The Effect of Intravenous Aminophylline on Preventing Acute Kidney Injury in Sick Neonates – A Multicentric Double blinded, Randomised, Placebo-controlled Clinical Trial

Neonatal acute kidney injury (nAKI) poses a significant mortality risk, particularly in lower-income countries where treatment options are limited and expertise in neonatal dialysis is scarce. Aminophylline, a non-selective adenosine receptor antagonist, may attenuate AKI by promoting renal blood flow and natriuresis. Although aminophylline has shown benefit in select neonatal subgroups like asphyxia, its efficacy in other critically ill term neonates at high risk for AKI remains unexplored. We hypothesise intravenous (IV) aminophylline(AP) is effective in preventing AKI compared to placebo in sick neonates admitted to neonatal intensive care unit (NICU).

In this multicentric, randomised, double-blinded placebo-controlled study we assessed the efficacy of single dose IV aminophylline at 8mg/kg vs placebo given at 12 hours of NICU admission in preventing AKI in neonates born at ≥ 36 weeks of gestation having a Score for Neonatal Acute Physiology with Perinatal Extension II (SNAPPE II) of ≥ 37 in 3 centres. The primary outcome of AKI at day 3, secondary outcomes of AKI at day 7 using modified neonatal KDIGO criteria, delta urinary neutrophil gelatinase-associated lipocalin (uNGAL), and fractional excretion of sodium (FeNa) at 48 hours, were compared.

A total of 110 critically ill neonates were analysed (Aminophylline: 54; Placebo: 56). Baseline demographics, illness severity (median SNAPPE II 48.5 vs 47.1), and primary diagnoses were comparable between groups. Unlike previous studies restricted to perinatal asphyxia, this trial included a heterogeneous cohort encompassing sepsis, pulmonary hypertension, and postsurgical conditions (see Table 1). At 72 hours, AKI) occurred in 31.5% of aminophylline-treated versus 35.7% of placebo infants (RR 0.88, 95% CI 0.52–1.49). Aminophylline was associated with fewer Stage 1 (16.7% vs 23.2%) and Stage 2 (9.3% vs 10.7%) events, while Stage 3 AKI was more frequent in the aminophylline group (5.6% vs 1.7%). At 7 days, persistent AKI was observed in 14.8% versus 8.9%, in aminophylline vs placebo group respectively (RR 1.66, 95% CI 0.58–4.75). Mean delta uNGAL (–113 ± 393 ng/mL vs –81 ± 384 ng/mL; p = 0.58) was higher in aminophylline group. FeNa (2.87 ± 1.34 vs 3.12 ± 2.49; p = 0.54) was comparable between groups. Mortality (9.3% vs 7.1%) and hospital stay (10.0 ± 6.9 vs 8.2 ± 4.8 days; p = 0.12) were comparable.

In this multicentre, randomised, double-blind trial, a single prophylactic dose of intravenous aminophylline (8 mg/kg) was safe and well tolerated in a heterogeneous group of critically ill term neonates—not limited to those with asphyxia, where its use has been traditionally studied. Results showed a consistent trend toward lower early AKI incidence and reduced severity in critically ill neonates ≥ 36 weeks gestation at high risk of renal injury. Although differences did not reach statistical significance, aminophylline was not associated with worsening renal function or adverse events. These findings suggest potential renoprotective benefit beyond asphyxiated neonates and support further evaluation of aminophylline as an adjunct for AKI prevention across diverse neonatal critical care populations. Larger adequately powered studies are warranted to confirm its protective role and define the subgroups most likely to benefit.