Clinical and technical evidence

Advice

Published evidence
Overall assessment of the evidence
Recent and ongoing studies

Clinical and technical evidence

A literature search was carried out for this briefing in accordance with the interim process and methods statement. This briefing includes the most relevant or best available published evidence relating to the clinical effectiveness of the technology. Further information about how the evidence for this briefing was selected is available on request by contacting mibs@nice.org.uk.

Published evidence

There are 4 studies summarised in this briefing: 1 systematic review, which includes 16 published studies, 2 randomised controlled crossover trials and a randomised controlled trial. A total of 415 babies and children were included in the studies.

Table 1 summarises the clinical evidence as well as its strengths and limitations.

Overall assessment of the evidence

In general, the evidence shows that the Servo‑i and Servo‑n with NAVA improves patient-ventilator synchrony in babies and children. One study showed that there is some reduction in intensive care unit stay associated with NAVA use. A limitation of the evidence is that the available studies report different short-term outcomes and there is no resource consequence information. All of the trials have relatively small numbers of people in the trial. One study done in the UK used Servo‑n. A substantial number of ongoing studies were identified that are expected to improve the evidence base.

Table 1 Summary of selected studies

Beck et al. (2016)
Study size, design and location	Systematic review of 16 published studies in 218 babies and children.
Intervention and comparator(s)	Intervention: Servo‑i with NAVA and NIV NAVA. Comparator: conventional ventilation.
Key outcomes	There were no reports of complications relating to catheter insertion or the use of NAVA. Bedside monitoring of Edi is a beneficial tool for assessing diaphragm function, clinical interventions and decision support. Some studies showed that NAVA may improve patient comfort, reduce the length of stay on PICU and reduce the amount of sedatives used. Patient-ventilator synchrony was improved in both invasive and non‑invasive NAVA compared with conventional ventilation.
Strengths and limitations	The studies in this systematic review used Servo‑i, which is a previous version of Servo‑n. The company has confirmed the Servo‑n is a newly released version of the Servo‑i with mainly enhanced or new features, therefore evidence on Servo‑i is likely to be generalisable to the Servo‑n. No PRISMA diagram was used to clearly display the included, excluded studies. The quality of the included studies is not clear. A meta-analysis was not done and no reason given. People in the trial were only monitored while they were on the ventilators; no long-term outcome data has been reported. Two of the authors have patents related to neural control of mechanical ventilation where future commercial use of the technology may provide financial benefit.
Chidini et al. (2016)
Study size, design and location	Prospective randomised crossover physiological study in a 6 bed PICU in Italy. 18 children aged 2 to 24 months (mean 13 months) with acute respiratory failure needing NIV ventilation.
Intervention and comparator(s)	Intervention: Servo‑i with NAVA. Comparator: NIV pressure support and NIV flow-triggered pressure support.
Key outcomes	NAVA showed a statistically significant reduction in the Asynchrony Index (p=0.001) and ineffective breathing efforts (p=0.001) compared with flow-triggered pressure support. NAVA had an increased neuroventilatory efficiency index (p=0.001), which the authors suggested could mean improved neuroventilatory coupling.
Strengths and limitations	This study used Servo‑i, which is a previous version of Servo‑n. The company has confirmed the Servo‑n is a newly released version of the Servo‑i with mainly enhanced or new features, therefore evidence on Servo‑i is likely to be generalisable to the Servo‑n. Because of the crossover design, each participant acted as their own control, reducing variability between people in the trial. People were only monitored for 2 hours while they were on the ventilators; no long-term outcome data are reported.
Shetty et al. (2017)
Study size, design and location	Randomised crossover study at Kings College, London assessing oxygenation. 9 babies born at less than 32 weeks gestation who were still ventilated at 1 week of age were included.
Intervention and comparator(s)	Intervention: Servo‑n in with NAVA. Comparator: ACV.
Key outcomes	The Servo‑n in NAVA mode provided improved oxygenation compared with ACV (mean oxygenation index NAVA 7.92 compared with ACV 11.06, p=0.0007).
Strengths and limitations	Because of the crossover design, each participant acted as their own control, therefore reducing variability between people in the trial. The same ventilator was used for both treatment modes, therefore the results show differences in the modes and not the ventilator. People were only monitored for 2 hours while they were on the ventilators; no long-term outcome data has been reported. One of the authors has held grants from various ventilator manufacturers and has received honoraria for giving lectures and advising them.
Kallio et al. (2015)
Study size, design and location	170 babies in intensive care in a randomised controlled trial in Finland.
Intervention and comparator(s)	NAVA. Current standard of care ventilation.
Key outcomes	The median time on the ventilator was lower in the NAVA group compared with standard ventilation (3.3 hours compared with 6.6 hours, p=0.17). The length of stay in the intensive care unit was lower in the NAVA group compared with standard ventilation (49.5 hours compared with 72.8 hours, p=0.10). This difference was more significant when analysed per protocol (p=0.03). The amount of sedation needed was similar across both groups (p=0.20), however, when post-operative babies were excluded (77.6% babies in NAVA group and 76.5% babies in standard ventilation group), sedation needed was significantly lower in the NAVA group compared with standard ventilation (0.80 compared with 2.23 units/hour, p=0.03). Oxygenation index was significantly lower in the NAVA group compared with the standard ventilation group (p=0.002). Peak inspiratory pressure and inspired oxygen fraction was significantly lower in the NAVA group compared with standard ventilation (p=0.001 for both). Arterial blood CO₂ tensions were slightly higher in the NAVA group at the beginning of treatment and lower levels after 32 hours (p=0.008). There were no other significant differences in ventilator or vital parameters, arterial blood gas values and complications were similar between the 2 groups.
Strengths and limitations	This study was funded by a Finnish academic institution and the authors disclose no manufacturer interests. Most babies included in this study were recovering from operations and only needed ventilation for a short time. This was usually determined by the anaesthesia and sedatives that had been given in the operating theatre. Blinding of investigators was not possible in this trial, which may have led to some bias.
Abbreviations: ACV: assist control ventilation, Edi: diaphragm electrical activity, NAVA: neutrally adjusted ventilatory assist, NIV: non‑invasive, NICU: neonatal intensive care unit, PICU: paediatric intensive care unit.

