Post on 23-Mar-2023
Universität Ulm
Klinik für Kinder- und Jugendmedizin
Prof. Dr. Klaus-Michael Debatin
Sektion Neonatologie und Pädiatrische Intensivmedizin
Sektionsleiter: Prof. Dr. Helmut D. Hummler
Non-invasive Intermittent Mandatory Ventilation in Preterm Infants with Respiratory Distress Syndrome Immediately after Extubation: a
Controlled Study on Synchronized Non-invasive Mechanical Ventilation and Review of the Literature
Dissertation
for the attainment of the
Doctoral Degree of Medicine
at the Faculty of Medicine, University of Ulm
Presented by Li Huang
born in Jinxian, Jiangxi Province, P. R. China
2014
Amtierender Dekan: Thomas Wirth
1. Berichterstatter: Hummler D Helmut
2. Berichterstatter: Calzia Enrico
Tag der Promotion: 24.10.2014
Contents
I
TABLE OF CONTENTS
List of abbreviations ......................................................................................................................III
1. Introduction ...........................................................................................................................1
1.1 Respiratory distress syndrome (RDS) ....................................................................................2
1.2 Broncho-Pulmonary Dysplasia (BPD).....................................................................................4
1.2.1 Definition and pathogenesis of BPD ...............................................................................4
1.2.2 Risk factors for BPD .......................................................................................................8
1.2.3 Comprehensive management of BPD .............................................................................8
1.3 Complications with invasive mechanical ventilation .............................................................9
1.4 Synchronized invasive mechanical ventilation ....................................................................11
1.5 Non-invasive ventilation .....................................................................................................14
1.5.1 Nasal positive continuous airway pressure (NCPAP) .....................................................14
1.5.2 Nasal intermittent positive pressure ventilation (NIPPV) ..............................................17
1.5.3 Synchronized nasal intermittent positive pressure ventilation (SNIPPV) .......................19
1.5.4 Possible advantages of SNIPPV ....................................................................................23
1.6 Near-infrared spectroscopy (NIRS)......................................................................................25
1.7 Hypothesis and aims ..........................................................................................................27
2. Materials and Methods ............................................................................................................29
2.1 Population..........................................................................................................................29
2.2 Design of the study.............................................................................................................29
2.3 Sample size calculation .......................................................................................................29
2.4 Study procedures ...............................................................................................................30
2.5 Measurements ...................................................................................................................33
2.5.1 Vital signs and gas exchange ........................................................................................33
2.5.2 Work of breathing .......................................................................................................35
2.5.3 Cerebral Oxygen Saturation .........................................................................................35
2.6 Data analysis ......................................................................................................................35
2.7 Statistical analysis...............................................................................................................36
3. Results .....................................................................................................................................37
3.1 Clinical variables .................................................................................................................37
Contents
II
3.2 Results of measurements ...................................................................................................41
4. Discussion ................................................................................................................................46
5. Summary..................................................................................................................................56
6. References ...............................................................................................................................59
7. Curriculum vitae .......................................................................................................................73
8. Acknowledgments ....................................................................................................................75
Abbreviations
III
List of abbreviations
ACV assist-control ventilation
AOP apnea of prematurity
ASD atrial septal defect
BP blood pressure
BPD Broncho-Pulmonary Dysplasia
BPM beats per minute
BW birth weight
CNS central nervous system
CPAP continuous positive airway pressure
ETT Endotracheal tube
FiO2 fraction of inspired oxygen
FTOE fractional tissue oxygen extraction
GA gestational age
HFOV high frequency oscillatory ventilation
HR heart rate
ICH intracranial hemorrhage
IMV intermittent mandatory ventilation
MAP mean airway pressure
NEC necrotizing enterocolitis
NIMV non-synchronized nasal IMV
Abbreviations
IV
NIPPV nasal intermittent positive pressure ventilation
NIRS near-infrared spectroscopy
NIV non-invasive ventilation
PAW airway pressure
PCO2 partial pressure of carbon dioxide
PDA patent ductus arteriosus
Pe deflection of esophageal pressure
PEEP positive end-expiratory pressure
PIP peak inspiratory pressure
PMA postmenstrual age
PO2 partial pressure of oxygen
PVL periventricular leukomalacia
RDS respiratory distress syndrome
RCT randomized control trial
ROP retinopathy of prematurity
RR respiratory rate
rSO2 regional cerebral oxygen saturation
S-NIMV synchronized nasal IMV
SNIPPV synchronized nasal intermittent positive
pressure ventilation
SpO2 oxyhemoglobin saturation by pulse oximetry
VAP ventilator associated pneumonia
Abbreviations
V
VILI ventilation induced lung injury
VLBWI very low birth weight infants
VSD ventricular septal defect
VTV volume-targeted ventilation
WOB work of breathing
g gram
d day
hr hour
Sec seconds
Introduction
1
1. Introduction
More and more very preterm infants survive because of improvements in neonatal
care, such as the development of new ventilation techniques and the use of pulmonary
surfactant. However, very immature preterm infants have a high risk for mortality and
especially morbidity, which may have a major impact on their quality of life. The most
common acute respiratory disease during early life for very immature infants is respiratory
distress syndrome (RDS). Treatment includes respiratory support and pulmonary
surfactant replacement therapy. One of the most common chronic conditions is
broncho-pulmonary dysplasia (BPD), which is often associated with further admissions to
hospitals because of respiratory problems during later life.
Mechanical invasive ventilation is often a life-saving support for very immature
infants whose respiratory drive is not sufficient, and whose respiratory muscles are not
strong enough. However, it also may cause complications such as acute or chronic trauma
to the upper and lower airways, subglottic stenosis, BPD, ventilator associated pneumonia
(VAP), inadvertent hypocapnia and other sequelae. Thus, in order to reduce complications
of invasive mechanical ventilation, non-invasive ventilation i.e. nasal ventilation is
increasingly being used in those fragile infants. In the last 4 decades, nasal continuous
positive airway pressure (NCPAP) has been used more and more as a primary method of
respiratory support (Gregory et al., 1971) or as a “bridge” after extubation from
mechanical ventilation to provide non-invasive respiratory support in preterm infants.
However, NCPAP alone may not provide sufficient respiratory support for all preterm
infants with respiratory failure. Efforts to reduce extubation failure prompted the use of
nasal intermittent positive pressure ventilation (NIPPV), which has been found to be
associated with advantages as compared to NCPAP in preventing extubation failure
(Barrington et al., 2001; Davis et al., 2001; Moretti et al., 1999) or as a primary mode of
respiratory support in premature infants with RDS to avoid endotracheal intubation and
mechanical ventilation (Kugelman et al., 2007).
Introduction
2
1.1 Respiratory distress syndrome (RDS)
Neonatal respiratory distress syndrome (RDS) also called Hyaline-Membrane-Disease
(HMD) is one of the most common acute lung diseases in preterm infants especially with a
gestational age less than 35 weeks. It is more frequent in infants born with less than 28
weeks’ gestation. The incidence of RDS is inversely related to both increasing gestational
age and birth weight (Figure1). It is reported that RDS affects one third of preterm infants
born at 28 to 34 weeks gestation, but occurs in less than 5 percent of those born after 34
weeks. The incidence of RDS is as high as 50% of infants with birth weight between
501-1500g (Lemons et al., 2001). Infants born before 29 weeks of gestation have a 60
percent risk to develop RDS (Robertson et al., 1992). Full-term infants rarely develop this
condition. Premature birth is the main cause of neonatal RDS.
Among preterm infants, the risk of developing RDS is increased with Caucasian race,
male sex (Ingemarsson, 2003), cesarean delivery, perinatal asphyxia (Altman et al., 2013),
and maternal diabetes (Bye et al., 1980; Robert et al., 1976). RDS is correlated with
structural and functional lung immaturity. The pathophysiology of RDS in preterm infants
is very complex. In 1959, Mary Ellen Avery and Jere Mead demonstrated that surfactant
deficiency was a key feature in the pathogenesis of neonatal RDS (AVERY and MEAD,
1959). Immature type II alveolar cells produce an insufficient amount of surfactant,
resulting in an increase in alveolar surface tension and decreased compliance, leading to
the collapse of the alveoli and atelectasis and reduced functional residual capacity (FRC).
In addition, immature respiratory drive and a highly compliant chest wall of preterm
infants may aggravate symptoms of preterm infants with RDS.
The clinical manifestation of RDS includes tachypnea, cyanosis, grunting, inspiratory
stridor, nasal flaring, cyanosis, and poor feeding. There might be retractions of the
intercostal, subcostal, or suprasternal spaces. Chest radiography shows reduced lung
volume and reduced transparency of both lungs with ground-glass appearance and
presence of bilateral air bronchograms, while completely white lungs might be seen in the
Introduction
3
most severely affected patients (Gibson and Steiner, 1997).
Standard therapeutic interventions for preterm infants with RDS include surfactant
replacement therapy, NCPAP and various modalities of respiratory mechanical support
and other supportive measures. Among those treatment modalities, surfactant
replacement therapy is critically important in many preterm infants with RDS, but the best
preparation, optimal dose and timing of administration at different gestational ages, and
prophylactic or rescue use are still subject of debates (Sweet et al., 2013). Despite
improvements in care, RDS remains one of the most common causes of death in the first
month of life in the industrialized world (Hermansen and Lorah, 2007).
In infants with more severe RDS and with more progressive severity of the disease,
patients may develop apnea and respiratory failure, requiring supplemental oxygen and
mechanical ventilation. Although respiratory support with invasive mechanical ventilation
might be lifesaving, it may simultaneously cause lung injury. The use of mechanical
ventilation often results in barotrauma, volutrauma resulting in chronic lung injury and
BPD (Ramanathan, 2010). More recently, treatment of RDS by means of NCPAP or nasal
ventilation after exogenous surfactant is more commonly used in order to reduce injury
from mechanical ventilation (Sweet et al., 2013). The introduction of antenatal steroids
for acceleration of lung maturity (Roberts and Dalziel, 2006) and the administration of
exogenous surfactants (Long et al., 1991) dramatically improved the outcomes of preterm
infants with RDS. However, the early administration of surfactant has not reduced the
incidence of BPD perhaps because very preterm infants who might not have survived
without surfactant replacement therapy do now survive and subsequently develop BPD.
Therefore, the development of BPD remains a substantial problem at present.
Introduction
4
Figure 1: Incidence of RDS in the United States relative to birth weight, which shows that it is more common with low birth weight. Horbar JD, arpenter JH, Kenny M,eds. Vermont Oxford Network 2002 Very Low Birth Weight Database Summary. Burlington, VT: Vermont Oxford Network; 2003.
1.2 Broncho-Pulmonary Dysplasia (BPD)
1.2.1 Definition and pathogenesis of BPD
BPD is the most common chronic respiratory condition that in the majority of cases
result from complications related to lung injury occurring during the care and treatment of
preterm infants with RDS. In 1967, at the Stanford Premature Infant Research Center,
Northway et al first described the disease, which occurred in preterm infants with RDS
after mechanical ventilation and oxygen supplementation (Northway et al., 1967). What is
now considered as the “old” broncho-pulmonary dysplasia (BPD) was initially described as
characteristic radiographic pulmonary changes in slightly preterm infants of gestational
age more than 32 weeks with RDS showing chronic respiratory failure, who had been
treated by invasive mechanical ventilation and high concentrations of inspired oxygen
(FiO2).
Introduction
5
Although BPD is most often associated with prematurity, it can also occur in full-term
infants who need invasive mechanical respiratory support for severe, acute lung disease
(Kinsella et al., 2006). With the improvement of perinatal care, especially by means of
antenatal steroids, surfactants, and gentle ventilation, more and more very immature
infants with 23-28 weeks’ gestational age and with RDS can survive and may develop a
“new form of BPD”, where respiratory symptoms and chest x-ray findings are less severe
as compared with those with the “old form of BPD”. The pathology and the severity of
“new BPD” are obviously different from “old BPD”. In preterm infants, the lungs are often
exposed to injury, both before and after birth. Such exposure and probable genetic
predisposition (Kwinta et al., 2008) might lead to direct upper and lower airway and
alveolar damage and cause abnormal development in the fragile immature lung.
Depending on the timing and extent of the exposures, lung injury may range from early
developmental arrest (new form of BPD) to severe structural damage of a slightly
premature lung (old form of BPD) (Figure 2) (Baraldi and Filippone, 2007).
Figure 2: Stages of lung development, potentially damaging factors, and types of lung injury in premature infants born at a gestational age of 23 to 30 weeks (region shaded light red) — during the canalicular and saccular stages of lung development — are at the greatest risk for BPD (Baraldi and Filippone, 2007).
Introduction
6
This “old” form of BPD was characterized by extensive inflammatory and fibrotic
changes in the airway and lung parenchyma due to the injury from invasive mechanical
ventilation and inspired high concentration oxygen before the era of surfactant
replacement treatment (Northway et al., 1967). However, the “new” form of BPD often
develops in more extreme immature infants with extremely low birth weight who
received surfactant, and needed only minor initial respiratory support or supplemental
oxygen during early course of the disease (Philip, 2012; Rojas et al., 1995).
The lung histology of preterm infants with new form of BPD shows pulmonary
developmental arrest with abnormal alveolarization and dysmorphic vascular growth with
a decrease in pulmonary microvasculature (Bhandari and Bhandari, 2009). The
inflammation and fibrosis in the lung of the new form of BPD is less prominent compared
with that in the old form of BPD (Coalson, 2006). This new presentation caused some
inconsistencies and confusion in the definition of BPD. That is still not in consensus in the
diagnostic criteria for BPD among neonatal intensive care units (NICUs) and in the
literature (Bancalari et al., 2003). The main problem with the definition of BPD is that, in
one hand, supplemental oxygen is an important treatment in the management of these
infants; while on the other hand, oxygen plays an important role in the pathogenesis of
BPD. Moreover, some therapeutic strategies such as steroids, diuretics, and respiratory
stimulants (caffeine), and mechanic respiratory support i.e. continuous positive airway
pressure (CPAP) or nasal intermittent mandatory ventilation (NIPPV) may influence the
need for oxygen in these infants (Bancalari and Claure, 2006).
