Changes in intra- and interlimb reflexes from hindlimb cutaneous afferents after staggered thoracic lateral hemisections during locomotion in cats.

When the foot dorsum contacts an obstacle during locomotion, cutaneous afferents signal central circuits to coordinate muscle activity in the four limbs. Spinal cord injury disrupts these interactions, impairing balance and interlimb coordination. We evoked cutaneous reflexes by electrically stimulating left and right superficial peroneal nerves before and after two thoracic lateral hemisections placed on opposite sides of the cord at 9- to 13-week interval in seven adult cats (4 males and 3 females). We recorded reflex responses in ten hindlimb and five forelimb muscles bilaterally. After the first (right T5-T6) and second (left T10-T11) hemisections, coordination of the fore- and hindlimbs was altered and/or became less consistent. After the second hemisection, cats required balance assistance to perform quadrupedal locomotion. Short-latency reflex responses in homonymous and crossed hindlimb muscles largely remained unaffected after staggered hemisections. However, mid- and long-latency homonymous and crossed responses in both hindlimbs occurred less frequently after staggered hemisections. In forelimb muscles, homolateral and diagonal mid- and long-latency response occurrence significantly decreased after the first and second hemisections. In all four limbs, however, when present, short-, mid- and long-latency responses maintained their phase-dependent modulation. We also observed reduced durations of short-latency inhibitory homonymous responses in left hindlimb extensors early after the first hemisection and delayed short-latency responses in the right ipsilesional hindlimb after the first hemisection. Therefore, changes in cutaneous reflex responses correlated with impaired balance/stability and interlimb coordination during locomotion after spinal cord injury. Restoring reflex transmission could be used as a biomarker to facilitate locomotor recovery. KEY POINTS: Cutaneous afferent inputs coordinate muscle activity in the four limbs during locomotion when the foot dorsum contacts an obstacle. Thoracic spinal cord injury disrupts communication between spinal locomotor centres located at cervical and lumbar levels, impairing balance and limb coordination. We investigated cutaneous reflexes during quadrupedal locomotion by electrically stimulating the superficial peroneal nerve bilaterally, before and after staggered lateral thoracic hemisections of the spinal cord in cats. We showed a loss/reduction of mid- and long-latency responses in all four limbs after staggered hemisections, which correlated with altered coordination of the fore- and hindlimbs and impaired balance. Targeting cutaneous reflex pathways projecting to the four limbs could help develop therapeutic approaches aimed at restoring transmission in ascending and descending spinal pathways.

Ovine model of congenital chest wall and spine deformity: From birth to 3 months follow-up.

Background: The evolution and treatment of lung alterations related to congenital spine and chest wall deformities (CWD) are poorly understood. Most animal models of CWD created postnatally were not evaluated for respiratory function. The goal of our study was to evaluate the effects of a CWD induced in utero on lung growth and function in an ovine model. Methods: A CWD was induced in utero at 70-75 days of gestation in 14 ovine fetuses by resection of the 7th and 8th left ribs. Each non-operated twin fetus was taken as control. Respiratory mechanics was studied postnatally in the first week and at 1, 2, and 3 months. Post-mortem respiratory mechanics and lung histomorphometry were also assessed at 3 months. Results: Eight out of 14 CWD lambs (57%) and 14 control lambs survived the postnatal period. One severe and five mild deformities were induced. At birth, inspiratory capacity (25 vs. 32 mL/kg in controls), and dynamic (1.4 vs. 1.8 mL/cmH2O/kg), and static (2.0 vs. 2.5 mL/cmH2O/kg) respiratory system compliances were decreased in CWD lambs. Apart from a slight decrease in inspiratory capacity at 1 month of life, no other differences were observed in respiratory mechanics measured in vivo thereafter. Postmortem measurements found a significant decrease in lung compliance-for each lung and for both lungs taken together-in CWD lambs. No differences in lung histology were detected at 3 months in CWD animals compared to controls. Conclusions: Our study is the first to assess the effects of a prenatally induced CWD on lung development and function from birth to 3 months in an ovine model. Our results show no significant differences in lung histomorphometry at 3 months in CWD lambs compared to controls. Resolution at 1 month of the alterations in respiratory mechanics present at birth may be related to the challenge in inducing severe deformities.

