Neurally Adjusted Ventilatory assist (NAVA) in Preterm Newborn Infants with Respiratory Distress Syndrome—a Randomized Controlled Trial

Neurally adjusted ventilatory assist (NAVA) in preterm newborn
infants with respiratory distress syndrome—a randomized
controlled trial
Merja Kallio1,2 & Ulla Koskela1,2 & Outi Peltoniemi1,2 & Tero Kontiokari 1 &
Tytti Pokka1,2 & Maria Suo-Palosaari3,4 & Timo Saarela1,2
Received: 18 April 2016 /Revised: 11 July 2016 /Accepted: 29 July 2016 /Published online: 9 August 2016
# Springer-Verlag Berlin Heidelberg 2016
Abstract Neurally adjusted ventilatory assist (NAVA) improves
patient-ventilator synchrony during invasive ventilation
and leads to lower peak inspiratory pressures (PIP)
and oxygen requirements. The aim of this trial was to
compare NAVA with current standard ventilation in preterm
infants in terms of the duration of invasive ventilation.
Sixty infants born between 28 + 0 and 36 + 6 weeks
of gestation and requiring invasive ventilation due to neonatal
respiratory distress syndrome (RDS) were randomized
to conventional ventilation or NAVA. The median
durations of invasive ventilation were 34.7 h (quartiles
22.8–67.9 h) and 25.8 h (15.6–52.1 h) in the NAVA and
control groups, respectively (P = 0.21). Lower PIPs were
achieved with NAVA (P = 0.02), and the rapid reduction
in PIP after changing the ventilation mode to NAVA made
following the predetermined extubation criteria challenging.
The other ventilatory and vital parameters did not
differ between the groups. Frequent apneas and persistent
pulmonary hypertension were conditions that limited the
use of NAVA in 17 % of the patients randomized to the
NAVA group. Similar cumulative doses of opiates were
used in both groups (P = 0.71).
Conclusions: NAVA was a safe and feasible ventilation
mode for the majority of preterm infants suffering from
RDS, but the traditional extubation criteria were not clinically
applicable during NAVA.
What is known:
• NAVA improves patient-ventilator synchrony during invasive
• Lower airway pressures and oxygen requirements are achieved with
NAVA during invasive ventilation in preterm infants by comparison with
conventional ventilation.
What is new:
• Infants suffering from PPHN did not tolerate NAVA in the acute phase of
their illness.
• The traditional extubation criteria relying on inspiratory pressures and
spontaneous breathing efforts were not clinically applicable during
Keywords Edi signal . Invasive ventilation . NAVA .
Neonate . Preterm infant . Respiratory distress
Revisions received: 22 May 2016; 12 July 2016
Communicated by Patrick Van Reempts
* Merja Kallio
Ulla Koskela
Outi Peltoniemi
Tero Kontiokari
Tytti Pokka
Maria Suo-Palosaari
Timo Saarela
1 PEDEGO Research Unit, Medical Research Center Oulu, University
of Oulu, Oulu, Finland
2 Department of Children and Adolescents, Oulu University Hospital,
BOX 5000, FIN-90014 Oulu, Finland
3 Medical Research Center Oulu, University of Oulu, Oulu, Finland
4 Department of Diagnostic Radiology, Oulu University Hospital and
University of Oulu, Oulu, Finland
Eur J Pediatr (2016) 175:1175–1183
DOI 10.1007/s00431-016-2758-y
ABG Arterial blood gas
BPD Bronchopulmonary dysplasia
Edi Electrical activity of the diaphragm
GA Gestational age
HFOV High-frequency oscillatory ventilation
IUGR Intrauterine growth retardation
LMM Linear mixed model
MAP Mean airway pressure
MED Morphine equivalent dose
NAVA Neurally adjusted ventilatory assist
NICU Neonatal intensive care unit
NIV Non-invasive ventilation
OI Oxygenation index
PC Pressure-controlled ventilation
PEEP Positive end-expiratory pressure
PIP Peak inspiratory pressure
PPHN Persistent pulmonary hypertension of the newborn
RDS Respiratory distress syndrome
TV Tidal volume
Respiratory distress syndrome (RDS), caused by lung immaturity
and surfactant deficiency, is the leading cause of neonatal
morbidity in preterm infants. Despite an increasing desire
to use non-invasive ventilatory support, RDS still remains the
main reason for invasive ventilation in neonates [12, 15, 19,
28]. Although mechanical ventilation is often life-saving, it
carries the risk of causing additional lung injury and plays a
role in the progression of bronchopulmonary dysplasia (BPD)
in markedly preterm infants [13].