To provide a uniform of BPD definition a consensus conference of the US National
Institutes of Health (NIH) was sponsored in 2000 and the experts in the field came up with
a new definition which nowadays is used widely around the world (Jobe and Bancalari,
2001). It is based on the need for supplemental oxygen for at least 28 days after birth, and
its severity is categorized according to the ventilation support and oxygen demand at 36
postmenstrual age (PMA) weeks. Mild BPD was defined as a need for supplemental
oxygen (O2) for at least 28 days but not at 36 weeks’ postmenstrual age (PMA) or
Introduction
7
discharge, moderate BPD as O2 for ≥28 days plus treatment with <30% O2 at 36 weeks’
PMA, and severe BPD as O2 for ≥28 days plus ≥30% O2 and/or positive pressure at 36
weeks’ PMA. This consensus definition of BPD incorporates many parameters of previous
diagnostic criteria.
To reduce the influence of different strategies for oxygen supplementation on the
reported incidence of BPD, BPD nowadays is defined using a so-called ‘‘physiological
definition’’ (as described by Walsh –Sukys et al, which means that the preterm infants at
36±1 weeks postmenstrual age requiring supplemental oxygen is challenged with room air
to observe if the oxygen saturation remains at more than 90%). In detail, infants receiving
≤30% oxygen or >30% oxygen with >96% oxygen saturation are given room-air challenges
for 30 min. Infants in whom oxygen saturation decreases to <90% are considered to have
moderate ‘‘physiological BPD’’ (Walsh et al., 2004). The use of this standardized
physiological BPD definition decreases the variability in diagnosing BPD in different
centers.
The pathogenesis of BPD is closely linked with lung injury secondary to the use of
oxygen and invasive mechanical ventilation of the immature lung. Oxygen toxicity and
barotrauma from mechanical ventilation cause injury on the immature lung of preterm
infants (Bhandari, 2010; Coalson, 2006; Taghizadeh and Reynolds, 1976). Preterm infants
are prone to oxygen toxicity because of insufficient antioxidant enzymes and with low
levels of vitamins C and E (Chess et al., 2006; Fu et al., 2008; Ogihara et al., 1996; Shenai
et al., 1981). In newborn animals, oxygen alone can induce the arrest of alveolar
development (Dong et al., 2012; Warner et al., 1998). A slightly higher SpO2 target range
together with slightly higher FiO2 exposure with persistent lung disease resulted in a
higher rate of BPD (STOP-ROP, 2000). In preterm animals, invasive mechanical ventilation
alone without high levels of supplemental oxygen may result in lung pathology similar to
BPD (Coalson et al., 1999).
Introduction
8
1.2.2 Risk factors for BPD
Many factors have been identified as risk factors to facilitate or promote injury in the
immature lung leading to BPD in preterm infants. Among them, prematurity and
prolonged invasive mechanical ventilation seem to be key factors (Bancalari and Claure,
2006; Coalson, 2006; Lopez et al., 2011; Van Marter et al., 2000). Other related risk
factors include pre-and postnatal infection and inflammation (Speer, 2003) and patent
ductus arteriosus (PDA) (Farstad et al., 2011; Gonzalez et al., 1996; Rojas et al., 1995).
Maternal risk factors such as preeclampsia (Hansen et al., 2010; Kurkinen-Raty et al.,
2000), chorioamnionitis (Jobe, 2003; Speer, 2009) increase the likelihood of preterm
infants to develop BPD. A higher birth weight was inversely correlated with the incidence
of BPD (Figure 3).
Figure 3: Incidence of BPD, defined as oxygen use at 36 weeks corrected postnatal age in premature babies. Horbar JD, Carpenter JH, Kenny M, eds. Vermont Oxford Network 2002 Very Low Birth Weight Database Summary. Burlington, VT: Vermont Oxford Network; 2003.
1.2.3 Comprehensive management of BPD
As BPD is a multifactorial disease, the strategy to prevent BPD must be based on the
Introduction
9
elimination of as many of the factors implicated in its pathogenesis as possible. Thus, the
“magic bullet” to prevent preterm infants from developing BPD would be to eliminate
preterm delivery (Dodd et al., 2005). Prenatal lung maturation by using antenatal steroids
to mothers at risk for preterm delivery was found to reduce the risk of BPD in one study
(Van Marter et al., 1990). Recently, European guidelines for preterm infants with RDS
suggest that clinicians should offer a single course of prenatal corticosteroids to all women
at high risk of preterm delivery from 23 weeks up to 34 weeks’ gestation (Sweet et al.,
2013).
Geary et al. suggested that early management strategies to reduce both the
incidence and severity of BPD should include: (1) reducing barotrauma and volutrauma by
means of early CPAP therapy, (2) decreasing oxidant injury by limiting oxygen exposure by
using lower oxygen saturation targets (i.e. within a range of 89% - 94%), and (3) improving
nutrition status by providing early parenteral amino acids along with adequate calories
(Geary et al., 2008). An aggressive approach to prevent and treat prenatal and neonatal
infections and an early closure of the PDA has been suggested (Bancalari, 2001).
In cases with severe respiratory failure, the use of inhaled nitric oxide or postnatal
steroids has been suggested by some experts (Geary et al., 2008), although the evidence
is very limited to support this. Caffeine might be the drug of choice for the prevention of
BPD in VLBW infants (Schmidt et al., 2007). Postnatal corticosteroids should be avoided
during the first few days of life because of its associated side effects on the developing
brain (Halliday et al., 2003). When given during the second week of life (the so-called
moderately early treatment onset) to infants at high risk of BPD corticosteroids may have
some short- and long-term benefits (Schmidt et al., 2008). The effect of Vitamin-A for
prevention of BPD is still discussed controversially in the literature (Ambalavanan et al.,
2005; Darlow and Graham, 2011).
1.3 Complications with invasive mechanical ventilation
For very immature infants with more severe respiratory failure, mechanical
Introduction
10
ventilation through endotracheal tube (ETT) i.e. invasive mechanical ventilation is a
life-saving therapy to provide adequate oxygenation, to reduce work of breathing (WOB)
and to assist in the removal of carbon dioxide (CO2) from the body. The premature lung is
more susceptible to ventilator induced lung injury (VILI). The complications from invasive
mechanical ventilation include local injury and systematic adverse effects. Increased
airway resistance due to secretions in ETT lumen may lead to respiratory failure
presenting with hypoxia and hypercapnia. ETT intubation might lead to local tissue trauma
to the larynx, trachea, nose and palate complicated with laryngeal edema and vocal cord
dysfunction, and subglottic stenosis, which may require tracheostomy. In addition,
laryngoscopy and intubation might stimulate irritant receptors presented with
irritation-related adverse physiological responses such as desaturation, bradycardia, other
cardiac arrhythmia, hypotension, and increased intracranial pressure with the increasing
risk of intracranial hemorrhage (ICH) and neuronal injury in immature infants.
Iatrogenic injury due to invasive mechanical ventilation can also cause damage to
other organs leading to organ dysfunction (Slutsky and Tremblay, 1998). Inadvertent
mechanical hyperventilation leads to cerebral vasoconstriction and reduced cerebral
blood flow (Greisen and Trojaborg, 1987) and may lead to periventricular leucomalacia
(PVL) (Okumura et al., 2001; Wiswell et al., 1996). Altered pulmonary and cerebral
haemodynamics potentially correlated with pulmonary hypertension and increased the
risk for ICH (Perlman et al., 1983).
The stimuli for ventilator-induced lung injury include biophysical and biochemical
factors. The biophysical factors include volutrauma, barotrauma, and atelectrauma.
Volutrauma is termed with the injury of high tidal volume from mechanical ventilation to
the lung, which may increase the alveolar/capillary permeability by over-distension of the
lungs (Jobe and Ikegami, 1998). Dreyfuss et al found that volutrauma rather than a high
ventilatory pressure is a major factor in causing lung injury (Dreyfuss et al., 1988).
Barotrauma is an injury to the immature lung from mechanical ventilation due to high
inspiratory peak pressure often leading to a large tidal volume (Rouby et al., 1993).
Introduction
11
Breathing with surfactant deficient lungs with collapsed alveoli causes regional
over-distension and shear stress resulting in injury termed atelectrauma (Duggan et al.,
2003). Shear stress can exacerbate lung damage due to the recruitment/derecruitment of
collapsed alveoli. Biotrauma is defined as damages due to the activation of inflammatory
processes from biochemical factors in immature lung (Tremblay et al., 1997). The
biochemical factors include inflammatory cell infiltration and activation and the release of
inflammatory mediators and reactive oxygen species.
The immature lung is prone to ventilator induced lung inflammation because of
developmental deficiencies in both the lung and neonatal immune system. Pulmonary
inflammation may affect alveolarization and postnatal lung development (Jobe and
Ikegami, 2000). Avoiding intubation may minimize nosocomial infections and
ventilator-associated pneumonia.
Clinicians have sought techniques that provide respiratory support while avoiding
invasive mechanical ventilation to minimize lung injury. Considering the risk of invasive
mechanical ventilation, non-invasive ventilation i.e. nasal ventilation is increasingly used
even in very immature infants. Thus, non-invasive ventilation is used more and more
nowadays in order to reduce the risk of trauma to the larynx and trachea, infection and
acute and chronic lung disease.
1.4 Synchronized invasive mechanical ventilation
There are many kinds of invasive mechanical ventilation to provide respiratory
support in critically ill preterm infants. They might be life saving in those infants but also
intrigues many complications due to baro/volutrauma and asynchrony. It is well known
that baro/volutrauma is associated with lung injury in critically ill infants.
Asynchrony and episodes of hypoxemia might occur in a spontaneously breathing
preterm infant supported by conventional intermittent mandatory ventilation (IMV). The
asynchrony between patient and ventilator is associated with many adverse outcomes,
Introduction
12
including a longer duration of invasive mechanical ventilation (Chao et al., 1997; Thille et
al., 2006), discomfort, pneumothorax (Greenough et al., 1983), and fluctuations of BP and
cerebral blood flow (Amitay et al., 1993; Rennie et al., 1987) which may increase the risk
for ICH in preterm infants (Perlman et al., 1983). Consequently, asynchrony might be
more deleterious to the ventilated preterm infant.
New modes of mechanical ventilation have been introduced into NICU in order to
reduce these complications. The modes include those which reduce volume injury such as
volume-targeted ventilation (VTV) and high-frequency oscillatory ventilation (HFOV);
modes which reduce asynchrony rate by synchronizing the infant’s spontaneous breaths
with ventilator back-up inflations, i.e. patient-triggered ventilation modes, including
assist-control ventilation (ACV) and synchronized intermittent mandatory ventilation
(SIMV). SIMV can detect the infant’s inspiratory effort and enables the infant to receive
“synchronized” patient-triggered mandatory breaths up to the set rate.
Compared to controlled mechanical ventilation, SIMV has the following physiological
advantages: It may prevent muscle atrophy, improve intrapulmonary gas distribution and
facilitate weaning patients from mechanical ventilation (Putensen et al., 2002; Van de
Graaff et al., 1991). Firme et al found that the use of SIMV in a population of VLBW
ventilator-dependent infants resulted in better oxygenation and decreased episodes of
hypoxemia as compared to IMV (Firme et al., 2005). Several studies showed that infants
might wean more rapidly from both invasively synchronized IMV (SIMV) and ACV
compared to non-synchronized IMV (Chan and Greenough, 1993; Chen et al., 1997; Donn
et al., 1994; Greenough et al., 2008). During synchronized mechanical ventilation, positive
airway pressure provided by the ventilator can coincide with the spontaneous inspiratory
breathing of the infants. In this situation, sufficient gas exchange would be achieved at
lower peak airway pressures only if synchronous ventilation can be provoked, thus
potentially reducing baro-trauma and hence air leak and even BPD.
Some clinical researches showed that synchronized IMV improved some short term
respiratory parameters, such as oxygenation, tidal volume, and minute volume in
Introduction
13
comparison to IMV in neonatal infants (Bernstein et al., 1994; Cleary et al., 1995;
Hummler et al., 1996; Mizuno et al., 1994). In addition, arterial partial pressure of carbon
dioxide (Cleary et al., 1995) and work of spontaneous breathing significantly decreased
during SIMV compared with non-synchronized IMV (Mizuno et al., 1994).
The improvement in oxygenation demonstrated with SIMV may allow a reduction in
ventilator pressure or oxygen exposure (Cleary et al., 1995), which may be beneficial for
the fragile immature infants. The advantages of SIMV are also better described by
reviewing short term benefits, including enhanced comfort and decreased need for
sedatives or paralytic agents in these infants (Bernstein et al., 1994; Cleary et al., 1995;
Hummler et al., 1996). Thus monitoring the infants’ own respiratory effort may ensure
the respiratory muscle regular development.
Hummler et al. compared SIMV and assist/control ventilation with IMV in terms of
gas exchange, patient inspiratory effort, and fluctuations of BP in 12 clinically stable
premature infants. The investigators found an increase in mechanical minute ventilation,
reduction in phasic esophageal pressure deflections i.e. reduction of WOB, and reduction
in arterial BP fluctuations during SIMV compared with IMV (Hummler et al., 1996).
Furthermore, one recent systematic review of available studies demonstrated that high
frequency positive pressure ventilation (HFPPV) compared to conventional mechanical
ventilation (CMV) was associated with a reduction in the risk of air leak. ACV/SIMV
compared to CMV was associated with a shorter duration of ventilation. ACV compared to
SIMV was associated with a trend to a shorter duration of weaning (Greenough et al.,
2008). However, the authors could not report on a significant reduction in the incidence of
BPD.
