Cardiorespiratory alterations in a newborn ovine model of systemic viral inflammation.

BACKGROUND: Respiratory viruses can be responsible for severe apneas and bradycardias in newborn infants. The link between systemic inflammation with viral sepsis and cardiorespiratory alterations remains poorly understood. We aimed to characterize these alterations by setting up a full-term newborn lamb model of systemic inflammation using polyinosinic:polycytidylic acid (Poly I:C). METHODS: Two 6-h polysomnographic recordings were carried out in eight lambs on two consecutive days, first after an IV saline injection, then after an IV injection of 300 µg/kg Poly I:C. RESULTS: Poly I:C injection decreased locomotor activity and increased NREM sleep. It also led to a biphasic increase in rectal temperature and heart rate. The latter was associated with an overall decrease in heart-rate variability, with no change in respiratory-rate variability. Lastly, brainstem inflammation was found in the areas of the cardiorespiratory control centers 6 h after Poly I:C injection. CONCLUSIONS: The alterations in heart-rate variability induced by Poly I:C injection may be, at least partly, of central origin. Meanwhile, the absence of alterations in respiratory-rate variability is intriguing and noteworthy. Although further studies are obviously needed, this might be a way to differentiate bacterial from viral sepsis in the neonatal period. IMPACT: Provides unique observations on the cardiorespiratory consequences of injecting Poly I:C in a full-term newborn lamb to mimic a systemic inflammation secondary to a viral sepsis. Poly I:C injection led to a biphasic increase in rectal temperature and heart rate associated with an overall decrease in heart-rate variability, with no change in respiratory-rate variability. Brainstem inflammation was found in the areas of the cardiorespiratory control centers.

Air distribution within the lungs after total liquid ventilation in a neonatal ovine model.

OBJECTIVE: To gain insight into the total and regional lung aeration dynamics at the transition from total liquid ventilation (TLV) to conventional mechanical ventilation (GV). METHODS: Neonatal lambs received either TLV for 4 h followed by GV (n = 15) or GV only (n = 11, controls). Monitoring was performed in the prone position with both videofluoroscopy and electrical impedance tomography (EIT) for the first 10 min of the transition. RESULTS: Total and regional end-expiratory lung volumes were stable throughout the transition (p < 0.05). The percentage of tidal volume, liquid and/or gaseous, distributed to the different regions was stable (p < 0.05). Radiopacity of the nondependent regions markedly decreased at end-expiration (p < 0.01), reflecting the progressive transition to a gaseous end-expiratory lung volume. CONCLUSION: Weaning to GV did not increase total or regional lung volumes, suggesting that the risk of overdistention was not increased. Residual perfluorocarbon in the dependent lung regions might account for the high O2 needs we observed in the first minutes of GV after TLV.

Cardiorespiratory Alterations in a Newborn Ovine Model of Systemic Inflammation Induced by Lipopolysaccharide Injection.

Although it is well known that neonatal sepsis can induce important alterations in cardiorespiratory control, their detailed early features and the mechanisms involved remain poorly understood. As a first step in resolving this issue, the main goal of this study was to characterize these alterations more extensively by setting up a full-term newborn lamb model of systemic inflammation using lipopolysaccharide (LPS) injection. Two 6-h polysomnographic recordings were performed on two consecutive days on eight full-term lambs: the first after an IV saline injection (control condition, CTRL); the second, after an IV injection of 2.5 µg/kg Escherichia coli LPS 0127:B8 (LPS condition). Rectal temperature, locomotor activity, state of alertness, arterial blood gases, respiratory frequency and heart rate, mean arterial blood pressure, apneas and cardiac decelerations, and heart-rate and respiratory-rate variability (HRV and RRV) were assessed. LPS injection decreased locomotor activity (p = 0.03) and active wakefulness (p = 0.01) compared to the CTRL. In addition, LPS injection led to a biphasic increase in rectal temperature (p = 0.01 at ∼30 and 180 min) and in respiratory frequency and heart rate (p = 0.0005 and 0.005, respectively), and to an increase in cardiac decelerations (p = 0.05). An overall decrease in HRV and RRV was also observed. Interestingly, the novel analysis of the representations of the horizontal and vertical visibility network yielded the most statistically significant alterations in HRV structure, suggesting its potential clinical importance for providing an earlier diagnosis of neonatal bacterial sepsis. A second goal was to assess whether the reflexivity of the autonomic nervous system was altered after LPS injection by studying the cardiorespiratory components of the laryngeal and pulmonary chemoreflexes. No difference was found. Lastly, preliminary results provide proof of principle that brainstem inflammation (increased IL-8 and TNF-α mRNA expression) can be shown 6 h after LPS injection. In conclusion, this full-term lamb model of systemic inflammation reproduces several important aspects of neonatal bacterial sepsis and paves the way for studies in preterm lambs aiming to assess both the effect of prematurity and the central neural mechanisms of cardiorespiratory control alterations observed during neonatal sepsis.

