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Neurally adjusted ventilatory assist in infants: A review article

  • Shih-Jou Fang
    Affiliations
    Section of Neonatology, Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taiwan
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  • Chih-Cheng Chen
    Affiliations
    Section of Neonatology, Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taiwan

    Department of Respiratory Care, Kaohsiung Chang Gung Memorial Hospital, Taiwan
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  • Da-Ling Liao
    Affiliations
    Department of Respiratory Care, Kaohsiung Chang Gung Memorial Hospital, Taiwan
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  • Mei-Yung Chung
    Correspondence
    Corresponding author. Section of Neonatology, Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, No. 123, Ta Pei Road, Niao Sung District, Kaohsiung City, Taiwan.
    Affiliations
    Section of Neonatology, Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taiwan

    Department of Respiratory Care, Kaohsiung Chang Gung Memorial Hospital, Taiwan

    Chang Gung University of Science and Technology, Chiayi Campus, Taiwan
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Open AccessPublished:September 28, 2022DOI:https://doi.org/10.1016/j.pedneo.2022.09.003
      Neurally adjusted ventilatory assist (NAVA) and non-invasive (NIV)-NAVA are innovative modes of synchronized and proportional respiratory support. They can synchronize with the patients' breathing and promote patient comfort. Both techniques are increasingly being used these years, however experience with their use in newborns and premature infants in Taiwan is relatively few. Because increasing evidence supports the use of NAVA and NIV-NAVA in newborns and premature infants requiring respiratory assist to achieve better synchrony, the aim of this article is to discuss whether NAVA can provide better synchronization and comfort for ventilated newborns and premature babies. In a review of recent literature, we found that NAVA and NIV-NAVA appear to be superior to conventional invasive and non-invasive ventilation. Nevertheless, some of the benefits are controversial. For example, treatment failure in premature infants is common due to insufficient triggering of electrical activity of the diaphragm (EAdi) and frequent apnea, highlighting the differences between premature infants and adults in settings and titration. Further, we suggest how to adjust the settings of NAVA and NIV-NAVA in premature infants to reduce clinical adverse events and extubation failure. In addition to assist in the use of NAVA, EAdi can also serve as a continuous and real-time monitor of vital signs, assisting physicians in the administration of sedatives, evaluation of successful extubation, and as a reference for the patient's respiratory condition during special procedures.

      Keywords

      1. Introduction

      Admitted neonates, and especially premature infants, usually require positive pressure ventilatory support during the transition period. With the administration of antenatal steroids and postnatal surfactant, most very low birth weight infants (VLBWIs) survive and need significantly long term respiratory support in the neonatal intensive care unit (NICU). Improving subject-ventilator synchrony is known to improve ventilation and decrease adverse effects. However, synchronously ventilating a premature infant is complicated because of the short inspiratory time, rapid respiratory rate, small tidal volume, and leakage around non-cuffed endotracheal tube. Neurally adjusted ventilator assist (NAVA) and non-invasive (NIV)-NAVA are innovative modes of neural-triggered ventilation that use the subject's electrical activity of the diaphragm (EAdi) as a trigger to deliver mechanical breaths that are synchronized to each breath of the subject. NAVA and NIV-NAVA can serve a potential solution for the difficult synchrony in ventilating premature infants. However, experience with their use in newborns and premature infants is limited in Taiwan because the fee of EAdi catheter was not included into national health insurance policy and patients must pay at their own expense. In this review, we describe the reasons for using NAVA, benefits of NAVA or NIV-NAVA, and how to set and titrate NAVA mode in premature infants and neonates. Lastly, we demonstrate how to use EAdi as a real-time monitor of respiration in these patients.