Total liquid ventilation in an ovine model of extreme prematurity: a randomized study.

BACKGROUND: This study aimed at comparing cardiorespiratory stability during total liquid ventilation (TLV)-prior to lung aeration-with conventional mechanical ventilation (CMV) in extremely preterm lambs during the first 6 h of life. METHODS: 23 lambs (11 females) were born by c-section at 118-120 days of gestational age (term = 147 days) to receive 6 h of TLV or CMV from birth. Lung samples were collected for RNA and histology analyses. RESULTS: The lambs under TLV had higher and more stable arterial oxygen saturation (p = 0.001) and cerebral tissue oxygenation (p = 0.02) than the lambs in the CMV group in the first 10 min of transition to extrauterine life. Although histological assessment of the lungs was similar between the groups, a significant upregulation of IL-1a, IL-6 and IL-8 RNA in the lungs was observed after TLV. CONCLUSIONS: Total liquid ventilation allowed for remarkably stable transition to extrauterine life in an extremely preterm lamb model. Refinement of our TLV prototype and ventilation algorithms is underway to address specific challenges in this population, such as minimizing tracheal deformation during the active expiration. IMPACT: Total liquid ventilation allows for remarkably stable transition to extrauterine life in an extremely preterm lamb model. Total liquid ventilation is systematically achievable over the first 6 h of life in the extremely premature lamb model. This study provides additional incentive to pursue further investigation of total liquid ventilation as a transition tool for the most extreme preterm neonates.

Effects of Nasal Respiratory Support on Laryngeal and Esophageal Reflexes in Preterm Lambs.

BACKGROUND: Significant cardiorespiratory events can be triggered in preterm infants as part of laryngeal chemoreflexes (LCRs) and esophageal reflexes (ERs). We previously showed that nasal continuous positive airway pressure (nCPAP) blunted the cardiorespiratory inhibition induced with LCRs. Therefore, we aimed to compare the effects of nCPAP and high-flow nasal cannulas (HFNC) on the cardiorespiratory events induced during LCRs and ERs. The hypothesis is that nCPAP but not HFNC decreases the cardiorespiratory inhibition observed during LCRs and ERs. METHODS: Eleven preterm lambs were instrumented to record respiration, ECG, oxygenation, and states of alertness. LCRs and ERs were induced during non-rapid eye movement sleep in a random order under these conditions: nCPAP 6 cmH2O, HFNC 7 L/min, high-flow nasal cannulas 7 L/min at a tracheal pressure of 6 cmH2O, and no respiratory support. RESULTS: nCPAP 6 cmH2O decreased the cardiorespiratory inhibition induced with LCRs, but not with ERs in preterm lambs. This blunting effect was less marked with HFNC 7 L/min, even when the tracheal pressure was maintained at 6 cmH2O. CONCLUSIONS: nCPAP might be a treatment for cardiorespiratory events related to LCRs in newborns, either in the context of laryngopharyngeal refluxes or swallowing immaturity. Our preclinical results merit to be confirmed through clinical studies. IMPACT: Laryngeal chemoreflexes can be responsible for significant cardiorespiratory inhibition in newborns, especially preterm. Nasal continuous positive airway pressure at 6 cmH2O significantly decreased this cardiorespiratory inhibition. High-flow nasal cannulas at 7 L/min had a lesser effect than nasal continuous positive airway pressure. Esophageal stimulation was responsible for a smaller cardiorespiratory inhibition, which was not significantly modified by nasal continuous positive airway pressure or high-flow nasal cannulas. Nasal continuous positive airway pressure should be tested for its beneficial effect on cardiorespiratory events related to laryngeal chemoreflexes in preterm newborns.

Hemodynamic impacts of apelin-13 in a neonatal lamb model of septic peritonitis.

