Neonatal Intensive Care Manual for the infants
born less than 28 weeks of gestation(Ver. 1.1)
Neonatal Research Network of Japan(http://plaza.umin.ac.jp/nrndata/)

Contributors (according to writing order)
Satoshi Kusuda

Kyorin University

Tetsuya Isayama

National Center for Child Health and Development

Shinya Hirano

Osaka Women’s and Children’s Hospital

Hidehiko Nakanishi

Kitasato University

Tomohiko Nakamura

Nagano Children’s Hospital

Hiroko Iwami

Osaka City General Hospital

Masahiro Hayakawa
Isamu Hokuto
Tokuo Miyazawa
Masanori Fujimura

Nagoya University
St. Marianna Medical University
Showa University
Osaka Women’s and Children’s Hospital(2019 All rights reserved by Neonatal Research Network of Japan)

This manual was first published by Neonatal Research Network of Japan, October
2019. No part of this this document may be reproduced without written permission
from the copyright owner, except brief quotations embodied in scientific articles andreviews.
This document reflects the consensus reached by all contributors. The contributors
have exerted every effort to ensure that the information in this manual is inaccordance with current recommendations and practice at the time of publication.
However, the contributors are not responsible for errors or omissions or for any
consequences from application of the information in this manual.

2

Contents
0 Introduction

4

1 Resuscitation

6

2 Respiratory support

16

Non-invasive respiratory support and conventional mechanical ventilation
High-Frequency-Oscillatory Ventilation
Prevention of CLD
3 Circulatory support

40

General support
Cardiovascular agonists
Management of PDA
Prevention of IVH
4 Intravenous fluid management

66

Fluid management
Parenteral nutrition
5 Enteral feeding80

6 Infection control

93

7 NICU environment100

30 Introduction

0.1 Extremely preterm infants
Infants born below 28 weeks gestation are usually called “extremely preterm (EP)” or“extremely low gestational age newborn” (ELGAN) infants. The introduction of modern
neonatal intensive care has improved the survival rates of these infants dramaticallyover the last several decades. The updated outcomes of EP infants in Japan areavailable on a Neonatal Research Network of Japan web site(http://plaza.umin.ac.jp/nrndata/indexe.htm). According to this database, the averagesurvival rate of EP infants born in 2016 was more than 90% but more than 20% of
survivors are left with residual disability, including cerebral palsy, suggesting that the
chances of intact survival remain questionable. In addition, survival rates of infants
born below 24 weeks gestation are low. Considerable efforts must therefore be made to
improve both survival and outcomes of all EP infants.

0.2 Features of this manualThis is not a general manual for NICU, rather a subdivided manual for EP infants
during the first several weeks in NICU as the type of care received by the infant during
the first several days and weeks of life is crucial for optimum survival andneurodevelopmental outcomes. The type of management discussed in this manual may
not be scientific or evidence based as NICU care is subject to center variations.
However, this manual is prepared from consensus amongst practicing Japaneseneonatologists and we believe that this manual can represent accept care of the EP
infant in Japan.
Since this is the first version of the manual, future modifications in line with practicechange are anticipated. Your opinions are therefore crucial to the development andrefinement of this manual and please do not hesitate to contact us as your involvement
will be crucial to improve this manual for the future.

0.3 Topics addressed by this manual:
1. Delivery room resuscitation and respiratory support
2. Respiratory care
3. Circulatory support
4. Intravenous fluid management

45. Enteral feeding
6. Infection control
7. The NICU environment

0.4 Acknowledgement
The contributors to this manual were entirely voluntary and we thank them for theirtime and expertise in its development.
We also express our sincere gratitude to Professor Ju Lee Oei at The Royal Hospital for
Women and University of New South Wales for her critical reading of this manual.

（Contributor: Satoshi Kusuda, Audit: Masanori Fujimura）

5

1 Resuscitation

1.1 The clinical scenario
At birth, newborn infants are removed from the placental circulation after theumbilical cords are ligated and pulmonary respiration is established. In order toestablish air breathing, the fluid that filled the lungs in-utero must be replaced withair. This instigates gas exchange within the lung. After initiation of respiration, it isimportant to prevent the expanded alveoli from collapsing, which establishes
functional residual capacity of the lung. Pulmonary surfactant from the alveoli plays acritical role here. With breathing, alveolar oxygen partial pressure dilates pulmonary
blood vessels that were contracted during the fetal period, leading to decreased
pulmonary vascular resistance, increased pulmonary blood flow and further promotionof pulmonary gas exchange.
The following physical features of the EP infant must be considered when providing
immediate care:⚫

Relatively large head compared to the body⚫

High position of the larynx⚫

Poor production of pulmonary surfactant increasing the risk of alveolar collapse⚫

Fragile skin susceptible to injury⚫

Large body surface area compared to body weight leading to hypothermia or poor
control of body temperature⚫

Fragile germinal matrix vasculature with which postnatal stress including
unstable circulation leads to intraventricular hemorrhage (IVH).

1.2 General Management
1.2.1 Prenatal counselingJapan has one of the lowest neonatal mortality rates in the world. This is also true for
EP infants. Even so, the mortality of preterm infants born at 22-23 weeks of gestation
or with birth weights under 500 g are still high and their long-term
neurodevelopmental outlook continues to be poor. Therefore, prenatal counseling is
crucial if time allows, in order to provide information for the parents and to discuss
their wishes. This is especially important if birth occurs at 22 weeks gestation becauseof extremely high morbidity and mortality rates. Ideally, the figures for each institution
should be used for counselling but if unavailable, Japanese national data can be used.

6

1.2.2 Mode of delivery
There is no specific opinion as to which delivery mode (transvaginal delivery, cesarean
section) is best for EP outcomes, including mortality. Policies differ from hospital tohospital. Some hospitals may advocate vaginal delivery if there are no contraindications whilst other hospitals may preferentially choose to deliver all EP infants bycesarean section to avoid any unexpected trauma from a vaginal birth. About 75% of
EP infants are delivered by cesarean section in Japan.
1.2.3 Prenatal glucocorticoid administration
Prenatal glucocorticoid administration is recommended for women below 34 weeks ofgestation who are expected to deliver within a week of presentation and if active
management is preferred. Prenatal glucocorticoids reduce the risk of respiratory
distress syndrome (RDS), IVH, and mortality in preterm infants. There are only a few
clinical trials regarding the efficacy of steroids for EP infants at 22-23 weeks ofgestation but observational studies suggest that they may decrease risk ofcomplications and death.
1.2.4 Preparation
Preparation is crucial for any preterm birth. The equipment that is required is shownin table 1. The following must be checked prior to birth:
1. Aspirator or suction device, set to below 100 mmHg [13 kPa]
2. Jackson Rees and T-piece resuscitation device
3. Laryngoscope light source.
It is important to use a check list and to obtain verbal confirmation because lack ofequipment or malfunction may be fatal for the infant.
1.2.5 Umbilical cord milking
If umbilical cord milking is planned, request that the obstetrician leave at least 30 cm
of cord after clamping at the placenta. Cord milking can be conducted after the infant
is transferred to the radiant warmer. Umbilical cords are often twisted, so remember to
untwist the cord (if needed) prior to milking it.
1.2.6 Temperature control
EP infants have a large body surface area relative to their weight and thin skin so they7are likely to lose heat energy rapidly and quickly become hypothermic. It is
recommended for the resuscitation room temperature to be kept at or above 26 °C andthat a radiant warmer, warm blankets, plastic wraps, a head cap, or thermal
mattresses be used during the resuscitation. After the resuscitation, in order to preventthe body temperature drop during the transport to NICU, the inside temperature of thetransport incubator should be maintained at 37 °C or higher. The target bodytemperature at reaching NICU is in the range of 36.5-37.5 °C.
1.2.7 Flow of resuscitation
Resuscitation is performed according to Neonatal Cardio-Pulmonary Resuscitation(NCPR) guidelines in Japan for both term and preterm infants, and the NCPR
algorithm of Figure 1 should be observed (1).
1.2.7.1 Resuscitation personal
A primary resuscitator whose role is to focus on the respiratory management of theinfant should stand at the head of the infant. The bed height should be adjusted to fit
this person. Assistants stand on either side of the infant. In addition, a team leader
whose role is to direct the resuscitation process as well as being additional help for theresuscitation team should be allocated.
1.2.7.2 Drying skin surface
Gentle handling is important for EP infants, especially those at 22-23 weeks ofgestation. Because the skin is very fragile, it is recommended that drying be achieved
by gentle wiping with warm gauze rather than by rubbing.
1.2.7.3 Probes and electrodes
One of the assistants should place ECG monitor electrodes on the infant’s chest andattach an SpO2 monitor probe on the right hand immediately after birth. Gauze can beplaced between the skin and the electrodes in order to prevent skin damage.
1.2.7.4 Respiratory management
The primary resuscitator evaluates the infant’s condition according to the NCPR
algorithm (Figure 1)(1). If required, the oropharynx should be suctioned to clear mucus
and other secretions. A shoulder pillow may be placed to assist appropriate positioningof the infant’s neck (sniffing position) to secure and open the airway. An under or overextended neck can both cause airway obstruction.

8

Then, continuous positive airway pressure (CPAP) or bag & mask ventilation should becommenced. Lung tissues of EP infants are fragile and susceptible to barotrauma,
volutrauma, atelectrauma, and oxygen toxicity during CPAP and bag & mask
ventilation. It is important to adjust the airway pressure and oxygen concentrationaccording to manometer and pulse oximeter readings.
Initial oxygen concentration can start between 30 and 60% and adjusted appropriately
to the target pre-ductal SpO2 cited in Figure 1 (1).
The alveoli of EP infants are easily collapsed because of pulmonary surfactant
deficiency. It is therefore important to apply positive end-expiratory pressure (PEEP) of
about 5 cmH2O at the expiratory phase during positive ventilation. In addition, a highairway pressure is often required at the first opening of the alveoli. Thus, positive
ventilation should be initially started with an inspiratory pressure of 20-25 cmH2O,
which can then be adjusted to thoracic movement and heart rate changes.
In almost all preterm infants of 22-23 weeks of gestation, assisted ventilation is
ultimately required. Resuscitation with bag & mask ventilation can be used
immediately after birth but after stabilization, tracheal intubation can be performed ina calm manner. If bradycardia (HR <100) continues even after appropriate bag & mask
ventilation, prompt tracheal intubation is necessary.
1.2.7.5 Circulatory management
Intravenous rapid volume loading is considered a risk of IVH, so rapid volume
infusions unless hypovolemia is suspected due to obvious bleeding or if the infant does
not respond to initial resuscitation efforts, should be avoided.
1.2.7.6 Tracheal intubation
It is most important to keep the infant’s head in the appropriate sniffing position, as
shown in Figure 2 for successful tracheal intubation (1). The infant should lie in asupine position with the axes of the head and trunk maintained in a straight position.
When placed in a supine position on a flat bed, the necks of EP infants may be bent due
to their large heads, leading to airway obstruction. For this reason, it is important tobend the head slightly back to extend the neck and lift the mandible slightly so that
there is adequate space between the mandible and the front neck (sniffing position).

9

The use of a shoulder pillow with hand towel (under the shoulders) makes it easy tobend the head back without undue (extension of the neck). Placing a pillow (under thehead) instead of the shoulder pillow, extending the neck and lifting the head caudally
forward may also be successful. Avoid hyperextension of the neck as it will obstruct the
airway and block adequate view of the glottis.
Table 2 shows the reference values of tracheal tube size and length of fixing tube
according to gestational age and birth weight (1). A 2.0 endotracheal tube may be used
if a 2.5 tube does not pass easily into an EP infant’s airway.
Laryngoscopes with a size of 00 or 0 blades must be used. In EP infants, stylets may
cause tracheal injury so to avoid using stylets if at all possible.
1.2.7.7 After tracheal intubation
After tracheal intubation, the tube position should be checked using a breath CO2
detector to confirm correct placement and that the esophagus has not been intubated.
Auscultation of the chest on both sides should be also performed to confirm that theendotracheal tube has not been passed into the right main bronchus.
EP infants often have RDS, and therefore, supplemental pulmonary surfactant should
be promptly administered. Ideally, a diagnosis of RDS should be based on a
combination of high oxygen concentration and inspiratory pressure needs, a micro
bubble test, and a chest x-ray. In recent years, it has been reported that a method
called Intubate-Surfactant-Extubation (INSURE), in which tracheal intubation,
pulmonary surfactant administration, and immediate extubation followed by CPAP iseffective in preventing chronic lung disease. However, in Japan, the INSURE method is
not commonly used for EP infants, (especially around 22-24 weeks of gestation) becauseof the risk of IVH from unstable respiratory and circulatory dynamics. For these
infants, it is recommended that they be placed on a mechanical ventilator for at least
72 hours after birth to stabilize their respiratory status and to avoid the stress of reintubation.
1.2.7.8 Post resuscitation treatment
Avoid hypothermia after resuscitation by placing the infant as soon as possible in aclosed incubator that is warmed in advance for the transport of infants to the NICU.
Warm towels, plastic wrap and head caps are also effective in retaining heat.

10

To prevent critical hypoglycemia, blood glucose levels must be checked as soon as
possible. However, regardless of this result, glucose must be infused through central
venous lines (umbilical vein line or peripheral inserted central catheter [PICC]) must
be started immediately after stabilization of the EP infant.
Infants requiring mechanical ventilator support must have an arterial line (umbilicalartery line or peripheral artery line) for continuous blood pressure measurements andblood sampling.
References
1) The Textbook of Neonatal Cardiopulmonary Resuscitation. Based on the 2015
Guidelines of the Japan Resuscitation Council. 3rd edition. (Available
from: https://www.ncpr.jp/eng/course_material.html, Accessed on Apr 13, 2019). Hosono
S, editor.

11

Table 1 Tools and devices required for resuscitation of EP infants
Open type incubator (radiant warmer)
Temperature

Transport incubator (warm)

ControlWarm towels and gauze
Plastic wrap (food wrap can be used)
Aspirator, suction catheter (for mouth and nose: 6-8 Fr, trachea: 5, 6

RespiratoryFr)assistFace masks for preterm infants (different sizes)
Jackson Reese (with manometer) or T-piece resuscitation device
Oxygen source (with flow meter), compressed air, oxygen air blender,
flow meter
Laryngoscope (handle, straight blade [size 00 or 0], spare battery andTrachealbulb. Make sure that the bulb is functional and not loose)

Intubation

Tracheal tube (inner diameter: 2 mm, 2.5 mm, 2 each), stylet
Tracheal tube fixing tape
Exhaled CO2 detector

Monitoring

Stethoscope
Pulse oximeter (SpO2 monitor) and probe
Respiratory and heart rate monitor, and electrodes

Lines

Umbilical catheter (5 Fr for veins, 3.5 Fr for arteries)
Peripheral vein catheter (24G)
Intravenous infusion set
Injection needle (23G, 22G, 18G)
Syringe (1 ml, 2.5 ml, 5 ml, 10 ml)
Alcohol cotton

Drugs

Saline solution, 5% glucose solution, 10% glucose solution, adrenalin,sodium bicarbonate, calcium gluconate
Pulmonary surfactant preparation

OthersSterile gloves, gowns, masks, caps
Feeding tube (3-5 Fr)
Scissors

12

Table 2 Selection of endotracheal tube
Weight (kg)

Gestational

Tube size (mm)weeks (weeks)

Estimated insertion length
up to the corner of themouth (cm)*

＜1.0

＜28

2.0, 2.5

6.0－7.0

1.0－2.0

28－34

2.5, 3.0

7.0－8.0

2.0－3.0

34－38

3.0, 3.5

8.0－9.0

＞3.0

＞38

3.5

>9.0

*The insertion length up to the corner of the mouth can be calculated by approximately
6 + body weight (kg) cm.

13

Figure 1 NCPR resuscitation algorithm

14Figure 2 Proper Sniffing position (Avoid neck hyperextension and flexion)（Contributor: Tetsuya Isayama, Audit: Shinya Hirano）

15

2. Respiratory support

2.1 Non-invasive respiratory support and conventional mechanical ventilation
2.1.1 Clinical situation
Newborns, especially EP infants, have immature anatomical and functional respiratory
systems. The smooth transition from placenta to independent air breathing is thus alsofrequently disrupted in EP infants, resulting in the need for respiratory support after
birth in almost all infants in some way. The anatomical characteristics of therespiratory system in EP infants include a small area of gas exchange, narrow airways,
and a soft and pliant chest wall. Functionally, respiratory control is immature, with thediaphragm acting as a dominant force in respiration. Breathing is predominantly nasal
and there is high pulmonary vascular resistance and insufficient pulmonary surfactant
secretion.
Unlike physiological respirations which is negative pressure ventilation, any kind of
respiratory support is performed under positive pressure and driven externally. Lungdamage is unavoidable long-term positive pressure is applied, especially on theimmature developing lungs (volutrauma, barotrauma, etc.). In addition, respiratory
support under tracheal intubation also increases the risk of respiratory tract infection
and subglottic stenosis. Thus, non-invasive respiratory support, which is defined as
respiratory support without tracheal intubation, is often preferred in order to reducelung injury and pulmonary complications in EP infants.
2.1.2 General Management
The purpose of respiratory support is to maintain partial oxygen and carbon dioxidepressures within normal limits and to stabilize the infant’s respiratory symptoms. Of
course, regardless of invasive- or non-invasive respiratory support, monitoring of bloodgases, including PO2 and PCO2 is essential and must be performed to prevent over orunder inflation of the lungs. During respiratory support, it is also necessary to evaluate
chest x-rays to ensure that lungs are not atelectatic due to alveolar collapse. Blood gas
sampling is invasive especially for preterm infants. Therefore, it is recommended for
non-invasive measurements to be used where available, including SpO2,transcutaneous (TC) O2 and Co2 monitoring. The values obtained from non-invasive
measurements must be confirmed by a direct blood gas analysis if necessary. It should
be noted that carbon dioxide partial pressure in venous blood is slightly higher than16

that in arterial blood.
2.1.2.1 Methods of Non-Invasive Respiratory Support
2.1.2.1.1 Oxygen
Oxygen should be administered if there is poor oxygenation despite adequate
spontaneous breathing. Both hyperoxia and hypoxemia should be avoided. FiO2 should
not be initiated at 100% unless further evidence becomes available. FiO2 should bestarted between 30-60% and changed appropriately to target 90-95% SpO2 with a pulse
oximeter (1).
2.1.2.1.2 Nasal-Continuous positive airway pressure (N-CPAP)
Spontaneously breathing infants may have respiratory distress with grunting and/or
retractive breathing due to collapse of alveoli. This is seldom improved with
supplemental oxygen alone and positive pressure ventilation is usually necessary to
alleviate symptoms. Respiratory diseases that often affect EP infants include transienttachypnea of the newborn (TTNB), mild RDS, and obstructive apnea attacks. N-CPAP
should be applied with a nasal prong closely connected with the nose and a warm andhumidified source of oxygen or room air. Continuously applied positive pressure to the
airway can prevent collapse of alveoli at the end of exhalation. In general, the pressuredelivered should start at 3-8 cm H2O. Lung expansion increases functional residual
capacity (FRC), increases gas exchange area, and improves oxygenation. It is also used
for post-INSURE management for the infants with mild RDS. Reduction of early lungdamage can ultimately decrease the need for mechanical ventilation.
2.1.2.1.3 Nasal-Directional positive airway pressure (N-DPAP)
The diseases indicated for N-DPAP is almost as same as N-CPAP. While N-CPAP
continuously applies the same positive pressure during the both inspiratory andexpiratory phases, N-DPAP can produce the different effects on inspiratory andexpiratory by using jet flow. At the time of inspiration, stable positive pressure isapplied by the jet stream flowing toward the infants, however, at expiration, thedirection of the jet stream is converted so that the flow does not disturb infant
expiration. As a result, excessive pressure is not applied to the lungs and the work ofbreathing is reduced with noninvasive respiratory support.
2.1.2.1.4 SiPAP"Sigh" (deep breathing) is added to N-DPAP to enable biphasic CPAP control. In this17

