Correlation between Serum Caffeine Levels and Changes in Cytokine Profile in a Cohort of Preterm Infants

Abstract

Objective To determine changes in cytokine levels associated with caffeine treatment in a cohort of preterm infants. Study design For this observational prospective study, we collected clinical data from 26 preterm infants (≤30 weeks gestational age). In addition to caffeine levels, cytokine profiles in peripheral blood (PB) and tracheal aspirates (TA) were determined with enzyme-linked immunosorbent assay at birth, before and after (at 24 hours and 1 week) initiation of caffeine. Non-parametric statistics were applied. Results Included infants were 26.9 1.7 weeks gestational age and weighed 985 ± 202 g. At birth, all cytokine concentrations were significantly greater in TA than PB. Serum caffeine levels were 11.1 μg/mL (interquartile range, 1.85) at approximately 24 hours post-load and 16.4 (8.7) μg/mL at 1 week on treatment. At approximately 24 hours post-load, interleukin (IL)-10 levels decreased by 47.5% (P = .01) in PB and 38.5% (P = .03) in TA, whereas other cytokine levels remained unchanged. At 1 week, caffeine levels were correlated (U-shaped) with changes in proinflammatory tumor necrosis factor-α (R2 = 0.65; P = .0008), interleukin (IL)-1β (R2 = 0.73; P = .0007), and IL-6 (R2 = 0.59; P = .003), whereas inversely correlated (linear) with the anti-inflammatory IL-10 (R2 = 0.64; P = .0008). Altogether, caffeine, at serum levels ≥20 μg/mL, was associated with a proinflammatory profile after 1 week of treatment. Conclusions Caffeine treatment for apnea of prematurity correlates with changes in cytokine profile. Caffeine levels ≥20 μg/mL are associated with a proinflammatory profile in our cohort of preterm infants.

Caffeine Prevents Hyperoxia-Induced Functional and Structural Lung Damage in Preterm Rabbits

“…A loading dose (10 mg/kg BW) and maintenance dose (5 mg/kg, q24 h BW) resulted in the target serum level range of 10-20 µg/ml [7]. Within this range, in preterm infants serum caffeine levels have a U-shaped correlation with cytokine profiles [18]. Furthermore, in a recent randomized controlled trial, higher doses of caffeine (40 mg/kg BW followed by 20 mg/kg BW and 10 mg/kg BW always after 24 h) were associated with a higher incidence in neurological impairment (e.g.…”

“…cerebellar hemorrhaging) and alterations in motor performance [22]. The effects of caffeine can be both anti- and proinflammatory, depending on the serum concentration [18]. In a cohort of preterm infants, it has been demonstrated that higher serum caffeine levels (≥20 μg/ml) were associated with an increase of proinflammatory cytokines such as TNF-α, IL-1 and IL-6.…”

“…We aimed for a pup serum level between 10 and 20 μg/ml after the administration as described previously in humans [18]. Fetal blood samples were collected at 12 h after the last caffeine administration.…”

Amplification of steroid-mediated SP-B expression by physiological levels of caffeine

“…A relationship between serum caffeine levels and cytokine concentrations was already observed in tracheal aspirates and peripheral blood of preterm infants (9). For low serum caffeine levels, concentrations of proinflammatory cytokines TNF-␣, IL-1, and IL-6 were reduced, but increased at higher levels, which could contribute to the severity of inflammatory conditions such as development of BPD (24).…”

“…Other protective mechanisms of caffeine in this regard are supposed to be anti-inflammatory actions (14), which include inhibition of proinflammatory cytokine production (9,29).…”