Background

Intestinal circulation and mesenteric arterial (MA) reactivity may play a role in preparing the fetus for enteral nutrition. We hypothesized that MA vasoreactivity changes with gestation and vasodilator pathways predominate in the postnatal period.

Methods

Small distal MA rings (0.5-mm diameter) were isolated from fetal (116-d, 128-d, 134-d, and 141-d gestation, term ~ 147 d) and postnatal lambs. Vasoreactivity was evaluated using vasoconstrictors (norepinephrine (NE) after pretreatment with propranolol and endothelin-1(ET-1)) and vasodilators (NO donors A23187 and s-nitrosopenicillamine (SNAP)). Protein and mRNA assays for receptors and enzymes (endothelin receptor A, alpha-adrenergic receptor 1A (ADRA1A), endothelial NO synthase (eNOS), soluble guanylyl cyclase (sGC), and phosphodiesterase5 (PDE5)) were performed in mesenteric arteries.

Results

MA constriction to NE and ET-1 peaked at 134 d. Relaxation to A23187 and SNAP was maximal after birth. Basal eNOS activity was low at 134 d. ADRA1A mRNA and protein increased significantly at 134 d and decreased postnatally. sGC and PDE5 protein increased from 134 to 141 d.

Conclusion

Mesenteric vasoconstriction predominates in late-preterm gestation (134 d; the postconceptional age with the highest incidence of necrotizing enterocolitis (NEC)) followed by a conversion to vasodilatory influences near the time of full-term birth. Perturbations in this ontogenic mechanism, including preterm birth, may be a risk factor for NEC.

Resuscitation with 21% O2 may not achieve target oxygenation in preterm infants and in neonates with persistent pulmonary hypertension of the newborn (PPHN). Inhaled nitric oxide (iNO) at birth can reduce pulmonary vascular resistance (PVR) and improve PaO2. We studied the effect of iNO on oxygenation and changes in PVR in preterm lambs with and without PPHN during resuscitation and stabilization at birth. Preterm lambs with and without PPHN (induced by antenatal ductal ligation) were delivered at 134 d gestation (term is 147-150 d). Lambs without PPHN were ventilated with 21% O2, titrated O2 to maintain target oxygenation or 21% O2 + iNO (20 ppm) at birth for 30 min. Preterm lambs with PPHN were ventilated with 50% O2, titrated O2 or 50% O2 + iNO. Resuscitation with 21% O2 in preterm lambs and 50%O2 in PPHN lambs did not achieve target oxygenation. Inhaled NO significantly decreased PVR in all lambs and increased PaO2 in preterm lambs ventilated with 21% O2 similar to that achieved by titrated O2 (41 ± 9% at 30 min). Inhaled NO increased PaO2 to 45 ± 13, 45 ± 20 and 76 ± 11 mmHg with 50% O2, titrated O2 up to 100% and 50% O2 + iNO, respectively, in PPHN lambs. We concluded that iNO at birth reduces PVR and FiO2 required to achieve target PaO2.

Background

The Neonatal Resuscitation Program recommends initial resuscitation of preterm infants with low oxygen (O₂) followed by titration to target preductal saturations (SpO₂). We studied the effect of resuscitation with titrated O₂ on gas exchange, pulmonary, and systemic hemodynamics.

Methodology

Twenty-nine preterm lambs (127 d gestation) were randomized to resuscitation with 21% O₂ (n = 7), 100% O₂ (n = 6), or initiation at 21% and titrated to target SpO₂ (n = 16). Seven healthy term control lambs were ventilated with 21% O₂.

Results

Preductal SpO₂ achieved by titrating O₂ was within the desired range similar to term lambs in 21% O₂. Resuscitation of preterm lambs with 21% and 100% O₂ resulted in SpO₂ below and above the target, respectively. Ventilation of preterm lambs with 100% O₂ and term lambs with 21% O₂ effectively decreased pulmonary vascular resistance (PVR). In contrast, preterm lambs with 21% O₂ and titrated O₂ demonstrated significantly higher PVR than term lambs on 21% O₂.

Conclusion(s)

Initial resuscitation with 21% O₂ followed by titration of O₂ led to suboptimal pulmonary vascular transition at birth in preterm lambs. Ventilation with 100% O₂ in preterm lambs caused hyperoxia but reduced PVR similar to term lambs on 21% O₂. Studies evaluating the initiation of resuscitation at a higher O₂ concentration followed by titration based on SpO₂ in preterm neonates are needed.

Background

Cases of necrotizing enterocolitis occurring within 48 h of packed red blood cell (PRBC) transfusions are increasingly being described in observational studies. Transfusion-associated gut injury is speculated to result from an abnormal mesenteric vascular response to transfusion. However, the mechanism of disruption of the balance between mesenteric vasoconstriction and relaxation following transfusion is not known.

