Article of the Month - May 2022

Renal tissue oxygenation after caffeine administration in preterm neonates

Pediatr Res. Dec 2021;90(6):1171-1176. doi:10.1038/s41390-021-01579-3

Harer MW, Rothwell AC, Richard LJ, Adegboro CO, McAdams RM.

Reviewed by: Cara Slagle, MD - Assistant Professor, Division of Neonatology, Co-Director, Center for Acute Care Nephrology, Cincinnati Children’s Hospital Medical Center

Background:

Poor renal perfusion is associated with neonatal AKI in preterm infants born at <32 weeks gestation. Near-infrared spectroscopy (NIRS) is a useful, non-invasive tool to measure renal regional saturation of oxygen (RrSO2).  As neonatal AKI and it’s long term consequences are becoming increasingly recognized, mitigation strategies and/or therapies is paramount. Methylxanthines, which are commonly given to neonates at this gestational age for apnea of prematurity, may have renal protective effects. This paper aims to understand the association of changes in RrSO2 and renal factional tissue oxygenation extraction (rFTOE) following maintenance caffeine dosing in preterm infants <32 weeks.

Methods:

Retrospective analysis performed on a prospective single-center study over 1.5 years. The primary hypothesis was that RrSO2 increases in preterm neonates with low baseline values following maintenance caffeine administration during the first 7 days of life. Inclusion criteria was neonates admitted to the level III NICU with a gestational age (GA) of <32 weeks. Exclusion criteria were inability to enroll and place NIRS by 48 hours of age or unavailability of NIRS, attending refusal, known congenital anomaly of the kidney or urinary tract, or inability to obtain informed consent. RrSO2 was measured by NIRS at the right or left flank for all neonates and tissue oxygenation was recorded every 3-10 seconds until 7 days of life. Study, clinical team and parents were blinded to RrSO2 values. Caffeine dose of 20 mg/kg was administered via intravenous solution within the first 6 hours followed 24 hours later by daily maintenance dosing of 8 mg/kg (oral or IV)  per standard of care for infants <30 weeks GA and at clinical team discretion for those 30-32 weeks GA. The primary outcome was to compare the difference in 20-minute averages of RrSO2 immediately prior to caffeine administration to 0.5, 1, 2, 3,4, 6, and 12 hours after dose. rFTOE was calculated by (SpO2-RrSO2)/SpO2. Statistical analysis included descriptive statistics, Mann-Whitney U test with a p value of <0.05 representing statistical significance.

Results

31 neonates who were enrolled received a total of 156 doses of caffeine. Median GA was 28.4 weeks and a median birthweight of 1050 grams. Subjects received a median of 5 doses (IQR: 4-6 doses) with a median dose of 8 mg/kg (IQR: 8-8 mg/kg).  There was no statistically significant difference in RrSO2 or rFTOE changes from baseline at any time point in the overall analysis. However, when baseline RrSO2 values were grouped by 10% increments ranging from <20% to ³60%, statistical significance was noted in the <20%, 20-29.9%, 30-39.9% and ³60%. The largest difference was noted at 2 hours in the 20-29.9% with a nearly 14% increase (p <0.0001). These differences correlated with analysis of rFOTE. Separate analysis of IV administration (n=119) was performed yielding similar results.

Conclusion

This small pilot study, demonstrates that renal NIRS offers a clinically useful tool to understand renal tissue oxygenation and association with medications, co-morbidities, etc. Specifically, caffeine, a commonly used methylxanthine in preterm neonates, can increase RrSO2 in preterm neonates with low baseline tissue oxygenation. Improvement in renal tissue oxygenationmaybe useful in preventing AKI.  This study highlights the importance of exploring this relationship further- through mechanistic actions, optimal administration and dosing, and association with functional outcomes and long-term outcomes.

Importance

This hypothesis generating study highlights the large knowledge gaps related to neonatal AKI, renal tissue oxygenation and the need for exploration into potential solutions to mitigate AKI and its consequences. Caffeine, which is routinely administered to preterm neonates, may have a protective effect against AKI. However site to site protocols related to administration and dosing in neonates vary. Importantly this study demonstrates caffeine administration may increase renal tissue perfusion, a known source of renal injury. It also, interestingly demonstrates variation of increase in oxygenation depending on the baseline oxygenation subgroup following caffeine administration.