perioperative care, balanced solutions are preferred.7 While previously published studies have shown that 0.9% NaCl (‘unbalanced’) HES solutions are associated with various clinical side-effects, balanced-HES solutions with electrolyte concentrations closer to human plasma have not been as rigorously examined. Interestingly, these newer solutions might improve postoperative acid-base status8 and potentially decrease the incidence of AKI and use of renal replacement therapy (RRT).9 Importantly, balanced tetrastarch solutions can be derived from two different raw materials (maize or potato). Maize and potato-derived HES differ in their molecular and chemical structures10 and are not bioequivalent.11 Maize starch is largely composed (98%) of highly branched amylopectin, while potato starch contains a lower degree of branching, consisting of a heterogeneous mixture of around 75% of amylopectin and 25% of linear chains of amylose. Potato starch contains several thousand esterified phosphate groups, whereas almost none can be detected in maize starch. Negatively charged phosphate-ester groups in potato-HES could impair coagulation and also metabolization in the liver. Jamnicki and colleagues12 demonstrated that potato-HES compromises in vitro blood coagulation more than maize-HES. There is clinical evidence supporting the clinical use of maize-HES, while published data are lacking with regards to potato-HES.13 Therefore, one cannot justify the clinical use of potato-HES with evidence derived from studies investigating maize-HES. The main objective of this prospective, randomized, double-blind trial was to compare two balanced tetrastarch solutions, one maize derived 6% HES 130/0.4 (Volulyte®, Fresenius Kabi GmbH, Bad Homburg, Germany) and one potato derived 6% HES 130/0.42 (Vitafusal®, Serum Werk Bernburg AG, Germany), on perioperative blood loss in patients undergoing cardiac surgery. Additionally, as the short and long-term safety profile of HES continues to fuel controversy, we secondarily examined both
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Study fluid administration using a goal directed haemodynamic protocol Perioperative study fluid administration was started immediately after induction of anaesthesia and was based on a goal-directed haemodynamic algorithm using stroke volume variation (SVV), to assess fluid responsiveness. This pre-defined algorithm allowed us to standardize study fluid administration and use of vasopressors and inotrope agents consistently in all subjects (Fig. 1). Study fluids were titrated as 250 ml boluses up until POD#2 to maintain SVV (during mechanical ventilation) less than 13%15 (Vigileo,
Perioperative goal-directed haemodynamic algorithm Stroke volume variation
>13%
<13%
250 ml of study HES
Cardiac index
<2.5 L /min
>2.5 L /min
Dobutamine infusion
Mean arterial pressure
<65 mmHg
Norepinephrine infusion
>65 mmHg
Nothing
Fig 1 The perioperative goal-directed haemodynamic algorithm used during the study to guide HES administration, vasopressor and inotropic drugs infusion.
Edwards LifeSciences, Irvine, USA). After extubation, fluid administration was at the discretion of the critical care provider.
Outcome variables The primary outcome was defined as calculated blood loss from the time of surgery up to POD#2. Calculated blood loss was quantified using a formula taking into account preoperative and postoperative haematocrit and estimated blood volume.16 Secondary outcomes were defined as short and long-term effects of study fluids on postoperative renal function. Short term renal function was assessed by quantifying the incidence of 1) AKI calculated using the Acute Kidney Injury Network (AKIN) classification (without taking into account urine output criteria) based on change in serum creatinine from preoperative baseline (day before surgery) to POD#217 and 2) requirement for the use of RRT. For long-term assessment of renal function, medical records were examined using our hospital database (Mediview® and Mediweb® software) in order to record urea and creatinine measurements and the estimated glomerular filtration rate (eGFR) during outpatient postoperative follow-up appointments. The eGFR was calculated using the CKD – EPI formula.18 When no results were found, the subjects’ general practitioner and/or cardiologist were contacted by telephone in order to inquire about health, potential delayed complications, and to obtain the urea and creatinine measurements. The goal was to collect at least one value between discharge and six months postoperatively and one additional value at one yr postoperatively. Tertiary outcomes included exposure to blood products, transfusion rates, ICU and hospital LOS, incidence of postoperative complications (new onset of atrial fibrillation, incidence of postoperative delirium [defined as acutely altered and fluctuating mental status with features of inattention and an altered level of consciousness], redo surgery for haemorrhage, respiratory insufficiency [defined as prolonged mechanical ventilation for hypoxaemia])
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adjusted intraoperatively to target a spectral entropy value between 50 and 60. Subjects were allowed to receive up to 500 ml of balanced crystalloid before CBP. The CPB circuit was primed exclusively with 150 ml of mannitol, 5000 i.v. of heparin and 1000 ml of the HES solution allocated to each subject, with the same CPB circuit was used in all subjects. Anticoagulation was achieved with heparin (400 IU kg−1), and activated clotting time (ACT) was kept >600 sec during CPB with repeated boluses of heparin when required. Mild to moderate hypothermia was induced (32–34°C) depending on the surgical procedure. Pump flow rate was maintained around 2.8 Litre min−1 m−2. Mean arterial pressure was kept between 50 and 70 mm Hg with phenylephrine boluses if required. Cold blood cardoplegia was used in all patients. In order to maintain the filling volume of the circuit, only the allocated study HES was added. All subjects were rewarmed to 35.5°C before weaning from CPB. Remaining heparin at the end of the CPB was neutralized with protamine sulfate at a ratio of heparin/protamine of 2:1. If necessary, additional protamine doses were administered to return the ACT value to baseline. The blood remaining in the CPB circuit was re-transfused without salvage processing after sternal closure. Insulin was administrated as a continuous infusion for blood glucose concentration >150 mg dl−1. The trigger for transfusion of allogeneic red blood cells was a haemoglobin <7 g dl−1 during CPB and <8 g dl−1 after the end of surgery. Fresh frozen plasma, platelets, or fibrinogen were given in the presence of diffuse microvascular bleeding, associated with abnormal coagulation values (either prothrombin time or activated partial thromboplastin time >1.5 of the normal value, platelet count <100 000 µl−1 or fibrinogen concentration <1.5 g l−1, respectively). All patients were performed on by three experienced senior cardiac anaesthetists and by the same two cardiac surgeons. After surgery, subjects were transferred to the ICU and controlled mechanical ventilation was maintained with the same ventilation settings used in the operating room. Postoperative sedation used either midazolam (1–3 mg h−1) or propofol (1–2 mg kg−1 h−1) and sufentanil (5 mcg h−1) or morphine (1–2 mg h−1), depending on the critical care physician taking care of the patient who was also blinded to the study fluids allocation. The trachea was extubated when subjects were haemodynamically stable, temperature >36°C, spontaneous respiration maintained with adequate blood gases, and no bleeding. Postoperative maintenance fluid was 5% dextrose -NaCl 0.45% (0.5 ml kg−1 h−1). In addition to this maintenance fluid, a maximum daily dose of 50 ml kg−1 of study fluid was allowed. If additional volume was required and the maximum dose of HES was reached, 3% modified fluid gelatin (Geloplasma®, Fresenius Kabi GmbH, Bad Homburg, Germany) or a crystalloid (normal saline 0.9%) was used, depending on physician preference. The decision for re-exploration for postoperative bleeding was made using our institution criteria: chest tube drainage ≥500 ml during the first h, ≥400 ml per h during the first 2 h, ≥300 ml per h during the first 3 h, ≥1000 ml during the first 4 h, ≥1200 ml during the first 5 h, 100 ml per h during the first 12 h and massive bleeding, cardiac tamponade, or sudden cardiac arrest in a bleeding patient.
Impact of tetrastarch raw material on perioperative blood loss in cardiac surgery
and mortality. All laboratory and arterial blood gas parameters were measured and recorded at different time points. Subjects were also personally contacted in order to assess potential pruritus experiences during their postoperative period and their health-related quality of life. For this last quantification we used the MacNew questionnaire19 20 which allowed us to assess how cardiac surgery impacted daily quality of life between one and two yr after surgery.
Power analysis
Statistical analysis The distribution of continuous variables was assessed using a Kolmogorov-Smirnov test. Parameters not normally distributed were compared using a Mann-Whitney U-test and expressed as median [25%–75%] percentiles. Creatinine and glomerular
filtration rate values were normally distributed. Linear mixed models21 were used to model the relationship of log(creatinine) and glomerular filtration rate (GFR) ratio through time (from pre-operation until one yr postoperatively). A multiple imputation for multiple level data was conducted with the mice R package22 23 for a missing at random process with 20 iterations, five imputed datasets and run linear mixed models on pooled data. The best maximum likelihood model found incorporates the following fixed effects: time, group, fluid balance at 48 h and an intervention effect. Data were expressed as mean (). Discrete variables were compared using a χ2 test and expressed as percentages. Significance was set at P<0.05.