Methods

Preterm lambs (n = 16, 134 d gestation; term: 145-147 d) were delivered and ventilated for 24 h. All the lambs received orogastric feeds with colostrum. In addition, 10 of these lambs received PRBC transfusions. Vasoreactivity was evaluated in isolated mesenteric arterial rings using norepinephrine and endothelin-1 as vasoconstrictors. Endothelium-dependent (A23187, a calcium ionophore) and endothelium-independent (SNAP) nitric oxide (NO) donors were used as vasorelaxants. Mesenteric arterial endothelial NO synthase (eNOS), soluble guanylyl cyclase (sGC), and phosphodiesterase 5 (PDE5) mRNA analyses and protein assays were performed.

Results

Transfusion with PRBC significantly increased mesenteric vasoconstriction to norepinephrine and endothelin-1 and impaired relaxation to A23187 and SNAP. Mesenteric arterial eNOS protein decreased following PRBC transfusion. No significant changes were noted in sGC and PDE5 mRNA or protein assays.

Conclusion

PRBC transfusion in enterally fed preterm lambs promotes mesenteric vasoconstriction and impairs vasorelaxation by reducing mesenteric arterial eNOS.

Background

Current neonatal resuscitation guidelines recommend tracheal suctioning of nonvigorous neonates born through meconium-stained amniotic fluid.

Methods

We evaluated the effect of tracheal suctioning at birth in 29 lambs with asphyxia induced by cord occlusion and meconium aspiration during gasping.

Results

Tracheal suctioning at birth (n = 15) decreased amount of meconium in distal airways (53 ± 29 particles/mm(2) lung area) compared to no suction (499 ± 109 particles/mm(2); n = 14; P < 0.001). Three lambs in the suction group had cardiac arrest during suctioning, requiring chest compressions and epinephrine. Onset of ventilation was delayed in the suction group (146 ± 11 vs. 47 ± 3 s in no-suction group; P = 0.005). There was no difference in pulmonary blood flow, carotid blood flow, and pulmonary or systemic blood pressure between the two groups. Left atrial pressure was significantly higher in the suction group. Tracheal suctioning resulted in higher Pao2/FiO2 levels (122 ± 21 vs. 78 ± 10 mm Hg) and ventilator efficiency index (0.3 ± 0.05 vs.0.16 ± 0.03). Two lambs in the no-suction group required inhaled nitric oxide. Lung 3-nitrotyrosine levels were higher in the suction group (0.65 ± 0.03 ng/µg protein) compared with the no-suction group (0.47 ± 0.06).

Conclusion

Tracheal suctioning improves oxygenation and ventilation. Suctioning does not improve pulmonary/systemic hemodynamics or oxidative stress in an ovine model of acute meconium aspiration with asphyxia.

Background: The developing lung is uniquely susceptible and may be at increased risk of injury with exposure to e-cigarette constituents. We hypothesize that cellular toxicity and airway and vascular responses with exposure to flavored refill solutions may be altered in the immature lung. Methods: Fetal, neonatal, and adult ovine pulmonary artery smooth muscle cells (PASMC) were exposed to popular flavored nicotine-free e-cigarette refill solutions (menthol, strawberry, tobacco, and vanilla) and unflavored solvents: propylene glycol (PG) or vegetable glycerin (VG). Viability was assessed by lactate dehydrogenase assay. Brochodilation and vasoreactivity were determined on isolated ovine bronchial rings (BR) and pulmonary arteries (PA). Results: Neither PG or VG impacted viability of immature or adult cells; however, exposure to menthol and strawberry flavored solutions increased cell death. Neonatal cells were uniquely susceptible to menthol flavoring-induced toxicity, and all four flavorings demonstrated lower lethal doses (LD50) in immature PASMC. Exposure to flavored solutions induced bronchodilation of neonatal BR, while only menthol induced airway relaxation in adults. In contrast, PG/VG and flavored solutions did not impact vasoreactivity with the exception of menthol-induced relaxation of adult PAs. Conclusion: The immature lung is uniquely susceptible to cellular toxicity and altered airway responses with exposure to common flavored e-cigarette solutions.

Background

In neonates requiring chest compression (CC) during resuscitation, neonatal resuscitation program (NRP) recommends against relying on a single feedback device such as end-tidal carbon dioxide (ETCO₂) or saturations (SpO₂) to determine return of spontaneous circulation (ROSC) until more evidence becomes available.

Methods

We evaluated the role of monitoring ETCO₂ during resuscitation in a lamb model of cardiac arrest induced by umbilical cord occlusion (n = 21). Lambs were resuscitated as per NRP guidelines. Systolic blood pressure (SBP), carotid and pulmonary blood flows along with ETCO₂ and blood gases were continuously monitored. Resuscitation was continued for 20 min or until ROSC (whichever was earlier). Adequate CC was arbitrarily defined as generation of 30 mmHg SBP during resuscitation. ETCO₂ thresholds to predict adequacy of CC and detect ROSC were determined.

Results

Significant relationship between ETCO₂ and adequate CC was noted during resuscitation (AUC-0.735, P < 0.01). At ROSC (n = 12), ETCO₂ rapidly increased to 57 ± 20 mmHg with a threshold of ≥32 mmHg being 100% sensitive and 97% specific to predict ROSC.