Similarly, although some improvements were found in some studies, other authors
could not show an overall improvement in BPD or mortality rate in infants supported by
synchronized ventilation (Baumer, 2000; Beresford et al., 2000; Bernstein et al., 1996).
Although synchronized ventilation has the above-mentioned short term benefits
compared with non-synchronized ventilation, chronic lung complications such as BPD
Introduction
14
continued to be a major problem.
1.5 Non-invasive ventilation
Non-invasive ventilation is a method to provide respiratory support via nose and/or
pharyngeal rather than via ETT. Non-invasive ventilation includes nasal continuous
positive airway pressure (NCPAP), humidified oxygen delivered by high-flow nasal
cannulae, and different kinds of respiratory support modes provided through different
interfaces such as nasal prongs or masks which defined as “nasal intermittent positive
pressure ventilation” (NIPPV) (Bancalari and Claure, 2013) .
Nasal ventilation via nares has been used in the early of 1970s. Gregory et al
(Gregory et al., 1971) first reported the treatment of newborns with RDS by means of
CPAP via ETT or without endotracheal intubation using the “so-called” Gregory box in
neonatal intensive care unit, at the University of California, San Francisco, in 1971. From
then on, CPAP gained widespread acceptance as a management of respiratory support for
neonatal infants with respiratory distress or apnea. The use of noninvasive ventilation as
an initial mode or in addition to surfactant administration was associated with improved
outcomes in immature infants with respiratory distress syndrome (Santin et al., 2004).
More recently, non-invasive respiratory support became increasingly popular as compared
to invasive ventilation, especially when prolonged mechanical respiratory support is
necessary.
1.5.1 Nasal positive continuous airway pressure (NCPAP)
NCPAP has been used as the initial respiratory support for many preterm infants with
mild to moderate respiratory distress syndrome (RDS). Continuous distending pressure
provided by NCPAP can improve oxygenation in preterm infants with RDS. Since the
introduction of NCPAP to preterm infants, several interfaces have been developed to
deliver positive pressure to the neonatal infants. Available for clinical use are tube or
prong devices such as long nasopharyngeal tubes, single nasal prongs, short bi-nasal
Introduction
15
prongs and nose masks. Among them, short binasal prongs are more effective preventing
reintubation than single nasal prongs which may be related to the larger internal
diameters resulting in a lower resistance (De Paoli et al., 2008).
The mechanism of action of NCPAP seems to be related to one or more of the
following mechanisms: (1) decreased neonatal apneic episodes (especially for obstructive
episodes) by relief of upper airway obstruction via ensuring maximum upper airway
patency or airflow stimulation of the nose or upper airway (Miller et al., 1985), (2)
improved oxygenation by increasing functional residual capacity (FRC) due to alveolar
recruitment secondary to the continuous distending positive airway pressure, and
decreased pulmonary vascular resistance and intrapulmonary shunting (Sankaran and
Adegbite, 2012), (3) improved synchrony of neonatal thoracic and abdominal movements
(Locke et al., 1991).
The early respiratory support from NCPAP is less invasive and might decrease the
need and frequency of the invasive mechanical ventilation. A NCPAP pressure of at least 5
cm water or more appears more effective than NCPAP at lower pressures. However, PaCO2
may increase with higher positive end-expiratory pressure (PEEP) levels more than 7 cm
water as tidal volume may decrease and dead space increases.
The use of NCPAP might be complicated by air leak syndromes, and compromised
cardiac output caused by an increasing intrathoracic pressure which may impair cardiac
output if it causes over-distention of the lung. In addition, several reports have
demonstrated that the NCPAP devices might cause nasal skin excoriation and nasal
traumal or infection (Bohlin et al., 2008; Courtney and Barrington, 2007). To avoid the
adverse effects from NCPAP, close observation of the immature infant during NCPAP use is
critically important. Prong sites need to be checked often and skin integrity need to be
maintained for those fragile infants. If necessary, an option is to alternate prongs and
masks at certain intervals.
Introduction
16
In order to minimize the complications from invasive mechanical ventilation,
respiratory support with NCPAP as either a primary mode to minimize invasive ventilation
or to facilitate weaning from the ventilator has become standard practice. In 1985, Avery
et al (Avery et al., 1987) compared rates of BPD in eight NICUs and found that Columbia
had one of the best outcomes for VLBWI and the lowest incidence of BPD, which was
thought to be related to the frequent use of NCPAP in comparison to other centers. Van
Marter et al (Van Marter et al., 2000) reported that BPD rates were significantly lower in
Infants' Hospital of New York as compared with Boston centers (4% versus 22%). After
adjusting for baseline risk, most of the increased risk of BPD among very low birth weight
infants hospitalized at 2 Boston NICUs, compared with those at Infants' Hospital, was
explained simply by the initiation of mechanical ventilation. Infants' Hospital is known for
its strategy of early and meticulous use of NCPAP. The use of nasal NCPAP may appear
beneficial for those preterm infants extubated after extubation from invasive mechanical
ventilation.
However, NCPAP does not always ensure that the lungs are opened up and kept open
or that hypoventilation due to apnea or low respiratory drive is avoided. It is reported that
about one third (Davis and Henderson-Smart, 2003) or even more than 50% (Kirchner et
al., 2005) of VLBWI failed to be extubated from invasive mechanical ventilation by using
NCPAP alone, which means that NCPAP might not provide sufficient respiratory support
for all premature infants after extubation from invasive mechanical ventilation. Thus, a
considerable number of premature infants needs to be re-intubated after the first
extubation attempt (Barrington et al., 2001; Khalaf et al., 2001). The high extubation
failure rate of NCPAP, when used after mechanical ventilation renews neonatologists’
interests in developing additional methods of nasal non-invasive respiratory support.
During spontaneous breathing very premature infants are prone to chest wall
distortion because of their weak musculature and a compliant ribcage especially in the
setting of residual lung disease. The respiratory workload of the preterm infants with RDS
increases obviously with chest wall distortion. In this case, the provision of continuous
Introduction
17
distending pressure alone may not be enough to support gas exchange. Nasal ventilation
such as NIPPV can potentially augment spontaneous inspiratory effort of preterm infants
and provide some unloading not achievable by NCPAP alone. Therefore, NIPPV seems to
be an attractive way to support preterm infants after extubation in order to shorten the
period of invasive mechanical ventilation by using nasal non-invasive mechanical
ventilation.
1.5.2 Nasal intermittent positive pressure ventilation (NIPPV)
NIPPV or nasal intermittent mandatory ventilation (NIMV) is a synonym used in the
literature. It is a form of respiratory support which can augment NCPAP by delivering
ventilator breaths (Davis et al., 2001). The interfaces of NIPPV are similar to those of
NCPAP. Bi-nasal short-prongs are the most commonly used in neonatal intensive care unit
because they are considered to impose lower resistance hence reduce the work of
breathing (WOB) (De Paoli et al., 2002).
NIPPV might be used in a synchronized (SNIPPV) or non-synchronized (NIPPV) way.
During SNIPPV and NIPPV positive end-expiratory pressure (PEEP), peak inspiratory
pressure (PIP), inflation rate (IR) and inspiratory time (Ti) can all be manipulated by the
clinicians in order to provide the optimal respiratory support for VLBW infants. NIPPV
working as the natural extension of NCPAP method increases successful extubation and
might reduce exposure to invasive ventilation and thus the incidence of BPD (Hutchison
and Bignall, 2008). Provided inflations above CPAP pressure can augment tidal volume if
breaths coincide with the inspiratory phase, and may help to recruit areas of
micro-atelectasis or airway collapse and hereby improve gas exchange. Compared to
NCPAP, a higher mean airway pressure supported by NIPPV might help to recruit collapsed
alveoli and decrease WOB (Aghai et al., 2006).
There are a number of studies suggesting that nasal non-invasive ventilation is more
effective to successfully extubate preterm infants from invasive mechanical ventilation as
compared with NCPAP alone (Barrington et al., 2001; Davis et al., 2001; Gao et al., 2010;
Introduction
18
Kumar et al., 2011; Lin et al., 2011; Moretti et al., 2008; Sai et al., 2009). The most
common reason for NCPAP failure after extubation in very immature infants seems to be
severe apnea (Moretti et al., 2008) and impaired lung mechanics due to residual lung
disease. Two randomized control trials (RCTs) compared NIPPV with NCPAP for the
management with apnea of prematurity (AOP). Their results are inconsistent. Ryan et al
found no benefit of NIPPV (Ryan et al., 1989). However, a significantly larger reduction in
the number of apneic events was demonstrated by Lin et al in the NIPPV group (Lin et al.,
1998). The contradictory results might be explained by the fact that in Ryan’s study
relatively stable infants with stable lung mechanics who just needed some positive airway
pressure, were studied. Thus, studies of smaller, more immature, or more symptomatic
infants might lead to different results.
According to the clinical observation, NIPPV demonstrated superiority as an initial
ventilation mode in very immature infants with severe rather than mild RDS as compared
with NCPAP. Recently, Shi Y et al found that in comparison to NCPAP, as a primary
respiratory support, SNIPPV is significantly more effective in preterm infants with RDS but
not significantly different in term infants with RDS (Shi et al., 2013). NIPPV is not likely to
offer significant advantages to those premature infants who just require respiratory
support by means of NCPAP alone (Bancalari and Claure, 2013).
In comparison to NCPAP, as the “bridge” from invasive mechanical ventilation to
spontaneous breathing for those immature infants with comparatively severe RDS after
surfactant treatment, NIPPV was more effective in preventing extubation failure, reducing
the duration of invasive mechanical ventilation (Barrington et al., 2001), and resulted in a
lower incidence of BPD (Bhandari et al., 2009). Complications such as air leak syndromes,
nasal injury, and abdominal distension during nasal ventilation were similar as compared
to NCPAP. The most common complication is nasal injury caused by misalignment or
improper fixation of nasal interfaces, especially in active infants moving their heads
(Diblasi, 2009). Close observation and readjustment of NIPPV devices are critically
important in preventing mucosal damage.
Introduction
19
In fact, nasal ventilation does not place the immature infants at any greater reported
risk for developing any of the above-mentioned complications than does NCPAP. Like
NCPAP, gastric insufflation of gases and abdominal distension frequently occurred during
nasal ventilation. In order to decompress the gastrointestinal tract, an orogastric feeding
tube is placed to decompress stomach and intestine. Theoretically, gastrointestinal
perforation and necrotizing enterocolitis (NEC) are the most severe adverse effects from
gastric insufflations. Despite the use of an orogastric tube, Garland et al reported in an
early study that routine use of mechanical ventilation with either nasal prongs or face
mask was highly associated with an unacceptable risk of gastrointestinal perforations in
sick neonates by means of inspiratory peak pressure of approximately 19 cmH2O (range
10–30 cmH2O) (Garland et al., 1985). Recent clinical studies have not confirmed the
findings of increased risks of gastrointestinal perforation due to nasal ventilation via short
prong or mask.
Respiratory support via nose rather than ETT might avoid many of the complications
related to a tube placed in the trachea, but still might not avoid all of the complications
due to mechanical ventilation induced lung injury (VILI). The settings and approach
administrated to support immature infants during nasal ventilation are comparable to
invasive ventilation, so VILI might still be a problem during nasal ventilation. However,
during nasal ventilation, air leak from nasal airway interface is a natural lung-protective
pressure-relief, which may reduce excessive pressure transmission to the distal airways
(Aly, 2009). However, non-synchronised NIPPV may deliver high pressure during expiration,
leading to increased risk of pneumothorax (Lin et al., 1998). Theoretically, synchronized
nasal ventilation would provide better respiratory support to those immature infants
compared to non-synchronized nasal ventilation does.
1.5.3 Synchronized nasal intermittent positive pressure ventilation (SNIPPV)
NIPPV is delivered through a ventilator, which has the capability to synchronize
breaths with infant’s respiratory efforts, and is defined as synchronized nasal intermittent
Introduction
20
positive pressure ventilation (SNIPPV). For invasive mechanical ventilation it is well known
that synchronized mechanical breathing to spontaneous respiratory efforts increase tidal
volume (Hummler et al., 1996) and improve gas exchange (Cleary et al., 1995). Therefore,
synchronized use of non-invasive IMV should also have beneficial physiologic effects as
compared to non-synchronized non-invasive IMV.
There is scarce information available to compare the effect of synchronized nasal IMV
with non-synchronized nasal IMV on VLBW infants (Roberts et al., 2013). Recently, there
were two reports comparing SNIPPV to NIPPV, evaluating the short term effects on
preterm infants. Chang et al have shown that synchronized nasal ventilation reduces
breathing effort and resulted in better infant-ventilator interaction than non-synchronized
nasal ventilation in stable preterm infants who were extubated already for some time
(Chang et al., 2011). Owen et al explored effects of NIPPV on spontaneous breathing and
found that synchronization of NIPPV pressure peaks with spontaneous inspiratory
breathing might increase the beneficial effects of NIPPV on neonatal infants (Owen et al.,
2011). However, Chang et al were not able to detect any beneficial effects on gas
exchange (Chang et al., 2011). The physiological effects of synchronization however, have
not been tested in VLBW infants with RDS immediately after extubation, whose lung
disease might be more severe and lung mechanics not stable.
Theoretically, synchronized nasal ventilation would provide more effective
respiratory support for immature infants compared to non-synchronized nasal ventilation.
However, one recent retrospective study showed that there was no significant difference
in clinical outcomes (BPD/death) in premature infants supported by SNIPPV compared to
those done by NIPPV (Dumpa et al., 2012). Furthermore, in this retrospective study, they
found that there were no instances of intestinal perforation in the group supported by
SNIPPV. However, there were twelve instances of intestinal perforation in the group
supported by NIPPV out of which ten were spontaneous intestinal perforation (SIP)
(Dumpa et al., 2012).
