The influence of chorioamnionitis on respiratory drive and spontaneous breathing of premature infants at birth: a narrative review.

Most very premature infants breathe at birth but require respiratory support in order to stimulate and support their breathing. A significant proportion of premature infants are affected by chorioamnionitis, defined as an umbrella term for antenatal inflammation of the foetal membranes and umbilical vessels. Chorioamnionitis produces inflammatory mediators that potentially depress the respiratory drive generated in the brainstem. Such respiratory depression could maintain itself by delaying lung aeration, hampering respiratory support at birth and putting infants at risk of hypoxic injury. This inflammatory-mediated respiratory depression may contribute to an association between chorioamnionitis and increased requirement of neonatal resuscitation in premature infants at birth. This narrative review summarises mechanisms on how respiratory drive and spontaneous breathing could be influenced by chorioamnionitis and provides possible interventions to stimulate spontaneous breathing.  Conclusion: Chorioamnionitis could possibly depress respiratory drive and spontaneous breathing in premature infants at birth. Interventions to stimulate spontaneous breathing could therefore be valuable. What is Known: • A large proportion of premature infants are affected by chorioamnionitis, antenatal inflammation of the foetal membranes and umbilical vessels. What is New: • Premature infants affected by chorioamnionitis might be exposed to higher concentrations of respiratory drive inhibitors which could depress breathing at birth. • Premature infants affected by chorioamnionitis seem to be associated with a higher and more extensive requirement of resuscitation at birth.

The effect of imposed resistance in neonatal resuscitators on pressure stability and peak flows: a bench test.

BACKGROUND: The importance of neonatal resuscitator resistance is currently unknown. In this study we investigated peak flows and pressure stability resulting from differences in imposed resistance during positive pressure ventilation(PPV) and simulated spontaneous breathing (SSB) between the r-PAP, low-resistance resuscitator, and Neopuff™, high-resistance resuscitator. METHODS: In a bench test, 20 inflations during PPV and 20 breaths during SSB were analysed on breath-by-breath basis to determine peak flow and pressure stability using the Neopuff™ with bias gas flow of 8, 12 or 15 L/min and the r-PAP with total gas flow of 15 L/min. RESULTS: Imposed resistance of the Neopuff™ was significantly reduced when the bias gas flow was increased from 8 to 15 L/min, which resulted in higher peak flows during PPV and SSB. Peak flows in the r-PAP were, however, significantly higher and fluctuations in CPAP during SSB were significantly smaller in the r-PAP compared to the Neopuff™ for all bias gas flow levels. During PPV, a pressure overshoot of 3.2 cmH2O was observed in the r-PAP. CONCLUSIONS: The r-PAP seemed to have a lower resistance than the Neopuff™ even when bias gas flows were increased. This resulted in more stable CPAP pressures with higher peak flows when using the r-PAP. IMPACT: The traditional T-piece system (Neopuff™) has a higher imposed resistance compared to a new neonatal resuscitator (r-PAP). This study shows that reducing imposed resistance leads to smaller CPAP fluctuations and higher inspiratory and expiratory peak flows. High peak flows might negatively affect lung function and/or cause lung injury in preterm infants at birth. This study will form the rationale for further studies investigating these effects. A possible compromise might be to use the traditional T-piece system with a higher bias gas flow (12 L/min), thereby reducing the imposed resistance and generating more stable PEEP/CPAP pressures, while limiting potentially harmful peak flows.

Effect of initial and subsequent mask applications on breathing and heart rate in preterm infants at birth.

OBJECTIVE: Application of a face mask may provoke the trigeminocardiac reflex, leading to apnoea and bradycardia. This study investigates whether re-application of a face mask in preterm infants at birth alters the risk of apnoea compared with the initial application, and identify factors that influence this risk. METHODS: Resuscitation videos and respiratory function monitor data collected from preterm infants <30 weeks gestation between 2018 and 2020 were reviewed. Breathing and heart rate before and after the initial and subsequent mask applications were analysed. RESULTS: In total, 111 infants were included with 404 mask applications (102 initial and 302 subsequent mask applications). In 254/404 (63%) applications, infants were breathing prior to mask application, followed by apnoea after 67/254 (26%) mask applications. Apnoea and bradycardia occurred significantly more often after the initial mask application compared with subsequent applications (apnoea initial: 32/67 (48%) and subsequent: 44/187 (24%), p<0.001; bradycardia initial: 61% and subsequent 21%, p<0.001). Apnoea was followed by bradycardia in 73% and 71% of the initial and subsequent mask applications, respectively (p=0.607).In a logistic regression model, a lower breathing rate (OR 0.908 (95% CI 0.847 to 0.974), p=0.007) and heart rate (OR 0.935 (95% CI 0.901 to 0.970), p<0.001) prior to mask application were associated with an increased likelihood of becoming apnoeic following subsequent mask applications. CONCLUSION: In preterm infants at birth, apnoea and bradycardia occurs more often after an initial mask application than subsequent applications, with lower heart and breathing rates increasing the risk of apnoea in subsequent applications.

