Souvenir Book Updated Compressed-1 PDF

Neo Pocket
IAPNEOCON 2019|Bengaluru
Nobody, but nobody,
is going to stop
breathing on me.
Dr. Virginia Apgar

Neo pocket:
Neo pocket:
PocketPocket
book inbook
Neonatology
on Neonatology IAPNEOCON
IAPNEOCON
2019, Bengaluru
2019, Bengaluru
EDITORIAL BOARD
Dr. N. Karthik Nagesh Dr. Srinivasa Murthy C L

MD, FRCPCH (UK), FNNF, MD (PGI), MRCPCH (UK), ENS,
Neonatal Intensive Care Fellowship (UK) Fellowship in Neonatal-Perinatal Medicine
Chairman and HOD, Neonatology (RCPSC Afliate, Ottawa, Canada)
Manipal Group of Hospitals Consultant Neonatologist,
Professor, Manipal University Motherhood Hospital, Bengaluru
Advisory Editors
Dr. Suman Rao Dr. Praveen Venkatagiri

MD, DM (Neonatology) MD, MRCPCH, FRCPCH, CCT (UK)
Consultant, Department of MCA, HOD& Consultant Neonatologist,
World health Organisation, HQ & CMH hospital, Bengaluru
Professor (Neonatology), St. John's Medical Founder NEOCLEUS EMR
College Hospital, Bengaluru Co-founder Ovum group of hospitals
Dr. Shivshankar Diggikar Dr. Bharathi Balachander Dr. Sandeep R

MD (Pediatrics), FIPM (IAP), MD (Pediatrics), DM (Neonatology) MD (Pediatrics), DNB
Fellowship in Neonatology Assistant Professor (Neonatology)
(RCPCH, UK) St. John's Medical College Hospital, Consultant Neonatologist,
Consultant Neonatologist, Bengaluru Manipal Northside Hospital,
Ovum Hospital, Bengaluru Bengaluru
Neo pocket: Pocket book on Neonatology IAPNEOCON 2019, Bengaluru
Dr. N Karthik Nagesh

MD,FRCPCH(UK),FNNF
Past President NNF (Karnataka) & IAP-Bengaluru
Chairman, Neonatology and NICUs,
Manipal Group of Hospitals,India.
Chairman,Manipal Advanced Children's Centre &
HOD of Department of Neonatology,
Manipal Hospitals,Bangalore.
Professor of Neonatology and Pediatrics, Manipal University.
Dear friends in Neonatology!
I bring to you gree ngs from the Organising Commi ee of IAPNEOCON 2019, Bangalore.
(The 12 Annual Conference of Neonatology Chapter of the Indian Academy of Pediatrics).
Day to Day neonatal prac ce demands a lot of reference material and calcula ons as well as charts
to be referred to. I have always found it difficult to memorise all this! Resources are sca ered and
many. Hence came up with this idea of a composite 'uptodate reference book', which will be of use
at all mes to the prac sing Neonatologist.
We from the Conference Souvenir Commi ee, are pleased to present you with the “Neo Pocket” a
ready reckoner in Neonatology to be kept at the Bedside in the Neonatal Unit for your daily
reference. The dedicated Editorial team of “Neo Pocket” has been brilliant in bringing out this
manual in a short me with a lot of hard work and me culous planning. I thank them with all my
heart for their sourcing and wri ng the script ably advised by Dr. Suman Rao and Dr. Praveen Special
thanks to Dr. C L Srinivasamurthy, who painstakingly put together the manuscript me culously
making it easier for me and the publisher to edit it finally to its present form! The manual comes
spiral and hard bound with addi onal space for you to add your own resources and keep upda ng.
We expect it to be pocket friendly and sturdy at the same me!
I acknowledge the advise and valuable guidance of my friend and Senior Pediatrician Dr. Jagdish
Chinnappa, Bangalore all through the planning and final publishing of this book. Also special thanks
to my Neonatal Fellow Dr. Sharath Keerthy for helping source the literature. Finally, my thanks to the
CIM-Global team of Karan Pa l and Sushanth Kumar for their Design and help in publishing.
I hope you will find the “Neo Pocket” useful and the Editorial team hopes this will become a popular
user friendly day to day reference tool in your Neonatal Unit.
With best wishes!
Warm Regards,
Dr. N. Karthik Nagesh
Editor in Chief , 'Neo Pocket’
Organising Chairman, IAPNEOCON 2019
Dr. Srinivasa Murthy C L

MD (PGI), MRCPCH (UK), ENS,
Fellowship in Neonatal-Perinatal Medicine
(RCPSC Affiliate, O awa, Canada)
Consultant Neonatologist,
Motherhood Hospital, Bengaluru
This is the first pocket book of its kind in India and comes in the wake of a number of changes in the
prac ce of Neonatology. Dr. Karthik Nagesh (Editor in Chief) was the one who wanted to create
something innova ve and useful for health care prac oners in day to day prac ce which finally
culminated into this concept of pocket friendly handbook on Neonatology (Ready Reckoner). A er
several mee ngs and discussions we planned the things to be incorporated in the book. Our team
worked hard day and night to collect the most recent evidence based data to integrate into the
book. This book has been extensively reviewed and revisited by all the editorial team members.
Special thanks to Dr. Karthik Nagesh, Dr. Suman Rao and Dr. Praveen Venkatagiri in giving extensive
feedback to our editorial team on the evolu on of the book.
The book has been specifically wri en, forma ed and designed to be carried whilst on duty, and
contains informa on that staff in neonatal units will need during the course of their day especially
informa on required o en, but not yet commi ed to memory. This informa on requires con nual
reinforcement and in a busy unit there is no me to consult other references such as textbooks or
computer based informa on. This book has key informa on on clinical reference, algorithms, ready
reckoner table, standard infusions, charts, lines and tube posi ons etc that are useful in day to day
prac ce. Special thanks to our editorial team Dr. Shivshankar, Dr. Bharthi Balachander, Dr. Sandeep
R for their excellent efforts on bringing this book in a fantas c and mely manner. We also thank
Dr. Chandrakala and IAP commi ee members for bringing out a unique and beau ful name
“NEOPOCKET” which we are hoping to be remembered for decades to come.
Our team is excited and delighted to see this wonderful book been released on IAPNEOCON 2019
na onal conference, Bengaluru.
Warm Regards
Dr. Srinivasa Murthy C L
Managing Editor (Neo Pocket)
1
Time of birth Pre-ductal saturation
1 min 60-65%
2min 65-70%
3min 70-75%
4min 75-80%
5min 80-85%
10min 85-95%
Reference: NRP 7th Edition
Oxygen saturation targets (NICU)

Target Alarm limit
Spo2
If baby is on If baby is on room air
supplemental oxygen
<36 weeks 90–94% Low alarm at 89% and Low alarm at 89% and
corrected age high alarm at 95% high alarm at 100%
=36 weeks =95% Low alarm at 94% and Low alarm at 94% and
corrected age or high alarm at 99% high alarm at 100%
born =34 weeks
Reference: Neoprom study 2014 and NICE guidelines 2017
Laryngoscope blade size

Blade size (straight ) Gestation
00 Extreme premature babies
0 Premature babies
1 Term babies
Reference: NRP 7th Edition
2
ETT
Depending on gestational age
Gestational age weight of baby (kg) Length of ETT in cm ( lips)
23-24 weeks 0.5-0.6 5.5
25-26 weeks 0.7-0.8 6.0
27-29 weeks 0.9-1.0 6.5
30-32 weeks 1.1-1.4 7.0
33-34 weeks 1.5-1.8 7.5
35-37 weeks 1.9-2.4 8.0
38-40 weeks 2.5-3.1 8.5
41-43 weeks 3.2-3.4 9.0
Kempley ST et al. Endotracheal tube length for neonatal intubation. Resuscitation 2008
ETT Size depending on weight and gestational age

Weight of baby ( grams) Gestational age ETT ( cm)
Below 1000 Below 28 weeks 2.5
1000-2000 28-34 weeks 3.0
>2000 Greater than 34 weeks 3.5

ETT size 2 are no more used
th
Reference: NRP 7 edition
Formula for ETT insertion length

Type of intubation Depth of insertion at lip or nares
Oral intubation Nasal septum to ear tragus length (NTL) plus 1 cm
Nasal intubation Nasal septum to ear tragus length (NTL) plus 1 cm
Reference: NRP 7th edition
3
APGAR score:
0 1 2
Heart rate Absent <100 >100
Grimace Flaccid Some flexion of Good sneeze /
(Reflex activity) extremities cough
Tone Absent Flexion of arms & Active movement
legs
Respiration Absent Slow Irregular Vigorous
Colour Central cyanosis/ Peripheral Completely pink
pallor Cyanosis
0-3 Severely Depressed

4-6 Moderately depressed
7-10 Normal
Reference: Dr. Virginia Apgar (1952)
Approximate insertion depth of Oro- gastric/nasogastric tube from

lip or nares
Weight of baby Length of insertion
< 750g 13cm
750g-1000g 14cm
1000g-1250g 15cm
1250g-1500g 17cm
1500g-1750g 18cm
1750g-2000g 19cm
2000g-2500g 19cm
2500g-3000g 21cm
3000g-3500g 23cm
3500g-4000g 24cm
<4000g 24cm
4
Premedication for intubation
The use of premedication reduces the adverse physiological responses of

bradycardia, systemic hypertension, intracranial hypertension and hypoxia in a
neonate. Based on current available evidence the most acceptable premedication for
neonatal intubation is mentioned below,
Order of medicines should be
1. Anticholinergic: Atropine 10-20 microgram/Kg IV
2. Sedation:
Fentanyl 2 microgram/Kg IV (Wait For 30 Sec) or
Morphine 100 microgram/Kg IV (Wait 2 Minutes)
3. Muscle Relaxation: Succinylcholine 2mg/Kg IV (Repeat dose can be given)
Note: Premedication should be used only for elective intubation and not during
resuscitation. Also it should be used by a person who is skilled in intubation.
Reference: KJ Barrington; Canadian Paediatric Society, Premedication for endotracheal intubation
in the new born infant: Paediatr Child Health 2011; 16 (3):159-64
Central line positions in babies

Central Line Ideal position
UVC T8-T9 ( below T10 high risk of extravasation)
UAC T6-T9 (High), L4-L5 (low). Low position should be accepted only
in emergencies.
PICC –Upper limb SVC ( outside cardiac silhouette)
PICC – Lower IVC above L4-L5. PICC line on left leg should always cross the
Limb midline.
1. All central catheter tips should be positioned outside the cardiac silhouette.
2. All central catheters should allow aspiration of blood in their final position, and
this aspiration should be documented.
3. A repeat X-ray should be performed following catheter adjustment to confirm tip
position and opportunistically on any x-rays undertaken for other clinical
indications.
Reference: ‘British Association of Perinatal Medicine’ (BAPM) guidelines 2018
5
CHAPTER 2: ROUTINE NEWBORN CARE
Ten steps to successful breastfeeding
Updated BFHI 2018, WHO/UNICEF
Critical management procedures
1a. Comply fully with the International Code of Marketing of Breast-milk

Substitutes and relevant World Health Assembly resolutions.
1b. Have a written infant feeding policy that is routinely communicated to staff and
parents.
1c. Establish ongoing monitoring and data-management systems.
2. Ensure that staff have sufficient knowledge, competence and skills to support
breastfeeding.
Key clinical practices
3. Discuss the importance and management of breastfeeding with pregnant

women and their families.
4. Facilitate immediate and uninterrupted skin-to-skin contact and support mothers

to initiate breastfeeding as soon as possible after birth.
5. Support mothers to initiate and maintain breastfeeding and manage common

difficulties.
6. Do not provide breastfed newborns any food or fluids other than breast milk,
unless medically indicated.
7. Enable mothers and their infants to remain together and to practise rooming-in
24 hours a day.
8. Support mothers to recognize and respond to their infants’ cues for feeding.
9. Counsel mothers on the use and risks of feeding bottles, teats and pacifiers.
10. Coordinate discharge so that parents and their infants have timely access to
ongoing support and care.
6
Neonatal Hearing Screening Algorithm

Reference: P Nagapoornima et al. IJP 2007
Well babies /NICU < 5 days Pass Follow up

No High Risk Factors for OAE/BOA
hearing loss Diagnostic
Refer
Protocol
NICU > 5 days / Pass Follow up

Screening
No High Risk Factors for OAE
hearing loss Diagnostic
Refer
Protocol
AABR when
Pass
weight > 2kg
Weight < 2 Screening
kg OAE
Diagnostic
NICU Stay > 10 days / Refer
Protocol
High Risk Factors for
Hearing Loss Pass Follow up
Weight > 2
AABR
kg
Diagnostic
Refer
Protocol
Newborn screening
Reference: NNF guideline, 2011
Which disorders are to be screened?
Group A Group B Group C
(All Neonates) (High risk) (Resource rich setting)
• CAH • Phenylketonuria • ‘Expanded Newborn
• G6PD • Homocystinuria screening’ for 30-40
• Hypothyroidism • Alkaptonuria inherited IEM’s
• Galactossemia
• Sickle Cell anemia
• Cystic Fibrosis
• MSUD
• Biotnidase deficiency
• MCAD
• Tyrosinemia
• FAO
Timing of Newborn screen

All neonates By 48- 72 hours
If screening done before 24 hours Re-screen by day 14
All sick infants, preterm Screen by day 7
7
Algorithm for screening and detection of congenital hypothyroidism
Reference: ISPAE guideline, 2018.
8
Pulse Oximetry Screening

Reference: Pediatrics-in review, 2016
Hip Evaluation Protocol

The Ortolani maneuver, in which a subluxated or dislocated femoral head is reduced
into the acetabulum with gentle hip abduction by the examiner, is the most
important clinical test for detecting newborn dysplasia. In contrast, the Barlow
maneuver, in which a reduced femoral head is gently adducted until it becomes
subluxated or dislocated, is a test of laxity or instability and has less clinical
significance than the Ortolani maneuver.
Periodicity. The hips must be examined at every well-baby visit according to the
recommended periodicity schedule for well-baby examinations (2–4 days for
newborns discharged in less than 48 hours after delivery, by 1 month, 2 months, 4
months, 6 months, 9 months, and 12 months of age)
Reference: Pediatrics April 2000, Volume 105 / Issue 4
9
Approach to developmental dysplasia of hip (DDH)

Reference: Pediatrics April 2000, Volume 105 / Issue 4
10
Immunization schedule (Reference: IAP Immunization schedule 2018-19)

Age Vaccines Comments
(completed)
Birth BCG OPV 0 Administer these vaccines to all newborns before hospital
Hep-B 1 discharge
6 weeks DTwP 1 DTP:
IPV 1 l DTaP vaccine/combinations should preferably
Hep-B 2 be avoided for the primary series
Hib 1 l DTaP vaccine/combinations should be preferred
Rotavirus 1 in certain specific circumstances/conditions
PCV 1 only
10 weeks DTwP 2 l No need of repeating/giving additional doses of whole-cell
IPV 2 pertussis (wP) vaccine to a child who has earlier completed
Hib 2 their primary schedule with acellular pertussis
Rotavirus 2 l (aP) vaccine-containing products
PCV 2 Polio:
14 weeks DTwP 3 l All doses of IPV may be replaced with OPV if
IPV 3 administration of the former is not feasible
Hib 3 l Additional doses of OPV on all supplementary immunization
Rotavirus 3 activities (SIAs)
PCV 3 l Two doses of IPV instead of 3 for primary series if started
at 8 weeks, and 8 weeks interval between the doses
l No child should leave the facility without polio
immunization (IPV or OPV), if indicated by the schedule
Rotavirus:
l 2 doses of RV1 and 3 doses of RV5
l RV1 should be employed in 10 and 14 week schedule, instead of 6
and 10 week. 10 and 14 week schedule of RV1 is found to be far
more immunogenic than existing 6 and 10 week schedule
Rotavirus:
l If RV1 is chosen, the first dose should be given at 10 weeks
6 months OPV 1 Hepatitis-B:
Hep-B 3 • The final (third or fourth) dose in the HepB vaccine series
should be administered no earlier than age 24 weeks and at
least 16 weeks after the first dose
9 months OPV 2 MMR:
MMR-1 l Measles-containing vaccine ideally should not be administered
before completing 270 days or 9 months of life
l The 2nd dose must follow in 2nd year of life
l No need to give stand-alone measles vaccine
l MR vaccine as part of the national campaign is to be
administered irrespective of previous vaccination.
9-12 months Typhoid Thyphoid:
Conjugate l An interval of at least 4 weeks with the MMR vaccine should be
Vaccine maintained while administering this vaccine
l Should follow a booster at 2 years of age
12 months Hep-A 1 Hepatitis A:
· Single dose for live attenuated H2-strain Hep-A vaccine
· Two doses for all killed Hep-A vaccines are recommended now
15 months MMR 2 MMR:
· The 2nd dose must follow in 2nd year of life
Varicella 1
· However, it can be given at any time 4-8 weeks after the 1st dose
PCV booster 2nd during
year Varicella:
· The risk of breakthrough varicella is lower if given 15 months
onwards
11
Influenza vaccine
Inactivated influenza vaccine (either trivalent or quadrivalent) is recommended routinely to all children
below 5 years of age starting from 6 months of age annually (2-4 weeks before influenza season).
Rabies vaccines
ACVIP IAP endorses administration of a 4-dose schedule of Rabies vaccine recommended by WHO
2018 for Post-exposure prophylaxis.
ACVIP also endorses administration of Rabies monoclonal antibody as an alternative to Rabies
immunoglobulin for category-III bites
12
Vaccination in Preterm and Low Birth Weight Babies
l Hepatitis B virus (HBV) is the only vaccine known to have a significantly

lower response in PT compared to FT infants (45%-85% vs 90%-100%
when given at birth).
l For infants who get HBV before they weigh at least 2 kg, the first dose is
discounted and they should get the usual three-dose schedule
afterwards
l Infants born to hepatitis B negative (HBsAg negative) mothers
prematurely and/or weighing less than 2000g can be adequately
protected against hepatitis B after three doses of vaccine beginning at 6
weeks of age.
l In PT who weighed more than 2,000 g the response was the same as in
FT infants.
l In PT with GA of 23 to 26 weeks, immunization if delayed until 30 days
or hospital discharge, seroconvertion rates comparable to FT infants
and maintained protection.
l Evidence supports immunization per routine schedule of the PTI prior to
32 weeks
l Medically stable PT and low birth weight (LBW) infants should receive
full doses of diphtheria, tetanus, acellular pertussis, Haemophilus
influenzae type b, hepatitis B, poliovirus, and pneumococcal conjugate
vaccines at a chronologic age consistent with the schedule
recommended for full-term infants
Reference: American Academy of Pediatrics Committee on Infectious
Diseases. Immunization of preterm and low birth weight infants.Saari TN;
Pediatrics. 2003 Jul; 112.
13
CHAPTER 3: THERMOREGULATION
Normal & Abnormal temperatures in neonates
Temp in Celsius Temperature in
0 0
( C) Fahrenheit ( F)
Axillary temperature 36.5-37.5 97.7-99.5

Euthermic
Skin temperature 36-36.5 96.8-97.7
Mild hypothermia Axillary temperature 36-36.4 96.8-97.5

