Postoperative Kidney Injury
Conditions
Brief summary
The purpose of this study is to evaluate the safety of a standard volume replacement called HES 130/0.4 (Voluven) during surgery on recovery. HES 130/0.4 (Voluven) may offer an alternative to pure fluid replacement solutions that are associated with problems after surgery including fluid overload and respiratory difficulties. The safety of HES 130/0.4 (Voluven) will be evaluated by examining its effects on kidney function, and coagulation parameters and platelet (part of the blood that help it clot) function. Participants will be randomized (like flipping a coin) to receive one of two possible volume replacements during surgery, if fluid volume decreases enough to need replacement with one of the fluids. The two possible volume replacements are Voluven (a starch-containing fluid) or human albumin 5% (a protein-containing solution). To examine kidney function, urine will be-sampled when the participant is put under general anesthesia, before surgical incision, within one hour of arrival to the ICU and 24 hours after completion of surgery. Two tubes (2 teaspoons) of blood (from an already established line) will be taken the morning of the surgery, within one hour of arrival to the ICU, 24 hours after surgery and every morning during the participants postoperative ICU stay. Additionally, health and recovery information will be recorded from the participant's medical record. We will phone participants around 90 days and one year after surgery to ask a few questions about one's health and recovery. We will also record blood sample analysis results from follow up appointments within the first year after surgery. If this analysis is not conducted at the Cleveland Clinic, with permission, we will obtain the results from a treating physician.
Interventions
DRUGhuman albumin 5%
DRUGHES 130/0.4 (Voluven)
Sponsors
Fresenius Kabi
The Cleveland Clinic
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Age 50 - 85 years old * Scheduled for elective aortic valve replacement with or without coronary artery bypass grafting with or without additional minor surgical procedure. * Written, informed consent for participation in this investigation.
Exclusion criteria
* Patients with renal failure with oliguria or anuria not related to hypovolemia. * Patients receiving dialysis. * Patients with preoperative renal insufficiency (Creatinine \> 1.6 mg/dL) * Anticipated deep hypothermic circulatory arrest * Known hypersensitivity or allergy to hydroxyethyl starch or the excipients of hydroxyethyl starch * Clinical conditions with volume overload (e.g., patients in pulmonary edema or congestive heart failure) * Patients with severe hypernatremia or severe hyperchloremia * Patients with intracranial bleeding * Pregnant or breast feeding women * Critically ill adult patients, including patients with sepsis, due to increased risk of mortality and renal replacement therapy, (e.g. patients who are hospitalized in the intensive care unit prior to surgery) * Severe liver disease * Pre-existing coagulation or bleeding disorders * Any contraindications to proposed interventions.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Urine Neutrophil Gelatinase-associated Lipocalin (NGAL) [Time Frame: 24 Hours After Surgery] [Designated as Safety Issue: Yes] | 3 measurements in total from baseline to 24 hours after surgery: the first one is at baseline; the second one is at one hour of arrive to ICU and last one is at 24 hours after surgery | To assess the safety of HES 130/0.4 (Voluven) versus albumin 5% on renal function we will measure urinary concentrations of neutrophil gelatinase-associated lipocalin (NGAL), an important marker of renal function, measured at baseline (following anesthetic induction and prior to surgical incision), at one hour of arrival to intensive care unit (ICU), at 24 hours following completion of surgery. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Kidney Function | within first 7 postoperative days | Postoperative kidney dysfunction using RIFLE diagnostic criteria was also assessed. Patients were assessed for risk for kidney dysfunction (RIFLE-R), injury to the kidney (RIFLE-I), failure of kidney function (RIFLE-F) using criteria based on only peak serum creatinine concentrations within the first seven postoperative days. Due to too few events, this outcome was redefined to risk (or worse) vs. no risk for this analysis. RIFLE classification criteria is listed below: Risk (RIFLE-R) Increase in serum creatinine x 1.5 from baseline Injury (RIFLE-I) Increase in serum creatinine x 2 from baseline Failure (RIFLE-F) Increase in serum creatinine x 3 from baseline Loss (RIFLE-L) Complete loss of kidney function \> 4 weeks End stage (RIFLE-E) End-stage kidney failure \> 3 months |
| Postop Urine IL-18 | postoperative 1 hour | Postop Urine IL-18 (interleukin-18) measured at 1 h of arrival to ICU |
Countries
United States
Participant flow
Recruitment details
9 more patients were recruited due to withdrawal (patients did not receive any treatment).
Pre-assignment details
9 more patients were recruited to ensure enough power after excluding patients who were randomized but they withdrew from the study and did not receive any treatment (see periods section for details).