BACKGROUND: Apelins are potential candidate therapeutic molecules for hemodynamic support. The objective of this study was to assess the hemodynamic impacts of apelin-13 in a neonatal lamb model of septic shock. METHODS: Lambs were randomized to receive apelin-13 or normal saline. Septic shock was induced by injecting a fecal slurry into the peritoneal cavity. Lambs underwent volume repletion (30 mL/kg over 1 h) followed by intravenous administration of 5 incremental doses (D) of apelin-13 (D1 = 0.039 to D5 = 19.5 µg/kg/h) or normal saline. RESULTS: Following fecal injection, mean arterial pressure (MAP) and cardiac index (CI) dropped in both groups (p < 0.05). The MAP decreased non-significantly from D1 to D5 (p = 0.12) in the saline group, while increasing significantly (p = 0.02) in the apelin group (-12 (-17; 12) vs. +15 (6; 23) % (p = 0.012)). Systemic vascular resistances were higher in the apelin-13 group at D5 compared to the saline group (4337 (3239, 5144) vs. 2532 (2286, 3966) mmHg/min/mL, respectively, p = 0.046). The CI increased non-significantly in the apelin-13 group. CONCLUSION: Apelin-13 increased MAP in a neonatal lamb septic shock model. IMPACT: Administration of apelin-13 stabilized hemodynamics during the progression of the sepsis induced in this neonatal lamb model. Systemic vascular resistances were higher in the apelin-13 group than in the placebo group. This suggests ontogenic differences in vascular response to apelin-13 and warrants further investigation. This study suggests that apelin-13 could eventually become a candidate for the treatment of neonatal septic shock.

Changes in intra- and interlimb reflexes from hindlimb cutaneous afferents after staggered thoracic lateral hemisections during locomotion in cats.

When the foot dorsum contacts an obstacle during locomotion, cutaneous afferents signal central circuits to coordinate muscle activity in the four limbs. Spinal cord injury disrupts these interactions, impairing balance and interlimb coordination. We evoked cutaneous reflexes by electrically stimulating left and right superficial peroneal nerves before and after two thoracic lateral hemisections placed on opposite sides of the cord at 9-13 weeks interval in seven adult cats (4 males and 3 females). We recorded reflex responses in ten hindlimb and five forelimb muscles bilaterally. After the first (right T5-T6) and second (left T10-T11) hemisections, coordination of the fore- and hindlimbs was altered and/or became less consistent. After the second hemisection, cats required balance assistance to perform quadrupedal locomotion. Short-latency reflex responses in homonymous and crossed hindlimb muscles largely remained unaffected after staggered hemisections. However, mid- and long-latency homonymous and crossed responses in both hindlimbs occurred less frequently after staggered hemisections. In forelimb muscles, homolateral and diagonal mid- and long-latency response occurrence significantly decreased after the first and second hemisections. In all four limbs, however, when present, short-, mid- and long-latency responses maintained their phase-dependent modulation. We also observed reduced durations of short-latency inhibitory homonymous responses in left hindlimb extensors early after the first hemisection and delayed short-latency responses in the right ipsilesional hindlimb after the first hemisection. Therefore, changes in cutaneous reflex responses correlated with impaired balance/stability and interlimb coordination during locomotion after spinal cord injury. Restoring reflex transmission could be used as a biomarker to facilitate locomotor recovery.

Corrigendum: Safety of Bottle-Feeding Under Nasal Respiratory Support in Preterm Lambs With and Without Tachypnoea.

[This corrects the article DOI: 10.3389/fphys.2021.785086.].

Conventional vs high-frequency ventilation for weaning from total liquid ventilation in lambs.

OBJECTIVE: To compare conventional gas ventilation (GV) and high-frequency oscillatory ventilation (HFOV) for weaning from total liquid ventilation (TLV). METHODS: Sixteen lambs were anesthetized. After 1 h of TLV with perflubron (PFOB), they were assigned to either GV or HFOV for 2 h. Oxygen requirements, electrical impedance tomography and videofluoroscopic sequences, and respiratory system compliance were recorded. RESULTS: The lambs under GV needed less oxygen at 20 min following TLV (40 [25, 45] and 83 [63, 98]%, p = 0.001 under GV and HFOV, respectively). During weaning, tidal volume distribution was increased in the nondependent regions in the GV group compared to baseline (p = 0.046). Furthermore, residual PFOB was observed in the most dependent region. No air was detected by fluoroscopy in that region at the end of expiration in the GV group. CONCLUSION: GV offers a transient advantage over HFOV with regards to oxygenation for TLV weaning.