      2. Why NAVA? How personalized?

      Breathing is controlled by rhythmic discharge from the respiratory center of the brain which travels to excite the diaphragm muscle via the phrenic nerve, resulting in muscle contraction and movement of the diaphragm. This then leads to a reduction in airway pressure and consequently inflow of air into the lungs. Conventional synchronized mechanical ventilation involves the use of flow or pressure sensors to detect inspiration via a reversal of flow or fall in airway pressure.
      • Beck J.
      • Sinderby C.
      Neurally adjusted ventilatory assist in newborns.
      However, this reversal of flow or fall in airway pressure is the last neurorespiratory event, leading to many triggering errors with a traditional synchronized ventilator, and increases sensitivity to hyperinflation and intrinsic positive end-expiratory pressure (PEEP). Especially in neonates and premature infants, synchronized ventilation is more difficult due to the need for small tidal volume, rapid respiratory rate and short inspiratory time. Leakage also reduces the reliability of monitoring of respiratory parameters. Moreover, neonates and premature infants have a strong vagal reflex leading to apnea and periodic breathing with a highly variable breathing pattern. In addition, traditional synchronized ventilators with present flow and pressure sensors only detect breathing initiation and deliver a preset ventilator breath. It then increases the difficulty of synchronization, especially with regards to tidal volume, breath triggering and breath termination. Mortamet et al.
      • Mortamet G.
      • Larouche A.
      • Ducharme-Crevier L.
      • Fléchelles O.
      • Constantin G.
      • Essouri S.
      • et al.
      Patient–ventilator asynchrony during conventional mechanical ventilation in children.
      described the characteristics of patient-ventilator asynchrony (PVA) in 34 critically ill children (median age 6 months) admitted to a pediatric intensive care unit (PICU) who received mechanical ventilation for at least 24 h. In total, 9806 breaths were analyzed, and their results showed that the 27% (interquartile 22–39%) of the time was asynchronous with the ventilator, most of which was due to errors with cycling-off and delays in triggering. An automated algorithm showed an asynchrony NeuroSync index of 45%, confirming the high prevalence of asynchrony. NAVA can optimize patient-ventilator synchronization through the EAdi. With NAVA, EAdi signals are captured by the electrodes of an EAdi catheter and sent to the ventilator, which then uses the signals to help the patient breathe. Since the diaphragm and ventilator use the same signal, mechanical coupling between the ventilator and diaphragm is almost immediate. The patient's EAdi triggers the mechanical ventilator to deliver synchronized breaths with the initiation, size and termination of the patient's breath. NAVA therefore offers a potential solution to many of the challenges posed by the ventilation of infants.

