Clinical trial NCT03897335: Preventing Acute Kidney Injury (AKI) in Pediatric Patients
Official title: The Effect of Aminophylline on Preventing Acute Kidney Injury in Pediatric Patients Undergoing Open Heart Surgery
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Acute Kidney Injury
Keywords: Aminophylline
Lead sponsor: Le Bonheur Children's Hospital
Sponsor class: OTHER
First posted: 2019-04-01
Enrollment: 80
Sex: ALL
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 1 Patient randomization groups

A) Group 1: Aminophylline pre CPB \& immediately post cardiopulmonary bypass (CPB)

B) Group 2: No aminophylline prophylaxis
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Acute kidney injury state II/III by AKIN criteria
timeFrame: At 48 hours post-operative
Secondary outcomes:
measure: Urine output during post op
timeFrame: first 12 hours post op
measure: Urine output during post op
timeFrame: daily until 3 days post op
measure: Concentration of Delta serum cystatin C
timeFrame: 24 hours post CPB
measure: Acute kidney injury stage
timeFrame: max point within post CPB 72 hours
Other outcomes:
measure: Concentration of Delta urinary neutrophil gelatinase-associated lipocalin (NGAL)
timeFrame: at 2 hours post CPB.
measure: Time to extubation (hours)
timeFrame: during hospitalization, up to 8 days
measure: Time to chest closure (hours)
timeFrame: during hospitalization, up to 3 days
measure: Time to discharge from cardiovascular intensive care unit (CVICU) (days)
timeFrame: during hospitalization, approximate 5 days
measure: Duration of hospital stay (Days).
timeFrame: during hospitalization, approximate 8 days
measure: Dialysis requirement (yes/no)
timeFrame: during hospitalization, approximate 5 days
measure: Time to return to preoperative weight.
timeFrame: during hospitalization, approximate 8 days
measure: Inotropic score
timeFrame: at 7 days post operative
measure: Peritoneal dialysis catheter output.
timeFrame: during hospitalization, up to 8 days
measure: Transfusion requirements intraoperatively and postoperatively
timeFrame: during hospitalization, up to 8 days
measure: Inotropic score
timeFrame: at 5 days post operative
Locations:
city: Memphis
country: United States
facility: LeBonheur Children's Hospital
state: Tennessee
city: Memphis
country: United States
facility: LeBonheur Children's Hospital
state: Tennessee
Study officials:
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