BiPhasic mode, pressure is generated by providing an additional flow to the baseline
flow that generates low CPAP. As a result, "Sighs" are created intermittently, which
expand collapsed alveoli, improve pulmonary recruitment and decrease ventilation
perfusion mismatch. The duration and frequency of SiPAP pressure can be adjustable.
The diseases indicated for SiPAP are almost the same as N-CPAP and N-DPAP. Whenused in apnea of prematurity, intermittent pressure changes may stimulate therespiratory center of the infants resulting in a reduction of the number of attacks.
2.1.2.1.5 High-flow nasal cannula (HFNC)
This is classified as oxygen therapy in respiratory management. A nasal cannula isused to provide warm and humidified oxygen at high flow rates. The high flow of gas
through the nasal cavity flushes the carbon dioxide in the nasopharyngeal cavity andcauses a mild PEEP to ease inspiration and lead to a reduction in work of breathing.
HFNC is positioned as a form of respiratory management between oxygen
administration and N-CPAP of N-DPAP. Oxygen concentration, flow rate, degree ofheating and humidification can be individually set. Flow rates usually starts at 2
L/kg/min and adjusted by 1-3 L/kg/min according to the respiratory condition of theinfants. Nasal prong size should not impede more than 50% of the nostril so thatexhalation pathways can be maintained.
N-CPAP, N-DPAP and HFNC produce PEEP which decreases the risk of atelectasis andapnea. These modalities lead to earlier extubation practices. In EP infants, however,respiratory drive is weaker and HFNC may not provide enough PEEP to ensure stable
respiratory effort. Therefore, N-CPAP or N-DPAP is preferred for this particularpatient group.
2.1.2.2 Methods of Mechanical Ventilation (2)3.1.2.2.1 Intermittent mandatory ventilation (IMV)
Respiratory support is performed with forced ventilation produced by a mechanicalventilator in IMV regardless of spontaneous breathing. Inhaled oxygen concentration,
maximum inspiratory pressure, PEEP, respiratory frequency, and inspiratory time areset. Since forced ventilation is applied regardless of the spontaneous respiratory phase,fighting between spontaneous and forced ventilations may be inevitable. For example,
forced ventilation may occur during the expiratory phase of the spontaneous breathingwhich may lead to excessive airway pressure and lung damage. Fighting does not occur
in the infants without spontaneous breathing obviously or when spontaneous breathing18

of the infants is suppressed with a muscle relaxant.
2.1.2.2.2 Synchronized intermittent mandatory ventilation (SIMV)In this mode, fighting between mechanical ventilation and spontaneous breathing canbe eliminated by synchronizing mechanical motions with the infants’ efforts through a
triggering system of inspiration. Theoretically, this can reduce lung damage. There are
two ways of the inspiratory triggering: with a flow sensor or with a pressure sensor. By
pre-setting the number of breaths per minute, the minimum frequency of breaths ismaintained even if prolonged apneas exist or a respiratory rate is less than the pre-set
frequency.
During the mechanical ventilation, the tidal volume is very important and is usually
set at 4 to 6 ml/kg. Tidal volume can be controlled by the adjusting the difference
between maximum inspiratory pressure and PEEP. Clinically, the setting is adjusted inconsideration of a combination of chest movement, chest X-ray findings, and blood gas
measurements.
2.1.2.2.3 Assist control ventilation (A/CV) or patient trigger ventilation (PTV)
Both modes are basically assisted ventilation achieved by forced mechanicalventilations synchronized with spontaneous inspiration. Oxygen concentration, peakinspiratory pressure, PEEP, and inspiratory times can be pre-set. The difference
between these modes and SIMV is that the respiratory rate cannot be controlled. These
modes assist all infant breaths and if spontaneous breathing rates decrease, aminimum respiratory rate cannot be guaranteed. This mode is therefore suitable for
infants with weak and inadequate spontaneous breathings. If spontaneous breathing
rates are too low, backup mechanical ventilation can be introduced.
In very preterm infants with unstable respiratory status and decreased spontaneous
breathing efforts are usually stabilized better with SIMV modes. Once spontaneous
breathing becomes more stable, A/CV can be used. After this, weaning from mechanicalventilation can be achieved by gradually decreasing peak inspiratory pressures.
2.1.2.2.4 Pressure support ventilation (PSV)
This method is characterized with a function not only to trigger the inspiration but also
to terminate the expiration according to the respiratory efforts of the infants. Once aflow of expiration becomes less than a certain level compared to the peak flow of it, the19ventilator terminates inspiration and shifts to expiration. In this way, the fighting can
be avoided, and the respiratory workforce can be also reduced. Inspiratory time andrespiratory rates are dependent on the infant and not the ventilator. EP infants whose
spontaneous breathing is already stable are candidates for this mode.
In the case of extremely premature infants who have weak spontaneous breathing andare not stable yet, forced mechanical ventilation with a fixed number of backup
respirations like SIMV plus PSV is preferable and may allow more rapid weaning frommechanical ventilation.
2.1.2.2.5 Neurally adjusted ventilatory assist (NAVA)
This is a relatively new mode of mechanical ventilation. Physiologically, respiratory
action is transmitted as an electrical signal from the respiratory center to thediaphragm, causing diaphragmatic contraction. This movement can create a negative
pressure in thorax and expand the lungs through the air entry into airways. NAVA isdesigned to trigger inspiration using the electrical signal of the diaphragm. The benefitof this triggering system is that the detection of spontaneous breathing is earlier thanother sensing systems e.g. SIMV to detect the changes in flow or pressure during theinspiration. Furthermore, the supportive pressure can be adjusted according to thepotential of the electrical signal to diaphragm, which represents the strength of
spontaneous breathings. Although this is a more physiological way to support
spontaneous breathing compared to other modes, it is still difficult to apply to EP
infants during the acute phase, because of the difficulty in a placement of electrodes inthe esophagus of small infants and the exclusive dependency of triggering on
spontaneous breathing efforts.
2.1.3 Evaluation
Generally, clinical symptoms such as grunting, tachypnea, retractive breathing,cyanosis, apnea, and wheezing, and findings from monitoring such as SpO2, TcPO2,
TcPCO2, and blood gas analyses must be considered to introduce any respiratory
support and for the selection of appropriate modes of respiratory support. Mechanicalventilation can be managed according to the type of respiratory failure as indicated inTable 1.
2.1.3.1 Laboratory examination
Normal value of blood gas analysis ：PaO250-80mmHg

20

PaCO2 40-50mmHg
pH

7.3-7.45

HCO3- 20-25mEq/L
Although there is a concept that “permissive hypercapnia” with generous respiratory
settings can reduce lung damage during the mechanical ventilation, hypercapnia also
increases cerebral blood flow, which may increase the risk of IVH. Therefore, it isimportant to obtain a balance towards protecting the developing brain and towards
reducing lung injury. In general, PCO2 should be maintained at 50-60 mmHg in EP
infants.
References
1) Saugstad OD, Aune D. Optimal oxygenation of extremely low birth weight infants: ameta-analysis and systematic review of the oxygen saturation target studies.
Neonatology. 2014;105:55-63.
2) Goldsmith J, Karotkin E, Suresh G, Keszler M. Assisted Ventilation of the Neonate.
6th ed. Evidence-Based Approach to Newborn Respiratory Care Philadelphia, PA:
Saunders-Elsevier; 2016.

21

Table 1 Type of respiratory failure and its management
PO2

PCO2

Pathophysiology (disease)Parameters toadjustVentilation↓↑

Upper and lower airway

Respiratory Rate

failurenarrowing

Tidal Volume(Low

Central hypoventilation andFiO2

ventilation)

apnea attacks

PEEP

Lung hypoplasia
Pneumothorax
RDS, TTNB
Diffusion failure

Right to left
shunt

↓

↓

→

→

Pulmonary hemorrhage

PEEP

RDS, TTNB

FiO2

PPHN

FiO2

Congenital heart diseases

Mean Airway

Atelectasispressure

RDS: respiratory distress syndrome, TTNB: transient tachypnea of the newborn,
PPHN: persistent pulmonary hypertension of the newborn（Contributor: Shinya Hirano, Audit: Tomohiko Nakamura）

22

2.2 High -Frequency-Oscillatory Ventilation (HFOV)
2.2.1 Clinical situation
High Frequency Oscillatory Ventilation (HFOV) is a mode of mechanical ventilationthat provides lung expansion with a constant mean airway pressure (MAP) to facilitate
gas exchange at the airway rather than at alveolar level.
It is possible to keep alveoli constantly and persistently opened by the MAP. In
addition, alveoli are expanded and deflated with a small volume that is lower thananatomical dead space if oscillation occurs at a frequency of around 15 Hz. In this way,
HFOV provides efficient mechanical ventilation and simultaneously, reduces the stressof volutrauma and barotrauma (Figure 1). This minimal volume exchange at alveoli
with HFOV is also maintains pulmonary surfactant function, making HFOV a
preferred mode of ventilation for preterm infants immediately after birth rather thanas a rescue (1,2).
2.2.2 Mechanism of HFOV
Gas exchange can be achieved by diffusion at the alveolar level by applying nonphysiological oscillations with volumes below that of dead space. Gas delivered to the
airways does not reach the alveoli immediately. but is subject to various physicalmodifications at each level of the airway and eventually reaches the alveolar level,
during which inspiration and expiration are repeated within a short time period.
However, the whole operating principle of HFOV is a very complicated and not fully
understood (3).
The pressure waveform and the pressure change of HFOV diminishes towards theperipheral airways and becomes very tiny within the alveoli (Figure 2). Pressure
differences in the Y-piece portion of the respiratory circuit are indicative of the overallpressure gradient between the inspiratory and expiratory phases. These values are
dependent on respiratory settings and the tracheal tube inner diameter but are usually
greater than normal mechanical ventilation. However, the pressure gradient at the
distal portion of the tracheal tube is usually less than half of that at the proximal
portion. The gradient further decreases with increasing airway resistance and becomes
1/10 or less of the original difference beyond the tracheal bifurcation. Even though thepressure gradient and the ventilation volume at the alveoli level is minimal, HFOV canmaintain ventilation volume while maintaining the mean airway pressure because of23

the high frequency of breaths.
2.2.3 General Management
2.2.3.1 Operator-selected parameters
HFOV can control oxygenation and ventilation independently, mainly by adjusting
MAP and piston amplitude (Figure 1).
There are two types of HFOV, a piston type and a diaphragm type, for creating thenecessary pressure gradients.
In the piston type, oscillation is produced by a piston moving at high speed, andventilation volume increases in proportion to the amplitude (Amp) which is controlled
by the stroke volume (SV). Even relatively large infants can be ventilated with thismodality. The frequency is often fixed at 15 Hz. A typical brand name is the Hamming
series.
In the diaphragm type, MAP and oscillation are created by the combination of highspeed valve opening and closing and a constant jet flow. The power to create oscillation
is limited compared with the piston type. In order to create appropriate MAP and
oscillation, it is necessary to adjust both amplitude and frequency parameters together.
On the other hand, expired tidal volume (VThf) can be adjusted independently. A
typical machine is the Babylog® series.
2.2.3.2 Adjustment of parameters
Regulation of oxygenation: If you want to improve oxygenation, raise FiO2 or raise
MAP (Table 1).
Ventilation volume adjustment: Increase the piston amplitude if you want to lower
PaCO2. By increasing the piston amplitude, the air turbulence created by pressure
gradient can reach more peripheral airways and increase the diffusion of CO2. If
PaCO2 does not decrease by increasing amplitude, lowering the frequency of breaths
will increase volume differences within the alveoli. However, this may also increase therisk of lung injury. A frequency of less than 15Hz is not recommended for EP infants.
The Babylog® has the capacity of providing HFOV with a Volume Guarantee mode thatallows automatic adjustment of the VThf constant. This function can prevent24

hyperventilation and volutrauma and may be used for EP infants (4). A suggestion is toset VThf at 1 to 2 ml/kg. For some CLD infants, 2-3 ml/kg of VThf might be needed toachieve stable ventilation.
2.2.3.3 Characteristics of HFOVAdvantages
Volume change in the alveoli is very small and HFOV can reduce barotrauma andvolutrauma compared to conventional mechanical ventilation.
Machine settings are easy because PaO2 and PaCO2 levels can be controlled
independently.
Disadvantages
If there is an obstruction or stenosis from the tracheal tube to the peripheral airway,
oscillations of HFOV will not be efficiently transmitted to the alveoli and therefore, its
use in obstructive diseases such as pulmonary hemorrhage may be diminished.
High MAP causes a continuous increase in intrathoracic pressure and diminishedvenous return, leading to decreased blood pressure and cerebral congestion.
Application of HFOV is shown in Table 2.
2.2.3.4 Evaluation
2.2.3.4.1 MAP adjustment
MAP setting is very critical in the effectiveness of HFOV. MAP that is insufficient tomaintain appropriate lung volume prevents the pressure gradient produced by HFOVfrom reaching the alveoli, resulting in vibration-related damage to the peripheral
airways. Therefore, in order to prevent alveolar collapse, it is recommended to MAP be
set by 2-5 cmH2O or 1.5 times higher than that of conventional mechanical ventilation.
Default setting: MAP 12 cm H2O for EP infants
It is necessary to adjust MAP so that the anterior surface of the diaphragm will bepositioned approximately at the ninth intercostal space, as visualized on chest X-ray.
During the acute phase, chest X-ray examination must be done at least once a day
determine adequacy of lung inflation because of the need to apply high MAP at the25beginning of respiratory support. Thereafter, adjust MAP in accordance to CXR andclinical findings.
HFOV uses higher MAP than CMV and this may compromise venous return, leading tohypotension. In such cases, volume infusions and catecholamine support may beneeded. If the infant’s circulatory condition cannot be maintained despite full inotropic
support, it is recommended HFOV be changed to CMV.
2.2.3.4.2 SV adjustment
Adjust SV according to target PCO2 and pH values, which should be approximately
PCO2 50-60 mmHg and pH 7.3, respectively.
If the tracheal tube is bent or obstructed with secretions, HFOV may not be effective
due to the failure of transmissions of oscillations to the periphery. This may be rectified
with endotracheal suctioning
It is desirable to use a closed circuit aspiration catheter to prevent alveolar collapse
after endotracheal aspiration.
2.2.3.4.3 Sustained inflation (SI: Sigh)
The alveoli may collapse after removal of the respiratory circuit or after endotracheal
aspiration. In this state, HFOV may not be effective. If oxygenation is insufficient, SI
may be necessary to recruit lung. This involves a SI breath for 5 to 10 seconds with anairway pressure 5 cm H2O higher than the current MAP. Be aware that excessive
pressure and duration of SI can cause hypotension and cerebral blood flow fluctuation,so an automated and fixed interval SIs should not be used.
2.2.3.4.4 WeaningFirst, lower the oxygen concentration, and decrease the MAP by every 1.0 cmH2O after
FIO2 decreases to below 0.4. MAPs that are too low can cause lung collapse and lungdamage, so do not lower MAPs below 6 cmH2O.
Lower the SV by 1 if PCO2 and pH are maintained at 50-60 mmHg and pH 7.3,
respectively.
2.2.3.4.5 Timing of extubation
It is possible to extubate directly from HFOV.

26

If MAP is between 7-8 cmH2o and FiO2 <0.3, consider extubation.
Lowering the MAP too much may cause obstruction of the peripheral airways,
resulting in atelectrauma. In addition, spontaneous breathing is difficult with low MAP
and a narrow tracheal tube. For the same reason, it is not recommended to shift to a
CPAP mode before extubation.
SpO2 levels may sometimes decline because of apnea attacks during the weaning
process. In this case, caffeine citrate administration may be considered, with a loadingdose of 20mg/kg, followed 24 hours later with a daily maintenance dose of 5-10mg/kg/d(5).
2.2.3.5 Note
The results of a study that examined the respiratory function of preterm infants born
less than 29 weeks of gestation at 11-14 years of age who were randomized to either
HFOV or CMV in NICU found significantly better respiratory function parameters inthe HFOV group, suggesting that HFOV at birth may have long-term respiratory
benefits even until adolescence (6).
References
1) Yoder, BA, et al. High-frequency oscillatory ventilation: effects on lung function,mechanics, and airway cytokines in the immature baboon model for neonatal chroniclung disease. Am J Respir Crit Care Med 2000;162:1867–1876.
2) Jobe AJ. The new BPD: an arrest of lung development. Pediatr Res. 46: 641-3, 1999
3) Slutsky AS, et al. Ventilation with small tidal volumes. N Engl J Med 2002;347:630631.
4) Sánchez Luna M, et al. High-frequency oscillatory ventilation combined with volume
guarantee in a neonatal animal model of respiratory distress syndrome. Crit Care Res
Pract. Available from: http://dx.doi.org/10.1155/2013/593915
5) Puia-Dumitrescu M, et al. Dosing and safety of off-label use of caffeine citrate inpremature infants. J Pediatr. 2019. Available from:https://doi.org/10.1016/j.jpeds.2019.04.028
6) Zivanovic S, Peacock J, Alcazar-Paris M, Lo JW, Lunt A, Marlow N, Calvert S,
Greenough A. Late outcomes of a randomized trial of high-frequency oscillation inneonates. N Engl J Med 2014;370:1121-1130.