      3. Benefits of NAVA&NIV-NAVA compared to conventional mode in infants

      NAVA allows the infants rather than the ventilators or physicians to regulate their own ventilation, and control the initiation, termination, size, rate and peak pressure of their breathing.
      • Jung Y.H.
      • Kim H.S.
      • Lee J.
      • Shin S.H.
      • Kim E.K.
      • Choi J.H.
      Neurally adjusted ventilatory assist in preterm infants with established or evolving bronchopulmonary dysplasia on high-intensity mechanical ventilatory support: a single-center experience.
      Shi et al.
      • Shi Y.
      • Muniraman H.
      • Biniwale M.
      • Ramanathan R.
      A review on non-invasive respiratory support for management of respiratory distress in extremely preterm infants.
      reviewed NAVA and NIV-NAVA articles since 2012, and found that EAdi monitoring and NAVA were safe and feasible. In comparison with conventional ventilators, NAVA provides a better gas exchange and patient-ventilator interaction, lower peak inspiratory pressure (PIP), lower oxygen requirement, and reduced respiratory muscle load. Compared with conventional non-invasive ventilation (NIV) such as nasal continuous positive airway pressure (NCPAP) and non-invasive mandatory ventilation (NIMV), non-invasive pressure support ventilation (NIV-PS), NIV-NAVA improves synchrony, reduces reintubation, complications and oxygen requirement. Rong
      • Rong X.
      • Liang F.
      • Li Y.J.
      • Liang H.
      • Zhao X.P.
      • Zou H.M.
      • et al.
      Application of neurally adjusted ventilatory assist in premature neonates less than 1,500 grams with established or evolving bronchopulmonary dysplasia.
      also suggested that NAVA improves comfort and requires less sedation in premature infants with bronchopulmonary dysplasia. Mally et al.
      • Mally P.V.
      • Beck J.
      • Sinderby C.
      • Caprio M.
      • Bailey S.M.
      Neural breathing pattern and patient-ventilator interaction during neurally adjusted ventilatory assist and conventional ventilation in newborns.
      reported a reduction in patient ventilator asynchrony, as quantified using the NeuroSync index, and central apnea with NAVA compared to synchronized intermittent mandatory ventilation (SIMV) in VLBW infants. Firestone et al.
      • Firestone K.
      • Horany B.A.
      • de Leon-Belden L.
      • Stein H.
      Nasal continuous positive airway pressure versus noninvasive NAVA in preterm neonates with apnea of prematurity: a pilot study with a novel approach.
      reported 17 preterm infants with apnea of prematurity, and found a decrease in clinical events from 17.9 ± 7.8/hour with CPAP to 10.2 ± 8.1/hour with NIV-NAVA of NAVA level 0 cmH2O/μV (NN0) (p = 0.00047). Gibu
      • Gibu C.K.
      • Cheng P.Y.
      • Ward R.J.
      • Castro B.
      • Heldt G.P.
      Feasibility and physiological effects of noninvasive neurally adjusted ventilatory assist in preterm infants.
      also found that NIV-NAVA decreased PIP, fraction of inspired oxygen (FiO2), frequency of desaturation and EAdi compared to NIMV. The EAdi catheter was used in 11 patients for a total of 81 days without complications. Xiao and colleagues
      • Xiao S.
      • Huang C.
      • Cheng Y.
      • Xia Z.
      • Li Y.
      • Tang W.
      • et al.
      Application of neurally adjusted ventilatory assist in ventilator weaning of infants ventilator weaning.
      conducted a crossover study in which 25 infants were given CPAP and NAVA mode, and found no significant differences in hemodynamic indexes or partial pressure of carbon dioxide (PaCO2) between the two modes, and both were in normal range. Peak pressure, mean pressure, and EAdi signal were correspondingly lower in NAVA mode. Lee
      • Lee B.K.
      • Shin S.H.
      • Jung Y.H.
      • Kim E.K.
      • Kim H.S.
      Comparison of NIV-NAVA and NCPAP in facilitating extubation for very preterm infants.
      et al. reported that extubation failed within 72 h in 6.3% of preterm infants (<30 weeks gestational age) who received NIV-NAVA and 37.5% of those who received NCPAP (p = 0.041). Reviewing all of these articles (Table 1), the results show that NAVA and NIV-NAVA can improve patient-ventilator interaction and comfort, decrease PIP, oxygen requirement, sedation requirement, apnea, clinically significant events, and extubation failure. Moreover, the application of NAVA and EAdi monitoring appears to be safe and feasible in premature infants.
      Table 1Studies published for NAVA or NIV-NAVA compared to conventional mechanical ventilators since 2016.
      First Author, YearInterventionType of studynPatientOutcome
      Jung et al.,
      • Jung Y.H.
      • Kim H.S.
      • Lee J.
      • Shin S.H.
      • Kim E.K.
      • Choi J.H.
      Neurally adjusted ventilatory assist in preterm infants with established or evolving bronchopulmonary dysplasia on high-intensity mechanical ventilatory support: a single-center experience.
      2016
      NAVA/PC-SIMV + PSRetrospective29Preterm infants<1500 gLower PIP, Pmean, work of breathing, and FiO2 in NAVA.
      Shi et al.,
      • Shi Y.
      • Muniraman H.
      • Biniwale M.
      • Ramanathan R.
      A review on non-invasive respiratory support for management of respiratory distress in extremely preterm infants.
      2016
      NIV-NAVA/NCPAP/NIPPV/NHFVRetrospective, review52Preterm infants<1500 gNAVA has better blood gas with lower PIP and FiO2.
      Rong et al.,
      • Rong X.
      • Liang F.
      • Li Y.J.
      • Liang H.
      • Zhao X.P.
      • Zou H.M.
      • et al.
      Application of neurally adjusted ventilatory assist in premature neonates less than 1,500 grams with established or evolving bronchopulmonary dysplasia.
      2020
      NAVA/TRADITIONAL RESPIRATORY SUPPORTRetrospective, matched

      cohort
      30Preterm infants<1500 gNo difference in duration of respiratory support.