Effect of clinical chorioamnionitis on breathing effort in premature infants at birth: a retrospective case-control study.

RATIONALE: Antenatal inflammation, usually associated with chorioamnionitis, is a major cause of premature birth. As inflammation could depress respiratory drive, we have examined the effect of clinical chorioamnionitis (CCA) on spontaneous breathing in premature infants at birth. METHODS: Infants with CCA born <30 weeks' gestation were matched with control infants based on gestational age (±6 days), birth weight (±300 g), antenatal corticosteroids, sex and general anaesthesia. The primary outcome was breathing effort, assessed as minute volume (MV) of spontaneous breathing. We also measured tidal volume (Vt), respiratory rate (RR) and apnoea in the first 5 min and additional physiological parameters in the first 10 min after start of respiratory support. RESULTS: Ninety-two infants were included (n=46 CCA infants vs n=46 controls; median (IQR) gestational age 26+4 (25+0-27+6) vs 26+6 (25+1-28+3) weeks). MV and Vt were significantly lower (MV: 43 (17-93) vs 70 (31-119) mL/kg/min, p=0.043; Vt: 2.6 (1.9-3.6) vs 2.9 (2.2-4.8) mL/kg/breath, p=0.046), whereas RR was similar in CCA infants compared with controls. Incidence of apnoea was higher (5 (2-6) vs 2 (1-4), p=0.002), and total duration of apnoea was longer (90 (21-139) vs 35 (12-98) s, p=0.025) in CCA infants. CCA infants took significantly longer to reach an oxygen saturation >80% (3:37 (2:10-4:29) vs 2:25 (1:06-3:52) min, p=0.016) and had a lower oxygen saturation at 5 min (77 (66-92) vs 91 (68-94) %, p=0.028), despite receiving more oxygen (62 (48-76) vs 54 (43-73) %, p=0.036). CONCLUSION: CCA is associated with reduced breathing effort and oxygenation in premature infants at birth.

Resuscitators' opinions on using a respiratory function monitor during neonatal resuscitation.

AIM: The aim of this study was to assess the resuscitators' opinions of the usefulness and clinical value of using a respiratory function monitor (RFM) when resuscitating extremely preterm infants with positive pressure ventilation. METHODS: The link to an online survey was sent to 106 resuscitators from six countries who were involved in a multicentre trial that compared the percentage of inflations within a predefined target range with and without the RFM. The resuscitators were asked to assess the usefulness and clinical value of the RFM. The survey was online for 4 months after the trial ended in May 2019. RESULTS: The survey was completed by 74 (70%) resuscitators of which 99% considered the RFM to be helpful during neonatal resuscitation and 92% indicated that it influenced their decision-making. The majority (76%) indicated that using the RFM improved their practice and made resuscitation more effective, even when the RFM was not available. Inadequate training was the key issue that limited the effectiveness of the RFM: 45% felt insufficiently trained, and 78% felt more training in using and interpreting the RFM would have been beneficial. CONCLUSION: Resuscitators considered the RFM to be helpful to guide neonatal resuscitation, but sufficient training was required to achieve the maximum benefit.

The Effect of a Higher Bias Gas Flow on Imposed T-Piece Resistance and Breathing in Preterm Infants at Birth.

Objective: The resistance created by the PEEP-valve of a T-piece resuscitator is bias gas flow dependent and might affect breathing in preterm infants. In this study we investigated the effect of a higher bias gas flow on the imposed inspiratory and expiratory T-piece resistance and expiratory breaking manoeuvres (EBM) in preterm infants during spontaneous breathing on CPAP at birth. Methods: In a retrospective pre-post implementation study of preterm infants <32 weeks gestation, who were stabilised with a T-piece resuscitator, a bias gas flow of 12 L/min was compared to 8 L/min. All spontaneous breaths on CPAP within the first 10 min of starting respiratory support were analysed on a breath-by-breath basis to determine the breathing pattern of each breath and to calculate the imposed inspiratory and expiratory T-piece resistance (Ri, Re), flow rates and tidal volume. Results: In total, 54 infants were included (bias gas flow 12 L/min: n = 27, 8 L/min: n = 27) with a median GA of 29+6 (28+4-30+3) and 28+5 (25+6-30+3), respectively (p = 0.182). Ri and Re were significantly lower in the 12 L/min compared to 8 L/min bias flow group [Ri: 29.6 (26.1-33.6) vs. 46.4 (43.0-54.1) cm H2O/L/s, p < 0.001; Re: 32.0 (30.0-35.1) vs. 48.0 (46.3-53.9) cm H2O/L/s, p < 0.001], while the incidence of EBM [77% (53-88) vs. 77% (58-90), p = 0.586] was similar. Conclusion: During stabilisation of preterm infants at birth with a T-piece resuscitator, the use of a higher bias gas flow reduced both the imposed inspiratory and expiratory T-piece resistance for the infant, but this did not influence the incidence of EBMs.