27

Table 1 How to change HFOV settings

Table 2 Indications of HFOVV28

Figure 1 Parameters in HFOVVAirway Pressure

Stroke Volume

MAP

AmplitudeTime

Figure 2 Airway pressure waveforms during HFOV（Contributor: Hidehiko Nakanishi, Audit: Tomohiko Nakamura）

29

2.3 Prevention of CLD
2.3.1 Clinical situation
2.3.1.1 Pathogenesis
The pathogenesis of CLD is multifactorial and the result of lung immaturity. The
process is initiated by activation of inflammatory cells such as alveolar macrophages
and multinucleated leukocytes induced either by intrauterine inflammation such as
chorioamnionitis (CAM) and/or postnatal inflammatory damages (biotrauma). In
addition to inflammatory damages, mechanical injuries to terminal bronchioles thatare adjacent to alveoli can be caused by atelectasis (atelectrauma) secondary tosurfactant deficiency and ventilator induced lung injury (VILI). In recent years,
environmental factors such as genetic predisposition and maternal smoking have also
been strongly implicated in the pathogenesis of CLD (Figure 1).
Furthermore, hyperinflation secondary to excessive mechanical ventilation can also
compress pulmonary blood vessels and increase pulmonary vascular resistance.
Hypoxemia and hypoventilation lead to pulmonary hypertension (Figure 1), which
complicates the long-term prognosis of EP respiratory distress and CLD.
2.3.1.2 Physical examination
Respiratory failure with hypoxemia, necessitating the need of supplemental oxygenand ventilatory support are the hallmarks of CLD. Lung damage may be compoundedby expiratory difficulties caused by narrowing of the peripheral airways and a bulging
thoracic cavity, due to chronic emphysema. Attention should also be paid to the signs ofright heart failure due to pulmonary hypertension.
2.3.1.3 Diagnosis
2.3.1.3.1 Japanese criteria
In Japan, CLD is classified into seven disease types according to the predisposing
pathological condition (RDS or CAM) and chest X-ray findings (foamy oremphysematous shadows (Table 1)(1).

30

The diagnostic criteria of the National Institute of Child Health and Human
Development (NICHD), which is regarded as the standard diagnostic method forbronchopulmonary dysplasia (BPD) worldwide, are shown in (Table 2)(2). However,there is no consensus on the treatment of BPD with HFNC, which was recently
introduced and disseminated.
Note that the need for oxygen supplementation and/or respiratory support at 36 weeks
of corrected age is critical for the diagnosis of CLD but this may be modified arbitrarily
by attending physicians.
2.3.1.3.2 Objective Diagnosis
The diagnosis of CLD is determined by the need for supplemental oxygen and/or
respiratory support but this may be subjective and dependent on the judgement of theattending physician. Oxygen, for example, may be used for other conditions other suchas apnea. There is thus a concern that that the diagnosis and rates of CLD may be
influenced by the facility or the attending physician. In order to standardize thediagnosis of CLD, the oxygen reduction test (ORT) at 36 weeks of corrected age has
been implemented in Japanese NICUs (3). This test determines the need for oxygen by
infants born below 35 weeks gestation and involves evaluation of the infant’s physicalcondition for 30 minutes after oxygen supplementation is ceased. The diagnostic flow
chart and test methodology are shown in Figure 2 and Table 4.
2.3.1.3.4 Optional diagnosis
Compared with CLD diagnosed at 28 days of age, the diagnosis at 36 or 40 weeks ofcorrected age correlated better with future neurological outcomes (4). Furthermore, the
CLD working group of International Neonatal Consortium (INC) has proposed a
respiration assessment method called Premature Infant Respiratory Status (PIRS)(Table 5). This diagnosis correlates well with the long term outcomes but is difficult tointerpret early on in life.
2.3.2 General management
2.3.2.1 Daily management
CLD is an independent predictor of future neurodevelopment and therefore, all efforts
should be made to 1. Prevent and 2. Ameliorate its severity. For example, attempts
must be made to minimize or avoid intrauterine inflammation or minimize lungdamage from mechanical ventilation.

31

Table 4 shows preventative and therapeutic strategies that are available in Japan.
There is no one best and established method, probably because of the multifactorial
nature of the disease. There are, however, some therapies with weak benefits. At the
moment, the combination of prenatal glucocorticoid and postnatal inhaledcorticosteroids appear beneficial in minimizing the need for mechanical ventilation,even in infants born at 24-26 weeks gestation. Indeed, it may even reduce the severityof CLD and the need for home oxygen in this gestation group (5).
2.3.2.2 Optional treatment
Infants dependent on mechanical ventilation for severe CLD are managed by different
policies at each facility. For example, the types of ventilators may be different, as may
be the ventilator settings. In Japan, may facilities use HFOV. CLD is a particularly
difficult disease to manage as any lung will have a combination of normal, hyper andhypo inflated areas. Adequate PEEP is vital to open atelectatic areas, as is sufficient
expiratory time (to avoid hyperinflation). Increased respiratory rates are usually not
warranted. In severe cases, tracheostomy may be needed to promote quality of life forthe infant, by allowing neurodevelopmental care that would otherwise be restricted in
the intubated patient.
In severe CLD, there may be concurrent pulmonary hypertension. In these cases,
pulmonary vasodilators and regular evaluation with echocardiography and thepulmonary hypertension score (PH score) is necessary to detect pulmonary
hypertensive crises (PH crisis). This may be fatal. Once the infants are discharged from
NICU, it is recommended that continued care be closely monitored by local primarycare physicians and PICU specialists.
References
1) Fujimura M. Study on prevention and intervention for neonatal chronic diseases.
Study on neonatal diseases and interventions. Grant-in-Aid for Scientific Research,
Ministry of Health and Labour, Research Report pp 35-39, 1996 (in Japanese)
2) Poindexter BB, Feng R, Schmidt B, Aschner JL, Ballard RA, Hamvas A, et al.
Comparisons and limitations of current definitions of bronchopulmonary dysplasia forthe prematurity and respiratory outcomes program. Ann Am Thorac Soc 2015;12:1822–
1830, 20153) Walsh MC. Impact of a Physiologic Definition on Bronchopulmonary Dysplasia
Rates. Pediatrics [Internet]. 2004;114:1305–11. Available from:32http://pediatrics.aappublications.org/cgi/doi/10.1542/peds.2004-0204
4) Isayama T, Lee SK, Yang J, Lee D, Daspal S, Dunn M, et al. Revisiting theDefinition of Bronchopulmonary Dysplasia. JAMA Pediatr 2017;171:271.
5) Nakamura T, Yonemoto N, Nakayama m et al. Early inhaled steroid use in
extremely low birthweight infants; a randomised controlled troial. Arch Dis Child Fetal
Neonatal Ed 2016;101:F552-556.
6) Gupta S, Sinha SK, Donn SM. Ventilatory management and bronchopulmonary
dysplasia in preterm infants. Semin Fetal Neonatal Med 2009;14:367–373.

33

Table 1 Classification of chronic lung diseases (Japan) (Reference 1)

Table 2 Definition of CLD and BPD

34

Table 3 Prevention and treatment of CLD
Procedure and Treatment

Effectiveness

Comment

Resuscitation〇

Limited use of oxygen after birth

Oxygen use at chronic phase〇

Keep SpO2 upper limit at 95% orless

Surfactant administration〇

Early prophylactic〇

Within 30 minutes after birth△

HFOV is preferred in Japan but

administration of surfactant
HFOV

there is no evidence for its use in
CLD outside of Japan
nCPAP

〇

To avoid tracheal intubation

NO inhalation△

Variable effect

Systemic steroid administration〇

Effective but serious adverse
events are concerned

Inhaled steroid〇

Effective to reduce severity

Caffeine administration〇

Effective to reduce severity,especially when used earlyDiuretic administration△

Bronchodilator β2 stimulant

×Vitamin A, vitamin E×administration
Stem cell therapy？

Waiting clinical application

35

Table 4 Method of ORT (Oxygen Reduction Test)① Check for the adverse events 1 hour before the reduction of nasal cannula oxygen
administration*
Nasal canula supply reduced gradually②

・Start at resting time of the infant and at least 30 minutes after the nutrition.
・Decrease flow rate gradually without changing the oxygen concentration and finallystop it
Flow rate 1.0-2.0 L/min: Decrease by 0.5 L/min. Every 5 minutes
Flow rate <1.0 L/min: Decrease by 0.1 L/min. At 1 minute intervals③ Tolerance test
・Continue 30 minute observation. Check if the following failure criteria are not met
or there are no adverse events
・The oxygen delivery device should be removed from the infant.
・If SpO2 is maintained at greater than 95% in the first 15 minutes, it is judged that
there is no CLD 36 and the test is completed (Rapid-pass criteria)④ Failure criteria
The diagnosis of CLD36 was made when the following conditions were met, and thetest must be completed promptly.
SpO2 80-89% is more than 5 minutes
SpO2 less than 80% is more than 15 seconds
Examiner decides that discontinuation is necessary, such as frequent occurrenceof apnea
If it does not meet the failure criteria, it is judged that there is no CLD 36.
⑤

Resume the original oxygen administration promptly after the test.
Check for the presence of adverse events for 1 hour after completion*※Adverse event
This must be observed from 1 hour before the test through 1 hour after.
・Apnea (respiratory arrest> 20 seconds or need of stimulation to recover)・Bradycardia (less than 80 HR> 10 seconds or need of stimulation to recover)・Need of FiO2 increases 5% or more within 1 hour after completion

36

Table 5 Premature Infant Respiratory Status (PIRS)
Evaluate according to following categories at 40 weeks of corrected age or at the time ofdischarge if discharge earlier,(1) Do not require oxygen or respiratory assistance more than last 7 days
(2) Do not require oxygen and respiratory support for the last 7 days, but require
medications(3) Oxygen and/or respiratory support were stopped within last 7 days(4) Oxygen supplementation with low flow nasal canula (flow≤ 1 L/m)
(5) Oxygen administration exceeding 1 L/min or respiratory support(6) Death due to respiratory failure from 2 weeks after birth through 40 weeks ofcorrected age
Respiratory support: Regardless of oxygen use, any respiratory supports including
HFNC, CPAP, tracheal intubation
Medications: diuretics, bronchodilators, steroids, caffeine, vasodilators

37

Figure 1 Pathogenesis of CLD

Figure 2 Criteria of Oxygen reduction test (ORT)38

Figure 3 Chest X-ray findings of severe CLD（Contributor: Tomohiko Nakamura, Audit: Hidehiko Nakanishi）

39

3 Circulatory support

3.1 General support
3.1.1 Clinical situation
3.1.1.1 Characteristics of cardiovascular system in preterm infant after birth
3.1.1.2 Transition from fetal circulation
Immediately after birth, the transition from fetal to neonatal circulation occurs as
follows: Firstly, an increase in systemic vascular resistance occurs after separation ofplacenta the placenta from the infant. The placenta has low vascular resistance andthis leads to a decrease in pulmonary vascular resistance due to pulmonary expansion
after the start of breathing. Thereafter, the closure of the ductus arteriosus andforamen ovale occurs and the transition from fetal to independent circulation iscomplete to allow blood flow from both ventricles to whole body (1). Because thistransition is a dramatic change for the infants, it is sometimes difficult for EP infants
to adapt correctly.
3.1.1.3 Cardiac function
EP infants have fewer myocardial fibers, contractility, lower catecholamine levels andless cardiac reactivity. In addition, the ventricular compliance is low, in both systoleand diastole and the EP heart is limited in its capacity for extra work. Therefore, it issometimes difficult for the cardiac function of EP infants, characterized by poor
contractility and low cardiac reserve, to confront any increase in after load. This leads
eventually to poor performance (2). The other characteristic of cardiac function is thatthe cardiac output from left ventricle is maintained by increased heart rate,
demonstrating a lack of adaptability when compared with an older child and an adult.
Any volume load due to a patent ductus arteriosus (PDA) or bradycardia will directly
lead to decreased cardiac function (3).
3.1.1.4 Adrenal function
The adrenal grand grows throughout fetal life through the actions of the corticotropinreleasing hormone (CRH) or estrogen from the placenta. Progesterone, a substrate forcortisol production, is also supplied by the placenta. The adrenal grand is not fully
developed in the preterm infant and placental supply of adrenal hormones e.g. cortisol
will stop suddenly at birth. EP infants are also exposed to many stresses before andafter birth and cortisol production is rarely adequate in this situation, leading tounstable hemodynamics due to lack of vasoconstrictive and sodium retention properties40

of cortisol.
3.1.2 General Management
3.1.2.1 First 24 hours after birth
The first 24 hours after birth is an extraordinarily acute phase characterized bydramatic transition from fetal to neonatal circulation, relative adrenal insufficiency
due to inadequate cortisol production under stress before and after birth,
hypercytokinemia due to intrauterine inflammation causing preterm delivery, andextravasation, especially antenatal steroids were not given. Maternal glucocorticoid
administration not only promotes maturation of lungs and surfactant production but
also promotes maturation of vasculature and digestive tract mucosa. Together withincreased insensible water loss through immature skin, all these conditions promote
intravascular dehydration and edema. Absolute insufficient intravascular watercontent eventually leads to hypotension.
The following management is important to maintain circulatory blood volume.
3.1.2.1.1 Water quantity
Water intake usually starts at 60-80 ml/kg /d. However, EP infants are prone todehydration as mentioned above and 80-100 ml/ kg/d, or even more is sometimes
required. In order to prevent overhydration, which increases cardiac load, the humidity
in the incubator should be maintained as close to 100% so as to minimize the insensible
water loss.
3.1.2.1.2 Dehydration after birthMarkers of hypotension due to dehydration are as follows; tachycardia without
hyperthermia, oliguria, a progression of metabolic acidosis, lactic acidosis, increasing
hematocrit and hypernatremia. Additionally, a low left atrium and aorta ratio (LA/Ao),a low left ventricular internal diameter diastolic (LVIDd), inferior vena cava collapse
on echocardiography, decreased cerebral and other organ flows on ultrasound, and adecreased cardio thoracic ratio (CTR) on chest X-ray can be used to evaluate
dehydration. However, a continuous and comprehensive assessment using all of theseparameters are often required. Do not correct dehydration too rapidly as this increases
the risk of IVH.
Hydration or volume loading41

・5% albumin
・FFP (especially for infants born at 22-24 weeks)
・SalineAdminister 10-20 ml/kg over 1-3 hours depending on the condition
・Red blood cell transfusion
If anemia is present (Hb <12 g/dl), this must be first line treatment.
Administer 10-15 ml/kg of packed blood over several hours to 6 hours.
3.1.2.1.3 Relative adrenal insufficiency
It should be recognized that EP infants are basically in the condition of relative
adrenal insufficiency and has impaired cortisol secretion in response to stressors. In
order to supplement impaired adrenal function, a single dose of intravenoushydrocortisone at 1-2 mg/kg is usually effective (4,5). Cytokine-mediated vascularpermeability is suppressed, resulting in decreased water leakage outside blood vessels
and need for fluid infusions. If not effective, the second dose should be considered basedon the following conditions; a degree of immaturity of the infants, a history of maternal
glucocorticoid treatment, the severity of edema, and the presence of hypotension.
3.1.2.1.4 Inotropes
If hypotension and oliguria are present with insufficient cardiac contractility despite
echocardiographic signs of appropriate intracardiac volume, cardiac function may be
impaired. If worsening, Additionally, inotropic agents as dobutamine (1-5 μg/kg/m), anddopamine (1-3 μg/kg/min) along with correction of acidosis may be needed. (Refer to thesection on Cardiovascular agents)
3.1.2.2 24 to 72 hours after birth
During this time, fluid that initially leaked out of blood vessels may return, leading toincreased blood pressure. At this time, it may be necessary to increase water content by
10-20 ml/kg per day if the infant is stable. Calcium is added to glucose in the first few
days but additional sodium may be needed once serum sodium starts to decrease.
3.1.2.2.1 Adjustment of intravascular volume
Venous congestion due to the increased intrathoracic pressure associated with invasive
procedures and any changes of respirator setting leading to increased MAP must be
avoided. It should be also considered that during this period, an afterload mismatch
due to increased blood pressure and afterload with a decreased cardiac contractility

42which is typically observed as cardiac dilation can frequently occurs. The afterload
mismatch can be assessed with a heart rate corrected mean velocity of circumferential
fiber shortening (mVcfc) as an index of left heart pump function and an endsystolic
wall stress (ESWS) as an index of afterload (3,6).
A comprehensive evaluation according to parameters such as heart rate, urine output,
blood test findings, cranial echography, and echocardiography is required for an
appropriate circulatory care. During the acute phase, rapid blood pressure changes
must be avoided to decrease risk of IVH (4).
If water overload is suspected, use diuretics, e.g. intravenous injection of furosemide at
a dose of 0.5-1 mg/kg
If afterload mismatch is suspected, use a vasodilator, e.g. continuous intravenous
administration of nitroglycerin at 0.3-1.5 μg/kg/min
3.1.2.3 More than 72 hours after birthBlood pressure and hemodynamics become relatively stable, and the risk of IVH also
decreases. However, for EP INFANTS at a gestational age of 22-23 weeks or of birthweight less than 500 g, it is sometimes necessary to continue the same care as during
the acute phase depending on the condition of the infant.
Once vital signs are stable, the arterial line should be removed. However, it isnecessary to continue evaluating vital signs and urine volume, and to perform cranial
ultrasound, echocardiography and blood laboratory tests as appropriate.
Sodium intake may need to be increased if serum sodium drops further due toimproving renal function. The intravascular volume and organ blood flows should beassessed with echography when necessary. It should be decided whether PDA is
symptomatic or not with echocardiography. Once the infants become more than one
week old, regardless of the gestational age at birth, the systolic blood pressure must be
maintained over 40 mmHg. Hypotensive treatment must be instituted if systolic bloodpressure decreases below this.
PDA care is described in detail in the session of “PDA Management”.
3.1.2.4 Late onset adrenal insufficiency

43

The pathogenesis of this condition is not yet fully understood, but 10-20% of EP
infants, according to the Neonatal Research Network of Japan database, may develop
late onset adrenal insufficiency (7,8). Symptoms include sudden hypotension, oliguria,
edema, hyponatremia, hyperkalemia, and worsening respiratory status but the only
sign during the early stages may only be a decrease in urine output. When this disease
is noted, other causes such as dehydration, sepsis, PDA, etc. must be excluded first. If
symptoms such as hypotension do not improve, intravenous hydrocortisone of 1-2
mg/kg/dose should be given. In many cases, symptom disappears with a single dose ofhydrocortisone within 30 minutes. If no response is observed after the first dose,hydrocortisone may be repeated. However, symptoms are refractory and severe,vasopressin 0.2-1 mU/kg/min may be considered. Although this condition naturally
resolves as the EP matures, it may recur until around 32 weeks of corrected age. PVL
may ensue after such events, so early detection of symptoms and early administrationof hydrocortisone are crucial (9).
3.1.3. Evaluation
3.1.3.1 Blood pressure monitoring
In order to evaluate the hemodynamics of EP infants, arterial blood (peripheral arteryor umbilical artery) monitoring is preferable. This is also necessary for appropriate andtimely interventions. However, this is not mandatory and placement depends on thecondition and needs of the infant.
Optimal blood pressure in EP infants is not clear, but during the acute phase, theaverage blood pressure should be maintained over the value of gestational age in
mmHg (for example, 27 mmHg for 27 weeks gestation).
3.1.3.2 Echocardiography
Repeated echocardiography performed at bedside by neonatologists is routine
procedure in Japan. It is not invasive and can be done several times a day during theacute phase. Since the purpose of repeated echocardiography is to evaluate cardiac
functions of the infants, it is possible to carry out tailor-made circulatory management
for each infant according to the echocardiographic measurements combined with otherparameters such as heart rate, urine volume, lactic acid concentration, and electrolyte
values.
References441) Japan Society for Neonatal Health and Development. Textbook of Neonatology. 1st
ed. Osaka: Medicus Shuppan; 2018 (in Japanese)2) Nakamura T. Nagano Children’s Hospital Handbook of Extremely low birth weight
infant. 1st ed. Tokyo: Medical View; 2019 (in Japanese)3) Oyama M, Kanagawa Children’s Medical Center. KCMC Manual of Neonatal Car. 6th
ed. Tokyo: TOKYO IGAKUSHA; 2015 (in Japanese)4) Yoda H. Stepup Neonatal Circulatory Care. Osaka: Medicus Shuppan; 2016 (inJapanese)5) Hosoi H, Kyoto Prefectural University of Medicine. Neonatal Intensive Care Unit
Manual 6th edition. Tokyo: ShindanToChiryosha; 2017 (in Japanese)6) Osaka City General Hospital NICU Manual 2018 (in Japanese)add) http://plaza.umin.ac.jp/nrndata Analysis from data in /syukei.htm
7) Masumoto K, et al. Comparison of serum cortisol concentrations in preterm infants
with or without late-onset circulatory collapse due to adrenal insufficiency ofrematurity. Pediatr Res 2008;63:686-690.
8) Network Database, Neonatal Research Network of Japan.
http://plaza.umin.ac.jp/nrndata/reports/nrn4_all.pdf.
9) Nakanishi H, et al. Clinical characterization and long-term prognosis of neurologicaldevelopment in preterm infants with late-onset circulatory collapse. J Perinatol.
2010;30:751-756.
（Contributor: Hiroko Iwami, Audit: Masahiro Hayakawa）