      NAVA decrease in the need of sedation.
      Mally et al.,
      • Mally P.V.
      • Beck J.
      • Sinderby C.
      • Caprio M.
      • Bailey S.M.
      Neural breathing pattern and patient-ventilator interaction during neurally adjusted ventilatory assist and conventional ventilation in newborns.
      2018
      NAVA/PC-SIMV + PSProspective, crossover23InfantsReduction in central apnea and improved patient-ventilator interaction with NAVA.
      Firestone et al.,
      • Firestone K.
      • Horany B.A.
      • de Leon-Belden L.
      • Stein H.
      Nasal continuous positive airway pressure versus noninvasive NAVA in preterm neonates with apnea of prematurity: a pilot study with a novel approach.
      2020
      NIV-NAVA/NCPAPRetrospective17Preterm infants<1500 gNIV-NAVA level 0 reduced periods of apnea and provide secure back-up rate.
      Gibu et al.,
      • Gibu C.K.
      • Cheng P.Y.
      • Ward R.J.
      • Castro B.
      • Heldt G.P.
      Feasibility and physiological effects of noninvasive neurally adjusted ventilatory assist in preterm infants.
      2017
      NIV-NAVA/NCPAP/HFNC/NIMVProspective pilot11Infants<2200 gNIV-NAVA was a safe, alternative mode that has significant reductions in PIP, FiO2, frequency of desaturations, length of desaturations, and phasic EAdi with no catheter complications.
      Xiao et al.,
      • Xiao S.
      • Huang C.
      • Cheng Y.
      • Xia Z.
      • Li Y.
      • Tang W.
      • et al.
      Application of neurally adjusted ventilatory assist in ventilator weaning of infants ventilator weaning.
      2021
      NAVA/CPAPProspective, crossover25InfantsPaCO2 is normal and not significantly different.

      Ppeak, Pmean, and mean arterial pressure are lower in NAVA.
      Lee et al.,
      • Lee B.K.
      • Shin S.H.
      • Jung Y.H.
      • Kim E.K.
      • Kim H.S.
      Comparison of NIV-NAVA and NCPAP in facilitating extubation for very preterm infants.
      2019
      NIV-NAVA/NCPAPRetrospective32Infants<30wksExtubation failure rate is lower in NIV-NAVA.