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.

Respiratory activity of the cricopharyngeus muscle in the neonatal period.

While phasic electrical activity of the cricopharyngeus muscle (EAcp)-the main component of the upper esophageal sphincter-occurs with inspiration and forceful expiration in adults, no such data is available for newborns. In addition, the effect of nasal respiratory support commonly used in newborns is unknown. We aimed to describe the phasic respiratory EAcp and to assess the potential effect of nasal CPAP (nCPAP, 6 cmH2O) or high-flow nasal cannula (HFNC, 7 L/min) in newborn lambs during 6-h recordings. Phasic EAcp was present in 11/17 lambs, including in 32 % (25, 81) [(median (Q1, Q3)] of respiratory cycles in wakefulness, 40 % (27, 70) in NREM sleep, and 10 % (0, 23) in REM sleep. In addition, EAcp was observed only during post-inspiration and/or expiration. Nasal CPAP or HFNC assessed in 7 of the 17 lambs did not have any effect. We conclude that phasic respiratory EAcp occurs in post-inspiration and expiration in newborn lambs.

Nasal respiratory support and tachypnea and oral feeding in full-term newborn lambs.

Newborn infants with respiratory difficulties frequently require nasal respiratory support such as nasal continuous positive airway pressure (nCPAP) or high-flow nasal cannulae (HFNC). Oral feeding of these infants under nasal respiratory support remains controversial out of fear of aspiration and cardiorespiratory events. The main objective of this study was to evaluate the safety of oral feeding under different types of nasal respiratory support in newborn lambs without or with tachypnea. Eight lambs aged 4-5 days were instrumented to record sucking, swallowing, respiration, ECG, oxygen saturation, and arterial blood gases. Each lamb was given two bottles of 30 mL of milk with a pause of 30 s under videofluoroscopy in four conditions [no respiratory support, nCPAP 6 cmH2O, HFNC 7 L/min, HFNCCPAP (= HFNC 7 L/min + CPAP 6 cmH2O)] administered in random order. The study was conducted in random order over 2 days, with or without standardized tachypnea induced by thoracic compression with a blood pressure cuff. Generalized linear mixed models were used to compare the four nasal respiratory supports in terms of safety (cardiorespiratory events and aspiration), sucking-swallowing-breathing coordination, and efficacy of oral feeding. Results reveal that no nasal respiratory support impaired the safety of oral feeding. Most of the few laryngeal penetrations we observed occurred with HFNCCPAP. Nasal CPAP modified sucking-swallowing-breathing coordination, whereas the efficiency of oral feeding decreased under HFNCCPAP. Results were similar with or without tachypnea. In conclusion, oral feeding under nasal respiratory support is generally safe in a term lamb, even with tachypnea.NEW & NOTEWORTHY The practice of orally feeding newborns suffering from respiratory problems while on nCPAP or HFNC remains controversial for fear of triggering cardiorespiratory events or aspiration pneumonia, or aggravating chronic lung disease. The present results show that bottle-feeding is generally safe in full-term lambs under nasal respiratory support, both without and with tachypnea.

Effects of upper airway obstruction or hypoxia on gastroesophageal reflux in newborn lambs.