In contrast, a recent case report demonstrated a female immature infant (GA: 29w,
Introduction
21
BW: 1310g) complicated with gastric pneumatosis after 2 days of the management of
SNIPPV supported by Star ventilator with the StarSync module (Infrasonics, San Diego, CA).
The reason for gastric pneumatosis in this case was not clear. Indomethacin might
exacerbate gastric mucosal injury. The condition was further aggravated by nasal S-NIMV,
which introduced air into the stomach (Ting et al., 2011). Closely observing infants’
abdominal condition during nasal ventilation no matter synchronized or non-synchronized
method seems to be critically important.
Nasal ventilation mimics invasive mechanical ventilation to provide respiratory
support for neonatal infants without ETT. Nowadays, almost all available neonatal
ventilators detect inspiratory movements by using pressure or flow signals for
synchronization. In neonates, especially immature infants, it is very difficult to detect the
inspiratory movements because their spontaneous breathing is shallow and variable, thus
their breathing signals are weak or are superimposed upon a leakage flow. In addition,
weak and variable signals and large and variable air leakage disturb synchronization
leading to ventilator autocycling (Bernstein et al., 1995).
The synchronization of nasal ventilation in neonatal infants is different from that in
older children or adults. A tight-fitting mask can be used to cover the mouth and nose,
allowing flow to trigger synchronization in children and adults. However, bi-nasal prongs
are frequently used in neonates. It is a very common phenomenon that air leak at the
nasal interface occurs in those immature infants. In this situation, the infant is usually not
able to trigger ventilator’s breaths using a flow sensor device. Furthermore, flow
measurement of nasal ventilation in newborns needs additional techniques that are still
not available in most ventilator devices used for clinical settings until now. Thus, the
technically troublesome problem is the reliable identification of spontaneous breathing
movements in very immature infants in an attempt to maintain synchronization during
nasal ventilation (Foitzik et al., 1998).
In previous studies of synchronized nasal ventilation, the Infant Star ventilator with
the Star Sync module (Star Sync; Infrasonics Inc., St Louis, USA) was used to deliver
Introduction
22
intermittent mandatory respiratory support via the short binasal prongs, and
synchronization with infant’s spontaneous breathing was achieved by means of the
Graseby capsule. In order to achieve synchronization of ventilator breaths to the patient’s
own respiratory efforts, the Graseby capsule was placed on the abdomen to detect
outward movement of the abdominal wall caused by diaphragmatic descent (Barrington
et al., 2001; Bhandari et al., 2007; Dumpa et al., 2012; Kulkarni et al., 2006; Santin et al.,
2004). Currently, the Infant Star ventilator is not available any more for clinical use.
Furthermore, use of the Graseby capule to synchronize ventilator breaths requires
considerable skills to position the capsule. Inaccurate position of the capsule might lead to
the contradictory action without synchronization. If the capsule was taped too close to the
rib margin of an immature infant who suffered from respiratory distress disease, the
retractions of subcostal muscle could lead to asynchrony. Moreover, if the capsule was
placed too high on the abdomen, respiratory movements could be out of the capsule
phase. Chang et al adjusted the position of the capsule and trigger sensitivity in every
preterm infant to achieve minimal trigger delay without autotriggering by observing the
timing of esophageal pressure deflection (Pe) during spontaneous inspiration (Chang et al.,
2011).
A device that synchronizes ventilation using a diaphragmatic electromyogram (EMG)
is already available. Neurally adjusted ventilator assist (NAVA) might provide not only
synchronization timed with the patient’s inspiratory effort, but also deliver respiratory
pressure support to the infant’s inspiratory effort (Beck et al., 2009). However, there is
little information on its use in VLBW infants and it requires the use of a specific gastric
tube in optimal position in gastro-esophageal junction (Beck et al., 2009). In addition, this
method requires manipulation of the position of the very specific gastric tube with the
EMG sensor device, which is quite expensive.
Currently, because the Infant Star ventilator was not available in NICU, few neonatal
centers have access to ventilators with flow drivers capable of delivering synchronized
nasal ventilation. Therefore, they have no choice but use non-synchronized nasal
Introduction
23
ventilation. In our unit, we use a Sophie ventilator (Sophie, Medizintechnik, Gackenbach,
Germany), capable to synchronize respiratory support to infants’ spontaneous breathing
during non-invasive ventilation using the Graseby capsule (Stephan, Vio Healthcare Ltd,
Ref. 103560103), which was placed on the abdomen to detect diaphragmatic descent
secured onto the anterior abdominal wall near to the right costal margin.
1.5.4 Possible advantages of SNIPPV
Physiologically, SNIPPV might provide superiority to NCPAP and non-synchronized
nasal ventilation. In one small study SNIPPV was used as a primary mode of respiratory
support, and significantly reduced the intubation rate in comparison to NCPAP (25% vs.
49%, p = 0.04) (Kugelman et al., 2007). In another study SNIPPV increased tidal volume
and minute volume compared with NCPAP (Moretti et al., 1999). SNIPPV also might
reduce thoraco-abdominal motion asynchrony, maintain end-expiratory lung volume, and
lead to more effective chest wall stabilization and lung mechanics (Kiciman et al., 1998).
The absence of a tracheal tube may help to preserve the neonate’s natural ability to
maintain lung volume. The glottis is undisturbed and closure of the vocal cords is possible,
which may help to maintain FRC. Bhandari et al demonstrated that very low birth weight
infants with a birth weight 600–1,250 g treated with the intubation-surfactant-extubation
(INSURE) approach followed by SNIPPV versus continued invasive ventilation via
endotracheal tube was associated with a significantly lower incidence of BPD/death
(Bhandari et al., 2007).
Several studies have demonstrated decreased WOB during SNIPPV as compared with
NCPAP (Aghai et al., 2006; Ali et al., 2007; Moretti et al., 1999). SNIPPV may decrease
inspiratory effort as measured by esophageal pressure monitoring leading to better gas
exchange with lower carbon dioxide and better oxygenation compared with NCPAP. In
addition, one clinical study demonstrated that during ‘synchronized’ NIPPV only
mechanical ‘inflations’ delivered during spontaneous inspiration produced relevant chest
inflations (Moretti et al., 1999). Gizzi et al evaluated the effect of SNIPPV after the
Introduction
24
intubation-surfactant-extubation (INSURE) procedure in preterm infants with RDS (Gizzi et
al., 2012). They found that use of SNIPPV after INSURE technique reduced the need for
invasive mechanical ventilation and decreased the rate of short term morbidities of
premature infants compared with NCPAP. It has been postulated that SNIPPV might
support exogenous surfactant distribution in the lungs and thus more effective action, and
thus lead to a reduced need for a second surfactant dose in SNIPPV group (Gizzi et al.,
2012).
Apnea of prematurity (AOP) is the most common reason for the prolonged invasive
mechanical ventilation. SNIPPV might compensate for decreased respiratory drive which is
poorly developed in very immature infants and may stimulate breathing and thus reduce
negative effects of apnea and periodic breathing of preterm infants on oxygen and CO2
exchange (Barrington et al., 2001). As mentioned above, synchronized nasal ventilation is
benefit for preterm infants (Gizzi et al., 2012). However, asynchronous breathing might
increase the risk for side effects such as pneumothorax (PNX) (Greenough et al., 1983),
blood pressure and cerebral blood flow velocity fluctuations (Perlman et al., 1983) and
increase WOB (Chang et al., 2011) in immature infants.
Systemic blood pressure and cerebral blood flow velocity fluctuations might cause
brain injury such as intracranial hemorrhage (ICH) and ischemic brain injury, which may be
associated with poor prognosis in very immature infants (Perlman et al., 1983). The
possible pathophysiology of pneumothorax during non-synchronised mechanical
ventilation might include delivery of high airway pressures during spontaneous expiration,
leading to increased upper airway and intrathoracic pressure, increasing the risk of
pneumothorax (Greenough et al., 1983).
There have been some case reports of gastrointestinal perforation (Garland et al.,
1985), but none when the mechanical breaths were synchronized with the infant’s
inspiratory effort. In very immature infants, the use of NIPPV rather than SNIPPV, does not
ensure that the pressure is delivered in synchrony with glottic opening. Children and adult
data demonstrated that nasal ventilation should be applied in the synchronized mode.
Introduction
25
Adult studies have demonstrated that non-synchronized NIPPV is less effective in
comparison to synchronized NIPPV (Jounieaux et al., 1995). To date, however, no
randomized, controlled trials comparing the short or long term effect of SNIPPV versus
non-synchronized NIPPV in preterm infants have been reported.
In summary, according to Hutchison et al (Hutchison and Bignall, 2008), the potential
benefits of synchronized non-invasive positive pressure ventilation might include: (1)
maintenance of end-expiratory lung volume (airway patency), (2) less ‘‘atelectatotrauma/
barotrauma/volutrauma/endotrauma’’ to lung, (3) less complications such as BPD, (4) less
local or systemic infection, (5) early weaning/less reintubation, (6) eventually improved
nutrition, (7) earlier parental interactions, (8) less tracheal/vocal cord/palatal injury.
Physiologically there is a rationale for the early use of synchronized nasal ventilation
rather than non-synchronized nasal ventilation or NCPAP and it might have the potential
to reduce the rate of BPD without worsening neurological outcomes. However, at this
time, before synchronized nasal ventilation is recommended as the first line respiratory
support for very immature infants, more scientific information is needed.
1.6 Near-infrared spectroscopy (NIRS)
Very immature infants have a high risk for cerebral injury caused by hypoxia-ischemia,
stroke, intracranial hemorrhage (ICH) and periventricular leukomalacia (PVL), which may
be associated with cerebral palsy, long-term epilepsy or neurological deficits, visual and
hearing problem (Kiechl-Kohlendorfer et al., 2009). In a recent clinical study, extremely
preterm infants whose gestational age was less than 28 weeks had an average mortality of
20 percent (Morley et al., 2008). Among the survivors, about 10 percent suffered from
cerebral palsy and approximately one fourth had severe neurological deficit in another
study (Vohr et al., 2005).
The vulnerable brain of the VLBWI may be injured by impaired gas exchange. Assisted
ventilation may be life-saving by promoting adequate oxygen delivery, but at the same
time potentially may impact vascular activity of the brain by affecting cerebral
Introduction
26
autoregulation when PaCO2 is beyond physiological range. In addition, the development
and autoregulation of brain perfusion of the central neuronal system (CNS) is immature in
comparison to term neonatal infants. The cerebral blood flow of premature infants tends
to be variable owing to the changes of systemic blood pressure, PaCO2, and PaO2/SaO2.
Among these factors, PaCO2 is a very important factor leading to fluctuations of cerebral
blood flow by means of vasoconstriction or vasodilatation. The vascular response to PaO2
changes is significantly less in comparison to PCO2 changes (Menke et al., 1993; Niijima et
al., 1988).
Inadvertent mechanical hyperventilation might lead to cerebral vasoconstriction and
decreased cerebral blood flow (Greisen and Trojaborg, 1987). The variable pattern of
cerebral blood-flow velocity in immature infants with RDS implies a high risk of the
development of ICH (Perlman et al., 1983). It may be extremely important to protect
premature infants with RDS from some potentially preventable etiologic factors by
monitoring their cerebral hemodynamics. Moreover, non-invasive devices to monitor
cerebral function even in the most immature infants, are now available for neonatal
intensive care units (NICUs). Consequently immature infants might benefit from
monitoring of brain function or perfusion to detect possible brain injury at the bedside.
There are very few tools available for routine evaluation of immature brain health at
the bedside. While amplitude-integrated electroencephalography (aEEG), head ultrasound
(US) and transcranial Doppler (TCD) are still the most commonly used bedside tools.
However their potential to assess cerebral hemodynamics and regional oxygenation is
very limited. There are now several studies on regional cerebral oxygenation for the
extremely premature infants by means of near-infrared spectroscopy (NIRS) available
(Lemmers et al., 2006; Naulaers et al., 2002).
NIRS is a noninvasive, optical technology to continuously monitor regional cerebral
oxygen saturation (rSO2) on real time at bedside. In 1977, Jobsis first reported the
application of NIRS for continuous monitoring of cerebral hemodynamic and oxygenation
(Jobsis, 1977). NIRS has become an effective research tool for studying infant cerebral
Introduction
27
hemodynamic and oxygenation. Since 1985 (Kariman and Burkhart, 1985), NIRS has been
used more and more to assess cerebral oxygenation in preterm newborns (Dehaes et al.,
2013; Fuchs et al., 2012; Fuchs et al., 2011; Lekic et al., 2011; Roche-Labarbe et al., 2012).
The technology is based on the relative transparency of biologic tissues to
near-infrared light (700–1000 nm wavelength). The near-infrared light can penetrate
through the skin and skull into the brain, which allows for non-invasive assessment of
cerebral oxygenation, which is dependent on perfusion and cerebral oxygenation. NIRS
can differentiate oxygenated hemoglobin from deoxygenated hemoglobin, because of
their different absorption spectra. The ratio of oxygenated hemoglobin to total
hemoglobin demonstrates the regional oxygen saturation of tissue (rSO2) (Wray et al.,
1988).
Cerebral oxygen saturation is a composite measurement of tissue oxygen saturation
through arterial, capillary and venous beds dominated by venous, which reflects a balance
between cerebral oxygen delivery and cerebral oxygen consumption. Some clinical studies
showed that the range of rSO2 values in neonatal infants and children usually is within the
range of 65% and 85% (Dullenkopf et al., 2003; Lemmers et al., 2006). However the
normal range of rSO2 in very immature infants is still not well defined.