      4. NAVA setting and titration in infants

      NAVA involves the use of EAdi for patient-directed ventilatory support. Physicians set NAVA level to determine how much ventilatory support is given. In adults,
      • Lecomte F.
      • Brander L.
      • Jalde F.
      • Beck J.
      • Qui H.
      • Elie C.
      • et al.
      Physiological response to increasing levels of neurally adjusted ventilatory assist (NAVA).
      ,
      • Patroniti N.
      • Bellani G.
      • Saccavino E.
      • Zanella A.
      • Grasselli G.
      • Isgrò S.
      • et al.
      Respiratory pattern during neurally adjusted ventilatory assist in acute respiratory failure patients.
      gradually increasing the NAVA level has been shown to increase the PIP, while keep a constant EAdi until reaching a breakpoint. A subsequent increase in the NAVA level then reduces EAdi while PIP reaches a plateau. Stein, Firestone, and LoVerde
      • Stein H.
      • Firestone K.
      NAVA ventilation in neonates: clinical guidelines and management strategies.
      • Firestone K.S.
      • Fisher S.
      • Reddy S.
      • White D.B.
      • Stein H.M.
      Effect of changing NAVA levels on peak inspiratory pressures and electrical activity of the diaphragm in premature neonates.
      • LoVerde B.
      • Firestone K.S.
      • Stein H.M.
      Comparing changing neurally adjusted ventilatory assist (NAVA) levels in intubated and recently extubated neonates.
      reported that neonates on NAVA and NIV-NAVA have the breakpoints as adults. They also found that premature infants also have intact neural feedback systems to find the breakpoints. The breakpoint is the NAVA level required to unload the respiratory load, a condition which is the same in neonates. With regards to the regulation of NAVA level after extubation to NIV-NAVA, LoVerde et al.
      • LoVerde B.
      • Firestone K.S.
      • Stein H.M.
      Comparing changing neurally adjusted ventilatory assist (NAVA) levels in intubated and recently extubated neonates.
      studied 15 infants for paired titration. Their results showed that the NAVA level increased, PIP plateaued at a higher level, and there was a lesser decrease in EAdi when using NIV-NAVA. The average NAVA level was 1.2 cmH2O/μV in NAVA which increased to 1.6 cmH2O/μV in NIV-NAVA, probably because of the inefficiency of NIV ventilation and leakage compensation. Hence, we suggest increasing the NAVA level 0.5–1.0 cmH2O/μV when weaning patients from NAVA to NIV-NAVA to increase PIP, and then gradually decreasing the NIV-NAVA level to 0 cmH2O/μV (NN0), which is similar to NCPAP. We choose a NIV-NAVA of NAVA level 0 cmH2O/μV (NN0) instead of NCPAP to support extubated premature infants because of the lower extubation failure rate
      • Lee B.K.
      • Shin S.H.
      • Jung Y.H.
      • Kim E.K.
      • Kim H.S.
      Comparison of NIV-NAVA and NCPAP in facilitating extubation for very preterm infants.
      and lower rate of clinically significant events.
      • Firestone K.
      • Horany B.A.
      • de Leon-Belden L.
      • Stein H.
      Nasal continuous positive airway pressure versus noninvasive NAVA in preterm neonates with apnea of prematurity: a pilot study with a novel approach.
      Apnea of prematurity (AOP) in preterm neonates is still a challenging issue. Many physicians stop using NAVA to support premature infants because of clinical deterioration from apnea. Henderson-Smart reported that 85% of preterm neonates born at 30 weeks of gestation and all of those born at <28 weeks of gestation have apnea.
      • Henderson-Smart D.J.
      • Subramaniam P.
      • Davis P.G.
      Continuous positive airway pressure versus theophylline for apnea in preterm infants.
      The first-line treatment for AOP is currently methylxanthines including caffeine citrate, aminophylline and theophylline, followed by NCPAP or NIMV if the apnea remains significant. NCPAP provides constant pressure (5–8 cmH2O) throughout respiration, controlled via a demand-flow system in an expiratory valve
      • DiBlasi R.M.
      Nasal continuous positive airway pressure (CPAP) for the respiratory care of the newborn infant.
      or insertion of expiratory tube under water, to help the spontaneous breathing in premature neonates. However, no extra support is given to the neonate during periods of apnea, increasing susceptibility to clinically significant events such as bradycardia and desaturation. NIV-PS can provide backup ventilation in cases of apnea with no detected flow. However, NIV-PS is unreliable with regards to the trigger of flow, and occasional backup breathing occurs during spontaneous respiration. Furthermore, necessary backup support is not provided by the ventilator in neonates with apnea.
      • Firestone K.
      • Horany B.A.
      • de Leon-Belden L.
