Interactive Ventilatory Effects of Two Respiratory Stimulants, Caffeine and Doxapram, in Newborn Lambs

Abstract

Caffeine and doxapram are two respiratory stimulants used in the treatment of apnea in newborns. When used concurrently, these drugs may produce interactive effects on the control of breathing in the newborn. The ventilatory effects of these drugs, given alone or together, were measured during 150 min of drug infusion in two groups of awake lambs 2-5 days old. The first group (n = 5) received a caffeine loading dose of 10 mg/kg followed by a maintenance dose of 0.1 mg/kg/h and incremental doses of doxapram: 0.25, 0.5, 1.25 and 2.5 mg/kg/30 min. The second group (n = 5) received a doxapram loading dose of 5.5 mg/kg followed by a maintenance dose of 1 mg/kg/h and incremental doses of caffeine: 2.5, 5.0, 7.5 and 10.0 mg/kg/30min. In the first group, ventilation increased after the caffeine loading dose from 566 ± 55 to 680 ± 74 ml/kg/min (plasma caffeine = 14.7 ± 1.6 mg/l) and progressively increased with the addition of incremental doses of doxapram upto 1,000 ± 108 ml/kg/min at 2.5 mg/kg of doxapram (p < 0.001 compared to baseline and caffeine loading dose). In contrast, in the second group, the doxapram loading dose markedly increased ventilation from 582 ± 50 to 936 ± 75 (p < 0.002 and p < 0.04 compared to caffeine loading dose) at plasma doxapram of 5.3 ± 0.8 mg/l, but incremental doses of caffeine had no effects. We conclude that doxapram exerts a brisk and powerful respiratory stimulant effect and produces an additional dose-dependent ventilatory response when added to caffeine.

Predictors of Bronchopulmonary Dysplasia

“…Caffeine has been shown to increase carbon dioxide chemoreceptor responsiveness, increase respiratory muscle performance and generally increase central nervous system excitability. 79–81 In the Caffeine for Apnea of Prematurity (CAP) trial, the infants randomized to caffeine therapy had a lower incidence of BPD (36% vs. 47%, adjusted OR 0.64 (0.52–0.78)), as defined by oxygen need at 36 weeks PMA. 82 …”

Caffeine to improve breathing effort of preterm infants at birth: a randomized controlled trial

“…Although these studies demonstrated the effects of caffeine in the first days after birth, there is little data on the direct effect of caffeine on respiratory effort or whether gestational age (GA) influences the effect of caffeine. Bairam et al (19) showed that in 2-5-day-old term lambs Vt i increased after a loading dose of caffeine. Kraaijenga et al (15) confirmed this in 1-4-day-old preterm infants by measuring diaphragmatic activity after caffeine administration (19).…”

“…Bairam et al (19) showed that in 2-5-day-old term lambs Vt i increased after a loading dose of caffeine. Kraaijenga et al (15) confirmed this in 1-4-day-old preterm infants by measuring diaphragmatic activity after caffeine administration (19). Within 5 min of administration, diaphragmatic activity increases, resulting in a 30% increase in tidal volumes (15).…”

Low‐dose doxapram for treatment of apnoea following early weaning in very low birthweight infants: a randomized, double‐blind study

“…The caffeine-doxapram combination has been used in only one human study (6). In newborn lambs, ventilation has been reported to increase after a loading dose of caffeine and to increase further with the addition of incremental doses of doxapram (18). Other authors have used aminophylline or theophylline combined with doxapram in premature infants (7,8).…”

“…The doxapram-related increase in blood pressure is well known (7,(19)(20)(21)(22). In human studies, surprisingly, it seems that blood pressure was not monitored in all treated infants (8) and blood pressure values were not always reported (5,18). Barrington et al (19), who used doxapram alone, reported an increase in blood pressure at doses Ͼ1.5 mg kg −1 h −1 .…”