Evaluate the Nephrotoxicity by 6% Hydroxyethyl Starch 130/0.4 in Old Patients During Orthopaedic Surgery

Evaluate the Nephrotoxicity by 6% Hydroxyethyl Starch 130/0.4 in Old Patients

Status

Completed

Phases

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02361736

Enrollment

120

Registered

2015-02-12

Start date

2015-03-31

Completion date

2016-01-31

Last updated

2016-03-24

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Total Fluid Volume Increased

Brief summary

Hydroxyethyl starch (HES) is commonly used as plasma expander during surgery but may be nephrotoxic as seen in studies in patients with sepsis. The investigators hypothesized that the possible nephrotoxicity of 6% HES 130/0.4 could be revealed by measurements of urinary and plasma neutrophil gelatinase-associated lipocalin and interleukin-18 (IL-18) in old patients with normal renal function during orthopaedic surgery.

Detailed description

Hydroxyethyl starch (HES) is widely used as volume expander to maintain circulation in patients during surgery, trauma, and in critical disease, where a rapid and sustained volume expansion is the goal. However, acute kidney injury (AKI) is sometimes a complication in these patients and HES might be a contributing factor. Acute kidney injury is often diagnosed using a sudden rise in plasma creatinine (p-crea) or an abrupt decrease in urine output. P-crea depends on sex, nutrition, medication,muscle mass, and age and it increases 24 to 48 h after renal injury, so the diagnosis of AKI is delayed when using p-crea alone as an indicator for renal damage. New technology allows for earlier diagnosis of AKI using measurements of biomarkers in urine. Neutrophil gelatinase-associated lipocalin (NGAL) is a small protein, which is filtered via the glomeruli and reabsorbed in the proximal tubules, and thus low concentrations of NGAL can be measured in the blood and urine. Approximately 6 h after a renal injury, NGAL increases rapidly due to an up-regulated expression and secretion in the epithelial cells of the thick ascending limb of Henle's loop, the distal tubules, and the collecting ducts. Thus, NGAL can be used as a marker of renal damage. However, infections and malignancies can give falsely increased levels. Interleukin-18 (IL-18) is mainly created from proximal kidney tubules which is a proinflammatory factor that can be detected in earlier urine of AKI animal models. There is significant rise in IL-18 levels in urine of AKI confirmed cases(no chronic kidney disease, no urinary tract infections, no prerenal factors), specificity and susceptibility is 90%. As a result, IL-18 can be selected as a biomarker. Intravenously administrated HES is excreted in urine but is also partly accumulated in the tissues. Studies in animals and humans showed that HES molecules were accumulated in the proximal tubule cells with subsequent vacuolization and swelling-a condition known as osmotic nephrosis. However, recent studies, primarily conducted in patients with sepsis, found impaired renal function even when using tetrastarch. In contrast, perioperative studies found no evidence of AKI after infusion of HES. The investigators hypothesized that 6% HES 130/0.4 had a nephrotoxic effect, which could be revealed by measurements of urinary and plasma NGAL and IL-18; that 6% HES 130/0.4 influenced kidney function differently than crystalloids(lactated Ringer's solution) due to the different pharmacokinetic properties of colloids compared with that of crystalloids.

Interventions

DRUGHydroxyethyl Starch

6% Hydroxyethyl Starch(HES) is intravenously given 7.5ml/kg for the first hour of surgery

DRUGLactate Ringers

Lactate Ringers is intravenously administrated at a dose of 7.5ml/kg during the surgery

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Masking

TRIPLE (Subject, Caregiver, Investigator)

Eligibility

Sex/Gender

ALL

Age

65 Years to 90 Years

Healthy volunteers

Inclusion criteria

* Old patients scheduled to undergo orthopaedic surgery under a intravertebral anesthesia. (American Society of Anesthesiologists physical status I-Ⅲ)

Exclusion criteria

* Allergy and contraindication to HES * Infections and malignancies * Sepsis * History of heart failure or New York Heart Association(NYHA)\>Ⅲ * Renal failure or Cr\>108μmol/L，BUN\>8.3mmol/L * Undergoing dialytic treatments * Intracranial hemorrhages * Taking non-steroidal antiinflammatory agent for a long time * Inability to understand the Study Information Sheet and provide a written consent to take part in the study

Design outcomes

Primary

Measure	Time frame	Description
Concentration of NGAL in Urine on 5 Time Point	-1d, 0d, 1d, 3d, 5d after surgery	Neutrophil gelatinase-associated lipocalin (NGAL) is a small protein, which is filtered via the glomeruli and reabsorbed in the proximal tubules, and thus low concentrations of NGAL can be measured in the blood and urine.
Concentration of IL-18 in Urine on 5 Time Point	-1d, 0d, 1d, 3d, 5d after surgery	IL-18 is mainly created from proximal kidney tubules which is a proinflammatory factor that can be detected in earlier urine of AKI animal models.
Concentration of IL-18 in Plasma on 5 Time Point	-1d, 0d, 1d, 3d, 5d after surgery	—
Concentration of NGAL in Plasma on 5 Time Point.	-1d, 0d, 1d, 3d, 5d after surgery	concentration of NGAL in plasma on 5 time point. Biomarkers are measured by ELISA.

Secondary

Measure	Time frame	Description
Estimated Glomerular Filtration Rate(eGFR) on 5 Time Point	-1d, 0d, 1d, 3d, 5d after surgery	eGFR is calculated by concentration of creatinine and CKD-EPI2009
Ratio of the Urine Trace Albumin and Creatinine(ACR) on 5 Time Point	-1d, 0d, 1d, 3d, 5d after surgery	ACR is calculated by the urine trace albumin divided by the urine creatinine
Concentration of β2 Microglobulin in Urine	-1d, 0d, 1d, 3d, 5d after surgery	—

Countries

China

Participant flow

Recruitment details

From February 2015 to January 2016, patients were recruited and estimated for eligibility.

Pre-assignment details

Exclusion criteria:Allergy and contraindication to HES; Infections and malignancies; Sepsis; History of heart failure or NYHA\>Ⅲ; Renal failure or Cr\>108μmol/L，BUN\>8.3mmol/L;Undergoing dialytic treatments; Intracranial hemorrhages;Taking non-steroidal antiinflammatory agent for a long time

Participants by arm

Arm	Count
Lactate Ringers Lactate Ringers is intravenously administrated at a dose of 7.5ml/kg during the surgery Lactate Ringers: Lactate Ringers is intravenously administrated at a dose of 7.5ml/kg during the surgery	59
Hydroxyethyl Starch 6% Hydroxyethyl Starch (HES) is intravenously administrated at a dose of 7.5ml/ kg in the first hour of surgery, and then, Lactate Ringers' is administrated to the patient until the end of the surgery Hydroxyethyl Starch: 6% Hydroxyethyl Starch(HES) is intravenously given 7.5ml/kg for the first hour of surgery	59
Total	118

Baseline characteristics

Characteristic	Lactate Ringers	Hydroxyethyl Starch	Total
Age, Continuous	76.4 age STANDARD_DEVIATION 8.1	75.9 age STANDARD_DEVIATION 7.5	76.2 age STANDARD_DEVIATION 7.7
Sex: Female, Male Female	28 Participants	30 Participants	58 Participants
Sex: Female, Male Male	31 Participants	29 Participants	60 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	0 / 59	0 / 59
serious Total, serious adverse events	0 / 59	0 / 59