BACKGROUND: Although it is commonly accepted that upper airway obstruction (UAO) increases gastroesophageal reflux (GER), the link is poorly understood and insufficiently documented. In addition, while hypoxia is often encountered in infants with UAO, its consequences on GER are virtually unknown. The two aims of the present study were to characterize the effects of (1) UAO and (2) hypoxia on GER. METHODS: Seventeen lambs underwent polysomnographic and esophageal impedance/pH-metry monitoring during UAO vs. a control condition (6 h, ten lambs) or 10% hypoxia vs. normoxic condition (3 h, seven other lambs). RESULTS: Moderate-to-severe UAO was maintained throughout monitoring (inspiratory tracheal pressure of -13 (-15, -12) cm H2O vs. -1 (-1, -1) cm H2O in control condition, p = 0.005). While the number of GERs increased with UAO (2 (1, 4) vs. 0 (0, 3) in the control condition, p = 0.03), the increase was less than anticipated and inconsistent among the lambs. Also, sustained 10% hypoxia did not alter the number of GERs (2 (1, 3) vs. 0 (0, 5) in the control condition, p = 0.9). CONCLUSIONS: The presence of an UAO for 6 h mildly increased the number of GERs, whereas hypoxia for 3 h had no significant effect. IMPACT: The effect of upper airway obstruction and hypoxia on gastroesophageal reflux is poorly documented in the neonatal period. A moderate-to-severe upper airway obstruction for 6 h results in a mild, inconsistent increase in the number of gastroesophageal refluxes. Overall, a hypoxia of 10% for 3 h had no significant impact on gastroesophageal reflux. The prescription of an antireflux medication in infants with upper airway obstruction must not be systematic but rely on objective signs of a pathologic gastroesophageal reflux.

Safety of Bottle-Feeding Under Nasal Respiratory Support in Preterm Lambs With and Without Tachypnoea.

Aim: Convalescing preterm infants often require non-invasive respiratory support, such as nasal continuous positive airway pressure or high-flow nasal cannulas. One challenging milestone for preterm infants is achieving full oral feeding. Some teams fear nasal respiratory support might disrupt sucking-swallowing-breathing coordination and induce severe cardiorespiratory events. The main objective of this study was to assess the safety of oral feeding of preterm lambs on nasal respiratory support, with or without tachypnoea. Methods: Sucking, swallowing and breathing functions, as well as electrocardiogram, oxygen haemoglobin saturation, arterial blood gases and videofluoroscopic swallowing study were recorded in 15 preterm lambs during bottle-feeding. Four randomly ordered conditions were studied: control, nasal continuous positive airway pressure (6 cmH2O), high-flow nasal cannulas (7 L•min-1), and high-flow nasal cannulas at 7 L•min-1 at a tracheal pressure of 6 cmH2O. The recordings were repeated on days 7-8 and 13-14 to assess the effect of maturation. Results: None of the respiratory support impaired the safety or efficiency of oral feeding, even with tachypnoea. No respiratory support systematically impacted sucking-swallowing-breathing coordination, with or without tachypnoea. No effect of maturation was found. Conclusion: This translational physiology study, uniquely conducted in a relevant animal model of preterm infant with respiratory impairment, shows that nasal respiratory support does not impact the safety or efficiency of bottle-feeding or sucking-swallowing-breathing coordination. These results suggest that clinical studies on bottle-feeding in preterm infants under nasal continuous positive airway pressure and/or high-flow nasal cannulas can be safely undertaken.

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.

Nasal high-frequency oscillatory ventilation inhibits gastroesophageal reflux in the neonatal period.

Nasal high-frequency oscillatory ventilation (nHFOV) in neonates is increasingly considered due to enhanced alveolar ventilation, absence of patient-ventilator asynchrony and lessened ventilator-induced lung injury. Although any type of non-invasive respiratory support can lead to gastric distension via esophageal air passage and thus promote gastroesophageal refluxes (GERs), we have shown that nasal continuous positive airway pressure (CPAP; 6 cmH2O) and intermittent positive pressure ventilation (15/4 cmH2O) conversely inhibit GERs in lambs. The current objective was to test the hypothesis that nHFOV also inhibits GERs compared to spontaneous ventilation without respiratory support. Eight lambs underwent five hours of polysomnographic and esophageal multichannel intraluminal impedance pHmetry recordings to assess GERs and air passage into the esophagus, with and without nHFOV (mean airway pressure = 8 cmH2O, oscillation frequency = 8 Hz, amplitude ≈ 20 cmH2O and I:E = 1:2). Results revealed that GERs were decreased with nHFOV (p = .03), despite an increase in gas-containing swallows (p = .01). In conclusion, similarly to nasal CPAP and intermittent positive pressure ventilation, nHFOV inhibits GERs in newborn lambs.