45

3.2 Cardiovascular agonists
3.2.1 Clinical situation
Since EP infants are more likely to develop heart failure compared with term infants
because of underdeveloped myocardial function, several cardiovascular agonists mayneed to be used.
Heart failure will lead to impaired oxygen supply to body tissues despite increased
demands from increased venous pressure and decreased cardiac output frommyocardial dysfunction. Cardiac output is defined by a series of cardiac indices;
diastolic capacity, preload, systolic capacity, afterload, and heart rats (1). Therefore, it
is important to use suitable agonists according to the cause of heart failure.
Furthermore, because the sudden transition from fetal to neonatal circulation isalways in the background of heart failure in those EP infants, the complete
understanding of basic physiology is essential for the treatment during the acutephase.
Generally, left ventricular ejection fraction (LVEF) in preterm infants temporarily
declines after birth and then rises during the next 12-24 hours after birth, and the left
ventricular outflow velocity (LVO) also changes in a same fashion. However, EP infants
especially less than 25 weeks of gestation may not be capable of this adaptation.
Therefore, volume loading, which is often necessary during the acute phase, can cause
heart failure easily. This is also explained by the characteristic of myocardial functionof EP infants. According to Frank-Starling's law, if left ventricular preload (watercontent) is increased, the left ventricular myocardial contraction force is increased, andthe left ventricular stroke volume and cardiac output are also increased (2). However,this phenomenon cannot be expected in EP infants because of immature myocardial
function. Therefore, attention must be paid if the preload is increased especially whenthe myocardial contraction force is not enough. Thus, it is important to assess
myocardial function and cardiac output properly with echocardiography in order toprovide appropriate supports.
3.2.1.1 Causes of cardiac failure
Immaturity
Severe asphyxia
Twin to twin transfusion syndrome（TTTS）

46

Maternal drug effect (such as Ritodrine)
Myocarditis, cardiomyopathy, transient myocardial ischemia
Severe respiratory failure/PPHN (right heart failure)
Acidosis, hyperkalemia, hypocalcemia, hypoglycemia
PDA
Hypothermia
SepsisArrhythmia
3.2.1.2 Symptom (1,3)
Decreased cardiac output: poor skin color, cold extremities, tachycardia, decreased
blood pressure, decreased urine output, reduced intestinal motility, abdominal
distension
Pulmonary congestion (left heart failure): tachypnea, retractive breathing, apnea,
wheezing, wet rales, poor oxygenation
Systemic congestion (right heart failure): edema, ascites, hepatomegaly, decreased
urine volume
3.2.1.3 Diagnosis
Chest X-ray: cardiomegaly (preload assessment), with or without pulmonary congestion
ECG: presence or absence of arrhythmia or myocardial damage
Laboratory test: CBC, biochemistry, blood gas analysis (gas exchange, acidosis), lactic
acid (marker for organ blood flow), brain natriureteric peptide (BNP), creatinine
kinase-muscle/brain (CK-MB), troponin T (if you suspect myocardial damage)
Echocardiography:
Evaluation of preload (2,4,5):
Left ventricular end diastolic dimension (LVDd) (reference range: ELBW 8-10 mm,
VLBW 10-12 mm, depends on BW, GA and time after birth)
LA/Ao (reference range 0.8-1.2)
Dimension of inferior vena cava (respiratory sift)
Left ventricular cardiac output (LVCO) (reference range 190-310 ml/kg/min)
Evaluation of afterload：
end systolic wall stress (ESWS) reference range <40 g/cm2
Evaluation of contractility:
Ejection fraction (EF) reference range >50 %47

Fractional shortening (FS) reference range >30 %mVcfc reference range >0.8 circ/s
Evaluation of diastolic ability:
Left ventricular inflow blood flow waveform
Peak velocity of early diastolic mitral annulus motion (E’) (reference range depends
on BW, GA and time after birth)
3.2.2 General Management
The general concept of treating heart failure is to increase oxygen supply and to reduce
oxygen and energy demand of body tissues and the etiology of the condition.
3.2.2.1 Respiratory support
Since respiratory effort increases oxygen consumption, positive pressure respiratory
support is effective especially for the heart failure complicated with pulmonary
congestion and respiratory failure. Respiratory support usually increases intrathoracic
pressure which results in reducing venous return and preload. Thus, the cardiac output
depends on afterload. However, if the cardiac output is already dependent on preload
such as hypovolemia, it should be recognized that the increased intrathoracic pressure
decreases the cardiac output. If severe oxygen diffusion failure and/or pulmonary
hypertension are observed, inhaled NO is recommended. Although sedation has theeffect to reduce the oxygen demand, it should be used with a caution because it cancause hypotension due to the decreased intrinsic catecholamine production and thevasodilate action.
3.2.2.2 Circulatory approach based on the etiology
Preloading
It is usually difficult to improve diastolic function, so excessive preload can be treatedwith water restriction and/or diuretics. In the case of insufficient preload, volume
loading is performed with saline or blood infusion.
Contraction
Catecholamines such as dopamine (DOA) and dobutamine (DOB) can be administered.
Milrinone can enhance cardiac contraction but has also a vasodilator action. So, pay
attention to this side effect.

48

Afterload
If cardiac contraction is relatively poor and blood pressure is high, there is a possibilityof increased afterload and milrinone is preferable. It should be noted that afterload canbe increased a few hours after birth in EP infants as already mentioned. Conversely,
sepsis and late circulatory collapse due to adrenal failure cause high cardiac output
heart failure with decreased afterload. Maintenance of afterload with administration of
catecholamine and vasopressin may be needed.
3.2.2.3 Agonist
Cardiovascular agonists have their own specific receptors. For example, adrenergic
receptors include α1 (vasoconstriction), β1 (enhancing cardiac contractility andincreasing heart rate), and β2 (vasodilatation and bronchial dilation). Dopamine
receptors (DR) can dilate renal arteries. On the other hand, phosphodiesterase-lll(PDElll) inhibitors (milrinone, olprinone) can enhance vasodilatation and cardiac
contraction through metabolic actions.
3.2.3.1 Catecholamine (1,6,7,8,9)
Dopamine hydrochloride
This is mainly β-acting, but exerts different pharmacological effects depending on bloodconcentration.
0.5-3.0 μg/kg/min (β1> β2, DA> α1) diuretic effect, cardiac contraction enhancement
3-10 μg/kg/min (β1> β2, α1, DA) both heart rate and blood pressure increase as cardio
tonic agent
10-20 μg/kg/min (α1 >> DA, β) risk of side effects such as increase in pulmonary
capillary pressure, contraction of peripheral blood vessels, renal artery
vasoconstriction, tachycardia and arrhythmia
Dobutamine hydrochloride
Strong β1 action and weak α and β2 action
No noradrenaline release effect, rarely causes tachycardia compared with dopamine
Selectively enhances cardiac contractility without increasing cardiac oxygen
consumption.
1-10 μg/kg/min recommended
High doses increase the risk of tachycardia and arrhythmia.
No significant difference between DOA and DOB in neonatal death, periventricularleukomalacia (PVL), and IVH incidence

49

DOA and DOB are often combined in a 1:1-2.
Isoproterenol
Powerful β1 and β2 action
Because of side effect of tachycardia, difficult to use for EP infants, who are alreadytachycardic
Sometimes causes hypotension due to vasodilation
0.01-0.2 μg/kg/min for shock, bradycardia, and atrioventricular block.
Adrenaline
Most potent endogenous catecholamine
Heart rate increased along with increased cardiac contraction and cardiac output
Although considered if DOA and DOB are not effective to maintain blood pressure inneonatal resuscitation, no scientific evidence of benefit is established0.01 μg/kg/min as a stating dose, then increase to 0.2 μg/kg/min if necessary.
3.2.3.2 Glucocorticoids (2,7,9)
Prevention of edema, maintaining circulating blood volume, increase preload,
prevention of excessive reduction in afterload, and enhancement of cardiac contractility
Genomic effect to enhances the reactivity to endogenous and exogenous catecholamines
Effective for circulatory failure due to relative renal failure with edema, hyponatremia,
and poor organ blood flow, if volume loading and catecholamine failed to improve.
Hydrocortisone 1-5 mg/kg
Adverse events include the risk of hyperglycemia and gastrointestinal perforation.
3.2.3.3 Diuretic
Furosemide
Effective to relieve heart pump failure and lung congestion due to excessive preload
associated with cardiac dilation and atrioventricular valve regurgitation.
Immediate action and strong diuretic action.
Half-life is about 20 hours in EP infants due to poor renal clearance.
0.5-1 mg/kg every 6-12 hours (7)3.2.3.4 Vasodilators (1,6,7)
3.2.3.4.1 Phosphodiesterase-lll (PDElll) inhibitor
Inodilator with cardiotonic and vasodilator actions

50

Has weaker action than in adults because of poor expression of PDEllI in the
myocardium of EP infants
0.1-0.3 μ/kg/min
Use in low doses to avoid exacerbating PDA
3.2.3.4.2 Nitroglycerin
Antidepressant for heart failure
Low dose dilates venous vessels and reduces preload
High dose dilates arteries and reduce afterload
In EP infants, even low dose dilates arteries
In addition, dilate the coronary artery and increases oxygen supply to myocardium
0.3-2 μg/kg/min
Increased incidence of PDA
3.2.3.4.3 Inhaled Nitric Oxide（iNO）
More than 70% of perinatal centers use iNO as treatment for PPHN in very prematureinfants in Japan (10).
Echocardiographic diagnosis
10 ppm as a stating dose
Cardiac function and pulmonary hypertension evaluated every 8 hours by
echocardiography
Use SpO2 for weaning
No noticeable side effects reported by evaluating hemodynamics appropriately withechocardiography
References
1) Japan Society for Neonatal Health and Development. Textbook of Neonatology. 1st
ed. Osaka: Medicus Shuppan; 2018.
2) Nakamura T. Nagano Children’s Hospital Handbook of Extremely low birth weight
infant. 1st ed. Tokyo: Medical View; 2019 (in Japanese).
3) Oyama M, Kanagawa Children’s Medical Center. KCMC Manual of Neonatal Car. 6th
ed. Tokyo: TOKYO IGAKUSHA; 2015 (in Japanese).
4) Yoda H. Stepup Neonatal Circulatory Care. Osaka: Medicus Shuppan; 2016 (inJapanese).
5) Hosoi H, Kyoto Prefectural University of Medicine. Neonatal Intensive Care Unit
Manual 6th edition. Tokyo: ShindanToChiryosha; 2017 (in Japanese).

516) Osaka City General Hospital NICU Manual 2018 (in Japanese).
7) Dempsey E, et al. The Use of Cardiotonic Drugs in Neonates. Clin Perinatol 2019;46:273-290.
8) Giesinger RE, et al. Hemodynamic instability in the critically ill neonate: An
approach to cardiovascular support. Semin Perinatol 2016;40:174-188.
9) Sehgal A, et al. Does echocardiography facilitate determination of hemodynamic
significance attributable to the ductus arteriosus? Eur J Pediatr 2009; 168:907-914.
10) Shiraishi J, et al. Standardization of nitric oxide inhalation in extremely preterm
infants in Japan. Pediatr Int 2019;61:152-157.

（Contributor: Hiroko Iwami, Audit: Masahiro Hayakawa）

52

3.3 Management of PDA
3.3.1 Clinical situation
Delayed physiological closure of ductus arteriosus in preterm infants is termed PDA.
A PDA with hemodynamically significant symptoms is defined as a symptomatic PDA.
According to the Neonatal Research Network of Japan database (2003-2014), theincidence of symptomatic PDA among extremely low birth weight infants isapproximately 58% at 24 weeks of gestation and approximately 38% at 28 weeks ofgestation. PDA is common among EP infants and daily, even multiple examinations
with echocardiography on the bedside to evaluate the presence of a PDA and associatedhemodynamic effects are recommended during the acute phase.
3.3.1.1 Pathogenesis
With gestational maturity, the intimal wall of the fetal ductus arteriosus thickens toallow closure after birth. However, this may be insufficient in EP infants, as the
response of the ductus arteriosus to oxygen-induced closure is weak. Physiologically,
there are persistently high levels of active substances that dilate the ductus arteriosus
such as prostaglandin E (PGE), nitric oxide (NO) and cytokines induced byinflammation such as inducible nitric oxide synthase (iNOS) and tumor necrosis
factor–α (TNF-α). These work together to delay ductal closure. Therefore, intrauterine
infection and neonatal infection like sepsis are risk factors for PDA, resulting indramatic increase in blood flow though the PDA when pulmonary vascular resistancefalls after birth.
3.3.1.2 Pathophysiology
Adverse effects of PDA are as follows;① Pulmonary congestion
tachypnea, respiratory distress, apnoea, heart murmurs, pulmonary hemorrhage,and exacerbation of CLD② Decreased systemic organ blood flow by the steal effect through PDA resulting
in increased pulse pressure (diastole <systole/2), decreased urine output,
prerenal renal failure, peripheral coldness, poor skin color, reduced intestinal
movement, necrotizing enteritis, gastrointestinal perforation, and PVL③ Left ventricular heart failure associated with increased preload
If the diastolic function maintained: left ventricular hypercontractility,
tachycardia, increased pulse pressure, hyperactive precordium.

53

If diastolic function is impaired: decreased left ventricular contraction, afterload
mismatch, pulmonary hemorrhage, IVH
3.3.1.3 Diagnosis
3.3.1.3.1 Chest x-ray
Pulmonary congestion, cardiac enlargement.
3.3.1.3.2 Echocardiography
The ductus arteriosus tends to narrow from the side of the pulmonary artery but
sometimes, closure from the aortic side may be noted on echocardiography. Therefore,both the short axis aortic view, which is a routine view, and the ductal view should bechecked. Measurement of the following indices are recommended:
・Minimum ductus arteriosus diameter: Always measured in B mode. If measured withcolor Doppler, it is likely to be overestimated.
・Ductus arteriosus blood flow: Use color Doppler to determine the direction of flow.
Soon after birth, because of the high pulmonary vascular resistance, right-to-left or
two-way blood flows can be seen. Check the blood flow pattern by pulse Doppler. If
the pattern is single peak and pulsatile with a low maximum blood flow velocity, theshunt flow is large, and PDA does not tend to close.
・Left pulmonary artery blood flow velocity: Use pulse Doppler. The left pulmonary
arterial endo-diastolic velocity (LPAedv) or diastolic/systolic blood flow velocity ratio
is proportional to the shunt blood flow.
・Left arterial-to-aoritic root diameter ratio (LA/Ao)：Indicates left atrial volume
overload
・Left ventricular and-diatstric diameter (LVDd)：Indicates left ventricular volume
overload
・Ejection fraction (EF)：Indicates left ventricular contraction capacity＊PDA dependent congenital heart diseases such as Coarctation of the Aorta must be
ruled out.
One of following findings generally indicates a hemodynamically significant PDA;
arterial duct diameter> 1.5 mm, LPAedv> 0.2 m/s, LA/Ao> 1.4. However, the necessityof treatment should be determined based on not only echocardiographic findings but
also on other ultrasound findings such as organ blood flow and clinical symptoms.
Echocardiography findings of GA 27wk infant with PDA on Day 0 (Figures 1, 2, 3)

54

3.3.1.3.4 Cranial and abdominal echography
The influence of impaired organ flows due to PDA can be assessed by measuring theresistance index (RI) of anterior and middle cerebral arteries, celiac artery, superior
mesenteric artery and renal artery. Normal range is usually 0.6-0.7. The higher RI
indicates the increased PDA shunt flow. In the severe case, the discontinuation orreversal of diastolic blood flow can be seen.
3.3.1.3.5 Laboratory blood test
Lactic acid levels, renal function, and natriuretic peptide levels are useful indicators ofvolume loading. Natriuretic peptides such as brain natriuretic peptide (BNP) and Nterminal pro b-type (NT-proBNP) are useful indicators of illness severity as levels
increase with worsening PDA.
3.3.2 Management
3.3.2.1 Supportive management
・Since excessive volume load worsens PDA symptoms such as pulmonary congestion,
careful fluid management is essential. However, it should be also understood that
excess fluid restriction and diuretics use can also cause intravascular dehydrationand impairment of blood flow to essential organs.
・If there is pulmonary edema, respiratory management with high PEEP and MAP isrecommended. In this care, permissive hypercapnia is also preferable because of its
vasoconstrictive action on pulmonary arteries.
・Keep Hgb more than 12 g/dl. Blood transfusion is necessary if anemic.
・Avoid other aggregating factors such as infection.
3.3.2.2 Medication
The decision to use medications to treat a PDA can be based on combination of clinicalsymptoms, echocardiographic findings including, blood flow to other organs, as well aslaboratory blood tests. Although there is a guideline for PDA treatment in Japan, eachhospital must still have its own policy for treatment. The majority of hospitals willtreat if the PDA is hemodynamically significant by echocardiography even before theinfant is symptomatic. In addition, over half of hospitals use prophylactic indomethacin
to prevent symptomatic PDA and IVH in EP infants.
3.3.2.2.1 Indomethacin