A great advantage of this technique is the fact that it can monitor cerebral oxygen
saturation in a real-time and non-invasive way and has no known side effects. The power
of laser light in NIRS devices on the surface of the local tissue is less than 1mW which is
very unlikely to cause the thermal stimulation of the tissue. To the best of our knowledge,
there are no studies available to assess the effect of synchronization of nasal ventilation
on cerebral oxygenation in premature infants using NIRS.
1.7 Hypothesis and aims
The aim of our prospective randomized crossover trial clinical research was to study
the short term effects of synchronized nasal IMV (S-NIMV) as compared to
Introduction
28
non-synchronized nasal IMV (NIMV) on breathing effort measured by phasic esophageal
pressure deflection (Pe), spontaneous respiratory rate (RR), and its effect on gas exchange,
cerebral tissue saturation, and intermittent episodes of bradycardia and desaturation in
VLBWI immediately after extubation recovering from RDS. We hypothesized that
synchronized nasal IMV (S-NIMV) as compared to non-synchronized nasal IMV (NIMV) will
decrease breathing effort in preterm infants immediately after extubation when
recovering from RDS, as measured by phasic esophageal pressure deflection (Pe). In our
study, we assessed the reliability of a newly developed abdominal pressure sensor device
for the S-NIMV mode in a commercially available ventilator device.
Materials and methods
29
2. Materials and Methods
2.1 Population
Preterm infants recovering from respiratory distress syndrome (RDS) with the
following criteria were eligible for this study: gestational age (GA) <32 wks, birth weight
(BW) <1500 grams, on invasive mechanical ventilation, ready for extubation as judged by
the clinical team, and informed consent from infants’ parents or legal guardian available.
Infants with major congenital anomalies involving the central nervous system, or the lung
(i.e. lung hypoplasia, active air leaks), the heart (atrial septal defect- ASD, ventricular
septal defect- VSD allowed), or known neuromuscular disease, requiring sedation, or with
ongoing severe infection such as sepsis or meningitis were excluded. The study was
conducted at the Children’s Hospital Neonatal Intensive Care Unit of Ulm University. The
study was reviewed and approved by the clinical ethics committee of the University of
Ulm. The study was registered at www.controlled.trials No. was NCT01664832).
2.2 Design of the study
The study was a randomized order cross-over design. Each infant served as its own
control during the study.
2.3 Sample size calculation
Primary outcome measure was peak esophageal pressure (Pe) deflection. Based on
the study of Chang et al (Chang et al., 2011) , peak Pe was reduced by 0.84 cmH2O when
breathing from NIMV to S-NIMV with 40 breaths/min. Based on this data and the standard
deviation of 0.97cmH2O for the observed difference between modes of ventilation and a
power of 0.80 and a 2-tailed α-error of 0.05, at least 13 patients had to be studied.
Materials and methods
30
2.4 Study procedures
All infants were studied in supine position in their incubators or overhead warmers as
soon as possible after extubation and but not later than 24h after extubation. As per unit
protocol the extubation criteria from invasive mechanical ventilation included the
following: (1) loading with caffeine, (2) stable SpO2 (for those premature infants whose
postmenstrual age <32weeks, SpO2 between 80-92%), requirement of FiO2 of 0.50 or less,
(3) good spontaneous respiratory effort without severe respiratory distress or apnea, (4)
stable cardio-pulmonary and hemodynamic condition.
During the study the routine care was continued as usual. Study infants received
either S-NIMV or NIMV mode in random order (using opaque envelopes drawn
immediately prior to start of study) for a study time of 2 hours in each mode. After the
first study period, infants were crossed over to the alternative mode and studied for
another 2 hours (Figure 4). There were 10 minutes intervals for stabilization before the
second 2-hour ventilation study. Investigators were not blinded to the ventilation mode.
We studied 14 patients. According to the randomization order, seven infants started on
S-NIMV first and another seven started on NIMV.
Figure 4: Randomized crossover study. (14 very low birth weight infants were studied in
Children’s hospital of Ulm university. NIMV: non-synchronized nasal intermittent
mandatory ventilation, S-NIMV: synchronized nasal intermittent mandatory ventilation)
Our standard ventilator for mechanical ventilation is the Stephanie or the Sophie
(Stephan Medizintechnik, Gackenbach, Germany), which can be used interchangeablely in
Materials and methods
31
their standard modes. For the purpose of this study infants were switched to a Sophie
ventilator (Sophie, No.43513 Medizintechnik, Gackenbach, Germany), capable of
synchronizing during non-invasive ventilation, and allowed to adapt for at least 30 min
before the study. The study time was scheduled in order to leave infants undisturbed after
routine nursing rounds. Immediately after extubation from invasive mechanical ventilation
eligible preterm infants received nasal IMV with short binasal prongs (Stephan,
Medizintechnik, Gackenbach, Germany) or nasopharyngeal tube (BW less than 1000g in
inner diameter 2 mm, BW more than 1000g in inner diameter 2.5 mm) (Portex Tracheal
Tube, Smiths Medical International Limited Hythe, kent, CT 216 Jl, UK) as the standard
interface. Settings (PIP, PEEP, inspiratory time and backup respiratory rate) were chosen by
the clinical team. Trigger sensitivity of pressure was adjusted at low levels for all infants to
reach a minimal response delay with little auto-triggering by artifacts. The choice of the
interface depended on clinician’s preference: 7 infants younger than 7days had a
nasopharyngeal tube, 1 infant older than 7days had a nasopharyngeal tube after
necrotizing enterocolitis (NEC) surgery, while 6 infants equal to or older than 7 days had
bi-nasal short prongs.
We did not take any measure to keep the infants’ mouth closed or to restrain them.
The position of the nasal short prong or nasopharyngeal tube was monitored by the
nursery staff for displacement and mucosal. The synchronization was achieved by using
the Graseby capsule (Stephan, Vio Healthcare Ltd, Ref. 103560103), which was taped onto
the anterior abdominal wall near to the right costal margin. The pressure of the ventilator
was monitored at the connector between the circuit and the nasal prongs or
nasopharyngeal tube. FiO2 was adjusted to keep the range of transcutaneous oxygenation
saturation (SpO2) from 80% to 92% by monitoring pulse oximetery (Dash 4000, General
Electric, Freiburg, Germany).
The infants were left undisturbed during both study periods. During the whole study,
every preterm infant was monitored at the bedside by the research team. When apneic
episodes occurred, the staff stimulated the infant gently by touching his/her limbs. In the
Materials and methods
32
event of desaturation (SpO2 <80%), FiO2 was adjusted by 0.2 increments every 30 seconds,
followed by 0.1 increments every 20 seconds from then on, and reduced to the previous
baseline level when the infant recovered. If infant still presented with severe events of
apnea or desaturation or even bradycardia (HR<100 beats per min), the attending doctor
would reintubate the infant if necessary according to an individual decision.
Guidlines for reintubation include: (1) recurrent apnea with >3 episodes per hour
associated with bradycardia after management with bag-and-mask respiratory support,
methylxanthines, or even tracheal suctioning if necessary, (2) transcutaneous
PCO2 >65-95mmHg, depending on the postnatal age, (3) continuous requirement
FiO2 >0.6-0.8 in order to maintain SpO2 >80%, (4) severe hemodynamic instability, (5)
requirement of respiratory assistance due to NEC ≥ stage 2 (Bell) if necessary.
NIRS was used to measure brain oxygenation during the study time (Foresight,
Casmed, CAS Medical Systems INC. Branford Connecticut, 06405 USA, CASMED.com). A
self-adhesive transducer that contains the light-emitting diode and a distant sensor was
fixed both on the left and right fronto-temporal region of the neonatal skull directly above
the auricle and held in place by flexible bandage. Measurement sites were selected to
ensure areas with homogenous skin (e.g. sites with no hair) in order to provide for
unimpaired measurement. The distance of interoptode is approximately 2.5 cm (Figure 5).
The cerebral oxygenation and changes in the relative concentrations of oxygenated and
deoxygenated hemoglobin were recorded. Measurements were carried out at sampling
frequency of 4 Hz.
Materials and methods
33
Figure 5: Probe and sensors of near-infrared spectroscopy (NIRS).
2.5 Measurements
2.5.1 Vital signs and gas exchange
The number of infants needing reintubation during any specific mode of support
(NIMV or S-NIMV) was recorded. Extubation failure was defined as requirement of
reintubation and invasive mechanical ventilation via endotracheal tube within 24 hours
after extubation.
Abdominal girth was measured clinically at the end of each study period before
crossover to the alternative mode. The respiratory rate was recorded from the Monitor
(Dash 4000, General Electric, Freiburg, Germany). The heart rate was obtained from the
electrocardiographic signal from the GE monitor. Blood pressure was recorded using the
same monitor invasively if the infant had an arterial line in place or non-invasively every
Materials and methods
34
15 minutes if there was no arterial line in place. Arterial oxygen saturation (SpO2) was
continuously measured by pulse oximetry (Dash 4000, General Electric, Freiburg, Germany)
with the probe on the right hand. The device was equipped with Masimo signal extraction
technique, showing less motion artifacts than other systems available. Transcutaneous
partial pressure of oxygen (PO2) and transcutaneous carbon dioxide (TcPCO2) levels were
recorded continuously (Micro Gas 7650 Rapid, Radiometer, Copenhagen, Denmark).
Fraction of inspired oxygen (FiO2) was measured with the sensor device of the ventilator.
Esophageal pressure (Pe) and airway pressure (PAW) measurements were acquired
using Sorensen Transpac 4 sensors (Gould Inc. T&G, Valley View. Ohio, USA. Model :
11-4183-09) connected to medical grade transducer couplers (B. Braun Melsungen AG ,
Ref. 8722960) and calibrated by water manometry.
Pe was recorded using a 5-F feeding tube (Conva Tec Kimited Deeside CH5 2NU, UK,
Ref. 0086) filled with sterile water with its tip placed in the distal esophagus. First, the
insertion length to the stomach was estimated (measuring the feeding tube from the
bridge of the nose to the earlobe, continuing to the point halfway between the lower end
of the sternum and the umbilicus, and the tip of the catheter was inserted into the
stomach according to the estimated length. Subsequently, the catheter was slowly
withdrawn (usually 2-3 cm) until the Pe curve on the computer screen during inspiration
became negative in synchrony with the outward movement of the abdomen. In this
position, the insertion length was noted and the catheter secured. Patency was
maintained during the course of the study by flushing the catheter with sterile water (rate:
0.2-0.3 ml/kg/hour). Esophageal pressure transmission was verified by a brief airway
occlusion. An additional orogastric 6-F feeding tube was placed into the stomach during
the study for feeding and intestinal-gastric decompression.
Airway pressure (PAW), which was delivered by the ventilator during the S-NIMV and
NIMV, was acquired at the connection between the ventilator circuit and the nasal short
prong or nasopharyngeal tube.
Materials and methods
35
All signals were digitized at 100 samples per second, and recorded on a personal
computer (ASUA Eee PC 1008 HA).
2.5.2 Work of breathing
The work of spontaneous breathing was estimated using the esophageal pressure
deflection (Pe) measurement. To evaluate the infant’s breathing effort the average phasic
deflection of esophageal pressure was calculated from 5 consecutive artifact-free breaths
every 6 min throughout each of the recording periods (i.e. in 100 breaths during the
recording period). From the acquired Pe trace, we also calculated the spontaneous
respiratory rate using the following calculation: 300 divided by the duration (unit: seconds)
of 5 consecutive breaths.
2.5.3 Cerebral Oxygen Saturation
Regional cerebral oxygen saturation (rSO2) was measured by NIRS both on the left
and right frontal- temporal side of the neonatal skull. For correction of differences in
peripheral oxygen saturation (SpO2), the fractional tissue oxygen extraction (FTOE) was
calculated as following formula: FTOE= (SpO2−rSO2)/SpO2. Transcutaneous oxygen
saturation by pulse oximetry (SpO2) was measured simultaneously. FTOE reflects the
balance between cerebral oxygen supply and cerebral oxygen consumption (Naulaers et
al., 2007). The increase of FTOE shows an increase of the oxygen extraction by brain tissue,
meaning higher oxygen consumption compared to oxygen delivery. On the contrary, the
decrease of FTOE suggests less utilization of oxygen by brain tissue in comparison with the
supply or increased blood flow.
2.6 Data analysis
Mean FiO2, TcPCO2, TcPO2, SpO2, RR, BP, rSO2 as well as the number of desaturation
episodes, and the number of bradycardic spells were recorded by automated analysis of
the whole recording periods during S-NIMV and NIMV. The above-mentioned parameters
Materials and methods
36
will be calculated by automated software throughout each of the recording periods
without operator intervention in order to avoid bias during the data analysis. Severe
bradycardia (HR < 100 beats per minute) or desaturation (SpO2 < 80%) episodes, defined
as the period of bradycardia or desaturation lasting at least 10 seconds were counted for
both of the two ventilation modes. Data on spontaneous breathing effort were calculated
from 5 consecutive artifact-free breaths as described in section 2.5.2.
2.7 Statistical analysis
All values were presented as means and standard deviation (SD) for data of normal
distribution, otherwise as medians and ranges for those variables with non-normal
distribution. Within subjects comparisons of the data were obtained using paired t-test
or the Wilcoxon signed rank test when differences are not normally distributed. A
two-tailed alpha value of 0.05 (p<0.05) was considered as significant. Statistical
comparisons were done using SPSS, version 19.0 (SPSS Inc., Chicago, IL, USA).
Results
37
3. Results
3.1 Clinical variables
Between July 1, 2012 and June 30, 2013, thirty-eight patients met study criteria.