Conclusion

In a large mammalian model of perinatal asphyxia, continuous ETCO₂ monitoring predicted adequacy of CC and detected ROSC. These findings suggest ETCO₂ in conjunction with other devices may be beneficial during CC and predict ROSC.

Background

Distressed infants in the delivery room and those that have completed postnatal transition are both resuscitated according to established neonatal resuscitation guidelines, often with endotracheal (ET) epinephrine at the same dose. We hypothesized that ET epinephrine would have higher bioavailability in a post-transitional compared to transitioning newborn model due to absence of fetal lung liquid and intra-cardiac shunts.

Methods

15 term fetal (transitioning newborn) and 6 postnatal lambs were asphyxiated by umbilical cord and ET tube occlusion respectively. Lambs were resuscitated after 5 min of asystole. ET epinephrine (0.1 mg/kg) was administered after 1 min of positive pressure ventilation (PPV) and chest compressions, and repeated 3 min later, followed by intravenous (IV) epinephrine (0.03 mg/kg) every 3 min until return of spontaneous circulation (ROSC). Serial plasma epinephrine concentrations were measured.

Results

Peak plasma epinephrine concentrations were lower in transitioning newborns as compared to postnatal lambs: after a single ET dose (145.36 ± 135.5 ng/ml vs 553.54 ± 215 ng/ml, p < 0.01) and after two ET doses (443 ± 192.49 ng/ml vs 1406 ± 420.8 ng/ml, p < 0.01). The rates of ROSC with a single ET dose were similar in both groups (40% vs 50% in newborn and postnatal respectively, p > 0.99). There was a higher incidence of post-ROSC tachycardia and increased carotid blood flow in the postnatal group.

Conclusions

In the postnatal period, ET epinephrine at currently recommended doses resulted in higher peak epinephrine concentrations, post-ROSC tachycardia and cerebral reperfusion without significant differences in incidence of ROSC. Further studies evaluating the optimal dose of ET epinephrine during the postnatal period are warranted.

Background

The Neonatal Resuscitation Program (NRP) recommends upper and lower limits of preductal saturations (SpO2) extrapolated from studies in infants resuscitated in room air. These limits have not been validated in asphyxia and lung disease.

Methods

Seven control term lambs delivered by cesarean section were ventilated with 21% O2. Thirty lambs with asphyxia with meconium aspiration were randomly assigned to resuscitation with 21% O2 (n = 6), 100% O2 (n = 6), or initiation with 21% O2 followed by variable FIO2 to maintain NRP target SpO2 ranges (n = 18). Hemodynamic and ventilation parameters were recorded for 15 min.

Results

Control lambs maintained preductal SpO2 near the lower limit of NRP target range. Asphyxiated lambs had low SpO2 (38 ± 2%), low arterial pH (6.99 ± 0.01), and high PaCO2 (96 ± 7 mm Hg) at birth. Resuscitation with 21% O2 resulted in SpO2 values below the target range with low pulmonary blood flow (Qp) compared to variable FIO2 group. The increase in PaO2 and Qp with variable FIO2 resuscitation was similar to control lambs.

Conclusion

Maintaining SpO2 as recommended by NRP by actively adjusting inspired O2 leads to effective oxygenation and higher Qp in asphyxiated lambs with lung disease. Our findings support the current NRP SpO2 guidelines for O2 supplementation during resuscitation of an asphyxiated neonate.

Background

The Neonatal Resuscitation Program (NRP) recommends close monitoring of oxygenation during the resuscitation of newborns using a pulse oximeter. However, there are no guidelines for monitoring carbon dioxide (CO2) to assess ventilation. Considering that cerebral blood flow (CBF) correlates directly with PaCO2, continuous capnography monitoring of end-tidal CO2 (ETCO2) may limit fluctuations in PaCO2 and, therefore, CBF during resuscitation of asphyxiated infants.

Objective

To evaluate whether continuous monitoring of ETCO2 with capnography during resuscitation of asphyxiated term lambs with meconium aspiration will prevent fluctuations in PaCO2 and carotid arterial blood flow (CABF).

Methods

Fifty-four asphyxiated term lambs with meconium aspiration syndrome were mechanically ventilated from birth to 60 min of age. Ventilatory parameters were adjusted based on clinical observation (chest excursion) and frequent arterial blood gas analysis in 24 lambs (control group) and 30 lambs (capnography group) received additional continuous ETCO2 monitoring. Left CABF was monitored. We aimed to maintain PaCO2 between 35 and 50 mm Hg and ETCO2 between 30 and 45 mm Hg.

Results

There was a significant correlation between ETCO2 and PaCO2 (R = 0.7, p < 0.001), between PaCO2 and carotid flow (R = 0.52, p < 0.001) and between ETCO2 and carotid flow (R = 0.5, p < 0.001). PaCO2 and CABF during the first 60 min of age showed significantly higher fluctuation in the control group compared to the capnography group.

Conclusion

Continuous monitoring of ETCO2 using capnography with mechanical ventilation during and after resuscitation in asphyxiated term lambs with meconium aspiration limits fluctuations in PaCO2 and CABF and may potentially limit brain injury.