Fluid Chloride and AKI in Cardiopulmonary Bypass

The Impact of Low Chloride Containing Fluids on Acute Kidney Injury After Cardiopulmonary Bypass as Assayed by Urinary [TIMP2*IGFBP7]

Acute kidney injury (AKI) is a potential complication of cardiac surgery. In animal models, excess exogenous Cl- ion in the bloodstream is associated with AKI. Normal saline IV fluid has higher levels of Cl- ion than the blood usually carries. An alternative IV fluid sold under the name Isolyte has lower Cl- ion levels. There is no literature comparing AKI outcomes in cardiac patients between patients receiving normal saline vs. Isolyte. The investigators propose to recruit and randomize 30 trial-completing cardiac surgery patients (up to 40 enrolled) into 2 study arms and compare renal outcomes.

Study Overview

• Status: Completed
• Conditions: Acute Kidney Injury
• Intervention / Treatment: Drug: 0.9% Normal Saline (0.9% Sodium Chloride) injection; Drug: Isolyte S injection

Detailed Description

Acute kidney injury (AKI) is a potential complication for patients undergoing cardiac surgery. AKI in post-cardiac surgery patients is associated with adverse outcomes, such as prolonged intensive care and hospital stay, diminished quality of life, increased long-term mortality, and an increased risk of chronic kidney disease requiring dialysis. The mortality in cardiac surgery patients with AKI severe enough to require renal replacement therapy (RRT) can be as high as 60%. One of the putative agents associated with AKI in animal models receiving crystalloid fluids for resuscitative interventions is excess exogenous chloride ion (Cl-). As compared to non-Cl- containing solutions in animal models, excess Cl- appears to lead to a hyperchloremic metabolic acidosis, increased renal vascular resistance, reduced renal blood flow, and reduced glomerular filtration rate - all of which are injurious to kidney function.

Historically, one of the most common balanced salt-solutions used in adult cardiac surgery has been 0.9% normal saline (NS), a crystalloid solution with 154 mmol/L of Cl-. This is much higher than physiologic plasma levels of 103 mmol/L. Isolyte, a less commonly used crystalloid solution, is much closer to physiologic levels at 98 mmol/L Cl-. In the context of cardiac surgery, there is no literature expressly comparing the effects of balanced crystalloid solution such as Isolyte versus NS on AKI incidence. There is a single trial examining a low-Cl- containing colloid solution in cardiac surgery that found less metabolic acidosis; however, AKI or markers of AKI were not measured outcomes in that lone trial, so it is not known whether low Cl- solution will have any effect on AKI risk in humans.

AKI results from a series of extremely complex cellular and molecular pathways involving endothelial, epithelial, inflammatory, and interstitial cells. The gold standard for identification and classification of AKI is dependent on serial serum creatinine (Scr) measurements, but this measurement can be unreliable during acute changes in kidney function. Recent studies have shown that tissue inhibitor of metalloproteinase (TIMP-2) performs better than existing markers for predicting the development of moderate or severe AKI (Kidney Disease: Improving Global Outcomes [KDIGO] stage 2 or 3) within 12 hours of sample collection. To further enhance the sensitivity of utilizing TIMP-2, the investigators plan on also measuring urinary insulin-like growth factor-binding protein 7 (IGFBP7). Along with TIMP-2, IGFBP7 is also an inducer of G1 cell cycle arrest, a key mechanism implicated in AKI.

This study will utilize the urinary [TIMP-2]*[IGFBP7] multiplicative product as a composite biomarker index to investigate the impact of intraoperative infusion of NS versus Isolyte on post-cardiac surgery renal function. This biomarker should identify patients at risk of imminent (within 12 hours) AKI KDIGO criteria.

Patients presenting for cardiac surgery are already quite ill often with multiple comorbidities. Acute kidney injury in this population is associated with significant morbidity and mortality. The available literature indicates that a fairly simple intervention could plausibly reduce the incidence of AKI, but it has not yet been examined in humans. Generating an evidence basis for it will substantially improve the safety of patients who need cardiac surgery. This intervention to reduce AKI may also then be applied to the broader non-cardiac surgery population as well.

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • New Mexico
    • Albuquerque, New Mexico, United States, 87106
      • University of New Mexico Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Planned on- or off-pump cardiac surgery including: bypass grafting, valvular procedures, congenital defect correction, and thoracic aortic procedures or a combination of these procedures

Exclusion Criteria:

• Emergency surgery
• Pregnancy
• Previous renal transplantation
• Documented moderate to severe acute kidney injury prior to enrollment (e.g. RIFLE-I or RIFLE-F/KDIGO stage 2 or 3)
• Patients already receiving dialysis (acute or chronic) or in imminent need of dialysis at time of enrollment
• Chronic kidney disease without baseline serum creatinine value obtained within 6 months of enrollment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Normal Saline group; 0.9% Normal Saline (0.9% Sodium Chloride) injection intravenously as needed. The amount administered (dosage, frequency, and duration) will be left to the clinical judgment of the attending physicians, and will follow usual patterns of use in cardiac surgery patients.	Drug: 0.9% Normal Saline (0.9% Sodium Chloride) injection
Experimental: Isolyte group; Isolyte S (B Braun, Irvine CA) injection intravenously as needed. The amount administered (dosage, frequency, and duration) will be left to the clinical judgment of the attending physicians, and will follow usual patterns of use in cardiac surgery patients. Isolyte S is a prepackaged solution containing sodium chloride 0.53%, sodium gluconate 0.5%, sodium acetate trihydrate 0.37%, potassium chloride 0.037%, and magnesium chloride hexahydrate 0.03% w/v.	Drug: Isolyte S injection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in [TIMP2]*[IGFBP7] Biomarker	The difference in the [TIMP2]*[IGFBP7] biomarker between the preoperative value and a repeated measurement at 24 hours postoperatively. Positive values represent increase; negative values represent decrease	Baseline and postoperatively at 24 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serum Creatinine Level at 24 Hours	Serum creatinine measurement at 24 hours	1 day
Serum Chloride Level at 24 Hours	Serum chloride ion measurement at 24 hours postoperatively	1 day
Proportion of Patients With Need for Dialysis	Clinically-determined need for dialysis prior to discharge from hospital	One week
Postoperative Arterial pH	Arterial pH, measured 24 hours after surgery	One day
Serum Creatinine Level at 48 Hours	Serum creatinine level 48 hours postoperatively	2 days
Serum Chloride at 48 Hours	Serum chloride measurement at 48 hours postoperatively	2 days

Collaborators and Investigators

• Sponsor: University of New Mexico
• Investigators: Principal Investigator: Neal S Gerstein, MD, University of New Mexico

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2016
• Primary Completion (Actual): February 4, 2017
• Study Completion (Actual): February 1, 2018

Study Registration Dates

• First Submitted: January 20, 2016
• First Submitted That Met QC Criteria: January 26, 2016
• First Posted (Estimate): January 29, 2016

Study Record Updates

• Last Update Posted (Actual): May 14, 2018
• Last Update Submitted That Met QC Criteria: April 13, 2018
• Last Verified: April 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Kidney Diseases; Urologic Diseases; Renal Insufficiency; Acute Kidney Injury
• Other Study ID Numbers: 15-572

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Upon publication of study results, qualified researchers may contact the PI for the deidentified dataset.