Among them, 8 infants were not available to be studied because informed consent from
their parents could not be obtained before extubation (Figure 6). Three patients could
not be studied because the Sophie ventilator or the recording system for Pe and PAW was
in use. Three patients were missed because other reasons. Two extremely small infants
could not be studied because their gestational age was less than 23 weeks and they were
considered too unstable by the clinicians to tolerate the study procedures. Finally,
informed consent was obtained from the parents of 22 infants and these 22 infants were
enrolled into the study. One infant had to be re-intubated due to severe desaturation and
bradycardia at the beginning of the second period study (S-NIMV) and was excluded from
analysis because of lack of data during S-NIMV. The data of another infant could not be
used due to a technical problem with recording of the esophagus pressure. The first 3
infants were exposed to an older software version of the ventilator. Thus their data could
not be analyzed. In another 3 infants there were too many artifacts of the Pe recording
trace to be analyzed. Finally, we collected the data of 14 eligible infants (Figure 6).
Among the 14 infants studied, 9 were male, while 5 female, GA was 26.3±2.3 wks;
birth weight (BW) 928 (475-1310) g; and postnatal age 6.5 (2-43) d, and weight on the
day of the study was 839 (450, 1310) g. All infants had been mechanically ventilated and
had received surfactant (200-300 mg/kg) (Curosurf-Chiesi Farmaceutici, Parma, Italy)
before the study. Before extubation, all infants had received caffeine (7.5±2.6 mg) by
intravenous route. Patient characteristics are shown in the table 1.
During synchronized nasal IMV(S-NIMV), two infants received a FiO2 = 0.21 and 12
required supplemental oxygen with their FiO2 ranging from 0.24 to 0.40; whereas 2
infants were on an FiO2 = 0.21, and 12 required supplemental oxygen ranging from FiO2 =
Results
38
0.23 to 0.39 at the time of non-synchronized ventilation. The ventilator settings were
similar for both study phases and were chosen by the clinical team (table 2). All 14
infants completed the study course, and no adverse events were observed. One infant
with suspected NEC failed extubation within 24 hours and was re-intubated. Five infants
were re-intubated after 24hours (39 hours-12 days), 1 at 39 hours, 1 at 69 hours, 1 at 3
days, 1 at 86 hours, and 1 at 12 days after extubation, due to either apnea-bradycardia
syndrome (ABS, 4 infants) or infection (1 infant). Among the 14 infants, 3 infants have
developed IVH (2 gradeⅡ, 1 grade Ⅳ), 1 infant had a pneumothorax and was stable
before we began the study.
Abdominal circumference did not significantly change between the two modes of
ventilation (22.04± 2.10 cm vs. 21.73±2.03 cm, S-NIMV vs. NIMV). All mothers received
antenatal steroid therapy before delivery. 4 mothers suffered from suspected
chorioamnionitis, and 3 from premature membrane rupture (PMR). Among the 14
mothers, 6 were treated with antibiotics before the delivery of the infants.
During the course of the study, no clinical adverse effect such as the breakage of the
nasal mucosa at the interface, pneumothorax, abdominal distention, necrotizing
enterocolitis (NEC), gastro-intestinal perforation, and intracranial hemorrhage (ICH)
occurred.
Results
39
Figure 6: Schematic diagram of participants (14 VLBWI were studied from 2012 to 2013
in Children’s Hospital, Ulm University. VLBWI: very low birth weight infants, S-NIMV:
synchronized nasal intermittent mandatory ventilation, NIMV: non-synchronized nasal
intermittent mandatory ventilation).
Results
40
Table 1. Demographic data of study infants (F: female, M: male, GA: gestational age; 14
very low birth weight infants were studied from 2012 to 2013 in Children’s Hospital, Ulm
University; red color refers to extubation failure within 24 hours, yellow color to failure
after 24 hours.)
Study Sex GA Birth
weight
(grams)
Age Weight Days of Surfactant Caffeine Reintubation
Infants (F/M) (weeks+days) (d) (g) ventilation (mg/kg) (mg/kg) time after
extubation
1 F 26+6 990 3 793 2 200 10 no
2 M 24+0 685 30 770 27 200 10 no
3 M 25+2 990 2 890 2 200 5 Yes (< 24h)
4 M 23+0 670 43 990 43 200 5 Yes (on 12d)
5 F 31+4 1290 6 1310 4 200 5 no
6 F 26+5 730 7 665 7 200 5 Yes (at 75h)
7 M 26+0 865 7 745 7 200 10 Yes (at 39h)
8 M 28+2 475 2 450 1 200 10 no
9 F 23+2 530 23 645 20 200 5 Yes (at 69h)
10 M 26+5 1180 4 1130 4 200 5 no
11 F 27+3 1010 5 885 5 300 10 no
12 M 24+4 615 5 575 5 200 10 Yes (at 86h)
13 M 28+1 1310 7 1250 7 300 10 no
14 M 27+0 1050 14 917 14 200 5 no
Results
41
Table 2. Ventilator setting in the two modes (S-NIMV & NIMV, S-NIMV: synchronized
nasal intermittent mandatory ventilation, NIMV: non-synchronized nasal intermittent
mandatory ventilation, FiO2: fraction of oxygen, PIP: peak inspiratory pressure, PEEP:
positive end expiratory pressure)
PIP
(cmH2O)
PEEP
(cmH2O)
Ventilator
rate
(Breaths/min)
FiO2
(%)
S-NIMV 14.98 ±2.00 5.61±0.74 38.21±14.62 28.74±6.19
NIMV 15.05±2.33 5.60±0.74 39.63±12.32 28.04± 6.01
p-value 0.61 0.10 0.33 0.31
3.2 Results of measurements
The spontaneous respiratory rate, deflection of esophagus pressure (Pe) (Figure 7),
and PCO2 significantly decreased while PO2 and synchrony rate significantly increased
during synchronized nasal IMV(S-NIMV) compared with non-synchronized IMV (NIMV)
(Table 3, Figure 8). There was a trend towards a lower blood pressure (diastolic, mean BP)
(Table 3), FTOE of brain (Table 4), and severe bradycardia time per event (Table 5) during
S-NIMV compared with NIMV. There was no difference in arterial oxygen saturation (SpO2)
(Table 3), regional cerebral tissue saturation (rSO2) (Table 4), and hypoxemic episodes
(Table 5) between the two modes. The mean airway pressure (PAW) was significantly
different between the two modes (Table 3). The ventilator provided more support and
synchrony during the synchronized mode than during the non-synchronized mode as
judged by the higher respiratory rate and PAW (Table 3). Synchrony rate (defined as the
rate of breaths when PIP of ventilator was delivered within the first half of spontaneous
inspiration) was significantly higher during S-NIMV as compared to NIMV. The results are
shown in the following tables (Table 3-6).
Results
42
Table 3. Vital signs (HR: heart rate, RR: respiratory rate, BP: blood pressure, sys: systolic,
dia: diastolic), gas exchange (PaO2: partial pressure of oxygen, PaCO2: partial pressure of
carbon dioxide), deflection of esophagus pressure (Pe), mean airway pressure (PAW) and
synchrony rate between the two modes (S-NIMV&NIMV, S-NIMV: synchronized nasal
intermittent mandatory ventilation, NIMV: non-synchronized nasal intermittent
mandatory ventilation); 14 very low birth weight infants were studied from 2012 to 2013
in Children’s Hospital, Ulm University.
Cohort S-NIMV NIMV p-value
HR (beats/min) 158.62±12.25 157.61±12.97 0.351
RR of ventilator
(breaths/min) 60.17±8.95 39.2±12.76 0.0003
SpO2 (%) 87.97±2.67 88.62±1.96 0.321
BP sys (mmHg) 55.17±8.08 55.91±5.49 0.533
BP dia (mmHg) 29.34±5.03 30.13±3.91 0.114
BP mean(mmHg) 38.27±6.38 39.25±4.64 0.205
PCO2 (mmHg) 55.71±12.07 57.45±11.03 0.031
PO2 (mmHg) 44.40±11.33 41.90±12.05 0.046
Pe (cmH2O) 5.70±1.71 7.02±2.52 0.024
Spontaneous
RR (breaths/min) 68.38±11.04 72.46±11.17 0.002
PAW (cmH2O) 8.55±1.14 7.91±1.34 0.002
Synchrony rate* 82% (59%-97 %) 26.5% (18%-33%) 0.001
Results
43
Table 4. Cerebral saturation (rSO2), SpO2 (oxyhemoglobin saturation by pulse oximetry)
fraction of tissue extraction (FTOE) between the two modes (S-NIMV&NIMV, S-NIMV:
synchronized nasal intermittent mandatory ventilation, NIMV: non-synchronized nasal
intermittent mandatory ventilation); 14 very low birth weight infants were studied from
2012 to 2013 in Children’s Hospital, Ulm University.
% SpO2 rSO2 (Right) FTOE(Right ) rSO2 (Left) FTOE(Left)
S-NIMV 87.97±2.67 67.39±6.43 23.4±7.22 67.59±7.14 23.17±7.36
NIMV 88.62±1.96 66.41±7.70 25.08±8.39 67.28±7.54 24.09±8.11
p-value 0.321 0.339 0.132 0.750 0.210
Most values were expressed as mean ± SD in Table 2, 3, 4 and analyzed by means of
paired T test. Synchrony rate* was expressed as median (range), and tested by Wilcoxon
Signed Ranks Test.
Results
44
Table 5. Bradycardia (heart rate <100 beats per minute) and desaturation (SpO2 <80%)
events during the two modes (S-NIMV&NIMV, S-NIMV: synchronized nasal intermittent
mandatory ventilation, NIMV: non-synchronized nasal intermittent mandatory ventilation).
Data were expressed as median (range), and tested by Wilcoxon Signed Rank Tests. 14
very low birth weight infants were studied from 2012 to 2013 in Children’s Hospital, Ulm
University.
Bradycardia Time/event
(seconds)
Hypoxia Time/event
(seconds) Time (seconds) Events Time(seconds) Events
S-NIMV 14(0-134) 2.5(0-8) 4.14(0-16.75) 271(0-2252) 11.5(0-56) 18.96(0-40.21)
NIMV 29(0-146) 3(0-13) 6.67(0-29) 310(0-1994) 14.5(0-62) 15.9(0-118)
p-value 0.476 0.679 0.424 0.463 0.807 0.249
Table 6. Severe bradycardia-desaturation (defined as the duration of per event with at
least 10 seconds duration) between synchronized and non-synchronized nasal ventilation
(Wilcoxon Signed Ranks Test); 14 very low birth weight infants were studied from 2012 to
2013 in Children’s Hospital, Ulm University
Bradycardia
Desaturation
Time(seconds) Events Time/event(seconds) Time(seconds) Events Time/event(seconds)
S-NIMV 0(0-116) 0(0-4) 0(0-38.67) 233.0(0-2224.0) 5.5(0-51) 28.38(0-47.33)
NIMV 11.0(0-134) 1(0-9) 11(0-29) 256(0-1912) 9.5(0-42) 31.16(0-232)
p-value 0.68 0.32 0.26 0.55 0.56 0.38
Results
45
Figure 7: Synchronized ventilator breath during the beginning of spontaneous inspiratory
breath in S-NIMV and NIMV respectively demonstrated by an arrow (S-NIMV&NIMV,
S-NIMV: synchronized nasal intermittent mandatory ventilation, NIMV: non-synchronized
nasal intermittent mandatory ventilation).
Figure 8: Example of Pe and PAW traces during S-NIMV and NIMV (Pe: deflection of
esophageal pressure, PAW: airway pressure, S-NIMV: synchronized nasal intermittent
mandatory ventilation, NIMV: non-synchronized nasal intermittent mandatory ventilation)
Discussion
46
4. Discussion
With the development of neonatal care and new treatment strategies in NICU, more
and more very immature infants can survive. Despite the use of antenatal steroids, early
use of surfactant, and “lung-protection strategies” (Wiswell, 2011) in very premature
infants with RDS, BPD is still a common chronic disease for very low birth weight preterm
infants. It is reported that RDS and BPD account for 21% of infant deaths each year due to
complications of prematurity (Mathews et al., 2002). The total incidence of BPD
complicated from premature infants with RDS is as high as 41% (Northway, 2001).
BPD is a multifactorial disease. Among these factors, lung immaturity and prolonged
mechanical ventilation are the critical factors (Bancalari and Claure, 2006; Brew et al.,
2013; Coalson, 2006; Demirel et al., 2009; Van Marter et al., 2000). BPD causes not only
the pulmonary adverse effects but also extra-pulmonary side effects such as neurological
sequelae and growth failure and adverse development (Doyle and Anderson, 2010;
Martins et al., 2010; Northway et al., 1990; Shepherd et al., 2012), which prolong
hospitalization and increase the economic burden on society and family.
Strategies to reduce BPD include avoiding delivery of very premature infants
(especially with a gestational age less than 28 weeks) and shortening the period of
prolonged invasive mechanical ventilation in order to reduce ventilator-induced lung
injury and oxygen toxicity. To prevent lung injury neonatologists use new methods of
respiratory support for the preterm infant such as non-invasive respiratory support i.e.
nasal ventilation more. The proclaimed benefit of non-invasive inspiratory pressure
support is less lung injury by reduction of volu- or barotrauma and atelectotrauma. Thus,
alternative techniques of nasal noninvasive ventilation such as NCPAP have been
advocated (Verder et al., 1994). However, NCPAP may not provide sufficient respiratory
support for extremely premature infants with severe RDS immediately after extubation.
Another way to support preterm infants after extubation in order to shorten the period of
invasive mechanical ventilation is the use of NIPPV.
Both NCPAP and NIPPV have the following desirable mechanism: preventing upper
Discussion
47
airway from collapse, maintaining FRC, recruitment of collapsed alveoli, and promoting
the release and conservation of surfactant (Gittermann et al., 1997). Moreover, NIPPV
may augment the beneficial effects of NCPAP by combining CPAP with additional inflations
thus decreasing the need for invasive mechanical ventilation (Barrington et al., 2001;
Friedlich et al., 1999). The latter effect may be particularly beneficial in very preterm
infants with poor and/or variable respiratory effort, who are prone to apnea and
desaturation.