55

・This is a prostaglandin synthesis inhibitor
・Most Japanese hospitals modify the dose according to the gestational age as shownin Table 1 because of side effects (Table 2) 2). The doses are basically reduced, and theintervals are prolonged for more premature infants with a course of 3 doses.
・Withholding of enteral feeding is not recommended unless there is a special reason.
・Prior to the second and third administration, echocardiography is mandatory. If PDA
is already closed, additional doses are not necessary. Based on echocardiographic
findings, including left ventricular overload and urine volumes as indicators ofadverse effects, subsequent doses may be delayed or skipped.
・Since the incidence of symptomatic PDA among EP infants is high, some hospitals
start treatment if PDA is present beyond the first day of life even if the infant is
asymptomatic.
3.3.2.2.2 Ibuprofen
・This is a prostaglandin synthesis inhibitor・Approved for use in Japan in 2018.
・Less side effects (e.g. renal) than indomethacin and has similar efficacy.
・Three doses for the first course: 10 mg/kg for the first time, 5 mg/kg for the second
and the third doses in 24 hour intervals.
・Between each dose, like indomethacin, echocardiography is mandatory. The next
dose can then be delayed/skipped depending on findings.
3.3.2.3 Surgical ligation
3.3.2.3.1 Indications
If the PDA remains symptomatic despite medication or if the infant has complications
from medications, consider surgical ligation. This includes:
・Unlikeliness of PDA closing even after maximum medical treatment has been
completed
・PDA has reopened and there is low possibility of closure with repeated medical
treatment
・Additional medical treatment is contraindicated due to severe complications and side
effects
・No time allowance for medical treatment to take effect due to imminent heart failure
3.3.2.3.2 Complications of surgical ligation

56

・Bleeding, infection, hypothermia during surgery, recurrent nerve paralysis(hoarseness, aspiration), phrenic nerve paralysis (eventration of diaphragm),
chylothorax, pneumothorax, surgical wound infection.
3.3.2.3.3 Postoperative management
Blood pressure always rises immediately after ligation. Monitoring of arterial bloodpressure is recommended to prevent IVH due to hemodynamic changes.
Echocardiography is also recommended to evaluate hemodynamics. If there was severe
and persistent heart failure before ligation, left ventricular dilatation must be
evaluated post-operatively with echocardiography. If this is present, the infant may be
at risk of post-operative heart failure, which is characterized with afterload mismatch
secondary to rapid cardiac load change. In this instance, support with vasodilators isindicated. However, if hypovolemia is also present, hypotension is likely to occur. Once
hypotension is observed, it is usually catecholamine refractory and glucocorticoids areneeded.
References
1) Shepherd JL, et al. What is a hemodynamically significant PDA in preterm infants?
Congenit. Heart Dis 2019;14:21-26.
2) Japan Society for Neonatal Health and Development. Textbook of Neonatology. 1st
ed. Osaka: Medica Shuppan; 2018 (in Japanese)3) Nakamura T. Nagano Children’s Hospital Handbook of Extremely low birth weight
infant. 1st ed. Tokyo: Medical View; 2019 (in Japanese)4) Oyama M, Kanagawa Children’s Medical Center. KCMC Manual of Neonatal Car. 6th
ed. Tokyo: TOKYO IGAKUSHA; 2015 (in Japanese)5) Yoda H. Stepup Neonatal Circulatory Care. Osaka: Medica Shuppan; 2016 (inJapanese)
6) Hosoi H, Kyoto Prefectural University of Medicine. Neonatal Intensive Care Unit
Manual 6th edition. Tokyo: Shindan To Chiryosha; 2017 (in Japanese)

57

Table 1 Doses of indomethacin for EP infants
Age

First

Second dose (mg/kg)

dose(mg/kg）

Third dose
(mg/kg)Within 48 hours

0.2

0.1

0.1

Age 2-7 days

0.2

0.2

0.2

Age 7 days or more

0.25

0.25

0.25
(Modified from reference 2)

Table 2 Adverse effects of indomethacin
Symptoms

Clinical findings

Renal disorder

Decreased urine output, progress of edema

Intestinal perforation, necrotic

Increased gastric residues, bile/bloody gastricenterocolitis

aspirates, bloody stool, abdominal color change,
abdominal distension

Hypoglycemia

Apnea, irritability, convulsion,
sometimes asymptomatic

Thrombocytopenia

Umbilical bleeding, bleeding at a needle insertion
site, abnormal hemostasis at a blood sampling site

(Modified from reference 2)58

Figure. 1 Arterial duct patency, 2D short-axis image and short-axis Doppler image:
PDA diameter 1.6mm

Figure.2 PDA flow velocity: Left to Right shunt, continuous wave patternFigure 3 Left PA flow velocity: LtPA end diastolic velocity 0.32m/s（Contributor: Hiroko Iwami, Audit: Tetsuya Isayama）

59

3.4 Prevention of IVH
3.4.1 Clinical situations.
IVH in EP infants is the result of ventricular extension of subependymal hemorrhage
from immature vessels. The incidence of IVH among extremely low birth weight
infants is reported to be 12.8% overall and 4.6% for severe IVH in Japan (born 2003 to2012) (1).
The pathogenesis of IVH involves anatomical and physiological immaturity. The
supraventricular subependymal layer surrounds the lateral ventricles and is mostprominent between the caudate nucleus to the thalamus. The size of the subependymal
layer increases until around 26 weeks of gestation, and gradually involutes thereafter.
This structure is crucial for fetal brain development, containing many cellularcomponents from which neurons and glial cells are generated. The walls of thesevessels are thin and very fragile and the vessels feeding to this area is the so-called
arterial border zone, consisting of peripheral branches of the medial striatum arteryand the lateral striatum artery which are greatly susceptible to hypoxic tissue damage.
The cranial veins are perfused from the cerebral medullary vein, through theepididymal region of the ventricle, and finally drains into the terminal vein and theinternal cerebral veins. Therefore, any increase in cerebral blood flow will increase thelikelihood of congestion at the lower ependymal region. There is no vessel valve
between the superior vena cava and the main cerebral veins, so right atrial pressure
directly impacts on cerebral venous pressure. In cases of cardiac dysfunction,
pulmonary hypertension and increased intrathoracic pressure, the pressure of cerebral
venous perfusion pressure may increase due to the increased right atrial pressure.
Since the autoregulation of cerebral blood flow in EP infants is immature and limited,the changes in blood pressure can directly cause cerebral blood flow fluctuation.
Cerebral autoregulation is particularly impaired in sepsis, acidosis and hypotension.
Hypercapnia, seizures, crying, intratracheal suctioning, administration of inotropic
agents, and a rapid administration of hypertonic solutions can also increase systemic
and cerebral pressures, increasing the risk of IVH. Intraparenchymal hemorrhage
associated with IVH is considered to be a venous hemorrhagic infarction resulting fromcongestion in the cerebral parenchyma and is a result of impaired intrathecal venous
perfusion due to hemorrhage in the lower ependymal region of the ventricle.

60

Post hemorrhagic hydrocephalus may occur due to the obstruction of cerebrospinal
fluid flow and absorption route due to hemorrhagic clots or decreased cerebrospinal
fluid absorption due to chronic arachnoiditis. Risk is increased with severity of IVH.
Once hydrocephalus occurs, brain growth is impaired due to the increased intracranialpressure from ventricular dilatation. This may then progress on to white matterdamage over several months due to free radicals released from the lysis of hemoglobin.
The prognosis of IVH depends on the severity and the presence or absence of brain
parenchymal lesions. The mortality, the incidence of hydrocephalus, and neurologicalsequalae are higher amongst infants with severe IVH group (Grade III or IV in theclassification of Papile or Grade III plus intraparenchymal hemorrhage in theclassification of Volpe (Table 1 and 2)(2,3). Among extremely low birth weight infants
born between 2003 and 2004 in Japan, NICU mortality rate is 4.4% without IVH,
11.6% in the mild IVH group (Grade I + Grade II according to Papile classification),and 44.5% in the severe IVH group. However, post-discharge mortality rate was notdifferent (0.6 and 0.7%, respectively). At 3 years of age, cerebral palsy was 6.9% in thegroup without IVH, 12.6% in the mild IVH group, and 39.7% in the severe IVH group.
Visual disorders (unilateral and bilateral) occurred 0.9% in the group without IVH,
3.6% in the mild IVH group, 6.8% in the severe IVH group. Neurodevelopmental delay
was observed 15.5% in the group without IVH, 19.7% in the mild IVH group, 41.2% in
the severe IVH group.
3.4.1.1 Diagnosis
Cranial echography is simple and useful for diagnosing IVH (Figure 1 and Table 1).
However, due to impairment of ultrasound imaging by bony windows, the diagnosis ofhemorrhages other than IVH such as subdural hemorrhage and epidural hemorrhage
is often difficult. Head CT and MRI are useful for these. Follow-up scans to gauge theprogress of IVH is necessary.
3.4.2 General Management
Clinical symptoms of intracranial hemorrhage include neonatal seizures, apnea attack,fever, hypotension, anemia, shock, jaundice. Infants may also be asymptomatic. The
Papile classification is widely used as a classification of severity of IVH (2). This
classification is based on CT findings, but it is also used as a classification ofechography. 50% of IVH occurs within 24 hours after birth, 25% on day 1 and 15% on
day 2 i.e. 90% of IVH develops within 72 hours of birth. Therefore, close observation

61

over this time period is particularly important.
3.4.2.1 Treatment
There is no direct and effective treatment for IVH. Treatment is supportive.
Circulatory and respiratory support is necessary for infants in shock and/or acidosis.
Blood transfusion is needed for the infants with anemia and/or coagulation disorders.
There is currently no effective intervention to prevent post IVH hydrocephalus in termsof timing and procedures. Acetazolamide and furosemide are not recommended,because they do not reduce the need of ventriculoperitoneal shunt (VP shunt), but
increase mortality, the incidence of neurological damages, and the risk of kidney
calcification. Repeated lumbar puncture has been reported to be effective, but it is notrecommended because of the risk of central nervous system infection in EP infants. Ifhydrocephalus progresses, a VP shunt is indicated. However, if infant is too sick or
small, a reservoir under the scalp to allow easy access for repeated ventricularpuncture may be used as an alternative. Early intervention improves mortality, VP
shunt avoidance, and neurological prognosis.
3.4.2.2 Prevention
Prevention is most important because IVH has a serious negative effect on prognosis.
3.4.2.2.1 Prenatal prevention
・Maternal transport to tertiary centers
The rate of severe IVH in outborn EP infants is higher than inborn infants.
・Maternal glucocorticoid administration (4)Maternal steroid administration reduces both RDS and IVH.
3.4.2.2.2 Postnatal prevention
・Professional management and minimal handling
IVH can be induced by routine cares such as tracheal aspiration. Therefore,
management by trained nurses and neonatologists is important.
・Indomethacin
Prophylactic indomethacin (0.1 mg/kg/6 hour continuous infusion, 3 days)
significantly reduces the risk of grade III or IV IVH (5,6)
・Sedation
Stabilizes hemodynamic changes
Morphine hydrochloride (100-200 µg/kg i.v., 10-50 µg/kg/hour div.)

62

Fentanyl (1-4 µg/kg i.v., 0.5-1.0 µg/kg/hour div.)
3.4.3 Evaluation
3.4.3.1 Laboratory test
Hematology, biochemistry, coagulation tests, blood gas analysis are conducted to
identify the cause of IVH and to evaluate the influence of bleeding. Hemorrhage may
result in neonatal seizures and suppression of brain function, so continuous EEG
monitoring is also recommended.
References minimum1) http://plaza.umin.ac.jp/nrndata Analysis from data in /syukei.htm
2) Papile LA, Burstein J, Burstein R, et al. Incidence and evolution of subependymal
and intraventricular hemorrhage: a study of infants with birth weights less than
1,500gm. J Pediatr 1978;92:529-534.
3) Volpe JJ. Intracranial Hemorrhage: Germinal Matrix Intraventricular Hemorrhage.
In: Neurology of the Newborn. 5th ed. Philadelphia (PA): Saunders Elsevier; 2008. p.
517- 588.
4) Wei JC, Catalano R, Profit J, et al. Impact of Antenatal Steroids on Intraventricular
Hemorrhage in Very Low Birth Weight Infants. J Perinatol 2016; 36: 352-356
5) Hirano S. Prevention of intraventricular hemorrhage in preterm infants.
Boshihokejoho 2010；62：25-26 (in Japanese).
6) Fowlie PW, Davis PG, McGuire W. Prophylactic intravenous indomethacin forpreventing mortality and morbidity in preterm infants. Cochrane Database Syst Rev.
(2010) CD000174.

63

Table 1 Classification of intraventricular hemorrhage by Papile (Reference 2)
Grade Ⅰ

Subependymal hemorrhage only

Grade Ⅱ

Intraventricular hemorrhage without ventricular enlargement

Grade Ⅲ

Intraventricular hemorrhage with ventricular enlargement

Grade Ⅳ

Intraventricular hemorrhage with intraparenchymal hemorrhage

Table 2 Classification of intraventricular hemorrhage by Volpe (Reference 3)
Grade Ⅰ

Subventricular hemorrhage ± mild intraventricularhemorrhage(less than 10% of the ventricular area in parasagittal
view)

Grade Ⅱ

Intraventricular hemorrhage without ventricularenlargement(10-50% of the ventricle are in parasagittal view)

Grade Ⅲ

Intraventricular hemorrhage with ventricularenlargement(greater than 50% of the ventricular area in parasagittal
view)

64

Figure 1 Echographic diagnosis of IVH- Classification of severity

A

B

C

D

A: Papile grade I, B: Papile grade II, C: Papile grade III, D: Papile grade VI（Contributor: Masahiro Hayakawa, Audit: Hiroko Iwami）

65

4 Intravenous fluid management

4.1 Fluid management
4.1.1 Clinical situation
Fluid supplementation and parenteral nutrition are vital for the management of EP
infants. Circulation is unstable in the first few days of life and careful adjustment of
fluid volume and contents is essential. Extracellular fluid volume immediately after
birth is greater in EP infants compared with that of more mature infants. As skinpermeability decreases and kidney function matures, extracellular fluid slowly
decreases and adapts to the extrauterine environment. Therefore, the main purpose of
fluid management during the acute phase is to promote the excretion of extracellular
fluid and to maintain the body water content along the same lines as mature infants It
is also important not to induce dehydration, which can lead to circulatory collapse. It
is important to consider insensible water loss, cardiac function, and renal function in
the fluid management of EP infants.
A general method for vascular accesses for the infants under 24 weeks of gestation isshown in Table. Umbilical veins can be used for a venous line during the first week
after birth. However, after that it should be removed to prevent catheter infection.
After this, a double lumen PICC (peripherally inserted central catheter) can beinserted. An arterial line is essential for accurate blood pressure management, butsometimes causes various complications. In particular, a decrease in blood pressure at
the time of blood collection through the catheter and infection caused by bloodcollection procedures are problematic. Therefore, the umbilical artery catheter is notessential, and is not necessarily required if the infant’s general condition is good andurine volume is maintained.
4.1.2 General management
4.1.2.1 Water
In Japan, most hospitals try to reduce the insensible water loss by providing
sufficiently humidity inside the incubator, which allows limitation of the amount of
fluid given to the infant during the early stages of life. Once circulatory condition
improves (as indicated by increased urine output, water infusion rates can be promptly
increase. On the other hand, high humidification is not common outside Japan. In
these circumstances, fluid volume given must be increased due to the surplus of huge

66

insensible water loss. As the results, some neonatal manuals recommend fluid
supplementation of 100-150 ml/kg/day on day1, 120-150 ml/day on day 2 (1). Table 1
shows the typical fluid supplementation schedule and the humidification managementin Japan. Water intake may need to be higher by about 10-20 ml/kg/day in SGA infants
due to lower body water content compared to AGA infants (2).
Water balance during the acute phase often changes rapidly with fluctuations inhemodynamics, often within a few hours. This necessitates vigilant monitoring of SVC
and IVC diameters with repeated ultrasonography. Changes of these values can help
the evaluate water balance.
4.1.2.2 Electrolyte
Electrolyte supplementation is not necessary during the early phase after birth. Oncethe diuretic phase starts, serum Na tends to be elevated. Therefore, early sodium
supplementation may increase the risk of hypernatremia. It is recommended to start
the Na supplementation when sodium concentration begins to decline. Generally,
sodium can be started on day 2-3 as shown in Table 3 (3). However, because renal
function in EP infants is poor with excessive sodium loss, some infants may need morethan 10 mEq/kg/day of sodium in later life.
Hyperkalemia may occur even during the diuretic phase, about 2 days after birth.
Therefore, supplemental K is unnecessary until almost day 3, usually after Na
supplementation starts. One the K supplementation started, as shown in Table 3, it isnecessary to replace about 2 to 3 mEq/kg/day.
4.1.2.3 Mineral
Ca needs to be replenished at the beginning. The starting dose is at 30 mg/kg/ day, thendaily doses should be increased up to 40-60 mg/kg/day (Table 3). Phosphorus also needs
to be administered at the early phase, but available preparation is as sodium
phosphate so do not replace with this combination until sodium levels are stable(usually after 24 hours after birth and after commencement of the diuretic phase).
Phosphate replacements can occur at 20-30 mg/kg/day (Table 3).
Mg, like calcium and phosphorus, is an important mineral for the human body. It isabundant in cells and plays an important role in enzyme activity andneurotransmission. According to the guidelines of ESPGHAN, Mg supplementation is67

recommended from the early postnatal period. However, in Japan, most hospitals do
not start Mg supplementation until day 4-5 (2).

68

4.2 Parenteral nutrition
4.2.1 Clinical situation
EP infants are born with a little accumulation of various nutrients. In addition, it
usually takes about 2-3 weeks to achieve sufficient enteral feeding for growth as EP
infants have reduced gastrointestinal tract motility and function. The lack of essential
nutrient supplementation after birth could result in rapid metabolic crisis. Therefore,
parenteral nutrition started immediately after birth is necessary to prevent these
problems. However, there is no clear evidence on the contents of nutrients and theduration 2). Recommended nutrients mentioned below are based on ESPGHAN
guidelines 2018.
4.2.2 General management
4.2.2.1 Glucose
Glucose is essential for maintaining brain activity. Neurons can also use ketone bodies,but this is insufficient in EP infants. The amount of glucose produced in the liver isabout 5 mg/kg/min. Because enzymes expression related to glycolysis andgluconeogenesis is low and there is a little glycogen storage, the initial glucose dose isstarted at 5 mg/kg/min and adjusted according to blood glucose levels (Table 3)(2).
During the first 24 hours, glucose homeostasis is unstable so hyperglycemia may occur
even at these doses. If blood glucose exceeds 200 mg/dL even after GIR is reduced,
insulin should be considered.
Once blood glucose levels become stable, 8-10 mg/kg/min of glucose infusion isrecommended from the ESPHHAN. Excess glucose cannot be used as an energy source
but can consume extra energy when converted into fatty acids. Most infants can be
maintained with doses below12 mg/kg/min.
4.2.2.2 Amino acids
Amino acids are essential to synthesize proteins which promote body growth. Cellularfunctions are believed to be depend on continuous supplementation of amino acids soonafter birth. About 3.5-4 g/kg/day amino acids is used for fetal development (4),suggesting that a similar amount should be given via a parenteral route is necessary.
Without this supplementation, protein can be catabolized at a rate of 1 g/kg/day 4). In
AGA infants, the administration of 3 g/kg/day after birth seems to be safe (Table 3)(5).