Results A total of 227 patients were screened for eligibility from March 2012 until September 2014 and 118 patients were included and prospectively randomized between the two groups (Fig. 2). Preoperative subject characteristics (Table 1) and intraoperative variables (Table 2) revealed no significant differences between groups. Similar volume of colloids were administered up to POD#2, but subjects in the Potato HES group received significantly more crystalloids (Table 3). Regarding our outcome variables (Table 3), calculated blood loss until POD#2 was similar in both groups as well as the cumulative measured 48 h blood loss. Transfusion of blood products ( packed red blood cells, fresh frozen plasma, platelets) was also comparable between groups. With respect to relevant postoperative complications, atrial
Assessed for eligibility (n=227)
Enrollment
Randomized (n=118)
Excluded (n=109) Atrial fibrillation (n=31) Preoperative renal failure (n=7) Aortic insufficiency (n=2) Heart failure (n=12) Pulmonary embolism (n=1) Cirrhosis (n=1) Declined to participate (n=21) Language barrier (n=8) Dementia (n=2) Logistic reasons (n=5) Emergency (n=9) Jehova’s witnesses (n=2) Minor patients (n=4) Off pump surgery (n=4)
Consort flow diagram
Allocation Allocated to the maize-HES (n=59) Received allocated intervention (n=59) Did not receive allocated intervention (n=0)
Allocated to the potato-HES (n=59) Received allocated intervention (n=59) Did not receive allocated (n=0)
Data analyzed in maize-HES (n=59)
Data analyzed in potato-HES (n=59) Follow-up
Long term follow-up
Long term follow-up
Kidney function : lost to follow-up (n=17)
Kidney function : lost to follow-up (n=10)
Quality of life : lost to follow-up (n=26)
Quality of life : lost to follow-up (n=15)
Reasons: death, wrong contact address, no control of kidney function available
Reasons: death, wrong contact address, no control of kidney function available Analysis
Long term: • Kidney function : analysed (n=42) • Quality of life : analysed (n=33)
Fig 2 Consort flow diagram.
Long term: • Kidney function : analysed (n=49) • Quality of life : analysed (n=44)
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A sample size calculation was determined a priori based on our primary outcome using the results of our institution database (Rans D BJ, Van der Linden P Blood sparing effect and safety of tranexamic acid compared to aprotinin in adult cardiac surgery. Eur J Anaesth 2010; 27) which demonstrated that the average calculated blood losses from surgery up to POD#2 was 692±288 ml. For a type I error of 0.05 and a power of 0.08, 59 subjects per group were needed to detect a blood loss difference of 150 ml (at 100% of haematocrit, corresponding to one unit of packed red blood cell) between groups.
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fibrillation occurred in 26% of subjects with no difference between groups (Table 3). Four patients (3.4%) needed surgical reexploration for postoperative bleeding: three in the potatogroup and one in the maize-group. With regard to mechanical
Table 1 Baseline subject characteristics. Population data are listed as ‘value (%)’ [range], and quantitative data as ‘median [25– 75 percentiles]’. BSA, body surface area; CABG, coronary artery bypass graft; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blockers; Combined procedures, CABG+valve surgery Maize-HES (N=59)
Potato-HES (N=59)
Age (yr) Gender (Male) Weight (kg) Height (cm) BSA (m2) Circulatory blood volume (ml) Predicted 30-day mortality (Euroscore II) ASA physical grade II III Medications Beta blocker ACEI ARB Statin Oral hypoglycaemic drugs Antiplatelet drugs Type of Surgery CABG Valve Combined procedures Other Redo surgery
63 [19–87] 43 (73) 78 (13) 169 (9) 1.90 [1.78–2.06] 4854 [4374–5169]
68 [18–90] 40 (68) 75 (14) 170 (10) 1.90 [1.77–2.06] 4736 [4296–5158]
1.6 [1.0–1.8]
1.1 [0.8–2.5]
4 (7) 55 (93)
5 (8) 54 (92)
31 (53) 24 (41) 9 (15) 31 (53) 12 (20)
35 (59) 23 (39) 10 (17) 33 (56) 11 (19)
20 (34)
21 (36)
30 (51) 14 (24) 4 (7)
26 (46) 20 (34) 9 (15)
11 (18) 8 (14)
4 (7) 6 (10)
Discussion No significant difference was found between the two balanced HES groups with regard to perioperative blood loss. This is in accordance with the only available study that compared the use of two balanced HES fluids from different vegetable sources in the perioperative setting. This study, published by Sethi and colleagues24 compared a waxy maize-based HES solution with a potato starch-based HES solution, in patients undergoing coronary artery bypass grafting (CABG), with the aim to assess their effects on haemostasis (chest tube blood drainage, re-exploration rate, transfusion rate) and organ function. Importantly however, both HES solutions were only used to prime the CPB circuit (intraoperative use exclusively). Moreover, that study was not
Table 2 Intraoperative characteristics. Population data are listed as ‘value (%)’ and quantitative data as ‘median [25–75 percentiles]’. CPB, cardiopulmonary bypass; HES, Hydroxyethyl starch Variables
Maize-HES (N=59)
Potato-HES (N=59)
P
Time of Anaesthesia (min) Time of Surgery (min) Time of CPB (min) Time of aortic clamp (min) Time of mechanical ventilation (h) Total volume of crystalloid (ml) Total volume of HES (ml) Tranexamic acid (g) Calcium (g) Urine output (ml) Total measured blood loss Fluid Balance (ml) Patients under vasoactive infusion agents
300 [260–330] 184 [150–240] 83 [67–100] 45 [34–55] 15 [11–18] 1055 [869–1255] 1000 [1000–1250] 4 [3–6] 0 [0–1] 482 [377–640] 378 [276–530] 1098 [722–1375] 30 (51)
285 [255–300] 180 [150–212] 81 [67–99] 47 [35–59] 15 [12–18] 1000 [850–1160] 1000 [1000–1200] 4 [3–5] 0 [0–1] 455 [355–660] 350 [300–500] 910 [500–1201] 28 (48)
0.152 0.360 0.667 0.517 0.800 0.185 0.832 0.515 0.849 0.974 0.874 0.141 0.644
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Variable
ventilation time, ICU and hospital LOS, no significant differences were observed between groups. Eight deaths occurred after the long-term follow-up (four in each group), all of which were not considered to be related to the study fluids. The incidence of AKI (14%) at POD#2 was comparable in both groups. Three patients required RRT during the postoperative ICU period: two in the maize group and one in the potato group. Of the 118 subjects included in the study, 91 had follow-up renal laboratory results recorded up to at least 360 days after surgery. Plasma creatinine concentration and glomerular filtration rate (GFR) varied over time, although these variations appear to be minimal and were not different between groups (Table 4). Two factors that were associated with a decrease in these two parameters were a positive fluid balance at POD#2 (P=0.003) and age (P<0.001). Regarding quality of life (Supplementary material, Appendix 1), 77 subjects answered the MacNew questionnaire in the postoperative period: 33 had received maize-HES and 44 had received potato-HES without significant difference between groups. The mean time for answering the questionnaire was 656 days after surgery. No subject described pruritus without being prompted during the postoperative period. Out of the 77 subjects who answered the question when specifically prompted about its occurrence, only 4 (5%) experienced pruritus during the postoperative period, two in each group. Finally, perioperative haemodynamic variables, laboratory values and blood gas measurements were similar between groups at multiple times points (data not shown). No patients in the current study presented any type of anaphylactic reaction after HES administration.