Participants by arm
| Arm | Count |
|---|---|
| HES 130/0.4 (Voluven) 6% HES 130/0.4 during surgery
HES 130/0.4 (Voluven) | 69 |
| Human Albumin 5% human albumin 5% during surgery
human albumin 5% | 72 |
| Total | 141 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | did not receive intervention due to circulatory arrest | 2 | 0 |
| Overall Study | Did not receive intervention due to euvolemia | 4 | 1 |
| Overall Study | did not receive intervention due to logistic reasons | 1 | 0 |
Baseline characteristics
| Characteristic | HES 130/0.4 (Voluven) | Human Albumin 5% | Total |
|---|---|---|---|
| Age, Continuous | 71 years STANDARD_DEVIATION 10 | 69 years STANDARD_DEVIATION 9 | 70 years STANDARD_DEVIATION 9 |
| Diabetes Type 1 | 3 Participants | 0 Participants | 3 Participants |
| Diabetes Type 2 | 15 Participants | 20 Participants | 35 Participants |
| Duration of aortic cross-clamp | 65 minutes | 60 minutes | 62 minutes |
| Hypertension | 53 Participants | 54 Participants | 107 Participants |
| Myocardial infarction | 4 Participants | 4 Participants | 8 Participants |
| Previous cardiac surgery | 13 Participants | 14 Participants | 27 Participants |
| Race/Ethnicity, Customized Not reported | 7 Participants | 4 Participants | 11 Participants |
| Race/Ethnicity, Customized White | 62 Participants | 68 Participants | 130 Participants |
| Sex: Female, Male Female | 22 Participants | 28 Participants | 50 Participants |
| Sex: Female, Male Male | 47 Participants | 44 Participants | 91 Participants |
| Stroke | 6 Participants | 3 Participants | 9 Participants |
| Surgery type Aortic valve + CABG | 12 Participants | 16 Participants | 28 Participants |
| Surgery type Aortic valve + CABG + other | 8 Participants | 6 Participants | 14 Participants |
| Surgery type Aortic valve only | 35 Participants | 32 Participants | 67 Participants |
| Surgery type Aortic valve + other | 14 Participants | 18 Participants | 32 Participants |
| Total fluid | 2.8 L | 2.8 L | 2.8 L |
| Transfusion Cryoprecipitate | 3 Participants | 4 Participants | 7 Participants |
| Transfusion Fresh frozen plasma | 8 Participants | 5 Participants | 13 Participants |
| Transfusion Platelets | 10 Participants | 10 Participants | 20 Participants |
| Transfusion Red blood cell | 13 Participants | 10 Participants | 23 Participants |
| Transfusion Transfusion | 19 Participants | 16 Participants | 35 Participants |
| Use of antifibrinolytic drug | 4 Participants | 7 Participants | 11 Participants |
| Volume of study solution | 500 ml | 750 ml | 620 ml |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 69 | 2 / 72 |
| other Total, other adverse events | 0 / 69 | 0 / 72 |
| serious Total, serious adverse events | 17 / 69 | 12 / 72 |
Outcome results
Primary
Urine Neutrophil Gelatinase-associated Lipocalin (NGAL) [Time Frame: 24 Hours After Surgery] [Designated as Safety Issue: Yes]
To assess the safety of HES 130/0.4 (Voluven) versus albumin 5% on renal function we will measure urinary concentrations of neutrophil gelatinase-associated lipocalin (NGAL), an important marker of renal function, measured at baseline (following anesthetic induction and prior to surgical incision), at one hour of arrival to intensive care unit (ICU), at 24 hours following completion of surgery.