The risk of ventilator-induced lung injury may be reduced
by using small tidal volumes, ensuring an adequate level of
positive end-expiratory pressure (PEEP) and synchronizing
the support with the patient’s spontaneous breaths [5, 22,
27]. Small tidal volumes, high breathing frequency, and the
use of uncuffed intubation tubes causing an air leak from the
circuit pose challenges for optimizing ventilation in a neonatal
population. Consequently, pneumatic triggers are suboptimal
in this group of patients [5]. Neurally adjusted ventilatory
assist (NAVA) provides ventilatory support proportional to
the electrical activity of the patient’s diaphragm (Edi) and
enables physiological variations in both tidal volume and inspiratory
time [23]. NAVA has been shown to reduce the work
of breathing and improve patient-ventilator synchrony in neonates,
resulting in lower peak inspiratory pressures (PIP) and
oxygen requirements than with conventional ventilation [2,
16, 24, 25]. NAVA is increasingly being used in neonatal
intensive care units, but data concerning its impact on clinical
outcomes in preterm population are sparse [1].
The aim of this trial was to compare NAVAwith the current
standard ventilation in preterm infants born between 28 + 0
and 36 + 6 weeks of gestation and requiring invasive ventilation
due to RDS. We hypothesized that the use of NAVA
ventilation would reduce the duration of mechanical
Materials and methods
All preterm infants born at Oulu University Hospital between
28 + 0 and 36 + 6 weeks of gestation, who required invasive
ventilation for at least 4 h due to RDS, were eligible for this
trial. Neonates with a known defect of the diaphragm and
those who were unable to receive a nasogastric or orogastric
tube due to congenital anomalies were excluded, as were patients
suffering from severe perinatal asphyxia (pH <7.0 or
signs of hypoxic-ischemic encephalopathy) or known chromosomal
abnormalities. Written informed consent was obtained
from a parent or legal guardian before performing any
procedures related to this trial. The patients were enrolled at
the neonatal (NICU) and pediatric intensive care units (PICU)
of Oulu University Hospital, Finland, from July 2010 to
May 2013. The Identifier for this study is
The sample size was calculated based on the Finnish
National Institute for Health and Welfare database information
concerning the duration of invasive ventilation among preterm
infants. The mean duration of invasive ventilation among infants
born at 32 + 0 weeks during the years 2005 and 2006 was
38.4 h, with a standard deviation (SD) of 15.6 h. We considered
a reduction of 12 h clinically significant. With α = 0.05
and a power of 0.8, the calculated sample size was 54 (27
patients/group). To ensure this number in the final analysis,
60 patients were recruited. A stratified randomization was
used to evenly allocate neonates below and above 32 weeks
of gestation to the NAVA and control groups for invasive
ventilation. A computerized random number generator was
used for randomization and each group code was sealed in
an opaque envelope that was opened after written informed
consent had been received. The protocol was approved by the
Research Ethics Committee of the Northern Ostrobothnia
Health Care District.
Detailed patient characteristics are shown in Table 1.
All the patients were invasively ventilated using a Servo-i
ventilator, versions 4.0 to 6.1 (Maquet Nordic, Solna,
Sweden). An Edi catheter was inserted for the patients
randomized to the NAVA group as soon as the procedures
required on arrival (intravenous and intra-arterial lines,
thorax x-ray, surfactant treatment if not given in the delivery
room) had been performed and a stable clinical
condition had been achieved so that changing a nasogastric
tube was not expected to cause significant