Technology in the delivery room supporting the neonatal healthcare provider's task.

Very preterm infants are a unique and highly vulnerable group of patients that have a narrow physiological margin within which interventions are safe and effective. The increased understanding of the foetal to neonatal transition marks the intricacy of the rapid and major physiological changes that take place, making delivery room stabilisation and resuscitation an increasingly complex and sophisticated activity for caregivers to perform. While modern, automated technologies are progressively implemented in the neonatal intensive care unit (NICU) to enhance the caregivers in providing the right care for these patients, the technology in the delivery room still lags far behind. Diligent translation of well-known and promising technological solutions from the NICU to the delivery room will allow for better support of the caregivers in performing their tasks. In this review we will discuss the current technology used for stabilisation of preterm infants in the delivery room and how this could be optimised in order to further improve care and outcomes of preterm infants in the near future.

A Step Further-The Role of Trigeminocardiac Reflex in Therapeutic Implications: Hypothesis, Evidence, and Experimental Models.

The trigeminocardiac reflex (TCR) is a well-recognized brainstem reflex that represents a unique interaction between the brain and the heart through the Vth and Xth cranial nerves and brainstem nuclei. The TCR has mainly been reported as an intraoperative phenomenon causing cardiovascular changes during skull-base surgeries. However, it is now appreciated that the TCR is implicated during non-neurosurgical procedures and in nonsurgical conditions, and its complex reflex pathways have been explored as potential therapeutic options in various neurological and cardiovascular diseases. This narrative review presents an in-depth overview of hypothetical and experimental models of the TCR phenomenon in relation to the Vth and Xth cranial nerves. In addition, primitive interactions between these 2 cranial nerves and their significance are highlighted. Finally, therapeutic models of the complex interactions of the TCR and areas for further research will be considered.

Feasibility and Effect of Physiological-Based CPAP in Preterm Infants at Birth.

Background: Preterm infants are commonly supported with 5-8 cmH2O CPAP. However, animal studies demonstrate that high initial CPAP levels (12-15 cmH2O) which are then reduced (termed physiological based (PB)-CPAP), improve lung aeration without adversely affecting cardiovascular function. We investigated the feasibility of PB-CPAP and the effect in preterm infants at birth. Methods: Preterm infants (24-30 weeks gestation) were randomized to PB-CPAP or 5-8 cmH2O CPAP for the first 10 min after birth. PB-CPAP consisted of 15 cmH2O CPAP that was decreased when infants were stabilized (heart rate ≥100 bpm, SpO2 ≥85%, FiO2 ≤ 0.4, spontaneous breathing) to 8 cmH2O with steps of ~2/3 cmH2O/min. Primary outcomes were feasibility and SpO2 in the first 5 min after birth. Secondary outcomes included physiological and breathing parameters and short-term neonatal outcomes. Planned enrollment was 42 infants. Results: The trial was stopped after enrolling 31 infants due to a low inclusion rate and recent changes in the local resuscitation guideline that conflict with the study protocol. Measurements were available for analysis in 28 infants (PB-CPAP n = 8, 5-8 cmH2O n = 20). Protocol deviations in the PB-CPAP group included one infant receiving 3 inflations with 15 cmH2O PEEP and two infants in which CPAP levels were decreased faster than described in the study protocol. In the 5-8 cmH2O CPAP group, three infants received 4, 10, and 12 cmH2O CPAP. During evaluations, caregivers indicated that the current PB-CPAP protocol was difficult to execute. The SpO2 in the first 5 min after birth was not different [61 (49-70) vs. 64 (47-74), p = 0.973]. However, infants receiving PB-CPAP achieved higher heart rates [121 (111-130) vs. 97 (82-119) bpm, p = 0.016] and duration of mask ventilation was shorter [0:42 (0:34-2:22) vs. 2:58 (1:36-6:03) min, p = 0.020]. Infants in the PB-CPAP group required 6:36 (5:49-11:03) min to stabilize, compared to 9:57 (6:58-15:06) min in the 5-8 cmH2O CPAP group (p = 0.256). There were no differences in short-term outcomes. Conclusion: Stabilization of preterm infants with PB-CPAP is feasible but tailoring CPAP appeared challenging. PB-CPAP did not lead to higher SpO2 but increased heart rate and shortened the duration of mask ventilation, which may reflect faster lung aeration.

A multi-centre randomised controlled trial of respiratory function monitoring during stabilisation of very preterm infants at birth.