Effect of Low Versus High Tidal-Volume Total Liquid Ventilation on Pulmonary Inflammation.

Animal experiments suggest that total liquid ventilation (TLV) induces less ventilator-induced lung injury (VILI) than conventional mechanical gas ventilation. However, TLV parameters that optimally minimize VILI in newborns remain unknown. Our objective was to compare lung inflammation between low (L-VT) and high (H-VT) liquid tidal volume and evaluate impacts on the weaning process. Sixteen anesthetized and paralyzed newborn lambs were randomized in an L-VT group (initial tidal volume of 10 mL/kg at 10/min) and an H-VT group (initial tidal volume of 20 mL/kg at 5/min). Five unventilated newborn lambs served as controls. After 4 h of TLV in the supine position, the lambs were weaned in the prone position for another 4 h. The levels of respiratory support needed during the 4 h post-TLV were compared. The anterior and posterior lung regions were assessed by a histological score and real-time quantitative PCR for IL1B, IL6, and TNF plus 12 other exploratory VILI-associated genes. All but one lamb were successfully extubated within 2 h post-TLV (72 ± 26 min vs. 63 ± 25 min, p = 0.5) with similar FiO2 at 4 h post-TLV (27 ± 6% vs. 33 ± 7%, p = 0.3) between the L-VT and H-VT lambs. No significant differences were measured in histological inflammation scores between L-VT and H-VT lambs, although lambs in both groups exhibited slightly higher scores than the control lambs. The L-VT group displayed higher IL1B mRNA expression than the H-VT group in both anterior (2.8 ± 1.5-fold increase vs. 1.3 ± 0.4-fold increase, p = 0.02) and posterior lung regions (3.0 ± 1.0-fold change increase vs. 1.1 ± 0.3-fold increase, p = 0.002), respectively. No significant differences were found in IL6 and TNF expression levels. Gene expression changes overall indicated that L-VT was associated with a qualitatively distinct inflammatory gene expression profiles compared to H-VT, which may indicate different clinical effects. In light of these findings, further mechanistic studies are warranted. In conclusion, we found no advantage of lower tidal volume use, which was in fact associated with a slightly unfavorable pattern of inflammatory gene expression.

Nasal continuous positive airway pressure influences bottle-feeding in preterm lambs.

BackgroundIn preterm infants, the time from initiation to full oral feeding can take weeks, which represents a very worrisome problem in neonatal medicine. Although current knowledge suggests that oral feeding should be introduced early, this is often delayed due to the need for prolonged nasal continuous positive airway pressure (nCPAP). Indeed, most caregivers fear that nCPAP could disrupt sucking-swallowing-breathing coordination and induce tracheal aspiration. The goal of the present study was to assess the impact of nCPAP delivered by the Infant Flow System on the physiology of sucking-swallowing-breathing coordination during bottle-feeding in preterm lambs over 24 h.MethodsSeventeen lambs (8 control, 9 nCPAP of 6 cmH2O) born 14 days prematurely were instrumented to record sucking, swallowing, respiration, ECG, and oxygenation. They were fed via a nasogastric tube for the first 5 days of life until introduction of bottle-feeding every 4 h for 24 h.ResultsnCPAP increased the feeding efficiency while maintaining higher oxygenation without any deleterious cardiorespiratory events. However, coughs were observed in lambs under nCPAP immediately following bottle-feeding and may be related to the high milk flow in preterm lambs.ConclusionFurther studies documenting tracheal aspirations are needed, especially in preterm lambs under nCPAP for moderate respiratory difficulties, to further inform future clinical studies.