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Impact of tetrastarch raw material on perioperative blood loss in cardiac surgery
Table 3 Outcome variables. Outcome data are presented as ‘value (%)’ and/or median [25–75 percentiles]. PRBC, packed red blood cell; FFP, fresh frozen plasma; ICU, Intensive care unit; AKI, acute kidney injury; POD#2, second postoperative day; AKIN, Acute Kidney Injury Network; RRT, renal replacement therapy; ICU LOS, intensive care unit length of stay. aCumulative intra and postoperative data (up to POD#2) Maize-HES (N=59)
Potato-HES (N=59)
P
Total crystalloid in the postoperative period up to POD#2 (ml) Total colloid in the postoperative period up to POD#2 (ml) Total measured blood loss in the postoperative period up to POD#2 (ml) Total diuresis in the postoperative period up to POD#2 (ml) Calculated blood loss up to POD#2 (ml) Total measured blood loss up to POD#2 (ml)a Total diuresis up to POD#2 (ml)a Total crystalloid up to POD#2 (ml)a Total Colloid up to POD#2 (ml)a Patients transfused up to POD#2 PRBC FFP Platelet Postoperative complications: Atrial Fibrillation Delirium - Confusion Redo surgery for haemorrhage Respiratory Insufficiency Length of stay in ICU (h) Hospital (days) AKI at POD#2 AKIN stage 1 (%) AKIN stage 2 (%) AKIN stage 3 (%) RRT during the entire ICU LOS Mortality Within 30 days after surgery Between 30 days and 90 days After 90 days after surgery
3690 [3299–4394] 500 [0–1000] 550 [405–708] 3035 [2215–3750] 504 [413–672] 934 [764–1221] 3488 [2705–4528] 4778 [4149–5456] 1950 [1250–2325]
4217 [3446–4907] 1000 [350–1500] 550 [395–920] 2755 [2070–3415] 530 [468–705] 951 [695–1410] 3330 [4160–4160] 5394 [4470–6043] 2000 [1500–2700]
0.029 0.052 0.515 0.248 0.107 0.611 0.456 0.038 0.204
13 (22%) 3 (5%) 3 (5%)
17 (29%) 6 (10%) 5 (8%)
0.398 0.294 0.462
14 (24%) 7 (12%) 1 (2%) 17 (29%)
17 (29%) 2 (3%) 3 (5%) 12 (20%)
0.530 0.083 0.309 0.285
96 [72–144] 10 [9–15]
72 [48–96] 11 [9–14]
0.318 0.842
3/59 (5%) 2/59 (3%) 1/59 (2%) 2/59 (3%)
10/59 (17%) 0/59 (0%) 1/59 (2%) 1/59 (2%)
0.111
2 (3%) 0 (0%) 2 (3%)
1 (2%) 1 (2%) 2 (3%)
Table 4 Long-term evolution of renal function. HES, Hydroxyethyl Starch; GFR, Glomerular Filtration Rate. Data are presented as mean () Time Day 0
HES - group
Maize-group Potato-group Day 2 Maize-group Potato-group Day 8 Maize-group Potato-group Day 93 Maize-group Potato-group Day 365 Maize-group Potato-group
Plasma creatinine GFR (ml min−1) (mg dl−1) mean () mean () 0.90 (2) 0.85 (2) 0.74 (3) 0.70 (3) 0.87 (2) 0.82 (2) 0.98 (2) 0.95 (2) 0.98 (1.78) 0.88 (1.68)
77.89 (22) 78.17 (22) 83.73 (31) 82.93 (31) 79.77 (24) 79.84 (25) 73.50 (22) 71.61 (22) 74.91 (23.24) 76.70 (20.49)
double blinded and was performed in patients with a relatively low risk of bleeding (CABG only). Furthermore, they did not use a haemodynamic algorithm to guide fluid administration. Interestingly, the transfusion rate was relatively low in our trial (25%) compared with the literature (>50%25–27). This finding is likely explained by the transfusion and fluid management algorithm we used in our trial, which has consistently been shown to improve
0.559
postoperative outcome28–32 and to decrease the amount of fluid given intraoperatively.33 An important positive effect of less fluid administration is less haemodilution and, therefore, less blood product administration. It is important to note that no algorithm was used to guide HES administration, in the vast majority of previous trials assessing HES utilization in cardiac surgery patients.8 24 34 This point becomes even more important when considering the actual haemodynamic end-points used in these trials, which was typically a static variable such as central venous pressure (CVP). Unfortunately, CVP has clearly been demonstrated to be a weak predictor of fluid responsiveness35 and could have confounded the results of these previous studies. In our study, the median amount of fluid administered up to POD#2 was ∼ 7000 ml (crystalloids and HES together). Much larger cumulative fluid administration, (up to 10–12 Litre in 24 h) was recently reported.8 26 In these studies, no goal directed protocol was used to guide fluid administration. These findings further support the results of a recent survey that suggests that goal-directed fluid management is still poorly adopted in clinical practice.36 Similar to the decreased fluid administration noted in our study, we observed a relatively low surgical re-exploration rate (3.4%) compared with the relevant literature.8 24 This observation might also be related to the fact that our surgeons were present from skin incision to closure, after careful haemostasis of the surgical field.
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Variables
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Strengths and limitations Strengths of this study indicate use of a pre-defined goal directed fluid algorithm perioperatively until extubation, and inclusion of multiple types of surgeries that required CPB, especially those with a high risk of bleeding (e.g. repeat surgery, combined surgery). In most published studies, only low to moderate risk patients were included.24 This is the first published study to assess the long-term (up to one yr after surgery) effects of HES administration on renal function, occurrence of pruritus and quality of life. In most surgical trials assessing the influence of HES on postoperative morbidity, study periods were quite short and ended before long-term adverse effects could be documented. Our study has several limitations. First, as the actual calculated blood loss difference between both HES types was only 26 ml (or a 4% effect size), our study was probably underpowered to demonstrate a significant difference in our primary outcome. Our study was also underpowered to detect differences in other complications, especially regarding renal function (AKI, RRT). The inclusion of significantly more subjects would have been necessary to effectively detect a difference. Additionally, the decision for starting RRT was not standardized in the study protocol and was instead based on clinician judgement. Similarly, the criteria for ICU and hospital discharge were not pre-defined and were instead determined based on clinical judgement. Hopefully, any resulting bias is limited by the prospective, randomized and double blinded study design we used.
Conclusions Under our study conditions, the HES 130/0.4 or 130/0.42 raw material does not seem to have an influence on perioperative blood loss. Moreover, we did not find any long-term effect of tetrastarch raw material composition on short and long term renal function, occurrence of pruritus or quality of life.
Authors’ contributions Study design/planning: A.J., R.T., S.A., P.V.dL. Study conduct: A.J., R.T., S.A., P.V.dL., P.G. Data analysis: A.J., R.T., S.A., P.V.dL., P.G. Writing paper: A.J., R.T., S.A., P.V.dL., P.G., P.W. Revising paper: all authors
Supplementary material Supplementary material is available at British Journal of Anaesthesia online.
Acknowledgements We would thank to thank our hospital pharmacist (Nabil Hayef ) for providing us the blinded study fluids, Jean-François Fils for statistical analysis and Brenton Alexander for English corrections.
Declaration of interest P.V.dL. has received, within the past five yr, fees for lectures and consultancies from Fresenius Kabi GmbH, and Janssen-Cilag SA, Belgium.