There are a number of studies demonstrating that NIPPV is more effective to
successfully extubate preterm infants from invasive mechanical ventilation as compared
with NCPAP alone suggesting that the non-invasive breaths may decrease the WOB in
premature infants (Barrington et al., 2001; Gao et al., 2010; Kumar et al., 2011; Lin et al.,
2011; Moretti et al., 2008; Sai et al., 2009). In some of these studies NIPPV was used in
the synchronized mode, but not in others. Synchronized mechanical support in addition to
spontaneous respiratory efforts increase tidal volume (Hummler et al., 1996) and improve
gas exchange (Cleary et al., 1995). Furthermore, delivering the peak inspiratory pressure
into the pharynx in the synchronized mode immediately after the initiation of a
spontaneous inspiratory effort, when the glottis is open, allows the inspiratory pressure to
be transmitted to the lungs more efficiently and may help to prevent gas to be delivered
into the gastrointestinal tract and might reduce the risk for gastrointestinal complications.
Therefore, synchronized use of non-invasive IMV (intermittent mandatory ventilation)
should have beneficial physiologic effects as compared to non-synchronized non-invasive
IMV.
Chang et al have shown that synchronized nasal ventilation reduces breathing effort
and resulted in better infant-ventilator interaction than non-synchronized nasal ventilation
in stable preterm infants who were extubated already for some time (Chang et al., 2011).
However, the investigators were not able to detect any beneficial effects on gas exchange.
In addition, the physiological effects of synchronization have not been tested in VLBW
infants with residual lung disease of the RDS immediately after extubation, where lung
mechanics might still be adversely affected.
Discussion
48
According to the clinical observations, sicker infants with impaired lung mechanics
seem to benefit more from nasal respiratory support with S-NIMV than stable preterm
infants. In comparison to NCPAP, the use of S/NIPPV in NICU has demonstrated effects
with better clinical outcomes on premature infants in some studies (Gizzi et al., 2012;
Ramanathan et al., 2012). To date, however, no randomized control trial (RCT) comparing
SNIPPV versus non-synchronized NIPPV for management of VLWB infants recovering from
RDS immediately after extubation has been reported. To the best of our knowledge, this is
the first study comparing the short-term effect between SNIPPV (S-NIMV) and NIPPV
(NIMV) in VLBW infants with comparatively severe RDS immediately after extubation in a
randomized crossover design.
Our results have shown that PO2 increased significantly and PCO2 decreased during
the S-NIMV mode compared to the NIMV mode suggesting improved alveolar ventilation.
The VLBW infants in our study were studied within a few hours after extubation and with
some degree of respiratory distress. Thus, the VLBW infants in our study probably
required more respiratory support from nasal non-invasive mechanical ventilation in
comparison to the relatively stable infants in the study of Chang et al (Chang et al., 2011).
This difference in severity of residual lung disease might be the reason for the different
findings in Chang’s study who did not observe any beneficial effects on gas exchange.
Furthermore, they demonstrated that tidal volume, minute ventilation, and gas exchange
did not differ significantly between NCPAP, NIMV, and S-NIMV. In contrast to Chang et al,
we demonstrated that S-NIMV might improve gas exchange by providing more efficient
respiratory support to VLBW infants with comparatively severe RDS immediately after
extubation. Therefore, the beneficial effects of synchronization during non-invasive
ventilation in preterm infants might be dependent on the severity of residual lung disease.
Our results demonstrated that S-NIMV provided slightly more MAP and a higher
ventilator rate than NIMV and reduced the work of breathing as measured by phasic
esophageal pressure deflection. Higher energy expenditure by increased WOB may lead to
poor growth in VLBW infants. The decreased WOB of our VLBW infants during S-NIMV
suggests that S-NIMV might reduce the energy expenditure of VLBW infants and might
have beneficial effects for the growth if used on a long-term range. Future studies should
Discussion
49
follow the long-term effects including growth in infants supported by S-NIMV. In relation
to spontaneous breathing effort, our results are very similar to the data provided by other
research groups, who were able to show that S-NIMV actually decreases WOB and
improves pulmonary mechanics (Chang et al., 2011; Jackson et al., 2003; Khalaf et al.,
2001; Santin et al., 2004).
Kulkarni et al showed that introduction of SNIPPV at Yale-New Haven Children’s
Hospital (YNHCH) resulted in infants having significantly less need for supplemental
oxygen and a decreased rate of BPD, without compromising their weight gain compared
with NCPAP (Kulkarni et al., 2006). Another prospective study demonstrated that infants
with a birth weight of 600 to 1250 g with RDS receiving surfactant with early extubation to
SNIPPV had a significantly lower incidence of BPD/death (20% versus 52%, p=0.03)
compared to conventional mechanical ventilation. The authors of the latter study
suggested that SNIPPV is a feasible and a safe method of respiratory support in small
premature infants with very low birth weight (Bhandari et al., 2007). In addition, another
retrospective clinical study demonstrated that SNIPPV used in infants at greatest risk of
BPD or death (500–750 g) was associated with decreased BPD, BPD/death,
neurodevelopmental impairment (NDI), and NDI/death when compared with infants
managed with NCPAP (Bhandari et al., 2009).
However, another retrospective clinical study comparing clinical outcomes of
premature infants on SNIPPV (S-NIMV) vs. NIPPV (NIMV) was undertaken. BPD was
defined using the NIH consensus definition (Ehrenkranz et al., 2005). After adjusting for
the significant variables, use of NIPPV vs. SNIPPV did not significantly affect the rate of
BPD/death (odds ratio 0.74; 95% confidence interval: 0.42, 1.30). The authors suggested
that the use of SNIPPV vs. NIPPV is not associated with a significant effect on clinical
outcomes (Dumpa et al., 2012). More recently, Kirpalani et al undertook a large clinical
trial to assess the long-term effects of NIPPV vs NCPAP on the extremely low birth weight
(ELBW) infants (Kirpalani et al., 2013). 1009 ELBW infants (BW<1000g, GA<30 weeks) were
randomly assigned to either NIPPV or NCPAP at the time of the first use of non-invasive
respiratory support during the first 28 days of life at 34 tertiary care neonatal intensive
care units in 10 countries. The study demonstrated that the rate of survival without BPD at
Discussion
50
36 weeks of postmenstrual age was not significantly different comparing NIPPV with
NCPAP. However, most study infants did not receive synchronized non-invasive ventilation
(Kirpalani et al., 2013).
Until now, no prospective randomized control trial (RCT) has been done reporting on
long-term outcomes on infants managed with SNIPPV vs. NIPPV (Bhandari et al., 2009).
Future study should be designed to focus on long-term outcomes on VLBW infants
managed with SNIPPV vs. NIPPV. More important clinical outcome measures such as BPD
and/or neurodevelopmental outcome are the key points for those vulnerable VLBW
infants.
After the study, all our infants were supported by S-NIMV mode. Only one infant was
re-intubated within 24 hours after extubation (due to suspected NEC). It was a male infant
with GA: 25+2w, BW: 990 g, chronological age: 2 days, and his mother suffered from
chorioamnionitis. The other five infants with extubation failure were re-intubated much
later than 24 hours after extubation (from 39 hours to12 days), due to either
apnea-bradycardia syndrome (ABS, 4 infants) or infection (1 infant). According to our
clinical observations, apnea-bradycardia syndrome is still a common reason for needing
prolonged invasive ventilation in very immature infants. One of our infants (female,
29+5W, BW: 1250g, 3d, no prenatal steroids) experienced progressive respiratory failure
during the study time and was re-intubated at 30 minutes after initiation of the second
mode ventilation (S-NIMV) due to recurrent desaturations and bradycardia. One could
consider this event as a failure of S-NIMV, but on the other hand respiratory failure was
already progressing during non-synchronized NIMV before the infant crossed-over to
synchronized NIMV. The data of this infant was not analyzed due to incompletion of the
study. Because of our study design it is not possible whether or not synchronization of
NIPPV may have a beneficial effect on the need for re-intubation.
The following two reasons probably caused a relevant rate of re-intubation in our
study. First, in order to minimize ventilation induced lung injury (VILI) we try to reduce the
period of “aggressive” invasive ventilation in VLBW infants with RDS by extubating them
to non-invasive ventilation as early as possible. Therefore, by definition, we expect a
Discussion
51
significant rate of extubation failure. Second, we re-intubated the infants with intractable
apnea spells in time in order to maintain their clinical status stable and minimize the
possible adverse effects related to desaturation and hypoxia.
Intermittent bradycardia and desaturations are frequent events in immature infants
due to the immature control of breathing and remain a challenge for the neonatologist.
Apnea (brief cessation of breathing) is known to be secondary to the physiologic
immaturity of the central nervous system (Abu-Shaweesh and Martin, 2008). Apnea is
often associated with an immediate or followed by a drop in heart rate (bradycardia). It
might cause a pro-inflammatory cascade with such multisystem morbidity as retinopathy
of prematurity (ROP) and impaired growth, as well as possible longer-term
cardiorespiratory instability and even neurological sequelae (Martin et al., 2011).
Pillekamp et al has demonstrated that recurrent and persistent apnea and bradycardia are
correlated with longer-term neurodevelopmental impairment (Pillekamp et al., 2007).
Widely used treatments of apnea include the application of NCPAP and the
prescription of a methylxanthines. The methylxanthines —aminophylline, theophylline,
and caffeine reduce the frequency of apnea and the need for mechanical ventilation
during the first week of life (Henderson-Smart and Steer, 2001). Methylxanthines have
been the mainstay of the pharmacologic treatment of apnea for the past 30 years (Martin
et al., 2004). In our study, all infants accepted caffeine (5-10mg) before extubation to
prevent apnea. But intermittent desaturation and bradycardia still occurred in those very
immature infants. We did not observe significant differences comparing the two modes of
ventilation.
Pulse oximetry offers a noninvasive technique for real time and continuous recording
of intermittent hypoxic and bradycardiac episodes in preterm infants. As mentioned above,
most VLBW infants failed to extubate from invasive mechanical ventilation due to
recurrent severe apnea, which is in line with results from other investigators (Moretti et
al., 2008). SNIPPV might provide more efficient respiratory support to increase the rate of
successful extubation by decreasing apneic episodes in comparison to NCPAP (Barrington
et al., 2001; Moretti et al., 2008). However, the evidence for the superiority of SNIPP to
Discussion
52
NIPPV in reducing apnea of those infants is still less convincing. Chang et al found that
apnea and hypoxemia spells did not differ in clinical stable VIBW infants supported by
either S-NIMV or NIMV after extubation (Chang et al., 2011). In our study, there was a
trend towards less severe bradycardia measured as the consecutive time of heart rate less
than 100 beats per minute lasting at least 10 seconds, but no significant difference was
found in hypoxic spells between the two mode ventilation. Therefore, similarly to Chang
et al (Chang et al., 2011), we cannot conclude that S-NIMV is more efficient in preventing
apnea of VLBW infants with RDS immediately after extubation in comparison to NIMV.
There is a concern that increasing PIP in SNIPPV (S-NIMV) may alter the infant’s
respiratory pattern and increase breathing asynchrony. However, in our study, we found
that most of the non-invasive breaths from the ventilator during synchronized ventilation
were provided simultaneously with the initiation of spontaneous inspiration of the infants.
Synchrony rate was much higher during S-NIMV with 82% (59%-97%) of ventilator cycles
as judged by mechanical breaths being delivered early in the spontaneous inspiration. In
contrast, during NIMV only 26.5% (18%-33%) of ventilator cycles were delivered during
initiation of spontaneous inspiration breathing (Figure 7). Therefore, our study
demonstrated that adequate synchrony between the ventilator cycle and spontaneous
respiratory activity was achieved by using the Graseby capsule using this newly develop
system.
Moreover, asynchronous breaths from the ventilator might increase the risk of side
effects as pneumothorax (Greenough et al., 1983), and blood pressure and cerebral blood
flow velocity fluctuations (Perlman et al., 1983). Systemic blood pressure and cerebral
blood flow velocity fluctuations might cause brain injury such as intracranial hemorrhage
(ICH) and ischemic brain injury, which are both associated with poor prognosis in this
population of very immature infants (Perlman et al., 1983). Asynchronous breaths from
the ventilator also might lead to discomfort to those very immature infants even requiring
some paralysis medicine to eliminating the asynchrony. Thus, synchronized respiratory
support from the ventilator is benefit to the very immature infants.
In our study, we found a trend towards a lower, but within normal range blood
Discussion
53
pressure (diastolic, mean BP) during S-NIMV compared with NIMV. A possible explanation
of this finding may be that infants “felt” more comfortable during S-NIMV and were less
agitated resulting in the lower blood pressure. It is possible that our 2-hour short-term
ventilation period was not long enough to show significantly different effects on BP or
other measures of hemodynamics. During our study, we did not find complications such as
pneumothorax and ICH from asynchrony. However, this would not be expected due to the
short-term study period and the cross-over design. Furthermore, at the chronological age
of our study infants the development of ICH is very unlikely.
Nowadays, what the neonatologists focus on is not only the survival rate of the VLBW
infants but also the life quality of those immature infants. Very immature infants have a
high risk for cerebral injury caused by hypoxia-ischemia, stroke, ICH and PVL, which may
be associated with cerebral palsy, long-term epilepsy or neurological deficits, visual and
hearing problem (Kiechl-Kohlendorfer et al., 2009). These neurological deficits are the
major causes of reduced quality of life resulting in increased use of medical care,
rehabilitation and special education in this population. It is a big burden on the family and
the society to rehabilitate, educate and take care of those infants.
The vulnerable brain of the VLBW infants may be injured by impaired gas exchange.
