P2.I177: ENA-001 improves ventilation in spontaneously breathing late-preterm lambs; Exploratory study for a novel respiratory stimulant

Background: Late preterm infants often demonstrate compromised breathing related to immaturity in components of the respiratory system, including diminished breathing drive and lung under-recruitment. ENA-001 is a novel compound that stimulates breathing by acting on the peripheral chemoreceptors, enhancing breathing drive through a mechanism mimicking hypoxia. We hypothesized that ENA-001 would improve breathing regularity and adequacy in a late-preterm model.

Methods: Late-preterm lambs (n=12) were delivered via cesarian section at 140 ± 1 days gestation, instrumented with carotid and jugular cannulae, intubated via mid-tracheal cutdown to facilitate spirometry, and placed on CPAP for support of spontaneous breathing. After a 15-min period for resuscitation and stabilization on a warmer bed, animals were randomized to ENA-001 (0.3 mg/kg bolus loading dose followed by 1.1 mg/kg/hr in D5W continuous infusion) or Sham (infusion of D5W) for 4 hours.

Results: Results revealed a significant interaction between group and time for Arterial pH and PaCO2 (Figure 1, P ≤ 0.01). Both of these parameters improved over time for the ENA-001 group nearing target values compared to Sham; (at T240) pH = 7.37 vs 7.32 and PaCO2 = 47.4 vs 68.4 mmHg for ENA-001 and Sham groups respectively. Pulmonary function data demonstrated improved minute ventilation in the ENA-001 group by way of greater tidal volumes (Figure 2, p< 0.01) with similar breathing frequency.

Conclusion: In the late-preterm lamb, ENA-001 improved tidal volumes leading to better ventilation in a more stable breathing pattern, without exceeding target blood gas values (i.e., absence of hyperventilation). These exploratory data demonstrate that ENA-001 may be a promising therapy for infants with breathing abnormalities associated with immaturity. Further research is required on dosage and safety.