References 1. Orbegozo Cortes D, Gamarano Barros T, Njimi H, Vincent JL. Crystalloids versus colloids: exploring differences in fluid requirements by systematic review and meta-regression. Anesth Analg 2015; 120: 389–402 2. Van Der Linden P, James M, Mythen M, Weiskopf RB. Safety of modern starches used during surgery. Anesth Analg 2013; 116: 35–48 3. Gillies MA, Habicher M, Jhanji S, et al. Incidence of postoperative death and acute kidney injury associated with i.v. 6% hydroxyethyl starch use: systematic review and metaanalysis. Br J Anaesth 2014; 112: 25–34 4. Martin C, Jacob M, Vicaut E, Guidet B, Van Aken H, Kurz A. Effect of waxy maize-derived hydroxyethyl starch 130/0.4 on renal function in surgical patients. Anesthesiology 2013; 118: 387–94 5. Jacob M, Fellahi JL, Chappell D, Kurz A. The impact of hydroxyethyl starches in cardiac surgery: a meta-analysis. Crit Care 2014; 18: 656 6. Raiman M, Mitchell CG, Biccard BM, Rodseth RN. Comparison of hydroxyethyl starch colloids with crystalloids for surgical patients: A systematic review and meta-analysis. Eur J Anaesthesiol 2016; 33: 42–8 7. Marx G, Schindler AW, Mosch C, et al. Intravascular volume therapy in adults: Guidelines from the Association of the Scientific Medical Societies in Germany. Eur J Anaesthesiol 2016; 33: 488–521 8. Base EM, Standl T, Lassnigg A, et al. Efficacy and safety of hydroxyethyl starch 6% 130/0.4 in a balanced electrolyte solution (Volulyte) during cardiac surgery. J Cardiothorac Vasc Anesth 2011; 25: 407–14 9. Yunos NM, Bellomo R, Hegarty C, Story D, Ho L, Bailey M. Association between a chloride-liberal vs chloride-restrictive intravenous fluid administration strategy and kidney injury in critically ill adults. JAMA 2012; 308: 1566–72 10. Sommermeyer KCF, Schossow R. Differences in chemical structures between waxy maize-and potato-starch-based hydroxyethylstarch volume therapeutics. Transfus Altern Transfus Med 2007; 9: 127–33 11. Lehmann G, Marx G, Forster H. Bioequivalence comparison between hydroxyethyl starch 130/0.42/6 : 1 and hydroxyethyl starch 130/0.4/9 : 1. Drugs R D 2007; 8: 229–40
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Concerning short term postoperative renal function, we observed an AKI (Stage 1 to stage 3 at POD#2) in 17 subjects (14%) and the need for RRT during the entire ICU LOS in three subjects (2.5%), consistent with what we can extrapolate from the literature (15%–30% for AKI37–41 and 2%–9% for RRT34 37 42). Our results also confirm what has been published recently in a systematic review2 and meta-analyses.3 4 6 These authors reviewed the literature evaluating short term renal function after intraoperative administration of a tetrastarch solution compared with any other fluid type, in patients undergoing elective surgical procedures. They all demonstrated that no differences were noted between the use of a tetrastarch and any of the other tested fluids. It is important to realize that the follow-up period of the different review articles was too short to assess long-term adverse renal effects of HES. Therefore, our longer follow-up period of at least one yr after surgery, helps to address this issue by demonstrating that the choice of balanced HES fluid does not appear to impact longterm renal function. Plasma creatinine concentration and glomerular filtration rates did vary over time, although changes were minimal. The two factors significantly affecting these parameters were a positive fluid balance at POD#2 and age. The deleterious effect of perioperative fluid balance on postoperative renal function has been already reported.43–45 Age has also been found to be a predictor for alteration of renal function in cardiac surgery.46 We did not find any influence of either HES fluid on patient quality of life. We also found no difference of the fluid type on the occurrence of pruritus. The incidence of pruritus was 5% in our trial which is similar to another study8 (4.6%), however the follow-up period was 60 days post-surgery which may be too short to adequately assess this issue.
Impact of tetrastarch raw material on perioperative blood loss in cardiac surgery
30. Ramsingh DS, Sanghvi C, Gamboa J, Cannesson M, Applegate RL 2nd. Outcome impact of goal directed fluid therapy during high risk abdominal surgery in low to moderate risk patients: a randomized controlled trial. J Clin Monit Comput 2013; 27: 249–57 31. Scheeren TW, Wiesenack C, Gerlach H, Marx G. Goal-directed intraoperative fluid therapy guided by stroke volume and its variation in high-risk surgical patients: a prospective randomized multicentre study. J Clin Monit Comput 2013; 27: 225–33 32. Aya HD, Cecconi M, Hamilton M, Rhodes A. Goal-directed therapy in cardiac surgery: a systematic review and metaanalysis. Br J Anaesth 2013; 110: 510–7 33. Cannesson M, Ramsingh D, Rinehart J, et al. Perioperative goaldirected therapy and postoperative outcomes in patients undergoing high-risk abdominal surgery: a historical-prospective, comparative effectiveness study. Crit Care 2015; 19: 261 34. Gurbuz HA, Durukan AB, Salman N, et al. Hydroxyethyl starch 6%, 130/0.4 vs. a balanced crystalloid solution in cardiopulmonary bypass priming: a randomized, prospective study. J Cardiothorac Surg 2013; 8: 71 35. Marik PE, Cavallazzi R. Does the central venous pressure predict fluid responsiveness? An updated meta-analysis and a plea for some common sense. Crit Care Med 2013; 41: 1774–81 36. Cannesson M, Pestel G, Ricks C, Hoeft A, Perel A. Hemodynamic monitoring and management in patients undergoing high risk surgery: a survey among North American and European anesthesiologists. Crit Care 2011; 15: R197 37. Thiele RH, Isbell JM, Rosner MH. AKI associated with cardiac surgery. Clin J Am Soc Nephrol 2015; 10: 500–14 38. Englberger L, Suri RM, Li Z, et al. Clinical accuracy of RIFLE and Acute Kidney Injury Network (AKIN) criteria for acute kidney injury in patients undergoing cardiac surgery. Crit Care 2011; 15: R16 39. Heringlake M, Knappe M, Vargas Hein O, et al. Renal dysfunction according to the ADQI-RIFLE system and clinical practice patterns after cardiac surgery in Germany. Minerva Anestesiol 2006; 72: 645–54 40. Mangano CM, Diamondstone LS, Ramsay JG, Aggarwal A, Herskowitz A, Mangano DT. Renal dysfunction after myocardial revascularization: risk factors, adverse outcomes, and hospital resource utilization. The multicenter study of perioperative ischemia research group. Ann Intern Med 1998; 128: 194–203 41. Robert AM, Kramer RS, Dacey LJ, et al. Cardiac surgery-associated acute kidney injury: a comparison of two consensus criteria. Ann Thorac Surg 2010; 90: 1939–43 42. Kiers HD, van den Boogaard M, Schoenmakers MC, et al. Comparison and clinical suitability of eight prediction models for cardiac surgery-related acute kidney injury. Nephrol Dial Transplant 2013; 28: 345–51 43. Macedo E, Bouchard J, Soroko SH, et al. Fluid accumulation, recognition and staging of acute kidney injury in criticallyill patients. Crit Care 2010; 14: R82 44. Liu KD, Thompson BT, Ancukiewicz M, et al. Acute kidney injury in patients with acute lung injury: impact of fluid accumulation on classification of acute kidney injury and associated outcomes. Crit Care Med 2011; 39: 2665–71 45. Kambhampati G, Ross EA, Alsabbagh MM, et al. Perioperative fluid balance and acute kidney injury. Clin Exp Nephrol 2012; 16: 730–8 46. Xu JR, Zhu JM, Jiang J, et al. Risk factors for long-term mortality and progressive chronic kidney disease associated with acute kidney injury after cardiac surgery. Medicine (Baltimore) 2015; 94: e2025 Handling editor: H. C. Hemmings