69

Although no amino acid preparation is produced exclusively for EP infants in Japan,
Pleamin-P® is available and used in most of Japanese hospitals. Table 4 shows the
product name of amino acid preparations and contents of each preparation currently
available in Japan and USA. Although they appear similar, Trophamine® andPremasol® contain higher amounts of glutamic acid (essential amino acids) andaspartic acid (non-essential amino acids).
4.2.2.3 Fat
Fat has the highest ratio of calorie per weight among nutrients and is a main source ofenergy for infants. Essential fatty acids are also important in many metabolic
pathways. If caloric supply from fat is not enough, amino acids become the default
source of energy, resulting in a catabolic state. Early administration of fat is therefore
recommended. However, fat administration may affect respiratory conditions and closemonitor is important during the acute phase. The recommended doses and timing areshown in Table 3 (6,7).
Currently, only the soybean oil derived preparations are available in Japan. Long term
fat administration may increase the risk of cholestasis due to inflammation caused byω6 fatty acids. On the other hand, the fish oil derived preparations containing a large
amount of ω-3 fatty acid is effective for prevention and treatment of cholestasis (8). The
preparation is already available outside Japan, but difficult to obtain inside Japan.
Table 5 shows the product names and their contents currently available inside Japan,
US, and Europe.
4.2.2.4 Vitamin and trace element
Like other preparations used for parenteral nutrition, no specific formulation ofvitamins and trace elements are available for EP infants. Table 6 shows available
vitamin product and their contents with recommend doses available in Japan andUSA. The estimated requirement of each vitamin is also provided (9). Table 7 shows
available trace element product in Japan and USA. The content of each trace element,
the recommended dose, and the estimated requirement are also shown (10). The
recommended doses fulfil the daily vitamin requirements, but overdose can occur forcertain trace elements. Therefore, the long term trace element supplementation withthese doses should be carefully considered. Each preparation should be administeredfrom 3 days after birth.

70

4.2.2.6 Method
Because of the high osmotic pressure of parental nutritional fluids, a central venous
catheter is always necessary. The catheters can be inserted via peripheral veins in EP
infants, but for the infants of 22-23 weeks of gestation this may not be possible due toskin immaturity. In this case, umbilical vein catheters can be used as Table 1. A double
lumen catheter is desirable to prevent composition changes inside a solution. No
commercially ready to use solution is available in Japan. Each hospital must makethem in house, so it is desirable to prepare inside a hood. The line for parenteralnutrition should be a closed circuit with an inline filter. Fat is preferably administeredthrough a peripheral vein but if this is not possible, it can be given through a central
catheter line without filtering.
The recommended composition of parenteral nutrition fluid until day 5 is shown in
Table 8 (11). Until then, no major changes in composition are needed. As enteralfeeding progresses, the amount of fluid for parenteral nutrition is reduced accordingly.
Once enteral feeding exceeds 100 ml/kg/day, parenteral nutrition is not an absolutenecessity. Trace element and vitamin supplementation can be discontinued. The lack ofnutrients at this point can be compensated with breast milk fortifier and oral
supplements. When enteral feeding reaches about 120-140 ml/kg/day, intravenous
infusions are no longer necessary. This can be achieved within 2-3 weeks after birth, if
there are no complications. Parenteral nutrition must be continued if enteral feeding isimpaired.
4.2 3 Evaluation
4.2.3.1 Monitoring
During the parenteral nutrition, close monitoring for complications are always
necessary and include regular blood chemical tests. Table 9 shows items to evaluate
and the frequency of assessment.
4.2.3.2 Complications
The most common complication is catheter related blood stream infection (CRBSI).
When inserting a PICC, maximum precaution is required like the insertion of central
venous catheter. Once inserted, a close inspection of color change at the insertion sitewith a repeated evaluation of CRP and CBC is useful to detect CRBSI early.
Cholestasis is also a common complication. The incidence of this is higher among SGA

71

and infants with difficulties tolerating enteral feeding.
Metabolic acidosis, hyperammonemia, and hyperlipidemia may be additionallyobserved. In this situation, it may be necessary to reduce the causative content.
Respiratory deterioration leading to death after fat infusion has been reported. The
autopsy of this case revealed fat deposition in the lungs. Close assessment of
respiratory condition is recommended during its administration.
References
1) Doherty E. Fluid and Electrolyte Management. In: Cloherty J, Eichenwald E,
Hansen A, Stark A, editors. Manual of Neonatal Care 7th Ed. 7th ed. Philadelphia:
Lippincott Williams & Wilkins; 2012. p. 269–283.
2) Itahashi K, Kusuda S, Tamura M, editors. Basic management of high risk infant. In:
Manual of NEonatal Intensive Care Unit. 5th ed. Tokyo: Kanehara & Co., Ltd.; 2014. p.
177–181.
3) Jochum F, Moltu SJ, Senterre T, Nomayo A, Goulet O, Iacobelli S, et al.
ESPGHAN/ESPEN/ESPR/CSPEN guidelines on pediatric parenteral nutrition: Fluidand electrolytes. Clin Nutr [Internet]. 2018 Dec 1 [cited 2019 Apr 11];37(6 Pt B):2344–
2353. Available from: http://www.ncbi.nlm.nih.gov/pubmed/30064846
4) Van Den Akker CHP, Van Goudoever JB. Defining Protein Requirements of Preterm
Infants by Using Metabolic Studies in Fetuses and Preterm Infants. Nestle Nutr Inst
Workshop Ser. 2016;86:139–149.
5) van Goudoever JB, Carnielli V, Darmaun D, Sainz de Pipaon M,
ESPGHAN/ESPEN/ESPR/CSPEN working group on pediatric parenteral nutrition C,
Bronsky J, et al. ESPGHAN/ESPEN/ESPR/CSPEN guidelines on pediatric parenteralnutrition: Amino acids. Clin Nutr [Internet]. 2018 Dec 1 [cited 2019 Apr 11];37(6 Pt
B):2315–2323. Available from: http://www.ncbi.nlm.nih.gov/pubmed/30100107
6) Levene M, Wigglesworth JS, Desai R. PULMONARY FAT ACCUMULATIONAFTER INTRALIPID INFUSION IN THE PRETERM INFANT. Lancet [Internet].
1980 Oct 18 [cited 2019 Apr 22];316(8199):815–819. Available from:https://www.sciencedirect.com/science/article/pii/S0140673680901701?via%3Dihub
7) Lapillonne A, Fidler Mis N, Goulet O, van den Akker CHP, Wu J, Koletzko B, et al.
ESPGHAN/ESPEN/ESPR/CSPEN guidelines on pediatric parenteral nutrition: Lipids.
Clin Nutr [Internet]. 2018 Dec 1 [cited 2019 Apr 11];37(6 Pt B):2324–2336. Available
from: http://www.ncbi.nlm.nih.gov/pubmed/30143306
8) Koletzko B, Goulet O. Fish oil containing intravenous lipid emulsions in parenteral72

nutrition-associated cholestatic liver disease. Curr Opin Clin Nutr Metab Care.
2010;13:321–326.
9) Bronsky J, Campoy C, Braegger C, ESPGHAN/ESPEN/ESPR/CSPEN working groupon pediatric parenteral nutrition C, Bronsky J, Cai W, et al.
ESPGHAN/ESPEN/ESPR/CSPEN guidelines on pediatric parenteral nutrition:
Vitamins. Clin Nutr [Internet]. 2018 Dec 1 [cited 2019 Apr 11];37(6 Pt B):2366–2378.
Available from: http://www.ncbi.nlm.nih.gov/pubmed/30100105
10) Domellöf M, Szitanyi P, Simchowitz V, Franz A, Mimouni F,
ESPGHAN/ESPEN/ESPR/CSPEN working group on pediatric parenteral nutrition C,
et al. ESPGHAN/ESPEN/ESPR/CSPEN guidelines on pediatric parenteral nutrition:
Iron and trace minerals. Clin Nutr [Internet]. 2018 Dec 1 [cited 2019 Apr 11];37(6 Pt
B):2354–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/30078716
11) Itahashi K, Kusuda S, Tamura M, editors. Basic Management of High risk infant.
In: Manual of Neonatal Intensive Care. 5th ed. Tokyo: Kanehara Co., Ltd.; 2014. p.
167–175. (in Japanese)73

Table 1 Vascular access lines
GW(wk)First 24 hours

-1wk

1wk-

V

A

P

V

A

P

V

A

P

22

UV

O

N

UV

O

M

N

N

M

23

UV

O

N

UV

O

M

N

N

M

24-

O

O

M

O

O

M

N

N

M

V: venous line, A: arterial line, P: peripherally inserted line
UV: umbilical vein, UA: umbilical artery, PICC: double lumen peripherally inserted
central cather
N: not necessary, O: optional, M: mandatory

Tabel 2 Initial fluid volume and humidity in the incubator

Hours of Age<24 h

24-48h48-72h72h<

Fluid volume(ml/kg/day)

50-60

70-80

90-100100-120

Humidity
(%)

90-95

85-90

80-85

80

74

Table 3. General dose of several nutrients for extremely preterm infants in Japan andrecommended dose by ESPGHAN<24 h

24-48 h48- 72 h

Amount during firstdays of life
(ESPGHAN 2018)

Target Amount for
Growing(ESPGHAN2018)

Energy(kcal/kg/day)

40-50

70-80

100

45-55

90-120GIR(mg/kg/min)

4-5

Increase gradually over
2-3 days

4-8

8-10

2-3

1.5-2.5

2.5-3.5

0-1

2-3

Amino Acid(g/kg/day)

1-1.5

2.5-3.5

Fat(g/kg/day)

0-1

1-2

Na
(mEq/kg/day)

0

2-3

3

0-2

3-5

K
(mEq/kg/day)

0

0-1

1-2

0-2

2-3

Ca
(mg/kg/day)

25-40

30-40

60-80

32-80

64-140P(mg/kg/day)

0

20-30

40-60

31-62

50-108Mg(mg/kg/day)

0

0

0

2.5-5.05-7.575

Table 4. Comparison of Amino Acid Products for Pediatric Patients in Japan and US
Japan

US

Pleamin-P®
(7.6%)

TrophAmine®
(10%)

Premasol®
(10%)

Primene®
(10%)

L-Isoleucine

0.8

0.82

0.82

0.67

L-Leucine

1.6

1.4

1.4

1.00

L-Lysine

0.48

0.82

0.82

1.10

L-Methionine

0.15

0.34

0.34

0.24

L-Phenylalanine

0.25

0.48

0.48

0.42

L-threonine

0.24

0.42

0.42

0.37

L-tryptophan

0.12

0.20

0.20

0.20

L-valine

060

0.78

0.78

0.76

L-arginine

1.0

1.2

1.2

0.84

L-histidine

0.25

0.48

0.48

0.38

L-Glycine

0.20

0.36

0.36

0.40

L-Alanine

0.52

0.54

0.54

0.80

L-glutamic acid

0.08

0.5

0.50

1.00

L-Aspartic acid

0.08

0.32

0.32

0.60

L-proline

0.6

0.68

0.68

0.30

L-Serine

0.4

0.38

0.38

0.40

L-Tyrosine

0.06

0.24

0.24

0.045

L-cysteine

0.15<0.016<0.016

0.189

Taurine

0.020

0.025

0.025

0.06

1.26

1.12

1.12

1.89

Each 100 mL contains:
Essencial
amino
acids
(g)

Nonessencial
amino
acids
(g)

E/N ratio76

Table 5. Comparison of Fat product in Japan and US and/or Europe

Product Name
Oil source(%)

Fatty Acid
Composition
(%)

Japan

EuropeUS, Europe

US, Europe

Intralipos®
(20%)

Lipoplus®
(20%)

SMOFlipid®
(20%)

Omegaven®
(10%)

Soybean oil

100

40

30

0

MCT

0

50

30

0

Fish oil

0

10

15

100

Olive oil

0

0

25

0

Linoleic acid (ω-6)

52.6

53

19.5

3.2

α-Linolenic acid (ω-3)

7.4

8

2.5

1.3

2.3

20.1

2.3

18.4

Eicosapentaenoic acid (ω-3)

0Docosahexaenoic acids (ω-3)

130Oleic acid (ω-9)
Ratio of ω-6:ω-3 Fatty acid
Energy (Kcal/ml)

24.5

8

29

9.5

7:1

2.7:1

2.5:1

1:8.2

2.0

1.9

1.9

1.12

Table 6. Comparison of Multi Vitamin Product for Parenteral Nutrition in Japan andUSJapan
Product Name

US

Estimated needs forpreterm infants(/kg/day)(ESPGAHAN 2018)

VITAJECT®
(per 1/5 kit/kg/day)

MULTAMIN®
(per 1/5 vial/kg/day)

INFUTIVE pediatric®
M.V.I. pediatric®
(per 2 ml/kg/day)

Vitamin A (IU)

660

800

690

700-1500

Vitamin D (IU)

80

80

160

80-400Vitamin E (IU)

3

3

2.8

2.8-3.5

Vitamin K (mcg)

0.4

0.4

80

10

Thiamine (mcg)

600

1000

480

350-500

Riboflavin (mcg)

800

1000

560

150-200

Niacin (mg)

8

8

6.8

4-6.8

Pantothenate (mg)

3

3

2

2.5

Pyridoxine (mcg)

800

1000

400

150-200

Biotin (mcg)

20

20

8

5-8

Vitamin B12 (mcg)

2

2

0.4

0.3

Ascorbic acid (mg)

20

20

32

15-25

Folic acid (mcg)

80

80

56

56

Lipid soluble

Water soluble77

Table 7. Comparison of Trace Element Product in Japan and US

Japan

US

Estimated needs for preterm infants( ESPGHAN guidelines on paediatricparenteral nutrition 2018)

Mineralin®
(per 1/10 ampoule/kg/day)

Neotrace®
(per 1/10 vial/kg/day)

Fe (mcg)

1960200-250 mcg/kg/day

Mn (mcg)

5.5

2.5≦1 mcg/kg/day in long term PN

Zn (mcg)

392

150

400-500 mcg/kg/day

Cu (mcg)

32

1040 mcg/kg/day

I (mcg)13

0

1-10 mcg/kg/day

Cr (mcg)

0

0.085

-

Se (mcg)

00

7 mcg/kg/day

Table 8. Examples of parenteral nutrition during 5 days of age for 1000 g infant

Day 0Route-1

Route-2

50% glucose
Pleamin-P®
Sterile water
Heparin

50% glucose
Pleamin-P®
Carcicol®
Sterile water
Heparin

Day 1
12 ml
16 ml
22 ml
0.05 ml

12 ml
16 ml
8 ml
14 ml
0.05 ml

1.5 ml/hr

1.0 ml/hr

Y-site ofRoute-1

Day 2

50% Glucose
Pleamin-P®
Sodium Phosphate
Corrective Injection(0.5 mmol/mL)
10% NaCl
Sterile water
Heparin

28 ml
44 ml
4 ml

50% glucose
Pleamin-P®
Carcicol®
Sterile water
Heparin

28 ml
44 ml
16 ml
12 ml
0.1 ml2.0 ml/hr

50% Glucose
Pleamin-P®
Sodium Phosphate
Corrective Injection(0.5 mmol/mL)
10% NaCl
1M KClSterile water
Heparin

28 ml
40 ml
4 ml

1.0 ml/hr

50% glucose
Pleamin-P®
Carcicol®
Sterile water
Heparin

28 ml
40 ml
24 ml
8 ml
0.1 ml

0.2ml/hr

Intralipos (20%)

2 ml
22 ml
0.1 mlIntralipos (20%)
Fluid volume

60

ml/kg/day

Fluid volume

77

ml/kg/day

Fluid volume

GIR

5

mg/kg/minGIR

7

mg/kg/min

Amino acid1.5

g/kg/dayAmino acid

2.4

Lipid

0

g/kg/day

Lipid

1.0

Na

0

mEq/kg/day

Na

K

0

mEq/kg/day

K

Ca

30

mg/kg/day

P

0mg/kg/day

2.8ml/hr

2 ml
3 ml
23 ml
0.1 ml
1.0 ml/hr

0.4ml/hr
100

ml/kg/dayGIR

9

mg/kg/min

g/kg/dayAmino acid2.8

g/kg/dayg/kg/day

Lipid

1.9

g/kg/day

3.1

mEq/kg/day

Na

4.0

mEq/kg/day

0

mEq/kg/day

K2

mEq/kg/day

Ca

30

mg/kg/day

Ca

45

mg/kg/day

P

30

mg/kg/day

P

43

mg/kg/day78

Table 8(continued). Examples of parenteral nutrition during 4 days of age for 1000 g
infantDay 3-4
Route-1

Route-2

Y-site ofRoute-1

50% Glucose
Pleamin-P®
Sodium Phosphate Corrective
Injection (0.5 mmol/mL)
10% NaCl
1M KClVitaject®
Sterile water
Heparin
50% glucose
Pleamin-P®
Carcicol®
Medlenic®
Heparin

Day 5
28 ml
40 ml
3 ml

3.5ml/hr

2 ml
3 ml
0.2 kit (2ml)
22 ml
0.1 ml

28 ml
40 ml
32 ml
0.5 ml0.1 mlIntralipos (20%)

1.0 ml/hr

50% Glucose
Pleamin-P®
Sodium Phosphate Corrective
Injection (0.5 mmol/mL)
10% NaCl
1M KClVitaject®
Sterile water
Heparin
50% glucose
Pleamin-P®
Carcicol®
Magnesium Sulfate corrective
Injection (1 mEq/mL)
Medlenic®
Heparin

0.6ml/hr

Intralipos (20%)

28 ml
40 ml
3 ml

3.5ml/hr

2 ml
3 ml
0.2 kit (2ml)
22 ml
0.1 ml

28 ml
40 ml
31 ml
1ml

1.0 ml/hr

0.5 ml0.1 ml
0.6ml/hr

Fluid volume

122

ml/kg/day

Fluid volume

122

ml/kg/dayGIR

10

mg/kg/minGIR

10

mg/kg/min

Amino acid3.3

g/kg/dayAmino acid3.3

g/kg/day

Lipid

2.9

g/kg/day

Lipid

2.9

g/kg/dayNa

4.8

mEq/kg/day

Na

4.8

mEq/kg/day

K

2.5

mEq/kg/day

K

2.5

mEq/kg/day

Ca

60

mg/kg/day

Ca

58

mg/kg/dayP

40

mg/kg/dayP

40

mg/kg/day

Mg

5.4

mg/kg/dayTable 9. Monitoring of infants receiving parenteral nutrition
Measurement

Frequency

Body weight

Daily if infant condition is stable

Height and Head circumference

WeeklyIn-Out balance

Every 8 hr

Glucose, electrolytes,
blood gas analysis

Daily during acute period

NH3

Daily, As clinically indicated

CRP

Daily

AST, ALT, Al-p, BUN, Cr, TB, DB,
Calcium, Phosphorus, TG, TC

Weekly（Contributor: Isamu Hokuto, Audit: Tokuo Miyazawa）

79

5 Enteral feeding

5.1. Clinical Situation
Nutritional management for EP infants during the stay in NICU involves not only
improving physical growth but also the prevention of mortality and morbidities
including NEC, CLD, and ROP (1). Furthermore, it is also correlated with theneurodevelopmental outcome after discharge (2). Extrauterine growth restriction(EUGR) which is defined as less than 10 percentile of body weight standard ofcorrected age at NICU discharge has a great influence on the subsequent neurologicaldevelopment. Therefore, early aggressive nutrition (EAN) aiming to avoid EUGR is
expected to improve the outcomes in EP infants.
EAN is a method to start parenteral nutrition composed of amino acids within 24 hours
after birth along with minimal enteral feeding (MEF) and human milk fortification(HMF). In Japan, until the early 2000s, parenteral nutrition and enteral nutrition were
withheld until the EP infant was stable, because of concerns of their immaturedigestive tract and metabolic function. However, since the early 2000s, EAN has been
accepted as a standard nutritional strategy in NICUs.
Although parenteral nutrition is essential as nutritional management until theestablishment of enteral nutrition, parenteral nutrition alone is not enough for
critically premature infants. Additionally, exclusive parenteral nutrition is a risk factor
for the atrophy of intestinal mucosa, bacterial translocation, parenteral nutrition
associated liver disease (PNALD), and catheter related blood stream infection (CRBSI).
Therefore, it is always desirable to establish enteral feeding and to withdraw theparenteral nutrition as early as possible.