Reflex cardiorespiratory events from esophageal origin are heightened by preterm birth.

The involvement of gastroesophageal refluxes in cardiorespiratory events of preterm infants remains controversial. While a few studies in full-term newborn animals have shown that stimulation of esophageal receptors leads to cardiorespiratory reflexes, the latter remain largely unknown, especially after premature birth. The present study aimed to 1) characterize the cardiorespiratory reflexes originating from esophageal receptors in newborn lambs and 2) test the hypotheses that preterm birth enhances reflex cardiorespiratory inhibition and that C-fibers are involved in these reflexes. Eight full-term lambs and 10 lambs born 14 days prematurely were studied. Following surgical instrumentation, a 6-h polysomnography was performed without sedation to record electrocardiogram, respiratory movements, arterial pressure, laryngeal constrictor muscle activity, state of alertness, and hemoglobin oxygen saturation. Five esophageal stimulations of the upper and/or lower esophagus, including rapid balloon inflation and/or HCl injection, were performed in random order. A second recording was performed in full-term lambs 24 h later, after C-fiber blockade by capsaicin. Results confirmed that esophageal stimulations induced inhibitory cardiorespiratory reflexes combined with protective mechanisms, including laryngeal closure, swallowing, coughing, increased arterial pressure, and arousal. Preterm birth heightened cardiorespiratory inhibition. The strongest cardiorespiratory inhibition was observed following simultaneous stimulation of the lower and upper esophagus. Finally, cardiorespiratory inhibition was decreased after C-fiber blockade. In conclusion, esophageal stimulation induces inhibitory cardiorespiratory reflexes, which are partly mediated by C-fibers and more pronounced in preterm lambs. Clinical relevance of these findings requires further studies, especially in conditions associated with increased cardiorespiratory events, e.g., neonatal infection.NEW & NOTEWORTHY Preterm birth heightens the cardiorespiratory events triggered by esophageal stimulation. The most extensive cardiorespiratory events are induced by simultaneous stimulation of the proximal and distal esophagus.

Inhibitory Effect of Nasal Intermittent Positive Pressure Ventilation on Gastroesophageal Reflux.

Non-invasive intermittent positive pressure ventilation can lead to esophageal insufflations and in turn to gastric distension. The fact that the latter induces transient relaxation of the lower esophageal sphincter implies that it may increase gastroesophageal refluxes. We previously reported that nasal Pressure Support Ventilation (nPSV), contrary to nasal Neurally-Adjusted Ventilatory Assist (nNAVA), triggers active inspiratory laryngeal closure. This suggests that esophageal insufflations are more frequent in nPSV than in nNAVA. The objectives of the present study were to test the hypotheses that: i) gastroesophageal refluxes are increased during nPSV compared to both control condition and nNAVA; ii) esophageal insufflations occur more frequently during nPSV than nNAVA. Polysomnographic recordings and esophageal multichannel intraluminal impedance pHmetry were performed in nine chronically instrumented newborn lambs to study gastroesophageal refluxes, esophageal insufflations, states of alertness, laryngeal closure and respiration. Recordings were repeated without sedation in control condition, nPSV (15/4 cmH2O) and nNAVA (~ 15/4 cmH2O). The number of gastroesophageal refluxes recorded over six hours, expressed as median (interquartile range), decreased during both nPSV (1 (0, 3)) and nNAVA [1 (0, 3)] compared to control condition (5 (3, 10)), (p < 0.05). Meanwhile, the esophageal insufflation index did not differ between nPSV (40 (11, 61) h-1) and nNAVA (10 (9, 56) h-1) (p = 0.8). In conclusion, nPSV and nNAVA similarly inhibit gastroesophageal refluxes in healthy newborn lambs at pressures that do not lead to gastric distension. In addition, the occurrence of esophageal insufflations is not significantly different between nPSV and nNAVA. The strong inhibitory effect of nIPPV on gastroesophageal refluxes appears identical to that reported with nasal continuous positive airway pressure.