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12. Jamnicki M, Zollinger A, Seifert B, Popovic D, Pasch T, Spahn DR. The effect of potato starch derived and corn starch derived hydroxyethyl starch on in vitro blood coagulation. Anaesthesia 1998; 53: 638–44 13. Westphal M, James MF, Kozek-Langenecker S, Stocker R, Guidet B, Van Aken H. Hydroxyethyl starches: different products–different effects. Anesthesiology 2009; 111: 187–202 14. Fergusson DA, Hebert PC, Mazer CD, et al. A comparison of aprotinin and lysine analogues in high-risk cardiac surgery. N Engl J Med 2008; 358: 2319–31 15. Cannesson M, Le Manach Y, Hofer CK, et al. Assessing the diagnostic accuracy of pulse pressure variations for the prediction of fluid responsiveness: a “gray zone” approach. Anesthesiology 2011; 115: 231–41 16. Samama CM, Langeron O, Rosencher N, et al. Aprotinin versus placebo in major orthopedic surgery: a randomized, doubleblinded, dose-ranging study. Anesth Analg 2002; 95: 287–93, table of contents 17. Bagshaw SM, George C, Bellomo R. A comparison of the RIFLE and AKIN criteria for acute kidney injury in critically ill patients. Nephrol Dial Transplant 2008; 23: 1569–74 18. Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med 2009; 150: 604–12 19. Valenti L, Lim L, Heller RF, Knapp J. An improved questionnaire for assessing quality of life after acute myocardial infarction. Qual Life Res 1996; 5: 151–61 20. Morys JM, Hofer S, Rynkiewicz A, Oldridge NB. The Polish MacNew heart disease health-related quality of life questionnaire: A validation study. Cardiol J 2015; 22: 541–50 21. Verbeke GMG. Linear mixed models in practice: A SASoriented approach. New York: Springer, 2001; 2 22. Raghunathan TE, LJ, Van Hoewyk J, Solenberger P. A multivariate technique for multiply imputing missing values using a sequence of regression models. Surv Methodol 2001; 27: 85–96 23. van Buuren SOC. Multivariate Imputation by Chained Equations: MICE V1.0 User’s Manual. TNO Report PG/VGZ/00.038 2000 24. Sethi BS, Chauhan S, Bisoi AK, Kapoor PM, Kiran U, Rajput RS. Comparison of a waxy maize and a potato starch-based balanced hydroxyethyl starch for priming in patients undergoing coronary artery bypass grafting. J Cardiothorac Vasc Anesth 2014; 28: 690–7 25. Mehta RH, Sheng S, O’Brien SM, et al. Reoperation for bleeding in patients undergoing coronary artery bypass surgery: incidence, risk factors, time trends, and outcomes. Circ Cardiovasc Qual Outcomes 2009; 2: 583–90 26. Skhirtladze K, Base EM, Lassnigg A, et al. Comparison of the effects of albumin 5%, hydroxyethyl starch 130/0.4 6%, and Ringer’s lactate on blood loss and coagulation after cardiac surgery. Br J Anaesth 2014; 112: 255–64 27. Mora Mangano CT, Neville MJ, Hsu PH, Mignea I, King J, Miller DC. Aprotinin, blood loss, and renal dysfunction in deep hypothermic circulatory arrest. Circulation 2001; 104: I276–81 28. Benes J, Chytra I, Altmann P, et al. Intraoperative fluid optimization using stroke volume variation in high risk surgical patients: results of prospective randomized study. Crit Care 2010; 14: R118 29. Mayer J, Boldt J, Mengistu AM, Rohm KD, Suttner S. Goal-directed intraoperative therapy based on autocalibrated arterial pressure waveform analysis reduces hospital stay in high-risk surgical patients: a randomized, controlled trial. Crit Care 2010; 14: R18
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A. Joosten1,‡,*, R. Tircoveanu2,‡, S. Arend2, P. Wauthy3, P. Gottignies4 and P. Van der Linden2 1
Department of Anesthesiology and Perioperative Care, Erasme University Hospital, Université Libre de Bruxelles, Brussels, Belgium, 2Department of Anesthesiology and Perioperative Care, CHU Brugmann, Université Libre de Bruxelles, Brussels, Belgium, 3Department of Cardiac Surgery, CHU Brugmann, Université Libre de Bruxelles, Brussels, Belgium, and 4Department of Intensive Care, CHU Brugmann, Université Libre de Bruxelles, Brussels, Belgium *Corresponding author. E-mail: [email protected]
Abstract Background: As 6% hydroxyethyl starch (HES) 130/0.40 or 130/0.42 can originate from different vegetable sources, they might have different clinical effects. The purpose of this prospective, randomized, double-blind controlled trial was to compare two balanced tetrastarch solutions, one maize-derived and one potato-derived, on perioperative blood loss in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). Methods: We randomly assigned 118 patients undergoing elective cardiac surgery into two groups, to receive either a maize- or a potato-derived HES solution. Study fluids were administered perioperatively (including priming of CPB) until the second postoperative day (POD#2) using a goal directed algorithm. The primary outcome was calculated postoperative blood loss up to POD#2. Secondary outcomes included short-term incidence of acute kidney injury (AKI), and long-term effect (up to one yr) on renal function. Results: Preoperative and intraoperative characteristics of the subjects were similar between groups. Similar volumes of HES were administered (1950 ml [1250–2325] for maize-HES and 2000 ml [1500–2700] for potato-HES; P=0.204). Calculated blood loss (504 ml [413–672] for maize-HES vs 530 ml [468–705] for potato-HES; P=0.107) and the need for blood components were not different between groups. The incidence of AKI was similar in both groups (P=0.111). Plasma creatinine concentration and glomerular filtration rates did vary over time, although changes were minimal. Conclusions: Under our study conditions, HES 130/0.4 or 130/0.42 raw material did not have a significant influence on perioperative blood loss. Moreover, we did not find any effect of tetrastarch raw material composition on short and long-term renal function. Clinical trial registration: EudraCT number: 2011-005920-16. Key words: acute kidney injury; blood loss; cardiac surgical procedures; colloids; hydroxyethyl starch
†
This Article is accompanied by Editorial Aew304. A. Joosten and R. Tircoveanu are co-first authors. Accepted: June 5, 2016 ‡
© The Author 2016. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: [email protected]
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Impact of balanced tetrastarch raw material on perioperative blood loss: a randomized double blind controlled trial†
Impact of tetrastarch raw material on perioperative blood loss in cardiac surgery
Editor’s key points • The influence of hydroxyethyl starch (HES) raw material on haemostasis and renal outcome in cardiac surgery is unknown. • Patients undergoing cardiac surgery with cardiopulmonary bypass were prospectively randomized to receive balanced tetrastarch solutions derived from either maize or potato. • Perioperative blood loss, transfusion, and kidney injury did not differ between groups in this study of 118 subjects. • These preliminary findings suggest no significant clinical differences between balanced tetrastarch solutions derived from two different sources.
perioperative and long-term renal function, patient quality of life and occurrence of pruritus.
Methods Ethics The investigation was approved by the Ethics Committee of Brugmann’s Hospital and registered under the EudraCT number: 2011-005920-16. All 118 subjects provided written informed consent the day before surgery.
Patients Inclusion criteria were patients >18 yr undergoing elective cardiac surgery with CPB. Exclusion criteria were patients with an ASA physical status greater than III, heart failure (left ventricular ejection fraction <30%), cardiac arrhythmias, significant aortic regurgitation, coagulation disorders ( platelet count <100 000 µl−1, activated partial thromboplastin time >1.5 normal), preoperative renal dysfunction (serum creatinine >2 mg ml−1, oliguria, anuria, or receiving haemodialysis), impaired hepatic function (aspartate amino-transferase, alanine amino-transferase >2 times normal), current pregnancy or lactation, and known allergy to HES.
Randomization and blinding Randomization of the study was created by our hospital pharmacist in blocks of 10 using an internet-based software (http://www. randomization.com). The morning of surgery, blinded solutions were provided in identical plastic bags (500 ml) which prevented identification of the type of fluid being used. All investigators and people taking care of the patients remained blinded until the completion of the study and finalization of the statistical analysis.