5.2. General Management
5.2.1 Breastfeeding
The best nutrition for EP infants is the own mother's milk (OMM). OMM has many
benefits such as the high bioavailability of various nutrients, the protective effects from
immune factors against infection and NEC. Furthermore, it can enhance theattachment between mothers and children and the long term psychomotor development
and prevent metabolic syndrome.
Prenatal visit to those who are in threatened preterm delivery should be considered as

80

much as possible to explain the benefits of breastfeeding for EP infants and toencourage the expression of breast milk at early stage (within 6 hours of birth, if
possible, within 1 hour).
Combining manual milking with a hospital-grade electric milking machine (double
pump type) may enhance the breast milk secretion. The effectiveness of manual
milking early in the postpartum period with a small amount of colostrum has beenreported
A system which allows colostrum to be given to the infants with an injection syringe
and/or a cotton into the infant’s mouth by the own mother should be established in thehospital.
If OMM is not available, AAP and ESPGHAN recommend the use of pasteurized donor
milk (DM). In Japan, the Japan Breast Milk Bank Association was established in 2017.
Donors are screened for infectious diseases including HIV, HTLV-1, HBV, HCV, andsyphilis. The expressed milk is pasteurized (62.5 °C, 30 minutes) and transferred to thehospitals on demand (3).
In the 2015, according to a nationwide survey, 32 NICUs (25%) out of 126 responded
that they used breast milk from other mothers (so-called “received milk”) (4). Most ofthese hospitals performed the screening for infectious diseases of donor mothers, butpasteurization of donor milk was rarely performed. Now this method is notrecommended due to the risk of infection.
5.2.2 Formula
Low birth weight infant formula is selected if breastfeeding is contraindicated or if
OMM is not available and DM is difficult to obtain.
5.2.3 Minimal enteral feeding (MEF)
It is recommended to start enteral feeding with small amounts of breast milk ideallywithin 24 hours after birth, at the latest within 72 hours after birth.
The volume for MEF is about 10 to 20 mL/kg/day and does not exceed 25% of the total
daily amount planned (Table 1)(5).
Immediately after MEF started, a small amount of residual milk with bile (gastricresidual) is often aspirated before each lactation. The amount of residual milk or bile-81

like properties are not considered as the onset of NEC or feeding intolerance (6).
Instead of interrupting enteral nutrition, it is desirable to continue MEF as much as
possible with carefully observing abdominal findings (such as abdominal distension,
abdominal wall tone, presence or absence of intestinal peristalsis, etc.).
Enteral feeding can be withheld for up to 72 hours if DM or OMM is not available. Useformula with caution due to its association with NEC.
5.2.4

Tube feeding (feeding interval and advancement of feeding dose)

Tube feeding is basically carried out by an intermittent administration of milk througha nasal or oral gastric tube.
The interval of feeding for EP infants is usually every three hours (8 times a day) or
every two hours (12 times a day). According to a survey of Japanese NICUs in 2017,
two thirds of the hospitals fed every 3 hours but some would feed every 2 hours becauseof concerns of aspiration (7).
Duodenal continuous feeds are used in some hospitals for infants with silent aspiration
or GER but its safety is not proven and there is an association with NEC. Carefulobservation is mandatory if this intervention is selected (8).
In general, the volume of enteral feeding can be safely increased by up to 20 mL/kg/day.
A Cochrane review reported no difference in the incidence of NEC between slow volume(15-20 mL/kg/day) and fast volume advancement (30-40 mL/kg/day) (9).
5.2.5 Human milk fortification
The nutritional stock of EP infants is very low and it is difficult to provide enoughnutrition for their requirements even after full enteral feeds are established (Table
2)(10). This increases the risk of poor growth and metabolic bone disease. In order toprevent those problems, human milk fortification (HMF) can be used to compensate forthe lack of nutrients in human milk while maintaining the benefits of breast feeding.
HMS-1 and HMS-2, which is further enriched with nutrients, Ca, and phosphorus, areproducts of Morinaga LTD, and are used in Japan (Table 3). Both of them are powdered
formulations produced from cow milk protein. Liquid fortifiers are not yet available inJapan.

82

5.2.5.1 Practice
The fortifiers available in Japan do not contain vitamins nor trace elements such asiron, zinc and copper, so they must be administered separately if a shortage issuspected.
Start with a 1/4 supplement (1 package (0.8 g) in 120 mL of breast milk) once breast
milk reaches 50 mL/kg/day for both HMS-1 and HMS-2.
Increase to a 1/4 supplement (1 package in 60 mL of breast milk) when reach 100
mL/kg/day.
Observe for several days, and if there is no abdominal distension or increase of residual
milk, then use standard fortification (1 package for 30 mL of breast milk)
There is no clear guideline as to when HMF should be stopped. This very muchdepends on the policies of individual hospitals and/or the condition of the infant.
Ileus may occur due to fecal stones (fatty acid and calcium stone: fecaliths) with HMF
supplementation. NEC has also been reported (11). Cases with poor gastrointestinal
function and/or fat absorption due to bile congestion need careful attention. Cases withgastrointestinal allergy against milk protein contained in HMF have also been reported(12).
Nutritional components in breast milk may vary among mothers and is also dependent
on the phase of lactation. In particular, protein concentration gradually decreases(Figure. 1). Even under standard HMS-2 fortification, inadequate intake of protein
compared with a target value of 4.0 g/kg/day may occur (Figure 2).
Exclusive human milk diet (EHMD) using human milk-derived breast milk fortifiers
has been reported to show beneficial effects such as a shortening of parenteralnutrition, preventions of NEC, CLD and ROP, and a shortening of hospitalization in
Europe and USA (13).
5.2.5.2 Individualized HMF
Two methods of individualized human milk fortification (Individualized HMF) are83

reported as effective for reaching target protein intake.


Targeted HMF: Determine the amount of protein fortification based o component
analysis of breast milk using human milk analyzer(14)Adjustable HMF: Adjust the amount of protein fortification to maintain 9-14
mg/dL of blood urea nitrogen value (BUN) as an index of protein intake without
the analysis of breast milk components (15)5.2.6 Probiotics
Administration of probiotics to EP infants are likely to delay or destroy theestablishment of normal intestinal flora. Administration of probiotics can be expected
to induce normal intestinal flora and to show beneficial effects on gastrointestinal
physical function and immune modulation. A systematic review of Cochrane has shownthat probiotics significantly reduce NEC (Bell classification stage II or grater) andsignificantly improve overall mortality and mortality associated with NEC (16).
The effectiveness of a single species such as Bifidobacterium and Lactobacillus has
been reported. The administration of multiple bacterial species are also reported as
effective. The majority of hospitals use Bifidobacterium breve in Japan.
5.2.6.1 PracticeThere is no consensus on duration nor dose has not been fixed. Generally, it isadministered from the beginning and until establishment of enteral feeding (average 4
weeks).
Bifidobacterium preparation of M-16V (Morinaga Milk Industry) distributed in Japan
contains B. breve 5×109 cfu bacteria per 1 packet (1.2 g). Since dextrin is an excipient,
the osmotic pressure significantly increases when the formulation is dissolved in breast
milk or formula. It is isotonic if dissolved in 4 mL of distilled water. 4 ml can be divided
if each enteral feeding is less than 4 ml or batch administered there is feeds are greaterthan 4 ml. Alternately, since ileus by corn starch as an excipient was reported, only thesupernatant of the dissolve can be administered (17).
The preparation provided from Meiji Milk Industry does not contain dextrin, so thewhole solution resolved in distilled water or milk can be administered.

84

5.2.6 Glycerin Enema
Glycerin enemas are widely used in Japanese NICUs for the purpose of preventing
delay in meconium passage and feeding intolerance among EP infants. However, there
is no clear evidence that glycerin enema can prevent NEC, meconium-related intestinal
obstruction (MRI), or localized intestinal perforation (FIP) (18).
5.2.6.1 PracticeThere is no definite consent about the start of administration, dilution method, dose,and interval of glycerin enema.
Start: From the initiation of MEF to 24 hours after birth
Dilution: 1/2 dilution (25%) or original solution (50%)
Dose: 1 to 2 mL/kg with original solution or 2 to 5 mL/kg with 1/2 diluted solution
Interval: every 6 to 8 hours
5.2.7 Standardization of enteral feedingStandardization of enteral feeding for preterm infants at each center has been reported
to reduce the risk of developing NEC by 78% (19). Therefore, it is recommended tostandardize and document the items in Table 4.
5.2.8

NEC

NEC is the most frequent acute digestive tract disease in the neonatal period among
preterm infants, and low birth weight infants account for over 90% of NEC cases. The
incidence is reported as 7-10% in very low birth weight children in other countries but
has been consistently maintained at a level of 1.5% in Japan for over 10 years (Figure3) (20). Despite the fact that donor milk is not widely used, the reason why Japan has alower incidence of NEC is unknown. Several factors including the difference in generalmanagement for EP infants such as nutritional care, circulatory care based on
echocardiography performed by neonatologists, repeated CRP measurement using a
POCT device as an inflammatory biomarker, use of antibiotics and antacid, genetic
backgrounds and environmental factors in NICU can be considered.
The diagnosis of NEC is based on general and abdominal symptoms and characterized
imaging findings. The Bell classification is used for staging (Table 5)(21). Stage IIa or
greater with intramural emphysema or portal vein gas is often confirmed as adefinitive diagnosis, but in EP infants, gastrointestinal perforation may occur suddenly
without these findings, followed by shock and/or DIC.

85

Suspected or mild cases of NEC can be treated with multidisciplinary medical
treatment. Discontinuation enteral feeding, decompression of the intestinal tract by
gastric tube, and broad-spectrum antibacterial and antifungal drugs according tosurveillance culture and antimicrobial susceptibility (antibiogram) of the indigenous
bacteria in each facility should be commenced. Active care including respiratory andcirculatory supports, parenteral nutrition, and treatment for DIC should be also
followed.
Cases with intestinal perforation or poor response to medical treatment surgicaltreatment. Although resection of necrotic or enlarged intestinal segment and fistula
formation may be needed, a one-step anastomosis may also be performed if the necrotic
intestine is localized and the general condition is maintained.
If the infant is severely unwell, abdominal drainage can temporize the situation until
definitive surgery can be performed.
Reference
1) Ehrenkranz RA, et al. Growth in the neonatal Intensive care unit influences
neurodevelopmental and growth outcomes of extremely low birth weight infants.
Pediatrics 2006;117:1253-1261.
2) Klevebr S, Westin V, Stolz SE et al. Early energy and protein intake and association
with growth, BPD, and ROP in extremely preterm infants. Clinical Nut 2018;38:12891295.
3) Mizuno K：Usefulness and issues of breast milk bank (in Japanese)．Shonika 2018;
59:321-325.
4) Mizuno K, Sakurai M, Itabashi K. Necessity of human milk banking in Japan:
Questionnaire survey of neonatologists. Pediatr Int 2015;57:639-644.
5) Japan Neonatologist Association、NICU manual 5th edition、Kanehara Shuppan;
2014 (in Japanese)
6) Singh B, Rochow N, Chessell L, et al. Gastric residual volume in feeding
advancement in preterm infants (GRIP Study): A randomized trial. J Pediatr 2018;200:
79-83.
7) Ashina M, Fujioka K, Totsu S, et al. Feeding interval and use of donor breast milk
for very low birthweight infants: A nationwide survey in Japan. Pediatr Neonatol 2018;60:245-251.
8) Wada N, Sato W, Yanagida E, et al. A case of neonatal chronic lung disease with86

immediate improvement of oxygenation by transduodenal tube nutrition. Journal ofJapan Society for premature and newborn medicine 2003; 15: 247-252. (in Japanese)
9) Oddie SJ, Young L, McGuire W. Slow advancement of enteral feed volumes toprevent necrotizing enterocolitis in very low birth weight infants. Cochrane Database
Syst Rev. 2017 Aug 30;8:CD001241.
10) Ziegler EE. Meeting the nutritional needs of the low-birth-weight infant. Ann Nutr
Metab 2011; 58 Suppl 1: 8-1811) Murase M, Miyazawa T, Taki M, et al. Development of fatty acid calcium stone ileus
after initiation of human milk fortifier. Pediatr Int 2013;55:114-116.
12) Miyazawa T, Itabashi K, Imai T. Retrospective multicenter survey on food-related
symptoms suggestive of cow’s milk allergy in NICU neonates. Allergol Int 2013;62:8590.
13) Sullivan S, Schanler RJ, Kim JH, et al. An exclusively human milk-based diet isassociated with a lower rate of necrotizing enterocolitis than a diet of human milk andbovine milk-based products. J Pediatr 2010;156:562-567.
14) Rochow N, Fusch G, Choi A, et al. Target fortification of breast milk with fat,protein, and carbohydrates for preterm infants. J Pediatr 2013;163:1001-1007.
15) Arslanoglu S, Moro GE, Ziegler EE. Adjustable fortification of human milk fed topreterm infants: does it make a difference? J Perinatol 2006;26:614-621.
16) AlFeleh K, Anabress J. Pobiotics for prevention of necrotizing enterocolitis inpreterm infants. Cochrane Database Syst Rev. 2014 Apr 10;(4):CD005496.
17) Hisada K：Probiotics, prebiotics．Shusanki-igaku 2016;46 supple:1065-1067. (inJapanese)18) Guideline of gastrointestinal dysfunction in very low birth weight infants (inJapanese) , Health Labour Sciences Research Grant, 2016 (Accessed on July-17-2019).
Available from: https://minds.jcqhc.or.jp/n/med/4/med0275/G0000934
19) Jasani B, Patole S. Standardized feeding regimen for reducing necrotizing
enterocolitis in preterm infants: an updated systematic review. J Perinatol 2017;37:
827-833.
20) Miyazawa T. The current situation of necrotizing enterocolitis in Japan. European
Medicine Agency (Accessed on May-19-2019). Available from:https://www.ema.europa.eu/en/events/second-annual-scientific-workshop-ema-applyingregulatory-science-neonates21) Walsh MC, Kliegman RM. Necrotizing enterocolitis: treatment based on staging
criteria. Pediatr Clin North Am 1986;33:179-201

87

Table 1 Feeding protocol for extremely preterm infants
Birth weight

0-23 hours

24-47 hours

48-71 hours

72-96 hours～599g

0.3mL×8/day

0.5mL×8/day

0.8mL×8/day

1.1mL×8/day

600～799g

0.5mL×8/day

0.8mL×8/day

1.3mL×8/day

1.8mL×8/day

800～999g

0.7mL×8/day

1.0mL×8/day

1.7mL×8/day

2.4mL×8/day

1,000g～1,250g

1.0mL×8/day

1.5mL×8/day

2.5mL×8/day

3.5mL×8/day(Modified from reference 5)

Table 2

Nutritional needs of the low-birth-weight infants calculated by factor

addition method
Birth weight
500-700g

700-900g

900-1,200g

1,200-1,500g

Loss

1.0

1.0

1.0

1.0

Accumulation

2.5

2.5

2.5

2.4

Requirement intravenously

3.5

3.5

3.5

3.4

Requirement enterally

4.0

4.0

4.0

3.9

Loss

60

60

65

70

Accumulation

29

32

36

38

Requirement intravenously

89

92

101

108

Requirement enterally

105

118

119

127

Intravenously

3.9

3.8

3.5

3.1

Enterally

3.8

3.7

3.4

3.1

Fetal body weight increase(g/kg/day)Protein(g/kg/day)

Energy (kcal/kg/day)Protein/Energy (g/100kcal)（Modified from reference 10)88

Table 3 Comparison of HMS-1 and HMS-2
Standard

Increment

breast milk

by HMS-1(per 100mL)

added

Protein (g)

1.3

0.7

2.0

1.0

2.3

Fat (g)

3.7

0

3.7

1

4.7

Carbohydrate (g)

7.7

1.5

9.2

1.8

9.5

Energy (kcal)

69

9

78

20

89

280

60

340

80

360

Osmolarity(mOsm)

HMS-1(per 100mL)

Increment
by HMS-2
added

HMS-2
(per 100mL)

Table 4 The items should be standardized about enteral feeding-----------------------------------------------------------------------------------------------------------------Timing of starting enteral feeding
Method of tube feeding (continuous or intermittent, interval, infusion rate)
Type of milk (OMM, DM, formula for low birth weight infants)
Increment of enteral feeding volume
Maximum volume
Extremely early feeding (timing, volume)
Responses to feeding intolerance and residual milk
Individualized responses according to different disorders (continue or discontinue,
increase volume or decrease)-Sepsis-Indomethacin for PDA-Blood transfusion
Breast milk fortification (timing, duration, concentration)-------------------------------------------------------------------------------------------------------------------

89

Table 5 Bell’s staging of NEC
Stage

Systemic signs
Temperature instability,

ⅠA
Suspected

apnea, bradycardia,
lethargy

Abdominal signs

Radiographic signs

Gastric retention,
abdominal distention,

Normal or intestinal dilation,

emesis, hemo-positive

mild ileus

stool

ⅠB
Suspected

Same as above

Grossly bloody stool

Same as above

Same as above, plus
ⅡA
Definite,

Same as above

mildly ill

absent bowel sounds

Intestinal dilation, ileus,

with or without

pneumatosis intestinalis

abdominal tenderness
Same as above, plus
absent bowel sounds,

ⅡB

Same as above, plus mild

definite tenderness,

Definite,

metabolic acidosis andwith or without

moderately ill

thrombocytopenica

abdominal cellulitis orSame as ⅡA, plus ascites

right lower quadrant
mass
Same as ⅡB, plus
ⅢA

hypotension, bradycardia,

Advanced,severe apnea, combined

severely ill,

respiratory and metabolic

intact bowel

acidosis, DIC, andneutropenia

Same as above, plus
signs of peritonitis,
marked tenderness,

Same as ⅡA, plus ascites

and abdominal
distention

ⅢB
Advanced,severely ill,

Same as ⅢASame as ⅢASame as above, plus
pneumoperitoneum

perforated bowel

90

Figure 1 Protein contents in breast milk sampled from mothers delivered extremely
low birth weight infants (Department of Pediatrics, Showa University)