      • Stein H.
      Nasal continuous positive airway pressure versus noninvasive NAVA in preterm neonates with apnea of prematurity: a pilot study with a novel approach.
      Hence, a NAVA level of 0 cmH2O/μV during NIV-NAVA (NN0) could be an alternative method to deliver CPAP with backup ventilation in neonates with AOP who fail CPAP.
      • Firestone K.S.
      • Beck J.
      • Stein H.
      Neurally adjusted ventilatory assist for noninvasive support in neonates.
      ,
      • Stein H.
      • Beck J.
      • Dunn M.
      Non-invasive ventilation with neurally adjusted ventilatory assist in newborns.
      Using this method, the neonates receive little support (2cmH2O) above CPAP during spontaneous breathing, and backup ventilation during episodes of apnea. The occurrence of auto triggering has not been reported, since the mechanism of initiation is via neural triggering.
      • Firestone K.
      • Horany B.A.
      • de Leon-Belden L.
      • Stein H.
      Nasal continuous positive airway pressure versus noninvasive NAVA in preterm neonates with apnea of prematurity: a pilot study with a novel approach.
      A set apnea time ensures the ventilated infants have a minimum spontaneous respiratory frequency. Regardless of whether NAVA or NIV-NAVA is used in premature infants, a shorter apnea time may result in more backup ventilation during periods of physiologic variability, leading to overventilation and suppressed spontaneous respiratory drive. A longer apnea time may result in a higher degree of spontaneous respiration, however it can also result in respiratory support insufficiency and more clinically significant events. Morgan
      • Morgan E.L.
      • Firestone K.S.
      • Schachinger S.W.
      • Stein H.M.
      Effects of changes in apnea time on the clinical status of neonates on NIV-NAVA.
      performed a prospective, interventional study of 15 neonates <30 weeks of gestational age receiving NIV-NAVA, and analyzed the ventilator data and clinically significant events for apnea times of 2 s and 5 s for 2 h, respectively. Compared with 5-s, the 2-s apnea time was associated with a higher rate of switching to backup ventilation from 0.5 to 2.5 switches/min (p < 0.001). Furthermore, the time receiving backup ventilation also extended from 2%/min to 9%/min (p < 0.001). However, the number of clinically significant events fell from 7 times/hour to 2 times/hour (p < 0.001). A shorter apnea time led to a higher rate of switching to backup ventilation and a longer duration of backup ventilation, however it also resulted in greater clinical stability. We suggest applying a 2-s apnea time for premature infants <30 weeks of gestational age initially, then increasing the apnea time as the infant grows and matures. If the apnea time can be extended to 5 s, the infant is ready to wean. NAVA ventilation allows the infants to control their PIP and tidal volume for each breath. There are concerns over whether a premature neonate can self-regulate tidal volume (Vt), especially when crying. Nam et al.
      • Nam S.K.
      • Lee J.
      • Jun Y.H.
      Neural feedback is insufficient in preterm infants during neurally adjusted ventilatory assist.
      reported excess variability in PIP and a higher rate of excess Vt with a higher level of NAVA. However, Protain
      • Protain A.P.
      • Firestone K.S.
      • McNinch N.L.
      • Stein H.M.
      Evaluating peak inspiratory pressures and tidal volume in premature neonates on NAVA ventilation.
      et al. reported that the majority of breaths in premature neonates on NAVA were less than 5 ml/kg of Vt or 20 cmH2O of PIP, which are the current recommendations in neonatal guidelines. Although neonates receiving NAVA occasionally take large breaths, we suggest that these may be intermittent signs or recruiting breaths allowing for optimal lung recruitment. Protain did not find excess Vt with a higher level of NAVA, but that a lower Vt was consistent with poor lung compliance. According to these two studies,
      • Nam S.K.
      • Lee J.
      • Jun Y.H.
      Neural feedback is insufficient in preterm infants during neurally adjusted ventilatory assist.
      ,
      • Protain A.P.
      • Firestone K.S.
      • McNinch N.L.
      • Stein H.M.
      Evaluating peak inspiratory pressures and tidal volume in premature neonates on NAVA ventilation.
      an excessively high NAVA level (>4 cmH2O/μV) is still not suggested. A letter to the editor
      • Bridier A.
      • François T.
      • Baudin F.
      • Emeriaud G.
      Neural feedback is effective in preterm infants during neurally adjusted ventilatory assist, when using clinically relevant settings.
      also pointed out that a NAVA level >2.5 cmH2O/μV is possibly excessive and provides over assistance for premature infants.