Anaesthesia procedures Premedication was standardized and consisted of 0.5 mg of alprazolam on the morning of surgery. Preoperative medications such as β-blockers, statins and calcium channel blockers were continued until the day of surgery. Preoperative antiplatelet drugs were stopped seven days before surgery, unless medical conditions required them to be maintained until the day of surgery. Angiotensin-converting enzyme inhibitors (ACEI), angiotensin II receptor blockers (ARB) and oral hypoglycaemic agents were stopped 24 to 48 h before surgery. Standard monitoring included 5-lead ECG, pulse oximetry, noninvasive blood pressure, central venous pressure, invasive radial artery catheter (using a Flotrac catheter connected to the Vigileo monitoring device, Edwards Lifesciences, Irvine, CA, USA), rectal temperature, inspiratory and expiratory gas concentrations, urine output, and depth of anaesthesia monitoring (Spectral Entropy, GE Healthcare, Helsinki, Finland). Anaesthesia was induced with lean body weight-adjusted doses of etomidate (0.2 mg kg−1), sufentanil (0.2 mcg kg−1), and rocuronium (0.5 mg kg−1), and was maintained with sufentanil (Geps PK model: 0.7–1.2 ng ml−1) and midazolam (0.05–0.1 mg kg−1 h−1) using a target-controlled infusion pump (Alaris® PK) syringe assessment. After intubation, lungs were ventilated with a tidal volume of 8 ml kg−1 lean body weight, PEEPof 5 cm H2O, and respiratory rate to achieve an end tidal carbon dioxide pressure between 4.3 and 4.8 Kpa. Prophylactic antibiotic (2 g of cefazolin), methylprednisolone (15 mg kg−1) and tranexamic acid (30 mg kg−1 loading dose +2 mg kg−1 pump prime +16 mg kg−1 h−1 maintenance infusion during CPB)14 were administered to all subjects. Anaesthetic drugs were
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Six percent hydroxyethyl starch (HES) 130/0.40 or 130/0.42, commonly known as tetrastarch, has been routinely used to treat hypovolaemia, in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB), as it is considered to be superior for volume expansion compared with crystalloid solutions.1 This fluid consists of large branched glucose molecules substituted with hydroxyethyl groups for increased solubility and intravascular persistence. They are formulated to a concentration of 6%, a mean molecular weight of 130 kDa, and a molar substitution of 0.40 or 0.42. There is an active debate over the use of tetrastarch in high risk surgical patients. However, five recent meta-analyses failed to identify an association between surgical HES administration and postoperative morbidity or mortality.2–6 Newer tetrastarch solutions have been developed in an electrolyte balanced solution. Recent German guidelines recommend that if colloids are used in perioperative care, balanced solutions are preferred.7 While previously published studies have shown that 0.9% NaCl (‘unbalanced’) HES solutions are associated with various clinical side-effects, balanced-HES solutions with electrolyte concentrations closer to human plasma have not been as rigorously examined. Interestingly, these newer solutions might improve postoperative acid-base status8 and potentially decrease the incidence of AKI and use of renal replacement therapy (RRT).9 Importantly, balanced tetrastarch solutions can be derived from two different raw materials (maize or potato). Maize and potato-derived HES differ in their molecular and chemical structures10 and are not bioequivalent.11 Maize starch is largely composed (98%) of highly branched amylopectin, while potato starch contains a lower degree of branching, consisting of a heterogeneous mixture of around 75% of amylopectin and 25% of linear chains of amylose. Potato starch contains several thousand esterified phosphate groups, whereas almost none can be detected in maize starch. Negatively charged phosphate-ester groups in potato-HES could impair coagulation and also metabolization in the liver. Jamnicki and colleagues12 demonstrated that potato-HES compromises in vitro blood coagulation more than maize-HES. There is clinical evidence supporting the clinical use of maize-HES, while published data are lacking with regards to potato-HES.13 Therefore, one cannot justify the clinical use of potato-HES with evidence derived from studies investigating maize-HES. The main objective of this prospective, randomized, double-blind trial was to compare two balanced tetrastarch solutions, one maize derived 6% HES 130/0.4 (Volulyte®, Fresenius Kabi GmbH, Bad Homburg, Germany) and one potato derived 6% HES 130/0.42 (Vitafusal®, Serum Werk Bernburg AG, Germany), on perioperative blood loss in patients undergoing cardiac surgery. Additionally, as the short and long-term safety profile of HES continues to fuel controversy, we secondarily examined both
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Study fluid administration using a goal directed haemodynamic protocol Perioperative study fluid administration was started immediately after induction of anaesthesia and was based on a goal-directed haemodynamic algorithm using stroke volume variation (SVV), to assess fluid responsiveness. This pre-defined algorithm allowed us to standardize study fluid administration and use of vasopressors and inotrope agents consistently in all subjects (Fig. 1). Study fluids were titrated as 250 ml boluses up until POD#2 to maintain SVV (during mechanical ventilation) less than 13%15 (Vigileo,
Perioperative goal-directed haemodynamic algorithm Stroke volume variation
>13%
<13%
250 ml of study HES
Cardiac index
<2.5 L /min
>2.5 L /min
Dobutamine infusion
Mean arterial pressure
<65 mmHg
Norepinephrine infusion
>65 mmHg
Nothing
Fig 1 The perioperative goal-directed haemodynamic algorithm used during the study to guide HES administration, vasopressor and inotropic drugs infusion.
Edwards LifeSciences, Irvine, USA). After extubation, fluid administration was at the discretion of the critical care provider.
Outcome variables The primary outcome was defined as calculated blood loss from the time of surgery up to POD#2. Calculated blood loss was quantified using a formula taking into account preoperative and postoperative haematocrit and estimated blood volume.16 Secondary outcomes were defined as short and long-term effects of study fluids on postoperative renal function. Short term renal function was assessed by quantifying the incidence of 1) AKI calculated using the Acute Kidney Injury Network (AKIN) classification (without taking into account urine output criteria) based on change in serum creatinine from preoperative baseline (day before surgery) to POD#217 and 2) requirement for the use of RRT. For long-term assessment of renal function, medical records were examined using our hospital database (Mediview® and Mediweb® software) in order to record urea and creatinine measurements and the estimated glomerular filtration rate (eGFR) during outpatient postoperative follow-up appointments. The eGFR was calculated using the CKD – EPI formula.18 When no results were found, the subjects’ general practitioner and/or cardiologist were contacted by telephone in order to inquire about health, potential delayed complications, and to obtain the urea and creatinine measurements. The goal was to collect at least one value between discharge and six months postoperatively and one additional value at one yr postoperatively. Tertiary outcomes included exposure to blood products, transfusion rates, ICU and hospital LOS, incidence of postoperative complications (new onset of atrial fibrillation, incidence of postoperative delirium [defined as acutely altered and fluctuating mental status with features of inattention and an altered level of consciousness], redo surgery for haemorrhage, respiratory insufficiency [defined as prolonged mechanical ventilation for hypoxaemia])
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adjusted intraoperatively to target a spectral entropy value between 50 and 60. Subjects were allowed to receive up to 500 ml of balanced crystalloid before CBP. The CPB circuit was primed exclusively with 150 ml of mannitol, 5000 i.v. of heparin and 1000 ml of the HES solution allocated to each subject, with the same CPB circuit was used in all subjects. Anticoagulation was achieved with heparin (400 IU kg−1), and activated clotting time (ACT) was kept >600 sec during CPB with repeated boluses of heparin when required. Mild to moderate hypothermia was induced (32–34°C) depending on the surgical procedure. Pump flow rate was maintained around 2.8 Litre min−1 m−2. Mean arterial pressure was kept between 50 and 70 mm Hg with phenylephrine boluses if required. Cold blood cardoplegia was used in all patients. In order to maintain the filling volume of the circuit, only the allocated study HES was added. All subjects were rewarmed to 35.5°C before weaning from CPB. Remaining heparin at the end of the CPB was neutralized with protamine sulfate at a ratio of heparin/protamine of 2:1. If necessary, additional protamine doses were administered to return the ACT value to baseline. The blood remaining in the CPB circuit was re-transfused without salvage processing after sternal closure. Insulin was administrated as a continuous infusion for blood glucose concentration >150 mg dl−1. The trigger for transfusion of allogeneic red blood cells was a haemoglobin <7 g dl−1 during CPB and <8 g dl−1 after the end of surgery. Fresh frozen plasma, platelets, or fibrinogen were given in the presence of diffuse microvascular bleeding, associated with abnormal coagulation values (either prothrombin time or activated partial thromboplastin time >1.5 of the normal value, platelet count <100 000 µl−1 or fibrinogen concentration <1.5 g l−1, respectively). All patients were performed on by three experienced senior cardiac anaesthetists and by the same two cardiac surgeons. After surgery, subjects were transferred to the ICU and controlled mechanical ventilation was maintained with the same ventilation settings used in the operating room. Postoperative sedation used either midazolam (1–3 mg h−1) or propofol (1–2 mg kg−1 h−1) and sufentanil (5 mcg h−1) or morphine (1–2 mg h−1), depending on the critical care physician taking care of the patient who was also blinded to the study fluids allocation. The trachea was extubated when subjects were haemodynamically stable, temperature >36°C, spontaneous respiration maintained with adequate blood gases, and no bleeding. Postoperative maintenance fluid was 5% dextrose -NaCl 0.45% (0.5 ml kg−1 h−1). In addition to this maintenance fluid, a maximum daily dose of 50 ml kg−1 of study fluid was allowed. If additional volume was required and the maximum dose of HES was reached, 3% modified fluid gelatin (Geloplasma®, Fresenius Kabi GmbH, Bad Homburg, Germany) or a crystalloid (normal saline 0.9%) was used, depending on physician preference. The decision for re-exploration for postoperative bleeding was made using our institution criteria: chest tube drainage ≥500 ml during the first h, ≥400 ml per h during the first 2 h, ≥300 ml per h during the first 3 h, ≥1000 ml during the first 4 h, ≥1200 ml during the first 5 h, 100 ml per h during the first 12 h and massive bleeding, cardiac tamponade, or sudden cardiac arrest in a bleeding patient.
Impact of tetrastarch raw material on perioperative blood loss in cardiac surgery
and mortality. All laboratory and arterial blood gas parameters were measured and recorded at different time points. Subjects were also personally contacted in order to assess potential pruritus experiences during their postoperative period and their health-related quality of life. For this last quantification we used the MacNew questionnaire19 20 which allowed us to assess how cardiac surgery impacted daily quality of life between one and two yr after surgery.