3.0

Protein, g/100mL

2.5
2.0
1.5
1.0
0.5
0.0
1

2

3

4

5

6

7

8

9

10 11 12 13 14 15 16(weeks after delivery)

Figure 2 Nutritional intake in the infants of breast feeding with fortified by HMS-1 andHMS-s (Department of Pediatrics, Showa University)

recommendation
recommendation

91

Figure 3 . Incidence of NEC in Japan (Data from Neonatal Research Network Japan)

4.5

Total of NEC and FIP

90
80

3.5

70

3

2.5

60

Focal Intestinal Perforation (FIP)

50
2

40

1.5
1

Cover rate(%)

Incidence (%)

4

100

30

Necrotizing Enterocolitis (NEC)

20

0.5

10

Cover rate of VLBWI

0

0
2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

(year)（Contributor: Tokuo Miyazawa, Audit: Isamu Hokuto）

92

6 Infection control

6.1 Clinical situations
Infection is one of the most important morbidities affecting the outcomes of EP infants.
Maternal conditions that significantly influence the risk of neonatal infection include
such conditions like vertical infection, ascending infection with bacteria in the vagina,
and birth canal infection. Since infants immediately after birth are basically in asterile condition, NICU commensals can could colonize many infants. EP infants are
particularly immature in immunity and, in addition, have low antibody transfer fromthe mother, which increases the risk of bacterial infection. Early diagnosis and early
treatment are the principle measures to avoid death or serious complications due toinfection. Therefore, it is very important not to overlook subtle changes in clinicalsymptoms and to confirm the diagnosis of infection referring several laboratory tests.
6.1.1 Classification by the timing of onset
Neonatal infections are divided into early-onset infection and late-onset infection
according to the timing of onset. Early-onset infection generally refers tosepsis/meningitis that occurs within 48-72 hours after birth. E. coli can be a main
pathogen as an ascending infection, a transplacental infection, and a birth tract
infection. Clinical symptoms are usually serious. Late-onset infection develops after 4872 hours of age. Although E. coli can be transmitted from the mother, horizontal
infections and medically associated infections are more common. Table 1 shows thedifferences between the early and late onset sepsis.
6.1.1.1 Early onset infection (1)Group B Streptococcus (GBS), E. coli and Listeria are representative pathogens. Since
the amniotic membrane normally acts as a barrier for bacteria, the fetus basicallyresides in a sterile environment. When the amniotic membrane is damaged,
chorioamnionitis due ascending to bacteria including E. coli can occur. The incidence ofchorioamnionitis depends on gestational age, with risks increasing with prematurity.
Risk factors for early onset infection includes prematurity, a GBS colonized pregnant
woman, prolonged premature rupture of membranes for more than 18 hours, andchorioamnionitis. Preterm birth and low birth weight infants are particularly
important risk factors.
6.1.1.2 Late onset infection (2)93Late onset infection may develop as sepsis after a certain period resulting frombacteria transfer from the birth canal at delivery or may develop as sepsis resulting
from horizontal infection. Besides S. epidermidis, S. aureus, and GBS, gram-negative
bacilli such as E. coli and P. aeruginosa, and Candida spp. can be pathogens. The risk
factors for EP infants of late onset infection include reduced transfer of antibodies fromthe mother, immaturity of neutrophil function, many occasions of bacterial invasionsuch as intratracheal intubation, central venous catheter insertion, etc.

6.2 General Management
Early detection of infection and early treatment improves prognosis. Although early
symptoms may be unclear, empirical treatment should be started any time when
infection is suspected.
6.2.1 Sepsis
Sepsis refers to a condition in which an infection causes serious organ damage. The
pathogens invading into the blood stream can cause circulatory failure, coagulation
disorders, organ damage, and when if severe, to multiple organ failure with
disseminated intravascular coagulation (DIC). Sepsis in EP infants may progress
rapidly and greatly affects mortality and neurological outcomes.
Symptoms at the early stage of onset are often nonspecific include general malaise,enteral intolerance, apnea, hypothermia or hyperthermia, jaundice, irritability and the
likewise. Diagnosis should be based on the positive blood culture and blood test values.
Early onset sepsis is often associated with meningitis.
Treatment involves the administration of antibacterial agents that covers putative
pathogens, a combination of penicillin and aminoglycoside should be started. Once thebacterial pathogen and its drug sensitivity have been identified, focusing on one
effective antibacterial drug and continuing for necessary and sufficient periods is therule. If hypotension and/or respiratory distress appeared, supportive treatment
including inotropic agents and mechanical ventilation. In the most severe cases,
exchange blood transfusion or plasmapheresis may be introduced to remove pathogens
and cytokines in the blood stream.
6.2.2 Meningitis
Meningitis, most often bacterial meningitis, is a serious disease associated with an94increased risk of mortality or neurological sequelae, Routes of infection include vertical
infection from the mother, horizontal infection, and nosocomial infection. In the early
onset type, GBS, E. coli and Listeria are the main causative bacteria as well as sepsis.
In the late onset type, in addition to GBS and E. coli, other gram-negative bacilli, S.
aureus and S. epidermidis become dominant. Typical signs of meningeal inflammationin older children such fever, neck stiffness, and loss of consciousness are usually notcommon. There are, instead, nonspecific symptoms such as malaise and lethargy,
sluggishness, poor feeding, apnea and vomiting are prominent.
Diagnosis is made by the detection of pathogenic organism from a spinal fluid sample.
Gram staining of cerebrospinal fluid is useful to estimate the causative organism.
Treatment is with the maximum dose of antimicrobial drugs that can cover theputative bacteria. After the bacterial pathogen and its drug sensitivity are identified,the appropriate antibiotics should be administered for a sufficient period. Retest the
cerebrospinal fluid 24-48 hours after the starting antibiotics to ensure acceptable
treatment effect.
6.2.3 Nosocomial infection
6.2.3.1 Catheter-related bloodstream infection
Catheter-related bloodstream infection (CRBSI) is a bloodstream infection thatoriginates after insertion or an infusion line site. The diagnosis is made when blood
culture becomes positive with signs of infection and other infections are ruled out.
Gram-positive cocci, in particular, S. epidermidis and S. aureus are the major causative
bacteria. In the cases with prolonged use line use, the risk of infection with gramnegative bacteria also increase. EP infants are also at risk of fungal infection.
The main principle of treatment is to administer effective antimicrobial drugs for a
sufficient duration. The decision of whether to remove the catheter should bedetermined according to the response to the initial treatment and the pathogen.
Prophylaxis is important. All medical personnel should adhere to the practice ofpreventing CRBSI during insertion and maintenance of catheter.
6.2.3.2 Ventilator-associated pneumonia
Ventilator-associated pneumonia (Ventilator associated pneumonia: VAP) refers to95

pneumonia that develops within 48 hours of mechanical ventilation. EP infants are athigh risk of developing VAP. Staphylococcal bacteria and Pseudomonas aeruginosa are
the main cause for VAP during the early stages of hospitalization. After prolonged
hospitalization, methicillin resistant Staphylococcus aureus (MRSA) and Pseudomonas
aeruginosa may colonize the infant and become pathogens. Again, fungi should beconsidered as a pathogen in EP infants.
The treatment is to administer effective antimicrobial drugs for a sufficient period. In
addition to this, appropriate hand hygiene should be implemented for all medical
personnel and use of a closed suction system and oral care are important for theprevention of VAP.
6.2.3.3 Fungal infection
Fungal infections in infants are mostly caused by Candida species, of which Candida
albicans is the most common. It is generally classified into superficial fungal infection
and deep fungal infection. In the early stages of the deep fungal infection, as withbacterial infections, no specific symptoms are noted. Central venous catheter
placement is one of the risk factors for deep fungal infection. The diagnosis is based on
the isolation of the fungus from culture tests. With blood tests, unknown and weak
inflammatory responses are often the only early signs. Therefore, early diagnosis is
usually difficult. Thrombocytopenia is often associated in systemic candidiasis.
Although β-D-glucan measurement is useful as an adjunct diagnosis, it is not a test
specific to the fungal infection. Systemic administration of antifungal drugs should be
used for treatment. Prophylactic administration of fluconazole, off-labelled use, occurs
in some hospitals in Japan.
6.2.4 Optional treatments
If the infection is severe, respiratory and circulatory supports should be provided. If theadministration of antimicrobial drugs is insufficient, the administrations of
immunoglobulin and granulocyte colony-stimulating factor (G-CSF) are considered. Inorder to remove inflammatory cytokines and endotoxins, exchange blood transfusion orplasmapheresis using endotoxin absorptive columns can be considered at selected
hospitals.

6.3 Evaluation
6.3.1 Physical examinations

96

The initial symptoms of infection among EP infants are non-specific, and this must be
reminded. In neonatal care, the condition of "somewhat worse than usual" is defined as"not doing well" which includes vague signs of poor feeding, poor skin color, etc. In suchcases, detailed observations and examinations are required. It is also important tocheck for common changes in vital signs, such as body temperature, respiratory rateand heart rate.
6.3.2 Laboratory test
6.3.2.1 Culture
If infection is suspect, cultures of various site must be always be obtained before
administering antibiotics. Blood culture is essential for the diagnosis of sepsis andbacteremia. The samples must be collected with an aseptic technique so that
contamination from the flora on skin surface can be avoided. Minimize blood sample
volumes to avoid iatrogenic anemia in EP infants. However, insufficient blood sample
volume risks false negative results. Therefore, a blood volume of at least 1.0 mL should
be taken. Other cultures of tracheal secretions, skin, urine, catheters, intratracheal
intubation tubes, etc. are only performed if indicated, based on the clinical symptoms of
the infant.
6.3.2.2 Blood test
Various blood tests are used as marker of infection or criteria for the diagnosis ofinfectious diseases. In particular, complete blood cell count (CBC) and C-reactive
reaction (CRP) are widely used. However, the interpretation of these results is
performed based of full understanding of the sensitivity and specificity of the diagnosis.
・ CBC
Because the white blood cell count (WBC) of newborns is affected by maternal status
such as gestational age and pregnancy hypertension syndrome, the sensitivity ofdiagnosis for infection is low with reduced WBC alone. On the other hand, the ratio of
white blood cell fraction is useful for diagnosis. The ratio of the number of immatureneutrophils to the total number of neutrophils (I/T ratio) over 0.2 is diagnostic 1).
However, since the white blood cell count and the I/T may change dramatically
immediately after birth, it should be careful to interpret the results immediately after
birth.
・ C-reactive protein (CRP)

97

CRP is an acute phase reactant that rises with inflammatory reaction and tissue
destruction. The sensitivity is low in early diagnosis because the response needs 6-8hours with infection or inflammation 2). Therefore, negative CRP only cannot rule out
infection. For an accurate diagnosis of infection among EP infants, it is important toevaluate CRP values over time using small blood samples and repeat evaluations inintervals e.g. every 6 hours. (2)・ Procalcitonin
Procalcitonin is a precursor of calcitonin and rises 3-6 hours after infection. Although asignificant difference can be seen between infectious disease and inflammatory
response, the usefulness of procalcitonin in EP infants is unknown and not established.
6.3.2.3 Cerebrospinal fluid examination
Sampling and culture of cerebrospinal fluid are essential in the diagnosis of bacterial
meningitis. Spinal tap is therefore mandatory for the infants of suspected meningitis.
However, since spinal tap is extremely invasive for EP infants, if general condition ispoor, it may be performed after general condition becoming relatively stable.
References
1) Polin RA, Parravicini E, Regan JA. Bacterial sepsis and menigitis. In Gleason C,
Ballard G eds. Avery's Disease of the Newborn, 8th ed. Philadelphia (PA)Elsevier, 2005.
p. 551-577,
2) Benitz WE, Han MY, Madan A, et al. Serial serum C-reactive protein levels in the
diagnosis of neonatal infection. Pediatrics 1998; 102:E141

98

Table 1

Timing of onset
Antepartum/intrapartum
complications
Percentage of preterm
birthInfection routes
Clinical symptoms
Mortality rate

Early onset infection

Late onset infection< 72hours>/= 72hours

commonless common

about 25%

less common

birth canal
respiratory distress,
shock
5-15%

birth canal, hospitalacquired
non-specific
2-10%（Contributor: Masahiro Hayakawa, Audit: Isamu Hokuto）

99

7 NICU environment

7.1 Medical Workforce in Japanese NICU
7.1.1 Relationship between prognosis of preterm infants and NICU volume
A high volume of admissions of VLBW infants (>100 per year) including higher levels ofcare were associated with significantly lower odds ratios for death.
・Guidelines in UK and Canada for operating NICU
NICUs in the UK should admit at least 100 very low birth-weight infants (VLBW)
infants per year
Canada recommends high volume and high level NICUs because high volume (> 100
per year) and higher levels of care are associated with significantly lower odds ratio fordeath.
In Japan, the mortality of VLBW infants also correlates with the number of deliveries,
the number of NICU doctors, and the number of nurses (1). (Figures 1 and 2). However,centralization of NICU hospitals in Japan is not similar to overseas (Figure 3)(2).
It is speculated that factors other than centralization may contribute towards lower
mortality VLBW rates in Japanese infants, as reported in the Neonatal Research
Network of Japan (1).
7.1.2 Characteristics of NICU in Japan
Professor Costeloe kindly gave us a comment at the lecture of network quality
improvement conference held in 2010 as shown in Figure 4.
7.1.3 Relationship between performance and several NICU characteristics in Japan
NRNJ examined the relationship between the NICU performance and several
characteristics (3,4).
76 perinatal centers were involved in the study. Standardized mortality ratio (SMR)
less than 1500g (born in 2009) was compared using several outcomes at each hospital.
SMR is calculated as follows; actual number of deaths/expected (adjusted) number ofdeaths × 100. Adjustment factors were chosen as follows; birth weight, gestational age,gender, multiple births, out-of-hospital birth, birth position, maternal PIH, maternal

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steroid administration, fetal heartbeat, delivery mode, 1 minute Apgar, congenitalabnormality.
The first analytic result is that the average years of experience of neonatologists (ie allphysicians including residents) working in each NICU was not correlated with SMR(Figure 5)(4). However, the year of experience of the neonatologist in the No. 2 position
was inversely correlated with SMR. The number of working years longer than 10 years
increases mortality significantly (p<0.043) (Figure 6). Furthermore, NICU ranks of
SMR and average years of pediatrician’s services in NICU were significantly correlated(Figure 7)(4). Facilities with an average working life of less than 5 years showedsignificantly poorer ranks of SMR (p<0.001) as did facilities with an average working
life of more than 12 years (p = 0.15).
As a result of this study, the following became clear;
Performance is best in NICUs where the average years of experience for the core groupof pediatricians is between 5 and 12 years.
SMR was worst in NICUs where the average years of experience of pediatricians wereless than 5 years.
The NICUs in USA and Europe are staffed with residents with less than 5 years’
experience as their core staff. This may correlate the outcomes of VLBW infants.
SMR may tend to increase when senior doctors of >12 years’ experience make up thecore staff.
In summary, neonatologists working in NICU between 5 and 12 years is best. Seniordoctor service rather than resident service can maintain the level of NICU in Japan.
Education to young neonatologists with less than 5 year experience and senior
neonatologists with more than 13 year experience is warranted.

7.2 Current neonatal care system in Japan
A nationwide survey on Japanese perinatal centers performed on December 2009
showed following results (2).
There are 76 facilities (response rate 97.4%) with the designation of general perinatal
centers from both national and prefectural governments are located in at least one
prefecture. 85.1% of them are equipped with a system to manage available NICU beds.

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but only 40% contribute to an NICU database.
Neonatal transport with center staff is performed in 90.5% of units, and a so-called
triangle neonatal transport is also performed in about 60%. Centers with a large
number of neonatal transports tend to be operated with a large number of fulltime
neonatologists. Neonatal transport is carried out by neonatologists only in 45%,
neonatologists and nurses in 44%. Only 42% of the centers have a special ambulance
designed for neonatal transport.
The average number of NICU is 13.1 and GCU is 20.9. The average number ofdeliveries per year is 778.2.
The highest distribution of the number of positions for fulltime neonatologists is 5 in 19
centers. The total number of the posts for neonatologists is 370 but 42 of them arevacant. The number of fulltime neonatologists is still not sufficient. The highest
distribution of the number of neonatal trainees is 1 or 2 in 29 centers. Only 9 centers
had 3. The total number of the posts for neonatal trainees exists 107.5 but 25 arevacant.
References
1) Fujimura M. Current situation survey on neonatal care among Level III perinatal
centers. Study on the establishment of perinatal center network system using
benchmarks with outcomes as indicators. Grant-in-Aid for Scientific Research,
Ministry of Health and Labour, Research Report pp 21:32, 2014.
2) Fujimura M, Matsunami K. Current situation survey on neonatal care among Level
III perinatal centers. Research on evaluation of medical quality of perinatal centersand outcome improvement by follow-up studies and interventions Grant-in-Aid for
Scientific Research, Ministry of Health and Labour, Research Report 20193) Fujimura M, Mitsuhashi I. Is the mortality rate inversely proportional to the total
medical workforce of doctors (etc.)?. Research to improve the quality and safety ofperinatal medical care. Grant-in-Aid for Scientific Research, Ministry of Health andLabour, Research Report 2013.
4) Fujimura M. Relationship between outcome of extremely low birth weight infants
and workforce of neonatologists. Grant-in-Aid for Scientific Research, Ministry of
Health and Labour, Research Report 2014.

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Figure 1 Correlation between the number of deliveries or the number of nurses at night
shift and mortality among very low birth weight infants in Japan

Figure 2 Correlation between neonatal mortality and the number of pediatricians

Neonatal mortality (/1000 births)

among very low birth weight infants in Japan

r=0.301, p=0.044

Number of pediatricians103

Figure 3 Number of very low birth weight infants admitted per year at each hospital

Figue 4 Neonatal network quality improvement conference in Tokyo in 2010

Impression of Neonatal Database Quality Improvement Conference in 2010 in Tokyo by
Prof. Kate Costeloe at Homerton University Hospital, London.
It was fascinating to be able to talk to people about the very high survival rates ofpreterm babies on Japanese units. The most striking difference is how hard the doctors
work and their level of involvement with the hands on care of the babies. I fear we havegone too far the other way.

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Figure 5 Correlation between the standardized mortality rate and the average years ofStandardized mortality rate (SMR)

service in NICU among very low birth weight infants in Japan

r=0.014, p=0.3593

Average years of service in NICU
Figure 6 Correlation between the standardized mortality rate and the years of theneonatologist in the No. 2 position working in NICU among very low birth weightStandardized mortality rate (SMR)

Standardized mortality rate (SMR)

infants in Japan

Average years in service

Average years in service

105Figure 7 Correlation of the ranking between the standardized mortality rate and theaverage years of neonatologists working in NICU among very low birth weight infants

NICU rank of Standardized Mortality Ratein Japan

Average years of service in NICU（Contributor: Masanori Fujimura, Audit: Satoshi Kusuda）

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