/ cold stress Skin temperature 35.5-35.9 95.9-96.6
Moderate Axillary temperature 32-35.9 89.6-96.6

hypothermia Skin temperature 31.5-35.4 88.7-95.7
Severe Axillary temperature <32 <89.6

hypothermia Skin temperature <31.5 <88.7
Reference: Fanaroff & Martin text book
Body temperature (Axillary temperature) in the new-born infant ( oC)
14
Humidity in preterm neonates

All babies less than 30 weeks should be started on humidity using incubators.
Babies ≤27 +6 weeks gestation Babies 28-29+6 weeks gestation
1) Commence humidity of at least 80%

2) Maintain humidification at 70-80%
1) Commence humidification at 70-80%
for first 7 days
2) If temperature and fluid balance stable
3) If temperature and fluid balance
after 48 hours, begin weaning by 5%
stable on day 8, begin to wean by 5%
each day
each day.
3) Discontinue incubator humidity when
4) Discontinue incubator humidity when
40% is achieved
40% is achieved or at 21 days
(whichever is reached first).
Humidity values for infants nursed in incubators:

Gestation, Humidity
Days of life
<28 weeks 28-29+6 weeks
0 80 80
1 80 80
2 80 75
3 80 70
4 80 65
5 80 60
6 80 55
7 75 50
8 70 45
9 65 40
10 60 Discontinue
11 55
12 50
13 45
14 40
15 Discontinue
Reference: Clinical Guideline: Humidity for infants, East of England Neonatal Nurses
Benchmarking Group
15
Reference: Fanaroff and Martin's (11th Edition)
16
CHAPTER 4: ENCEPHALOPATHY
17
18
Reference: Johnson et al. Pediatrics 1999
19
New Ballard Score
20
21
2011
22
23
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Silverman anderson score

Reference: Silverman et al. Pediatrics 1956
Reference: Wood DW, Downes' JJ. Amer J Dis Child 1972

F e a tu r e S c o re 0 S c o re 1 S c o re 2
R e s p ir a to r y <60 6 0 -8 0 >80 or apnoea
r a te e p is o d e
R e tr a c tio n None M in im a l S e v e re
C y a n o s is None R e lie v e d w ith o x y g e n P r e s e n t e v e n w ith
s u p p o r t ( F io 2 < 0 .4 ) o x y g e n s u p p o rt
( F io 2 > 0 .4 )
A ir e n tr y B ila te r a l g o o d M ild d e c r e a s e in a ir e n tr y N o a ir e n tr y
a ir e n tr y
G r u n tin g None A u d ib le w ith s te th o s c o p e A u d ib le w ith n a k e d
ear
E v a lu a tio n
S c o re In te r p r e ta tio n
0 -3 M ild
4 -6 M o d e r a te
>6 Im p e n d in g r e s p ir a to r y fa ilu r e
Reference: AIIMS Protocol 2019
26
Reference: Nelson Text Book of Pediatrics: 20th edition, 2016
27
28
Reference: Neoreviews 2016
Reference: Shannon et al. Pediatrics 2010
29
Reference: Shannon et al. Pediatrics 2010
30
31
32
33
34
Current WHO guidance on ARV use in HIV-infected pregnant women

Reference: Programmatic update on ARVs for pregnant women and PMTCT: WHO April 2012
Three options for PMTCT programmes
Note: “Triple ARVs” refers to the use of one of the recommended

3-drug fully suppressive treatment options
a) Recommended in WHO 2010 PMTCT guidelines
b) only for EFV-based first-line ART; NVP-based ART not recommended for
prophylaxis (CD4 >350)
c) Formal recommendations for Option B+ have not been made, but
presumably ART would start at diagnosis
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
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59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
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Hour-specific nomogram for predischarge bilirubin measurement for

assessment for subsequent severe hyperbilirubinemia
Reference: Bhutani VK, Johnson L, Sivieri EM. Predictive ability of a
predischarge hour-specific serum bilirubin for subsequent significant
hyperbilirubinemia in healthy-term and near-term newborns. Pediatrics. 1999;
103:6–14
81
82
Neonatal Jaundice guidelines for Phototherapy in Preterm Neonates:

NICE guidelines 2010
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Phototherapy and exchange transfusion guidelines for management of

hyperbilirubinemia in the preterm infant less than 35 weeks of gestation
Phototherapy Exchange transfusion
Gestational age Initiate phototherapy Total serum bilirubin

(week)
total serum bilirubin
<28 0/7 5–6 mg/dl 11–14 mg/dl
(86-103 micromol/l) (188-239 micromol/l)
28 0/7–29 6/7 6–8 mg/dl 12–14mg/dl
30 0/7–31 6/7 8–10 mg/dl 13–16 mg/dl
32 0/7–33 6/7 10–12 mg/dl 15–18 mg/dl
34 0/7–34 6/7 12–14mg/dl 17–19 mg/dl
(205-239 micromol/l ) (291-325 micromol/l)
Reference: UpTodate, 2019. Hyperbilirubinemia in the preterm infant

(less than 35 weeks gestation). Vinod K Bhutani, Ronald J Wong.
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CHAPTER 17
ARTICLES BY EMINENT AUTHORS
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CELL-BASED & CELL-DERIVED THERAPIES FOR HYPOXIC-ISCHEMIC
INJURY IN THE NEWBORN BABY
Professor Boris W. Kramer, MD, PhD

Maastricht University Medical Center,
The Netherlands
Background and aims
Term babies are at risk for perinatal hypoxic-ischemic encephalopathy. Unfortunately, no

therapy exists to treat the brain injury in this patient population in addition to therapeutic
hypothermia. The aims of this presentation is to assess the neuroprotective effects of exogenous
administration of mesenchymal stem cells (MSC), extracellular vesicles (EV; “exosomes”) from
MSCs and the mobilization of endogenous hematopoietic stem cells in the newborn brain after
global hypoxia-ischemia. After reviewing the clinical data and the general biological ideas, the
results of preclinical studies will be discussed.
Methods
Instrumented preterm sheep were subjected to global hypoxia-ischemia by 25 minutes of

umbilical cord occlusion at a gestational age of 104 (term is 150) days. During a 7 day reperfusion
period all vital parameters, including (amplitude-integrated) electroencephalogram, were
recorded. At the end of the experiment, the preterm brain was assessed using histology and
magnetic resonance imaging (diffusion tensor imaging (DTI)). In three separate experimental
set-ups, exogenous MSCs or granulocyte-colony stimulating factor (G-CSF) and extracellular
vesicles from MSCs (MSC-EV) were administered intravenously with the appropriate control
groups.
Results
Administration of exogenous MSCs and MSC-EV reduced cerebral inammation and white
matter injury. MSCs induced T-cell tolerance, which was paralleled with diminished mobilization
and invasion of these cells in the preterm brain. In addition, MSCs established functional
improvement, as shown by decreased number of seizures after global hypoxia-ischemia.
Similarly mobilization of endogenous stem cells using systemic granulocyte-colony stimulating
factor (G-CSF) reduced cerebral inammation and white matter injury. However, G-CSF did not
reduce the number of seizures after global hypoxia-ischemia.
Conclusion
We have shown for the rst time in a translational animal model that cell-based therapy is
effective in protecting the preterm developing brain against the cerebral and peripheral
inammatory responses which are involved in the etiology of white matter injury in the newborn
brain after global hypoxia-ischemia. Our studies form the basis for future clinical trials studying
feasibility of cell-based therapy in infants with hypoxic-ischemic encephalopathy in addition to
existing therapeutic hypothermia.
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THE NEW EMERGING ROLE FOR PEDIATRICIANS IN GLOBAL NEWBORN CARE
Indira Narayanan MD
Adjunct Professor, Pediatrics/Neonatology
Georgetown University Medical Center, Washington, DC, USA,
Consultant, Global Maternal and Newborn Health and Nutrition
Background
Initially, prior to establishment of a more organized global newborn health, care of newborns was
considered feasible primarily through “high tech” interventions. The seminal study of Bang et al
highlighted the importance and feasibility of community-based care. In contrast to maternal
health that focused on skilled birth attendants (SBAs) who primarily worked in facilities, global
newborn health commenced with community-based interventions along with basic care at the
facilities, frequently termed as “essential newborn care”. Along with this there was a strong
promotion of births by SBAs which resulted in a global increase in facility deliveries with midwives
playing an important role in maternal and newborn care. Increased facility births, however, did
not result in the expected improved institutional outcome. Inadequacy in facility readiness for
the care of the at-risk/small and sick newborns was felt to be important inuencing factor. While
midwives still play a major role, this changing landscape has brought into prominence the
necessity for Pediatricians/Neonatologists, in LMICs and in high-income countries (HICs),
individually and through their professional bodies to address the needs of these vulnerable
babies.
Gaps in Facility Readiness for Newborn Care in LMICs
Facility readiness, especially for the care of the at-risk, small and sick newborns, is very variable in
LMICs, some being well functioning while others are not. Challenges include, among others,
inadequate infrastructure including space, clean 24-hr water supply, toilet facilities, and waste
disposal. In-sufcient human resources, especially trained Pediatricians/ Neonatologists,
neonatal nurses and other supportive staff, rapid inappropriate transfer of trained personnel and
inadequate equipment and supplies constitute other constraints. Equally important is poor
quality of care with inadequate focus on practices such as prevention of infection and data
maintenance. Essential elements e.g. proper cleaning of surfaces, adequate supplies of clean
linen and single use items, optimal and safe use of breast milk both for nutritive and anti-infective
properties, safe administration of injections and intravenous uids, and capability for
identication of causative microbes along with susceptibility testing may be signicantly
decient in some centers in LMICs. Infection control committees, that can be linked with the
quality control activities is also extremely important but is not effectively in place nor optimally
functional in many of the facilities . The widespread advocacy for addressing prematurity,
important as it is, and complications due to prematurity increasing over the years to become the
leading cause of neonatal mortality, now exceeding the proportion of deaths due to infection,
has perhaps detracted some attention from prevention of infection.
Pediatricians need to keep in mind that it is possible that infections may also be under-estimated
as some of the “complications of prematurity” are likely to be infections that are being missed
because of difculties in diagnosis. Improving quality of care requires not only includes better
competency of the care providers but also addressing adequately the various components of
the health system.
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The Emerging Role for Pediatricians
To have a real impact on newborn outcome, Pediatricians, especially in LMICs, need to come
out of their comfort zone of just dispensing clinical care to addressing other key issues. These
include, among others, understanding and advocating for appropriate policies related to the
health systems, improvement in infrastructure, design, stafng (numbers and rotation), suitable
equipment and supplies, effective follow-up care and sound data management, ensuring its use
in monitoring quality improvement. Training and mentoring of other physicians and nurses,
notably specialized, neonatal nurses for compassionate, quality care, till requirements can be
addressed through in-country nursing councils promoting advanced courses. Pediatricians need
to focus on quality of care rendered by themselves as well as the nurses and other supporting
staff, not only within the special care neonatal unit (SCNU) and Neonatal intensive care unit
(NICU), but work with the obstetric staff to focus on care in the labor/delivery rooms and
postnatal wards. They can be effective promoters of maternal involvement, family centered
newborn care and kangaroo mother care, all of which have short and long-term benets for the
babies.
Safe use of oxygen is essential with the ability to provide varying required percentages of oxygen
along with monitoring of the babies with pulse oximeters. India contributes to 10% of cases of
blindness and visual impairment due to retinopathy of prematurity. They can also have closer on-
going links with referral hospitals, so as to give appropriate guidance for stabilizing babies before
transfer. Eventually, arrangements should be made to pick up at-risk and sick babies with
ambulances with trained staff. Till then, it will be better to promote transfer of mothers in whom
high risk babies are anticipated.
Evaluation and counseling at discharge needs to be improved through innovative methods such
as mobile health, facilitation of links with the community-based care and health workers to
ensure adequate follow-up and care-seeking for problems and emergencies to ensure optimal
outcome of all babies after discharge, especially these high-risk and sick babies. These are
particularly important in LMICs where, in contrast to HICs, there is often not the support of
additional personnel/teams who are appointed to establish these links and facilitate follow-up of
mothers and babies after discharge.
Pediatricians in HICs can also facilitate running suitable units and improve quality of care in
LMICs. ideally this should be done after understanding, preferably through visits and discussions
with in-country Pediatricians running better performing units, local priorities, challenges and
optimal remedial methods with suitable adaptations where required. All practices and
commodities cannot be necessarily directly “transplanted” from HICs to LMICs. Some,
particularly, may need adaptation but based on evidence-based information/data.
Pediatricians should also consider donations carefully, both when planning for them in HICs and
requesting for and accepting them in LMICs. WHO estimates that up to 80% of medical
equipment in developing countries is donated or funded by international donors and foreign
governments. Health care equipment donations should benet the recipients to the maximum
extent possible and should conform to policies of the recipient government and wishes of the
recipient organization(s), provided, of course the latter have the ability and suitable personnel
and resources to manage them appropriately. There should be no double standards. Items of
poor quality and unacceptable in the donor country are also unacceptable as a donation.
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Donations should be established through effective communication and consensus between the
donor and the recipient. Maintenance constitutes a very major challenge in LMICs. Nurses may
often not be trained/skilled in day-to-day maintenance of the equipment, biomedical
engineering units are few and far between and the possibility of getting extended periods of
warranty and support by the manufacturers/ suppliers may often not apply to donations of used
items. With these challenges, equipment such as incubators that get out of order, just become
expensive “beds” that may additionally increase risk of infection as cleaning them is more
difcult and time-consuming than the simple conventional cots. LMICs experience these
challenges to varying extents, with some, such as several Sub-Saharan Africa countries having
greater problems and poorer outcomes. However, even better performing countries have
facilities where services and outcomes are far poorer, especially in some regions. Hence equity
issues and marginalized areas have to be kept in mind in planning for universal health coverage.
Pediatricians and, more so their professional bodies, need to play and further strengthen their
roles in state and national committees.
Too Little Too Late and Too Much Too Soon
We need further to ensure problems are addressed appropriately. There is always a risk of doing
too little too late as focusing just on essential newborn care in the community and facilities
without addressing compassionate/nurturing quality of care at facility level for all newborns
including the at-risk, small and sick newborns along with follow-up with suitable community-
based care and strong links between facilities and communities. At the same time doing too
much too soon, as in commencing components of NICU care such as mechanical ventilation
even before ensuring quality implementation of basic care including addressing human
resource issues and critical challenges such as inadequate prevention of infection may cause
problems that may actually result in increased institutional mortality.
Conclusion
High neonatal mortality rates prevented some LMICs achieving MDG 4 of decreasing under ve
mortality by two-thirds. Let us promote optimal, survive and thrive newborn care approach to
promote achievement of SDG 3.2.2 by decreasing neonatal mortality to 12/1000 live births by.
THE OMICS OF BRONCHOPULMONARY DYSPLASIA
Vineet Bhandari, MD, DM

St. Christopher's Hospital for Children,
Drexel University College of Medicine, Philadelphia, PA, USA
Abstract:
Bronchopulmonary Dysplasia (BPD) is the most common chronic lung disease in infants. It occurs
on the foundation of an immature lung secondary to genetic interactions with exposure to
multiple environmental factors (sepsis, invasive mechanical ventilation, exposure to hyperoxia),
resulting in variable clinical phenotypes. While several biomarkers (mostly, inammatory
cytokines) have been proposed for the early identication of the infant predisposed to BPD, none
have proved to be useful in the clinical setting. In recent years, newer technologies have allowed
'omic' approaches to be potentially useful in this regard. The presentation will summarize
information related to genomics, transcriptomics (microRNAs), proteomics, microbiomics, and
metabolomics of BPD
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Denition
Currently, Bronchopulmonary Dysplasia (BPD) is most commonly clinically dened as the

requirement of supplemental oxygen for at least 28 days and then further assessment at 36 weeks
postmenstrual age (PMA), with categorization as mild, moderate, or severe. Further renements
of using a “physiological” denition and incorporating oxygen saturation targeting, along with
the mode of respiratory (invasive/noninvasive) support, with radiographic changes, assessed at
the above mentioned time point of 36 weeks PMA have been proposed. The major fallacy of this
approach is using a therapy for the diagnosis of a disease, especially given the fact that the
therapy does not have standardized guidelines in preterm neonates.
Omics
It has been suggested that utilizing biomarkers may help better dene the clinical pulmonary
phenotypes of BPD. These have mostly been focused on inammatory cytokines; however,
detecting them in peripheral blood samples may not be ideal, as they may not necessarily reect
what goes on in the lung. Use of tracheal aspirates (TA) and utilizing an “omics” approach may
perhaps allow us a better denition of BPD. “Omics” refers to large data sets about the genome,
transcriptome, proteome, microbiome, and metabolome, which are often obtained by high
throughput assays from various biological uids, with bioinformatic analyses.
Genomics
Genetic predisposition to BPD was rst quantied by Bhandari et al and later independently
conrmed by Lavoie et al to be in the range of 53-79%. While SPOCK2 has been suggested as a
candidate gene, this was not conrmed by others. Genome-wide association studies have
implicated molecules and pathways related to CD44, phosphorus oxygen lyase activity,
adenosine deaminase, and targets of microRNA or miR219. Whole exome sequencing identied
the following candidate genes: nitric oxide synthase 2 (NOS2), matrix metalloproteinase 1
(MMP1), C-reactive protein (CRP), lipopolysaccharide-binding protein (LBP) and the toll-like
receptor (TLR) family.
Transcriptomics (microRNAs or miRs)
Focusing on miRs, we have recently identied miR876-3p in TA exosomes which are predictive of,
and are involved in the pathogenesis of BPD. We also recently reported that miR34a inhibition
may be a therapeutic option to ameliorate experimental BPD and associated pulmonary
hypertension.17 In addition, we reported increased lung miR-34a expression in human neonates
17 with early, evolving and established BPD.18
Proteomics
In the only such study to date, Magagnotti et al conducted a proteomic analysis of TA from
infants with BPD and controls. They noted a developmental regulation of the proteome between
23-25 week and 26-29 weeks gestational age samples. In the former group, surfactant protein-A2
and annexin-3 were increased. In contrast, calcium and integrin binding protein-1, leukocyte
elastase inhibitor, chloride intracellular channel protein 1 and calcyphosine were decreased.
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Microbiomics
TA from infants with BPD showed increased presence of Proteobacteria and decreased
Lactobacillus. In addition, decreased Lactobacillus at birth was predictive for the development
of severe BPD. In another study, there was increased Staphylococcus and Ureaplasma species,
in infants developing BPD.
Metabolomics
Recently we identied 18 metabolites belonging to acylcarnitines, amino acids, biogenic

amines, lysophosphatidylcholine, phosphatidylcholine and sphingomyelin from TA that were
able to distinguish between those with or without BPD.22 Specically, the amino acids histidine,
glutamic acid, citrulline, glycine and isoleucine levels were higher in neonates with BPD.
Furthermore, acylcarnitines C16-OH and C18:1-OH were higher in neonates who developed
BPD, but especially in neonates < 27 weeks gestational age. In another study metabolites
associated with fatty acids oxidation and estrogen and androgen biosynthesis/metabolism
were able to differentiate infants with or without BPD.
Finally, a study of adolescent survivors of BPD identied lysophosphatidylcholine, platelet
activating factor and unsaturated phosphatidylcholine from exhaled breath condensate as
metabolites that were different from healthy controls.
Conclusion
Detailed evaluation of genomic, transcriptomic (miRs), proteomic, microbiomic and

metabolomic data may provide not only a better understanding of the predisposition to BPD
(e.g. from genomic data) but also information about the pathogenesis of disease (e.g. by
comparing gene expression, proteomic, or metabolomic data from TA, from infants with versus
those without BPD), and prediction of therapeutic response (e.g. alteration in 'omic' biomarkers
after use of specic therapies)
QUALITY IMPROVEMENT IN NEONATAL CARE-NEED OF THE HOUR
Dr. Kedar Sawleshwarkar, Dr. Vikram Datta, Dr. Sushil Srivastava
Chief Neonatologist, Deogiri Children's Hospital, Aurangabad.