      5. EAdi monitoring the vital signs of a patient

      Without EAdi there is no NAVA. NAVA uses the EAdi waveform to provide ventilated patients with synchronized and proportional support with invasive and non-invasive interfaces. A patients’ neural respiratory drive and breathing pattern can be monitored as a vital sign via the EAdi waveform. An increase in EAdi may indicate that the patient is not receiving adequate assistance, that there is inadequately low PEEP, worsened disease condition, agitation, or that the patient is not ready for a support ventilation mode. A decrease in EAdi may represent that the patient is receiving too much assistance, that there is a high sedation level, phrenic nerve injury, abdominal distention, or long-term conventional mode use with poor diaphragm drive. EAdi monitoring can provide clinicians with a continuous evaluation of the intensity and frequency of diaphragm activity. Iyer et al.
      • Iyer N.P.
      • Dickson J.
      • Ruiz M.E.
      • Chatburn R.
      • Beck J.
      • Sinderby C.
      • et al.
      Neural breathing pattern in newborn infants pre-and postextubation.
      analyzed the EAdi values before and after extubation to predict the successful extubation rate in infants, and found that EAdi peak and ΔEAdi increased after extubation in both successful and failure extubation groups. Failed extubation was associated with a smaller increase in EAdi peak and ΔEAdi after extubation. Amigoni et al.
      • Amigoni A.
      • Rizzi G.
      • Divisic A.
      • Brugnaro L.
      • Conti G.
      • Pettenazzo A.
      Effects of propofol on diaphragmatic electrical activity in mechanically ventilated pediatric patients.
      used EAdi monitoring to investigate the effects of a bolus of propofol (1 mg/kg) on the magnitude of respiratory depression in children. They found a significantly different distribution frequency of EAdi values before and after the administration of propofol, with a mean decrease of 32%. Via EAdi monitoring, physicians can understand the degree and duration of respiration depression. With NAVA, a depression in EAdi triggers backup ventilation to prevent desaturation. The continuous monitoring of spontaneous breathing provided by the EAdi signal allows for more accurate adjustments of sedation dose, thus improves patient safety and reduced the amount of sedation used. Snow et al.
      • Snow T.M.
      • Brinck M.J.
      Assessing the response to inhaled albuterol by monitoring patient effort-related trends with a servo-I ventilator in neurally adjusted ventilatory assist mode: a case presentation.
      assessed the response to inhaled albuterol in infants with chronic lung disease by monitoring EAdi peak, EAdi min, peak pressure, mean pressure, respiratory rate, and end expiratory flow (Vee). After inhalation, the EAdi peak decreased from 38 to 10 μV, and the respiratory rate decreased from 70 to 48 breaths per minute. EAdi monitoring can therefore show whether a drug is effective or not, and provide information on adjusting the dose, frequency and when to discontinue treatment. Baudin et al.
      • Baudin F.
      • Emeriaud G.
      • Essouri S.
      • Beck J.
      • Portefaix A.
      • Javouhey E.
      • et al.
      Physiological effect of prone position in children with severe bronchiolitis: a randomized cross-over study (BRONCHIO-DV).
      used EAdi to evaluate the benefits of the prone position in infants with severe bronchiolitis requiring noninvasive ventilation. Their results showed that the prone position significantly decreased the inspiratory effort (EAdi max) and the metabolic cost of breathing (△EAdi). Lee et al.
      • Lee J.
      • Parikka V.
      • Lehtonen L.
      • Soukka H.
      Parent–infant skin-to-skin contact reduces the electrical activity of the diaphragm and stabilizes respiratory function inpreterm infants.
      used EAdi monitoring to investigate the effect of skin-to-skin contact (SSC) on respiratory stabilization in premature infants. During NAVA and NIV-NAVA, EAdi peak, EAdi min, respiratory rate, time on backup ventilation, and PIP were all significantly lower in SSC than in incubator care.
      EAdi monitoring can inform physicians about whether the diaphragm keeps moving under mechanical ventilation and to adjust the settings accordingly to prevent excessive or insufficient support. In addition, a smaller increase in EAdi peak and ΔEAdi after extubation suggests that the patient may need more respiratory support. Moreover, precise procedural sedation with an acceptably lower EAdi signal can decrease the need for sedation. Lastly, medical treatment such as the prone position or nebulizer therapy can be evaluated via the change in EAdi. The EAdi signal can provide a personalized neural control mode, and also continuous vital sign monitoring to more precisely evaluate the patient's status.

      6. Conclusions

      EAdi monitoring is an important physiological indicator which can be used to assess an infant's breathing status in real time and continuously, allowing physicians to understand changes in respiratory work and diaphragm status, assess the extubation timing/re-intubation needs, and sedative dosage for pain. NAVA is currently the only mode which can provide personalized ventilation according to the demands of each breath. Compared to conventional ventilation mode, it can effectively improve patient-ventilator synchrony, increase oxygenation, reduce FiO2 requirements, lower PIP and tidal volume, provide better comfort, reduce sedative use, reduce the number of days in hospital, and reduce the incidence of apnea/bradycardia/cyanosis. When using NAVA in premature infants, we recommend the following settings: NAVA level <2.5 cmH2O/μV; upper pressure limit at 5cmH2O above measured PIP of the patient and <35–40 cmH2O (=PIP 30–35 cmH2O) as possible; apnea time 2 s which can be extended to 5 s as the patient's condition improves. After extubation, a NIV-NAVA level of 0 can be used as a substitute for NCPAP, and studies have confirmed that it can reduce apnea and increase the success rate of extubation. The NAVA setting and titration in infants seem complicated. As a matter of fact, it is simple. We designed a flow sheet (Fig. 1) to make it easier for the readers to understand.
      Fig. 1
      Fig. 1Flow sheet of NAVA setting and titration in infants.

      Declaration of competing interest

      The authors have no conflicts of interest relevant to this article.

      Abbreviations

      NAVA
      neurally adjusted ventilatory assist
      VLBWIs
      very low birth weight infants
      NICU
      neonatal intensive care unit
      CMV
      conventional mandatory ventilator
      EAdi
      electrical activity of diaphragm
      PEEP
      positive end-expiratory pressure
      PIP
      peak inspiratory pressure
      NIV
      non-invasive ventilation
      NCPAP
      nasal continuous positive airway pressure
      NIV-PS
      non-invasive pressure support
      NIMV
      non-invasive mandatory ventilation
      SIMV
      synchronized intermittent mandatory ventilation

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