AIM: To determine whether the use of a respiratory function monitor (RFM) during PPV of extremely preterm infants at birth, compared with no RFM, leads to an increase in percentage of inflations with an expiratory tidal volume (Vte) within a predefined target range. METHODS: Unmasked, randomised clinical trial conducted October 2013 - May 2019 in 7 neonatal intensive care units in 6 countries. Very preterm infants (24-27 weeks of gestation) receiving PPV at birth were randomised to have a RFM screen visible or not. The primary outcome was the median proportion of inflations during manual PPV (face mask or intubated) within the target range (Vte 4-8 mL/kg). There were 42 other prespecified monitor measurements and clinical outcomes. RESULTS: Among 288 infants randomised (median (IQR) gestational age 26+2 (25+3-27+1) weeks), a total number of 51,352 inflations were analysed. The median (IQR) percentage of inflations within the target range in the RFM visible group was 30.0 (18.0-42.2)% vs 30.2 (14.8-43.1)% in the RFM non-visible group (p = 0.721). There were no differences in other respiratory function measurements, oxygen saturation, heart rate or FiO2. There were no differences in clinical outcomes, except for the incidence of intraventricular haemorrhage (all grades) and/or cystic periventricular leukomalacia (visible RFM: 26.7% vs non-visible RFM: 39.0%; RR 0.71 (0.68-0.97); p = 0.028). CONCLUSION: In very preterm infants receiving PPV at birth, the use of a RFM, compared to no RFM as guidance for tidal volume delivery, did not increase the percentage of inflations in a predefined target range. TRIAL REGISTRATION: Dutch Trial Register NTR4104, clinicaltrials.gov NCT03256578.

Comparing the effect of two different interfaces on breathing of preterm infants at birth: A matched-pairs analysis.

OBJECTIVE: Applying a face mask could provoke a trigeminocardiac reflex. We compared the effect of applying bi-nasal prongs with a face mask on breathing and heart rate of preterm infants at birth. METHODS: In a retrospective matched-pairs study of infants <32 weeks of gestation, the use of bi-nasal prongs for respiratory support at birth was compared to the use of a face mask. Infants who were initially breathing at birth and subsequently received respiratory support were matched for gestational age (±4 days), birth weight (±300 g), general anaesthesia and gender. Breathing, heart rate and other parameters were collected before and after interface application and in the first 5 min thereafter. RESULTS: In total, 130 infants were included (n = 65 bi-nasal prongs, n = 65 face mask) with a median (IQR) gestational age of 27+2 (25+3-28+4) vs 26+6 (25+3-28+5) weeks. The proportion of infants who stopped breathing after applying the interface was not different between the groups (bi-nasal prongs 43/65 (66%) vs face mask 46/65 (71%), p = 0.70). Positive pressure ventilation was given more often when bi-nasal prongs were used (55/65 (85%) vs 40/65 (62%), p < 0.001). Heart rate (101 (75-145) vs 110 (68-149) bpm, p = 0.496) and oxygen saturation (59% (48-87) vs 56% (35-84), p = 0.178) were similar in the first 5 min after an interface was applied in the infants who stopped breathing. CONCLUSION: Apnoea and bradycardia occurred often after applying either bi-nasal prongs or a face mask on the face for respiratory support in preterm infants at birth.

The effect of a face mask for respiratory support on breathing in preterm infants at birth.

OBJECTIVE: Applying a mask on the face for respiratory support could induce a trigeminocardiac reflex leading to apnoea and bradycardia. We have examined the effect of applying a face mask on breathing and heart rate in preterm infants at birth. METHODS: Resuscitation videos of infants ≤ 32 weeks gestation recorded from 2010 until 2018 at the Leiden University Medical Centre and the General University Hospital in Prague were reviewed. All infants received respiratory support via face mask. Breathing and heart rate were noted before and after application of the face mask and over the first 5 min. RESULTS: Recordings of 429 infants were included (median (IQR) gestational age of 28+6 (27+1-30+4) weeks). In 368/429 (86%) infants breathing was observed before application of the face mask and 197/368 (54%) of these infants stopped breathing following application of the face mask. Apnoea occurred at a median of 5 (3-17) seconds after application of the face mask with a duration of 28 (22-34) seconds of the first minute. In a logistic regression model, the occurrence of apnoea after face mask application was inversely associated with gestational age (OR = 1.424 (1.281-1.583), p < 0.001). Infants who stopped breathing had a significantly lower heart rate 82 (66-123) vs 134 (97-151) bpm, p < 0.001) and oxygen saturation (49% (33-59) vs 66% (50-82), p < 0.001) over the first minute after face mask application, compared to infants who continued breathing. CONCLUSION: Applying a face mask for respiratory support affects breathing in a large proportion (54%) of preterm infants and this effect is gestational age dependent.