Neonatology, Lady Harding Medical College, Delhi.
UCMS, Former deputy suptd, JPCH, Delhi.
Although health outcomes have improved in low-income and middle-income countries (LMICs)
in the past several decades, changing health needs, growing public expectations, and
ambitious new health goals are raising the bar for health systems to produce better health
outcomes. A high-quality health system that optimizes health care in each given context by
consistently delivering care that improves or maintains health, by being valued and trusted by all
people, and by responding to changing population needs is the need of the hour.
Quality should not be the purview of the elite or an aspiration for some distant future; it should be
the DNA of all health systems.
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What is Quality in healthcare?
Quality of healthcare is dened as 'the degree to which health services for individuals and
populations increase the likelihood of desired health outcomes and are consistent with current
professional knowledge'.
A unit providing neonatal care should try to provide optimal care in all six dimensions of quality
safety, timeliness, effectiveness, efciency, equity, and patient-centeredness.The care that
people receive is often inadequate, and poor quality care is common across conditions and
countries, with the most vulnerable populations faring the worst. In LMICs, mothers and children
receive less than half of recommended clinical actions in a typical preventive or curative visit.
More than 8 million people per year in LMICs die from conditions that should be treatable by the
health system. In 2015 alone, these deaths resulted in US$6 trillion in economic losses. Poor-quality
care is now a bigger barrier to reducing mortality than insufcient access. 60% of deaths from
conditions amenable to health care are due to poor-quality care, whereas the remaining deaths
result from non-utilization of the health system. High-quality health systems could prevent 2·5
million deaths from cardiovascular disease, 1 million newborn deaths, 900 000 deaths from
tuberculosis, and half of all maternal deaths each year.
India has achieved major progress over the last decade in improving the care provided to infants
and young child. The current Infant mortality rate (IMR) in India is 41.4 per 1000 live births
compared to global average of 34 per 1000 live births. Maternal mortality rate in India has
improved signicantly from 556 per 10000 live births in 1990 to 130 per 10000 live births in 2016.
Current infant mortality rate (IMR) and maternal mortality rates (MMR) have been achieved after
years of investment on trainings, building infrastructure and allocating resources to healthcare
delivery systems. Based on global data it is now clear that further decline in IMR and MMR is
possible only with the introduction of quality in the existing health care services. Mere enhanced
utilization of health services without an element of quality will not guarantee desired health
outcomes for the community.
Why India needs Quality improvement?

In its National Health Policy 2017, India has vowed to decrease Maternal Mortality Rate (MMR) to
100 by 2020, under ve mortality to 23 by 2025, Infant mortality rate to 28 by 2019, and Neonatal
mortality to 16 and still birth rate to “single digit” by 2025. In order to achieve this target we have to
improvise the existing quality of health care and bridge the gap between the expected and
observed outcome of health service delivery. Various professional bodies have developed
evidence-based guidelines for management of mother and child. But when it comes to
implementation of these protocols, there is a wide variation in compliance to these guidelines.
Hence the development of guidelines and protocols alone cannot justify its signicance unless it
is implemented at the point of care. The report of Lancet Commission on Quality in the
Sustainable Development Goal found that over 24 lakh deaths in India occur due to treatable
conditions and of them more than 60% had availed health care facility. More than 30% of
patients requiring health facility treatment provided negative experiences. The quality of care is
worst for the poor. Hence India urgently requires improvement in health care quality. Quality
improvement aims at reducing the 'Know-Do' gap by improving the processes of care.
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How to improve Quality in Neonatal healthcare?
The Neonatal Intensive Care Unit (NICU) is a highly complex adaptive system that lends itself to
the application of QI principles. The concepts of quality improvement, however, are not new.
Deming and Shewhart pioneered them in the early 1920s, and they have since been applied with
success in many industries, ranging from manufacturing to aviation. The variations in outcomes of
different units have been attributed to
1) Difference in illness severity of admitted neonates,
2) Differences in infrastructure for clinical care and
3)Random variation. However, even after accounting for these factors there are unexplained
variations in observed and expected rates of mortality and morbidities. Differences in the quality
of clinical care provided, account for majority of this residual unexplained variation. Quality
problems in health care can arise from variations in practice; underuse, overuse, or misuse of
health care services; and disparities in quality of care.
Model for improvement

One simple and effective model that can be used to improve the quality is the Point of care
quality improvement (POCQI) simplied by WHO with its partners & consists of 4 steps.
1-Identifying a problem, making an aim statement & forming a team

The rst step in any improvement project is to select a clear aim.
· Team formation- Most critical step for a successful quality improvement project. All
stakeholders including the patients or community members must be the part of
improvement team.
· Identication of problem-Prepare a list of problems or areas for improvement by the
unit. The existence of Quality Indicators as described above will assist the compilation
of such a list.
· Prioritize the problems identied using prioritization matrix by answering questions like -
How important is the problem to the patients? Feasibility in terms of resources
available, how much is the problem solving within control of the team? Has short
turnaround time.
· SMART Aim statement- Aim statement should be Specic, Measurable, Achievable yet
challenging, Recordable & Relevant, Time bound.
2- Analysis and measurement of quality of care

What is not measured is not done. Every improvement requires a change although not every
change results in improvement. And, to document an improvement, we need to measure it. For
measurement, we need indicators, namely,
Process indicator (to know how effectively the change is being tried) e.g., hand washing &
Outcome indicator (to know whether the change is resulting in desired improvement), e.g.,
incidence of sepsis.
Root cause analysis

In order to identify root cause/s of the problem, many tools are available, namely-
· Process ow chart- Analyses the current process in healthcare delivery pertaining to the
problem to identify gaps or waste in the process
· Fish bone diagram- When the problem is complex, sh bone analysis gives an overview
of all the factors responsible for a good or undesired outcome like issues with the
people(e.g., lack of skill/training, lack of awareness), place( e.g., non-availability of
drug at a proper place resulting in delayed or forgotten administration), procedural
issue(e.g., weighing and giving vit K preventing breastfeeding to be initiated within 1
hour after birth), policy issue(e.g., lack of antibiotic policy resulting misuse and resistant
bug)
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· 5 Why's- Ask why till you reach to the root cause of the problem?
Pareto principle- 80% of the problem are due to 20% of causes, (e.g., medication errors)
3-Developing & Testing changes-Plan-Do-Study-Act Cycles
Every change needs to be tested before being implemented to know the feasibility of executing
the change in the context in which it is being carried out. This process of testing a change is called
a Plan-Do-Study-Act (PDSA) cycle. (Fig 1) (9)
PDSA's are meant for learning irrespective of the results so that the change idea can be either
adopted as it is (which is less likely), modied and then adapted (most likely) or abandoned
because it is not feasible or not useful to achieve desired outcome.
By doing a series of PDSA cycles and thus, learning from each effort at improvement, one can
achieve sustained improvements. Data collected as part of the quality improvement cycle can
be plotted as incidence of outcome against a time-interval (e.g., week or fortnight). This graphic
depiction of change in incidence, known as 'run chart' is helpful in detection of change in
incidence of an outcome.
Challenges for Quality improvement-
1. Absence of formal national quality policy
for India.
2. Strong hierarchy.
3. Deficient data collection & analysis
mechanism
4. Lack of formal cadre of quality managers
5. Specific QI indicators not integrated in
flagship national program
6. Multiple point of care interventions
undertaken in 'project’ mode with no plan
for handover to the facility.
7. Multiple development partners, having own
agenda
8. Ambiguous funding mechanisms
9. Critical deficit in skilled human resource
4-Sustaining improvement
Making successful ideas embed into system requires concrete actions e.g. framing guidelines,
standard operating procedures or job responsibilities. QI is contextual but learning's can be
shared Building a culture in the unit focused on improvement and looking for opportunities to
improve is also important.
Conclusion: A consistent effort is needed in order to apply the quality improvement approach.
Quality improvement should be part of the core training and practice of all clinicians
(incorporated into medical school curriculum, residency training, and postgraduate medical
education) and should be required for recertication. Without leadership support many
improvement efforts will be doomed to failure and frustration. Leaders of neonatal units must
focus on the quality of care as an important part of the mission of their units and must actively
work to create an organizational culture in the unit that will encourage efforts to improve the
quality of care. WHO SDG 3.8 universal health care (UHC) and Ayushman bharat scheme can
be efciently implemented across India only if QI is poured into the existing primary, secondary
and tertiary health care delivery systems.
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COOLING IN LOW AND MIDDLE INCOME COUNTRIES - WHERE DO WE STAND?
Dr. Vishnu Bhat. B

Professor of Pediatrics, PIMS
Former Director, Senior Professor and Head,
Department of Neonatology, JIPMER, Pondicherry
Introduction
Hypoxic ischemic encephalopathy (HIE) occurs in 1 to 3 per 1000 live births in high-income
countries, and up to 14 per 1000 live births in low and middle-income countries. According to
National Neonatal Perinatal Database (NNPD) report from India, incidence of HIE is 5% among
institutional deliveries and it accounts for 28.8% neonatal deaths. Despite intense efforts of
reducing HIE through training in neonatal resuscitation it remains a major cause of neonatal
morbidity with obvious inuence on their long term neurodevelopmental outcome. The
management of HIE is currently limited to supportive intensive care. Though, therapeutic
hypothermia has been established as standard of care for term babies with perinatal asphyxia in
developed countries, it is yet to gain momentum in low and middle income countries like India
Pathophysiology of HIE and Therapeutic Cooling

Though asphyxia can affect all organ systems of the body, the resulting neuronal damage is
often permanent and hence a matter of concern. HIE, the pathognomonic clinical syndrome
of asphyxial neuronal insult occurs in 50-60% of babies with Perinatal Asphyxia . HIE is not a
single 'event' but is rather a continuing process over a period starting from the time of insult. Two
distinct episodes of neuronal impairment are known to occur during this time. The immediate
(primary) hypoxic insult is followed by a latent period of recovery which lasts for almost six
hours. Subsequently there is a longer and profound period of secondary neuronal damage
due to the release of chemical mediators. Neural tissue may die initially during the actual
ischemic or asphyxial event. Several neurons however recover at least partially from the primary
insult in a 'latent' phase but die hours or even days later (secondary or delayed cell death) (Fig.1).
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Fig 1. Stages of neuronal injury in HIE
Mechanisms that have been related to the latent phase include suppression of programmed
cell death ('apoptosis'), inammation and the extrinsic cell death pathway and abnormal
receptor activity. Reduction of cerebral metabolism, suppression of cytotoxic edema and
moderation of seizure intensity are some proposed mechanisms by which TH is useful in HIE.
Suppressing free radical production and excitotoxin release contribute to protection when
cooling is initiated during hypoxia-ischemia or reperfusion (Fig.2).
Evidence for benet from therapeutic hypothermia

According to a recent Cochrane review, therapeutic hypothermia is helpful in term and late
preterm neonates with hypoxic ischemic encephalopathy (HIE). It can signicantly reduce
mortality without increasing major disability in survivors. The utility of therapeutic hypothermia on
survival and neurodevelopment outweigh the short term adverse effects. Usually therapeutic
hypothermia is benecial when initiated before six hours of age in neonates with moderate to
severe HIE.
Cooling in Low and middle income countries

Cooling therapy was not associated with a statistically signicant reduction in neonatal mortality
in low-and middle-income countries although the condence intervals were wide and not
incompatible with results seen in high-income countries. Effective TH can be provided using a
low-cost servo-controlled cooling device in low-income and middle-income countries. Bleeding
problems, particularly gastric bleeds, frequently occur in babies with encephalopathy
undergoing cooling therapy in these settings and are associated with high mortality. The
apparent lack of treatment effect may be due to heterogeneity and poor quality of the
included studies, inefciency of the low technology cooling devices, lack of optimal neonatal
intensive care, sedation and ventilatory support, overuse of oxygen, intrinsic difference in the
population, for example higher rates of perinatal infection, obstructed labor, intrauterine growth
retardation and maternal malnutrition.
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The Indian scenario
Indian studies have shown that therapeutic hypothermia for perinatal asphyxia can be done
safely and with less cost in low resource settings. Most of the studies have involved whole body
cooling (33°C -34°C) for a period of 72 hours followed by slow rewarming. A summary of
therapeutic hypothermia trials in India is summarized in Table 1. Table 1. Therapeutic
Hypothermia trials in India for HIE
Sl. Study Device used No. Observation

sites
No. of
cases
es
1 Pondic Frozen gel 271 Whole body cooling is feasible and safe in a low
herry packs resource settings
and Therapeutic hypothermia group had reduction in the
combined rate of death or developmental delay at 6
Vellor months of age by 21%. Therapeutic hypothermia
e reduces oxidative stress and DNA damage and
improves neurodevelopmental outcome at 18
months
2 Pondic PCM 221 PCM provides a low cost and effective method to
herry, maintain therapeutic hypothermia
Vellor Therapeutic hypothermia reduces the incidence and
e severity of AKI and myocardial injury among term
neonates with perinatal asphyxia .
and
Asphyxiated term neonates treated with therapeutic
others hypothermia had better motor and mental scores
(DASII) at 18 months compared to those in
normothermia group
Whole body cooling using frozen gel packs have been used in most of the studies. In the
developed countries, body wraps and mattresses are used for whole body cooling (Blanketerol
III, Tecotherm TS med 200, MTRE CritiCool, Tecotherm-Servo) and Cool cap for selective head
cooling. Phase changing materials (PCMs) are gaining popularity as low cost devices for cooling
in India. PCMs are made of salt hydride, fatty acid and esters or parafn which melt at a set point.
When a neonate is placed on a bed made of PCM, heat from the baby is transferred to the PCM
which absorbs the heat till it melts. Hence, PCM has the potential to provide a mechanism of heat
removal which will be easier and safer to use than ice packs. Keeping the melting point of the
PCM at the target temperature will ensure that the baby's temperature will not fall below this
temperature. However, careful monitoring is required during induction and the rewarming phase
to avoid temperature outside the therapeutic range. The criteria for initiating therapeutic
hypothermia in neonates with perinatal asphyxia are described in Table 2.
Table 2. Criteria for initiating Therapeutic hypothermia
127
Neonates with perinatal asphyxia presenting within six hours of birth and fulllinthe following
criteria:
A+B+C + Any two of D.
A. Gestational age ≥ 37 weeks
B. ABG (umbilical cord or 1st postnatal hour) showing

pH ≤7 or Base decit ≥ 12meq
C. Evidence of encephalopathy
D. Any two of the following
i. APGAR ≤5 at 10 minutes
ii. Evidence of fetal distress
iii. Assisted ventilation for at least 10 min after birth
iv. Evidence of any organ dysfunction
v. History of acute perinatal event- intrapartum fetal distress, cord prolapse, placental
abruption, uterine rupture, maternal trauma, cardiac arrest.
Pre requisites for initiating therapeutic hypothermia

Strict guidelines and adequate supervision are essential for implementing therapeutic
hypothermia for HIE. Monitoring facilities of the NICU, trained personnel and a backup system to
manage complications should be in place. Inadvertent or accidental excessive hypothermia
should be a “never event” in the NICU, especially in low-birth-weight infants. The minimum
prerequisites (4Ps) for an optimum therapeutic hypothermia implementation are described in
Table 3.
Table 3. Prerequisites for an optimum Therapeutic hypothermia implementation
Place Personnel Paraphernalia Protocols

Level III Trained Radiant Warmer Timely identification of HIE
NICU neonatologist
and nursing Cooling device Ensuring TH for eligible
staff with round infants within 6 hours of
Rectal and surface probes birth
the clock for temperature monitoring
monitoring Evidence-based standard
Multiparameter monitors protocol for providing and
(Temperature, NIBP , monitoring TH
SPO2, Heart rate ,
Respiratory rate) Standardized neuro
developmental follow-up
ABG Machine
Continuing staff education
Mechanical ventilator
Glucometer
aEEG (desirable)
MRI (desirable)
128
Problems in instituting therapeutic hypothermia in India
In resource restricted settings like India, brain damage due to perinatal asphyxia may be more
severe owing to malnutrition in the mother, intrauterine growth restriction, obstructed labor
and suboptimal perinatal care. Many a time the secondary energy failure could have already
occurred before the neonate is admitted in the neonatal unit. Perinatal asphyxia may also co-
occur with neonatal sepsis, and it may be challenging to differentiate both the conditions at
birth. Excluding infected infants may not be practically possible and applying therapeutic
hypothermia for these neonates may compromise neutrophil function which in turn can worsen
sepsis and pneumonia. Accidental hypothermia and inadequately controlled cooling during
transport of sick infants can also be harmful. The adverse effects associated with therapeutic
hypothermia are summarized in Table. 4.
Table 4. Complications of Therapeutic hypothermia
· Bradycardia (25%) and other cardiac arrhythmia (1%)

· Thrombocytopenia (13% - 25%)
· Hypoglycemia (10%)
· Shock (8%)
· Hypocalcemia (6%)
· Sclerema and Subcutaneous fat necrosis (6%)
· DIC (5%)
· Acid-base and electrolyte disturbances
· Pulmonary hemorrhage
· Increased blood viscosity- hemoconcentration
The outcome of neonates treated with therapeutic hypothermia is described in Table. 5.