Effects of Inspiratory Pressure Rise Time and Hypoxic or Hypercapnic Breathing on Inspiratory Laryngeal Constrictor Muscle Activity During Nasal Pressure Support Ventilation.

OBJECTIVE: We previously reported the development of an active inspiratory laryngeal narrowing against ventilator insufflations when inspiratory pressure is increased during nasal pressure support ventilation in lambs. The present study aimed to further understand the factors involved in this inspiratory laryngeal narrowing. More specifically, we tested the hypothesis that a short inspiratory pressure rise time or a low PaCO2 level promotes inspiratory laryngeal narrowing observed in nasal pressure support ventilation. The effect of hypoxia was also assessed. DESIGN: Prospective, randomized, interventional study. SETTING: Animal research laboratory at the Faculty of Medicine and Health Sciences, Université de Sherbrooke, Canada. SUBJECTS: Thirteen lambs aged 4-5 days. INTERVENTIONS: Polysomnographic recordings were performed in chronically instrumented lambs to study states of alertness, glottal muscle electrical activity, tracheal pressure, SpO2, and respiratory movements. Lambs were ventilated with progressively increasing levels of nasal pressure support ventilation (10/4, 15/4, and 20/4 cm H2O), using a broad range of inspiratory rise times from 0.05 to 0.4 s. Thereafter, either CO2 (PaCO2 = baseline value + 10 mm Hg) or N2 (PaO2 = 45-55 mm Hg) was added to the inspiratory line. MEASUREMENTS AND MAIN RESULTS: The percentage of respiratory cycles with phasic inspiratory activity of glottal constrictor muscle was measured and compared between the various experimental conditions. The different inspiratory pressure rise times tested did not alter the phasic inspiratory activity of glottal constrictor muscle during nasal pressure support ventilation. By contrast, this activity was virtually abolished by increasing PaCO2 in all lambs. Finally, no alterations in the phasic inspiratory activity of glottal constrictor muscle during nasal pressure support ventilation were observed during hypoxia. CONCLUSIONS: Active inspiratory laryngeal narrowing during nasal pressure support ventilation is not altered by inspiratory rise times ranging from 0.05 to 0.4 s or by moderate hypoxia, whereas a moderate increase in PaCO2 abolishes this activity.

Laryngeal narrowing during nasal ventilation does not originate from bronchopulmonary C-fibers.

We previously showed that nasal pressure support ventilation (nPSV) can lead to active inspiratory laryngeal narrowing, which originates from the stimulation of bronchopulmonary receptors. Among the three major types of bronchopulmonary receptors, which are variably stimulated by lung distension, C-fiber endings are remarkable, given that their stimulation can also trigger laryngeal closure. Taking advantage of our lamb model with blocked C-fibers, we aimed to assess whether bronchopulmonary C-fiber endings are involved in the active inspiratory laryngeal narrowing during nPSV. Nine lambs were surgically instrumented to assess states of alertness, electrical activity of a glottal constrictor (EaTA), respiratory movements and arterial blood gases. Forty-eight hours later, two polysomnographic recordings were performed during nPSV 15/4 cmH2O, before and after C-fiber blockade. During nPSV, blockade of C-fibers did not prevent inspiratory EaTA (present for 74±41% of respiratory cycles vs. 64±35%, p=0.9). We conclude that active inspiratory laryngeal narrowing during nPSV does not originate from bronchopulmonary C-fiber endings.