Recent and ongoing studies

There were 5 randomised clinical trials identified:

Optimisation of Neonatal Ventilation – NAVA vs PAV (UK study). ClinicalTrials.gov identifier: NCT02967549. Status: ongoing but not recruiting. Indication: children up to 1 year old with bronchopulmonary dysplasia. Devices: NAVA delivered by the Servo‑n ventilator, PAV (proportional assist ventilation) delivered by the Stephanie ventilator. Primary outcome measure: oxygenation index.
Neurally Adjusted Ventilatory Assist (NAVA) Versus Conventional Biphasic Positive End Expiratory Pressure (BiPAP) Non\u2011\invasive Respiratory Support in Infants Following Congenital Heart Surgery (US study). ClinicalTrials.gov identifier: NCT03180385. Status: recruiting (enrolment target: 40). Indication: children up to 1 year old with respiratory failure. Devices: NAVA, Biphasic Positive Airway Pressure Support (BiPAP). Primary outcome measures: post-operative pain/sedation medication dose, post-operative pain scores-FLACC, post-operative sedation scores-SBS, length of intubation, length of non‑invasive respiratory support.
Comparison of Primary Extubation Failure Between Non\u2011\invasive Positive Pressure Ventilation (NIPPV) and Non Invasive Neural Access Ventilatory Assist (NI\u2011\nAVA) (US study). ClinicalTrials.gov identifier: NCT03242057. Status: recruiting (enrolment target: 30). Indication: pre-term babies with bronchopulmonary dysplasia. Devices: NAVA, NIPPV. Primary outcome measure: extubation success.
Noninvasive NAVA Versus NIPPV in Low Birthweight Premature Infants (US study). ClinicalTrials.gov identifier: NCT03137225. Status: recruiting (enrolment target: 15). Indication: low birth weight premature infants who need respiratory support via non‑invasive ventilation. Devices: NAVA, NIPPV. Primary outcome measure: number of unexpected events.
Non\u2011\invasive Neurally Adjusted Ventilatory Assist Versus nCPAP or Non Synchronized NIPPV in Preterm Infants Under 32 Weeks Gestational Age: A Randomized Clinical Trial (Spanish study). ClinicalTrials.gov identifier: NCT02860325. Status: completed. 56 people recruited. Indication: babies with respiratory distress syndrome. Devices: NIV NAVA delivered by the Servo‑n ventilator, NIV delivered by nCPAP or non-synchronised NIPPV. Primary outcome measure: survival without moderate or severe bronchopulmonary dysplasia.