Effect of Early Caffeine Therapy on the Prevention of Severe Hyperkalemia in Preterm Infants

Background: Hyperkalemia is common in preterm infants and the prevention of severe hyperkalemia may decrease the incidence of fatal arrhythmia and the intervention rate of glucose-insulin therapy. Caffeine therapy is indicated for apnea of prematurity. Pharmacologically, caffeine enhances potassium excretion through diuresis. The aim of this study was to evaluate the effect of early caffeine therapy on potassium levels within the first three days of life in preterm infants.

Methods: We conducted a single-center retrospective chart review of preterm infants who were admitted to our neonatal intensive care unit from January 2019 to August 2020. Infants were divided into two groups; the early caffeine group (within 12 hours of life) and the control group (after 12 hours of life). The loading dose of caffeine citrate was 20 mg/kg/dose along with a maintenance dose of 6-10 mg/kg q12h. We started early caffeine therapy for all the infants of 25-29 weeks gestational since December 2019.

Results: A total of 33 infants were included; 15 (45%) in the early caffeine group and, 18 (55%) in the control group (Table 1). Overall, the median gestational age and birth weight were 27.1 weeks (range, 26.0-29.9) and 903 g (range, 598-1546). The median time to the loading dose was 3 hours (range, 1-10) and 126 hours (range, 15-350) in the early caffeine and control group, respectively; the median baseline potassium levels (day 0), 5.30 mEq/L (range, 3.68-6.40), 4.81 mEq/L (range, 3.70-6.10) (p=0.27). The incidence of severe hyperkalemia (>6.5 mEq/L) were none (0%) and 7 (39%) in the early caffeine and control group, respectively (p < 0.01); the maximum potassium levels, 5.57 mEq/L (range, 3.92-6.41) and 6.01 mEq/L (range, 5.13-7.25), respectively (p=0.02) (Figure 1A). Among selected covariates, the early caffeine therapy was the only negative associations with potassium levels on days 1-3 (Figure 1B). Multivariate binary logistic regression for the incidence of severe hyperkalemia showed an exclusive correlation of early caffeine therapy with lower potassium levels within the first three days of life (p= 0.015; odds ratio, 0.051; 95% confidence interval [CI], 0.000-0.615). Multivariate linear mixed effect models for the estimation of potassium levels within 3 days of life showed early caffeine therapy lowered potassium levels by -0.946 mEq/L (p < 0.001; 95% CI, -1.459 to -0.433) on day 1, compared to the control group; -0.427 mEq/L (p= 0.108; 95% CI, -0.942 to 0.089) on day 2; -0.117 mEq/L (p= 0.660; 95% CI, -0.635 to 0.401) on day 3. We did not observe therapy-related adverse events. The incidence of retinopathy of prematurity worse than stage 2, and the number of blood samplings were lower in the early caffeine group.

Conclusion: We conclude that early caffeine therapy reduces the incidence of severe hyperkalemia in preterm infants at 25 to 29 weeks gestation.