Caffeine Reduces Apnea Frequency and Enhances Ventilatory Long-Term Facilitation in Rat Pups Raised in Chronic Intermittent Hypoxia

Abstract

The mechanisms underlying the therapeutic function of caffeine on apneas in preterm neonates are not well determined. To better understand these effects, we exposed rat pups from postnatal d 3-12 to chronic intermittent hypoxia (5% O2/100 s every 10 min; 6 cycles/h followed by 1 h at 21% O2, 24 h/d), a model mimicking hypoxemic exposure in apneic neonates. Then, using whole-body plethysmography, we evaluated minute ventilation, apnea frequency, and duration after i.p injection of caffeine citrate (20 mg/kg) or saline under normoxia and in response to either sustained (FiO2 12%, 20 min) or brief (FiO2 5%, 60 s, total 10 episodes of 8 min each) hypoxia. These tests were used to assess peripheral and central components of hypoxic response. The latter also assessed the ventilatory long-term facilitation during recovery (2 h). Caffeine injection increased minute ventilation under baseline and during recovery. This effect was correlated with a decrease in apnea frequency (not duration). On the contrary, caffeine did not change the ventilatory response to sustained or brief hypoxic exposure. These results suggest that the effects of caffeine on apnea depend on increased central normoxic respiratory drive and enhancement of ventilatory long-term facilitation rather than on higher hypoxic ventilatory response.

Respiratory regulation by steroids in newborn rats: a sex‐specific balance between allopregnanolone and progesterone receptors

“…This caffeine dose generates a plasma caffeine concentration of 15.4 ± 2.8 mg l −1 (range 8.7–24.1 mg l −1 ; Julien et al . ), matching the therapeutic level in premature infants (Bairam et al . ; Schoen et al .…”

Conditioned breathing depression during neonatal life as a function of associating ethanol odor and the drug's intoxicating effects

“…Respiratory responses were registered during 4 consecutive minutes. To avoid neonatal ethanol‐related thermal disruptions that can cause neonatal bradycardia and respiratory arrest (Duxbury, ; Hunt, Spear, & Spear, ), the temperature inside the plethysmograph was kept at 31–32 °C through the use of heating pads placed beneath the chambers (Culleré et al, ; Julien, Joseph, & Bairam, ). An air conditioning system was employed to maintain room temperature at 24 ± 1 °C.…”

Neonatal experiences with ethanol intoxication modify respiratory and thermoregulatory plasticity and affect subsequent ethanol intake in rats

“…The apneic episodes were also measured. The criterion used to determine an apneic episode was the interruption of air flow for at least two normal respiratory cycles (.5 s or more; Julien, Joseph, & Bairam, ).…”

“…An air conditioner kept the room temperature at 22 ± 1 °C during experimental sessions. The temperature was kept at 31–32 °C inside the plethysmograph chambers, similar to their maternal nest, through heating pads placed beneath the chambers (Julien et al, ). The overall procedure has been previously used to evaluate breathing disruptions as a function of pre‐ and postnatal ethanol exposure (Cullere et al, ; Macchione et al, ; respectively).…”