Inadvertent mechanical hyperventilation might lead to cerebral vasoconstriction and
decreased cerebral blood flow (Greisen and Trojaborg, 1987). The variable pattern of
cerebral blood-flow velocity in immature infants with RDS implies a high risk of the
development of ICH (Perlman et al., 1983). It may be extremely important to protect those
immature infants with RDS from some potentially preventable etiologic factors by means
of monitoring their cerebral hemodynamics. Moreover, monitoring of cerebral function
has become available during recent years and might be a valuable adjunct for unstable
immature infants. Portable non-invasive devices are now available to assess brain
oxygenation and do not interfere with other diagnostic and therapeutic equipments in
neonatal intensive care units (NICUs).
NIRS has become an effective research tool for studying infant cerebral
hemodynamic and oxygenation (Wintermark et al., 2013). Some clinical studies
Discussion
54
demonstrated that the range of rSO2 values in neonatal infants and children usually is
anywhere between 65% and 85% (Dullenkopf et al., 2003; Lemmers et al., 2006). However
the normal range of rSO2 in very immature infants is still not well defined. Until now, there
are no studies available on cerebral oxygenation to compare synchronized nasal IMV and
non-synchronized nasal IMV in premature infants by means of NIRS.
Inadequate cerebral oxygenation is an important factor intrigued with neonatal brain
injury. In the immature infant, lower cerebral oxygenation might lead to ICH (Verhagen et
al., 2010). In our study, the results of rSO2 are within the normal range of newborns
between 65% and 85% (Dullenkopf et al., 2003; Lemmers et al., 2006). Even if S-NIMV
provided improving gas exchange in comparison to NIMV in our study, no difference of
rSO2 was found between the two ventilation modes. The possible reason may be that the
variance of gas exchange between the two modes was still within the physiologic range.
Furthermore, as infants were studied at a mean of 6.5 days it may be that auto-regulation
of cerebral blood flow is functioning well at this age in most infants. In addition, their
systemic BP was also in normal range.
For correction of differences in peripheral oxygen saturation (SpO2), the fractional
tissue oxygen extraction (FTOE) was calculated as following formula: FTOE=
(SpO2−rSo2)/SpO2. FTOE is a measure of oxygen utilization of the brain, which reflects the
balance between cerebral oxygen supply and cerebral oxygen consumption (Naulaers et
al., 2007). The increase of FTOE shows an increase of the oxygen extraction by brain tissue,
meaning higher oxygen consumption as compared to oxygen delivery. On the contrary, the
decrease of FTOE suggests less utilization of oxygen by brain tissue in comparison with the
supply. There was a trend towards a lower FTOE of brain during S-NIMV compared with
NIMV in our study, which means that a trend towards a lower cerebral oxygen
consumption during S-NIMV in comparison to NIMV. One possibility of this finding is that
infants were less agitated during S-NIMV and therefore cerebral oxygen consumption was
reduced. Another explanation would be increased blood flow resulting in a lower oxygen
extraction. The observed changes in FTOE, however, were not significant, but they are
somewhat in line with the observed trend towards a lower BP and a significantly lower
asynchrony rate during S-NIMV in comparison to NIMV. The lower but still normal blood
Discussion
55
pressure could be an indicator for less agitation.
In our study, no adverse effect was found during either S-NIMV or NIMV mode of
assisted ventilation. We did not find any gastrointestinal complications during either
S-NIMV or NIMV period. The abdominal girth was not significantly different between the
two ventilation modes. No presentation of significant abdominal distention, necrotizing
enterocolitis, gastrointestinal perforation, pulmonary air leak, upper airway injury
including erosion of the nasal septum, or cardiovascular adverse effect was found in our
study. This is probably related to the design of the study (short-term crossover).
There were some limitations in our study. First, due to the study design we could
only document only short-term effects of the nasal intermittent mandatory ventilation by
either synchronized or non-synchronized method. Second, the sample size of the study is
small. We cannot exclude that there might be more striking effects of synchronization
during longer periods of nasal respiratory support in a large population of VLBWI. We
cannot tell if the advantages of SNIPPV in the short-term over NIPPV following extubation
lead to real and meaningful clinical long-term outcomes. In future studies, large sample
size RCT in VLBW infants with RDS immediately after extubation supported by S-NIMV
versus NIMV need to be performed to detect differences in clinically relevant long-term
outcomes, such as BPD, ROP and neurodevelopment outcome.
Summery
56
5. Summary
More and more very preterm infants survive because of the improvement of new
ventilation techniques and the use of surfactant. However, very immature preterm infants
have a high risk for mortality and especially morbidity, which may have a major impact on
the quality of life. One of the most common chronic conditions is
Broncho-Pulmonary-Dysplasia (BPD), which is closely linked with lung injury secondary to
the use of invasive mechanical ventilation of the immature lung. Thus, in order to reduce
invasive mechanical ventilation, non-invasive ventilation i.e. nasal ventilation is
increasingly used in those infants. The physiological effects of synchronization during
non-invasive nasal intermittent mandatory ventilation (IMV) have not been tested in very
low birth weight infants (VLBWI) immediately after extubation.
Objectives: The objective was to study the short-term effects of synchronized nasal
IMV (S-NIMV) as compared to non-synchronized nasal IMV (NIMV) on breathing effort as
measured by phasic esophageal pressure deflection (Pe), spontaneous respiratory rate
(RR), gas exchange, cerebral tissue saturation, and intermittent episodes of bradycardia or
hypoxemia in VLBWI immediately after extubation recovering from respiratory distress
syndrome (RDS). We hypothesized that synchronized nasal IMV (S-NIMV) as compared to
non-synchronized nasal IMV (NIMV) will decrease breathing effort in preterm infants
immediately after extubation when recovering from RDS, as measured by phasic
esophageal pressure deflection (Pe). Furthermore, we assessed the reliability of a newly
developed abdominal pressure sensor device for the S-NIMV mode in a commercially
available ventilator device.
Methods: Fourteen VLBWI with RDS were studied using a randomized cross-over
design during either S-NIMV or NIMV for 2 hours each immediately after extubation. A
SophieR -Ventilator (Stephan GmbH, Medizintechnik, Gackenbach, Germany) capable to
synchronize mechanical breaths with a Graseby-Capsule was used for the study. The
ventilator settings were similar for both study phases and were chosen by the clinical
Summery
57
team. Cerebral tissue oxygenation was measured using near infrared spectroscopy
(FORE-SIGHT, Casmed, Branford CT). The characteristics of the 14 infants were: five female,
nine male; GA 26.3±2.3 wks; birth weight (BW) 928 (475-1310) g; and postnatal age 6.5
(2-43) d, weight 839(450, 1310) g on the day of study.
Results: The spontaneous respiratory rate (RR), deflection of esophagus pressure (Pe),
and PCO2 significantly decreased while PO2 and synchrony (defined as peak inspiratory
pressure-PIP of ventilator delivered within the first half of spontaneous inspiration) rate
was significantly higher during S-NIMV as compared to NIMV. There was a trend towards a
lower blood pressure (diastolic, mean BP), fractional tissue oxygen extraction (FTOE) of
brain, and a less severe bradycardia (the consecutive time of heart rate less than 100
beats per minute lasting at least 10 seconds) period per event during S-NIMV compared
with NIMV. There was no difference in arterial oxygen saturation (SpO2), cerebral tissue
saturation (rSO2), and hypoxemic episodes between the two modes. The mean airway
pressure (PAW) was significantly different between the two modes (8.55±1.14 vs.
7.91±1.34 cmH2O, p<0.01, S-NIMV vs. NIMV), while the respiratory rate from the
ventilator was also significantly different (60.17±8.95 vs. 39.20±12.76 breathing per
minute, p<0.01, S-NIMV vs. NIMV).
Discussion: We demonstrated the beneficial short-term effects of synchronized nasal
IMV (S-NIMV) versus non-synchronized nasal IMV (NIMV) on spontaneous breathing effort.
Similarly to Chang et al (Chang et al., 2011), respiratory support from S-NIMV can reduce
spontaneous respiratory effort of VLBW infants with RDS. In our study, gas exchange was
improved during S-NIMV but not in the study of Chang et al, which might be related to our
study population, which had more severe lung disease.
Conclusion: Synchronization during nasal ventilation immediately after extubation in
VLBWI recovering from RDS seems to result in a more efficient respiratory support and
improve gas exchange by decreasing the respiratory effort and providing the more
respiratory support and synchrony. Large randomized studies are needed to prove
long-term beneficial effects of synchronizing nasal ventilation in preterm infants with
references
59
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Curriculum vitae
73
7. Curriculum vitae
Name Huang Li Birthdate 29th, Aug, 1969
Date Education and Work Experience
09.1987----07.1992 Medical University of China (in Shen Yang),B.A
09.1992----12.1998 Qing Hai Children’s Hospital----resident Doctor (Pediatrician)
12.1998----09.2001 Qing Hai Children’s Hospital---- attending physician (Pediatrician)
09.1999----09.2000 The Affiliated Hospital of Aarhus University, Denmark---visiting scholar
09.2001----07.2004 Medical College, Southeast University, M.A.
07.2004----10.2011 Zhong Da Hospital, Southeast University, associate professor
10.2011----12.2013 Children’s hospital of Ulm university, Germany, M.D.
Publications:
1. The intervention of mechanical ventilation on neonatal pulmonary hemorrhage.
Clinical Focus, 2002, 17(2):67
2. Electrogastrography in neonates related to postconceptional age. Journal of Qinghai
Medical College, 2003, 24(2): 78-83
3. The clinical application of neonatal behavioral neurological assessment in newborns
with Hypoxic-ischemic Brain Damage. Journal of Qinghai Medicine, 2003, 33(7): 8-10
4. Brain-derived neurotrophic factors and neonatal HIBD. Foreign Medical Sciences
Section of Maternal and Child Health, 2003, 14(5): 279-281
5. To explore the related factors affected the prognosis of neonatal ICH. The Journal of
Clinical Pediatrics, 2004, 22(1): 15-18
6. To explore the hemodynamics change of newborns with HIE. The Journal of Clinical
Pediatrics, 2004, 22(12): 802-804
7. Electrogastrograph in gastroenterology neonates related to postconceptional age.
First world congress of pediatric, hepatology and nutrition. 2000.8.
Curriculum vitae
74
8. Electrogastrograph in preterm infants treated with phototherapy for neonatal
jaundice. The first world congress of pediatric gastroenterology, hepatology and
nutrition. 2000.8
9. The protective effect of NGF on Hypoxic-ischemic neuronal cells in neonatal brain.
Chinese Journal of Clinical Rehabilitation, 2005 12 (9 ): 82-84
10. Electrogastrography in neonates. Lange A, Huang L, Funch-Jense. P
Neurogastroenterol Motil, 2005 17(4): 512-7
11. No request from others for healthy baby. Nanjing university publishing house.2004,3
ISBN:7-305-04127-0/R.147
12. The physical examination of child.(DVD teaching material of healthy ministry, 2007)
13. Pediatrician’s handbook. Anhui scientific-technologic publishing house, 2007.
14. Therapeutic efficacy of high frequency oscillatory ventilation on neonates with acute
respiratory distress syndrome. Bi MY, Huang L. Jiangsu Med J, 2009, 35(3): 266-268
15. Preventive effect of microecological preparation on neonatal necrotizing enterocolitis
of 412 Premature Infants. Li H, Qiao LX, Huang L, et al. J Appl Clin Pediatr, 2011, 26(8):
622-623
16. The effect of Budesonide inhaled on newborns with ventilator-associated laryngeal
edema. Wen Q, Li HL, Huang L, et al. ACTA UNIVERSITATIS MEDICINALIS NANJING
(Natural Science), 32(11):1579-1580
17. The therapeutic effect of Curosurf combined with high frequency oscillatory
ventilation on neonatal infants with moderate-severe RDS. Huang L, Zhu H, Qiao LX,
et al. Jiangsu Med J, 2013, 39(4): 471-473
18. Effects of synchronization during noninvasive intermittent mandatory ventilation in
very low birth weight infants (VLBWI) recovering from RDS immediately after
extubation. Huang L, Mendler MR, Waitz M, Hassan M, Hopfner R, Fuchs H, Schmid M,
Hummler HD.PAS, 2013
Acknowledgement
75
8. Acknowledgments
I would like to take this opportunity to express my limitless thanks to many people
who contributed to the completion of the clinical research. First and foremost, I would
like to express my deepest respect and gratitude to Prof. Dr. Helmut D Hummler who
undertook to act as my research supervisor despite his many other academic and
professional commitments. He is not only a great professor with deep vision, but a very
kind, warm-hearted, and easy-going person as well. During the course of the clinical trial,
even during midnight, he still stayed in the hospital and provided guidance to me. His
generous help and suggestive discussion have been benefiting me so much during past
two years, and still in my future clinical and research work.
My thanks go out to Dr. Marc Robin Mendler, Dr. Markus Waitz M, Mohammad
Ahmad Hassan who provided me the support for the trial and helped me to communicate
with patients’ parents in their native language. In addition, I should express my gratitude
to Dr. Schmid M, Dr. Hopfner R, Dr. Fuchs H and all of the colleagues (doctors and nurses)
of neonatal intensive care unit of children’s hospital affiliated Ulm University. I own
special gratitude to the very low birth weight infants and their guardians who agreed and
cooperated with the study.
It is no doubt that I must thank University of Ulm, especially the Medical Faculty, for
providing the stipend in terms of partner cooperation with my home university, the
Southeast University, for my research and stay in the University of Ulm. I extend this
gratitude to all people involved in this program especially Prof. Dr. Yuefei Liu. I would like
to thank my former Chinese advisor Prof. Dr. Jiang Li for her trust and recommendation.
Thanks would be expressed to many Chinese friends for their friendship and support
during my stay in Germany.
Last but not least, I deeply appreciate the great encouragement and love from my
dear parents, sisters, brother, husband and my lovely daughter because their