Power analysis
Statistical analysis The distribution of continuous variables was assessed using a Kolmogorov-Smirnov test. Parameters not normally distributed were compared using a Mann-Whitney U-test and expressed as median [25%–75%] percentiles. Creatinine and glomerular
filtration rate values were normally distributed. Linear mixed models21 were used to model the relationship of log(creatinine) and glomerular filtration rate (GFR) ratio through time (from pre-operation until one yr postoperatively). A multiple imputation for multiple level data was conducted with the mice R package22 23 for a missing at random process with 20 iterations, five imputed datasets and run linear mixed models on pooled data. The best maximum likelihood model found incorporates the following fixed effects: time, group, fluid balance at 48 h and an intervention effect. Data were expressed as mean (). Discrete variables were compared using a χ2 test and expressed as percentages. Significance was set at P<0.05.
Results A total of 227 patients were screened for eligibility from March 2012 until September 2014 and 118 patients were included and prospectively randomized between the two groups (Fig. 2). Preoperative subject characteristics (Table 1) and intraoperative variables (Table 2) revealed no significant differences between groups. Similar volume of colloids were administered up to POD#2, but subjects in the Potato HES group received significantly more crystalloids (Table 3). Regarding our outcome variables (Table 3), calculated blood loss until POD#2 was similar in both groups as well as the cumulative measured 48 h blood loss. Transfusion of blood products ( packed red blood cells, fresh frozen plasma, platelets) was also comparable between groups. With respect to relevant postoperative complications, atrial
Assessed for eligibility (n=227)
Enrollment
Randomized (n=118)
Excluded (n=109) Atrial fibrillation (n=31) Preoperative renal failure (n=7) Aortic insufficiency (n=2) Heart failure (n=12) Pulmonary embolism (n=1) Cirrhosis (n=1) Declined to participate (n=21) Language barrier (n=8) Dementia (n=2) Logistic reasons (n=5) Emergency (n=9) Jehova’s witnesses (n=2) Minor patients (n=4) Off pump surgery (n=4)
Consort flow diagram
Allocation Allocated to the maize-HES (n=59) Received allocated intervention (n=59) Did not receive allocated intervention (n=0)
Allocated to the potato-HES (n=59) Received allocated intervention (n=59) Did not receive allocated (n=0)
Data analyzed in maize-HES (n=59)
Data analyzed in potato-HES (n=59) Follow-up
Long term follow-up
Long term follow-up
Kidney function : lost to follow-up (n=17)
Kidney function : lost to follow-up (n=10)
Quality of life : lost to follow-up (n=26)
Quality of life : lost to follow-up (n=15)
Reasons: death, wrong contact address, no control of kidney function available
Reasons: death, wrong contact address, no control of kidney function available Analysis
Long term: • Kidney function : analysed (n=42) • Quality of life : analysed (n=33)
Fig 2 Consort flow diagram.
Long term: • Kidney function : analysed (n=49) • Quality of life : analysed (n=44)
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A sample size calculation was determined a priori based on our primary outcome using the results of our institution database (Rans D BJ, Van der Linden P Blood sparing effect and safety of tranexamic acid compared to aprotinin in adult cardiac surgery. Eur J Anaesth 2010; 27) which demonstrated that the average calculated blood losses from surgery up to POD#2 was 692±288 ml. For a type I error of 0.05 and a power of 0.08, 59 subjects per group were needed to detect a blood loss difference of 150 ml (at 100% of haematocrit, corresponding to one unit of packed red blood cell) between groups.
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fibrillation occurred in 26% of subjects with no difference between groups (Table 3). Four patients (3.4%) needed surgical reexploration for postoperative bleeding: three in the potatogroup and one in the maize-group. With regard to mechanical
Table 1 Baseline subject characteristics. Population data are listed as ‘value (%)’ [range], and quantitative data as ‘median [25– 75 percentiles]’. BSA, body surface area; CABG, coronary artery bypass graft; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blockers; Combined procedures, CABG+valve surgery Maize-HES (N=59)
Potato-HES (N=59)
Age (yr) Gender (Male) Weight (kg) Height (cm) BSA (m2) Circulatory blood volume (ml) Predicted 30-day mortality (Euroscore II) ASA physical grade II III Medications Beta blocker ACEI ARB Statin Oral hypoglycaemic drugs Antiplatelet drugs Type of Surgery CABG Valve Combined procedures Other Redo surgery
63 [19–87] 43 (73) 78 (13) 169 (9) 1.90 [1.78–2.06] 4854 [4374–5169]
68 [18–90] 40 (68) 75 (14) 170 (10) 1.90 [1.77–2.06] 4736 [4296–5158]
1.6 [1.0–1.8]
1.1 [0.8–2.5]
4 (7) 55 (93)
5 (8) 54 (92)
31 (53) 24 (41) 9 (15) 31 (53) 12 (20)
35 (59) 23 (39) 10 (17) 33 (56) 11 (19)
20 (34)
21 (36)
30 (51) 14 (24) 4 (7)
26 (46) 20 (34) 9 (15)
11 (18) 8 (14)
4 (7) 6 (10)
Discussion No significant difference was found between the two balanced HES groups with regard to perioperative blood loss. This is in accordance with the only available study that compared the use of two balanced HES fluids from different vegetable sources in the perioperative setting. This study, published by Sethi and colleagues24 compared a waxy maize-based HES solution with a potato starch-based HES solution, in patients undergoing coronary artery bypass grafting (CABG), with the aim to assess their effects on haemostasis (chest tube blood drainage, re-exploration rate, transfusion rate) and organ function. Importantly however, both HES solutions were only used to prime the CPB circuit (intraoperative use exclusively). Moreover, that study was not
Table 2 Intraoperative characteristics. Population data are listed as ‘value (%)’ and quantitative data as ‘median [25–75 percentiles]’. CPB, cardiopulmonary bypass; HES, Hydroxyethyl starch Variables
Maize-HES (N=59)
Potato-HES (N=59)
P
Time of Anaesthesia (min) Time of Surgery (min) Time of CPB (min) Time of aortic clamp (min) Time of mechanical ventilation (h) Total volume of crystalloid (ml) Total volume of HES (ml) Tranexamic acid (g) Calcium (g) Urine output (ml) Total measured blood loss Fluid Balance (ml) Patients under vasoactive infusion agents
300 [260–330] 184 [150–240] 83 [67–100] 45 [34–55] 15 [11–18] 1055 [869–1255] 1000 [1000–1250] 4 [3–6] 0 [0–1] 482 [377–640] 378 [276–530] 1098 [722–1375] 30 (51)
285 [255–300] 180 [150–212] 81 [67–99] 47 [35–59] 15 [12–18] 1000 [850–1160] 1000 [1000–1200] 4 [3–5] 0 [0–1] 455 [355–660] 350 [300–500] 910 [500–1201] 28 (48)
0.152 0.360 0.667 0.517 0.800 0.185 0.832 0.515 0.849 0.974 0.874 0.141 0.644
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Variable
ventilation time, ICU and hospital LOS, no significant differences were observed between groups. Eight deaths occurred after the long-term follow-up (four in each group), all of which were not considered to be related to the study fluids. The incidence of AKI (14%) at POD#2 was comparable in both groups. Three patients required RRT during the postoperative ICU period: two in the maize group and one in the potato group. Of the 118 subjects included in the study, 91 had follow-up renal laboratory results recorded up to at least 360 days after surgery. Plasma creatinine concentration and glomerular filtration rate (GFR) varied over time, although these variations appear to be minimal and were not different between groups (Table 4). Two factors that were associated with a decrease in these two parameters were a positive fluid balance at POD#2 (P=0.003) and age (P<0.001). Regarding quality of life (Supplementary material, Appendix 1), 77 subjects answered the MacNew questionnaire in the postoperative period: 33 had received maize-HES and 44 had received potato-HES without significant difference between groups. The mean time for answering the questionnaire was 656 days after surgery. No subject described pruritus without being prompted during the postoperative period. Out of the 77 subjects who answered the question when specifically prompted about its occurrence, only 4 (5%) experienced pruritus during the postoperative period, two in each group. Finally, perioperative haemodynamic variables, laboratory values and blood gas measurements were similar between groups at multiple times points (data not shown). No patients in the current study presented any type of anaphylactic reaction after HES administration.