Table 5. Outcome of Therapeutic hypothermia
Outcome Study results
· Reduces mortality Babies who received therapeutic hypothermia

· Reduces incidence and had a significantly better neurological status at
severity of AKI and discharge (84%) compared to the control group
myocardial injury (9) (60%) (p<0.05; RR: 0.4, 95% CI: 0.21–0.76).
· Better neurological status Mean developmental score, developmental age
at discharge and quotient were higher in the TH group than
· Reduces developmental the control at 6 months of age.
delay Neurodevelopmental assessment at 18 months
showed significantly better motor and mental
developmental quotient in the hypothermia group
than in the control group.
Although all published data so far showed benefit

from therapeutic hypothermia, one study with
small sample did not reveal better outcome.
Authors suggested that high rate of infection
among cooled babies could be the cause (11)
129
Cost of therapeutic hypothermia using innovative methods
Reusable ice gel packs originally used for immunization have been utilized at JIPMER and CMC,
Vellore cooling trials with no additional expenditure. For monitoring purpose, reusable rectal
probes (Rs 900/probe) are also required. Cold water and ice gel packs have been used in earlier
studies either for selective head or whole body cooling. In contrast, the servo controlled standard
equipment used in cooling is expensive. The cooling mattress costs Rs 12, 00,000. The Indian
experience indicates that therapeutic hypothermia is possible in low resource settings and can
be made less expensive by innovative equipments and methods.
Conclusion
Therapeutic hypothermia, a safe and effective neuroprotective therapy demonstrated in
developed countries should not become an unsafe and ineffective practice for the resource
restricted countries. The burden of death and disability in developing countries demands that, as
evidence based intervention strategies are implemented, a possibly low cost and effective
therapy should be assessed urgently through adequately powered studies initially in some
carefully chosen tertiary centers with standard perinatal care which will be meticulously
monitored by data and safety monitoring committee personnel
NEONATAL PHOTOTHERAPY.
DO NOT USE DIRECT SUNLIGHT
Vinod K. Bhutani. MD and Ronald J. Wong

Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford
Children's Health, Stanford University School of Medicine, Stanford, CA, USA
Introduction
Cremer (junior physician), Perryman (chemistry expert) and Richards (device engineer) used a
problem solving approach to engineer a clinical device based on serendipitous breakthrough
observation of Nurse Judy Ward that sunlight and specialized devices lower total bilirubin (TB)
levels. The key component of sunlight was to provide irradiance in the blue-green ranges 425 to
475 nm. A signicant fraction of sunlight is in the UV region, <400 nm, and absorbed by various
biologic substances. Therefore, unltered sunlight should not be used for phototherapy. The
extent of light safety during the rst week after birth regarding both immediate and long-term
consequences. Even though for our postnatal life routine exposure to visible sunlight is generally
considered safe, fetal life and development is shaded away from direct light exposure. More
recently, clinical practice has been governed by the Institute of Medicine's patient safety
standards (Table 1). Signicant pre-clinical (photobiologists) contributions of Anthony
McDonagh and David Lightener demonstrated that the action spectrum of the photonic
congurations matched that of bilirubin and its facilitated elimination. A breakthrough design of
blue light-emitting-diode (LED) light source by physicist Shuji Nakamura led to blue LED bulbs
(1993).
130
Patient- Safety-oriented Timeliness Effective
centered
Diagnosis Accurate
Correct Access to Preventive
evaluation
guidelines are providers care
established
Treatment Clinical Treatment safety Getting right Predictable
relationship is proven and timely care response
Communication Trustworthy Physical space Technology/ Continuity
and monitoring Technique of care
Use of sunlight for bilirubin reduction

How light causes levels of circulating bilirubin and how this mechanism leads to the reduction of
possible toxic byproducts has been the subject of intense inquiry and debate since the 1960s. The
seminal phototherapy proceedings that introduced phototherapy in USA (In: Odell GB, Schaffer
R, Simopoulos AP, eds. Phototherapy in the newborn: an overview. Washington, DC: National
Academy of Sciences, 1974) provided key recommendations for the clinical use of light with a
directive to “involve judgments similar to those made in deciding upon the clinical use of a new
drug”. A new standard of care is to advantage risks versus likelihood of injury from
hyperbilirubinemia to risks of alternative treatment strategies. The primary success of
phototherapy has been attributed to its ability to reduce risk for bilirubin neurotoxicity and the
need for exchange transfusions.
Figure 1. Emission Spectra of Blue LED superimposed on that for Bilirubin

Mechanism: Light as a Drug
131
Checklist Recommendation
Light source Emission spectrum in 460 to 490 nm blue-
1
(nm) green light region
2
Light irradiance Irradiance: >30 µWMCH2nm- 1 within the
(µWcm- 2nm- 1) 460 to 490 nm waveband
Body surface area Expose maximal skin area (35 to 80%)
3
(cm2)
Timeliness of Urgent or “crash-cart” intervention for
4 phototherapy excessive hyperbilirubinemia
implementation
Continuity of therapy May briefly interrupt for feeding, parental
5
Continuity vs cycled bonding, nursing care
Measured efficacy Periodically measure rate of response in
6
of phototherapy bilirubin load reduction
Duration of exposure Discontinue at desired bilirubin threshold;
7
to phototherapy be aware of possible rebound increase.
Table 2. Indices for optimal administration of phototherapy
Light absorption in the vasculature and extravascular space in the skin transforms the native
toxic, non-polar Z,Z-bilirubin into more excretable polar photoisomers: the congurational
isomers Z,E- and E,Z-bilirubin, and the structural isomers Z- and E-lumirubin and thereby decreases
TB. The matching of the absorption spectrum of a bilirubin-albumin solution in vitro with a source
of blue light with a peak emission of about 460 nm is now considered the global standard of
treatment for hyperbilirubinemia. The understanding of light and photochemistry that underlies
this connection is described in several recent reviews (Table 2). Our perception of light as a
continuous energy stream obscures the reality that it comprises discrete packets (quanta) of
energy called photons.
Photons are analogous to molecules of a drug

Analogous to the design of the molecular structure of a drug to interact with a specic site on a
molecular target, the wavelength of light (color) can be chosen to be absorbed by specic
target molecules. Additional specicity of the wavelength range may be dictated by various
needs such as the avoidance of untoward side effects. For example, bilirubin absorbs ultra-violet
radiation (UVR) , as do almost all biological molecules, such as proteins and nucleic acids. UVR
absorption by the latter can lead to photochemical alterations that can be deleterious. Because
nucleic acids and proteins without prosthetic groups do not absorb blue light, it is possible to
have blue light absorbed by bilirubin without affecting proteins and nucleic acids. The number of
therapeutic photons absorbed by the molecular target is analogous to the dose of a drug. The
intensity or irradiance (photons per unit time) of the light is analogous to the drug dose rate. One
way absorbed light generally differs from molecular drugs is in the deposition of heat. When a
photon is absorbed by a molecule, the energy of the photon is transferred to the molecule and
transformed into heat within the molecule that is quickly transferred to the surrounding
environment. These principles of molecular photochemistry are well described.
132
Therapeutic Determinants for Bilirubin Reduction
For optimal phototherapy, as dened by AAP Technical Report), the light source should:
emit light in the blue-to-green range ( 460–490 nm); produce an irradiance of at least
25 to 30 µW/cm2/nm (and conrmed with an appropriate irradiance meter calibrated over
the appropriate wavelength range); and illuminate the maximal body surface area upto
80% of BSA.
Onset of therapeutic effect

It has been reported that therapeutic photon-bilirubin interaction occurs within 15 to 30 min of
light exposure (Figure 2); whereas, decreases in TB levels occur within 4 to 6 hours of light
exposure. A recent systematic review reported that one out of six to ten healthy neonates will
need phototherapy; (II). Studies on the reported implementation of universal bilirubin screening
showed use of phototherapy was performed on 6.6 % (95% condence interval, CI, range of 4.4
to 8.7 of live births >34 weeks of GA.Caution is necessary to prevent misuse in the treatment of
neonatal hyperbilirubinemia. Firstly, light should be considered a “drug”, and thus accurate
measurement of irradiance is a must. Secondly, phototherapy should be adjusted for use in
infants with fragile skin, low antioxidant reserves, and disordered bilirubin- albumin binding.
Thirdly, phototherapy does not need to be applied continuously and or cycled to promote and
maternal/infant bonding
Figure 2. Post- light exposure formation of 4Z,15 E isomers as a % total serum bilirubin. Blue
bar: Fluorescent—single bank. Red bar: Fluorescent double bank. Black bar: photodiodes.
On each box, the central mark (in black) is the median, the edges of the box are the 25th
and 75th percentiles, respectively, the whiskers extend to the most extreme data points not
considered outliers. Outliers were excluded.
133
UV Radiation, Mutagenic effects and Light Source
Recently, nine semi-transparent plastic window-tinting lms for their ltering ability to block UVA
and infrared (IR) radiation from the sun to selectively transmit therapeutic blue light. Compared
with unltered solar radiation, blue light transmission through lms ranged from 24 to 83%.
Concurrently, near UV transmission ranged from 0.1 % to 7.1%, and IR light associated ambient
temperature in the therapy unit was reduced by 6 to 12°C. Safe exposure of a nude newborn to
the sun either inside or outside a health care facility can visibly lead to sunburn, aggravate the
postnatal weight loss that may even result in dehydration and hypernatremia. Absence of
predictable and reliable therapeutic tool have led to recommendations against its prescription.
A recent Nigerian study has demonstrated that sun when ltered could minimize UV exposure
while utilizing the benet of sunlight to lower TB. The operational and cost of such an approach
has yet to be validated.
Guidelines for standards of practice

Most researchers agree that although UV wavelengths (A, B and C) may contribute to
photodegradation of bilirubin, but the effects are small and the major contributions are from blue
or green light. Some possible long-term consequences of mutagenic action of unltered UV
associated with phototherapy may be a contribution to developing skin cancers. From the
hazard viewpoint, it is desirable to remove all UV from the phototherapy lamp emission. A study of
a number of phototherapy units demonstrate UV contamination in 1/9 devices. Operators are
unaware of this danger and should be alerted and trained.
In summary, the origin of phototherapy for neonatal hyperbilirubinemia is attributed to sunlight
exposure and decreased serum bilirubin levels. Both phototherapy and sunlight can be
comparable and equally effective. However, only 16% of bilirubin is isomerized in the rst 5 min of
exposure to sunlight as compared to 65% with phototherapy. Direct sunlight exposure can lead
to excessive heat and dehydration, skin effects such as sunburn; photoaging; skin cancer,
including basal cell and squamous cell carcinomas an. For safety considerations, the AAP
Guideline on Management of Hyperbilirubinemia does not recommend the use of sunlight as a
reliable therapeutic tool
134
OXYGEN THERAPY OF THE NEWBORN FROM MOLECULAR UNDERSTANDING TO
CLINICAL PRACTICE
Ola Didrik Saugstad, Ju-Lee Oei, Satyan Lakshminrusimha, Maximo Vento

Department of Pediatric Research, University of Oslo, Oslo, Norway;
Department of Newborn Care, the Royal Hospital for Women, Randwick, NSW, Australia; School of
Women's and Children's Health, the University of New South Wales, Randwick, NSW, Australia
Department of Pediatrics, UC Davis, Sacramento, CA, USA and Division of Neonatology,
University and Polytechnic Hospital La Fe, Valencia, Spain
Oxygen is one of the most critical components of life. Nature has taken billions of years to
develop optimal atmospheric oxygen concentrations for human life, evolving from very low,
peaking at 30% before reaching 20.95%. There is now increased understanding of the potential
toxicity of both too much and too little oxygen, especially for preterm and asphyxiated infants
and of the potential and lifelong impact of oxygen exposure, even for a few minutes after birth. In
this review, we discuss the contribution of knowledge gleaned from basic science studies and
their implication in the care and outcomes of the human infant within the rst few minutes of life
and afterwards. We emphasize current knowledge gaps and research that is needed to answer
a problem that has taken Nature a considerably longer time to resolve.
Introduction
Today, one-fth (20.95%) of the Earth's atmosphere consists of oxygen, but this has not always
been so. During the Great Oxygenation Event (GOE) approximately 2.3 billion years ago, a rapid
increase from low atmospheric oxygen occurred, resulting in oxygen levels that at some stage
were probably as high as 30%. This phenomenon most likely explained the great size of organisms
from that era where fossils of insects with wingspans as large as 2 m have been found.Life,
however, evolved within an oxygen-poor atmosphere before the GOE. Oxygen was primarily
produced by photosynthesis as a waste product by prokaryotic (and later, eukaryotic)
organisms 3.5 billion years ago and by oceanic cyanobacteria a billion years after this. Primitive
bacteria then merged with eukaryotes and became organelles (chloroplasts and mitochon-
dria, respectively), which provided cells with energy. These organelles eventually lost their ability
to live independently outside cells, in a process called endosymbiosis. Photosynthesis by
cyanobacteria soon led to the eventual accumulation of atmospheric oxygen, which oxidized
methane, a strong greenhouse gas, to carbon dioxide and water which then reduced the
greenhouse effect with subsequent planetary cooling.
Higher atmospheric oxygen levels not only cooled the planet but also provided biological
diversication. Achieving the perfect balance between protection and lethality is a delicate
process. It has taken Nature billions of years to reach the present (and probably) optimal
atmospheric oxygen levels for human life, and, therefore, it is perhaps understandable that
neonatology and modern medicine have not had the time to catch up with this need, especially
in the case of preterm and asphyxiated newborn infants, who are physiologically unstable and
who only a few decades ago were at extremely high chance of death. In 1954, Gerschman et al.
described what had been known by Nature for billions of years: that injury from irradiation and
oxygen is both mediated via the same mechanisms (free radicals) and that protection is
conferred also by identical means.
135
This led to a better understanding of how humans, especially newborn infants, are injured by
oxygen. In the 1980s, a new dimension in the understanding of the ill effects of oxygen was
established, where it was shown that oxidative stress was caused not only by hyperoxia but also
by factors related to oxidative defense, including inammation. This contributed to a renewed
interest in oxygen management of newborn infants. Valuable observational studies regarding
associations between adverse clinical sequel and oxygenation, particularly in premature infants,
were published around the turn of the century. It also rapidly became clear that randomized
controlled trials (RCTs) were needed to nd the right balance between too much and too little
oxygen. In the 1990s, the rst delivery room studies showed that term or near-term infants could
be given respiratory support with air as well as oxygen. This practice was found to be associated
with a 30% decrease in the risk of early death and led to major changes in recommendations for
oxygen delivery at birth. Similar studies were then conducted in premature infants with
pulmonary immaturitywith parallel examination of the impact of hyperoxia and oxidative stress in
non-human subjects. Currently, we know that evidence is still lacking regarding the optimum
amount of oxygenation required for newborn infants, especially those who are premature or
asphyxiated, who may need supplemental oxygen but at the same time are poorly equipped to
deal with oxidative stress. We recognize that sufciently large, well-designed RCTs are required to
answer the question of best oxygen strategies in newborn infants. There is a need to incorporate
individualized medicine into the equation, to recognize that oxygen exposure could create
long-lasting and even inter-generational epigenetic changes. There has been a frantic
exchange of information between experimental and preclinical studies with human application
and today we know more about how genes and pathways are affected by hypoxia as well as
hyperoxia. These studies now lead to one major question: can basic science studies contribute to
improving our practice of providing best oxygenation for newborn infants and can we ever
reach a satisfactory understanding of this very important process?
Fig. 1 The great oxygenation event and endosymbiosis. The presence of low oxygen levels
and greenhouse gases such as methane (CH4) increased planetary heat. Photosynthesis led
to increasing oxygen levels following the “great oxygenation event”
136
2.3 billion years ago. Increased oxygen led to removal of methane, reduction of greenhouse
gases and planetary cooling. Irradiation and oxidative stress both lead to free radical formation.
Primitive cells engulfed aerobic bacteria and cyanobacteria leading to the formation of the
“modern” eukaryotic cell with mitochondria and chloroplasts by a mechanism called
endosymbiosis (see text for details)
Oxygen Toxicity
Oxygen was discovered independently by Carl Wilhelm Scheele in 1772 and by Joseph Priestley
in 1774. The name oxygene (acid former) was coined by Antoine Lavoisier in 1777, but it seemed
clear that the Polish alchemist, Michael Sendivogius, had already described the element as arial
nitrate from as early as 1604. Priestly quickly realized the toxicity of oxygen. Di-oxygen has four
unpaired electrons in its outer shell that spin in opposite directions giving O2 its paramagnetic and
reactive properties, slowing the establishment of covalent bonds. Oxygen's role in energy
metabolism is to be an electron acceptor in the respiratory chain. By accepting four electrons,
oxygen is reduced to water, but a small part of the oxygen requires not one but four steps for this
process to be complete. Each intermediate step occurs within the mitochondria and generates
reactive oxygen species (ROS), including superoxide radical (O2−), hydrogen peroxide (H2O2),
and the hydroxyl radical (OH). Superoxide and hydroxyl radicals are free radicals and therefore
highly toxic and have the capacity to destroy cell membranes by lipid peroxidation, structural
and enzymatic proteins, and DNA oxidation. Free radicals may interfere with protein folding and
unfolding leading to abnormal function or structure. In the presence of transition metals (copper,
iron, zinc, manganese, selenium), the reactivity of oxygen to capture electrons from other
molecules gets enormously enhanced. The Haber–Weiss reaction for instance generates
hydroxyl radicals from hydrogen peroxide and superoxide. The reaction is slow but is catalyzed
by iron. Hydrogen peroxide is, however, not a free radical and acts as a signaling molecule
essential for cell cross-talk (e.g., regulating blood ow within the ductus arteriosus and the
pulmonary circulation). There are several reasons that newborn infants, especially those born
preterm, are at risk of oxidative stress. First, relative oxidative stress is generally high within the rst
weeks of birth after transitioning from the low oxygen environment of the uterus to air. Sick
newborns may need supplemental oxygen if there is respiratory insufciency. The addition of
asphyxia as well as free iron increases the risk of oxidative stress as described above. Most
importantly, preterm infants do not have sufcient antioxidant defense, either de novo or
passively acquired from the mother, until the third trimester, which increases susceptibility to
oxidative stress. Current lung protective strategies, such as antenatal steroids, only have minor
inuence on the maturation of the antioxidant defense system.
Oxygen sensing
The carotid bodies. Precise co-ordination of oxygen supply with demand is essential to meet the
needs of metabolism. In the 1920s, the carotid bodies, located at the bifurcation of the common
carotid artery, were identied as the organs responsible for the sensing of arterial blood oxygen
levels. Hypoxemia induces stimulation of breathing due to a chemosensory reex arising from the
carotid body. This process is fast (<1 s) and is assumed to involve change to existing proteins
rather than de novo synthesis. Hypoxic sensing appears to utilize two gaseous messengers:
carbon monoxide (CO) and hydrogen sulde (H2S). CO is generated by heme oxygenase 2,
which is constitutively expressed in a number of tissues as the brain and the carotid body and
suppresses carotid body sensory activity. H2S varies inversely with the oxygenation status of the
carotid body such that hypoxia causes a rise in intracellular H2S. H2S may have several actions but
also inhibits Ca2+-activated K+ channel conductance within the glomus cells of the carotid body,
consequently inhibiting excitatory neurotransmitter release and preventing stimulation of
afferent nerve endings (which would increase activity of the carotid sinus nerve).
137
Hypoxia-inducible factor. Many different molecular mechanisms are utilized to maintain oxygen
homeostasis. One of the most important ones is hypoxia-inducible factor (HIF), the master
regulator of oxygen
Poor antioxidant defense mechanisms
Fig. 2 The role of hypoxia-inducible factor (HIF) in normal lung development alveologenesis and
angiogenesis. During fetal period, relative low levels of oxygen promote lung development.
Following preterm delivery, “normoxia” or hyperoxia can lead to degradation of HIF, poor
alveolarization and vascular pruning. ROS: reactive oxygen species, HRE: hypoxia-responsive
element, PHD: prolyl-4-hydroxylase enzyme, VEGF: vascular endothelial growth factor, BPD:
bronchopulmonary dysplasia. Please see text for details
Homeostasis at the transcriptional level. Today it is known that more than 2500 target genes are
activated by HIF. Within any given cell, HIF activates promoters in the region of hypoxia-
responsive elements (HREs) and increases the expression of hundreds of messenger RNAs and
decreases the expression of a similar number. These molecular mechanisms lead to either an
increase in oxygen delivery or a decrease in oxygen consumption. Under normoxic conditions,
HIF-1α is rapidly degraded by hydroxylation of a family of prolyl-4-hydroxylase (PHD) enzymes.
The hydroxylated prolines are then recognized by the Von Hippel-Lindau/ E3 ubiquitin ligase
complex, which targets HIF-1α for proteasomal degradation. This system is sensitive to oxygen.
Following as little as 5 min of reoxygenation, most stabilized HIF-1α is degraded. During oxygen
deprivation, mitochondria increase their production of ROS. Serving as signaling molecules these
ROS then inhibit hydroxylation of HIF-1α, preventing proteasomal degradation.
138
HIF regulates erythropoiesis by activating transcription of erythropoietin. Other examples of HIF-
induced action are regulation of angiogenesis via HIF-dependent production of angiogenic
cytokines and growth factors such as vascular endothelial growth factor as well as regulation of
angiopoietins, placental growth factor, and platelet-derived growth factor B. These responses
are slow, occurring over days to weeks. In contrast, responses designed to reduce oxygen
consumption are rapid: occurring over hours to days, mediated through the switch from
oxidative to glycolytic metabolism. HIF-1 controls expression of multiple genes that mediate this
metabolic switch via several mechanisms. One is gene activation of the LDHA gene encoding
lactate dehydrogenase, which converts pyruvate to lactate. HIF-1 also mediates an increased
efciency of electron transfer, and processes that trigger mitochondrial autophagy in this way
reducing cellular oxidation of both glucose and fatty acids.A fundamental physiological
response to hypoxia is cell cycle arrest, which necessitates HIF-1α. Cyclin-dependent kinase 2
(CDK2), active in the cell cycle from late G1 through S phase and G2 binds to HIF-1α and triggers
lysosomal degradation. CDK1, active from late G2 through M phase, binds to HIF-1α and protects
it from lysosomal degradation, thus controlling HIF-1α's (with HIF- 1β) role to mediate adaptive
responses to hypoxia. HIF-1 therefore increases erythropoiesis, enhances breathing, glucose
uptake, promotes angiogenesis, reduces mitochondrial oxygen consumption, and induces cell
cycle arrest (Fig. 2).
NEWBORN EXPERIMENTAL OXYGEN STUDIES
A number of newborn animal models have been employed to study effects of oxygenation of
different organs.
Inammation and DNA damage