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.

Effects of Nasal Continuous Positive Airway Pressure and High-Flow Nasal Cannula on Sucking, Swallowing, and Breathing during Bottle-Feeding in Lambs.

The use of prolonged respiratory support under the form of high-flow nasal cannula (HFNC) or nasal continuous positive airway pressure (nCPAP) is frequent in newborn infants. Introduction of oral feeding under such nasal respiratory support is, however, highly controversial among neonatologists, due to the fear that it could disrupt sucking, swallowing, and breathing coordination and in turn induce cardiorespiratory events. The recent observation of tracheal aspirations during bottle-feeding in preterm infants under nCPAP justifies the use of animal models to perform more comprehensive physiological studies on the subject, in order to gain further insights for clinical studies. The objective of this study was to assess and compare the impact of HFNC and nCPAP on bottle-feeding in newborn lambs, in terms of bottle-feeding efficiency and safety as well as sucking-swallowing-breathing coordination. Eight full-term lambs were instrumented to record sucking, swallowing, and respiration as well as electrocardiogram and oxygenation. Lambs were bottle-fed in a standardized manner during three randomly ordered conditions, namely nCPAP 6 cmH2O, HFNC 7 L/min, and no respiratory support. Results revealed that nCPAP decreased feeding duration [25 vs. 31 s (control) vs. 57 s (HFNC), p = 0.03] and increased the rate of milk transfer [2.4 vs. 1.9 mL/s (control) vs.1.1 mL/s (HFNC), p = 0.03]. No other indices of bottle-feeding safety or sucking-swallowing-breathing coordination were significantly altered by HFNC or nCPAP. In conclusion, our results obtained in full-term newborn lambs suggest that: (i) nCPAP 6 cmH2O, but not HFNC 7 L/min, increases bottle-feeding efficiency; (ii) bottle-feeding is safe under nCPAP 6 cmH2O and HFNC 7 L/min, with no significant alteration in sucking-swallowing-breathing coordination. The present informative and reassuring data in full-term healthy lambs must be complemented by similar studies in preterm lambs, including mild-to-moderate respiratory distress alleviated by respiratory support in order to mimic preterm infants with bronchopulmonary dysplasia and pave the way for clinical studies.

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.

Effects of Moderate Hyperbilirubinemia on Nutritive Swallowing and Swallowing-Breathing Coordination in Preterm Lambs.

BACKGROUND: Hyperbilirubinemia (HB) occurs in 90% of preterm newborns. HB induces acute neurological disorders (somnolence, abnormal tone, feeding difficulties, auditory dysfunction) and alterations in respiratory control. These findings suggest brainstem neurotoxicity that could also affect swallowing centers. OBJECTIVE: To test the hypothesis that HB impairs nutritive swallowing (NS) and swallowing-breathing coordination. METHODS: Two groups of preterm lambs (born 14 days prior to term), namely control (n = 6) and HB (n = 5), were studied. On day 5 of life (D0), moderate HB (150-250 µmol/l) was induced during 17 h in the HB group. Swallowing was assessed via recording of pharyngeal pressure and respiration by respiratory inductance plethysmography and pulse oximetry. The effect of HB on NS was assessed during standardized bottle-feeding. A second recording was performed 48 h after recovery from HB (D3). RESULTS: Swallows were less frequent (p = 0.003) and of smaller volume (p = 0.01) in HB lambs while swallowing frequency was decreased (p = 0.004). These differences disappeared after HB normalization. Swallowing-breathing coordination was impaired in HB lambs, with a decrease in percent time with NS burst-related apneas/hypopneas at D0 and D3. Simultaneously, HB lambs tended to experience more severe desaturations (<80%) during bottle-feeding. Finally, following bottle-feeding, the respiratory rate was significantly lower, along with an increased apnea duration in HB lambs. CONCLUSIONS: Swallowing and swallowing-breathing coordination are altered by acute moderate HB in preterm lambs. Decreased efficiency at bottle-feeding is accompanied by continuation of breathing during swallow bursts, which may promote lung aspiration.