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

Summery

58

respiratory failure recovering from RDS.

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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

Acknowledgement

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unconditional support and love gave me the strength and confidence to stay alone in

Germany and finish this thesis.