Preventing Acute Kidney Injury (AKI) in Pediatric Patients (AKI)

April 11, 2022 updated by: Umar S. Boston, Le Bonheur Children's Hospital

The Effect of Aminophylline on Preventing Acute Kidney Injury in Pediatric Patients Undergoing Open Heart Surgery

The purpose of this study is to compare the effects of peri-operative administration of Aminophylline versus Saline placebo in the preservation of renal function and the attenuation of renal injury in pediatric patients undergoing open heart surgery.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Cardiac palliative/ correction surgeries in pediatric patients involve significant morbidity and mortality risks. Kidney function is frequently affected from cardiac surgery in these children. Studies identify the incidence of acute kidney injury (AKI) to be approximately 54% when defined by serum biomarkers (e.g. serum creatinine) and urine output criteria. The need for renal replacement therapy (RRT) for newborns and infants after cardiac surgery is reported as 2% to 17% in the literature. There are several reported risk factors for the development of AKI in this population. These are the complexities of the underlying heart disease and the surgical procedure, duration of cardiopulmonary bypass, functional single ventricle heart disease, circulatory arrest and low cardiac output syndrome in the post-operative period. AKI can cause worsening fluid overload compromising ventilation and lung function, predisposition to overwhelming infections and cytokine-mediated inflammatory state. The presence of AKI significantly increases the mortality that is associated with cardiac surgery in these very young patients, reported as high as 79% in the literature. There have been several reports suggesting that early intervention with AKI using renal replacement therapy (RRT) may improve patient mortality. Successful prevention strategies for AKI have not been reported for this high-risk population.

Adenosine has been demonstrated to regulate renal circulation and metabolism. It is a breakdown product of adenosine triphosphate/adenosine diphosphate (ATP/ADP) metabolism and accumulates in AKI. At baseline, the barely detectable renal parenchymal adenosine levels can increase to 10-100 times following an ischemic insult. These are typical seven trans-membrane spanning domains with a coupled G-protein at the intracellular end. Adenosine receptors are located ubiquitously in many tissues. Adenosine acts as a vasodilator in all other tissues but the renal parenchyma. The interaction of AT-II with adenosine converts adenosine to a vasoconstrictor in renal microvasculature. Adenosine acts on the A1 receptors (A1 R) in the afferent arterioles, causing reduced glomerular blood flow and glomerular filtration rate (GFR), as well as stimulating renin release from the kidney parenchyma. Adenosine plays an important role in generating the vasoconstrictive response in the renal vasculature to hypoxia and ischemia. Early interventions by blocking the actions of adenosine on A1 R may restore glomerular blood flow and recover GFR.

The study rationale is that Aminophylline and Theophylline are competitive non-selective inhibitors of adenosine. Therefore, even though aminophylline infusion (iv) has no effect on renal blood flow rate at baseline, it can ameliorate the decrease in renal blood flow rate following adenosine infusion. This property can improve renal function when the main mechanism of insult induces vasoconstriction. Both early and late administration of aminophylline protects renal function after ischemia-reperfusion injury in rats. Aminophylline has also been reported to successfully reverse newborn renal failure, prevent renal failure in perinatal asphyxia, and reverse acute kidney injury secondary to calcineurin induced nephropathy. Both theophylline and aminophylline have been used for prophylaxis of renal impairment during aorto-coronary bypass surgery in adults and the results have not been consistent for either a positive or negative effect. There have been no trials reported on the effect of aminophylline or theophylline to prevent or ameliorate acute kidney injury in children with congenital heart defects going through cardiac surgery.

Additionally, we are examining the components of serotonin biosynthesis to determine if these levels can act as markers of acute kidney injury in pediatric patients undergoing open heart surgery.

Study Type

Interventional

Enrollment (Anticipated)

80

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

No older than 18 years (Child, Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

Cohort 1

  • All children undergoing open heart surgery for congenital heart defects with or without circulatory arrest
  • Neonates (<28 days old) and infants (<1 years of age)
  • Hypoplastic L heart syndrome or its variants.
  • Coarctation with aortic arch hypoplasia.
  • Interrupted aortic arch.
  • TAPVR (Total anomalous pulmonary venous return)
  • Patients with complex congenital heart defects

Cohort 2:

  • Orthotopic heart transplantation patients.
  • Patients ≤ 18 years of age
  • Congenital heart defects
  • Cardiomyopathy (Dilated/Hypertrophic/Restrictive/Left Ventricular Non-compaction)

Exclusion Criteria:

  • Children under the age of 12 months undergoing bypass for any condition that is not categorized as congenital heart defect
  • History of seizures
  • History of significant tachyarrhythmia.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Placebo Comparator: Placebo
Drug: Placebo
The placebo group will not receive any aminophylline treatments for the first post-op five days
Other Names:
  • Normal Saline
Active Comparator: Aminophylline pre CPB & immediately post CPB
Drug: Aminophylline
Aminophylline pre cardiopulmonary bypass and immediately post cardiopulmonary bypass. The dose will be Aminophylline 5 mg/kg/dose, max 350 mg slow infusion. The infusion rate duration will be standardized to 20 minutes. There will be no other aminophylline treatments for the first post-op five days.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Acute kidney injury state II/III by AKIN criteria
Time Frame: At 48 hours post-operative
Acute kidney injury state II/III by AKIN criteria
At 48 hours post-operative

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Urine output during post op
Time Frame: first 12 hours post op
Urine output during post op
first 12 hours post op
Urine output during post op
Time Frame: daily until 3 days post op
Urine output during post op
daily until 3 days post op
Concentration of Delta serum cystatin C
Time Frame: 24 hours post CPB
Delta serum cystatin C
24 hours post CPB
Acute kidney injury stage
Time Frame: max point within post CPB 72 hours

Acute kidney injury stage Pediatric modified Acute Kidney Injury Network criteria (pAKIN) AKI Stage I-<0.5mL (milliliter)/kg/hour for 8 hours AKI Stage II-<0.5mL/kg/hour for 16 hours AKI Stage III-<0.3mL/kg/hour for 24 hours OR Anuria for 16 hours

Using serum creatinine and AKIN criteria
max point within post CPB 72 hours

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Concentration of Delta urinary neutrophil gelatinase-associated lipocalin (NGAL)
Time Frame: at 2 hours post CPB.
1 Delta urinary NGAL at 6 hours post cardiopulmonary (CPB) and Delta plasma NGAL at 2 hours post CPB.
at 2 hours post CPB.
Time to extubation (hours)
Time Frame: during hospitalization, up to 8 days
Time to extubation (hours) number of hours post surgery
during hospitalization, up to 8 days
Time to chest closure (hours)
Time Frame: during hospitalization, up to 3 days
Time to chest closure (hours) from start time of incision to chest closure during procedure
during hospitalization, up to 3 days
Time to discharge from cardiovascular intensive care unit (CVICU) (days)
Time Frame: during hospitalization, approximate 5 days
Time to discharge from CVICU (days)
during hospitalization, approximate 5 days
Duration of hospital stay (Days).
Time Frame: during hospitalization, approximate 8 days
Duration of hospital stay (Days).
during hospitalization, approximate 8 days
Dialysis requirement (yes/no)
Time Frame: during hospitalization, approximate 5 days
Dialysis requirement (yes/no)
during hospitalization, approximate 5 days
Time to return to preoperative weight.
Time Frame: during hospitalization, approximate 8 days
Time to return to preoperative weight.
during hospitalization, approximate 8 days
Inotropic score
Time Frame: at 7 days post operative
Inotropic score Calculation of Inotropic score (IS) and Vasoactive inotropic score (VIS). IS(a) = dopamine dose (lg/kg/min) ? dobutamine dose (lg/kg/min) ? 100 9 epinephrine dose (lg/kg/min) VIS(b) = IS ? 10 9 milrinone dose (lg/kg/ min) ? 10,000 9 vasopressin dose (U/kg/ min) ? 100 9 norepinephrine dose (lg/kg/min) IS inotrope score, VIS vasoactive-inotropic score
at 7 days post operative
Peritoneal dialysis catheter output.
Time Frame: during hospitalization, up to 8 days
Peritoneal dialysis catheter output through study completion
during hospitalization, up to 8 days
Transfusion requirements intraoperatively and postoperatively
Time Frame: during hospitalization, up to 8 days
Transfusion requirements intraoperatively and postoperatively through study completion
during hospitalization, up to 8 days
Inotropic score
Time Frame: at 5 days post operative
Inotropic score Calculation of Inotropic score (IS) and Vasoactive inotropic score (VIS). IS(a) = dopamine dose (lg/kg/min) ? dobutamine dose (lg/kg/min) ? 100 9 epinephrine dose (lg/kg/min) VIS(b) = IS ? 10 9 milrinone dose (lg/kg/ min) ? 10,000 9 vasopressin dose (U/kg/ min) ? 100 9 norepinephrine dose (lg/kg/min) IS inotrope score, VIS vasoactive-inotropic score
at 5 days post operative

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Le Bonheur Children's Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

February 7, 2019

Primary Completion (Anticipated)

February 1, 2023

Study Completion (Anticipated)

February 1, 2024

Study Registration Dates

First Submitted

February 20, 2019

First Submitted That Met QC Criteria

March 28, 2019

First Posted (Actual)

April 1, 2019

Study Record Updates

Last Update Posted (Actual)

April 18, 2022

Last Update Submitted That Met QC Criteria

April 11, 2022

Last Verified

April 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • acute kidney injury

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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