Reoxygenation with hyperoxia (60 or 100% O2) not only induces inammation in the lungs but also
in the brain and probably in other organs as well. Even a brief (minutes) hyperoxic exposure
immediately after birth has been epidemiologically linked to conditions associated with
inammation and DNA damage, such as childhood malignan- cies.It is therefore of interest that
hyperoxic resuscitation in both newborn piglets and mice increases the level of 8- oxoguanine in
tissues and urine, indicating oxidation of guanine into this mutagenic base lesion,which in turn
suggests that oxygen may be a mutagen. Furthermore, it has been demonstrated that base
repair mechanisms are affected by hyperoxic reoxygenation, and if protective DNA
glycosylases are knocked out, DNA injury increases. The DNA glycosylase Neil 3 is important for
removal of oxidative base lesions on single-stranded DNA, cellular-dependent cellular responses
to hypoxia–ischemia in the perinatal mouse brain, and maintenance of microglia number.
Profound neuropathology was found in Neil 3-knockout mice characterized by a reduced
number of microglia and loss of proliferating neuronal progenitors in the striatum after
hypoxia–ischemia. In vitro expansion of Neil 3-decient neural stem/progenitor cells revealed an
inability to augment neurogenesis and a reduced capacity to repair for oxidative base lesions in
single-stranded DNA.
Metabolomics
Metabolomic studies suggest that resuscitation with air from a metabolic viewpoint is more
optimal than resuscitation with either 18% or 100% oxygen. Hypoxia leads to elevation of Krebs'
cycle intermediates, such as α-ketoglutarate, succinate, and fumarate. However, these
intermediates decrease more slowly after resuscitation with 100% oxygen, suggesting that
hyperoxia leads to mitochondrial dysfunction.
139
Different FiO2 may also impact of metabolic recovery. In a piglet model of asphyxia, Fanos et al.
showed with nuclear magnetic resonance spectroscopy that resuscitation with 18% oxygen led
to carbohydrate exhaustion, while using supraphysiologic (40% or 100%) oxygen led to the
generation of free radicals and activation of scavenging systems. This suggested that 21%
oxygen could lead to best physiologic recovery after hypoxemia.Furthermore, succinate,
considered a highly relevant marker of mitochondrial dysfunction due to its ability to regulate
electron ow across the electron respiratory chain, creates the so- called reverse electron
transport from Complex-II to Complex-I, which generates a many-fold increased production of
ROS compared to the conventional forward electron transport from Complex-I to Complex-
II.Therapeutic hypothermia in asphyxiated babies after reoxygenation, for example, favors
normalization of energy metabolites such as pyruvate and Krebs' cycle components, particularly
succinate. Several studies and a recent review have now outlined the molecular and
metabolomics changes associated with asphyxia and resuscitation with various concentrations
of oxygen.
Gene regulation and epigenetic changes. Gene regulation in different organs of newborn
animal models after brief hyperoxia at resuscitation and after long-term oxygen exposure has
been studied. Several hundred genes were changed within the lungs of newborn mice
reoxygenated with 60% or 100% oxygen (hyperoxia) when compared to air. HIF-1-responsive
genes and pathways related to cell cycling and nucleotide excision repair are up-regulated with
involvement of the mammalian target of rapamycin signaling pathway, including genes related
to growth (VegfC, Pgf) and signal transduction. This pathway plays a crucial role in the regulation
of cell proliferation, survival, and energy metabolism in response to stress. An indication of DNA-
damage response includes the up-regulation of nucleotide excision repair mechanisms after
hyperoxic (60% O2) reoxygenation. Conversely, DNA polymerase is down- regulated by
hyperoxia, leading to reduction of DNA replication and hyperoxic reoxygenation induces a
stronger brain inammatory gene response than reoxygenation with air.
Chen et al. studied epigenetic changes in the lungs of newborn rats breathing either air or 85% O2
from day 1 to 14. On day 14, rats exposed to hyperoxia had signicantly lower body and lung
weights than rats breathing air. Hyperoxia also induced alveolar arrest. In total, four DNA
methylated genes associated with hyperoxia-induced inhibition of alveolarization were found,
including a growth factor receptor-bound protein involved in signal transduction and cell
communication and a β1-integrin that links cytoskeleton to the extracellular environment, acting
as adhesion receptors, signaling receptors, and mechanoreceptors to regulate cell growth,
migration, and differentiation. β1-Integrin is also required for lung branching morphogenesis and
alveolarization. At 4 weeks of age, the lungs of mice exposed to hyperoxia for 14 days were
changed, suggesting an overall DNA- hypermethylation effect of hyperoxia. The
hypermethylated genes, including Tgfbr1, Crebbp, and Creb1, play central roles in the tumor
growth factor-β (TGF-β) signaling pathway and cell cycle regulation. They also had a statistically
signicant enrichment of ve pathways, particularly of the TGF-β signaling pathway, that is
involved in the inhibition of branching morphogenesis in embryonic lung development.Whether
these ndings are clinically pertinent are uncertain. In preterm infants, apnea leads to the major
clinical problem of intermittent hypoxia (IH), when carotid body chemo-reexes and
catecholamine secretion from adrenal medullary chromafn cells are important for
maintenance of cardio-respiratory homeostasis.
140
The effects of neonatal IH may persist into adulthood by triggering epigenetic mechanisms
involving DNA hypermethylation, which in turn contribute to long-lasting increase in ROS
levels. Adults born preterm exhibit a higher incidence of sleep-disordered breathing and
hypertension that is associated with elevated oxidative stress, decreased expression of
genes encoding anti-oxidant enzymes, and increased expression of pro-oxidant enzymes.
DNA hypermethylation of a single CpG nucleoside has the capacity to alter expression of
manganese superoxide dismutase 2 (mitochondrial SOD) and DNA-hypomethylating
agents such as decitabine prevents oxidative stress, enhances hypoxic sensitivity, and reduces
autonomic dysfunction. The use of DNA-hypomethylating agents might offer a novel
therapeutic intervention to decrease long-term cardio-respiratory morbidity caused by
neonatal IH.
Overall, these studies indicate that long-term hyperoxic exposure leads to DNA methylation of
genes that are related to lung growth and development including lung morphogenesis,
branching, and alveolarization that are typical features of bronchopulmonary dysplasia.
Epigenetic silencing may therefore potentially contribute to pathogenesis and lifelong
consequence of bronchopulmonary dysplasia and other aspects of hyperoxia. Fig. 3 summarizes
some of the relevant mechanisms and pathways for newborn hyperoxic exposure.
HUMAN DATA
In the delivery room: term infants. Pure oxygen has been integral to the delivery room support of
newborn infants for 200 years, but in 1998 the World Health Organization (WHO) recommended
that air (FiO2 0.21) could be used instead of pure oxygen (FiO2 1.0) for basic newborn
resuscitation. In 2010, the International Liaison Committee on Resuscitation (ILCOR) followed up
with a similar recommendation for term or near-term infants based on clinical data acquired
over the previous decade, suggesting that pure oxygen resuscitation could lead to unfavorable
outcomes, including increased time to rst breath and mortality, when compared to the use of
air. These recommendations were supported by human and animal data showing that even a
brief exposure of pure oxygen in the delivery room could trigger long-term inammation and
oxidative stress that could last for weeks. This, however, does not mean that supplemental
oxygen should never be used. The rst studies conducted in the 1990s used pure oxygen to
supplement air in infants that did not respond to resuscitative efforts within 90 s of life. Oxygen
levels were not titrated as per today's practice because “normative” data from spontaneously
breathing term infants were not obtained until the next decade. Such data showed that
preductal peripheral capillary oxygen saturation (SpO2) increased only gradually over 10 min of
life and that using 100% oxygen for respiratory support led to a more rapid increase in SpO2 than
was observed during normal transition of the healthy infant.Despite this, the optimum evolution of
SpO2 following a pathological birth such as birth asphyxia or preterm delivery is unknown and
could be very different to that of normal, full-term and healthy infants.
There are few data regarding optimal oxygenation immediately after completion of active
resuscitation for pathological conditions such as hypoxic encephalopathy. Klinger et al.showed
that the combination of hyperoxia and hypocapnia in the rst hours after birth is especially
detrimental for long-term outcome.
141
Fig. 3 Summary of some pathways and mechanisms relevant for newborn hyperoxic exposure.
Adapted from Bhandari. Please see text for details.
In an observational study, Kapadia et al. observed a fourfold increased risk of moderate to

severe hypoxic–ischemic encephalopathy within infants having a very high admission partial
pressure of oxygen (PaO2) (>231 mmHg, 30.8 kPa) compared to those with PaO2 within
physiological norms (<114 mmHg, 15.2 kPa) PaO2.
In the delivery room: preterm infants. The case for preterm infants is more ambiguous.
(Fig. 4). Currently, data from 11 published studies for babies <32 weeks gestation who were
resuscitated with either initial FiO2≤0.3 or ≥0.6 and titrated to varying SpO2 targets in the rst 10 min
of life suggest that there is little benet/ risk to using different levels of initial FiO2. However, it must
be recognized that these studies were planned and mostly completed prior to the availability of
evidence for normal physiological SpO2 changes seen in healthy full-term infants.
Fig. 4 Possible mechanisms explaining the need for higher FiO2 in preterm infants in the delivery
room. Ineffective gas exchange, vascular insensitivity to oxygen, and poor antioxidant defense
may play a role in increasing the risk of respiratory failure
142
Indeed, none were designed to examine the impact of SpO2 targeting on infant outcomes and
none were powered sufciently to examine either short-term or long-term outcomes including
death and bronchopulmonary dysplasia (BPD). Nevertheless, a recent meta-analysis of these
studies showed no difference in major outcomes, including death and morbidities such as BPD,
regardless of initial FiO2, even though it was noted that none of these studies examined the most
commonly used initial FiO2: 0.4–0.5. A recent Cochrane review of 10 of these studies continued to
emphasize the uncertainty of this practice, nding that only one study showed an increased
mortality rate in infants <28 weeks gestation resuscitated with lower (0.21) vs. higher (1.0) initial
FiO2,but other factors may play a part in infant outcome, including SpO2. Oei et al. showed that
regardless of initial FiO2, infants that did not reach SpO2 80% by 5 min of age were at signicantly
increased risk of bradycardia, intraventricular hemorrhage (IVH), and death. Whether these
infants were unable to reach target SpO2 due to inherent clinical instability or whether they were
given less oxygen than required is uncertain. Most clinicians will now use lower amounts of
oxygen (FiO2 ≤ 0.4) to initiate preterm infant resuscitation despite lack of evidence for both short-
term and long-term outcomes. The lack of evidence is reected in the astoundingly wide
variations in clinical practice guidelines for oxygen use around the world, where SpO2
recommendations can vary by as much as 25%. Certainly, due to the widespread
implementation of low oxygenation resuscitation within the last decade, sufciently powered
studies to determine the impact of both starting FiO2 and recommended FiO2 targets of preterm
infants are needed.
The case of biological uncertainty in preterm infants. There is underlying pathophysiological

evidence that hyperoxic resuscitation may cause as much biochemical derangement in
preterm infants as hypoxia but whether this leads to clinical morbidity and mortality is unclear. For
example, Vento et al. found that using higher FiO2 (0.9) to initiate preterm infant (≤28 weeks'
gestation) resuscitation signicantly increased urinary 8-oxo-dihydroguano- sine, isoprostanes,
and isofurans, suggesting oxidative damage to cell components, when compared to
resuscitation with FiO2 0.3, but whether this leads to clinically relevant outcomes is again unclear.
Consideration must also be given to the potential long- term, including epigenetic,
consequences of preterm oxygen exposure. As mentioned, hyperoxia is associated with
signicant changes to genes related to the cell cycle, antioxidant defense enzymes, DNA repair,
and inammation. Of note, DNA methylation was signicantly increased when the oxygen load
in the delivery room reached values above 500 mL O2/kg body weight a possible explanation for
the long-lasting effects of oxygen supplementation in the fetal to neonatal transition. Further
analytical determinations are needed to assess long- lasting permanence of the effects of
oxygen upon the methylome of preterm infants.
Should oxygen delivery be individualized? Preterm and term infants for different reasons require
respiratory stabilization at birth.Currently, systematic reviews suggest that term and near- term
infants (≥32 weeks GA) may benet from initial resuscitation with 0.21 rather than 1.0 initial FiO2,
but that lower FiO2 (≤0.3) should be used for infants <28 weeks gestation. Initial FiO2 appears to
have minimal impact on mortality or short-term morbidity for infants between 28 and 31 weeks
gestations. Data for infants <28 weeks gestation remain unclear, but there is indication from
current evidence that regardless of initial FiO2, the amount of oxygen given to the infants should
be manipulated to reach a target SpO2 of 80–85% and a heart rate of 100 bpm within 5 min to
decrease the risk of serious IVH and death.
143
It must also be remembered that data for “normal” physiological development of postnatal SpO2
in this group are lacking and that clinicians must be cognizant of the need to adjust FiO2 in
response to the infant's individual need.
The association between oxygen at birth and longer-term outcomes in preterm infants. There is
emerging evidence that the amount of oxygen received at birth may have profound
implications for the long-term outcomes of the high-risk newborn. In the initial studies, using air or
pure oxygen to initiate delivery room resuscitation of asphyxiated term or near-term infants made
no difference to the neurodevelopmental outcomes of survivors. However, the majority of these
infants were recruited from low- income countries from more than 20 years ago, when
resuscitation practices were very different. The infants were given either air or pure oxygen that
was not titrated to SpO2 changes, and whether oxygen titration would have affected
neurodevelopment in asphyxiated full-term newborn survivors is unclear. There is slightly more
information on preterm infants. A population review of preterm (<29 weeks) Canadian children
found no difference in death or neurodevelopmental impairment after Canadian resuscitation
guidelines were changed from FiO2 1.0 (n = 581) to FiO2 0.21 (n = 445)/intermediate FiO2 (0.22–0.99,
n = 483). The use of pure oxygen, however, was associated with an increased risk of severe
neurodevelopmental injury when compared to air (adjusted odds ratio (OR) 1.57, 95%
condence interval (CI): 1.05–2.35). Boronat et al. reported on the outcomes of 206 children
enrolled in three multicenter RCTs examining infants <32 weeks gestation after resuscitation with
either initial FiO2 0.3 or 0.6 and found no difference in the risk of major disability or death. In a meta-
analysis involving 542 infants, a 5-min SpO2<80% was associated with IVH (OR 2.04, 95% CI
1.01–4.11, p < 0.05). Bradycardia (heart rate <100 bpm) at 5 min increased risk of death (OR 4.57,
95% CI 1.62–13.98, p < 0.05), while no differences were seen with initial FiO2
Secondary analyses follow-up to the Torpido study, the largest RCT to examine low (0.21) vs. high
(1.0) initial FiO2 for preterm (<32 weeks gestation) infant resuscitation found no difference in the
risk of death and/or major disability at 2 years. However, in exploratory, secondary analyses,
infants who did not attain a minimum 5 min SpO2 of 80% were signicantly more likely to be
disabled/deceased than those with SpO2≥80% (OR 1.33). Cognitive subscales on the Bayley III test
were also higher, especially in infants ≥28 weeks gestation who had SpO2≥80% (mean (SD) 100.8
(12.5) vs. 95.2 (12.4)). It must be acknowledged again that SpO2 targeting was not part of the
study protocol and again, as noted previously, whether infants failed to achieve SpO2 80% by 5
min (a target that was only introduced in 2010) whether they were too sick or were not given
enough oxygen is unclear.
Immature infants beyond the delivery room. Clinical guidelines for optimal oxygenation of
preterm infants beyond the delivery room were based on weak evidence, such as observational
studies. Such data suggest that low SpO2 or PaO2 may protect premature infants against the
development of severe retinopathy of prematurity (ROP), without increase in mortality. However,
these data were quickly challenged and the need for RCTs to obtain evidence-based data
became clear. The ve NeOProM (Neonatal Oxygen Prospective Meta-analysis) studies were the
rst RCTs to determine the effects of lower vs. higher SpO2 targets in newborn infants <28 weeks
before the age of 24 h. In total, 4911 infants were enrolled: 2456 to low (85–89%) and 2455 to high
(91–95%) SpO2 targets. Although no difference was found in the primary outcome (dened as
combined death and/or major disability, i.e., neurodevelopmental impairment), infants nursed
in lower SpO2 had a signicantly increased risk (relative risk (RR) 1.18) of death. Survivors were at
decreased risk of BPD (dened as O2 requirement at 36 weeks corrected gestation (RR 0.81)), but
there was no difference in the risk of other outcomes, such as PDA, IVH or blindness, which was, in
any case, a rare event (see Fig. 5). The combined outcome of death and/or physiological BPD at
36 weeks was not uniformly reported in all of these studies. Only one study, the SUPPORT trial,
provided data on this combined outcome (85–89% target group—319/654–49% and 91–95%
144
Fig. 5 Infographic outlining the main results of the NEOPROM studies and changes in
recommendations to European Consensus Guidelines and American Academy of Pediatrics
based on these studies
target group—331/662 (50%) with an adjusted relative risk of 0.99 (95% CI: 0.9–1.1), but whether
this outcome was based on physiological need or prescription of oxygen cannot be deter-
mined (i.e., need vs. use). Recommendations for oxygen therapy are summarized in Table
145
CONCLUSION
Experimental and clinical studies have promoted changes in clinical practice regarding
newborn oxygenation. The understanding of the signicance of oxidative stress in the 1980s led
to a renewed interest for clinical studies a decade later. The demonstration that pure oxygen
might be harmful in newborn resuscitation triggered a series of new studies leading to the
dramatic change of clinical practice the last years. This new understanding conrms the
importance of ventilation rather than oxygen as the basis of new resuscitation programs in
developing and low resourced countries, such as Helping Babies Breathe.
The quest to determine best oxygen therapy for sick patients seems to have even reached the
echelons of adult medicine. The results from a meta-analysis of 16,037 patients with critical
illnesses of comparable severity (e.g., stroke, trauma, myocardial infarction, cardiac arrest, etc.)
from 25 RCTs showed that treatment with liberal oxygen therapies signicantly increased the risk
of death in hospital, at 30 days and at longest follow-up, when compared to treatment with
conservative oxygen therapies.
The enormous accumulation of knowledge and massive amounts of change in the recent years
for the eld of newborn oxygenation needs to be harnessed. Experimental data as well as large
RCTs have contributed greatly to this knowledge, but there is increasing awareness that more
data are needed. The amount of oxygen given to newborn infants has been substantially
reduced over the last two decades, but whether this is best for survival and long-term outcomes is
unclear, especially for preterm infants, who may need some amount of oxygen to decrease
pulmonary arterial pressure and to stimulate the respiratory center to open their glottis and to
initiate breathing or to remove the hypoxic inhibition of breathing. Until we solve this problem, the
oxygen dilemma remains.
The balance between death and morbidity for newborn infants is delicate. Higher oxygen levels
may increase survival, but survivors may be left with serious morbidities such as ROP and BPD.
Conversely, lower oxygen levels may lead to an increased risk of death, but survivors could be at
lower risk of problems caused by oxygen toxicity. Much more information is needed to allow
clinicians to choose between the lesser of two evils as whatever happens in the newborn period
will impact on the infants for the whole of their lives.
146
CONTINUOUS NON-INVASIVE MONITORING IN THE NEONATAL ICU
Rakesh Sahni,
Division of Neonatal-Perinatal Medicine, Department of Pediatrics, Columbia University College
of Physicians and Surgeons, USA.
Purpose of review
Standard hemodynamic monitoring such as heart rate and systemic blood pressure may only
provide a crude estimation of organ perfusion during neonatal intensive care. Pulse oximetry
monitoring allows for continuous noninvasive monitoring of hemoglobin oxygenation and thus
provides estimation of end-organ oxygenation. This review aims to provide an overview of pulse
oximetry and discuss its current and potential clinical use during neonatal intensive care.
Recent ndings
Technological advances in continuous assessment of dynamic changes in systemic oxygenation
with pulse oximetry during transition to extrauterine life and beyond provide additional details
about physiological interactions among the key hemodynamic factors regulating systemic
blood ow distribution along with the subtle changes that are frequently transient and
undetectable with standard monitoring.
Summary
Noninvasive real-time continuous systemic oxygen monitoring has the potential to serve as
biomarkers for early-organ dysfunction, to predict adverse short-term and long-term outcomes in
critically ill neonates, and to optimize outcomes. Further studies are needed to establish values
predicting adverse outcomes and to validate targeted interventions to normalize abnormal
values to improve outcomes.
INTRODUCTION
In the intensive care setting, it is vital to assess the hemodynamic status of the tissues for
optimization of end-organ tissue oxygenation and to hopefully decrease morbidity and mortality.
.
PULSE OXIMETRY
Pulse oximetry development is arguably one of the most important advances in clinical
monitoring during the past 3 decades. Its introduction has led to a revolutionary advancement in
patient assessment and monitoring because it allows for a simple, non-invasive, and reasonably
accurate estimation of arterial oxygen saturation (SpO2). Pulse oximeters have become
available for widespread application in neonatal care, and SpO2 has even been proposed as
the 'fth pediatric vital sign'. Pulse oximeters, which compute SpO2 using photoplethysmography
with at least two different light wavelengths [red and infrared (IR)], often display a
photoplethysmogram (PPG) to help clinicians distinguish between reliable SpO2 measurements
(associated with clean, physiologic waveforms) and unreliable measurements (associated with
noisy waveforms). Recent technological advances in pulse oximetry focusing on the
morphologic analysis of the PPG waveform have dened new indices, such as the perfusion
index and the pleth variability index (PVI), that are capable of assessing and monitoring the
microcirculation and intravascular uid volume status during intensive care
147
PULSE OXIMETRY
Pulse oximetry development is arguably one of the most important advances in clinical
monitoring during the past 3 decades. Its introduction has led to a revolutionary advancement in
patient assessment and monitoring because it allows for a simple, non-invasive, and reasonably
accurate estimation of arterial oxygen saturation (SpO2). Pulse oximeters have become
available for widespread application in neonatal care, and SpO2 has even been proposed as
the 'fth pediatric vital sign'. Pulse oximeters, which compute SpO2 using photoplethysmography
with at least two different light wavelengths [red and infrared (IR)], often display a
photoplethysmogram (PPG) to help clinicians distinguish between reliable SpO2 measurements
(associated with clean, physiologic waveforms) and unreliable measurements (associated with
noisy waveforms). Recent technological advances in pulse oximetry focusing on the
morphologic analysis of the PPG waveform have dened new indices, such as the perfusion
index and the pleth variability index (PVI), that are capable of assessing and monitoring the
microcirculation and intravascular uid volume status during intensive care
Clinical applications of pulse oximetry
In neonatal care, pulse oximetry is readily

