Association Between Early Caffeine Citrate Administration and Risk of Acute Kidney Injury in Preterm Neonates: Results From the AWAKEN Study

Abstract

Importance: Acute kidney injury (AKI) occurs commonly in preterm neonates and is associated with increased morbidity and mortality.

Objectives: To examine the association between caffeine citrate administration and AKI in preterm neonates in the first 7 days after birth and to test the hypothesis that caffeine administration would be associated with reduced incidence and severity of AKI.

Design, setting, and participants: This study was a secondary analysis of the Assessment of Worldwide Acute Kidney Injury Epidemiology in Neonates (AWAKEN) study, a retrospective observational cohort that enrolled neonates born from January 1 to March 31, 2014. The dates of analysis were October 2016 to December 2017. The setting was an international, multicenter cohort study of neonates admitted to 24 participating level III or IV neonatal intensive care units. Participants met the original inclusion and exclusion criteria of the AWAKEN study. Additional exclusion criteria for this study included participants greater than or equal to 33 weeks' gestation at birth, admission after age 7 days, use of theophylline in the neonatal intensive care unit, or lack of data to define AKI. There were 675 preterm neonates available for analysis.

Exposure: Administration of caffeine in the first 7 days after birth.

Main outcomes and measures: The primary outcome was the incidence of AKI (based on the modified neonatal Kidney Disease: Improving Global Outcomes [KDIGO] definition) in the first 7 days after birth. The hypothesis that caffeine administration would be associated with reduced AKI incidence was formulated before data analysis.

Results: The study cohort (n = 675) was 55.4% (n = 374) male, with a mean (SD) gestational age of 28.9 (2.8) weeks and a mean (SD) birth weight of 1285 (477) g. Acute kidney injury occurred in 122 neonates (18.1%) in the first 7 days after birth. Acute kidney injury occurred less frequently among neonates who received caffeine than among those who did not (50 of 447 [11.2%] vs 72 of 228 [31.6%], P < .01). After multivariable adjustment, administration of caffeine remained associated with reduced odds of developing AKI (adjusted odds ratio, 0.20; 95% CI, 0.11-0.34), indicating that for every 4.3 neonates exposed to caffeine one case of AKI was prevented. Among neonates with early AKI, those receiving caffeine were less likely to develop stage 2 or 3 AKI (adjusted odds ratio, 0.20; 95% CI, 0.12-0.34).

Conclusions and relevance: Caffeine administration in preterm neonates is associated with reduced incidence and severity of AKI. Further studies should focus on the timing and dosage of caffeine to optimize the prevention of AKI.

Conflict of interest statement

Conflict of Interest Disclosures: All authors reported no real or perceived conflicts of interest that could affect the study design; the collection, analysis, and interpretation of data; the writing of the report; or the decision to submit the manuscript for publication. For full disclosure, we provide the following additional list of authors’ other commitments and funding sources that are not directly related to this study. Dr Askenazi reported serving on the speaker board for Baxter and for the Acute Kidney Injury Foundation; he also reported receiving grant funding for studies not related to this work: grant R01 DK103608 from the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases and grant R01 FD005092 from the National Institutes of Health/US Food and Drug Administration. Dr Guillet reported receiving grant funding unrelated to this study: grant CTSI UL1 TR002001 from the Patient-Centered Outcomes Research Institute. Dr Charlton reported being the co-owner of Sindri Technologies, LLC, which is not related to this study and reported receiving grants 3P50DK096373, R01DK110622, and R01DK111861 from the National Institutes of Health. No other disclosures were reported.

Figures

Figure.. Study Flow Diagram

Acute kidney injury (AKI) was defined as occurring in the first 7 days after birth, and caffeine citrate administration was defined as occurring before an AKI event. AWAKEN indicates Assessment of Worldwide Acute Kidney Injury Epidemiology in Neonates; GA, gestational age; IV, intravenous; SCr, serum creatinine; and UOP, urine output. aBecause exclusion criteria are not mutually exclusive, some potential participants could have been excluded for multiple reasons and are counted in each exclusion category.