Time frame: 3 measurements in total from baseline to 24 hours after surgery: the first one is at baseline; the second one is at one hour of arrive to ICU and last one is at 24 hours after surgery
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| HES 130/0.4 (Voluven) | Urine Neutrophil Gelatinase-associated Lipocalin (NGAL) [Time Frame: 24 Hours After Surgery] [Designated as Safety Issue: Yes] | baseline | 2.9 ng/ml |
| HES 130/0.4 (Voluven) | Urine Neutrophil Gelatinase-associated Lipocalin (NGAL) [Time Frame: 24 Hours After Surgery] [Designated as Safety Issue: Yes] | at 1 hour after surgery | 5.0 ng/ml |
| HES 130/0.4 (Voluven) | Urine Neutrophil Gelatinase-associated Lipocalin (NGAL) [Time Frame: 24 Hours After Surgery] [Designated as Safety Issue: Yes] | at 24 hours after surgery | 12 ng/ml |
| Human Albumin 5% | Urine Neutrophil Gelatinase-associated Lipocalin (NGAL) [Time Frame: 24 Hours After Surgery] [Designated as Safety Issue: Yes] | baseline | 4.0 ng/ml |
| Human Albumin 5% | Urine Neutrophil Gelatinase-associated Lipocalin (NGAL) [Time Frame: 24 Hours After Surgery] [Designated as Safety Issue: Yes] | at 1 hour after surgery | 4.7 ng/ml |
| Human Albumin 5% | Urine Neutrophil Gelatinase-associated Lipocalin (NGAL) [Time Frame: 24 Hours After Surgery] [Designated as Safety Issue: Yes] | at 24 hours after surgery | 15 ng/ml |
Comparison: Assuming that NGAL values follow a log normal distribution as in previous studies with a coefficient of variation of 25%, we need 52 patients per group to have 90% power at the 0.025 significance level to be able to claim non-inferiority of HES to albumin using a non-inferiority delta of a ratio of geometric means of 1.15. After Adjusting for the interim monitoring and five potential dropouts and five pilot patients (which were not included in the analyses), we planned to enroll 140 patientsp-value: 0.1595% CI: [0.57, 1.44]generalized linear model
Secondary
Kidney Function
Postoperative kidney dysfunction using RIFLE diagnostic criteria was also assessed. Patients were assessed for risk for kidney dysfunction (RIFLE-R), injury to the kidney (RIFLE-I), failure of kidney function (RIFLE-F) using criteria based on only peak serum creatinine concentrations within the first seven postoperative days. Due to too few events, this outcome was redefined to risk (or worse) vs. no risk for this analysis. RIFLE classification criteria is listed below: Risk (RIFLE-R) Increase in serum creatinine x 1.5 from baseline Injury (RIFLE-I) Increase in serum creatinine x 2 from baseline Failure (RIFLE-F) Increase in serum creatinine x 3 from baseline Loss (RIFLE-L) Complete loss of kidney function \> 4 weeks End stage (RIFLE-E) End-stage kidney failure \> 3 months
Time frame: within first 7 postoperative days
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| HES 130/0.4 (Voluven) | Kidney Function | No risk | 61 Participants |
| HES 130/0.4 (Voluven) | Kidney Function | Risk | 5 Participants |
| HES 130/0.4 (Voluven) | Kidney Function | Injury | 2 Participants |
| HES 130/0.4 (Voluven) | Kidney Function | Failure | 1 Participants |
| Human Albumin 5% | Kidney Function | Failure | 0 Participants |
| Human Albumin 5% | Kidney Function | No risk | 69 Participants |
| Human Albumin 5% | Kidney Function | Injury | 1 Participants |
| Human Albumin 5% | Kidney Function | Risk | 2 Participants |
p-value: 0.9295% CI: [0.64, 12.1]Chi-squared
Secondary
Postop Urine IL-18
Postop Urine IL-18 (interleukin-18) measured at 1 h of arrival to ICU
Time frame: postoperative 1 hour
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| HES 130/0.4 (Voluven) | Postop Urine IL-18 | 10 pg/ml |
| Human Albumin 5% | Postop Urine IL-18 | 16 pg/ml |
p-value: 0.0025% CI: [0.21, 0.95]Regression, Linear
Secondary
Postop Urine IL-18
Postoperative urine IL-18 (interleukin-18) measured at 24 hours after surgery
Time frame: 24 hours after surgery
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| HES 130/0.4 (Voluven) | Postop Urine IL-18 | 60 pg/ml |
| Human Albumin 5% | Postop Urine IL-18 | 53 pg/ml |
p-value: 0.3195% CI: [0.45, 2.1]Regression, Linear
Post Hoc
Kidney Function
kidney injury using RIFLE criteria based on both peak creatinine levels and urine output, as recommended by Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group RIFLE classification criteria is listed below: Risk (RIFLE-R) Increase in serum creatinine x 1.5 from baseline urine output \< 0.5 mL/kg/hr for more than 6 hrs Injury (RIFLE-I) Increase in serum creatinine x 2 from baseline urine output \< 0.5 mL/kg/hr for more than 12 hrs Failure (RIFLE-F) Increase in serum creatinine x 3 from baseline urine output \< 0.3 mL/kg/hr for 24 hrs or anuria for 12 hrs Loss (RIFLE-L) Complete loss of kidney function \> 4 weeks End stage (RIFLE-E) End-stage kidney failure \> 3 months
Time frame: within the first seven postoperative days
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| HES 130/0.4 (Voluven) | Kidney Function | No risk | 27 Participants |
| HES 130/0.4 (Voluven) | Kidney Function | Risk | 18 Participants |
| HES 130/0.4 (Voluven) | Kidney Function | Injury | 23 Participants |
| HES 130/0.4 (Voluven) | Kidney Function | Failure | 1 Participants |
| Human Albumin 5% | Kidney Function | Failure | 0 Participants |
| Human Albumin 5% | Kidney Function | No risk | 16 Participants |
| Human Albumin 5% | Kidney Function | Injury | 31 Participants |
| Human Albumin 5% | Kidney Function | Risk | 24 Participants |
p-value: <0.00195% CI: [0.61, 1.03]Chi-squared