used to target SpO2 during delivery room
resuscitation, in situations associated with
an increased risk of hypoxemia (e.g., during
intubation), in prevention of hyperoxia, and
for screening of congenital heart disease.
Accumulating evidence from large, blinded,
randomized, and controlled trials in
neonates shows that relatively small
differences in SpO2 target ranges can have
a surprisingly strong influence on important
clinical outcomes. The optimal SpO2 for
very low-birth-weight (VLBW) neonates
remains a moving target, because
uncertainty
still exists as to the appropriate range.
Pulse oximetry in delivery room
Continuous pulse oximetry in the delivery room is considered standard of care and
recommended by the International Liaison Committee on Resuscitation (ILCOR)/and the
American Heart Association (AHA) for the following situations: when resuscitation is anticipated,
when positive pressure ventilationis used for more than a few breaths, when supplementary
oxygen is needed, or when cyanosis is persistent . The pulse oximeter probe should be attached
to a preductal site (right upper extremity). ILCOR guidelines recommend that a pulse oximeter be
attached within 60 s of birth. In term and preterm neonates who do not require any resuscitation
(including oxygen), SpO2 increase slowly following delivery and achieve values greater than 90%
by 5–8 min of life. Values in neonates delivered vaginally rise more quickly than those delivered by
cesarean section.
148
Dawson et al. published normative values for SpO2 (10–97th percentile) for the rst 10 min of life in
a large number of term and moderately preterm neonates. They have published three sets of
percentile charts based on gestation (>37, 32–37, and <32 weeks) to guide the neonatal team in
titrating oxygen therapy in the delivery room. Smit et al. assessed over 100 term neonates with
delayed cord clamping and concluded that the Dawson curves are still relevant; however, they
reported higher initial SpO2 values, lower HRs, and a slower increase in HR over the rst 3 min of
life. ILCOR and the AHA recommend that the goal in neonates being resuscitated, whether born
at term or preterm, should be an SpO2 value in the interquartile range of preductal saturations
measured in healthy term babies following vaginal birth at sea level. Preterm neonates receiving
continuous positive airway pressure achieve reference oxygen values more quickly than
spontaneously breathing preterm neonates. SpO2 targets may be achieved by initiating
resuscitation with air or blended oxygen. In term newborn neonates, resuscitation should
generally be initiated with room air; however, if the neonate's HR is less than 60/min or SpO2
values do not increase as expected, the concentration of oxygen should be increased to 100% .
Given that cerebral blood ow is restored more quickly with 100% oxygen in animals with
circulatory collapse, it is recommend that neonates who are severely bradycardic or asystolic
should receive 100% oxygen until the HR is restored and then rapidly weaned . The choice of an
inspired oxygen concentration for resuscitation of preterm neonates is controversial. ILCOR
recommends resuscitation of preterm newborns of less than 35 weeks of gestation should be
initiated with low oxygen (21–30%), and the oxygen concentration should be titrated to achieve
recommended saturation value ranges . Initiating resuscitation of preterm newborns with high
oxygen (65% or greater) is not recommended. In a meta-analysis of seven randomized trials,
comparing initiation of resuscitation of preterm neonates less than 35 weeks with a high (>65%) or
low (21–30%) oxygen concentration, the higher oxygen concentration was not associated with
any improvement in survival. Furthermore, the incidences of bronchopulmonary dysplasia (BPD),
intraventricular hemorrhage (IVH) and retinopathy of prematurity (ROP) were unaffected by the
concentration of oxygen used for resuscitation. However, one study noted an increase in
markers of oxidative stress when a higher concentration of oxygen was used. A more recent
meta-analysis of outcomes of infants at 28+6 weeks or less gestation randomized to resuscitation
with low (30%) versus high (60%) oxygen at delivery in eight studies (three masked and ve
unmasked ) showed no differences in BPD [relative risk, 95% condence intervals 0.88
(0.68–1.14)], IVH [0.81 (0.52–1.27)], ROP [0.82 (0.46–1.46)], patent ductus arteriosus [0.95
(0.80–1.14)], necrotizing enterocolitis (NEC) [1.61 (0.67–3.36)], and overall mortality [0.99
(0.52–1.91)]. Mortality was lower in the low oxygen arms of masked studies [0.46 (0.23–0.92)] and
higher in low oxygen arms of unmasked studies [1.94 (1.02–3.68)]. The opposing results for masked
and unmasked trials were attributed to represent a Type I error, emphasizing the need for larger,
well designed studies. Rabi et al. have shown that titrating from an initial oxygen concentration
of 100% was more effective than giving a static concentration of 100% oxygen in maintaining
preterm infants in a target SpO2 range. In another retrospective cohort study from 17 centers
participating in the Canadian Neonatal network, Rabi et al. observed a higher risk of severe
neurologic injury or death among preterm neonates 27 weeks or less gestation following a
change in practice to initiating resuscitation with either room air or an intermediate oxygen
concentration, raising concerns about the use of room air during resuscitation of very preterm
neonates. Although ILCOR/AHA guidelines precisely dene SpO2 targets, it is difcult to achieve
them. Goos et al. demonstrated that, during the resuscitation of preterm neonates less than 30
weeks gestation, there were large deviations from the European Resuscitation Council
guidelines in the rst 10 min after birth.
149
Gandhi et al.have reported the use of a transitional oxygen targeting system that plots real-time
SpO2 values in relation to the 10 and 50th percentiles and enabled a greater proportion of total
resuscitation time (52%) within the target range compared with controls (37%).
Perfusion index
Perfusion index is an assessment of the pulsatile strength at a specic monitoring site (e.g., the
hand, nger, or foot) and as such is an indirect and noninvasive measure of peripheral perfusion.
It is calculated by expressing the pulsatile (AC) component of the PPG signal (during arterial
inow) as a percentage of the non pulsatile (DC) component of PPG signal, both of which are
derived from the amount of IR (940 nm) light absorbed. The perfusion index value is relative to a
particular monitoring site of each patient as physiologic conditions vary between monitoring
sites and amongst individual patients. The perfusion index display ranges from 0.02% (very weak
pulse strength) to 20% (very strong pulse strength). The Masimo signal extraction technology
(Masimo Corporation; Irvine, California, USA) uses ve signal processing algorithms to deliver
high-precision sensitivity and specicity in the continuous measurement of the perfusion index
parameter, which can yield clinically useful information regarding the peripheral perfusion status
of the patient . The ability to trend perfusion index is critical because only trends reveal the often
subtle changes in perfusion that can be missed by static displays. These subtle changes captured
by the real-time trends provide immediate feedback on the perfusion status and/or efcacy of
therapeutic interventions, thus guiding clinical management. Changes in perfusion index can
also occur as a result of local vasoconstriction (decrease in perfusion index) or vasodilatation
(increase in perfusion index) at the monitoring site. The measurement of perfusion index is
independent of other physiologic variables such as HR variability, arterial SpO2, or oxygen
consumption. However, perfusion index is sensitive to several things such as temperature of the
measurement site, exogenous vasoactive drugs, sympathetic nervous system tone (pain and
anxiety), and stroke volume (SV) .
Pulse oximetry and oxygen saturation targeting during neonatal intensive care
Oxygen is the most frequently used therapy during neonatal intensive care, and yet the
appropriate use of oxygen as a therapeutic drug is one of the most complex issues during
neonatal intensive care. Short-term and long-term risks of overuse (hyperoxemia) and underuse
(hypoxemia) are well dened and include ROP, blindness, BPD, cognitive delay,
cerebral palsy, and impaired survival . These relationships are most pronounced in extremely low-
gestational-age neonates, especially those born at 28 weeks or less. Oxygen monitoring with
pulse oximetry has gained widespread acceptance in neonatal ICUs (NICUs) over the past 3
decades because of its ease of use, particularly in extremely preterm neonates.
Yet, there remain wide variations in monitoring policies to guide oxygen therapy. Despite the
available literature showing that SpO2 more than 95% may be associated with hyperoxemia ,
many neonatologists have attempted to keep SpO2 in that high range for preterm neonates.
Since 2001,several observational studies comparing the use of a liberal approach with targeted
SpO2 more than 95% versus the use of a restrictive approach aiming at a lower SpO2 range
suggested clinical benets of restrictive targeting Five large, collaborative, multicenter, masked
randomized control trials that included more than 4800 infants have been reported from the US,
Canada, UK, Australia, and New Zealand in the past 10 years .
150
These trials were designed to be similar in terms of the population enrolled, interventions tested,
and outcomes measured to facilitate an individual patient data meta-analysis: Neonatal
Oxygen Prospective Meta-Analysis (NeOProM), to provide further insights. The trials addressed
whether maintaining a low SpO2 range (85–89%) versus a high SpO2 range (91–95%) in neonates
less than 28 weeks of gestation from the day of birth until breathing room air affected the
incidence of death, severe neurosensory disability. In the Benets of Oxygen Saturation Targeting
trial II and Canadian oxygen trials, the software used to calculate SpO2 was changed part way
through the trials. The short-term outcomes at discharge as well as the available data related to
the primary outcomes are summarized in Table 1. Preliminary analyses showed that the lower
SpO2 range was associated with a signicant increase in the risk of mortality (including data from
the oximeters using the old and revised software); however, there was no signicant difference
between the two target ranges in the rate of death or disability at 18–24 months, including
blindness . The lower SpO2 target range reduced oxygen dependency at 36 weeks,but
increased the risk of NEC requiring surgery or causing death. Results from NeOProM are still
pending. The safety of SpO2 targets above 95% has not been evaluated. Interestingly,
Cayabyab et al. recently reported that implementing graded oxygen targets during neonatal
care based on vaso-obliterative (83–89% during postmenstrual age <33weeks) and
vasoproliferative (90–94% during postmenstrual age 33 weeks) phases of ROP in neonates with
birth weight less than 1000 g decreased severe ROP and the need for laser therapy, without
increasing mortality. In summary, data from these trials suggest that use of a higher SpO2 target
range than previously recommended (e.g., 90–95%) is prudent in the management of preterm
neonates receiving supplemental oxygen.
Pulse oximetry for newborn critical congenital heart disease screening
Early detection of critical congenital heart disease (CCHD) in asymptomatic newborns poses an
important challenge for clinicians. Current screening strategies for the detection of CCHD
include antenatal ultrasound and newborn physical examination, but both have low detection
rates for isolated defects. Thus, many neonates are discharged undiagnosed. The rationale for
pulse oximetry as a screening tool for CCHD is to detect hypoxemia in the absence of clinical
cyanosis. Richmond et al.described the use of routine pulse oximetry within 24 h of birth and
before hospital discharge and found a sensitivity of 88.9% and specicity of 99% in detecting
CCHD.
151
The timing of pulse oximetry after 24h compared with within 24h of birth leads to a signicant
reduction in the false positive rate (0.05 and 0.50%, respectively) without compromising sensitivity
and specicity .Consistent identication of all critical left-heart obstructive conditions, such as
aortic coarctation and interrupted aortic arch, may still not be achieved through all three
screening tests currently available (antenatal ultrasound, newborn examination, and pulse
oximetry); however, a combination of all three will identify most affected infants. Although
screening in the NICUs is feasible, underlying illnesses and timing of the screening increases the
false positive rates. The use of pulse oximetry for newborn screening has already been
implemented as a standard of care in the United States and some Scandinavian countries and is
under consideration within Europe and the United Kingdom.
Perfusion index
Perfusion index is an assessment of the pulsatile strength at a specic monitoring site (e.g., the
hand,nger, or foot) and as such is an indirect and non-invasive measure of peripheral perfusion.
It is calculated by expressing the pulsatile (AC) component of the PPGsignal (during arterial
inow) as a percentage of the non-pulsatile (DC) component of PPG signal,
both of which are derived from the amount of IR (940nm) light absorbed.
The perfusion index value is relative to a particular monitoring site of each patient as physiologic
conditions vary between monitoring sites and amongst individual patients. The perfusion index
display ranges from 0.02% (very weak pulse strength) to 20% (very strong pulse strength). The
Masimo signal extraction technology (Masimo Corporation; Irvine, California, USA) uses ve
signal processing algorithms to deliver high-precision sensitivity and specicity in the continuous
measurement of the perfusion index parameter, which can yield clinically useful information
regarding the peripheral perfusion status of the patient .The ability to trend perfusion index is
critical because only trends reveal the often subtle changes in perfusion that can be missed by
static displays.
These subtle changes captured by the real-time trends provide immediate feedback on the
perfusion status and/or efcacy of therapeutic interventions, thus guiding clinical management.
Changes in perfusion index can also occur as a result of local vasoconstriction (decrease in
perfusion index) or vasodilatation (increase in perfusion index) at the monitoring site. The
measurement of perfusion index is independent of other physiologic variables such as HR
variability, arterial SpO2, or oxygen consumption. However, perfusion index is sensitive to several
things such as temperature of the measurement site, exogenous vasoactive drugs, sympathetic
nervous system tone (pain and anxiety), and stroke volume (SV).
Perfusion index and microvascular circulation assessment
The perfusion index obtained from the PPG signal has been suggested to reect changes in
peripheral perfusion. This ratio has been used as a noninvasive index of peripheral perfusion in
critically ill patients. Lima et al. showed that a perfusion index with a threshold value of 1.4 can be
used to detect abnormal peripheral perfusion in patients receiving intensive care. In particular, a
perfusion index value of 1.24 or less has been shown to be an accurate predictor of high illness
severity in newborns. Perfusion index monitoring has been shown to be helpful in identifying
preterm and term neonates born to mothers with chorioamnionitis, a major predictor of morbidity
and mortality in VLBW neonates.
152
Moreover, perfusion index values might be useful for early detection of ductus arteriosus–
dependent systemic circulation (left heart obstructive disease) . In addition, perfusion index is a
useful index for detecting low superior vena cava ow, which is a risk factor for IVH in preterm
neonates. In contrast, a decreased perfusion index value in the preanesthesia phase of the
elective cesarean section is a maternal predictor of increased neonatal morbidity, in particular
early respiratory complications. Higher values of perfusion index are associated with prone
sleeping position in VLBW neonates, presumably reecting thermoregulatory adjustments in
peripheral perfusion, and perfusion index correlates signicantly with other indirect measures of
tissue perfusion such as HR and central-to-peripheral thermal gradients. However, although
perfusion index values are easily obtained, and normative values for preterm and term neonates
in the rst day of life are available they are highly variable in the immediate newborn period, for
both term and preterm neonates.
Pleth variability index
Another variable that is derived from the PPG waveform is PVI. PVI is a measure of the dynamic
changes in the PPG waveform (i.e., perfusion index) that occur during the respiratory cycle and is
thought to be a surrogate measure of intravascular volume. It is theorized that, with each
inspiration, venous return to the heart is impeded, resulting in a temporary reduction in CO. As a
patient becomes volume depleted, with a resulting decrease in venous pressure, positive
pressure ventilation has an exaggerated impact on the arterial BP and the plethysmograph.
Monitoring the respiratory variability in the PPG waveform may be a useful method of evaluating
uid status, The PVI reects measurements of ventilation-induced respiratory changes in
perfusion index over a constant period of time and is calculated as follows:
PVI = [(PImax-Pimin)/PImax]/100
where PImax and PImin are the maximum and minimum values of perfusion index, respectively.
PVI therefore is displayed continuously as a percentage. The lower the number, the less
variability there is in the perfusion index over a respiratory cycle. It is speculated that PVI has the
potential to provide useful information concerning changes in the balance between
intravascular uid volume and intrathoracic airway pressure. For example, PVI may help
clinicians noninvasively and continuously assess the uid status of patients. An increasing PVI may
indicate developing hypovolemia. In addition, the greater the PVI, the more likely the patient will
respond to uid administration. Trending of PVI may also be useful in monitoring patients with
respiratory or cardiac failure, helping to evaluate the interrelationship between intrathoracic
pressures and cardiac function.
Pleth variability index and assessment of intravascular uid volume
Estimation of intravascular volume is still a challenge in both adults and neonates, in whom
hypovolemia is a common cause of perioperative circulatory failure. In conjunction with clinical
assessment, HR, mean arterial pressure, and central venous pressure are frequently used to guide
uid therapy in neonates. However, numerous studies have shown that values of preload, or
change in preload to a uid load, are poor indicators of whether a patient will benet from
additional uid. Investigations have progressed beyond static measurement of cardiac lling
pressures to a more dynamic approach using invasive variables such as pulse pressure variation,
SV variation, and noninvasive measurements of PVI, which are based on heart–lung interaction
induced by mechanical ventilation.
153
These dynamic variables have been shown to reliably predict the response to a uid load in
adults in different clinical scenarios. Cannesson et al. showed that a PVI at least 14% before
volume expansion discriminates between responders and non-responders with a sensitivity of
81% and specicity of 100% in adult patients under general anesthesia. Renner et al. recently
showed that PVI can predict uid responsiveness in neonates undergoing congenital heart
surgery, with a threshold value of greater than or equal to 13%, helping to discriminate between
responders and non- responders. Sahni et al. have recently shown that PVI can predict
ventricular preload and uid responsiveness in mechanically ventilated neonates with
congenital heart disease. Neonates with trans- position of great arteries showed superior
postoperative uid responsiveness compared with those with hypoplastic left heart syndrome,
suggesting greater preload dependence. These data suggest that PVI may have clinical
applications for the noninvasive detection of hypovolemia and for monitoring the response to a
uid challenge.
Limitations of pulse oximetry
The main physiological limitation of pulse oximetry is the inability to detect hyperoxemia at
functional SpO2 of more than 94% because the shape of the oxygen hemoglobin dissociation
curve and relatively small increases in SpO2 can be associated with a large increase in arterial
oxygenation Calibration and accuracy are other concerns as pulse oximeters are calibrated by
the data obtained from healthy adults with normal adult hemoglobin, and correlated to arterial
blood samples tested in vitro by a co-oximeter that actually measured SaO2. Further, calibration
for SpO2 values less than 80% can only be made by extrapolation and are less likely to be
accurate. Response delay is another issue due to signal averaging time of the oximeter. Most
pulse oximeters have a default time of 8 s to display the average value of SpO2 measured over this
period, but that time interval can be modied. Long averaging times may reduce the frequency
of alarms but will delay the response time and may not detect brief hypoxemic episodes. Motion
artifacts due to movement and poor peripheral perfusion is another issue but the newer pulse
oximeters with signal extraction technology can measure the SpO2 during patient motion and
low perfusion by separating the pulsatile arterial signal from the other signals.
CONCLUSION
In conclusion, noninvasive real-time continuous bedside monitoring with pulse oximetry has the
potential to serve as a biomarker for early organ dysfunction, to predict adverse short-term and
long-term outcomes in critically ill neonates, and to optimize outcomes. Further studies are
needed to establish normative data and absolute cut-off values predicting adverse outcomes. It
is also important to determine whether targeted interventions to normalize abnormal values
actually improve outcomes. In the future, a combination of pulse oximetry with other noninvasive
modalities such as near-IR spectroscopy (NIRS), electroencephalography, ultrasound, and/or
other imaging into single devices will provide comprehensive information of organ health
through multimodal monitoring. In addition, availability of frequency domain NIRS and diffusion
correlation spectroscopy will allow bedside monitoring of cerebral blood volume, absolute
hemoglobin SpO2, blood ow index, and relative cerebral metabolic rate of oxygen.
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NEONATAL NOSOCOMIAL SEPSIS – THE SWORD OF DAMOCLES IN NICU
Christian P. Speer, University of Würzburg,

