CO(2) inhalation as a treatment for apnea of prematurity: a randomized double-blind controlled trial.

OBJECTIVE: To compare the effect of prolonged inhalation of a low concentration of CO(2) with theophylline for the treatment of apnea of prematurity. STUDY DESIGN: Prospective, randomized, double-blind controlled trial of 87 preterm infants with apnea of prematurity (27-32 weeks' gestational age) assigned to either theophylline plus 0.5 L/min of room air via nasal prongs or placebo plus 0.5 L/min with CO(2) (about 1% inhaled) by nasal prongs for 3 days. RESULTS: Apnea time significantly decreased in the theophylline group from 189±33 s/h (control) to 57±11, 50±9, and 61±13 (days 1-3) (P=.0001) and in the CO(2) group from 183±44 (control) to 101±26, 105±29, and 94±26 s/h (days 1-3) (P=.03). Seven infants in the CO(2) group but none in the theophylline group failed to complete the study due to severe apneas (P=.003). CONCLUSIONS: Because theophylline was more effective in reducing the number and severity of apneas, inhalation of low concentration of CO(2), as used in the present study, cannot be considered as an alternative to theophylline in the treatment of apnea of prematurity. The less effectiveness of CO(2) treatment may have been related to the variability of the delivery of CO(2).

A randomized controlled trial of theophylline versus CO2 inhalation for treating apnea of prematurity.

OBJECTIVE: To determine whether inhalation of 0.8% CO(2) in preterm infants decreases the duration and rate of apnea as effectively as or better than theophylline with fewer adverse side effects. STUDY DESIGN: A prospective, randomized, control study of 42 preterm infants of gestational age 27 to 32 weeks assigned to receive inhaled CO(2) (n = 21) or theophylline (n = 21). The study group had a mean (+/- standard error of the mean) birth weight of 1437 +/- 57 g, gestational age of 29.4 +/- 0.3 weeks, and postnatal age of 43 +/- 4 days. After a control period, 0.8% CO(2) or theophylline was given for 2 hours, followed by a recovery period. RESULTS: In the CO(2) group, apneic time and rate decreased significantly, from 9.4 +/- 1.6 seconds/minute and 94 +/- 15 apneic episodes/hour to 3.0 +/- 0.5 seconds/minute and 34 +/- 5 apneic episodes/hour. In the theophylline group, apneic time and rate decreased significantly, from 8 +/- 1 seconds/minute and 80 +/- 8 apneic episodes/hour to 2.5 +/- 0.4 seconds/minute and 28 +/- 3 apneic episodes/hour. Cerebral blood flow velocity (CBFV) decreased only during theophylline administration. CONCLUSIONS: Our findings suggest that inhaled low (0.8%) CO(2) concentrations in preterm infants is at least as effective as theophylline in decreasing the duration and number of apneic episodes, has fewer side effects, and causes no changes in CBFV. We speculate that CO(2) may be a better treatment for apnea of prematurity than methylxanthines.

Measurement of the CO2 apneic threshold in newborn infants: possible relevance for periodic breathing and apnea.

We measured the PCO2 apneic threshold in preterm and term infants. We hypothesized that, compared with adult subjects, the PCO2 apneic threshold in neonates is very close to the eupneic PCO2, likely facilitating the appearance of periodic breathing and apnea. In contrast with adults, who need to be artificially hyperventilated to switch from regular to periodic breathing, neonates do this spontaneously. We therefore measured the apneic threshold as the average alveolar PCO2 (PaCO2) of the last three breaths of regular breathing preceding the first apnea of an epoch of periodic breathing. We also measured the PaCO2 of the first three breaths of regular breathing after the last apnea of the same periodic breathing epoch. In preterm infants, eupneic PaCO2 was 38.6 +/- 1.4 Torr, the preperiodic PaCO2 apneic threshold was 37.3 +/- 1.4 Torr, and the postperiodic PaCO2 was 37.2 +/- 1.4 Torr. In term infants, the eupneic PaCO2 was 39.7 +/- 1.1 Torr, the preperiodic PaCO2 apneic threshold was 38.7 +/- 1.0 Torr, and the postperiodic value was 37.9 +/- 1.2 Torr. This means that the PaCO2 apneic thresholds were 1.3 +/- 0.1 and 1.0 +/- 0.2 Torr below eupneic PaCO2 in preterm and term infants, respectively. The transition from eupneic PaCO2 to PaCO2 apneic threshold preceding periodic breathing was accompanied by a minor and nonsignificant increase in ventilation, primarily related to a slight increase in frequency. The findings suggest that neonates breathe very close to their PCO2 apneic threshold, the overall average eupneic PCO2 being only 1.15 +/- 0.2 Torr (0.95-1.79, 95% confidence interval) above the apneic threshold. This value is much lower than that reported for adult subjects (3.5 +/- 0.4 Torr). We speculate that this closeness of eupneic and apneic PCO2 thresholds confers great vulnerability to the respiratory control system in neonates, because minor oscillations in breathing may bring eupneic PCO2 below threshold, causing apnea.

Increased peripheral chemoreceptor activity may be critical in destabilizing breathing in neonates.

Periodic breathing and apnea are common in neonates, yet the physiological mechanisms involved are not clear. A low arterial PO2 might magnify peripheral chemoreceptor contribution to breathing, with its baseline variability inducing major changes in ventilation, leading to instability of the respiratory control system. We hypothesized that neonates: (1) would depend much more on the peripheral chemoreceptor contribution to breathing than adult subjects and (2) their baseline arterial PO2 would sit on the steep portion of the ventilation/arterial PO2 relationship on the adult nomogram, making breathing prone to oscillate. We analyzed data from previous polygraphic recordings in four groups of subjects: small preterm infants [SPI; postconceptional age (PCA) 33+/-2 weeks; n = 40], large preterm infants (LPI; PCA 36+/-2 weeks; n = 34), term infants (TI; PCA 42+/-1 week; n = 24), and adult subjects (AS; weight 63+/-2 kg; age 29+/-3 years, n = 16). Peripheral chemoreceptor activity was measured by: (1) the immediate decrease in ventilation and (2) apnea time during brief inhalation of 100% O2 (about 1 minute). We found that: (1) the immediate decrease in ventilation with 100% O2 was more pronounced in infants than in adult subjects (38+/-2 versus 6+/-5%), and in infants breathing periodically versus those breathing continuously; (2) the apnea time during 100% O2 was also significantly longer in periodic breathing infants; and (3) the TcPO2 was much lower in infants than in adult subjects (65+/-1 versus 93+/-1 Torr), and also lower in periodic versus continuously breathing infants. It was located significantly to the left of values for the adult subject, on the ventilation/arterial PO2 diagram. The data suggest that: (1) a substantial portion of baseline breathing activity early in life is maintained by increased peripheral chemoreceptor activity; and (2) neonates breathe irregularly with apneas due to the position of their arterial PO2 values on the ventilation/arterial PO2 diagram, in which a change in PO2 produces a more significant change in ventilation than that observed later in life.