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Impact of tetrastarch raw material on perioperative blood loss in cardiac surgery
Table 3 Outcome variables. Outcome data are presented as ‘value (%)’ and/or median [25–75 percentiles]. PRBC, packed red blood cell; FFP, fresh frozen plasma; ICU, Intensive care unit; AKI, acute kidney injury; POD#2, second postoperative day; AKIN, Acute Kidney Injury Network; RRT, renal replacement therapy; ICU LOS, intensive care unit length of stay. aCumulative intra and postoperative data (up to POD#2) Maize-HES (N=59)
Potato-HES (N=59)
P
Total crystalloid in the postoperative period up to POD#2 (ml) Total colloid in the postoperative period up to POD#2 (ml) Total measured blood loss in the postoperative period up to POD#2 (ml) Total diuresis in the postoperative period up to POD#2 (ml) Calculated blood loss up to POD#2 (ml) Total measured blood loss up to POD#2 (ml)a Total diuresis up to POD#2 (ml)a Total crystalloid up to POD#2 (ml)a Total Colloid up to POD#2 (ml)a Patients transfused up to POD#2 PRBC FFP Platelet Postoperative complications: Atrial Fibrillation Delirium - Confusion Redo surgery for haemorrhage Respiratory Insufficiency Length of stay in ICU (h) Hospital (days) AKI at POD#2 AKIN stage 1 (%) AKIN stage 2 (%) AKIN stage 3 (%) RRT during the entire ICU LOS Mortality Within 30 days after surgery Between 30 days and 90 days After 90 days after surgery
3690 [3299–4394] 500 [0–1000] 550 [405–708] 3035 [2215–3750] 504 [413–672] 934 [764–1221] 3488 [2705–4528] 4778 [4149–5456] 1950 [1250–2325]
4217 [3446–4907] 1000 [350–1500] 550 [395–920] 2755 [2070–3415] 530 [468–705] 951 [695–1410] 3330 [4160–4160] 5394 [4470–6043] 2000 [1500–2700]
0.029 0.052 0.515 0.248 0.107 0.611 0.456 0.038 0.204
13 (22%) 3 (5%) 3 (5%)
17 (29%) 6 (10%) 5 (8%)
0.398 0.294 0.462
14 (24%) 7 (12%) 1 (2%) 17 (29%)
17 (29%) 2 (3%) 3 (5%) 12 (20%)
0.530 0.083 0.309 0.285
96 [72–144] 10 [9–15]
72 [48–96] 11 [9–14]
0.318 0.842
3/59 (5%) 2/59 (3%) 1/59 (2%) 2/59 (3%)
10/59 (17%) 0/59 (0%) 1/59 (2%) 1/59 (2%)
0.111
2 (3%) 0 (0%) 2 (3%)
1 (2%) 1 (2%) 2 (3%)
Table 4 Long-term evolution of renal function. HES, Hydroxyethyl Starch; GFR, Glomerular Filtration Rate. Data are presented as mean () Time Day 0
HES - group
Maize-group Potato-group Day 2 Maize-group Potato-group Day 8 Maize-group Potato-group Day 93 Maize-group Potato-group Day 365 Maize-group Potato-group
Plasma creatinine GFR (ml min−1) (mg dl−1) mean () mean () 0.90 (2) 0.85 (2) 0.74 (3) 0.70 (3) 0.87 (2) 0.82 (2) 0.98 (2) 0.95 (2) 0.98 (1.78) 0.88 (1.68)
77.89 (22) 78.17 (22) 83.73 (31) 82.93 (31) 79.77 (24) 79.84 (25) 73.50 (22) 71.61 (22) 74.91 (23.24) 76.70 (20.49)
double blinded and was performed in patients with a relatively low risk of bleeding (CABG only). Furthermore, they did not use a haemodynamic algorithm to guide fluid administration. Interestingly, the transfusion rate was relatively low in our trial (25%) compared with the literature (>50%25–27). This finding is likely explained by the transfusion and fluid management algorithm we used in our trial, which has consistently been shown to improve
0.559
postoperative outcome28–32 and to decrease the amount of fluid given intraoperatively.33 An important positive effect of less fluid administration is less haemodilution and, therefore, less blood product administration. It is important to note that no algorithm was used to guide HES administration, in the vast majority of previous trials assessing HES utilization in cardiac surgery patients.8 24 34 This point becomes even more important when considering the actual haemodynamic end-points used in these trials, which was typically a static variable such as central venous pressure (CVP). Unfortunately, CVP has clearly been demonstrated to be a weak predictor of fluid responsiveness35 and could have confounded the results of these previous studies. In our study, the median amount of fluid administered up to POD#2 was ∼ 7000 ml (crystalloids and HES together). Much larger cumulative fluid administration, (up to 10–12 Litre in 24 h) was recently reported.8 26 In these studies, no goal directed protocol was used to guide fluid administration. These findings further support the results of a recent survey that suggests that goal-directed fluid management is still poorly adopted in clinical practice.36 Similar to the decreased fluid administration noted in our study, we observed a relatively low surgical re-exploration rate (3.4%) compared with the relevant literature.8 24 This observation might also be related to the fact that our surgeons were present from skin incision to closure, after careful haemostasis of the surgical field.
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Variables
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Joosten et al.
Strengths and limitations Strengths of this study indicate use of a pre-defined goal directed fluid algorithm perioperatively until extubation, and inclusion of multiple types of surgeries that required CPB, especially those with a high risk of bleeding (e.g. repeat surgery, combined surgery). In most published studies, only low to moderate risk patients were included.24 This is the first published study to assess the long-term (up to one yr after surgery) effects of HES administration on renal function, occurrence of pruritus and quality of life. In most surgical trials assessing the influence of HES on postoperative morbidity, study periods were quite short and ended before long-term adverse effects could be documented. Our study has several limitations. First, as the actual calculated blood loss difference between both HES types was only 26 ml (or a 4% effect size), our study was probably underpowered to demonstrate a significant difference in our primary outcome. Our study was also underpowered to detect differences in other complications, especially regarding renal function (AKI, RRT). The inclusion of significantly more subjects would have been necessary to effectively detect a difference. Additionally, the decision for starting RRT was not standardized in the study protocol and was instead based on clinician judgement. Similarly, the criteria for ICU and hospital discharge were not pre-defined and were instead determined based on clinical judgement. Hopefully, any resulting bias is limited by the prospective, randomized and double blinded study design we used.
Conclusions Under our study conditions, the HES 130/0.4 or 130/0.42 raw material does not seem to have an influence on perioperative blood loss. Moreover, we did not find any long-term effect of tetrastarch raw material composition on short and long term renal function, occurrence of pruritus or quality of life.
Authors’ contributions Study design/planning: A.J., R.T., S.A., P.V.dL. Study conduct: A.J., R.T., S.A., P.V.dL., P.G. Data analysis: A.J., R.T., S.A., P.V.dL., P.G. Writing paper: A.J., R.T., S.A., P.V.dL., P.G., P.W. Revising paper: all authors
Supplementary material Supplementary material is available at British Journal of Anaesthesia online.
Acknowledgements We would thank to thank our hospital pharmacist (Nabil Hayef ) for providing us the blinded study fluids, Jean-François Fils for statistical analysis and Brenton Alexander for English corrections.
Declaration of interest P.V.dL. has received, within the past five yr, fees for lectures and consultancies from Fresenius Kabi GmbH, and Janssen-Cilag SA, Belgium.
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Concerning short term postoperative renal function, we observed an AKI (Stage 1 to stage 3 at POD#2) in 17 subjects (14%) and the need for RRT during the entire ICU LOS in three subjects (2.5%), consistent with what we can extrapolate from the literature (15%–30% for AKI37–41 and 2%–9% for RRT34 37 42). Our results also confirm what has been published recently in a systematic review2 and meta-analyses.3 4 6 These authors reviewed the literature evaluating short term renal function after intraoperative administration of a tetrastarch solution compared with any other fluid type, in patients undergoing elective surgical procedures. They all demonstrated that no differences were noted between the use of a tetrastarch and any of the other tested fluids. It is important to realize that the follow-up period of the different review articles was too short to assess long-term adverse renal effects of HES. Therefore, our longer follow-up period of at least one yr after surgery, helps to address this issue by demonstrating that the choice of balanced HES fluid does not appear to impact longterm renal function. Plasma creatinine concentration and glomerular filtration rates did vary over time, although changes were minimal. The two factors significantly affecting these parameters were a positive fluid balance at POD#2 and age. The deleterious effect of perioperative fluid balance on postoperative renal function has been already reported.43–45 Age has also been found to be a predictor for alteration of renal function in cardiac surgery.46 We did not find any influence of either HES fluid on patient quality of life. We also found no difference of the fluid type on the occurrence of pruritus. The incidence of pruritus was 5% in our trial which is similar to another study8 (4.6%), however the follow-up period was 60 days post-surgery which may be too short to adequately assess this issue.
Impact of tetrastarch raw material on perioperative blood loss in cardiac surgery
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