University Children's Hospital, Würzburg, Germany
The incidence of neonatal late-onset sepsis (LOS) is inversely related to the degree of maturity
and varies geographically from 0.6 % to 15 % among hospitalised newborns . Epidemiological
data on very low birth weight infants show that the predominant pathogens of neonatal LOS are
coagulase-negative staphylococci, followed by Gram-negative bacilli and fungi . Well dened
risk factors of nosocomial sepsis are mechanical ventilation, central catheters, i.v.-lipids and late
enteral feeding. In addition, staff hands, insufcient hand washing practices and an
overcrowded NICU have been shown to contribute signicantly to the transmission of
pathogens. Due to difculties in a prompt diagnosis of LOS and LOS-associated high risk of
mortality and long-term neurodevelopmental sequelae, empirical antibiotic treatment is
initiated on suspicion of LOS. However, empirical therapy is often inappropriately used with
unnecessary broad-spectrum antibiotics and a prolonged duration of treatment. The increasing
number of multidrug-resistant Gram-negative micro-organisms in neonatal intensive care units
(NICU) worldwide is a serious concern, which requires thorough and efcient surveillance
strategies and appropriate treatment regimens . Especially very immature preterm infants suffer
from a considerable number of partial immuno-deciencies which predispose these babies at
risk for microbial infections. However, neither prophylactic nor therapeutic application of i.v.
immunoglobulins was shown to improve outcome of this high risk population. Similarly,
substitution of colony stimulating factors for granulocytes and macrophages failed to reduce
mortality and the incidence of sepsis.
Nevertheless, a number of better practices may help to reduce the incidence of nosocomial
infections: strict adherence to hygiene protocols, reduction of invasive procedures associated
with neonatal intensive care, early enteral feeding with breast milk, rational strategy for antibiotic
treatment and others. In addition, a regular and sensitive clinical monitoring of neonates at risk
will help to identify early signs of infection and to initiate a timely therapy.
RECENT ADVANCES IN SURFACTANT THERAPY
Christian P. Speer, University Children's Hospital,

University of Würzburg, Würzburg, Germany
Surfactant replacement in preterm infants with respiratory distress syndrome (RDS) has been a
major therapeutic breakthrough and the most intensively studied intervention in neonatal
medicine. Surfactant reduces the severity of RDS, the incidence of air leaks and pneumothorax
and, most importantly, neonatal death. Many randomized controlled trials have explored
different strategies to optimize the effect of surfactant administration and have further improved
neonatal outcome. The European Consensus Guidelines 2019 state that all preterm infants with
RDS should be given a natural surfactant preparation . A policy of early rescue surfactant should
be standard, however, there are occasions when surfactant should be administered in the
delivery suite.
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A suggested protocol would be to treat preterm infants who are worsening when FiO2 > 0.30 on
CPAP pressure of at least 6 cm H2O. Poractant alfa at an initial dose of 200 mg/kg is better than
100 mg/kg of poractant alfa or 100 mg/kg of beractant for rescue therapy. Less invasive
surfactant administration may be the preferred mode of surfactant administration for
spontaneously breathing preterm infant on CPAP, provided that clinicians are experienced with
this technique. A second and sometimes a third dose of surfactant should be administered if
there is evidence on ongoing RDS such as oxygen requirement and need for mechanical
ventilation. Future surfactant research will focus on the development of fully synthetic surfactant
preparations , new application techniques and surfactant as carrier of topical drugs.
PALLIATIVE CARE FOR THE NEWBORN - BEING KIND TILL THE END
Dr Arun Kumar MD, MRCP (U.K), FRCPCH

Consultant Neonatologist, Mayday hospital, London (U.K)
As Neonatologists, we will all face situations where infants under our care will not respond to our
best efforts and technical expertise. Care in these situations may then require redirecting
towards providing comfort, relief from pain and suffering, minimising procedures considered
futile, and limiting or withdrawing intensive care. Such care could last for months or years
especially for conditions where it is impossible to predict duration of survival. As technology
advances in fetal diagnoses, the arena for these discussions will increasingly shift to the antenatal
period. Engaging and involving parents in these discussions is paramount and will call on our best
communication skills.
Training in Neonatology imparts excellent clinical and technical skills, but junior colleagues may
often nd the prospect of such discussions and decision making distressing and daunting.
Trainees must use every opportunity to observe and imbibe these skills from senior colleagues.
Palliative care interfaces medicine with ethics, law, religious beliefs and emotions like none other.
Every situation will be unique and impart learning to practitioners. For mothers who have bonded
with their babies for months in utero, these discussions will undoubtedly be deeply traumatic. A
kind and compassionate approach with involvement of professionals across disciplines and
allowing plenty of time for discussion and resolution of disagreement will pave the way for
successful management. Disagreements invariably stem from fears and misunderstandings that
a skilled professional may be able to unravel and provide reassurance.
In my talk, I will cover neonatal palliative care as practiced in the United Kingdom. I will outline the
guideline framework that supports practice, categorize situations in which such discussions
usually ensue, cover multidisciplinary input, withdrawal of intensive care, symptom
management, and the role of supporting charities. Avenues for addressing disagreement will
also be touched upon.
While the principles of palliative care will be the same worldwide, practice would be governed
by local legal, medical and sociological factors. There can never be a one- size- ts- all protocol
that will work in all countries or even every baby, and clinicians would need to evolve
individualized plans in negotiation with parents.
156
INTERPRETATION OF THE BLOOD GAS
N. Karthik Nagesh, Abdul Razak and Mrinal Pillai
Chairman and HOD of Neonatology & Chairman of Manipal Advanced Children's Centre,
Manipal Hospitals, Bangalore; Adjunct Professor of Pediatrics, Manipal University,
Bangalore, India and Fellow in Neonatal Perinatal Medicine, Mc Master's University,
Ontario, Canada and Consultant Neonatologist, Sree Uthradom Thirunal Hospital, Pattom,
Thiruvananthapuram, Kerala, India
E-mail: drkarthiknagesh@gmail.com
Introduction
Interpretation of the blood gas by health-care personnel is a critical step in the management of
sick infants and newborns. Blood gas aids the clinician in treatment plan and prognostication. It
reects the sickness of the infant and provides essential information of an ongoing change in the
clinical status of the sick infant. The measurement of blood gas can be challenging because of
the rapidly changing physiology, practical issues in obtaining the blood sample and only small
volumes of blood available for analysis. Such facilities are available only at tertiary care centers.
The interpretation is often easy, however, correlating the same with the infant's status can
sometimes be complicated. Various methods have been reported in the literature. This chapter
will focus on interpreting blood gas in a stepwise and sequential manner.
Indications for Performing a Blood Gas Test
A blood gas test is commonly performed in critically ill infants admitted to the neonatal intensive
care unit with following conditions.
Fig. 1: Acid-base nomogram- Relationship between partial pressure of carbon dioxide and
bicarbonate with blood pH. Downloaded from https://commons.wikimedia.org/wiki/le:Acid-
base_nomogram.svg
157
(1) Infants with respiratory distress on oxygen therapy, non-invasive/ invasive ventilation to know
oxygenation and ventilation status
(2) Sick infants with sepsis, shock, decreased cardiac output, PDA to assess organ perfusion status
(3) Metabolic disorders (perinatal asphyxia, renal failure, suspected or proven inborn error of
metabolism)
(4) Monitoring neonates on therapeutic hypothermia, circulatory support, renal replacement
therapy
(5) Post-surgery monitoring
The results of blood gas test will help in understanding underlying pathophysiology and develop
proper treatment plan.3 (Fig. 1) Maintenance of normal blood pH and oxygenation are crucial
factors in the survival of infants. A blood pH below 6.8 and over 7.8 is incompatible with life and
results in irreversible cell damage. An arterial pO2below 40 mm Hg is life threatening while over 100
mm Hg is damaging to retinal vessels. It is to be recognized that the metabolic status in a sick
infant is constantly changing in response to treatment and hence repeated measurements
may be necessary to follow the course of the disease.
Terminologies Used in Blood Gas Analysis

Temperature
All tests are measured at 37oC. However in case of therapeutic hypothermia or in case of
hyperthermia, measured values have to be corrected. Hence patient's temperature needs to be
entered in to the machine as the machine will automatically corrects for patient's temperature.
If the patients temperature is not entered then the blood gas values can be estimated as follows:4
1) Subtract 5 mm Hg pO2per 1ºC below 37ºC
2) Subtract 2 mm Hg PCO2per 1ºC below 37ºC
3) Add 0.012 pH units per 1ºC below 37ºC
pH
pH is dened as decimal logarithm of the reciprocal of the hydrogen ion. Blood pH is acidity or
alkalinity of blood. Normal pH is maintained between 7.35 to 7.45.
PaO2
The partial pressure of oxygen in arterial blood (paO2) refers to pressure exerted by oxygen in the
blood and expressed as millimeters of mercury or tor. The normal values for PaO2is 60-80 mmHg.
PaCO2
The partial pressure of Carbon dioxide in arterial blood (PaCO2) refers to pressure exerted by
carbon dioxide in the blood and expressed as millimeters of mercury or tor. The normal values
for PaCO2 is 35-45 mmHg.
158
Base Excess (BE)
Buffer base (BB) is a mixture of weak acid and conjugate base which prevents changes in pH.
Twenty ve percent of BB is constituted by hemoglobin buffer, 50% by bicarbonate and 25% by
other buffers (proteins, phosphate, sulphate). Normal BB is 48-49 mmol/L. Base excess (BE) refers
to actual base excess in variance from (above or below) total buffer base (BB). If BB is 38, it means
BE is –10 (also called base decit). If BB is 56, it means BE is +8.
Standard HCO3(SBC)
It is used to denote value of HCO-3, at standard pCO2 of 40mmHg and temperature of 37oC. This
is used to separate respiratory effect of pCO2 on actual HCO-3 (ABC) and evaluate metabolic
status (Copenhagen approach). Total CO2 (TCO2) is the sum of HCO-3 and CO2 (0.03ml
dissolved CO2 per 100ml of plasma for every mmHg pCO2) dissolved in plasma. Standard pH (St.
pH) is the pH purely due to metabolic status, adjusted for pCO2 of 40 mmHg and temperature of
37C.
Standard Base Excess (SBE)
Extracellular uid (ECF) compartment is most reective of the immeasurable intracellular

environment. Standard base excess is the amount of alkali available to return the ECF pH to
normal pH (7.40) under2standard conditions (at 37oC at a PCO of 40 mm Hg), assuming that
hemoglobin is 5gm/dl. Hemoglobin which buffers entire ECF is taken as 1/3rd of the standard
hemoglobin (15 g/dl) because extracellular uid is constituted by interstitial uid compartment
(2/3rd) and intravascular compartment (1/3rd).
Oxygen Content (O2CT)

Oxygen content is the sum of oxygen bound to hemoglobin and oxygen dissolved in plasma. For
each gm of saturated hemoglobin (Hb), 1.34 ml O2 is bound to hemoglobin and for each mm Hg
pO20.003 ml oxygen is dissolved per 100 ml of plasma.
O2CT = 1.34 x Saturation x Hb/100 + 0.003 x Po2
Blood Sampling and Normal Blood Gas Values

Arterial blood gas values given in Table 1 are general ranges for reference. If regular blood gas
analysis is indicated then indwelling arterial catheters should be used for taking arterial samples
otherwise heelstick capillary blood gas should be the rst-line sampling method for acid-base
analysis. Repeated peripheral arterial stab sampling should be avoided.
Capillary blood can be arterialized usually by immersing the heel in warm water (40°C to 45°C) for
10 minutes prior to heel stab. Covering the heel with wet warm towel is preferred to avoid thermal
injury and to avoid burns. Although pre-warming of the heel does not provide results signicantly
different from non-warmed heel, the increased blood ow due to arterialization is necessary to
prevent hemolysis or contamination with tissue uid. Note that capillary pO2 correlates well with
arterial pO2 only within the range of 60 – 90 mmHg. Any capillary pO2 above 90 mmHg should be
cross checked with arterial pO2 to avoid hyperoxemia. Consider procedural analgesia before
performing any painful procedure with 0.5 - 2 ml of 25% dextrose,
Gestational Age pH PaO2 (mmHg) PaCO2 (mmHg) HCO3 (mEq/L) BE (mEq/L)

Term 7.32-7.38 80-95 35-45 24-26 ±3
Preterm (30-36 weeks) 7.30-7.35 60-80 35-45 22-25 ±4
Preterm (< 30 weeks) 7.27-7.32 45-60 38-50 19-22 ±4
Term umbilical artery 7.10 – 7.38 4.1 – 31.7 39.1 – 73.5 22-23.1 -9.0 – 1.8
Term umbilical vein 7.20 – 7.44 30.4 – 57.2 14.1 – 43.3 - 7.7 – 1.9
159
BE Base excess; HCO3Bicarbonate; PaCO2Partial pressure of carbon dioxide; PaO2Partial pressure
of oxygen. Values are arterial unless specied otherwise.
on the tongue 2 minutes before the procedure (See chapter on pain). The baby's heel should be
held with non-dominant hand, with ngers around the ankle and lower leg, while partly encircling
the baby's heel with thumb. Medial or lateral aspect of the heel is chosen for heelstick puncture.
The posterior and central regions of the heel are avoided because puncture of these sites can
cause damage to nerves, tendon, cartilage and bone. Clean the site with an appropriate
neonatal antiseptic solution and allow drying. Puncture the skin using an appropriate lancet
device (depth 0.85 mm for a premature baby, 1.0 mm for a term baby). Wipe away initial blood
ow with cotton wool. Maintain grip while doing cycles of gentle compression, releasing to allow
reperfusion and re-compressing the heel to produce droplets of blood. Collect the droplet of
blood using pre-heparinised capillary tube.
The blood gas sample should be processed immediately because the blood cells consume
oxygen and produce CO2. Slush of ice should be used for preserving samples until processing.
Blood sample should be stored at 4oC, if it cannot be processed immediately for minimal error.
Buffer System and Compensation
The acid-base homeostasis (Table 2) is steadily maintained by buffers regulated by the
respiratory and renal systems. The normal values for various blood gas parameters does vary with
gestation and acceptable targets for various neonatal conditions is individualized and differ
across centers. For example, the acceptable partial pressure of carbon dioxide for a term infant
with severe pulmonary hypertension (45-55 mm Hg) is completely different as compared to a
preterm infant with chronic lung disease without pulmonary hypertension (up to 70-75 mm Hg).
Similarly, For example, many neonatologists tolerate permissive hypercapnia as long as the pH is
above 7.25.
The most important buffer system is the bicarbonate buffer system, responsible for 80% of
extracellular buffering, which is as follows:
H2O + CO2= H2CO–3(Carbonic acid) = HCO–3(bicarbonate) + H+(hydrogen ion)
Acidosis due to hydrogen ion accumulation will result in left-shift of equation and increased
carbon dioxide which is cleared by lungs. Similarly, increased CO2 levels due to respiratory
disease are compensated by the kidneys by increased excretion of H+ ions. The respiratory
compensation is faster than the renal compensation. The constituents of bicarbonate buffer
system can be related to pH of blood by Henderson-
Hasselbalch equation.
pH = pKa H2CO3+Log [HCO–3/H2CO3] or pH = 6.1+Log [HCO–3/0.03× pCO2]
Determine the Oxygenation Status Oxygenation and Partial Pressure of Oxygen Table 2. Blood
acid-base parameters
Blood Gas Parameter Normal Values Low High

pH 7.35-7.45 Acidosis pH <7.35 Alkalosis pH >7.45
PaO2 50-80 mm Hg Hypoxemia <50 mm Hg Hyperoxemia >80 mm Hg
PaCO2 35-45 mm Hg Respiratory alkalosis Respiratory acidosis
<35 mm Hg (Hypocapnia) >45mm Hg (Hypercapnia)
HCO3 20-24 meq/L Metabolic acidosis <20 meq/L Metabolic alkalosis >24 meq/L
Base excess/deficit ±4 Metabolic acidosis <-4 Metabolic alkalosis >+4
SaO2 90-95 Low saturation <90 High saturation >95
160
The partial pressure of oxygen in arterial blood (paO2) refers to pressure exerted by oxygen in the
blood and expressed as millimeters of mercury or tor. Hypoxia refers to the deciency in the
amount of oxygen reaching the tissue cells. On the other hand, hypoxemia refers to the low
concentration of oxygen in the blood. The acceptable PaO2 for term infants, preterm infants >32
weeks' gestation and infants with chronic lung disease/Pulmonary hypertension is 60-80mm Hg.
Acceptable PaO2 in preterm infants <32 weeks' gestation is 50-70 mm Hg. Hypoxemia is dened
as PaO2 <50mm Hg. The common causes of hypoxemia are listed in Table 3. Hyperoxemia, PaO2
>80 mmHg commonly occurs due to inadvertent oxygen administration.
In the neonatal population, the oxygenation status is often assessed by measuring oxygen
saturations using pulse oximetry. The ideal oxygen saturations for extremely preterm infants is
unknown, though recent trials suggest keeping saturation targets between 90-95% appears safer
than 85-89% in some infants.7 Measurement of PaO2 gives a snapshot of oxygenation at that point
compared to oxygen saturations which give the trend. On the other hand, oxygen saturations by
pulse oximetry is relatively insensitive in detecting hyperoxemia. The reason behind this is the
sigmoid-shaped curve of oxygen dissociation which plateaus off at PaO2 >70 mm Hg (Fig. 2). The
oxygen saturation of 95-98% could be equivalent to PaO2 of 70 mm Hg or could be as high as 200
mm Hg. On the other hand, low oxygen saturations are associated with low PaO2. The exception
to this rule is methemoglobinemia where the infant has profound cyanosis however PaO2 is
normal. Newborns who have not received a packed RBC transfusion have up to 60-80% fetal
hemoglobin (HbF), which has higher afnity to oxygen. When the temperature, PCO2, 2, 3
diphosphoglycerate (glycolysis pathway metabolite) decreases or the pH increases, the OHDC
curve is shifted to the left. As the curve shifts to the left, hemoglobin releases less oxygen to the
tissues, leading to tissue hypoxia.
Oxygen delivery to tissues depends on tissue perfusion (cardiac output and hemoglobin
concentration) apart from the partial pressure of oxygen. Hence, assessing infant's oxygenation
does not necessarily depend only on the partial pressure of oxygen, although it is a crucial factor.
The common indices used to assess oxygenation are oxygenation index OI, AaDO2 gradient, and
a/A ratio.
1. Oxygenation Index (OI)
OI = Mean airway pressure × Fraction inspired oxygen / Post-ductal PaO2
There is no normal value for OI as the normal infant is not ventilated. Some authors believe less
than ve is normal and more than 5 indicate lung disease. In general, OI is used to dene the
severity of lung disease. OI more than 15 would characterize infant having a severe respiratory
disease. Different criteria have been employed to initiate nitric oxide therapy and
extracorporeal membrane oxygenation. OI >25 is employed to initiate inhaled nitric oxide
therapy for infants with pulmonary hypertension.8 Similarly, OI > 40 for 1 hour or > 40 with
hemodynamic instability or >60 on HFOV is used to initiate extracorporeal membrane
oxygenation
Table 3. Causes of hypoxemia in neonate

Mechanism for Hypoxemia Causes for Hypoxemia
Decrease in oxygen reaching lungs Obstructive airway-mechanical or anatomical
Reduced/suppressed respiratory drive-Central
(hypoventilation), infections
Decrease in blood reaching the lungs because of PPHN
right to left shunting Cyanotic congenital heart disease
Normal oxygen delivery to lungs but ventilation/ Parenchymal lung disease–hyaline membrane disease,
perfusion mismatch pneumonia, meconium aspiration
Anatomical lung disease–diaphragmatic hernia, cystic
malformation, lobar emphysema
161
employed to initiate nitric oxide therapy and extracorporeal membrane oxygenation. OI >25 is
employed to initiate inhaled nitric oxide therapy for infants with pulmonary hypertension.8
Similarly, OI > 40 for 1 hour or > 40 with hemodynamic instability or >60 on HFOV is used to initiate
extracorporeal membrane oxygenation.
2. Alveolar-Arterial Oxygen Gradient or Difference/AaDO2

This is calculated by the formula;
AaDO2= Partial Pressure of alveolar oxygen - Partial pressure of arterial oxygen
or
AaDO2 = {[760(barometric pressure)-47(water pressure) × FiO2]-(PaCO2/0.8)} - {PaO2}. This value
shows the difference between the alveolar pO2and arterial pO2
In healthy infants with normal lungs and normal pulmonary circulation breathing room air, AaDO2
is less than 20 mmHg in room air and AaDO2> 40 mm Hg is abnormal.
3. a/A Ratio
The a/A ratio is arterial to alveolar tension ratio. The ratio is calculated by dividing the arterial
oxygen tension by the alveolar oxygen tension
a/A ratio= Partial pressure of arterial oxygen/Partial Pressure of alveolar oxygen

a/A ratio of less than 0.3 indicates a severe compromise of oxygen transfer.
Base Excess/Decit
The base excess is the actual reection of metabolic component of acid-base disturbance. The
calculation is derived based on pH and PaCO2. Base excess is dened as the amount of acid
that would be required to restore a liter of fully oxygenated blood to return to its normal pH at a
temperature of 37°C and a pCO2 of 40 mmHg. Similarly, a base decit is dened as the amount of
base that would require restoring the normal pH. The reference range is between -4 to +4 meq/L.
Left Shift Right Shift

What it means Increased Decreased
affinity to affinity to
oxygen oxyg en
Temperature Low high

PaCO2 Low (Alk alosis) High (Acidosis)
Hydro gen Low (Alk alosis) High (Acidosis)
concentration
2, 3 DPG Low high
Factors affecting the Oxygen dissociation curve (Note: Presence of fetal hemoglobin will result in
left shift of ODC)
Fig. 2. Oxygen-hemoglobin dissociation curve.
162
A high base excess is associated with excess bicarbonate (metabolic alkalosis). This can be
caused by loss of chloride ion or excess of bicarbonate. Although it is uncommon to see
metabolic alkalosis because of excess bicarbonate, however, excess sodium
bicarbonate/citrate therapy and acetate infusion can result in metabolic alkalosis.
The common cause of metabolic alkalosis in a neonate is due to chloride losses associated with
diuretic therapy (chronic lung disease or cardiac disease) or due to vomiting (pyloric stenosis).
The increased bicarbonate is a compensatory mechanism of kidneys due to increased chloride
losses.
A high base decit can occur due to loss of bicarbonate or due to neutralization of bicarbonate
by organic acids in higher concentration.
An anion gap will determine the metabolic acidosis is due to loss of bicarbonate or neutralization
of bicarbonate. The anion gap is the difference between anions and cations.3Anion gap = (Na+ +
K+) - [Cl-+ HCO -]
The kidneys compensate for a loss of anion by an anion, i.e., loss of bicarbonate is compensated
by retaining a chloride ion to maintain the electrochemical difference (hyperchloremic
metabolic acidosis). Hence, the anion gap is normal. On the contrary, if the acidosis is due to an
excess of organic acids neutralizing bicarbonate, the anion gap is increased (normochloremic
metabolic acidosis).
The common causes of metabolic acidosis with normal anion gap are bicarbonate loss (low
threshold in premature infants), diarrhea and renal tubular acidosis. The reasons for high anion
gap are listed in Table 4.
Stepwise Approach to Interpretation of Blood Gas Report
It is important to understand that the blood gas analyzer measures only pH, PaO2, and PaCO2.
Bicarbonate and base excess are calculated based on pH and PaCO2. The formulas to calculate
base excess and bicarbonate are based on Henderson-Hasselbalch equation. The following
approach can be utilized to interpret the blood gas (Fig. 3).
1. Assess the internal consistency of blood gas values.
2. Is the pH normal ?
3. Is the PaCO2normal?
Table 4. Causes of high anion gap metabolic acidosis

Cause Anions Diagnostic Investigations
Renal failure Phosphates, sulfates Blood urea and creatinine
Ketoacidosis Ketoacids, Ketones in blood and urine
Diabetic/Starvation/inborn errors of metabolism b-Hydroxybutyrate
Lactic acidosis
Hypovolemia/Hypothermia/Hypoxic ischemic Lactate Lactate
encephalopathy/Sepsis/Cardiac failure/Liver
failure/Inborn error of metabolism
Toxin ingestion Salicylate/lactate Toxin levels
163
1. Is the HCO3normal ?
2. Match the PaCO2and HCO3with pH
3. Is the compensation appropriate for primary disorder ?
4. Calculate anion gap if there is metabolic acidosis
5. Are the PaO2or O2sats values normal ?
1. Step 1- Assess the Internal Consistency of Blood Gas Values

The rst step is to check the internal consistency of blood gas values by using Henderson-
Hasselbach equation.6[H+] = 24 × PaCO2/[HCO3]
For example, considering this blood gas,

pH: 7.20, pCO : 50, HCO–: 18.9, BE -7.9, H+: 60.3. The H+ 50, HCO–
ion calculated from the formula is 60, approximately equal to the measured H+ ion in the gas.
Alternatively,
Fig. 3. Stepwise approach in interpreting blood gas.
164
the hydrogen ion is obtained by subtracting the two digits after the decimal point of pH from 80.
From the example, the pH is 7.20 then [H+] =80-20=60. This may not apply if pH is very abnormal
(pH <7.1).
1. Step 2- Is the pH Normal?

The primary disorder can be identied by looking at pH pH >7.45—Alkalemia pH<7.35—Acidemia
The normal pH range is 7.35 to 7.45. An acidosis or alkalosis can be present even if pH is in the
normal range (7.35-7.45). The normal values for blood gas is provided in Table 1 (Please note
that these are for term newborns, children and adults).
2. Step 3- Is the CO Normal?

2
The relationship between the direction of change in pH and the direction of PaCO2is inverse
(Table 5).
Table 5. Relationship of partial pressure of carbon dioxide with pH
pH PaCO2
Respiratory acidosis ? ?
Respiratory alkalosis ? ?
The common causes for respiratory acidosis are;

1. Hypoventilation
2. Parenchymal lung disease (RDS/Pneumonia/Meconium aspiration/Transient tachypnea)
3. ET tube block, Lung collapse, Pulmonary hypertension, PDA
4. Pulmonary air leak syndromes.
Respiratory alkalosis is commonly seen in
1. Over-ventilation & hyperventilation
2. Air bubble in the blood sample
3. Crying infant
4. Hyperammonemia.
4. Step 4- Is the HCO3 Normal?

The relationship between the direction of change in pH and the direction of HCO3 is same and is shown
in Table 6.
The relationship between pH and PaCO2/HCO3 can be remembered with the acronym “ROME,” which
is “respiratory opposite and metabolic equals.” The common causes of metabolic acidosis in the neonate
are bicarbonate losses (renal immaturity), hypovolemia/fluid losses, hypoxia, hypotension, hypothermia,
Table 6. Relation of bicarbonate with pH

pH HCO3
Metabolic acidosis ? ?
Metabolic alkalosis ? ?
165
Table 7. Relation of partial pressure of carbon dioxide with bicarbonate
HCO3 PaCO2
Simple respiratory acidosis or metabolic alkalosis ? ?
Simple respiratory alkalosis or metabolic acidosis ? ?
Mixed metabolic acidosis and respiratory acidosis ? ?
Mixed metabolic alkalosis and respiratory alkalosis ? ?
Table 8. Formula(s) for compensation of acid base imbalance

Disorder Expected Compensation
Metabolic acidosis PaCO2 = (1.5 × [HCO3]) +8± 2
Metabolic alkalosis Increase in PaCO2 = 40 + 0.6(? HCO3-)
Acute respiratory acidosis Increase in [HCO3-]= ? PaCO2/10± 3
Chronic respiratory acidosis Increase in [HCO3-]= 3.5(? PaCO2/10)
Acute respiratory alkalosis Decrease in [HCO3-]= 2(? PaCO2/10)
Chronic respiratory alkalosis Decrease in [HCO3-]= 5(? PaCO2/10) to 7(? PaCO2/10)
166
The change in hydrogen ion is calculated by subtracting the normal hydrogen ion (40) from
observed/ expected hydrogen ion.
[H+]/ PaCO2= X
If X <0.3—chronic, X= 0.3-0.8—acute on chronic, and X>0.8—acute
7. Step 7- Calculate Anion Gap If There is Metabolic Acidosis
The anion gap is the difference between anions and cations. It reects the unmeasured
anions in the blood. The Anion gap is calculated by the formula,
Anion gap = (Na+ + K+) - [Cl- + HCO3-]
Under normal circumstances, anion gap represents weak acids (A-) like albumin, phosphates,
sulfates, and lactates. The normal value of anion gap is 12 ± 4 meq/L. Potassium is sometimes
omitted because of low extracellular concentration. Serum albumin levels should be
accounted for while calculating anion gap; infants with low albumin have low anion gap. With
each decrease in 1g/dl of albumin, the anion gap falls by 2.5meq/
L. If the anion gap is higher than what is accounted by albumin/phosphate/sulfates then
there are other anions contributing to high anion gap. The high anion gap can be
contributed by anions mentioned in Table 4.
The most common cause of low anion gap is laboratory error followed by hypoalbuminemia.
Normal anion gap acidosis is seen in bicarbonate losses due to prematurity, diarrhea, renal
tubular acidosis.
Errors in ABG Interpretation or Analysis
The common errors while processing ABG are listed in Table 9. It is essential while
interpreting the blood gas as sometimes these errors can jeopardize the patient safety.
Table 9. Common errors in blood gas analysis

Cause of Error Impact of Error Prevention of Error
Patient identification Misdiagnosis, improper treatment, Use two patient identifiers, pre-barcoding
resampling
Dilution Low PaCO2 Avoid excess heparin/flush-blood should
High PaO2 (depends on patient PaO2) not be diluted more than 5 percent.
High Na/Cl Discard at least 3 times of the dead space
Low Glucose, calcium, lactate, potassium for arterial sampling. Use dry electrolyte-
based heparin.
Air bubbles in blood sample Increase pH Good seal while collecting
Low PaCO2 Expel or discard air
High PaO2 (depends of patient PaO2)
Clotting Increase potassium Heparinized sample
Avoid delay
Good mixing
Hemolysis Low sodium/calcium Avoid vigorous mixing
High potassium Avoid direct placement on ice cubes
Avoid turbulence while sampling
Prolonged storage Effect because of continued cellular Analyse within 30min (for special samples-
metabolism high platelet, WBC count-analyse within
High calcium, lactate 5 minutes)
Low PaO2, High PaCO2, low pH
Low glucose
Insufficient mixing Low hemoglobin Good mixing-rolling, inverting vertically to
avoid sedimentation
167
168
169
170
171
172
173
174
175
176

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Dr. Virginia Apgar

Dr. N. Karthik Nagesh Dr. Srinivasa Murthy C L

Dr. Suman Rao Dr. Praveen Venkatagiri

Dr. Shivshankar Diggikar Dr. Bharathi Balachander Dr. Sandeep R

Dr. N Karthik Nagesh

Dear friends in Neonatology!

Dr. Srinivasa Murthy C L

Time of birth Pre-ductal saturation

Reference: NRP 7th Edition

Oxygen saturation targets (NICU)

Reference: Neoprom study 2014 and NICE guidelines 2017

Laryngoscope blade size

25-26 weeks 0.7-0.8 6.0

27-29 weeks 0.9-1.0 6.5

30-32 weeks 1.1-1.4 7.0

33-34 weeks 1.5-1.8 7.5

35-37 weeks 1.9-2.4 8.0

38-40 weeks 2.5-3.1 8.5

41-43 weeks 3.2-3.4 9.0

ETT Size depending on weight and gestational age

1000-2000 28-34 weeks 3.0

>2000 Greater than 34 weeks 3.5

Formula for ETT insertion length

Oral intubation Nasal septum to ear tragus length (NTL) plus 1 cm

Nasal intubation Nasal septum to ear tragus length (NTL) plus 1 cm

Reference: NRP 7th edition

0-3 Severely Depressed

Approximate insertion depth of Oro- gastric/nasogastric tube from

< 750g 13cm

Premedication for intubation

The use of premedication reduces the adverse physiological responses of

1. Anticholinergic: Atropine 10-20 microgram/Kg IV

3. Muscle Relaxation: Succinylcholine 2mg/Kg IV (Repeat dose can be given)

Central line positions in babies

CHAPTER 2: ROUTINE NEWBORN CARE

Ten steps to successful breastfeeding

Updated BFHI 2018, WHO/UNICEF

Critical management procedures

1a. Comply fully with the International Code of Marketing of Breast-milk

1c. Establish ongoing monitoring and data-management systems.

Key clinical practices

3. Discuss the importance and management of breastfeeding with pregnant

4. Facilitate immediate and uninterrupted skin-to-skin contact and support mothers

5. Support mothers to initiate and maintain breastfeeding and manage common

Neonatal Hearing Screening Algorithm

Well babies /NICU < 5 days Pass Follow up

NICU > 5 days / Pass Follow up

Timing of Newborn screen

Algorithm for screening and detection of congenital hypothyroidism

Reference: ISPAE guideline, 2018.

Pulse Oximetry Screening

Hip Evaluation Protocol

Approach to developmental dysplasia of hip (DDH)

Immunization schedule (Reference: IAP Immunization schedule 2018-19)

Vaccination in Preterm and Low Birth Weight Babies

l Hepatitis B virus (HBV) is the only vaccine known to have a significantly

Axillary temperature 36.5-37.5 97.7-99.5

Mild hypothermia Axillary temperature 36-36.4 96.8-97.5

Moderate Axillary temperature 32-35.9 89.6-96.6

Severe Axillary temperature <32 <89.6

Body temperature (Axillary temperature) in the new-born infant ( oC)

Humidity in preterm neonates